Editorial
Oral health: prevention is key Oral health is a neglected area of global health and has traditionally registered low on the radar of national policy makers. The reasons for this situation are complex and varied. In many countries oral health is not included in national health surveys. And, if data are collected, it is usually in isolation from the context of general health. Moreover, in some cultures, oral health is neglected because teeth are seen as expendable. Dentists have also taken little interest in advocacy to promote good oral health, preferring to treat rather than prevent oral diseases. And, because poor oral health affects morbidity more than mortality, governments have viewed oral conditions as less important than other, more life-threatening diseases. Yet, globally, the burden of major oral diseases and conditions is high. Dental caries are one of the most common chronic diseases worldwide. 90% of people have had dental problems or toothache caused by caries, and in low-to-middle income countries most caries remains untreated. Severe periodontitis affects 5–15% of most populations. Oral cancer is the eighth most common cancer worldwide and the most common in men in southeast Asia. And 40–50% of people who are HIV positive have oral fungal, bacterial, or viral infections. Access to oral care is a global problem, particularly in low-to-middle income countries. The workforce available to treat the most common oral health problems—dentists—are in short supply in these nations. Whereas countries such as Germany and the UK have one dentist per 1000 population, low-income and middle-income countries have one dentist per 50 000 people, and in some sub-Saharan African countries the ratio is one per 900 000 people. Dentists also cluster in cities where populations that can afford treatment usually live, leaving rural areas deprived of even the most basic emergency dental care. But training more dentists and building dental clinics—the western curative model of care—is costly and unrealistic in most low-income and middle-income countries. Prevention of oral disease is therefore key, largely possible, and should be a routine part of other health professionals’ work. What can be done? The daily use of fluoride is the most cost-effective, evidence-based approach to reduce dental decay. Water or salt fluoridation are possible populationwide approaches but their implementation depends on www.thelancet.com Vol 373 January 3, 2009
the development and infrastructure of the country as well as political will and community acceptance. Promoting the daily use of effective fluoride toothpaste is a more realistic strategy but its cost prohibits its widespread use in many low-income and middle-income countries. Governments can remove taxes on fluoride toothpaste, which in some countries represent up to 50% of the product’s price, and they can work with manufacturers to produce lower cost toothpaste. In the Philippines, for example—where 97% of schoolchildren aged 6 years have dental caries—a programme that combines the promotion of daily handwashing with soap, tooth brushing with subsidised fluoride toothpaste, and twice-yearly deworming, is proving effective, affordable, and sustainable at US$0·56 per child per year. Policies that address the risk factors for oral diseases, such as intake of sugars and tobacco use, can also be implemented, especially because these moves will help reduce chronic diseases. Oral diseases and chronic diseases, such as cardiovascular diseases, cancer, chronic respiratory diseases, and diabetes share many common risk factors. In 2007, a World Health Assembly resolution called for oral health to be integrated into chronic disease prevention programmes. Promoting good oral health could also help countries to achieve child-related development goals. Caries can negatively affect a child’s ability to eat, sleep, and do school work. Preliminary studies have suggested that dental caries and related pain and sepsis might contribute to undernutrition and low weight and height in children in developing countries. In developed countries, studies show that when dental caries are treated, children start to put on weight and thrive. Oral pain is also one of the most common reasons for school absenteeism. Preventing oral disease is important and achievable. Evidence-based, simple, and cost-effective preventive approaches exist, but they need to be rigorously promoted and implemented. Professionally, health workers, including physicians, nurses, paediatricians, and pharmacists can all deliver prevention messages about the use of fluoride and the risk factors for oral disease. Politically, commitment is needed to integrate oral disease prevention into programmes to prevent chronic diseases and into public-health systems. Good oral The Lancet health should be everybody’s business.
The printed journal includes an image merely for illustration
For more on the Philippines school programme see Development & Coorperation 2008; 49: 8–12; http://www. inwent.org/ez/articles/082726/ index.en.shtml
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Editorial
A favourable (molecular) signal for personalised medicine
Science Photo Library
With all the important advances in genomic sequencing, one can sometimes forget that molecular oncologists have been busy for decades to uncover what happens at the molecular level in oncogenesis. They have found mutation routes that are of more immediate practical and clinical value than knowing the whole genome. A mid-December meeting of the Oncologic Drugs Advisory Panel of the US Food and Drug Administration (FDA) discussed the retrospective analysis of biomarkers from completed trials to support drug-company labelling claims for anticancer agents in subgroups of patients. Provisos were: the analysis needs to be hypothesisdriven, adequately powered (presumably, in retrospect), and prespecified for tissue collection and data analysis. For example, the Panel used data for the monoclonal antibodies cetuximab and panitumumab, which inhibit the EGF receptor (EGFR) in metastatic colorectal cancer. About 40% of these patients have a KRAS gene mutation, and respond poorly to such antibodies. The KRAS protooncogene product lies downstream of EGFR, and the
mutation frees the receptor from normal regulation in cell-growth control. One important implication for this pair of monoclonals is that prospective trials in patients with metastatic colorectal cancer who harbour wildtype KRAS (ie, the non-mutated form) might no longer be ethical. EMEA, the European Medicines Agency, has already restricted use of cetuximab and panitumumab to such patients. The FDA’s decision is a major step towards the idea of personalised medicine, a concept that genomic research hails as one of its reasons for existence but one that has come from molecular oncology. Being able to identify potential responders or non-responders means that patients can be selected for therapies that could have side-effects and, if they are one of the new biologicals, are expensive. This step by the FDA means that the wealth of data harboured in completed trials in cancer, and other diseases, could be plundered with more confidence, for the benefit of patients and of those who have to pay for expensive treatments. The Lancet
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America’s commitment to global health
For the Institute of Medicine (IOM) report see www.iom.edu/ usandglobalhealth
2
Over the past decade, the US Government has spent record amounts on global health: in 2008 spending peaked at US$7·5 billion. Still, the share of the country’s gross national income allocated to development aid is only about one-third of the target set by the UN’s Millennium Development Goals. More than 70% of this money is aimed at AIDS programmes, even though chronic and non-communicable diseases account for more than half of all deaths in low-income and middleincome countries. Perhaps not surprisingly, then, mid-December’s US Institute of Medicine (IOM) report was devoted to the global-health commitment of the government under the incoming administration of President-elect Barack Obama. Created by an independent committee of four US government agencies and five private foundations, the report discusses several key recommendations. First, the new administration should highlight health as a pillar of US foreign policy. Second, a White House Interagency Committee on Global Health be formed and chaired by a White House global-health tsar, who
will serve as deputy assistant to the President. Third, a balanced aid portfolio should be created to cover diverse global-health issues including AIDS, malaria, tuberculosis, children’s and women’s health, nutrition, family planning and reproductive health, chronic and non-communicable disease, injury, and health systems. Fourth, the US Government should enhance partnerships with national governments, support the leadership of WHO, and fund research for health. Last, the budget for US global-health assistance should be increased annually and doubled to $15 billion by the year 2012. Before the second IOM report on the US commitment to global health is released in April, 2009, the new Obama administration must seize this opportunity to show leadership and take the initiative in expressing its determination to save lives overseas. As Bill Gates indicated, “sending this critical message at this critical time” will strengthen the country’s international relations and help to restore the global credibility of, and respect for, the US Government and its people. The Lancet www.thelancet.com Vol 373 January 3, 2009
Editorial
A favourable (molecular) signal for personalised medicine
Science Photo Library
With all the important advances in genomic sequencing, one can sometimes forget that molecular oncologists have been busy for decades to uncover what happens at the molecular level in oncogenesis. They have found mutation routes that are of more immediate practical and clinical value than knowing the whole genome. A mid-December meeting of the Oncologic Drugs Advisory Panel of the US Food and Drug Administration (FDA) discussed the retrospective analysis of biomarkers from completed trials to support drug-company labelling claims for anticancer agents in subgroups of patients. Provisos were: the analysis needs to be hypothesisdriven, adequately powered (presumably, in retrospect), and prespecified for tissue collection and data analysis. For example, the Panel used data for the monoclonal antibodies cetuximab and panitumumab, which inhibit the EGF receptor (EGFR) in metastatic colorectal cancer. About 40% of these patients have a KRAS gene mutation, and respond poorly to such antibodies. The KRAS protooncogene product lies downstream of EGFR, and the
mutation frees the receptor from normal regulation in cell-growth control. One important implication for this pair of monoclonals is that prospective trials in patients with metastatic colorectal cancer who harbour wildtype KRAS (ie, the non-mutated form) might no longer be ethical. EMEA, the European Medicines Agency, has already restricted use of cetuximab and panitumumab to such patients. The FDA’s decision is a major step towards the idea of personalised medicine, a concept that genomic research hails as one of its reasons for existence but one that has come from molecular oncology. Being able to identify potential responders or non-responders means that patients can be selected for therapies that could have side-effects and, if they are one of the new biologicals, are expensive. This step by the FDA means that the wealth of data harboured in completed trials in cancer, and other diseases, could be plundered with more confidence, for the benefit of patients and of those who have to pay for expensive treatments. The Lancet
Getty Images
America’s commitment to global health
For the Institute of Medicine (IOM) report see www.iom.edu/ usandglobalhealth
2
Over the past decade, the US Government has spent record amounts on global health: in 2008 spending peaked at US$7·5 billion. Still, the share of the country’s gross national income allocated to development aid is only about one-third of the target set by the UN’s Millennium Development Goals. More than 70% of this money is aimed at AIDS programmes, even though chronic and non-communicable diseases account for more than half of all deaths in low-income and middleincome countries. Perhaps not surprisingly, then, mid-December’s US Institute of Medicine (IOM) report was devoted to the global-health commitment of the government under the incoming administration of President-elect Barack Obama. Created by an independent committee of four US government agencies and five private foundations, the report discusses several key recommendations. First, the new administration should highlight health as a pillar of US foreign policy. Second, a White House Interagency Committee on Global Health be formed and chaired by a White House global-health tsar, who
will serve as deputy assistant to the President. Third, a balanced aid portfolio should be created to cover diverse global-health issues including AIDS, malaria, tuberculosis, children’s and women’s health, nutrition, family planning and reproductive health, chronic and non-communicable disease, injury, and health systems. Fourth, the US Government should enhance partnerships with national governments, support the leadership of WHO, and fund research for health. Last, the budget for US global-health assistance should be increased annually and doubled to $15 billion by the year 2012. Before the second IOM report on the US commitment to global health is released in April, 2009, the new Obama administration must seize this opportunity to show leadership and take the initiative in expressing its determination to save lives overseas. As Bill Gates indicated, “sending this critical message at this critical time” will strengthen the country’s international relations and help to restore the global credibility of, and respect for, the US Government and its people. The Lancet www.thelancet.com Vol 373 January 3, 2009
Comment
When childhood dies
www.thelancet.com Vol 373 January 3, 2009
summarise the evidence base on interventions that are available to prevent child maltreatment and mitigate its effects; and finally Richard Reading and colleagues6 acknowledge the complexity of social influences and policy involving children, and argue in favour of a human-rights approach to child maltreatment. Too often, the safety of children is debated in the polarising light of litigation or political division. Whilst this outcome is inevitable because of the public outrage child maltreatment engenders, a damaging consequence is that the evidence surrounding child neglect and abuse often fails to influence serious policy discussion. It is this marginalisation of the science of child maltreatment that we are seeking to reverse. We would like to extend warm thanks to Patricia Hamilton of the Royal College of Paediatrics and Child Health for supporting this Series, and to the authors and peer reviewers of the accompanying papers and Comments for their unstinting work. This Lancet Series will unfortunately not halt the blight of child abuse, because the phenomenon is too common, too surreptitious, and too deeply rooted in deprivation and other social ills—but we nonetheless hope to raise awareness of the scientific evidence that is available, and indeed essential, to guide paediatricians and other professionals in their practice with children who might have been abused; and to help bring a new logic and clarity to public debate about this contentious area.
Published Online December 3, 2008 DOI:10.1016/S01406736(08)61701-8 See Series page 68
PA Photos
Few topics are more emotive than child maltreatment. Human societies place a high value on the richness and diversity that parents contribute to their children’s upbringing, and bystanders and professionals alike will hesitate to intervene in or undermine the parent–child relationship unless there is definitive evidence that serious harm is being done. Yet the grating litany of child abuse by parents and other carers is familiar to all. The forced child labour endured by children in Victorian England more than a century ago remains common in developing countries today, and in the developed world formal child-protection systems document a depressing range of maltreatment, from deliberate neglect to the vilest sexual abuse. This cruel treatment can lead to serious physical and mental-health consequences, and risks creating a damaging intergenerational cycle of maltreatment, disadvantage, and ill health. Children, the most precious and vulnerable members of our societies, deserve closer attention to their care and education and better protection against abuse. Child maltreatment can be especially difficult to ascertain—after all, the victim might be unwilling or unable to provide an accurate account of abuse, the perpetrator bent on concealment, witnesses silent, clinical signs equivocal, and professionals reluctant to act owing to uncertainty about the existence or severity of abuse, or concern that the treatment of abuse will itself lead to undue disruption or damage to a child’s upbringing. When severe child abuse culminates in death, however, as in the tragic recent cases of Victoria Climbié and Baby P in the UK,1,2 the law, news media, and public can be expected to cast a harsh and unforgiving spotlight on social workers and doctors who might be perceived or portrayed as having missed opportunities to help the victims. It is to clinicians and other professionals responsible for caring for children that The Lancet‘s Child Maltreatment Series is aimed, with the intention of providing them with a rigorous and up-to-date summary of scientific evidence and conceptual work on this complex and demanding topic. Ruth Gilbert and colleagues3 begin by reviewing the literature on the classification and worldwide burden of child maltreatment, and in a second paper4 discuss the methodology and challenges involved in identifying abuse. Harriet MacMillan and coauthors5
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Comment
Richard Turner, Richard Horton
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The Lancet, London NW1 7BY, UK 1
2 3
Laming. The Victoria Climbié inquiry: report of an inquiry by Lord Laming. January, 2003. http://www.victoria-climbie-inquiry.org.uk/finreport/ finreport.htm (accessed Nov 13, 2008). BBC News Channel. Men found guilty of baby’s death. Nov 11, 2008. http:// news.bbc.co.uk/1/hi/england/london/7706598.stm (accessed Nov 17, 2008). Gilbert R, Spatz Widom C, Browne K, Fergusson D, Webb E, Janson S. Burden and consequences of child maltreatment in high-income countries. Lancet 2008; published online Dec 3. DOI:10.1016/S0140-6736(08)61706-7.
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Gilbert R, Kemp A, Thoburn J, et al. Recognising and responding to child maltreatment. Lancet 2008; published online Dec 3. DOI:10.1016/S01406736(08)61707-9. MacMillan HL, Wathen CN, Barlow J, Fergusson DM, Leventhal JM, Taussig HN. Interventions to prevent child maltreatment and associated impairment. Lancet 2008; published online Dec 3. DOI:10.1016/S01406736(08)61708-0. Reading R, Bissell S, Goldhagen J, et al. Promotion of children’s rights and prevention of child maltreatment. Lancet 2008; published online Dec 3. DOI:10.1016/S0140-6736(08)61709-2.
The spurious advance of antipsychotic drug therapy Published Online December 5, 2008 DOI:10.1016/S01406736(08)61765-1
Clinicians are familiar with studies that claim to show major advances in therapy. They tend to greet early reports of such advances with a touch of scepticism and wait, usually for at least 10 years, for a raft of independent studies that show that the advance is genuine and not just another minor ripple in the treatment stream. In The Lancet today, Stefan Leucht and colleagues1 deviate from this pattern by suggesting that what was seen as an advance 20 years ago—when a new generation of antipsychotic drugs with additional benefits and fewer adverse effects was introduced2—is now, and only now, seen as a chimera that has passed
Science Photo Library
See Articles page 31
4
spectacularly before our eyes before disappearing and leaving puzzlement and many questions in its wake. Leucht and colleagues’ analysis of ten outcomes from 150 randomised trials, supported by some powerful studies,3–5 shows that the name “second-generation antipsychotics” is inaccurate. This group of drugs is in fact a heterogeneous mix of compounds, with some superior to others. Antipsychotic drugs differ in their potencies and have a wide range of adverse-effect profiles, with nothing that clearly distinguishes the two major groups. Importantly, the second-generation drugs have no special atypical characteristics that separate them from the typical, or first-generation, antipsychotics. As a group they are no more efficacious, do not improve specific symptoms, have no clearly different side-effect profiles than the first-generation antipsychotics, and are less cost effective.6–8 The spurious invention of the atypicals can now be regarded as invention only, cleverly manipulated by the drug industry for marketing purposes and only now being exposed. But how is it that for nearly two decades we have, as some have put it,9 “been beguiled” into thinking they were superior? Leucht and co-workers provide some clues. Of 150 trials in their meta-analysis, in 95 the secondgeneration antipsychotic was compared with the high-potency first-generation antipsychotic haloperidol. The use of haloperidol as the first-generation antipsychotic in these trials means that they were biased in favour of the second-generation drugs. This bias has been achieved through several routes—eg, by comparing the second-generation antipsychotic with a high-potency first-generation antipsychotic likely to be associated with a high rate of extrapyramidal side-effects. Another obvious way of favouring the second-generation drugs has been to avoid comparison with a medium-potency first-generation antipsychotic, because these drugs are www.thelancet.com Vol 373 January 3, 2009
Comment
Richard Turner, Richard Horton
4
The Lancet, London NW1 7BY, UK 1
2 3
Laming. The Victoria Climbié inquiry: report of an inquiry by Lord Laming. January, 2003. http://www.victoria-climbie-inquiry.org.uk/finreport/ finreport.htm (accessed Nov 13, 2008). BBC News Channel. Men found guilty of baby’s death. Nov 11, 2008. http:// news.bbc.co.uk/1/hi/england/london/7706598.stm (accessed Nov 17, 2008). Gilbert R, Spatz Widom C, Browne K, Fergusson D, Webb E, Janson S. Burden and consequences of child maltreatment in high-income countries. Lancet 2008; published online Dec 3. DOI:10.1016/S0140-6736(08)61706-7.
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Gilbert R, Kemp A, Thoburn J, et al. Recognising and responding to child maltreatment. Lancet 2008; published online Dec 3. DOI:10.1016/S01406736(08)61707-9. MacMillan HL, Wathen CN, Barlow J, Fergusson DM, Leventhal JM, Taussig HN. Interventions to prevent child maltreatment and associated impairment. Lancet 2008; published online Dec 3. DOI:10.1016/S01406736(08)61708-0. Reading R, Bissell S, Goldhagen J, et al. Promotion of children’s rights and prevention of child maltreatment. Lancet 2008; published online Dec 3. DOI:10.1016/S0140-6736(08)61709-2.
The spurious advance of antipsychotic drug therapy Published Online December 5, 2008 DOI:10.1016/S01406736(08)61765-1
Clinicians are familiar with studies that claim to show major advances in therapy. They tend to greet early reports of such advances with a touch of scepticism and wait, usually for at least 10 years, for a raft of independent studies that show that the advance is genuine and not just another minor ripple in the treatment stream. In The Lancet today, Stefan Leucht and colleagues1 deviate from this pattern by suggesting that what was seen as an advance 20 years ago—when a new generation of antipsychotic drugs with additional benefits and fewer adverse effects was introduced2—is now, and only now, seen as a chimera that has passed
Science Photo Library
See Articles page 31
4
spectacularly before our eyes before disappearing and leaving puzzlement and many questions in its wake. Leucht and colleagues’ analysis of ten outcomes from 150 randomised trials, supported by some powerful studies,3–5 shows that the name “second-generation antipsychotics” is inaccurate. This group of drugs is in fact a heterogeneous mix of compounds, with some superior to others. Antipsychotic drugs differ in their potencies and have a wide range of adverse-effect profiles, with nothing that clearly distinguishes the two major groups. Importantly, the second-generation drugs have no special atypical characteristics that separate them from the typical, or first-generation, antipsychotics. As a group they are no more efficacious, do not improve specific symptoms, have no clearly different side-effect profiles than the first-generation antipsychotics, and are less cost effective.6–8 The spurious invention of the atypicals can now be regarded as invention only, cleverly manipulated by the drug industry for marketing purposes and only now being exposed. But how is it that for nearly two decades we have, as some have put it,9 “been beguiled” into thinking they were superior? Leucht and co-workers provide some clues. Of 150 trials in their meta-analysis, in 95 the secondgeneration antipsychotic was compared with the high-potency first-generation antipsychotic haloperidol. The use of haloperidol as the first-generation antipsychotic in these trials means that they were biased in favour of the second-generation drugs. This bias has been achieved through several routes—eg, by comparing the second-generation antipsychotic with a high-potency first-generation antipsychotic likely to be associated with a high rate of extrapyramidal side-effects. Another obvious way of favouring the second-generation drugs has been to avoid comparison with a medium-potency first-generation antipsychotic, because these drugs are www.thelancet.com Vol 373 January 3, 2009
Comment
likely to be just as efficacious as the second-generation drug, but less likely than haloperidol to induce Parkinsonism. The picture can be complicated further with high doses of the first-generation drug. This approach favours the second-generation antipsychotic because side-effect rates are much lower than with the first-generation antipsychotic.10 Moreover, there is often selective publication of trials11–13 that can skew the evidence base in favour of a drug favoured by the investigators. On present evidence from all sources it is difficult not to conclude that the trials of the second-generation antipsychotics seem to be driven more by marketing strategy than to clarify their role for clinicians and patients. This is not to say that all antipsychotic drugs are the same, they are not. Individual responses vary, and so a range of drugs is needed for good clinical practice. So where should we go now? First, the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction. The only second-generation antipsychotic that is obviously better than other drugs in resistant schizophrenia is clozapine,14 and this is a very old drug indeed. Second, clinicians must remember to keep the benefit–risk ratio of each antipsychotic drug in constant perspective because all are associated in different ways with serious adverse effects, which should be important outcome measures.13 Finally, it is prudent to remember that although science rules during a drug’s development, the market usurps control once the drug is released for care of patients.
PT declares that he has no conflict of interest. TK is involved in updating the schizophrenia guideline for the National Institute for Health and Clinical Excellence, including a review of antipsychotic drugs in the treatment of schizophrenia. 1
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*Peter Tyrer, Tim Kendall Department of Psychological Medicine, Imperial College London, London W6 8RP, UK (PT); and National Collaborating Centre for Mental Health, Royal College of Psychiatrists’ Research Unit, London, UK (TK)
[email protected] 13 14
Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a metaanalysis. Lancet 2008; published online Dec 5. DOI:10.1016/S01406736(08)61764-X. Janssen PA, Niemegeers CJ, Awouters F, Schellekens KH, Megens AA, Meert TF. Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 1988; 244: 685–93. Lieberman JA, Stroup S, McEvoy JP, et al, for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209–23. Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: 1079–87. Keefe RS, Bilder RM, Davis SM, et al, for the CATIE Investigators and the Neurocognitive Working Group. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiatry 2007; 64: 633–47. Rosenheck RA, Leslie D, Sindelar J, et al, for the CATIE Study Investigators. Cost-effectiveness of second generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia. Am J Psychiatry 2006; 163: 2080–89. Davies LM, Lewis S, Jones PB, et al, on behalf of the CUtLASS team. Cost-effectiveness of first- v. second-generation antipsychotic drugs: results from a randomised controlled trial in schizophrenia responding poorly to previous therapy. Br J Psychiatry 2007; 191: 14–22. Lewis S, Lieberman J. CATIE and CUtLASS: can we handle the truth? Br J Psychiatry 2008; 192: 161–63. Vedantam S. In antipsychotics, newer isn’t better. Washington Post (Washington) Oct 3, 2006. http://www.washingtonpost.com/wp-dyn/ content/article/2006/10/02/AR2006100201378.html (accessed Sept 8, 2008). Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ 2000; 321: 1371–76. Turner EH, Matthews AM, Linardatos E, Tell TA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358: 252–60. Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004; 363: 1341–45. Tungeraza T, Poole R. Influence of drug company authorship and sponsorship on drug trial outcomes. Br J Psychiatry 2007; 191: 82–83. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789–96.
Assessing bleeds clinically: what’s the score? Acute upper-gastrointestinal haemorrhage is the most common life-threatening medical emergency faced by gastroenterologists, with an annual incidence of 50–150 per 100 000 people.1 Mortality has been stubbornly high (14% in 1995), although a reaudit in 2007 by the British Society of Gastroenterology showed a UK mortality of 10%.2 That reaudit identified several trends, including a doubling of cases due to www.thelancet.com Vol 373 January 3, 2009
variceal bleeding and a striking reduction in the use of surgery. Whether the falling mortality reflects improved management or an altered case-mix is not clear. Certainly, several mild cases do not undergo endoscopy or need blood transfusion. Measures need to be developed to identify patients at low risk, who can be discharged early or for whom admission can be avoided, as well as to improve
Published Online December 15, 2008 DOI:10.1016/S01406736(08)61770-5 See Articles page 42
5
Comment
likely to be just as efficacious as the second-generation drug, but less likely than haloperidol to induce Parkinsonism. The picture can be complicated further with high doses of the first-generation drug. This approach favours the second-generation antipsychotic because side-effect rates are much lower than with the first-generation antipsychotic.10 Moreover, there is often selective publication of trials11–13 that can skew the evidence base in favour of a drug favoured by the investigators. On present evidence from all sources it is difficult not to conclude that the trials of the second-generation antipsychotics seem to be driven more by marketing strategy than to clarify their role for clinicians and patients. This is not to say that all antipsychotic drugs are the same, they are not. Individual responses vary, and so a range of drugs is needed for good clinical practice. So where should we go now? First, the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction. The only second-generation antipsychotic that is obviously better than other drugs in resistant schizophrenia is clozapine,14 and this is a very old drug indeed. Second, clinicians must remember to keep the benefit–risk ratio of each antipsychotic drug in constant perspective because all are associated in different ways with serious adverse effects, which should be important outcome measures.13 Finally, it is prudent to remember that although science rules during a drug’s development, the market usurps control once the drug is released for care of patients.
PT declares that he has no conflict of interest. TK is involved in updating the schizophrenia guideline for the National Institute for Health and Clinical Excellence, including a review of antipsychotic drugs in the treatment of schizophrenia. 1
2
3
4
5
6
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8 9
10
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*Peter Tyrer, Tim Kendall Department of Psychological Medicine, Imperial College London, London W6 8RP, UK (PT); and National Collaborating Centre for Mental Health, Royal College of Psychiatrists’ Research Unit, London, UK (TK)
[email protected] 13 14
Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a metaanalysis. Lancet 2008; published online Dec 5. DOI:10.1016/S01406736(08)61764-X. Janssen PA, Niemegeers CJ, Awouters F, Schellekens KH, Megens AA, Meert TF. Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 1988; 244: 685–93. Lieberman JA, Stroup S, McEvoy JP, et al, for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209–23. Jones PB, Barnes TR, Davies L, et al. Randomized controlled trial of effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: 1079–87. Keefe RS, Bilder RM, Davis SM, et al, for the CATIE Investigators and the Neurocognitive Working Group. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trial. Arch Gen Psychiatry 2007; 64: 633–47. Rosenheck RA, Leslie D, Sindelar J, et al, for the CATIE Study Investigators. Cost-effectiveness of second generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia. Am J Psychiatry 2006; 163: 2080–89. Davies LM, Lewis S, Jones PB, et al, on behalf of the CUtLASS team. Cost-effectiveness of first- v. second-generation antipsychotic drugs: results from a randomised controlled trial in schizophrenia responding poorly to previous therapy. Br J Psychiatry 2007; 191: 14–22. Lewis S, Lieberman J. CATIE and CUtLASS: can we handle the truth? Br J Psychiatry 2008; 192: 161–63. Vedantam S. In antipsychotics, newer isn’t better. Washington Post (Washington) Oct 3, 2006. http://www.washingtonpost.com/wp-dyn/ content/article/2006/10/02/AR2006100201378.html (accessed Sept 8, 2008). Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ 2000; 321: 1371–76. Turner EH, Matthews AM, Linardatos E, Tell TA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358: 252–60. Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004; 363: 1341–45. Tungeraza T, Poole R. Influence of drug company authorship and sponsorship on drug trial outcomes. Br J Psychiatry 2007; 191: 82–83. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789–96.
Assessing bleeds clinically: what’s the score? Acute upper-gastrointestinal haemorrhage is the most common life-threatening medical emergency faced by gastroenterologists, with an annual incidence of 50–150 per 100 000 people.1 Mortality has been stubbornly high (14% in 1995), although a reaudit in 2007 by the British Society of Gastroenterology showed a UK mortality of 10%.2 That reaudit identified several trends, including a doubling of cases due to www.thelancet.com Vol 373 January 3, 2009
variceal bleeding and a striking reduction in the use of surgery. Whether the falling mortality reflects improved management or an altered case-mix is not clear. Certainly, several mild cases do not undergo endoscopy or need blood transfusion. Measures need to be developed to identify patients at low risk, who can be discharged early or for whom admission can be avoided, as well as to improve
Published Online December 15, 2008 DOI:10.1016/S01406736(08)61770-5 See Articles page 42
5
Comment
Year
Country
Type of study
Low-risk patients (n [%])
Interventions (n [%])
Blatchford8
2000
UK
Retrospective
276 (15·8%)
5 (0·3%)
Gralnek10
2004
USA
Retrospective
14 (8·0%)
0
Chen9
2007
Taiwan
Retrospective
28 (8·9%)
1 (0·3%)
Masaoka11
2007
Japan
Retrospective
3 (3·4%)
0
Stanley13
2008
UK
Prospective
228 (18·7%)
0
Table: Studies of patients identified as low risk and their outcomes in studies that used GBS of 0 for identifying low-risk patients with acute upper-gastrointestinal haemorrhage
management of high-risk patients with bleeds. Most risk-determination systems3–5 include endoscopy, and protocols allowing safe early discharge have been developed.6,7 The Glasgow-Blatchford score (GBS),8 which was first reported in 2000, needs only simple clinical and laboratory data, and can potentially be used for front-door decisions. Since then, a few retrospective studies have suggested that the GBS9–11 and the modified GBS12 predict outcomes accurately. In The Lancet today, Adrian Stanley and colleagues,13 who studied prospective cohorts in two phases in Scotland and England, confirm these findings and specifically address the question of whether patients presenting with a score of 0 could be managed as outpatients. To achieve a score of 0, a patient would have to have a pulse of less than 100 beats per min, systolic blood pressure of 110 mm Hg or more, absence of melaena, syncope, cardiac failure, or liver disease, haemoglobin of 130 g/L or more for men or 120 g/L or more for women, and urea of less than 6·5 mmol/L. In phase one of Stanley and colleagues’ study (case ascertainment), 105 (16·2%) of 649 patients had a GBS of 0 (low risk), with no interventions or death in this group. In phase two (validation), 123 (21·5%) of 572 patients were considered low risk, of whom 84 (14·7% of the total population in phase two) were not admitted, with none of the low-risk patients needing interventions. The GBS outperformed the Rockall scores (both pre-endoscopic and full) in this population in phase one of the trial. The pre-endoscopic Rockall score takes only clinical parameters (age, shock, and comorbidities) into account and has been shown to predict death but not rebleed rates.4 The full Rockall score includes the pre-endocscopic score and the results of endoscopy (diagnosis and presence of stigmata of bleed) and predicts mortality more reliably than does the pre-endoscopic score alone.4 The Rockall score had been designed to assess mortality and not rebleed or need for 6
interventions, unlike GBS which was designed to assess mortality or need for in-hospital interventions.8 Has the GBS done enough to merit being rolled out in all emergency departments? The table lists the studies (including that by Stanley and colleagues) with data on the use of a score of 0 in predicting outcomes. In three small retrospective studies, a score of 0 stratified less than 10% of patients with uppergastrointestinal haemorrhage as low risk, and all had excellent outcomes.9–11 By contrast, the Scottish studies (by Stanley13 and Blatchford and colleagues8) identified 15–20% of patients as low risk. These findings would imply either a different case-mix in Scotland or that the GBS is not transferable geographically. However, the score does have excellent predictive ability and results were similar over time in both Scottish studies. Stanley and colleagues’ study is the first prospective one to assess the use and feasibility of the GBS system in the emergency department. Their calculation of a mean reduction of 1·2 days in bed-days per patient presenting would translate to a direct saving of £13·6 million in a population of 60 million, with the assumptions that hospital cost is £227 per day14 and an annual rate of uppergastrointestinal haemorrhage of 100 per 100 000 people. Further studies will need to compare the costeffectiveness of the GBS with outpatient endoscopy and strategies that involve early endoscopy and discharge.6,7 Another approach uses an artificial neural network with 27 clinical variables to predict the need for endoscopic intervention.15 In a recent study,15 this model was no better than the complete Rockall score in an external validation cohort, which would imply better use for the simpler GBS. Avoiding unnecessary admission of such patients will reduce cost and exposure of patients to hospitalassociated hazards. But to reduce mortality from uppergastrointestinal haemorrhage, the standard of care in the UK needs enhancement. Socially, a sustained www.thelancet.com Vol 373 January 3, 2009
Comment
successful campaign to reduce alcohol consumption and stem the rising incidence of variceal bleeding as well as the other tragic consequences of alcoholic liver disease is essential.16 Organisationally, the patchwork service in which patients can still be admitted to hospitals without out-of-hours endoscopy needs to be replaced with one that ensures that all necessary diagnostic and treatment facilities are available.
6
7
8
9
10
Venkataraman Subramanian, *Christopher J Hawkey Wolfson Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2UH, UK
[email protected] VS declares that he has no conflict of interest. CJH has received research funding and/or honoraria from GlaxoSmithKline, MerckSerono, and Bayer. 1 2
3
4 5
British Society of Gastroenterology Endoscopy Committee. Non-variceal upper gastrointestinal haemorrhage: guidelines. Gut 2002; 51 (suppl 4): iv1–6. Clinical Effectiveness and Evaluation Unit, British Society of Gastroenterology, NHS Blood and Transplant. UK comparative audit of upper gastrointestinal bleeding and the use of blood. December, 2007. http://www.bsg.org.uk/pdf_word_docs/blood_audit_report_07.pdf (accessed Sept 4, 2008). Hay JA, Lyubashevsky E, Elashoff J, Maldonado L, Weingarten SR, Ellrodt AG. Upper gastrointestinal hemorrhage clinical guideline—determining the optimal hospital length of stay. Am J Med 1996; 100: 313–22. Rockall TA, Logan RF, Devlin HB, Northfield TC. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 1996; 38: 316–21. Saeed ZA, Winchester CB, Michaletz PA, Woods KL, Graham DY. A scoring system to predict rebleeding after endoscopic therapy of nonvariceal upper gastrointestinal hemorrhage, with a comparison of heat probe and ethanol injection. Am J Gastroenterol 1993; 88: 1842–49.
11
12
13
14 15
16
Cipolletta L, Bianco MA, Rotondano G, Marmo R, Piscopo R. Outpatient management for low-risk nonvariceal upper GI bleeding: a randomized controlled trial. Gastrointest Endosc 2002; 55: 1–5. Longstreth GF, Feitelberg SP. Successful outpatient management of acute upper gastrointestinal hemorrhage: use of practice guidelines in a large patient series. Gastrointest Endosc 1998; 47: 219–22. Blatchford O, Murray WR, Blatchford M. A risk score to predict need for treatment for uppergastrointestinal haemorrhage. Lancet 2000; 356: 1318–21. Chen IC, Hung MS, Chiu TF, Chen JC, Hsiao CT. Risk scoring systems to predict need for clinical intervention for patients with nonvariceal upper gastrointestinal tract bleeding. Am J Emerg Med 2007; 25: 774–79. Gralnek IM, Dulai GS. Incremental value of upper endoscopy for triage of patients with acute non-variceal upper-GI hemorrhage. Gastrointest Endosc 2004; 60: 9–14. Masaoka T, Suzuki H, Hori S, Aikawa N, Hibi T. Blatchford scoring system is a useful scoring system for detecting patients with upper gastrointestinal bleeding who do not need endoscopic intervention. J Gastroenterol Hepatol 2007; 22: 1404–08. Romagnuolo J, Barkun AN, Enns R, Armstrong D, Gregor J. Simple clinical predictors may obviate urgent endoscopy in selected patients with nonvariceal upper gastrointestinal tract bleeding. Arch Intern Med 2007; 167: 265–70. Stanley AJ, Ashley D, Dalton HR, et al. Outpatient management of patients with low-risk upper-gastrointestinal haemorrhage: multicentre validation and prospective evaluation. Lancet 2008; published online Dec 15. DOI:10.1016/S0140-6736(08)61769-9. Netten A, Curtis L. Unit costs of health and social care. 2006. http://www. pssru.ac.uk/pdf/uc/uc2006/uc2006.pdf (accessed Sept 4, 2008). Das A, Ben-Menachem T, Farooq FT, et al. Artificial neural network as a predictive instrument in patients with acute nonvariceal upper gastrointestinal hemorrhage. Gastroenterology 2008; 134: 65–74. Department of Health, Home Office, Department for Education and Skills and Department for Culture, Media and Sport. Safe. Sensible. Social. The next steps in the National Alcohol Strategy. June 5, 2007. http://www. dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAn dGuidance/DH_075218 (accessed Sept 4, 2008).
Can antiretroviral therapy eliminate HIV transmission? In The Lancet today, Reuben Granich and colleagues (including two of us, KMDC and CFG) use mathematical modelling to assess the impact of expanded HIV testing and earlier antiretroviral therapy (ART) on HIV transmission.1 These researchers evaluated a theoretical programme of annual universal HIV testing and immediate treatment on HIV diagnosis, irrespective of CD4+ cell count, in an HIV epidemic with southern African population dynamics. The exercise suggested that HIV transmission could be substantially reduced within a few years. Elimination of HIV transmission, defined as an incidence below one case per 1000 population per year, could be achieved within a decade, and the overall prevalence of HIV infection reduced to below 1% before the middle of the century. Compared with current practice of starting ART at a specific CD4+ count, deaths would be halved between now and 2050. www.thelancet.com Vol 373 January 3, 2009
The uncontrolled number of new HIV infections, despite years of prevention effort, represents a crisis: 2·7 million incident HIV infections occurred globally in 2007.2 By contrast, only 1 million additional individuals were placed on ART that year;3 about 6·7 million were in danger of their lives for lack of treatment, and over 20 million other HIV-infected individuals were waiting, mostly unknowingly, for immune deficiency to progress. Universal access to HIV treatment and care is an unrealistic aspiration unless HIV transmission can be interrupted. Behavioural interventions are essential but incompletely efficacious.4 For biomedical interventions, only four of 24 randomised trials showed protection; three assessed male circumcision.5 All vaccine and microbicide trials were negative. Unsurprisingly, how best to use ART for prevention has emerged as the most pressing question that faces HIV/AIDS science.
Published Online November 26, 2008 DOI:10.1016/S01406736(08)61732-8 See Comment page 9 See Articles page 48
7
Comment
successful campaign to reduce alcohol consumption and stem the rising incidence of variceal bleeding as well as the other tragic consequences of alcoholic liver disease is essential.16 Organisationally, the patchwork service in which patients can still be admitted to hospitals without out-of-hours endoscopy needs to be replaced with one that ensures that all necessary diagnostic and treatment facilities are available.
6
7
8
9
10
Venkataraman Subramanian, *Christopher J Hawkey Wolfson Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2UH, UK
[email protected] VS declares that he has no conflict of interest. CJH has received research funding and/or honoraria from GlaxoSmithKline, MerckSerono, and Bayer. 1 2
3
4 5
British Society of Gastroenterology Endoscopy Committee. Non-variceal upper gastrointestinal haemorrhage: guidelines. Gut 2002; 51 (suppl 4): iv1–6. Clinical Effectiveness and Evaluation Unit, British Society of Gastroenterology, NHS Blood and Transplant. UK comparative audit of upper gastrointestinal bleeding and the use of blood. December, 2007. http://www.bsg.org.uk/pdf_word_docs/blood_audit_report_07.pdf (accessed Sept 4, 2008). Hay JA, Lyubashevsky E, Elashoff J, Maldonado L, Weingarten SR, Ellrodt AG. Upper gastrointestinal hemorrhage clinical guideline—determining the optimal hospital length of stay. Am J Med 1996; 100: 313–22. Rockall TA, Logan RF, Devlin HB, Northfield TC. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 1996; 38: 316–21. Saeed ZA, Winchester CB, Michaletz PA, Woods KL, Graham DY. A scoring system to predict rebleeding after endoscopic therapy of nonvariceal upper gastrointestinal hemorrhage, with a comparison of heat probe and ethanol injection. Am J Gastroenterol 1993; 88: 1842–49.
11
12
13
14 15
16
Cipolletta L, Bianco MA, Rotondano G, Marmo R, Piscopo R. Outpatient management for low-risk nonvariceal upper GI bleeding: a randomized controlled trial. Gastrointest Endosc 2002; 55: 1–5. Longstreth GF, Feitelberg SP. Successful outpatient management of acute upper gastrointestinal hemorrhage: use of practice guidelines in a large patient series. Gastrointest Endosc 1998; 47: 219–22. Blatchford O, Murray WR, Blatchford M. A risk score to predict need for treatment for uppergastrointestinal haemorrhage. Lancet 2000; 356: 1318–21. Chen IC, Hung MS, Chiu TF, Chen JC, Hsiao CT. Risk scoring systems to predict need for clinical intervention for patients with nonvariceal upper gastrointestinal tract bleeding. Am J Emerg Med 2007; 25: 774–79. Gralnek IM, Dulai GS. Incremental value of upper endoscopy for triage of patients with acute non-variceal upper-GI hemorrhage. Gastrointest Endosc 2004; 60: 9–14. Masaoka T, Suzuki H, Hori S, Aikawa N, Hibi T. Blatchford scoring system is a useful scoring system for detecting patients with upper gastrointestinal bleeding who do not need endoscopic intervention. J Gastroenterol Hepatol 2007; 22: 1404–08. Romagnuolo J, Barkun AN, Enns R, Armstrong D, Gregor J. Simple clinical predictors may obviate urgent endoscopy in selected patients with nonvariceal upper gastrointestinal tract bleeding. Arch Intern Med 2007; 167: 265–70. Stanley AJ, Ashley D, Dalton HR, et al. Outpatient management of patients with low-risk upper-gastrointestinal haemorrhage: multicentre validation and prospective evaluation. Lancet 2008; published online Dec 15. DOI:10.1016/S0140-6736(08)61769-9. Netten A, Curtis L. Unit costs of health and social care. 2006. http://www. pssru.ac.uk/pdf/uc/uc2006/uc2006.pdf (accessed Sept 4, 2008). Das A, Ben-Menachem T, Farooq FT, et al. Artificial neural network as a predictive instrument in patients with acute nonvariceal upper gastrointestinal hemorrhage. Gastroenterology 2008; 134: 65–74. Department of Health, Home Office, Department for Education and Skills and Department for Culture, Media and Sport. Safe. Sensible. Social. The next steps in the National Alcohol Strategy. June 5, 2007. http://www. dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAn dGuidance/DH_075218 (accessed Sept 4, 2008).
Can antiretroviral therapy eliminate HIV transmission? In The Lancet today, Reuben Granich and colleagues (including two of us, KMDC and CFG) use mathematical modelling to assess the impact of expanded HIV testing and earlier antiretroviral therapy (ART) on HIV transmission.1 These researchers evaluated a theoretical programme of annual universal HIV testing and immediate treatment on HIV diagnosis, irrespective of CD4+ cell count, in an HIV epidemic with southern African population dynamics. The exercise suggested that HIV transmission could be substantially reduced within a few years. Elimination of HIV transmission, defined as an incidence below one case per 1000 population per year, could be achieved within a decade, and the overall prevalence of HIV infection reduced to below 1% before the middle of the century. Compared with current practice of starting ART at a specific CD4+ count, deaths would be halved between now and 2050. www.thelancet.com Vol 373 January 3, 2009
The uncontrolled number of new HIV infections, despite years of prevention effort, represents a crisis: 2·7 million incident HIV infections occurred globally in 2007.2 By contrast, only 1 million additional individuals were placed on ART that year;3 about 6·7 million were in danger of their lives for lack of treatment, and over 20 million other HIV-infected individuals were waiting, mostly unknowingly, for immune deficiency to progress. Universal access to HIV treatment and care is an unrealistic aspiration unless HIV transmission can be interrupted. Behavioural interventions are essential but incompletely efficacious.4 For biomedical interventions, only four of 24 randomised trials showed protection; three assessed male circumcision.5 All vaccine and microbicide trials were negative. Unsurprisingly, how best to use ART for prevention has emerged as the most pressing question that faces HIV/AIDS science.
Published Online November 26, 2008 DOI:10.1016/S01406736(08)61732-8 See Comment page 9 See Articles page 48
7
Reuben Granich
Comment
Sculpture by Zimbabwean Mike Munyaradzi, 2007 “Symbolizing the fragile world we live in today, the hollowed sphere signifies the destruction of our globe and the difficult issue of our time including AIDS. The leaf represents the life we are struggling to sustain.”
ART may be used to prevent acquisition of HIV infection when delivered as prophylaxis before or after HIV exposure, or to prevent transmission from HIV-infected persons when provided as treatment that renders them less infectious. Prophylactic approaches are challenged by the large numbers having to be treated to prevent a single infection, and ART for preventing transmission from infected persons will have the greatest impact.6 Biological plausibility is provided by evidence that viral load is the major risk factor for all modes of HIV transmission and that ART lowers viral load in plasma and in genital secretions.7 Proof of concept is offered by the virtual elimination of paediatric HIV disease in highincome countries by universal voluntary HIV testing of pregnant women and appropriate provision of ART. By lowering viral load, ART reduces transmissibility as well as duration of infectiousness, the key determinants (along with rate of partner change) of the basic reproductive rate (R₀), the number of secondary infections generated by one primary case.8 Epidemic control requires that R₀ be reduced below 1. Observational data have shown reduced HIV transmission in discordant couples after the 8
introduction of combination ART,9 and programmatic data supported reduction in HIV transmission at the population level.10 Current clinical practice, however, limits the preventive efficacy of ART because substantial HIV transmission can occur around the time of seroconversion, when viral load is highest, ample opportunity for transmission exists before reaching the CD4+ count threshold for treatment, and many HIV-infected individuals are tested late or not at all. Dominant concerns of the approach modelled by Granich and colleagues relate to necessary protection of voluntariness and individual rights. Feasibility is challenged by: weak health systems and insufficient health personnel; choice of appropriate drug regimens; treatment adherence; drug toxicity; drug resistance and need for durable second-line and third-line regimens; the logistics, reliability, and acceptability of regularly testing a whole population for HIV infection; and behavioural risk compensation.11 Initial costs would be high and scepticism should be expected towards large-scale topdown efforts that appear to medicalise HIV prevention. By contrast, advantages of immediate treatment at diagnosis could include: simplified clinical management; reduction in the high mortality rates from late diagnosis;12 control of HIV-associated tuberculosis;13,14 and effective prevention of mother-to-child transmission of HIV, including through breastfeeding. The approach could be cost-saving over the longer term, because over time fewer individuals would be living with HIV and efforts would increasingly focus on treatment adherence and localised HIV transmission. Appropriately, Granich and colleagues emphasise that all current preventive interventions should be enhanced. Currently, only 20% of individuals with HIV in lowincome and middle-income countries know their serostatus,3 but most infected individuals will eventually require ART if they are not to die of AIDS. Because of newly recognised, non-AIDS-defining complications of uncontrolled HIV replication,15 as well as better treatment options,16 the pendulum around when to start therapy is again swinging towards earlier starting.16,17 Expanded HIV testing and immediate treatment would offer opportunity for highest quality positive prevention, a holistic approach that protects the physical, sexual, and reproductive health of individuals with HIV, and maximally reduces onward transmission.18 Provided www.thelancet.com Vol 373 January 3, 2009
Comment
coercion is avoided and confidentiality and dignity maintained, individual health and societal safety should benefit through reduced HIV transmission, which would enhance human rights overall. The approach could represent a conceptual redefinition of universal access and combination prevention, reframe the debate around when to start ART, and counter prevention pessimism. There is currently inadequate evidence for WHO to define policy and guidance about the role of ART in HIV prevention. Research is needed to assess the feasibility, safety, acceptability, impact, and cost of innovations such as the universal voluntary testing and immediate treatment approach, and broad consultation must address community, human rights, ethical, and political concerns. Research on male circumcision offers encouraging as well as cautionary experience about translation of research findings on controversial interventions into practice.19 Discussion will also be needed on ART for prevention in populations most at risk in epidemics of varying intensity. WHO is committed to promoting consultation among countries and stakeholders about the pressing biomedical issue of ART for HIV prevention.
2
3
4 5 6
7
8
9
10
11
12
13
14
*Kevin M De Cock, Charles F Gilks, Ying-Ru Lo, Teguest Guerma
15
HIV/AIDS Department, WHO, 1211 Geneva 27, Switzerland (KMDC, TG); Antiretroviral Treatment and HIV Care Unit, HIV/AIDS Department, WHO, Geneva, Switzerland (CFG); and Prevention in the Health Sector Unit, HIV/AIDS Department, WHO, Geneva, Switzerland (Y-RL)
[email protected] 16
We thank Christopher Dye, Brian Williams, and Reuben Granich for helpful discussions about this Comment. We declare that we have no conflict of interest. 1
Granich RM, Gilks CF, Dye C, De Cock KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet 2008; published online Nov 26. DOI:10.1016/S0140-6736(08)61697-9.
17 18
19
UNAIDS. 2008 Report on the global AIDS epidemic: executive summary. July, 2008. http://data.unaids.org/pub/GlobalReport/2008/JC1511_GR08_ ExecutiveSummary_en.pdf (accessed Nov 12, 2008). WHO. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector. 2008. http://www.who.int/hiv/pub/towards_ universal_access_report_2008.pdf (accessed Nov 12, 2008). Coates TJ, Richter L, Caceres C. Behavioural strategies to reduce HIV transmission: how to make them work better. Lancet 2008; 372: 669–84. Cohen J. Treatment and prevention exchange vows at International Conference. Science 2008; 321: 902–03. Montaner JS, Hogg R, Wood E, et al. The case for expanding access to highly active antiretroviral therapy to curb the growth of the HIV epidemic. Lancet 2006; 368: 531–36. Janssen RS, Holtgrave DR, Valdiserri RO, Shepherd M, Gayle HD, De Cock KM. The serostatus approach to fighting the HIV epidemic: prevention strategies for infected individuals. Am J Public Health 2001; 91: 1019–24. May RM, Anderson RM. The transmission dynamics of human immunodeficiency virus (HIV). Phil Trans R Soc Lond B Biol Sci 1988; 321: 565–607. Castilla J, Del Romero J, Hernando V, et al. Effectiveness of highly active antiretroviral therapy in reducing heterosexual transmission of HIV. J Acquir Immune Defic Syndr 2005; 40: 96–101. Fang CT, Hsu HM, Twu SJ, et al. Decreased HIV transmission after a policy of providing free access to highly active antiretroviral therapy in Taiwan. J Infect Dis 2004; 190: 879–85. Velasco-Hernandez JX, Gershengorn HB, Blower SM. Could widespread use of combination antiretroviral therapy eradicate HIV epidemics? Lancet Infect Dis 2002; 2: 487–93. Lawn SD, Harries AD, Anglaret X, Myer L, Wood R. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS 2008; 22: 1897–908. Corbett EL, Marston B, Churchyard GJ, De Cock KM. Tuberculosis in subSaharan Africa: opportunities, challenges, and change in the era of antiretroviral therapy. Lancet 2006; 367: 926–37. Williams BG, Dye C. Antiretroviral drugs for tuberculosis control in the era of HIV/AIDS. Science 2003; 301: 1535–37. Phillips A. Morbidity and mortality in the HAART era. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA; Feb 3–6, 2008: 8 (abstr). http://www.retroconference.org/2008/Abstracts/33423. htm (accessed Nov 12, 2008). Hammer SM, Eron JJ, Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society USA Panel. JAMA 2008; 300: 555–70. Hirsch MS. Initiating therapy: when to start, what to use. J Infect Dis 2008; 197 (suppl 3): S252–60. WHO. Essential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings. 2008. http://www.who.int/hiv/ pub/prev_care/OMS_EPP_AFF_en.pdf (accessed Nov 12, 2008). WHO, UNAIDS. New data on male circumcision and HIV prevention: policy and programme implications. http://data.unaids.org/pub/Report/2007/ mc_recommendations_en.pdf (accessed Nov 12, 2008).
Treating our way out of the HIV pandemic: could we, would we, should we? HIV prevention is easy in theory—the practice is hard. In models, HIV can be eliminated if risk behaviours or viral transmissibility are reduced substantially. Unfortunately, in many places, achievement of these reductions has not been possible and HIV incidence has remained high. In The Lancet today, Reuben Granich and colleagues use mathematical models to show that annual screening of most adults for HIV, with immediate commencement www.thelancet.com Vol 373 January 3, 2009
of antiretroviral therapy (ART) for all those infected, would dramatically reduce HIV incidence.1 This strategy would be a bold move away from the current approach of treatment on the basis of clinical need, in which the hoped-for synergies between treatment and prevention will remain limited because testing and counselling focus on individuals who have probably already transmitted infection.2
Published Online November 26, 2008 DOI:10.1016/S01406736(08)61698-0 See Comment page 7 See Articles page 48
9
Comment
coercion is avoided and confidentiality and dignity maintained, individual health and societal safety should benefit through reduced HIV transmission, which would enhance human rights overall. The approach could represent a conceptual redefinition of universal access and combination prevention, reframe the debate around when to start ART, and counter prevention pessimism. There is currently inadequate evidence for WHO to define policy and guidance about the role of ART in HIV prevention. Research is needed to assess the feasibility, safety, acceptability, impact, and cost of innovations such as the universal voluntary testing and immediate treatment approach, and broad consultation must address community, human rights, ethical, and political concerns. Research on male circumcision offers encouraging as well as cautionary experience about translation of research findings on controversial interventions into practice.19 Discussion will also be needed on ART for prevention in populations most at risk in epidemics of varying intensity. WHO is committed to promoting consultation among countries and stakeholders about the pressing biomedical issue of ART for HIV prevention.
2
3
4 5 6
7
8
9
10
11
12
13
14
*Kevin M De Cock, Charles F Gilks, Ying-Ru Lo, Teguest Guerma
15
HIV/AIDS Department, WHO, 1211 Geneva 27, Switzerland (KMDC, TG); Antiretroviral Treatment and HIV Care Unit, HIV/AIDS Department, WHO, Geneva, Switzerland (CFG); and Prevention in the Health Sector Unit, HIV/AIDS Department, WHO, Geneva, Switzerland (Y-RL)
[email protected] 16
We thank Christopher Dye, Brian Williams, and Reuben Granich for helpful discussions about this Comment. We declare that we have no conflict of interest. 1
Granich RM, Gilks CF, Dye C, De Cock KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet 2008; published online Nov 26. DOI:10.1016/S0140-6736(08)61697-9.
17 18
19
UNAIDS. 2008 Report on the global AIDS epidemic: executive summary. July, 2008. http://data.unaids.org/pub/GlobalReport/2008/JC1511_GR08_ ExecutiveSummary_en.pdf (accessed Nov 12, 2008). WHO. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector. 2008. http://www.who.int/hiv/pub/towards_ universal_access_report_2008.pdf (accessed Nov 12, 2008). Coates TJ, Richter L, Caceres C. Behavioural strategies to reduce HIV transmission: how to make them work better. Lancet 2008; 372: 669–84. Cohen J. Treatment and prevention exchange vows at International Conference. Science 2008; 321: 902–03. Montaner JS, Hogg R, Wood E, et al. The case for expanding access to highly active antiretroviral therapy to curb the growth of the HIV epidemic. Lancet 2006; 368: 531–36. Janssen RS, Holtgrave DR, Valdiserri RO, Shepherd M, Gayle HD, De Cock KM. The serostatus approach to fighting the HIV epidemic: prevention strategies for infected individuals. Am J Public Health 2001; 91: 1019–24. May RM, Anderson RM. The transmission dynamics of human immunodeficiency virus (HIV). Phil Trans R Soc Lond B Biol Sci 1988; 321: 565–607. Castilla J, Del Romero J, Hernando V, et al. Effectiveness of highly active antiretroviral therapy in reducing heterosexual transmission of HIV. J Acquir Immune Defic Syndr 2005; 40: 96–101. Fang CT, Hsu HM, Twu SJ, et al. Decreased HIV transmission after a policy of providing free access to highly active antiretroviral therapy in Taiwan. J Infect Dis 2004; 190: 879–85. Velasco-Hernandez JX, Gershengorn HB, Blower SM. Could widespread use of combination antiretroviral therapy eradicate HIV epidemics? Lancet Infect Dis 2002; 2: 487–93. Lawn SD, Harries AD, Anglaret X, Myer L, Wood R. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS 2008; 22: 1897–908. Corbett EL, Marston B, Churchyard GJ, De Cock KM. Tuberculosis in subSaharan Africa: opportunities, challenges, and change in the era of antiretroviral therapy. Lancet 2006; 367: 926–37. Williams BG, Dye C. Antiretroviral drugs for tuberculosis control in the era of HIV/AIDS. Science 2003; 301: 1535–37. Phillips A. Morbidity and mortality in the HAART era. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, USA; Feb 3–6, 2008: 8 (abstr). http://www.retroconference.org/2008/Abstracts/33423. htm (accessed Nov 12, 2008). Hammer SM, Eron JJ, Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society USA Panel. JAMA 2008; 300: 555–70. Hirsch MS. Initiating therapy: when to start, what to use. J Infect Dis 2008; 197 (suppl 3): S252–60. WHO. Essential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings. 2008. http://www.who.int/hiv/ pub/prev_care/OMS_EPP_AFF_en.pdf (accessed Nov 12, 2008). WHO, UNAIDS. New data on male circumcision and HIV prevention: policy and programme implications. http://data.unaids.org/pub/Report/2007/ mc_recommendations_en.pdf (accessed Nov 12, 2008).
Treating our way out of the HIV pandemic: could we, would we, should we? HIV prevention is easy in theory—the practice is hard. In models, HIV can be eliminated if risk behaviours or viral transmissibility are reduced substantially. Unfortunately, in many places, achievement of these reductions has not been possible and HIV incidence has remained high. In The Lancet today, Reuben Granich and colleagues use mathematical models to show that annual screening of most adults for HIV, with immediate commencement www.thelancet.com Vol 373 January 3, 2009
of antiretroviral therapy (ART) for all those infected, would dramatically reduce HIV incidence.1 This strategy would be a bold move away from the current approach of treatment on the basis of clinical need, in which the hoped-for synergies between treatment and prevention will remain limited because testing and counselling focus on individuals who have probably already transmitted infection.2
Published Online November 26, 2008 DOI:10.1016/S01406736(08)61698-0 See Comment page 7 See Articles page 48
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Relative transmissibility Total new infections generated by a case (R0) 10 5 2
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Figure: Cumulative number of new HIV infections transmitted per infected individual As function of time since infection for scenarios in which each individual generates two, five, and ten new infections. Infectiousness is assumed to be ten-fold higher in first 2 months than in long asymptomatic period, and four-fold higher in final 1·5 years of average infection of 10 years.
The “treat early, treat hard” approach of the early era of triple ART fell out of favour due to drug toxicities, concerns over the evolution of drug resistance, and potential limits to the duration of treatment efficacy in the patient. Therefore, when Velasco-Hernandez and colleagues first showed in simple models that ART could eliminate HIV infection, their findings appeared extremely unrealistic.3 Since then, clinical opinions have changed with improved regimens and evidence of lower death rates if ART is started before CD4+ cell counts fall below 350 per μL, which makes earlier treatment more acceptable.4 When early treatment is considered as a prevention tool, success will require substantial resources and depend on a remarkable degree of acceptance and cooperation across populations. If we could eliminate HIV this way would we, given the will needed, and should we, given the conflict between utilitarianism and individualism5 inherent in this strategy? Granich and colleagues’ model findings appear robust and the critical mathematics is straightforward. At the start of an epidemic, the number of subsequent 10
infections generated by each infection (the basic reproductive number, R₀) determines how difficult it will be to control the infection.6 Reductions in variables that contribute to R₀, such as the average transmission probability, will reduce the spread of infection. There is a simple rule that, for a given value of R₀, an equivalent fold reduction, reducing R₀ to its tipping point of one, will eliminate the infection. Secondary infections over the course of infection and when individuals need to be treated are shown in the figure. To eliminate infection, the individual must be treated and become noninfectious at the point when the cumulative number of infections passes through one. To allow for early high infectiousness and potentially high R₀ values, Granich’s model represents a very intensive screening programme. Such a programme and additional interventions in those with highest risk would probably be required if elimination was truly the goal. However, real elimination (ie, an incidence of zero in a large geographic area7) is unlikely. There will be some people whose risk is sufficient to maintain pockets of transmission within a very small fraction of the population. Probably, some individuals would not be screened and treated, and if these individuals have high risks of HIV acquisition and transmission, they will maintain infection within the population. Nonetheless, dramatic reductions in incidence are likely to be achieved. Granich and colleagues’ suggested strategy would be extremely radical, with medical intervention for public-health benefits rather than individual patient’s benefits; more so, if the costs of toxicity and inconvenience for the individual outweigh the clinical benefits. Because screening and treatment would be for the public good, resources would have to come from the public purse. Current studies of uptake of and adherence to ART represent the case when mostly sick people are motivated to seek care. The strategy would rely on people, who feel well, regularly seeking care and adhering to ART. The prevention impact of the treatment depends on those who receive ART having a much reduced transmissibility, which seems reasonable, but there would be concern over other sexually transmitted infections, poor adherence, and treatment failure all reconstituting infectiousness, or the evolution and spread of resistant virus undermining treatment. There would also be questions about the epidemic contexts in which such a strategy should be used, the www.thelancet.com Vol 373 January 3, 2009
Comment
required frequency of testing, and how that frequency would change as prevalence falls. The suggested strategy would reflect public health at its best and its worst. At its best, the strategy would prevent morbidity and mortality for the population, both through better treatment of the individual and reduced spread of HIV. At its worst, the strategy will involve over-testing, over-treatment, side-effects, resistance, and potentially reduced autonomy of the individual in their choices of care. The individual might gain no personal benefit from testing and early treatment, but they would benefit from protecting partners—and who could object to that, unless they were recklessly exposing others to infection? It is easy to see how enforced testing and treatment for the good of society would follow from such an argument. Partial success would lead to infection becoming concentrated in those with a high risk, with an increased danger of stigma and coercion. The history of the control of sexually transmitted infections documents several examples of compulsory screening and treatment of stigmatised populations,8 and there is a danger of a well-meaning paternalistic medical model following such a route. Capacity—financial, physical, and human—as well as effectiveness and cost-effectiveness are important. The relative power of curative versus preventive medicine
and the priority of health enforcement would be crucial in implementation. Challenges will rightly come from those concerned about individuals’ rights and patients’ autonomy, as well as from those who moralistically fear an “easy” solution to HIV rather than behavioural change. *Geoffrey P Garnett, Rebecca F Baggaley Department of Infectious Disease Epidemiology, Imperial College London, London W2 1PG, UK
[email protected] We declare that we have no conflict of interest. 1
2 3
4 5 6 7
8
Granich RM, Gilks CF, Dye C, De Cock KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet 2008; published online Nov 26. DOI:10.1016/S0140-6736(08)61697-9. Baggaley RF, Garnett GP, Ferguson NM. Modelling the impact of antiretroviral use in resource-poor settings. PLoS Med 2006; 3: e124. Velasco-Hernandez JX, Gershengorn HB, Blower SM. Could widespread use of combination antiretroviral therapy eradicate HIV epidemics? Lancet Infect Dis 2002; 2: 487–93. Wilkin TJ, Gulick RM. When to start antiretroviral therapy? Clin Infect Dis 2008; published online Nov 6. DOI:10.1086/593311. Looker KJ, Hallet TB. Individual freedom versus collective responsibility: too many rights make a wrong? Emerging Themes Epidemiol 2006; 3: 14. Anderson RM, May RM: Infectious diseases of humans: dynamics and control. Oxford, Oxford University Press, 1991. Molyneux DH, Hopkins DR, Zagaria N. Disease eradication, elimination and control: the need for accurate and consistent usage. Trends Parasitol 2004; 20: 347–51. Porter D, Porter R. The enforcement of health: the British debate. In: Fee E, Fox DM, eds. AIDS the burdens of history. Berkeley and Los Angeles, CA: University of California Press, 1988: 97–120.
Malaria scale-up progress: is the glass half-empty or half-full? In The Lancet today, Abdisalan Noor and colleagues analyse progress in achieving coverage in Africa with insecticide-treated bednets.1 In 2007, 90 million children in stable endemic areas were not protected by such nets. Yet, overall, coverage has increased about six-fold since 2000. So, is the glass half-empty or half-full for malaria scale-up progress? Some would say half-empty. Noor and colleagues show that some large countries with substantial populations at risk, such as the Democratic Republic of Congo, Nigeria, and Sudan—that together account for a major part of Africa’s malaria-related morbidity and mortality—have so far achieved minimal scaleup. Coverage as documented by Noor and elsewhere2 remains unacceptably low. The scale of what yet needs to be achieved is both sobering and a reality check. The usage rates of insecticide-treated bednets reported by Noor and colwww.thelancet.com Vol 373 January 3, 2009
leagues are for children under 5 years of age. Although this criterion is the accepted indicator for bednet use as defined by Roll Back Malaria, it is worth reminding ourselves that the goal of Roll Back Malaria is now universal coverage—defined as one long-lasting insecticide-treated bednet for every two people in the household—with 80% usage. To achieve universal coverage by 2010, about 250–300 million new long-lasting insecticide-treated bednets will need to be distributed in Africa.3 Clearly, to achieve this ambitious goal in about 2 years, the pace of distribution of insecticide-treated bednets will need to increase dramatically, especially in places where little has been achieved so far. In countries with well-developed national distribution strategies, various approaches to catch up and keep up with coverage may be useful.4 However, rapid progress towards 2010 goals of Roll Back Malaria for bednets in countries where usage currently languishes in single
Published Online November 18, 2008 DOI:10.1016/S01406736(08)61597-4 See Articles page 58
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Comment
required frequency of testing, and how that frequency would change as prevalence falls. The suggested strategy would reflect public health at its best and its worst. At its best, the strategy would prevent morbidity and mortality for the population, both through better treatment of the individual and reduced spread of HIV. At its worst, the strategy will involve over-testing, over-treatment, side-effects, resistance, and potentially reduced autonomy of the individual in their choices of care. The individual might gain no personal benefit from testing and early treatment, but they would benefit from protecting partners—and who could object to that, unless they were recklessly exposing others to infection? It is easy to see how enforced testing and treatment for the good of society would follow from such an argument. Partial success would lead to infection becoming concentrated in those with a high risk, with an increased danger of stigma and coercion. The history of the control of sexually transmitted infections documents several examples of compulsory screening and treatment of stigmatised populations,8 and there is a danger of a well-meaning paternalistic medical model following such a route. Capacity—financial, physical, and human—as well as effectiveness and cost-effectiveness are important. The relative power of curative versus preventive medicine
and the priority of health enforcement would be crucial in implementation. Challenges will rightly come from those concerned about individuals’ rights and patients’ autonomy, as well as from those who moralistically fear an “easy” solution to HIV rather than behavioural change. *Geoffrey P Garnett, Rebecca F Baggaley Department of Infectious Disease Epidemiology, Imperial College London, London W2 1PG, UK
[email protected] We declare that we have no conflict of interest. 1
2 3
4 5 6 7
8
Granich RM, Gilks CF, Dye C, De Cock KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet 2008; published online Nov 26. DOI:10.1016/S0140-6736(08)61697-9. Baggaley RF, Garnett GP, Ferguson NM. Modelling the impact of antiretroviral use in resource-poor settings. PLoS Med 2006; 3: e124. Velasco-Hernandez JX, Gershengorn HB, Blower SM. Could widespread use of combination antiretroviral therapy eradicate HIV epidemics? Lancet Infect Dis 2002; 2: 487–93. Wilkin TJ, Gulick RM. When to start antiretroviral therapy? Clin Infect Dis 2008; published online Nov 6. DOI:10.1086/593311. Looker KJ, Hallet TB. Individual freedom versus collective responsibility: too many rights make a wrong? Emerging Themes Epidemiol 2006; 3: 14. Anderson RM, May RM: Infectious diseases of humans: dynamics and control. Oxford, Oxford University Press, 1991. Molyneux DH, Hopkins DR, Zagaria N. Disease eradication, elimination and control: the need for accurate and consistent usage. Trends Parasitol 2004; 20: 347–51. Porter D, Porter R. The enforcement of health: the British debate. In: Fee E, Fox DM, eds. AIDS the burdens of history. Berkeley and Los Angeles, CA: University of California Press, 1988: 97–120.
Malaria scale-up progress: is the glass half-empty or half-full? In The Lancet today, Abdisalan Noor and colleagues analyse progress in achieving coverage in Africa with insecticide-treated bednets.1 In 2007, 90 million children in stable endemic areas were not protected by such nets. Yet, overall, coverage has increased about six-fold since 2000. So, is the glass half-empty or half-full for malaria scale-up progress? Some would say half-empty. Noor and colleagues show that some large countries with substantial populations at risk, such as the Democratic Republic of Congo, Nigeria, and Sudan—that together account for a major part of Africa’s malaria-related morbidity and mortality—have so far achieved minimal scaleup. Coverage as documented by Noor and elsewhere2 remains unacceptably low. The scale of what yet needs to be achieved is both sobering and a reality check. The usage rates of insecticide-treated bednets reported by Noor and colwww.thelancet.com Vol 373 January 3, 2009
leagues are for children under 5 years of age. Although this criterion is the accepted indicator for bednet use as defined by Roll Back Malaria, it is worth reminding ourselves that the goal of Roll Back Malaria is now universal coverage—defined as one long-lasting insecticide-treated bednet for every two people in the household—with 80% usage. To achieve universal coverage by 2010, about 250–300 million new long-lasting insecticide-treated bednets will need to be distributed in Africa.3 Clearly, to achieve this ambitious goal in about 2 years, the pace of distribution of insecticide-treated bednets will need to increase dramatically, especially in places where little has been achieved so far. In countries with well-developed national distribution strategies, various approaches to catch up and keep up with coverage may be useful.4 However, rapid progress towards 2010 goals of Roll Back Malaria for bednets in countries where usage currently languishes in single
Published Online November 18, 2008 DOI:10.1016/S01406736(08)61597-4 See Articles page 58
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Comment
or low-double digits will need to rely initially on mass free distributions to achieve major improvements in coverage in this compressed timeline.5 Moreover, the progress in scale-up of other malaria interventions (case management with artemisinincontaining combinations, intermittent preventive treatment in pregnancy) has lagged behind that for insecticide-treated bednets. For example, a recent estimate in 14 African countries of use of artemisinin combinations in febrile children was 6% or less.2 In view of the fact that many antimalarial treatments are sought outside the public health system, private sector and community access to effective antimalarials and diagnostics will need to be vastly improved if we are to make significant inroads in improving these numbers. We have our work cut out for us. Nonetheless, there are several reasons to view the malaria scale-up glass as half-full. First, as noted by Noor and colleagues, some success has been achieved: seven African countries had projected use of insecticide-treated bednets of more than 40% by July, 2007. The challenge will be to document the lessons learned from those experiences and apply them elsewhere.6,7 Second, international funding for malaria control has increased three-fold from 2004 to 2007.8 Recent commitments include US$1·1 billion to expand the World Bank Malaria Booster Program (with targeted funding for the Democratic Republic of Congo and Nigeria),9 and $1·62 billion in new malaria grants from 12
the Global Fund to Fight AIDS, Tuberculosis and Malaria.10 Bilateral donors, such as the US President’s Malaria Initiative11 and the UK’s Department for International Development,10 have also pledged substantial amounts. About $2–3 billion is needed annually in Africa over the next several years to achieve control targets. Demonstration of impact from these investments will be critical for sustained commitment. Third, leadership has been more effective at global and national levels, and has resulted in improved coordination and more effective advocacy. After the Change Initiative in 2006,12 the Roll Back Malaria Partnership has become an authoritative convener for discussion of global strategies—including the recently released Global Malaria Action Plan3—and ways to improve country support. Most importantly, some African leaders have stepped forward to promote ambitious national programmes based on sound action plans.13 Without this national ownership and commitment, sustained success will not be achieved. Noor and colleagues highlight that there are mismatches between malaria burden and coverage with insecticide-treated bednets. To facilitate local decision making, it will be critical moving forward to increase support for gathering useful programme data on malaria burden and intervention coverage at subnational levels. Local data about confirmed cases of malaria, and bednet ownership, use, and durability should help to better match availability of bednets with needs. Some would question the wisdom of discussing regional malaria elimination or global eradication in view of reports such as that of Noor and colleagues. We believe, however, that those working on malaria today can and must strike a delicate balance. Focus must be maintained on improving and sustaining scale-up in highburden countries. At the same time, the strategies and planning for strengthening surveillance, health systems, human-resource capacity, and regional coordination mechanisms must proceed. Lessons learned over the next 5–10 years in pursuing elimination in areas with lower transmission rates will help to guide future approaches in countries with currently intolerable malaria burdens.14 *Laurence Slutsker, Robert D Newman Malaria Branch, Centers for Disease Control and Prevention, Atlanta, GA 30307, USA
[email protected] Our views are not necessarily those of the Centers for Disease Control and Prevention. We declare that we have no conflict of interest.
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Noor AM, Mutheu JJ, Tatem AJ, Hay SI, Snow RW. Insecticide-treated net coverage in Africa: mapping progress in 2000–07. Lancet 2008; published online Nov 18. DOI:10.1016/S0140-6736(08)61596-2. UNICEF, Roll Back Malaria Partnership. Malaria and children: progress in intervention coverage, 2007. http://www.unicef.org/health/files/Malaria Oct6forweb_final.pdf (accessed Oct 25, 2008). Roll Back Malaria. The global malaria action plan. http://www. rollbackmalaria.org/gmap (accessed Oct 25, 2008). Lengeler C, deSavigny D. Programme diversity is the key to success of insecticide treated bednets. Lancet 2007; 370: 1009–10. Teklehaimanot A, Sachs JD, Curtis C. Malaria control needs mass distribution of insecticidal bednets. Lancet 2007; 369: 2143–46. Steketee RW, Sipilanyambe N, Chimumbwa J, et al. National malaria control and scaling up for impact: the Zambia experience through 2006. Am J Trop Med Hyg 2008; 79: 45–52. Chambers RG, Gupta RK, Ghebreyesus TA. Responding to the challenge to end malaria deaths in Africa. Lancet 2008; 371: 1399–401. Snow RW, Guerra CA, Mutheu J, Hay SI. International funding for malaria control in relation to populations at risk of stable Plasmodium falciparum transmission. PLoS Medicine 2008; 7: e142.
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World Bank. World Bank to give $1 billion boost to fighting malaria in Africa. Sept 25, 2008. http://web.worldbank.org/WBSITE/EXTERNAL/ COUNTRIES/AFRICAEXT/0,,contentMDK:21914969~menuPK:258 658~page PK:2865106~piPK:286512 8~theSitePK:258644,00.html (accessed Nov 2, 2008). Malaria No More. World leaders make an unprecedented commitment to fight malaria. Sept 25, 2009. http://www.malarianomore. org/news/features/mdg_092508.php (accessed Nov 4, 2008). Fast Facts. The President’s malaria initiative (PMI). April, 2008. http://www.fightingmalaria.gov/resources/reports/pmi_fastfacts.pdf (accessed Nov 4, 2008). Rollback Malaria Partnership. RBM Partnership Framework. December, 2006. http://rbmwhoint/changeinitiative/ PartnershipFramework.pdf (accessed Nov 4, 2008). Campbell CC. Halting the toll of malaria in Africa. Am J Trop Med Hyg 2008; 78: 851–53. Feachem R, Sabot O. A new global malaria eradication strategy. Lancet 2008; 371: 1633–35.
Helsinki discords: FDA, ethics, and international drug trials Since 1964, the Declaration of Helsinki has stood as one of the world’s most authoritative statements on ethical standards for human research.1 Drafted by the World Medical Association to provide medical researchers with ethical guidance, the Declaration has undergone six major revisions, most recently in October, 2008.2 For many years the US Food and Drug Administration (FDA) has required that foreign clinical studies supporting applications for drug licensure comply with the Declaration. However, on Oct 27, 2008, the FDA formally discontinued its reliance on the Declaration and substituted the International Conference on Harmonization’s Guideline for Good Clinical Practice (GCP).3 The rationale behind the FDA’s action is complex, and no doubt reflects an effort to balance important interests and public-policy goals. Among the FDA’s reasons are the need to assure the quality of foreign data submitted to the agency, a wish to prevent confusion among researchers when the Declaration of Helsinki undergoes revision, and a worry that future modifications could “contain provisions that are inconsistent with US laws and regulations”.3 The FDA’s latest action completes a process begun in 2001 when the agency declined to recognise the 2000 revision, in part due to the Declaration’s restrictive stance on placebo-controlled trials in economically developing countries.4 The practical consequences of the FDA’s current action are unclear because the ruling applies to only a subset of clinical trials—ie, international trials. Moreover, several countries that host such www.thelancet.com Vol 373 January 3, 2009
research have regulations that endorse or emulate the Declaration of Helsinki. Nevertheless, at a time when the volume of overseas trials is increasing,5 the FDA’s new policy is troubling. First, the Declaration of Helsinki has a moral authority that GCP lacks. The Declaration has long been recognised as a leading international ethical standard for research. Whereas the World Medical Association includes 85 national medical societies from every part of the globe, the International Conference on Harmonization consists of only voting members from the USA, the European Union, and Japan. Indeed, the authors of GCP acknowledge the authority of the Declaration of Helsinki when they state that a goal of GCP is “consisten[cy] with the principles that have their origin in the Declaration of Helsinki”.6 The FDA regulates the largest drug market in the world and we worry that its replacement of the Declaration of Helsinki with a less morally authoritative document may cause others to follow suit, thereby undermining international ethical standards for research. Second, the Declaration of Helsinki has a breadth and depth that GCP lacks.1 For sure, GCP covers similar topics to the Declaration, but the focus of GCP is regulatory harmonisation, not the articulation of ethical commitments. Careful examination of the two documents reveals several important ethical issues that are addressed in the Declaration about which GCP is silent (panel). Thus reliance on GCP rather than on the Declaration of Helsinki may result in less protection for research 13
Comment
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Noor AM, Mutheu JJ, Tatem AJ, Hay SI, Snow RW. Insecticide-treated net coverage in Africa: mapping progress in 2000–07. Lancet 2008; published online Nov 18. DOI:10.1016/S0140-6736(08)61596-2. UNICEF, Roll Back Malaria Partnership. Malaria and children: progress in intervention coverage, 2007. http://www.unicef.org/health/files/Malaria Oct6forweb_final.pdf (accessed Oct 25, 2008). Roll Back Malaria. The global malaria action plan. http://www. rollbackmalaria.org/gmap (accessed Oct 25, 2008). Lengeler C, deSavigny D. Programme diversity is the key to success of insecticide treated bednets. Lancet 2007; 370: 1009–10. Teklehaimanot A, Sachs JD, Curtis C. Malaria control needs mass distribution of insecticidal bednets. Lancet 2007; 369: 2143–46. Steketee RW, Sipilanyambe N, Chimumbwa J, et al. National malaria control and scaling up for impact: the Zambia experience through 2006. Am J Trop Med Hyg 2008; 79: 45–52. Chambers RG, Gupta RK, Ghebreyesus TA. Responding to the challenge to end malaria deaths in Africa. Lancet 2008; 371: 1399–401. Snow RW, Guerra CA, Mutheu J, Hay SI. International funding for malaria control in relation to populations at risk of stable Plasmodium falciparum transmission. PLoS Medicine 2008; 7: e142.
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World Bank. World Bank to give $1 billion boost to fighting malaria in Africa. Sept 25, 2008. http://web.worldbank.org/WBSITE/EXTERNAL/ COUNTRIES/AFRICAEXT/0,,contentMDK:21914969~menuPK:258 658~page PK:2865106~piPK:286512 8~theSitePK:258644,00.html (accessed Nov 2, 2008). Malaria No More. World leaders make an unprecedented commitment to fight malaria. Sept 25, 2009. http://www.malarianomore. org/news/features/mdg_092508.php (accessed Nov 4, 2008). Fast Facts. The President’s malaria initiative (PMI). April, 2008. http://www.fightingmalaria.gov/resources/reports/pmi_fastfacts.pdf (accessed Nov 4, 2008). Rollback Malaria Partnership. RBM Partnership Framework. December, 2006. http://rbmwhoint/changeinitiative/ PartnershipFramework.pdf (accessed Nov 4, 2008). Campbell CC. Halting the toll of malaria in Africa. Am J Trop Med Hyg 2008; 78: 851–53. Feachem R, Sabot O. A new global malaria eradication strategy. Lancet 2008; 371: 1633–35.
Helsinki discords: FDA, ethics, and international drug trials Since 1964, the Declaration of Helsinki has stood as one of the world’s most authoritative statements on ethical standards for human research.1 Drafted by the World Medical Association to provide medical researchers with ethical guidance, the Declaration has undergone six major revisions, most recently in October, 2008.2 For many years the US Food and Drug Administration (FDA) has required that foreign clinical studies supporting applications for drug licensure comply with the Declaration. However, on Oct 27, 2008, the FDA formally discontinued its reliance on the Declaration and substituted the International Conference on Harmonization’s Guideline for Good Clinical Practice (GCP).3 The rationale behind the FDA’s action is complex, and no doubt reflects an effort to balance important interests and public-policy goals. Among the FDA’s reasons are the need to assure the quality of foreign data submitted to the agency, a wish to prevent confusion among researchers when the Declaration of Helsinki undergoes revision, and a worry that future modifications could “contain provisions that are inconsistent with US laws and regulations”.3 The FDA’s latest action completes a process begun in 2001 when the agency declined to recognise the 2000 revision, in part due to the Declaration’s restrictive stance on placebo-controlled trials in economically developing countries.4 The practical consequences of the FDA’s current action are unclear because the ruling applies to only a subset of clinical trials—ie, international trials. Moreover, several countries that host such www.thelancet.com Vol 373 January 3, 2009
research have regulations that endorse or emulate the Declaration of Helsinki. Nevertheless, at a time when the volume of overseas trials is increasing,5 the FDA’s new policy is troubling. First, the Declaration of Helsinki has a moral authority that GCP lacks. The Declaration has long been recognised as a leading international ethical standard for research. Whereas the World Medical Association includes 85 national medical societies from every part of the globe, the International Conference on Harmonization consists of only voting members from the USA, the European Union, and Japan. Indeed, the authors of GCP acknowledge the authority of the Declaration of Helsinki when they state that a goal of GCP is “consisten[cy] with the principles that have their origin in the Declaration of Helsinki”.6 The FDA regulates the largest drug market in the world and we worry that its replacement of the Declaration of Helsinki with a less morally authoritative document may cause others to follow suit, thereby undermining international ethical standards for research. Second, the Declaration of Helsinki has a breadth and depth that GCP lacks.1 For sure, GCP covers similar topics to the Declaration, but the focus of GCP is regulatory harmonisation, not the articulation of ethical commitments. Careful examination of the two documents reveals several important ethical issues that are addressed in the Declaration about which GCP is silent (panel). Thus reliance on GCP rather than on the Declaration of Helsinki may result in less protection for research 13
Comment
Panel: Requirements in latest revision of Declaration of Helsinki2 but absent in GCP6 • Investigators to disclose funding, sponsors, and other potential conflicts of interest to both research ethics committees and study participants • Study design to be disclosed publicly (eg, in clinical trial registries) • Research, notably that in developing countries, to benefit and be responsive to health needs of populations in which it is done • Restricted use of placebo controls in approval process for new drugs and in research done in developing countries • Post-trial access to treatment • Authors to report results accurately, and publish or make public negative findings
participants. If so, the FDA’s action might lower the bar for international research under its purview—a scenario that has worried previous commentators.7,8 Third, the FDA’s departure from the Declaration of Helsinki could undermine its stated goals of clarity and regulatory harmonisation. For example, if many countries continue to use the Declaration, US researchers will encounter the same “confusion” that the FDA is attempting to prevent with its new rule. Similarly, should other countries follow the FDA’s lead and abandon the Declaration of Helsinki, the result could be the balkanisation of ethical standards in international research. In view of these concerns, we suggest the new US administration suspend this rule pending a review of the implications for US-sponsored research overseas. If such review confirms our concerns, the FDA should be directed to rejoin the international community in requiring that studies be done in accordance with the Declaration of Helsinki. We also see an important role for major medical societies—though they lack regulatory authority, collectively these organisations can give voice to the commitment of medical researchers to
the Declaration’s high ethical standards. The American Society of Gene Therapy is considering policy on this issue9 and others should follow suit. *Jonathan Kimmelman, Charles Weijer, Eric M Meslin Biomedical Ethics Unit and Department of Social Studies of Medicine, McGill University, Montreal, QC, Canada H3A 1X1(JK); Departments of Philosophy and Medicine, University of Western Ontario, London, ON, Canada (CW); and Indiana University Center for Bioethics, Indianapolis, IN, USA (EMM)
[email protected] We are members of the Canadian Network for the Governance of Ethical Health Research Involving Humans, supported by the Canadian Institutes of Health Research (CIHR). JK’s research is supported by a New Investigator award from CIHR. CW’s research is supported by a Canada Research Chair and CIHR operating grant. EMM’s research is supported in part by grant R25TW006070 from the Fogarty International Center at the National Institutes of Health. Our views do not necessarily represent the official views of the CIHR, Fogarty International Center, or the NIH. We thank Daryl Pullman and Heather Sampson for contributions to this Comment. 1
2 3
4
5 6
7
8
9
Aschcroft RE. The Declaration of Helsinki. In: Emanuel EJ, Grady C, Crouch RA et al, eds. The Oxford Textbook of Clinical Research Ethics. New York: Oxford University Press, 2007. World Medical Association. Declaration of Helsinki. October, 2008. http://www.wma.net/e/policy/b3.htm (accessed Oct 25, 2008). Department of Health and Human Services, Food and Drug Administration. Human subject protection; foreign clinical studies not conducted under an investigational new drug application. Fed Reg April 28, 2008. 22800-16. http://www.fda.gov/cber/rules/forclinstud.pdf (accessed Nov 9, 2008). Department of Health and Human Services, Food and Drug Administration. Guidance for industry: acceptance of foreign studies. March, 2001. http://www.fda.gov/cber/gdlns/clinical031301.pdf (accessed Nov 9, 2008). Thiers FA, Sinskey AJ, Berndt ER. Trends in the globalization of clinical trials. Nat Rev Drug Discov 2008; 7: 13–14. International Conference on Harmonization. Guideline for good clinical practice (e6). 1996. http://www.ich.org/LOB/media/MEDIA482.pdf (accessed Oct 25, 2008). National Bioethics Advisory Commission. Ethical and policy issues in international research: clinical trials in developing countries, vol 1. 2001. http://bioethics.georgetown.edu/nbac/clinical/Vol1.pdf (accessed Oct 25, 2008). Nuffield Council on Bioethics. The ethics of research related to healthcare in developing countries. 2002. http://www.nuffieldbioethics.org/fileLibrary/ pdf/errhdc_fullreport001.pdf (accessed Nov 9, 2008). Friedmann T. The ASGT and ethical codes for research. Mol Ther 2008; 16: 1643–44.
Cardiology: a call for papers To submit a paper go to http://ees.elsevier.com/thelancet
14
The Lancet is dedicating a special issue to cardiology to coincide with the American College of Cardiology meeting to be held in Orlando, FL, USA, on March 28 to April 1, 2009. In particular, we will consider high-quality research papers that report results of randomised trials. If your work is being presented at the meeting and falls under an embargo policy, please tell us the date, time, and manner of presentation (poster or oral). If your paper is accepted here, publication on
our website can be scheduled to coincide with the presentation. The deadline for submissions is March 2, 2009, via our online submission system. Please state in your covering letter that the submission is in response to this call for papers.
Stuart Spencer The Lancet, London NW1 7BY, UK
www.thelancet.com Vol 373 January 3, 2009
Comment
Panel: Requirements in latest revision of Declaration of Helsinki2 but absent in GCP6 • Investigators to disclose funding, sponsors, and other potential conflicts of interest to both research ethics committees and study participants • Study design to be disclosed publicly (eg, in clinical trial registries) • Research, notably that in developing countries, to benefit and be responsive to health needs of populations in which it is done • Restricted use of placebo controls in approval process for new drugs and in research done in developing countries • Post-trial access to treatment • Authors to report results accurately, and publish or make public negative findings
participants. If so, the FDA’s action might lower the bar for international research under its purview—a scenario that has worried previous commentators.7,8 Third, the FDA’s departure from the Declaration of Helsinki could undermine its stated goals of clarity and regulatory harmonisation. For example, if many countries continue to use the Declaration, US researchers will encounter the same “confusion” that the FDA is attempting to prevent with its new rule. Similarly, should other countries follow the FDA’s lead and abandon the Declaration of Helsinki, the result could be the balkanisation of ethical standards in international research. In view of these concerns, we suggest the new US administration suspend this rule pending a review of the implications for US-sponsored research overseas. If such review confirms our concerns, the FDA should be directed to rejoin the international community in requiring that studies be done in accordance with the Declaration of Helsinki. We also see an important role for major medical societies—though they lack regulatory authority, collectively these organisations can give voice to the commitment of medical researchers to
the Declaration’s high ethical standards. The American Society of Gene Therapy is considering policy on this issue9 and others should follow suit. *Jonathan Kimmelman, Charles Weijer, Eric M Meslin Biomedical Ethics Unit and Department of Social Studies of Medicine, McGill University, Montreal, QC, Canada H3A 1X1(JK); Departments of Philosophy and Medicine, University of Western Ontario, London, ON, Canada (CW); and Indiana University Center for Bioethics, Indianapolis, IN, USA (EMM)
[email protected] We are members of the Canadian Network for the Governance of Ethical Health Research Involving Humans, supported by the Canadian Institutes of Health Research (CIHR). JK’s research is supported by a New Investigator award from CIHR. CW’s research is supported by a Canada Research Chair and CIHR operating grant. EMM’s research is supported in part by grant R25TW006070 from the Fogarty International Center at the National Institutes of Health. Our views do not necessarily represent the official views of the CIHR, Fogarty International Center, or the NIH. We thank Daryl Pullman and Heather Sampson for contributions to this Comment. 1
2 3
4
5 6
7
8
9
Aschcroft RE. The Declaration of Helsinki. In: Emanuel EJ, Grady C, Crouch RA et al, eds. The Oxford Textbook of Clinical Research Ethics. New York: Oxford University Press, 2007. World Medical Association. Declaration of Helsinki. October, 2008. http://www.wma.net/e/policy/b3.htm (accessed Oct 25, 2008). Department of Health and Human Services, Food and Drug Administration. Human subject protection; foreign clinical studies not conducted under an investigational new drug application. Fed Reg April 28, 2008. 22800-16. http://www.fda.gov/cber/rules/forclinstud.pdf (accessed Nov 9, 2008). Department of Health and Human Services, Food and Drug Administration. Guidance for industry: acceptance of foreign studies. March, 2001. http://www.fda.gov/cber/gdlns/clinical031301.pdf (accessed Nov 9, 2008). Thiers FA, Sinskey AJ, Berndt ER. Trends in the globalization of clinical trials. Nat Rev Drug Discov 2008; 7: 13–14. International Conference on Harmonization. Guideline for good clinical practice (e6). 1996. http://www.ich.org/LOB/media/MEDIA482.pdf (accessed Oct 25, 2008). National Bioethics Advisory Commission. Ethical and policy issues in international research: clinical trials in developing countries, vol 1. 2001. http://bioethics.georgetown.edu/nbac/clinical/Vol1.pdf (accessed Oct 25, 2008). Nuffield Council on Bioethics. The ethics of research related to healthcare in developing countries. 2002. http://www.nuffieldbioethics.org/fileLibrary/ pdf/errhdc_fullreport001.pdf (accessed Nov 9, 2008). Friedmann T. The ASGT and ethical codes for research. Mol Ther 2008; 16: 1643–44.
Cardiology: a call for papers To submit a paper go to http://ees.elsevier.com/thelancet
14
The Lancet is dedicating a special issue to cardiology to coincide with the American College of Cardiology meeting to be held in Orlando, FL, USA, on March 28 to April 1, 2009. In particular, we will consider high-quality research papers that report results of randomised trials. If your work is being presented at the meeting and falls under an embargo policy, please tell us the date, time, and manner of presentation (poster or oral). If your paper is accepted here, publication on
our website can be scheduled to coincide with the presentation. The deadline for submissions is March 2, 2009, via our online submission system. Please state in your covering letter that the submission is in response to this call for papers.
Stuart Spencer The Lancet, London NW1 7BY, UK
www.thelancet.com Vol 373 January 3, 2009
World Report
Text messages could hasten tuberculosis drug compliance Mobile phone technologies are being harnessed to help patients with tuberculosis keep up with their treatment regimens, with some promising preliminary results. Eliza Barclay reports. A handful of new technologies designed to connect tuberculosis patients with their caregivers using text messaging, or SMS (short message service), hold potential for helping to improve adherence to gruelling drug regimens. The treatment for tuberculosis is a combination of strong antibiotics that must be taken daily for at least 6 months. But side-effects, such as nausea and heartburn, dissuade some patients from sticking with the treatment. Other patients endure the side-effects only to drop the medication once they feel better 1 or 2 months into the regimen. The Stop TB Partnership reports that on average 5% of tuberculosis patients abandon treatment, although the figure is as high as 20% in some countries. Those patients who cannot or do not adhere to the treatment remain infectious longer and are more likely to relapse and die. They are also vulnerable to developing multidrug-resistant tuberculosis, a strain resistant to two or more first-line drugs, or extensively drug-resistant tuberculosis, a strain resistant to three or more second-line drugs. To help people complete their treatment WHO recommends a strategy known as DOTS (directly observed treatment, short course). As part of this strategy, a health worker or a tuberculosis treatment supporter watches the patient take their antibiotics every day. Patients also receive counselling and support to ensure they do not stray from their treatment course. Although DOTS has helped to dramatically improve tuberculosis control around the world, it is insufficient or inaccessible for thousands of patients. Many seek treatment in private clinics without close monitoring from their doctor. “Patients that most often fall through the cracks are usually the ones www.thelancet.com Vol 373 January 3, 2009
that first [go] to private clinics”, said Aamir Khan, the executive director of Interactive Researchand Development in Karachi, Pakistan and a faculty member at Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. “While the DOTS programme is not perfect, my experience is that there
“...disease control and technology specialists are now looking to SMS as a costeffective way to communicate with...hard-to-reach patients...“ are many more patients in the private sector that have been mismanaged and abused by unscrupulous health practitioners.” Khan noted that private doctors often overprescribe. He has seen patients taking nine expensive antibiotics when only four are required. Other experts note that DOTS is expensive and human-resource intensive. They say it is unrealistic to expect health workers to monitor patients on a daily basis. Several disease control and technology specialists are now looking to SMS as a cost-effective way to communicate with and monitor hard-
to-reach patients in remote locations. “The problem is enormous, and everything has to be done in order to prevent patients from defaulting”, said Mario Raviglione, director of WHO’s Stop TB Department. “Anything that can be done technologically to help solve this issue like these cellphone technologies would be useful.” Although tuberculosis is a disease affecting poor people, even those living on US$1 per day increasingly have access to mobile phones. There are more than 3·3 billion mobile-phone subscriptions worldwide. By the end of 2006, according to the International Telecommunications Union, 68% of those subscriptions were in developing countries. South Africa has proven a fertile testing ground for new drugcompliance technologies. According to WHO, South Africa had a 71% DOTS treatment success rate in 2005; most patients who were not successfully treated under DOTS defaulted on their treatment. Several companies have addressed the compliance problem by developing devices that remind patients to take their medication, and feature back-
The printed journal includes an image merely for illustration
A nurse explains the treatment for tuberculosis to a patient in the Democratic Republic of the Congo
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World Report
A mobile phone owner in Khayelitsha, one of the poorest townships in South Africa
up links to health workers, friends, or family members if the patient fails to respond to the first reminder. One reminder product is a small pill bottle made by London-based SIMpill that contains a SIM card and when opened, the SIM card delivers a SMS with a unique pill box identification number to a central server. The central server receives the incoming SMS and stores the data, but if no SMS is received at the designated time, the server contacts the patient via phone alerting them to take their medication. If the patient does not respond, the server contacts a caregiver who can follow-up with the patient. From July, 2006, to April, 2007, SIMpill did a pilot study in 155 tuberculosis patients at three clinics in the Cape Town area with the Western Cape Department of Health. After patients used the SIMpill for 10 months, drug adherence stabilised between 86–92% with a treatment success rate of 94%, according to SIMpill. Ann-Mari Albertsen, managing director of SIMpill, says, in addition to helping patients adhere to their treatment, SIMpill also frees up health workers from daily observation of patients taking their medication. Albertsen noted that with SIMpill, a nurse could keep tabs on 50–60 patients rather than just ten patients. “We see staff focusing on other parts of their job, like counselling, training, and actual follow-up with 16
patients who need more attention, instead of keeping up with tablets and glass of water”, said Albertsen. Albertsen would not reveal the cost of the technology but says the company is signing a contract with a major international public-health organisation working in South Africa, which plans to deploy the product on a larger scale. SIMmed, developed by CompuTainer, is a direct competitor of SIMpill in South Africa, and claims to be a less expensive and equally effective product. Instead of monitoring patients through a pill bottle, SIMmed asks patients to press the speed dial button on their mobile phone after taking their medication. The number dials into a server, which records the medication event, and reminds the patient by SMS or contacts a caregiver if the patient fails to call. The first SIMmed trial in Khayelitsha, South Africa, yielded a compliance rate of over 90%. CompuTainer is now working with the South African Government to reach 45 000 new patients with the programme. Other groups are using SMS messaging in combination with economic incentives to improve treatment adherence. X out TB is an SMS-based system invented by a group of scientists and entrepreneurs with the Innovations for International Health project at the Massachusetts Institute of Technology, Cambridge, MA, USA. Each day after taking their medication, tuberculosis patients urinate on a filter paper diagnostic, which detects the metabolites of the first-line tuberculosis drug isoniazid and reveals a code. The patient sends the code over SMS where it is stored on a server. Based on accumulated right answers (correct codes) at the end of the month, patients receive rewards. In the first trial in Nicaragua, patients received $2 worth of mobile phone minutes each month. “We are concerned people just don’t behave rationally in conditions like DOTS”, said Jose Gomez-Marquez, programme director of Innovations
for International Health. “If they can shortcut something, they’ll do it. But if there’s an economic reward involved, there’s a bigger incentive to follow the rules of the programme.” In the next X out TB trial in Pakistan, Khan will target patients attending DOTS clinics. He said X out TB would like to compare compliance between the routine DOTS programme and one with X out TB integrated into it. However, some experts question whether SMS technologies will effectively replace thorough face-toface monitoring from a community health worker. Partners in Health (PIH), a Boston-based non-profit organisation, working in several of the poorest developing countries has developed one of the most effective programmes for tuberculosis treatment using community health workers. Every day, the workers visit patients in their homes to supervise treatment. PIH also developed DOTS Plus, a regimen for treating multidrug-resistant tuberculosis, where patients receive daily nutritional support as a supplement and incentive for treatment. According to Hamish Fraser, director of informatics and telemedicine for PIH and assistant professor at Harvard Medical School, the success of PIH’s programmes without the use of SMS communication indicate that SMSbased health technologies may be unnecessary. “I think in developing countries, having a DOTS worker visit patient in their home is extremely effective”, said Fraser. “We don’t immediately feel there’s a big gap there so I’m less sold on cellphones.” Raviglione, however, believes that SMS health technologies could have a role in improving communication in tuberculosis treatment and care. “Though the human aspect of tuberculosis care and control must not be forgotten or underemphasised, there’s always great value in increasing communication between the patients and the clinicians”, he said.
Eliza Barclay www.thelancet.com Vol 373 January 3, 2009
World Report
Alcohol use on the rise in India With more than half of all alcohol drinkers in India falling into the criteria for hazardous drinking, alcohol abuse is emerging as a major public-health problem in the country. Raekha Prasad reports.
www.thelancet.com Vol 373 January 3, 2009
that the “average age of initiation” had dropped from 19 years to 13 years in the past two decades. The centre points out that a “powerful international and domestic alcohol lobby” is purposely targeting young Indians. The local industry has introduced flavoured alcohol drinks to attract previously non-drinking women and young men. Multinational companies have identified India with
“The shifting composition of Indian drinkers has seen a rise in the number of Indian women drinking regularly and heavily.” its vast unexploited markets as one of the world’s most sought after places for investment. Many alcohol adverts now feature spirited groups of young people having a good time. Although alcohol advertising is banned in the electronic and print media, surrogate advertising is rife, argues Monika Arora, director of the NGO, Health Related Information Dissemination Amongst Youth Student Health Action Network. “Drinking water and apple juice is packaged by alcohol companies. It’s all about getting young people to start early and be life-long consumers. Bollywood films now glorify alcohol where the good guys drink.”
The shifting composition of Indian drinkers has seen a rise in the number of Indian women drinking regularly and heavily. One recent study in the southern state of Karnataka found young women consumed similar amounts of alcohol to young men on any typical drinking occasion. What is of particular concern—and an important indicator of health risks—is that the signature pattern of alcohol consumption in India is frequent and heavy drinking. More than half of all drinkers fall into the criteria for hazardous drinking, which is characterised by bingeing and solitary consumption to the point of intoxication. Moreover, spirits account for 95% of the beverages drunk in India. Another problem for policy makers is the fact that two thirds of the alcohol drunk in India is unrecorded because it is either illicit local home brew or has been smuggled into the country. Employers in poor, marginalised communities sometimes pay wages in alcohol rather than cash, according to WHO. The hazards of spurious liquor can be fatal, with frequent reports of death, disability, and hospitalisation resulting from its consumption across the country. One barrier to developing a national alcohol policy for India, experts say, is the woeful lack of data and research on
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India’s reputation as a country with a culture of abstinence especially in matters regarding alcohol is underserved, say experts. The country, which has seen a rapid proliferation of city bars and nightclubs in recent years, is fast shedding its inhibitions about alcohol as a lifestyle choice. This situation has led to fears of an undocumented rise in alcohol abuse not only among poorer classes but also in sections of society that were previously considered dry. The health minister has recognised the scale of the problem—and has called for a policy that will regulate sales and the pricing of drink. Many experts say that although this move is welcome it may not be enough to curb the harmful effects of the rise in alcohol consumption in society. The increasing production, distribution, and promotion of alcohol has already seen drink-related problems emerging as a major publichealth concern in India. Sales of alcohol have seen a growth rate of 8% in the past 3 years. Officially, Indians are still among the world’s lowest consumers of alcohol— government statistics show only 21% of adult men and around 2% of women drink. But up to a fifth of this group—about 14 million people—are dependent drinkers requiring “help”. The concern, say experts, is that there has been a rapid change in patterns and trends of alcohol use in India. Chief among them is people are beginning to drink at ever-younger ages. The percentage of the drinking population aged under 21 years has increased from 2% to more than 14% in the past 15 years, according to studies in the southern state of Kerala by Alcohol and Drugs Information Centre India, a non-governmental organisation (NGO). Alarmingly, the study found
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The printed journal includes an image merely for illustration
Billboard advertising alcoholic drinks in Mumbai
its national health, social, and economic effect. What is known is that alcoholrelated problems account for more than a fifth of hospital admissions; 18% of psychiatric emergencies; more than 20% of all brain injuries and 60% of all injuries reporting to India’s emergency rooms. The role of alcohol in domestic violence is substantial: a third of violent husbands drink, according to a WHO study in 2004. Most of the violence took place during intoxication. There is evidence even to suggest that the poor are beginning to drink more than they earn—a deadly spiral of alcohol and debt. One recent study by the National Institute of Mental Health and Neuro Sciences (NIMHANS) in households of rural, urban, town, and slum populations of 28 500 people in and around the city of Bangalore, Karnataka, found that the average monthly expenditure on alcohol of patients with alcohol addiction is more than the average monthly salary. Although the Indian constitution includes the prohibition of alcohol among its directive principles, alcohol policy is devolved to individual states—as is the levying of taxes on it. Since most states derive around a fifth of their revenue from alcohol taxation—the second largest source after sales tax—they are generally ambivalent towards stemming its flow. Moreover, there is a long history 18
in India of a powerful alcohol lobby with industry figures influencing the political process, both in the form of party donations and as representatives. But experts argue that Indian society is losing considerably more than it gains. “Because of the political expediency surrounding prohibition, what is not being looked at is demand reduction strategies”, says Vivek Benegal, one of the authors of the report and assistant professor of psychiatry at NIMHANS. Using their findings in the Bangalore study, researchers from NIMHANS have calculated that the direct and indirect costs attributable to alcohol addiction is more than triple the profits of alcohol taxation and several times more than the annual health budget of Karnataka. Extrapolating their findings to the whole of India they estimate the total alcohol revenue for 2003–04 of 216 billion rupees falls 28 billion rupees short of the total cost of managing the effects of alcohol addiction. These included the tangible costs of health care, occupational, financial, social, and legal factors. The official response to India’s problem remains focused on those in acute need rather than on prevention. This situation means that official policy concentrates on just the 4% of the alcohol-dependent adult male population—and ignores the 20% of the population who are “at risk” of serious alcohol abuse. Experts argue that government thinking on how best to mitigate the risks for alcohol are 20 years behind that of tobacco. Under its National Drug De-addiction Programme, the Government of India has funded 483 detoxification and 90 counselling centres. Almost half of attendees are being treated for alcohol dependency. But the success of the programmes is low and states fail to adequately fund them, health professionals say. Doctors working with addicts in government hospitals report a “complete lack” of non-pharmacological care and training. “Once we’ve treated them there’s no social worker or clinical psychologist
to refer them to so we just send them to AA (Alcoholics Anonymous)”, says Smita Deshpande, a senior psychiatrist working in a Delhi state hospital. The problem is that the treatment of alcoholism is a low priority in Indian’s health sector, says Rajat Ray, professor and chief of the National Drug Dependence Treatment Centre at All India Institute of Medical Sciences. (AIIMS). Just 600 doctors have been trained to treat alcohol abuse in the past decade. “It’s seen as deviant behaviour among most doctors: a hopeless situation that is unrewarding to treat and so there’s no motivation or financial incentive on doctors to work in this field”, Ray says. To address this, the Indian Government has set a target to train, via AIIMS, 1000 doctors, as many paramedics, and 500 nurses to specialise in alcohol-abuse treatment in the next 4 years. Once trained, the plan is to deploy them across India’s 560 district hospitals to increase access to treatment. Ray and his team are currently piloting three district training projects in Madhya Pradesh, Assam, and Uttar Pradesh. There is, however, a growing lobby urging the health ministry to act. Indian Alcohol Policy Alliance, an NGO aiming to prevent alcohol-related harm through evidence-based policy intervention, says that the key is to break the stranglehold of state revenue departments who see increasing consumption of alcohol as a boon to treasury coffers. It is pressing the ministry of health, headed by a minister who has advocated prohibition in certain states, to take a lead in passing a law that privileges public health over tax receipts. The lack of a national alcohol policy creates “a very difficult situation” for health professionals working to tackle alcoholism, Ray says. Discussions are taking place, but an actual policy, he says, “is still in a formative state”.
Raekha Prasad www.thelancet.com Vol 373 January 3, 2009
Perspectives
Book Time to medicalise child maltreatment Last year marked the 50th anniversary of the founding of one of the original multidisciplinary childprotection teams, in the US city of Denver, by paediatrician C Henry Kempe and psychiatrist Brandt F Steele. Their experience with nine children treated on the paediatric service of Colorado General Hospital led to the publication of their landmark paper, “The Battered Child Syndrome” (JAMA 1962; 181: 17–24). That paper estimated that there might be as many as 749 abused children in the USA annually at that time. On the basis of the public and professional horror that such maltreatment could be happening, all 50 US states passed laws in the mid-1960s that mandated all professionals to report suspected cases of abuse and neglect, and fixed the responsibility for investigating and treating the children and families with public child-welfare agencies. In 1975, Kempe brought several dozen of his colleagues from around the world to a meeting in Bellagio, Italy. This gathering led to the founding of the International Society for the Prevention of Child Abuse and Neglect, the First International Congress held in Geneva, in 1976, and many other efforts to address child maltreatment throughout the world, including work by WHO and UNICEF. The next three decades saw consistent increases in the number of reports of child maltreatment in the USA: from 60 000 in 1970, to 669 000 in 1980, to well over 2 million in the early 1990s. The re-recognition of sexual abuse in the late 1970s and 1980s significantly complicated the ability of child-welfare agencies to function adequately, since that form of abuse is clearly a crime and requires law-enforcement involvement (whereas the beating of children in the earlier period was not noted for such interest by the law-enforcement www.thelancet.com Vol 373 January 3, 2009
agencies). In 1990, the US Advisory Board on Child Abuse and Neglect called the situation “a national emergency”. Their report, among many recommendations, decried the lack of data collected by federal, state, and local agencies that could guide policy on child maltreatment, called for the professionalisation of childprotection-services personnel, pled
“…the single greatest difficulty we faced as a specialty in the USA is that child maltreatment is viewed by the public and our politicians as a social problem, not as a health problem.” for the specific elucidation of childprotection policies at national and local levels, and suggested a focus on prevention. The Board’s recommendations were mostly ignored and the Board was eliminated by the Clinton Administration. Nearly two decades later, David Finkelhor, a long-time scholar in the field, has published a must-read book, Childhood Victimization: Violence, Crime and Abuse in the Lives of Young People. There is a great deal to learn about the fields of child maltreatment and violence in this book, but in particular the chapter called “Good news: child victimization is declining—but why?” is enormously important from my perspective. I have worked in child maltreatment since 1981. I moved to Denver in 1968 to work with Henry Kempe after hearing his presentation on “The Battered Child” as a medical student in New York in 1967. For all those years, the assumption by the public and professionals has been that child maltreatment was increasing. So caught up were many of us in our zeal to help increase public and professional awareness that we always spoke of the epidemic of more and more cases in somewhat desperate attempts to
get attention from those in political power and from those philanthropists who have fuelled most of the research, training, and programmatic activity in the USA. We decried the lack of precise data that would tell us how many child abuse fatalities there were each year, and how many children were being maltreated. We always assumed things were getting worse. We almost needed it to be getting worse. Now, it seems, things are improving in the USA. Finkelhor has tracked the notoriously poor (but consistently poor) child maltreatment estimates of incidence in the USA and has shown that physical and sexual abuse has declined by 46% and 51%, respectively, between 1990 and 2005. I guess I could claim that the US Advisory Board reports were a success after all, but I know better than that. I will not go into all the proposed reasons why this decline could be happening—there are 11 that are enumerated by Finkelhor—but I will highlight one because in my personal view, just the possibility that it could be true may be enough to tweak the interest of medical scientists and researchers and help maintain the decline, and even accelerate it. I refer explicitly to the possibility that the dramatic increase in the use of psychopharmacological agents in our population over the past decade could explain part of the decline in rates of child maltreatment. I believe this is an important hypothesis to study further because, quite independently, there has been increasing attention paid to the genetic and biological aspects of abusive and neglectful behaviour in animal and human studies. In a 1996 editorial written as editorin-chief of Child Abuse and Neglect: The International Journal, I asked our readers “Suppose it were a genetic problem?” I asked this on the basis of a study of knockout mice missing
Childhood Victimization: Violence, Crime, and Abuse in the Lives of Young People David Finkelhor. Oxford University Press, 2008. Pp 248. US$37·95. ISBN 0-195-34285-2.
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Perspectives
the immediate early gene fosB. I was accused by many of our readers of “medicalising” a social problem. The accusation is valid, but I do not view it as a pejorative. Rather, I have always felt that the single greatest difficulty we faced as a specialty in the USA is that child maltreatment is viewed by the public and our politicians as a social problem, not as a health problem. Truth be told, we do not raise private funds for social problems, and further, our politicians will not put government resources where there is not a lot of public support. In the past 5 years, the US National Institutes of Health allocated only about US$36 million of its nearly $30 billion budget to study child maltreatment. The American Board of Pediatrics has certified Child Abuse Pediatrics as a subspecialty, but there are few funds
available for training or research to fuel the growth of this discipline. Finkelhor picks up many of the recommendations of the Advisory Boards and Commissions of yesteryear in his constructive suggestions that include the professionalisation of workers in child-protection services and increasing community-based prevention programmes. He also points out that no one has ever accused the child-protection system anywhere of having an evidence base to their practice. Few, if any, systems collect and maintain data for the decades necessary to know whether their practice has been of quality. This is certainly something the medical profession can bring to bear. Could we imagine that certain drug therapies could help depressed parents treat their children better? Could we imagine that certain therapies could
even out the behaviour of individuals who find themselves exploding with rage at some of the behaviours of their children? Could we actually have clinical trials that include the standard social interventions of “parenting classes” with and without pharmacotherapy? We have spent a half century building the child welfare and legal responses to child maltreatment. These systems are struggling under the weight of the task. Although we must acknowledge how much they have done given the capacity and resources they have had, the time is now right to spend the next decade building what has been a far less well developed medical response to its full potential. Abused children and their families deserve no less.
Richard Krugman
[email protected] In brief Seventh Art Releasing
Film A child soldier’s story
Feuerherz (Heart of Fire) Directed by Luigi Falorni. TV60 Filmproduktion, 2008. See http://www.feuerherz-info.de.
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Modern firearms are lightweight. Automatic weapons such as the AK-47 weigh a few kilograms. They don’t have the crashing recoil of earlier models. With practice, a child aged 9 or 10 years can operate an AK-47: it’s just a case of becoming accustomed to firing the thing—machine guns don’t require much aim. The superb Heart of Fire is set in 1981. Eritrea is in the midst of a lengthy war of independence with Ethiopia and Eritrean militias are fighting among themselves. A previous conflict had been resolved in 1974, but in 1980 it reignited. The Eritrean Liberation Front—also known as the Jebha— battle the Eritrean People’s Liberation Front—the Shabia—for control of the fight against the Ethiopians. Letekidan Micael plays the fierytempered Awet, a 10-year-old girl delivered by her blustery father into the hands of the Jebha. The troop is
led by the charismatic Ma’aza (Seble Tilahun), a wild-haired and pretty woman in her twenties. Children learn from adults: Awet copies Ma’aza’s hairstyle, and she and the other children—known within the troop as “pioneers”—demand guns of their own. They are provided with wooden machine guns, and given rudimentary lessons in geography. But their education is soon trammelled into lessons on guerilla warfare, their ersatz weapons replaced by real ones. These are children without sanctuary: the relentless sun and dusty landscape offers no protection, the adult world is endlessly and violently treacherous. The mayhem of war is powerfully conveyed. It is brutalising to dodge bullets—director Luigi Falorni reminds us—to watch those around you die, and to be forced to kill. It’s an excellent performance from Micael and an absorbing and moving film. Awet’s burgeoning understanding and
unshakeable morality lead her to resist Ma’aza’s murderous inculcations. Senait Mehari—on whose memoir this film is based—fled to Germany in 1983, where she remains today. In Eritrea, the Shabia drove the Jebha into Sudan, thus putting an end to the second act of the civil war, itself an entr’acte in a war of independence that served as prelude to the 1998– 2000 war between the separated nations of Eritrea and Ethiopia; that war destabilised the entire region, and last year, UN Secretary-General Ban Ki-moon warned that hostilities could easily resume. Eritrea is presently involved in skirmishes with Djiboutian soldiers. War exerts a force of its own, dragging those around into the chaos; UNICEF estimates that 300 000 children serve as soldiers in armed conflicts around the world.
Talha Burki
[email protected] www.thelancet.com Vol 373 January 3, 2009
Perspectives
the immediate early gene fosB. I was accused by many of our readers of “medicalising” a social problem. The accusation is valid, but I do not view it as a pejorative. Rather, I have always felt that the single greatest difficulty we faced as a specialty in the USA is that child maltreatment is viewed by the public and our politicians as a social problem, not as a health problem. Truth be told, we do not raise private funds for social problems, and further, our politicians will not put government resources where there is not a lot of public support. In the past 5 years, the US National Institutes of Health allocated only about US$36 million of its nearly $30 billion budget to study child maltreatment. The American Board of Pediatrics has certified Child Abuse Pediatrics as a subspecialty, but there are few funds
available for training or research to fuel the growth of this discipline. Finkelhor picks up many of the recommendations of the Advisory Boards and Commissions of yesteryear in his constructive suggestions that include the professionalisation of workers in child-protection services and increasing community-based prevention programmes. He also points out that no one has ever accused the child-protection system anywhere of having an evidence base to their practice. Few, if any, systems collect and maintain data for the decades necessary to know whether their practice has been of quality. This is certainly something the medical profession can bring to bear. Could we imagine that certain drug therapies could help depressed parents treat their children better? Could we imagine that certain therapies could
even out the behaviour of individuals who find themselves exploding with rage at some of the behaviours of their children? Could we actually have clinical trials that include the standard social interventions of “parenting classes” with and without pharmacotherapy? We have spent a half century building the child welfare and legal responses to child maltreatment. These systems are struggling under the weight of the task. Although we must acknowledge how much they have done given the capacity and resources they have had, the time is now right to spend the next decade building what has been a far less well developed medical response to its full potential. Abused children and their families deserve no less.
Richard Krugman
[email protected] In brief Seventh Art Releasing
Film A child soldier’s story
Feuerherz (Heart of Fire) Directed by Luigi Falorni. TV60 Filmproduktion, 2008. See http://www.feuerherz-info.de.
20
Modern firearms are lightweight. Automatic weapons such as the AK-47 weigh a few kilograms. They don’t have the crashing recoil of earlier models. With practice, a child aged 9 or 10 years can operate an AK-47: it’s just a case of becoming accustomed to firing the thing—machine guns don’t require much aim. The superb Heart of Fire is set in 1981. Eritrea is in the midst of a lengthy war of independence with Ethiopia and Eritrean militias are fighting among themselves. A previous conflict had been resolved in 1974, but in 1980 it reignited. The Eritrean Liberation Front—also known as the Jebha— battle the Eritrean People’s Liberation Front—the Shabia—for control of the fight against the Ethiopians. Letekidan Micael plays the fierytempered Awet, a 10-year-old girl delivered by her blustery father into the hands of the Jebha. The troop is
led by the charismatic Ma’aza (Seble Tilahun), a wild-haired and pretty woman in her twenties. Children learn from adults: Awet copies Ma’aza’s hairstyle, and she and the other children—known within the troop as “pioneers”—demand guns of their own. They are provided with wooden machine guns, and given rudimentary lessons in geography. But their education is soon trammelled into lessons on guerilla warfare, their ersatz weapons replaced by real ones. These are children without sanctuary: the relentless sun and dusty landscape offers no protection, the adult world is endlessly and violently treacherous. The mayhem of war is powerfully conveyed. It is brutalising to dodge bullets—director Luigi Falorni reminds us—to watch those around you die, and to be forced to kill. It’s an excellent performance from Micael and an absorbing and moving film. Awet’s burgeoning understanding and
unshakeable morality lead her to resist Ma’aza’s murderous inculcations. Senait Mehari—on whose memoir this film is based—fled to Germany in 1983, where she remains today. In Eritrea, the Shabia drove the Jebha into Sudan, thus putting an end to the second act of the civil war, itself an entr’acte in a war of independence that served as prelude to the 1998– 2000 war between the separated nations of Eritrea and Ethiopia; that war destabilised the entire region, and last year, UN Secretary-General Ban Ki-moon warned that hostilities could easily resume. Eritrea is presently involved in skirmishes with Djiboutian soldiers. War exerts a force of its own, dragging those around into the chaos; UNICEF estimates that 300 000 children serve as soldiers in armed conflicts around the world.
Talha Burki
[email protected] www.thelancet.com Vol 373 January 3, 2009
Perspectives
Profile Paulo Sérgio Pinheiro: giving a voice to children In early 2003, the then UN Secretary-General Kofi Annan asked the Brazilian human rights expert Paulo Sérgio Pinheiro to lead a study into the violence perpetrated against the world’s children. During the next 3 years, he worked to expose the scope of violence against children and its impact on their lives. Pinheiro’s report made unhappy reading. Violence against children was widespread, he found: about 53 000 children died in 2002 as a result of homicide, while 150 million girls and 73 million boys under the age of 18 years experienced forced sexual intercourse or other forms of sexual violence. In 2004, 218 million children were involved in child labour, of whom 126 million worked in hazardous conditions. But these figures do not tell the full story, as Pinheiro told the UN General Assembly in 2006. Although the world’s media focuses attention on brutal crimes, such as sexual abuse and human trafficking, other more insidious forms of violence take place every day in homes and schools. “Much violence against children, whether in the family, schools, alternative care and justice institutions, the workplace or the community is implicitly socially condoned or legally sanctioned”, he told the international community. In an interview with The Lancet, Pinheiro describes these everyday places as the “invisible sanctuaries” of violence against children, and argues that they challenge the fundamental principles of democracy. “There is a basic contradiction in the world today”, he says. “A contradiction between the advancement of democracy all over the world and the continuation of the authoritarian treatment of children. There are millions of children suffering this authoritarianism. It’s a kind of power-struggle. Governments, families, and caregivers feel threatened if the child has a voice.” Bringing together the report allowed Pinheiro a direct channel to the voices of the world’s children. Their message came through loud and clear. “All over the world, from Europe to Palestine, they can’t bear parents beating them. It was a sort of chorus—children complaining about teachers, about parents, about caregivers. For me this was very dramatic.” Although the report’s scope stretched far beyond the realm of corporal punishment, Pinheiro says he found himself becoming “militant” about banning all corporal punishment. “I think this is the basic message of the report”, he says. “This the children understood very well.“ Pinheiro’s own childhood in Rio de Janeiro, in the 1940s and 1950s, was happily free from violence. “I think that I had a very protected childhood”, he says. “My grandmother was the oldest of her sisters and I remember having many great-aunts around me. Looking back, I think this helped me to have a lot of self-assurance. It was a very important www.thelancet.com Vol 373 January 3, 2009
foundation for my evolution.” Pinheiro adds that “I think most of the people of my generation have been smacked, but I on the contrary have a sensation of protection and I think that this has helped me to do more things than my social class would give conditions for me to do.” Pinheiro’s family had him earmarked for a diplomatic career, so his grandmother paid for private tuition in English and French from an early age. Later, he earned a law degree but was then unwilling to work with the military dictatorship that had been established in Brazil in 1964. Instead, he left for Paris, France, where he earned a doctorate and was profoundly changed by the student protests in May, 1968. “I think my real turning point was coming to France.” Returning to Brazil, he began what has proven to be a long and fruitful international academic career, focusing on topics including social history and police violence. In the mid-1990s, Pinheiro was rapporteur of the Brazilian National Human Rights Plan, and began working with the United Nations—among other things as a Special Rapporteur on the situation of human rights in Burundi and, later, in Burma (Myanmar). He also served as Secretary of State for Human Rights in Brazil from 2001 to 2002. “Looking back, I think that most of the phases of my career were unexpected”, he says. “I never planned to do what I have done. I think that all these phases were possible because I have a sense of self-sufficiency. Not a single one of these involvements was very dramatic—they just came.” Taking on the role of Independent Expert for the United Nations Secretary General’s Study on Violence Against Children in 2003, Pinheiro was surprised at the positive attitude of countries. “I was able to work very closely with the Arab League and the Conference of Islamic countries in a very positive basis, and countries like Thailand or China. Even countries that are very enthusiastic about corporal punishment, they supported the report as a whole.” Now 64-year-old Pinheiro is still working to further the rights of children, as one of the seven commissioners of the Organization of American States’s Inter-American Commission on Human Rights. His academic work in political science, at Brown University, Providence, RI, USA, also continues. Meanwhile, he hopes the UN report on violence against children may have an impact. “Of course the law is not a magic wand, but even if law isn’t immediately implemented, the report is a framework for implementation by civil society. Without a framework, the struggle to combat violence against children will be much more difficult.”
Stephen Pincock
[email protected] 21
Perspectives
The art of medicine Landscape and health
The Bridgeman Art Library
“My soul hurt”, writes Paul Theroux at the beginning of The Happy Isles of Oceania, “my heart was damaged. I was lonely. I did not want to see another big city. I wanted to be purified by water and wilderness.” His marriage coming apart, the threat of cancer hanging over him, Theroux gives in to what must be an ancient impulse: he turns his back on the known and the civilised and strikes out into the wild. “Where there is wilderness”, he writes a little later, “there is hope”. The link between health and certain kinds of natural landscape is interesting and strong. Although the technology of medicine is increasingly metropolitan, the search for health has often led out of the city and into nature. Where the city has been seen as a source of sickness and contagion, of confusion and disorder, the rhythms of the natural world have offered the hope of cure or relief. It has been said that fewer than half of all ill people have an identifiable underlying pathology. They may feel ill, they may in fact be ill—perhaps the two amount to the same thing—but there is no recognisable organic dysfunction. Although we have to be wary of our terminology—it is easy to slip between illness, the subjective sense of being ill, and disease, the identifiable biochemical disorder—it would seem that much sickness lies beyond the reach of
Bill Jacklin, Walking Down Broadway (1998)
22
orthodox medicine. Where biochemical interventions fail or fall short, where a literal cure is unavailable, we sometimes have recourse to symbolic means. Theroux’s escape into wilderness, his search for purification, has obvious symbolic content. He sees his sickness as a case of impurity. The natural world will cleanse him and return him to a state of native health. Given the lack of an organic origin for so much of our sickness, this use of symbolic resources may not be entirely fanciful. Human beings inhabit a world of matter and of meaning, of fact and symbol. If our sickness is of symbolic origin it may be amenable to symbolic cure, or at least to symbolic amelioration. Psychoanalysis is only the most obvious, the most organised example of such a cure; homoeopathy may be another. In our search for symbolic sources of healing, we have heavily mined the idea of the natural. Ideas of wellbeing and human wholeness have helped structure our idea of landscape itself. Take this habit of opposing the natural landscape to the urban. It extends at least as far back as the Greek pastoral poets of the 3rd century BC and has set up an enduring, if mutable, set of contrasts between two ways of life: one rooted in agriculture and the natural world, the other in the complex economic practices that have their origin in trade and finance and are located in the city. Although the lived experience of the country and the city may have borne no real relation to this set of oppositions—poverty, ignorance, disease, and malnutrition were as much a part of rural life as fresh air and Edenic plenty—the symbolic link between health and natural landscapes has endured. There is clearly a moral dimension to this association. The word “sick” is often used to describe depraved or immoral behaviour and sickness has often been seen as an embodied punishment for sin. Moll, the harlot in Hogarth’s A Harlot’s Progress, falls apart physically as well as morally, the one a vivid visual counterpart to the other. This association is still with us. Despite the alleged neutrality of the state towards the life choices of its citizens, the question of personal responsibility for health is never far away. As Lord Darzi has said: “The NHS in the 21st century increasingly faces a disease burden determined by the choices people make: to smoke, drink excessively, eat poorly and not take enough exercise. Today, countless years of healthy life are lost as the result of these known behavioural or lifestyle factors.” The association between the city and immorality and therefore with illness is also an ancient one. The simple economics of pleasure concentrates the possibilities for vice in centres of population: Sodom and Gomorrah were both cities of the plain. The city also offers anonymity, and with www.thelancet.com Vol 373 January 3, 2009
it the possibility of escaping moral surveillance. Take one of the greatest of rural novels, George Eliot’s Middlemarch, one of the few novels, according to Virginia Woolf, written for grown-up people. Its moral order depends upon a network of cause and effect in which good and bad actions have inevitable consequences. This moral causality only works, however, in face-to-face communities, in the sort of human associations that the German sociologist Ferdinand Tönnies called Gemeinschafts, communities of shared values and relatively simple structures in which people know each other over time. It is difficult to imagine how such a moral order could survive transplantation to a city. Cities are just too impersonal, too anonymous, too full of possibilities for evading the slow-moving moral consequences of our actions. The association of the city with immorality also owes something to the fact that the city, especially the capital city, has traditionally been the location of the Court. Intrigue, corruption, sophistication, and vice all dance attendance on the Crown. In the country, manners may be rude, and wits may not sparkle, but plain living and open air are more likely to keep us on the path of righteousness, both physically and morally. Jean-Jacques Rousseau, writing in the mid-18th century, bequeathed to modernity the most passionate and systematic account of the moral and physical superiority of the state of nature. “I dared to strip man’s nature naked”, he writes in Confessions, “to follow the evolution of those times and things which have disfigured him; I compared man-made man with natural man, and I discovered that his supposed improvement had generated all his miseries.” It would be difficult to exaggerate the extent and importance of Rousseau’s influence. Sigmund Freud is indebted to him. Rousseau’s fearlessly honest selfscrutiny in his Confessions lies close to the root of our developmental understanding of human personality, and Freud’s Civilization and its Discontents at times reads like the work of a disciple. Karl Marx can also feel like an heir. “Man is born free”, wrote Rousseau, in words that could easily have come from Marx, “but everywhere lives in chains”. Rousseau was a central figure in the Romantic onslaught on the Enlightenment—on the great 18thcentury belief in reason and progress, in science and the perfectibility of mankind. For Rousseau, so-called progress was itself the problem, leading us further and further from our original nature: our civilisation is our sickness, and recovery lies in a return to our essential, our natural goodness. The Romantic mistrust of science and progress, of the relentless march of western technological civilisation, can be felt in much contemporary unease about medicine. The sense that the sophisticated, invasive, and alienating technologies of medicine are somehow generative, or www.thelancet.com Vol 373 January 3, 2009
Getty Images
Perspectives
Vincent van Gogh, Wheatfield with Lark (1887)
at lease symptomatic of the very maladies they seek to cure, lies behind the appeal of much alternative and complementary therapy with its stress on “natural” remedies and non-invasive techniques. Against the forces of technology, are amassed the symbolic resources of nature, which seem to lie so close to the sources of health and, in the end, to the sources of life itself. Modern western medicine is often criticised for mission creep. The net of sickness is cast ever wider, bringing more of our life into its purview. States that were once considered ordinary parts of human character or experience—shyness, heartbreak, inattentiveness— are gradually becoming pathologised, offered up for biochemical tweaking, seen less as facts to be lived with than disorders to be purged or overcome. And yet a reaction to the medicalisation of human experience is setting in, a reaction that is mining a deep stratum of symbolic resources linked to the idea of the natural. Against ideas of engineered human perfectibility is set the sheer, fertile, haphazard, and exuberant contingency of nature. Thinking about this reaction, it is beginning to look as if we are fearful that we might have paid a high price for our triumph over the natural landscape. We may have subdued the external world but the idea of nature has come back to haunt us, holding out the possibility of a wellbeing we fear we may have lost forever.
Julian Sheather Deputy Head Ethics, British Medical Association, London WC1H 9JP, UK
[email protected] 23
Obituary
PA Photos
The printed journal includes an image merely for illustration
Adrian Kantrowitz Pioneering heart surgeon who invented devices to assist failing hearts. He was born on Oct 4, 1918, in New York City, NY, USA, and died from complications of heart failure on Nov 14, 2008, in Ann Arbor, MI, USA, aged 90 years. Adrian Kantrowitz may be most famous as the man who was poised to do the world’s first heart transplantation, and wound up doing the second. But the devices he developed for treating heart failure have helped millions of people worldwide and will be his lasting legacy. “He’s probably saved more lives than just about anybody else in the heart business”, says Larry Stephenson, professor in chief of cardiothoracic surgery at Wayne State University, Detroit, MI, USA. Kantrowitz first tackled the problem of helping the heart pump as a surgical resident, and continued to wrestle with how to assist failing hearts mechanically up to the end of his life. As a resident at Montefiore Medical Center in the Bronx, NY, USA, fresh out of a short stint as an Army medic in World War II, Kantrowitz was given 6 months and US$300 to research anything he chose. He decided to investigate whether it would be possible to bypass the mitral valve by putting a cannula into the veins leading to the heart, diverting the blood to a pump, and then returning it to the aorta. The 60th animal to undergo the procedure survived. Soon after publishing his results, Kantrowitz decided that he wanted to be a heart surgeon. Having started out in general surgery, he soon learned about a technique for repairing mitral valve stenosis, in which the surgeon placed a finger, “blind”, into the valve and pushed it open. “That 24
then really started heart surgery”, Kantrowitz said in 1999. “My first year in practice, I must have done 100 of them.” Open heart surgery soon followed. In 1955, Kantrowitz was named chief of surgery at Maimonides Hospital in Brooklyn, NY, USA, where he operated and did research with the help of a $3 million grant from the National Institutes of Health (NIH). In 1961, as an offshoot of his research on heart pacing, he used electrodes to help a paralysed person stand up and sit down under computer control. In 1966, he implanted a left-ventricular device in a patient with heart failure for the first time. The next year, he invented the intra-aortic balloon pump. The device, which came into widespread use in the early 1980s, has now been used in more than 3 million people. In 1967, after an aborted attempt the previous year, Kantrowitz and his colleagues were given approval to do a heart transplantation in a human baby and had found a recipient and an anencephalic newborn donor. Just before the surgery was to take place, word came that Christiaan Barnard had done the world’s first heart transplantation. Kantrowitz and his colleagues proceeded with their own operation shortly afterwards. The infant died 6·5 h after the operation. The next month, Kantrowitz did another heart transplantation—the fifth in the world—this time in an adult, who also died within hours. As worldwide controversy raged over the ethics of heart transplantation, which after 1 year and 101 procedures still seemed of questionable benefit, Kantrowitz moved to Sinai Hospital in Detroit, where he also taught at Wayne State University, taking his team of engineers, surgeons, and nurses with him—along with his NIH funding. Kantrowitz refined the devices he invented for the rest of his life. Just before his death, he won Food and Drug Administration approval for a second pilot trial of a version of his balloon pump for long-term and ambulatory use. “That’s what he had in mind from the beginning”, says his wife of 60 years, Jean, who worked with him to help administer his NIH grants. The way he saw it, she adds, “the heart is a pump, that’s all it is, you don’t have to take it out. You just leave it there and a little bit of help will do a lot for the patient.” “Adrian Kantrowitz was a very, very nice man, and a real inspiration for guys like me”, says Stephen Lahey, chief of cardiac and thoracic surgery at Maimonides Medical Center. Lahey likens Kantrowitz and other early heart surgeons to the first astronauts, “They were way out on the fringe and pushing the technological envelope and it was a very difficult job, because most of the people they operated on died. The psychological toll on these guys was incredible.” Kantrowitz is survived by his wife; his three children, Niki, a cardiologist, Lisa, a radiologist, and Allen, a neurologist; and nine grandchildren.
Anne Harding
[email protected] www.thelancet.com Vol 373 January 3, 2009
Correspondence
In 2003, the potential risks to children arising from information being held in different locations led Lord Laming to recommend that “within a given location, health professionals should work from a single set of records for each child”.1 In 2004, British Medical Association guidance on medical note-keeping2 recommended that there should be clear means of identifying records of children about whom there were child protection concerns, usually with the consent of the parent. One of the factors that led to the UK General Medical Council’s decision to erase paediatrician David Southall’s name from the medical register was the keeping of children’s records separately from the main hospital notes. Recognising that, within our own organisations, information on children is still held in different places, we sent questionnaires to 135 consultant paediatricians in the UK. We received responses from 32. The questions included whether for any particular child: (a) medical records including child protection records were kept together; (b) reasons why this would not be so; (c) whether notes were tagged to indicate that there were separate records; and (d) whether permission to keep records separately was obtained from parents. Only five organisations had completely combined records including child protection records, and merging had only occurred since the Laming report in 2003.1 Tertiary records were often held separately—eg, nephrology, oncology, paediatric intensive-care unit, and sleep laboratory records. Reasons given for keeping separate records were many but included maintaining confidentiality, having different locations within the same Trust, convenience of access, www.thelancet.com Vol 373 January 3, 2009
historical processes, and shortage of administration staff. In 11 organisations, child protection notes were in the main records; five always kept the notes separately. In other organisations, records could be in the hospital or community notes, depending on where the child had been seen, and some kept case conference minutes and legal documents separately. If children were seen or examined at the request of police or social care, most units created hospital or community records for them, but six did not. Where tagging might be applicable, there was again variation, including no tagging, inconsistent use of written methods in the notes, and electronic tagging. No permission was sought anywhere. Several responses indicated that advice on consistent practice across the UK would be welcome. Some organisations had grappled with single records and were struggling. In conclusion, achieving a single clinical record for a particular child in the UK is not straightforward and the all-encompassing electronic record is still some years away. We all undertake child protection work to a greater or lesser extent. PF and MC prepared reports on the topic of keeping separate files for the General Medical Council hearing concerning David Southall, but were not called to give evidence. MC is a member of Professionals Against Child Abuse.
*Margaret Crawford, Peter Fleming, Nadeem Moghal
[email protected] Pilgrim Hospital, United Lincolnshire Hospitals Trust, Boston PE21 9QS, UK (MC); Department of Community Based Medicine, University of Bristol, Bristol, UK (PF); and Department of Paediatric Nephrology, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK (NM) 1
2
The Victoria Climbie Inquiry. Report of an inquiry by Lord Laming. London: HMSO, 2003. http://www.victoria-climbie-inquiry.org.uk/ finreport/finreport.htm (accessed Dec 5, 2008). British Medical Association. Doctors’ responsibilities in child protection cases: guidance from the ethics department. London: BMA, 2004. http://www.bma.org.uk/ap.nsf/ content/childprotection#Summary (accessed Dec 5, 2008).
Association between cerebral palsy and erythromycin In the ORACLE II follow-up study (Oct 11, p 1310),1 Sara Kenyon and colleagues report increased functional impairment and cerebral palsy among children who were exposed to erythromycin while their mothers were in preterm labour. We would like to draw attention to several key features of this trial that could affect the conclusions drawn. First, only a minority of women were actually in preterm labour and no objective criterion was applied to stratify women on the basis of infection. It is clearly possible that a disproportionate number of women with infection were allocated to the treatment groups. Second, neonates in the treatment groups might have been more immature than those in the control group and had resulting poorer outcomes irrespective of erythromycin exposure. Kenyon and colleagues should provide data on the distribution of immaturity in the different groups. Additionally, we are disappointed that though a Bonferroni correction is mentioned in the text, it has not been applied to the dataset. Finally, Kenyon and colleagues strengthen their argument by providing parent-reported data on functional impairment. Clearly these data are unreliable because close to 40% of children age 7 years were reported as being neurologically impaired yet with normal educational achievements. Multi-Attribute Health Status scales have been known to overestimate quality-of-life indices,2 and we suspect that this has happened here. The role of infection and inflammation in preterm labour and its poor outcome3,4 is clearly established. We fear that this study will add to the climate generated by the PREMET study5 and could therefore lead to reluctance in prescribing and using antibiotics.
The printed journal includes an image merely for illustration PA Photos
The fragmented clinical record: a risk to at-risk children
Lord Laming
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
25
Correspondence
In 2003, the potential risks to children arising from information being held in different locations led Lord Laming to recommend that “within a given location, health professionals should work from a single set of records for each child”.1 In 2004, British Medical Association guidance on medical note-keeping2 recommended that there should be clear means of identifying records of children about whom there were child protection concerns, usually with the consent of the parent. One of the factors that led to the UK General Medical Council’s decision to erase paediatrician David Southall’s name from the medical register was the keeping of children’s records separately from the main hospital notes. Recognising that, within our own organisations, information on children is still held in different places, we sent questionnaires to 135 consultant paediatricians in the UK. We received responses from 32. The questions included whether for any particular child: (a) medical records including child protection records were kept together; (b) reasons why this would not be so; (c) whether notes were tagged to indicate that there were separate records; and (d) whether permission to keep records separately was obtained from parents. Only five organisations had completely combined records including child protection records, and merging had only occurred since the Laming report in 2003.1 Tertiary records were often held separately—eg, nephrology, oncology, paediatric intensive-care unit, and sleep laboratory records. Reasons given for keeping separate records were many but included maintaining confidentiality, having different locations within the same Trust, convenience of access, www.thelancet.com Vol 373 January 3, 2009
historical processes, and shortage of administration staff. In 11 organisations, child protection notes were in the main records; five always kept the notes separately. In other organisations, records could be in the hospital or community notes, depending on where the child had been seen, and some kept case conference minutes and legal documents separately. If children were seen or examined at the request of police or social care, most units created hospital or community records for them, but six did not. Where tagging might be applicable, there was again variation, including no tagging, inconsistent use of written methods in the notes, and electronic tagging. No permission was sought anywhere. Several responses indicated that advice on consistent practice across the UK would be welcome. Some organisations had grappled with single records and were struggling. In conclusion, achieving a single clinical record for a particular child in the UK is not straightforward and the all-encompassing electronic record is still some years away. We all undertake child protection work to a greater or lesser extent. PF and MC prepared reports on the topic of keeping separate files for the General Medical Council hearing concerning David Southall, but were not called to give evidence. MC is a member of Professionals Against Child Abuse.
*Margaret Crawford, Peter Fleming, Nadeem Moghal
[email protected] Pilgrim Hospital, United Lincolnshire Hospitals Trust, Boston PE21 9QS, UK (MC); Department of Community Based Medicine, University of Bristol, Bristol, UK (PF); and Department of Paediatric Nephrology, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK (NM) 1
2
The Victoria Climbie Inquiry. Report of an inquiry by Lord Laming. London: HMSO, 2003. http://www.victoria-climbie-inquiry.org.uk/ finreport/finreport.htm (accessed Dec 5, 2008). British Medical Association. Doctors’ responsibilities in child protection cases: guidance from the ethics department. London: BMA, 2004. http://www.bma.org.uk/ap.nsf/ content/childprotection#Summary (accessed Dec 5, 2008).
Association between cerebral palsy and erythromycin In the ORACLE II follow-up study (Oct 11, p 1310),1 Sara Kenyon and colleagues report increased functional impairment and cerebral palsy among children who were exposed to erythromycin while their mothers were in preterm labour. We would like to draw attention to several key features of this trial that could affect the conclusions drawn. First, only a minority of women were actually in preterm labour and no objective criterion was applied to stratify women on the basis of infection. It is clearly possible that a disproportionate number of women with infection were allocated to the treatment groups. Second, neonates in the treatment groups might have been more immature than those in the control group and had resulting poorer outcomes irrespective of erythromycin exposure. Kenyon and colleagues should provide data on the distribution of immaturity in the different groups. Additionally, we are disappointed that though a Bonferroni correction is mentioned in the text, it has not been applied to the dataset. Finally, Kenyon and colleagues strengthen their argument by providing parent-reported data on functional impairment. Clearly these data are unreliable because close to 40% of children age 7 years were reported as being neurologically impaired yet with normal educational achievements. Multi-Attribute Health Status scales have been known to overestimate quality-of-life indices,2 and we suspect that this has happened here. The role of infection and inflammation in preterm labour and its poor outcome3,4 is clearly established. We fear that this study will add to the climate generated by the PREMET study5 and could therefore lead to reluctance in prescribing and using antibiotics.
The printed journal includes an image merely for illustration PA Photos
The fragmented clinical record: a risk to at-risk children
Lord Laming
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
25
Correspondence
We declare that we have no conflict of interest.
*Mallika Azizia, Momin Ahmed
[email protected] University Hospital Basildon, East of England Deanery, London CB21 5EE, UK (MaA); and Institute of Cell and Molecular Sciences, London, UK (MoA) 1
2
3
4
5
Kenyon S, Pike K, Jones D, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 2008; 372: 1319–27. Saigal S, Rosenbaum PL, Feeny D, et al. Parental perspectives of the health status and health-related quality of life of teen-aged children who were extremely low birth weight and term controls. Pediatrics 2000; 105 (3 pt 1): 569–74. Azizia M, Lloyd J, Allen M, Klein N, Peebles D. Low cord blood monocytes MHC class II expression is associated with sepsis in term and preterm neonates. Arch Dis Child Fetal Neonatal Edn 2008; 93 (suppl 1): F6–F8. Lloyd J, Allen M, Azizia M, Klein N, Peebles D. Monocyte major histocompatibility complex class II expression in term and preterm labor. Obstet Gynecol 2007; 110: 1335–42. Shennan A, Crawshaw S, Briley A, et al. A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study. BJOG 2006; 113: 65–74.
Authors’ reply
Getty Images
Mallika Azizia and Momin Ahmed are correct that most of the women in the ORACLE II trial (64%) gave birth after 37 weeks, but this reflects the clinical situation in which the diagnosis of preterm labour remains imperfect. At the point at which these women were recruited they showed no obvious signs of infection and markers of infection collected after birth do not seem to be unequally distributed across the treatment groups, as shown in table 1 of the paper. That table also shows no differences in gestational age at birth for each treatment. Assessment of causality demands more than mechanical application of Bonferroni corrections for multiplicity. Chance is one possible explanation for an observed association such as that between cerebral palsy and either erythromycin or co-amoxiclav. However, we explored the observed excess as fully as possible, and sought to follow Hill’s approach1 to assessing causality. We briefly indicated other characteristics of the association that might suggest 26
it is not just a chance finding. We cannot be certain about this, but, as we wrote originally, it would be unwise to dismiss it as chance. We do not present data as to the children’s neurological status, but parental reports of the children’s functional impairment, as derived from the Mark III classification system.2 This was intended as further exploration not to strengthen the argument.
high incidence of adverse pregnancy outcome, suggesting that whatever damage is done by infection occurs early and persists. It follows that, if antibiotics are to be effective in preventing preterm birth of infectious cause (which in itself is associated with cerebral palsy), these must be used early in pregnancy before inflammatory tissue damage has occurred.
I declare that I have no conflict of interest.
Ronald F Lamont
*Sara Kenyon, on behalf of the authors
[email protected] [email protected] Imperial College, London and Northwick Park Institute of Medical Research, Harrow HA1 3UJ, UK
Reproductive Sciences Section, Cancer Studies and Molecular Medicine, University of Leicester, 22–28 Princess Road West, Leicester LE1 6TP, UK 1
2
Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965; 58: 295–300. Saigal S, Rosenbaum P, Stoskupf B, et al. Comprehensive assessment of the health status of extremely low birthweight children at eight years of age: comparisons with a reference group. J Pediatr 1994; 125: 411–17.
Using proxy information, Sara Kenyon and colleagues1 show that erythromycin and co-amoxiclav given to women in spontaneous preterm labour might result in more harm than good. With no objective evidence of abnormal genital-tract colonisation, these antibiotics might be causing harm by decimating normal flora rather than correcting abnormal flora. By contrast, even in a low-risk population, the appropriate antibiotics (clindamycin is active against most organisms that cause bacterial vaginosis) given to appropriate women (those at risk of preterm birth because of a proven imbalance of genital-tract flora) early in pregnancy has shown a significant 40–60% reduction in the incidence of preterm birth.2–5 The earlier in pregnancy at which spontaneous preterm birth occurs, the more likely this is to be due to an abnormal trigger such as infection. The earlier in pregnancy at which abnormal genital colonisation is detected, the greater is the risk of late miscarriage and early preterm birth. Even if abnormal genital-tract colonisation in early pregnancy resolves, there is still a
I declare that I have no conflict of interest.
1
2
3
4
5
Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7 year follow up of the ORACLE II trial. Lancet 2008; 372: 1319–27. Lamont RF, Duncan S, Mandal D, Bassett P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol 2003; 101: 516–22. Ugwumadu A, Manyonda I, Reid F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised clinical trial. Lancet 2003; 361: 983–88. Kiss H, Petricevic L, Husslein P. Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery. BMJ 2004; 329: 371–75. Larsson P-G, Carlsson B, Jakobsson T, Forsum U. Late miscarriage and preterm birth after treatment with clindamycin: a randomised consent design study according to Zelen. BJOG 2006; 113: 629–37.
Treatment of extensively drug-resistant tuberculosis Salmaan Keshavjee and colleagues (Oct 18, p 1403)1 achieved a 48% cure or treatment completion rate for extensively drug-resistant tuberculosis (XDRTB), despite the fact that 96%, 46%, and around 60% of the patients with XDR-TB were resistant to the second-line antitubercular drugs ofloxacin, capreomycin, and ethionamide, respectively. It would be useful for readers if Keshavjee and colleagues could provide details of the antitubercular regimens, including drug doses, since the efficacy and adverse effects of www.thelancet.com Vol 373 January 3, 2009
Correspondence
We declare that we have no conflict of interest.
*Mallika Azizia, Momin Ahmed
[email protected] University Hospital Basildon, East of England Deanery, London CB21 5EE, UK (MaA); and Institute of Cell and Molecular Sciences, London, UK (MoA) 1
2
3
4
5
Kenyon S, Pike K, Jones D, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 2008; 372: 1319–27. Saigal S, Rosenbaum PL, Feeny D, et al. Parental perspectives of the health status and health-related quality of life of teen-aged children who were extremely low birth weight and term controls. Pediatrics 2000; 105 (3 pt 1): 569–74. Azizia M, Lloyd J, Allen M, Klein N, Peebles D. Low cord blood monocytes MHC class II expression is associated with sepsis in term and preterm neonates. Arch Dis Child Fetal Neonatal Edn 2008; 93 (suppl 1): F6–F8. Lloyd J, Allen M, Azizia M, Klein N, Peebles D. Monocyte major histocompatibility complex class II expression in term and preterm labor. Obstet Gynecol 2007; 110: 1335–42. Shennan A, Crawshaw S, Briley A, et al. A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study. BJOG 2006; 113: 65–74.
Authors’ reply
Getty Images
Mallika Azizia and Momin Ahmed are correct that most of the women in the ORACLE II trial (64%) gave birth after 37 weeks, but this reflects the clinical situation in which the diagnosis of preterm labour remains imperfect. At the point at which these women were recruited they showed no obvious signs of infection and markers of infection collected after birth do not seem to be unequally distributed across the treatment groups, as shown in table 1 of the paper. That table also shows no differences in gestational age at birth for each treatment. Assessment of causality demands more than mechanical application of Bonferroni corrections for multiplicity. Chance is one possible explanation for an observed association such as that between cerebral palsy and either erythromycin or co-amoxiclav. However, we explored the observed excess as fully as possible, and sought to follow Hill’s approach1 to assessing causality. We briefly indicated other characteristics of the association that might suggest 26
it is not just a chance finding. We cannot be certain about this, but, as we wrote originally, it would be unwise to dismiss it as chance. We do not present data as to the children’s neurological status, but parental reports of the children’s functional impairment, as derived from the Mark III classification system.2 This was intended as further exploration not to strengthen the argument.
high incidence of adverse pregnancy outcome, suggesting that whatever damage is done by infection occurs early and persists. It follows that, if antibiotics are to be effective in preventing preterm birth of infectious cause (which in itself is associated with cerebral palsy), these must be used early in pregnancy before inflammatory tissue damage has occurred.
I declare that I have no conflict of interest.
Ronald F Lamont
*Sara Kenyon, on behalf of the authors
[email protected] [email protected] Imperial College, London and Northwick Park Institute of Medical Research, Harrow HA1 3UJ, UK
Reproductive Sciences Section, Cancer Studies and Molecular Medicine, University of Leicester, 22–28 Princess Road West, Leicester LE1 6TP, UK 1
2
Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965; 58: 295–300. Saigal S, Rosenbaum P, Stoskupf B, et al. Comprehensive assessment of the health status of extremely low birthweight children at eight years of age: comparisons with a reference group. J Pediatr 1994; 125: 411–17.
Using proxy information, Sara Kenyon and colleagues1 show that erythromycin and co-amoxiclav given to women in spontaneous preterm labour might result in more harm than good. With no objective evidence of abnormal genital-tract colonisation, these antibiotics might be causing harm by decimating normal flora rather than correcting abnormal flora. By contrast, even in a low-risk population, the appropriate antibiotics (clindamycin is active against most organisms that cause bacterial vaginosis) given to appropriate women (those at risk of preterm birth because of a proven imbalance of genital-tract flora) early in pregnancy has shown a significant 40–60% reduction in the incidence of preterm birth.2–5 The earlier in pregnancy at which spontaneous preterm birth occurs, the more likely this is to be due to an abnormal trigger such as infection. The earlier in pregnancy at which abnormal genital colonisation is detected, the greater is the risk of late miscarriage and early preterm birth. Even if abnormal genital-tract colonisation in early pregnancy resolves, there is still a
I declare that I have no conflict of interest.
1
2
3
4
5
Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7 year follow up of the ORACLE II trial. Lancet 2008; 372: 1319–27. Lamont RF, Duncan S, Mandal D, Bassett P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol 2003; 101: 516–22. Ugwumadu A, Manyonda I, Reid F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised clinical trial. Lancet 2003; 361: 983–88. Kiss H, Petricevic L, Husslein P. Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery. BMJ 2004; 329: 371–75. Larsson P-G, Carlsson B, Jakobsson T, Forsum U. Late miscarriage and preterm birth after treatment with clindamycin: a randomised consent design study according to Zelen. BJOG 2006; 113: 629–37.
Treatment of extensively drug-resistant tuberculosis Salmaan Keshavjee and colleagues (Oct 18, p 1403)1 achieved a 48% cure or treatment completion rate for extensively drug-resistant tuberculosis (XDRTB), despite the fact that 96%, 46%, and around 60% of the patients with XDR-TB were resistant to the second-line antitubercular drugs ofloxacin, capreomycin, and ethionamide, respectively. It would be useful for readers if Keshavjee and colleagues could provide details of the antitubercular regimens, including drug doses, since the efficacy and adverse effects of www.thelancet.com Vol 373 January 3, 2009
Correspondence
We declare that we have no conflict of interest.
*Mallika Azizia, Momin Ahmed
[email protected] University Hospital Basildon, East of England Deanery, London CB21 5EE, UK (MaA); and Institute of Cell and Molecular Sciences, London, UK (MoA) 1
2
3
4
5
Kenyon S, Pike K, Jones D, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 2008; 372: 1319–27. Saigal S, Rosenbaum PL, Feeny D, et al. Parental perspectives of the health status and health-related quality of life of teen-aged children who were extremely low birth weight and term controls. Pediatrics 2000; 105 (3 pt 1): 569–74. Azizia M, Lloyd J, Allen M, Klein N, Peebles D. Low cord blood monocytes MHC class II expression is associated with sepsis in term and preterm neonates. Arch Dis Child Fetal Neonatal Edn 2008; 93 (suppl 1): F6–F8. Lloyd J, Allen M, Azizia M, Klein N, Peebles D. Monocyte major histocompatibility complex class II expression in term and preterm labor. Obstet Gynecol 2007; 110: 1335–42. Shennan A, Crawshaw S, Briley A, et al. A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study. BJOG 2006; 113: 65–74.
Authors’ reply
Getty Images
Mallika Azizia and Momin Ahmed are correct that most of the women in the ORACLE II trial (64%) gave birth after 37 weeks, but this reflects the clinical situation in which the diagnosis of preterm labour remains imperfect. At the point at which these women were recruited they showed no obvious signs of infection and markers of infection collected after birth do not seem to be unequally distributed across the treatment groups, as shown in table 1 of the paper. That table also shows no differences in gestational age at birth for each treatment. Assessment of causality demands more than mechanical application of Bonferroni corrections for multiplicity. Chance is one possible explanation for an observed association such as that between cerebral palsy and either erythromycin or co-amoxiclav. However, we explored the observed excess as fully as possible, and sought to follow Hill’s approach1 to assessing causality. We briefly indicated other characteristics of the association that might suggest 26
it is not just a chance finding. We cannot be certain about this, but, as we wrote originally, it would be unwise to dismiss it as chance. We do not present data as to the children’s neurological status, but parental reports of the children’s functional impairment, as derived from the Mark III classification system.2 This was intended as further exploration not to strengthen the argument.
high incidence of adverse pregnancy outcome, suggesting that whatever damage is done by infection occurs early and persists. It follows that, if antibiotics are to be effective in preventing preterm birth of infectious cause (which in itself is associated with cerebral palsy), these must be used early in pregnancy before inflammatory tissue damage has occurred.
I declare that I have no conflict of interest.
Ronald F Lamont
*Sara Kenyon, on behalf of the authors
[email protected] [email protected] Imperial College, London and Northwick Park Institute of Medical Research, Harrow HA1 3UJ, UK
Reproductive Sciences Section, Cancer Studies and Molecular Medicine, University of Leicester, 22–28 Princess Road West, Leicester LE1 6TP, UK 1
2
Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965; 58: 295–300. Saigal S, Rosenbaum P, Stoskupf B, et al. Comprehensive assessment of the health status of extremely low birthweight children at eight years of age: comparisons with a reference group. J Pediatr 1994; 125: 411–17.
Using proxy information, Sara Kenyon and colleagues1 show that erythromycin and co-amoxiclav given to women in spontaneous preterm labour might result in more harm than good. With no objective evidence of abnormal genital-tract colonisation, these antibiotics might be causing harm by decimating normal flora rather than correcting abnormal flora. By contrast, even in a low-risk population, the appropriate antibiotics (clindamycin is active against most organisms that cause bacterial vaginosis) given to appropriate women (those at risk of preterm birth because of a proven imbalance of genital-tract flora) early in pregnancy has shown a significant 40–60% reduction in the incidence of preterm birth.2–5 The earlier in pregnancy at which spontaneous preterm birth occurs, the more likely this is to be due to an abnormal trigger such as infection. The earlier in pregnancy at which abnormal genital colonisation is detected, the greater is the risk of late miscarriage and early preterm birth. Even if abnormal genital-tract colonisation in early pregnancy resolves, there is still a
I declare that I have no conflict of interest.
1
2
3
4
5
Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7 year follow up of the ORACLE II trial. Lancet 2008; 372: 1319–27. Lamont RF, Duncan S, Mandal D, Bassett P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol 2003; 101: 516–22. Ugwumadu A, Manyonda I, Reid F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised clinical trial. Lancet 2003; 361: 983–88. Kiss H, Petricevic L, Husslein P. Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery. BMJ 2004; 329: 371–75. Larsson P-G, Carlsson B, Jakobsson T, Forsum U. Late miscarriage and preterm birth after treatment with clindamycin: a randomised consent design study according to Zelen. BJOG 2006; 113: 629–37.
Treatment of extensively drug-resistant tuberculosis Salmaan Keshavjee and colleagues (Oct 18, p 1403)1 achieved a 48% cure or treatment completion rate for extensively drug-resistant tuberculosis (XDRTB), despite the fact that 96%, 46%, and around 60% of the patients with XDR-TB were resistant to the second-line antitubercular drugs ofloxacin, capreomycin, and ethionamide, respectively. It would be useful for readers if Keshavjee and colleagues could provide details of the antitubercular regimens, including drug doses, since the efficacy and adverse effects of www.thelancet.com Vol 373 January 3, 2009
Correspondence
We declare that we have no conflict of interest.
*Mallika Azizia, Momin Ahmed
[email protected] University Hospital Basildon, East of England Deanery, London CB21 5EE, UK (MaA); and Institute of Cell and Molecular Sciences, London, UK (MoA) 1
2
3
4
5
Kenyon S, Pike K, Jones D, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 2008; 372: 1319–27. Saigal S, Rosenbaum PL, Feeny D, et al. Parental perspectives of the health status and health-related quality of life of teen-aged children who were extremely low birth weight and term controls. Pediatrics 2000; 105 (3 pt 1): 569–74. Azizia M, Lloyd J, Allen M, Klein N, Peebles D. Low cord blood monocytes MHC class II expression is associated with sepsis in term and preterm neonates. Arch Dis Child Fetal Neonatal Edn 2008; 93 (suppl 1): F6–F8. Lloyd J, Allen M, Azizia M, Klein N, Peebles D. Monocyte major histocompatibility complex class II expression in term and preterm labor. Obstet Gynecol 2007; 110: 1335–42. Shennan A, Crawshaw S, Briley A, et al. A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study. BJOG 2006; 113: 65–74.
Authors’ reply
Getty Images
Mallika Azizia and Momin Ahmed are correct that most of the women in the ORACLE II trial (64%) gave birth after 37 weeks, but this reflects the clinical situation in which the diagnosis of preterm labour remains imperfect. At the point at which these women were recruited they showed no obvious signs of infection and markers of infection collected after birth do not seem to be unequally distributed across the treatment groups, as shown in table 1 of the paper. That table also shows no differences in gestational age at birth for each treatment. Assessment of causality demands more than mechanical application of Bonferroni corrections for multiplicity. Chance is one possible explanation for an observed association such as that between cerebral palsy and either erythromycin or co-amoxiclav. However, we explored the observed excess as fully as possible, and sought to follow Hill’s approach1 to assessing causality. We briefly indicated other characteristics of the association that might suggest 26
it is not just a chance finding. We cannot be certain about this, but, as we wrote originally, it would be unwise to dismiss it as chance. We do not present data as to the children’s neurological status, but parental reports of the children’s functional impairment, as derived from the Mark III classification system.2 This was intended as further exploration not to strengthen the argument.
high incidence of adverse pregnancy outcome, suggesting that whatever damage is done by infection occurs early and persists. It follows that, if antibiotics are to be effective in preventing preterm birth of infectious cause (which in itself is associated with cerebral palsy), these must be used early in pregnancy before inflammatory tissue damage has occurred.
I declare that I have no conflict of interest.
Ronald F Lamont
*Sara Kenyon, on behalf of the authors
[email protected] [email protected] Imperial College, London and Northwick Park Institute of Medical Research, Harrow HA1 3UJ, UK
Reproductive Sciences Section, Cancer Studies and Molecular Medicine, University of Leicester, 22–28 Princess Road West, Leicester LE1 6TP, UK 1
2
Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965; 58: 295–300. Saigal S, Rosenbaum P, Stoskupf B, et al. Comprehensive assessment of the health status of extremely low birthweight children at eight years of age: comparisons with a reference group. J Pediatr 1994; 125: 411–17.
Using proxy information, Sara Kenyon and colleagues1 show that erythromycin and co-amoxiclav given to women in spontaneous preterm labour might result in more harm than good. With no objective evidence of abnormal genital-tract colonisation, these antibiotics might be causing harm by decimating normal flora rather than correcting abnormal flora. By contrast, even in a low-risk population, the appropriate antibiotics (clindamycin is active against most organisms that cause bacterial vaginosis) given to appropriate women (those at risk of preterm birth because of a proven imbalance of genital-tract flora) early in pregnancy has shown a significant 40–60% reduction in the incidence of preterm birth.2–5 The earlier in pregnancy at which spontaneous preterm birth occurs, the more likely this is to be due to an abnormal trigger such as infection. The earlier in pregnancy at which abnormal genital colonisation is detected, the greater is the risk of late miscarriage and early preterm birth. Even if abnormal genital-tract colonisation in early pregnancy resolves, there is still a
I declare that I have no conflict of interest.
1
2
3
4
5
Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7 year follow up of the ORACLE II trial. Lancet 2008; 372: 1319–27. Lamont RF, Duncan S, Mandal D, Bassett P. Intravaginal clindamycin to reduce preterm birth in women with abnormal genital tract flora. Obstet Gynecol 2003; 101: 516–22. Ugwumadu A, Manyonda I, Reid F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: a randomised clinical trial. Lancet 2003; 361: 983–88. Kiss H, Petricevic L, Husslein P. Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery. BMJ 2004; 329: 371–75. Larsson P-G, Carlsson B, Jakobsson T, Forsum U. Late miscarriage and preterm birth after treatment with clindamycin: a randomised consent design study according to Zelen. BJOG 2006; 113: 629–37.
Treatment of extensively drug-resistant tuberculosis Salmaan Keshavjee and colleagues (Oct 18, p 1403)1 achieved a 48% cure or treatment completion rate for extensively drug-resistant tuberculosis (XDRTB), despite the fact that 96%, 46%, and around 60% of the patients with XDR-TB were resistant to the second-line antitubercular drugs ofloxacin, capreomycin, and ethionamide, respectively. It would be useful for readers if Keshavjee and colleagues could provide details of the antitubercular regimens, including drug doses, since the efficacy and adverse effects of www.thelancet.com Vol 373 January 3, 2009
Correspondence
the drugs go hand in hand with the administered doses. Moreover, levels of fluoroquinolones above mutant prevention concentration also prevent selection of resistant mutants.2 Nevertheless, the facts enforce the need for long-term follow-up of such patients for chances of relapse. Extrapolating the results of the study and considering the data on the presence of multiple tubercular strains in sputum isolates from an individual patient,3 further trials are required to reassess the degree of reliance on drug susceptibility tests, especially the in context of XDR-TB. Linezolid, a new drug in the oxazolidinone class, and moxifloxacin are promising additions to the antitubercular drug armamentarium.4,5 The outcome of Keshavjee and colleagues’ study might have been very different if these new agents had been incorporated in the treatment algorithm.
TB patients with treatment failure had a significantly shorter duration of treatment (median 10·9 months) than nonXDR-TB patients (median 18·2 months, p=0·02), a finding that could not be explained by lower adherence to treatment, since there was no difference between the groups in that regard.1 Keshajvee and colleagues, taking into account previous knowledge on this hard-to-treat infection,2,3 state that longer treatments are necessary to cure XDR-TB.1 Our main concern is that duration of treatment was not included in the multivariate model. Thus, we do not know whether XDR-TB was really independently and adversely associated with treatment success, as shown in the final model (adjusted odds ratio 0·41, 95% CI 0·19–0·91), or whether it might be confounded by the fact that those with treatment failure were treated for a significantly shorter period.
We declare that we have no conflict of interest.
We declare that we have no conflict of interest.
*Deepak Aggarwal, Prasanta R Mohapatra, Ashok K Janmeja
*Jussara Munareto Silva, Sandra C Fuchs, Nêmora T Barcellos, Alexandre P Zavascki
[email protected] Government Medical College and Hospital, Chandigarh 160030, India 1
2
3
4
5
Keshavjee S, Gelmanova IY, Farmer PE, et al. Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 2008; 372: 1403–09. Almeida D, Nuermberger E, Tyagi S, Bishai WR, Grosset J. In vivo validation of the mutant selection window hypothesis with moxifloxacin in a murine model of tuberculosis. Antimicrob Agents Chemother 2007; 51: 4261–66. Braden CR, Morlock GP, Woodley CL, et al. Simultaneous infection with multiple strains of Mycobacterium tuberculosis. Clin Infect Dis 2001; 33: e42–47. Condos R, Hadgiangelis N, Leibert E, Jacquette G, Harkin T, Rom WN. Case series report of a linezolid-containing regimen for extensively drug-resistant tuberculosis. Chest 2008; 134: 187–92. Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563–74.
Salmaan Keshavjee and colleagues1 compared treatment outcomes of patients with extensively drugresistant tuberculosis (XDR-TB) and non-XDR-TB and investigated factors associated with treatment failure. XDRwww.thelancet.com Vol 373 January 3, 2009
[email protected] Medical Sciences Post-graduate Program, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (JMS); Department of Social Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (SCF); Hospital Sanatório Partenon, Health State Secretariat, Porto Alegre, Brazil (NTB); and Infectious Diseases Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (APZ) 1
2
3
Keshavjee S, Gelmanova IY, Farmer PE, et al. Treatment of extensively drug resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 2008; 372: 1403–09. Madariaga MG, Lalloo UG, Swindells S. Extensively drug-resistant tuberculosis. Am J Med 2008; 121: 835–44. Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563–74.
Authors’ reply We agree with Deepak Aggarwal and colleagues that it would be useful to report details of antituberculosis regimens, including doses and adverse events. Although this was beyond the scope of our paper, Mitnick and colleagues1 reported details of specific regimens (although not adverse
events) in the online appendix of their paper. In Tomsk, all patients received the highest doses of second-line antituberculosis medications that they could tolerate in regimens formulated by use of the algorithm described by Mukherjee and colleagues.2 We agree that further analysis of the associations between doses, efficacy, and adverse events is very important. The small number of patients with extensively drug-resistant tuberculosis (XDR-TB) in our report constrained our ability to examine these associations. What we did see is that the overall incidence of adverse events was not higher among XDR-TB patients, and we do not have strong clinical reasons to suspect that it would be. As for the ideal drugs to use for XDR-TB patients, one study in human beings3 suggests that later-generation fluoroquinolones have greater antituberculosis activity than earlier ones; this improvement might contribute to better outcomes. Tomsk patients did not receive third-line antituberculosis drugs such as clofazimine or linezolid. Questions about the best drug combinations and doses for XDR-TB highlight the urgent need for clinical trials to optimise current treatment approaches.4 Indeed, scientists and activists have called attention to this need.5 Jussara Silva and colleagues raise the crucial question of whether treatment duration itself should be regarded as an exposure variable in the multivariable model used in our analysis. Although we agree that the shorter treatment duration in XDR-TB patients was a notable finding, we felt that it was more likely to be a consequence of poor clinical response and not a contributing factor to poor outcome. Tomsk physicians weighed up publichealth considerations and the likelihood of treatment response, and only stopped treatment when they felt that the patient had clinically declared himself or herself as a treatment failure. Treatment was discontinued well after the median culture conversion time to 27
Correspondence
the drugs go hand in hand with the administered doses. Moreover, levels of fluoroquinolones above mutant prevention concentration also prevent selection of resistant mutants.2 Nevertheless, the facts enforce the need for long-term follow-up of such patients for chances of relapse. Extrapolating the results of the study and considering the data on the presence of multiple tubercular strains in sputum isolates from an individual patient,3 further trials are required to reassess the degree of reliance on drug susceptibility tests, especially the in context of XDR-TB. Linezolid, a new drug in the oxazolidinone class, and moxifloxacin are promising additions to the antitubercular drug armamentarium.4,5 The outcome of Keshavjee and colleagues’ study might have been very different if these new agents had been incorporated in the treatment algorithm.
TB patients with treatment failure had a significantly shorter duration of treatment (median 10·9 months) than nonXDR-TB patients (median 18·2 months, p=0·02), a finding that could not be explained by lower adherence to treatment, since there was no difference between the groups in that regard.1 Keshajvee and colleagues, taking into account previous knowledge on this hard-to-treat infection,2,3 state that longer treatments are necessary to cure XDR-TB.1 Our main concern is that duration of treatment was not included in the multivariate model. Thus, we do not know whether XDR-TB was really independently and adversely associated with treatment success, as shown in the final model (adjusted odds ratio 0·41, 95% CI 0·19–0·91), or whether it might be confounded by the fact that those with treatment failure were treated for a significantly shorter period.
We declare that we have no conflict of interest.
We declare that we have no conflict of interest.
*Deepak Aggarwal, Prasanta R Mohapatra, Ashok K Janmeja
*Jussara Munareto Silva, Sandra C Fuchs, Nêmora T Barcellos, Alexandre P Zavascki
[email protected] Government Medical College and Hospital, Chandigarh 160030, India 1
2
3
4
5
Keshavjee S, Gelmanova IY, Farmer PE, et al. Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 2008; 372: 1403–09. Almeida D, Nuermberger E, Tyagi S, Bishai WR, Grosset J. In vivo validation of the mutant selection window hypothesis with moxifloxacin in a murine model of tuberculosis. Antimicrob Agents Chemother 2007; 51: 4261–66. Braden CR, Morlock GP, Woodley CL, et al. Simultaneous infection with multiple strains of Mycobacterium tuberculosis. Clin Infect Dis 2001; 33: e42–47. Condos R, Hadgiangelis N, Leibert E, Jacquette G, Harkin T, Rom WN. Case series report of a linezolid-containing regimen for extensively drug-resistant tuberculosis. Chest 2008; 134: 187–92. Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563–74.
Salmaan Keshavjee and colleagues1 compared treatment outcomes of patients with extensively drugresistant tuberculosis (XDR-TB) and non-XDR-TB and investigated factors associated with treatment failure. XDRwww.thelancet.com Vol 373 January 3, 2009
[email protected] Medical Sciences Post-graduate Program, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (JMS); Department of Social Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (SCF); Hospital Sanatório Partenon, Health State Secretariat, Porto Alegre, Brazil (NTB); and Infectious Diseases Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (APZ) 1
2
3
Keshavjee S, Gelmanova IY, Farmer PE, et al. Treatment of extensively drug resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 2008; 372: 1403–09. Madariaga MG, Lalloo UG, Swindells S. Extensively drug-resistant tuberculosis. Am J Med 2008; 121: 835–44. Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563–74.
Authors’ reply We agree with Deepak Aggarwal and colleagues that it would be useful to report details of antituberculosis regimens, including doses and adverse events. Although this was beyond the scope of our paper, Mitnick and colleagues1 reported details of specific regimens (although not adverse
events) in the online appendix of their paper. In Tomsk, all patients received the highest doses of second-line antituberculosis medications that they could tolerate in regimens formulated by use of the algorithm described by Mukherjee and colleagues.2 We agree that further analysis of the associations between doses, efficacy, and adverse events is very important. The small number of patients with extensively drug-resistant tuberculosis (XDR-TB) in our report constrained our ability to examine these associations. What we did see is that the overall incidence of adverse events was not higher among XDR-TB patients, and we do not have strong clinical reasons to suspect that it would be. As for the ideal drugs to use for XDR-TB patients, one study in human beings3 suggests that later-generation fluoroquinolones have greater antituberculosis activity than earlier ones; this improvement might contribute to better outcomes. Tomsk patients did not receive third-line antituberculosis drugs such as clofazimine or linezolid. Questions about the best drug combinations and doses for XDR-TB highlight the urgent need for clinical trials to optimise current treatment approaches.4 Indeed, scientists and activists have called attention to this need.5 Jussara Silva and colleagues raise the crucial question of whether treatment duration itself should be regarded as an exposure variable in the multivariable model used in our analysis. Although we agree that the shorter treatment duration in XDR-TB patients was a notable finding, we felt that it was more likely to be a consequence of poor clinical response and not a contributing factor to poor outcome. Tomsk physicians weighed up publichealth considerations and the likelihood of treatment response, and only stopped treatment when they felt that the patient had clinically declared himself or herself as a treatment failure. Treatment was discontinued well after the median culture conversion time to 27
Correspondence
the drugs go hand in hand with the administered doses. Moreover, levels of fluoroquinolones above mutant prevention concentration also prevent selection of resistant mutants.2 Nevertheless, the facts enforce the need for long-term follow-up of such patients for chances of relapse. Extrapolating the results of the study and considering the data on the presence of multiple tubercular strains in sputum isolates from an individual patient,3 further trials are required to reassess the degree of reliance on drug susceptibility tests, especially the in context of XDR-TB. Linezolid, a new drug in the oxazolidinone class, and moxifloxacin are promising additions to the antitubercular drug armamentarium.4,5 The outcome of Keshavjee and colleagues’ study might have been very different if these new agents had been incorporated in the treatment algorithm.
TB patients with treatment failure had a significantly shorter duration of treatment (median 10·9 months) than nonXDR-TB patients (median 18·2 months, p=0·02), a finding that could not be explained by lower adherence to treatment, since there was no difference between the groups in that regard.1 Keshajvee and colleagues, taking into account previous knowledge on this hard-to-treat infection,2,3 state that longer treatments are necessary to cure XDR-TB.1 Our main concern is that duration of treatment was not included in the multivariate model. Thus, we do not know whether XDR-TB was really independently and adversely associated with treatment success, as shown in the final model (adjusted odds ratio 0·41, 95% CI 0·19–0·91), or whether it might be confounded by the fact that those with treatment failure were treated for a significantly shorter period.
We declare that we have no conflict of interest.
We declare that we have no conflict of interest.
*Deepak Aggarwal, Prasanta R Mohapatra, Ashok K Janmeja
*Jussara Munareto Silva, Sandra C Fuchs, Nêmora T Barcellos, Alexandre P Zavascki
[email protected] Government Medical College and Hospital, Chandigarh 160030, India 1
2
3
4
5
Keshavjee S, Gelmanova IY, Farmer PE, et al. Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 2008; 372: 1403–09. Almeida D, Nuermberger E, Tyagi S, Bishai WR, Grosset J. In vivo validation of the mutant selection window hypothesis with moxifloxacin in a murine model of tuberculosis. Antimicrob Agents Chemother 2007; 51: 4261–66. Braden CR, Morlock GP, Woodley CL, et al. Simultaneous infection with multiple strains of Mycobacterium tuberculosis. Clin Infect Dis 2001; 33: e42–47. Condos R, Hadgiangelis N, Leibert E, Jacquette G, Harkin T, Rom WN. Case series report of a linezolid-containing regimen for extensively drug-resistant tuberculosis. Chest 2008; 134: 187–92. Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563–74.
Salmaan Keshavjee and colleagues1 compared treatment outcomes of patients with extensively drugresistant tuberculosis (XDR-TB) and non-XDR-TB and investigated factors associated with treatment failure. XDRwww.thelancet.com Vol 373 January 3, 2009
[email protected] Medical Sciences Post-graduate Program, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (JMS); Department of Social Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil (SCF); Hospital Sanatório Partenon, Health State Secretariat, Porto Alegre, Brazil (NTB); and Infectious Diseases Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (APZ) 1
2
3
Keshavjee S, Gelmanova IY, Farmer PE, et al. Treatment of extensively drug resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 2008; 372: 1403–09. Madariaga MG, Lalloo UG, Swindells S. Extensively drug-resistant tuberculosis. Am J Med 2008; 121: 835–44. Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563–74.
Authors’ reply We agree with Deepak Aggarwal and colleagues that it would be useful to report details of antituberculosis regimens, including doses and adverse events. Although this was beyond the scope of our paper, Mitnick and colleagues1 reported details of specific regimens (although not adverse
events) in the online appendix of their paper. In Tomsk, all patients received the highest doses of second-line antituberculosis medications that they could tolerate in regimens formulated by use of the algorithm described by Mukherjee and colleagues.2 We agree that further analysis of the associations between doses, efficacy, and adverse events is very important. The small number of patients with extensively drug-resistant tuberculosis (XDR-TB) in our report constrained our ability to examine these associations. What we did see is that the overall incidence of adverse events was not higher among XDR-TB patients, and we do not have strong clinical reasons to suspect that it would be. As for the ideal drugs to use for XDR-TB patients, one study in human beings3 suggests that later-generation fluoroquinolones have greater antituberculosis activity than earlier ones; this improvement might contribute to better outcomes. Tomsk patients did not receive third-line antituberculosis drugs such as clofazimine or linezolid. Questions about the best drug combinations and doses for XDR-TB highlight the urgent need for clinical trials to optimise current treatment approaches.4 Indeed, scientists and activists have called attention to this need.5 Jussara Silva and colleagues raise the crucial question of whether treatment duration itself should be regarded as an exposure variable in the multivariable model used in our analysis. Although we agree that the shorter treatment duration in XDR-TB patients was a notable finding, we felt that it was more likely to be a consequence of poor clinical response and not a contributing factor to poor outcome. Tomsk physicians weighed up publichealth considerations and the likelihood of treatment response, and only stopped treatment when they felt that the patient had clinically declared himself or herself as a treatment failure. Treatment was discontinued well after the median culture conversion time to 27
Correspondence
avoid unnecessary toxic effects and the potential for selection of pan-resistant strains. We conclude that use of aggressive second-line antituberculosis treatment regimens from the outset— with proper management of adverse events—can lead to positive outcomes in a significant proportion of patients. Treatment duration is another timely question that requires rigorous examination through clinical trials. SK, IG, and SS received partial salary support or travel support from the Bill & Melinda Gates Foundation and from the Eli Lilly Foundation. SK and SS received salary support from the Frank Hatch Fellowships in Global Health Equity at the Brigham & Women’s Hospital. SS received additional salary support from the Infectious Disease Society of America, the Heiser Foundation, and the US National Institutes of Health. SK received travel and research funding from the John D and Catherine T MacArthur Foundation.
*Salmaan Keshavjee, Irina Gelmanova, Sid Atwood, Sonya Shin
[email protected] Department of Global Health and Social Medicine, Harvard Medical School, 641 Huntington Avenue, Boston, MA 02115, USA (SK); Division of Global Health Equity, Brigham and Women’s Hospital, Boston, MA, USA (SK, SA, SS); and Partners In Health, Boston, MA, USA (IG) 1
2
3
4
5
Panos Pictures
The printed journal includes an image merely for illustration See Department of Error page 30
28
Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563–74. Mukherjee JS, Rich ML, Socci AR, et al. Programmes and principles in treatment of multidrug-resistant tuberculosis. Lancet 2004; 363: 474–81. Johnson JL, Hadad DJ, Boom WH, et al. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis 2006; 10: 605–12. Mitnick CD, Castro KG, Harrington M, Sacks LV, Burman W. Randomized trials to optimize treatment of multidrug-resistant tuberculosis. PLoS Med 2007; 4: e292. The Cambridge Declaration: towards clinical trials for drug-resistant tuberculosis. Cambridge, MA, USA; June 12, 2008. http://www.ghdonline. org/drtb/resource/the-cambridge-declarationtowards-clinical-trials-/ (accessed Dec 3, 2008).
Unsexy tuberculosis XDR-TB—extensively drug-resistant tuberculosis. The acronym makes one cringe with fear. Here we have an increasingly prevalent disease that is potentially as lethal as any weapon
of terrorism. But what is it really, and what is the secret to conquering it? First described in 2006 in KwaZulu Natal, South Africa,1 XDR-TB killed 52 of the 53 HIV-infected people it affected. In 2007, when Andrew Speaker was diagnosed in Atlanta, GA, USA and placed on (but did not heed) a “no-fly” order on the basis of his potential for disease transmission, the world’s press reacted with almost unprecedented concern. As reports of cohorts of patients followed from reputable centres,2,3 with cure rates similar to survival rates for tuberculosis in the “pre-drug” era, the Stop TB Department of WHO published an emergency response plan appropriately calling for integration of global resistant and sensitive tuberculosis control programmes.4 Cries for new drugs, diagnostics, and vaccines soon followed. Although all of this concern and attention is appropriate, it seems to skip the more important message. Certainly XDR-TB or MDR-TB (multiple-drug-resistant tuberculosis) is frightening. Certainly we need new drugs and diagnostics and the capacity to allow us to address the specifics of drug-resistant tuberculosis. But the key aspect that has been largely forgotten in all of the hype is that XDR-TB, MDR-TB, and drug-sensitive tuberculosis are all the same disease. The only difference is that MDRTB is drug-sensitive tuberculosis modified by inappropriate treatment or drug taking, and XDR-TB is MDRTB thus modified. In other words, every person with MDR-TB or XDRTB was not treated properly, did not take their drugs properly, or were infected by somebody who was not treated properly or did not take their medicines properly. In 2000, I coauthored an editorial5 pointing out that, with the growing acceptance of the necessity for prescribing MDR-TB drug therapy (then called DOTS Plus), this far more “sexy” aspect of tuberculosis care and control would distract attention
and resources away from basic tuberculosis control and therefore interfere with solving the problem. I am afraid that that is exactly what is being seen now. We need to recognise that there are more than 9 000 000 new active drugsensitive cases of tuberculosis globally that could be feeding drug resistance. It might be a less sexy concept, but they all must be appropriately treated with current strategies (as well as new diagnostics, drugs, vaccines, and proper infection control measures) to avoid preventable MDR-TB and XDR-TB, which are always lurking. Preventing active, drug-sensitive tuberculosis, or treating it properly, should be everybody’s priority: it is the only way to prevent MDR-TB and XDR-TB. I declare that I have no conflict of interest.
Lee B Reichman
[email protected] New Jersey Medical School, Global Tuberculosis Institute, Newark, NJ 07101, USA 1
2
3
4
5
Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368: 1575–80. Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563–74. Keshavjee S, Gelmanova IY, Farmer PE, et al. Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 2008; 372: 1403–09. Stop TB Partnership. The global MDR-TB and XDR-TB response plan 2007–2008. Geneva: World Health Organization, 2007. Lambregts-Van Weezenbeek K, Reichman LB. DOTS and DOTS-Plus: what’s in a name. Int J Tuberc Lung Dis 2000; 4: 995–96.
Intermittent preventive treatment with antimalarial drugs The Article by Siân Clarke and colleagues (July 12, p 127)1 provides valuable information about the efficacy of intermittent preventive treatment (IPT) of malaria on health and education in schoolchildren in Kenya. We have a few concerns, however. www.thelancet.com Vol 373 January 3, 2009
Correspondence
avoid unnecessary toxic effects and the potential for selection of pan-resistant strains. We conclude that use of aggressive second-line antituberculosis treatment regimens from the outset— with proper management of adverse events—can lead to positive outcomes in a significant proportion of patients. Treatment duration is another timely question that requires rigorous examination through clinical trials. SK, IG, and SS received partial salary support or travel support from the Bill & Melinda Gates Foundation and from the Eli Lilly Foundation. SK and SS received salary support from the Frank Hatch Fellowships in Global Health Equity at the Brigham & Women’s Hospital. SS received additional salary support from the Infectious Disease Society of America, the Heiser Foundation, and the US National Institutes of Health. SK received travel and research funding from the John D and Catherine T MacArthur Foundation.
*Salmaan Keshavjee, Irina Gelmanova, Sid Atwood, Sonya Shin
[email protected] Department of Global Health and Social Medicine, Harvard Medical School, 641 Huntington Avenue, Boston, MA 02115, USA (SK); Division of Global Health Equity, Brigham and Women’s Hospital, Boston, MA, USA (SK, SA, SS); and Partners In Health, Boston, MA, USA (IG) 1
2
3
4
5
Panos Pictures
The printed journal includes an image merely for illustration See Department of Error page 30
28
Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563–74. Mukherjee JS, Rich ML, Socci AR, et al. Programmes and principles in treatment of multidrug-resistant tuberculosis. Lancet 2004; 363: 474–81. Johnson JL, Hadad DJ, Boom WH, et al. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis 2006; 10: 605–12. Mitnick CD, Castro KG, Harrington M, Sacks LV, Burman W. Randomized trials to optimize treatment of multidrug-resistant tuberculosis. PLoS Med 2007; 4: e292. The Cambridge Declaration: towards clinical trials for drug-resistant tuberculosis. Cambridge, MA, USA; June 12, 2008. http://www.ghdonline. org/drtb/resource/the-cambridge-declarationtowards-clinical-trials-/ (accessed Dec 3, 2008).
Unsexy tuberculosis XDR-TB—extensively drug-resistant tuberculosis. The acronym makes one cringe with fear. Here we have an increasingly prevalent disease that is potentially as lethal as any weapon
of terrorism. But what is it really, and what is the secret to conquering it? First described in 2006 in KwaZulu Natal, South Africa,1 XDR-TB killed 52 of the 53 HIV-infected people it affected. In 2007, when Andrew Speaker was diagnosed in Atlanta, GA, USA and placed on (but did not heed) a “no-fly” order on the basis of his potential for disease transmission, the world’s press reacted with almost unprecedented concern. As reports of cohorts of patients followed from reputable centres,2,3 with cure rates similar to survival rates for tuberculosis in the “pre-drug” era, the Stop TB Department of WHO published an emergency response plan appropriately calling for integration of global resistant and sensitive tuberculosis control programmes.4 Cries for new drugs, diagnostics, and vaccines soon followed. Although all of this concern and attention is appropriate, it seems to skip the more important message. Certainly XDR-TB or MDR-TB (multiple-drug-resistant tuberculosis) is frightening. Certainly we need new drugs and diagnostics and the capacity to allow us to address the specifics of drug-resistant tuberculosis. But the key aspect that has been largely forgotten in all of the hype is that XDR-TB, MDR-TB, and drug-sensitive tuberculosis are all the same disease. The only difference is that MDRTB is drug-sensitive tuberculosis modified by inappropriate treatment or drug taking, and XDR-TB is MDRTB thus modified. In other words, every person with MDR-TB or XDRTB was not treated properly, did not take their drugs properly, or were infected by somebody who was not treated properly or did not take their medicines properly. In 2000, I coauthored an editorial5 pointing out that, with the growing acceptance of the necessity for prescribing MDR-TB drug therapy (then called DOTS Plus), this far more “sexy” aspect of tuberculosis care and control would distract attention
and resources away from basic tuberculosis control and therefore interfere with solving the problem. I am afraid that that is exactly what is being seen now. We need to recognise that there are more than 9 000 000 new active drugsensitive cases of tuberculosis globally that could be feeding drug resistance. It might be a less sexy concept, but they all must be appropriately treated with current strategies (as well as new diagnostics, drugs, vaccines, and proper infection control measures) to avoid preventable MDR-TB and XDR-TB, which are always lurking. Preventing active, drug-sensitive tuberculosis, or treating it properly, should be everybody’s priority: it is the only way to prevent MDR-TB and XDR-TB. I declare that I have no conflict of interest.
Lee B Reichman
[email protected] New Jersey Medical School, Global Tuberculosis Institute, Newark, NJ 07101, USA 1
2
3
4
5
Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368: 1575–80. Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563–74. Keshavjee S, Gelmanova IY, Farmer PE, et al. Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 2008; 372: 1403–09. Stop TB Partnership. The global MDR-TB and XDR-TB response plan 2007–2008. Geneva: World Health Organization, 2007. Lambregts-Van Weezenbeek K, Reichman LB. DOTS and DOTS-Plus: what’s in a name. Int J Tuberc Lung Dis 2000; 4: 995–96.
Intermittent preventive treatment with antimalarial drugs The Article by Siân Clarke and colleagues (July 12, p 127)1 provides valuable information about the efficacy of intermittent preventive treatment (IPT) of malaria on health and education in schoolchildren in Kenya. We have a few concerns, however. www.thelancet.com Vol 373 January 3, 2009
Correspondence
avoid unnecessary toxic effects and the potential for selection of pan-resistant strains. We conclude that use of aggressive second-line antituberculosis treatment regimens from the outset— with proper management of adverse events—can lead to positive outcomes in a significant proportion of patients. Treatment duration is another timely question that requires rigorous examination through clinical trials. SK, IG, and SS received partial salary support or travel support from the Bill & Melinda Gates Foundation and from the Eli Lilly Foundation. SK and SS received salary support from the Frank Hatch Fellowships in Global Health Equity at the Brigham & Women’s Hospital. SS received additional salary support from the Infectious Disease Society of America, the Heiser Foundation, and the US National Institutes of Health. SK received travel and research funding from the John D and Catherine T MacArthur Foundation.
*Salmaan Keshavjee, Irina Gelmanova, Sid Atwood, Sonya Shin
[email protected] Department of Global Health and Social Medicine, Harvard Medical School, 641 Huntington Avenue, Boston, MA 02115, USA (SK); Division of Global Health Equity, Brigham and Women’s Hospital, Boston, MA, USA (SK, SA, SS); and Partners In Health, Boston, MA, USA (IG) 1
2
3
4
5
Panos Pictures
The printed journal includes an image merely for illustration See Department of Error page 30
28
Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563–74. Mukherjee JS, Rich ML, Socci AR, et al. Programmes and principles in treatment of multidrug-resistant tuberculosis. Lancet 2004; 363: 474–81. Johnson JL, Hadad DJ, Boom WH, et al. Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis 2006; 10: 605–12. Mitnick CD, Castro KG, Harrington M, Sacks LV, Burman W. Randomized trials to optimize treatment of multidrug-resistant tuberculosis. PLoS Med 2007; 4: e292. The Cambridge Declaration: towards clinical trials for drug-resistant tuberculosis. Cambridge, MA, USA; June 12, 2008. http://www.ghdonline. org/drtb/resource/the-cambridge-declarationtowards-clinical-trials-/ (accessed Dec 3, 2008).
Unsexy tuberculosis XDR-TB—extensively drug-resistant tuberculosis. The acronym makes one cringe with fear. Here we have an increasingly prevalent disease that is potentially as lethal as any weapon
of terrorism. But what is it really, and what is the secret to conquering it? First described in 2006 in KwaZulu Natal, South Africa,1 XDR-TB killed 52 of the 53 HIV-infected people it affected. In 2007, when Andrew Speaker was diagnosed in Atlanta, GA, USA and placed on (but did not heed) a “no-fly” order on the basis of his potential for disease transmission, the world’s press reacted with almost unprecedented concern. As reports of cohorts of patients followed from reputable centres,2,3 with cure rates similar to survival rates for tuberculosis in the “pre-drug” era, the Stop TB Department of WHO published an emergency response plan appropriately calling for integration of global resistant and sensitive tuberculosis control programmes.4 Cries for new drugs, diagnostics, and vaccines soon followed. Although all of this concern and attention is appropriate, it seems to skip the more important message. Certainly XDR-TB or MDR-TB (multiple-drug-resistant tuberculosis) is frightening. Certainly we need new drugs and diagnostics and the capacity to allow us to address the specifics of drug-resistant tuberculosis. But the key aspect that has been largely forgotten in all of the hype is that XDR-TB, MDR-TB, and drug-sensitive tuberculosis are all the same disease. The only difference is that MDRTB is drug-sensitive tuberculosis modified by inappropriate treatment or drug taking, and XDR-TB is MDRTB thus modified. In other words, every person with MDR-TB or XDRTB was not treated properly, did not take their drugs properly, or were infected by somebody who was not treated properly or did not take their medicines properly. In 2000, I coauthored an editorial5 pointing out that, with the growing acceptance of the necessity for prescribing MDR-TB drug therapy (then called DOTS Plus), this far more “sexy” aspect of tuberculosis care and control would distract attention
and resources away from basic tuberculosis control and therefore interfere with solving the problem. I am afraid that that is exactly what is being seen now. We need to recognise that there are more than 9 000 000 new active drugsensitive cases of tuberculosis globally that could be feeding drug resistance. It might be a less sexy concept, but they all must be appropriately treated with current strategies (as well as new diagnostics, drugs, vaccines, and proper infection control measures) to avoid preventable MDR-TB and XDR-TB, which are always lurking. Preventing active, drug-sensitive tuberculosis, or treating it properly, should be everybody’s priority: it is the only way to prevent MDR-TB and XDR-TB. I declare that I have no conflict of interest.
Lee B Reichman
[email protected] New Jersey Medical School, Global Tuberculosis Institute, Newark, NJ 07101, USA 1
2
3
4
5
Gandhi NR, Moll A, Sturm AW, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 2006; 368: 1575–80. Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med 2008; 359: 563–74. Keshavjee S, Gelmanova IY, Farmer PE, et al. Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 2008; 372: 1403–09. Stop TB Partnership. The global MDR-TB and XDR-TB response plan 2007–2008. Geneva: World Health Organization, 2007. Lambregts-Van Weezenbeek K, Reichman LB. DOTS and DOTS-Plus: what’s in a name. Int J Tuberc Lung Dis 2000; 4: 995–96.
Intermittent preventive treatment with antimalarial drugs The Article by Siân Clarke and colleagues (July 12, p 127)1 provides valuable information about the efficacy of intermittent preventive treatment (IPT) of malaria on health and education in schoolchildren in Kenya. We have a few concerns, however. www.thelancet.com Vol 373 January 3, 2009
Correspondence
The average prevalence of anaemia at 12 months was 6·3% in the IPT group and 12·6% in the placebo group (risk ratio 0·52, 95% CI 0·29–0·93; p=0·028).1 However, the prevalence of anaemia at baseline was 3% higher in the placebo group than the IPT group.2 This difference should have been adjusted for. Widespread use of IPT antibiotics can introduce selection pressure for resistance to antimalarial drugs in the community. Bell and colleagues2 in Malawi reported that the prevalence of the pfmdr1 86Y mutation was higher after prophylaxis with sulfadoxinepyrimethamine plus amodiaquine than after sulfadoxine-pyrimethamine alone (p=0·002); amodiaquine exerted selective pressure for resistanceassociated mutations many weeks after treatment.3 Additionally, prophylaxis with sulfadoxine-pyrimethamine plus amodiaquine has been associated with striking declines in neutrophil counts compared with other IPT regimens.2 Has there been any emergence of amodiaquine resistance in the malarial parasite due to IPT? Are there any data on the children’s neutrophil counts and any associated ill effects? There are about 500 million cases of malaria and 1 million deaths from malaria each year, mainly in poor populations in tropical and subtropical areas where the temperature and rainfall are most suitable for the development of the malaria-causing Plasmodium parasites in Anopheles mosquitoes.3 We feel that concepts other than IPT are required to achieve eradication here. Transmission blocking, live attenuated parasite vaccines, and vector targeting are potential new candidates. We declare that we have no conflict of interest.
*Dewan Sakhawat Billal, Muneki Hotomi, Noboru Yamanaka
[email protected] Division of Infection and Immunity Research Center, Department of Otolaryngology-Head and Neck Surgery, Wakayama Medical University, Wakayama 641-8509, Japan
www.thelancet.com Vol 373 January 3, 2009
1
2
3
Clarke SE, Jukes MC, Njagi JK, et al. Effect of intermittent preventive treatment of malaria on health and education in schoolchildren: a cluster-randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 127–38. Bell DJ, Nyirongo SK, Mukaka M, et al. Sulfadoxine-pyrimethamine-based combinations for malaria: a randomised blinded trial to compare efficacy, safety and selection of resistance in Malawi. PLoS ONE 2008; 3: e1578. Greenwood BM, Fidock DA, Kyle DE, et al. Malaria: progress, perils, and prospects for eradication. J Clin Invest 2008; 118: 1266–76.
Authors’ reply Dewan Billal and colleagues highlight two important issues for intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine and amodiaquine, namely the potential selection of drug-resistant parasites and the safety of amodiaquine. In our study, we compared the prevalence of mutations in the pfdhfr and pfdhps genes, associated with resistance to sulfadoxine-pyrimethamine, among 537 children who were parasite-positive 12 months after the intervention. No differences between the intervention and placebo groups were evident, but the prevalence of resistance-associated alleles was already close to 100% in both groups. The prevalence of pfdhps alleles associated with sulfadoxine-pyrimethamine sensitivity also did not differ; however, wild-type alleles of pfdhfr were significantly less prevalent in the IPT group: 6% versus 18% (p=0·03) and 20% versus 42% (p=0·001) for codons 51-N and 59-C, respectively. It is possible, therefore, that selection against wild-type parasites could lead to a gradual increase in resistance within the parasite population over time, although such risks could be balanced by the small proportion of children still infected after treatment (
