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Rapid Responses: Rapid Responses published:
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The continuing doom's day propaganda
- Chikwe Ihekweazu (3 February 2004)
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Antiretroviral therapy in Africa: "learning while doing"
- Anthony D Harries (4 February 2004)
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Insufficient evidence for poor adherence in Africa
- H.Florian Neuhann, Mina C. Hosseinipour (5 February 2004)
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Insufficient evidence for poor adherence in Africa
- Catherine J Orrell, Robin Wood, Linda-Gail Bekker (6 February 2004)
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International Double Standards for Adherence and Development of HIV Drug Resistance
- David R. Bangsberg (17 February 2004)
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Chikwe Ihekweazu, Fellow of the European Programme for Intervention Epidemiology (EPIET) Health Protection Agency, South West, The Wheelhouse, Bonds Mill, Stonehouse, Stroud, GL10 3RF
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Authors (including this one) often cite the potential for resistance to currently available antiretroviral medicines as a reason not to encourage their use in developing countries. Evidence used to support this argument is often (as is the case here) from studies involving treatment for malaria and tuberculosis. As we all know the reality of being infected with HIV is fundamentally different to being infected by tuberculosis. This obviously will affect adherence. There is compelling and overwhelming evidence currently available that the adherence to antiretroviral treatment regimens is at least as good as, and in many cases better than what has been reported in developed countries. (1,2,3,4) Saving the lives of the over 35 million people currently living with HIV in developing countries to enable them actively participate in their families, communities and countries can hardly be described as a “potential short term gain”! The author describes the introduction of antiretrovirals in Africa as “random and haphazard”. I would rather describe it as painfully slow and grossly inadequate. It is my suspicion that that most people infected and affected on the continent will agree with me. By the author’s own admission, drug resistance has developed in the developed world, despite apparently “consistent prescribing practices” and perfect “monitoring of therapy” as he insinuates. Yet would he dare suggest that treatment with antiretrovirals for people infected by the virus in these countries only be available in what he describes as “controlled settings” while “research programmes go on to determine rational approaches to treatment? I dare say not! Inadequate infrastructure for the treatment of ALL those infected is often quoted (including this author) as a reason for not treating ANY. This is indeed a new ethical paradigm! I humbly suggest that rather than wait until we can treat ALL, we start treating one by one, ten by ten and take it from there. Those living in these countries make difficult prioritising decisions everyday of their lives and one more such decision is well worth it, if lives will be saved. Antiretrovirals are currently available, increasingly affordable, and life saving. By suggesting that people living in developing countries wait until they have built up their infrastructure so they can regularly assay the plasma viral load for each infected person, before treatment is implemented is the equivalent of sentencing each of them to death. Let the truth be told. References 1. Weiser S, et al.. Barriers to antiretroviral adherence for patients living with HIV infection and AIDS in Botswana. J Acquir Immune Defic Syndr. 2003 Nov 1;34(3):281-8. 2. Laniece I, et al. Adherence to HAART and its principal determinants in a cohort of Senegalese adults. AIDS. 2003 Jul;17 Suppl 3:S103-8. 3. Bekker LG, et al. Antiretroviral therapy in a community clinic-- early lessons from a pilot project. S Afr Med J. 2003 Jun;93(6):458-62. 4. Orrell C, et al. Adherence is not a barrier to successful antiretroviral therapy in South Africa. AIDS. 2003 Jun 13;17(9):1369-75. Competing interests: None declared |
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Anthony D Harries, Technical assistant HIV Care and Support Ministry of Health, Lilongwe, Malawi
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Dear Sir, Stevens and colleagues cite poor success rates in several African TB control programmes as evidence that the DOTS strategy may fail to ensure the necessary adherence demanded in the delivery of antiretroviral therapy (ART)[1]. However, one needs to be careful in interpreting this data. Malawi, for example, has a treatment success rate of 71%, but this does not mean that the other 29% of patients are non-adherent to therapy. Of those not having a successful treatment, 20% die, 1% fail treatment and start a re-treatment regimen, 4 % transfer-out to another treatment facility and 4% default (source – Malawi National TB Programme reports) . The deaths are usually due to severe tuberculosis or the consequences of HIV-related disease. Of those who default, the main problem is often documentation, and many of the so-called defaulters have either died or in fact have successfully completed treatment [2]. The way forward, as Stevens et al state, is to introduce ART in controlled settings. In principle, the full DOTS strategy for delivering ART provides this controlled setting. It is not just a question of directly observed treatment. DOTS is a much wider strategy embracing principles of standardised case finding, standardised treatment, regular monitoring and evaluation and regular uninterrupted supplies of drugs and HIV test kits. Of course, we have yet to test whether, on a large scale, the DOTS model can actually work for ART delivery, and it is likely in a resource-poor setting to depend on whether the model is well-implemented or not. Can we wait until research programmes and pilot studies show us the way? Unfortunately not. We know that ART drugs are effective and save lives. We are learning how to use them in resource-constrained settings. We must develop a rigorous policy of “learning while doing”, otherwise countless thousands of men, women and children in sub-Saharan Africa will die while we learn to perfect the system. Anthony D Harries,
References: 1. Stevens W, Kaye S, Corrah T. Antiretroviral therapy in Africa. BMJ 2004; 328: 280-2. 2. Kruyt ML, Kruyt ND, Boeree MJ, Harries AD, Salaniponi FM, van Noord PA. True status of smear-positive pulmonary tuberculosis defaulters in Malawi. Bull WHO 1999; 77: 386 – 391. Competing interests: None declared |
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H.Florian Neuhann, Consultant Physician Lilongwe Central Hopsital, Clinical Advisor Lighthouse Lilongwe, Malawi, Mina C. Hosseinipour
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Stevens, Kaye and Corrah raise important issue in respect to antiretroviral therapy in Africa (BMJ 2004, 328, 280-2) and rightly point out the risks associated with a potential “ random and haphazard” introduction of antiretroviral therapy. They do however not present sufficient data to support their statement “evidence suggests adherence with drug treatment in Africa is low compared with that in industrialized nations”. It would be necessary to specify what treatment they are referring to and how the comparison was made. For example in industrialized countries adherence to antihypertensive treatment is notoriously poor. In contrast data from our own cohort on antiretroviral treatment in Lilongwe, Malawi, (N=753), where an introductory ART education session is mandatory, suggests that adherence levels are high. In a survey done in our clinic from July to December 2003 self reported adherence rates of > =95% were at 95% (unpublished data). Preliminary data from a prospective safety and efficacy study of our first line treatment also shows a high percentage of undetectable viral load at month 6 and supports the assumption that the self reported adherence rate is reliable. Our observations concur with similar results from other ART providing sites in Sub Saharan Africa. While it is justified to say that the current results may not be representative and cannot be extrapolated for the envisaged scale up in access to ART, the available data is nevertheless very encouraging. Being concerned about the potential dangers for the future should not blind us against the already existing bleak presence. Competing interests: None declared |
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Catherine J Orrell, CIPRA-SA site investigator Desmond Tutu HIv Centre, UCT, Cape Town, 7708, Robin Wood, Linda-Gail Bekker
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Re : Antiretroviral therapy in Africa ( BMJ 31st January 2004). Stevens, Kaye and Corrah (1) propose that increased access to antiretroviral therapy in Africa should be delayed as evidence suggests that African adherence with drug therapy is low compared with industralised nations and viral resistance may occur. We agree with the authors that widespread viral resistance will negatively impact on antiretroviral programmes and that strategies to improve adherence need to be included in ART programmes. While there is a need to strive for high levels of adherence in both industrialised and resource- poor settings, this should not be a rationale for maintaining inequitable access to antiretroviral therapy. In industrialised countries HIV- infection frequently occurs in marginised populations. Sub-optimal mono and dual nucleoside therapy was widely used prior to 1996, adherence levels are low and less than 60% of patients achieve long-term viral suppression (2). Despite sub-optimal virologic suppression and increasing resistance, AIDS morbidity and mortality have been significantly reduced in industrialised countries. It is the urgent need to reduce increasing AIDS mortality that has driven the demands for antiretroviral introduction into Africa. The authors refer to the high levels of adherence achieved in our study within the public health sector of Cape Town, South Africa (3) but add a statement that the study population was “urban and of above average education and income”. We believe that the results of our study should not be so easily dismissed and remain a serious challenge to those who hold to the stereotype that African drug adherence is inevitably bad. Sub-Saharan Africa is not homogeneously rural and 193 million Africans are urbanised (4). In South Africa, 47% of the population live in towns and cities where HIV infection rates are high. Our study was performed in a diverse, indigent population attending a public health facility and specifically addressed the relationship between socio-economic status and adherence. A major finding was that low socio-economic status was not associated with poor adherence. We have subsequently expanded ART access to over 600 indigent patients in Cape Town with continued high adherence levels and associated reduction in AIDS mortality. In Gugulethu, a poor urban township, free antiretroviral therapy has been dispensed to 205 patients attending the primary health care clinic. These patients are educated about their treatment and receive ongoing support from Sizophila (Xhosa for we shall survive) therapeutic counsellors. The counsellors are themselves HIV-infected, live in the township, receive a small stipend for supporting 20-30 patients and enjoy high acceptability amongst the patient population (figure 1). They perform home visits including unscheduled pill counts, which have recorded a mean adherence of 91%. Loss to follow up is less than 2% and viral suppression (< 50 copies/ml) at 48 weeks is 72%. We agree with Stevens et al that poverty may negatively impact on the ability of individuals to travel to distant health care facilities or pay for medical care however, in our experience, it does not predict poor adherence to freely available therapy delivered in the community. Poor adherence to medical therapy is not restricted to the poor or to Africa. Adherence to medical therapy appears to be a related to the quality of health care programmes rather than a socio-economic, educational or intrinsic racial attribute. Without antiretroviral therapy, 6.5 million South Africans are predicted to die of AIDS by 2010 (5) and calls for delay in increasing antiretroviral access should evidence based and made with extreme circumspection. Dr Catherine Orrell, Dr Linda-Gail Bekker, Professor Robin Wood Desmond Tutu HIV Centre, Department of Medicine, University of Cape Town. References 1. Stevens W, Kaye S, Corrah T. Antiretroviral therapy in Africa. BMJ 2004;328:280-282 2. Gilick RM, Meibohm A, Havlir D et al. Six-year follow-up of HIV-1 infected adults in a clinical trial of antiretroviral therapy with indinavir, zidovudine and lamivudine. AIDS 203;17(16);2345-49 3. Orrell C, Bangsberg DR, Badri M, Wood R. Adherence is not a barrier to successful antiretroviral therapy in South Africa. AIDS 2003;17:1369-75 4. Urban population in Sub-Saharan African Countries. <www.worldbank.org/urban/env/publications-regions.htm> accessed 4th February 2004. 5. The impact of HIV/AIDS on adult mortality in South Africa. Technical Report of the Burden of Disease Research Unit. Medical Research Unit South Africa. www.mrc.ac.za/bod Figure 1. A “Sizophila” therapeutic counsellor visiting a client’s home in Gugulethu, Cape Town. Competing interests: None declared |
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David R. Bangsberg, Associate Professor of Medicine UCSF, Box 1372 San Francisco, CA 94143
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In the July 31, 2004 edition of the British Medical Journal, Stevens and colleagues argue that “we should stop and think about the risks of resistance and ways of minimizing them, before increasing access to antiretroviral therapy in Africa”. The authors caution that “short term gains from reducing individual morbidity and mortality may be far outweighed by the potential for the long term spread of drug resistance”. Stevens and colleagues suggest that lack of education and income in Africa is likely to lead to suboptimal adherence. However, income and education have not been consistently associated with adherence to HIV therapy in any setting (1). Evidence to date suggests that Africans receiving antiretroviral therapy, including those in poverty and with little education, adhere far better than those in industrialized countries. Most African studies to date find adherence near 90% (2-6). These estimates unavoidably suffer from selection bias and are likely to decline as access to therapy improves. Nonetheless, they have a long way to fall before they reach 70% average adherence in industrialized countries (7) where it is not uncommon to prescribe therapy to patients with less than 50% adherence (8). This begs the question of why Stevens and colleagues suggest we have two standards of adherence: a high standard for Africa and a low standard for industrialized countries? Industrialized patients have not only fallen below the adherence mark, they have also generated the global burden of drug resistance. 50% of HIV infected people engaged in clinical care in the USA have evidence of drug resistance (9) and 10% of new infections in industrialized countries occur with drug resistant HIV (10). Although incomplete adherence may have contributed to this high level of drug-resistance, it is likely that most of this resistance occurred as a consequence of suboptimal treatment strategies. Many patients harboring drug-resistant HIV today acquired resistance due to sequential exposure to nucleoside analogues, followed later by the addition of protease inhibitors and non- nucleoside reverse transcriptase inhibitors (11,12). Because we have better drugs and we have learned from our mistakes, it is unlikely that the introduction of antiretroviral therapy in Africa will generate similar population levels of resistance, regardless of adherence. Industrialized countries generate the global burden of resistant HIV now, and will continue to for some time to come. If Stevens and colleagues truly believe that the prevention of antiretroviral drug resistance trumps individual benefits of therapy, then they should argue for rapid scale back of therapy in industrialized nations rather than African nations. Withholding therapy from the industrialized nations would be the most effective way to slow global drug resistance. The reason we do not stop providing antiretroviral therapy in the setting of endemic resistance in industrialized settings is that antiretroviral therapy continues to save lives. The survival benefit continues in the face of growing levels of drug resistance. Indeed, mortality in some HIV-infected populations may be comparable to HIV negative people with chronic diseases (13). Patients with incomplete adherence, partial viral suppression, and evolution of resistant virus enjoy preserved immunologic function and survival relative to untreated individuals (12). I agree that the delivery of antiretroviral in Africa should proceed with careful planning and should target reliable drug supply and distribution as well as support optimal adherence (14). This priority, however, should be driven by the goal to prevent morbidity and mortality. Good adherence with fully suppressive regimens in antiretroviral naïve patients may indeed limit the development of drug resistance, an important secondary goal. Nonetheless, some patients even with good adherence may have incomplete viral suppression, likely due to individual variations in phramacokinetics, and will develop resistance (15). Resistance in these patients does not preclude benefit of therapy. Many patients with good adherence, partial viral suppression and resistant virus receive significant and sustained benefits from continuing therapy(16). These patients continue therapy precisely because the individual benefits of therapy outweigh population concerns of drug resistance. The primary argument to provide HIV therapy to Africa and resource poor countries is based on equity. We should not assume inequity with respect to our expectations of adherence and/or the development of drug resistance. References 1. Stone VE. Strategies for optimizing adherence to highly active antiretroviral therapy: lessons from research and clinical practice. Clin Infect Dis 2001;33(6):865-72. 2. Laurent C, Diakhate N, Gueye NF, Toure MA, Sow PS, Faye MA, et al. The Senegalese government's highly active antiretroviral therapy initiative: an 18-month follow-up study. Aids 2002;16(10):1363-70. 3. Byakika-Tusiime J, Oyugi J, Tumwikirize W, Katabira E, Mugyenyi P, Bangsberg D. Ability to Purchase and Secure Stable Therapy are Significant Predictors of Non-adherence to Antiretroviral Therapy in Kampala, Uganda. Int J HIV and STDS, 2003. 4. Feasibility and validity of multiple measures of adhernece to HIV antiretroviral therapy in Kampala, Uganda. 2nd IAS Conference on HIV Pathogenesis and Treatment; 2003; Paris. 686. 5. Orrell C, Bangsberg D, Badri M, Wood R. Adherence is not a barrier to delivery of HIV antiretroviral therapy in resource-poor countries. AIDS (in press) 2003. 6. Weiser S, Wolfe W, Bangsberg D, Thior I, Gilbert P, Makhema J, et al. Barriers to antiretroviral adherence for patients living with HIV infection and AIDS in Botswana. J Acquir Immune Defic Syndr 2003;34(3):281 -8. 7. Bangsberg DR, Deeks SG. Is average adherence to HIV antiretroviral therapy enough? J Gen Intern Med 2002;17(10):812-3. 8. Arnsten JH, Demas PA, Farzadegan H, Grant RW, Gourevitch MN, Chang CJ, et al. Antiretroviral therapy adherence and viral suppression in HIV- infected drug users: comparison of self-report and electronic monitoring. Clin Infect Dis 2001;33(8):1417-23. 9. Ricmond D, Bozette S, et al. The prevalence of antiretroviral drug resistance in the US. ICAAC; 2001; Chicago. 10. Analysis from more than 1600 newly diagnosed patients with HIV from 17 European countries shows that 10% of the patients carry primary drug resistance: the CATCH-Study. 2nd Conference on HIV Pathogenesis and Treatment; 2003; Paris. 11. Bangsberg D, Charlebois E, Grant R, Holodniy M, Deeks S, Nugent- Conroy K, et al. High levels of adherence do not prevent accumulation of HIV drug resistance mutations. AIDS 2003;17(13):1925-32. 12. Deeks S. The treatment of drug-resistant HIV. Lancet 2003; 362(9400):2002-11 13. Jensen-Fangel S, Pedersen L, Pedersen C, Larsen CS, Tauris P, Moller A, et al. Low mortality in HIV-infected patients starting highly active antiretroviral therapy: a comparison with the general population. Aids 2004;18(1):89-97. 14. Liechty CA, Bangsberg DR. Doubts about DOT: antiretroviral therapy for resource-poor countries. Aids 2003;17(9):1383-7. 15. Bangsberg DR, Charlebois ED, Grant RM, Holodniy M, Deeks SG, Perry S, et al. High levels of adherence do not prevent accumulation of HIV drug resistance mutations. Aids 2003;17(13):1925-32. 16. Deeks SG, Barbour JD, Martin JN, Swanson MS, Grant RM. Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection. J Infect Dis 2000;181(3):946-53. Competing interests: None declared |
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