Medical Research Council Programme on AIDS in Uganda, Uganda Virus Research Institute, Entebbe, Uganda and Department of Immunology, Imperial College London, Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK
Keywords: HIV-1, antiretroviral therapy, Uganda
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Introduction |
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However, many issues remain to be resolved, some real and others myths. When is it appropriate to initiate ART and with which drugs? Are the drugs available at a reasonable price? Should monitoring follow the same approach as in the developed world or should Africa develop its own monitoring protocols? Is ART equally efficacious against non-B subtypes that predominate in Africa? How will the management of opportunistic infections (OIs) be addressed? How should adherence and the associated non-structured treatment interruptions be dealt with? Perhaps the most important question concerns the under-resourced health sector: will it be able to deliver and regulate access to ART and will this divert attention from other important healthy priorities like malaria?
It is, however, not realistic to expect or demand that all requirements be fulfilled before access initiatives are implemented. Much has been learned about ART from the experiences in treatment centres like the Joint Clinical Research Centre (JCRC) in Kampala, Uganda, and reinforced during the UNAIDS Drug Access Initiative (DAI). ART in Africa is now a reality. This personal perspective attempts to review the current situation and anticipate future directions.
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Health infrastructures and ART in Africa |
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Pilot programmes like the UNAIDS DAI demonstrated that by strengthening existing facilities, an effective central system for drug procurement, distribution and accountability could be implemented and ensure an uninterrupted supply of drugs to support sustainable management of AIDS patients. It is thus likely that in the implementation phase, expanded access to ART in sub-Saharan Africa will start with utilizing and strengthening existing central health infrastructures. However, because provision of ART on an expanded scale involves more than distributing antiretroviral drugs, other health infrastructure requirements will need to be addressed. These are likely to include reviewing best practices, developing standard operating procedures for all components involved, establishing quality assurance programmes, training of health care personnel and planning for staff retention, and renovating physical structures. Of paramount importance will be the need to strengthen drug control mechanisms so as to provide a means of supervision, especially for the informal sector. Although an emotive issue, there will eventually be a need to control unregulated access to antiretroviral drugs and discourage practices such as making antiretroviral drugs available on the street and the selling to patients of single pills, even without prescription.
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When to start ART and with what first-line regimen? Does ART work in Africans? |
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In those who initiate ART, choice of the first-line regimen is mainly governed by cost. This partly explains the significant shifts in treatment practices in Uganda following the introduction of non-nucleoside reverse transcriptase inhibitors (NNRTIs), which, in combination with two NRTIs, are less costly than either triple nucleosides or two NRTIs plus protease inhibitors. To date, the leading antiretroviral regimen prescribed (nevirapine, lamivudine and stavudine, dispensed as the generic Triomune) is also the cheapest (J. Takubwa, personal communication). Approximately 11% of patients develop pulmonary tuberculosis during the first 12 weeks of ART (A. Kebba, unpublished observations) and would require switching or stopping therapy shortly afterwards to avoid potential drug interactions. Importantly, the choice of first-line antiretroviral regimen may significantly influence all subsequent ART. Countries scaling up access to ART should therefore adopt an approach that rationally sequences antiretroviral drugs in order to preserve future treatment options for as long as possible, but again cost will often compromise this recommendation.3,4
Concerns also exist as to the efficacy of ART against Africas predominantly non-B HIV-1 subtypes, particularly subtype D.5 ART has not been carefully evaluated against these subtypes. A retrospective analysis showed that 80% of antiretroviral-drug-naïve HIV-1-infected Ugandans initiated on zidovudine, 3TC and efavirenz at the JCRC achieved and maintained optimal virological suppression associated with significant quantitative immunological reconstitution.6 The Lazarus-like improvement in clinical condition is also observed. This suggests that subtypes A and D, which predominate in HIV-1-infected Ugandans,7 are susceptible to ART. ART does work in HIV-1-infected African patients.
Unfortunately, between 6% and 11% of patients are antiretroviral-drug experienced, usually in an unsupervised and irregular manner, prior to their first visit to a treatment centre (A. Kebba, unpublished observations). This figure will rise, because price reductions of antiretroviral agents will inevitably increase uncontrolled access. This carries with it the risk of drug resistance, which will have an impact on therapeutic responses to ART in the future.
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Monitoring ART amidst limited resources |
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Ironically, monitoring schedules used in the Western world may be best suited for Africa, considering the following behaviours that are said to be typical: patients interrupt therapy in a haphazard way, reduce dosages or change administration schedules because of lack of funds to maintain a steady supply of medications; they switch regimen when prices of antiretroviral drugs change or drug stocks run out; and many also take herbal preparations the content and interaction with antiretroviral agents of which is largely unknown. These would affect adherence and bioavailability of antiretroviral drugs and compromise achieving optimal virological outcomes. Complete and sustained virological suppression are of great importance for clinical success.810
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Patient adherence to ART amidst limited resources |
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However, caution needs to be exercised. STI should be avoided when ART is unsuccessful, which is likely in advanced patients in whom immune reconstitution may not occur despite optimal virological suppression.1214 STI requires that patients are under careful medical supervision, and their VL and CD4+ T cell counts regularly monitored, which is costly. Caution is also required when dealing with antiretroviral drugs that have long half lives. Although earlier studies had suggested that STI does not reduce overall efficacy of ART,15,16 it can still delay reduction of VL and increase in CD4+ T cell counts on re-initiation. Furthermore, STI may have immunological con-sequences.17,18 It is appropriate to mention here that STIs are unlikely to result in enhanced immune control of virus19 in chronically infected Africans. Lastly, the optimistic view that no drug selection would be applied if interruptions were carried out safely has been brought into question by studies in which the emergence of resistance mutations occurred in closely monitored patients.20 Notwithstanding these concerns, treatment interruptions are inevitable for a substantial number of patients given the existing financial constraints in sub-Saharan Africa. If current conditions remain, STIs will be inevitable in order to make interruptions safer.
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What does the future hold? |
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Acknowledgements |
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Footnotes |
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References |
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2 . Joint United Nations Programme on HIV/AIDS. (2002). AIDS epidemic update: report on the global HIV/AIDS epidemic. Original English version released in July 2002. UNAIDS, Geneva, Switzerland (http://www.unaids.org).
3 . Panel on Clinical Practices for Treatment of HIV Infection convened by the US Department of Health and Human Services (DHHS) and the Henry J. Kaiser Family Foundation. (2002). Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Document issued on February 4, 2002. pp. 1104 (http://aidsinfo.nih.gov/guidelines/).
4 . World Health Organization. (2002). Scaling up antiretroviral therapy in resource-limited settings: guidelines for a public health approach. Document issued in June 2002. pp. 1165. WHO, Geneva, Switzerland (http://who.int/hiv/pub/).
5 . Palmer, S., Alaeus, A., Albert, J. et al. (1998). Drug susceptibility of subtypes A, B, C, D and E human immunodeficiency virus type 1 primary isolates. AIDS Research and Human Retroviruses 14, 15762.[ISI][Medline]
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7 . Hu, D. J., Baggs, J., Downing, R. et al. (2000). Predominance of HIV-1 subtype A and D infections in Uganda. Emerging Infectious Diseases 6, 60915.[ISI][Medline]
8 . Ledergerber, B., Egger, M., Opravil, M. et al. (1999). Clinical progression and virological failure on HAART in HIV-1 patients: a prospective cohort study. Lancet 353, 8638.[CrossRef][ISI][Medline]
9 . Salzeberger, B., Rockstroh, J., Wieland, U. et al. (1999). Clinical efficacy of protease inhibitor based antiretroviral combination therapy a prospective cohort study. European Journal of Medical Research 4, 44955.[Medline]
10 . Thiebaut, R., Morlat, P., Jacqmin-Gadda, H. et al. (2000). Clinical progression of HIV-1 infection according to the viral response during the first year of antiretroviral treatment. Groupe dEpidemiologie du SIDA en Acquitaine (GECSA). AIDS 14, 9718.[CrossRef][ISI][Medline]
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15 . Ruiz, L., Martinez-Picado, J., Romeu, J. et al. (2000). Structured treatment interruption in chronically HIV-1 infected patients after long-term viral suppression. AIDS 14, 397403.[CrossRef][ISI][Medline]
16 . Neumann, A. U., Tubiana, R., Calvez, V. et al. (1999). HIV-1 rebound during interruption of highly active antiretroviral therapy has no deleterious effect on reinitiated treatment. Comet Study Group. AIDS 13, 67783.[CrossRef][ISI][Medline]
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Blankson, J., Gallant, J., Quinn, T. et al. (2002). Loss of HIV-1-specific immunity during treatment interruption in 2 chronically infected patients. Journal of the American Medical Association 288, 1624.
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Martini, F., Poccia, F., Goletti, D. et al. (2002). Acute human immunodeficiency virus replication causes a rapid and persistent impairment of V9V
2 T cells in chronically infected patients undergoing structured treatment interruption. Journal of Infectious Diseases 186, 84750.[CrossRef][ISI][Medline]
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Oxenius, A., Price, D. A., Gunthard, H. F. et al. (2002). Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection. Proceedings of the National Academy of Sciences, USA 99, 1374752.
20 . Dybul, M., Nies-Kraske, E., Daucher, M. et al. (2003). Long-cycle structured intermittent versus continuous highly active antiretroviral therapy for the treatment of chronic infection with human immunodeficiency virus: effects on drug toxicity and on immunologic and virologic parameters. Journal of Infectious Diseases 188, 38895.[CrossRef][ISI][Medline]
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