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Session 30
Symposium The Promise and Challenge of Antiretroviral Therapy in Developing Countries Session Time: Wednesday, 2 - 4 pm Room 6A-B |
Background: Antiretroviral (ARV) therapy exerts selective pressure for ARV resistance if the existing regimen is not fully suppressive. In the poorest countries where ARV will never be considered for large-scale use, ARV resistance will be less a problem. However, in countries with some resources, such as Thailand, ARV resistance can be a serious problem if sub-optimal regimens are being used. Although HAART is ideal, it is largely unaffordable. Physicians in many developing countries are forced by their dying patients to prescribe sub-optimal but affordable therapy because they realize that some ARV is better than no ARV. AZT and ddI were the 2 nucleosides most commonly used in Thailand since they were the first to come out, relatively cheap, and generic drugs were widely available. For the same financial reason, viral load is rarely used to measure therapeutic response. Immunological (CD4) failure was usually used to determine treatment failure. Even when treatment failure was evident, the patient had to be kept on the same regimen since the second-line regimen such as d4T/3TC after AZT/ddI failure was 3 times more expensive. As a result, thousands of patients in Thailand were maintained on AZT/ddI for as long as 6-8 years or until they died of AIDS. Methods: Genotypic resistance data were obtained from 30 Thai patients failing prolonged AZT/ddI use. Results: AZT resistance was found in all cases whereas ddI resistance was found in only 1. Interestingly, 3TC resistance was found in 8, d4T resistance in 2, ddC resistance in 2, NNRTI resistance in 1, and multi-drug resistance in 2. These patients had never been exposed to any other NRTI or NNRTI besides AZT/ddI. Cross-resistance within the class of NRTI was also seen in non-suppressive d4T/ddI use. In a cohort of patients receiving low- and high-dose combinations of d4T/ddI for 48-96 weeks, we observed 4 cases of thymidine analogue mutations (TAM) and 4 cases of Q151M multi-drug resistance mutation out of 25 patients who had viral load over 1000 copies/mL. Our data and data from others confirm that intra-class cross-resistance also happens with NRTI in addition to NNRTI and protease inhibitors. The interclass cross-resistance (between NRTI and NNRTI) as observed in one of our patients, if confirmed, will be more alarming. The risk of ARV resistance is of particular concern for countries with limited resources, since long-term sub-optimal therapy is common. Interrupted therapy is frequent due to financial constraint, inconsistent medical supply and poor compliance, viral load and resistance assays are not readily available and option for salvage regimens is limited. Single ARV such as AZT and nevirapine (NVP) is still being used in developing countries to prevent mother-to-child transmission of HIV. Fortunately, the course of treatment is short, but NVP resistance has been observed even with a single dose. In Thailand, single-dose NVP has been added to some of the existing regimens of AZT with the hope to enhance the protective efficacy. How this combined regimen will affect the outcome of AZT and NVP resistance remains to be seen. Conclusions: Public health implications of ARV resistance are many. Transmission of resistant virus is the obvious concern. Although we could not find any baseline resistance in the RT genes in the patients enrolling in ARV trials during 1997-1998, periodic surveillance is needed. At the same time, prevention effort has to go hand in hand with ARV use. Conventional simple ARV regimens to prevent mother-to-child transmission or accidental needle stick injury may become ineffective if ARV resistance becomes widespread. Scarcity of effective salvage regimens is a threat of cross-resistance. Measures to minimize ARV resistance in developing countries are definitely needed. Maximally suppressive ARV regimens should be the goal. This goal requires drastic reduction in ARV price, government and international funding agencies commitment to care, as well as training of ARV prescribers. Adherence to ARV regimens must be stressed. Viral load and resistance assays as well as therapeutic drug monitoring should be made available, again with a much lower price. Uninterrupted supply of ARV must be ensured as well as the potency of ARV, especially if generic drugs are used. Alternative regimens for intolerance or treatment failure must also be available. Regular national surveillance for ARV resistance is required for constant update of national guidelines for first-line therapy, for prevention of mother-to-child transmission and for prevention of needle stick injury. Last but not least is to maintain a strong prevention program in order to prevent the transmission of resistant virus. The task is tremendous even for developed countries. Is it realistic for developing countries? No matter what the answer is, the concern of ARV resistance should not delay the political decision to start up a large-scale ARV use in developing countries. |
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©2002 9th Conference on Retroviruses and Opportunistic Infections |
