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The rollout of antiretroviral therapy (ART) in resource-limited settings has been a stunning success, with more than 3 million adults and children initiating ART in the past 4 years. Two thirds of these individuals are in sub-Saharan Africa, the most underresourced area in the world. Although initial skepticism about infrastructure and medication adherence has abated somewhat, new (but not unexpected) concerns have arisen.
One set of concerns is specific to the most frequently used initial regimen worldwide — d4T + 3TC + efavirenz or nevirapine. Although this combination is potent, easily administered, and relatively inexpensive, it carries the risk of substantial cumulative toxicity. Furthermore, because 3TC and the NNRTIs have low genetic barriers to resistance, the regimen is associated with selection of resistance mutations and subsequent therapeutic failure. This shortcoming is made worse in resource-limited settings, where the use of clinical or CD4-cell–count criteria rather than viral-load monitoring results in late recognition of treatment failure, and the boosted PIs necessary for second-line regimens are prohibitively expensive and limited in availability. At several meetings this year, researchers described antiretroviral resistance in Africa and Asia (AIDS Clin Care Sep 15 2008; Abstract O113, 9th International Congress on Drug Therapy in HIV Infection, 2008, and Abstract 796, 2008 HIV Implementers’ Meeting). What is particularly disturbing is that about 5% of patients initiating ART in some of these regions had primary resistance, most likely acquired through high-risk sexual or drug-use behavior with patients who had resistant virus.
Another worrisome development in many antiretroviral programs is substantial loss to follow-up. Such loss is not unexpected, given the limited resources available to continue prioritizing enrollment and initiation of ART for the millions of patients who still require it while also providing long-term follow-up care for those already in treatment. Although precise outcomes are generally not known for patients lost to follow-up, suspicion is increasing that many of these patients are dying prematurely (Bull World Health Organ 2008; 86:559, PLoS Med 2007; 4:e298, and J Aquir Immune Defic Syndr 2008; 47:101).
The extraordinary success of ART rollout will continue to expand, but the issues described here must be addressed now to maximize benefit. Potential solutions include (1) reducing the cost and increasing the availability of nonthymidine analogues (tenofovir and abacavir) so that they can be used in place of d4T and AZT in initial regimens, (2) reducing the cost and increasing the availability of boosted PIs, (3) reducing the cost of viral-load monitoring and resistance testing while developing new technologies appropriate for resource-constrained environments, and (4) training and deploying much larger numbers of community workers to support and follow-up on patients receiving ART.