Knowledge of viral dynamics through the use of viral load and resistance testing has made it clear that combination therapy with maximally potent agents will reduce viral replication to the lowest possible level, thereby reducing the number of cumulative mutations and decreasing the likelihood of emergence of resistance. Thus, administration of combination antiretroviral therapy, typically including at least three antiretroviral agents with differing susceptibility patterns, has become the standard of care. Viral susceptibility to specific agents varies among patients and may change with time. Therefore, such combinations must be chosen with care and tailored to the individual, as must changes to a given regimen. In addition to potency and susceptibility, important factors in the selection of agents for any given patient are tolerability, convenience, and optimization of adherence. New drugs with high potency, low toxicity, and good tolerability increase the feasibility of early, lifelong treatment. As new agents have become available, several older ones have had diminished usage, because of either suboptimal safety or inferior efficacy. Zalcitabine (ddC; dideoxycytidine) is no longer marketed, and regimens containing zidovudine (AZT; azidothymidine), ddI (didanosine), or stavudine (d4T) are infrequently recommended as first-line regimens.
Decrease of the circulating viral load by antiretroviral therapy is correlated with enhanced survival as well as decreased morbidity. Also, the use of antiretroviral therapy strongly reduces the risk for heterosexual and same-sex HIV transmission.
Discussion of antiretroviral agents in this chapter is specific to HIV-1. Patterns of susceptibility of HIV-2 to these agents may vary; however, there is innate resistance to the NNRTIs and enfuvirtide as well as a lower barrier of resistance to NRTIs and PIs.
The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase; incorporation into the growing viral DNA chain causes premature chain termination due to inhibition of binding with the incoming nucleotide (Figure 49–3). Each agent requires intra-cytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate form.
Typical resistance mutations include M184V, L74V, D67N, and M41L. Lamivudine or emtricitabine therapy tends to select rapidly for the M184V mutation in regimens that are not fully suppressive. While the M184V mutation confers reduced susceptibility to abacavir, didanosine, and zalcitabine, its presence may restore phenotypic susceptibility to zidovudine. The K65R/N mutation is associated with reduced susceptibility to tenofovir, abacavir, lamivudine, and emtricitabine.
All NRTIs may be associated with mitochondrial toxicity, which may manifest as peripheral neuropathy, pancreatitis, lipoatrophy, and hepatic steatosis. Less commonly, lactic acidosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. Lipoatrophy and insulin resistance may occur most frequently with use of the thymidine analogs stavudine and zidovudine, and least frequently with use of tenofovir, lamivudine, emtricitabine, and abacavir.