Optimal Timing and Duration of Induction Therapy for HIV-1 Infection

The tradeoff between the need to suppress drug-resistant viruses and the problem of treatment toxicity has led to the development of various drug-sparing HIV-1 treatment strategies. Here we use a stochastic simulation model for viral dynamics to investigate how the timing and duration of the induction phase of induction–maintenance therapies might be optimized. Our model suggests that under a variety of biologically plausible conditions, 6–10 mo of induction therapy are needed to achieve durable suppression and maximize the probability of eradicating viruses resistant to the maintenance regimen. For induction regimens of more limited duration, a delayed-induction or -intensification period initiated sometime after the start of maintenance therapy appears to be optimal. The optimal delay length depends on the fitness of resistant viruses and the rate at which target-cell populations recover after therapy is initiated. These observations have implications for both the timing and the kinds of drugs selected for induction–maintenance and therapy-intensification strategies.: Clinicians treating HIV infection must balance the need to suppress viral replication against the harmful side effects and significant cost of antiretroviral therapy. Inadequate therapy often results in the emergence of resistant viruses and treatment failure. These difficulties are especially acute in resource-poor settings, where antiretroviral agents are limited. This has prompted an interest in induction–maintenance (IM) treatment strategies, in which brief intensive therapy is used to reduce host viral levels. Induction is followed by a simplified and more easily tolerated maintenance regimen. IM approaches remain an unproven concept in HIV therapy. We have developed a mathematical model to simulate clinical responses to antiretroviral drug therapy. We account for latent infection, partial drug efficacy, cross-resistance, viral recombination, and other factors. This model accurately reflects expected outcomes under single, double, and standard three-drug antiretroviral therapy. When applied to IM therapy, we find that (1) IM is expected to be successful beyond 3 y under a variety of conditions; (2) short-term induction therapy is optimally started several days to weeks after the start of maintenance; and (3) IM therapy may eradicate some preexisting drug-resistant viral strains from the host. Our simulations may help develop new treatment strategies and optimize future clinical trials.