Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

Abstract

Massive research efforts are now underway to develop a cure for HIV infection, allowing patients to discontinue lifelong combination antiretroviral therapy (ART). New latency-reversing agents (LRAs) may be able to purge the persistent reservoir of latent virus in resting memory CD4[superscript +] T cells, but the degree of reservoir reduction needed for cure remains unknown. Here we use a stochastic model of infection dynamics to estimate the efficacy of LRA needed to prevent viral rebound after ART interruption. We incorporate clinical data to estimate population-level parameter distributions and outcomes. Our findings suggest that ~2,000-fold reductions are required to permit a majority of patients to interrupt ART for 1 y without rebound and that rebound may occur suddenly after multiple years. Greater than 10,000-fold reductions may be required to prevent rebound altogether. Our results predict large variation in rebound times following LRA therapy, which will complicate clinical management. This model provides benchmarks for moving LRAs from the laboratory to the clinic and can aid in the design and interpretation of clinical trials. These results also apply to other interventions to reduce the latent reservoir and can explain the observed return of viremia after months of apparent cure in recent bone marrow transplant recipients and an immediately-treated neonate.American Foundation for AIDS Research. Research Consortium on HIV Eradication (Grant 108165-50-RGRL)Howard Hughes Medical InstituteJohns Hopkins Center for AIDS ResearchBill & Melinda Gates Foundation (Grand Challenges Explorations Grant OPP1044503)National Institutes of Health (U.S.) (Martin Delaney Collaboratory of AIDS Researchers for Eradication. Grant AI096113)National Institutes of Health (U.S.) (Delaney AIDS Research Enterprise Collaboratory. Grant 1U19AI096109