Modeling of Antilatency Treatment in HIV: What Is the Optimal Duration of Antiretroviral Therapy-Free HIV Remission?

Abstract

A number of treatment strategies are currently being developed to promote antiretroviral therapy-free HIV cure or remission. While complete elimination of the HIV reservoir would prevent recurrence of infection, it is not clear how different remission lengths would affect viral rebound and transmission. In this work, we use a stochastic model to show that a treatment that achieves a 1-year average time to viral remission will still lead to nearly a quarter of subjects experiencing viral rebound within the first 3 months. Given quarterly viral testing intervals, this leads to an expected 39 (95% uncertainty interval [UI], 22 to 69) heterosexual transmissions and up to 262 (95% UI, 107 to 534) homosexual transmissions per 1,000 treated subjects over a 10-year period. Thus, a balance between high initial treatment levels, risk of recrudescence, and risk of transmission should be considered when assessing the "useful" or optimal length of antiretroviral therapy-free HIV remission to be targeted. We also investigate the trade-off between increasing the average duration of remission versus the risk of treatment failure (viral recrudescence) and the need for retreatment. To minimize drug exposure, we found that the optimal target of antilatency interventions is a 1,700-fold reduction in the size of the reservoir, which leads to an average time to recrudescence of 30 years. Interestingly, this is a significantly lower level of reduction than that required for complete elimination of the viral reservoir. Additionally, we show that when shorter periods are targeted, there is a real probability of viral transmission occurring between tests for viral rebound.IMPORTANCE Current treatment of HIV involves patients taking antiretroviral therapy to ensure that the level of virus remains very low or undetectable. Continuous therapy is required, as the virus persists in a latent state within cells, and when therapy is stopped, the virus rebounds, usually within 2 weeks. A major question is how to reduce the amount of persistent virus and therefore allow a delay or remission until the virus returns after ceasing therapy. In this work, we consider the probability that HIV will still rebound even after this reduction and ask what the likelihood of viral transmission would be in this case.

Keywords: HIV; latency; reactivation; remission.

FIG 1

Depiction of the stochastic model to determine the chance of viral reactivation from latency and subsequent viral growth and detection after introduction of a latency-reducing intervention.

FIG 2

Probability of viral rebound following treatment with latency-reducing interventions that achieve different durations of ART-free remission. (A) Proportions of patients experiencing viral rebound at various times after the latency-reducing intervention is completed if the initial average duration of ART-free remission effected by the intervention is 1 year, 4 years, or 20 years. (B) The probability of viral rebound within the next year decreases as the length of time already spent in ART-free remission increases.

FIG 3

Viral reservoir sizes and reactivation. (A) Survival curve of time to viral rebound for subjects with either a smaller than average or larger than average latent reservoir. (B) Duration of viral remission for subjects with a smaller than average or larger than average latent reservoir.

FIG 4

(A) Total numbers of half-reductions that would be given over 5- and 10-year periods as the initial average duration of ART-free remission afforded by an intervention is varied. This assumes a baseline average time between reactivation events of 1 week. Minimum total numbers of half-reductions administered over 5- and 10-year periods are shown by the dots. (B) Optimal target duration of ART-free remission over 5 years (green) and 10 years (blue) given different initial baseline average times between viral rebounds. If the average time between viral reactivation events prior to a latency-reducing intervention is short, then the optimal duration of ART-free remission to be targeted is higher than if the baseline average time between viral reactivation events is longer.