Investigation of the Impact of Inducible, Replication-competent Latent HIV-1 as an Impediment to HIV/AIDS Cure in the Context of Sustained Viral Suppression

Background: Based on the 2013 Kenya AIDS Indicator Survey, 58% of people living with HIV/AIDS (PLWHA) aged 15-64 years in Kenya were eligible for Antiretroviral Therapy (ART), but only 63% of them were found to have been initiated. Previous studies have shown that an estimated 33% to 40% of patients are expected to fail treatment in the first 12 months of second-line ART. In many low and middle income countries (LMIC) with no third-line regimens available, second-line ART is the last option for patients hence failure greatly impacts patients management. A study in Kenyan national ART program suggests that about 27% of patients with second-line failure are in need of a switch to third-line therapy, with 25% demonstrating complete exhaustion of alternative first and second-line regimens. Although new drugs for HIV treatment are being developed, HIV treatment options within national programmes remain limited. Therefore, the durability of switch to second-line regimens as well as durability to second-line regimens is critical for the long-term success of ART and ultimately patient survival. Fortunately, virological (VL) failure on second-line ART does not necessarily warrant a switch to a third-line regimen, as Protease Inhibitors (PIs) have a high genetic barrier to resistance mutations, particularly among PI naïve patients. As failure on second-line ART is more related to suboptimal adherence than drug resistance, the management of VL failure on second-line typically involves intensified adherence counselling with drug substitutions recommended in cases of documented resistance mutations, severe adverse drug reactions (ADR) or drug interactions. While rates of drug substitutions and the durability of first-line ART have been previously described, there is very little information on patterns of drug substitutions for patients on second-line ART across ART national guideline-specific periods. Additionally, little is known about the impact of ART guideline changes on the durability of second-line ART and continuity of care.

While determining the durability of ART is critical in terms of monitoring success and possible ART mutations, the desired outcome is eradication of HIV by 2030.The concept of eradication of the HIV from infected patients has therefore gained much attention in the last few years. ART has changed the dynamic of the HIV epidemic through suppression of HIV-1 RNA to undetectable plasma levels. As a sign of the seriousness of countries to achieve 90-90-90, it is important to track success results at each stage of the HIV continuum of care and most importantly the viral suppression. Although antiretroviral therapy can suppress HIV-1 infection to undetectable levels of plasma viremia, HIV DNA integrate and persist in resting CD4+ T cells. Latent HIV infection of CD4+ T cells, established during the early stages of infection, necessitates lifelong ART, and treatment failure can lead to the selection of drug resistance mutations in the viral genome, which may be archived in the cellular reservoir. Most of the HIV DNA in these cells is defective and cannot cause infection. However, latent HIV-1 genomes that encode replication- competent virus can resurface once ART is discontinued. This latent reservoir having replication- competent virus has a long half-life, and is believed to be the largest impediment to a cure by ART alone. This justifies expansion of research examining HIV latency in the context of sustained viral suppression with an eye towards developing a possible cure regimen that could be used on a large scale. Recently, pharmaceutical approaches have focused on the development of molecules able to reactivate HIV from latently infected cells in order to render them susceptible to combined antiretroviral therapy (c-ART), viral cytopathic effects and host immune responses. Obviously, exposing latent virus and killing it with ART rests on an assumption that the activated virus will be susceptible to the ART a person takes. As such, it is important to discern whether reactivated HIV proviruses are susceptible to the ART regimen for maximum benefit to the patient.

The vast majority of HIV-infected individuals currently live in sub-Saharan Africa where fully suppressive ART is expanding rapidly. Due to this expansion, a large number of patients are expected to achieve full viral suppression. There is need therefore to quantify and document the size of latent HIV reservoir in virally suppressed patients in this region for individualized treatment. To date, there have been no systematic studies to quantify the latent reservoir in virally suppressed HIV-infected patients in Africa. Detecting how much of the inducible virus is left in the human body after antiretroviral therapy poses the greatest challenge to fully curing HIV. Stratifying virally suppressed patients base on the quantity of latent HIV, ART regimens and immune status may inform eligible candidates for latency reactivation care when one comes available.

Hypothesis: Archived proviruses in the latent reservoir are sustained in aviremic patients and are an impediment to HIV cure.

General Objective: Investigate the impact of inducible, replication-competent latent HIV-1 as an impediment to HIV/AIDS cure.