ABSTRACT
Despite remarkable progress, a cure for HIV-1 infection remains elusive. Rebound competent latent and transcriptionally active reservoir cells persevere despite antiretroviral therapy and rekindle infection due to inefficient proviral silencing. We propose a novel "block-lock-stop" approach, entailing long term durable silencing of viral expression towards an irreversible transcriptionally inactive latent provirus to achieve long term antiretroviral free control of the virus. A graded transformation of remnant HIV-1 in PLWH from persistent into silent to permanently defective proviruses is proposed, emulating and accelerating the natural path that human endogenous retroviruses (HERVs) take over millions of years. This hypothesis was based on research into delineating the mechanisms of HIV-1 latency, lessons from latency reversing agents and advances of Tat inhibitors, as well as expertise in the biology of HERVs. Insights from elite controllers and the availability of advanced genome engineering technologies for the direct excision of remnant virus set the stage for a rapid path to an HIV-1 cure.
Subject(s)
Endogenous Retroviruses , HIV Infections , HIV Seropositivity , HIV-1 , Humans , HIV-1/genetics , Virus Latency , Proviruses/genetics , HIV Seropositivity/genetics , CD4-Positive T-LymphocytesABSTRACT
BACKGROUND: Sex hormone and preexposure prophylaxis (PrEP) drug interactions among transgender women (TGW), transgender men (TGM), and cisgender men (CGM) are not fully understood. METHODS: TGM and TGW on at least 6 months of stable sex hormone therapy containing testosterone or estradiol (respectively) were enrolled in a 4-week study of directly observed dosing of daily oral coformulated emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). TFV-DP in dried blood spots and sex hormones in serum were measured at weekly intervals. TFV-DP was compared with 2- and 4-week samples from Directly Observed Therapy Dried Blood Spots (DOT-DBS) Study (NCT02022657). RESULTS: From May 2017 to June 2018, 24 TGM and 24 TGW were enrolled. Testosterone (total and free) and estradiol concentrations were comparable before and after 4 weeks of PrEP use in TGM and TGW, respectively. Historical controls included 17 cisgender women (CGW) and 15 CGM. TFV-DP concentrations at week 4 were comparable between TGW and TGM (mean difference, -6%; 95% confidence interval [CI], -21% to 12%; Pâ =â .47), comparable between TGW and CGM (mean difference, -12%; 95% CI, -27% to 7%; Pâ =â .21) and were lower among TGM compared with CGW (mean difference, -23%; 95% CI, -36% to -7%; Pâ =â .007). All persons in all groups were projected to reach the TFV-DP threshold that has been associated with high protection from human immunodeficiency virus. CONCLUSIONS: CGM, TGM, and TGW had comparable TFV-DP concentrations in dried blood spots after 4 weeks of directly observed daily FTC/TDF PrEP use. Serum hormone concentrations were not affected by FTC/TDF PrEP use. CLINICAL TRIALS REGISTRATION: NCT04050371.
Subject(s)
Anti-HIV Agents , HIV Infections , Pre-Exposure Prophylaxis , Transgender Persons , Adenine/analogs & derivatives , Anti-HIV Agents/therapeutic use , Emtricitabine/therapeutic use , Estradiol , Female , HIV Infections/drug therapy , HIV Infections/prevention & control , Humans , Male , OrganophosphatesABSTRACT
We conducted a longitudinal and cross-sectional analysis of depressive symptomology in iPrEx, a randomized, placebo-controlled trial of daily, oral FTC/TDF HIV pre-exposure prophylaxis (PrEP) in men and transgender women who have sex with men. Depression-related adverse events (AEs) were the most frequently reported severe or life-threatening AEs and were not associated with being randomized to the FTC/TDF arm (152 vs. 144 respectively OR 0.66 95 % CI 0.35-1.25). Center for Epidemiologic Studies Depression scale (CES-D) and a four questions suicidal ideation scale scores did not differ by arm. Participants reporting forced sex at anal sexual debut had higher CES-D scores (coeff: 3.23; 95 % CI 1.24-5.23) and were more likely to have suicidal ideation (OR 2.2; 95 % CI 1.09-4.26). CES-D scores were higher among people reporting non-condom receptive anal intercourse (ncRAI) (OR 1.46; 95 % CI 1.09-1.94). We recommend continuing PrEP during periods of depression in conjunction with provision of mental health services.
