Ian McGowan

The availability of oral and long-acting injectable pre-exposure prophylaxis (PrEP) has transformed human immunodeficiency virus (HIV) prevention; however, some individuals may prefer behaviorally congruent, nonsystemic, on-demand rectal PrEP options that avoid chronic systemic exposure. The Q-Griffithsin (Q-GRFT) rectal douche is a novel, user-controlled PrEP candidate, containing a natural (red alga–derived), potent broad-spectrum antiviral lectin for pericoital rectal use. This first-in-human Phase 1 trial evaluated the safety, pharmacokinetics (PKs), pharmacodynamics (PDs), and acceptability of a single Q-GRFT rectal douche dose. Sixteen HIV-negative participants (eight female and eight male) with a history of recent receptive anal intercourse were enrolled in this randomized, double-blind study. Following single-dose administration, blood, rectal fluid, and rectal tissue samples were collected for safety, PK, and PD analyses using an ex vivo rectal explant HIV challenge model. Acceptability was measured using structured questionnaires. The Q-GRFT douche was safe with no Grade 3 or 4 adverse events or significant histological abnormalities. Acceptability was high at 93% of the study product. At 1 h postdose, geometric mean (range) Q-GRFT concentrations were 522.18 ng/mL (52.8–12,482.2) in rectal swab eluate and 6.85 µg (0.80–51.07) in rectal tissue, declining over 24 h. Q-GRFT was not detectable in plasma. Higher individual tissue drug levels correlated with reduced HIV infectivity in both rectal eluate ( p = 0.036) and tissue explant ( p = 0.003). In this first-in-human study, a single administration of Q-GRFT as a rectal douche demonstrated favorable safety, acceptability, and high local drug exposure without systemic absorption, supporting further evaluation as an on-demand, nonsystemic rectal PrEP strategy.

Oral tenofovir is a key antiretroviral used for treatment and pre-exposure prophylaxis (PrEP) of human immunodeficiency virus (HIV). A gel form has been tested for vaginal and rectal PrEP. We have shown that 7 days of tenofovir 1% gel had broad-ranging effects on gene expression in the rectum, especially suppression of anti-inflammatory mediators and induction of cell proliferation. Similarly, oral PrEP induced type I/III interferon-stimulated genes in the gut. It is unknown how long these effects last and whether they occur in other relevant body compartments. We measured the transcriptomes and proteomes of tissue samples obtained before and after daily topical tenofovir 1% gel application for 14 days (Microbicide Trials Network [MTN]-014 trial, rectal and vaginal) or 56 days (MTN-017 trial, rectal). While many changes seen after 7 days diminish after 14 and 56 days, some remain, notably increases in cell proliferation- and type I/III interferon-related genes. Vaginal gel uniquely induces changes related to epithelial-mesenchymal transition and angiogenesis. Induction of type I/III interferon-related genes is the most consistent and persistent mucosal response to tenofovir, occurring after both oral and topical use and at all tested time points. Hypothetically, interferon induction could improve antiviral efficacy, but also contribute to an increased chronic disease burden in people with HIV. IMPORTANCE: Analyzing gene expression data from three separate clinical trials, we find that the antiretroviral drug tenofovir, which belongs to the class of nucleotide analogue reverse transcriptase inhibitors, induces the type I/III interferon system of innate immunity in the mucosa. This effect occurs in the absence of HIV infection and manifests itself over various treatment durations and after both oral and topical drug delivery. Tenofovir and other related medications are important components of long-term antiretroviral treatment taken by people living with HIV. Therefore, this unexpected immunological effect might need to be considered as a potential contributor to comorbidities in people living with HIV, as well as an immunopharmacological co-factor when testing novel HIV cure interventions. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT01768962 , NCT01687218 , and NCT01232803 .

Building on results from the AELIX-002 trial with HIVACAT T-cell immunogen (HTI)-based vaccines, the AELIX-003 (NCT04364035) trial tested the safety of the combination of ChAdOx1.HTI (C) and MVA.HTI (M), with the TLR7 agonist vesatolimod (VES), in a double-blind, placebo-controlled, randomized clinical trial in 50 virally suppressed early-treated men with HIV-1 infection. Secondary objectives included immunogenicity and effects on viral rebound kinetics during a 24-week antiretroviral treatment interruption (ATI). The most common treatment-related adverse events were mild-to-moderate injection-site pain, influenza-like illness, headache, and fatigue. Strong, broad, and HTI-focused T-cell responses were induced by vaccination. All participants experienced viral rebound in ATI; 33.3% and 23.5% (P = 0.4494) of CCMM + VES and placebo recipients, respectively, remained off antiretroviral therapy for 24 weeks. Post hoc analysis confirmed a correlation between levels of HTI-specific T cells and prolonged time off antiretroviral therapy. The combination of HTI vaccines and VES was safe and elicited robust T-cell responses.

HIVACAT T-cell immunogen (HTI) is a novel human immunodeficiency virus (HIV) vaccine immunogen designed to elicit cellular immune responses to HIV targets associated with viral control in humans. The AELIX-002 trial was a randomized, placebo-controlled trial to evaluate as a primary objective the safety of a combination of DNA.HTI (D), MVA.HTI (M) and ChAdOx1.HTI (C) vaccines in 45 early-antiretroviral (ART)-treated individuals (44 men, 1 woman; NCT03204617). Secondary objectives included T-cell immunogenicity, the effect on viral rebound and the safety of an antiretroviral treatment interruption (ATI). Adverse events were mostly mild and transient. No related serious adverse events were observed. We show here that HTI vaccines were able to induce strong, polyfunctional and broad CD4 and CD8 T-cell responses. All participants experienced detectable viral rebound during ATI, and resumed ART when plasma HIV-1 viral load reached either >100,000 copies ml⁻¹, >10,000 copies ml⁻¹ for eight consecutive weeks, or after 24 weeks of ATI. In post-hoc analyses, HTI vaccines were associated with a prolonged time off ART in vaccinees without beneficial HLA (human leukocyte antigen) class I alleles. Plasma viral load at the end of ATI and time off ART positively correlated with vaccine-induced HTI-specific T-cell responses at ART cessation. Despite limited efficacy of the vaccines in preventing viral rebound, their ability to elicit robust T-cell responses towards HTI may be beneficial in combination cure strategies, which are currently being tested in clinical trials.

Receptive anal intercourse (RAI) may substantially increase HIV acquisition risk per sex act compared to receptive vaginal intercourse (RVI). To understand how levels of RAI change over time and evaluate the impact of exposure definitions for RAI on HIV incidence, we analysed three prospective HIV cohorts of women: RV217, MTN-003 (VOICE), and HVTN 907. At baseline 16.0% (RV 217), 17.5% (VOICE) of women reported RAI in the past 3 months and 27.3% (HVTN 907) in the past 6 months, with RAI declining during follow-up by around 3-fold. Hazard ratios, adjusted for potential confounders (aHR), indicate that reporting RAI at baseline increased HIV incidence in the three cohorts: 1.1 (95% Confidence interval: 0.8-1.5) for VOICE, aHR of 3.3 (1.6-6.8) for RV 217, and 1.9 (0.6-6) for HVTN 907. Using time-varying exposure definition slightly increased the estimated association for VOICE (aHR=1.2; 0.9-1.6), however reporting >30% RAI sex acts during VOICE follow-up was not associated with higher HIV incidence (aHR=0.7 (0.4-1.1)). Women who always reported RAI during follow-up where also at increased HIV acquisition risk. Overall, we found that precisely estimating RAI and HIV association after multiple RVI/RAI exposures is sensitive to RAI exposure definitions and may be influenced by measurement errors.

The Microbicide Trials Network-017 study was undertaken to characterize the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic profile of the reduced-glycerin (RG) 1% tenofovir (RG-TFV) gel compared to oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF). The study was a Phase 2, three-period, randomized sequence, open-label, expanded safety and acceptability crossover study. In each 8-week study period, HIV-1-uninfected participants were randomized to RG-TFV rectal gel daily or RG-TFV rectal gel before and after receptive anal intercourse (RAI) (or at least twice weekly in the event of no RAI), or daily oral FTC/TDF. A mucosal substudy was conducted at sites in the United States and Thailand. Samples were collected to evaluate PK and ex vivo biopsy challenge with HIV-1. A total of 195 men who have sex with men and transgender women were enrolled in the parent study and 37 in the mucosal substudy. As previously reported, both products were found to be safe and acceptable. Systemic TFV concentrations were significantly higher following oral exposure and daily rectal administration compared to RAI-associated product use ( p < .001). All three routes of pre-exposure prophylaxis (PrEP) administration resulted in the inhibition of explant infection ( p < .05), and there was a significant inverse correlation between explant HIV-1 p24 and tissue concentrations of TFV and FTC ( p < .0001). Despite significant differences in systemic and mucosal drug concentrations, all three PrEP regimens were able to protect rectal explants from ex vivo HIV infection. These data suggest that there is a rationale for co-development of oral and topical antiretroviral PrEP for HIV prevention. Clinical Trial Registration number: NCT01687218.

The Combination HIV Antiretroviral Rectal Microbicide-3 (CHARM-03) study was a randomized, open-label, crossover Phase 1 safety and pharmacokinetic (PK) study of oral maraviroc (MVC) and MVC 1% gel. At a single site, healthy HIV-uninfected men and women were enrolled and randomized to an open label crossover sequence of eight consecutive daily exposures to MVC 300 mg dosed orally, MCV 1% gel dosed rectally, and MVC 1% gel dosed vaginally. Male participants received oral and rectal dosing and female participants received oral, rectal, and vaginal dosing. Assessments were undertaken at baseline and following each 8-day period and included collection of plasma, rectal/cervical tissue (CT), and rectal/endocervical/vaginal fluids. Eleven men and nine women were enrolled. Two participants withdrew from the study before receiving study product. There were 25 adverse events, of which 24 were Grade 1 (G1) and one was G2 (unrelated). After eight doses, MVC was quantifiable in all samples following oral, rectal, or vaginal product administration. The highest drug concentrations in plasma, rectal tissue (RT), and CT were associated with oral, rectal, and vaginal drug delivery, respectively. There were significant reductions in tissue drug concentrations when rectal and cervical biopsies were incubated in media before tissue processing for PK ( p < .0001). Only oral MVC was associated with limited protection in the rectal explant HIV challenge model ( p < .05). There were no immunological changes in RT, and all products were acceptable to participants. In conclusion, all products were found to be safe and acceptable and did not induce local inflammation. The lack of ex vivo efficacy demonstrated in study samples may be due to rapid disassociation of MVC from the explant tissue. ClinicalTrials.gov Identifier: NCT02346084.

OB-002 is an extremely potent CCR5 antagonist that has previously been shown to completely block transmission in a nonhuman primate model of HIV infection. The purpose of this study was to characterize the safety, acceptability, and pharmacokinetic profile of a gel formulation of OB-002 (OB-002H). The trial had two phases, an open label single dose exposure (vaginal and rectal) and a randomized placebo controlled multiple dose phase during which study participants received five vaginal daily doses of OB-002H gel or matched placebo in a 2:1 ratio. Serum OB-002 levels were quantified at multiple time points up to 24 h after the first dose. A total of thirty female and male participants were enrolled in the study (12 in the single dose phase and 18 in the multiple dose phase). All adverse events were Grade 1 or 2, and the majority was unrelated to study product. Only two product-related transient Grade 2 events (both vulval dryness) occurred in the study, both in the OB-002H gel randomized multiple dose arm. All colposcopic and anoscopic assessments following product exposure were normal. There was no evidence of systemic absorption of OB-002. Overall, the product had a positive acceptability profile, and most study participants would consider using the product for protection against HIV or pregnancy. Future studies are needed to assess the extended safety and acceptability of OB-002H gel in sexually active participants. Clinical Trial Registration Number: NCT04791007