 |
|
|
| |
HIV Prevention and Resistance on PrEP
|
| |
| |
By Christina K. Psomas MD PhD
European Hospital Marseille
Department of Infectious Diseases and Internal Medicine
In terms of HIV prevention, presentations mainly concerned long-acting antiretroviral cabotegravir (CAB-LA) and islatravir. In December 2021 US FDA approved CAB-LA to reduce the risk of sexual HIV transmission. Dr Deborah Donnell (Fred Hutchinson Cancer Research Center) presented the first counterfactual estimation of CAB-LA efficacy against placebo using external trials (A86). Placebo arm data were used from women enrolled in three contemporaneous randomized HIV prevention trials conducted in Southern Africa to construct estimates of counterfactual (CF) placebo rates of HIV infection and efficacy for CAB-LA against a CF placebo: the ECHO trial, the placebo arms of the AMP trial (HVTN 703/HPTN 081) and an HIV vaccine trial in South Africa (HVTN 702). The placebo counterfactual studies included 637 women from AMP, 7829 from ECHO and 1884 from HVTN702; HPTN 084 had 1614 women in the CAB-LA arm. Counterfactual placebo HIV incidence rates in women in the multi-country settings were 2.6/100PY (AMP), 4.5/100PY (ECHO) and 4.2/100PY (HVTN702); compared to 0.19/100PY, 0.23/100PY, and 0.28/100PY in the CAB-LA arm, respectively. Estimates of CAB-LA versus placebo efficacy consistently showed CF placebo-based efficacy of 93-95%, supporting the high efficacy rates of CAB-LA for HIV prevention in women.
Dr Raphael J Landovitz (University of California Los Angeles) presented updated efficacy and safety results of CAB-LA vs TDF/FTC for PrEP in HPTN 083 (A96). Updated HIV incidence rates in both study arms were reported during the blinded phase of the trial (original primary analysis period) and for one year of follow-up, presupposing detection of infection by study sites before 8/15/21. 46 additional incident HIV infections in the pre-planned analysis period (13 CAB, 33 TDF/FTC) were identified with this additional follow-up period; 4 occurred during the blinded phase (2 CAB, 2 TDF/FTC), 42 after unblinding (11 CAB, 31 TDF/FTC). Reduction in risk for CAB-LA vs. FTC/TDF remained similar in blinded and unblinded phases (HR=0.33 95%CI (0.18-0.62) and HR=0.34 95%CI (0.17-0.67)), while HIV incidence was higher in both arms in the unblinded phase. The 2 newly identified blinded CAB arm infections were both in the setting of on-time injections with a potential role of increased relative contributions to overall person-time from high incidence regions; the 11 newly identified unblinded CAB arm infections included 1 with on-time injections, 3 with delayed injections, and 7 that occurred ≥6 months after the last CAB exposure (2 of these 7 never received a CAB injection) probably due to reduced CAB injection coverage.
Even if long-acting injectable cabotegravir (CAB-LA) was highly effective in HPTN 083 and 084 trials, detection of rare breakthrough HIV infections was often delayed when using rapid tests, Ag/Ab assays or even HIV RNA levels (Marzinke JID 2021; Eshleman JID 2022 In Press). Dr Susan Eshleman (The Johns Hopkins University School of Medicine) showed results of single-genome sequencing (SGS) testing in samples from 7 participants (1 baseline infection; 6 incident infections) of the HPTN 083 and 084 studies (A95). 5 CAB-exposed participants with HIV infection displayed integrase strand transfer inhibitor (INSTI) resistance-associated mutations (RAMs) in HPTN 083. The SGS assay detected INSTI RAMs in 6/7 participants (4/5 with prior genotyping results, 2/2 with no prior genotyping results). Use of an RNA assay with an LOD of 30 copies/mL detected infection before a major INSTI RAM was detected (4 cases) or before additional major INSTI RAMs accumulated (2 cases). In the last case SGS was not successful before the first site-positive visit.
This presentation suggests that earlier detection of HIV infection using an HIV RNA assay in the setting of CAB-LA PrEP would allow for earlier ART initiation which may reduce the risk of INSTI resistance, which is consistent with the newly released CDC guidelines. Given the low levels of viremia often seen in this setting, VL testing for HIV screening should be performed using the most sensitive assay available.
Although the islatravir PrEP program has been placed on clinical hold by the US FDA based on changes in lymphocytes observed in clinical trials of this molecule, it is interesting to report recent results on safety and tissue PK outcomes of once-monthly oral islatravir in adults at low risk for HIV-1. Of note, no new participants are being screened or randomized at this time, dosing of investigational product has been stopped and all participants are already enrolled in the phase 3 efficacy trials are being offered open-label daily PrEP.
Dr Pippa J Macdonald (Desmond Tutu HIV Centre) described metabolic (weight, total hip and lumbar spine BMD, peripheral and truncal fat) and renal outcomes (serum creatinine, estimated GFR, retinol-binding-protein to creatinine ratio) through W24 after administration of islatravir (60 mg or 120 mg) once monthly (QM) for HIV PrEP (A85). This was a double-blind, placebo-controlled, dose-ranging, parallel-group, multi-center trial (Israel, South Africa, and USA) which assessed the safety, tolerability, and pharmacokinetics of monthly oral ISL in adults aged between 18 and 65 years, all at low risk for HIV-1 acquisition (NCT04003103). They were randomized (2:2:1) to receive a total of 6 QM doses of ISL 60 mg, ISL 120 mg, or matching placebo. 222 out of 242 randomized participants (median age, 31 years; male, 33%; White, 53%; Black or African American, 42%) completed dosing, without any discontinuation due to metabolic or renal AEs. Median percent changes from baseline in weight, peripheral fat, and trunk fat were small and comparable for ISL 60 mg QM and placebo groups. However, there were slight increases in weight, peripheral fat, and trunk fat in the higher ISL 120 mg QM group. Median percent changes from baseline through W24 in total hip and lumbar spine BMD were small and comparable across all groups. No changes in serum creatinine or eGFR were observed across treatment groups when compared to baseline; small and similar decreases in urinary retinol-binding protein to creatinine ratios were seen across all treatment groups during the active treatment phase, which is a reassuring renal picture depicting no proximal tubular dysfunction.
In conclusion, no clinically meaningful differences were observed at week 24 from baseline in metabolic and renal parameters with islatravir 60 mg or 120 mg after 6 monthly doses.
Dr Craig Walter Hendrix (Johns Hopkins Hospital) described results of an exploratory tissue PK substudy of a phase 2a, double-blind, randomized, placebo-controlled trial in adults at low risk for HIV-1 infection (NCT04003103) (A83). Researchers collected plasma, peripheral blood mononuclear cells (PBMC), and cervical, vaginal, and rectal tissue samples at study Weeks 1 and 4 (1 and 4 weeks, respectively, after the first dose) and at study Week 24 (4 weeks after the last [6th] dose of study intervention) to assess drug penetration in genital and rectal tissue mucosa. They enrolled 54 participants (21 in US, 33 in South Africa; 41 females). Mean age was 32 years and mean baseline weight was 81 kg. Following ISL administration, ≥95% of samples had quantifiable parent ISL and ≥88% had ISL-triphosphate (ISL-TP) across all tissues and time points. ISL-TP trough concentrations were comparable across cervical, vaginal, and rectal tissues, with a parallel decline from W1 to 4 after the first dose and a consistent similar concentration at trough at W4 and W24 (respectively 4 weeks after the first and the sixth dose). Plasma ISL and ISL-TP in cervical, vaginal, and rectal tissues were highly correlated (adjusted R2 ≥0.7, p<0.001); ISL-TP across tissue types and across rectal matrices were also strongly correlated (adjusted R2 ≥0.6, p<0.001). Week 4 ISL-TP in PBMC and in rectal cells remained above the desired PK threshold for prophylaxis (0.05 pmol/106 PBMC) by >20 and >4 fold, respectively. These findings suggest that the PBMC-based PK threshold was achieved in all target tissues, given correlations within rectal matrices and similarities among all tissue homogenates. Moreover ISLA-TP levels were moderately to strongly correlated between systemic and within tissue compartments, suggesting that plasma islatravir PK measurement may be useful as a surrogate for some tissue exposures.
Given the need for optimal adherence to PrEP for effectiveness, assessment of vaginal rings for HIV prevention is crucial, especially in developing countries. Dr Albert Liu (San Francisco Department of Public Health) presented results of a phase I PK, safety, and acceptability study of a 90-day tenofovir vaginal ring (A82). MTN-038 enrolled 49 HIV-negative participants into a multi-site, randomized (2:1) trial comparing a 90-day ring containing 1.4 grams (g) TFV used continuously to a placebo ring. TFV concentrations were quantified in plasma, cervicovaginal fluid (CVF), rectal fluid, and cervical tissue, and TFV-diphosphate (TFV-DP) in cervical tissue. The 90-day TFV ring was well-tolerated, acceptable, and exceeded target cervical tissue concentrations through day 56, but declined thereafter. Additional studies are needed to characterize the higher release from TFV rings in some participants and the optimal duration of use.
Choice and adherence to dapivirine ring or oral PrEP by young African women within the MTN-034/REACH crossover trial was presented by Dr Kenneth Ngure (Jomo Kenyatta University of Agriculture and Technology) (A88). REACH enrolled 247 HIV-negative, non-pregnant AGYW ages 16-21 from South Africa, Zimbabwe, and Uganda from February 2019 to April 2021. Participants were randomized to the monthly ring or daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for the first 6-month period, then switched to the other product for the second 6-month period. They were given a choice of ring, oral PrEP, or neither in the third 6-month period. Adherence was assessed by residual drug levels in returned rings and Dried blood spots for oral PrEP. Of 227 (92%) who continued in the choice period, 152 (67%) chose the ring, 71 (31%) oral PrEP, and 4 (2%) neither with no influence of the product choice by the sequence in the crossover period. Residual DPV levels in used rings and TFV-DP levels in DBS showed participants had some to high use of the ring and moderate to high adherence to oral PrEP with <5% of visits with no adherence.
High adherence to oral PrEP in the crossover period was strongly associated with choice of oral PrEP (p<0.001); an association was not observed for rings (p=0.85). In the choice period among African AGYW who had 6 months use of both the ring and oral PrEP, 2/3 opted to use the ring; those with high adherence to oral PrEP in the crossover periods were likely to choose oral PrEP.
|
| |
|
|
|
|
|
