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Division of Infectious Diseases
University of Toronto
Division of Infectious Diseases
St. Michael's Hospital
Darrell H. S. Tan, MD, FRCPC, PhD, has disclosed that he has received funds for research support from AbbVie, Gilead Sciences, and GlaxoSmithKline.
To date, the uptake of daily oral tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) as pre-exposure prophylaxis (PrEP) among women in Canada has been low, with an estimated prevalence of only 20.0/million vs 821.4/million among men in 2018. Unlike for sexual minority men, in whom on-demand TDF/FTC and daily oral tenofovir alafenamide/FTC also are viable options, cisgender women are currently restricted to daily oral TDF/FTC. An expanded menu of PrEP options for cisgender women would thus be welcome.
That’s why I was excited to see an excellent oral abstract session at the 2022 Conference on Retroviruses and Opportunistic Infection (CROI) that examined emerging HIV PrEP modalities in women.
MTN-038: Phase I Pharmacokinetics, Safety, and Acceptability Study of a 90-Day Tenofovir (TFV) Vaginal Ring
MTN-038 was a phase I trial in which 49 individuals assigned female sex at birth from 3 sites in the United States were randomized 2:1 to receive either a vaginal ring containing 1.4 grams of TFV or placebo.
Overall results reported by Liu and colleagues were encouraging, with 84% being fully adherent by self-report (no removal of the ring during 91 days of follow-up) and no differences between groups in genitourinary adverse events of at least grade 2 in severity. No adverse events of at least grade 3 were reported. Participants reported liking the ring (median rating of 8, interquartile range [IQR] 7-9, on a Likert scale from 0-10) and being likely to use it if ultimately proven effective (median 9, IQR 7-10).
After ring insertion, geometric mean drug concentrations rose rapidly in the plasma and cervicovaginal and rectal fluids. In addition, cervical tissue TFV diphosphate concentrations exceeded 1000 fmol/mg (tissue target level based on animal studies) through Day 56 but declined by Day 91 in more than one third of participants. Among 32 returned rings, 13 had no/minimal drug remaining, consistent with almost all of the TFV being released from the rings during the study period. Of interest, participants with no/minimal residual TFV in the rings had lower geometric mean fluid and tissue concentrations of TFV. The high degree of variability seen in the residual TFV levels in returned rings is a key finding that will require greater study. Of importance, differences in vaginal microbiota could be an important cofactor, as was the case in TFV microbicide trials.
Counterfactual Estimation of Long-Acting (LA) Cabotegravir (CAB) Efficacy Against Placebo Using External Trials
Another interesting study evaluated LA CAB as PrEP among women in Sub-Saharan Africa. The HPTN-084 trial previously demonstrated an 89% lower risk of HIV acquisition with LA CAB compared with daily oral TDF/FTC as PrEP, but efficacy compared with placebo is not known.
Donnell and colleagues used data from 3 other prevention trials conducted contemporaneously to HPTN-084 (2016-2020) in many of the same 6 countries—including South Africa, Eswatini, Botswana, Malawi, and Kenya—to construct a “counterfactual placebo” to compare the LA CAB data from HPTN-084 with HIV incidence rates in similar populations with oral PrEP uptake of <5%. To generate the estimates, the authors weighted HIV incidence data from (1) the AMP trial of the broadly neutralizing antibody VRC01, (2) the ECHO contraception trial, and (3) the HVTN-702 vaccine trial using country- or age-standardized numbers of person-years of follow-up. They assumed that similarities in trial eligibility criteria implied that all trials drew participants from comparable populations; there was no explicit adjustment for covariates. Results showed LA CAB intention-to-treat efficacy estimates vs counterfactual placebo of 93% (95% CI: 76%-98%), 95% (95% CI: 79%-99%), and 93% (95% CI: 73%-98%) for the 3 trial comparisons, respectively.
Implications in Canada
Canada was the first country in the world to approve LA CAB with long-acting rilpivirine as antiretroviral therapy, and it is hoped that approval for LA CAB as PrEP will follow in the near future. For daily oral TDF/FTC as PrEP, poor adherence in prior trials has likely obscured accurate interpretation of its efficacy at preventing new HIV infection. By contrast, the impressive efficacy estimates from the analysis of HPTN-084 will be helpful in educating patients and healthcare professionals alike about this forthcoming prevention option of LA CAB.
Structural barriers to PrEP uptake also persist, however, including insufficient promotion of PrEP to cisgender women, perceptions that PrEP is primarily for gay men, lack of universal coverage for medication costs in many provinces/territories, and inadequate clinical guidance on how to identify female PrEP candidates.
Furthermore, Canada’s shameful history of forced sterilization of Indigenous people suggests that efforts to promote vaginal ring and long-acting injectable PrEP formulations in these communities will require particular sensitivity and respect for prior trauma. Such barriers may remain relevant despite the availability of newer PrEP modalities unless systematic efforts are made to address them. Given the promising pipeline of PrEP modalities, it is imperative that communities be engaged in discussions about future PrEP options in culturally appropriate ways as early as possible.
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