Long-acting injectable PrEP in women: laboratory analysis of HIV infections in HPTN 084


BACKGROUND: HPTN 084 was a phase 3 randomized, double-blind, double-dummy superiority trial that showed that tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and long-acting injectable cabotegravir (CAB) were highly effective for HIV prevention in women in sub-Saharan Africa. Participants were randomized 1:1 to active CAB + TDF/FTC placebo or active TDF/FTC + CAB placebo. CAB was superior, with an 89% lower risk of HIV infection compared to TDF/FTC. We characterized the 40 observed infections in HPTN 084 (4 CAB, 36 TDF/FTC) using virology and pharmacology assays.
METHODS: Participants received 5 weeks of daily oral product followed by intramuscular injections every 8 weeks (after an initial 4-week interval) and daily oral pills. The blinded trial was stopped at a planned interim Data Safety Monitoring Board review in November 2020. Further testing was conducted for all confirmed HIV infections. HIV status and the timing of infection were assessed using an antigen/antibody test, a discriminatory HIV test, a qualitative HIV RNA assay, and viral load assays. Drug resistance was assessed for samples with >500 copies/mL HIV RNA (viremic visits). Concentrations of plasma CAB, plasma tenofovir (TFV), and intraerythrocytic TFV-diphosphate (TFV-DP) were determined by liquid chromatography-tandem mass spectrometry.
RESULTS: At the time of unblinding, the 4 infections in the CAB arm occurred in 2 women who never received injections and 2 who received injections: 1 one with episodes of delayed dosing and suboptimal drug concentrations, and one with on-time dosing. Major integrase resistance mutations were not detected. In the TDF/FTC arm, 35/36 infections occurred in women with poor or inadequate adherence (<4 pills/week based on TFV and TFV-DP concentrations) near the first HIV positive visit. One of the 36 women had the M184V mutation. Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) was also detected in 9/40 HIV cases overall.
CONCLUSIONS: Three of four infections in the CAB arm occurred in women who did not receive injections or received delayed injections. No major integrase resistance mutations were observed. Non-adherence to daily oral TDF/FTC likely contributed to the higher number of infections in this group. The prevalence of transmitted NNRTI drug resistance is a concern.