HPTN 083 showed a 66% reduction in HIV incidence in cisgender men and transgender women who have sex with men (MSM/TGW) randomized to cabotegravir (CAB) 600 mg injections every 8 weeks (after an oral lead-in) vs. daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP). We originally reported 52 incident infections among 4566 participants (13 CAB, 39 TDF/FTC; annual incidence: 0.41% vs. 1.22%) with 5 additional baseline infections (2 CAB, 3 TDF/FTC). In post-hoc analysis, 1 incident infection in the CAB arm was later reclassified as a baseline infection; 1 additional baseline infection was also identified. We used virology and pharmacology assays to characterize these 58 cases (Table).
Concentrations of CAB and tenofovir (TFV) in plasma and TFV-diphosphate in dried blood spots were quantified by liquid chromatography-tandem mass spectrometry. HIV status and timing of HIV infection were assessed with an antigen/antibody (Ag/Ab) test, a discriminatory test, and RNA assays. Drug resistance testing was performed for samples with HIV RNA >500 copies/mL.
Among 12 incident infections in the CAB arm: 5 had no recent CAB dosing; 3 occurred in the oral lead-in phase (1 had no CAB detected); 4 occurred despite on-time CAB injections and targeted CAB concentrations. Five of the 16 infections in the CAB arm had integrase resistance associated mutations (RAMs; Q148R or Q148K with accessory mutations, or R263K); 1 of these cases also had a non-nucleoside reverse transcriptase inhibitor (NNRTI) RAM. One case had NNRTI RAMs only and 1 had NNRTI RAMs with nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) RAMs. In the TDF/FTC arm, 37/39 incident infections occurred in participants with drug concentrations indicating sub-optimal or non-adherence. One infection was likely due to transmission of TDF/FTC-resistant HIV; 1 occurred despite targeted drug concentrations. Thirteen the 42 infections in the TDF/FTC arm had RAMs: 3 had NRTI RAMs only; 3 had NRTI and NNRTI RAMs; and 7 had NNRTI RAMs only. Retrospective HIV RNA testing identified HIV infection earlier than Ag/Ab testing performed at study sites.
TDF/FTC and CAB are highly effective for HIV PrEP in MSM/TGW. Oral pill non-adherence likely contributed to higher HIV incidence among those randomized to TDF/FTC. Integrase inhibitor resistance was observed in some cases in the CAB arm. Long-acting CAB is an important addition to HIV prevention options.