Characterization of Human Immunodeficiency Virus (HIV) Infections in Women Who Received Injectable Cabotegravir or Tenofovir Disoproxil Fumarate/Emtricitabine for HIV Prevention: HPTN 084

Abstract

Background: HIV Prevention Trials Network 084 demonstrated that long-acting injectable cabotegravir (CAB) was superior to daily oral tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) for preventing human immunodeficiency virus (HIV) infection in sub-Saharan African women. This report describes HIV infections that occurred in the trial before unblinding.

Methods: Testing was performed using HIV diagnostic assays, viral load testing, a single-copy RNA assay, and HIV genotyping. Plasma CAB, plasma TFV, and intraerythrocytic TFV-diphosphate concentrations were determined by liquid chromatography-tandem mass spectrometry.

Results: Forty HIV infections were identified (CAB arm, 1 baseline infection, 3 incident infections; TDF/FTC arm, 36 incident infections). The incident infections in the CAB arm included 2 with no recent drug exposure and no CAB injections and 1 with delayed injections; in 35 of 36 cases in the TDF/FTC arm, drug concentrations indicated low or no adherence. None of the cases had CAB resistance. Nine women in the TDF/FTC arm had nonnucleoside reverse-transcriptase inhibitor resistance; 1 had the nucleoside reverse-transcriptase inhibitor resistance mutation, M184V.

Conclusions: Almost all incident HIV infections occurred in the setting of unquantifiable or low drug concentrations. CAB resistance was not detected. Transmitted nonnucleoside reverse-transcriptase inhibitor resistance was common; 1 woman may have acquired nucleoside reverse-transcriptase inhibitor resistance from study drug exposure.

Keywords: Africa; HIV; HPTN 084; TDF/FTC; cabotegravir; injectable; long-acting; preexposure prophylaxis; prevention; women.

Figure 1.

HIV Prevention Trials Network (HPTN) 084 study schema. The study included 3 steps: an oral lead-in phase (step 1), an injection phase (step 2), and an open-label tail phase (step 3). In the tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) arm, participants received daily TDF/FTC in steps 1 and 2 (coformulated tablets; 300-mg TDF plus 200-mg FTC), along with placebo tablets (in step 1) and placebo injections (in step 2). In the cabotegravir (CAB) arm, participants received oral daily CAB in step 1 (30-mg tablets) and long-acting CAB (CAB-LA) injections in step 2 (600 mg; 3 mL), with placebo tablets in steps 1 and 2. All participants received daily open-label TDF/FTC in step 3. The first and second injections were given 4 weeks apart at weeks 5 and 9; participants then received injections every 8 weeks (arrows). Plasma samples were collected at every visit. Dried blood spot (DBS) samples were prepared and stored at weeks 4 and week 33, followed by every third injection visit (asterisks); DBS samples were also stored at weeks 24 and 48 in step 3. Study drugs were discontinued if participants had a reactive or positive human immunodeficiency virus (HIV) test result, declined drug administration, or had significant adverse events. Study drugs were also stopped for other reasons at the discretion of the site principal investigator.

Figure 2.

Case summaries for the cabotegravir (CAB) arm), including laboratory results and key events for participants (cases A1, B1, B2, and DX). The full set of laboratory data for these cases, including results from testing performed at study sites and results from human immunodeficiency virus (HIV) resistance testing, is provided in Supplementary File 2. Annotations above each graph show results obtained from testing performed at the HIV Prevention Trials Network (HPTN) Laboratory Center, displayed as reactive/positive (plus sign [+]), negative/nonreactive (minus sign [−]), or indeterminate (IND). Viral load values represent HIV RNA copies per milliliter; a value <40 copies/mL indicates that HIV RNA was detected but was below the limit of quantification (BLQ). Asterisks signify negative single-copy RNA test results (no RNA detected). The graphs show plasma CAB concentrations and key events by weeks since study enrollment. The arrow in A shows the weeks between the first HIV-positive visit and the first site-positive visit (visit at which the site had a reactive or positive HIV test result); the arrow in D, the weeks between the eighth injection and the first HIV-positive visit. Horizontal lines indicate the following CAB concentration cutoffs: 1.33 mcg/mL, 8× the protein-adjusted in vitro 90% inhibitory concentration (PA-IC₉₀); 0.664 mcg/mL, 4× PA-IC₉₀, and 0.166 mcg/mL, 1× PA-IC₉₀. BLQ indicates that the CAB concentration was <0.025 mcg/mL, shaded areas indicate periods of antiretroviral treatment (ART). Abbreviations: 3TC: lamivudine; Ab, antibody; Ag/Ab, antigen-antibody test; DTG, dolutegravir; FTC, emtricitabine. ND, not detected; TDF, tenofovir disoproxil fumarate; TFV, tenofovir.

Figure 3.

Selected case summaries for the tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) arm, including laboratory results and key events for the 4 participants for whom antibody detection at the study sites was delayed >1 study visit (cases E31, E32, E34, and E35). The full set of laboratory data for these cases, including results from testing performed at study sites and results from human immunodeficiency virus (HIV) resistance testing, is provided in Supplementary File 4. Annotations above each graph show results obtained from testing performed at the HIV Prevention Trials Network (HPTN) Laboratory Center, displayed as reactive/positive (plus sign [+]), negative/nonreactive (minus sign [−]), or indeterminate (IND). Viral load values represent the HIV RNA copies per milliliter; a value <40 copies/mL indicates that HIV RNA was detected but was below the limit of quantification (BLQ). Asterisks signify negative single-copy RNA test results (no RNA detected). The graphs show tenofovir (TFV) and TFV-diphosphate (TFV-DP) concentrations and key events by weeks since study enrollment. Arrows show the weeks between the first HIV-positive visit (red vertical line) and the first site-positive visit (visit at which the site had a reactive or positive HIV test result (blue vertical line); dashed black lines, TFV concentration cutoffs used for adherence assessments (10 and 40 ng/mL, which correspond to 4 and 7 doses per week, respectively); dashed gray lines, TFV-DP concentrations cutoffs used for adherence assessments (350, 700, and 1250 fmol per punch, correspond to 2, 4, and 7 doses per week, respectively). The dashed line labeled BLQ indicates drug concentrations <0.31 ng/mL for TFV and <31.3 fmol per punch for TFV-DP, and shaded areas indicate periods of antiretroviral treatment (ART). Abbreviations: 3TC, lamivudine; Ab, antibody; Ag/Ab: antigen-antibody; DTG, dolutegravir; ND, not detected.