Characterization of Human Immunodeficiency Virus (HIV) Infection in Cisgender Men and Transgender Women Who Have Sex With Men Receiving Injectable Cabotegravir for HIV Prevention: HPTN 083

Abstract

Background: The HIV Prevention Trials Network (HPTN) 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was more effective than tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) in preventing human immunodeficiency virus (HIV) in cisgender men and transgender women who have sex with men. We characterized HIV infections that occurred in the blinded phase of HPTN 083.

Methods: Retrospective testing included HIV testing, viral load testing, quantification of study drugs, and HIV drug resistance testing.

Results: Fifty-eight infections were evaluated, including 51 incident infections (12 in CAB arm and 39 in TDF/FTC arm). In many cases (5 in CAB arm and 37 in TDF/FTC arm), infection was associated with low or unquantifiable study drug concentrations. In 4 cases, infection occurred with on-time CAB-LA injections and expected plasma CAB concentrations. CAB exposure was associated with prolonged viral suppression and delayed antibody expression. In some cases, delayed HIV diagnosis resulted in CAB provision to participants with undetected infection, delayed antiretroviral therapy, and emergence of drug resistance; most of these infections would have been detected earlier with viral load testing.

Conclusions: Early detection of HIV infection and prompt antiretroviral therapy initiation could improve clinical outcomes in persons who become infected despite CAB-LA prophylaxis. Further studies are needed to elucidate the correlates of HIV protection in persons receiving CAB-LA.

Keywords: HIV; HPTN 083; TDF/FTC; cabotegravir; injectable; long-acting; men who have sex with men; preexposure prophylaxis; prevention.

Figure 1.

HIV Prevention Trials Network (HPTN) 083 study design. Figure shows an overview of the HPTN 083 trial design. The study included a 5-week oral lead-in phase (step 1), a 148-week injection phase (step 2), and a 48-week open-label tail phase (step 3). Participants randomized to the tenofovir disoproxil fumarate–emtricitabine (TDF/FTC) arm received daily coformulated tablets with 300 mg of TDF and 200 mg of FTC in steps 1 and 2, with placebo tablets in step 1 and placebo injections in step 2. Participants randomized to the cabotegravir (CAB) arm received oral daily CAB (30-mg tablets) in step 1, followed by long-acting CAB (CAB-LA) injections (600 mg) in step 2, with placebo tablets in both phases. Participants in both arms received open-label daily TDF/FTC in step 3. The first 2 injections were given 4 weeks apart starting at week 5, followed by injections 8 weeks apart starting at week 9 (arrows). A nonreactive rapid test was required before each injection. Study drugs were stopped if the participant had a reactive or positive human immunodeficiency virus test at the study site, if the participant declined drug administration, if this was deemed necessary owing to an adverse event, or for another reason at the discretion of the site principal investigator.

Figure 2.

Case summaries (cabotegravir [CAB] arm; group D). The figure shows a summary of laboratory results and key events for participants in the CAB study arm for cases in which infection occurred despite on-time injections. A, Case D1. B, Case D2. C, Case D3. D, Case D4. Additional information, including results from testing performed at study sites, is provided in Supplementary File 5. Data are shown as a function of time (weeks since enrollment, based on calendar dates). Annotations above graphs show results obtained from testing performed at the HIV Prevention Trials Network (HPTN) Laboratory Center. Plus signs indicate reactive or positive test results; minus signs, nonreactive or negative test results. Viral load values represent the number of human immunodeficiency virus (HIV) RNA copies per milliliter; 1 viral load result for case D2 was obtained using a single-copy RNA assay. Viral load results noted as <40 indicate that HIV RNA was detected at <40 copies/mL. Results from HIV genotyping are shown. All drug resistance mutations are shown for integrase strand transfer inhibitors (INSTIs); major drug resistance mutations are shown for nonnucleoside reverse-transcriptase inhibitors (NNRTIs). Brackets show numbers of days between the last injection and the first HIV-positive visit, graphs show plasma CAB concentrations and key events, and horizontal lines mark the following concentration cutoffs: 1.33 µg/mL (8 times the in vitro protein-adjusted 90% CAB inhibitory concentration [8× PA-IC₉₀], 0.664 µg/mL (4× PA-IC₉₀), and 0.166 µg/mL (1× PA-IC₉₀). Shaded areas indicate that the participant was receiving antiretroviral therapy (cases D1, D3, and D4) or postexposure prophylaxis (case D2). Abbreviations: Ag/Ab: antigen-antibody test; BLQ, below the limit of quantification (<0.025 µg/mL); IND, indeterminate test result; ND, not detected.

Figure 2.

Case summaries (cabotegravir [CAB] arm; group D). The figure shows a summary of laboratory results and key events for participants in the CAB study arm for cases in which infection occurred despite on-time injections. A, Case D1. B, Case D2. C, Case D3. D, Case D4. Additional information, including results from testing performed at study sites, is provided in Supplementary File 5. Data are shown as a function of time (weeks since enrollment, based on calendar dates). Annotations above graphs show results obtained from testing performed at the HIV Prevention Trials Network (HPTN) Laboratory Center. Plus signs indicate reactive or positive test results; minus signs, nonreactive or negative test results. Viral load values represent the number of human immunodeficiency virus (HIV) RNA copies per milliliter; 1 viral load result for case D2 was obtained using a single-copy RNA assay. Viral load results noted as <40 indicate that HIV RNA was detected at <40 copies/mL. Results from HIV genotyping are shown. All drug resistance mutations are shown for integrase strand transfer inhibitors (INSTIs); major drug resistance mutations are shown for nonnucleoside reverse-transcriptase inhibitors (NNRTIs). Brackets show numbers of days between the last injection and the first HIV-positive visit, graphs show plasma CAB concentrations and key events, and horizontal lines mark the following concentration cutoffs: 1.33 µg/mL (8 times the in vitro protein-adjusted 90% CAB inhibitory concentration [8× PA-IC₉₀], 0.664 µg/mL (4× PA-IC₉₀), and 0.166 µg/mL (1× PA-IC₉₀). Shaded areas indicate that the participant was receiving antiretroviral therapy (cases D1, D3, and D4) or postexposure prophylaxis (case D2). Abbreviations: Ag/Ab: antigen-antibody test; BLQ, below the limit of quantification (<0.025 µg/mL); IND, indeterminate test result; ND, not detected.

Figure 3.

Case summary (tenofovir [TFV] disoproxil fumarate–emtricitabine [TDF/FTC] arm, cases E16 and E34). Figure shows a summary of laboratory results and key events for 2 cases in the TDF/FTC study arm. A, Case E16. B, Case E34. Data are shown as a function of time (weeks since enrollment, based on calendar dates). Annotations above each graph show results obtained from testing performed at the HIV Prevention Trials Network (HPTN) Laboratory Center. Plus signs indicate reactive or positive test results; minus signs, nonreactive or negative test results. Viral load values indicate numbers of human immunodeficiency virus (HIV) RNA copies per milliliter. Major drug resistance mutations are shown. Graphs show TFV and TFV diphosphate (TFV-DP) concentrations and key events. Black dashed horizontal lines indicate plasma TFV concentrations of 10 and 40 ng/mL, which correspond to 4 and 7 doses per week, respectively; gray dashed lines, TFV-DP concentrations of 350, 700, and 1250 fmol per punch, which correspond to 2, 4, and 7 doses per week, respectively. For case E16 (A), all drug concentrations after the week 9 study visit were consistent with daily oral TDF/FTC dosing, except for the result obtained at week 43; At that visit, the TFV concentration was 22.5 ng/mL, which is consistent with 4 doses per week. For case E34 (B), results from dried blood spot testing were not available at the first HIV-positive visit; this participant had plasma TFV and TFV-DP concentrations consistent with daily TDF/FTC use in the preceding months. Abbreviations: Ag/Ab: antigen-antibody; BLQ, below the limit of quantification (0.31 ng/mL for TFV; 31.3 fmol per punch for TFV-DP); IND, indeterminate test result; NNRTI, nonnucleoside reverse-transcriptase inhibitor; NRTI, nucleoside/nucleotide reverse-transcriptase inhibitor.