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Characterization of Human Immunodeficiency Virus (HIV) Infections in Women Who Received Injectable Cabotegravir or Tenofovir Disoproxil Fumarate/Emtricitabine for HIV Prevention: HPTN 084
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The Journal of Infectious Diseases 15 May 2022
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.
In HPTN 083, CAB exposure was associated with prolonged viral suppression and diminished/delayed HIV antibody expression among infected participants [7]. This resulted in a delay in HIV diagnosis at study sites in most incident HIV infections; in many cases, participants received study drug after they were infected. Delays in HIV diagnosis contributed to emergence of INSTI resistance in some cases. Low or unquantifiable concentrations of study drugs near the time of the first HIV-positive visit accounted for almost half of the incident infections in the CAB arm and the majority of them in the TDF/FTC arm [7]. This report includes analysis of HIV infections observed in the blinded phase of HPTN 084, including analysis of drug concentrations, the impact of CAB and TDF/FTC on detection of HIV infection, and HIV drug resistance.
Forty HIV infections were identified (4 in the CAB arm, 36 in the TDF/FTC arm). Case numbers were assigned using a classification system similar to that used in HPTN 083 (Table 1). At the time of study unblinding, all 4 infections in the CAB arm were classified as incident infections. Subsequent testing at the HPTN Laboratory Center revealed that 1 of 4 participants had HIV infection at enrollment; this case was reclassified as a baseline infection (case A1). In the CAB arm, 2 participants with incident infection received no CAB injections and had no recent CAB exposure (cases B1 and B2). The third incident infection occurred during the injection phase of the study in a participant with delayed injection visits (case DX). All 36 infections in the TDF/FTC arm were incident infections.
Study Drug Exposure and Drug Concentrations
CAB Arm
Laboratory results and key events for the 4 CAB cases are shown in Figure 2. Additional information is provided in Supplementary File 2. In case A1, the participant had HIV infection at study enrollment, before CAB administration (Figure 2A). The site first detected evidence of HIV infection 32.3 weeks later. This participant received oral CAB and 5 CAB injections before the first site-positive visit. CAB concentrations indicate that the participant was not taking CAB consistently during the oral lead-in period. During the injection phase of the study, CAB concentrations did not exceed 8× PA-IC90 until after the second injection and remained above this level through the first site-positive visit. At that time, the CAB concentration was 2.58 mcg/mL..
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.
DISCUSSION
In HPTN 084, CAB-LA and oral TDF/FTC were both highly effective for HIV prevention.
Detailed characterization of HIV infections helps explain why some women acquired HIV and provides new insights into the impact of CAB-LA PrEP on detection of HIV infection.
In all 3 incident cases in the CAB arm of HPTN 084, the CAB concentration at the first HIV-positive visit was below the level predicted to be protective against HIV infection based on nonhuman primate simian-human immunodeficiency virus challenge studies [10, 13]. Two of these cases were in women who had no recent CAB exposure and received no CAB injections. The third occurred in a woman who had delayed CAB injections; this woman had a low CAB concentration at the first HIV-positive visit which was >16 weeks after the previous injection. The low CAB concentration at the first HIV-positive visit in this case is not unexpected based on the apparent terminal phase half-life of CAB-LA in cisgender women (8.6 weeks) [14]. In HPTN 084, none of the cisgender women in the CAB arm acquired HIV infection while receiving on-time injections. In contrast, in the HPTN 083 trial of cisgender men and transgender women, 4 participants with incident infection in the CAB arm were infected despite on-time injections with expected drug concentrations at the first HIV-positive visit [7].
In HPTN 084, retrospective testing revealed that 1 woman in the CAB arm had HIV infection at enrollment; retrospective testing also identified 7 baseline infections in HPTN 083 (4 in the CAB arm, 3 in the TDF/FTC arm). In both trials, all baseline infections would have been detected at enrollment, and almost all incident infections would have been detected at the first HIV-positive visit using a viral load assay with a limit of quantification of 40 copies/mL.
HPTN 083 and 084 are now transitioning to open-label extension studies in which all participants will be offered CAB-LA. In extension studies, HIV RNA testing will be performed at every study visit to screen for HIV infection. Even with this approach, it is still possible that some participants with HIV infection will receive a single CAB-LA injection before the RNA result is available, and that some will have HIV RNA levels below the limit of detection of most viral load assays. Further analyses are needed to evaluate the usefulness and cost of using HIV RNA testing to screen for HIV infection in persons receiving CAB-LA for PrEP outside a clinical trial setting.
None of the women acquired HIV infection during the CAB oral lead-in period. It is notable that all 3 women with incident infection in the CAB arm had low or unquantifiable CAB concentrations during this phase of the study, indicating low or nonadherence to blinded oral CAB. Participants in the open-label extension studies will have the option of starting CAB injections without an oral lead-in period. Suboptimal adherence to daily pill taking was observed in the TDF/FTC arm of HPTN 084. Adherence to daily TDF/FTC is especially important for women; a prior study suggests that 6–7 doses per week are required to achieve vaginal TFV concentrations associated with HIV protection [15]. Thirty-five of the 36 incident infections in the TDF/FTC arm of HPTN 084 occurred in women who had suboptimal drug concentrations near the time of the first HIV-positive visit. Discordant plasma TFV and DBS TFV-DP concentrations were observed in some women, suggesting that dosing may have occurred directly before a study visit without consistent study product use. TDF/FTC adherence was also assessed in both trials in a random subset of participants; the portion of participants with good adherence was much lower in HPTN 084 than in HPTN 083 [5, 6]. These findings highlight the need for PrEP products for women that do not rely on daily oral pill taking.
Detection of HIV infection was also delayed in both trials for some cases in the TDF/FTC arm. These delays were usually short, with HIV infection confirmed at the next study visit. Many of these cases occurred because the participant had acute HIV infection at the first HIV-positive visit, reflecting the frequency of study visits. These delays may not affect detection of HIV infection in clinical practice, since all of these infections were detected within 3 months of the first HIV-positive visit, the maximum recommended interval for HIV testing in persons receiving oral TDF/FTC PrEP [16].
We did not identify any cases with INSTI resistance in HPTN 084. The high frequency of transmitted NNRTI drug resistance observed in this cohort is concerning and emphasizes the importance of drug resistance testing and use of protease inhibitor– or INSTI-based treatment regimens where appropriate. Emergence of NRTI resistance in participants in the TDF/FTC arms of both trials was rare, most likely because most participants who acquired HIV infection in the TDF/FTC arms had poor adherence to the TDF/FTC regimen.
HPTN 084 demonstrated that CAB-LA and oral TDF/FTC are both highly effective for HIV prevention in women. All but 1 of the 39 incident infections occurred in women with delayed or discontinued CAB use or inconsistent or poor adherence to TDF/FTC. Drug concentrations were below predicted protective target concentrations in all of these cases. Detection of HIV infection was delayed in some participants in both study arms. Data from HPTN 084 and HPTN 083 show that these delays were more frequent and longer in persons receiving CAB than in those receiving TDF/FTC. These delays resulted in drug administration to persons with undetected HIV infection in almost all cases; INSTI resistance emerged in some of these cases in HPTN 083 [7]. HPTN 084 and 083 are transitioning to extension studies in which all participants will be offered open-label CAB-LA. Ongoing analysis of samples and data from the 2 trials will provide more information about the correlates of HIV protection with CAB-LA PrEP and the impact of CAB-LA on viral replication, antibody expression, and drug resistance.
RESULTS
Classification of HIV Infections
Forty HIV infections were identified (4 in the CAB arm, 36 in the TDF/FTC arm). Case numbers were assigned using a classification system similar to that used in HPTN 083 (Table 1). At the time of study unblinding, all 4 infections in the CAB arm were classified as incident infections. Subsequent testing at the HPTN Laboratory Center revealed that 1 of 4 participants had HIV infection at enrollment; this case was reclassified as a baseline infection (case A1). In the CAB arm, 2 participants with incident infection received no CAB injections and had no recent CAB exposure (cases B1 and B2). The third incident infection occurred during the injection phase of the study in a participant with delayed injection visits (case DX). All 36 infections in the TDF/FTC arm were incident infections.
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