Features of HIV Infection in Long-Acting Cabotegravir Pre-Exposure Prophylaxis

To the Editor:

HIV Prevention Trials Network (HPTN) 083 and 084 demonstrated that long-acting injectable cabotegravir (CAB-LA) was superior to daily oral tenofovir disoproxil fumarate/emtricitabine for prevention of sexual HIV transmission. In these trials, we observed an altered presentation of acute HIV infection in the setting of CAB-LA pre-exposure prophylaxis (PrEP) which we term “long-acting early viral inhibition (LEVI)”.^1–5

Data are emerging that the laboratory and clinical presentations of HIV infection in the setting of LEVI may be different from acute HIV infection in general (Figure, Supplementary Appendix). These cases are characterized by low or undetectable HIV viral load and diminished/delayed antibody production and are usually clinically silent. Levels of HIV antigen, antibody, RNA, and DNA are often near the level of detection of available assays and may revert from reactive, indeterminate, or positive to non-reactive or negative, making confirmation of HIV infection challenging.⁵

Figure: Key features of early HIV infection with long-acting early viral inhibition compared to classical acute/primary HIV infection.

Key features of classical acute/primary HIV infection (AHI, left) and long-acting early viral inhibition (LEVI, right) are illustrated in the figure.

Panel A: Abbreviations: AHI: acute HIV infection; Ab: antibody; Ag: antigen; CAB-LA: long-acting injectable cabotegravir; LEVI: long-acting early viral inhibition; POC: point-of-care; PrEP: pre-exposure prophylaxis.

Panel B: HIV RNA levels are shown with purple lines; HIV antibody levels are shown with blue lines.

In the absence of antiretroviral drugs, AHI usually exhibits unconstrained, explosive viral replication following infection with peak viremia 7–14 days after infection. AHI can be detected in the first days of infection using an RNA assay. Ag/Ab assays usually become reactive 12–15 days after infection. Antibody-based confirmatory/discriminatory assays usually become positive around one month after infection. Antibody expression is associated with a rapid decline in viral load followed by establishment of a viral load set point.

In LEVI, HIV acquisition may occur before or after PrEP initiation. HIV drug resistance often emerges early when viral loads are low; additional resistance associated mutations may emerge over time before viral breakthrough occurs. Viral breakthrough can occur with on-time drug administration and expected drug levels (left dashed lines) or after drug administration stops and drug levels decline (right dashed lines). In some cases, viral breakthrough was not observed even after drug concentrations dropped below detectable levels (right dotted lines). Antibody-based confirmatory/discriminatory assays often remain negative or indeterminate for long periods and may still not be positive even one year after HIV infection.

In HPTN 083 and 084, 41 HIV infections were identified among 3,446 participants randomized to CAB. In 17/41 (41.5%) cases, detection of infection was delayed when HIV rapid tests and an antigen/antibody test were used for HIV screening. Fourteen of these 17 cases had at least one CAB injection and had the last CAB injection within 6 months of the first HIV-positive visit (see Supplementary Appendix). Ten of the 14 cases had integrase strand transfer inhibitor (INSTI) resistance, including all six incident cases that occurred with on-time injections.

INSTI resistance often emerges early in LEVI.³ In biologic males, INSTI resistance was only observed when HIV infection occurred within 6 months of CAB-LA injection;⁴ these intervals may be longer in biologic females. In LEVI, HIV RNA screening detects infection earlier than standard HIV screening assays and often detects infection before INSTI resistance emerges.³ However, false-positive HIV RNA tests may also occur in this setting, complicating clinical management. False-positive results can create confusion and distress for patients and providers in this setting, since it may be difficult to determine whether HIV infection has occurred. False-positive results may also lead to unnecesary cessation of CAB-LA PrEP and unnecessary initiation of HIV treatment. Current guidelines from the United States Centers for Disease Control include HIV RNA screening for persons using CAB-LA PrEP. We are evaluating use of RNA screening with CAB-LA PrEP in the open-label HPTN 083/084 studies, where RNA screening is performed as part of the HIV testing algorithm at all scheduled study visits.

When interpreting HIV test results in persons receiving CAB-LA PrEP, providers should recognize that a prolonged period of observation with frequent retesting may be needed before infection can be confirmed or excluded, and that delays in diagnosis may be associated with INSTI resistance, including resistance to dolutegravir and bictegravir. Research is needed to identify the most effective treatment regimen for persons with CAB-LA PrEP breakthrough infection, to identify improved HIV screening assays and algorithms for use with CAB-LA PrEP, and to determine whether LEVI occurs with other long-acting PrEP agents.