Impressive results from two efficacy trials of a long-acting form of the integrase inhibitor cabotegravir (CAB LA) have boosted prospects for long-acting HIV pre-exposure prophylaxis (PrEP). In both cases, CAB LA proved superior to oral Truvada PrEP (see table below).
Analyses of the trial data have also revealed a wrinkle associated with the approach: among the small number of HIV acquisition events that occurred, the capacity of CAB LA to suppress viral replication masked the presence of the virus by reducing viral load and preventing seroconversion to HIV antibody positive (delaying HIV diagnosis). In most cases, these HIV acquisition events had occurred either immediately prior to PrEP initiation or during windows of suboptimal LA CAB levels associated with delayed (or lack of) receipt of scheduled drug doses. In two trial participants who acquired HIV despite adequate drug levels, the virus had mutations associated with resistance to CAB LA.
The researchers identified these masked HIV acquisition events retrospectively by testing stored blood samples for low levels of HIV viral load. Once identified, antiretroviral treatment (ART) regimens were successfully initiated. In a few cases, HIV had developed CAB LA resistance due to the trial participants having spent an extended period on monotherapy after acquiring HIV, rather than appropriate combination ART.
The potential occurrence of masked HIV acquisition events in users of LA PrEP raises the question of how best to diagnose HIV in future studies and when LA PrEP becomes available on the market. (ViiV Healthcare announced the submission of a new drug application to the U.S. Food and Drug Administration on May 4, 2021.
Currently, it appears that monitoring for HIV will require intermittent use of sensitive viral load tests. This approach is under evaluation in the open label extension phases of HPTN 083 and 084. The researchers are assessing a variety of point-of-care and rapid viral load tests to better understand whether their use in the context of LA PrEP can identify incident HIV acquisition events sooner and prevent the emergence of drug resistance.
| Study | HPTN 83 | HPTN 084 |
|---|---|---|
| Population | 4,566 cisgender men and transgender women who have sex with men | 3,223 cisgender women |
| HIV infection endpoints (CAB LA / Truvada) | 12 / 39 | 3 / 36 |
| HIV incidence per 100 person-years (CAB LA / Truvada) | 0.37 / 1.22 | 0.15 / 1.85 |
| Incidence reduction (CAB LA vs. Truvada) | 68% | 92% |
Another idea in development that might offer enhanced convenience is home viral load testing. For example, the pharmaceutical company Merck is collaborating with researchers at the BEAT-HIV Martin Delaney Collaboratory in Philadelphia to assess whether a system that allows an individual to draw blood at home and mail for testing can be used to monitor for HIV viral load rebound in clinical trials involving an ART interruption. The National Institutes of Health is also supporting research into finger-prick viral load tests that could be self-administered at home.
Before these tests could become HIV diagnostics for people on LA PrEP, they would need to overcome an important hurdle: the need for very low thresholds of viral load detection (e.g., 20 copies/mL of HIV RNA). Currently the Merck at-home testing technology has a lower cut-off of 1,000 copies/mL; in the ART interruption trial in which it’s being evaluated, 1,000 copies/mL or greater is the viral load level that triggers restarting treatment. There is hope, however, that this lower limit of viral load detection can be improved.
As long-acting approaches to HIV prevention become more widely used, attention will also need to be paid to developing appropriate tools for diagnosing HIV among recipients. The issue highlights how new and successful interventions can sometimes create novel challenges that need to be addressed for optimal implementation.
In his current role as TAG’s Basic Science, Vaccines and Cure Project Director, Richard Jefferys is particularly focused on HIV cure research, education, and advocacy. Richard began working in HIV in 1994 at the AIDS Treatment Data Network in NYC, helped establish the Health GAP Coalition in 1999, and has written for a wide range of publications, including Positively Aware.
Reprinted with permission from TAGline.