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By Richard Jefferys

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).1,2 In both cases, CAB LA proved superior to oral Truvada PrEP (see table).

Analyses of the trial data have also revealed a wrinkle associated with the approach: among the small number of HIV infections 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).3,4 In most cases, these HIV infections 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 infections 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 infections 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, 2021.5)

Currently, it appears that monitoring for HIV infection 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 infections sooner and prevent the emergence of drug resistance.

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.6 The National Institutes of Health is also supporting research into finger-prick viral load tests that could be self-administered at home.7

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 infection among recipients. The issue highlights how new and successful interventions can sometimes create novel challenges that need to be addressed for optimal implementation.

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%


1 Landovitz RJ, Donnell D, Clement ME, et al. Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women. N Engl J Med. 2021 Aug 12;385(7):595-608. doi: 10.1056/NEJMoa2101016.

2 Delany-Moretlwe S, Hughes J, Bock P, et al. Long acting injectable cabotegravir is safe and effective in preventing HIV infection in cisgender women: interim results from HPTN 084 (Abstract HY01.02LB). Paper presented at: HIV R4P; 2021 January 27-28, February 3-4; Virtual.

3 Marzinke M, Grinsztejn B, Fogel J, et al. Laboratory Analysis of HIV Infections in HPTN 083: Injectable CAB for PrEP (Abstract 153). Paper presented at: Conference on Retroviruses and Opportunistic Infections 2021; 2021 March 6–10; Virtual.

4 Marzinke M, Delany-Moretlwe S, Agyei Y, et al. Long-acting injectable PrEP in women: laboratory analysis of HIV infections in HPTN 084 (Abstract PECLB25). Paper presented at: IAS 2021; 2021 July 18-21; Virtual.

5 ViiV Healthcare (Press Release). ViiV Healthcare initiates rolling submission of new drug application with US FDA for long-acting cabotegravir for prevention of HIV. 2021 May 4.

6 BEAT-HIV Delaney Collaboratory. Clinical Trials. BEAT-HIV Delaney Collaboratory [Internet]. 2020 (cited 2021 September 5).

7 Penn State (Press Release). Researchers explore at-home testing method of viral loads for HIV patients. 2020 October 20.

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