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Professor of Medicine
Division of HIV, Infectious Diseases, and Global Medicine
University of California, San Francisco
Ward 86 HIV Clinic
San Francisco General Hospital
San Francisco, California
Monica Gandhi, MD, MPH, has no relevant conflicts of interest to report.
The Virtual 2021 Conference on Retroviruses and Opportunistic Infections (CROI 2021) highlighted the development of long-acting (LA) pre-exposure prophylaxis (PrEP) options. Among the most anticipated data presented were findings from a study investigating drug levels and resistance with LA injectable cabotegravir (CAB) for the prevention of HIV and a study investigating the pharmacokinetics and safety of LA islatravir-eluting implants. Here are some of my interpretations of these data.
HPTN 083: Incident Infections and Emergent Resistance in MSM and TGW Receiving Cabotegravir LA PrEP
HPTN 083 is a phase IIb/III study in which men who have sex with men (MSM) and transgender women (TGW) at high risk of HIV infection received an oral lead-in of CAB plus placebo or emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) plus placebo for 5 weeks followed by intramuscular LA CAB every 2 months plus daily oral placebo compared with daily oral FTC/TDF plus intramuscular placebo every 2 months (N = 4566). As a reminder, data presented at AIDS 2020 from HPTN 083 demonstrated that injectable LA CAB was significantly superior to daily oral FTC/TDF in reducing incident HIV infection among MSM and TGW at high risk of HIV infection. In the data presented at CROI 2021, updated laboratory analyses involving diagnostic testing at baseline, drug levels, and resistance testing upon PrEP failure (HIV infection) indicated that there were 4 baseline infections (prior to starting LA CAB) and 12 incident infections in the LA CAB arm.
It is important to note that in 5 (31%) of the 16 infections in the LA CAB arm (including 1 infection that was originally undetected at baseline and 4 incident infections), integrase strand transfer inhibitor (INSTI) resistance evolved after exposure to CAB. The breakdown of participants with INSTI mutations after exposure to CAB among the total number of infections include:
Of the 5 participants with emergent INSTI resistance, 1 was lost to follow-up and the other 4 were subsequently virologically suppressed on boosted protease inhibitor regimens or an efavirenz-based regimen.
I think this study brings up some important considerations for LA CAB as PrEP. First, it reveals that HIV infections may be missed using the standard testing algorithms and that HIV-1 RNA testing at initiation of CAB may be required. This will be evaluated further in the HPTN 083 open-label extension study.
The second major concern is that after CAB exposure, evolution of INSTI resistance in breakthrough infections and in cases of undetected HIV infection is not uncommon and must be carefully evaluated during roll-out. I am very concerned about the potential for this to result in INSTI resistance in patients with breakthrough infections that are not rapidly detected, which would then limit first-line treatment options for those patients.
Next-Generation Islatravir Implants Projected to Provide Yearly HIV Prophylaxis
We also saw data from a phase I study investigating the pharmacokinetics, safety, and tolerability of implants containing 48 mg, 52 mg, or 56 mg of islatravir, a next-generation nucleoside reverse transcription translocation inhibitor (NRTTI) with a long half-life, compared with a placebo implant. This study demonstrated that the 56-mg implant was projected to release islatravir above the pharmacokinetic threshold for HIV prevention for more than 52 weeks. The implant was generally well tolerated, with only mild or moderate adverse events: 61% of participants reported at least 1 implant site adverse event, but there were no discontinuations due to adverse events. These data are very exciting as they suggest that the islatravir-eluting implants will release drug projected to be sufficient for HIV prophylaxis for at least 1 year. I look forward to seeing the next phase data on this exciting option.
What are your thoughts on the INSTI resistance reported with LA CAB as PrEP? Do you have patients on PrEP who may be interested in a LA implant if approved in the future? Join the discussion by posting a comment.