In trial, cabotegravir delayed detection of some incident HIV infections
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In a trial assessing cabotegravir for HIV PrEP, the long-acting injectable appeared to delay the detection of a small number of incident HIV infections using standard HIV testing, researchers reported.
Additional laboratory testing of samples from four study participants who received cabotegravir during the trial was able to identify their infections between 6 and 17 weeks earlier than site testing had, said Raphael J. Landovitz, MD, MSc, a professor of medicine at the University of California, Los Angeles Center for Clinical AIDS Research and Education.
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In a presentation given during the Conference on Retroviruses and Opportunistic Infections, Landovitz said two of the four participants who acquired HIV despite on-time cabotegravir injections developed integrase inhibitor resistance-associated mutations, and the other two did not have samples with sufficient levels of virus for genotypic testing before they were started on ART.
The delayed diagnoses were discovered during a laboratory analysis of HIV infections from the HIV Prevention Trials Network 083 study (HPTN 083), a phase 2b/3 randomized, double-blind clinical trial that enrolled more than 4,500 transgender women and cisgender men who have sex with men (MSM) at 43 sites in Africa, Asia, Latin America and the United States. All four participants had expected concentrations of cabotegravir in their blood plasma, Landovitz said.
Data from HPTN 083 previously showed that cabotegravir provides superior protection against HIV compared with daily oral PrEP using emtricitabine/tenofovir disoproxil fumarate (FTC/TDF). A companion study, HPTN 084, demonstrated a similar result among cisgender women.
Experts have said that the added protection seen in the cabotegravir arms of the trials is likely a result of participants in the daily oral PrEP arms not always taking the medication as prescribed. In Tuesday’s presentation and others, Landovitz has noted that, in fact, both options are highly effective at preventing HIV infection. Oral PrEP has been approved in the U.S. since 2012. Last November, the FDA designated cabotegravir for PrEP a breakthrough therapy.
According to Landovitz, most incident infections that occur among participants taking FTC/TDF during PrEP trials — including 37 of 39 in HPTN 083 — can be attributed to nonadherence. However, when these breakthrough infections have occurred with intermittent use, the identification of new HIV cases is often delayed, he said.
“Cabotegravir — and long-acting cabotegravir in particular — appears to also delay conventional diagnostics,” Landovitz said during a press conference describing the results. “We had to expand from our original plans — our diagnostic testing and scope — to best characterize the first detectable evidence of HIV infection.”
Overall, Landovitz and colleagues detected 12 incident and four baseline infections in the cabotegravir arm of the study, for a rate of 0.37 infections per 100 person-years. There were 39 incident and three baseline infections in the FTC/TDF arm for a rate of 1.22 infections per 100 person-years.
The added testing resulted in minor updates to the primary results of the trial but no change in the overall interpretation that long-acting cabotegravir was superior to daily oral PrEP for HIV prevention, Landovitz said.
In a “reassuring” finding, Landovitz said none of the three participants infected during the tail phase of the study developed integrase inhibitor resistance, “despite a tremendous amount of interest and concern” about that possibility. He said larger data sets will be needed to confirm the finding.
He said an open-label extension (OLE) trial will explore making the oral cabotegravir lead-in phase of the study optional, and using viral load testing as primary screening for HIV infection.
References:
Landovitz R, et al. Abstract 153LB. Presented at: Conference on Retroviruses and Opportunistic Infections; March 6-10, 2021 (virtual meeting).
Landovitz R, et al. HPTN 083 interim results: Pre-exposure prophylaxis containing long-acting injectable cabotegravir is safe and highly effective for cisgender men and transgender women who have sex with men. Presented at: International AIDS Conference; July 6-10, 2020 (virtual meeting).
Perspective
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HPTN provided the pharmacokinetics data and the resistance profile of the 16 failures recorded on injectable cabotegravir given every 8 weeks for HIV prevention among MSM and transgender women who were enrolled in the HPTN 083 study at virtual CROI 2021. As a reminder, data presented at AIDS 2020 from HPTN 083 showed that the estimated HIV incidence in the long-acting cabotegravir arm was 66% lower than that in the oral TDF/FTC-containing arm. The abstract presented at CROI 2021 was entitled “Laboratory Analysis of HIV Infections in HPTN 083: Injectable cabotegravir for PrEP” and verified a 68% lower incidence with long-acting cabotegravir than oral TDF/FTC. The abstract also provided further detail on the now four baseline infections and the 12 incident or breakthrough infections in the long-acting cabotegravir arm. Dr. Landovitz stressed that typical diagnostic tests for HIV did not reveal the four prevalent (baseline) infections, and so the open-label extension study of HPTN 083 will include HIV RNA testing to rule out acute infection.
In five (31%) of the 16 infections (including one infection that was undetected at baseline and four incident infections), integrase inhibitor resistance evolved after exposure to cabotegravir:
- Q148K/E138K integrase strand transfer inhibitor (INSTI) mutations in a participant who had undetected HIV infection at baseline with wild-type virus and evolved INSTI resistance after exposure to oral cabotegravir lead-in and long-acting cabotegravir (A2);
- Q148R/L74I/E138K/G140S INSTI mutations in the second (C1);
- Q148R and E138A in the third (C3);
- a R263K INSTI mutation in the fourth (D3); and
- a Q148R and G140A in the fifth (D4).
Although phenotypic susceptibility testing was performed on some of these failures, darunavir/ritonavir with two nucleoside reverse transcriptase inhibitors was used as the treatment for these breakthrough infections.
Therefore, this study showed that:
- Diagnostic testing may require HIV RNA testing at initiation of cabotegravir, which will be tested in HPTN 083 OLE.
- After cabotegravir exposure, evolution of INSTI resistance in breakthrough infections and cases of undetected HIV infection is not uncommon and must be carefully evaluated during rollout.
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Landovitz R, et al. Abstract 153LB. Presented at: Conference on Retroviruses and Opportunistic Infections; March 6-10, 2021 (virtual meeting).
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