Infectious Disease

Within the examine, cabotegravir delayed the detection of some HIV infections

March 10, 2021

3 min read

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Landovitz R, et al. Abstract 153LB. Presented at: Conference on Retroviruses and Opportunistic Infections; 6-10 March 2021 (virtual meeting).

Disclosure:
Landovitz does not report any relevant financial information.

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In a study testing cabotegravir for HIV-PrEP, the long-acting injectable appeared to delay the detection of a small number of HIV infections using standard HIV tests, researchers reported.

Additional laboratory tests on samples from four study participants who received cabotegravir during the study were able to identify their infections between 6 and 17 weeks earlier than the on-site tests Raphael J. Landovitz, MD, MSc, Professor of Medicine at the University of California at the Los Angeles Center for Clinical AIDS Research and Education.

HIV under the microscope

Some breakthrough HIV infections in a study of long-acting cabotegravir versus PrEP were not detected by standard testing for weeks.
Photo credit: Adobe Stock

In a presentation during the conference on retroviruses and opportunistic infections, Landovitz said that two of the four participants with delayed diagnosis developed mutations related to integrase inhibitor resistance and the other two did not have samples with sufficient virus concentrations for genotypic testing before they did were started on ART.

The delayed diagnoses were discovered during laboratory analysis of HIV infection from the HIV Prevention Trials Network 083 (HPTN 083), a randomized, double-blind, phase 2b / 3 clinical trial involving more than 4,500 transgender women and cisgender women. Men Having Sex participated with Men (MSM) in 43 locations in Africa, Asia, Latin America, and the United States. All four participants were expecting levels of cabotegravir in their blood plasma, Landovitz said.

Raphael J. Landovitz

Data from HPTN 083 previously demonstrated that cabotegravir provided superior protection against HIV when compared to daily oral PrEP using emtricitabine / tenofovir disoproxil fumarate (FTC / TDF). A companion study, HPTN 084, showed a similar result in cisgender women.

Experts have said that the extra protection in the studies’ dolutegravir arms is likely due to participants in the daily oral PrEP arms not always taking the drugs as prescribed. In Tuesday’s presentation and others, Landovitz found that both options are actually very effective in preventing HIV infection. Oral PrEP has been approved in the US since 2012. Last November, the FDA identified cabotegravir as a breakthrough therapy for PrEP.

Landovitz said most of the infections that occur in participants who use FTC / TDF during PrEP studies – including 37 out of 39 in HPTN 083 – are due to non-compliance. However, when these breakthrough infections have occurred with intermittent use, the identification of new HIV cases is often delayed, he said.

“Cabotegravir – and especially long-acting cabotegravir – also appears to delay conventional diagnostics,” Landovitz said during a press conference describing the results. “We had to expand our original plans – our diagnostic tests and scope – to best characterize the first detectable evidence of HIV infection.”

Overall, Landovitz and colleagues found 12 incidents and four basic infections in the cabotegravir arm of the study, which corresponds to a rate of 0.37 infections per 100 person-years. There were 39 incidents and three base infections in the FTC / TDF arm at a rate of 1.22 infections per 100 person-years.

The additional testing resulted in minor updates to the study’s primary results, 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 final phase of the study had developed integrase inhibitor resistance “despite tremendous interest and concern” about the possibility. He said larger data sets are needed to confirm the finding.

He said an open-label extension study (OLE) will investigate whether the oral cabotegravir lead-in phase of the study is optional and whether viral load testing is used as a primary screen for HIV infection.

References:

Landovitz R, et al. Interim results on HPTN 083: Pre-exposure prophylaxis with 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).

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Monica Gandhi, MD, MPH)

Monica Gandhi, MD, MPH

Dr. In one of the most anticipated presentations of the meeting, Raphy Landovitz provided the pharmacokinetic data and resistance profile of the 16 errors made when injecting cabotegravir every 8 weeks for HIV prevention in MSM and transgender women participating in the HPTN 083 study, were recorded. As a reminder, HPTN 083 data presented in AIDS 2020 showed that the estimated HIV incidence in the long-acting cabotegravir arm was 66% lower than in the oral FTC / TDF-containing arm.

The summary presented at the virtual CROI 2021 confirmed a lower incidence of long-acting cabotegraviruses compared to oral FTC / TDF. It also provided further details on the now four basic infections and the twelve incidents or breakthrough infections in the long-acting cabotegravir arm. Dr. Landovitz emphasized that typical diagnostic tests for HIV did not reveal four types of infections. Therefore, the OLE study on HPTN 083 will include HIV RNA testing to rule out acute infection.

With regard to the 12 infections that occurred, five participants developed integrase inhibitor resistance:

  1. Q148K and E138K integrase strand transfer inhibitor (INSTI) mutations in one;
  2. Q148R, L74I, E138K, and G140S INSTI mutations in the second;
  3. Q148R and E138A in the third;
  4. an R263K INSTI mutation in the fourth; and
  5. a Q148R and G140A in the fifth.

Although phenotypic susceptibility testing was performed for some of these errors, darunavir / ritonavir with two nucleoside / nucleotide reverse transcriptase inhibitors was used to treat these breakthrough infections. Hence this study showed:

  1. Diagnostic testing may require HIV-RNA testing at the start of cabotegravir, which is reviewed in HPTN 083 OLE. and
  2. The development of INSTI resistance in breakthrough infections with cabotegravir is not uncommon and must be carefully assessed during the rollout.

Monica Gandhi, MD, MPH

Professor of Medicine

Associate Chief, Division of HIV, Infectious Diseases, and Global Medicine

University of California, San Francisco

Disclosure: Gandhi does not report any relevant information.

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Conference on Retroviruses and Opportunistic Infections (CROI)

Conference on Retroviruses and Opportunistic Infections (CROI)

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