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RNA Assay Spots HIV Earlier in
CAB-LA PrEP Users, May Avert Resistance
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2022 CROI, February 12-16 and 22-24, 2022
Mark Mascolini
Using a sensitive RNA assay—instead of relying on current HIV detection algorithms—may spot HIV infection early enough to avoid or limit integrase inhibitor resistance when long-acting cabotegravir (CAB-LA) PrEP fails to prevent infection, according to analysis of 7 HIV breakthrough cases in the HPTN 083 trial [1]. For people taking CAB-LA PrEP, the investigators advise HIV testing “using the most sensitive RNA assay available.”
In the HPTN 083 and HPTN 084 trials, a CAB-LA shot every 2 months proved superior to daily TDF/FTC tablets in preventing HIV infection in cisgender men, transgender women, and cisgender women at high risk for HIV [2,3]. HPTN 083 investigators detected 7 breakthrough HIV infections in CAB-LA users who got their shots on time. But HIV detection often proved slow in these people because clinicians relied on standard testing algorithms using rapid tests and antigen/antibody assays. Supplemental antibody tests may be negative or indeterminate for months [4]. And because of continuing HIV suppression with CAB-LA PrEP even after infection, viral loads can remain low and hard to detect for long periods. But because HIV is replicating at low levels in such people with breakthrough infections, HIV may evolve to carry mutations making it resistant to integrase inhibitors.
This study by researchers from Johns Hopkins University and collaborators at other centers used sensitive assays to detect HIV infection earlier and to spot emergence of HIV integrase resistance mutations as soon as possible. The ultimate goal was to figure whether earlier HIV detection would give clinicians a chance to start antiretroviral therapy before HIV resistant to integrase inhibitors emerged or got worse.
Among 2282 people randomized to CAB-LA in HPTN 083, researchers discovered 16 HIV infections, 4 at the study baseline visit and 12 that arose during the trial [4]. Prior analysis showed that 5 of these 16 people had integrase inhibitor-resistant virus, including 1 person already infected with HIV at baseline. Resistance could not be assessed in 2 people whose viral load stayed below 500 copies at all study visits.
The new analysis focused on these 7 people—the 5 with detectable resistance and the 2 in whom resistance could not be assessed. To further examine HIV in these 7 individuals, the investigators used (1) a qualitative RNA test with a 30-copy lower limit of detection and (2) a single-genome sequencing assay developed at the University of Pittsburgh.
With this approach the researchers established that using an RNA assay with a 30-copy lower limit of detection to screen for HIV in CAB-LA PrEP users would have uncovered infection in 4 of 7 people before a major integrase inhibitor resistance mutation arose and before additional major integrase inhibitor mutations accumulated in 2 more people. In the seventh person the investigators could not figure when the sensitive RNA assay would have detected HIV infection relative to resistance emergence because single-genome sequencing was not successful in samples before the person tested positive at a study visit.
The research team proposed that using a sensitive RNA assay to screen for HIV in people using CAB-LA PrEP could unmask HIV infection earlier. And that earlier detection would allow clinicians to start antiretroviral therapy sooner to cut the risk of integrase inhibitor resistance. The investigators stressed that they spotted major integrase inhibitor resistance mutations in 5 of 7 people who still had low viral loads. They added that their findings support what current CDC PrEP guidelines [5] and CAB-LA product information [6] say about testing for HIV in people using CAB-LA for PrEP.
Finally the researchers noted that none of the people with integrase inhibitor-resistant HIV in HPTN 083 started an integrase inhibitor combination. There are no data on using such a combination in people who become infected while using CAB-LA PrEP.
References
1. Eshleman S, Fogel JM, Halvas EK, et al. CAB-LA-PrEP: Early detection of HIV infection may reduce InSTI resistance risk. 2022 CROI, February 12-16 and 22-24, 2022. Abstract 95.
2. Landovitz RJ, Donnell D, Clement ME, et al. Cabotegravir for HIV prevention in cisgender men and transgender women. N Engl J Med. 2021;385:595-608. doi: 10.1056/NEJMoa2101016. https://www.nejm.org/doi/10.1056/NEJMoa2101016
3. HPTN HIV Prevention Trials Network. HPTN 084 study demonstrates superiority of CAB LA to oral TDF/FTC for the prevention of HIV. November 9, 2020. https://www.hptn.org/news-and-events/press-releases/hptn-084-study-demonstrates-superiority-of-cab-la-to-oral-tdfftc-for
4. Marzinke MA, Grinsztejn B, Fogel JM, et al. Characterization of human immunodeficiency virus (HIV) infection in cisgender men and transgender women who have sex with men receiving injectable cabotegravir for HIV prevention: HPTN 083. J Infect Dis. 2021;224:1581-1592. doi: 10.1093/infdis/jiab152. https://pubmed.ncbi.nlm.nih.gov/33740057/
5. Centers for Disease Control and Prevention: US Public Health Service: Preexposure prophylaxis for the prevention of HIV infection in the United States—2021 Update: a clinical practice guideline. December 2021. https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf.
6. Apretude cabotegravir 20 mg/mL extended-release injectable suspension for PrEP preexposure prophylaxis. https://apretudehcp.com/
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