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CAB-LA PrEP Keeps Advantage Over TDF/FTC in 1-Year Unblinded Phase-
Seven Breakthrough Infections Despite On-Time CAB-LA Injections
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2022 CROI, February 12-16 and 22-24, 2022
Mark Mascolini
Long-acting injected cabotegravir (CAB-LA) maintained a significant advantage over oral tenofovir/emtricitabine (TDF/FTC) as PrEP against HIV infection in an additional year of unblinded study after the 3-year blinded phase of HPTN 083 [1]. Trial investigators reported 7 breakthrough HIV infections throughout the entire study despite on-time CAB-LA shots.
HPTN 083 randomized cisgender men and transgender women who have sex with men to a CAB-LA shot every 2 months (after 5 weeks of oral CAB) or to a daily TDF/FTC tablet [2,3]. The study enrolled 4566 people at 43 sites in the United States, Latin America, Asia, and Africa [2]. Participants included 570 transgender women (12.5%) and a broad mix of blacks, whites, Asians, Hispanics, and indigenous people. Median age stood at 26 years.
In the initial analysis after 153 weeks of follow-up [2], researchers counted 13 HIV infections in the CAB-LA group and 39 in the TDF/FTC group for incidence rates of 0.41 per 100 person-years (PY) with CAB-LA and 1.22 per 100 PY with TDF/FTC. Those rates meant CAB-LA cut the risk of HIV infection by two-thirds (hazard ratio [HR] 0.34, 95% confidence interval [CI] 0.18 to 0.62), showing that CAB-LA is superior to TDF/FTC in preventing HIV infection in this population.
At the 2022 CROI, HPTN 083 investigators updated results from the 153-week blinded period to count 14 HIV infections in the CAB-LA group for an incidence of 0.44 per 100 PY, compared with 41 infections in the TDF/FTC group for an incidence of 1.29 per 100 PY, results yielding the same two-thirds lower HIV risk with CAB-LA (HR 0.34, 95% CI 0.18 to 0.62).
In the newly analyzed 1-year unblinded period, the researchers tallied 11 HIV infections in the CAB-LA group for an incidence of 0.76 per 100 PY versus 31 infections with TDF/FTC for an incidence of 2.20 per 100 PY, which meant CAB-LA still trimmed HIV risk by two-thirds (HR 0.33, 95% CI 0.17 to 0.66). The 11 infections with CAB-LA included 1 person who got injections on time, 3 who had delayed injections, and 7 who got infected 6 or more months after the last CAB exposure-and 2 of these 7 people never got a CAB-LA shot.
In the combined 4.4 year blinded plus unblinded analysis, there were 25 infections in CAB-LA users for an incidence of 0.54 per 100 PY versus 72 infections with TDF/FTC for an incidence of 1.57 per 100 PY. HIV risk reduction with CAB-LA stayed the same: HR 0.34, 95% CI 0.22 to 0.54.
In the 3-year primary blinded analysis, 47% of analyzed participants lived in the US, 32% in Latin America, 18% in Asia, and only 3% in Africa. In the 1-year unblinded analysis, people from Latin America made up 54% of the study group, US residents 22%, Asians 20%, and Africans still 3%.
CAB-LA breakthrough infections (those occurring despite getting injections on schedule) remained rare-only 7 cases during 4660 PY of follow-up for an incidence of 0.15 per 100 PY (versus an overall 4.4-year incidence of 0.54 per 100 PY). Careful case-by-case analysis could not discern a reason for these breakthroughs.
The HPTN team surmised that the higher HIV incidence in the 1-year unblinded analysis than in the updated primary analysis (0.76 vs 0.44 per 100 PY for CAB-LA; 2.20 vs 1.29 for TDF/FTC) may have resulted from "decreased TDF/FTC adherence [from 73% in the blinded period to 59% in the unblinded period], reduced CAB injection coverage, and increased relative contributions to overall person-time from high incidence regions" (though the proportion from Africa remained 3% throughout the study).
No new safety problems arose during the 1-year unblinded phase. The researchers continue work to understand the CAB-LA breakthrough infections. In a study reviewed separately by NATAP, HPTN analyzed the impact of earlier detection of infection during CAB-LA PrEP on resistance to integrase inhibitors [4].
References
1. Landovitz RJ, Donnell D, Tran H, et al. Updated efficacy, safety, and case studies in HPTN 083: CAB-LA vs TDF/FTC for PrEP. 2022 CROI, February 12-16 and 22-24, 2022. Abstract 96.
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. 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/
4. 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.
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