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Early virologic success on ART following breakthrough infection on CAB-LA PrEP
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Urvi M. Parikh
Three of 3 With Breakthrough on CAB-LA PrEP Control HIV With Standard ART
HIVR4P 2024, Fifth HIV Research and Prevention Conference, October 6-10, 2024, Lima
Mark Mascolini
All 3 people who acquired HIV infection despite missing no doses of long-acting cabotegravir (CAB-LA) preexposure prophylaxis (PrEP) controlled their HIV with standard antiretroviral therapy (ART) through 5 or more months of follow-up [1]. This small patient series confirms earlier reports of HIV suppression after breakthrough on CAB-LA PrEP, and the researchers found major integrase inhibitor (INSTI) mutations in 2 of these 3 patients with assays more sensitive than standard resistance tests.
The observational SeroPrEP study tracks people in routine US care who become infected with HIV while using oral or injected PrEP [2]. SeroPrEP aims to analyze outcomes with provider-prescribed ART regimens. In the 3-person study, researchers used a single-copy assay to measure HIV RNA levels as low as 1 copy per milliliter. They used single-genome sequencing of full-length integrase to spot INSTI mutations making up as little as 1% of the viral population.
All 3 people in this series (Cases A, B, and C) were cisgender men 40, 31, and 67 years old. All switched from oral PrEP to CAB-LA, and none had detectable HIV RNA when starting CAB-LA. All had multiple sex partners, and none injected drugs. All got their CAB-LA shots on time for 5, 6, and 13 months before HIV diagnosis at initial viral loads of 4880, 3940, and 2.43 million copies. In samples collected 21 days, 42 days, and 8 weeks after their last CAB-LA injection (in random, random, and trough samples) troughs were 16, 4, and 6 times higher than the 90% protein-adjusted inhibitory concentration for cabotegravir. All 3 men started the same protease inhibitor regimen: darunavir/cobicistat/emtricitabine/tenofovir alafenamide.
Standard commercial sequencing for resistance mutations (Sanger sequencing) detected no INSTI mutations in samples collected 7 days after HIV diagnosis (Case A), 13 days after diagnosis (Case B), or 6 days after HIV diagnosis (Case C). But single-genome sequencing found (1) the signature INSTI mutation E138K in 1 of 56 sequences from Case B, (2) the accessory INSTI mutation N155K in 1 of 43 sequences from Case B, and (3) the signature Q148R mutation in 10 of 33 sequences from Case C. The researchers did not perform single-genome sequencing for Case A because his viral load was too low to allow sensitive genotyping when samples were collected.
Upon HIV diagnosis, clinicians treated all 3 men with the above-noted darunavir combination. One month after treatment began in Case A, a single-copy HIV RNA assay recorded a viral load of 3 copies/mL. No HIV RNA could be detected after 5 to 6 months of therapy. Case B had a viral load detectable at fewer than 20 copies/mL after 1 month of therapy, a load of 51 copies/mL with a single-copy assay 5 to 6 months after treatment began, and no detectable HIV RNA 10 months after treatment began.
Case C started the same darunavir combination after HIV diagnosis but switched to the INSTI combination bictegravir/emtricitabine/tenofovir alafenamide 26 days after diagnosis because of drug-drug interactions and intolerance. Six months later his viral load had dropped to 4 copies read by a single-copy RNA research assay.
Parikh and coworkers posed three questions for researchers who study HIV emergence in people faithfully taking their PrEP doses.
1. "What is the clinical significance of INSTI mutations selected by CAB that are detected at low frequency?"
2. "Which CAB-selected mutations have the greatest impact on outcomes with INSTI-based ART?"
3. "What is the long-term durability of viral suppression on INSTI + 2 NRTIs after HIV infection on CAB-LA PrEP?"
References
1. Parikh UM, Altamirano J, Safa H, et al. Early virologic success on ART following breakthrough infection on CAB-LA PrEP. HIVR4P 2024, Fifth HIV Research and Prevention Conference, October 6-10, 2024, Lima, Abstract PRC003.
2. The SeroPrEP Study. University of California, San Francisco. https://seroprep.ucsf.edu/
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