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. 2024 Aug 26;11(9):ofae468.
doi: 10.1093/ofid/ofae468. eCollection 2024 Sep.

First Case of HIV Seroconversion With Integrase Resistance Mutations on Long-Acting Cabotegravir for Prevention in Routine Care

Catherine A Koss  1 , Monica Gandhi  1 , Elias K Halvas  2 , Hideaki Okochi  1 , Carolyn Chu  1 , David V Glidden  1 , Lisa Georgetti Gomez  1 , Amy L Heaps  2 , Amy A Conroy  1 , Michael Tran  3 , Cory Shetler  2 , Dianna Hoeth  2 , Karen Kuncze  1 , Alexander Louie  1 , Hana Rivera Garza  1 , Erick Wafula Mugoma  4 , Kerri J Penrose  2 , Bhavna H Chohan  5 , James O Ayieko  6 , Anthony Mills  3 , Rupa R Patel  7   8 , John W Mellors  2 , Urvi M Parikh  2
Affiliations

First Case of HIV Seroconversion With Integrase Resistance Mutations on Long-Acting Cabotegravir for Prevention in Routine Care

Catherine A Koss et al. Open Forum Infect Dis. .

Abstract

Background: Long-acting cabotegravir (CAB-LA) is highly effective for HIV prevention, but delayed HIV diagnoses and integrase strand transfer inhibitor (INSTI) resistance were observed in trials. We report the first case in routine clinical care of HIV infection on CAB-LA with INSTI resistance.

Methods: The SeroPrEP study enrolls individuals in the United States who acquire HIV on pre-exposure prophylaxis modalities to assess diagnostics, antiretroviral (ARV) drug levels, resistance, and treatment outcomes. Resistance mutations in full-length HIV-1 integrase were identified by single-genome sequencing (SGS). Cabotegravir concentrations in plasma and hair segments were measured by liquid chromatography-tandem mass spectrometry.

Results: A 23-year-old gender-nonbinary person, male at birth, restarted CAB-LA 6 months after discontinuation due to losing insurance. Prior to restart, HIV-1 RNA was not detected, but 20 days elapsed before CAB-LA injection. After the second CAB-LA injection, HIV antigen/antibody returned reactive (HIV-1 RNA 451 copies/mL). SGS of plasma HIV-1 RNA identified INSTI mutation Q148R in 2/24 sequences 2 days postdiagnosis; commercial genotype failed amplification. Cabotegravir hair concentration was 0.190 ng/mg 2 weeks prediagnosis; plasma cabotegravir was high (3.37 μg/mL; ∼20× PA-IC90) 14 days postdiagnosis. Viral suppression was maintained for 6 months on darunavir/cobicistat/emtricitabine/tenofovir alafenamide, then switched to doravirine + emtricitabine/tenofovir alafenamide due to nausea.

Conclusions: In this first case of HIV infection on CAB-LA with INSTI resistance in routine care, cabotegravir resistance was detected only with a sensitive research assay. Accelerated pathways to minimize time between HIV testing and CAB-LA initiation are needed to optimize acute HIV detection and mitigate resistance risk. Sustained product access regardless of insurance is imperative to reduce HIV infections on CAB-LA.

Keywords: HIV prevention; breakthrough infection; pharmacokinetics; pre-exposure prophylaxis; resistance.

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Conflict of interest statement

Potential conflicts of interest. C.A.K. reports research grant funding to institution from the NIH and Gilead Sciences. DVG reports research grant funding to institution from the NIH and receipt of consulting fees from Gilead Sciences and Merck. MT reports receipt of lunch for institution/clinic from Gilead Sciences and ViiV Healthcare and brand medication samples provided by Gilead Sciences to institution/clinic to be used as per standard of HIV prevention/care. AM reports research funding to institution from Gilead Sciences, ViiV, and Merck, and serving on advisory boards for Gilead, ViiV, and EMD Serono. JWM reports research grant funding to institution from the NIH, USAID, and Gilead Sciences; consulting fees from Gilead Sciences; travel support from the Conference on Retroviruses and Opportunistic Infections to attend the CROI meeting as a member of the CROI Scientific Program Committee; membership in the CROI Foundation (non-profit); President of the Foundation for Control of HIV Drug Resistance (non-profit); share options in Galapagos NV, Infectious Disease Connect, Inc, and MingMed Biotechnology Co., Ltd. UMP reports research grant funding to institution from the NIH; payments in the past (2021-2023) from Merck and Company for work that is now completed and unrelated to the current manuscript; and payment and one night of lodging from Thermo-Fisher for a presentation at a scientific conference. All other authors report no potential conflicts.

Figures

Figure 1.
Figure 1.
Timeline of ARV administration and research and clinical testing for HIV diagnosis, PK, and ARV resistance. 1. ARCHITECT HIV Ag/Ab Combo; signal to cutoff value ≥1.00 considered reactive. 2. Clinic #1: Hologic Aptima HIV Quant Dx Assay, LOQ 30 copies/mL; Clinic #2: COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, version 2.0; LOQ (limit of quantitation) 20 copies/mL. 3. No result due to failed PCR amplification in the commercial HIV genotyping assay. 4. Q148R was detected at 8% frequency and A128T was detected at 4% frequency on separate genomes. Full genotype is presented in Table 1. 5. Day 42 SGS limited in sensitivity to detect resistance due to HIV-1 RNA 23 copies/mL and only 3 genomes sequenced. 6. Plasma CAB concentration on day 42 (14 days after second injection) was ∼20× PA-IC90 (well above 8× PA-IC90). Abbreviations: Ag/Ab, antigen/antibody; ART, antiretroviral therapy; ARV, antiretroviral; CAB, cabotegravir; CAB-LA, long-acting cabotegravir; DOR, doravirine; DRV/c/FTC/TAF, darunavir/cobicistat/emtricitabine/tenofovir alafenamide; equiv, equivocal; FTC/TAF, emtricitabine/tenofovir alafenamide; INSTI, integrase strand transfer inhibitor; ND, not detected; NR, nonreactive; PK, pharmacokinetics; PrEP, pre-exposure prophylaxis; R, reactive; S/CO, signal to cutoff; SGS, single-genome sequencing.
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