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Laboratory Analysis of HIV Infections in HPTN 083: Injectable CAB for PrEP
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CROI 2021 March 6-10
webcast: http://www.croiwebcasts.org/console/player/48236?mediaType=slideVideo&
Mark Marzinke1, Beatriz Grinsztejn2, Jessica Fogel1, Estelle M. Piwowar- Manning1, Brett Hanscom3, Lara Coelho2, Myron S. Cohen4, Alex R. Rinehart5, James F. Rooney6, Adeola Adeyeye7, Peter Anderson8, Marybeth McCauley9, Raphael J. Landovitz10, Susan Eshleman1, for the HPTN 083 Study Team
1The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2Instituto Nacional de Infectologia Evandro Chagas, Rio de Janeiro, Brazil, 3Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 4University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 5ViiV Healthcare, Research Triangle Park, NC, USA, 6Gilead Sciences, Inc, Foster City, CA, USA, 7National Institute of Allergy and Infectious Diseases, Baltimore, MD, USA, 8University of Colorado, Aurora, CO, USA, 9FHI 360, Washington, DC, USA, 10University of California Los Angeles, Los Angeles, CA, USA
Program abstract
Background: HPTN 083 showed a 66% reduction in HIV incidence in cisgender men and transgender women who have sex with men (MSM/TGW) randomized to cabotegravir (CAB) 600 mg injections every 8 weeks (after an oral lead-in) vs. daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for pre- exposure prophylaxis (PrEP). We originally reported 52 incident infections among 4566 participants (13 CAB, 39 TDF/FTC; annual incidence: 0.41% vs. 1.22%) with 5 additional baseline infections (2 CAB, 3 TDF/FTC). In post-hoc analysis, 1 incident infection in the CAB arm was later reclassified as a baseline infection; 1 additional baseline infection was also identified. We used virology and pharmacology assays to characterize these 58 cases (Table).
Methods: Concentrations of CAB and tenofovir (TFV) in plasma and TFV- diphosphate in dried blood spots were quantified by liquid chromatography- tandem mass spectrometry. HIV status and timing of HIV infection were assessed with an antigen/antibody (Ag/Ab) test, a discriminatory test, and RNA assays. Drug resistance testing was performed for samples with HIV RNA >500 copies/mL.
Results: Among 12 incident infections in the CAB arm: 5 had no recent CAB dosing; 3 occurred in the oral lead-in phase (1 had no CAB detected); 4 occurred despite on-time CAB injections and targeted CAB concentrations. Five of the 16 infections in the CAB arm had integrase resistance associated mutations (RAMs; Q148R or Q148K with accessory mutations, or R263K); 1 of these cases also had a non-nucleoside reverse transcriptase inhibitor (NNRTI) RAM. One case had NNRTI RAMs only and 1 had NNRTI RAMs with nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) RAMs. In the TDF/FTC arm, 37/39 incident infections occurred in participants with drug concentrations indicating sub- optimal or non-adherence. One infection was likely due to transmission of TDF/ FTC-resistant HIV; 1 occurred despite targeted drug concentrations. Thirteen the 42 infections in the TDF/FTC arm had RAMs: 3 had NRTI RAMs only; 3 had NRTI and NNRTI RAMs; and 7 had NNRTI RAMs only. Retrospective HIV RNA testing identified HIV infection earlier than Ag/Ab testing performed at study sites.
Conclusion: TDF/FTC and CAB are highly effective for HIV PrEP in MSM/TGW. Oral pill non-adherence likely contributed to higher HIV incidence among those randomized to TDF/FTC. Integrase inhibitor resistance was observed in some cases in the CAB arm. Long-acting CAB is an important addition to HIV prevention options.
The pre-specified algorithm identified 13 incident & 2 baseline HIV infections in the CAB arm.
Identified to have been infected prior to CAB administration of study products Group A.
Group B if they had prolonged hiatus from since last CAB administration at the time of detection.
Group C if infection were detected during the oral lead-in phase.
Group D if infection were detected despite on-time CAB injections.
The extended testing employed post-hoc revised the adjudication of time of first HIV positivity in 2 cases previously identified as D2 & D5. D5 was reclassified as a baseline infection & renamed A3. An additional baseline infection A4 was identified. This resulted in a final dataset that included 12 incident & 4 baseline in the CAB arm & 39 incident & 3 baseline infections in the TDF/FTC arm. This also resulted in a post-hoc revision in the CAB arm incident rate of 0.37 per 100 person years & a revised hazard ratio of 0.32 with an unchanged interpretation.
In A3 escape viremia during the tail did not lead to resistance. A2 experienced treatment emergent integrase resistance. Red line is central lab identification of HIV positivity. Blue line is first HIV positive test at site. CAB injections are the green line.
B1, B3, & B4 likely got HIV infected during the PK tail. None developed integrase resistance.
Only C1 & C3 had evidence of CAB exposure & developed integrase resistance.
D1 was detected after 10 injections in the site based algorithm. Central lab testing identified the infection 16 weeks earlier. The decrease in PK was over 4x between injections 1 & 2.
A genotype was not obtained due to low viral loads. Boosted PI therapy was maintained viral suppression subsequently.
D2 was detected by site based testing after 6 CAB LA injections. Central testing retrospectively identified the infection 14 weeks earlier.
Plasma CAB levels were consistently 8X during the injection phase. Person refused to believe they had HIV so had viral detectability but no integrase mutation was observed & the person eventually suppressed on Darunavir-based regimen.
D3 - Detected at the site after 5 injections but central lab testing identified 17 weeks earlier. PK decreased to just over 4X between injections 1 & 2. Participant suppressed on a boosted PI regimen.
D4 - detected at the site after 4 injections & central testing identified 6 weeks earlier. CAB concentrations were 8x with a decline to 2x between weeks 1 & 2 of injections.
A delay in ART due to linkage was associated with viremia escape along with integrase mutations but was suppressed with EFV+TDF/FTC regimen.
No changes with the extended testing algorithm. 37 of 39 infections explaining by sub optimal or non adherence.
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