Bictegravir exposures in adults with HIV and tuberculosis on a rifampicin-based tuberculosis treatment regimen

Abstract

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Bictegravir exposures in adults with HIV and tuberculosis on a rifampicin-based tuberculosis treatment regimen

Anushka Naidoo^1,2, Hylke Waalewijn³, Kogieleum Naidoo^1,2, Marothi Letsoalo¹, Gillian Dorse¹, Rubeshan Perumal^1,2, Emmanuella Osuala¹, Nonpumelelo Zungu¹, Phindile Msomi¹, Paolo Denti³ and Kelly Dooley⁴

¹Center for the AIDS Program of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal; ²Centre for the AIDS Programme of Research in South Africa (CAPRISA), South African Medical Research Council (SAMRC)-CAPRISA-TB-HIV Pathogenesis and Treatment Research Unit, University of KwaZulu-Natal Nelson R Mandela School of Medicine; ³Division of Clinical Pharmacology, Department of Medicine, University of Cape Town; ⁴Vanderbilt University Medical Center

Background: Bictegravir (BIC) has not been evaluated in people with HIV (PWH) and tuberculosis (TB) taking rifampicin-based TB treatment. Healthy volunteer data showed that rifampicin reduced BIC exposure by about 80%; however, trough concentrations remained threefold above the inhibitory quotient (IQ1) of 0.162 mg/L. Potential exposures below IQ1 in few individuals or breakthrough viremia may be mitigated by a long dissociation half-life of BIC from the HIV-1 integrase enzyme.

Methods: INSIGHT (NCT04734652) is an open-label, non-comparative phase 2b randomized controlled trial in ART-naïve or non-naïve adults with HIV and TB, initiated on a rifampicin-based TB regimen (<8 weeks). Participants were randomized in a 2:1 ratio to either the BIC arm (bictegravir/emtricitabine/tenofovir alafenamide) or a standard of care dolutegravir arm (TLD), dosed twice daily until 2 weeks' post-TB treatment and once daily thereafter, until 48 weeks. Forty-three participants in the BIC arm were enrolled in a semi-intensive pharmacokinetic (PK) sub-study. Semi-intensive PK sampling was done at pre-dose, 1, 2, 4, 6 and 8–12 h post-dose during TB treatment and pre-dose, 1, 2, 4, 6–8 and 24–25 h post-dose after TB treatment. BIC concentrations were assayed using a validated LC-MS/MS method. Non-compartmental PK analyses for BIC were conducted in R using the PKNCA package (version 10.2). Participants underwent regular clinical and safety visits, including HIV viral load measurements at baseline, weeks 4, 8, 12, 24, 40 and 48. We report the preliminary PK data and primary endpoint results for the proportion of participants with plasma HIV-1-RNA < 50 copies/mL at the end of TB treatment (week 24).

Results: We enrolled 122 participants: 80 in the BIC and 42 in the DTG arm. Forty-three (35%) were female, with median (IQR) baseline viral load (copies/mL) and CD4 + (cells/μL) of 75 649 (22 784–391 299) and 172 (108–352) (BIC arm) and 73 735 (21 242–544 830) and 139 (97–237) (DTG arm). In participants in the semi-intensive PK sub-study, 75 PK profiles were evaluated during TB treatment and 22 PK profiles' post-TB treatment. Geometric mean (GM), (CV%) of area under the concentration-time curve from 0 to 24 h (AUC_0–24) and the trough concentration (C_tau) for twice-daily BIC during TB treatment were 30.9 mg*h/L (42.2%) and 0.397 mg/L (73.4%) and for once-daily BIC post-TB treatment were 94.9 mg*h/L (35.9%) and 2.29 mg/L (45.1%), respectively. BIC C_tau during TB treatment were reduced but remained above IQ1 in >98% of participants. HIV-1-RNA at week 24 was <50 copies/mL in 71/73 (97%) and 36/37 (97%) of participants in the BIC and DTG arms, respectively, in the per-protocol analysis, [71/75 (95%) in BIC (two early withdrawals) and 36/38 (95%) in DTG arm (one death) in FDA snapshot analysis]. None of the 15 reported serious adverse events were related to study treatment.

Conclusions: INSIGHT interim results suggest that twice-daily bictegravir/emtricitabine/tenofovir alafenamide with rifampicin-based TB treatment achieves target concentrations for viral efficacy. In the <2% of participants with C_tau below IQ1, viral suppression was maintained, likely due to the long dissociation half-life of BIC from HIV-1 integrase enzyme (163 h). PK, efficacy and safety data support the use of this regimen in PWH and TB.