Exposure and virologic outcomes of dolutegravir combined with ritonavir boosted darunavir in treatment-naïve individuals enrolled in the Netherlands Cohort Study on Acute HIV infection (NOVA)

H. A.B. Prins, L. Zino*, NOVA Study Team, E. M. Svensson, A. Verbon, G. J. de Bree, J. M. Prins, P. Reiss, D. M. Burger, C. Rokx, A. Colbers

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

To the authors’ knowledge, there is currently no literature or guidance recommendation regarding whether the dose of dolutegravir (DTG) should be increased when co-administered with darunavir/ritonavir (DRV/r) in patients with acute human immunodeficiency virus infection (AHI). This study assessed the pharmacokinetics (PK) of twice-daily (BID) DTG and once-daily (QD) DRV/r, and compared this with DTG QD without DRV/r in patients with AHI. Forty-six participants initiated antiretroviral therapy within <24 h of enrolment: DTG 50 mg BID, DRV/r 800/100 mg QD, and two nucleoside reverse transcriptase inhibitors (NRTIs) for 4 weeks (Phase I); and DTG 50 mg QD with two NRTIs thereafter (Phase II: reference). Total DTG trough concentration (Ctrough) and area under the concentration–time profile of 0–24 h (AUC0–24h) were predicted using a population PK model. DTG glucuronidation metabolic ratio (MR) and DTG free fraction were determined and compared per treatment phase using geometric mean ratio (GMR) and 90% confidence interval (CI). Participants had a predicted geometric mean steady-state DTG Ctrough of 2.83 [coefficient of variation (CV%) 30.3%] mg/L (Phase I) and 1.28 (CV% 52.4%) mg/L (Phase II), with GMR of 2.20 (90% CI 1.90–2.55). Total exposure during DTG BID increased but did not double [AUC0–24h GMR 1.65 (90% CI 1.50–1.81) h.mg/L]. DTG glucuronidation MR increased by approximately 29% during Phase I. DTG Ctrough was above in-vivo EC90 (0.32 mg/L) during both phases, except in one participant during Phase I. At Week 8, 84% of participants had viral loads ≤40 copies/mL. The drug–drug interaction between DTG (BID) and DRV/r (QD) was due to induced glucuronidation, and is not clinically relevant in patients with AHI.

Original languageEnglish
Article number106697
JournalInternational Journal of Antimicrobial Agents
Volume61
Issue number1
DOIs
Publication statusPublished - Jan 2023

Bibliographical note

Funding:
The NOVA study is part of the H-TEAM Initiative which
is supported by Aids Fonds (Grant No. 2013169); AmsterdamDiner Foundation, Bristol-Myers Squibb International Corp
(Study No. AI424-541); Gilead Sciences Europe Ltd (Grant No.
PA-HIV-PREP-16-0024); Gilead Sciences (Protocol Nos. CO-NL-276-
4222, CO-US-276-1712); Janssen Pharmaceuticals (Reference No.
PHNL/JAN/0714/0005b/1912fde); M.A.C. AIDS Fund, ViiV Healthcare (PO Nos. 3000268822, 3000747780); and ZonMw (Grant No.
522002003). The ATHENA cohort is managed by Stichting HIV
Monitoring and supported by a grant from the Dutch Ministry of
Health, Welfare and Sport through the Centre for Infectious Disease
Control of the National Institute for Public Health and the Environment.

Publisher Copyright:
© 2022 The Author(s)

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