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Introduction: Long-acting injectable cabotegravir + rilpivirine (CAB + RPV LAI) was approved for use in virally suppressed adults in the England and Wales national health service in November 2021. We describe a service evaluation of delivery processes and outcomes in 12 clinics., Methods: Centres populated a database using information from local policies and clinical records. Services were asked to describe approval processes, clinic pathways, and adherence to national guidelines. Additional data were collected on reasons for regimen choice, treatment discontinuations, and management of viraemia., Results: In total, 518 adults from 12 clinics were approved for CAB + RPV LAI between February 2022 and December 2023. Of the 518 people approved for CAB + RPV LAI, 423 received at least one injection. Median duration on CAB + RPV was 7.5 months (interquartile range 3.7-11.3). In total, 97% of injections were administered within the ±7-day window. Virological failure occurred in 0.7%, and 6% discontinued CAB + RPV., Conclusion: In this large UK-based cohort, robust approval processes and clinic protocols facilitated on-time injections and low rates of both discontinuation and virological failure., (© 2024 The Author(s). HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Following changes in national antiretroviral therapy (ART) guidelines removing the CD4 threshold for initiation of ART, we evaluated the time to ART initiation and reasons for delayed or non-initiation. A retrospective notes review of 292 newly diagnosed HIV-positive individuals attending two London clinics between August 2015 and December 2016 was performed. Two hundred and fifty-four of 292 (87%) individuals started ART. Median time to ART initiation was 29 days (range: 0-514). Thirty of 292 (13%) did not start ART. Rates of virological suppression at six months were similar regardless of time to ART initiation. People who inject drugs (16.7% vs. 3.6%) (p = 0.009), having a higher median baseline CD4 cell count (500 vs. 388 cells/mm 3 , p = 0.001), and having gastrointestinal/liver co-morbidities (23% vs. 9%, p = 0.001) were associated with delayed ART initiation. The cohort not on ART had a higher median baseline CD4 cell count (500 vs. 388 cells/mm 3 , p < 0.001). Documented reasons for delayed or ART non-initiation included patient's choice, prolonged adjustment periods, and difficulty leaving work. We conclude that delayed or non-initiation of ART was associated with injecting drug use and prolonged adjustment to a new HIV diagnosis. Clinician factors may include lack of urgency with higher baseline CD4 cell counts. Improved linkage to care and drug services pathways may encourage timely ART initiation.

Objectives: Pharmacokinetic parameters following modifications to antiretroviral therapy and sanctuary site exposure are often unknown for recently licensed antiretrovirals. We assessed plasma, CSF and seminal plasma (SP) exposure of rilpivirine after switching from nevirapine., Methods: HIV-infected male subjects receiving tenofovir/emtricitabine/nevirapine (245/200/400 mg) once daily switched to tenofovir/emtricitabine/rilpivirine (245/200/25 mg) once daily for 60 days when CSF and semen samples were collected. Mean and individual plasma concentrations of nevirapine and rilpivirine were compared with the proposed plasma target concentration for nevirapine (3000 ng/mL) and the protein binding-adjusted EC90 for rilpivirine (12.1 ng/mL). Mean rilpivirine CSF and SP concentrations were calculated and individual values compared with the EC50 and EC90 for wild-type virus (0.27 and 0.66 ng/mL, respectively)., Results: Of 13 subjects completing study procedures including CSF examination, 8 provided seminal samples. By day 3, the mean plasma rilpivirine trough concentration was 29.7 ng/mL (95% CI: 23.8-37). No patient presented rilpivirine plasma concentrations under the proposed threshold. The mean rilpivirine concentration in CSF was 0.8 ng/mL (95% CI: 0.7-1.0), representing a CSF : plasma ratio of 1.4%, with concentrations above the EC90 in 85% (11/13) of patients. In SP, the mean rilpivirine concentration was 4.9 ng/mL (95% CI: 3.3-7.2), representing an SP : plasma ratio of 9.5%, with all concentrations above the EC90., Conclusions: Switching from nevirapine- to rilpivirine-containing antiretroviral therapy was safe and well tolerated, with plasma rilpivirine concentrations above the protein binding-adjusted EC90 in all subjects. Rilpivirine concentrations were always above the EC50 in the CSF and the EC90 in SP., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: HIV-1 genetic variability may influence antiretroviral therapy (ART) outcomes. The study aim was to determine the impact of polymorphisms in regions known to harbor major nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations (codons 90-108, 135-138, 179-190, 225-348) on virologic responses to first-line NNRTI-based ART., Methods: Reverse transcriptase sequences from ART-naive individuals who commenced efavirenz (EFV) or nevirapine (NVP) with at least two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) without major drug resistance mutations were analyzed. The impact of polymorphisms on week 4 viral load decrease and time to virologic failure was measured over a median 97 weeks., Results: Among 4528 patients, most were infected with HIV-1 subtype B (67%) and commenced EFV-based ART (84%). Overall, 2598 (57%) had at least one polymorphism, most frequently at codons 90, 98, 101, 103, 106, 135, 138, 179, and 238. Virologic failure rates were increased in patients with two (n = 597) or more than two (n = 72) polymorphisms [adjusted hazard ratio 1.43; 95% confidence interval (CI) 1.07-1.92; P = 0.016]. Polymorphisms associated with virologic failure occurred at codons 90 (mostly V90I), 98 (mostly A98S), and 103 (mostly K103R), with adjusted hazard ratios of 1.78 (1.15-2.73; P = 0.009), 1.55 (1.16-2.08; P = 0.003), and 1.75 (1.00-3.05: P = 0.049), respectively. Polymorphisms at codon 179, especially V179D/E/T, predicted reduced week 4 responses (P = 0.001) but not virologic failure., Conclusion: The occurrence of multiple polymorphisms, though uncommon, was associated with a small increase in the risk of NNRTI treatment failure; significant effects were seen with polymorphisms at codon 90, 98, and 103. The mechanisms underlying the slower suppression seen with V179D/E/T deserve further investigation.

This study characterized the prevalence and patterns of antiretroviral-drug-resistance mutations according to plasma human immunodeficiency virus type 1 (HIV-1) RNA load in a large population of patients with HIV-1 infection who underwent testing for resistance mutations in routine clinical practice. HIV-1 genotypic resistance test results with linked clinical data were obtained from national resistance and clinical databases in the United Kingdom. Among 7861 tests, detection of > or =1 resistance mutation was most frequent at viral loads of 300-10,000 copies/mL and decreased statistically significantly at viral loads of >10,000 copies/mL. Major resistance mutations were commonly detected in the subset of tests that were performed among patients with viral loads of <1000 copies/mL (1001 [12.7%] of 7861 tests). We conclude that HIV-1 genotypic resistance testing is informative for patients with low viral loads.

Background: Nucleoside-sparing combination antiretroviral therapy (cART) regimens might be an attractive therapeutic option for HIV type-1 (HIV-1)-infected patients; however, the pharmacokinetic profiles of such regimens are frequently unknown., Methods: Fourteen HIV-1-infected patients (age 21-55 years, 64% male) on stable cART with plasma HIV RNA <50 copies/ml entered this Phase I pharmacokinetic study. In period 1, patients received tenofovir/emtricitabine/-darunavir/ritonavir (300/200/800/100 mg) all once daily. During period 2, raltegravir 400 mg twice daily was added to the regimen and in period 3 tenofovir/emtricitabine was discontinued. At steady state, intensive pharmacokinetic sampling was undertaken. Differences in the geometric mean ratio (GMR) for pharmacokinetic parameters between periods 2 versus 1 and period 3 versus 1 were assessed for darunavir and ritonavir (period 3 versus 2 for raltegravir)., Results: No statistically significant differences in pharmacokinetic parameters were observed between period 2 versus period 1. During period 3, darunavir GMR (95% confidence interval) values for trough and maximum plasma concentration (C(trough) and C(max)), area under the plasma concentration-time curve (AUC) and elimination half-life (t(1/2)) were 0.64 ng/ml (0.44-0.93), 1.05 ng/ml (0.90-1.24), 0.92 ng h/ml (0.78-1.08) and 0.69 h (0.46-1.05), respectively, when compared with period 1. No statistically significant changes were observed in ritonavir or raltegravir pharmacokinetic parameters. Darunavir C(trough)<550 ng/ml (the minimum effective concentration for protease-resistant HIV viral isolates) was observed in four patients during period 3 only. No clinically significant safety concerns were reported., Conclusions: Darunavir C(trough) is reduced by 36% when administered without tenofovir/emtricitabine in HIV-1-infected patients. This interaction might be of clinical significance in the management of individuals with protease-resistant HIV viral isolates.

Abacavir is metabolized primarily by two enzymes: alcohol dehydrogenase and gluconyl transferase. Under normal conditions, alcohol is hepatically cleared via alcohol dehydrogenase to acetaldehyde, and subsequently by acetaldehyde dehydrogenase (ACD) to acetic acid. Disulfiram acts as an ACD blocker. Abacavir may also act as an inhibitor of alcohol dehydrogenase, which raises the possibility of disulfiram-like reactions (if complete inhibition occurs) or reduced alcohol tolerance (if partial inhibition occurs) occurring with abacavir therapy.