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BackgroundSuboptimal adherence to antiretroviral therapy (ART) is responsible for most virologic failure among adolescents with HIV. Methods for objectively measuring adherence to ART are limited. This study assessed the association between ritonavir concentrations in hair and self-reported adherence and modified directly administered ART on virologic outcomes among HIV-infected adolescents who were virologically failing second-line ART in Harare, Zimbabwe.MethodsHIV-infected adolescents on atazanavir-based or ritonavir-based second-line treatment for >6 months with viral load ≥1000 copies/mL were randomized to either modified directly administered ART (mDAART) plus standard of care (intervention) or standard of care alone (control). Questionnaires were administered; viral load and hair samples were collected at baseline and after 90 days. Virological suppression was defned as

VRC07-523LS is a safe and well-tolerated monoclonal antibody (mAb) targeting the CD4 binding site on the HIV envelope (Env) trimer. Efficacy of VRC07-523LS, in combination with mAbs targeting other HIV epitopes, will be evaluated in upcoming trials to prevent HIV acquisition in adults. However, differences in the pharmacokinetics (PK) of VRC07-523LS when administered alone vs. in combination with other mAbs have not been formally assessed. We performed a cross-protocol analysis of three clinical trials and included data from a total of 146 adults without HIV who received intravenous (n = 95) or subcutaneous (n = 51) VRC07-523LS, either alone ('single'; n = 100) or in combination with 1 or 2 other mAbs ('combined'; n = 46). We used an open, two-compartment population PK model to describe serum concentrations of VRC07-523LS over time, accounting for inter-individual variabilities. We compared individual-level PK parameters between the combined vs. single groups using the targeted maximum likelihood estimation method to adjust for participant characteristics. No significant differences were observed in clearance rate, inter-compartmental clearance, distribution half-life, or total VRC07-523LS exposure over time. However, for the combined group, mean central volume of distribution, peripheral volume of distribution, and elimination half-life were slightly greater, corresponding to slightly lower predicted concentrations early post-administration with high levels being maintained in both groups. These results suggest potential PK interactions between VRC07-523LS and other mAbs, but with small clinical impact in the context of HIV prevention. Our findings support coadministration of VRC07-523LS with other mAbs, and the use of the developed PK models to design future trials for HIV prevention. [ABSTRACT FROM AUTHOR]

RationaleAssays to quantify antiretrovirals in hair samples are increasingly used to monitor adherence and exposure in both HIV prevention and treatment studies. Atazanavir (ATV) is a protease inhibitor used in combination antiretroviral therapy (ART). We developed and validated a liquid chromatography/tandem mass spectrometry (LC/MS/MS)-based method to quantify ATV in human hair, per the NIH Division of AIDS Clinical Pharmacology Quality Assurance (CPQA) program and the FDA bioanalytical method validation guidelines.MethodsATV was extracted from hair using optimized methods and the extracts were injected onto a BDS C-18 column (5 μm, 4.6 × 100 mm), followed by isocratic elution via a mobile phase composed of 55% acetonitrile, 45% water, 0.15% acetic acid, and 4 mM ammonium acetate, at a flow rate of 0.8 mL/min prior to analysis by MS/MS. Levels were quantified using positive electrospray ionization by multiple reaction monitoring (MRM) for the transitions MH+ m/z 705.3 to m/z 168.0 and MH+ m/z 710.2 to m/z 168.0 for ATV and ATV-d5 (internal standard), respectively.ResultsOur assay demonstrated a linear standard curve (r = 0.99) over the concentration range of 0.0500 ng ATV/mg hair to 20.0 ng/mg hair. The inter- and intraday accuracy of ATV quality control (QC) samples was -1.33 to 4.00% and precision (% coefficient of variation (%CV)) was 1.75 to 6.31%. The %CV for ATV levels in hair samples from highly adherent patients (incurred samples) was less than 10%. No significant endogenous peaks or crosstalk were observed in the specificity test with other HIV drugs. The overall extraction efficiency of ATV from incurred hair samples was greater than 95%.ConclusionsThis highly sensitive, highly specific and validated assay can be considered for therapeutic drug monitoring for HIV-infected patients on ATV-based ART.

BackgroundAdequate antiretroviral exposure is crucial to virological suppression. We assessed the relationship between atazanavir hair levels with self-reported adherence, virological outcomes, and the effect of a home-based adherence intervention in HIV-infected adolescents failing second-line antiretroviral treatment in Zimbabwe.MethodsHIV-infected adolescents on atazanavir/ritonavir-based second-line treatment for ≥6 months with viral load (VL) >1000 copies/mL were randomized to either standard care (control) or standard care plus modified directly administered antiretroviral therapy (intervention). Questionnaires were administered; VL and hair samples were collected at baseline and after 90 days in each group. Viral suppression was defined as 2.35 ng/mg) hair concentrations. Participants with virological failure were more likely to have suboptimal atazanavir hair concentrations (RR = 7.2, 95% CI: 1 to 51, P = 0.049). There were no differences in atazanavir hair concentration between the arms after follow-up.ConclusionsA threshold of atazanavir concentrations in hair (2.35 ng/mg), above which virological suppression was likely, was defined for adolescents failing second-line atazanavir/ritonavir-based ART in Zimbabwe. Male sex and better self-reported adherence were associated with adequate atazanavir hair concentrations. Antiretroviral hair concentrations may serve as a useful clinical tool among adolescents.

Background: Suboptimal adherence to antiretroviral therapy (ART) is responsible for most virologic failure among adolescents with HIV. Methods for objectively measuring adherence to ART are limited. This study assessed the association between ritonavir concentrations in hair and self-reported adherence and modified directly administered ART on virologic outcomes among HIV-infected adolescents who were virologically failing second-line ART in Harare, Zimbabwe. Methods: HIV-infected adolescents on atazanavir-based or ritonavir-based second-line treatment for >6 months with viral load =1000 copies/mL were randomized to either modified directly administered ART (mDAART) plus standard of care (intervention) or standard of care alone (control). Questionnaires were administered; viral load and hair samples were collected at baseline and after 90 days. Virological suppression was defned as <1000 copies/mL after follow-up. Results: Fifty adolescents (13-19 years) were enrolled in the study, and 42 adolescents had ritonavir concentrations measured in hair at baseline and at 90 days. Twenty-three participants (46%) were randomized to mDAART. Viral load suppression at follow-up [regression coefficient (standard error): -0.3 (0.1); 95% confidence interval (CI): -0.5 to -0.06; P = 0.01], self-reported adherence at follow-up [regression coefficient (standard error): 0.01 (0.005); 95% CI: 0.004 to 0.02; P = 0.006], and being male sex [regression coefficient (standard error): 0.3 (0.1); 95% CI: 0.08 to 0.5; P = 0.008] were associated with ritonavir concentrations in hair. The intervention, mDAART, was not associated with ritonavir concentrations [regression coefficient (standard error) 0.2 (0.1); 95% CI: -0.07 to 0.4; P = 0.2]. Conclusions: Ritonavir concentrations in hair predicted virological suppression and were associated with self-reported adherence and being male in this cohort of adolescents with treatment failure to atazanavir-based or ritonavir-based second-line ART. Measuring ritonavir concentrations in hair in adolescents on protease inhibitor-based regimens could assess adherence in this vulnerable group to avert subsequent virologic failure. [ABSTRACT FROM AUTHOR]