Background: Objective adherence measures are of increasing interest in antiretroviral treatment (ART) monitoring. Hair ART levels predict virologic suppression and hair is easy to collect and store. No prior study has examined hair levels in an India-based cohort or laboratory. Methods: Small hair samples were collected from HIV-positive participants on either efavirenzbased or nevirapine-based ART in a South India-based study. Hair samples were split and analyzed for efavirenz or nevirapine in the UCSF-based Hair Analytical Laboratory (HAL) and the Division of Nutrition-analytic lab based at St. John's Research Institute (SJRI), Bangalore, India using liquid chromatography/tandem-mass-spectrometry. Agreement (using Bland-Altman methods) and rank correlation between the two laboratories' hair levels were calculated. Rank correlation between self-reported adherence (SRA) over the prior month using a visual analog scale and hair ART levels was calculated. Results: Among 75 participants (38 on nevirapine; 37 on efavirenz), the correlation between nevirapine levels generated by the two laboratories was 0.66 (p <0.0001) and between efavirenz levels was 0.87 (p <0.0001). Measurements from SJRI were usually within 20% of those from the

Hair concentrations of antiretrovirals are associated with virologic outcomes in cohorts of HIV-positive individuals but have never before been examined in a clinical trial. We show for the first time the predictive utility of hair antiretroviral concentrations in a large HIV treatment-naïve trial, AIDS Clinical Trials Group (ACTG) protocol A5257.

Human bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) represent promising stem cell therapy for the treatment of type 2 diabetes mellitus (T2DM), but the results of autologous BM-MSC administration in T2DM patients are contradictory. The purpose of this study was to test the hypothesis that autologous BM-MSC administration in T2DM patient is safe and that the efficacy of the treatment is dependant on the quality of the autologous BM-MSC population and administration routes. T2DM patients were enrolled, randomly assigned (1:1) by a computer-based system into the intravenous and dorsal pancreatic arterial groups. The safety was assessed in all the treated patients, and the efficacy was evaluated based on the absolute changes in the hemoglobin A1c, fasting blood glucose, and C-peptide levels throughout the 12-month follow-up. Our data indicated that autologous BM-MSC administration was well tolerated in 30 T2DM patients. Short-term therapeutic effects were observed in patients with T2DM duration of <10 years and a body mass index <23, which is in line with the phenotypic analysis of the autologous BM-MSC population. T2DM duration directly altered the proliferation rate of BM-MSCs, abrogated the glycolysis and mitochondria respiration of BM-MSCs, and induced the accumulation of mitochondria DNA mutation. Our data suggest that autologous administration of BM-MSCs in the treatment of T2DM should be performed in patients with T2DM duration <10 years and no obesity. Prior to further confirming the effects of T2DM on BM-MSC biology, future work with a larger cohort focusing on patients with different T2DM history is needed to understand the mechanism underlying our observation.

Background Children/adolescents display suboptimal antiretroviral therapy (ART) adherence and outcomes versus adults. Hair ART concentrations are objective adherence measures that predict viremia in adults but longitudinal data on hair levels in pediatric populations is limited. We assessed the predictive utility of hair lopinavir levels on viremia among youth on second-line ART. Methods We examined predictors of viremia (HIV-1 RNA >400 and >1000 copies/ml) at least 24 weeks after switch to lopinavir-based second-line ART in a cohort of HIV-infected Asian children followed between 2011 and 2014. Small hair samples, HIV-1 RNA, and self-reported adherence were collected biannually. Hair concentrations of lopinavir were measured via liquid-chromatography/tandem-mass-spectrometry using validated methods. Time-to-first viremia was examined using discrete-time Cox models. Results Overall, 244 children met inclusion criteria for the present analysis. Approximately half (55%) were males and the median age 10 years (interquartile range [IQR] 7–13); 40% were >11 years. At switch to second-line ART, median CD4 count was 300 (IQR 146–547) cells/mm3 and median HIV-RNA level was 5.0 (IQR 4.3–5.6) log10/mL. Median time of study follow-up was 48 weeks and a median of 3 (range 1–5) hair samples collected from each participant. Adjusting for age, sex, country, self-reported adherence, CD4, and HIV-RNA, higher lopinavir hair concentrations were the strongest predictor of lower odds of viremia (HIV-RNA >400 copies/ml adjusted odds ratio [aOR]=0.41 per doubling in hair concentration, 95% 0.29–0.58, p<0.001; HIV-RNA >1000 copies/ml aOR=0.54, 95% CI 0.45–0.65, p<0.001). Conclusions Hair concentrations predict viremia among children with HIV on 2nd-line ART and could guide clinical decisions for this population.

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Data on the relationship of antiretroviral exposure to measures of human immunodeficiency virus (HIV) persistence are limited. To address this gap, multiple viral, immunologic, and pharmacologic measures were analyzed from individuals with sustained virologic suppression on therapy (median 7 years) in the AIDS Clinical Trials Group A5321 cohort. Among 110 participants on tenofovir-(TFV)-disoproxil-fumarate (TDF)/emtricitabine (FTC)-containing regimens, we found no significant correlation between hair concentrations of individual antiretrovirals (ARVs) in the regimen and measures of HIV persistence (plasma HIV-1 RNA by single copy assay, cell-associated-DNA, cell-associated RNA) or soluble markers of inflammation. These findings suggest that higher systemic ARV exposure may not impact HIV persistence or inflammation.

Rationale Assays 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. Methods ATV 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. Results Our 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%. Conclusions This highly sensitive, highly specific and validated assay can be considered for therapeutic drug monitoring for HIV-infected patients on ATV-based ART.

Cases of seroconversion on PrEP should be carefully investigated given their public health implications and rarity. We report a case of transmitted drug resistance causing seroconversion on PrEP in spite of high adherence, confirmed with dried blood spot and segmental hair drug-level testing and single-genome sequencing.