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BackgroundWomen are underrepresented in human immunodeficiency virus (HIV) research in the United States. To determine if women screening for HIV clinical trials enrolled at lower rates than men, we performed a retrospective, cross-trial analysis.MethodsWe conducted an analysis of screening and enrollment during 2003–2013 to 31 clinical trials at 99 AIDS Clinical Trials Group network research sites in the United States. Random-effects meta regression estimated whether sex differences in not enrolling (“screen out”) varied by various individual, trial, or site characteristics.ResultsOf 10 744 persons screened, 18.9% were women. The percentages of women and men who screened out were 27.9% and 26.5%, respectively (P = .19); this small difference did not significantly vary by race, ethnicity, or age group. Most common reasons for screening out were not meeting eligibility criteria (30–35%) and opting out (23%), and these did not differ by sex. Trial and research site characteristics associated with variable screen-out by sex included HIV research domain and type of hemoglobin eligibility criterion, but individual associations did not persist after adjustment for multiple testing.ConclusionsIn the absence of evidence of significantly higher trial screen-out for women, approaching more women to screen may increase female representation in HIV trials.

Summary Background Drug-drug interactions between orally administered antiretroviral therapy (ART) and hormones released from an intravaginal ring are not known. We hypothesised that ART containing either efavirenz or ritonavir-boosted atazanavir would alter plasma concentrations of vaginally administered etonogestrel and ethinylestradiol but that ART concentrations would be unchanged during use of an intravaginal ring. Methods We did a parallel, three-group, pharmacokinetic evaluation at HIV clinics in Asia (two sites), South America (five), sub-Saharan Africa (three), and the USA (11) between Dec 30, 2014, and Sept 12, 2016. We enrolled women with HIV who were either ART-naive (control group; n=25), receiving efavirenz-based ART (n=25), or receiving atazanavir–ritonavir-based ART (n=24). Women receiving ART were required to be on the same regimen for at least 30 days, with 400 copies or less per mL of plasma HIV-1 RNA; women not receiving ART had CD4 counts of 350 cells per μL or less. We excluded participants who had a bilateral oophorectomy or conditions that were contraindicated in the intravaginal ring product labelling. An intravaginal ring releasing etonogestrel and ethinylestradiol was inserted at entry (day 0). Single plasma samples for hormone concentrations were collected on days 7, 14, and 21 after intravaginal ring insertion. The primary outcome was the plasma concentration of etonogestrel and ethinylestradiol on day 21. Etonogestrel and ethinylestradiol concentrations were compared between each ART group and the control group by geometric mean ratio (GMR) with 90% CIs and Wilcoxon rank-sum test. As secondary outcomes, efavirenz or ritonavir-boosted atazanavir concentrations were assessed by 8-h intensive pharmacokinetic sampling at entry before intravaginal ring insertion and before intravaginal ring removal on day 21. Antiretroviral areas under the concentration-time curve (AUC0–8 h) were compared before and after intravaginal ring insertion by GMR (90% CI) and Wilcoxon signed-rank test. This study is registered with ClinicalTrials.gov , number NCT01903031 . Findings Between Dec 30, 2014, and Sept 12, 2016, we enrolled 84 participants in the study; ten participants were excluded from the primary hormone analysis. 74 participants met the primary endpoint: 25 in the control group, 25 in the efavirenz group, and 24 in the atazanavir group. On day 21 of intravaginal ring use, participants receiving efavirenz had 79% lower etonogestrel (GMR 0·21, 90% CI 0·16–0·28; p Interpretation Hormone exposure was significantly lower when an intravaginal ring contraceptive was combined with efavirenz-based ART. Further studies designed to examine pharmacodynamic endpoints, such as ovulation, when intravaginal ring hormones are combined with efavirenz are warranted. Funding National Institutes of Health, through the AIDS Clinical Trials Group and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

OBJECTIVE: In AIDS Clinical Trials Group study A5316, efavirenz significantly lowered plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring, while atazanavir/ritonavir increased etonogestrel and lowered ethinyl estradiol concentrations. We characterized the pharmacogenetics of these interactions. METHODS: In A5316, women with HIV enrolled into control (no antiretrovirals), efavirenz (600 mg daily with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)), and atazanavir/ritonavir (300/100mg daily with NRTIs) groups. On day 0, a vaginal ring was inserted, releasing etonogestrel/ethinyl estradiol 120/15 mcg/day. Intensive plasma sampling for antiretrovirals was obtained on days 0 and 21, and single samples for etonogestrel and ethinyl estradiol were obtained on days 7, 14 and 21. Seventeen genetic polymorphisms were analyzed. RESULTS: The 72 participants in this analysis included 25, 24 and 23 in the control, efavirenz and atazanavir/ritonavir group, respectively. At day 21 in the efavirenz group, CYP2B6 genotype was associated with increased plasma efavirenz exposure (p=3.2×10(−3)), decreased plasma concentrations of etonogestrel (p=1.7×10(−3)), and decreased ethinyl estradiol (p=6.7×10(−4)). Compared to controls, efavirenz reduced median etonogestrel concentrations by at least 93% in CYP2B6 slow metabolizers versus ~75% in normal and intermediate metabolizers. Efavirenz reduced median ethinyl estradiol concentrations by 75% in CYP2B6 slow metabolizers versus ~41% in normal and intermediate metabolizers. No other polymorphisms were significantly associated with hormone or antiretroviral pharmacokinetics. CONCLUSIONS: CYP2B6 slow metabolizer genotype worsens the pharmacokinetic interaction of efavirenz with hormonal contraceptives administered by vaginal ring. Efavirenz dose reduction in CYP2B6 slow metabolizers may reduce, but will likely not eliminate, this interaction.

Background Effective contraception is critical to young women with HIV-associated tuberculosis (TB), as unintended pregnancy is associated with increased perinatal morbidity and mortality. The effects of co-administration of efavirenz and rifampicin on the pharmacokinetics of depot medroxyprogesterone acetate (DMPA) are unknown. We hypothesized that clearance of medroxyprogesterone acetate (MPA) would increase when given with rifampicin and efavirenz, thus increasing risk of ovulation. Methods This pharmacokinetics (PK) study assessed DMPA among HIV/TB coinfected women on an efavirenz-based antiretroviral treatment and rifampicin-based TB treatment. Plasma MPA concentrations and progesterone were measured predose (MPA only) and 2, 4, 6, 8, 10, and 12 weeks after a single DMPA 150 mg intramuscular injection. The primary outcome measure, MPA concentration ( Results Among 42 PK-evaluable women from 5 African countries, median age was 32 years and median CD4 was 414 cells/mm3. Five women (11.9%; 95% CI, 4.0–25.6%) had MPA Conclusions DMPA, when given with rifampicin and efavirenz, was safe. MPA clearance was higher than in women with HIV not on ART, leading to subtherapeutic concentrations of MPA in 12% of women, suggesting that more frequent dosing might be needed. Clinical Trials Registration NCT02412436.

Chronic hepatitis C virus (HCV) infection is a major cause of liver-related morbidity and mortality due to cirrhosis and hepatocellular carcinoma (HCC) [1]. Current HCV therapy is suboptimal due to toxicity, lack of broad efficacy, and poor compliance [2–4]. Although over 2 dozen drugs are being developed against the replicative enzymes of HCV (eg, NS3/4A protease and NS5B polymerase), the area of entry inhibitors is largely unexplored [5]. The use of the in vitro full length JFH-1 (HCV genotype 2a) virus replication system as well as the pseudotyped viruses has allowed characterization of HCV entry [6]. Although many details remain unclear, cellular receptors necessary for HCV entry include scavenger receptor class B, type1 (SR-B1), cluster of differentiation 81 (CD81), claudin-1, and occluding [7–10]. ITX5061 is a high-potency small molecule inhibitor of SR-B1, which is an integral transmembrane protein found in numerous cell types, including the liver. It is a functionally active cell surface high-density lipoprotein (HDL) receptor and is an important component of the reverse cholesterol transport pathway, mediating selective HDL delivery from plasma HDL to the liver [11–13]. Because inhibition of SR-B1 is associated with increases in plasma HDL, ITX5061 was evaluated for treatment of hypoalphalipoproteinemia [14, 15]. Although subsequent trials did not support this, ITX5061 was administered to approximately 280 humans with good safety and reproducible pharmacokinetics (unpublished data). In vitro, ITX5061 differentially binds to SR-B1 expressing cells and specifically inhibits the binding of soluble HCV E2. Further, ITX5061 inhibits HCV cell culture derived (HCVcc) infection at subnanomolar potency, with a therapeutic window >10 000-fold [14]. In vitro, it acts additively with interferon, ribavirin and the protease inhibitor, telaprevir and, based on its unique mechanism of action, no cross-resistance is expected between ITX5061 and HCV polymerase or protease inhibitors [16]. The objective of A5277 was to assess the safety and antiviral activity of ITX5061 in patients infected with HCV genotype 1 who had not previously received HCV treatment.

An understanding of the relationships among allelic variability and clinical outcomes will be critical if HIV-infected patients are to benefit from the explosion in knowledge in human genomics. Human DNA banks must allow future analyses while addressing confidentiality, ethical, and regulatory issues.A multidisciplinary group of clinical investigators, ethicists, data managers, regulatory specialists, and community representatives developed Adult AIDS Clinical Trials Group (AACTG) Protocol A5128. Participants in past or present AACTG clinical trials may contribute DNA. Extraction from whole blood is performed at a central laboratory, where participants' unique identifiers are replaced by randomly assigned identifiers prior to DNA storage. To identify genotype-phenotype relationships, genetic assay results can be temporarily linked to clinical trials data.Institutional review boards in 21 states and Puerto Rico have approved Protocol A5128, and accrual is ongoing. Of the first 4,247 enrollees, 82% are male, 56% are white, 26% are African American, and 15% are Hispanic. Because participants may participate in multiple AACTG protocols, these represent 11,424 cases in 324 different AACTG studies and substudies, with at least 100 participants from 24 different studies. Studies exploring specific genotype-phenotype relationships are underway.The AACTG DNA bank will be an important resource for genomic discovery relevant to HIV therapy.

Poor CD4 lymphocyte recovery on antiretroviral therapy (ART) is associated with reduced function of the thymus. Palifermin (keratinocyte growth factor), by providing support to the thymic epithelium, promotes lymphopoiesis in animal models of bone marrow transplantation and graft-versus-host disease.In AIDS Clinical Trials Group A5212, a randomized, double-blind, placebo-controlled study, 99 HIV-infected patients on ART with plasma HIV-1 RNA levels ≤200 copies per milliliter for ≥6 months and CD4 lymphocyte counts200 cells per cubic milliliter were randomized 1:1:1:1 to receive once daily intravenous administration of placebo or 20, 40, or 60 μg/kg of palifermin on 3 consecutive days.The median change in the CD4 T-cell count from baseline to week 12 was not significantly different between the placebo arm [15 (-16, 23) cells/mm] and the 20-μg/kg dose [11 (2, 32) cells/mm], the 40-μg/kg dose [12 (-2, 25) cells/mm], or the 60-μg/kg dose arm [8 (-13, 35) cells/mm] of palifermin. No significant changes were observed in thymus size or in the number of naive T cells or recent thymic emigrants.Palifermin in the doses studied was not effective in improving thymic function and did not raise CD4 lymphocyte counts in HIV-infected patients with low CD4 cell counts despite virologically effective ART.