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Objective In AIDS Clinical Trials Group study A5338, concomitant rifampicin, isoniazid, and efavirenz was associated with more rapid plasma medroxyprogesterone acetate (MPA) clearance compared to historical controls without tuberculosis or HIV therapy. We characterized the pharmacogenetics of this interaction. Methods In A5338, women receiving efavirenz-based HIV therapy and rifampicin plus isoniazid for tuberculosis underwent pharmacokinetic evaluations over 12 weeks following a 150-mg intramuscular injection of depot MPA. Data were interpreted with nonlinear mixed-effects modelling. Associations between individual pharmacokinetic parameters and polymorphisms relevant to rifampicin, isoniazid, efavirenz, and MPA were assessed. Results Of 62 A5338 participants in four African countries, 44 were evaluable for pharmacokinetic associations, with 17 CYP2B6 normal, 21 intermediate, and 6 poor metabolizers, and 5 NAT2 rapid, 20 intermediate, and 19 slow acetylators. There were no associations between either CYP2B6 or NAT2 genotype and MPA Cmin at week 12, apparent clearance, Cmax, area under the concentration-time curve (AUC) or half-life, or unexplained interindividual variability in clearance, and uptake rate constant or mean transit time of the slow-release fraction (P > 0.05 for each). In exploratory analyses, none of 28 polymorphisms in 14 genes were consistently associated with MPA pharmacokinetic parameters, and none withstood correction for multiple testing. Conclusions Study A5338 suggested that more frequent depot MPA dosing may be appropriate for women receiving rifampicin, isoniazid, and efavirenz. The present results suggest that knowledge of CYP2B6 metabolizer or NAT2 acetylator status does not inform individualized DMPA dosing in this setting.

HIV protease inhibitors anti-Plasmodium falciparum activity in adults remains uncertain.Adults with HIV CD4+ counts200 cells/mm3 starting antiretroviral therapy (ART) with P. falciparum subclinical parasitemia (Pf SCP) were randomized 1:1 to (step 1) protease inhibitor lopinavir/ritonavir (LPV/r)-based (arm A) or nonnucleoside reverse transcriptase inhibitor (nNRTI)-based ART (arm B) for 15 days. In step 2, participants received nNRTI-based ART and trimethoprim/sulfamethoxazole prophylaxis for 15 days. P. falciparum SCP clearance was measured by polymerase chain reaction. The Fisher exact test [95% exact confidence interval (CI)] was used to compare proportions of P. falciparum SCP clearance (10 parasites/μL on 3 occasions within 24 hours) between LPV/r and nNRTI arms at day 15. The Kaplan-Meier method and log-rank test were used to compare time-to-clearance.Fifty-two adults from Kenya, Malawi, and Uganda with a median age = 31 (Q1, Q3: 24-39) years, 33% women, with baseline median CD4+ counts of 324 (259-404) cells/mm3, median HIV-1 RNA viremia of 5.18 log10 copies/mL (4.60-5.71), and median estimated P. falciparum density of 454 parasites/μL (83-2219) enrolled in the study. Forty-nine (94%) participants completed the study. At day 15, there was no statistically significant difference in the proportions of P. falciparum SCP clearance between the LPV/r (23.1% clearance; 6 of the 26) and nNRTI (26.9% clearance; 7 of the 26) arms [between-arm difference 3.9% (95% CI, -21.1% to 28.4%; P = 1.00)]. No significant difference in time-to-clearance was observed between the arms (P = 0.80).In a small randomized study of adults starting ART with P. falciparum SCP, no statistically significant differences were seen between LPV/r- and nNRTI-based ART in P. falciparum SCP clearance after 15 days of treatment.

Background:The BD FACSPresto™system uses capillary and venous blood to measure CD4 absolute counts (CD4), %CD4 in lymphocytes, and hemoglobin (Hb) in approximately 25 minutes. CD4 cell count is used with portable CD4 counters in resource-limited settings to manage HIV/AIDS patients. A method comparison was performed using capillary and venous samples from seven clinical laboratories in five countries. The BD FACSPresto system was assessed for variability between laboratory, instrument/operators, cartridge lots and within-run at four sites.Methods:Samples were collected under approved voluntary consent. EDTA-anticoagulated venous samples were tested for CD4 and %CD4 T cells using the gold-standard BD FACSCalibur™system, and for Hb, using the Sysmex®KX-21N™analyzer. Venous and capillary samples were tested on the BD FACSPresto system. Matched data was analyzed for bias (Deming linear regression and Bland-Altman methods), and for concordance around the clinical decision point. The coefficient of variation was estimated per site, instrument/operator, cartridge-lot and between-runs.Results:For method comparison, 93% of the 720 samples were from HIV-positive and 7% from HIV-negative or normal subjects. CD4 and %CD4 T cells venous and capillary results gave slopes within 0.96–1.05 and R2≥0.96; Hb slopes were ≥1.00 and R2≥0.89. Variability across sites/operators gave %CV Conclusion:The BD FACSPresto system provides accurate, reliable, precise CD4/%CD4/Hb results compared to gold-standard methods, irrespective of venous or capillary blood sampling. The data showed good agreement between the BD FACSPresto, BD FACSCalibur and Sysmex systems.

The Dutch Disciplinary Tribunal officially ‘warned’ two Dutch physicians following their study with a Kenyan collaborator on the efficacy of the homeopathic substance Iquilai (‘a potentized mineral supplement’) in 228 HIV/AIDS patients in Kenya.1,2 The case was brought forward by the Dutch Health Inspectorate, who had launched an investigation into the practice of the two involved physicians. The Tribunal deemed the study incompatible with basic medical ethical principles for human subjects’ research, as laid down in the World Medical Association’s Declaration of Helsinki: the study lacked a proper study protocol, informed consent forms, risk assessment, and ethical approval.2,3 \ud \ud This case and its ruling are remarkable for at least two reasons. First, we appreciate the Tribunal’s recognition of previous jurisprudence that their mandate in oversight over Dutch doctors extends beyond the country’s borders. This strengthens the extent to which foreign physicians working in low resource countries can be held accountable for their actions. \ud Second, given the misconduct, the lack of a ‘reprimand’ seems mild. The Tribunal justified it’s ruling with the ‘good intentions’ of the involved researchers, and the assumptions that ‘patients were well informed’ and ‘were not exposed to health risks’. Although we cannot comment on the former, there was no evidence to substantiate the latter two considerations; consent forms were lacking and data collection was inconsistent. We strongly believe that for all research – and especially in low resource settings where institutional ethical safeguards may be limited or easier to circumvent – that the burden to understand and comply with ethical principles is on the researcher, whether foreign or local, all good intentions aside. Finally, research collaborators from low resource settings must also be held accountable and every opportunity seized to collaboratively strengthen institutional ethical protection systems in low resource settings.

BackgroundUse of antiretroviral drugs (ARVs) for a discrete period for Preventing Mother-to-Child HIV transmission (PMTCT) only may be compared to Structured Treatment Interruption, which has been associated with virologic failure (VF). We sought to determine factors associated with VF among women on Antiretroviral Therapy (ART) but with prior exposure to short-term ARVs for PMTCT.MethodsHIV-infected women presenting for ART initiation in three HIV care clinics in Kisumu County, Kenya were enrolled in the KiBS follow-up study (2010–2013) if they had previously received triple ARVs for PMTCT (Group 1) or short-course ARVs for PMTCT (Group 2) or were ARVs-naïve (Group 3). First-line ART was provided as per 2010 WHO treatment guidelines and viral load (VL) tests were conducted every six months for 24 months. VF was defined as any confirmed VL value ≥400 copies/ml after 6 months of ART initiation. Frequencies and proportions were used in the descriptive analysis while Pearson’s Chi-square/Fisher’s exact test was used to determine the association between VF and eight independent variables. Univariate and Multivariate Cox-proportional regression model was fitted to investigate factors associated with VF.ResultsOut of 284 participants data for 245 were analysed (Group 1: 27; Group 2: 107; Group 3: 111). Majority were aged 25–29 years and over 60% had primary/lesser education. There were 39 (Group 1: 5; Group 2: 16; Group 3: 18) VFs with a total VF incidence of 8.12 [95% CI (5.96, 11.17)] per 1000 Person months of observation (PMOs). Group 2 had the lowest VF incidence. Baseline CD4 3 and initiation/use of TDF/3TC/EFV were associated with virologic failure (VF).ConclusionWomen at risk of VF based on the identified risk factors should be identified and targeted with appropriate intervention. Further studies are needed to verify and understand the mechanisms of association between VF and TDF/3TC/EFV which is a WHO-recommended first-line ART regimen.

Background The BD FACSPresto™ Near-Patient CD4 Counter was developed to expand HIV/AIDS management in resource-limited settings. It measures absolute CD4 counts (AbsCD4), percent CD4 (%CD4), and hemoglobin (Hb) from a single drop of capillary or venous blood in approximately 23 minutes, with throughput of 10 samples per hour. We assessed the performance of the BD FACSPresto system, evaluating accuracy, stability, linearity, precision, and reference intervals using capillary and venous blood at KEMRI/CDC HIV-research laboratory, Kisumu, Kenya, and precision and linearity at BD Biosciences, California, USA. Methods For accuracy, venous samples were tested using the BD FACSCalibur™ instrument with BD Tritest™ CD3/CD4/CD45 reagent, BD Trucount™ tubes, and BD Multiset™ software for AbsCD4 and %CD4, and the Sysmex™ KX-21N for Hb. Stability studies evaluated duration of staining (18–120-minute incubation), and effects of venous blood storage