Pharmacogenetics contributes to inter-individual variability in pharmacokinetics (PK) of efavirenz (EFV), leading to variations in both efficacy and toxicity. The purpose of this study was to assess the effect of genetic factors on EFV pharmacokinetics, treatment outcomes and genotype based EFV dose recommendations for adult HIV-1 infected Ugandans. In total, 556 steady-state plasma EFV concentrations from 99 HIV infected patients (64 female) treated with EFV/lamivudine/zidovidine were analyzed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1 c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEM) was used to estimate genotype effects on EFV pharmacokinetics. PK simulations were performed based upon population genotype frequencies. Predicted AUCs were compared between the product label and simulations for doses of 300 mg, 450 mg, and 600 mg. EFV apparent clearance (CL/F) was 2.2 and 1.74 fold higher in CYP2B6*6 (*1/*1) and CYP2B6*6 (*1/*6) compared CYP2B6*6 (*6/*6) carriers, while a 22% increase in F1 was observed for carriers of ABCB1 c.4046A>G variant allele. Higher mean AUC was attained in CYP2B6 *6/*6 genotypes compared to CYP2B6 *1/*1 (p40 copies/mL after 84 days of treatment. No trend with exposure was noted for these six patients. Results of this study suggest that daily doses of 450 mg and 300 mg might meet the EFV treatment needs of HIV-1 infected Ugandans in general and individuals homozygous for CYP2B6*6 mutation, respectively.

Treatment with effective antiretroviral therapy (ART) lowers morbidity and mortality among HIV positive individuals. Effective highly active antiretroviral therapy (HAART) should lead to undetectable viral load within 6 months of initiation of therapy. Failure to achieve and maintain viral suppression may lead to development of resistance and increase the risk of viral transmission. In this paper three logistic regression based machine learning approaches are developed to predict early virological outcomes using easily measurable baseline demographic and clinical variables (age, body weight, sex, TB disease status, ART regimen, viral load, CD4 count). The predictive performance and generalizability of the approaches are compared. The multitask temporal logistic regression (MTLR), patient specific survival prediction (PSSP) and simple logistic regression (SLR) models were developed and validated using the IDI research cohort data and predictive performance tested on an external dataset from the EFV cohort. The model calibration and discrimination plots, discriminatory measures (AUROC, F1) and overall predictive performance (brier score) were assessed. The MTLR model outperformed the PSSP and SLR models in terms of goodness of fit (RMSE = 0.053, 0.1, and 0.14 respectively), discrimination (AUROC = 0.92, 0.75 and 0.53 respectively) and general predictive performance (Brier score= 0.08, 0.19, 0.11 respectively). The predictive importance of variables varied with time after initiation of ART. The final MTLR model accurately (accuracy = 92.9%) predicted outcomes in the external (EFV cohort) dataset with satisfactory discrimination (0.878) and a low (6.9%) false positive rate. Multitask Logistic regression based models are capable of accurately predicting early virological suppression using readily available baseline demographic and clinical variables and could be used to derive a risk score for use in resource limited settings.

The WHO recommends supervised administration of sulphadoxine-pyrimethamine (SP) as intermittent preventive treatment for malaria (IPTp) during pregnancy. Logistical constraints have however favoured unsupervised intake of SP-IPTp, casting doubts whether recent guidelines requiring more frequent intake can be effectively implemented. To propose strategies for enhancing compliance under limited supervision, this study sought to identify pregnant women’s knowledge and practices gaps as well as determine predictors of compliance with SP-IPTp, given under limited supervision. A cross-sectional study of 700 women used exit interviews at an urban clinic in Uganda to obtain a descriptive summary of demographic and obstetric characteristics, including knowledge, practice and experiences with SP. Predictors of compliance with SP intake instructions were explored using logistic regression. Median age of respondents was 25 (IQR 22–28) and median parity was two (IQR one to three) while median number of antenatal clinic (ANC) visits was 3.0 (IQR three to four). Most women had completed primary (36%) or ordinary secondary education (25.6%) while 16.1% had not completed primary education. Awareness about SP was high (99.4%) although correct knowledge regarding its use in pregnancy was low (57%), with 15.4% thinking it was used to treat malaria and 26.7% lacking any idea about its use. Correct knowledge on SP use during pregnancy significantly predicted compliance with SP-IPTp instructions (OR 1.98, C.I. 1.12-3.55), while age, education level, parity, number of ANC visits, or history of unwanted effects with SP did not. SP was mostly accessed from hospitals (64.4%) followed by private clinics (16.9%) both for preventive and treatment purposes. SP was considered safe by most women, who were willing to take it again in future, without supervision. Despite high awareness, knowledge of SP as an intervention for malaria prevention in pregnancy was low. Correct knowledge on use of SP predicted compliance with SP-IPTp intake instructions. Focused malaria-related education during ANC visits may improve compliance with SP intake amidst limited supervision.

Purpose: Plasma albumin, a biomarker for hepatic function, is reported to correspondingly decrease in concentration as disease severity increases in chronic infections including HIV and TB. Our objective was to develop a semi-mechanistic disease progression model to quantify plasma albumin concentration changes during TB and HIV therapy and identify the associated covariate factors. Methods: Plasma albumin concentration data was collected at specified times for 3 months from 262 HIV participants receiving efavirenz based anti retroviral therapy. Of these, 158 were TB co-infected and on Rifampicin based anti –tuberculosis co-treatment. An indirect response model with zero order albumin production and first order elimination was developed in NONMEM version 7.2 to describe our data. Genotype (CYP2B6*6 and 11, CYP3A5, ABCB1c.3435C>T and ABCB1rs), TB disease status, baseline age, body weight, plasma creatinine, alanine transaminase enzyme and CD4⁺ count were the potential model covariates tested. Results: The proposed model successfully described plasma albumin concentration changes in the study population. There was a 10.9% and 48.6% increase in albumin production rates in HIV only and TB co-infected participants respectively. Participants co-infected with TB showed a 44.2% lower baseline albumin secretion rate than those without TB while ABCB1c.3435C>T mutation was associated with a 16% higher steady state albumin secretion rate following treatment. Conclusion: A semi-mechanistic model describes plasma albumin concentration changes in HIV patients on ART. Further work is required to establish the utility of the model in monitoring disease progression and predicting prognosis in HIV and TB co-infected patients in absence of or during treatment.

Background Sulphadoxine–pyrimethamine (SP) is widely used as an intermittent preventive treatment for malaria in pregnancy (IPTp). However, pharmacokinetic studies in pregnancy show variable and often contradictory findings. We describe population and trimester-specific differences in SP pharmacokinetics among Ugandan women. Methods SP (three tablets) were administered to 34 nonpregnant and 87 pregnant women in the second trimester. Seventy-eight pregnant women were redosed in the third trimester. Blood was collected over time points ranging from 0.5 h to 42 days postdose. Data on the variables age, body weight, height, parity, gestational age, and serum creatinine, alanine transaminase and albumin levels were collected at baseline. Plasma drug assays were performed using high-performance liquid chromatography with ultraviolet detection. Population pharmacokinetic analysis was done using NONMEM software. Results A two-compartment model with first-order absorption and a lag time best described both the sulphadoxine and pyrimethamine data. Between trimesters, statistically significant differences in central volumes of distribution (V ₂) were observed for both drugs, while differences in the distribution half-life and the terminal elimination half-life were observed for pyrimethamine and sulphadoxine, respectively. Significant covariate relationships were identified on clearance (pregnancy status and serum albumin level) and V ₂ (gestational age) for sulphadoxine. For pyrimethamine, clearance (pregnancy status and age) and V ₂ (gestational age and body weight) were significant. Considering a 25 % threshold for clinical relevance, only differences in clearance of both drugs between pregnant and nonpregnant women were significant. Conclusion While clinically relevant differences in SP disposition between trimesters were not seen, increased clearance with pregnancy and the increasing volume of distribution in the central compartment with gestational age lend support to the revised World Health Organization guidelines advocating more frequent dosing of SP for IPTp.