SummaryObjectiveInformation on the current burden of stroke in Africa is limited. The aim of this review was to comprehensively examine the current and projected burden of stroke in Africa.MethodsWe systematically reviewed the available literature (PubMed and AJOL) from January 1960 and June 2014 on stroke in Africa. Percentage change in age-adjusted stroke incidence, mortality and disability-adjusted life years (DALYs) for African countries between 1990 and 2010 were calculated from the Global Burden of Diseases (GBD) model-derived figures.ResultsCommunity-based studies revealed an age-standardised annual stroke incidence rate of up to 316 per 100 000 population, and age-standardised prevalence rates of up to 981 per 100 000. Model-based estimates showed significant mean increases in age-standardised stroke incidence. The peculiar factors responsible for the substantial disparities in incidence velocity, ischaemic stroke proportion, mean age and case fatality compared to high-income countries remain unknown.ConclusionsWhile the available study data and evidence are limited, the burden of stroke in Africa appears to be increasing.

H3Africa is developing capacity for health-related genomics research in Africa

Objective UDP-glucuronosyltransferase (UGT) 2B7 was recently identified as the main enzyme mediating efavirenz N-glucuronidation. In this study we determined whether selected UGT2B7 polymorphisms could be used to enhance the prediction of efavirenz plasma concentrations from CYP2B6 and CYP2A6 genotypes. Methods Mid-dose efavirenz plasma concentrations were determined in 94 HIV-infected Ghanaian patients at 2–8 weeks of antiretroviral therapy. CYP2B6 and CYP2A6 genotypes had been previously reported. UGT2B7 exon 2 SNPs c.735A>G (UGT2B7*1c; rs28365062) and c.802C>T (H268Y; UGT2B7*2; rs7439366) were determined by direct sequencing with UGT2B7*1a defined as the reference allele. Relationships between efavirenz plasma concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches. Results The mean (±SD) mid-dose efavirenz plasma concentration was 3218 (±3905) ng/mL with coefficient of variation of 121%. Independent predictors of efavirenz concentration included CYP2B6 c.516TT genotype (4,030 ng/mL increase; 95% CI, 2,882–5,505 ng/mL, P<0.001), UGT2B7*1a carrier status (475 ng/mL increase; 95% CI, 138–899 ng/mL, P=0.004) and CYP2A6*9 and/or *17 carrier status (372 ng/mL increase; 95% CI, 74–742 ng/mL, P=0.013). Overall, CYP2B6 c.516TT genotype, UGT2B7*1a carrier status and CYP2A6*9 or *17 carrier status accounted for 45.2%, 10.1%, and 8.6% of the total variance, respectively. Conclusions Our findings demonstrate independent effects of CYP2A6 and UGT2B7 genetic variation on efavirenz disposition beyond that of the CYP2B6 polymorphisms. The development and testing of a pharmacogenetic algorithm for estimating the appropriate dose of efavirenz should incorporate genotypic data from both the oxidative and glucuronidation pathways.

Background: As the second leading cause of death and the leading cause of adult-onset disability, stroke is a major public health concern particularly pertinent in Sub-Saharan Africa (SSA), where nearly 80% of all global stroke mortalities occur, and stroke burden is projected to increase in the coming decades. However, traditional and emerging risk factors for stroke in SSA have not been well characterized, thus limiting efforts at curbing its devastating toll. The Stroke Investigative Research and Education Network (SIREN) project is aimed at comprehensively evaluating the key environmental and genomic risk factors for stroke (and its subtypes) in SSA while simultaneously building capacities in phenomics, biobanking, genomics, biostatistics, and bioinformatics for brain research. Methods: SIREN is a transnational, multicentre, hospital and community-based study involving 3,000 cases and 3,000 controls recruited from 8 sites in Ghana and Nigeria. Cases will be hospital-based patients with first stroke within 10 days of onset in whom neurovascular imaging will be performed. Etiological and topographical stroke subtypes will be documented for all cases. Controls will be hospital- and community-based participants, matched to cases on the basis of gender, ethnicity, and age (±5 years). Information will be collected on known and proposed emerging risk factors for stroke. Study Significance: SIREN is the largest study of stroke in Africa to date. It is anticipated that it will shed light on the phenotypic characteristics and risk factors of stroke and ultimately provide evidence base for strategic interventions to curtail the burgeoning burden of stroke on the sub-continent.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Cytochrome P450 (CYP) 2B6 polymorphisms, particularly c.516G→T, are strongly associated with plasma efavirenz concentrations, but do not entirely explain interindividual variability in efavirenz exposure.• In vitro data suggest that CYP2A6 is involved in the metabolism of efavirenz.• Rifampicin can induce the function and activity of the main metabolizing for efavirenz and causes small (22-26%) reductions in efavirenz area under the curve during co-administration, although with wide interindividual variability. WHAT THIS STUDY ADDS• Identifies CYP2B6 516G→T polymorphism and carriers of CYP2A6*9B and/or *17 variants as independent predictors of efavirenz mid-dose concentration in human immunodeficiency virus-infected patients.• Factors such as concurrent therapy with rifampicin-containing tuberculosis regimen, gender and body mass index had no a significant influence on efavirenz mid-dose concentration.• Provides in vivo evidence that CYP2A6 is likely to be involved in the metabolism of efavirenz. AIMSInterindividual variability in efavirenz pharmacokinetics is not entirely explained by the well-recognized CYP2B6 516G→T single nucleotide polymorphism. The aim of this study was to determine whether polymorphisms in the CYP2A6 gene can be used to enhance the predictability of efavirenz concentrations in human immunodeficiency virus (HIV)-infected native African patients. METHODSMid-dose efavirenz plasma concentrations were determined at 4 and 8 weeks following initiation of antiretroviral therapy in 65 HIV-infected Ghanaian patients. Selected CYP2B6 and CYP2A6 genotypes were determined by commercial 5′-nuclease assays. Relationships between averaged 4-and 8-week mid-dose efavirenz concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches including gene-gene interactions. RESULTSCYP2B6 c.516G→T, CYP2B6 c.983T→C, CYP2A6*9B and CYP2A6*17 allele frequencies were 45, 4, 5 and 12%, respectively. Rifampicin therapy, gender, age and body mass index had no significant influence on efavirenz mid-dose concentrations. Median efavirenz concentrations were more than five times higher (P < 0.001) in patients with CYP2B6 c.516TT genotype compared with GG and GT genotypes. Although none of the CYP2A6 genotypes was associated with altered efavirenz concentrations individually, CYP2A6*9B and/or CYP2A6*17 carriers showed a 1.8 times higher median efavirenz concentration (P = 0.017) compared with noncarriers. Multiple linear regression analysis indicated that the CYP2B6 c.516G→T polymorphism and CYP2A6 slow-metabolizing variants accounted for as much as 36 and 12% of the total variance in efavirenz concentrations, respectively. CONCLUSIONSOur findings support previous work showing efavirenz oxidation by CYP2A6, and suggest that both CYP2A6 and CYP2B6 genotyping may be useful for predicting efavirenz plasma concentrations.

Summary Some individuals have higher efavirenz plasma concentrations during rifampin-containing tuberculosis (TB) therapy, contrary to the expected induction effect of rifampin. Among HIV-infected patients without (N=38) and with TB on rifampin-containing therapy (N=18), we tested the hypothesis that drug-gene interaction may explain the highly variable drug interactions. Two-way analysis of variance revealed a significant interaction between CYP2B6 516G→T polymorphism and rifampin-containing therapy, suggesting that efavirenz dose-adjustment may need to be individualized based on the patient’s genotype.

The goal of this study was to determine the effect of CYP2B6 genetic variation on the steady-state pharmacokinetics of efavirenz (600 mg/day) in TB/HIV co-infected patients receiving concomitant rifampin, a potent CYP inducer. In the 26 patients studied, CYP2B6 c.516GG, GT and TT genotype frequencies were 0.27, 0.50 and 0.23, respectively. Mean plasma efavirenz area-under-the-curve was significantly higher in patients with CYP2B6 c.516TT than in those with GT (107 vs. 27.6 μg.h/mL, P < 0.0001), or GG genotype (107 vs. 23.0 μg.h/mL, P < 0.0001). Apparent oral clearance (CL/F) was significantly lower in patients with CYP2B6 c.516TT than in those with GT genotype (2.1 vs. 8.4 mL/min/kg, P < 0.0001), and GG genotype (2.1 vs. 9.9 mL/min/kg, P < 0.0001). No differences in efavirenz exposure or CL/F existed between patients with CYP2B6 c.516GT and GG genotypes. Our results indicate that CYP2B6 c.516TT genotype can be used to identify efavirenz poor metabolizers in patients co-treated with rifampin. KeywordsCytochrome P450 2B6; genetic polymorphisms; efavirenz exposure; rifampin Tuberculosis (TB) is the most common complication of human immunodeficiency virus (HIV) infection and is associated with high fatality rates. 1,2 While highly active antiretroviral therapy (HAART) improves survival in co-infected patients, 3-5 potential overlapping drug toxicities, and cytochrome P450 (CYP)-mediated drug-drug interactions constitute major challenges to early initiation of HAART. The magnitude of drug-drug interactions due to rifampin is a major factor in selecting an effective HAART regimen. 6-8 Rifampin is a critical component of TB therapy, 9 but is also a potent inducer of CYP enzyme activity, 10-12 as well as the Pglycoprotein (P-gp) transport system. 13 As a result, the exposure to the HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) is reduced during Currently, it is not known whether CYP induction by rifampin will affect the relationship between CYP2B6 c.516G>T genotype and efavirenz exposure. The reported magnitude of induction of CYP2B6 activity by rifampin in primary human hepatocytes varies. While some authors reported a 7 − 13-fold induction, 10,11 others found only 2.5-fold increase in activity. 12 In one in vivo study, CYP2B6 activity in the presence of rifampin was only 2.1 times that in the absence of rifampin. 23 Co-administration of rifampin with efavirenz 600 mg daily caused a 22% reduction in efavirenz area under the curve (AUC) in HIV/TB co-infected patients, which was overcome by increasing the dose to 800 mg/day. 24 This finding led some experts to recommend an increased efavirenz dose when co-administered with rifampin. 6,7,25 Although an increased efavirenz dose might be appropriate for some persons, it does not take into consideration the variable effect of rifampin on CYP2B6 activity. In the aforementioned pharmacokinetic study, the change in efavirenz AUC with concomitant rifampin ranged from a decrease of 65% to an increase of 37%. 24 Furthermore, vari...

Background: Antiretroviral therapy (ART) scale-up in resource-limited countries, with limited capacity for CD4 and HIV viral load monitoring, presents a unique challenge. We determined the effectiveness of first-line ART in a real world pediatric HIV clinic and explored associations between readily obtainable patient data and the trajectories of change in CD4 count and HIV viral load. Methods: We performed a longitudinal study of a cohort of HIV-infected children initiating ART at the Korle-Bu Teaching Hospital Pediatric HIV clinic in Accra, Ghana, aged 0-13 years from 2009-2012. CD4 and viral load testing were done every 4 to 6 months and genotypic resistance testing was performed for children failing therapy. A mixed linear modeling approach, combining fixed and random subject effects, was employed for data analysis.