Kwamena W. Sagoe

CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients

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 single-nucleotide polymorphisms (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 (4030 ng/ml increase; 95% confidence interval 2882–5505 ng/ml, P < 0.001), UGT2B7*1a carrier status (475 ng/ml increase; 95% confidence interval 138–899 ng/ml, P = 0.004) and CYP2A6*9 and/or *17 carrier status (372 ng/ml increase; 95% confidence interval 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. Conclusion: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.

The burden of stroke in Africa: a glance at the present and a glimpse into the future.

Summary Objective Information 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. Methods We 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. Results Community-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. Conclusions While the available study data and evidence are limited, the burden of stroke in Africa appears to be increasing.

Pharmacokinetics of Efavirenz When Co‐administered With Rifampin in TB/HIV Co‐infected Patients: Pharmacogenetic Effect of CYP2B6 Variation

The goal of this study was to determine the effect of CYP2B6 genetic variation on the steady‐state pharmacokinetics of efavirenz (600 mg/d) 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 < .0001) or GG genotype (107 vs 23.0 μg·h/mL, P < .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 < .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.

Paradoxically elevated efavirenz concentrations in HIV/tuberculosis-coinfected patients with CYP2B6 516TT genotype on rifampin-containing antituberculous therapy

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 on the basis of the patients genotype.

Prevalence and impact of hepatitis B and C virus co-infections in antiretroviral treatment naïve patients with HIV infection at a major treatment center in Ghana.

Data on the effects of the presence of hepatitis B virus (HBV) and hepatitis C virus (HCV) in patients co‐infected with these viruses and HIV in West Africa are conflicting and little information is available in Ghana. A cohort of 138 treatment naïve individuals infected with HIV was screened for HBV and HCV serologic markers; HBsAg positive patients were tested for HBeAg, anti‐HBe, and anti‐HBc IgM. The viral load of HIV‐1 in the plasma was determined in 81 patients. Eighteen of the 138 patients (13%) and 5 (3.6%) had HBsAg and anti‐HCV, respectively. None of the patients had anti‐HBc IgM, but 10 (55.6%) and 8 (44.4%) of the 18 patients who were HBsAg positive had HBeAg and anti‐HBe, respectively. In patients with measurement of CD4+ undertaken within 1 month (n = 83), CD4+ count was significantly lower in patients with HBeAg (median [IQR], 81 [22–144]) as compared to those with anti‐HBe (median [IQR], 210 [197–222]) (P = 0.002, CI: −96.46 to 51.21). However, those with HIV mono‐infection had similar CD4+ counts (median [IQR], 57 [14–159]) compared to those with HBeAg (P = 1.0, CI: −71.75 to 73.66). Similar results were obtained if CD4+ count was measured within 2 months prior to initiation of HAART (n = 119). Generally, HBV and anti‐HCV did not affect CD4+ and viral loads of HIV‐1 in plasma but patients with HIV and HBV co‐infection who had HBeAg had more severe immune suppression as compared to those with anti‐HBe. This may have implication for initiating HAART in HBV endemic areas. J. Med. Virol. 84:6–10, 2011.

Web interface-supported transmission risk assessment and cost-effectiveness analysis of postdonation screening: a global model applied to Ghana, Thailand, and the Netherlands.

BACKGROUND: The goal of our research was to actively involve decision makers in the economic assessment of screening strategies in their region. This study attempted to accomplish this by providing an easy‐to‐use Web interface at http://www.bloodsafety.info that allows decision makers to adapt this model to local conditions.

Phenotyping Stroke in Sub-Saharan Africa: Stroke Investigative Research and Education Network (SIREN) Phenomics Protocol

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.

Cost-effectiveness of HIV screening of blood donations in Accra (Ghana)

OBJECTIVES Areas with high HIV-incidence rates compared to the developed world may benefit from additional testing in blood banks and may show more favorable cost-effectiveness ratios. We evaluated the cost-effectiveness of adding p24 antigen, mini pool nucleic acid amplification testing (MP-NAT), or individual donation NAT (ID-NAT) to the HIV-antibody screening at the Korle Bu Teaching Hospital (Accra, Ghana), where currently only HIV-antibody screening is undertaken. METHODS The residual risk of HIV transmission was derived from blood donations to the blood bank of the Korle Bu Teaching Hospital in 2004. Remaining life expectancies of patients receiving blood transfusion were estimated using the World Health Organization life expectancies. Cost-effectiveness ratios for adding the tests to HIV-antibody screening only were determined using a decision tree model and a Markov model for HIV. RESULTS The prevalence of HIV was estimated at 1.51% in 18,714 donations during 2004. The incremental cost per disability-adjusted life-year (DALY) averted was US

Stroke genomics in people of African ancestry: charting new paths.

1237 for p24 antigen, US

Severe acute rotavirus gastroenteritis in children less than 5 years in southern Ghana: 2006-2011.

3142 for MP-NAT and US