Ernest Kenu

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.

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.

Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected Ghanaian patients: UGT2B7*1c is associated with faster zidovudine clearance and glucuronidation.

There are limited data on the pharmacokinetics of generic nucleoside reverse transcriptase inhibitors (NRTIs) in native African populations, in whom they are commonly used. The authors characterized the pharmacokinetics of lamivudine (n = 27), zidovudine (n = 16), and stavudine (n = 11) in human immunodeficiency virus (HIV)/tuberculosis (TB)‐coinfected Ghanaians and evaluated associations between zidovudine metabolism and UDP‐glucuronosyltransferase (UGT) 2B7 polymorphisms. Lamivudine, zidovudine, and stavudine apparent oral clearance (CL/F) values (mean ± SD [% coefficient of variation [CV]) were 7.3 ± 2.8 (39%), 31.9 ± 33.6 (106%), and 16.4 ± 5.8 (35%) mL/min/kg, respectively, whereas half‐life values were 4.2 ± 1.9 (46%), 8.1 ± 7.9 (98%), and 1.5 ± 1.0 (65%) hours, respectively. Zidovudine CL/F was 196% higher (P = .004) in UGT2B7*1c (c.735A>G) carriers versus noncarriers. This was confirmed using human liver bank samples (n = 52), which showed 48% higher (P = .020) zidovudine glucuronidation and 33% higher (P = .015) UGT2B7 protein inUGT2B 7*1c carriers versus noncarriers. In conclusion, generic NRTI pharmacokinetics in HIV/TB‐coinfected Ghanaians are similar to other populations, whereas the UGT2B7*1c polymorphism may explain in part relatively high interindividual variability in zidovudine clearance

Risk factors for buruli ulcer in ghana-a case control study in the suhum-kraboa-coaltar and akuapem South districts of the eastern region

Background Buruli ulcer (BU) is a skin disease caused by Mycobacterium ulcerans. Its exact mode of transmission is not known. Previous studies have identified demographic, socio-economic, health and hygiene as well as environment related risk factors. We investigated whether the same factors pertain in Suhum-Kraboa-Coaltar (SKC) and Akuapem South (AS) Districts in Ghana which previously were not endemic for BU. Methods We conducted a case control study. A case of BU was defined as any person aged 2 years or more who resided in study area (SKC or AS District) diagnosed according to the WHO clinical case definition for BU and matched with age- (+/−5 years), gender-, and community controls. A structured questionnaire on host, demographic, environmental, and behavioural factors was administered to participants. Results A total of 113 cases and 113 community controls were interviewed. Multivariate conditional logistic regression analysis identified presence of wetland in the neighborhood (OR = 3.9, 95% CI = 1.9–8.2), insect bites in water/mud (OR = 5.7, 95% CI = 2.5–13.1), use of adhesive when injured (OR = 2.7, 95% CI = 1.1–6.8), and washing in the Densu river (OR = 2.3, 95% CI = 1.1–4.96) as risk factors associated with BU. Rubbing an injured area with alcohol (OR = 0.21, 95% CI = 0.008–0.57) and wearing long sleeves for farming (OR = 0.29, 95% CI = 0.14–0.62) showed protection against BU. Conclusion This study identified the presence of wetland, insect bites in water, use of adhesive when injured, and washing in the river as risk factors for BU; and covering limbs during farming as well as use of alcohol after insect bites as protective factors against BU in Ghana. Until paths of transmission are unraveled, control strategies in BU endemic areas should focus on these known risk factors.

Cancer complicating systemic lupus erythematosus – a dichotomy emerging from a nested case-control study

Objectives We determined whether any individual cancers are increased or decreased in a cohort of 595 patients with systemic lupus erythematosus (SLE) followed for up to 32 years at the University College London Hospitals Lupus Clinic, looking for any associated clinical or serological factors and the prognosis after cancer diagnosis. Methods We undertook a careful retrospective review of the medical records and identified all individuals diagnosed with cancer. For controls, we selected three other patients in the cohort who had not developed cancer, carefully matched for age, sex, ethnicity and disease duration, to determine if any obvious differences emerged in a nested case-control design. Results Thirty-three patients developed cancer after being diagnosed with SLE. There was a statistically insignificant small increase in overall cancer risk, standardized incidence ratios (SIRs) 1.05 (95% CI 0.52–1.58) and increased SIRs for cervical, prostate, anal and pancreatic cancers and reduction in breast cancer SIRs. Haematological and musculoskeletal manifestations, anticardiolipin and antithyroid globulin antibodies were found to be positively associated with cancer risk in multivariate analysis. There was no drug, dose or duration was associated with cancer risk. There was a reduction in survival with a cancer fatality rate of 84.2% (p < 0.0001). Conclusion We found a very small but statistically insignificant increased cancer risk with reduction in survival. Whereas some cancers appear to be more common in SLE, notably prostate and cervical cancer, others, particularly breast cancer, are less frequent. Multiple clinical and serological factors are involved in the increased risk of malignancy in SLE. No drug dose or duration effect was identified.

Knowledge and disclosure of HIV status among adolescents and young adults attending an adolescent HIV clinic in Accra, Ghana

BackgroundIn Ghana it is estimated that 1.2% of HIV infections occur in young people aged 15-24 but the representation in our clinics is small. Adherence to treatment, appointment keeping and knowledge of HIV status remains a challenge. Disclosure has been shown to result in better adherence to therapy, good clinical outcomes, psychological adjustment and reduction in the risk of HIV transmission when the young person becomes sexually active. A baseline study was conducted to ascertain if adolescents and young adults knew their HIV status and their knowledge on HIV. Informed consent and assent were obtained from willing participants. Self-administered questionnaires on general knowledge of HIV, HIV treatment and disclosure were collected and analyzed.ResultsThirty-four young persons participated in the study. The mean age was 16.9 ± SD 2.5 and 62% (21/32) were female. All of them were still in school. Eighty-five percent were aware that young people their age could fall sick, 91% had heard of HIV, 70% knew someone with HIV and 45% thought that adolescents were not at risk of HIV. On modes of HIV transmission, 66.7% knew HIV was transmitted through sex and 63.6% knew about mother to child transmission. Fifty three percent (18/34) knew their HIV status, 50% (17/34) were on antiretroviral and 35% (6/17) of them admitted to missing ARV doses. One person who said he was HIV negative and another who did not know his status were both on ARVs.ConclusionDisclosure of HIV status to adolescents and young people is dependent on a complex mix of factors and most practitioners recommend an age and developmentally appropriate disclosure. Thus it is highly individualized. The knowledge and awareness of HIV was 91% compared to 97% of adults in the most recent Ghana Demographic and Health Survey however only about two thirds had acceptable in depth knowledge on HIV. Only half knew their HIV status which was not the best considering their ages. There is the need to strengthen education to young persons with HIV, support adhere to ARVs for better outcomes and assist care givers to disclose HIV status to them.

Modeling the environmental suitability of anthrax in Ghana and estimating populations at risk: Implications for vaccination and control

Anthrax is hyper-endemic in West Africa. Despite the effectiveness of livestock vaccines in controlling anthrax, underreporting, logistics, and limited resources makes implementing vaccination campaigns difficult. To better understand the geographic limits of anthrax, elucidate environmental factors related to its occurrence, and identify human and livestock populations at risk, we developed predictive models of the environmental suitability of anthrax in Ghana. We obtained data on the location and date of livestock anthrax from veterinary and outbreak response records in Ghana during 2005–2016, as well as livestock vaccination registers and population estimates of characteristically high-risk groups. To predict the environmental suitability of anthrax, we used an ensemble of random forest (RF) models built using a combination of climatic and environmental factors. From 2005 through the first six months of 2016, there were 67 anthrax outbreaks (851 cases) in livestock; outbreaks showed a seasonal peak during February through April and primarily involved cattle. There was a median of 19,709 vaccine doses [range: 0–175 thousand] administered annually. Results from the RF model suggest a marked ecological divide separating the broad areas of environmental suitability in northern Ghana from the southern part of the country. Increasing alkaline soil pH was associated with a higher probability of anthrax occurrence. We estimated 2.2 (95% CI: 2.0, 2.5) million livestock and 805 (95% CI: 519, 890) thousand low income rural livestock keepers were located in anthrax risk areas. Based on our estimates, the current anthrax vaccination efforts in Ghana cover a fraction of the livestock potentially at risk, thus control efforts should be focused on improving vaccine coverage among high risk groups.

HBV genotypes and drug resistance mutations in antiretroviral treatment-naive and treatment-experienced HBV-HIV-coinfected patients.

BACKGROUND The presence of HBV resistance mutations upon initiation or during antiretroviral therapy (ART) in HIV-coinfected patients is an important determinant of treatment response. The main objective of the study was to determine the prevalence of HBV resistance mutations in antiretroviral treatment-naive and treatment-experienced HBV-HIV-coinfected Ghanaian patients with detectable HBV viraemia. METHODS HBV-HIV-coinfected patients who were ART-naive or had received at least 9 months of lamivudine (3TC)-containing ART were enrolled in a cross-sectional study. Demographic and clinical data were collected and HBV DNA quantified. Partial HBV sequences were amplified by PCR and sequenced bi-directionally to obtain a 2.1-2.2 kb fragment for phylogenetic analysis of HBV genotypes and evaluation of drug resistance mutations. RESULTS Of the 100 HBV-HIV-coinfected study patients, 75 were successfully PCR-amplified, and 63 were successfully sequenced. Of these 63 patients, 27 (42.9%) were ART-experienced and 58 (92.1%) had HBV genotype E. No resistance mutations were observed in the 36 ART-naive patients, while 21 (77.8%) of 27 treatment-experienced patients had resistance mutations. All patients with resistance mutations had no tenofovir in their regimens, and 80% of them had HIV RNA <40 copies/ml. The 3TC resistance mutations rtL180M and rtM204V were observed in 10 (47.6%) of the 21 patients, while 5 patients (23.8%) had rtV173L, rtL180M and rtM204V mutations. CONCLUSIONS A high proportion of HBV-HIV-coinfected patients with detectable viraemia on 3TC-containing ART had resistance mutations despite good ART adherence as determined by HIV RNA suppression. This study emphasizes the need for dual therapy as part of a fully suppressive ART in all HBV-HIV-coinfected patients in Ghana.

Adverse drug reactions to antiretroviral therapy during the early art period at a tertiary hospital in Ghana.

Introduction Antiretroviral therapy (ART) has reduced HIV morbidity and mortality worldwide but has many adverse effects. These adverse drug reactions (ADRs) lead to discontinuations, disease progression or treatment failure. We explored the types and risk factors for ADRs in a cohort starting ART in a teaching hospital in Accra, Ghana where the main regimens used were a combination of nucleotide and non nucleotide reverse transcriptase inhibitors. Methods A Cross-sectional retrospective study was conducted reviewing data of 2042 patients initiated on HAART from 2003 to 2007. Univariate analysis was done for the dependent and independent variables. Stepwise logistic regression procedures were used to model the effect of gender on the development of ADRs controlling for other variables like age, marital status, weight at baseline and CD4 at baseline. Results The period prevalence of ADRs was 9.4%. The two most common adverse reactions were anaemia and diarrhoea. Female sex was a statistically significant independent predictor of an adverse drug reaction (AOR: 1.66, p = 0.01, CI: 1.16-2.36). CD4 counts 250 cells/mm3 or more was significantly associated with the occurrence of an ADR. The occurrence of anaemia in females was statistically significant compared to males. Conclusion Adverse drug reactions were less common than expected, anaemia was the commonest ADR. Female sex and high CD4 counts >250mm3 were predictors of ADRs whereas females were significantly more likely to develop anaemia than males. Recommendations were made for interventions to prevent and also mitigate the high levels of anaemia especially among women in the ART scale up.

Viral Decay Rates are Similar in HIV-infected Patients with and without TB Coinfection during Treatment with an Efavirenz-based Regimen

Viral decay rates during efavirenz-based therapy were compared between human immunodeficiency virus (HIV)-infected patients without tuberculosis (n = 40) and those with tuberculosis coinfection who were receiving concurrent antituberculous therapy (n = 34). Phase I and II viral decay rates were similar in the 2 groups (P > .05). Overall, concurrent antituberculous therapy did not reduce the efficacy of the HIV treatment.