Margaret Lartey

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

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.

High prevalence of unique recombinant forms of HIV-1 in Ghana: molecular epidemiology from an antiretroviral resistance study

Background:In Ghana, programs to expand antiretroviral access are being implemented. In this context, the dynamic genetic evolution of HIV-1 requires continuous surveillance, particularly when diverse genetic forms co-circulate. Methods:Phylogenetic and antiretroviral resistance analyses of HIV-1 partial pol sequences from plasma RNA samples from 207 Ghanaian individuals were performed. Results:66% of infections were CRF02_AG, whereas 25% were unique recombinant forms (URFs). All 52 URFs were characterized by bootscanning. CRF02_AG was parental strain in 87% of URFs, forming recombinants with genetic forms circulating in minor proportions: CRF06_cpx, sub-subtype A3, CRF09_cpx and subtypes G and D. Two triple recombinants (CRF02_AG/A3/CRF06_cpx and CRF02_AG/A3/CRF09_cpx) were identified. Antiretroviral resistance analyses revealed that six individuals, five of which were antiretroviral drug-experienced, harbored mutations conferring high level of resistance to reverse transcriptase inhibitors. No major resistance mutations were identified in the protease, although insertions of one and three amino acids were detected. Conclusions:The high frequency of URFs detected probably reflects a significant incidence of coinfections or superinfections with diverse viral strains, which increases the genetic complexity of the HIV-1 epidemic in West Africa. Monitoring of HIV-1 drug resistance might provide data on the implications of intersubtype recombination in response to antiretrovirals.

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.

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.

Initiating antiretroviral treatment in a resource-constrained setting: does clinical staging effectively identify patients in need?

In industrialized countries, the initiation of antiretroviral therapy (ART) is based on virological, immunological and clinical markers. The objective of this study was to identify treatment gaps when ART initiation is based on clinical staging alone. The method employed was a retrospective study of 5784 patients enrolled in an HIV treatment programme in two urban and two rural sites in Ghana. Of the patients, 29.5% were in clinical Stages I and II and had a CD4+ T-lymphocyte count less than 200 cells/mm3. Significantly more patients in clinical Stage I from urban sites (37.0%) had a CD4+ T-lymphocyte count less than 200 cells/mm3 as compared with patients from rural sites (23.8%) (P value <0.05). In addition, more men (39.9%) in clinical Stage I had a CD4+ T-lymphocyte count less than 200 cells/mm3 when compared with women (27.4%) (P value <0.05). In conclusion, clinical staging cannot identify a relatively large number of patients who need ART. A wider availability of CD4+ T-lymphocyte count testing will optimize the identification of patients eligible for ART.

Facilitators and barriers to antiretroviral therapy adherence among adolescents in Ghana

Introduction Adherence to antiretroviral therapy (ART) is known to be challenging among adolescents living with HIV/AIDS, notwithstanding the life-saving importance of this therapy. Of the global total number of adolescents living with HIV in 2013, 83% reside in sub-Saharan Africa. The study aimed to identify facilitators of and barriers to antiretroviral treatment adherence among adolescents in Ghana. Methods A cross-sectional qualitative study using semi-structured interviews for data collection was carried out among adolescents (aged 12–19 years) at the adolescents HIV clinic at the Korle-Bu Teaching Hospital in Ghana. Predominantly open-ended questions relating to ART were used. Interviews were done until saturation. In total, 19 interviews were conducted. Analysis was done manually to maintain proximity with the text. Findings The main facilitators were support from health care providers, parental support, patient’s knowledge of disease and self-motivation, patient’s perceived positive outcomes, and dispensed formulation. The identified barriers were patient’s forgetfulness to take medicines, perceived stigmatization due to disclosure, financial barriers, and adverse effects of ART. Support from health care workers was the most frequently mentioned facilitator, and patient’s forgetfulness and perceived stigmatization after disclosure were the most frequently mentioned barriers. Self-motivation (knowledge induced) to adhere to treatment was a specific facilitator among older adolescents. Conclusion Continuous information provision in addition to unflinching support from health care workers and parents or guardians may improve adherence among adolescents. Also, interventions to reduce patient forgetfulness may be beneficial. A multi-sectorial approach would be needed to address adolescent disclosure of HIV/AIDS status.

SANKOFA: a multisite collaboration on paediatric HIV disclosure in Ghana.

With the scale-up of effective antiretroviral therapy in resource-limited settings, many HIV-infected children are now able to survive into adulthood. To achieve this potential, children must navigate normative developmental processes and challenges while living with an unusually complex, stigmatizing, potentially fatal chronic illness and meeting the demands of treatment.Yet many of these children, especially preadolescents, do not know they are HIV-infected. Despite compelling evidence supporting the merits of informing children of their HIV status, there has been little emphasis on equipping the childs caregiver with information and skills to promote disclosure, particularly, when the caregiver faces a variety of sociocultural barriers and is reluctant to do so. In this study, we present the background, process and methods for a first of its kind collaboration that is examining the efficacy of an intervention developed to facilitate the engagement of caregivers in the process of disclosure in a manner suitable to the sociocultural context and developmental age and needs of the child in Ghana. We also report preliminary data that supported the design of the intervention approach and currently available domains of the data system. Finally, we discuss challenges and implications for future research.