HIV-1 Genetic Diversity and Natural Polymorphisms of the Integrase Gene in Integrase Inhibitor-Naive Patients in Harare, Zimbabwe.

Previously used as part of salvage therapy, integrase strand transfer inhibitors (INSTIs) have become part of the preferred antiretroviral therapy (ART) first-line regimen in most low- to middle-income countries. With the extensive use of dolutegravir in first-line ART, drug resistance mutations to INSTIs are inevitable. Therefore, active monitoring and surveillance of INSTI drug resistance is required. The aim of this study was to evaluate the genetic diversity of the integrase gene and determine pretreatment INSTI resistance in Harare, Zimbabwe. Forty-four HIV-1 Integrase sequences from 65 were obtained from treatment-naive individuals using a custom genotyping method. Drug resistance mutations were determined using the Stanford HIV Drug Resistance Interpretation program. Viral subtyping was done by phylogenetic analysis and the REGA HIV subtyping tool determined recombinants. Natural polymorphisms were evaluated relative to the global subtype B and C consensus sequences. One hundred ninety-two sequences from the region were accessed from GenBank to assess differences between the Zimbabwean sequences and those from neighboring countries. No major INSTI resistance mutations were detected; however, the L74I polymorphism was detected in three sequences of the 44 (6.8%). There was little genetic variability in the Integrase gene, with a mean genetic distance range of 0.053015. The subtype C consensus was identical to the global subtype C consensus and varied from the global subtype B consensus at five major positions: T124A, V201I, T218I, D278A, and S283G. This study has provided baseline sequence data on the presence of HIV-1 subtype C Integrase gene drug resistance mutations from Harare, Zimbabwe.

Knowledge, Attitude, and Perceptions of Pharmacists and Pharmacy Students towards Pharmacogenomics in Zimbabwe.

The potential of pharmacogenomics (PGx) to positively impact health outcomes and quality of healthcare is well-established. However, the application of available evidence into clinical practice is still limited due to limited knowledge among healthcare professionals, including pharmacists. As a start towards building capacity for PGx education, we assessed knowledge, attitudes, and perceptions about PGx among practising pharmacists and pharmacy students. A cross-sectional study was conducted among pharmacists and undergraduate pharmacy students selected using a convenient sampling method-a 37-question survey instrument was used to obtain information regarding PGx among the participants. Out of a total of 131 participants, 56% of respondents showed fair-to-good PGx knowledge. Respondents' self-reported assessment indicated that 88% had average and above knowledge scores in PGx. Practising pharmacists in Zimbabwe have positive attitudes towards PGx and would support its application to improve treatments. However, there were concerns about security and discrimination when genomics data is used by those who do not understand its meaning. Participants agreed that they would play a leading role in PGx testing if provided with appropriate training. The interest in PGx is challenged by their limited knowledge and understanding of genetics, suggesting a need to update curricula for pharmacy students and for continuing health education programmes.

Practical Approach to Biobanking in Zimbabwe: Establishment of an Inclusive Stakeholder Framework.

The growing need for biobanks in health research presents an opportunity for building capacity in developing countries. In Zimbabwe, there is limited knowledge and awareness about biobanking. As such we report the proceedings of a biobanking course, which included research scientists, healthcare professionals, and regulatory authorities as a start to developing a framework for biobanking practice. The aim was to educate stakeholders about biobanking and to understand the current and future regulatory and infrastructure requirements for biobanking. Using an inclusive stakeholder approach, we sought to articulate the strengths, weaknesses, opportunities, and threats. This report highlights a practical method to providing basic education to stakeholders, building awareness and consensus about building capacity for biobanking in a developing country.

CYP2B6*6, CYP2B6*18, Body weight and sex are predictors of efavirenz pharmacokinetics and treatment response: population pharmacokinetic modeling in an HIV/AIDS and TB cohort in Zimbabwe.

BACKGROUND: Efavirenz (EFV) therapeutic response and toxicity are associated with high inter-individual variability attributed to variation in its pharmacokinetics. Plasma concentrations below 1 µg/ml may result in virologic failure and above 4 µg/ml, may result in central nervous system adverse effects. This study used population pharmacokinetics modeling to explore the influence of demographic and pharmacogenetic factors including efavirenz-rifampicin interaction on EFV pharmacokinetics, towards safer dosing of EFV. METHODS: Patients receiving an EFV-based regimen for their antiretroviral therapy and a rifampicin-containing anti-TB regimen were recruited. EFV plasma concentrations were measured by HPLC and genomic DNA genotyped for variants in the CYP2B6, CYP2A6 and ABCB1 genes. All patients were evaluated for central nervous system adverse effects characterised as sleep disorders, hallucinations and headaches using the WHO ADR grading system. A pharmacokinetic model was built in a forward and reverse procedure using nonlinear mixed effect modeling in NONMEM VI followed by model-based simulations for optimal doses. RESULTS: CYP2B6*6 and *18 variant alleles, weight and sex were the most significant covariates explaining 55% of inter-individual variability in EFV clearance. Patients with the CYP2B6*6TT genotype had a 63% decrease in EFV clearance despite their CYP2B6*18 genotypes with females having 22% higher clearance compared to males. There was a 21% increase in clearance for every 10 kg increase in weight. The effect of TB/HIV co-treatment versus HIV treatment only was not statistically significant. No clinically relevant association between CYP2B6 genotypes and CNS adverse effects was seen, but patients with CNS adverse effects had a 27% lower clearance compared to those without. Model- based simulations indicated that all carriers of CYP2B6*6 TT genotype would be recommended a dose reduction to 200 mg/day, while the majority of extensive metabolisers may be given 400 mg/day and still maintain therapeutic levels. CONCLUSION: This study showed that screening for CYP2B6 functional variants has a high predictability for efavirenz plasma levels and could be used in prescribing optimal and safe EFV doses.

Genetic variants of drug metabolizing enzymes and drug transporter (ABCB1) as possible biomarkers for adverse drug reactions in an HIV/AIDS cohort in Zimbabwe.

A study was conducted in an HIV/AIDS Zimbabwean cohort to assess possible associations of pharmacogenetic variants with common adverse drug reactions (ADRs) during anti-retroviral treatment (ART) and/or tuberculosis (TB) treatment. Genotype and allele frequencies for CYP2B6 G516T, CYP2B6 T983C, CYP2A6*17, ABCB1 rs10276036 C>T, NAT2*5 and NAT2*14 were similar to those reported in literature for other African populations. The CYP2B6 516TT genotype and male gender were significantly associated with occurrence of Efavirenz induced central nervous system disorders (OR 20.58, p=0.004) and the ABCB1 rs10276036TT genotype with Nevirapine induced skin hypersensitivity (OR 4.01, p=0.04). For Stavudine, time on treatment was the main factor in development of lipodystrophy (OR 1.06, p<0.0001). For isoniazid, increasing patient age was associated with peripheral neuropathy (OR 1.05, p=0.001). Although genetic polymorphisms may play a role in predicting occurrence of ADRs, this study also indicates that other factors (gender, age, treatment time) are crucial in predicting drug-induced adverse effects.