Collen Masimirembwa

1. 1.1. Medications remain an important modality in the treatment of most diseases or disorders. But, about 25–80% of patients respond to a specific drug therapy and some of them cannot tolerate tr...

Background: Infection with HIV increases the risk of developing hepatocellular carcinoma, and the albumin–bilirubin grade assesses liver function and has been shown to be prognostic. We evaluated the albumin–bilirubin score/grade and the HIV status of hepatocellular carcinoma patients in Zimbabwe and explored the impact on median survival. Methods: A 10-year retrospective observational study of hepatocellular carcinoma patients was conducted at a single tertiary-level cancer center in Harare, Zimbabwe. Survival probabilities were estimated using the Kaplan–Meier method, and differences between groups were compared using the log-rank test and Cox proportional hazards regression. Results: A total of 95 participants were evaluated, of whom 72.6% were male. Most HCC cases were diagnosed using imaging and serum alpha-fetoprotein, with 59% presenting at Barcelona Clinic Liver Cancer stage C or D. Compared with patients who were HIV-negative, patients who were HIV-positive (OR 2.2; 95% CI 1.54–5.26, p = 0.0008) or had an unknown HIV status (OR 4.2; 95% CI 2.2–8; p < 0.0001) had higher odds of being at ALBI grade 3 at the time of HCC diagnosis. ALBI grade 1 patients had better median survival compared to grade 2 and 3 patients, though this result was statistically insignificant (grade 2: HR = 1.45, 95% CI: 0.30–7.13; grade 3: HR = 1.47, 95% CI: 0.28–7.60). Regarding HIV status, median survival was 2.4 months for HIV-positive patients and 2.6 months for HIV-negative patients (p = 0.51); HIV positivity was not significantly associated with median survival (HR = 1.50, 95% CI: 0.46–4.91). Only 30.5% of patients received cancer therapy, all of which was palliative, with no observed survival benefit. Conclusions: The majority of hepatocellular carcinoma patients in Zimbabwe were diagnosed at an advanced stage, with hepatitis B or C viral infections and alcohol consumption identified as primary risk factors. Median survival rates were low. Neither HIV infection nor ALBI score grading had a significant impact on median survival.

The World Health Organization Model Essential Medicines List and African national essential medicines lists (EMLs) detail drugs intended to be consistently available within national health systems, thereby supporting clinicians and pharmacists in making evidence‐based treatment decisions. At present, these EMLs do not account for pharmacogenomics, despite known drug‐gene interactions and the considerable genetic diversity found throughout Africa. In the absence of pharmacogenomic considerations, the medicines lead to sub‐optimal treatment outcomes, especially across a continent such as Africa which represents more genetic variation that the rest of the world combined. Herein, we review EMLs from the WHO, and from 52 African countries, highlighting systemic medicines for which actionable pharmacogenomic‐biomarker testing recommendations exist. Furthermore, we assess the feasibility of PGx‐guided dosing in eight African countries by examining the availability of registered drug formulations that facilitate dose adjustment. The 2023 WHO EML comprised 447 unique systemic medicines, with 58 (13%) categorized as medicines with actionable pharmacogenomic biomarkers. African country EMLs collectively featured 774 such medicines, with an average of 294 per country (range: 125–465). On average, for each country one in every eight medicines in the Essential Medicines List was associated with established pharmacogenomic guidance. PGx recommendation. Cumulatively in African EMLS the most frequent drug classes with this designation are anti‐infectives (25.6%), immunomodulators/antineoplastics (16.7%), and medicines for mental and behavioral disorders (14.1%). Analysis of eight African countries determined that implementability ranged from 75% to 96% based on product formulation and strength availability to enable drug or dose modification. We provide data that contributes towards a foundation of increasing evidence showing that integrating pharmacogenomic knowledge into the selection processes for essential medicines and ensuring the availability of appropriate drug formulations can enhance treatment safety and efficacy across Africa.

Genetic variation has a significant impact on patients' response to medicines. Variations in important pharmacogenes have been evaluated in several studies and consequently led to international guidelines from clinical pharmacogenomics consortia. However, there are limited examples of these being implemented across the African continent despite the increased evidence of how these variants contribute to adverse drug reactions (ADRs) or ineffective treatments. Considering the vast genetic diversity in Africa, there are significant gaps in understanding how much of a negative effect this might be having across healthcare across the continent. We therefore sought to establish the extent of ADRs from a subset of medicines shown to be associated with pharmacogenetic biomarkers from the last 10 years across 47 countries on the African continent. In the absence of pharmacogenetic testing on the African continent, we used international guidelines to derive a subset of definitions associated with published drug‐gene‐interaction associated ADRs to infer the role of pharmacogenetic variation on the prevalence of ADRs. The data showed that African countries report only 1% of ADRs in the VigiBase database, indicative of weak pharmacovigilance programs on the continent. Our analysis revealed that ADRs were mainly caused by anti‐infectives such as efavirenz. The inferred pharmacogenes associated with high prevalence of ADRs were CYP2B6 , CYP2D6 , and CYP2C19 . Using limited data, this foundational analysis may serve as the basis for stakeholders to prioritize pharmacogenetic interventions across the African continent.

Background Sickle Cell Disease (SCD) is highly prevalent in Nigeria, with severe pain crises being a primary cause of morbidity. Codeine and tramadol are frequently used opioids, but their effectiveness and safety are significantly influenced by CYP2D6 genetic variations. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines exist for opioid therapy based on CYP2D6 phenotypes. There’s a critical need for pre-emptive pharmacogenomic (PGx) testing in African SCD patients to guide opioid selection. This study aimed to determine CYP2D6 allele, phenotype frequencies and evaluate the feasibility of implementing pre-emptive pharmacogenomic (PGx) testing to guide opioid therapy for SCD patients in Nigeria. Methods This prospective, multicenter implementation study recruited 503 consenting SCD patients (HbSS or HbSC) aged ≥15 years from five Nigerian sites. Blood samples were collected for DNA extraction. CYP2D6 single-nucleotide polymorphisms and copy number variations were determined using Taqman assays based open array, GenoPharm. Phenotypes were assigned based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines using the Genomics Information Management System (GIMS). and patient-specific medication safety cards were generated. Results We successfully genotyped 503 SCD patients with a mean age of 25.1 years, while 61.4% were female, and hydroxyurea use was less than 9.4%. Actionable CYP2D6 variants were found in 36.6% of participants. The predicted phenotype distribution was 8.8% Ultrarapid Metabolizers (UM), 54.1% Normal Metabolizers (NM), 26.0% Intermediate Metabolizers (IM), and 1.8% Poor Metabolizers (PM), with 9.3% undetermined. Patient medication safety cards were provided to guide prescriptions. Conclusions This study successfully established a genotyped cohort of 503 Nigerian SCD patients, demonstrating the feasibility of pre-emptive pharmacogenetic testing through a Pan-African collaborative model in a resource-limited setting. The identification of PM and UM provides direct clinical guidance, as CPIC guidelines recommend avoiding codeine and tramadol in these groups due to the high risk of diminished efficacy or serious toxicity, respectively. The high prevalence of actionable CYP2D6 variants indicates a substantial proportion of Nigerian SCD patients may experience altered opioid responses, underscoring the need for tailored prescribing to optimise pain control and minimise adverse drug reactions.

PURPOSE: About one in three Black Africans carry the African-predominant allele variants CYP2D6*17 and/or CYP2D6*29, which confer a reduced enzymatic activity. CYP2D6 intermediate metabolizers (IM) have a reduced biotransformation rate of tamoxifen compared with its more active metabolite endoxifen. METHODS: A prospective cohort study of Black Zimbabwean patients with hormone receptor–positive breast cancer on tamoxifen therapy was conducted. Patients were genotyped for CYP2D6 and followed up for event-free survival (EFS) on tamoxifen. RESULTS: In total, 18 CYP2D6 IM and 33 normal metabolizers (NM) were enrolled. At 2 years, the estimated EFS was 40.1% (95% CI, 20.3 to 79.4) for the IM group and 84.0% (95% CI, 72.1 to 97.9) for the NM group (log-rank P = .0021). A Cox proportional hazards model, after adjusting for BMI, stage at diagnosis, and previous breast cancer surgery, estimated about a 5.5-fold higher hazard of recurrence, progression, or death in IM compared with NM. CONCLUSION: Individuals with hormone receptor–positive breast cancer who are CYP2D6 NM had better disease recurrence and progression-free survival outcomes compared with IM.

Tuberculosis (TB) is a global health challenge. Use of anti-TB drugs to treat TB is associated with high prevalence of side effects that include anti-TB drug induced liver injury (ATDILI). The aim of this study was to determine the incidence and associated clinical risk factors of ATDILI among South African patients on treatment for TB disease. This was an ambispective case-control study of patients on treatment for TB disease receiving drug sensitive and drug resistant treatment regimens. The retrospective and prospective studies were done from January 2021 to June 2024, involving a total of 610 patients on treatment for TB disease from whom 13 had ATDILI. From the retrospective and prospective cohorts, we extracted 13 ATDILI cases and 276 controls. Additionally, 44 severe ATDILI cases were directly recruited from the hospital to enrich the number of cases in the study. Prospective patients were followed for up to 6 months, while retrospective participants had a single visit with follow-up durations determined by their parent studies. Logistic regression analysis was performed to identify clinical and demographic factors associated with the development of ATDILI). In the studied cohorts, the incidence of ATDILI was 2.1% (13/610). The ATDILI cases and controls consisted of 215 (64.6%) male patients; 57 patients were diagnosed with hepatotoxicity, 44 from the hospitalized cohort,12 from the retrospective cohort and 1 patient from the prospective cohort. The median time from the initiation of treatment to the onset of hepatotoxicity was approximately 30 days. Univariate logistic regression revealed significant differences (p < 0.05) in sex (p = 0.003), HIV status (p = 0.002), BMI (p = 0.038), hypertension (p = 0.047) smoking (p = 0.006), and alcohol consumption (p = 0.001) in relation to ATDILI. Multivariate analysis further revealed that female sex (p = 0.041), HIV status (0.022) and alcohol consumption (0.048) were independently associated with an increased risk of ATDILI. The incidence of ATDILI in this study was 2.1%, lower than the previously reported range of 3–36% and highlights the need for standardized definitions of phenotypes across studies. In univariable analysis, female sex, HIV status, BMI, hypertension, smoking, and alcohol consumption were identified as potential risk factors for ATDILI. Among these, multivariable analysis suggested that female sex, HIV status and alcohol consumption were associated with an increased risk of developing ATDILI.

Genetic variation is a major determinant of drug response across populations. Owing to advances in sequencing technologies over the last two decades, several clinically actionable variants or haplotypes have been characterized in genes that encode proteins mediating drug pharmacokinetics or pharmacodynamics. Therefore, clinical application of pharmacogenomics has gained significant traction as a promising tool for enabling drug therapy optimization to mitigate adverse drug reactions while promoting drug efficacy. However, the implementation of pharmacogenetics testing has been slow in African settings and other resource-limited global regions. Moreover, there is a need to address gaps in various pharmacogenomics knowledgebases, especially regarding the genetic diversity in underrepresented populations. It is also important to ensure that emerging assays and technologies do not heighten existing healthcare disparities affecting African populations. We present the status of pharmacogenomics in Africa, highlighting its potential to impact health outcomes in the safe and efficacious use of medicines.

Africa bears the largest burden of morbidity and mortality from hypertension (HT) and related cardiovascular diseases. Thiazide diuretics, including hydrochlorothiazide (HCTZ), are the most prescribed hypertension medicines globally due to their cost effectiveness and minimal side effects. However, studies investigating the genetic variation in HCTZ‐related genes and their effect on drug response have been mainly conducted in European, American, and Asian populations. This study aimed to examine genetic variation in HCTZ response‐related genes among newly diagnosed hypertensives from Soweto, South Africa, irrespective of the treatment approach, and to assess its potential impact on medication response. Using targeted NGS on 364 newly diagnosed hypertensives with at least one follow‐up visit, we identified 1258 unique variants in 16 key HCTZ response genes. Among these, 89 were novel variants, of which 12 were protein‐altering, including 8 predicted to be deleterious. Association analyses with 882 independent variants revealed that carriers of the intronic variant rs1025450259 in GNB3 had significantly greater reduction in BP compared to other patients on heterogeneous treatment strategies, but no significant associations were detected in the subset of individuals treated with HCTZ monotherapy only ( n = 103). For variants previously associated with HCTZ response, we did not replicate prior associations (e.g., rs2611316 in ALDH1A2 ) but highlight important allele frequency differences across global populations. Despite the limitations, the study outcomes support the need for larger, controlled trials to assess genetic influences on HT treatment outcomes, advancing personalized medicine for African populations. This research further underscores the importance of pharmacogenetic studies in continental African populations.