The long-term effectiveness of efavirenz-based combination antiretroviral therapy, the impact of pharmacogenomics and pharmacokinetic interaction of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients

Dr. Fred Stephen Sarfo, The long-term effectiveness of efavirenz-based combination antiretroviral therapy, the impact of pharmacogenomics and pharmacokinetic interaction of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients. PhD dissertation, Durham University, January 2013. Introduction: In sub-Saharan Africa, HIV treatment is initiated with combination of antiretroviral medications comprising of a backbone of either stavudine or zidovudine plus lamivudine with a non-nucleoside reverse transcriptase inhibitor of either efavirenz or nevirapine. Efavirenz is highly efficacious, durable and well tolerated. The risk for toxicity of efavirenz is determined by several factors including single nucleotide polymorphisms in the hepatic enzymes responsible for its metabolism and concurrently administered medications such as antimalarials, which share common metabolic pathways. The aims of this dissertation are to assess the long-term effectiveness of efavirenz-based antiretroviral therapy and the impact of pharmogenomics and pharmacokinetic interactions of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients. Methods: The effectiveness of efavirenz- compared with nevirapine-based antiretroviral therapy was assessed retrospectively in nearly 4000 patients starting treatment between 2004 and 2010. The main outcome measure was a composite of toxicity, disease progression and attrition, and CD4 count changes. A prospective pharmacokinetic study of artesunate and efavirenz was conducted among 22 HIV-infected and 21 controls. Plasma efavirenz and artesunate/ dihydroartemisinin concentrations were measured using validated and standardised methods. Genotyping for single nucleotide polymorphisms in CYP2B6 G516T, T983C; CYP2A6*9B, UGT2B7*735 and *802 as well as CAR rs2307424 were performed for 800 patients with real-time polymerase chain reaction with allelic discrimination. Results: Antiretroviral therapy was associated with robust CD4 increases. Efavirenz was comparable with nevirapine in composite outcomes but better tolerated. Artesunate was well tolerated when administered to HIV-infected patients on efavirenz. Single nucleotide polymorphisms in the CYP2B6 G516T and T983C were associated with increased plasma efavirenz concentrations. Conclusions/Recommendation: Among this Ghanaian cohort, both efavirenz and nevirapine-based antiretroviral therapy were effective. The better tolerability of efavirenz compared with nevirapine means it can be safely used as the preferred first line non-nucleoside reverse transcriptase inhibitor in sub-Saharan Africa

Thyroid Disorders in Central Ghana: The Influence of 20 Years of Iodization

Background. Ghana began mandatory iodization of salt in 1996. This study compares the prevalence of thyroid disorders before and after the introduction of iodization. Methods. This is a retrospective study of thyroid cases from the middle belt of Ghana between 1982 and 2014. To demonstrate a link between iodization and hyperthyroidism and autoimmunity, we compared the prevalence of hyperthyroidism and autoimmune thyroid disorders before and after the iodization programme. Results. A total of 10,484 (7548 females, 2936 males) cases were recorded. The rate of thyroid cases seen was 343/100,000. Nontoxic nodular goiters (25.7%) and toxic nodular goiters (22.5%) represented the second commonest thyroid disorders recorded. The prevalence of hyperthyroid disorders seen after 1996 was significantly higher than the prevalence seen before the iodization (40.0 versus 21.1%, p<0.001). The prevalence of autoimmune disorders recorded after iodization was significantly higher than that before the iodization programme started (22.3% versus 9.6%, p<0.001). Conclusions. This study has revealed a significant increase in thyroid admissions in Central Ghana over the decades. A connection between iodine fortification and iodine-induced hyperthyroidism and between iodine fortification and autoimmune thyroiditis has been shown in this study

Spectrum of Endocrine Disorders in Central Ghana

Background. Although an increasing burden of endocrine disorders is recorded worldwide, the greatest increase is occurring in developing countries. However, the spectrum of these disorders is not well described in most developing countries. Objective. The objective of this study was to profile the frequency of endocrine disorders and their basic demographic characteristics in an endocrine outpatient clinic in Kumasi, central Ghana. Methods. A retrospective review was conducted on endocrine disorders seen over a five-year period between January 2011 and December 2015 at the outpatient endocrine clinic of Komfo Anokye Teaching Hospital. All medical records of patients seen at the endocrine clinic were reviewed by endocrinologists and all endocrinological diagnoses were classified according to ICD-10. Results. 3070 adults enrolled for care in the endocrine outpatient service between 2011 and 2015. This comprised 2056 females and 1014 males (female : male ratio of 2.0 : 1.0) with an overall median age of 54 (IQR, 41–64) years. The commonest primary endocrine disorders seen were diabetes, thyroid, and adrenal disorders at frequencies of 79.1%, 13.1%, and 2.2%, respectively. Conclusions. Type 2 diabetes and thyroid disorders represent by far the two commonest disorders seen at the endocrine clinic. The increased frequency and wide spectrum of endocrine disorders suggest the need for well-trained endocrinologists to improve the health of the population

Acceptance of Artificial Intelligence (ChatGPT) in Education: Trust, Innovativeness and Psychological Need of Students

Since students are key stakeholders and reliable sources of information, their acceptance or rejection of artificial intelligence (AI) tools like ChatGPT can influence the general student population’s uptake of AI in education. In this study, we investigated the acceptability of AI tools among students in higher education in Ghana. A cross-sectional design was used to collect data from 146 students through a self-administered online survey. Descriptive analysis and structural equation modelling were performed and a conceptual framework was developed to explore the interplay between perceived usefulness, social influence, innovation characteristics, and psychological needs of students. The findings indicated that more than half (n = 102, 69.9%) of them indicated acceptance of AI in education if available while about one-third (n = 44, 30.1%) indicated non-acceptance of AI, prompting policies to be in place for its acceptance and use in education. Additionally, the results demonstrate that the effect of perceived usefulness, social influence, innovation characteristics, and psychological needs of students on AI acceptance in education is positively significant. Concerns about lack of awareness (n = 33, 35.1%), privacy and consent (n = 19, 20.2%) and disruption of the traditional teacher-student relationship (n = 15, 16%) were identified as the main reasons students would decline uptake of AI tools in education. Action from authorities in higher education is needed to address students’ hesitancy about AI tools and such interventions must consider the age and sex of the students. Keywords: artificial intelligence, education, ChatGPT, innovation, trust, technology acceptance DOI: 10.7176/IKM/13-4-03 Publication date:July 31st 202

Drug resistance outcomes of long-term ART with tenofovir disoproxil fumarate in the absence of virological monitoring

Objectives: The resistance profiles of patients receiving long-term ART in sub-Saharan Africa have been poorly described. This study obtained a sensitive assessment of the resistance patterns associated with long-term tenofovir-based ART in a programmatic setting where virological monitoring is yet to become part of routine care. Methods: We studied subjects who, after a median of 4.2 years of ART, replaced zidovudine or stavudine with tenofovir disoproxil fumarate while continuing lamivudine and an NNRTI. Using deep sequencing, resistance-associated mutations (RAMs) were detected in stored samples collected at tenofovir introduction (T0) and after a median of 4.0 years (T1). Results: At T0, 19/87 (21.8%) subjects showed a detectable viral load and 8/87 (9.2%) had one or more major NNRTI RAMs, whereas 82/87 (94.3%) retained full tenofovir susceptibility. At T1, 79/87 (90.8%) subjects remained on NNRTI-based ART, 5/87 (5.7%) had introduced lopinavir/ritonavir due to immunological failure, and 3/87 (3.4%) had interrupted ART. Whilst 68/87 (78.2%) subjects maintained or achieved virological suppression between T0 and T1, a detectable viral load with NNRTI RAMs at T0 predicted lack of virological suppression at T1. Each treatment interruption, usually reflecting unavailability of the dispensary, doubled the risk of T1 viraemia. Tenofovir, lamivudine and efavirenz selected for K65R, K70E/T, L74I/V and Y115F, alongside M184V and multiple NNRTI RAMs; this resistance profile was accompanied by high viral loads and low CD4 cell counts. Conclusions: Viraemia on tenofovir, lamivudine and efavirenz led to complex resistance patterns with implications for continued drug activity and risk of onward transmission

Combined Inflammatory and Metabolic Defects Reflected by Reduced Serum Protein Levels in Patients with Buruli Ulcer Disease

Buruli ulcer is a skin disease caused by Mycobacterium ulcerans that is spreading in tropical countries, with major public health and economic implications in West Africa. Multi-analyte profiling of serum proteins in patients and endemic controls revealed that Buruli ulcer disease down-regulates the circulating levels of a large array of inflammatory mediators, without impacting on the leukocyte composition of peripheral blood. Notably, several proteins contributing to acute phase reaction, lipid metabolism, coagulation and tissue remodelling were also impacted. Their down-regulation was selective and persisted after the elimination of bacteria with antibiotic therapy. It involved proteins with various functions and origins, suggesting that M. ulcerans infection causes global and chronic defects in the host’s protein metabolism. Accordingly, patients had reduced levels of total serum proteins and blood urea, in the absence of signs of malnutrition, or functional failure of liver or kidney. Interestingly, slow healers had deeper metabolic and coagulation defects at the start of antibiotic therapy. In addition to providing novel insight into Buruli ulcer pathogenesis, our study therefore identifies a unique proteomic signature for this disease

Mycolactone Diffuses into the Peripheral Blood of Buruli Ulcer Patients - Implications for Diagnosis and Disease Monitoring.

BACKGROUND: Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU), is unique among human pathogens in its capacity to produce a polyketide-derived macrolide called mycolactone, making this molecule an attractive candidate target for diagnosis and disease monitoring. Whether mycolactone diffuses from ulcerated lesions in clinically accessible samples and is modulated by antibiotic therapy remained to be established. METHODOLOGY/PRINCIPAL FINDING: Peripheral blood and ulcer exudates were sampled from patients at various stages of antibiotic therapy in Ghana and Ivory Coast. Total lipids were extracted from serum, white cell pellets and ulcer exudates with organic solvents. The presence of mycolactone in these extracts was then analyzed by a recently published, field-friendly method using thin layer chromatography and fluorescence detection. This approach did not allow us to detect mycolactone accurately, because of a high background due to co-extracted human lipids. We thus used a previously established approach based on high performance liquid chromatography coupled to mass spectrometry. By this means, we could identify structurally intact mycolactone in ulcer exudates and serum of patients, and evaluate the impact of antibiotic treatment on the concentration of mycolactone. CONCLUSIONS/SIGNIFICANCE: Our study provides the proof of concept that assays based on mycolactone detection in serum and ulcer exudates can form the basis of BU diagnostic tests. However, the identification of mycolactone required a technology that is not compatible with field conditions and point-of-care assays for mycolactone detection remain to be worked out. Notably, we found mycolactone in ulcer exudates harvested at the end of antibiotic therapy, suggesting that the toxin is eliminated by BU patients at a slow rate. Our results also indicated that mycolactone titres in the serum may reflect a positive response to antibiotics, a possibility that it will be interesting to examine further through longitudinal studies

Determinants of first‐ever stroke severity in West Africans: evidence from the SIREN study

Background: Baseline stroke severity is probably partly responsible for poor stroke outcomes in sub-Saharan Africa. However, there is a paucity of information on determinants of stroke severity among indigenous Africans. We sought to identify the factors associated with stroke severity among West Africans in the SIREN (Stroke Investigative Research and Educational Networks) study. Methods and Results: Stroke was diagnosed clinically and confirmed with brain neuroimaging. Severe stroke was defined as a Stroke Levity Scale score of ≤5. A multivariate logistic regression model was constructed to identify factors associated with stroke severity at 95% CI and a nominal cutoff of 5% type 1 error. A total of 3660 stroke cases were included. Overall, 50.7%% had severe stroke, including 47.6% of all ischemic strokes and 56.1% of intracerebral hemorrhage. Factors independently associated with severe stroke were meat consumption (adjusted odds ratio [aOR], 1.97 [95% CI, 1.43-2.73]), low vegetable consumption (aOR, 2.45 [95% CI, 1.93-3.12]), and lesion volume, with an aOR of 1.67 (95% CI, 1.03-2.72) for lesion volume of 10 to 30 cm3 and aOR of 3.88 (95% CI, 1.93-7.81) for lesion volume \u3e30 cm3. Severe ischemic stroke was independently associated with total anterior circulation infarction (aOR, 3.1 [95% CI, 1.5-6.9]), posterior circulation infarction (aOR, 2.2 [95% CI, 1.1-4.2]), and partial anterior circulation infarction (aOR, 2.0 [95% CI, 1.2-3.3]) compared with lacunar stroke. Increasing age (aOR, 2.6 [95% CI, 1.3-5.2]) and lesion volume \u3e30 cm3 (aOR, 6.2 [95% CI, 2.0-19.3]) were independently associated with severe intracerebral hemorrhage. Conclusions: Severe stroke is common among indigenous West Africans, where modifiable dietary factors are independently associated with it. These factors could be targeted to reduce the burden of severe stroke

Profile and outcomes of hospitalized patients with COVID-19 at a tertiary institution hospital in Ghana

Background: In high-income countries, mortality related to hospitalized patients with the Coronavirus disease 2019 (COVID-19) is approximately 4-5%. However, data on COVID-19 admissions from sub-Saharan Africa are scanty.Objective: To describe the clinical profile and determinants of outcomes of patients with confirmed COVID-19 admitted at a hospital in Ghana.Methods: A prospective study involving 25 patients with real time polymerase chain reaction confirmed COVID-19 admitted to the treatment centre of the University Hospital, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana from 1st June to 27th July, 2020. They were managed and followed up for outcomes. Data were analysed descriptively, and predictors of mortality assessed using a multivariate logistic regression modelling.Results: The mean age of the patients was 59.3 ± 20.6 years, and 14 (56%) were males. The main symptoms at presentation were breathlessness (68%) followed by fever (56%). The cases were categorized as mild (6), moderate (6), severe (10) and critical (3). Hypertension was the commonest comorbidity present in 72% of patients. Medications used in patient management included dexamethasone (68%), azithromycin (96%), and hydroxychloroquine (4%). Five of 25 cases died (Case fatality ratio 20%). Increasing age and high systolic blood pressure were associated with mortality.Conclusion: Case fatality in this sample of hospitalized COVID-19 patients was high. Thorough clinical assessment, severity stratification, aggressive management of underlying co-morbidities and standardized protocols incountry might improve outcomes

Kinetics of mycolactone in human subcutaneous tissue during antibiotic therapy for Mycobacterium ulcerans disease.

BACKGROUND: Mycobacterium ulcerans (M. ulcerans) causes a devastating necrotising infection of skin tissue leading to progressive ulceration. M. ulcerans is the only human pathogen that secretes mycolactone, a polyketide molecule with potent cytotoxic and immunomodulatory properties. These unique features make mycolactone an attractive biomarker for M. ulcerans disease. We sought to measure the concentration of mycolactone within lesions of patients with Buruli ulcer before, during and after antibiotic treatment to evaluate its association with the clinical and bacteriological response to therapy. METHODS: Biopsies of M. ulcerans infected skin lesions were obtained from patients before, during and after antibiotic therapy. Lipids were extracted from the biopsies and concentration of mycolactone was assayed by mass spectrometry and a cytotoxicity assay and correlated with clinical and bacteriological response to therapy. RESULTS: Baseline concentration of mycolactone measured by mass spectrometry predicted time to complete healing of small nodules and ulcers. Even though intra-lesional concentrations of mycolactone declined with antibiotic treatment, the toxin was still present after antibiotic treatment for 6 weeks and also 4 weeks after the end of treatment for 8 weeks in a subgroup of patients with slowly healing lesions. Additionally viable bacilli were detected in a proportion of these slowly healing lesions during and after treatment. CONCLUSIONS: Our findings indicate that baseline intra-lesional mycolactone concentration and its kinetics with antibiotic therapy are important prognostic determinants of clinical and bacteriological response to antibiotic treatment for Mycobacterium ulcerans disease. Mycolactone may be a useful biomarker with potential utility in optimising antibiotic therapy