Non-cigarette tobacco use and stroke among West Africans: evidence from the SIREN study.

INTRODUCTION: Non-cigarette tobacco (NCT) represents a form of tobacco use with a misperceived significance in chronic disease events. Whether NCT use is sufficient to promote stroke events, especially among Africans, is yet to be understood. This study assessed the relationship between NCT use and stroke among indigenous Africans. METHODS: A total of 7,617 respondents (NCT users: 41 vs. non-NCT: 7576) from the Stroke Investigation Research and Educational Network study were included in the current analysis. NCT use was defined as self-reported use of smoked (cigars or piper) or smokeless (snuff or chewed) tobacco in the past year preceding stroke events. Stroke was defined based on clinical presentation and confirmed with a cranial CT/MRI. Multivariable-adjusted logistic regression was applied to estimate the odds ratio (OR) and 95% confidence interval (CI) for the relationship between NCT and stroke at p<0.05. RESULTS: Out of the 41 (0.54%) who reported NCT use, 27 (65.9%) reported using smokeless NCT. NCT users were older than non-smokers (62.8±15.7 vs 57.7±14.8 years). Overall, NCT use was associated with first-ever stroke (OR: 2.08; 95%CI: 1.02, 4.23) in the entire sample. Notably, smokeless NCT use was independently associated with higher odds of stroke (OR: 2.74; 95%CI: 1.15, 6.54), but smoked NCT use (OR: 0.16; 95%CI: 0.02, 1.63) presented a statistically insignificant association after adjusting for hypertension and other covariates. CONCLUSIONS: NCT use was associated with higher odds of stroke, and public health interventions targeting NCT use might be promising in reducing the burden of stroke among indigenous Africans. IMPLICATIONS: A detailed understanding of the relationship between NCT use and stroke will likely inform well-articulated policy guidance to promote evidence-based recommendations for public health prevention and management of stroke on the African continent.

Risk factors and outcomes of delirium in hospitalized older Ghanaians.

OBJECTIVES: Delirium has been rarely studied in older West Africans. We sought to investigate its correlates and outcomes in hospitalized older Ghanaians. METHODS: This was a one-month prospective observational study. Delirium prevalence was assessed within 24 h of admission using the Confusion Assessment Method (CAM). Incident delirium was determined with repeat CAM assessments on post-admission days 4, 7, 14, 21 and 28, after censoring participants with prevalent delirium. Multivariate logistic regression analyses were used to explore risk factors. Estimates of adjusted hazard ratios for mortality were derived with the discrete time version of the Cox regression model for time invariant explanatory variables. RESULTS: Among 483 participants, 250 (51.8%, 95% CI: 47.3-56.3) had prevalent delirium while 10 of the remaining 233 (4.3%, 95% CI: 2.1-7.8) developed incident delirium. Being older than 80 years (adjusted odds ratio (OR) = 2.1, 95% CI: 1.2-3.6), having no formal education (OR = 2.2, 95% CI: 1.4-3.4), stroke (OR = 1.8, 95% CI: 1.1-3.0), infection (OR = 1.9, 95% CI: 1.2-3.0), and high Triage Early Warning Score (OR = 6.9, 95% CI: 2.5-19.0) predicted delirium. Delirium (adjusted hazard ratio (HR) = 1.8, 95% CI: 1.0-3.3) and high TEWS (HR = 4.6 (95% CI: 1.7-12.7) at baseline predicted mortality. These factors also predicted longer hospital stay. CONCLUSION: Over half of hospital-treated older Ghanaians in the present study had delirium on the first day of admission. The syndrome prolonged hospitalisation and increased mortality risk. Future studies in West Africa may investigate the epidemiology of delirium in primary care and community settings.

Are there differences in perceptions, preferences and attitudes towards disclosure of genetic testing for Stroke? A qualitative study among stroke-free SIREN-SIBS genomics study participants.

OBJECTIVE: This study explored perceptions, preferences and attitudes towards disclosure of genetic testing results for stroke among stroke-free controls (and their family members) in the SIREN-SIBS Genomics Study, healthcare providers and policymakers. MATERIALS AND METHODS: We conducted a qualitative thematic analysis of key informant interviews with 61 participants recruited from community advisory boards (30) and health care providers (31) across seven sites in Nigeria and Ghana. RESULTS: Major findings illustrate differences in the knowledge of genetic testing with superior knowledge among health care professionals. Relatives and religious leaders were opined as the best to receive the disclosure as they would be able to break the news to the patient in a culturally sensitive manner to reduce the likely resultant emotional outburst. Poor level of awareness of national guidelines for disclosing genetic results exist. Key facilitating factors for disclosure are education, enabling environment, involvement of religious and community leaders, campaigns, and possible treatment options. Disclosure inhibitors include inadequate information, fear of marital break-up or family displacement, fear of stigmatization, fear of isolation, religious beliefs, health worker attitude, and lack of preparedness to accept results. CONCLUSIONS: These necessitate culturally sensitive interventions for continuing education, increased awareness and sustained engagement to equip all stakeholders in genetic testing disclosure process.

Risk Factor Characterization of Ischemic Stroke Subtypes Among West Africans.

BACKGROUND AND PURPOSE: To identify the qualitative and quantitative contributions of conventional risk factors for occurrence of ischemic stroke and its key pathophysiologic subtypes among West Africans. METHODS: The SIREN (Stroke Investigative Research and Educational Network) is a multicenter, case-control study involving 15 sites in Ghana and Nigeria. Cases include adults aged ≥18 years with ischemic stroke who were etiologically subtyped using the A-S-C-O-D classification into atherosclerosis, small-vessel occlusion, cardiac pathology, other causes, and dissection. Controls were age- and gender-matched stroke-free adults. Detailed evaluations for vascular, lifestyle, and psychosocial factors were performed. We used conditional logistic regression to estimate adjusted odds ratios with 95% CI. RESULTS: There were 2431 ischemic stroke case and stroke-free control pairs with respective mean ages of 62.2±14.0 versus 60.9±13.7 years. There were 1024 (42.1%) small vessel occlusions, 427 (17.6%) large-artery atherosclerosis, 258 (10.6%) cardio-embolic, 3 (0.1%) carotid dissections, and 719 (29.6%) undetermined/other causes. The adjusted odds ratio (95% CI) for the 8 dominant risk factors for ischemic stroke were hypertension, 10.34 (6.91-15.45); dyslipidemia, 5.16 (3.78-7.03); diabetes, 3.44 (2.60-4.56); low green vegetable consumption, 1.89 (1.45-2.46); red meat consumption, 1.89 (1.45-2.46); cardiac disease, 1.88 (1.22-2.90); monthly income $100 or more, 1.72 (1.24-2.39); and psychosocial stress, 1.62 (1.18-2.21). Hypertension, dyslipidemia, diabetes were confluent factors shared by small-vessel, large-vessel and cardio-embolic subtypes. Stroke cases and stroke-free controls had a mean of 5.3±1.5 versus 3.2±1.0 adverse cardio-metabolic risk factors respectively (P<0.0001). CONCLUSIONS: Traditional vascular risk factors demonstrate important differential effect sizes with pathophysiologic, clinical and preventative implications on the occurrence of ischemic stroke among indigenous West Africans.

Dementia in Africa: Current evidence, knowledge gaps, and future directions.

In tandem with the ever-increasing aging population in low and middle-income countries, the burden of dementia is rising on the African continent. Dementia prevalence varies from 2.3% to 20.0% and incidence rates are 13.3 per 1000 person-years with increasing mortality in parts of rapidly transforming Africa. Differences in nutrition, cardiovascular factors, comorbidities, infections, mortality, and detection likely contribute to lower incidence. Alzheimer's disease, vascular dementia, and human immunodeficiency virus/acquired immunodeficiency syndrome-associated neurocognitive disorders are the most common dementia subtypes. Comprehensive longitudinal studies with robust methodology and regional coverage would provide more reliable information. The apolipoprotein E (APOE) ε4 allele is most studied but has shown differential effects within African ancestry compared to Caucasian. More candidate gene and genome-wide association studies are needed to relate to dementia phenotypes. Validated culture-sensitive cognitive tools not influenced by education and language differences are critically needed for implementation across multidisciplinary groupings such as the proposed African Dementia Consortium.

Legal Implications of Stroke Biobanking and Genomics Research in Sub-Saharan Africa.

Stroke is a major cause of death in Sub-Saharan Africa (SSA) and genetic factors appear to play a part. This has led to stroke biobanking and genomics research in SSA. Existing stroke studies have focused on causes, incidence rates, fatalities and effects. However, scant attention has been paid to the legal issues in stroke biobanking and genomics research in the sub-region. Therefore, this article examines the legal implications of stroke biobanking and genomics research in SSA. The article adopts a textual analysis of primary and secondary sources in law. It reports that there are laws from the perspectives of human right, the common law, and intellectual property. However, there are gaps to be filled. The article therefore argues for legislative intervention. It concludes that pending the time the statute will be enacted, genomics researchers in Africa should adopt the ethical guidelines prepared by Human Heredity and Health in Africa (H3 Africa).

A Novel Afrocentric Stroke Risk Assessment Score: Models from the Siren Study.

BACKGROUND: Stroke risk can be quantified using risk factors whose effect sizes vary by geography and race. No stroke risk assessment tool exists to estimate aggregate stroke risk for indigenous African. OBJECTIVES: To develop Afrocentric risk-scoring models for stroke occurrence. MATERIALS AND METHODS: We evaluated 3533 radiologically confirmed West African stroke cases paired 1:1 with age-, and sex-matched stroke-free controls in the SIREN study. The 7,066 subjects were randomly split into a training and testing set at the ratio of 85:15. Conditional logistic regression models were constructed by including 17 putative factors linked to stroke occurrence using the training set. Significant risk factors were assigned constant and standardized statistical weights based on regression coefficients (ß) to develop an additive risk scoring system on a scale of 0-100%. Using the testing set, Receiver Operating Characteristics (ROC) curves were constructed to obtain a total score to serve as cut-off to discriminate between cases and controls. We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) at this cut-off. RESULTS: For stroke occurrence, we identified 15 traditional vascular factors. Cohen's kappa for validity was maximal at a total risk score of 56% using both statistical weighting approaches to risk quantification and in both datasets. The risk score had a predictive accuracy of 76% (95%CI: 74-79%), sensitivity of 80.3%, specificity of 63.0%, PPV of 68.5% and NPV of 76.2% in the test dataset. For ischemic strokes, 12 risk factors had predictive accuracy of 78% (95%CI: 74-81%). For hemorrhagic strokes, 7 factors had a predictive accuracy of 79% (95%CI: 73-84%). CONCLUSIONS: The SIREN models quantify aggregate stroke risk in indigenous West Africans with good accuracy. Prospective studies are needed to validate this instrument for stroke prevention.

Improving the quality of care for people who had a stroke in a low-/middle-income country: A qualitative analysis of health-care professionals' perspectives.

BACKGROUND AND OBJECTIVE: Efforts to improve the adoption of evidence-based interventions for optimal patient outcomes in low-/middle-income countries (LMICs) are persistently hampered by a plethora of barriers. Yet, little is known about strategies to address such barriers to improve quality stroke care. This study seeks to explore health professionals' views on strategies to improve quality stroke care for people who had a stroke in a LMIC. METHODS: A qualitative interview study design was adopted. A semi-structured interview guide was used to conduct in-depth interviews among forty stroke care providers in major referral centres in Ghana. Participants were from nursing, medical, specialist and allied health professional groups. A purposive sample was recruited to share their views on practical strategies to improve quality stroke care in clinical settings. A thematic analysis approach was utilized to inductively analyse the data. RESULTS: A number of overarching themes of strategies to improve quality stroke care were identified: computerization and digitization of medical practice, allocation of adequate resources, increase the human resource capacity to deliver stroke care, development of clinical guideline/treatment protocols, institutionalization of multidisciplinary care and professional development opportunities. These strategies were however differentially prioritized among different categories of stroke care providers. CONCLUSION: Closing the gap between existing knowledge on how to improve quality of stroke care in LMICs has the potential to be successful if unique and context-specific measures from the views of stroke care providers are considered in developing quality improvement strategies and health systems and policy reforms. However, for optimal outcomes, further research into the effectiveness and feasibility of the proposed strategies by stroke care providers is needed.

Quality of life among patients with moderate to advanced chronic kidney disease in Ghana - a single centre study.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing worldwide and in Africa. Health related quality of life (QOL) has become an essential outcome measure for patients with CKD and end stage renal disease (ESRD). There is growing interest worldwide in QOL of CKD patients but paucity of data in Ghana. This study sought to assess QOL in patients with moderate to advanced CKD (not on dialysis) and establish its determinants. METHODS: We conducted a cross sectional observational study at the renal outpatient clinic at Komfo Anokye Teaching Hospital (KATH). We collected demographic, clinical and laboratory data. A pretested self-administered Research and Development corporation (RAND®) 36-Item Health Survey questionnaire was administered and QOL scores in physical component summary (PCS) and mental component summary (MCS) were computed. Determinants of QOL were established by simple and multiple linear regression. P value of < 0.05 was considered statistically significant. RESULTS: The study included 202 patients with CKD not on dialysis. There were 118(58.5%) males. Mean age was 46.7 ± 16.2 years. The majority, 165(81.7%) of patients were on monthly salaries of less than GHS 500 (~USD 125). Chronic glomerulonephritis was the most common cause of CKD in 118 (58.5%) patients followed by diabetes mellitus in 40 (19.8%) patients and hypertension in 19 (9.4%) patients. The median serum creatinine was 634.2 µmol/L (IQR 333-1248) and the median eGFR was 7 ml/min/1.73m2 (IQR 3-16). The most common stage was CKD stage 5 accounting for 143 (71.1%), followed by CKD stage 4 with 45 (22.4%) of cases and 13 (6.5%) of CKD stage 3. The overall mean QOL score was 40.3 ± 15.4. MCS score was significantly lower than PCS score (37.3 ± 10.8 versus 43.3 ± 21.6, P < 0.001). Multiple linear regression showed that low monthly income (p = 0.002) and low haemoglobin levels (p = 0.003) were predictive of overall mean QOL. CONCLUSION: Patients with moderate to advanced CKD had low-income status, presented with advanced disease and had poor QOL. Anaemia and low-income status were significantly associated with poor QOL.

Prevalence, Trajectory, and Predictors of Poststroke Fatigue among Ghanaians.

BACKGROUND AND PURPOSE: Poststroke fatigue (PSF) is rife among stroke survivors and it exerts a detrimental toll on recovery from functional deficits. The burden of PSF is unknown in sub-Saharan Africa. We have assessed the prevalence, trajectory, and predictors of PSF among 60 recent Ghanaian stroke patients. METHODS: Study participants in this prospective cohort (recruited between January 2017 and June 2017) were stroke survivors, aged greater than 18 years, with CT scan confirmed stroke of less than 1-month onset. PSF was assessed using the Fatigue Severity Scale (FSS) at enrollment, months 3, 6, and 9. Those with a score of greater than or equal to 4 points on FSS were categorized as "fatigued." A multivariate logistic regression analysis was performed to identify independent predictors of PSF at enrollment and at month 9. RESULTS: Sixty-five percent (65%) of our sample were males with a mean age of 55.1 ± 12.7 years. In addition to all participants having hypertension, 85% had dyslipidemia and 25% had diabetes mellitus. Ischemic strokes comprised 76.6% of the study population. The prevalence of PSF was 58.9% at baseline and declined to 23.6% at month 9, P = .0002. Diabetes mellitus was significantly associated with PSF at baseline with an adjusted odds ratio of 15.12 (95% CI: 1.70-134.30), P = .01. However, at month 9, age greater than or equal to 65 years, adjusted odds ratio (aOR) of 7.02 (95% CI: 1.16-42.52); female sex, aOR of 8.52 (1.23-59.16), and depression, aOR of 8.86 (1.19-65.88) were independently associated with PSF. CONCLUSIONS: Approximately 6 out of 10 Ghanaian stroke survivors experience PSF within the first month of stroke onset. PSF persists in approximately 1 out of 4 stroke survivors at 10 months after the index stroke. Further studies to elucidate the underlying mechanisms for PSF are required and adequately powered interventional multicenter trials are eagerly awaited to provide solid evidence base for the clinical management of PSF.

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.

Tele-Rehabilitation after Stroke: An Updated Systematic Review of the Literature.

BACKGROUND: Tele-rehabilitation for stroke survivors has emerged as a promising intervention for remotely supervised administration of physical, occupational, speech, and other forms of therapies aimed at improving motor, cognitive, and neuropsychiatric deficits from stroke. OBJECTIVE: We aimed to provide an updated systematic review on the efficacy of tele-rehabilitation interventions for recovery from motor, higher cortical dysfunction, and poststroke depression among stroke survivors. METHODS: We searched PubMed and Cochrane library from January 1, 1980 to July 15, 2017 using the following keywords: "Telerehabilitation stroke," "Mobile health rehabilitation," "Telemedicine stroke rehabilitation," and "Telerehabilitation." Our inclusion criteria were randomized controlled trials, pilot trials, or feasibility trials that included an intervention group that received any tele-rehabilitation therapy for stroke survivors compared with a control group on usual or standard of care. RESULTS: This search yielded 49 abstracts. By consensus between 2 investigators, 22 publications met the criteria for inclusion and further review. Tele-rehabilitation interventions focused on motor recovery (n = 18), depression, or caregiver strain (n = 2) and higher cortical dysfunction (n = 2). Overall, tele-rehabilitation interventions were associated with significant improvements in recovery from motor deficits, higher cortical dysfunction, and depression in the intervention groups in all studies assessed, but significant differences between intervention versus control groups were reported in 8 of 22 studies in favor of tele-rehabilitation group while the remaining studies reported nonsignificant differences. CONCLUSION: This updated systematic review provides evidence to suggest that tele-rehabilitation interventions have either better or equal salutary effects on motor, higher cortical, and mood disorders compared with conventional face-to-face therapy.

Long-Term Outcomes of Stroke in a Ghanaian Outpatient Clinic.

BACKGROUND: Compared with high-income countries, sub-Saharan African (SSA) countries experience a comparatively higher early mortality from stroke. However, data on long-term mortality from stroke in SSA are lacking. OBJECTIVE: Our aim is to assess long-term outcomes of stroke in an SSA setting. METHODS: We conducted a retrospective analysis of longitudinal data involving 607 consecutive stroke survivor encountered at an outpatient clinic in Kumasi, Ghana, between January 2012 and June 2014. Data were closed for analysis in June 2016. Data on demography, presence of vascular risk factors, stroke type, and functional status were evaluated. We followed up subjects who were no longer attending clinic by phone to assess their vital status. Primary outcome was death after initiation of clinic care, and its predictors were determined using a Cox proportional hazards regression model. RESULTS: Mean ± standard deviation (SD) age of cohort was 59.9 ± 13.9 years and 50.3% were female. Of the 607 stroke survivors, 377 (62.1%) were still alive, 59 (9.7%) were confirmed to have died, whereas 171 (28.2%) were lost to follow-up at the clinic. Mean ± SD observation time for the cohort was 32 ± 30 months. Upon adjustment for confounders, the independent predictors of mortality were age (adjusted hazard ratio [aHR] of 1.41 [95% confidence interval 1.15-1.73] for a 10-year increase in age) and diabetes mellitus (aHR of 2.24 [1.32-3.80]). CONCLUSIONS: Diabetes mellitus, a modifiable risk factor for stroke, is associated with an increased risk of mortality among West African stroke survivors over the long term.

Plasma Glial Fibrillary Acidic Protein, Copeptin, and Matrix Metalloproteinase-9 Concentrations among West African Stroke Subjects Compared with Stroke-Free Controls.

BACKGROUND: Measurement of plasma molecular markers among stroke patients has been proposed as an avenue for improving the accuracy of stroke diagnosis. There is paucity of data on the potential role of these markers in resource-limited settings, where the burden of stroke is greatest. OBJECTIVE: To assess the potential diagnostic and prognostic performance of 3 proposed biomarkers for stroke in a resource-constrained setting. METHODS: Consecutive stroke subjects presenting at a tertiary medical center in Kumasi, Ghana, with radiologically confirmed diagnosis and etiologic subtype information available were recruited along with age- and gender-matched controls in a 2:1 ratio. Plasma concentrations of glial fibrillary acidic protein (GFAP), copeptin, and matrix metalloproteinase-9 (MMP-9) among stroke patients and stroke-free controls were measured in duplicates using enzyme linked immunoassays. Diagnostic and prognostic correlates were assessed using area-under-the-curve (AUC) measures of receiver operator curves and logistic regression analysis, respectively. RESULTS: There were 156 stroke subjects with a mean age of 61.3 years of which 47.4% were females and 74 age- and gender-matched stroke-free controls. Median (interquartile range) time from symptom onset to hospital presentation for care was 7 days (5-11). Diagnostic accuracy of a single measurement of the 3 biomarkers for stroke using AUC (95% confidence interval) plots were as follows: .84 (.77-0.91), P < .0001, for GFAP; .85 (.79-0.92), P < .0001, for copeptin; and .65 (.56-0.73), P = .0003, for MMP-9. None of the biomarkers was associated with stroke severity or mortality. CONCLUSION: Plasma concentrations of GFAP and copeptin demonstrated stronger associations with stroke occurrence in this West African cohort compared with controls.

Tenofovir is associated with increased tubular proteinuria and asymptomatic renal tubular dysfunction in Ghana.

BACKGROUND: HIV infection is associated with increased risk of renal dysfunction, including tubular dysfunction (TD) related to antiretroviral therapy (ART). Tenofovir disoproxil fumarate (TDF) is becoming available for ART in sub-Saharan Africa, although data on its long-term safety there is limited. We aimed to study the prevalence of HIV-associated renal dysfunction in Ghana and explore associations between proteinuria or TD and potential risk factors, including TDF use. METHODS: A single-centre cross-sectional observational study of patients taking ART was undertaken. Creatinine clearance (CrCl) was calculated and proteinuria detected with dipsticks. Spot urinary albumin and protein:creatinine ratios (uACR/uPCR) were measured and further evidence of TD (defined as having two or more characteristic features) sought. Logistic regression analysis identified factors associated with proteinuria or TD. RESULTS: In 330 patients, of whom 101 were taking TDF (median 20 months), the prevalence of CrCl < 60 ml/min/1.73 m(2), dipstick proteinuria and TD was 7 %, 37 % and 15 %. Factors associated with proteinuria were baseline CD4-count [aOR 0.86/100 cell increment (95 % CI, 0.74-0.99)] and TDF use [aOR 2.74 (95 % CI, 1.38-5.43)]. The only factor associated with TD was TDF use [aOR 3.43 (95 % CI, 1.10-10.69)]. In a subset with uPCR measurements, uPCRs were significantly higher in patients taking TDF than those on other drugs (10.8 vs. 5.7 mg/mmol, p < 0.001), and urinary albuin:protein ratios significantly lower (0.24 vs. 0.58, p < 0.001). CONCLUSIONS: Both proteinuria and TD are common and associated with TDF use in Ghana. Further longitudinal studies to determine whether proteinuria, TD or TDF use are linked to progressive decline in renal function or other adverse outcomes are needed in Africa.

Infection with Mansonella perstans Nematodes in Buruli Ulcer Patients, Ghana.

During August 2010-December 2012, we conducted a study of patients in Ghana who had Buruli ulcer, caused by Mycobacterium ulcerans, and found that 23% were co-infected with Mansonella perstans nematodes; 13% of controls also had M. perstans infection. M. perstans co-infection should be considered in the diagnosis and treatment of Buruli ulcer.

Clinical and bacteriological efficacy of rifampin-streptomycin combination for two weeks followed by rifampin and clarithromycin for six weeks for treatment of Mycobacterium ulcerans disease.

Buruli ulcer, an ulcerating skin disease caused by Mycobacterium ulcerans infection, is common in tropical areas of western Africa. We determined the clinical and microbiological responses to administration of rifampin and streptomycin for 2 weeks followed by administration of rifampin and clarithromycin for 6 weeks in 43 patients with small laboratory-confirmed Buruli lesions and monitored for recurrence-free healing. Bacterial load in tissue samples before and after treatment for 6 and 12 weeks was monitored by semiquantitative culture. The success rate was 93%, and there was no recurrence after a 12-month follow-up. Eight percent had a positive culture 4 weeks after antibiotic treatment, but their lesions went on to heal. The findings indicate that rifampin and clarithromycin can replace rifampin and streptomycin for the continuation phase after rifampin and streptomycin administration for 2 weeks without any apparent loss of efficacy.

Long-term effectiveness of first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy in Ghana.

OBJECTIVES: Information on the long-term effectiveness and tolerability of efavirenz- or nevirapine-based antiretroviral therapy (ART) in Africa is lacking. The primary objective of this retrospective observational study was to compare the long-term clinical and immunological outcomes of efavirenz- versus nevirapine-based first-line ART in a large government clinic in Ghana. PATIENTS AND METHODS: The main outcomes were AIDS, death, ART-related toxicity, discontinuation of ART and a composite endpoint of death, AIDS or ART discontinuation. These time-to-event outcomes were compared using a Cox proportional hazards regression model. CD4 counts on ART were compared using a mixed-effects model. RESULTS: A total of 3990 patients started non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART between 2004 and 2010, of which 2369 (59%) were on efavirenz. No significant differences were apparent between each NNRTI for subsequent risk of AIDS, death or the composite of treatment failure; however, stavudine use was independently associated with an increased risk of death [adjusted hazard ratio (HR) 1.60 (95% CI: 1.21-2.11)]. There was an increased risk of early toxicity with nevirapine leading to discontinuation [adjusted HR 1.53 (95% CI: 1.23-1.97)], mostly due to excess skin rashes in the first 2 months of treatment; however, overall discontinuation rates were low. CONCLUSIONS: There was no difference in the long-term effectiveness of efavirenz- and nevirapine-based ART in this population; however, patients initiating nevirapine were more likely to develop early toxicity and discontinue this drug. The excess mortality observed in patients taking stavudine is of concern and should prompt increased efforts to replace it with alternative antiretroviral drugs in developing countries.

Pharmacogenetic associations with plasma efavirenz concentrations and clinical correlates in a retrospective cohort of Ghanaian HIV-infected patients.

OBJECTIVES: Efavirenz is widely used in first-line antiretroviral therapy in sub-Saharan Africa. However, exposure to efavirenz shows marked interindividual variability that is genetically mediated with potential for important pharmacodynamic consequences. The aims of this study were to assess the frequencies of CYP2B6, CYP2A6, UGT2B7 and CAR single nucleotide polymorphisms (SNPs) and their impact on plasma efavirenz concentration and clinical/immunological responses in Ghanaian patients. METHODS: Genomic DNA from 800 HIV-infected patients was genotyped for selected SNPs by real-time PCR-based allelic discrimination. Mid-dose plasma efavirenz concentrations were measured for 521 patients using HPLC with UV detection. Clinical outcomes in 299 patients on efavirenz were retrospectively assessed. Univariate and multivariate linear regression were performed using best subset selection. Time-to-event outcomes were analysed using a Cox proportional hazards regression model. RESULTS: The variant allele frequencies for CYP2B6 516G>T (rs3745274), CYP2B6 983T>C (rs28399499), CYP2A6 -48T>G (CYP2B6*9B; rs28399433), UGT2B7 802C>T (UGT2B7*2; rs7439366), UGT2B7 735A>G (UGT2B7*1c; rs28365062) and CAR 540C>T (rs2307424) were 48%, 4%, 3%, 23%, 15% and 7%, respectively. CYP2B6 516G>T, CYP2B6 983T>C and CYP2A6 -48T>G were associated with significantly elevated efavirenz concentrations. A trend towards association between plasma efavirenz concentration and CAR 540C>T was observed. CYP2B6 516G homozygosity was associated with immunological failure [adjusted hazards ratio compared with T homozygosity, 1.70 (1.04-2.76); P = 0.03]. CONCLUSIONS: CYP2B6 and CYP2A6 SNPs were associated with higher plasma efavirenz concentrations due to reduction in major and minor phase I routes of elimination, respectively. Further prospective studies are needed to validate the pharmacodynamic correlates of these polymorphisms in this population.

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.