Malawian Patients Research Articles

Lessons in Cultural Adaptations: Translation of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Cervical Cancer Module From English to Chichewa in Malawi

IntroductionTo complete a culturally appropriate translation of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Cervical Cancer module (QLQ-CX24) from English to Chichewa (one of the official languages of Malawi) in preparation for postsurgical outcomes research in rural Malawian cervical cancer patients. MethodsFollowing the EORTC translation procedure manual, two distinct forward translations from English were reconciled into a preliminary Chichewa translation, followed by two distinct back-translations to English. The English back-translation was reconciled and the translation report sent for discussion and proofreading by EORTC; this was followed by pilot testing. All translators were physicians fluent in English and Chichewa. ResultsOf 24 questions in QLQ-CX24, three had prior translations available; all three required revision to clarify tense or wording. Three discussion exchanges with EORTC refined the translation and ensured faithfulness to the original English meaning; proofreaders contributed minor changes. Pilot testing was completed on 10 female patients (three with cervical cancer, four suspicious cervical lesions, and three screening only). Three patients were illiterate. During pilot testing, translation of question 46 (Q46) was misunderstood as referring to vaginal discharge instead of feeling “feminine”. The remaining questions were understood, with minor feedback for six questions. Final revision of Q46 yielded a phrase describing “feminine” as “appearance or activities as a woman”. Concepts comparable to “feminine” were absent in the Chichewa language/regional Malawian culture. The final revision of Q46 was pilot-tested on five patients (three illiterate) and found acceptable. ConclusionsTranslation of the QLQ-CX24 module was completed successfully and revealed absence of the modern concept of femininity in Chichewa language and regional Malawian culture. Care should be taken when creating and translating healthcare-related documents for surgical research to ensure broad applicability across cultures.

Development of a Therapeutic Drug Monitoring Strategy for the Optimization of Vincristine Treatment in Pediatric Oncology Populations in Africa

Recent studies have reported ethnic differences in vincristine exposure and outcomes such as toxicity. This resulted in the hypothesis of subtherapeutic dosing in African children. To optimize individual treatment, a strategy to identify subtherapeutic exposure using therapeutic drug monitoring is essential. The aim of the current study was to develop a strategy for therapeutic drug monitoring of vincristine in African children to meet the following criteria: (1) identify patients with low vincristine exposure with sufficient sensitivity (>70%), (2) determine vincristine exposure with a limited sampling strategy design of 3 samples, and (3) allow all samples to be collected within 4 hours after administration. An in silico simulation study was performed using a previously described population pharmacokinetic model and real-life demographic dataset of Kenyan and Malawian pediatric oncology patients. Two different therapeutic drug monitoring strategies were evaluated: (1) Bayesian approach and (2) pharmacometric nomogram. The sampling design was optimized using the constraints described above. Sensitivity analysis was performed to investigate the influence of missing samples, erroneous sampling times, and different boundaries on the nomogram weight bands. With the Bayesian approach, 43.3% of the estimated individual exposure values had a prediction error of ≥20% owing to extremely high shrinkage. The Bayesian approach did not improve with alternative sampling designs within sampling constraints. However, the pharmacometric nomogram could identify patients with low vincristine exposure with a sensitivity, specificity, and accuracy of 75.1%, 76.4%, and 75.9%, respectively. The pharmacometric nomogram performed similarly for different weight bands. The pharmacometric nomogram was able to identify patients with low vincristine exposure with high sensitivity, with 3 blood samples collected at 1, 1.5, and 4 hours after administration. Missing samples should be avoided, and the 3 scheduled samples should be collected within 15, 5, and 15 minutes of 1, 1.5, and 4 hours after administration, respectively.

Saliva urea nitrogen dipsticks to predict acute kidney injury in Malawian trauma patients

Background: Many low-resource settings have limited access to serum creatinine tests necessary for kidney disease identification. Among Malawian patients who are hospitalized after trauma, we evaluated the use of point-of-care saliva urea nitrogen (SUN) dipsticks to predict acute kidney injury (AKI). Methods: In a nested prospective cohort study, we enrolled hospitalized acute trauma patients aged ≥6 months to evaluate AKI (defined by KDIGO criteria) and the test characteristics of SUN to predict AKI.

High risk of acute kidney injury in Malawian trauma patients: a prospective observational cohort study

BackgroundTrauma is a common cause of acute kidney injury (AKI). Yet little data exist regarding trauma-related-AKI in low-resourced settings, where the majority of deaths from AKI and trauma occur. We prospectively evaluated epidemiology of AKI in hospitalized Malawian trauma patients.MethodsAKI was defined by creatinine-only Kidney Disease Improving Global Outcomes (KDIGO) criteria. Those with AKI were followed up 3–6 months later to determine persistent kidney abnormalities. We calculated univariate statistics with Wilcoxon rank sum tests, Fisher’s exact, and chi-square tests to compare those with and without AKI. Multivariate log-risk regression modelling was used to determine risk ratios (RR) and 95% confidence intervals (CI) for AKI development.ResultsOf 223 participants, 14.4% (n = 32) developed AKI. Most patients were young (median age 32) males (n = 193, 86.5%) involved in road traffic injuries (n = 120, 53.8%). After adjusting for confounders, those with severe anemia during their admission were 1.4 times (RR 1.4, 95% CI 1.1–1.8) more likely to develop AKI than those without. Overall mortality was 7.6% (n = 17), and those who developed AKI were more likely to die than those who did not (18.8% vs 5.6%, p-value = 0.02). Almost half of those with AKI (n = 32) either died (n = 6) or had persistent kidney dysfunction at follow-up (n = 8).ConclusionIn one of the few African studies on trauma-related AKI, we found a high incidence of AKI (14.4%) in Malawian trauma patients with associated poor outcomes. Given AKI’s association with increased mortality and potential ramifications on long-term morbidity, urgent attention is needed to improve AKI-related outcomes.

Emerging treatment options for cryptosporidiosis.

Purpose of reviewSubstantial progress has been made recently on the development of new therapeutics for cryptosporidiosis, an infection by the protozoan parasite Cryptosporidium that is associated with diarrhea, malnutrition, growth stunting, cognitive deficits, and oral vaccine failure in children living in low-resource settings.Recent findingsVarious drug discovery approaches have generated promising lead candidates. The repurposed antimycobacterial drug clofazimine was tested in Malawian HIV patients with cryptosporidiosis but was ineffective. Target-based screens identified inhibitors of lysyl-tRNA synthetase, phenylalanyl-tRNA synthetase, methionyl-tRNA synthetase, and calcium-dependent protein kinase 1. Phenotypic screens led to discovery of a phosphatidylinositol 4-kinase inhibitor, the piperazine MMV665917, and the benzoxaborole AN7973. The relationship between pharmacokinetic properties and in-vivo efficacy is gradually emerging. A pathway to clinical trials, regulatory approval, and introduction has been proposed but additional work is needed to strengthen the route.SummarySeveral lead compounds with potent activity in animal models and a favorable safety profile have been identified. A sustained effort will be required to advance at least one to clinical proof-of-concept studies. The demonstrated risk of resistance indicates multiple candidates should be advanced as potential components of a combination therapy.

Cardiovascular risk assessment for primary prevention in Malawian HIV patients on ART: are measurements of glycated hemoglobin and lipids worth the effort?

Cardiovascular risk assessment for primary prevention in Malawian HIV patients on ART: are measurements of glycated hemoglobin and lipids worth the effort?

Intrapulmonary Pharmacokinetics of First-line Anti-tuberculosis Drugs in Malawian Patients With Tuberculosis.

BackgroundFurther work is required to understand the intrapulmonary pharmacokinetics of first-line anti-tuberculosis drugs. This study aimed to describe the plasma and intrapulmonary pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol, and explore relationships with clinical treatment outcomes in patients with pulmonary tuberculosis.MethodsMalawian adults with a first presentation of microbiologically confirmed pulmonary tuberculosis received standard 6-month first-line therapy. Plasma and intrapulmonary samples were collected 8 and 16 weeks into treatment and drug concentrations measured in plasma, lung/airway epithelial lining fluid (ELF), and alveolar cells. Population pharmacokinetic modeling generated estimates of drug exposure (Cmax and AUC) from individual-level post hoc Bayesian estimates of plasma and intrapulmonary pharmacokinetics.ResultsOne-hundred fifty-seven patients (58% HIV coinfected) participated. Despite standard weight-based dosing, peak plasma concentrations of first-line drugs were below therapeutic drug-monitoring targets. Rifampicin concentrations were low in all 3 compartments. Isoniazid, pyrazinamide, and ethambutol achieved higher concentrations in ELF and alveolar cells than plasma. Isoniazid and pyrazinamide concentrations were 14.6-fold (95% CI, 11.2–18.0-fold) and 49.8-fold (95% CI, 34.2–65.3-fold) higher in ELF than plasma, respectively. Ethambutol concentrations were highest in alveolar cells (alveolar cell–plasma ratio, 15.0; 95% CI, 11.4–18.6). Plasma or intrapulmonary pharmacokinetics did not predict clinical treatment response.ConclusionsWe report differential drug concentrations between plasma and the lung. While plasma concentrations were below therapeutic monitoring targets, accumulation of drugs at the site of disease may explain the success of the first-line regimen. The low rifampicin concentrations observed in all compartments lend strong support for ongoing clinical trials of high-dose rifampicin regimens.

Longitudinal Pharmacokinetic-Pharmacodynamic Biomarkers Correlate With Treatment Outcome in Drug-Sensitive Pulmonary Tuberculosis: A Population Pharmacokinetic-Pharmacodynamic Analysis.

BackgroundThis study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions.MethodsData were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing.ResultsHigher isoniazid exposure correlated with increased bacillary killing in sputum (P < .01). Bacillary killing in sputum remained fast, with later progression to biphasic decline, in patients with higher rifampicin area under the curve (AUC)0-24 (P < .01). Serial sputum colony counting negativity at month 2 (P < .05), isoniazid CMAX (P < .05), isoniazid CMAX/minimum inhibitory concentration ([MIC] P < .01), and isoniazid AUC0-24/MIC (P < .01) correlated with treatment success but not with remaining free of TB. Slower bacillary killing (P < .05) and earlier progression to biphasic bacillary decline (P < .01) both correlate with treatment failure. Posttreatment recurrence only correlated with slower bacillary killing (P < .05).ConclusionsPatterns of early bacillary clearance matter. Static measurements such as month 2 sputum conversion and pharmacokinetic parameters such as CMAX/MIC and AUC0-24/MIC were predictive of treatment failure, but modeling of quantitative longitudinal data was required to assess the risk of recurrence. Pooled individual patient data analyses from larger datasets are needed to confirm these findings.

The role of patient-provider communication: a qualitative study of patient attitudes regarding co-occurring depression and chronic diseases in Malawi

BackgroundGlobally, depression is a leading cause of morbidity and mortality particularly in Low and Middle-Income Countries (LMICs). The burden of non-communicable diseases (NCDs) are also increasing in LMICs, the conditions frequently co-occur and exacerbate NCD outcomes. Depression interventions alone are not effective at improving NCD outcomes, resulting in wide-reaching calls for integrated services. Integrated services are in a nascent phase in LMICs in general and in Malawi in particular. This manuscript serves to clarify Malawian patients’ attitudes and perceptions towards depression integration into routine NCD services.MethodsTen District Hospitals were selected for data collection and 2 participants were interviewed from each site (N = 20). An iterative approach to concept-driven coding was applied to facilitate the formation of similarities, differences, and connections between codes.ResultsWhile patients infrequently described moderate depression as a medical condition, and held various attitudes regarding treatments, they agreed on the appropriateness of integrated services. Patients’ respect for their providers led them to support integration. Patients discussed how medical knowledge is highly regarded, revealing a power dynamic with their providers. Patients further acknowledged the importance of a provider’s communication in shaping a patient’s feelings about depression.ConclusionsTraining and interventions that facilitate providers’ abilities to transfer their medical knowledge, use strategies to channel their power, and engage patients in a meaningful and collaborative relationship will be key to successfully integrating depression treatment into Malawian NCD clinics.Trial registrationThis work served as part of formative data collection for National Institute of Mental Health (NIMH) Trail NCT03711786 registered on 10th October, 2018.

SUN-175 EPIDEMIOLOGY OF ACUTE KIDNEY INJURY IN A MALAWIAN ADULT TRAUMA COHORT

Acute kidney injury (AKI) remains a major cause of morbidity and mortality worldwide with the majority of cases occurring in low- and middle-income countries (LMICs). Trauma is a common cause of AKI, yet little is known about the incidence, risk factors or patient outcomes associated with trauma-related-AKI in LMICs. Though more than 12,000 patients are evaluated for traumatic injuries annually at Kamuzu Central Hospital (KCH), a large referral hospital in the sub-Saharan Africa country Malawi, the incidence of AKI amongst Malawian trauma patients is unknown.

Detection of minority drug resistant mutations in Malawian HIV-1 subtype C-positive patients initiating and on first-line antiretroviral therapy.

BackgroundMinority drug resistance mutations (DRMs) that are often missed by Sanger sequencing are clinically significant, as they can cause virologic failure in individuals treated with antiretroviral therapy (ART) drugs.ObjectiveThis study aimed to estimate the prevalence of minor DRMs among patients enrolled in a Malawi HIV drug resistance monitoring survey at baseline and at one year after initiation of ART.MethodsForty-one plasma specimens collected from HIV-1 subtype C-positive patients and seven clonal control samples were analysed using ultra-deep sequencing technology.ResultsDeep sequencing identified all 72 DRMs detected by Sanger sequencing at the level of ≥20% and 79 additional minority DRMs at the level of < 20% from the 41 Malawian clinical specimens. Overall, DRMs were detected in 85% of pre-ART and 90.5% of virologic failure patients by deep sequencing. Among pre-ART patients, deep sequencing identified a statistically significant higher prevalence of DRMs to nucleoside reverse transcriptase inhibitors (NRTIs) compared with Sanger sequencing. The difference was mainly due to the high prevalence of minority K65R and M184I mutations. Most virologic failure patients harboured DRMs against both NRTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs). These minority DRMs contributed to the increased or enhanced virologic failures in these patients.ConclusionThe results revealed the presence of minority DRMs to NRTIs and NNRTIs in specimens collected at baseline and virologic failure time points. These minority DRMs not only increased resistance levels to NRTIs and NNRTIs for the prescribed ART, but also expanded resistance to additional major first-line ART drugs. This study suggested that drug resistance testing that uses more sensitive technologies, is needed in this setting.

Abstract IA8: The genetics and genomics of African esophageal cancer

Abstract Esophageal squamous cell carcinoma (ESCC) is common in many Black populations of sub-Saharan Africa, with high incidence regions in Eastern and Southern Africa. Clinical presentation in Africa is late, and treatment is mainly palliative with a very poor prognosis. Various environmental risk factors have been identified, but the possible contribution of inherited genetic variants to disease risk is an important question which is unresolved. Also, limited data are available on the somatic mutations which are driving tumor development. This presentation will review current knowledge on the role of germline genetic variants and somatic mutations in the development of African ESCC. Genetic association studies of African ESCC have been limited to the analysis of small numbers of single nucleotide polymorphisms (SNPs) in candidate genes, and carried out only in the Black and Mixed Ancestry populations of the Western Cape of South Africa. Several positive associations have been reported, particularly in the Mixed Ancestry population, but none have achieved genome-wide levels of significance or been replicated in independent studies. We are currently testing SNPs which have been associated with ESCC in genome-wide association studies (GWAS) from Asian and European populations for association with ESCC in the South African population. Black cases with a histologically confirmed diagnosis of ESCC and matching population controls were recruited, after informed consent and institutional ethical approval, from the Western Cape and Gauteng provinces of South Africa. SNPs were genotyped either by individual TaqMan assays (Applied Biosystems) or in a multiplex MassARRAY (Agena Bioscience) and genotypes were tested for association. Our initial studies found no significant evidence of association at previously reported GWAS loci ATP1B2, CASP8, c20orf54, HEATR3, PDE4D, PLCE1, PTPN2, RUNX1, SMG6, ST6GAL1, TMEM173 and UNC5L loci. However, evidence for association was observed for the SNP rs2239815 at XBP1 on chromosome 22q12 (OR =1.41, P = 0.00087), and the SNPs rs4822983 (OR = 1.31, P = 0.0013) and rs1033667 (OR = 1.29, P = 0.0025) in CHEK2. Genotyping of a larger SNP panel in an expanded collection of cases and controls is in progress to extend these findings. Detection of somatic mutations in ESCC tumour tissue has in the past been limited to sequencing of candidate genes and copy number studies, with TP53 mutations being detected in a minority of South African and Kenyan patients. We have carried out pilot whole exome sequencing in 10 matched blood/tumour pairs from South African ESCC patients and detected mutations in TP53, ATR, GNAS, MAGI2, FBXW7, FLT3, NFE2L2, TET2 and ZNF750. Follow up sequencing of the TP53 gene detected missense or truncating mutations in 18/26 (69%) of tumours. A recent sequencing study of 59 Malawian ESCC patients (Liu et al) observed recurrent mutations in TP53, CDKN2A, NFE2L2, CHEK2, NOTCH1, FAT1 and FBXW7, and transcriptomic profiles were used to divide ESCCs into 3 subtypes. Priorities for the future should include well powered GWAS in high risk populations from several African countries, with collaborative studies to compare genetic risk factors across populations and meta-analysis to provide power to detect risk loci with moderate effects. Whole-exome or whole genome sequencing of substantial panels of blood/tumour pairs are needed to establish the major drivers of tumorigenesis in African ESCC and to derive mutational signatures which may provide insight into causal environmental factors. Citation Format: Christopher G. Mathew. The genetics and genomics of African esophageal cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA8.

Application of the qSOFA score to predict mortality in patients with suspected infection in a resource-limited setting in Malawi

PurposeTo determine the predictive value of qSOFA (quick Sequential Organ Failure Assessment) in Malawian patients with suspected infection.MethodsProspective observational study in a tertiary referral hospital in Malawi.ResultsPredictive ability of qSOFA was reasonable [AUROC 0.73 (95% CI 0.68–0.78)], increasing to 0.77 (95% CI 0.72–0.82) when classifying all patients with altered mental status as high risk. Adding HIV status as a variable to the qSOFA score did not improve predictive value.ConclusionqSOFA is a simple tool that can aid risk stratification in resource-limited settings.

Prediction of Outcome From Adult Bacterial Meningitis in a High-HIV-Seroprevalence, Resource-Poor Setting Using the Malawi Adult Meningitis Score (MAMS).

Acute bacterial meningitis (ABM) in adults residing in resource-poor countries is associated with mortality rates >50%. To improve outcome, interventional trials and standardized clinical algorithms are urgently required. To optimize these processes, we developed and validated an outcome prediction tool to identify ABM patients at greatest risk of death. We derived a nomogram using mortality predictors derived from a logistic regression model of a discovery database of adult Malawian patients with ABM (n = 523 [65%] cerebrospinal fluid [CSF] culture positive). We validated the nomogram internally using a bootstrap procedure and subsequently used the nomogram scores to further interpret the effects of adjunctive dexamethasone and glycerol using clinical trial data from Malawi. ABM mortality at 6-week follow-up was 54%. Five of 15 variables tested were strongly associated with poor outcome (CSF culture positivity, CSF white blood cell count, hemoglobin, Glasgow Coma Scale, and pulse rate), and were used in the derivation of the Malawi Adult Meningitis Score (MAMS) nomogram. The C-index (area under the curve) was 0.76 (95% confidence interval, .71-.80) and calibration was good (Hosmer-Lemeshow C-statistic = 5.48, df = 8, P = .705). Harmful effects of adjunctive glycerol were observed in groups with relatively low predicted risk of poor outcome (25%-50% risk): Case Fatality Rate of 21% in the placebo group and 52% in the glycerol group (P < .001). This effect was not seen with adjunctive dexamethasone. MAMS provides a novel tool for predicting prognosis and improving interpretation of ABM clinical trials by risk stratification in resource-poor settings. Whether MAMS can be applied to non-HIV-endemic countries requires further evaluation.

Perceptions of Research Bronchoscopy in Malawian Adults with Pulmonary Tuberculosis: A Cross-Sectional Study.

Bronchoscopy is an established research tool in Malawi, enabling collection of pulmonary samples for immunological, pharmacological, and microbiological studies. It is, however, an invasive clinical procedure that offers no direct benefit to volunteering participants when used in a research capacity alone, and thus informed consent is essential. This study aimed to explore TB patients’ understanding of research bronchoscopy, what would motivate them to participate in research bronchoscopy, and their concerns, in order to inform consenting processes for future clinical studies. We used a qualitative research design. Two focus group discussions were conducted with community members and TB patients to understand their perceptions of bronchoscopy. Transcripts were coded by multiple co-authors and thematic content analysis was used to analyse main findings. We found that Malawian patients with pulmonary TB were willing to participate in a study using research bronchoscopy for health assessment and access to improved healthcare. We identified information of value to potential participants when consenting to that may lessen some of the anxieties expressed by participants. Patient and public involvement is essential to improve informed consent and institutional trust.

A framework for improving early detection of breast cancer in sub-Saharan Africa: A qualitative study of help-seeking behaviors among Malawian women

ObjectiveMany women in Africa are diagnosed with advanced breast cancer. We explored Malawian breast cancer patients’ perspectives about their diagnosis and ability to access care to identify help-seeking behaviors and to describe factors influencing delay. MethodsWe purposively sampled 20 Malawian breast cancer patients to conduct in-depth interviews. Transcripts were double coded to identify major themes of breast cancer help-seeking behaviors and what delayed or facilitated access to care. ResultsWe outlined a breast cancer help-seeking pathway describing decisions, behaviors, and interactions from symptom presentation to receipt of cancer care. Patients were largely unaware of breast cancer and did not immediately notice or interpret symptoms. As symptoms progressed, women inferred illness and sought help from social networks, traditional remedies, and medical care. Economic hardship, distance to the facility, provider knowledge, health system factors, and social norms often delayed reaching the facility, referrals, diagnosis, and receipt of care. ConclusionsSocial-contextual factors at the individual, interpersonal, health system, and societal levels delay decisions, behaviors, and access to breast cancer detection and appropriate care. Practice implicationsA comprehensive approach to improving breast cancer early detection must address public awareness and misconceptions, provider knowledge and communication, and cancer care delivery.

Severe tetanus in Malawi: where are the female patients?

The treatment of severe tetanus is a challenge for the resource-poor countries in Africa. In the critical care unit at the University of Malawi’s largest teaching hospital (Queen Elizabeth Central Hospital), we have seen more male than female adult patients suffering from severe tetanus. Here we tried to determine, whether it is true or not, that what we are seeing is a developing “gender-shift” in Malawian adult patients with severe tetanus. We retrospectively reviewed medical records of patients treated at the critical care unit of the Queen Elizabeth Central Hospital during 2006–2015 and interviewed senior staff in the four central hospitals and in 20 hospitals in the districts. From 2006 to 2015 we treated 21 adult patients (≥18 years) suffering from severe tetanus in our intensive care unit (ICU). There were 19 male patients (90.4 %), 1 female patient (4.8 %) and one patient with missing data on gender (4.8 %). Staff interviewed countrywide identified eight cases of severe tetanus in the other three central hospitals (all male) and two male patients in the 20 hospitals in the districts since 2013. Countrywide we found 31 cases of severe tetanus of which 29 (93.9 %) were male and only 1 female (3.05 %). We have not been able to identify any female adult patients suffering from severe tetanus in Malawi since 2012. Adult generalized tetanus is no longer very common in Malawi. Severe tetanus nowadays seems to be a predominantly male disease in Malawi. Post-exposure immunization and co-immunization for the male partner during antenatal care should be intensified.

Ethnicity and patient satisfaction with tuberculosis care: A cross-sectional study.

Patients presenting in major tuberculosis (TB) centres in two Australian metropolitan hospitals and three central hospitals in Malawi were interviewed for health and other information, including their satisfaction with nursing care. The main objective of the study was to investigate differences in satisfaction rates among ethnically similar and different patients coming from two dissimilar health systems. A multivariable Generalized Estimating Equations model was constructed to identify sociodemographic and health-related factors associated with dissatisfaction, while focusing on ethnic differences between and within each country. The Australian and Malawian patients were similar in age, gender, marital status, and employment. However, the Malawians were mostly inpatients, with recurrent TB episodes, and were more seriously ill with impaired physical and mental wellbeing. Nonetheless, being Australian was more associated with dissatisfaction observed in all components of care. However, Australian ethnic minorities were less dissatisfied than their Anglo-Saxon or European counterparts, being more similar to Malawian patients irrespective of the health care provided. Our study suggests that patients coming from similar ethnic backgrounds may express similar satisfaction irrespective of the health system they belong to.

S75 Risk Factors And Therapeutic Implications Of Vitamin D Deficiency In Malawian Adults With Pulmonary Tuberculosis

Introduction and objectives Pre-treatment Vitamin D deficiency (VDD) is well described amongst adult TB patients in Malawi and has been associated with impaired mycobacterial immunity. Anti-TB drugs and antiretroviral therapy (ART) for HIV may induce hepatic Vitamin D metabolism, further reducing the serum concentration of active metabolites including 25-OH D3. This study identified risk factors for baseline VDD, assessed the effect of therapy on 25-OH D3 concentrations, and evaluated whether VDD deficiency has prognostic implications for treatment response. Methods Adults with pulmonary TB were treated with standard 6 month therapy. Serum 25-OH D3 concentrations were measured at baseline, 8 weeks and end of treatment. Serial sputum samples were used to model the rate of bacterial elimination for each patient. Patients were followed until 1 year post-treatment and final outcomes were defined as favourable (stable cure) or unfavourable (failure/relapse). Linear and logistic regression analyses were used to identify risk factors for VDD and assess relationships between VDD and treatment response. Results 133 patients were studied. 75 (56%) were HIV-infected and 24 (18%) were on ART. 118 (89%) had favourable and 15 (11%) had unfavourable outcomes. The median baseline 25-OH D3 concentration was 57.3 nmol/l. 47 (28%) patients had concentrations Conclusions The presence and extent of VDD in Malawian TB patients was determined by environmental factors (sunlight exposure and dietary intake) rather than HIV status or ART. 25 OH D3 levels improved during therapy, suggesting that induction of Vitamin D metabolites by anti-TB drugs or ART is adequately compensated by improved Vitamin D uptake during disease recovery. VDD did not have prognostic implications for treatment response.

Peripheral Blood Mitochondrial DNA/Nuclear DNA (mtDNA/nDNA) Ratio as a Marker of Mitochondrial Toxicities of Stavudine Containing Antiretroviral Therapy in HIV-Infected Malawian Patients

Mitochondrial toxicity is a major concern related to nucleoside reverse transcriptase inhibitors. Common manifestations are peripheral neuropathy and lipodystrophy. Depletion of mitochondria has been associated with mitochondrial dysfunction. We investigated whether mitochondria DNA (mtDNA) levels in peripheral blood can be used as biomarker of stavudine-associated mitochondrial toxicities. We enrolled 203 HIV-infected Malawian adult patients on stavudine-containing ART and 64 healthy controls of Bantu origin in a cross-sectional study. Total DNA was extracted from whole blood.The glyceraldehyde-3-phosphate dehydrogenase gene was used to estimate nuclear DNA (nDNA) levels and the ATP synthase-8 mitochondrial DNA gene to estimate mtDNA levels, from which mtDNA/nDNA ratios were determined. MtDNA subhaplogroups were established by sequencing. Among patients, peripheral neuropathy was present in 21% (43/203), lipodystrophy in 18% (20/112), elevated lactate level (>2.5 mmol/L) in 17% (19/113). Healthy controls had a higher median mtDNA/nDNA ratio when compared to HIV/AIDS patients (6.64 vs. 5.08; p=0.05), patients presenting with peripheral neuropathy (6.64 vs. 3.40, p=0.039), and patients with high lactate levels (6.64 vs. 0.68, p=0.024), respectively. Significant differences in median mtDNA/nDNA ratios were observed between patients with high and normal lactate levels (5.88 vs. 0.68, p=0.018). The median mtDNA/nDNA ratio of patients in subhaplogroup L0a2 was much lower (0.62 vs. 8.50, p=0.01) than that of those in subhaplogroup L2a. Our data indicate that peripheral blood mtDNA/nDNA ratio is a marker of mitochondrial toxicities of stavudine and is associated with elevated lactate levels and mtDNA subhaplogroups. This could open the prospect to select a substantial group of patients who will not have problematic side effects from stavudine, an affordable and effective antiretroviral drug that is being phased out in Africa due to its toxicity.