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ABSTRACT: Stavudine is an effective and inexpensive antiretroviral drug, but no longer recommended by WHO for first-line antiretroviral regimens in resource-limited settings due to toxicity concerns. Because of the high cost of alternative drugs, it has not been feasible to replace stavudine in most adults in the Malawi ART programme. We aimed to provide policy makers with a detailed picture of stavudine toxicities in Malawians on longer-term ART, in order to facilitate prioritization of stavudine replacement among other measures to improve the quality of ART programmes.
Prospective cohort of Malawian adults who had just completed one year of stavudine containing ART in an urban clinic, studying peripheral neuropathy, lipodystrophy, diabetes mellitus, high lactate syndromes, pancreatitis and dyslipidemia during 12 months follow up. Stavudine dosage was 30 mg irrespective of weight. Cox regression was used to determine associations with incident toxicities.
253 patients were enrolled, median age 36 years, 62.5% females. Prevalence rates (95%-confidence interval) of toxicities after one year on stavudine were: peripheral neuropathy 21.3% (16.5-26.9), lipodystrophy 14.7% (2.4-8.1), high lactate syndromes 0.0% (0-1.4), diabetes mellitus 0.8% (0-2.8), pancreatitis 0.0% (0-1.5). Incidence rates per 100 person-years (95%-confidence interval) during the second year on stavudine were: peripheral neuropathy 19.8 (14.3-26.6), lipodystrophy 11.4 (7.5-16.3), high lactate syndromes 2.1 (0.7-4.9), diabetes mellitus 0.4 (0.0-1.4), pancreatitis 0.0 (0.0-0.2). Prevalence of hypercholesterolemia and hypertriglyceridemia increased from 12.1% to 21.1% and from 29.5% to 37.6% respectively between 12 and 24 months. 5.5% stopped stavudine, 1.3% died and 4.0% defaulted during follow up. Higher age was an independent risk factor for incident peripheral neuropathy and lipodystrophy.
Stavudine associated toxicities continued to accumulate during the second year of ART, especially peripheral neuropathy and lipodystrophy and more so at increasing age. Our findings support investments for replacing stavudine in first-line regimens in sub-Saharan Africa.
PLoS ONE 01/2012; 7(7):e42029. · 4.09 Impact Factor
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ABSTRACT: To document trends in invasive pneumococcal disease (IPD) in a central hospital in Malawi during the period of national scale-up of antiretroviral therapy (ART) and cotrimoxazole prophylaxis.
Between 1 January 2000 and 31 December 2009 almost 100,000 blood cultures and 40,000 cerebrospinal fluid (CSF) cultures were obtained from adults and children admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi with suspected severe bacterial infection.
4,445 pneumococcal isolates were obtained over the 10 year period. 1,837 were from children: 885 (19.9%) from blood and 952 (21.4%) from CSF. 2,608 were from adults: 1,813 (40.8%) from blood and 795 (17.9%) from CSF. At the start of the surveillance period cotrimoxazole resistance was 73.8% and at the end was 92.6%. Multidrug resistance (MDR) was present in almost one third of isolates and was constant over time. Free ART was introduced in Malawi in 2004. From 2005 onwards there was a decline in invasive pneumococcal infections with a negative correlation between ART scale-up and the decline in IPD (Pearson's correlation r = -0.91; p<0.001).
During 2004-2009, national ART scale-up in Malawi was associated with a downward trend in IPD at QECH. The introduction of cotrimoxazole prophylaxis in HIV-infected groups has not coincided with a further increase in pneumococcal cotrimoxazole or multidrug resistance. These data highlight the importance of surveillance for high disease burden infections such as IPD in the region, which will be vital for monitoring pneumococcal conjugate vaccine introduction into national immunisation programmes.
PLoS ONE 01/2011; 6(3):e17765. · 4.09 Impact Factor
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ABSTRACT: HIV infection is a major risk factor for death in childhood pneumonia in HIV-endemic regions. Improved case management and preventive strategies require better understanding of the impact of HIV on causes, clinical presentation, and outcome.
A prospective, clinical descriptive study of Malawian infants and children with severe pneumonia included blood culture and nasopharyngeal aspiration for diagnosis of pneumocystis pneumonia (PcP). A select group with consolidation on chest radiograph, and without severe hypoxia or hyperinflation, also had lung aspirate taken for culture and identification of bacterial deoxyribonucleic acid by real-time polymerase chain reaction (PCR).
There were 327 study patients with a median age of 11 months (range, 2 months-14 years). HIV prevalence was 51%. There were 58 cases of confirmed bacterial pneumonia, of which the most common bacterial isolates were Streptococcus pneumoniae and Salmonella typhimurium. Of the 54 lung aspirates, only 2 were positive on culture but 27 were positive for bacterial deoxyribonucleic acid by PCR. PcP was confirmed in 16 patients, and was associated with young age, severe hypoxia, HIV infection, and a very poor outcome. The overall case-fatality rate was 10% despite presumptive therapy for PcP and routine broad-spectrum antibiotic treatment appropriate for local antimicrobial susceptibility data. Most of the deaths occurred in infants of 2 to 6 months of age and PcP was associated with 57% of these deaths.
PcP is a major barrier in reducing the case-fatality rate of severe pneumonia in infants of HIV-endemic communities. The use of PCR on lung aspirate specimens greatly increased the diagnostic yield.
The Pediatric Infectious Disease Journal 01/2011; 30(1):33-8. · 3.58 Impact Factor
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ABSTRACT: Cryptococcal meningitis (CM) and tuberculous meningitis (TBM) are common in HIV-infected adults in Africa and difficult to diagnose. Inaccurate diagnosis results in adverse outcomes. We describe patterns of meningitis in a Malawian hospital, focusing on features which differentiate CM and TBM with the aim to derive an algorithm using only clinical and basic laboratory data available in this resource-poor setting.
Consecutive patients admitted with meningitis were prospectively recruited, clinical features were recorded and cerebrospinal fluid (CSF) was examined.
A total of 573 patients were recruited, and 263 (46%) had CSF consistent with meningitis. One hundred and twelve (43%) had CM and 46 (18%) had TBM. CM was associated with high CSF opening pressure and low CSF leukocyte count. Fever, neck stiffness and reduced conscious level were associated with TBM. A diagnostic index was constructed demonstrating sensitivity 83%and specificity 79% for the differentiation of CM and TBM. An algorithm was derived with 92% sensitivity for the diagnosis of CM, but only 58% specificity.
Although we demonstrate features associated with CM and TBM, a sufficiently sensitive and specific diagnostic algorithm could not be derived, suggesting that the diagnosis of CM and TBM in resource-limited settings still requires better access to laboratory tools.
Tropical Medicine & International Health 08/2010; 15(8):910-7. · 2.80 Impact Factor
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ABSTRACT: Objectives Cryptococcal meningitis (CM) and tuberculous meningitis (TBM) are common in HIV-infected adults in Africa and difficult to diagnose. Inaccurate diagnosis results in adverse outcomes. We describe patterns of meningitis in a Malawian hospital, focusing on features which differentiate CM and TBM with the aim to derive an algorithm using only clinical and basic laboratory data available in this resource-poor setting.Methods Consecutive patients admitted with meningitis were prospectively recruited, clinical features were recorded and cerebrospinal fluid (CSF) was examined.Results A total of 573 patients were recruited, and 263 (46%) had CSF consistent with meningitis. One hundred and twelve (43%) had CM and 46 (18%) had TBM. CM was associated with high CSF opening pressure and low CSF leukocyte count. Fever, neck stiffness and reduced conscious level were associated with TBM. A diagnostic index was constructed demonstrating sensitivity 83%and specificity 79% for the differentiation of CM and TBM. An algorithm was derived with 92% sensitivity for the diagnosis of CM, but only 58% specificity.Conclusions Although we demonstrate features associated with CM and TBM, a sufficiently sensitive and specific diagnostic algorithm could not be derived, suggesting that the diagnosis of CM and TBM in resource-limited settings still requires better access to laboratory tools.Diagnostic de la méningite tuberculeuse et cryptococcale dans un contexte africain à ressources limitéesObjectifs: La méningite cryptococcale (MC) et la méningite tuberculeuse (MTB) sont courantes chez les adultes infectés par le VIH en Afrique et difficiles à diagnostiquer. Un diagnostic imprécis mène à des résultats adverses. Nous décrivons des profils de méningite dans un hôpital du Malawi, en se concentrant sur les caractéristiques qui différencient la MC de la MTB dans le but d’en tirer un algorithme basé uniquement sur des données cliniques et de laboratoire de base disponibles dans ce cadre pauvre.Méthodes: Des patients consécutifs admis avec méningite ont été recrutés de façon prospective, les caractéristiques cliniques ont été enregistrés et le liquide céphalo-rachidien (LCR) a été examiné.Résultats: 573 patients ont été recrutés et 263 (46%) avaient un LCR cohérent avec la méningite. 112 (43%) avaient une MC et 46 (18%), une MTB. La MC a été associée à une pression d’ouverture élevée du LCR et une basse numération leucocytaire du LCR. Fièvre, raideur de la nuque et niveau de conscience réduit étaient associés avec une MTB. Un indice de diagnostic a été construit démontrant une sensibilité de 83% et une spécificité de 79% pour la différenciation des MC et MTB. Un algorithme en a été dérivé avec 92% de sensibilité pour le diagnostic de MC, mais seulement 58% de spécificité.Conclusions: Bien que nous démontrions les caractéristiques associées à la MC et la MTB, un algorithme de diagnostic suffisamment sensible et spécifique n’a pas pu être établi, ce qui suggère que le diagnostic de MC et de MTB dans un contexte à ressources limitées exige encore un meilleur accès aux outils de laboratoire.Diagnóstico de meningitis criptocócica y tuberculosa en un zona con recursos limitados del ÁfricaObjetivos: La meningitis criptocócica (MC) y la meningitis tuberculosa (MT) son comunes en adultos infectados con VIH en África, y son difíciles de diagnosticar. Un diagnóstico erróneo tiene resultados adversos. Hemos descrito los patrones de meningitis en un hospital de Malawi, enfocándonos en las características que diferencian la MC y MT, con el objetivo de derivar un algoritmo utilizando solo los datos clínicos y básicos de laboratorio disponibles en el lugar del estudio.Métodos: Se reclutó de manera prospectiva a los pacientes admitidos consecutivamente con meningitis. Se anotaron las características clínicas y se examinó el líquido cefalorraquídeo (LCR).Resultados: Se reclutaron 573 pacientes de los cuales 263(46%) tenían un LCR consistente con meningitis. 112(43%) tenían MC y 46(18%) tenían MT. La MC estaba asociada con una presión alta en la apertura del LCR y un bajo número de leucocitos en el LCR. Fiebre, rigidez en la nuca y un bajo nivel de conciencia estaban asociados a una MT. Se construyó un índice diagnóstico con una sensibilidad del 83% y una especificidad del 79% para diferenciar la MC de la MT. Se derivó un algoritmo con una sensibilidad del 92% para el diagnóstico de MC, pero con una especificidad de solo un 58%.Conclusiones: Aunque se han demostrado las características asociadas a la MC y MT, no se ha podido derivar un algoritmo diagnóstico lo suficientemente sensible y específico, lo cual sugiere que el diagnóstico de MC y MT en un lugar con recursos limitados aún requiere de mejorar el acceso a herramientas de laboratorio.
Tropical Medicine & International Health 06/2010; 15(8):910 - 917. · 2.80 Impact Factor
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ABSTRACT: Trachoma, one of the neglected tropical diseases is suspected to be endemic in Malawi.
To determine the prevalence of trachoma and associated risk factors in central and southern Malawi.
A population based survey conducted in randomly selected clusters in Chikwawa district (population 438,895), southern Malawi and Mchinji district (population 456,558), central Malawi. Children aged 1-9 years and adults aged 15 and above were assessed for clinical signs of trachoma. In total, 1010 households in Chikwawa and 1016 households in Mchinji districts were enumerated within 108 clusters (54 clusters in each district). A total of 6,792 persons were examined for ocular signs of trachoma. The prevalence of trachomatous inflammation, follicular (TF) among children aged 1-9 years was 13.6% (CI 11.6-15.6) in Chikwawa and 21.7% (CI 19.5-23.9) in Mchinji districts respectively. The prevalence of trachoma trichiasis (TT) in women and men aged 15 years and above was 0.6% (CI 0.2-0.9) in Chikwawa and 0.3% (CI 0.04-0.6) in Mchinji respectively. The presence of a dirty face was significantly associated with trachoma follicular (TF) in both Chikwawa and Mchinji districts (P<0.001).
Prevalence rates of trachoma follicles (TF) in Central and Southern Malawi exceeds the WHO guidelines for the intervention with mass antibiotic distribution (TF>10%), and warrants the trachoma SAFE control strategy to be undertaken in Chikwawa and Mchinji districts.
PLoS ONE 01/2010; 5(2):e9067. · 4.09 Impact Factor
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David J Bell,
Dan Wootton, Mavuto Mukaka,
Jacqui Montgomery,
Noel Kayange,
Phillips Chimpeni,
Dyfrig A Hughes,
Malcolm E Molyneux,
Steve A Ward,
Peter A Winstanley,
David G Lalloo
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ABSTRACT: Sulphadoxine-pyrimethamine (SP) is the only single dose therapy for uncomplicated malaria, but there is widespread resistance. At the time of this study, artemether-lumefantrine (AL) and chlorproguanil-dapsone (CPD), both multi-dose regimes, were considered possible alternatives to SP in Malawi. The aim of this study was to investigate the impact of poor adherence on the effectiveness of AL and CPD.
Children > or =12 months and adults with uncomplicated malaria were randomized to receive AL, CPD or SP. Adherence was measured using a questionnaire and electronic monitoring devices, MEMS, pill bottles that recorded the date and time of opening. Day-7 plasma dapsone or lumefantrine concentrations were measured to examine their relationship with adherence and clinical response.
841 patients were recruited. The day-28 adequate clinical and parasitological response (ACPR) rates, using intention to treat analysis (missing data treated as failure), were AL 85.2%, CPD 63.7% and SP 50%. ACPR rates for AL were higher than CPD or SP on days 28 and 42 (p < or = 0.002 for all comparisons). CPD was more effective than SP on day-28 (p = 0.01), but not day-42.Very high adherence was reported using the questionnaire, 100% for AL treated patients and 99.2% for the CPD group. Only three CPD participants admitted missing any doses. 164/181 (90.6%) of CPD treated patients took all their doses out of the MEMS container and they were more likely to have a day-28 ACPR than those who did not take all their medication out of the container, p = 0.024. Only 7/87 (8%) AL treated patients did not take all of their doses out of their MEMS container and none had treatment failure.Median day-7 dapsone concentrations were higher in CPD treated patients with ACPR than in treatment failures, p = 0.012. There were no differences in day-7 dapsone or lumefantrine concentrations between those who took all their doses from the MEMS container and those who did not. A day-7 lumefantrine concentration reported to be predictive of AL treatment failure in Thailand was not useful in this population; only one of 16 participants with a concentration below this threshold (175 ng/ml) had treatment failure.
This study provides reassurance of the effectiveness of AL, even with unsupervised dosing, as it is rolled out across sub-Saharan Africa. Self-reported adherence appears to be an unreliable measure of adherence in this population.
Malaria Journal 09/2009; 8:204. · 3.19 Impact Factor
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ABSTRACT: We genotyped 160 P. falciparum infections from Malawi for pfmdr-1 copy number changes and SNPs associated with in vivo tolerance and poor in vitro sensitivity to the component drugs of Coartem. We also measured in vitro susceptibility of 49 of these isolates to a variety of drugs in clinical use or with a potential for use in Africa. All 160 infections carried a single copy of pfmdr-1 but 34% exhibited sequence variation at 4 of the 5 polymorphic sites in pfmdr-1. Isolates carrying 86-Asn and 184-Tyr pfmdr-1 alleles were significantly less sensitive (p<0.001) to mefloquine, lumefantrine, artemether and dihydroartemisinin compared with those bearing 86-Tyr and 184-Phe polymorphisms. This study provides baseline measures prior to policy change: continued surveillance for changes in baseline drug susceptibility, pfmdr-1 copy number and SNPs, and other putative Coartem resistance loci will be necessary to provide an early warning of emerging Coartem resistance in this setting.
Acta tropica 07/2009; 111(1):78-81. · 2.22 Impact Factor
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ABSTRACT: Platelets may play a role in the pathogenesis of human cerebral malaria (CM), and they have been shown to induce clumping of Plasmodium falciparum-parasitized red blood cells (PRBCs) in vitro. Both thrombocytopenia and platelet-induced PRBC clumping are associated with severe malaria and, especially, with CM. In the present study, we investigated the occurrence of the clumping phenomenon in patients with CM by isolating and coincubating their plasma and PRBCs ex vivo. Malawian children with CM all had low platelet counts, with the degree of thrombocytopenia directly proportional to the density of parasitemia. Plasma samples obtained from these patients subsequently induced weak PRBC clumping. When the assays were repeated, with the plasma platelet concentrations adjusted to within the physiological range considered to be normal, massive clumping occurred. The results of this study suggest that thrombocytopenia may, through reduction of platelet-mediated clumping of PRBCs, provide a protective mechanism for the host during CM.
The Journal of Infectious Diseases 02/2008; 197(1):72-8. · 6.41 Impact Factor
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ABSTRACT: In Malawi, there has been a return of Plasmodium falciparum sensitivity to chloroquine (CQ) since sulfadoxine-pyrimethamine (SP) replaced CQ as first line treatment for uncomplicated malaria. When used for prophylaxis, Amodiaquine (AQ) was associated with agranulocytosis but is considered safe for treatment and is increasingly being used in Africa. Here we compare the efficacy, safety and selection of resistance using SP or CQ+SP or artesunate (ART)+SP or AQ+SP for the treatment of uncomplicated falciparum malaria.
455 children aged 1-5 years were recruited into a double-blinded randomised trial comparing SP to the three combination therapies. Using intention to treat analysis with missing outcomes treated as successes, and without adjustment to distinguish recrudescence from new infections, the day 28 adequate clinical and parasitological response (ACPR) rate for SP was 25%, inferior to each of the three combination therapies (p<0.001). AQ+SP had an ACPR rate of 97%, higher than CQ+SP (81%) and ART+SP (70%), p<0.001. Nineteen children developed a neutropenia of </=0.5x10(3) cells/microl by day 14, more commonly after AQ+SP (p = 0.03). The mutation pfcrt 76T, associated with CQ resistance, was detected in none of the pre-treatment or post-treatment parasites. The prevalence of the pfmdr1 86Y mutation was higher after treatment with AQ+SP than after SP, p = 0.002.
The combination AQ+SP was highly efficacious, despite the low efficacy of SP alone; however, we found evidence that AQ may exert selective pressure for resistance associated mutations many weeks after treatment. This study confirms the return of CQ sensitivity in Malawi and importantly, shows no evidence of the re-emergence of pfcrt 76T after treatment with CQ or AQ. Given the safety record of AQ when used as a prophylaxis, our observations of marked falls in neutrophil counts in the AQ+SP group requires further scrutiny.
Controlled-Trials.com ISRCTN22075368.
PLoS ONE 01/2008; 3(2):e1578. · 4.09 Impact Factor
