Search

article i nfo Objective: To determine the factors associated with resumption of sexual activity and regular menses after childbirth among women infected with HIV-1. Methods: Information on sociodemographic, behavioral, and clinical factors was obtained from 2 HIV perinatal studies (NVAZ and PEPI trials) conducted in Malawi, 2000- 2009. Factors associated with resumption of sexual activity and menses were analyzed using Cox proportional hazard models. Results: A total of 1838 women from the NVAZ study and 2982 women from the PEPI study were included in the analysis. Resumption of sexual activity was primarily associated with sociodemographic factors (e.g. in the PEPI study, marital status (adjusted hazard ratio (aHR) 0.56, P

This study aimed to determine changes in fertility intentions of HIV-1 infected and uninfected reproductive age women in Blantyre, Malawi. Participants were asked about their fertility intentions at baseline and at 3-month visits for 1 year. Time-to-event statistical models were used to determine factors associated with changes in fertility intentions. Overall, 842 HIV uninfected and 844 HIV infected women were enrolled. The hazard of changing from wanting no more children at baseline to wanting more children at follow-up was 61% lower among HIV infected women compared to HIV uninfected women (P0.01) after adjusting for other factors, while HIV infected women were approximately 3 times more likely to change to wanting no more children. The overall pregnancy rate after 12 months was 14.9 per 100 person-years and did not differ among 102 HIV uninfected and 100 infected women who became pregnant. HIV infection is a significant predictor of fertility intentions over time.

Background The tuberculosis (TB) mortality rate of registered TB patients in Malawi is 23%, and 59% of the deaths occur in the first 2 months of treatment. HIV-related complications appear to be an important cause. Starting antiretroviral therapy early during tuberculosis treatment may improve outcome but problems often arise with drug interactions, adherence, toxicity and immune reconstitution disease (IRD). Methods We prospectively followed 27 HIV-infected adult Malawians after starting Triomune® (a generic fixed drug combination of stavudine, lamivudine and nevirapine) in the second week of tuberculosis treatment. Results At baseline, 88% had CD4+ T-cell counts + T cell increase was 170 cells/ml. Adverse events were numerous, particularly in the first 2 months. Suspected IRD episodes could be managed without treatment interruptions. During the lead-in phase, 59% of nevirapine plasma levels were sub-therapeutic despite good adherence, compared with only 14% during weeks 4 and 8. Conclusion It is feasible to start Triomune® early during TB treatment with good treatment outcome. The nevirapine lead-in phase should be avoided when rifampicin-based tuberculosis treatment is started >1 week beforehand.

We assessed the safety of short-term antiretroviral prophylaxis to prevent mother-to-child transmission (MTCT) of HIV by monitoring haematological changes in children up to the age of 18 months. Babies of HIV-infected women were randomised at birth to receive a single dose of nevirapine (NVP) alone or with zidovudine (ZDV) twice daily for a week. Based on the time of presentation to the labour ward, mothers of these babies might or might not have received intrapartum NVP. Complete blood counts were performed at birth and at 1.5, 3, 6, 9, 12, 15 and 18 months. Babies' HIV status was determined by HIV-1 RNA testing. A total of 1755 babies were included in the study. Age-specific mean haemoglobin levels and prevalence of anaemia (haemoglobin < 10 g/dL) were not significantly different in cases where only the babies received a single dose of NVP and cases where NVP was given to mother/infant pairs or additional ZDV to the baby. Among HIV-infected children compared with uninfected children, the age-specific frequency of anaemia was significantly greater, anaemia started earlier and recovery to normal levels was slower and prolonged. A reversible granulocytopenia was observed in all children between 1.5 and 3 months of age. HIV infection significantly increased the children's risk of death. Antiretroviral prophylaxis appeared to protect against anaemia and child death. Short regimens of antiretrovirals to prevent MTCT of HIV are not associated with long-term adverse haematological changes.

Background: The increasing investment in malaria rapid diagnostic tests (RDTs) to differentiate malarial and non-malarial fevers, and an awareness of the need to improve case management of non-malarial fever, indicates an urgent need for high quality evidence on how best to improve prescribers’ practices. Methods: A three-arm stratified cluster-randomised trial was conducted in 36 primary healthcare facilities from September 2010 to March 2012 within two rural districts in northeast Tanzania where malaria transmission has been declining. Interventions were guided by formative mixed-methods research and were introduced in phases. Prescribing staff from all facilities received standard Ministry of Health RDT training. Prescribers from facilities in the health worker (HW) and health worker-patient (HWP) arms further participated in small interactive peer-group training sessions with the HWP additionally receiving clinic posters and patient leaflets. Performance feedback and motivational mobile-phone text messaging (SMS) were added to the HW and HWP arms in later phases. The primary outcome was the proportion of patients with a non-severe, non-malarial illness incorrectly prescribed a (recommended) antimalarial. Secondary outcomes investigated RDT uptake, adherence to results, and antibiotic prescribing. Results: Standard RDT training reduced pre-trial levels of antimalarial prescribing, which was sustained throughout the trial. Both interventions significantly lowered incorrect prescribing of recommended antimalarials from 8% (749/8,942) in the standard training arm to 2% (250/10,118) in the HW arm (adjusted RD (aRD) 4%; 95% confidence interval (CI) 1% to 6%; P = 0.008) and 2% (184/10,163) in the HWP arm (aRD 4%; 95% CI 1% to 6%; P = 0.005). Small group training and SMS were incrementally effective. There was also a significant reduction in the prescribing of antimalarials to RDT-negatives but no effect on RDT-positives receiving an ACT. Antibiotic prescribing was significantly lower in the HWP arm but had increased in all arms compared with pre-trial levels. Conclusions: Small group training with SMS was associated with an incremental and sustained improvement in prescriber adherence to RDT results and reducing over-prescribing of antimalarials to close to zero. These interventions may become increasingly important to cope with the wider range of diagnostic and treatment options for patients with acute febrile illness in Africa. Trial registration: ClinicalTrials.gov (#NCT01292707) 29 January 2011.

Background HIV-1 and Plasmodium falciparum malaria cause substantial morbidity in Sub-Saharan Africa, especially as co-infecting pathogens. We examined the relationship between presence of P. falciparum DNA in plasma samples and clinical malaria as well as the impact of atazanavir, an HIV-1 protease inhibitor (PI), on P. falciparum PCR positivity. Methods ACTG study A5175 compared two NNRTI-based regimens and one PI-based anti-retroviral (ARV) regimen in antiretroviral therapy naïve participants. We performed nested PCR on plasma samples for the P. falciparum 18s rRNA gene to detect the presence of malaria DNA in 215 of the 221 participants enrolled in Blantyre and Lilongwe, Malawi. We also studied the closest sample preceding the first malaria diagnosis from 102 persons with clinical malaria and randomly selected follow up samples from 88 persons without clinical malaria. Results PCR positivity was observed in 18 (8%) baseline samples and was not significantly associated with age, sex, screening CD4+ T-cell count, baseline HIV-1 RNA level or co-trimoxazole use within the first 8 weeks. Neither baseline PCR positivity (p = 0.45) nor PCR positivity after initiation of antiretroviral therapy (p = 1.0) were significantly associated with subsequent clinical malaria. Randomization to the PI versus NNRTI ARV regimens was not significantly associated with either PCR positivity (p = 0.5) or clinical malaria (p = 0.609). Clinical malaria was associated with a history of tuberculosis (p = 0.006) and a lower BMI (p = 0.004). Conclusion P. falciparum DNA was detected in 8% of participants at baseline, but was not significantly associated with subsequent development of clinical malaria. HIV PI therapy did not decrease the prevalence of PCR positivity or incidence of clinical disease.

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.

Background & aim: Lipodystrophy remains a significant problem in HIV/AIDS patients, especially those on regimens containing either protease inhibitors or thymidine analogs (stavudine or zidovudine). Many of the manifestations of lipodystrophy have been linked to mitochondrial dysfunction. We set out to investigate whether mtDNA variation is associated with the development of stavudine-induced lipodystrophy among adult Malawian HIV/AIDS patients on antiretroviral therapy that included stavudine. Materials & methods: A total of 117 adult HIV/AIDS patients on stavudine-containing antiretroviral therapy (ART) were recruited from the ART clinic at the Queen Elizabeth Central Hospital, Malawi. The patients were categorized according to whether or not they had developed lipodystrophy after being on a stavudine-containing ART regimen for at least 6 months. Whole mtDNA-coding regions of each patient were sequenced and correlated with clinical characteristics. Results: Lipodystrophy was apparent in 16% (n = 19) of the participants. In multivariate analysis, age >40 years (odds ratio: 4.43; 95% CI: 1.36–14.47; p = 0.014) was significantly associated with the presence of lipodystrophy. The mtDNA subhaplogroup L3e appeared to be protective against lipodystrophy, as none of 11 subjects with this subhaplogroup presented with lipodystrophy. Conclusion: mtDNA subhaplogroups seem to differentially affect susceptibility to lipodystrophy. More research is required in order to identify patients who are more or less likely to benefit from stavudine-containing ART. Original submitted 28 June 2013; Revision submitted 16 September 2013

Background: Peripheral neuropathy (PN) is one of the main toxicities associated with stavudine. Genetic variants in mitochondrial DNA (mtDNA) haplogroups have been associated with increased risk of developing PN in European non-Hispanic and black patients on stavudine containing antiretroviral therapy (ART). We investigated mtDNA haplogroups and their role in susceptibility to stavudine-induced peripheral in Malawian patients on ART. Method: Two hundred and fifteen adults on stavudine containing regimens were recruited from the ART clinic at Queen Elizabeth Central Hospital, Blantyre, into a cross-sectional study to investigate the effects of genetic variants in mtDNA of individuals in relation to response to treatment. Patients were categorized according to whether or not they had developed PN after a minimum of 6 months on stavudine containing ART. Whole mtDNA coding regions of each patient were sequenced, and CD4 count, viral load, and creatinine were determined. The mtDNA variation was correlated with clinical characteristics. Results: Fifty-three (25%) of the participants developed PN after starting stavudine containing ART. Mitochondrial DNA subhaplogroup L0a2 was independently associated with increased risk of PN in a multivariate model (odds ratio, 2.23; 95% confidence interval, 1.14 to 4.39; P = 0.019), and subhaplogroup L2a was independently associated with reduced risk of PN (odds ratio, 0.39; 95% confidence interval, 0.16 to 0.94; P = 0.036). Conclusions: Genetic variation in mtDNA confers differential risk of developing PN in patients on stavudine containing ART among Malawians.

Introduction The Post-exposure Prophylaxis in Infants (PEPI)-Malawi trial evaluated infant antiretroviral regimens for prevention of post-natal HIV transmission. A multi-assay algorithm (MAA) that includes the BED capture immunoassay, an avidity assay, CD4 cell count, and viral load was used to identify women who were vs. were not recently infected at the time of enrollment (MAA recent, N = 73; MAA non-recent, N = 2,488); a subset of the women in the MAA non-recent group known to have been HIV infected for at least 2 years before enrollment (known non-recent, N = 54). Antibody maturation and viral diversification were examined in these women. Methods Samples collected at enrollment (N = 2,561) and 12–24 months later (N = 1,306) were available for serologic analysis using the BED and avidity assays. A subset of those samples was used for analysis of viral diversity, which was performed using a high resolution melting (HRM) diversity assay. Viral diversity analysis was performed using all available samples from women in the MAA recent group (61 enrollment samples, 38 follow-up samples) and the known non-recent group (43 enrollment samples, 22 follow-up samples). Diversity data from PEPI-Malawi were also compared to similar data from 169 adults in the United States (US) with known recent infection (N = 102) and known non-recent infection (N = 67). Results In PEPI-Malawi, results from the BED and avidity assays increased over time in the MAA recent group, but did not change significantly in the MAA non-recent group. At enrollment, HIV diversity was lower in the MAA recent group than in the known non-recent group. HRM diversity assay results from women in PEPI-Malawi were similar to those from adults in the US with known duration of HIV infection. Conclusions Antibody maturation and HIV diversification patterns in African women provide additional support for use of the MAA to identify populations with recent HIV infection.

The global scale-up of antiretroviral (ARV) therapy has dramatically reduced human immunodeficiency virus (HIV) morbidity and mortality. Stavudine (d4T) has been among the most commonly used ARVs in resource-limited settings because of its efficacy, short-term tolerability, low cost, and availability in coformulated form. However, many countries are transitioning away from d4T, mainly because of mitochondrial toxicities associated with long-term d4T use. In 2010, the World Health Organization (WHO) recommended phasing out d4T even in patients without documented virological failure [1]. There are two distinct mutational pathways of d4T resistance with different implications for zidovudine (AZT) and tenofovir (TDF) cross-resistance, the primary candidates for replacing d4T [2–4]. However, genotypic resistance testing is usually not available in the resource-limited settings where d4T-containing regimens are most commonly used. It is therefore important to determine the extent of nucleoside reverse-transcriptase inhibitor (NRTI) cross-resistance in viruses from individuals with virological failure on d4T-containing first-line therapy undergoing genotypic resistance testing. In this study, we combined genetic sequence data from 35 different studies to characterize the patterns of NRTI resistance mutations in viruses from individuals with virological failure on the 2 widely used d4T-containing ARV regimens: d4T/lamivudine(3TC)/nevirapine(NVP) and d4T/3TC/efavirenz(EFV). We also examine the effects of HIV-1 subtype, duration of therapy, and concomitant nonnucleoside reverse-transcriptase inhibitor (NNRTI) on the selection of specific mutations. We focused our analysis on NRTI resistance mutations with differential effects on the residual activity of AZT compared with TDF. The implications of these data for optimal replacement of d4T and subsequent NRTI options are discussed.

Background Stroke contributes significantly to disability and mortality in developing countries yet little is known about the determinants of stroke outcomes in such countries. 12% of Malawian adults have HIV/AIDS. It is not known whether having HIV-infection alters the outcome of stroke. The aim of this study was to document the functional outcome and mortality at 1 year of first-ever acute stroke in Malawi. Also to find out if the baseline variables, including HIV-infection, affect the outcome of stroke. Methods and Findings 147 adult patients with first-ever acute stroke were prospectively followed up for 12 months. Conventional risk factors and HIV-infection were assessed at baseline. Stroke severity was evaluated with modified National Institute of Health Stroke Scale (mNIHSS) and functional outcome with modified Rankin scale (mRS). Fifty (34%) of patients were HIV-seropositive. 53.4% of patients had a poor outcome (severe disability or death, mRS 4–6) at 1 year. Poor outcome was related to stroke severity and female gender but not to presence of HIV-infection. HIV-seropositive patients were younger and had less often common risk factors for stroke. They suffer more often ischemic stroke than HIV-seronegative patients. Conclusions Mild stroke and male gender were associated with favourable outcome. HIV-infection is common in stroke patients in Malawi but does not worsen the outcome of stroke. However, it may be a risk factor for ischemic stroke for young people, who do not have the common stroke risk factors. Our results are significant, because stroke outcome in HIV-seropositive patients has not been studied before in a setting such as ours, with very limited resources and a high prevalence of HIV.

AIDS Clinical Trials Group (ACTG) A5199 compared the neurological and neuropsychological (NP) effects of 3 antiretroviral regimens in participants infected with human immunodeficiency virus type 1 (HIV-1) in resource-limited settings.Participants from Brazil, India, Malawi, Peru, South Africa, Thailand, and Zimbabwe were randomized to 3 antiretroviral treatment arms: A (lamivudine-zidovudine plus efavirenz, n = 289), B (atazanavir, emtricitabine, and didanosine-EC, n = 293), and C (emtricitabine-tenofovir-disoproxil fumarate plus efavirenz, n = 278) as part of the ACTG PEARLS study (A5175). Standardized neurological and neuropsychological (NP) screening examinations (grooved pegboard, timed gait, semantic verbal fluency, and finger tapping) were administered every 24 weeks from February 2006 to May 2010. Associations with neurological and neuropsychological function were estimated from linear and logistic regression models using generalized estimating equations.The median weeks on study was 168 (Q1 = 96, Q3 = 192) for the 860 participants. NP test scores improved (P.05) with the exception of semantic verbal fluency. No differences in neurological and neuropsychological functioning between treatment regimens were detected (P.10). Significant country effects were noted on all NP tests and neurological outcomes (P.01).The study detected no significant differences in neuropsychological and neurological outcomes between randomized ART regimens. Significant improvement occurred in neurocognitive and neurological functioning over time after initiation of ARTs. The etiology of these improvements is likely multifactorial, reflecting reduced central nervous system HIV infection, better general health, and practice effects. This study suggests that treatment with either of the World Health Organization -recommended first-line antiretroviral regimens in resource-limited settings will improve neuropsychological functioning and reduce neurological dysfunction.NCT00096824.

Background. The HIV Prevention Trials Network (HPTN) 052 trial demonstrated that early initiation of antiretroviral therapy (ART) reduces human immunodeficiency virus (HIV) transmission from HIV-infected adults (index participants) to their HIV-uninfected sexual partners. We analyzed HIV from 38 index-partner pairs and 80 unrelated index participants (controls) to assess the linkage of seroconversion events. Methods. Linkage was assessed using phylogenetic analysis of HIV pol sequences and Bayesian analysis of genetic distances between pol sequences from index-partner pairs and controls. Selected samples were also analyzed using next-generation sequencing (env region). Results. In 29 of the 38 (76.3%) cases analyzed, the index was the likely source of the partner’s HIV infection (linked). In 7 cases (18.4%), the partner was most likely infected from a source other than the index participant (unlinked). In 2 cases (5.3%), linkage status could not be definitively established. Conclusions. Nearly one-fifth of the seroconversion events in HPTN 052 were unlinked. The association of early ART and reduced HIV transmission was stronger when the analysis included only linked events. This underscores the importance of assessing the genetic linkage of HIV seroconversion events in HIV prevention studies involving serodiscordant couples.

Background: Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. Methods: In nine countries, we enrolled 1763 couples in which one partner was HIV-1–positive and the other was HIV-1–negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1–infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1–related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1–negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death. Results: As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the earlytherapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P

Background. The World Health Organization currently recommends initiation of highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV)‐infected lactating women with CD41 cell counts ,350 cells/lL or stage 3 or 4 disease. We analyzed antiretroviral drug resistance in HIV-infected infants in the Post Exposure Prophylaxis of Infants trial whose mothers initiated HAART postpartum (with a regimen of nevirapine [NVP], stavudine, and lamivudine). Infants in the trial received single-dose NVP and a week of zidovudine (ZDV) at birth; some infants also received extended daily NVP prophylaxis, with or without extended ZDV prophylaxis. Methods. We analyzed drug resistance in plasma samples collected from all HIV-infected infants whose mothers started HAART in the first postpartum year. Resistance testing was performed using the first plasma sample collected within 6 months after maternal HAART initiation. Categorical variables were compared by exact or trend tests; continuous variables were compared using rank-sum tests. Results. Multiclass resistance (MCR) was detected in HIV from 11 (29.7%) of 37 infants. Infants were more likely to develop MCR infection if their mothers initiated HAART earlier in the postpartum period (by 14 weeks vs after 14 weeks and up to 6 months vs after 6 months, P 5 .0009), or if the mother was exclusively breastfeeding at the time of HAART initiation (exclusive breastfeeding vs mixed feeding vs no breastfeeding, P 5 .003). Conclusions. postpartum maternal HAART initiation was associated with acquisition of MCR in HIV-infected breastfeeding infants. The risk was higher among infants whose mothers initiated HAART closer to the time of delivery or were still exclusively breastfeeding when they first reported HAART use.

BACKGROUND: This analysis updates and extends efficacy estimates of the PEPI-Malawi trial through age 24 months at study completion in September 2009. METHODS: Infants of breastfeeding HIV-infected women were randomized at birth to the following: (1) single-dose nevirapine (NVP) + 1-week zidovudine (ZDV) (control); (2) control + extended daily NVP (ExtNVP) through 14 weeks; (3) control + extended daily NVP + ZDV (ExtNVP/ZDV) through 14 weeks. We estimated rates of HIV infection death and HIV infection or death using Kaplan-Meier analysis. RESULTS: This analysis includes 3126 infants uninfected at birth as follows: 1004 control 1071 ExtNVP and 1051 ExtNVP/ZDV. By 9 months HIV infection rates were 5.0% in ExtNVP 6.0% in ExtNVP/ZDV and 11.1% in control (P < 0.001 comparing extended regimens with control). At age 24 months HIV infection rates had risen to ~11% in the extended arms compared with 15.6% in the controls (P < 0.05). The rates of HIV infection or death were also significantly lower in extended arms. There were no differences in severe adverse events with the exception of higher possibly related events in the ExtNVP/ZDV arm. CONCLUSIONS: Daily infant antiretroviral prophylaxis reduces postnatal HIV infection by ~70% during the period of prophylaxis. But continued HIV transmission after prophylaxis stops suggests more prolonged infant prophylaxis is needed.

Little is known about how the prevalence and incidence of neurological disease in HIV-infected patients in resource-limited settings. We present an analysis of neurological and neurocognitive function in antiretroviral naive individuals in multinational resource-limited settings. This prospective multinational cohort study, a substudy of a large international randomized antiretroviral treatment trial, was conducted in seven low- and middle-income countries in sub-Saharan Africa, South America, and Asia. Subjects were HIV-infected and met regional criteria to initiate antiretroviral therapy. Standardized neurological examination and a brief motor-based neuropsychological examination were administered. A total of 860 subjects were studied. Overall 249 (29%) had one or more abnormalities on neurological examinations, but there was a low prevalence of HIV-associated dementia (HAD) and minor neurocognitive disorder (MND). Twenty percent of subjects had evidence of peripheral neuropathy. There were significant differences across countries (p

Summary Around 225 000 patients currently receive antiretroviral therapy (ART) in the Malawi scale-up programme that uses the public health approach to ART. There are concerns that cardiovascular disease risk factors are common in ART patients, but few data exist from sub-Saharan Africa, and none from Malawi. We did a cross-sectional study of cardiovascular risk factors in urban, adult, Malawian ART patients, with the WHO STEP-wise surveillance tool. We enrolled 174 long-term (>1 year) ART patients during routine clinic visits, mean age 40.8 years (range 18–69), 61.5% female, 97.1% on first-line regimens, median duration ART 35.5 months. Insufficient fruit and vegetable diet (67.6%), raised blood pressure (45.9%), increased waist–hip ratio (45.4%), raised total cholesterol levels (31.0%) and low physical activity level (27.0%) were common, while current smoking (0.6%), current alcohol consumption (2.3%) and elevated glucose levels (1.2%) were rare. In multivariable analyses, higher age was associated with low physical activity, raised blood pressure, being overweight, and increased waist–hip ratio. Longer duration of ART was not associated with any risk factor and was protective for being overweight. Cardiovascular risk factors were common among long-term ART patients in Malawi. This requires more attention and further study in programmes using the public health approach to ART.

OBJECTIVE: To date, CCR5 variants remain the only human genetic factors to be confirmed to impact HIV-1 acquisition. However, protective CCR5 variants are largely absent in African populations, in which sporadic resistance to HIV-1 infection is still unexplained. We investigated whether common genetic variants associate with HIV-1 susceptibility in Africans. METHODS: We performed a genome-wide association study (GWAS) in a population of 1532 individuals from Malawi, a country with high prevalence of HIV-1 infection. Using single-nucleotide polymorphisms (SNPs) present on the genome-wide chip, we also investigated previously reported associations with HIV-1 susceptibility or acquisition. Recruitment was coordinated by the Center for HIV/AIDS Vaccine Immunology at two sexually transmitted infection clinics. HIV status was determined by HIV rapid tests and nucleic acid testing. RESULTS: After quality control, the population consisted of 848 high-risk seronegative and 531 HIV-1 seropositive individuals. Logistic regression testing in an additive genetic model was performed for SNPs that passed quality control. No single SNP yielded a significant P value after correction for multiple testing. The study was sufficiently powered to detect markers with genotype relative risk 2.0 or more and minor allele frequencies 12% or more. CONCLUSION: This is the first GWAS of host determinants of HIV-1 susceptibility, performed in an African population. The absence of any significant association can have many possible explanations: rarer genetic variants or common variants with weaker effect could be responsible for the resistance phenotype; alternatively, resistance to HIV-1 infection might be due to nongenetic parameters or to complex interactions between genes, immunity and environment.

www.thelancet.com/lancetgh Vol 2 December 2014 e689 schools have “a nervousness about not being seen to conform to Western educational imperatives”. This unease impels these schools to use accreditation systems from developed countries (a trend that has proven lucrative for some American educational organisations). Disfavouring this model, CONSAMS has instead innovated networks of external examiners who monitor assessment and evaluation standards at partner schools and are also developing context-appropriate accreditation standards. The CONSAMS schools have sought to promote health-worker capacitybuilding through interprofessional and transprofessional training programmes. The University of Oulu in Finland has for several years been doing interprofessional programmes with the University of Namibia School of Medicine and the Lurio University Medical School that involves students in medicine, nursing, pharmacology, and optometry working in teams within local communities. The OneStudent-One-Family programme at Lurio also includes community workers in the health-care team and is thus an example of what The Lancet report terms “transprofessional learning”. In conclusion, new medical schools that have decided to work together in consortia such as CONSAMS have strengthened their ability to face challenges and succeeded at educational innovation. The creation of networks, alliances, and consortia between medical schools should be supported as an effective strategy for health-care strengthening and capacity-building in Africa.

A 35 year old woman was admitted to Queen Elizabeth Central Hospital (QECH) with fever, abdominal pain and vomiting for 3 days. A week earlier she had started antiretroviral therapy (ART) in a clinical trial in Blantyre, Malawi, after meeting all the requirements of the study. At the time of enrolment, her CD4 count was 19/µl, and viral load >400,000 copies/ml. She was started on a combination of amtricitabine (FTC), tenofivir (TDF) and atazanavir (ATV). At the present admission, she looked ill. Her axillary temperature was 38°C, blood pressure 110/70 mmHg, pulse rate 100/minute, weight 56Kg. The abdomen was tender to touch without any palpable enlarged organs. A full blood count showed a haemoglobin concentration of 9.8g/dl, other parameters being within normal limits. Blood biochemistry and liver function tests were normal. A blood sample for culture was taken which remained sterile after 7 days of incubation. The patient was started on empirical intravenous broad spectrum antibiotic (ceftriaxone 2g once a day) for possible sepsis. Two days later the patient remained ill and examination now revealed a right iliac fossa mass which was tender to touch. A bimanual pelvic examination suggested that the mass was arising from the pelvis. A gynecological review confirmed the findings. An ultrasound of the abdomen and pelvis identified a mass arising from the pelvis but was unable to define the organ of origin. Intravenous metronidazole was added to ceftriaxone. After ten days of antibiotic treatment, there was no clinical response. The gynecologists decided to take the patient for surgical exploration. During the procedure a mass was found affecting the ileocaecal junction and the whole of the ascending colon. The visual findings were suggestive of a carcinoma of the ascending colon with areas of perforation. A hemi-colectomy was done (see figure 1-gross specimen of the colon) Figure 1 Part of the resected tumor The patient remained unwell and died two weeks later in hospital after repeated breakdown of the anastomosis site. A histology report came out two days after the patient died. What is the diagnosis?

Food insecurity is considered to be an important contributor to HIV associated wasting in sub-Saharan Africa. Low body mass index (BMI) is a strong risk factor for early mortality during antiretroviral therapy (ART). Nutritional supplementation has become standard of care in wasted patients starting ART in many countries in the region, but there is no unequivocal evidence base for this intervention. Against this background, we performed a retrospective study to compare food supplementation versus no nutritional intervention in wasted adults starting ART in Blantyre, Malawi. All patients received free nevirapine, lamivudine, and stavudine. Participants in an effectiveness trial of two food supplements received either corn-soy blend (CSB) or ready-to-use food spread (RUFS) during the first 14 weeks of ART. Results were compared with a historical control group receiving no food supplement that was part of an observational cohort study of outcomes of the same ART regimen. Characteristics on initiation of ART were similar in the three groups, except the use of cotrimoxazole prophylaxis which was more frequent in the food-supplemented groups. Linear regression analysis showed that increase in BMI was greatest in the RUFS group and better in the CSB group than in those receiving no food supplementation at 14 weeks. These differences were no longer significant at 26 weeks. Lower BMI, CD4 count and hemoglobin, WHO clinical stage IV, male gender, and not receiving cotrimoxazole prophylaxis were independent risk factors for mortality at 14 and 26 weeks in the logistic regression analysis. Supplementary food use was not directly associated with improved survival.

Objectives: The Malawi antiretroviral therapy (ART) programme uses the public health approach to identify ART failure. Advanced disease progression may occur before switching to second-line ART. We report outcomes for patients evaluated and initiated on second-line treatment in Malawi. Methods: Patients meeting Malawi immunological or clinical criteria for ART failure in two large urban ART clinics were evaluated for virological failure (viral load >400 HIV-1 RNA copies/mL) and if failure was confirmed initiated on second-line ART (zidovudine/lamivudine/tenofovir/lopinavir/ritonavir). Patients were seen monthly and laboratory evaluations were performed quarterly and as needed. We performed logistic regression modelling to identify factors associated with mortality mortality or new HIV illnesses and virological suppression at 12 months. Results: Of the 109 patients with confirmed virological failure five patients died prior to initiation three declined switching and 101 patients initiated second-line treatment. Over 12 months 10 additional patients died 34 patients experienced 45 HIV-related events and 19 patients experienced grade 3 or 4 toxicities. Among survivors 85.2% had HIV-1 RNA

Summary Objectives In antiretroviral therapy (ART) scale-up programmes in sub-Saharan Africa viral load monitoring is not recommended. We wanted to study the impact of only using clinical and immunological monitoring on the diagnosis of virological ART failure under routine circumstances. Methods Clinicians in two urban ART clinics in Malawi used clinical and immunological monitoring to identify adult patients for switching to second-line ART. If patients met clinical and/or immunological failure criteria of WHO guidelines and had a viral load

The aim of this study was to determine HIV-1 incidence among women of reproductive age in Malawi. A prospective study design was followed. HIV-1 uninfected women were followed up for nine visits during a period of 12 months. At baseline, women received HIV-1 counselling and testing. At each visit, venous blood was collected for HIV-1 testing. Incidence rate for HIV-1 was estimated using person-years of follow up (PYFU). Risk factors for HIV acquisition were assessed using Cox proportional hazard models. A total of 842 HIV-1 negative women were enrolled in the study. Of these, 787 had subsequent HIV testing and 31 were found HIV-1 infected; an overall incidence rate of 4.51 (95% confidence interval: 2.96–6.06) per 100 PYFU was obtained. Young age, using hormonal injectable contraceptives and bacterial vaginosis were the main predictors of HIV acquisition. The incidence of HIV continues to be high among women in Malawi, and young women appear to be at higher risk.

Data evaluating the biological events and determinants of early human immunodeficiency virus type 1 (HIV-1) infection are limited in sub-Saharan Africa. We examined plasma viral levels and trends during early and established HIV-1 infection among reproductive-age women who participated in a randomized trial to treat genital tract infection in Malawi. We also assessed the association of injectable hormonal contraceptive use with HIV-1 infection.We studied 3 groups of women who were infected or uninfected with HIV-1: seroconverters, seroprevalent women, and seronegative women. Questionnaires and blood samples were collected at baseline and every 3 months for 1 year. The virus set point in seroconverters and levels and trends of viral load over time were determined. The associations of injectable hormonal contraceptive use with HIV-1 infection and viral load were assessed using conditional logistic regression and mixed-effect models, respectively.In the original clinical trial, 844 women infected with HIV-1 and 842 women not infected with HIV-1 were enrolled. Of 31 women who experienced seroconversion during 12 months, 27 were matched with 54 seroprevalent and 54 seronegative women. The estimated median plasma virus set point was 4.45 log(10) copies/mL (interquartile range, 4.32-5.14 log(10) copies/mL). Injectable hormonal contraceptive use was significantly associated with HIV-1 seroconversion (adjusted odds ratio, 10.42; P = .03) but not with established HIV-1 infection. Among the seroconverters, a statistically significant interaction was found between the linear association of viral load and time of injectable hormonal contraceptive use (regression coefficient, -0.14; P = .02).Knowledge of virus set point and trends of viral load in HIV-1 seroincident and seroprevalent asymptomatic women could assist in antiretroviral treatment management.

We describe the evaluation of the HIV post-exposure prophylaxis (PEP) programme for occupational injuries in Queen Elizabeth Central Hospital, Blantyre, Malawi. An audit was performed 1 year after introduction, by reviewing files of all clients who sought advice regarding PEP. In addition, the incidence of occupational injuries and awareness of the programme were assessed through interviews with nurses. The logistics of the programme were adequate. Of 29 clients who reported occupational injuries,19 started PEP. Only double antiretroviral drug therapy was available; side-effects were common but generally mild. Attendance of scheduled follow-up visits was poor, and few HIV test results after completion of PEP were obtained. Interviews with nurses revealed a high incidence of occupational injuries, but many did not report for advice about PEP; mostly because of unawareness of the programme and a reluctance to be tested for HIV.

We performed a cross sectional study to evaluate treatment results of the paying antiretroviral therapy clinic of Queen Elizabeth Central Hospital, Blantyre. The only antiretroviral therapy was a fixed drug combination of stavudine, lamivudine and nevirapine. Methods : Interviews, laboratory tests (CD4 count, viral load, nevirapine plasma levels, transaminases) and data extraction from files. 422 (59 %) of the patients who started antiretroviral therapy since 2000 were lost to follow up. The 176 patients enrolled in the study had good virological and excellent clinical treatment results. The most common side effect was peripheral neuropathy. Nevirapine plasma levels were remarkably high and associated with successful virological treatment results. Two simple adherence questions pertaining to the use of medication in the previous 8 days corresponded well with nevirapine levels. The most important reasons for non-adherence were shortage of drugs in the hospital pharmacy and personal financial constraints. Conclusions : Many patients were lost to follow up. High nevirapine levels contributed to good therapy results in those studied. Simple adherence questions predicted sub-therapeutic nevirapine levels. Antiretroviral drug supply needs to be uninterrupted and free of charge, to prevent avoidable non-adherence. Malawi Medical Journal Vol. 17(4) 2005: 112-116

Contains fulltext : 47457.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To evaluate treatment results of the paying antiretroviral therapy (ART) clinic of Queen Elizabeth Central Hospital, a large public and teaching hospital in Blantyre, Malawi. The only ART was a fixed drug combination of stavudine, lamivudine and nevirapine. METHODS: Cross sectional study with interviews, laboratory tests (CD4 count, viral load, nevirapine plasma levels, transaminases) and data extraction from files. RESULTS: A total of 422 (59%) of the patients who started ART since 2000 were lost to follow-up. The 176 patients enrolled in the study had good virological and excellent clinical treatment results. The most common side effect was peripheral neuropathy. Nevirapine plasma levels were remarkably high and associated with successful virological treatment results. Two simple adherence questions pertaining to the use of medication in the previous 8 days corresponded well with nevirapine levels. The most important reasons for non-adherence were shortage of drugs in the hospital pharmacy and personal financial constraints. CONCLUSIONS: (1) Many patients were lost to follow-up. (2) High nevirapine levels contributed to good therapy results in those studied. (3) Simple adherence questions predicted subtherapeutic nevirapine levels. (4) Antiretroviral drug supply needs to be uninterrupted and free of charge, to prevent avoidable non-adherence.

Background and Purpose— The differential diagnosis of stroke in Africa in areas with high HIV prevalence includes brain infections. We studied causes of stroke in Blantyre, Malawi, where HIV prevalence among medical inpatients is 70%. Methods— In a descriptive study of 8-month duration, all patients presenting at Queen Elizabeth Central Hospital, Blantyre, with central neurological deficit of acute onset ( Results— Ninety-eight consecutive patients (49 males) were studied. In those who were HIV positive (48%), the mean age was 37.5 years; ischemic stroke was the commonest diagnosis (n=25; 58%), followed by infection (n=11; 23%; including tuberculous [n=4] and cryptococcal [n=2] meningitis; toxoplasmic encephalitis [n=1]; neurocysticercosis [n=1]; brain abscess [n=1]; and progressive multifocal leucoencephalopathy [n=2]). No clinical or laboratory parameters could be identified as predictors for infection, but 3 of 5 patients with fever on admission had tuberculous meningitis. In HIV-negative patients (mean age 58.6 years), 55% had ischemic stroke and 31% had intracerebral hemorrhage; no brain infection was diagnosed. Presence of vascular disease correlated with age but not with HIV status. Conclusions— Ischemic stroke was found in half of patients irrespective of HIV status. In those who are HIV positive, brain infection should be considered for which the presence of fever and examination of cerebrospinal fluid seem most useful in diagnosis.

The aims of the study were to measure the prevalence and outcome of mycobacteraemia in febrile hospitalised adults; to determine what proportion could be identified using routine methods; to assess clinical indicators of mycobacteraemia and the usefulness of a diagnostic trial of anti-TB treatment. We prospectively examined adults with fever or a history of fever admitted to adult medical wards of QECH, Blantyre. All had blood cultured for bacteria and mycobacteria, chest x-ray and sputum smears. M. tuberculosis was the commonest blood isolate, affecting 57 of 344 patients (17%). In 44 (77%) patients with mycobacteraemia, TB was identified using routine investigations; in only 6 (11%) it was not suspected. Strong clinical indicators of mycobacteraemia were anaemia, HIV seropositivity, cough, chronic fever, and a clinical diagnosis of AIDS on the day of admission. Of nine patients selected for a therapeutic trial of TB treatment, six had mycobacteraemia, of whom five died during the trial. Mortality on short course chemotherapy, on the TB ward after one month, was similar whether patients had mycobacteramia (21%) or not (32%). TB can be identified with routine methods in most patients with mycobacteraemia. If treated, mycobacteraemia has as good an early outcome as TB without mycobacteraemia. Strengthening of basic facilities is likely to improve detection and treatment of mycobacterial disease. [Malawi Med J, Vol.15(2) 2003: 56-60]

Aims: To investigate ocular disease in patients with tuberculosis (TB) and HIV in Africa presenting with fever, and to determine if indirect ophthalmoscopy is useful in the diagnosis of mycobacteraemia. Methods: A prospective study of all adult patients admitted with fever to a large central hospital in Malawi, Africa. All recruited patients had an ophthalmic examination, HIV tests, chest x ray, sputum examinations, bacterial and mycobacterial blood cultures, and malaria slide to observe the presence of parasites. Results: 307 patients were recruited; 109 (36%) had TB, including 53 (17%) with mycobacteraemia; 255 (83%) had HIV and 191 (62%) had AIDS. Of the patients with TB 102 (94%) had HIV. Choroidal granulomas were found in four patients, all of whom had AIDS; three (2.8% of those with TB) had disseminated TB with mycobacteraemia, and one had persistent fever but no other evidence of TB. Among the patients with AIDS, 32 (17%) had microangiopathy manifest by cotton wool spots; one (0.5%) had signs of active cytomegalovirus (CMV) retinitis. The presence of microangiopathy was not related to TB. Conclusions: In Malawian patients with TB presenting acutely with fever, choroidal granulomas were found in 2.8%, and were concurrent with mycobacteraemia and AIDS. Ophthalmoscopy was not a useful aid in the diagnosis of mycobacteraemia. Cytomegalovirus (CMV) retinitis is rarely seen in African AIDS patients. This may be the result of mortality early in the disease course, or differences in race, HIV subtype, or comorbidity.

A randomized clinical trial, the PostExposure Prophylaxis of Infants trial in Blantyre, Malawi, (PEPI-Malawi), which was carried out in a resource-limited setting showed that antiretroviral prophylaxis (nevirapine alone or nevirapine plus zidovu- dine) extended to age 14 weeks in infants who were breast-fed by human immunodeficiency virus (HIV)-infected mothers, reduced the risk of HIV-1 infection by 67%. In a similar setting, use of maternal highly active antiretroviral therapy (HAART) has also reduced postnatal HIV transmission; its efficacy, however, has not been confirmed in a randomized trial. The availability of antiretroviral therapy in 2006 provided the opportunity to evaluate, in the PEPI-Malawi trial, the complementary effects of infant prophylaxis and maternal HAART in reducing transmission of HIV through breast milk. This follow-up observational study determined the incidence of HIV infection and the association between postnatal HIV transmission and maternal HAART among breast-fed infants born to HIV-1-infected women in the PEPI-Malawi trial who were HIV negative after 14 weeks of extended antiretroviral prophylaxis. The infants were randomized at birth to receive either oral single-dose nevirapine plus 1 week of zidovudine (control), control plus nevirapine daily to age 14 weeks, or control followed by nevirapine plus zidovudine daily to age 14 weeks. Three maternal exposure categories were examined as follows: The HAART-eligible/untreated category consisted of infants whose mothers were eligible (defined as CD4 cell count

SummaryBackgroundHematological abnormalities are common manifestations of advanced HIV-1 infection that could affect the outcomes of highly-active antiretroviral therapy (HAART). Although most HIV-1-infected individuals live in resource-constrained countries, there is little information about the frequency of hematological abnormalities such as anemia, neutropenia, and thrombocytopenia among individuals with advanced HIV-1 disease.MethodsThis study compared the prevalence of pre-antiretroviral therapy hematological abnormalities among 1571 participants in a randomized trial of antiretroviral efficacy in Africa, Asia, South America, the Caribbean, and the USA. Potential covariates for anemia, neutropenia, and thrombocytopenia were identified in univariate analyses and evaluated in separate multivariable models for each hematological condition.ResultsThe frequencies of neutropenia (absolute neutrophil count ≤1.3×109/l), anemia (hemoglobin ≤10g/dl), and thrombocytopenia (platelets ≤125×109/l) at initiation of antiretroviral therapy were 14%, 12%, and 7%, respectively, and varied by country (p