Hazzie Mvula

Population-level effect of HIV on adult mortality and early evidence of reversal after introduction of antiretroviral therapy in Malawi

Summary Background Malawi, which has about 80 000 deaths from AIDS every year, made free antiretroviral therapy available to more than 80 000 patients between 2004 and 2006. We aimed to investigate mortality in a population before and after the introduction of free antiretroviral therapy, and therefore to assess the effects of such programmes on survival at the population level. Methods We used a demographic surveillance system to measure mortality in a population of 32 000 in northern Malawi, from August, 2002, when free antiretroviral therapy was not available in the study district, until February, 2006, 8 months after a clinic opened. Causes of death were established through verbal autopsies (retrospective interviews). Patients who registered for antiretroviral therapy at the clinic were identified and linked to the population under surveillance. Trends in mortality were analysed by age, sex, cause of death, and zone of residence. Findings Before antiretroviral therapy became available in June, 2005, mortality in adults (aged 15–59 years) was 9·8 deaths for 1000 person-years of observation (95% CI 8·9–10·9). The probability of dying between the ages of 15 and 60 years was 43% (39–49) for men and 43% (38–47) for women; 229 of 352 deaths (65·1%) were attributed to AIDS. 8 months after the clinic that provided antiretroviral therapy opened, 107 adults from the study population had accessed treatment, out of an estimated 334 in need of treatment. Overall mortality in adults had decreased by 10% from 10·2 to 8·7 deaths for 1000 person-years of observation (adjusted rate ratio 0·90, 95% CI 0·70–1·14). Mortality was reduced by 35% (adjusted rate ratio 0·65, 0·46–0·92) in adults near the main road, where mortality before antiretroviral therapy was highest (from 13·2 to 8·5 deaths per 1000 person-years of observation before and after antiretroviral therapy). Mortality in adults aged 60 years or older did not change. Interpretation Our findings of a reduction in mortality in adults aged between 15 and 59 years, with no change in those older than 60 years, suggests that deaths from AIDS were averted by the rapid scale-up of free antiretroviral therapy in rural Malawi, which led to a decline in adult mortality that was detectable at the population level. Funding Wellcome Trust and British Leprosy Relief Association.

Population Differences in Immune Responses to Bacille Calmette-Guérin Vaccination in Infancy

Bacille Calmette-Guérin (BCG) vaccination induces a marked increase in the interferon (IFN)-gamma response to Mycobacterium tuberculosis purified protein derivative (Mtb PPD) in UK adolescents, but not in Malawian adolescents. We hypothesized that Mtb PPD-induced IFN-gamma after BCG vaccination would be similar in infants from these 2 countries. Infants were vaccinated with BCG during the first 3-13 weeks of life. Three months after BCG vaccination, 51 (100%) of 51 UK infants had an IFN-gamma response to Mtb PPD, compared to 41 (53%) of 78 of Malawian infants, in whom responses varied according to their season of birth. We conclude that population differences in immune responses after BCG vaccination are observed among infants, as well as among young adults.

BCG Vaccination Induces Different Cytokine Profiles Following Infant BCG Vaccination in the UK and Malawi

Background. BCG vaccination of infants is thought to provide good protection in all settings. This study investigated whether Malawian infants made weaker responses across a cytokine panel after BCG vaccination, compared with UK infants. Methods. Diluted whole-blood samples were cultured with Mycobacterium tuberculosis purified protein derivative for 6 days from BCG-vaccinated infants 3 months (n = 40 Malawi, 28 UK) and 12 months (n = 34 Malawi, 26 UK) after vaccination, and also from UK unvaccinated infants (n = 9 at 3 months, n = 10 at 12 months). Forty-two cytokines were measured in supernatants using a multiplex bead array assay. Principal component analysis was used to summarize the overall patterns in cytokine responses. Results. We found differences in median responses in 27 of the 42 cytokines: 7 higher in the UK and 20 higher in Malawi. The cytokines with higher responses in the UK were all T helper 1 related. The cytokines with higher responses in Malawi included innate proinflammatory cytokines, regulatory cytokines, interleukin 17, T helper 2 cytokines, chemokines, and growth factors. Principal component analysis separated the BCG-vaccinated infants from Malawi from the UK vaccinated infants and from the unvaccinated infants. Conclusions. Malawian infants make cytokine responses following BCG vaccination, but the cytokine profile is different from that in the UK. The different biosignatures following BCG vaccination in the 2 settings may indicate variability in the protective efficacy of infant BCG vaccination.

What happens to ART-eligible patients who do not start ART? Dropout between screening and ART initiation: a cohort study in Karonga, Malawi

BackgroundRoutine ART programme statistics generally only provide information about individuals who start treatment. We aimed to investigate the outcome of those who are eligible but do not start ART in the Malawi programme, factors associated with this dropout, and reasons for not starting treatment, in a prospective cohort study.MethodsIndividuals having a first screening visit at the ART clinic at Karonga District Hospital, northern Malawi, between September 2005 and July 2006 were interviewed. Study follow-up to identify treatment outcomes was conducted at the clinic and in the community. Logistic regression models were used to identify factors associated with dropout before ART initiation among participants identified as clinically eligible for ART.Results88 participants eligible for ART at their first screening visit (out of 633, 13.9%) defaulted before starting ART. Participants with less education, difficulties in dressing, a more delayed ART initiation appointment, and mid-upper arm circumference (MUAC) < 22 cm were significantly less likely to have visited the clinic subsequently. Thirty-five (58%) of the 60 participants who defaulted and were tracked at home had died, 21 before their ART initiation appointment.ConclusionsMUAC and reported difficulties in dressing may provide useful screening indicators to identify sicker ART-eligible individuals at high risk of dropping out of the programme who might benefit from being brought back quickly or admitted to hospital for observation. Individuals with less education may need adapted health information at screening. Deaths of ART-eligible individuals occurring prior to ART initiation are not included in routine programme statistics. Considering all those who are eligible for ART as a denominator for programme indicators would help to highlight this vulnerable group, in order to identify new opportunities for further improving ART programmes.

Adult mortality and probable cause of death in rural northern Malawi in the era of HIV treatment

Objectives  Developing countries are undergoing demographic transition with a shift from high mortality caused by communicable diseases (CD) to lower mortality rates caused by non‐communicable diseases (NCD). HIV/AIDS has disrupted this trend in sub‐Saharan Africa. However, in recent years, HIV‐associated mortality has been reduced with the introduction of widely available antiretroviral therapy (ART). Side effects of ART may lead to increased risk of cardiovascular diseases, raising the prospects of an accelerated transition towards NCD as the primary cause of death. We report population‐based data to investigate changes in cause of death owing to NCD during the first 4 years after introduction of HIV treatment.

Differences between naive and memory T cell phenotype in Malawian and UK adolescents: a role for Cytomegalovirus?

BackgroundDifferences in degree of environmental exposure to antigens in early life have been hypothesized to lead to differences in immune status in individuals from different populations, which may have implications for immune responses in later years.MethodsVenous blood from HIV-negative adolescents and blood from the umbilical cords of babies, born to HIV-negative women, post-delivery was collected and analysed using flow cytometry. T cell phenotype was determined from peripheral blood lymphocytes and cytomegalovirus (CMV) seropositivity was assessed by ELISA in adolescents.ResultsHIV-negative Malawian adolescents were shown to have a lower percentage of naïve T cells (CD45RO-CD62Lhi CD11alo), a higher proportion of memory T cells and a higher percentage of CD28- memory (CD28-CD45RO+) T cells compared to age-matched UK adolescents. Malawian adolescents also had a lower percentage of central memory (CD45RA-CCR7+) T cells and a higher percentage of stable memory (CD45RA+CCR7-) T cells than UK adolescents. All of the adolescents tested in Malawi were seropositive for CMV (59/59), compared to 21/58 (36%) of UK adolescents. CMV seropositivity in the UK was associated with a reduced percentage of naïve T cells and an increased percentage of CD28- memory T cells in the periphery. No differences in the proportions of naïve and memory T cell populations were observed in cord blood samples from the two sites.ConclusionIt is likely that these differences between Malawian and UK adolescents reflect a greater natural exposure to various infections, including CMV, in the African environment and may imply differences in the ability of these populations to induce and maintain immunological memory to vaccines and natural infections.

Implication of new WHO growth standards on identification of risk factors and estimated prevalence of malnutrition in rural Malawian infants.

Background The World Health Organization (WHO) released new Child Growth Standards in 2006 to replace the current National Center for Health Statistics (NCHS) growth reference. We assessed how switching from the NCHS to the newly released WHO Growth Standards affects the estimated prevalence of wasting, underweight and stunting, and the pattern of risk factors identified. Methodology/Principal Findings Data were drawn from a village-informant driven Demographic Surveillance System in Northern Malawi. Children (n = 1328) were visited twice at 0–4 months and 11–15 months. Data were collected on the demographic and socio-economic environment of the child, health history, maternal and child anthropometry and child feeding practices. Weight-for-length, weight-for-age and length-for-age were derived in z-scores using the two growth references. In early infancy, prevalence estimates were 2.9, 6.1, and 8.5 fold higher for stunting, underweight, and wasting respectively using the WHO standards compared to NCHS reference (p<0.001 for all). At one year, prevalence estimates for wasting and stunting did not differ significantly according to reference used, but the prevalence of underweight was half that with the NCHS reference (p<0.001). Patterns of risk factors were similar with the two growth references for all outcomes at one year although the strength of association was higher with WHO standards. Conclusions/Significance Differences in prevalence estimates differed in magnitude but not direction from previous studies. The scale of these differences depends on the populations nutritional status thus it should not be assumed a priori. The increase in estimated prevalence of wasting in early infancy has implications for feeding programs targeting lactating mothers and ante-natal multiple micronutrients supplementation to tackle small birth size. Risk factors identified using WHO standards remain comparable with findings based on the NCHS reference in similar settings. Further research should aim to identify whether the young infants additionally diagnosed as malnourished by this new standard are more appropriate targets for interventions than those identified with the NCHS reference.

Cost-Effectiveness of Monovalent Rotavirus Vaccination of Infants in Malawi: A Postintroduction Analysis Using Individual Patient–Level Costing Data

Background. Rotavirus vaccination reduces childhood hospitalization in Africa, but cost-effectiveness has not been determined using real-world effectiveness and costing data. We sought to determine monovalent rotavirus vaccine cost-effectiveness in Malawi, one of Africas poorest countries and the first Gavi-eligible country to report disease reduction following introduction in 2012. Methods. This was a prospective cohort study of children with acute gastroenteritis at a rural primary health center, a rural first referral–level hospital and an urban regional referral hospital in Malawi. For each participant we itemized household costs of illness and direct medical expenditures incurred. We also collected Ministry of Health vaccine implementation costs. Using a standard tool (TRIVAC), we derived cost-effectiveness. Results. Between 1 January 2013 and 21 November 2014, we recruited 530 children aged <5 years with gastroenteritis. Costs did not differ by rotavirus test result, but were significantly higher for admitted children and those with increased severity on Vesikari scale. Adding rotavirus vaccine to the national schedule costs Malawi

Declining child mortality in northern Malawi despite high rates of infection with HIV

0.42 per dose in system costs. Vaccine copayment is an additional

Methods and challenges in measuring the impact of national pneumococcal and rotavirus vaccine introduction on morbidity and mortality in Malawi

0.20. Over 20 years, the vaccine program will avert 1 026 000 cases of rotavirus gastroenteritis, 78 000 inpatient admissions, 4300 deaths, and 136 000 disability-adjusted-life-years (DALYs). For this years birth cohort, it will avert 54 000 cases of rotavirus and 281 deaths in children aged <5 years. The program will cost