Elwyn Chomba

Genetic and Neutralization Properties of Subtype C Human Immunodeficiency Virus Type 1 Molecular env Clones from Acute and Early Heterosexually Acquired Infections in Southern Africa

ABSTRACT A standard panel of subtype C human immunodeficiency virus type 1 (HIV-1) Env-pseudotyped viruses was created by cloning, sequencing, and characterizing functional gp160 genes from 18 acute and early heterosexually acquired infections in South Africa and Zambia. In general, the gp120 region of these clones was shorter (most evident in V1 and V4) and less glycosylated compared to newly transmitted subtype B viruses, and it was underglycosylated but no different in length compared to chronic subtype C viruses. The gp120s also exhibited low amino acid sequence variability (12%) in V3 and high variability (39%) immediately downstream of V3, a feature shared with newly transmitted subtype B viruses and chronic viruses of both subtypes. When tested as Env-pseudotyped viruses in a luciferase reporter gene assay, all clones possessed an R5 phenotype and resembled primary isolates in their sensitivity to neutralization by HIV-1-positive plasmas. Results obtained with a multisubtype plasma panel suggested partial subtype preference in the neutralizing antibody response to infection. The clones were typical of subtype C in that all were resistant to 2G12 (associated with loss of N-glycosylation at position 295) and most were resistant to 2F5, but all were sensitive to 4E10 and many were sensitive to immunoglobulin G1b12. Finally, conserved neutralization epitopes in the CD4-induced coreceptor binding domain of gp120 were poorly accessible and were difficult to induce and stabilize with soluble CD4 on Env-pseudotyped viruses. These results illustrate key genetic and antigenic properties of subtype C HIV-1 that might impact the design and testing of candidate vaccines. A subset of these gp160 clones are suitable for use as reference reagents to facilitate standardized assessments of vaccine-elicited neutralizing antibody responses.

Investigating the utility of the HIV-1 BED capture enzyme immunoassay using cross-sectional and longitudinal seroconverter specimens from Africa.

Background:The identification of populations at risk of HIV infection is a priority for trials of preventive technologies, including HIV vaccines. To quantify incidence traditionally requires laborious and expensive prospective studies. Methods:The BED IgG–Capture enzyme immunoassay (EIA) was developed to estimate HIV-1 incidence using cross-sectional data by measuring increasing levels of HIV-specific IgG as a proportion of total IgG. To evaluate this assay, we tested 189 seroconversion samples taken at 3-monthly intervals from 15 Rwandan and 26 Zambian volunteers with known time of infection and cross-sectional specimens from 617 Kenyan and Ugandan volunteers with prevalent infection. Results:The BED–EIA-estimated incidence in Uganda was unexpectedly high, at 6.1%/year [95% confidence interval (CI) 4.2–8.0] in Masaka and 6.0%/year (95% CI 4.3–7.7) in Kakira. Prospective incidence data in Masaka from the same population was 1.7%/year before and 1.4%/year after the study. Kenyan estimates were 3.5%/year in Kilifi (95% CI 2.1–4.9) and 3.4%/year in Nairobi (95% CI 1.5–5.3). From the Rwandan and Zambian data, the sensitivity of the assay was 81.2% and the specificity was 67.8%. After approximately one year, subjects misclassified as recently infected tended to have lower plasma viral loads compared with those not misclassified as recent (median copies/ml 14 773 versus 93 560; P = 0.02). Clinical presentation, sex and HIV subtype were not significantly associated with BED–EIA misclassification in seroconverter samples. Conclusion:These data suggest that this assay does not perform reliably in all populations. Further research is warranted before using this assay to estimate incidence from prevalent HIV samples.

A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: The ACT cluster-randomised trial

BACKGROUND Antenatal corticosteroids for pregnant women at risk of preterm birth are among the most effective hospital-based interventions to reduce neonatal mortality. We aimed to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of antenatal corticosteroids at all levels of health care in low-income and middle-income countries. METHODS In this 18-month, cluster-randomised trial, we randomly assigned (1:1) rural and semi-urban clusters within six countries (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia) to standard care or a multifaceted intervention including components to improve identification of women at risk of preterm birth and to facilitate appropriate use of antenatal corticosteroids. The primary outcome was 28-day neonatal mortality among infants less than the 5th percentile for birthweight (a proxy for preterm birth) across the clusters. Use of antenatal corticosteroids and suspected maternal infection were additional main outcomes. This trial is registered with ClinicalTrials.gov, number NCT01084096. FINDINGS The ACT trial took place between October, 2011, and March, 2014 (start dates varied by site). 51 intervention clusters with 47,394 livebirths (2520 [5%] less than 5th percentile for birthweight) and 50 control clusters with 50,743 livebirths (2258 [4%] less than 5th percentile) completed follow-up. 1052 (45%) of 2327 women in intervention clusters who delivered less-than-5th-percentile infants received antenatal corticosteroids, compared with 215 (10%) of 2062 in control clusters (p<0·0001). Among the less-than-5th-percentile infants, 28-day neonatal mortality was 225 per 1000 livebirths for the intervention group and 232 per 1000 livebirths for the control group (relative risk [RR] 0·96, 95% CI 0·87-1·06, p=0·65) and suspected maternal infection was reported in 236 (10%) of 2361 women in the intervention group and 133 (6%) of 2094 in the control group (odds ratio [OR] 1·67, 1·33-2·09, p<0·0001). Among the whole population, 28-day neonatal mortality was 27·4 per 1000 livebirths for the intervention group and 23·9 per 1000 livebirths for the control group (RR 1·12, 1·02-1·22, p=0·0127) and suspected maternal infection was reported in 1207 (3%) of 48,219 women in the intervention group and 867 (2%) of 51,523 in the control group (OR 1·45, 1·33-1·58, p<0·0001). INTERPRETATION Despite increased use of antenatal corticosteroids in low-birthweight infants in the intervention groups, neonatal mortality did not decrease in this group, and increased in the population overall. For every 1000 women exposed to this strategy, an excess of 3·5 neonatal deaths occurred, and the risk of maternal infection seems to have been increased. FUNDING Eunice Kennedy Shriver National Institute of Child Health and Human Development.

The social and economic impact of epilepsy in Zambia: a cross-sectional study

BACKGROUND Among the 40 million people with epilepsy worldwide, 80% reside in low-income regions where human and technological resources for care are extremely limited. Qualitative and experiential reports indicate that people with epilepsy in Africa are also disadvantaged socially and economically, but few quantitative systematic data are available. We sought to assess the social and economic effect of living with epilepsy in sub-Saharan Africa. METHODS We did a cross-sectional study of people with epilepsy concurrently matched for age, sex, and site of care to individuals with a non-stigmatised chronic medical condition. Verbally administered questionnaires provided comparison data for demographic characteristics, education, employment status, housing and environment quality, food security, healthcare use, personal safety, and perceived stigma. FINDINGS People with epilepsy had higher mean perceived stigma scores (1.8 vs 0.4; p<0.0001), poorer employment status (p=0.0001), and less education (7.1 vs 9.4 years; p<0.0001) than did the comparison group. People with epilepsy also had less education than their nearest-age same sex sibling (7.1 vs 9.1 years; p<0.0001), whereas the comparison group did not (9.4 vs 9.6 years; p=0.42). Housing and environmental quality were poorer for people with epilepsy, who had little access to water, were unlikely to have electricity in their home (19%vs 51%; p<0.0001), and who had greater food insecurity than did the control group. During pregnancy, women with epilepsy were more likely to deliver at home rather than in a hospital or clinic (40%vs 15%; p=0.0007). Personal safety for people with epilepsy was also more problematic; rape rates were 20% among women with epilepsy vs 3% in the control group (p=0.004). INTERPRETATION People with epilepsy in Zambia have substantially poorer social and economic status than do their peers with non-stigmatised chronic medical conditions. Suboptimum housing quality differentially exposes these individuals to the risk of burns and drowning during a seizure. Vulnerability to physical violence is extreme, especially for women with epilepsy.

The Maternal and Newborn Health Registry Study of the Global Network for Women's and Children's Health Research

To implement a vital statistics registry system to register pregnant women and document birth outcomes in the Global Network for Womens and Childrens Health Research sites in Asia, Africa, and Latin America.

Effect of WHO newborn care training on neonatal mortality by education

BACKGROUND Ninety-nine percent of the 4 million neonatal deaths per year occur in developing countries. The World Health Organization (WHO) Essential Newborn Care (ENC) course sets the minimum accepted standard for training midwives on aspects of infant care (neonatal resuscitation, breastfeeding, kangaroo care, small baby care, and thermoregulation), many of which are provided by the mother. OBJECTIVE The aim of this study was to determine the association of ENC with all-cause 7-day (early) neonatal mortality among infants of less educated mothers compared with those of mothers with more education. METHODS Protocol- and ENC-certified research nurses trained all 123 college-educated midwives from 18 low-risk, first-level urban community health centers (Zambia) in data collection (1 week) and ENC (1 week) as part of a controlled study to test the clinical impact of ENC implementation. The mothers were categorized into 2 groups, those who had completed 7 years of school education (primary education) and those with 8 or more years of education. RESULTS ENC training is associated with decreases in early neonatal mortality; rates decreased from 11.2 per 1000 live births pre-ENC to 6.2 per 1000 following ENC implementation (P < .001). Prenatal care, birth weight, race, and gender did not differ between the groups. Mortality for infants of mothers with 7 years of education decreased from 12.4 to 6.0 per 1000 (P < .0001) but did not change significantly for those with 8 or more years of education (8.7 to 6.3 per 1000, P = .14). CONCLUSIONS ENC training decreases early neonatal mortality, and the impact is larger in infants of mothers without secondary education. The impact of ENC may be optimized by training health care workers who treat women with less formal education.

Educational Impact of the Neonatal Resuscitation Program in Low-Risk Delivery Centers in a Developing Country

OBJECTIVE To evaluate the effectiveness of the American Academy of Pediatrics Neonatal Resuscitation Program (NRP) in improving knowledge, skills, and self-efficacy of nurse midwives in low-risk delivery clinics in a developing country. STUDY DESIGN We used the content specifications of the NRP material applicable to college-educated nurse midwives working in low-risk clinics in Zambia to develop performance and self-efficacy evaluations focused on principles of resuscitation, initial steps, ventilation, and chest compressions. These evaluations were administered to 127 nurse midwives before and after NRP training and 6-months later. RESULTS After training, written scores (knowledge evaluation) improved from 57%+/-14% to 80%+/-12% (mean+/-SD; P< .0001); performance scores (skills evaluation) improved the most from 43%+/-21% to 88%+/-9% (P< .0001); self-efficacy scores improved from 74%+/-14% to 90%+/-10% (P< .0001). Written and performance scores decreased significantly 6 months after training, but self-efficacy scores remained high. CONCLUSIONS As conducted, the NRP training improved educational outcomes in college-educated practicing nurse midwives. Pre-training knowledge and skills scores were relatively low despite the advanced formal education and experience of the participants, whereas the self-efficacy scores were high. NRP training has the potential to substantially improve knowledge and skills of neonatal resuscitation.

A prospective study of maternal, fetal and neonatal deaths in low- and middle-income countries.

OBJECTIVE To quantify maternal, fetal and neonatal mortality in low- and middle-income countries, to identify when deaths occur and to identify relationships between maternal deaths and stillbirths and neonatal deaths. METHODS A prospective study of pregnancy outcomes was performed in 106 communities at seven sites in Argentina, Guatemala, India, Kenya, Pakistan and Zambia. Pregnant women were enrolled and followed until six weeks postpartum. FINDINGS Between 2010 and 2012, 214,070 of 220,235 enrolled women (97.2%) completed follow-up. The maternal mortality ratio was 168 per 100,000 live births, ranging from 69 per 100,000 in Argentina to 316 per 100,000 in Pakistan. Overall, 29% (98/336) of maternal deaths occurred around the time of delivery: most were attributed to haemorrhage (86/336), pre-eclampsia or eclampsia (55/336) or sepsis (39/336). Around 70% (4349/6213) of stillbirths were probably intrapartum; 34% (1804/5230) of neonates died on the day of delivery and 14% (755/5230) died the day after. Stillbirths were more common in women who died than in those alive six weeks postpartum (risk ratio, RR: 9.48; 95% confidence interval, CI: 7.97-11.27), as were perinatal deaths (RR: 4.30; 95% CI: 3.26-5.67) and 7-day (RR: 3.94; 95% CI: 2.74-5.65) and 28-day neonatal deaths (RR: 7.36; 95% CI: 5.54-9.77). CONCLUSION Most maternal, fetal and neonatal deaths occurred at or around delivery and were attributed to preventable causes. Maternal death increased the risk of perinatal and neonatal death. Improving obstetric and neonatal care around the time of birth offers the greatest chance of reducing mortality.

Epidemiology of stillbirth in low-middle income countries: A Global Network Study

Objective. To determine population‐based stillbirth rates and to determine whether the timing and maturity of the stillbirths suggest a high proportion of potentially preventable deaths. Design. Prospective observational study. Setting. Communities in six low‐income countries (Democratic Republic of Congo, Kenya, Zambia, Guatemala, India, and Pakistan) and one site in a mid‐income country (Argentina). Population. Pregnant women residing in the study communities. Methods. Over a five‐year period, in selected catchment areas, using multiple methodologies, trained study staff obtained pregnancy outcomes on each delivery in their area. Main outcome measures. Pregnancy outcome, stillbirth characteristics. Results. Outcomes of 195 400 deliveries were included. Stillbirth rates ranged from 32 per 1 000 in Pakistan to 8 per 1 000 births in Argentina. Three‐fourths (76%) of stillbirth offspring were not macerated, 63% were ≥37 weeks and 48% weighed 2 500g or more. Across all sites, women with no education, of high and low parity, of older age, and without access to antenatal care were at significantly greater risk for stillbirth (p<0.001). Compared to those delivered by a physician, women delivered by nurses and traditional birth attendants had a lower risk of stillbirth. Conclusions. In these low‐middle income countries, most stillbirth offspring were not macerated, were reported as ≥37 weeks’ gestation, and almost half weighed at least 2 500g. With access to better medical care, especially in the intrapartum period, many of these stillbirths could likely be prevented.

Plastic Bags for Prevention of Hypothermia in Preterm and Low Birth Weight Infants

BACKGROUND AND OBJECTIVES: Hypothermia contributes to neonatal mortality and morbidity, especially in preterm and low birth weight infants in developing countries. Plastic bags covering the trunk and extremities of very low birth weight infants reduces hypothermia. This technique has not been studied in larger infants or in many resource-limited settings. The objective was to determine if placing preterm and low birth weight infants inside a plastic bag at birth maintains normothermia. METHODS: Infants at 26 to 36 weeks’ gestational age and/or with a birth weight of 1000 to 2500 g born at the University Teaching Hospital in Lusaka, Zambia, were randomized by using a 1:1 allocation and parallel design to standard thermoregulation (blanket or radiant warmer) care or to standard thermoregulation care plus placement inside a plastic bag at birth. The primary outcome measure was axillary temperature in the World Health Organization–defined normal range (36.5–37.5°C) at 1 hour after birth. RESULTS: A total of 104 infants were randomized. At 1 hour after birth, infants randomized to plastic bag (n = 49) were more likely to have a temperature in the normal range as compared with infants in the standard thermoregulation care group (n = 55; 59.2% vs 32.7%; relative risk 1.81; 95% confidence interval 1.16–2.81; P = .007). The temperature at 1 hour after birth in the infants randomized to plastic bag was 36.5 ± 0.5°C compared with 36.1 ± 0.6°C in standard care infants (P < .001). Hyperthermia (>38.0°C) did not occur in any infant. CONCLUSIONS: Placement of preterm/low birth weight infants inside a plastic bag at birth compared with standard thermoregulation care reduced hypothermia without resulting in hyperthermia, and is a low-cost, low-technology tool for resource-limited settings.