Early life adversity, biological adaptation, and human capital: evidence from an interrupted malaria control program in Zambia.

Growing evidence from evolutionary biology demonstrates how early life shocks trigger physiological changes designed to be adaptive in challenging environments. We examine the implications of one type of physiological adaptation - immunity formation - for human capital accumulation. Using variation in early life malaria risk generated by an interrupted disease control program in Zambia, we show that exposure to infectious diseases during the first two years of life can reduce the harmful effects of malaria exposure on cognitive development during the preschool years. These findings suggest a non-linear and trajectory-dependent relationship between early life adversity and human capital formation.

Eligibility for hepatitis B antiviral therapy among adults in the general population in Zambia.

INTRODUCTION: We evaluated antiviral therapy (AVT) eligibility in a population-based sample of adults with chronic hepatitis B virus (HBV) infection in Zambia. MATERIALS AND METHODS: Using a household survey, adults (18+ years) were tested for hepatitis B surface antigen (HBsAg). Sociodemographic correlates of HBsAg-positivity were identified with multivariable regression. HBsAg-positive individuals were referred to a central hospital for physical examination, elastography, and phlebotomy for HBV DNA, hepatitis B e antigen, serum transaminases, platelet count, and HIV-1/2 antibody. We determined the proportion of HBV monoinfected adults eligible for antiviral therapy (AVT) based on European Association for the Study of the Liver (EASL) 2017 guidelines. We also evaluated the performance of two alternative criteria developed for use in sub-Saharan Africa, the World Health Organization (WHO) and Treat-B guidelines. RESULTS: Across 12 urban and 4 rural communities, 4,961 adults (62.9% female) were tested and 182 (3.7%) were HBsAg-positive, 80% of whom attended hospital follow-up. HBsAg-positivity was higher among men (adjusted odds ratio [AOR], 1.37; 95% confidence interval [CI], 0.99-1.87) and with decreasing income (AOR, 0.89 per household asset; 95% CI, 0.81-0.98). Trends toward higher HBsAg-positivity were also seen at ages 30-39 years (AOR, 2.11; 95% CI, 0.96-4.63) and among pregnant women (AOR, 1.74; 95% CI, 0.93-3.25). Among HBV monoinfected individuals (i.e., HIV-negative) evaluated for AVT, median age was 31 years, 24.6% were HBeAg-positive, and 27.9% had HBV DNA >2,000 IU/ml. AVT-eligibility was 17.0% by EASL, 10.2% by WHO, and 31.1% by Treat-B. Men had increased odds of eligibility. WHO (area under the receiver operating curve [AUROC], 0.68) and Treat-B criteria (AUROC, 0.76) had modest accuracy. Fourteen percent of HBsAg-positive individuals were HIV coinfection, and most coinfected individuals were taking tenofovir-containing antiretroviral therapy (ART). CONCLUSION: Approximately 1 in 6 HBV monoinfected adults in the general population in Zambia may be AVT-eligible. Men should be a major focus of hepatitis B diagnosis and treatment. Further development and evaluation of HBV treatment criteria for resource-limited settings is needed. In settings with overlapping HIV and HBV epidemics, scale-up of ART has contributed towards hepatitis B elimination.

Understanding preferences for HIV care and treatment in Zambia: Evidence from a discrete choice experiment among patients who have been lost to follow-up.

BACKGROUND: In public health HIV treatment programs in Africa, long-term retention remains a challenge. A number of improvement strategies exist (e.g., bring services closer to home, reduce visit frequency, expand hours of clinic operation, improve provider attitude), but implementers lack data about which to prioritize when resource constraints preclude implementing all. We used a discrete choice experiment (DCE) to quantify preferences for a number of potential clinic improvements to enhance retention. METHODS AND FINDINGS: We sought a random sample of HIV patients who were lost to follow-up (defined as >90 days late for their last scheduled appointment) from treatment facilities in Lusaka Province, Zambia. Among those contacted, we asked patients to choose between 2 hypothetical clinics in which the following 5 attributes of those facilities were varied: waiting time at the clinic (1, 3, or 5 hours), distance from residence to clinic (5, 10, or 20 km), ART supply given at each refill (1, 3, or 5 months), hours of operation (morning only, morning and afternoon, or morning and Saturday), and staff attitude ("rude" or "nice"). We used mixed-effects logistic regression to estimate relative utility (i.e., preference) for each attribute level. We calculated how much additional waiting time or travel distance patients were willing to accept in order to obtain other desired features of care. Between December 9, 2015 and May 31, 2016, we offered the survey to 385 patients, and 280 participated (average age 35; 60% female). Patients exhibited a strong preference for nice as opposed to rude providers (relative utility of 2.66; 95% CI 1.9-3.42; p < 0.001). In a standard willingness to wait or willingness to travel analysis, patients were willing to wait 19 hours more or travel 45 km farther to see nice rather than rude providers. An alternative analysis, in which trade-offs were constrained to values actually posed to patients in the experiment, suggested that patients were willing to accept a facility located 10 km from home (as opposed to 5) that required 5 hours of waiting per visit (as opposed to 1 hour) and that dispensed 3 months of medications (instead of 5) in order to access nice (as opposed to rude) providers. This study was limited by the fact that attributes included in the experiment may not have captured additional important determinants of preference. CONCLUSIONS: In this study, patients were willing to expend considerable time and effort as well as accept substantial inconvenience in order to access providers with a nice attitude. In addition to service delivery redesign (e.g., differentiated service delivery models), current improvement strategies should also prioritize improving provider attitude and promoting patient centeredness-an area of limited policy attention to date.

Medication Side Effects and Retention in HIV Treatment: A Regression Discontinuity Study of Tenofovir Implementation in South Africa and Zambia.

Tenofovir is less toxic than other nucleoside reverse-transcriptase inhibitors used in antiretroviral therapy (ART) and may improve retention of human immunodeficiency virus (HIV)-infected patients on ART. We assessed the impact of national guideline changes in South Africa (2010) and Zambia (2007) recommending tenofovir for first-line ART. We applied regression discontinuity in a prospective cohort study of 52,294 HIV-infected adults initiating first-line ART within 12 months (±12 months) of each guideline change. We compared outcomes in patients presenting just before and after the guideline changes using local linear regression and estimated intention-to-treat effects on initiation of tenofovir, retention in care, and other treatment outcomes at 24 months. We assessed complier causal effects among patients starting tenofovir. The new guidelines increased the percentages of patients initiating tenofovir in South Africa (risk difference (RD) = 81 percentage points, 95% confidence interval (CI): 73, 89) and Zambia (RD = 42 percentage points, 95% CI: 38, 45). With the guideline change, the percentage of single-drug substitutions decreased substantially in South Africa (RD = -15 percentage points, 95% CI: -18, -12). Starting tenofovir also reduced attrition in Zambia (intent-to-treat RD = -1.8% (95% CI: -3.5, -0.1); complier relative risk = 0.74) but not in South Africa (RD = -0.9% (95% CI: -5.9, 4.1); complier relative risk = 0.94). These results highlight the importance of reducing side effects for increasing retention in care, as well as the differences in population impact of policies with heterogeneous treatment effects implemented in different contexts.

Two-year impact of community-based health screening and parenting groups on child development in Zambia: Follow-up to a cluster-randomized controlled trial.

BACKGROUND: Early childhood interventions have potential to offset the negative impact of early adversity. We evaluated the impact of a community-based parenting group intervention on child development in Zambia. METHODS AND FINDINGS: We conducted a non-masked cluster-randomized controlled trial in Southern Province, Zambia. Thirty clusters of villages were matched based on population density and distance from the nearest health center, and randomly assigned to intervention (15 clusters, 268 caregiver-child dyads) or control (15 clusters, 258 caregiver-child dyads). Caregivers were eligible if they had a child 6 to 12 months old at baseline. In intervention clusters, caregivers were visited twice per month during the first year of the study by child development agents (CDAs) and were invited to attend fortnightly parenting group meetings. Parenting groups selected "head mothers" from their communities who were trained by CDAs to facilitate meetings and deliver a diverse parenting curriculum. The parenting group intervention, originally designed to run for 1 year, was extended, and households were visited for a follow-up assessment at the end of year 2. The control group did not receive any intervention. Intention-to-treat analysis was performed for primary outcomes measured at the year 2 follow-up: stunting and 5 domains of neurocognitive development measured using the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). In order to show Cohen's d estimates, BSID-III composite scores were converted to z-scores by standardizing within the study population. In all, 195/268 children (73%) in the intervention group and 182/258 children (71%) in the control group were assessed at endline after 2 years. The intervention significantly reduced stunting (56/195 versus 72/182; adjusted odds ratio 0.45, 95% CI 0.22 to 0.92; p = 0.028) and had a significant positive impact on language (ß 0.14, 95% CI 0.01 to 0.27; p = 0.039). The intervention did not significantly impact cognition (ß 0.11, 95% CI -0.06 to 0.29; p = 0.196), motor skills (ß -0.01, 95% CI -0.25 to 0.24; p = 0.964), adaptive behavior (ß 0.21, 95% CI -0.03 to 0.44; p = 0.088), or social-emotional development (ß 0.20, 95% CI -0.04 to 0.44; p = 0.098). Observed impacts may have been due in part to home visits by CDAs during the first year of the intervention. CONCLUSIONS: The results of this trial suggest that parenting groups hold promise for improving child development, particularly physical growth, in low-resource settings like Zambia. TRIAL REGISTRATION: ClinicalTrials.gov NCT02234726.

HIV Self-Testing in Lusaka Province, Zambia: Acceptability, Comprehension of Testing Instructions, and Individual Preferences for Self-Test Kit Distribution in a Population-Based Sample of Adolescents and Adults.

We assessed attitudes and preferences toward HIV self-testing (HIVST) among Zambian adolescents and adults. We conducted a population-based survey of individuals aged 16-49 years old in Lusaka Province, Zambia. HIVST was shown to participants through a short video on oral fluid-based self-testing. In addition to demographics, HIV risk perceptions, and HIV testing history, we assessed participants' acceptability and concerns regarding HIVST. Using a discrete choice experiment, we investigated preferences for the location of self-test pickup, availability of counseling, and cost. After reviewing an instructional sheet or an additional video, we assessed participants' understanding of self-test performance. Among 1617 participants, 647 (40.0%) were male, 269 (16.6%) were adolescents and 754 (46.6%) were nontesters (i.e., no HIV test in the past 12 months). After viewing the video, 1392 (86.0%) reported that HIVST would make them more likely to test and while 35.0% reported some concerns with HIVST, only 2% had serious concerns. Participants strongly preferred HIVST over finger prick testing as well as having counseling and reported willingness to pay out-of-pocket (US$3.5 for testers and US$5.5 for nontesters). Viewing an HIVST demonstration video did not improve participant understanding of self-test usage procedures compared to an instructional sheet alone, but it increased confidence in the ability to self-test. In conclusion, HIVST was highly acceptable and desirable, especially among those not accessing existing HIV testing services. Participants expressed a strong preference for counseling and a willingness to pay for test kits. These data can guide piloting and scaling-up of HIVST in Zambia and elsewhere in Africa.

Understanding linkage to care with HIV self-test approach in Lusaka, Zambia - A mixed method approach.

INTRODUCTION: HIV self-testing (HIVST) is a novel approach designed to assist in achieving the goal of at least 90% of the population that learn their HIV status. A self-test user with a positive test is required to visit a clinic to link into HIV care, yet little is known about patient preferences for linkage strategies. We examined the intention to link to care amongst potential HIVST users and the suitability of three linkage to care strategies in Lusaka Province, Zambia. METHODS: We conducted a representative cross sectional survey of 1,617 individuals aged 16-49 years old in Lusaka Province. Participants were shown a video of the HIVST. Data on intention to link to care and preferred linkage to care strategies-text message, phone call and home visits were collected. Eight focus group discussions were held concurrently with survey respondents to understand their preferences between the three linkage to care strategies. RESULTS: Of 1617 enrolled, 60% were women, 40% were men, with an average age of 27years (IQR = 22, 35). More men than women had at least secondary education (84% vs 77%) and were either employed or self-employed (67% vs. 41%). 85% (95%CI = 83 to 86) of participants said they would link to care within the first week of a positive self-test. Income >2,000 Kwacha (USD 200) per month versus income < 2,000 Kwacha (Adjusted odds ratio (AOR) = 0.59; 95%CI: 0.40 to 0.88; p = 0.009) and never versus prior HIV testers (AOR = 0.54; 95%CI: 0.32 to 0.91; p = 0.020) were associated with reduced odds of intention to link to care. 53% (95%CI = 50 to 55) preferred being prompted to link to care by home visits compared to phone call (30%) or SMS (17%). CONCLUSION: We found almost nine out of ten potential HIVST users in the general population intend to link to care shortly after a positive test, and preferred home visits or phone calls to facilitate linkage, rather than SMS. Also, higher income earners and those who never tested for HIV were associated with reduced odds of intention to link to care. Policy guidelines and implementation strategies for HIVST should be responsive to patient preferences for linkage to care strategies to achieve the continuum of HIV care.

Feasibility and Effectiveness of a Peer Referral Incentive Intervention to Promote Male Circumcision Uptake in Zambia.

BACKGROUND: Medical male circumcision is a promising HIV prevention tool in countries with generalized HIV epidemics, but demand creation interventions are needed to support scale-up. We piloted a peer referral intervention in which circumcision clients were offered incentives for referring their peers for circumcision. METHODS: The intervention was implemented between June 2014 and February 2015 in 6 randomly selected health facilities in Southern Province, Zambia. For the first 5 months, circumcision clients ≥18 years of age were given referral vouchers that allowed them to refer up to 5 peers for circumcision within a 3-month period. An incentive of US$2 was offered for each referral. The primary outcome was the number of circumcisions performed per month in each facility. To assess the effect of the intervention, a difference-in-difference analysis was performed using longitudinal data from the intervention facilities and 22 nonintervention facilities. A questionnaire was also implemented to understand men's perceptions of the intervention. RESULTS: During the 8-month intervention period, 1222 men over 18 years of age were circumcised in intervention facilities. In the first 5 months, 699 circumcision clients were enrolled and 385 clients brought a referral voucher given to them by an enrolled client. Difference-in-difference analyses did not show a significant increase in circumcisions performed in intervention facilities. However, circumcision clients reported that the referral incentive motivated them to encourage their friends to seek male circumcision. Peer referrals were also reported to be an important factor in men's decisions because 78% of clients who were referred reported that talking with a circumcised friend was important for their decision to get circumcised. CONCLUSIONS: The peer referral incentive intervention for male circumcision was feasible and acceptable. However, the intervention did not have a significant effect on demand for male circumcision. Barriers to circumcision and features of the intervention may have limited the effect of the intervention. Further efforts regarding encouraging male-to-male communication and evaluations with larger sample sizes are needed.

Predictors and outcomes of low birth weight in Lusaka, Zambia.

OBJECTIVE: To determine factors associated with low birth weight (LBW) in an urban Zambian cohort and investigate risk of adverse outcomes for LBW neonates. METHODS: The present retrospective cohort analysis used data recorded between February 2006 and December 2012 for singletons and first-born twins delivered in the public health system of Lusaka, Zambia. Routine clinical data and generalized estimating equations were used to examine covariates associated with LBW (<2500 g) and describe outcomes of LBW. RESULTS: In total, 200 557 neonates were included, 21 125 (10.5%) of whom were LBW. Placental abruption, delivery before 37 weeks, and twin pregnancy were associated with LBW in multivariable analysis (P<0.01 for all). Compared with neonates weighing more than 2500 g, LBW neonates were at higher risk of stillbirth (adjusted odds ratio [AOR] 8.6, 95% confidence interval [CI] 6.5-11.5), low Apgar score (AOR 5.7, 95% CI 4.6-7.2), admission to the neonatal intensive care unit (AOR 5.4, 95% CI 3.5-8.3), and very early neonatal death (AOR 6.2, 95% CI 3.7-10.3). CONCLUSION: LBW neonates are at increased risk of adverse outcomes, including stillbirth and neonatal death, independent of pregnancy duration at delivery and multiple pregnancy. These findings underscore the need for early, comprehensive, and high-quality prenatal care.

Impact of a community-based package of interventions on child development in Zambia: a cluster-randomised controlled trial.

BACKGROUND: Community-based programmes are a critical platform for improving child health and development. We tested the impact of a community-based early childhood intervention package in rural Zambia. METHODS: We conducted a non-blinded cluster randomised controlled trial in Southern Province, Zambia. 30 clusters of villages were matched based on population density and distance from the nearest health centre, and randomly assigned to intervention (15 clusters and 268 caregiver-child dyads) or control (15 clusters and 258 caregiver-child dyads). Caregivers were eligible if they had a child aged 6-12 months at baseline. In intervention clusters, health workers screened children for infections and malnutrition, and invited caregivers to attend fortnightly group meetings covering a nutrition and child development curriculum. 220 intervention and 215 control dyads were evaluated after 1 year. The primary outcomes were stunting and INTERGROWTH-21st neurodevelopmental assessment (NDA) scores. Weight-for-age and height-for-age z-scores based on WHO growth standards were also analysed. Secondary outcomes were child illness symptoms, dietary intake and caregiver-child interactions based on self-report. Impact was estimated using intention-to-treat analysis. RESULTS: The intervention package was associated with a 0.12 SD increase in weight-for-age (95% CI -0.14 to 0.38), a 0.15 SD increase in height-for-age (95% CI -0.18 to 0.48) and a reduction in stunting (OR 0.68; 95% CI 0.36 to 1.28), whereas there was no measurable impact on NDA score. Children receiving the intervention package had fewer symptoms, a more diverse diet and more caregiver interactions. CONCLUSIONS: In settings like Zambia, community-based early childhood programmes appear to be feasible and appreciated by caregivers, as evidenced by high rates of uptake. The intervention package improved parenting behaviours and had a small positive, though statistically insignificant, impact on child development. Given the short time frame of the project, larger developmental impact is likely if differential parenting behaviours persist. TRIAL REGISTRATION NUMBER: NCT02234726; Results.

Implementation and Operational Research: Reconstructing the PMTCT Cascade Using Cross-sectional Household Survey Data: The PEARL Study.

BACKGROUND: Given the ambitious targets to reduce pediatric AIDS worldwide, ongoing assessment of programs to prevent mother-to-child HIV transmission (PMTCT) is critical. The concept of a "PMTCT cascade" has been used widely to identify bottlenecks in program implementation; however, most efforts to reconstruct the cascade have relied on facility-based approaches that may limit external validity. METHODS: We analyzed data from the PEARL household survey, which measured PMTCT effectiveness in 26 communities across Zambia, South Africa, Cote d'Ivoire, and Cameroon. We recruited women who reported a delivery in the past 2 years. Among mothers confirmed to be HIV infected at the time of survey, we reconstructed the PMTCT cascade with self-reported participant information. We also analyzed data about the child's vital status; for those still alive, HIV testing was performed by DNA polymerase chain reaction testing. RESULTS: Of the 976 eligible women, only 355 (36%) completed every step of the PMTCT cascade. Among the 621 mother-child pairs who did not, 22 (4%) reported never seeking antenatal care, 103 (17%) were not tested for HIV during pregnancy, 395 (64%) reported testing but never received their HIV-positive result, 48 (8%) did not receive maternal antiretroviral prophylaxis, and 53 (9%) did not receive infant antiretroviral prophylaxis. The lowest prevalence of infant HIV infection or death was observed in those completing the cascade (10%, 95% confidence interval: 7% to 12%). CONCLUSIONS: Future efforts to measure population PMTCT impact should incorporate dimensions explored in the PEARL study-including HIV testing of HIV-exposed children in household surveys-to better understand program effectiveness.

Elevated AST-to-platelet ratio index is associated with increased all-cause mortality among HIV-infected adults in Zambia.

BACKGROUND & AIMS: We investigated the association between significant liver fibrosis, determined by AST-to-platelet ratio index (APRI), and all-cause mortality among HIV-infected patients prescribed antiretroviral therapy (ART) in Zambia. METHODS: Among HIV-infected adults who initiated ART, we categorized baseline APRI scores according to established thresholds for significant hepatic fibrosis (APRI ≥1.5) and cirrhosis (APRI ≥2.0). Using multivariable logistic regression we identified risk factors for elevated APRI including demographic characteristics, body mass index (BMI), HIV clinical and immunological status, and tuberculosis. In the subset tested for hepatitis B surface antigen (HBsAg), we investigated the association of hepatitis B virus co-infection with APRI score. Using Kaplan-Meier analysis and Cox proportional hazards regression we determined the association of elevated APRI with death during ART. RESULTS: Among 20 308 adults in the analysis cohort, 1027 (5.1%) had significant liver fibrosis at ART initiation including 616 (3.0%) with cirrhosis. Risk factors for significant fibrosis or cirrhosis included male sex, BMI <18, WHO clinical stage 3 or 4, CD4(+) count <200 cells/mm(3) , and tuberculosis. Among the 237 (1.2%) who were tested, HBsAg-positive patients had four times the odds (adjusted odds ratio, 4.15; 95% CI, 1.71-10.04) of significant fibrosis compared HBsAg-negatives. Both significant fibrosis (adjusted hazard ratio 1.41, 95% CI, 1.21-1.64) and cirrhosis (adjusted hazard ratio 1.57, 95% CI, 1.31-1.89) were associated with increased all-cause mortality. CONCLUSION: Liver fibrosis may be a risk factor for mortality during ART among HIV-infected individuals in Africa. APRI is an inexpensive and potentially useful test for liver fibrosis in resource-constrained settings.

Chronic hepatitis B virus coinfection is associated with renal impairment among Zambian HIV-infected adults.

Among 6789 HIV-infected Zambian adults screened for hepatitis B virus (HBV) coinfection, estimated glomerular filtration rate (eGFR) was 50-90 mL/minute/1.73 m(2) in 17.6% and <50 mL/minute/1.73 m(2) in 2.5%. Human immunodeficiency virus/HBV coinfection was associated with eGFR <50 mL/minute/1.73 m(2) (adjusted odds ratio, 1.96 [95% confidence interval, 1.34-2.86]), adjusted for age, sex, CD4(+) count, and World Health Organization disease stage.

Labor market returns to an early childhood stimulation intervention in Jamaica.

A substantial literature shows that U.S. early childhood interventions have important long-term economic benefits. However, there is little evidence on this question for developing countries. We report substantial effects on the earnings of participants in a randomized intervention conducted in 1986-1987 that gave psychosocial stimulation to growth-stunted Jamaican toddlers. The intervention consisted of weekly visits from community health workers over a 2-year period that taught parenting skills and encouraged mothers and children to interact in ways that develop cognitive and socioemotional skills. The authors reinterviewed 105 out of 129 study participants 20 years later and found that the intervention increased earnings by 25%, enough for them to catch up to the earnings of a nonstunted comparison group identified at baseline (65 out of 84 participants).

Culture sometimes matters: intra-cultural variation in pro-social behavior among Tsimane Amerindians.

Agent-centered models usually consider only individual-level variables in calculations of economic costs and benefits. There has been little consideration of social or cultural history on shaping payoffs in ways that impact decisions. To examine the role of local expectations on economic behavior, we explore whether village affiliation accounts for the variation in Dictator Game offers among the Tsimane of the Bolivian Amazon independently of other factors that could confound such an effect. Our analysis shows that significant differences in altruistic giving exist among villages, village patterns are recognized by residents, and offers likely reflect variation in social expectations rather than stable differences in norms of fairness.