What more can be done? Prioritizing the most promising antenatal interventions to improve birth weight.

BACKGROUND: Low birth weight (LBW) is associated with neonatal mortality and sequelae of lifelong health problems; prioritizing the most promising antenatal interventions may guide resource allocation and improve health outcomes. OBJECTIVE: We sought to identify the most promising interventions that are not yet included in the policy recommendations of the World Health Organization (WHO) but could complement antenatal care and reduce the prevalence of LBW and related adverse birth outcomes in low- and middle-income settings. METHODS: We utilized an adapted Child Health and Nutrition Research Initiative (CHNRI) prioritization method. RESULTS: In addition to procedures already recommended by WHO for the prevention of LBW, we identified six promising antenatal interventions that are not currently recommended by WHO with an indication for LBW prevention, namely: (1) provision of multiple micronutrients; (2) low-dose aspirin; (3) high-dose calcium; (4) prophylactic cervical cerclage; (5) psychosocial support for smoking cessation; and (6) other psychosocial support for targeted populations and settings. We also identified seven interventions for further implementation research and six interventions for efficacy research. CONCLUSION: These promising interventions, coupled with increasing coverage of currently recommended antenatal care, could accelerate progress toward the global target of a 30% reduction in the number of LBW infants born in 2025 compared to 2006-10.

Feeding practices and growth patterns of moderately low birthweight infants in resource-limited settings: results from a multisite, longitudinal observational study.

OBJECTIVES: To describe the feeding profile of low birthweight (LBW) infants in the first half of infancy; and to examine growth patterns and early risk factors of poor 6-month growth outcomes. DESIGN: Prospective observational cohort study. SETTING AND PARTICIPANTS: Stable, moderately LBW (1.50 to <2.50 kg) infants were enrolled at birth from 12 secondary/tertiary facilities in India, Malawi and Tanzania and visited nine times over 6 months. VARIABLES OF INTEREST: Key variables of interest included birth weight, LBW type (combination of preterm/term status and size-for-gestational age at birth), lactation practices and support, feeding profile, birthweight regain by 2 weeks of age and poor 6-month growth outcomes. RESULTS: Between 13 September 2019 and 27 January 2021, 1114 infants were enrolled, comprising 4 LBW types. 363 (37.3%) infants initiated early breast feeding and 425 (43.8%) were exclusively breastfed to 6 months. 231 (22.3%) did not regain birthweight by 2 weeks; at 6 months, 280 (32.6%) were stunted, 222 (25.8%) underweight and 88 (10.2%) wasted. Preterm-small-for-gestational age (SGA) infants had 1.89 (95% CI 1.37 to 2.62) and 2.32 (95% CI 1.48 to 3.62) times greater risks of being stunted and underweight at 6 months compared with preterm-appropriate-for-gestational age (AGA) infants. Term-SGA infants had 2.33 (95% CI 1.77 to 3.08), 2.89 (95% CI 1.97 to 4.24) and 1.99 (95% CI 1.13 to 3.51) times higher risks of being stunted, underweight and wasted compared with preterm-AGA infants. Those not regaining their birthweight by 2 weeks had 1.51 (95% CI 1.23 to 1.85) and 1.55 (95% CI 1.21 to 1.99) times greater risks of being stunted and underweight compared with infants regaining. CONCLUSION: LBW type, particularly SGA regardless of preterm or term status, and lack of birthweight regain by 2 weeks are important risk identification parameters. Early interventions are needed that include optimal feeding support, action-oriented growth monitoring and understanding of the needs and growth patterns of SGA infants to enable appropriate weight gain and proactive management of vulnerable infants. TRIAL REGISTRATION NUMBER: NCT04002908.

Safe recovery after cesarean in rural Africa: Technical consensus guidelines for post-discharge care.

Despite increasing cesarean rates in Africa, there remain extensive gaps in the standard provision of care after cesarean birth. We present recommendations for discharge instructions to be provided to women following cesarean delivery in Rwanda, particularly rural Rwanda, and with consideration of adaptable guidelines for sub-Saharan Africa, to support recovery during the postpartum period. These guidelines were developed by a Technical Advisory Group comprised of clinical, program, policy, and research experts with extensive knowledge of cesarean care in Africa. The final instructions delineate between normal and abnormal recovery symptoms and advise when to seek care. The instructions align with global postpartum care guidelines, with additional emphasis on care practices more common in the region and address barriers that women delivering via cesarean may encounter in Africa. The recommended timeline of postpartum visits and visit activities reflect the World Health Organization protocols and provide additional activities to support women who give birth via cesarean. These guidelines aim to standardize communication with women at the time of discharge after cesarean birth in Africa, with the goal of improved confidence and clinical outcomes among these individuals.

Effectiveness of community outreach HIV prevention programs in Vietnam: a mixed methods evaluation.

BACKGROUND: In 2014, Vietnam was the first Southeast Asian country to commit to achieving the World Health Organization's 90-90-90 global HIV targets (90% know their HIV status, 90% on sustained treatment, and 90% virally suppressed) by 2020. This pledge represented further confirmation of Vietnam's efforts to respond to the HIV epidemic, one feature of which has been close collaboration with the U.S. President's Emergency Plan for AIDS Relief (PEPFAR). Starting in 2004, PEPFAR supported community outreach programs targeting high-risk populations (people who inject drugs, men who have sex with men, and sex workers). To provide early evidence on program impact, in 2007-2008 we conducted a nationwide evaluation of PEPFAR-supported outreach programs in Vietnam. The evaluation focused on assessing program effect on HIV knowledge, high-risk behaviors, and HIV testing among high-risk populations-results relevant to Vietnam's push to meet global HIV goals. METHODS: We used a mixed-methods cross-sectional evaluation design. Data collection encompassed a quantitative survey of 2199 individuals, supplemented by 125 in-depth interviews. Participants were members of high-risk populations who reported recent contact with an outreach worker (intervention group) or no recent contact (comparison group). We assessed differences in HIV knowledge, risky behaviors, and HIV testing between groups, and between high-risk populations. RESULTS: Intervention participants knew significantly more about transmission, prevention, and treatment than comparison participants. We found low levels of injection drug-use-related risk behaviors and little evidence of program impact on such behaviors. In contrast, a significantly smaller proportion of intervention than comparison participants reported risky sexual behaviors generally and within each high-risk population. Intervention participants were also more likely to have undergone HIV testing (76.1% vs. 47.0%, p < 0.0001) and to have received pre-test (78.0% vs. 33.7%, p < 0.0001) and post-test counseling (80.9% vs. 60.5%, p < 0.0001). Interviews supported evidence of high impact of outreach among all high-risk populations. CONCLUSIONS: Outreach programs appear to have reduced risky sexual behaviors and increased use of HIV testing services among high-risk populations in Vietnam. These programs can play a key role in reducing gaps in the HIV care cascade, achieving the global 90-90-90 goals, and creating an AIDS-free generation.

In-home HIV testing and nevirapine dosing by traditional birth attendants in rural Zambia: a feasibility study.

INTRODUCTION: Access to lifesaving prevention of mother-to-child transmission (PMTCT) services is problematic in rural Zambia. The simplest intervention used in Zambia has been 2-dose nevirapine (NVP) administration in the peripartum period, a regimen of 1 NVP tablet to the mother at the onset of labor and 1 dose in the form of syrup to the newborn within 4 to 72 hours after birth. This 2-dose regimen has been shown to reduce MTCT by nearly 50%. We set out to demonstrate that in-home HIV testing and NVP dosing by traditional birth attendants (TBAs) is feasible and acceptable by women in rural Zambia. METHODS: This was a pilot program using TBAs to perform rapid saliva-based HIV testing and administer single-dose NVP in tablet form to the mother at the onset of labor and syrup to the infant after birth. RESULTS: A total of 280 pregnant women were consented and enrolled into the program, of whom 124 (44.3%) gave birth at home with the assistance of a trained TBA. Of those, 16 (12.9%) were known to be HIV positive, and 101 of the remaining 108 (93.5%) accepted a rapid HIV test. All these women tested HIV negative. In the subset of 16 mothers who were HIV positive, 13 (81.3%) took single-dose NVP administered by a TBA between 1 and 24 hours prior to birth and 100% of exposed newborns (16 of 16) received NVP syrup within 72 hours after birth, 80% of whom were dosed in the first 24 hours of life. DISCUSSION: With the substantial shortage of human resources in public health care throughout sub-Saharan Africa, it is extremely valuable to utilize lay health care workers to help extended services beyond the level of the facility. Given the high uptake of PMTCT services we believe that TBAs with proper training and support can successfully provide country-approved PMTCT.

4E10-resistant HIV-1 isolated from four subjects with rare membrane-proximal external region polymorphisms.

Human antibody 4E10 targets the highly conserved membrane-proximal external region (MPER) of the HIV-1 transmembrane glycoprotein, gp41, and has extraordinarily broad neutralizing activity. It is considered by many to be a prototype for vaccine development. In this study, we describe four subjects infected with viruses carrying rare MPER polymorphisms associated with resistance to 4E10 neutralization. In one case resistant virus carrying a W680G substitution was transmitted from mother to infant. We used site-directed mutagenesis to demonstrate that the W680G substitution is necessary for conferring the 4E10-resistant phenotype, but that it is not sufficient to transfer the phenotype to a 4E10-sensitive Env. Our third subject carried Envs with a W680R substitution causing variable resistance to 4E10, indicating that residues outside the MPER are required to confer the phenotype. A fourth subject possessed a F673L substitution previously associated with 4E10 resistance. For all three subjects with W680 polymorphisms, we observed additional residues in the MPER that co-varied with position 680 and preserved charged distributions across this region. Our data provide important caveats for vaccine development targeting the MPER. Naturally occurring Env variants described in our study also represent unique tools for probing the structure-function of HIV-1 envelope.

Detection of low levels of human immunodeficiency virus (HIV) may be critical for early diagnosis of pediatric HIV infection by use of dried blood spots.

We compared a DNA-based assay with a total nucleic acid-based assay for early detection of infant human immunodeficiency virus (HIV) infection. The codetection of DNA and RNA did not result in an overall higher sensitivity compared to that of DNA alone. Discordant results were associated with low levels of HIV DNA, indicating that the sample amount may be critical.

Effects of early, abrupt weaning on HIV-free survival of children in Zambia.

BACKGROUND: In low-resource settings, many programs recommend that women who are infected with the human immunodeficiency virus (HIV) stop breast-feeding early. We conducted a randomized trial to evaluate whether abrupt weaning at 4 months as compared with the standard practice has a net benefit for HIV-free survival of children. METHODS: We enrolled 958 HIV-infected women and their infants in Lusaka, Zambia. All the women planned to breast-feed exclusively to 4 months; 481 were randomly assigned to a counseling program that encouraged abrupt weaning at 4 months, and 477 to a program that encouraged continued breast-feeding for as long as the women chose. The primary outcome was either HIV infection or death of the child by 24 months. RESULTS: In the intervention group, 69.0% of the mothers stopped breast-feeding at 5 months or earlier; 68.8% of these women reported the completion of weaning in less than 2 days. In the control group, the median duration of breast-feeding was 16 months. In the overall cohort, there was no significant difference between the groups in the rate of HIV-free survival among the children; 68.4% and 64.0% survived to 24 months without HIV infection in the intervention and control groups, respectively (P=0.13). Among infants who were still being breast-fed and were not infected with HIV at 4 months, there was no significant difference between the groups in HIV-free survival at 24 months (83.9% and 80.7% in the intervention and control groups, respectively; P=0.27). Children who were infected with HIV by 4 months had a higher mortality by 24 months if they had been assigned to the intervention group than if they had been assigned to the control group (73.6% vs. 54.8%, P=0.007). CONCLUSIONS: Early, abrupt cessation of breast-feeding by HIV-infected women in a low-resource setting, such as Lusaka, Zambia, does not improve the rate of HIV-free survival among children born to HIV-infected mothers and is harmful to HIV-infected infants.(ClinicalTrials.gov number, NCT00310726.)

Reuse of single-dose nevirapine in subsequent pregnancies for the prevention of mother-to-child HIV transmission in Lusaka, Zambia: a cohort study.

BACKGROUND: Single-dose nevirapine (SDNVP) for the prevention of mother-to-child HIV transmission (PMTCT) results in the selection of resistance mutants among HIV-infected mothers. The effects of these mutations on the efficacy of SDNVP use in a subsequent pregnancy are not well understood. METHODS: We compared risks of perinatal HIV transmission between multiparous women who had previously received a dose of SDNVP (exposed) and those that had not (unexposed) and who were given SDNVP for the index pregnancy within a PMTCT clinical study. We also compared transmission risks among exposed and unexposed women who had two consecutive pregnancies within the trial. Logistic regression modeling was used to adjust for possible confounders. RESULTS: Transmission risks did not differ between 59 SDNVP-exposed and 782 unexposed women in unadjusted analysis or after adjustment for viral load and disease stage (adjusted odds ratio 0.6, 95% confidence interval [CI] 0.2 to 2.0). Among 43 women who had two consecutive pregnancies during the study, transmission risks were 7% (95% CI 1% to 19%) at both the first (unexposed) and second (exposed) delivery. The results were unchanged, if infant death was included as an outcome. CONCLUSION: These data suggest that the efficacy of SDNVP may not be diminished when reused in subsequent pregnancies.

Veterinary field test as screening tool for mastitis and HIV-1 viral load in breastmilk from HIV-infected Zambian women.

Clinical and subclinical mastitis increase the risk of mother-to-child transmission (MTCT) of HIV-1 through breastfeeding. We hypothesized that a field test for mastitis used for bovine milk, the California Mastitis Test, would detect high cell counts in milk of HIV-infected women. We also investigated whether total milk cell count would positively correlate with viral HIV-1 RNA in the milk of 128 HIV-positive Zambian women. Mean cell counts in each California Mastitis Test scoring category were significantly different (p < 0.01, n = 232). In a subset of 4-month postpartum milk samples tested for HIV-1 RNA, viral RNA levels did not significantly correlate with total cell count (r = 0.166, p = .244). The CMT may serve as a screening tool for mastitis in breastmilk, but total cell count does not correlate with HIV-1 RNA levels. Since both cell-free and cell-associated virus are associated with increased risk of MTCT, investigation of the relationship between total milk cell count and HIV-1 proviral DNA is warranted before a conclusive determination is made regarding use of the CMT as a clinical screening tool to detect cases at high risk for breastmilk transmission.

Issues in the design of a clinical trial with a behavioral intervention--the Zambia exclusive breast-feeding study.

PURPOSE: We present the rationale and design of the Zambian Exclusive Breast-feeding Study (ZEBS), a randomized trial evaluating the efficacy of short-duration exclusive breast-feeding (EBF) as a strategy to reduce postnatal human immunodeficiency virus (HIV) transmission while preserving the other health benefits of this important mode of infant feeding. METHODS: One thousand two hundred HIV-positive pregnant women were recruited in Lusaka, Zambia, and followed with their infants for 24 months. In addition to Nevirapine (NVP), all women received intensive and frequent clinic- and home-based counseling to support exclusive breast-feeding. When the infant was 1 week of age, half of the women were randomly assigned to a group encouraged to abruptly (<24 h) cease all breast-feeding at 4 months. The primary outcome of the experimental (randomized) comparison is HIV-free survival at 24 months. The design is also observational and will compare HIV transmission rates between those who do and do not adhere to the counseling intervention promoting exclusive breast-feeding. CONCLUSION: Our study aims to quantify the benefit-risk ratio of early cessation of exclusive breast-feeding to interrupt mother-to-child transmission of HIV with an intensive behavioral intervention and has both observational and experimental analytic approaches. Our study design assesses efficacy and also has a prominent applied component that if the intervention is effective, it will permit rapid and sustainable adoption within low-resource communities.

Human immunodeficiency virus-specific CD8(+) T cells in human breast milk.

Breast-feeding infants of human immunodeficiency virus (HIV)-infected women ingest large amounts of HIV, but most escape infection. While the factors affecting transmission risk are poorly understood, HIV-specific cytotoxic T-lymphocyte (CTL) responses play a critical role in controlling HIV levels in blood. We therefore investigated the ability of breast milk cells (BMC) from HIV-infected women from the United States and Zambia to respond to HIV-1 peptides in a gamma interferon enzyme-linked immunospot assay. All (n = 11) HIV-infected women had responses to pools of Gag peptide (range, 105 to 1,400 spot-forming cells/million; mean = 718), 8 of 11 reacted to Pol, 7 reacted to Nef, and 2 of 5 reacted to Env. Conversely, of four HIV-negative women, none responded to any of the tested HIV peptide pools. Depletion and tetramer staining studies demonstrated that CD8(+) T cells mediated these responses, and a chromium-release assay showed that these BMC were capable of lysing target cells in an HIV-specific manner. These data demonstrate the presence of HIV-specific major histocompatibility complex class I-restricted CD8(+) CTLs in breast milk. Their presence suggests a role in limiting transmission and provides a rationale for vaccine strategies to enhance these responses.