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Background: Natural variations in IL-15 concentration have not been investigated for an association with an immune-protection against HIV. Given IL-15's central role in anti-HIV immunity, we hypothesized that higher concentrations of IL-15 in breast milk may protect against postnatal mother-to-child HIV transmission. Methods: In a case-control study nested within a clinical trial in Zambia, we compared IL-15 concentrations in breast milk of 22 HIV-infected women who transmitted HIV to their infants through breastfeeding with those of 72 who did not, as well as 18 HIV-uninfected women. Breast milk HIV RNA quantity, sodium, CXCL12, CCL5, and IL-8 concentrations were measured as well as maternal plasma HIV RNA concentrations and CD4 cell count. We used logistic regression modeling to adjust for potential confounders. Results: Higher concentrations of IL-15 in breast milk (adjusted odds ratio [AOR]: 0.01 per log10 pg/ml increase, 95% confidence interval [CI]

Sub-Saharan Africa contains over 60% of the world's HIV infections and Zambia is among the most severely affected countries in the region. As antiretroviral programs have been rapidly expanding, the long-term success of these programs depends on a good understanding of the behavioral determinants of acceptance and adherence to antiretroviral therapy (ART). The study used qualitative methods to gain local insight into potentially important factors affecting HIV-infected women's decision to accept or continue with ART. Some of the barriers identified by this study are consistent with factors cited in the existing adherence literature from both developed and developing nations such as side effects, hunger and stigma; other factors have not been previously reported. One major theme was unfamiliarity with the implications of having a chronic, potentially deadly disease. Other emerging themes from this study include the complicated effect of ART on interpersonal relationship, particularly between husbands and wives, the presence of depression and hopelessness, and lack of accurate information. The results suggest that the reasons for non-uptake of treatment include issues related to local cultural frameworks (e.g., illness ideology), mental and behavioral health (e.g., depression and/or interpersonal challenges), stigma, and motivating factors (e.g., values of church or marriage) of different cultures that affect the ability and willingness to take life-saving medicine for a long period of time. Qualitative studies are critical to better understand why ART eligible individuals are choosing not to initiate or continue treatment to achieve needed adherence levels.

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.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.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).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.)

The objective was to better understand the dynamics of breast milk HIV shedding and its relation to postnatal HIV transmission we investigated the temporal and lateral relations of breast milk viral shedding and sodium concentrations in HIV-positive women. This was a longitudinal cohort study in Lusaka Zambia. We examined patterns of HIV shedding in breast milk over the first 4 months of breast-feeding and their correlations with postnatal HIV transmission among 138 breast-feeding mothers. Sodium concentration in breast milk was also examined in the same samples and in breast milk from 23 HIV-negative controls. Higher breast milk viral load at 1 week 1 month and 4 months and consistent viral shedding in breast milk were significantly associated with increased risk of HIV transmission. Elevated breast milk sodium concentration (greater than or equal to 13 mmol/L) at 4 months was associated with HIV transmission low maternal CD4 cell count and high maternal plasma viral load. Elevated sodium concentration at 1 week postpartum was common and was not associated with any of these parameters. Consistent viral shedding and high breast milk viral load are strong predictors of mother-to-child HIV transmission. Although sodium concentrations later in breast-feeding correlate with breast milk viral load increased breast milk sodium is normal in early lactation and does not predict HIV transmission. (authors)

The objective was to investigate if breast milk interleukin [IL]-7 concentrations are associated with postnatal HIV transmission. A case-control study nested within a cohort of women recruited in Lusaka Zambia. IL-7 breast milk concentrations were measured in samples from 24 HIV-infected breast-feeding women who transmitted HIV to their child after the neonatal period and from 47 women who did not transmit. Samples were frequency-matched by the time of sample collection (1 week and 1 month postpartum). Logistic regression was used to adjust for possible confounders. For comparison samples from 18 HIV-uninfected women from the same community were included in the analysis and plasma IL-7 was determined. Breast milk IL-7 concentrations were significantly higher than plasma IL-7 concentrations in all 3 groups. In contrast to levels among transmitters and HIV-uninfected women breast milk IL-7 concentrations exhibited a bimodal distribution among nontransmitters. Breast milk IL-7 concentrations undetectable or less than 30 pg/mL were significantly associated with less HIV transmission (odds ratio = 0.13 95% confidence interval: 0.03 to 0.64). The association remained strong after adjustment for breast milk viral load and sodium maternal CD4 cell counts parity and time of sample collection Breast milk IL-7 may be necessary for effective HIV transmission. (authors)

Adequate adherence is required for prevention of mother-to-child transmission of HIV (pMTCT) programs to be effective. We investigated predictors and extent of nonadherence to singledose nevirapine. Data on nevirapine intake and possible predictors were collected among 760 HIV-positive women with liveborn babies enrolled in a study in Lusaka Zambia. Most (94%) women took nevirapine before delivery and most (91%) newborns received it soon after delivery. Maternal nonadherence was associated with home births (odds ratio [OR]: 3.2; 95% confidence interval [CI]: 1.3 to 7.4) no high school education (OR: 2.4; 95% CI: 1.1 to 5.3) and low newborn birth weight (OR: 4.6; 95% CI: 1.3 to 20.1). Disclosure of HIV status and couples counseling was only associated with adherence among home births. Failure to administer nevirapine to the newborn was associated with birth at the tertiary hospital (OR: 7.2; 95% CI: 3.7 to 13.8) lower 5-minute Apgar scores (OR: 0.5; 95% CI: 0.4 to 0.7) and neonatal death (OR: 5.8; 95% CI: 2.0 to 16.3). Excellent adherence to single-dose nevirapine for pMTCT can be achieved. Nonadherence seems to be affected by place of birth and by poor health status of the newborn. Procedures to ensure that viable yet ill neonates receive nevirapine should be part of clinical protocols and training within pMTCT programs. (authors)

A previously reported association between prolonged lactation and maternal mortality has generated concern that breast-feeding may be detrimental for HIV-positive women. As part of a trial conducted in Lusaka Zambia 653 HIV-positive women were randomly assigned either to a counseling program that encouraged abrupt cessation of breast-feeding at 4 months (group A) or to a program that encouraged prolonged breast-feeding for the duration of the woman’s own informed choice (group B). We examined whether mortality up to 2 years post-partum increased with breastfeeding for a longer duration. There was no difference in mortality 12 months after delivery between 326 HIV-positive women randomly assigned to short breast-feeding [group A: 4.93%; 95% confidence interval (CI) 2.42–7.46] versus 327 women assigned to long breast-feeding (group B: 4.89%; 95% CI 2.38–7.40). Analysis based on actual practice rather than random assignment also demonstrated no increased mortality due to breast-feeding. Although HIV-related mortality was high in this cohort of untreated HIV positive women prolonged lactation was not associated with increased mortality. (authors)

Infants born to HIV-infected mothers are at risk of acquiring HIV infection. The risk is serious, but it can be substantially reduced with antiretroviral drugs [1–3]. Yet, even in the absence of interventions, the majority of infants born to HIV-infected mothers do not acquire infection. However, these infants risk losing their mother (and father) to HIV infection during childhood, with the social dislocation of orphanhood posing obvious dangers to their well-being [4–6]. But do HIV-uninfected children have other risks associated with having an HIV-infected mother? There is surprisingly little known about morbidity and mortality among HIV-exposed, HIV-uninfected infants. Demographic studies estimate that mortality among children born to HIV-infected mothers is higher than that among children born to mothers without HIV infection, but interpretation is limited because the proportion of HIV-infected children is not known [6–9]. Factors affecting morbidity and mortality in general (e.g., lack of breastfeeding, unhygienic living conditions, and malaria exposure) are also likely to be important among HIV–exposed, HIV-uninfected infants. In addition, HIV exposure directly or indirectly in utero, intrapartum, and during breastfeeding may confer risks to infants, even in the absence of vertical transmission. Perinatal transmission and disease progression among infected infants are higher among those born to mothers with more advanced HIV disease [10–12]. The effect, if any, on uninfected offspring is unclear. Here, we investigate whether advanced HIV disease and/or immune dysfunction among HIV-infected mothers increases mortality and morbidity among their uninfected infants. Any effect will have substantial public health consequences, because the absolute number of reproductive-aged women with HIV infection continues to increase.

Alpha-defensins have been observed to have anti-HIV activity but have not been investigated in relation to mother-to-child HIV transmission. We measured the concentration of alpha-defensins in breast milk of HIV-positive mothers and tested whether the concentrations were associated with HIV transmission. A nested case-control study of 32 HIV-positive women who transmitted HIV to their infants and 52 randomly selected HIV-positive women who did not transmit HIV to their infants was conducted in Lusaka, Zambia. alpha-Defensins were detected in most (79%) of the milk samples tested. Concentrations of alpha-defensins increased as breast milk HIV RNA quantity increased, and breast milk HIV RNA quantity was, in turn, a strong and significant predictor of HIV transmission. After adjustment for milk HIV RNA quantity, however, alpha-defensin concentration was significantly associated with a decreased risk of intrapartum and postnatal HIV transmission (odds ratio = 0.3, 95% confidence interval: 0.09-0.93). Our data suggest that there may be a role for alpha-defensins in prevention of HIV transmission to breastfed infants.

Couple counseling has been promoted as a strategy to improve uptake of interventions to prevent mother-to-child HIV transmission (pMTCT) and to minimize adverse social outcomes associated with disclosure of HIV status.We tested whether women counseled antenatally as part of a couple were more likely to accept HIV testing and nevirapine in a pMTCT program, and whether they would be less likely to experience later adverse social events than women counseled alone.A pMTCT program that included active community education and outreach to encourage couple counseling and testing was implemented in two antenatal clinics in Lusaka, Zambia. A subset of HIV-positive women was asked to report their experience of adverse social events 6 months after delivery. Couple-counseled women were compared with individual-counseled women stratified by whether or not they had disclosed their HIV status to their partners.Nine percent (868) of 9409 women counseled antenatally were counseled with their husband. Couple-counseled women were more likely to accept HIV testing (96%) than women counseled alone (79%); however uptake of nevirapine was not improved. Six months after delivery, 28% of 324 HIV-positive women reported at least one adverse social event (including physical violence, verbal abuse, divorce or separation). There were no significant differences in reported adverse social events between couple- and individual-counseled women.Couple counseling did not increase the risk of adverse social events associated with HIV disclosure. Support services and interventions to improve social situations for people living with HIV need to be further evaluated.

The distribution and stability of human immunodeficiency virus type 1 (HIV-1) in breast milk (BM) components remain largely unknown. Inhibitory effects, if any, of BM on HIV RNA and DNA PCR amplification are poorly understood. We have addressed these issues by using virus-spiked BM samples from HIV-negative women. BM samples from HIV-negative women were spiked with HIV-1 virions or cells containing a single integrated copy of HIV DNA (8E5/LAV). After incubation under different experimental conditions, viral RNA was detected by the Roche Amplicor UltraSensitive assay in whole-milk, skim milk, and lipid fractions. We found excellent correlation between HIV-1 input copy and recovery in whole milk ( r = 0.965, P < 0.0001), skim milk ( r = 0.972, P < 0.0001), and the lipid fraction ( r = 0.905, P < 0.001). PCR inhibition was observed in less than 10% of the spiked samples. Similar levels of inhibition were noted in BM samples collected from HIV-infected women. HIV proviral DNA was detected in BM samples using real-time PCR (linear correlation between the threshold cycle versus log DNA copy number, >0.982). The effects of incubation duration and temperature and repeated freeze-thaw cycles on HIV RNA recovery were analyzed. HIV RNA levels were remarkably stable in whole milk after three freeze-thaw cycles and for up to 30 h at room temperature. Our findings improve the understanding of the dynamics of HIV detection in BM and the conditions for BM sample collection, storage, and processing.

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.

Objective The objective of the study was to examine the relationship between breastfeeding patterns, markers of maternal human immunodeficiency virus (HIV) disease, and woman's breast pathology. Study Design Secondary data analysis from a randomized breastfeeding trial including 947 HIV-infected women (n = 5982 visits) from breastfeeding initiation until 6 months postpartum; 1 month after breastfeeding cessation; or loss to follow-up or death. Generalized estimating equations assessed the effects of breastfeeding pattern and maternal HIV status on breast pathology. Results One hundred ninety women (20.1%) had a breast problem; 86 (9.1%) had mastitis; and 31 (3.3%) had abscess. After confounder adjustment, nonexclusively breastfeeding women had an increased risk of breast problems (odds ratio, 1.98; 95% confidence interval, 1.33–2.95) and mastitis (odds ratio, 2.87, 95% confidence interval, 1.69–4.88) compared with exclusive breastfeeders. Women with a CD4 count less than 200 cells/μL tended to have an increased risk of abscess. Conclusion Nonexclusive breastfeeding significantly increased the risk of breast pathology. Exclusive breastfeeding is not only optimal for infant health but it also benefits mothers by reducing breast problems.

Background Sexual violence against children is a major global health and human rights problem. In order to address this issue there needs to be a better understanding of the issue and the consequences. One major challenge in accomplishing this goal has been a lack of validated child mental health assessments in low-resource countries where the prevalence of sexual violence is high. This paper presents results from a validation study of a trauma-focused mental health assessment tool - the UCLA Post-traumatic Stress Disorder - Reaction Index (PTSD-RI) in Zambia. Methods The PTSD-RI was adapted through the addition of locally relevant items and validated using local responses to three cross-cultural criterion validity questions. Reliability of the symptoms scale was assessed using Cronbach alpha analyses. Discriminant validity was assessed comparing mean scale scores of cases and non-cases. Concurrent validity was assessed comparing mean scale scores to a traumatic experience index. Sensitivity and specificity analyses were run using receiver operating curves. Results Analysis of data from 352 youth attending a clinic specializing in sexual abuse showed that this adapted PTSD-RI demonstrated good reliability, with Cronbach alpha scores greater than .90 on all the evaluated scales. The symptom scales were able to statistically significantly discriminate between locally identified cases and non-cases, and higher symptom scale scores were associated with increased numbers of trauma exposures which is an indication of concurrent validity. Sensitivity and specificity analyses resulted in an adequate area under the curve, indicating that this tool was appropriate for case definition. Conclusions This study has shown that validating mental health assessment tools in a low-resource country is feasible, and that by taking the time to adapt a measure to the local context, a useful and valid Zambian version of the PTSD-RI was developed to detect traumatic stress among youth. This valid tool can now be used to appropriately measure treatment effectiveness, and more effectively and efficiently triage youth to appropriate services.

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.

Background Teaming is an accepted approach in health care settings but rarely practiced at the community level in developing countries. Save the Children trained and deployed teams of volunteer community health workers (CHWs) and trained traditional birth attendants (TBAs) to provide essential newborn and curative care for children aged 0–59 months in rural Zambia. This paper assessed whether CHWs and trained TBAs can work as teams to deliver interventions and ensure a continuum of care for all children under-five, including newborns. Methods We trained CHW-TBA teams in teaming concepts and assessed their level of teaming prospectively every six months for two years. The overall score was a function of both teamwork and taskwork. We also assessed personal, community and service factors likely to influence the level of teaming. Results We created forty-seven teams of predominantly younger, male CHWs and older, female trained TBAs. After two years of deployment, twenty-one teams scored “high”, twelve scored “low,” and fourteen were inactive. Teamwork was high for mutual trust, team cohesion, comprehension of team goals and objectives, and communication, but not for decision making/planning. Taskwork was high for joint behavior change communication and outreach services with local health workers, but not for intra-team referral. Teams with members residing within one hour’s walking distance were more likely to score high. Conclusion It is feasible for a CHW and a trained TBA to work as a team. This may be an approach to provide a continuum of care for children under-five including newborns.