There are limited data describing the functional characteristics of HIV-1 specific antibodies in breast milk (BM) and their role in breastfeeding transmission. The ability of BM antibodies to bind HIV-1 envelope, neutralize heterologous and autologous viruses and direct antibody-dependent cell cytotoxicity (ADCC) were analyzed in BM and plasma obtained soon after delivery from 10 non-transmitting and 9 transmitting women with high systemic viral loads and plasma neutralizing antibodies (NAbs). Because subtype A is the dominant subtype in this cohort, a subtype A envelope variant that was sensitive to plasma NAbs was used to assess the different antibody activities. We found that NAbs against the subtype A heterologous virus and/or the woman’s autologous viruses were rare in IgG and IgA purified from breast milk supernatant (BMS) – only 4 of 19 women had any detectable NAb activity against either virus. Detected NAbs were of low potency (median IC50 value of 10 versus 647 for the corresponding plasma) and were not associated with infant infection (p=0.58). The low NAb activity in BMS versus plasma was reflected in binding antibody levels: HIV-1 envelope specific IgG titers were 2.2 log10 lower (compared to 0.59 log10 lower for IgA) in BMS versus plasma. In contrast, antibodies capable of ADCC were common and could be detected in the BMS from all 19 women. BMS envelope-specific IgG titers were associated with both detection of IgG NAbs (p=0.0001)and BMS ADCC activity (p=0.014). Importantly, BMS ADCC capacity was inversely associated with infant infection risk (p=0.039). Our findings indicate that BMS has low levels of envelope specific IgG and IgA with limited neutralizing activity. However, this small study of women with high plasma viral loads suggests that breastmilk ADCC activity is a correlate of transmission that may impact infant infection risk.

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HIV-Specific Antibodies Capable of ADCC Are Common in Breastmilk and Are Associated with Reduced Risk of Transmission in Women with High Viral Loads

Introduction:
Although prevention of mother-to-child HIV transmission (PMTCT) programs are widely implemented, many children do not benefit from them because of loss to follow-up (LTFU). We conducted a systematic review to determine the magnitude of infant/baby LTFU along the PMTCT cascade.

Methods:
Eligible publications reported infant LTFU outcomes from standard care PMTCT programs (not intervention studies) at any stage of the cascade. Literature searches were conducted in Medline, Embase, Web of Knowledge, CINAHL Plus, and Maternity and Infant Care. Extracted data included setting, methods of follow-up, PMTCT regimens, and proportion and timing of LTFU. For programs in sub-Saharan Africa, random-effects meta-analysis was done using Stata v10. Because of heterogeneity, predictive intervals (PrIs; approximate 95% confidence intervals of a future study based on extent of observed heterogeneity) were computed.

Results:
A total of 826 papers were identified; 25 publications were eligible. Studies were published from 2001 to 2012 and were mostly from sub-Saharan Africa (three were from India, one from UK and one from Ireland). There was extensive heterogeneity in findings. Eight studies reported on LTFU of pregnant HIV-positive women between antenatal care (ANC) registration and delivery, which ranged from 10.9 to 68.1%, pooled proportion 49.08% [95% confidence interval (CI) 39.6–60.9%], and PrI 22.0–100%. Fourteen studies reported LTFU of infants within 3 months of delivery, range 4.8–75%, pooled proportion 33.9% (27.6–41.5), and PrI 15.4–74.2. Children were also lost after HIV testing; this was reported in five studies, pooled estimate 45.5% (35.9–57.6), PrI 18.7–100%. Programs that actively tracked defaulters had better retention outcomes.

Conclusion:
There is unacceptable infant LTFU from PMTCT programs. Countries should incorporate defaulter-tracking as standard to improve retention.

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The magnitude of loss to follow-up of HIV-exposed infants along the prevention of mother-to-child HIV transmission continuum of care: a systematic review and meta-analysis

The concept of immunological memory stipulates that past exposures shape present immune function. These exposures include not only specific antigens impacting adaptive immune memory, but also conserved pathogen or danger associated molecular patterns that mold innate immune responses for prolonged periods of time. It should thus not come as a surprise that there is a vast range of external or environmental factors that impact immunity. The importance of environmental factors modulating immunity is most readily recognized in early life, a period of rapidly changing environments. We here summarize available data on the role of environment shaping immune development and from it derive an overarching hypothesis relating the underlying molecular mechanisms and evolutionary principles involved.

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The Role of Environmental Factors in Modulating Immune Responses in Early Life

BACKGROUND: Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)-recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure. METHODS AND FINDINGS: Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models. 382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0-4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages ( 0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12-38) months. From mothers' ART, 62/9/111 infants had no/20%-89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75-212) days. Overall, 14 infants died at median (IQR) age 9 (3-23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens. CONCLUSIONS: Overall 1-year 5% infant mortality was similar to the 2%-4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children. TRIAL REGISTRATION: www.controlled-trials.com ISRCTN13968779

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Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial.

OBJECTIVE: To assess the 9-month HIV-free survival of children with two strategies to prevent HIV mother-to-child transmission. DESIGN: Nonrandomized interventional cohort study. SETTING: Four public health centres in Rwanda. PARTICIPANTS: Between May 2005 and January 2007 all consenting HIV-infected pregnant women were included. INTERVENTION: Women could choose the mode of feeding for their infant: breastfeeding with maternal HAART for 6 months or formula feeding. All received HAART from 28 weeks of gestation. Nine-month cumulative probabilities of HIV transmission and HIV-free survival were determined using the Kaplan-Meier method and compared using the log-rank test. Determinants were analysed using a Cox model analysis. RESULTS: Of the 532 first-liveborn infants 227 (43%) were breastfeeding and 305 (57%) were formula feeding. Overall seven (1.3%) children were HIV-infected of whom six were infected in utero. Only one child in the breastfeeding group became infected between months 3 and 7 corresponding to a 9-month cumulative risk of postnatal infection of 0.5% [95% confidence interval (CI) 0.1-3.4%; P = 0.24] with breastfeeding. Nine-month cumulative mortality was 3.3% (95% CI 1.6-6.9%) in the breastfeeding arm group and 5.7% (95% CI 3.6-9.2%) for the formula feeding group (P = 0.20). HIV-free survival by 9 months was 95% (95% CI 91-97%) in the breastfeeding group and 94% (95% CI 91-96%) for the formula feeding group (P = 0.66) with no significant difference in the adjusted analysis (adjusted hazard ratio for breastfeeding: 1.2 (95% CI 0.5-2.9%). CONCLUSION: : Maternal HAART while breastfeeding could be a promising alternative strategy in resource-limited countries.

https://www.ph.ucla.edu/epi/faculty/detels/Epi293/Peltier_AIDS_2009.pdf

Breastfeeding with maternal antiretroviral therapy or formula feeding to prevent HIV postnatal mother-to-child transmission in Rwanda.

Background: Data comparing survival of formula-fed to breast-fed infants in programmatic settings are limited. We compared mortality and HIV-free of breast and formula-fed infants born to HIV-positive mothers in a program in rural, Rakai District Uganda. Methodology/Principal Findings: One hundred eighty two infants born to HIV-positive mothers were followed at one, six and twelve months postpartum. Mothers were given infant-feeding counseling and allowed to make informed choices as to whether to formula-feed or breast-feed. Eligible mothers and infants received antiretroviral therapy (ART) if indicated. Mothers and their newborns received prophylaxis for prevention of mother-to-child HIV transmission (pMTCT) if they were not receiving ART. Infant HIV infection was detected by PCR (Roche Amplicor 1.5) during the follow-up visits. Kaplan Meier time-to-event methods were used to compare mortality and HIV-free survival. The adjusted hazard ratio (Adjusted HR) of infant HIV-free survival was estimated by Cox regression. Seventy-five infants (41%) were formula-fed while 107 (59%) were breast-fed. Exclusive breast-feeding was practiced by only 25% of breast-feeding women at one month postpartum. The cumulative 12-month probability of infant mortality was 18% (95% CI=11%–29%) among the formula-fed compared to 3% (95% CI=1%–9%) among the breast-fed infants (unadjusted hazard ratio (HR) =6.1(95% CI=1.7–21.4, P-value,0.01). There were no statistically significant differentials in HIV-free survival by feeding choice (86% in the formula-fed compared to 96% in breast-fed group (Adjusted RH=2.8[95%CI=0.67–11.7, P-value=0.16] Conclusions/Significance: Formula-feeding was associated with a higher risk of infant mortality than breastfeeding in this rural population. Our findings suggest that formula-feeding should be discouraged in similar African settings.

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Survival of infants born to HIV-positive mothers, by feeding modality, in Rakai, Uganda.

Introduction Tetanus infection associated with men who had male circumcision has been reported in East Africa, suggesting a need for tetanus toxoid-containing vaccines (TTCV). Objective To determine the prevalence of tetanus toxoid antibodies following vaccination among men seeking circumcision. Methods We enrolled 620 consenting men who completed a questionnaire and received TTCV at enrollment (day 0) prior to circumcision on day 28. Blood samples were obtained at day 0 from all enrollees and on days 14, 28 and 42 from a random sample of 237 participants. Tetanus toxoid (TT) IgG antibody levels were assayed using EUROIMMUN. Analyses included prevalence of TT antibodies at enrollment and used a mixed effects model to determine the immunological response. Results Mean age was 21.4 years, 65.2% had knowledge of tetanus, 56.6% knew how tetanus was contracted, 22.8% reported ever receipt of TTCV, and 16.8% had current/recently healed wounds. Insufficient tetanus immunity was 57.1% at enrollment, 7.2% at day 14, 3.8% at day 28, and 0% at day 42. Antibody concentration was 0.44IU/ml (CI 0.35-0.53) on day 0, 3.86IU/ml (CI 3.60-4.11) on day 14, 4.05IU/ml (CI 3.81-4.29) on day 28, and 4.48IU/ml (CI 4.28-4.68) on day 42. TT antibodies increased by 0.24IU/ml (CI 0.23, 0.26) between days 0 and 14 and by 0.023IU/ml (CI 0.015, 0.031) between days 14 and 42 days. Immunological response was poorer in HIV-infected clients and men aged 35+ years. Conclusion Insufficient immunity was common prior to TTCV, and a protective immunological response was achieved by day 14. Circumcision may safely be provided 14 days after vaccination in HIV-uninfected men aged less than 35 years.

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Prevalence of protective tetanus antibodies and immunological response following tetanus toxoid vaccination among men seeking medical circumcision services in Uganda

Darix Ssebagala

Papers

Survival of infants born to HIV-positive mothers, by feeding modality, in Rakai, Uganda.

Prevalence of protective tetanus antibodies and immunological response following tetanus toxoid vaccination among men seeking medical circumcision services in Uganda