Primary HIV-1 infection in African children infected through breastfeeding

OBJECTIVES: To describe acute retroviral syndrome and associated primary viraemia in African children infected with HIV-1 through breastfeeding. DESIGN: Matched case-control study performed retrospectively within the ANRS 049 DITRAME project conducted in 1995-1998 in Abidjan, C?te d'Ivoire. METHODS: Cases were children infected by HIV-1 postnatally through breastfeeding. All were HIV-1 negative by DNA PCR at least 45 days of age, but positive on a subsequent sample. This period was considered as surrounding the estimated date of postnatal contamination. Signs/symptoms occurring within this period were recorded in cases and compared with those occurring during the same time period in uninfected breastfed children (controls). For cases, plasma specimens were tested for HIV-1 plasma RNA using the branched DNA assay. RESULTS: Of 22 infants infected postnatally (median age at first positive sample, 185 days; range, 87-373 days), 21 (95.5%) exhibited at least one clinical sign, compared with only 27 of the 44 (61.4%) uninfected children (P = 0.003). Three independent factors were associated with primary HIV-1 infection: mononucleosis-like syndrome [odds ratio (OR), 8.3; 95% confidence interval (CI), 1.4-47.8], dermatitis (OR, 6.0; CI, 1.1-31.9), and generalized lymphadenopathy (OR, 26.5; CI, 2.0-348.4). Among cases, initial median plasma HIV-1 RNA viral load was 5.92 log10 copies/ml; this declined to 4.96 log10 12 months after the first positive viral load. CONCLUSIONS: These results may be useful for the recognition of early paediatric cases of postnatal transmission in Africa and could enable targeting of those who should benefit from HIV RNA or DNA testing for primary HIV-1 infection and their subsequent care.     

Randomized trial testing the effect of vitamin A supplementation on pregnancy outcomes and early mother-to-child HIV-1 transmission in Durban, South Africa. South African Vitamin A Study Group.

OBJECTIVE: Poor vitamin A status has been associated with a higher risk for mother-to-child transmission of HIV-1 and there is contradictory evidence on the impact of vitamin A on perinatal outcome. We therefore assessed the effect of vitamin A supplementation to mothers on birth outcome and mother-to-child transmission of HIV-1. DESIGN AND METHODS: In Durban, South Africa 728 pregnant HIV infected women received either vitamin A (368) or placebo (360) in a randomized, double-blind trial. The vitamin A treatment consisted of a daily dose of 5000 IU retinyl palmitate and 30 mg beta-carotene during the third trimester of pregnancy and 200000 IU retinyl palmitate at delivery. HIV infection results were available on 632 children who were included in the Kaplan-Meier transmission analysis. Results are reported on mother-to-child transmission rates up to 3 months of age. RESULTS: There was no difference in the risk of HIV infection by 3 months of age between the vitamin A [20.3%; 95% confidence interval (CI), 15.7-24.9] and placebo groups (22.3%; 95% CI, 17.5-27.1), nor were there differences in foetal or infant mortality rates between the two groups. Women receiving vitamin A supplement were, however, less likely to have a preterm delivery (11.4% in the vitamin A and 17.4% in the placebo group; P = 0.03) and among the 80 preterm deliveries, those assigned to the vitamin A group were less likely to be infected (17.9%; 95% CI, 3.5-32.2) than those assigned to the placebo group (33.8%; 95% CI, 19.8-47.8). CONCLUSION: Vitamin A supplementation, a low-cost intervention, does not appear to be effective in reducing overall mother-to-child transmission of HIV; however, its potential for reducing the incidence of preterm births, and the risk of mother-to-child transmission of HIV in these infants needs further investigation.     

HIV-1 in placentas of untreated HIV-1-infected women in relation to viral transmission, infectious HIV-1 and RNA load in plasma

The presence of HIV in the placenta was analysed in relation to virological and immunological factors and vertical transmission of HIV in 39 pregnancies between 1989 and 1993 among 37 HIV-1-infected women without zidovudine prophylaxis. HIV-1 was detected in 12 of 37 (31%) placentas by immunohistochemistry and in 3 of 18 by PCR. Altogether 14/39 (36%) placentas bore evidence of HIV-1 infection, although there was no relation with the outcome of HIV infection in the child. Neither was there a relation between placental infection and either CD4 cell counts or HIV-1 RNA levels. However, HIV-1 was isolated from plasma in 20 of 39 (50%) pregnancies, which was inversely related to the presence of HIV in the placenta. When HIV-1 was identified in the placenta, HIV-1 was isolated from plasma in 3/14 (21%) pregnancies, vs 17/25 (68%) when it was not (p = 0.01), with a relative risk of having a placenta positive for HIV of 3.9 in pregnancies with a negative plasma HIV isolation. This inverse relation may point to differences in tropism between HIV-1 in placenta and plasma. The results show that the placental barrier prevents HIV transmission, irrespective of whether HIV enters the placenta or not.     

Early exclusive breastfeeding reduces the risk of postnatal HIV-1 transmission and increases HIV-free survival

OBJECTIVES: The promotion of exclusive breastfeeding (EBF) to reduce the postnatal transmission (PNT) of HIV is based on limited data. In the context of a trial of postpartum vitamin A supplementation, we provided education and counseling about infant feeding and HIV, prospectively collected information on infant feeding practices, and measured associated infant infections and deaths. DESIGN AND METHODS: A total of 14 110 mother-newborn pairs were enrolled, randomly assigned to vitamin A treatment group after delivery, and followed for 2 years. At baseline, 6 weeks and 3 months, mothers were asked whether they were still breastfeeding, and whether any of 22 liquids or foods had been given to the infant. Breastfed infants were classified as exclusive, predominant, or mixed breastfed. RESULTS: A total of 4495 mothers tested HIV positive at baseline; 2060 of their babies were alive, polymerase chain reaction negative at 6 weeks, and provided complete feeding information. All infants initiated breastfeeding. Overall PNT (defined by a positive HIV test after the 6-week negative test) was 12.1%, 68.2% of which occurred after 6 months. Compared with EBF, early mixed breastfeeding was associated with a 4.03 (95% CI 0.98, 16.61), 3.79 (95% CI 1.40-10.29), and 2.60 (95% CI 1.21-5.55) greater risk of PNT at 6, 12, and 18 months, respectively. Predominant breastfeeding was associated with a 2.63 (95% CI 0.59-11.67), 2.69 (95% CI 0.95-7.63) and 1.61 (95% CI 0.72-3.64) trend towards greater PNT risk at 6, 12, and 18 months, compared with EBF. CONCLUSION: EBF may substantially reduce breastfeeding-associated HIV transmission.     

Cloning and characterization of functional subtype A HIV-1 envelope variants transmitted through breastfeeding

Previous studies of HIV-1 variants transmitted from mother-to-infant have focused primarily on computational analyses of partial envelope gene sequences, rather than analyses of functional envelope variants. There are very few examples of well-characterized functional envelope clones from mother-infant pairs, especially from envelope variants representing the most prevalent subtypes worldwide. To address this, we amplified the envelope variants present in 4 mother-infant transmission pairs, all of whom were infected with subtype A and three of whom presumably transmitted HIV-1 during the breastfeeding period. Functional envelope clones were constructed, either encoding full-length envelope sequences from the mother and baby or by making chimeric envelope clones in a common backbone sequence. The infant envelope sequences were genetically homogeneous compared to the maternal viruses, and pseudoviruses bearing these envelopes all used CCR5 as a coreceptor. The infant viruses were generally resistant to neutralization by maternal antibodies present near the time of transmission. There were no notable differences in sensitivity of the mother and infant envelope variants to neutralization by heterologous plasma or monoclonal antibodies 2G12 and b12, or to inhibition by sCD4, PSC-RANTES or TAK779. This collection of viral envelopes, which can be used for making pseudotyped viruses, may be useful for examining the efficacy of interventions to block mother-infant transmission, including sera from vaccine candidates, purified antibodies under consideration for passive immunization and viral entry inhibitors.     

A phase III clinical trial of antibiotics to reduce chorioamnionitis-related perinatal HIV-1 transmission

OBJECTIVE: A multisite study was conducted in Africa to assess the efficacy of antibiotics to reduce mother-to-child transmission (MTCT) of HIV-1. DESIGN: A randomized, double-blinded, placebo-controlled, phase III clinical trial. METHODS: HIV-1-infected women were randomly assigned at 20-24 weeks' gestation to receive either antibiotics (metronidazole plus erythromycin antenatally and metronidazole plus ampicillin intrapartum) or placebo. Maternal study procedures were performed at 20-24, 26-30, and 36 weeks antenatally, and at labor/delivery. Infants were seen at birth, 4-6 weeks, and 3, 6, 9 and 12 months. The primary efficacy endpoints were overall infant HIV-1 infection and HIV-1-free survival at 4-6 weeks. All women and infants received single-dose nevirapine prophylaxis in this study. RESULTS: A total of 1510 live-born infants were included in the primary analysis. The proportions of HIV-1-infected infants at birth were similar (antibiotics 7.1%; placebo 8.3%; P = 0.41). Likewise, there were no statistically significant differences at 4-6 weeks in the overall risk of MTCT of HIV-1 (antibiotics 16.2%; placebo 15.8%; P = 0.89) or HIV-1-free survival (79.4% in each study arm). Post-randomization, the proportion of women with bacterial vaginosis at the second antenatal visit was significantly lower in the antibiotics arm compared with the placebo arm (23.8 versus 39.7%; P < 0.001), but the frequency of histological chorioamnionitis was not different (antibiotics 36.9%; placebo 39.7%; P = 0.30). Adverse events in mothers and their infants did not differ by randomization arm. CONCLUSION: This simple antepartum and peripartum antibiotic regimen did not reduce the risk of MTCT of HIV-1.     

Phase I/II trial of HIV-1 hyperimmune globulin for the prevention of HIV-1 vertical transmission in Uganda

OBJECTIVES: To assess the safety, tolerance, pharmacokinetics, and virologic and immunologic changes associated with the use of Ugandan HIV hyperimmune globulin (HIVIGLOB) in HIV infected pregnant Ugandan women and their infants. DESIGN: A prospective, phase I/II, three-arm dose escalation trial of HIVIGLOB. METHODS: HIVIGLOB was prepared from discarded HIV infected units of blood collected from the National Blood Bank in Kampala. From June 1996 to April 1997, 31 HIV positive pregnant women were enrolled with HIVIGLOB infusions given at 37 weeks gestation and within 16 h of birth for infants. The first 10 mother-infant pairs were infused at a dose of 50 mg/kg, followed by 11 pairs at 200 mg/kg, and 10 pairs at 400 mg/kg. Study participants were followed for 30 months. RESULTS: Thirty-one women and 29 infants were infused with HIVIGLOB. The infusions were safe and well tolerated by the women and their infants at all doses. There were no significant changes in virologic or immunologic parameters after HIVIGLOB infusion. Pharmacokinetic properties of this product were similar to other immune globulin products with a median half-life of 28 days in women and 30 days in infants. CONCLUSION: An HIV immune globulin product derived from HIV infected Ugandan donors is safe, well tolerated, and has pharmacokinetic properties consistent with other immunoglobulin products. Data suggest that a 400 mg/kg dose of HIVIGLOB would be the most appropriate dose for a subsequent efficacy trial of HIVIGLOB for the prevention of mother to child HIV transmission.     

HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding.

OBJECTIVES: To estimate the risk of HIV-1 transmission through breast-milk in children born to infected mothers, and to determine the relationship between duration of breast-feeding and risk. DESIGN AND METHODS: The study population included 168 breast-fed and 793 bottle-fed children born to seropositive mothers. All subjects were enrolled and followed-up in the Italian Register for HIV Infection in Children; HIV sero-status was defined in all children. Multivariate analysis was performed using a logistic regression model. Independent variables included biological factors (duration of breast-feeding, gestational age, clinical condition of mother at delivery, mode of delivery, birth-weight and sex). Year of birth and age when HIV infection was diagnosed were also considered in the analysis attempting to control for possible selection biases. RESULTS: Breast-feeding increased the risk of HIV-1 transmission. The estimated adjusted odds ratio for 1 day of breast- versus bottle-feeding was 1.19 (95% confidence interval, 1.10-1.28). The infection odds ratio of breast- versus bottle-feeding increased with the natural logarithm of the duration of practice. CONCLUSIONS: These results are the first to provide an appraisal of the additional risk of HIV-1 transmission associated with a seropositive mother breast-feeding her child. Biological significance of this route of transmission was supported by demonstration of a relationship between duration of breast-feeding and risk of HIV-1 transmission.     

Various viral compartments in HIV-1-infected mothers contribute to in utero transmission of HIV-1

Perinatal HIV transmission occurs in utero or intrapartum. The mechanisms and timing of transmission are not clearly understood. To compare the genetic sequences of the V3 envelope region of infant's plasma HIV to that of the mother's plasma, peripheral blood mononuclear cells (PBMC) and vaginal secretions, and correlate with timing of transmission. All 3 infants had a positive HIV PCR in the first days of life, thus classified as in utero infections. In the first mother-infant pair, two different variants were present in the infant, one correlating with maternal PBMC virus and highly homologous to virus from vaginal secretions and the other identical to sequences in maternal plasma. In the second pair, the infant plasma virus was similar to that of maternal PBMC. In the third pair, the cord blood and infant plasma virus were highly similar to maternal vaginal virus. The presence of more than one HIV variant from the maternal blood and from the vaginal compartment in the cord blood of infants presumably infected in utero could point to more than one episode of transmission or, alternatively, to transmission of PBMC virus.     

Exposure to HIV-1 during delivery and mother-to-child transmission

BACKGROUND: The correlation between the presence of HIV-1 in maternal cervicovaginal secretions and in the infant's oro-pharyngal secretions at birth, and mother-to-child HIV transmission (MTCT) were examined to obtain a better understanding of its mechanism. METHODS: Women without medical and obstetrical complications, living within a reasonable distance of the government hospital in Mombasa, Kenya, were recruited after informed consent. Maternal and infant characteristics were collected. Polymerase chain reaction was used to detect HIV-1 in cervico-vaginal and oro-pharyngal secretions. Infants were tested for HIV-1 by polymerase chain reaction within 48 h and at 6 weeks after delivery. RESULTS: Between April 1998 and April 1999, 228 woman-infant pairs were included in the study. HIV-1 DNA in cervico-vaginal secretions was independently associated with HIV-1 maternal viral load and with infant birth-weight, whereas HIV-1 RNA was associated with maternal viral load and maternal age. HIV-1 DNA in the oropharyngal secretions was also independently associated with maternal viral load. MTCT rate at the age of 6 weeks was 23.6%. Intrapartum and early postpartum HIV transmission was independently associated with maternal viral load [adjusted odds ratio (OR), 1.6; 95% confidence interval (CI),1.0-2.7], detection of HIV-1 RNA in cervico-vaginal secretions (adjusted OR, 3.2; 95% CI, 1.5-7.3) and of HIV-1 DNA in oro-pharyngeal secretions (adjusted OR, 3.2; 95% CI, 1.1-9.0). DISCUSSION: As far as is known, this is the first study showing that infant exposure to HIV-1 in the birth canal and the presence of HIV-infected cells in the infant's oropharyngeal cavity are independently associated with intrapartum and early postpartum MTCT. It supports the hypothesis that MTCT could occur through the oral route.     

The risk of transmission of HIV-1 through non-percutaneous, non-sexual modes--a review

To date, three well-documented modes of transmission of HIV-1 (sexual, percutaneous and perinatal) have been described. Although the theoretical possibility exists for HIV-1 transmission through other routes, including non-percutaneous, non-sexual modes often referred to as 'casual' contact (and several anecdotal reports suggest this possibility), there is no credible epidemiological evidence to support this. Fourteen combined surveys, with over 750 individuals with potential exposure through non-percutaneous, non-sexual modes of contact, have failed to find a single case of HIV-1 infection (upper bound of 95% confidence interval = 0.40%), indicating that the risk of transmission by non-percutaneous, non-sexual modes is remote. Given the emotionally charged concerns about transmission of an infection which may end fatally in a high proportion of affected individuals, critical review of the low probability of transmission through non-percutaneous, non-sexual modes is important so that preventive efforts can be focused appropriately.     

High rates of forward transmission events after acute/early HIV-1 infection

BACKGROUND: A population-based phylogenetic approach was used to characterize human immunodeficiency virus (HIV)-transmission dynamics in Quebec. METHODS: HIV-1 pol sequences included primary HIV infections (PHIs; <6 months after seroconversion) from the Quebec PHI cohort (1998-2005; n=215) and the provincial genotyping program (2001-2005; n=481). Phylogenetic analysis determined sequence interrelationships among unique PHIs (n=593) and infections from untreated (n=135) and treated (n=660) chronically infected (CI) potential transmitter populations (2001-2005). Clinical features, risk factors, and drug resistance for clustered and nonclustered transmission events were ascertained. RESULTS: Viruses from 49.4% (293/593) of PHIs cosegregated into 75 transmission chains with 2-17 transmissions/cluster. Half of the clusters included 2.7+/-0.8 (mean+/-SD) transmissions, whereas the remainder had 8.8+/-3.5 transmissions. Maximum periods for onward transmission in clusters were 15.2+/-9.5 months. Coclustering of untreated and treated CIs with PHIs were infrequent (6.2% and 4.8%, respectively). The ages, viremia, and risk factors were similar for clustered and nonclustered transmission events. Low prevalence of drug resistance in PHI supported amplified transmissions at early stages. CONCLUSIONS: Early infection accounts for approximately half of onward transmissions in this urban North American study. Therapy at early stages of disease may prevent onward HIV transmission.     

Vertical transmission of HIV-1 in Poland

The aim of our study was to evaluate changes in vertical transmission of HIV infection in Poland after introducing zidovudine prophylactic strategies. Data from the Department of Children's Infectious Diseases (a paediatric HIV referral centre) at the Medical University, Warsaw was studied. Since 1989 vertical transmission of HIV-1 has been studied in 100 children born to 91 HIV-positive mothers (2 sets of twins). Zidovudine therapy, mode and timing of delivery and their relationship to perinatal HIV-1 infection were analysed. From 1989 to 1994 the transmission rate was 31.5%. Since 1995, when recommendations based on ACTG 076 were issued, a decline in a transmission rate to 19.6% was reported. 62% (32 out of 52) mother-infant pairs received zidovudine therapy. None of those children have become HIV infected. Zidovudine chemoprophylaxis regimen reduces the risk for mother to child transmission. It should be recommended for all HIV-infected pregnant women or women in labour and their infants.     

Interventions to prevent vertical transmission of HIV-1: effect on viral detection rate in early infant samples

OBJECTIVE: To determine whether mode of delivery or the use of maternal or neonatal antiretroviral prophylaxis influence the age when HIV-1 can first be detected in infected infants, particularly the probability of detection at birth. METHODS: In a collaboration between four multicentre studies, data on 422 HIV-1 infected infants who were assessed by HIV-1 DNA PCR or cell culture before 14 days of age were analysed. Weibull mixture models were used to estimate the cumulative proportion of infants with detectable levels of HIV-1 according to use of maternal/neonatal antiretroviral therapy (mainly zidovudine monotherapy) and mode of delivery. RESULTS: HIV-1 was detected in 162 infants (38%) when they were first tested, at a median age of 2 days. At birth, it was estimated that 36% [95% confidence interval (CI), 31-41%] of infants have levels of virus that can be detected by DNA PCR or cell culture. This percentage was not associated with either mode of delivery (35% for vaginal delivery versus 40% for cesarean section delivery; P = 0.4) or the use of maternal or neonatal antiretroviral prophylaxis. Among infants with undetectable levels of HIV-1 at birth, the median time to viral detectability was estimated to be 14.8 days (95% CI, 12.9-16.8 days). This time was increased by 15% (95% CI, -11 to 48%; P = 0.3) among infants who were exposed to antiretroviral therapy postnatally compared with infants who were not exposed. No effect was observed for mode of delivery. CONCLUSIONS: The outcome of an early virological test for HIV-1 is thought to be related directly to the timing of transmission and cesarean section delivery primarily reduces the risk of intrapartum transmission. The absence of an association between mode of delivery and viral detectability at birth was therefore unexpected. There was no evidence that foetal or neonatal exposure to prophylactic zidovudine delays substantially the diagnosis of infection, although this cannot be inferred for combination antiretroviral therapy.     

Rates of HIV-1 transmission within marriage in rural Uganda in relation to the HIV sero-status of the partners.

OBJECTIVE: To assess the efficacy of transmission of HIV-1 within married couples in rural Uganda according to the sero-status of the partners. DESIGN: Estimation of HIV incidence rates for 2200 adults in a population cohort followed for 7 years comparing male-to-female with female-to-male transmission and sero-discordant with concordant sero-negative couples. METHODS: Each year, adults (over 12 years of age) resident in the study area were linked to their spouses if also censused as resident. The HIV sero-status was determined annually. RESULTS: At baseline 7% of married adults were in sero-discordant marriages and in half of these the man was HIV-positive. Among those with HIV-positive spouses, the age-adjusted HIV incidence in women was twice that of men (rate ratio (RR) = 2.2 95% confidence interval (CI) 0.9-5.4) whereas, among those with HIV-negative spouses, the incidence in women was less than half that of men (RR = 0.4, 95% CI 0.2-0.8). The age-adjusted incidence among women with HIV-positive spouses was 105.8 times (95% CI 33.6-332.7) that of women with HIV-negative spouses, the equivalent ratio for men being 11.6 (95% CI 5.8-23.4). CONCLUSION: Men are twice as likely as women to bring HIV infection into a marriage, presumably through extra-marital sexual behaviour. Within sero-discordant marriages women become infected twice as fast as men, probably because of increased biological susceptibility. Married adults, particularly women, with HIV-positive spouses are at very high risk of HIV infection. Married couples in this population should be encouraged to attend for HIV counselling together so that sero-discordant couples can be identified and advised accordingly.     

A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child HIV-1 transmission in infants of untreated mothers

BACKGROUND: Single-dose nevirapine (NVP) prophylaxis to mother and infant is widely used in resource-constrained settings for preventing mother-to-child transmission (MTCT) of HIV-1. Where women do not access antenatal care or HIV testing, postexposure prophylaxis to the infant may be an important preventative strategy. METHODS: This multicentre, randomized, open-label clinical trial (October 2000 to September 2002) in South Africa compared single-dose NVP with 6 weeks of zidovudine (ZDV), commenced within 24 h of delivery among 1051 infants whose mothers had no prior antiretroviral therapy. HIV-1 infection rates were ascertained at birth, and at 6 and 12 weeks of age. Kaplan-Meier survival methods were used to estimate HIV-1 infection rates in an intention-to-treat analysis. RESULTS: Overall, 6 week and 12 week MTCT probability was 12.8% [95% confidence interval (CI),10.5-15.0] and 16.3% (95% CI,13.4-19.2), respectively. At 12 weeks, among infants who were not infected at birth, 24 (7.9%) infections occurred in the NVP arm and 41 (13.1%) in the ZDV arm (log rank P = 0.06). Using multivariate analysis, factors associated with infection following birth were ZDV use [odds ratio (OR), 1.8; 95% CI,1.1-3.2; P = 0.032), maternal CD4 cell count < 500 x 10(6) cells/l (OR, 2.5; 95% CI,1.3-5.0; P = 0.007), maternal viral load > 50 000 copies/ml (OR, 3.6; 95% CI,2.0-6.2; P < 0.0001) and breastfeeding (OR, 2.2; 95% CI,1.3-3.8; P = 0.006). CONCLUSION: A single-dose of NVP given to infants offers protection against HIV-1 infection and should be a strategy used in infants of mothers with untreated HIV infection.