Maternal plasma viral load, zidovudine and mother-to-child transmission of HIV-1 in Africa: DITRAME ANRS 049a trial

OBJECTIVE: To study the relationship between maternal plasma RNA levels and mother-to-child transmission (MTCT) of HIV-1 in African breastfed children. DESIGN: Nested case-control study within a randomized trial assessing the efficacy of a short maternal zidovudine (ZDV) regimen to reduce MTCT. METHODS: Eligible women received either 300 mg of ZDV twice a day until labour, 600 mg at the beginning of labour and 300 mg twice a day for 7 days post-partum or a placebo. The diagnosis of paediatric HIV-1 infection was based on PCR tests at days 1--8, 45, 90 and 180 then on serology performed at 3 monthl intervals. Plasma HIV-1 RNA was measured at inclusion and on day 8 after delivery for all women who did transmit HIV to their children (cases) using a Chiron branched DNA assay (sensitivity 50 copies/ml) and compared with women who did not transmit (two per case) matched for phase trial, treatment allocation and site. RESULTS: At inclusion, mean log10 viral load was 4.6 among 55 transmitting mothers and 3.7 among 117 non transmitters (P = 0.0001). Among transmitters, the mean difference in log10 viral load between day 8 post-partum and inclusion was -0.13 in the ZDV group (n = 23) versus 0.27 in the placebo group (n = 32; P = 0.01); among non transmitters it was -0.35 for the ZDV group (n = 47) versus 0.27 in the placebo group (n = 70; P < 10(-4)). In multivariate logistic regression analysis, odds ratios for MTCT were 8.7 (95% confidence interval, 3.7-20.6) for 1 log(10) increase of maternal RNA at inclusion and 4.2 (95% confidence interval, 1.7--10.3) for 1 log(10) increase difference from inclusion to day 8 post-partum. CONCLUSION: High maternal viral load at inclusion strongly predicts MTCT of HIV in Africa. A short ZDV treatment regimen decreases significantly maternal viral load from its pretreatment level.     

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.     

Maternal viral load and vertical transmission of HIV-1 in mid-trimester gestation.

BACKGROUND: It is now accepted that the majority of HIV-1 vertical transmissions occur in late gestation and at the time of delivery. However, there is wide variation in the prevalence rate of mid-trimester vertical transmission. We assessed the maternal HIV-1 RNA viral load and in utero transmission during mid-trimester gestation. METHODS: Patients were enrolled when they decided to have their pregnancies terminated between 17 and 24 weeks of gestation. Prostaglandin-induced abortion with PGE1 analogue vaginal administration was carried out in all patients. Maternal plasma HIV-1 RNA viral load and plasma HIV-1 RNA (qualitative) from abortus heart blood were assessed. RESULTS: Amongst 41 HIV-1 seropositive pregnant women not receiving antiretroviral therapy plasma HIV-1 RNA was detected in the abortus heart blood from two women (4.9%; 95% confidence interval (CI), 0.6-16.5). Transmission occurred in one out of nine (11.1%; 95% CI, 0.3-48.2) with maternal viral load > or =100000 copies/ml versus one out of 32 (3.1%; 95% CI, 0.1-16.2) of those with <100000 copies/ml (P = 0.39). CONCLUSIONS: The frequency of HIV-1 vertical transmission during mid-trimester was approximately 5% as detected by plasma HIV-1 RNA (qualitative) method in the fetuses aborted from the prostaglandin termination of pregnancy. During mid-trimester gestation there was no correlation between high maternal viral load and vertical transmission.     

Correlates of mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission: association with maternal plasma HIV-1 RNA load, genital HIV-1 DNA shedding, and breast infections

To determine the effects of plasma, genital, and breast milk human immunodeficiency virus type 1 (HIV-1) and breast infections on perinatal HIV-1 transmission, a nested case-control study was conducted within a randomized clinical trial of breast-feeding and formula feeding among HIV-1-seropositive mothers in Nairobi, Kenya. In analyses comparing 92 infected infants with 187 infants who were uninfected at 2 years, maternal viral RNA levels >43,000 copies/mL (cohort median) were associated with a 4-fold increase in risk of transmission (95% confidence interval [CI], 2.2-7.2). Maternal cervical HIV-1 DNA (odds ratio [OR], 2.4; 95% CI, 1.3-4.4), vaginal HIV-1 DNA (OR, 2.3; 95% CI, 1.1-4.7), and cervical or vaginal ulcers (OR, 2.7; 95% CI, 1.2-5.8) were significantly associated with infant infection, independent of plasma virus load. Breast-feeding (OR, 1.7; 95% CI, 1.0-2.9) and mastitis (relative risk [RR], 3.9; 95% CI, 1.2-12.7) were associated with increased transmission overall, and mastitis (RR, 21.8; 95% CI, 2.3-211.0) and breast abscess (RR, 51.6; 95% CI, 4.7-571.0) were associated with late transmission (occurring >2 months postpartum). Use of methods that decrease infant exposure to HIV-1 in maternal genital secretions or breast milk may enhance currently recommended perinatal HIV-1 interventions.     

Domestic violence and prevention of mother-to-child transmission of HIV-1

OBJECTIVES: To determine the prevalence of life-time domestic violence by the current partner before HIV-1 testing, its impact on the uptake of prevention of mother-to-child transmission (PMTCT) interventions and frequency after testing. DESIGN: A prospective cohort. METHODS: Antenatally, women and their partners were interviewed regarding physical, financial, and psychological abuse by the male partner before HIV-1 testing and 2 weeks after receiving results. RESULTS: Before testing, 804 of 2836 women (28%) reported previous domestic violence, which tended to be associated with increased odds of HIV-1 infection [univariate odds ratio (OR) 1.7, 95% confidence interval (CI) 1.3-2.2; P < 0.0001, adjusted OR 1.2, 95% CI 0.9-1.6; P = 0.1], decreased odds of coming with partners for counseling (adjusted OR 0.7, 95% CI 0.5-1.0; P = 0.04), and decreased odds of partner notification (adjusted OR 0.7, 95% CI 0.5-1.1; P = 0.09). Previous domestic violence was not associated with a reduced uptake of HIV-1 counseling, HIV-1 testing, or nevirapine. After receiving results, 15 out of 1638 women (0.9%) reported domestic violence. After notifying partners of results, the odds of HIV-1-seropositive women reporting domestic violence were 4.8 times those of HIV-1-seronegative women (95% CI 1.4-16; P = 0.01). Compared with women, men reported similar or more male-perpetrated domestic violence, suggesting a cultural acceptability of violence. CONCLUSION: Domestic violence before testing may limit partner involvement in PMTCT. Although infrequent, immediate post-test domestic violence is more common among HIV-1-infected than uninfected women. Domestic violence prevention programmes need to be integrated into PMTCT, particularly for HIV-1-seropositive women.     

AIDS following mother-to-child transmission of HIV-2

Mother-to-child infection with HIV-2 is thought to be rare, and there have been few previous reports of transmission by this route. Reports of morbidity associated with HIV-2 infection in children are also rare. We describe eight children born to mothers who were infected with HIV-2; five developed AIDS, and three were still seropositive at 17-49 months of age. The only apparent route of HIV-2 transmission was from mother to child, except for one child who had been transfused. Three of the children with AIDS died, all having decreased CD4+ lymphocytes and mitogen responses. Further studies are needed to determine the prevalence and natural history of mother-to-child transmission of HIV-2.     

Advances and research directions in the prevention of mother-to-child HIV-1 transmission

Although substantial progress has been made in preventing mother-to-child HIV-1 transmission in the past decade, critical research questions remain. Two perinatal epidemics now exist. In more-developed countries, integration of prenatal HIV-1 counselling and testing programmes into an existing antenatal infrastructure, availability of effective antiretroviral prophylaxis, and access to infant formula have resulted in new perinatal infections becoming rare. However, identification of missed prevention opportunities, the causes of prophylaxis failure, and the potential effects of in-utero antiretroviral exposure have become a priority. In less-developed countries, antenatal care is limited, testing programmes are almost non-existent, effective interventions remain unimplemented, and prevention of postnatal transmission through breastmilk while maintaining adequate infant nutrition is a major dilemma. The challenge for the next decade is to simultaneously address questions relevant to both epidemics while bridging the gap in prevention of perinatal transmission between more-developed and less-developed countries.     

Maternal-fetal DNA admixture is associated with intrapartum mother-to-child transmission of HIV-1 in Blantyre, Malawi

BACKGROUND: The mechanism of mother-to-child transmission (MTCT) of HIV-1 is not well described. METHODS: Of 328 HIV-infected mother-infant pairs, we identified 91 that had discordant angiotensin I-converting enzyme and glutathione S-transferase M1 alleles. Maternal alleles in cord blood were quantified with real-time polymerase chain reaction, as indicators of microtransfusions. RESULTS: HIV-1 infected infants had more maternal DNA in cord blood than their uninfected counterparts. Increased maternal DNA in cord blood was associated with preterm delivery, low birth weight, and maternal immunosuppression. CONCLUSION: Intrapartum MTCT was associated with placental microtransfusions. The associations among placental microtransfusion, in-utero MTCT, maternal immunosuppression, and poor birth outcome should be further investigated.     

Assessment of mother-to-child HIV-1 and HIV-2 transmission: an AIDS reference laboratory collaborative study

Objective

A prospective study was carried out to assess HIV‐1 and HIV‐2 mother‐to‐child transmission (MTCT) rates in Portugal between 1999 and 2005 by analysing the proportion of diagnosed infected children born to HIV‐positive mothers.

Materials and methods

Serial blood samples were collected from 1315 children at risk of HIV‐1 infection, 131 children at risk of HIV‐2 infection and six children at risk of both HIV‐1 and HIV‐2 infections attending 25 Health Institutions. HIV proviral DNA was detected by nested polymerase chain reaction (PCR) and statistical analysis was performed using spss .

Results

DNA PCR using HIV‐1 and HIV‐2 long terminal repeat (LTR) primers amplified 92.5% and 75% of maternal HIV infections, respectively. Overall, MTCT occurred in 3.4% [95% confidence interval (CI) 2.5–4.6%] of HIV‐1 and 1.5% (95% CI 0.2–5.4%) of HIV‐2 mother–child pairs. A significant decrease in HIV‐1 MTCT was observed with time, from 7.0% (95% CI 2.6–14.6%) in 1999 to 0.5% (95% CI 0.0–2.5%) in 2005. HIV MTCT was associated with an absence of antiretroviral therapy in infected pregnant women (P<0.0001). Of the 48 infected children (46 with HIV‐1 and two with HIV‐2), the schedule of blood sample collection was followed for only 26 children. In 14 (53.8%) of those 26 children the infections were diagnosed in the first sample collected before they were 48 h old, suggesting in utero transmission. Despite the national recommendations for antenatal HIV testing, a high overall proportion (22.2% for HIV‐1 and 44.3% for HIV‐2) of mothers did not access any MTCT prevention measures, mostly because of late diagnosis in pregnancy. A small but significant proportion of HIV‐2 infection was found in mothers with no identifiable link with West Africa.

Conclusion

HIV‐2 transmission rates are low (1.5% in this study), and this may have led to a lower uptake of interventions, but in the absence of interventions transmission does occur. HIV‐1 transmission was also associated with a lack of intervention, mostly as a result of late presentation. Use of primers restricted to a single sequence led to false‐negative maternal results in a significant proportion of cases. In part this may have been attributable to very low HIV DNA loads as well as primer template mismatches. HIV infection was not documented in children born to mothers with negative HIV DNA PCR results.     

Cost-effectiveness of cesarean section delivery to prevent mother-to-child transmission of HIV-1

OBJECTIVE: To evaluate costs and outcomes of cesarean section performed before onset of labor and before rupture of membranes (elective cesarean section) compared to vaginal delivery among HIV-infected women. DESIGN: Cost-effectiveness and cost-benefit analysis. Participants and setting: Pregnant HIV-infected women in the US who refrain from breastfeeding. INTERVENTION: Elective cesarean section versus vaginal delivery by antiretroviral therapy regimen. Main outcome measures: Pediatric HIV cases avoided, years of life saved, and direct medical costs for maternal interventions and pediatric HIV treatment. RESULTS: Elective cesarean section (versus vaginal delivery) was cost-effective among women receiving zidovudine prophylaxis (US$1131 per case avoided, US$17 per year of life saved) and combination antiretroviral therapy (US$112693 per case avoided, US$1697 per year of life saved), and cost saving among women receiving no antiretroviral therapy during pregnancy (benefit-cost ratio of 2.23). Although elective cesarean section remained cost-effective, results were sensitive to variations in vertical transmission rates and to pediatric HIV treatment costs. Population-based analyses indicated that elective cesarean section could prevent 239 pediatric HIV cases annually with a savings of over US$4 million. CONCLUSIONS: Elective cesarean section is a cost-effective intervention to prevent vertical transmission of HIV among women receiving various antiretroviral therapy regimens, who refrain from breastfeeding.     

Revisiting the role of neutralizing antibodies in mother-to-child transmission of HIV-1

We analyzed the association between mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1) and maternal neutralizing antibodies to heterologous primary isolates of various HIV-1 clades, to test the hypothesis that protective antibodies are those with broad neutralizing activity. Our study sample included 90 Thai women for whom the timing of HIV-1 transmission (in utero or intrapartum) was known. The statistical analysis included a conditional logistic-regression model to control for both plasma viral load and duration of zidovudine prophylaxis. The higher the titer of neutralizing antibodies to a heterologous strain of the same clade, the lower the rate of MTCT of HIV-1. More specifically, high levels of neutralizing antibodies to the MBA (CRF01_AE) strain were associated with low intrapartum transmission of HIV-1. This suggested that such heterologous neutralizing antibodies may be involved in the natural prevention of late perinatal HIV transmission. These data are consistent with the hypothesis that the use of some antibodies might help to prevent perinatal HIV transmission, through passive immunoprophylaxis. Moreover, the study of humoral factors associated with MTCT of HIV-1 may identify correlates of protection that should help in the design of efficient HIV/acquired immunodeficiency syndrome vaccines.     

CC and CXC chemokines in breastmilk are associated with mother-to-child HIV-1 transmission

INTRODUCTION: CC and CXC chemokines may play a role in mother-to-child HIV-1 transmission by blocking HIV-1 binding to chemokine receptors and impeding viral entry into cells. METHODS: To define correlates of breastmilk chemokines and associations with infant HIV-1 acquisition, chemokines in breastmilk and infant HIV-1 infection risk were assessed in an observational, longitudinal cohort study. We measured MIP-1alpha, MIP-1beta, RANTES, and SDF-1 in month 1 breastmilk specimens from HIV-1-infected women in Nairobi and HIV-1 viral load was calculated in maternal plasma and breastmilk at delivery and 1 month postpartum. Infant infection status was determined at birth and months 1, 3, 6, 9, and 12. RESULTS: Among 281 breastfeeding women, 60 (21%) of their infants acquired HIV-1 during follow-up, 39 (65%) of whom became infected intrapartum or after birth. MIP-1alpha, MIP-1beta, RANTES, and SDF-1 were all positively correlated with breastmilk HIV-1 RNA (P<0.0005). Women with clinical mastitis had 50% higher MIP-1alpha and MIP-1beta levels (P<0.001 and P=0.006, respectively) and women with subclinical mastitis (breastmilk Na(+)/K(+)>1) had approximately 70% higher MIP-1alpha, MIP-1beta and RANTES (P<0.002 for all) compared to women without mastitis. Independent of breastmilk HIV-1, increased MIP-1beta and SDF-1 were associated with reduced risk of infant HIV-1 (RR=0.4; 95% CI 0.2-0.9; P=0.03 and RR=0.5; 95% CI=0.3-0.9; P=0.02, respectively) and increased RANTES was associated with higher transmission risk (RR=2.3; 95% CI 1.1- 5.3; P=0.04). CONCLUSIONS: These observations suggest a complex interplay between virus levels, breastmilk chemokines, and mother-to-child HIV-1 transmission and may provide insight into developing novel strategies to reduce infection across mucosal surfaces.     

Preventing mother-to-child transmission of HIV-1 in Africa in the year 2000

OBJECTIVES: Various approaches to preventing mother-to-child transmission (MTCT) of HIV have recently been, or are being, evaluated in developing countries, especially in Africa. New findings from these trials are now becoming available, the implications of which, for population-based intervention programmes, need urgent consideration. METHOD: A critical review of 18 randomized trials and other relevant studies from developing and industrialized countries. RESULTS: Most African results relate to trials of antiretroviral agents (ARV). They demonstrate efficacy in reducing transmission in the first 6 months of life with short regimens of zidovudine (ZDV), with or without lamivudine (3TC), and nevirapine (NVP) alone. Preliminary results suggest the long-term efficacy of zidovudine. Antiseptic and nutritional interventions have been shown to reduce maternal and infant mortality and morbidity but not MTCT of HIV. HIV confidential voluntary counselling and testing for pregnant women, a short regimen of peripartum ARV with alternatives to breastfeeding such as early weaning or breast milk substitutes from birth currently represent the best option to reduce MTCTof HIV in Africa. However, the prevention of postnatal transmission requires further research, particularly in view of the consequences of different feeding options and the possibility of post-perinatal exposure prophylaxis of newborns with ARV. Issues relating to the implementation of currently validated strategies are discussed.     

Prevalence,incidence, and mother-to-child transmission of HIV-1 in rural South Africa

Simple, robust approaches are needed to monitor prevalence, incidence, and mother-to-child transmission of HIV-1 in rural Africa. We have designed a method that uses antibody and viral RNA testing of dried blood spots obtained from mother-infant pairs attending routine immunisation clinics. In our study, prevalence and incidence of HIV-1 was highest in young women in their late teens and early twenties. In children born to infected mothers, prevalence increased from 14% in infants younger than 6 weeks of age to 24% at 3-6 months. The blood-spot approach is an effective method for surveillance of HIV-1 in women and children, and for early identification of incidence of this infection in women of child-bearing age.     

Persistence of K103N-containing HIV-1 variants after single-dose nevirapine for prevention of HIV-1 mother-to-child transmission

K103N-containing human immunodeficiency virus (HIV)-1 variants are selected in some women who receive single-dose (SD) nevirapine (NVP) for prevention of HIV-1 mother-infant transmission. We examined the persistence of K103N in women who received SD NVP prophylaxis. K103N was detected using the LigAmp assay (assay cutoff, 0.5% K103N). K103N was detected at 6-8 weeks in 60 (41.7%) of 144 women. Fading (lack of detection) of K103N was documented in 16 women by 2 years, 43 women by 3 years, and 55 women by 4 and 5 years. Slower fading was independently associated with HIV-1 subtype (D>A) and higher pre-NVP viral load.