Selenium status, pregnancy outcomes, and mother-to-child transmission of HIV-1

BACKGROUND: Among HIV-infected pregnant women, low selenium status may increase risk of mother-to-child transmission (MTCT) of HIV and poor pregnancy outcomes (low birthweight, small for gestational age, preterm birth, and fetal death) through several mechanisms, such as by promoting maternal HIV disease progression, viral shedding in the genital tract, and development of mastitis. However, there is no direct epidemiologic evidence on these relations among HIV-infected pregnant women. OBJECTIVE: To investigate the association between selenium status during pregnancy and pregnancy outcomes, MTCT of HIV, and child mortality. DESIGN: Baseline plasma selenium measurements from HIV-positive pregnant women (n = 670) were obtained between 12-27 weeks of gestation and mother-child pairs were followed prospectively until 24 months after delivery. RESULTS: Low plasma selenium levels were associated with increased risks of fetal death, child death, and HIV transmission through the intrapartum route. Low selenium status was not associated with risks of low birthweight or preterm birth but was associated with an apparently lower risk of small for gestational age. CONCLUSION: Adequate selenium status may be beneficial for some but not all pregnancy outcomes. Further studies are needed to better understand the role of selenium status in pregnancy outcomes, HIV transmission, and child health.     

Reactivation of Polyomavirus hominis 1 (BKV) during pregnancy and the risk of mother-to-child transmission

BACKGROUND: Pregnancy is associated with down-regulation of immune responses of the mother. This might lead to reactivation and vertical transmission of latent viral infections such as BK virus (BKV). OBJECTIVES: To determine the presence of BKV in the urine of pregnant women and in cord blood at delivery. STUDY DESIGN: We examined urines from 52 pregnant women and 51 cord blood samples for BKV by real-time SYBR green PCR. RESULTS: BKV DNA was found in the urine of 18 (34.6%) pregnant women. No BKV DNA was detected by SYBR green PCR in the cord blood specimens. CONCLUSIONS: BKV reactivation is common during pregnancy but this is not associated with BKV in cord blood.     

Immunoprophylaxis to prevent mother-to-child transmission of HIV-1

Antiretroviral therapy can profoundly reduce the risk of mother-to-child transmission (MTCT) of HIV, but the drugs have a relatively short half-life and should thus be administered throughout breast-feeding to optimally prevent postnatal infection of the infant. The potential toxicities and the development of resistance may limit the long-term efficacy of antiretroviral prophylaxis, and a safe and effective active/passive immunoprophylaxis regimen, begun at birth, and potentially overlapping with interpartum or neonatal chemoprophylaxis, would pose an attractive alternative. This review draws on data presented at the Ghent Workshop on prevention of breast milk transmission and on selected issues from a workshop specifically relating to immunoprophylaxis held in Seattle in October 2002. This purpose of this review is to address the scientific rationale for the development of passive (antibody) and active (vaccine) immunization strategies for prevention of MTCT. Data regarding currently or imminently available passive and active immunoprophylaxis products are reviewed for their potential use in neonatal trials within the coming 1-2 years.     

Diversity of the HIV-1 long terminal repeat following mother-to-child transmission

A study of the human immunodeficiency virus Type 1 (HIV-1) 5' long terminal repeat (LTR) was performed to determine the extent of variation found within the LTR from 19 mother-infant pairs in Tanzania and to assess whether the LTR is useful in distinguishing maternal sequences that were transmitted to infants. HIV-1 subtypes A, C, and D as well as intersubtype recombinant LTR sequences were detected in mothers and infants. The LTR subtype was 100% concordant between mothers and their infants. Diversity calculations showed a significant reduction in LTR variation in infants compared to their mothers. However, the overall magnitude of LTR variation was less than that found in the env gene from the same individuals. These data suggest a selective constraint active upon the 5' long terminal repeat that is distinct from immune selective pressure(s) directed against HIV-1 structural genes. Detection of maternal LTR variants that were transmitted to infants may yield important information concerning nonstructural determinants of HIV-1 transmission from mother to infant.     

HIV-1 viral load and other risk factors for mother-to-child transmission of HIV-1 in a breast-feeding population in Cote d'Ivoire

Short-course antiretroviral regimens have been evaluated to reduce mother-to-child transmission of HIV in resource-limited settings. This report from Abidjan, Cote d'Ivoire, examines the risk factors for HIV transmission by 1 and 24 months among breast-feeding women. Eligible HIV-1-seropositive pregnant women enrolled in this randomized double-blind clinical trial were randomly assigned to receive either oral zidovudine (ZDV) (n = 126) prophylaxis or placebo (n = 124). Maternal prophylaxis began at 36 weeks of gestation (300 mg ZDV twice daily antepartum and 300 mg every 3 hours intrapartum); there was no neonatal prophylaxis component. The cumulative risk of transmission in the treatment group was 11.9% and 22.1% by 1 and 24 months, respectively. In adjusted analyses, viral load at enrollment was the strongest predictor of transmission (per log increment: odds ratio [OR] = 4.8, 95% confidence interval [CI]: 2.5-9.5 at 1 month; OR = 5.7; 95% CI: 3.1-10.8 at 24 months). Overall, ZDV prophylaxis was not significantly protective for infection at 1 or 24 months. Comparing ZDV with placebo following dichotomization of viral load (<50,000 vs. > or =50,000 copies/mL) at enrollment, however, there was a significant effect of ZDV seen only among those women with a low viral load at enrollment. The substantial risk of transmission despite ZDV prophylaxis, particularly among those with higher viral loads, underscores the need to find more effective regimens appropriate for use in resource-limited settings.     

HIV-1 seroconversion during pregnancy resulting in vertical transmission.

The uptake of antenatal HIV testing in England and Scotland improved from 33% in 1998 to 92% in 2004 after implementing an opt-out policy. However, there is the potential for missing HIV seroconversion during pregnancy unless a further test is carried out between antenatal booking, which mostly occurs between 12-14 weeks, and delivery. We report a 32-year old Caucasian woman who developed a primary symptomatic HIV infection late in pregnancy. Unfortunately, despite antiretroviral treatment, caesarean section and formula feeding to reduce the risk of mother to child transmission (MCT), the baby was found to be infected by 12 weeks of age. Despite a 95% uptake rate at King's College Hospital, another HIV seroconversion during late pregnancy was detected after the partner was admitted with AIDS defining diagnoses. In the absence of national data on HIV seroconversion rates in pregnancy, further maternal HIV testing later in pregnancy, especially for women at-risk in an ethnically diverse area such as London, should be considered.     

CCR5, RANTES and SDF-1 polymorphisms and mother-to-child HIV-1 transmission

Among 288 HIV-1-infected, breastfeeding women who received zidovudine prophylaxis and were followed with their infants in Nairobi, we found no associations between maternal genetic polymorphisms in CCR5 (59029G/A, 59353T/C, 59356T/C, 59402G/A), RANTES (-403G/A) and SDF-1 (3’801G/A) and mother-to-child HIV-1 transmission; plasma, cervical and breastmilk viral loads; or breastmilk chemokine concentrations.     

Advances in the prevention of mother-to-child transmission of HIV-1 infection in resource-limited settings

Ten years after the first trials demonstrating the efficacy of zidovudine (ZDV) for the prevention of mother-to-child transmission (pMTCT) of HIV, different antiretroviral approaches have been validated in resource-limited settings. Remarkable progress has been made in the last 4 years, with trials demonstrating the efficacy of postexposure antiretroviral prophylaxis in Malawi, as well as studies in Thailand and C?te d'Ivoire assessing the efficacy and viral resistance patterns of short-course regimens combining ZDV plus single-dose nevirapine (sdNVP). The field efficacy of a short course of ZDV plus lamivudine (3TC), together with sdNVP, has also been recently reported, with 6-week transmission rates below 5% for the first time in Africa in a population in which 40% breast-feed. The introduction of HAART for pregnant women has begun on a small scale in resource-limited settings and will hopefully further reduce transmission. What remains is the crucial issue of viral resistance after antiretroviral therapy for pMTCT, especially in the context of the growing availability and use of sdNVP in national pMTCT programs. Preliminary data from South Africa and C?te d'Ivoire suggest that the maternal use of ZDV plus 3TC for at least 3 days postpartum may reduce the occurrence of resistance mutations after maternal exposure to sdNVP. In the context of increasing controversy surrounding the use of sdNVP for pMTCT, the World Health Organization has recently reiterate its recommendations for its use for pMTCT in resource-constrained settings within a wide panel of antiretroviral regimens, in order to allow greater and quicker population coverage. The field application of pMTCT study results is a real challenge, and innovative approaches need to be designed an evaluated ot increase uptake of pMTCT programs in resource-poor settings. Research must continue to identify new interventions and new antiretroviral drugs for pMTCT.     

HIV-1 co-receptor usage: influence on mother-to-child transmission and pediatric infection

Viral CCR5 usage is not a predictive marker of mother to child transmission (MTCT) of HIV-1. CXCR4-using viral variants are little represented in pregnant women, have an increased although not significant risk of transmission and can be eventually also detected in the neonates. Genetic polymorphisms are more frequently of relevance in the child than in the mother. However, specific tissues as the placenta or the intestine, which are involved in the prevalent routes of infection in MTCT, may play an important role of selective barriers. The virus phenotype of the infected children, like that of adults, can evolve from R5 to CXCR4-using phenotype or remain R5 despite clinical progression to overt immune deficiency. The refined classification of R5 viruses into R5(narrow) and R5(broad) resolves the enigma of the R5 phenotype being associated with the state of immune deficiency. Studies are needed to address more in specific the relevance of these factors in HIV-1 MTCT and pediatric infection of non-B subtypes.     

Functional properties of the HIV-1 subtype C envelope glycoprotein associated with mother-to-child transmission

Understanding the properties of viruses capable of establishing infection during perinatal transmission of HIV-1 is critical for designing effective means of limiting transmission. We previously demonstrated that the newly transmitted viruses (in infant) were more fit in growth, as imparted by their envelope glycoproteins, than those in their corresponding mothers. Here, we further characterized the viral envelope glycoproteins from six mother-infant transmission pairs and determined whether any specific envelope functions correlate with HIV-1 subtype C perinatal transmission. We found that most newly transmitted viruses were less susceptible to neutralization by their maternal plasma compared to contemporaneous maternal viruses. However, the newly transmitted variants were sensitive to neutralization by pooled heterologous plasma but in general were resistant to IgG1 b12. Neither Env processing nor incorporation efficiency was predictive of viral transmissibility. These findings provide further insight into the characteristics of perinatally transmissible HIV-1 and may have implications for intervention approaches.     

Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission

High plasma HIV-1 RNA concentrations are associated with an increased risk of HIV-1 transmission. Although plasma and genital HIV-1 RNA concentrations are correlated, no study has evaluated the relationship between genital HIV-1 RNA and the risk of heterosexual HIV-1 transmission. In a prospective study of 2521 African HIV-1 serodiscordant couples, we assessed genital HIV-1 RNA quantity and HIV-1 transmission risk. HIV-1 transmission linkage was established within the partnership by viral sequence analysis. We tested endocervical samples from 1805 women, including 46 who transmitted HIV-1 to their partner, and semen samples from 716 men, including 32 who transmitted HIV-1 to their partner. There was a correlation between genital and plasma HIV-1 RNA concentrations: For endocervical swabs, Spearman's rank correlation coefficient ρ was 0.56, and for semen, ρ was 0.55. Each 1.0 log(10) increase in genital HIV-1 RNA was associated with a 2.20-fold (for endocervical swabs: 95% confidence interval, 1.60 to 3.04) and a 1.79-fold (for semen: 95% confidence interval, 1.30 to 2.47) increased risk of HIV-1 transmission. Genital HIV-1 RNA independently predicted HIV-1 transmission risk after adjusting for plasma HIV-1 quantity (hazard ratio, 1.67 for endocervical swabs and 1.68 for semen). Seven female-to-male and four male-to-female HIV-1 transmissions (incidence <1% per year) occurred from persons with undetectable genital HIV-1 RNA, but in all 11 cases, plasma HIV-1 RNA was detected. Thus, higher genital HIV-1 RNA concentrations are associated with greater risk of heterosexual HIV-1 transmission, and this effect was independent of plasma HIV-1 concentrations. These data suggest that HIV-1 RNA in genital secretions could be used as a marker of HIV-1 sexual transmission risk.     

Efficacy of strategies to reduce mother-to-child HIV-1 transmission in Argentina, 1993-2000

This study evaluated the success of a national program for the prevention of mother-to-child transmission (MTCT) of HIV-1 in 874 mother-infant pairs from Buenos Aires and surroundings. This population was referred to the National Reference Center for AIDS for diagnosis of neonatal infection during 1993-2000. The data revealed an increase in the use of antiretroviral therapy during pregnancy from 3.2% in 1993-1994 to 73.1% in 1999-2000 and in the use of cesarean delivery (reaching 54.8% in 1999-2000). However, the proportion of HIV-infected women who continued to breast-feed their children remained steady (around 12%). General improvement of the conditions for decreasing MTCT resulted in a significant decrease in the proportion of infected infants from 37.3% before 1995 to 10.7% in 1999-2000 and even 6.5% during 2001. Data on the time of diagnosis indicated that only 42.7% of the women knew about their HIV status before pregnancy, 44.8 knew during pregnancy, and 12.3% knew after the birth of their child. The main risk factor for HIV infection in the mothers was heterosexual contact (73%), and in the fathers, it was injection drug use (67%). These results point out the urgent need to develop additional strategies for prevention of MTCT of HIV-1 to generalize education, counseling, and testing of young women.     

Intracellular sequestration and transmission of HIV-1 in pregnancy.

30-50% of infants born to HIV-1 seropositive mothers are infected. Although a vertical transmission of the virus to the foetus via trophoblastic cells and mechanisms of its access thereof have been made, one of several questions which remains is: how do HIV-1 infected cells of monocyte/macrophage (MM) lineage, i.e. Hofbauer cells, which facilitate viral transmission, avoid cytolytic destruction vs. that which occurs in infected CD4+ T-cells and serve as a reservoir for virus, wherein it replicates? Recent studies of transglutaminases (TGases), a ubiquitous family of Ca(2+)-dependent peptide ligases catalyzing the post-translational covalent cross-linking of proteins and incorporation of amines into proteins have revealed a unique spectrum of immunoregulatory (IR) properties. In consonance with these studies, the biochemical and immunohistochemical identification of decidual and placental TGases, and their associated IR properties, and earlier studies of uterine and placental macrophages, a hypothesis is purposed to account for the intracellular assembly and accumulation of HIV-1 within cells of MM lineage, and transmission therefrom, in pregnancy.     

Immune status and uptake of antiretroviral interventions to prevent mother-to-child transmission of HIV-1 in Africa

The aim of this study performed in Abidjan, C?te d'Ivoire, was to describe the distribution of CD4+ T-cell lymphocytes (CD4) in HIV-1-infected (HIV+) pregnant women diagnosed during prenatal voluntary counseling and testing and to assess whether HIV-related immunodeficiency influenced the acceptance of an antiretroviral (ARV) package (zidovudine beginning at 36 weeks of amenorrhea plus intrapartum nevirapine) to prevent mother-to-child transmission. Between April and June 2002, a CD4 count was systematically performed in all HIV+ women (n=221) in 5 antenatal clinics carrying out voluntary counseling and testing. No difference in CD4 count was found in HIV+ women who did not return for their test result (n=50) and those who were informed of their positive serostatus (n=171) (median CD4 count: 389/mm3 vs. 420/mm3; P=0.19). We also found a lack of difference in CD4 count in those who accepted ARV (n=72) and those who did not but knew their HIV status (n=99) (median CD4 count: 405/mm3 vs. 425/mm3; P=0.47). The overall uptake of the intervention (31.9%) appeared to be independent of the maternal immune status.     

Antenatal couple counseling increases uptake of interventions to prevent HIV-1 transmission

To determine effect of partner involvement and couple counseling on uptake of interventions to prevent HIV-1 transmission, women attending a Nairobi antenatal clinic were encouraged to return with partners for voluntary HIV-1 counseling and testing (VCT) and offered individual or couple posttest counseling. Nevirapine was provided to HIV-1-seropositive women and condoms distributed to all participants. Among 2104 women accepting testing, 308 (15%) had partners participate in VCT, of whom 116 (38%) were couple counseled. Thirty-two (10%) of 314 HIV-1-seropositive women came with partners for VCT; these women were 3-fold more likely to return for nevirapine (P = 0.02) and to report administering nevirapine at delivery (P = 0.009). Nevirapine use was reported by 88% of HIV-infected women who were couple counseled, 67% whose partners came but were not couple counseled, and 45%whose partners did not present for VCT (P for trend = 0.006). HIV-1-seropositive women receiving couple counseling were 5-fold more likely to avoid breast-feeding (P = 0.03) compared with those counseled individually. Partner notification of HIV-1-positive results was reported by 138 women (64%) and was associated with 4-fold greater likelihood of condom use (P = 0.004). Partner participation in VCT and couple counseling increased uptake of nevirapine and formula feeding. Antenatal couple counseling may be a useful strategy to promote HIV-1 prevention interventions.     

The safety of antiviral therapy and drug withdrawal for the prevention of mother-to-child transmission of HBV during pregnancy

The efficacy of prenatal antiviral therapy (AVT) for preventing the vertical transmission of hepatitis B virus (HBV) is well demonstrated. However, data are limited regarding the safety of postpartum cessation of AVT, which may induce alanine aminotransferase (ALT) elevation. We aimed to investigate the necessity of prolonging maternal AVT after delivery. Chronic hepatitis B mothers at the immune-tolerant phase with HBV DNA levels >6 log₁₀ IU/mL were prospectively enrolled and received AVT during the third trimester until delivery. Patients were offered to discontinue AVT either at delivery or postpartum week (PPW) 6. In addition, mothers who deferred AVT during pregnancy served as the control group. All mothers were followed until PPW 52 for clinical and virological parameters of hepatitis flares. Among 118 mothers recruited, 91 received AVT with 53 (group A) and 24 (group B) discontinue their treatment at delivery and PPW 6, respectively. Twenty-seven mothers who deferred AVT during pregnancy were followed as the control (group C). A total of 104 of 118 mothers who completed the study, 50% (52/104) had postpartum-elevated ALT levels, which were mild and moderate except 6 of 104 (5.77%) of patients had levels ≥5 times the upper limit of normal; 70% (36/52) of the ALT flares occurred within 12 weeks after delivery. In subgroup analyses, the frequency of ALT elevation was similar among the groups A vs B vs C (50.9% [27/53] vs 58.3% [14/24] vs 40.7% [11/27], respectively; P = .447), as well as the mean peak ALT level (108.4/74.1/126.7 U/L in groups A/B/C, respectively; P = .291). Although postpartum ALT flares were common for mothers with or without AVT during pregnancy, most cases of ALT elevation were mild to moderate. Our study observed that extending AVT to PPW 6 did not affect maternal outcomes and ATV should be discontinued at birth. Close monitoring is warranted as severe flares rarely occurred.