Placental membrane inflammation and risks of maternal-to-child transmission of HIV-1 in Uganda

Prospective follow-up of 172 HIV-infected pregnant women and their infants was conducted at Mulago Hospital, Kampala, Uganda during 1990 to 1992. Information was collected on maternal immune status (CD4 counts or clinical AIDS), and concurrent infections with sexually transmitted diseases. Infants were observed on a follow-up basis to determine HIV infection, using polymerase chain reaction (PCR) under 15 months of age and enzyme immunoassay/Western blot for those older than 15 months. Placental membrane inflammation (chorioamnionitis and funisitis), and placental villous inflammation (villitis, intervillitis, and deciduitis) were diagnosed by histopathology. Mother-to-child HIV transmission rates were assessed, and adjusted odds ratios (OR) and 95% confidence intervals (95% CI) of transmission were estimated using women with no placental pathology or evidence of immune suppression as a reference group. RESULTS: The overall mother-to-child HIV transmission rate was 23.3%. Women with no placental membrane inflammation or immune suppression had a transmission rate of 11.3%; compared with 25.5% in women with placental inflammation and no immunosuppression (adjusted OR, 2.87; 95% CI, 1.04-7.90), and 37.0% in immunosuppressed women (OR, 3.07; 95% CI, 1.42-6.67). We estimate that 34% of HIV transmission could be prevented by treatment of placental membrane inflammation in nonimmunocompromised women. Transmission rates were 40.9% with genital ulcer disease (OR, 3.57; 95% CI, 1.28-9.66). Placental villous inflammation and artificial rupture of membranes did not increase transmission rates and cesarean section was associated with a nonsignificant reduction of risk (OR, 0.70; 95% CI 0.24-2.06). CONCLUSION: Placental membrane inflammation increases the rate of mother-to-child HIV transmission.     

HIV-1 LTR subtype and perinatal transmission

Multiple subtypes of HIV-1 have been identified; however, there is little data on the relative transmissibility of viruses belonging to different subtypes. A matched case-control study addressed whether viruses with different long terminal repeat (LTR) subtypes were transmitted equally from mother to infant. The LTR subtype was determined for 45 matched cases and controls who participated in a clinical trial in Tanzania. HIV-1 subtypes A, C, and D and intersubtype recombinant sequences were identified. Exact matched logistic regression analysis showed that viruses containing subtype A or intersubtype recombinant LTRs were 3.2 and 4.8 times more likely to be transmitted from mother to infant than viruses with subtype D LTRs. Viruses containing subtype C LTRs were 6.1 times more likely to be transmitted than those with subtype D LTRs. These differences in transmission were independent of maternal CD4 at enrollment. Thus, it appears that HIV-1 subtype may be associated with differing rates of perinatal transmission in Tanzania.     

HLA-G DNA sequence variants and risk of perinatal HIV-1 transmission

Background  

HLA-G gene is a non-classical MHC class 1 molecule that is highly expressed in the trophoblast at the maternal-fetal interface. In an attempt to elucidate possible immunological mechanisms facilitating protection of infants born to human immunodeficiency virus type (HIV-1) infected mothers, we have been studying genetic variations in the coding and untranslated regions of HLA-G antigen between HIV-1-infected mothers and their infected or uninfected infants. This study investigated whether HLA-G DNA sequence variants are associated with perinatal HIV-1 transmission.     

Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission

CONTEXT: The Women and Infants Transmission Study is a prospective natural history study that has been enrolling HIV-1-infected pregnant women and their infants since 1989. OBJECTIVE: To evaluate the impact of different antiretroviral regimens on perinatal HIV-1 transmission at the population level. DESIGN: Prospective cohort study. Plasma HIV-1 RNA levels were serially measured in 1542 HIV-1-infected women with singleton live births between January 1990 and June 2000. MAIN OUTCOME MEASURE: HIV-1 status of the infant. RESULTS: HIV-1 transmission was 20.0% (95% confidence interval [CI], 16.1%-23.9%) for 396 women who not receiving prenatal antiretroviral therapy; 10.4% (95% CI, 8.2%-12.6%) for 710 receiving zidovudine monotherapy; 3.8% (95% CI, 1.1%-6.5%) for 186 receiving dual antiretroviral therapy with no or one highly active drug (Multi-ART); and 1.2% (95% CI, 0-2.5%) for 250 receiving highly active antiretroviral therapy (HAART). Transmission also varied by maternal delivery HIV RNA level: 1.0% for <400; 5.3% for 400 to 3499; 9.3% for 3500 to 9999; 14.7% for 10,000 to 29,999; and 23.4% for >30,000 copies/mL (p =.0001 for trend). The odds of transmission increased 2.4-fold (95% CI, 1.7-3.5) for every log10 increase in delivery viral load. In multivariate analyses adjusting for maternal viral load, duration of therapy, and other factors, the odds ratio for transmission for women receiving Multi-ART and HAART compared with those receiving ZDV monotherapy was 0.30 (95% CI, 0.09-1.02) and 0.27 (95% CI, 0.08-0.94), respectively. CONCLUSION: Levels of HIV-1 RNA at delivery and prenatal antiretroviral therapy were independently associated with transmission. The protective effect of therapy increased with the complexity and duration of the regimen. HAART was associated with the lowest rates of transmission.     

Independent effects of nevirapine prophylaxis and HIV-1 RNA suppression in breast milk on early perinatal HIV-1 transmission

BACKGROUND: The mechanism of action of single-dose nevirapine on reducing mother-to-child transmission of HIV-1 may involve reduction of maternal HIV-1 or prophylaxis of infants. METHODS: In a study that randomized pregnant mothers to HIVNET 012 nevirapine versus short-course antenatal zidovudine, we compared breast milk HIV-1 RNA viral shedding and administration of single-dose nevirapine between mothers who transmitted HIV-1 to their infants at 6 weeks postpartum and those who did not. RESULTS: In multivariate analyses, maximum breast milk HIV-1 RNA levels (hazard ratio [HR] = 2.50, 95% confidence interval [CI]: 1.25 to 4.99; P = 0.01) and nevirapine use (HR = 0.12, 95% CI: 0.02 to 0.97; P = 0.05) were each independently associated with perinatal transmission at 6 weeks postpartum. Mothers who transmitted HIV-1 to their infants had significantly higher HIV-1 RNA levels in their breast milk between the second day and sixth week postpartum. Among mothers with maximum breast milk virus levels less than a median of 3.5 log(10) copies/mL, the administration of nevirapine further decreased HIV-1 transmission risk from 22.2% to 0.0% (P = 0.04). CONCLUSIONS: Peripartum administration of single-dose nevirapine to mother and infant decreases early perinatal HIV-1 transmission by means of breast milk HIV-1 RNA suppression and, independently, by providing the infant with exposure prophylaxis.     

Antiretroviral prophylaxis of perinatal HIV-1 transmission and the potential impact of antiretroviral resistance

Since 1994, trials of zidovudine, zidovudine and lamivudine, and nevirapine have demonstrated that these antiretroviral drugs can substantially reduce the risk of perinatal HIV-1 transmission. With reductions in drug price, identification of simple, effective antiretroviral regimens to prevent perinatal HIV-1 transmission, and an increasing international commitment to support health care infrastructure, antiretrovirals for both perinatal HIV-1 prevention and HIV-1 treatment will likely become more widely available to HIV-1-infected persons in resource-limited countries.In the United States, widespread antiretroviral usage has been associated with increased antiretroviral drug resistance. This raises concern that drug resistance may reduce the effectiveness of perinatal antiretroviral prophylaxis as well as therapeutic intervention strategies. The purpose of this article is to review what is known about resistance and risk of perinatal HIV transmission, assess the interaction between antiretroviral resistance and the prevention of perinatal HIV-1 transmission, and discuss implications for current global prevention and treatment strategies.     

Association of HIV-1 viral phenotype in the MT-2 assay with perinatal HIV transmission

A case-control design study was used to investigate the association of maternal HIV-1 phenotype in MT-2 cells at or near the time of delivery with perinatal transmission of HIV-1, controlling for maternal CD4 percentage and duration of rupture of membranes, in 48 transmitting and 96 non-transmitting HIV-1-infected mothers who gave birth between 1990 and 1995. The non-syncytium-inducing (NSI) phenotype was more commonly seen in transmitting mothers compared with non-transmitting mothers (90% vs. 75%, p =.04). In a multivariable logistic regression model, the following maternal characteristics were significantly associated with HIV transmission: NSI phenotype (odds ratio [OR] = 6.08; 95% confidence interval [CI]: 1.73-21.35) and log(10) viral load (OR = 2.11; CI: 1.19-3.74). Finally, the association of NSI phenotype with transmission was stronger in transmitting women who received azidothymidine during pregnancy compared with transmitters who did not.     

Hormonal contraception and HIV-1 transmission

Safe and effective contraceptive choices are essential for women with HIV-1 infection and at risk for HIV-1 infection. Epidemiological and laboratory-based studies suggest that hormonal contraception may influence HIV-1 transmission. Several large studies in high-risk populations indicate that hormonal contraceptive use may modestly increase the risk of HIV-1 acquisition. In addition, HIV-1-infected users of hormonal contraceptives may be more infectious to their uninfected partners, although no studies have directly measured HIV-1 transmission risk from women to men. However, several studies failed to demonstrate a link between contraceptive use and HIV-1 acquisition or transmission, and interpretation of many studies limited by methodological considerations, such as infrequent measurements of contraceptive exposure and HIV-1 status. As a result, many questions remain, and high-quality studies remain needed. It is clear that hormonal contraceptives are not protective against HIV-1 infection and that dual protection with condoms should be the goal for women using hormonal contraception.     

Dendritic cells and transmission of HIV-1

Sexual transmission of HIV-1 requires that small amounts of virus at mucosal sites of inoculation gain access to replication-permissive cells. Recent observations have increased our understanding of the mechanisms by which this relatively inefficient virus can exploit the migratory nature of dendritic cells to establish infection within the host.     

Zidovudine resistance phenotype and risk of perinatal HIV-1 transmission in zidovudine monotherapy-treated mothers with moderately advanced disease

The association of phenotypic zidovudine resistance with perinatal transmission was evaluated in 74 zidovudine-treated mothers enrolled in the Women and Infants Transmission Study through September 1994. Women in the sample had moderately advanced disease, with a median CD4+ cell count of 271/microL and a median plasma HIV-1 RNA level of 39,811 copies/mL. Factors independently associated with zidovudine resistance at delivery (50% inhibitory concentration [IC50], >/=0.1 microM) in multiple logistic regression included prepregnancy zidovudine use, high log plasma HIV-1 RNA level, and low CD4+ cell count. Of 74 mothers, 16 (22%) transmitted HIV-1 to their infants. After adjustment for duration of membrane rupture and CD8+ cell count, zidovudine resistance (IC50 range, 0.01-2.2 microM) was associated with an increased odds of transmission (ORadj, 1.25 per 0.1 microM; 95% confidence interval, 1.01-1.54), suggesting a decreased effect of prenatal zidovudine on preventing transmission in mothers infected with zidovudine-resistant virus. However, when the analysis was limited only to those mothers infected with virus containing zidovudine resistance mutations, no association between phenotypic resistance and transmission remained, indicating that phenotype may not provide significant additional information in predicting transmission where resistance genotype is known.     

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.     

Performance characteristics of HIV-1 culture and HIV-1 DNA and RNA amplification assays for early diagnosis of perinatal HIV-1 infection

A plasma HIV-1 RNA amplification assay (RNA assay), a quantitative peripheral blood mononuclear cell (PBMC) microculture (culture), and a PBMC HIV-1 DNA amplification assay (DNA assay) were compared for diagnosis of HIV-1 infection in infants receiving zidovudine in Pediatric AIDS Clinical Trials Group protocol 185; assays were performed for all 24 infected and 100 uninfected infants. HIV-1 infection was defined as >or=2 positive cultures or positive antibody to HIV-1 at >or=18 months. Cultures were performed at birth and 6 and 24 weeks of age; DNA and RNA assays were performed on cryopreserved specimens. The sensitivity of culture and DNA and RNA assays at birth was 20.8%, 10.5%, and 26.7%, respectively. At older ages, sensitivity typically exceeded 80%, remaining highest for the RNA assay (>85%). Assay specificity was >99%. Positive predictive values exceeded 93% for each assay at each age; negative predictive values were highest (>90%) for the RNA assay. At birth (P < 0.005) and age 6 weeks (P < 0.001), a significantly larger proportion of infected infants were identified by means of the RNA assay than by the other assays. The diagnostic performance of the RNA assay matched or exceeded that of culture and the DNA assay. Given that RNA assays require less blood volume and yield rapid results, our study adds to existing data suggesting that RNA assays may be used for early diagnosis of HIV-1 infection in infants.     

Neutralization titres and vertical HIV-1 transmission

Replication of the human immunodeficiency virus type 1 (HIV-1) isolate MN in CEM cells was less neutralized by the plasma from the mothers of infected children (MIC) in comparison with the plasma from the mothers of uninfected children (MUC). Significantly higher neutralization titres were observed for the sera from MUCs compared with MICs, and only the sera from MUC showed 100% neutralization of the HIV-1 MN strain. We suggest that a simple neutralization assay as described here could be useful in prognostic analyses.     

Analysis of immunological markers associated with pregnancy and HIV-1 infection: relevance in perinatal transmission in HIV-1-infected pregnant women with low plasma viral load

PROBLEM: In HIV-1-infected pregnant women with low plasma viral load, risk factors associated with perinatal HIV-1 transmission are not clearly understood. METHOD OF STUDY: We analyzed distribution of peripheral CD8 T-cell subsets, plasma cytokines and measured secretory leukocyte peptidase inhibitor (SLPI) and myeloid-related protein (MRP)-8 levels in whole-blood and cervico-vaginal fluid (CVF) specimens obtained from 35 HIV-1-infected pregnant women (group 1), 12 HIV-1-infected non-pregnant women (group 2) and 15 HIV-1 uninfected pregnant women (group 3). RESULTS: The group 1 women had higher expression of CD38, human leukocyte antigen-DR and CD95 on CD8 T-cells and higher levels of plasma tumor necrosis factor-alpha and epidermal growth factor. CVF-SLPI levels were the highest in group-3, while MRP-8 levels were the highest in group 1 women in plasma and CVF (P < 0.01). Although there were no cases of perinatal HIV-1 transmission, group 1 women undergoing HIV-1-indicated cesarean section had lower levels of CVF-SLPI as compared with those undergoing normal vaginal delivery. CONCLUSION: Pregnancy contributes to the activation of peripheral CD8 T cells and increase in pro-inflammatory cytokines. Production of protective mucosal secretory factors such as SLPI is affected by HIV-1 infection in pregnant women and down-regulated SLPI levels may indirectly indicate a higher possibility of perinatal HIV-1 transmission.     

Breast-feeding and HIV-1 transmission in resource-limited settings

In many international settings, transmission of the HIV virus during lactation accounts for one third to one half of all HIV transmission from mothers to infants. Reduction of HIV transmission during lactation is one of the most pressing public health dilemmas confronting perinatal researchers, health policy makers, and HIV-infected women in many areas of the world. While results of clinical trials, laboratory and observational studies have increased our understanding of risk factors for breast-feeding transmission and the timing of postnatal transmission, there are no proven strategies known to reduce the risk of HIV transmission during breast-feeding for those HIV-infected women who opt to breast-feed in developing countries. Approaches to decreasing transmission of HIV through breast-feeding that will be studied include trials of combination antiretrovirals given to mothers during lactation. These research efforts using maternal antiretrovirals for perinatal HIV prevention during breast-feeding will interface with emerging plans for treatment programs in developing countries.     

Maternal scleroderma: Placental findings and perinatal outcome

Pregnancy after the onset of scleroderma is uncommon; therefore, placental findings and perinatal outcome have rarely been correlated. The histopathologic features of placentas from 13 pregnancies in eight women with scleroderma were recorded and correlated with the clinical features of the mother and fetus. Adverse perinatal outcome included intrauterine fetal demise in five, and previable or preterm delivery in four. A decidual vasculopathy was seen in 5 of the 13 placentas, four of which were associated with intrauterine fetal demise. Decidual blood vessels in the scleroderma patients were evaluated immunohistochemically for platelet-derived growth factor (PDGF), transforming growth factor β1 (TGF-β1), T-helper and T-suppressor lymphocytes, macrophages, immunoglobulin (Ig) M, and IgG, and compared with those from hypertensive and uncomplicated third-trimester pregnancies. The atherotic blood vessels in scleroderma were characterized by mural macrophages and IgM and IgG deposition and were similar to those seen in placentas from hypertensive pregnancies. CD8-positive T cells predominated in normal and hypertensive decidua compared with scleroderma, in which CD4-positive T cells were more frequent. No difference in PDGF or TGF-β1 staining was found between scleroderma and control groups. In conclusion, decidual vasculopathy is common in scleroderma, is similar to that seen in hypertension, and is associated with poor perinatal outcome. A trend toward a reversed ratio of decidual CD4- to CD8-positive T cells is seen in scleroderma compared with hypertension and uncomplicated pregnancies. PDGF and TGF-β1 do not appear to be involved in the pathogenesis of decidual vasculopathy in scleroderma.