Birth defects among a cohort of infants born to HIV-infected women on antiretroviral medication.

OBJECTIVE: To determine rate of and risk factors for birth defects in infants born to HIV-infected women receiving nucleoside and protease inhibitor antiretroviral (ARV) therapy. METHODS: Birth defects were evaluated among infants on the Pediatric AIDS Clinical Trials Group 316 trial that studied addition of peripartum nevirapine to established ARV regimen for prevention of mother-to-child transmission. Maternal therapy was categorized by trimester of earliest exposure. Birth defects were coded using conventions of the Antiretroviral Pregnancy Registry. RESULTS: Birth defects were detected in 60/1414 (4.2%; 95% CI 3.3-5.4%) infants including 30/636 (4.7%; 95% CI 3.2-6.7%) with first trimester ARV exposure and 30/778 (3.9%; 95% CI 2.6-5.5%) with exposure only after the first trimester (P=0.51). Rates of classes of defects were similar between first trimester compared to later exposure groups except heart defects which occurred in 16 (2.5%; 95% CI 1.4-4.1%) with first trimester ARV exposure and in six (0.8%; 95% CI 0.3-1.7%) infants with later exposure (P=0.02). Exposure to ARV was not associated with specific types of heart defects. Two cases of cardiomyopathy were noted. CONCLUSION: ARV use in early pregnancy was not associated with an increased risk of birth defects overall. The possible association of ARV exposure with heart defects requires further surveillance.

Antiretroviral resistance patterns and HIV-1 subtype in mother-infant pairs after the administration of combination short-course zidovudine plus single-dose nevirapine for the prevention of mother-to-child transmission of HIV.

BACKGROUND: World Health Organization guidelines for prevention of mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) recommend administration of zidovudine and single-dose nevirapine (NVP) for HIV-1-infected women who are not receiving treatment for their own health or if complex regimens are not available. This study assessed antiretroviral resistance patterns among HIV-infected women and infants receiving single-dose NVP in Thailand, where the predominant circulating HIV-1 strains are CRF01_AE recombinants and where the minority are subtype B. METHODS: Venous blood samples were obtained from (1) HIV-infected women who received zidovudine from 34 weeks' gestation and single-dose NVP plus oral zidovudine during labor and (2) HIV-infected infants who received single-dose NVP after birth plus zidovudine for 4 weeks after delivery. HIV-1 drug resistance testing was performed using the TruGene assay (Bayer HealthCare). RESULTS: Most mothers and infants were infected with CRF01_AE. NVP resistance was detected in 34 (18%) of 190 women and 2 (20%) of 10 infants. There was a significantly higher proportion of NVP mutations in women with delivery viral loads of >50,000 copies/mL (adjusted odds ratio, 8.5; 95% confidence interval, 2.2-32.8, P = .002 for linear trend) and in those with subtype B rather than CRF01_AE infections (38% vs. 16%; adjusted odds ratio, 3.6; 95% confidence interval, 1.1-11.8; P = .038). CONCLUSIONS: The lower frequency of NVP mutations among mothers infected with subtype CRF01_AE, compared with mothers infected with subtype B, suggests that individuals infected with subtype CRF01_AE may be less susceptible to the induction of NVP resistance than are individuals infected with subtype B.

Reduced mother-to-child transmission of HIV associated with infant but not maternal GB virus C infection.

BACKGROUND: Prolonged coinfection with GB virus C (GBV-C) has been associated with improved survival in human immunodeficiency virus (HIV)-infected adults. We investigated whether maternal or infant GBV-C infection was associated with mother-to-child transmission (MTCT) of HIV-1 infection. METHODS: The study population included 1364 HIV-infected pregnant women enrolled in 3 studies of MTCT of HIV in Bangkok, Thailand (the studies were conducted from 1992-1994, 1996-1997, and 1999-2004, respectively). We tested plasma collected from pregnant women at delivery for GBV-C RNA, GBV-C antibody, and GBV-C viral genotype. If GBV-C RNA was detected in the maternal samples, the 4- or 6-month infant sample was tested for GBV-C RNA. The rates of MTCT of HIV among GBV-C-infected women and infants were compared with the rates among women and infants without GBV-C infection. RESULTS: The prevalence of GBV-C RNA in maternal samples was 19%. Of 245 women who were GBV-C RNA positive, 101 (41%) transmitted GBV-C to their infants. Of 101 infants who were GBV-C RNA positive, 2 (2%) were infected with HIV, compared with 162 (13%) of 1232 infants who were GBV-C RNA negative (odds ratio [OR] adjusted for study, 0.13 [95% confidence interval {CI}, 0.03-0.54]). This association remained after adjustment for maternal HIV viral load, receipt of antiretroviral prophylaxis, CD4(+) count, and other covariates. MTCT of HIV was not associated with the presence of GBV-C RNA (adjusted OR [aOR], 0.94 [95% CI, 0.62-1.42]) or GBV-C antibody (aOR, 0.90 [95% CI, 0.54-1.50]) in maternal samples. CONCLUSIONS: Reduced MTCT of HIV was significantly associated with infant acquisition of GBV-C but not with maternal GBV-C infection. The mechanism for this association remains unknown.

Assessment of bacille Calmette-Guérin vaccine reaction in HIV-exposed Thai infants.

We evaluated local reactions at 1, 2, and 4 months of age to bacille Calmette-Guérin vaccine given at birth to 1058 infants who were exposed to human immunodeficiency virus (HIV). No scar was discernible in 12 (12.4%) of 97 HIV-infected infants and 20 (2.1%) of 961 uninfected infants (relative risk, 5.9; 95% confidence interval, 3.0-11.8). This difference may reflect poorer immunogenicity in HIV-infected infants.

Reduction in mother-to-child transmission of HIV in Thailand, 2001-2003: Results from population-based surveillance in six provinces.

BACKGROUND: In 2000, Thailand implemented a national program to prevent mother-to-child HIV transmission (PMTCT). OBJECTIVE: To describe the effectiveness of the prevention of mother-to-child HIV transmission program in Thailand. DESIGN AND METHODS: A register of HIV-exposed children at birth was created with follow-up of infection status. The register included children born to HIV-infected women between 1 January 2001 and 31 December 2003 at 84 public health hospitals in six provinces of Thailand. The main outcome measure was HIV infection in children. RESULTS: A total of 2200 children born to HIV-infected mothers were registered. Of these mother-infant pairs, 2105 (95.7%) received some antiretroviral prophylaxis, including 1358 (61.7%) who received the complete short-course zidovudine regimen during pregnancy and labor for the mother and after birth for the infant, with or without other antiretrovirals. HIV infection outcome was determined for 1667 (75.8%) children, of whom 158 [9.5%, 95% confidence interval (CI), 8.1-11.0%] were infected. Transmission risk was 6.8% (95% CI 5.2-8.9%) among 761 mother-infant pairs that received the complete zidovudine regimen alone, and 3.9% (95% CI, 2.2-6.6%) among 361 mother-infant pairs that received the complete zidovudine regimen combined with other antiretrovirals, usually nevirapine. The overall transmission risk from this cohort, including all antiretroviral prophylaxis combinations, is estimated to be 10.2%. CONCLUSIONS: The Thai national PMTCT program is effective in reducing mother-to-child transmission risk from the historical risk of 18.9-24.2%. The addition of nevirapine to short-course zidovudine beginning in 2004 may further improve program effectiveness in Thailand.

Factors associated with non-disclosure of HIV infection status of new mothers in Bangkok.

The objective of this study was to estimate HIV disclosure rates and identify factors that predict non-disclosure in Thai women who tested HIV positive during pregnancy or at delivery. This was a cohort study evaluating the implementation of prevention of mother-to-child HIV transmission programs at two Bangkok hospitals in 1999-2003. All HIV-infected women who delivered during the study period were enrollment eligible. Thai-language questionnaires were used to collect baseline data before discharge from the hospital. At the 1 and 4 month follow-up visits, women were asked if they had disclosed their HIV status. Of the 799 women who enrolled, 647 (81.0%) completed follow-up at 1 and 4 months. Four hundred fifty-three (70.0%) women disclosed their status by 1 month. Of the 194 women who had not disclosed by 1 month, 48 (24.7%) had disclosed their status by 4 months. An independent increased odds of non-disclosure by 1 month was associated with not having a partner tested for HIV (OR=5.83, 95% CI=3.19-9.08) or not knowing if the partner was ever tested for HIV (OR=1 3.02, 95% Cl=5.26-32.28), first learning of HIV positive status during delivery (OR=6.84, 95% CI=2.36-19.81) or after delivery (OR=3.14, 95% CI=1.57-6.26) and having >2 lifetime sexual partners (OR=1.71, 95% CI=1.04-2.82). Not living with a partner every day was associated with non-disclosure by 4 months in those women who had not disclosed by 1 month (OR=2.28, 95% CI=1.43-3.64). Despite high rates of disclosure by 1 month, 22.6% of women still had not disclosed their HIV status to their partners by 4 months. The benefits of disclosure warrant effective interventions targeted at women at risk for non-disclosure.

Human papillomavirus (HPV) detection among human immunodeficiency virus-infected pregnant Thai women: implications for future HPV immunization.

BACKGROUND: Human immunodeficiency virus (HIV)-infected women are at increased risk for developing cervical cancer and for infection with human papillomavirus (HPV). Prophylactic vaccines targeting HPV types 16 and 18 are being evaluated for efficacy among young women. GOAL: The goal was to assess the prevalence of HPV among HIV-infected pregnant women in Bangkok and to evaluate the need for prophylactic HPV vaccines studies in this population. STUDY DESIGN: The study population consisted of 256 HIV-infected pregnant women who participated in a mother-to-child HIV transmission trial. Stored cervicovaginal lavage samples were tested for the presence of HPV DNA by polymerase chain reaction with PGMY09/11 primers and reverse line-blot hybridization for determination of anogenital HPV types. RESULTS: HPV prevalence was 35.5% (91/256); high-risk HPV prevalence was 23.4% (60/256). HPV type 16 or 18 was present in 8.2% (21/256). Almost half of all infections were multiple. Furthermore, overall HPV detection was associated with abnormal cervical cytology (P<0.001) and higher HIV-plasma viral load (P=0.007). CONCLUSIONS: Only one-quarter of HIV-infected pregnant women in Bangkok had high-risk HPV types; less than 10% had HPV types 16 or 18. As the HPV prevalence is expected to increase during HIV disease, prophylactic vaccines targeting HPV types 16 and 18 should be studied among HIV-infected women not yet infected with these HPV types and not previously exposed.

Evaluating programs to prevent mother-to-child HIV transmission in two large Bangkok hospitals, 1999-2001.

The 2 largest maternity hospitals in Bangkok implemented comprehensive programs to prevent mother-to-child HIV transmission in 1998. We conducted a cross-sectional survey of post-partum HIV-infected women in 1999 through 2001 to evaluate these programs. Women were given structured interviews at 0 to 3 days, 1 month, and 2 months postpartum. Medical records of women and their newborns were reviewed. Of 488 enrolled women, 443 (91%) had antenatal care: 391 (88%) at study hospitals and 52 (12%) elsewhere. The HIV diagnosis was first known before pregnancy for 61 (13%) women, during pregnancy for 357 (73%) women, during labor for 22 (5%) women, and shortly after delivery for 48 (10%) women. Antenatal zidovudine (ZDV) was used by 347 (71%) women, and intrapartum ZDV was used by 372 (76%) women. Twelve (55%) of the 22 women who first learned of their HIV infection during labor took intrapartum ZDV. All 495 newborn infants started prophylactic ZDV; the first dose was given within 12 hours for 491 (99%) children. Ten (2%) children were breast-fed at least once by their mother, and 10 (2%) were breast-fed at least once by someone else. Although uptake of services was high, inconsistent antenatal care, fear of stigmatization, and difficulty in disclosing HIV status prevented some women from using services.

Maternal toxicity and pregnancy complications in human immunodeficiency virus-infected women receiving antiretroviral therapy: PACTG 316.

OBJECTIVE: The purpose of this study was to evaluate rates of maternal toxicity, pregnancy complications, and peripartum morbidity by type and duration of antiretroviral therapy (ART) during pregnancy. STUDY DESIGN: The Pediatric AIDS Clinical Trials Group (PACTG) Protocol 316 (PACTG 316) study evaluated the addition of intrapartum/neonatal nevirapine to background ART to reduce perinatal transmission of human immunodeficiency virus-1 (HIV-1). For this secondary analysis, women were categorized into one of six groups on the basis of ART during pregnancy (monotherapy [monoRx], combination without protease inhibitor [PI], combination with PI), and start time (early: before or during first trimester; late: second or third trimester). RESULTS: One thousand four hundred seven women were included: 288 monoRx late, 34 monoRx early, 327 combo, no PI late, 175 combo, no PI early, 320 combo, PI late, and 263 combo, PI early. Symptoms and laboratory abnormalities of moderate grade or more occurred in less than 5% of women. Only gestational diabetes (highest in combo PI early) varied significantly by therapy group. CONCLUSION: In HIV-infected women receiving prenatal care and ART, adverse events were uncommon.

Predose infant nevirapine concentration with the two-dose intrapartum neonatal nevirapine regimen: association with timing of maternal intrapartum nevirapine dose.

OBJECTIVE: To evaluate cord blood and predose nevirapine concentrations in infants exposed to the two-dose intrapartum neonatal nevirapine regimen. METHODS: The authors obtained plasma samples for nevirapine assay from cord blood and just prior to the 48-hours to 72-hours after birth neonatal nevirapine dose from a subset of infants participating in PACTG 316, a randomized, placebo-controlled trial of the two-dose intrapartum neonatal nevirapine regimen added to standard antiretroviral therapy. RESULTS: Nevirapine concentrations were measured in 109 cord blood samples and 149 predose samples. Cord blood nevirapine concentrations were below the target concentration of 100 ng/mL (10-times the in vitro IC(50) of nevirapine against wild-type HIV) in eight (7%) of 109 infants (95% confidence interval [CI], 3%-14%); the concentrations in six of these infants were below the assay limit of quantitation. Predose infant nevirapine concentrations were below 100 ng/mL in 23 (15%) of 149 infants (95% CI, 10%-22%); the concentrations in 13 of these infants were below the assay limit of quantitation. Lower predose nevirapine concentrations were associated with lower cord blood concentrations and a shorter interval between maternal dosing and delivery. All but one of the infants with predose nevirapine concentrations below the assay limit of quantitation were born less than 2 hours after maternal dosing. CONCLUSION: Infants born less than 2 hours after maternal nevirapine dosing during labor should receive a dose of nevirapine immediately after birth in addition to the standard infant dose at 48 to 72 hours.

Concentrations of protease inhibitors in cord blood after in utero exposure.

OBJECTIVE: To determine the concentrations of protease inhibitors in cord blood after prenatal protease inhibitor use by pregnant women. DESIGN: Retrospective analysis of samples collected in a clinical trial. METHODS: Protease inhibitor concentrations were measured in cord blood samples collected from women enrolling in the PACTG 316 study who were receiving prenatal protease inhibitor antiretroviral therapy. RESULTS: In cord blood samples from 68 women treated with protease inhibitors during pregnancy, the concentration of these drugs was below the assay lower limit of detection in most samples, including all samples from women receiving indinavir (n = 21) and saquinavir (n = 8), 5 of 6 samples (83%) from women receiving ritonavir and 24 of 38 samples (63%) from women receiving nelfinavir. CONCLUSIONS: Low protease inhibitor concentrations in the fetus decrease the likelihood of teratogenic and toxic effects of these drugs but could fail to provide protection from transplacental or intrapartum transmission of HIV-1.

Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission: a randomized trial.

CONTEXT: A 2-dose intrapartum/newborn nevirapine regimen reduced perinatal human immunodeficiency virus (HIV) transmission in Ugandan women not receiving antenatal antiretroviral therapy (ART). However, it is unknown whether the addition of the 2-dose nevirapine regimen to standard ART would further reduce perinatal HIV transmission. OBJECTIVE: To determine whether a 2-dose nevirapine regimen can decrease perinatal transmission of HIV in nonbreastfeeding women receiving standard ART. DESIGN AND SETTING: International, blinded, placebo-controlled, phase 3 trial enrolling women between May 1997 and June 2000 at clinical sites providing care for HIV infection throughout the United States, Europe, Brazil, and the Bahamas. PARTICIPANTS: A total of 1270 women received nevirapine (n = 642) or placebo (n = 628). Infants were followed up for 6 months to determine HIV-infection status, which was available for 1248 deliveries. INTERVENTION: A 200-mg dose of oral nevirapine to women after onset of labor and a 2-mg/kg dose of oral nevirapine to newborns between 48 and 72 hours after birth. MAIN OUTCOME MEASURES: Detection of HIV infection in infants and grade 3 and 4 toxic effects in women and newborns. RESULTS: After review by the data and safety monitoring board, the trial was stopped early because the overall transmission rates were significantly lower than assumed for the study design. Antenatal ART included zidovudine alone in 23%; combinations without protease inhibitors in 36%; and combinations with protease inhibitors in 41%. Thirty-four percent of women had elective cesarean delivery. No significant safety concerns were identified for women or infants. Detection of HIV infection occurred in 9 (1.4%; 95% confidence interval [CI], 0.6%-2.7%) of 631 nevirapine group deliveries and 10 (1.6%; 95% CI, 0.8%-2.9%) of 617 placebo group deliveries. The 95% CI for the difference in transmission rate (-0.2) between the 2 study arms ranged from -1.5% in favor of nevirapine to 1.2% in favor of placebo (P =.82, Fisher exact test). The transmission rate was higher in women with lower baseline CD4 cell counts and higher delivery HIV RNA levels, but there was no significant difference between treatment arms in any subgroup. CONCLUSION: Risk of perinatal HIV transmission was low and no benefit from additional intrapartum/newborn nevirapine was demonstrated when women received prenatal care and antenatal ART, and elective cesarean section was made available.

Preventing mother-to-child HIV transmission: the first year of Thailand's national program.

CONTEXT: Each year in Thailand, about 10,000 children are born at risk for mother-to-child human immunodeficiency virus (HIV) transmission. In 2000, Thailand implemented a national program to prevent mother-to-child HIV transmission. OBJECTIVE: To describe the results of implementation of the program. DESIGN: Monthly collection of summary data from hospitals. SETTING: Public health hospitals (n = 822) in all 12 regions of Thailand, representing 75 provinces, excluding Bangkok. PARTICIPANTS: Women giving birth from October 2000 through September 2001, including HIV-seropositive women and their neonates. MAIN OUTCOME MEASURES: Percentages of women giving birth who were tested for HIV, HIV-seropositive women giving birth who received antenatal prophylactic antiretroviral drugs, and HIV-exposed neonates who received prophylactic antiretroviral drugs and infant formula. RESULTS: Among 573,655 women (range, 27,344-77,806 by region) giving birth, 554,912 (96.7%) received antenatal care (range, 91.9%-98.8% by region). Of 554,912 women giving birth who had antenatal care, 517,488 (93.3%) were tested for HIV (range, 87.7%-99.4% by region) before giving birth; of 18,743 women giving birth who did not have antenatal care, 13,314 (71.0%) were tested for HIV (range, 21.7%-92.9% by region). Of 6646 HIV-seropositive women giving birth, 4659 (70.1%) received prophylactic antiretroviral drugs before delivery (range, 55.3%-81.2% by region). Of 6475 neonates of HIV-seropositive women, 5741 (88.7%) received prophylactic antiretroviral drugs (range, 67.4%-96.9% by region) and 5386 (83.2%) received infant formula (range, 65.3%-100% by region). CONCLUSIONS: Major program components of Thailand's national program for preventing mother-to-child HIV transmission were implemented. Thailand's experience may encourage other developing countries to implement or expand similar national programs.

Antiretroviral therapy during pregnancy and the risk of an adverse outcome.

BACKGROUND: Some studies suggest that combination antiretroviral therapy in pregnant women with human immunodeficiency virus type 1 (HIV-1) infection increases the risk of premature birth and other adverse outcomes of pregnancy. METHODS: We studied pregnant women with HIV-1 infection who were enrolled in seven clinical studies and delivered their infants from 1990 through 1998. The cohort comprised 2123 women who received antiretroviral therapy during pregnancy (monotherapy in 1590, combination therapy without protease inhibitors in 396, and combination therapy with protease inhibitors in 137) and 1143 women who did not receive antiretroviral therapy. RESULTS: After standardization for the CD4+ cell count and use or nonuse of tobacco, alcohol, and illicit drugs, the rate of premature delivery (<37 weeks of gestation) was similar among the women who received antiretroviral therapy and those who did not (16 percent and 17 percent, respectively); the rate of low birth weight (<2500 g) was 16 percent among the infants born to both groups; and the rate of very low birth weight (<1500 g) was 2 percent for the group that received antiretroviral therapy and 1 percent for the group that did not. The rates of low Apgar scores (<7) and stillbirth were also similar or the same in the two groups. After adjustment for multiple risk factors, combination antiretroviral therapy was not associated with an increased risk of premature delivery as compared with monotherapy (odds ratio, 1.08; 95 percent confidence interval, 0.71 to 1.62) or delivery of an infant with low birth weight (odds ratio, 1.03; 95 percent confidence interval, 0.64 to 1.63). Seven of the women who received combination therapy with protease inhibitors (5 percent) had infants with very low birth weight, as compared with nine women who received combination therapy without protease inhibitors (2 percent) (adjusted odds ratio, 3.56; 95 percent confidence interval, 1.04 to 12.19). CONCLUSIONS: As compared with no antiretroviral therapy or monotherapy, combination therapy for HIV-1 infection in pregnant women is not associated with increased rates of premature delivery or with low birth weight, low Apgar scores, or stillbirth in their infants. The association between combination therapy with protease inhibitors and an increased risk of very low birth weight requires confirmation.