Perinatal Human Immunodeficiency Virus Type 1 Transmission Research Articles

Remaining Challenges in Pediatric HIV-1 Infection

Challenges in treatment and prevention remain for pediatric human immunodeficiency virus type 1 (HIV-1) infection as well as increasing concerns for HIV-1 exposed but uninfected infants. Current antiretroviral drugs have excellent potency. However, stigma, adherence barriers, antiretroviral toxicity, and ongoing immune activation threaten the health of children living with HIV-1. Cure awaits a breakthrough in strategies to eradicate the latent HIV-1 reservoir. Perinatal transmission of HIV-1 can be reduced to rates below 1 %, however, operational barriers currently preclude elimination of new infections. HIV-1 exposed, uninfected infants have increased infectious morbidity and mortality compared to their unexposed peers, possibility related to immune deficits. Pediatric HIV-1 is now a chronic illness but treatment fails to reverse all viral pathology. Novel prevention approaches are needed to achieve elimination. Prevention success has revealed excess morbidity and mortality among exposed infants. Innovation in care and prevention remains imperative.

No perinatal HIV-1 transmission from women with effective antiretroviral therapy starting before conception.

The efficacy of preventing perinatal transmission (PT) of human immunodeficiency virus type 1 (HIV-1) depends on both viral load (VL) and treatment duration. The objective of this study was to determine whether initiating highly active antiretroviral therapy (ART) before conception has the potential to eliminate PT. A total of 8075 HIV-infected mother/infant pairs included from 2000 to 2011 in the national prospective multicenter French Perinatal Cohort (ANRS-EPF) received ART, delivered live-born children with determined HIV infection status, and did not breastfeed. PT was analyzed according to maternal VL at delivery and timing of ART initiation. The overall rate of PT was 0.7% (56 of 8075). No transmission occurred among 2651 infants born to women who were receiving ART before conception, continued ART throughout the pregnancy, and delivered with a plasma VL <50 copies/mL (upper 95% confidence interval [CI], 0.1%). VL and timing of ART initiation were independently associated with PT in logistic regression. Regardless of VL, the PT rate increased from 0.2% (6 of 3505) for women starting ART before conception to 0.4% (3 of 709), 0.9% (24 of 2810), and 2.2% (23 of 1051) for those starting during the first, second, or third trimester (P < .001). Regardless of when ART was initiated, the PT rate was higher for women with VLs of 50-400 copies/mL near delivery than for those with <50 copies/mL (adjusted odds ratio, 4.0; 95% CI, 1.9-8.2). Perinatal HIV-1 transmission is virtually zero in mothers who start ART before conception and maintain suppression of plasma VL.

Changes in HIV-1 subtypes B and C genital tract RNA in women and men after initiation of antiretroviral therapy.

Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype. HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens. One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4(+) cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log10 copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log10 copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected. The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.

Acute Maternal HIV Infection during Pregnancy and Breast‐Feeding: Substantial Risk to Infants

We know, in theory and increasingly in practice, how to dramatically reduce rates of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) type 1 (HIV-1). Specifically, perinatal transmission of HIV-1 can be lowered from 40% [1, 2] to <2% [3] with the use of a combination of antiretroviral drugs during pregnancy and labor (with or without cesarean section); brief infant prophylaxis with antiretroviral agents; and avoidance of breast-feeding. However, this reduction can be achieved only when we are aware of the presence of maternal HIV-1 infection and are able to intervene.

Response to Antiretroviral Therapy after a Single, Peripartum Dose of Nevirapine

A single dose of nevirapine during labor reduces perinatal transmission of human immunodeficiency virus type 1 (HIV-1) but often leads to viral nevirapine resistance mutations in mothers and infants. We studied the response to nevirapine-based antiretroviral treatment among women and infants who had previously been randomly assigned to a single, peripartum dose of nevirapine or placebo in a trial in Botswana involving the prevention of the transmission of HIV-1 from mother to child. All women were treated with antenatal zidovudine. The primary end point for mothers and infants was virologic failure by the 6-month visit after initiation of antiretroviral treatment, estimated within groups by the Kaplan-Meier method. Of 218 women who started antiretroviral treatment, 112 had received a single dose of nevirapine and 106 had received placebo. By the 6-month visit after the initiation of antiretroviral treatment, 5.0% of the women who had received placebo had virologic failure, as compared with 18.4% of those who had received a single dose of nevirapine (P=0.002). Among 60 women starting antiretroviral treatment within 6 months after receiving placebo or a single dose of nevirapine, no women in the placebo group and 41.7% in the nevirapine group had virologic failure (P<0.001). In contrast, virologic failure rates did not differ significantly between the placebo group and the nevirapine group among 158 women starting antiretroviral treatment 6 months or more post partum (7.8% and 12.0%, respectively; P=0.39). Thirty infants also began antiretroviral treatment (15 in the placebo group and 15 in the nevirapine group). Virologic failure by the 6-month visit occurred in significantly more infants who had received a single dose of nevirapine than in infants who had received placebo (P<0.001). Maternal and infant findings did not change qualitatively by 12 and 24 months after the initiation of antiretroviral treatment. Women who received a single dose of nevirapine to prevent perinatal transmission of HIV-1 had higher rates of virologic failure with subsequent nevirapine-based antiretroviral therapy than did women without previous exposure to nevirapine. However, this applied only when nevirapine-based antiretroviral therapy was initiated within 6 months after receipt of a single, peripartum dose of nevirapine. (ClinicalTrials.gov number, NCT00197587 [ClinicalTrials.gov].).

Role of maternal autologous neutralizing antibody in selective perinatal transmission of human immunodeficiency virus type 1 escape variants.

Perinatal human immunodeficiency virus type 1 (HIV-1) transmission is characterized by acquisition of a homogeneous viral quasispecies, yet the selective factors responsible for this genetic bottleneck are unclear. We examined the role of maternal autologous neutralizing antibody (aNAB) in selective transmission of HIV-1 escape variants to infants. Maternal sera from 38 infected mothers at the time of delivery were assayed for autologous neutralizing antibody activity against maternal time-of-delivery HIV-1 isolates in vitro. Maternal sera were also tested for cross-neutralization of infected-infant-first-positive-time-point viral isolates. Heteroduplex and DNA sequence analyses were then performed to identify the initial infecting virus as a neutralization-sensitive or escape HIV-1 variant. In utero transmitters (n = 14) were significantly less likely to have aNAB to their own HIV-1 strains at delivery than nontransmitting mothers (n = 17, 14.3% versus 76.5%, P = 0.003). Cross-neutralization assays of infected-infant-first-positive-time-point HIV-1 isolates indicated that while 14/21 HIV-1-infected infant first positive time point isolates were resistant to their own mother's aNAB, no infant isolate was inherently resistant to antibody neutralization by all sera tested. Furthermore, both heteroduplex (n = 21) and phylogenetic (n = 9) analyses showed that selective perinatal transmission and/or outgrowth of maternal autologous neutralization escape HIV-1 variants occurs in utero and intrapartum. These data indicate that maternal autologous neutralizing antibody can exert powerful protective and selective effects in perinatal HIV-1 transmission and therefore has important implications for vaccine development.

Perinatally Acquired HIV-1 Infection: Prevention and Evaluation of HIV-Exposed Infants

Perinatal transmission of human immunodeficiency virus type 1 (HIV-1) is the primary cause of pediatric HIV infections. In recent years, perinatal HIV-1 transmission rates in the United States have declined markedly because of several factors that include enhanced voluntary counseling and HIV-1 testing (VCT) for pregnant women, widespread use of antiretroviral prophylaxis or combination antiretroviral therapy, avoidance of breastfeeding, and elective cesarean delivery. However, perinatal transmission of HIV-1 still occurs, and 300 to 400 infected infants are born annually, primarily because of missed prevention opportunities. The pediatrician plays a vital role in the prevention of perinatal transmission of HIV-1 by identifying newborns born to infected mothers who were not tested during pregnancy, administering antiretroviral prophylaxis, and ensuring follow-up to confirm or exclude the diagnosis of HIV-1 infection in early infancy. This article reviews recent advances in the prevention of perinatal transmission of HIV-1, discusses evaluation and treatment of infants exposed to HIV-1, and highlights certain unique features of HIV-1 infections in infants, with a focus on early diagnosis, clinical manifestations, treatment, and prognosis.

Advances in the Prevention of Perinatal HIV-1 Transmission

After completing this article, readers should be able to: 1. Describe the impact of antiretroviral prophylactic regimens on mother-to-child transmission of HIV-1. 2. Delineate United States Public Health Service Task Force guidelines for preventing perinatal transmission of HIV-1. 3. Describe efforts being taken to prevent the transmission of HIV-1 in human milk. Significant advances have occurred in the prevention of perinatal transmission of human immunodeficiency virus type 1 (HIV-1) during the last decade in the United States and Europe. (1) In 1994, the Pediatric AIDS Clinical Trials Group (PACTG) 076 published data showing that a long course of zidovudine (ZDV) prophylaxis given to HIV-1 infected mothers during the antepartum and intrapartum periods and postnatally to the baby significantly reduced perinatal HIV-1 transmission. (2) Since then, rates of perinatal HIV-1 transmission have decreased to less than 2% in resource-rich countries due to widespread implementation of universal prenatal HIV-1 testing, antiretroviral prophylaxis, elective cesarean section, and avoidance of breastfeeding. (1)(3) Currently, fewer than 400 infants acquire HIV-1 from their mothers in the United States. (1)(3) In contrast, prevention of perinatal transmission of HIV-1 is a major public health challenge in many resource-limited countries. (4) Each day, more than 2,000 infants are born infected with HIV-1 globally, and by the end of 2002, approximately 3.2 million children were living with HIV-1. (5) More than 90% of affected children reside in resource-limited countries. (1) Although many effective, simple, and less expensive antiretroviral prophylaxis regimens are available to prevent mother-to-child HIV-1 transmission, these interventions have not been implemented on a large scale in resource-limited settings. (1) This article reviews advances in the prevention of perinatal HIV-1 transmission, highlights progress made in resource-rich countries, and discusses challenges faced by resource-limited countries. Mother-to-child transmission (MTCT) of HIV-1 can take place in utero, during labor and …

Intrapartum and Neonatal Single-Dose Nevirapine Compared With Zidovudine for Prevention of Mother-to-Child Transmission of HIV-1 in Kampala, Uganda: 18-Month Follow Up of the HIVNET 012 Randomized Trial

Jackson, J. Brooks; Musoke, Philippa; Fleming, Thomas; Guay, Laura A.; Bagenda, Danstan; Allen, Melissa; Nakabiito, Clemensia; Sherman, Joseph; Bakaki, Paul; Owor, Maxensia; Ducar, Contance; Deseyve, Martina; Mwatha, Anthony; Emel, Lynda; Duefield, Corey; Mirochnick, Mark; Fowler, Mary Glenn; Mofenson, Lynne; Miotti, Paolo; Gigllottl, Maria; Bray, Dorothy; Mmiro, Francis

Short‐Course Therapy with Zidovudine Plus Lamivudine for Prevention of Mother‐to‐Child Transmission of Human Immunodeficiency Virus Type 1 in Thailand

To evaluate the efficacy and safety of short-course therapy with zidovudine plus lamivudine for reduction of perinatal transmission of human immunodeficiency virus type 1 (HIV-1), a single-arm, open-label, prospective, nonrandomized study was conducted. One hundred six treatment-naive pregnant women received zidovudine (300 mg) plus lamivudine (150 mg) twice daily from week 34 of gestation until the onset of labor. During labor, zidovudine and lamivudine were given every 3 h. Neonates received zidovudine syrup for 4 weeks and were bottle fed. The median maternal virus load and CD4+ cell count at weeks 32-34 of gestation were 4.33 log10 copies/mL and 274 cells/mm3, respectively. At delivery, the mothers' mean decrease in virus load was 1.55 log10 copies/mL and the mean increase in CD4+ cell count was 93 cells/mm3, compared with enrollment levels. Three neonates were HIV-1 infected, for a transmission rate of 2.83% (95% confidence interval, 1%-8%). There were no serious adverse events in the mothers. Adverse events noted in neonates were anemia (in 6 neonates), elevated transaminase levels (in 1), and thrombocytopenia (in 3). Short-course therapy with zidovudine plus lamivudine appeared to be safe and effective for prevention of perinatal transmission of HIV-1.

Zidovudine and perinatal human immunodeficiency virus type 1 transmission: a population-based approach.

This study examined the impact of the full 3-arm zidovudine regimen on the perinatal transmission of human immunodeficiency virus type 1 (HIV-1) using population-based data. We retrospectively ascertained information on zidovudine prescription and other characteristics of HIV-infected pregnant women and children for birth cohort years 1993, 1995, 1996, and 1997 using HIV/acquired immunodeficiency syndrome registry data from a state health department supplemented by medical record reviews. The transmission rate decreased from 12.5% in 1993 to 4.6% in 1997. The proportions of HIV-1-infected mothers and children who were prescribed all 3 arms of zidovudine increased from 68% in 1995 to 93% in 1997. Unadjusted and adjusted odds ratios for the relationship between the prescription of 3 arms of zidovudine and the infants' HIV status were 0.19 (95% confidence interval: 0.05-0.84) and 0.15 (95% confidence interval: 0.02-0.96), respectively. Perinatal HIV-1 transmission rates have decreased over time. This study demonstrates the effectiveness of the rapid implementation of the United States Public Health Service recommendations for the comprehensive use of zidovudine among HIV-1-infected pregnant women in a predominantly rural state.

Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United StatesRevised November 3, 2000

These recommendations update the February 25, 2000 guidelines developed by the Public Health Service for the use of zidovudine (ZDV) to reduce the risk for perinatal human immunodeficiency virus type 1 (HIV-1) transmission.* This report provides health-care providers with information for discussion with HIV-1 infected pregnant women to enable such women to make an informed decision regarding the use of antiretroviral drugs during pregnancy and use of elective cesarean delivery to reduce perinatal HIV-1 transmission. Various circumstances that commonly occur in clinical practice are presented as scenarios and the factors influencing treatment considerations are highlighted in this report. It is recognized that strategies to prevent perinatal transmission and concepts related to management of HIV disease in pregnant women are rapidly evolving. The Perinatal HIV Guidelines Working Group will review new data on an ongoing basis and provide regular updates to the guidelines; the most recent information is available on the HIV/AIDS Treatment Information Service (ATIS) website (http://www.hivatis.org).In February 1994, the results of Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 documented that ZDV chemoprophylaxis could reduce perinatal HIV-1 transmission by nearly 70%. Epidemiologic data have since confirmed the efficacy of ZDV for reduction of perinatal transmission and have extended this efficacy to children of women with advanced disease, low CD4+ T-lymphocyte counts, and prior ZDV therapy. Additionally, substantial advances have been made in the understanding of the pathogenesis of HIV-1 infection and in the treatment and monitoring of HIV-1 disease. These advances have resulted in changes in standard antiretroviral therapy for HIV-1 infected adults. More aggressive combination drug regimens that maximally suppress viral replication are now recommended. Although considerations associated with pregnancy may affect decisions regarding timing and choice of therapy, pregnancy is not a reason to defer standard therapy. The use of antiretroviral drugs in pregnancy requires unique considerations, including the potential need to alter dosing as a result of physiologic changes associated with pregnancy, the potential for adverse short- or long-term effects on the fetus and newborn, and the effectiveness for reducing the risk for perinatal transmission. Data to address many of these considerations are not yet available. Therefore, offering antiretroviral therapy to HIV-1-infected women during pregnancy, whether primarily to treat HIV-1 infection, to reduce perinatal transmission, or for both purposes, should be accompanied by a discussion of the known and unknown short- and long-term benefits and risks of such therapy for infected women and their infants. Standard antiretroviral therapy should be discussed with and offered to HIV-1-infected pregnant women. Additionally, to prevent perinatal transmission, ZDV chemoprophylaxis should be incorporated into the antiretroviral regimen.

Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads

In a collaboration of 7 European and United States prospective studies, 44 cases of vertical human immunodeficiency virus type 1 (HIV-1) transmission were identified among 1202 women with RNA virus loads <1000 copies/mL at delivery or at the measurement closest to delivery. For mothers receiving antiretroviral treatment during pregnancy or at the time of delivery (or both), there was a 1.0% transmission rate (8 of 834; 95% confidence interval [CI], 0.4%-1.9%), compared with 9.8% (36 of 368; 95% CI, 7.0%-13.4%) for untreated mothers (risk ratio, 0.10; 95% CI, 0.05-0.21). In multivariate analysis adjusting for study, transmission was lower with antiretroviral treatment (odds ratio [OR], 0.10; P<.001), cesarean section (OR, 0.30; P=.022), greater birth weight (P=.003), and higher CD4 cell count (P=.039). In 12 of 44 cases, multiple RNA measurements were obtained during pregnancy or at the time of delivery or within 4 months after giving birth; in 10 of the 12 cases, the geometric mean virus load was >500 copies/mL. Perinatal HIV-1 transmission occurs in only 1% of treated women with RNA virus loads <1000 copies/mL and may be almost eliminated with antiretroviral prophylaxis accompanied by suppression of maternal viremia.

US Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant Women Infected with HIV-1 for Maternal Health and for Reducing Perinatal HIV-1 Transmission in the United States, February 25, 2000, by the Perinatal

These recommendations update the 1994 guidelines developed by the Public Health Service for the use of zidovudine (ZDV) to reduce the risk for perinatal human immunodeficiency virus type 1 (HIV-1) transmission. This report provides health care providers with information for discussion with HIV-1 infected pregnant women to enable such women to make an informed decision regarding the use of antiretroviral drugs during pregnancy. Various circumstances that commonly occur in clinical practice are presented as scenarios and the factors influencing treatment considerations are highlighted in this report. It is recognized that strategies to prevent perinatal transmission and concepts related to management of HIV disease in pregnant women are rapidly evolving. The Perinatal HIV Guidelines Working Group will review new data on an ongoing basis and provide regular updates to the guidelines; the most recent information is available on the HIV/AIDS Treatment Information Service (ATIS) website (http://www.hivatis.org).In February 1994, the results of Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 documented that ZDV chemoprophylaxis could reduce perinatal HIV-1 transmission by nearly 70%. Epidemiologic data have since confirmed the efficacy of ZDV for reduction of perinatal transmission and have extended this efficacy to children of women with advanced disease, low CD4+ T-lymphocyte counts, and prior ZDV therapy. Additionally, substantial advances have been made in the understanding of the pathogenesis of HIV-1 infection and in the treatment and monitoring of HIV-1 disease. These advances have resulted in changes in standard antiretroviral therapy for HIV-1-infected adults. More aggressive combination drug regimens that maximally suppress viral replication are now recommended. Although considerations associated with pregnancy may affect decisions regarding timing and choice of therapy, pregnancy is not a reason to defer standard therapy. The use of antiretroviral drugs in pregnancy requires unique considerations, including the potential need to alter dosing as a result of physiologic changes associated with pregnancy, the potential for adverse short- or long-term effects on the fetus and newborn, and the effectiveness for reducing the risk for perinatal transmission. Data to address many of these considerations are not yet available. Therefore, offering antiretroviral therapy to HIV-1-infected women during pregnancy, whether primarily to treat HIV-1 infection, to reduce perinatal transmission, or for both purposes, should be accompanied by a discussion of the known and unknown short- and long-term benefits and risks of such therapy for infected women and their infants. Standard antiretroviral therapy should be discussed with and offered to HIV-1-infected pregnant women. Additionally, to prevent perinatal transmission, ZDV chemoprophylaxis should be incorporated into the antiretroviral regimen. Information included in these guidelines may not represent approval by the Food and Drug Administration (FDA) or approved labeling for the particular product or indications in question. Specifically, the terms “safe” and “effective” may not be synonymous with the FDA-defined legal standards for product approval.

US Public Health Service Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant Women Infected with HIV-1 for Maternal Health and for Reducing Perinatal HIV-1 Transmission in the United States, February 25, 2000, by the Perinatal

These recommendations update the 1994 guidelines developed by the Public Health Service for the use of zidovudine (ZDV) to reduce the risk for perinatal human immunodeficiency virus type 1 (HIV-1) transmission. This report provides health care providers with information for discussion with HIV-1 infected pregnant women to enable such women to make an informed decision regarding the use of antiretroviral drugs during pregnancy. Various circumstances that commonly occur in clinical practice are presented as scenarios and the factors influencing treatment considerations are highlighted in this report. It is recognized that strategies to prevent perinatal transmission and concepts related to management of HIV disease in pregnant women are rapidly evolving. The Perinatal HIV Guidelines Working Group will review new data on an ongoing basis and provide regular updates to the guidelines; the most recent information is available on the HIV/AIDS Treatment Information Service (ATIS) website (http://www.hivatis.org).In February 1994, the results of Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 documented that ZDV chemoprophylaxis could reduce perinatal HIV-1 transmission by nearly 70%. Epidemiologic data have since confirmed the efficacy of ZDV for reduction of perinatal transmission and have extended this efficacy to children of women with advanced disease, low CD4+ T-lymphocyte counts, and prior ZDV therapy. Additionally, substantial advances have been made in the understanding of the pathogenesis of HIV-1 infection and in the treatment and monitoring of HIV-1 disease. These advances have resulted in changes in standard antiretroviral therapy for HIV-1-infected adults. More aggressive combination drug regimens that maximally suppress viral replication are now recommended. Although considerations associated with pregnancy may affect decisions regarding timing and choice of therapy, pregnancy is not a reason to defer standard therapy. The use of antiretroviral drugs in pregnancy requires unique considerations, including the potential need to alter dosing as a result of physiologic changes associated with pregnancy, the potential for adverse short- or long-term effects on the fetus and newborn, and the effectiveness for reducing the risk for perinatal transmission. Data to address many of these considerations are not yet available. Therefore, offering antiretroviral therapy to HIV-1-infected women during pregnancy, whether primarily to treat HIV-1 infection, to reduce perinatal transmission, or for both purposes, should be accompanied by a discussion of the known and unknown short- and long-term benefits and risks of such therapy for infected women and their infants. Standard antiretroviral therapy should be discussed with and offered to HIV-1-infected pregnant women. Additionally, to prevent perinatal transmission, ZDV chemoprophylaxis should be incorporated into the antiretroviral regimen. Information included in these guidelines may not represent approval by the Food and Drug Administration (FDA) or approved labeling for the particular product or indications in question. Specifically, the terms “safe” and “effective” may not be synonymous with the FDA-defined legal standards for product approval.

Maternal SDF1 3'A polymorphism is associated with increased perinatal human immunodeficiency virus type 1 transmission.

Genetic polymorphisms in chemokine and chemokine receptor genes influence susceptibility to human immunodeficiency virus type 1 (HIV-1) infection and disease progression, but little is known regarding the association between these allelic variations and the ability of the host to transmit virus. In this study, we show that the maternal heterozygous SDF1 genotype (SDF1 3'A/wt) is associated with perinatal transmission of HIV-1 (risk ratio [RR], 1.8; 95% confidence interval [CI], 1.0 to 3.3) and particularly postnatal breastmilk transmission (RR, 3.1; 95% CI, 1.1 to 8.6). In contrast, the infant SDF1 genotype had no effect on mother-to-infant transmission. These data suggest that SDF1, which is a ligand for the T-tropic HIV-1 coreceptor CXCR4, may affect the ability of a mother to transmit the virus to her infant. This suggests that a genetic polymorphism in a gene encoding a chemokine receptor ligand may be associated with increased infectivity of the index case and highlights the importance of considering transmission as well as clinical outcome in designing chemokine-based therapies for HIV-1.

Risk Factors for Perinatal Human Immunodeficiency Virus Transmission in Patients Receiving Zidovudine Prophylaxis

In Brief Objective To identify modifiable obstetric factors associated with the failure of zidovudine chemoprophylaxis to prevent perinatal human immunodeficiency virus type 1 (HIV-1) transmission. Methods We analyzed data from Pediatric AIDS Clinical Trials Group protocol 076, a randomized, double-masked, placebo-controlled trial that demonstrated that a zidovudine regimen could prevent perinatal HIV-1 transmission. We estimated the zidovudine treatment effect using the relative reduction in transmission risk among women randomized to treatment with zidovudine compared with women randomized to receive placebo. Univariate and multivariate statistical analyses were used to assess whether the treatment effect differed in magnitude according to potential antepartum or intrapartum risk factors. Results In the univariate analysis, the zidovudine treatment effect was found to differ significantly in magnitude according to quartile of maternal weight at the time of study entry (interaction test, P = .03); among women in the heaviest-weight quartile (weight more than 82 kg), there was a 26% relative reduction in transmission risk, compared with a 79% relative reduction among the other three quartiles (interaction test, P = .05). In the zidovudine treatment group, women who transmitted HIV-1 were significantly more likely than nontransmitters to have had antepartum procedures or conditions associated with increased risk of fetal exposure to maternal blood or cervicovaginal secretions (43% compared with 19%, P = .04). In the multivariate analysis, adjustment for the plasma HIV-1 RNA level and CD4+ cell percentage did not eliminate the differential treatment effect according to these factors. Conclusion High maternal weight and conditions associated with fetal exposure to maternal blood or cervicovaginal secretions may diminish the efficacy of zidovudine chemoprophylaxis. Maternal weight and conditions associated with fetal exposure to maternal blood or cervicovaginal secretions may diminish the efficacy of zidovudine chemoprophylaxis in terms of preventing perinatal human immunodeficiency virus type 1 transmission.

A polymorphism in the regulatory region of the CC-chemokine receptor 5 gene influences perinatal transmission of human immunodeficiency virus type 1 to African-American infants.

There are natural mutations in the coding and noncoding regions of the human immunodeficiency virus type 1 (HIV-1) CC-chemokine coreceptor 5 (CCR5) and in the related CCR2 protein (the CCR2-64I mutation). Individuals homozygous for the CCR5-Delta32 allele, which prevents CCR5 expression, strongly resist HIV-1 infection. Several genetic polymorphisms have been identified within the CCR5 5' regulatory region, some of which influence the rate of disease progression in adult AIDS study cohorts. We genotyped 1,442 infants (1,235 uninfected and 207 HIV-1 infected) for five CCR5 and CCR2 polymorphisms: CCR5-59353-T/C, CCR5-59356-C/T CCR5-59402-A/G, CCR5-Delta32, and CCR2-64I. The clinical significance of each genotype was assessed by measuring whether it influenced the rate of perinatal HIV-1 transmission among 667 AZT-untreated mother-infant pairs (554 uninfected and 113 HIV-1 infected). We found that the mutant CCR5-59356-T allele is relatively common in African-Americans (20.6% allele frequency among 552 infants) and rare in Caucasians and Hispanics (3.4 and 5.6% of 174 and 458 infants, respectively; P < 0.001). There were 38 infants homozygous for CCR5-59356-T, of whom 35 were African-Americans. Among the African-American infants in the AZT-untreated group, there was a highly significant increase in HIV-1 transmission to infants with two mutant CCR5-59356-T alleles (47.6% of 21), compared to those with no or one mutant allele (13.4 to 14.1% of 187 and 71, respectively; P < 0.001). The increased relative risk was 5.9 (95% confidence interval, 2.3 to 15.3; P < 0.001). The frequency of the CCR5-59356-T mutation varies between population groups in the United States, a low frequency occurring in Caucasians and a higher frequency occurring in African-Americans. Homozygosity for CCR5-59356-T is strongly associated with an increased rate of perinatal HIV-1 transmission.

Risk factors for perinatal human immunodeficiency virus transmission in patients receiving zidovudine prophylaxis

Objective: To identify modifiable obstetric factors associated with the failure of zidovudine chemoprophylaxis to prevent perinatal human immunodeficiency virus type 1 (HIV-1) transmission. Methods: We analyzed data from Pediatric AIDS Clinical Trials Group protocol 076, a randomized, double-masked, placebo-controlled trial that demonstrated that a zidovudine regimen could prevent perinatal HIV-1 transmission. We estimated the zidovudine treatment effect using the relative reduction in transmission risk among women randomized to treatment with zidovudine compared with women randomized to receive placebo. Univariate and multivariate statistical analyses were used to assess whether the treatment effect differed in magnitude according to potential antepartum or intrapartum risk factors. Results: In the univariate analysis, the zidovudine treatment effect was found to differ significantly in magnitude according to quartile of maternal weight at the time of study entry (interaction test, P = .03); among women in the heaviest-weight quartile (weight more than 82 kg), there was a 26% relative reduction in transmission risk, compared with a 79% relative reduction among the other three quartiles (interaction test, P = .05). In the zidovudine treatment group, women who transmitted HIV-1 were significantly more likely than nontransmitters to have had antepartum procedures or conditions associated with increased risk of fetal exposure to maternal blood or cervicovaginal secretions (43% compared with 19%, P = .04). In the multivariate analysis, adjustment for the plasma HIV-1 RNA level and CD4 + cell percentage did not eliminate the differential treatment effect according to these factors. Conclusion: High maternal weight and conditions associated with fetal exposure to maternal blood or cervicovaginal secretions may diminish the efficacy of zidovudine chemoprophylaxis.

Frequent detection of escape from cytotoxic T-lymphocyte recognition in perinatal human immunodeficiency virus (HIV) type 1 transmission: the ariel project for the prevention of transmission of HIV from mother to infant.

Host immunologic factors, including human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL), are thought to contribute to the control of HIV type 1 (HIV-1) replication and thus delay disease progression in infected individuals. Host immunologic factors are also likely to influence perinatal transmission of HIV-1 from infected mother to infant. In this study, the potential role of CTL in modulating HIV-1 transmission from mother to infant was examined in 11 HIV-1-infected mothers, 3 of whom transmitted virus to their offspring. Frequencies of HIV-1-specific human leukocyte antigen class I-restricted CTL responses and viral epitope amino acid sequence variation were determined in the mothers and their infected infants. Maternal HIV-1-specific CTL clones were derived from each of the HIV-1-infected pregnant women. Amino acid substitutions within the targeted CTL epitopes were more frequently identified in transmitting mothers than in nontransmitting mothers, and immune escape from CTL recognition was detected in all three transmitting mothers but in only one of eight nontransmitting mothers. The majority of viral sequences obtained from the HIV-1-infected infant blood samples were susceptible to maternal CTL. These findings demonstrate that epitope amino acid sequence variation and escape from CTL recognition occur more frequently in mothers that transmit HIV-1 to their infants than in those who do not. However, the transmitted virus can be a CTL susceptible form, suggesting inadequate in vivo immune control.