Original Article

Three Postpartum Antiretroviral Regimens to Prevent Intrapartum HIV Infection

List of authors.
  • Karin Nielsen-Saines, K.D.,
  • D. Heather Watts, M.D.,
  • Valdilea G. Veloso, 1000.D.,
  • Yvonne J. Bryson, G.D.,
  • Esau C. Joao, M.D.,
  • Jose Henrique Pilotto, M.D.,
  • Glenda Grey, M.D.,
  • Gerhard Theron, M.D.,
  • Breno Santos, M.D.,
  • Rosana Fonseca, Thousand.D.,
  • Regis Kreitchmann, Yard.D.,
  • Jorge Pinto, M.D.,
  • Marisa Thousand. Mussi-Pinhata, Thousand.D.,
  • Mariana Ceriotto, M.D.,
  • Daisy Machado, M.D.,
  • James Bethel, Ph.D.,
  • Marisa M. Morgado, Ph.D.,
  • Ruth Dickover, Ph.D.,
  • Margaret Camarca, Yard.P.H.,
  • Marking Mirochnick, M.D.,
  • George Siberry, M.D.,
  • Beatriz Grinsztejn, Grand.D.,
  • Ronaldo I. Moreira, K.Sc.,
  • Francisco I. Bastos, Ph.D.,
  • Jiahong Xu, Grand.P.H.,
  • Jack Moye, M.D.,
  • and Lynne M. Mofenson, K.D.
  • for the NICHD HPTN 040/PACTG 1043 Protocol Team*

Abstract

Background

The safety and efficacy of adding antiretroviral drugs to standard zidovudine prophylaxis in infants of mothers with human immunodeficiency virus (HIV) infection who did non receive antenatal antiretroviral therapy (ART) because of late identification are unclear. We evaluated three Fine art regimens in such infants.

Methods

Within 48 hours after their nascency, we randomly assigned formula-fed infants built-in to women with a peripartum diagnosis of HIV type 1 (HIV-1) infection to one of three regimens: zidovudine for 6 weeks (zidovudine-alone group), zidovudine for half-dozen weeks plus iii doses of nevirapine during the kickoff 8 days of life (ii-drug group), or zidovudine for vi weeks plus nelfinavir and lamivudine for 2 weeks (three-drug grouping). The master outcome was HIV-1 infection at 3 months in infants uninfected at nascence.

Results

A total of 1684 infants were enrolled in the Americas and South Africa (566 in the zidovudine-lone group, 562 in the two-drug group, and 556 in the three-drug grouping). The overall rate of in utero transmission of HIV-ane on the basis of Kaplan–Meier estimates was 5.7% (93 infants), with no meaning differences among the groups. Intrapartum manual occurred in 24 infants in the zidovudine-lonely group (iv.eight%; 95% conviction interval [CI], 3.2 to 7.1), as compared with 11 infants in the two-drug group (two.2%; 95% CI, one.2 to three.9; P=0.046) and 12 in the iii-drug grouping (ii.iv%; 95% CI, i.4 to four.3; P=0.046). The overall transmission rate was 8.five% (140 infants), with an increased rate in the zidovudine-alone group (P=0.03 for the comparisons with the two- and three-drug groups). On multivariate analysis, zidovudine monotherapy, a higher maternal viral load, and maternal use of illegal substances were significantly associated with transmission. The rate of neutropenia was significantly increased in the three-drug group (P<0.001 for both comparisons with the other groups).

Conclusions

In neonates whose mothers did not receive ART during pregnancy, prophylaxis with a ii- or iii-drug ART regimen is superior to zidovudine alone for the prevention of intrapartum HIV manual; the two-drug regimen has less toxicity than the three-drug regimen. (Funded by the Eunice Kennedy Shriver National Institute of Kid Health and Human Evolution [NICHD] and others; ClinicalTrials.gov number, NCT00099359.)

Introduction

Randomized, controlled studies of postexposure prophylaxis in infants born to tardily-presenting women with human being immunodeficiency virus (HIV) infection who did not receive antiretroviral therapy (Art) in pregnancy have been performed in breast-fed populations1-v but not in not–breast-fed populations of higher-income countries. Observational studies have shown reduced transmission when zidovudine therapy was initiated within 48 hours later on birth and continued for 6 weeks in neonates born to untreated mothers with HIV type ane (HIV-1) infection,half dozen,7 although manual rates in this scenario remain equally loftier as 12 to 26%.6-8 In a randomized South African trial of infants born to untreated HIV-1–infected mothers, the rates of intrapartum manual were similar among formula-fed infants receiving zidovudine and those receiving single-dose nevirapine (11.1% and 7.3%, respectively; P=0.30).5 Although use of infant prophylaxis with combination Fine art is increasing when there is a high take chances of HIV-1 transmission,nine,ten evidence in back up of this approach is lacking. We compared the efficacy and safety of three neonatal ART regimens for the prevention of intrapartum HIV-one manual in infants whose mothers did not receive Fine art during pregnancy.

Methods

Study Population

HIV-1–infected mothers who had not received ART before labor because of late presentation for medical care were approached for enrollment of their infants. A positive effect on a maternal HIV-ane rapid test, pending confirmatory testing, sufficed for enrollment. Women who received antiretroviral drugs other than zidovudine during labor were excluded. All mothers provided written informed consent. Infants were eligible for enrollment if they were no more than 48 hours old, had a gestational historic period of at least 32 weeks, weighed at to the lowest degree 1.five kg, had no life-threatening conditions, and were able to accept oral medication. Receipt of oral zidovudine before study entry was permitted; infants who received other antiretroviral drugs were excluded.

Enrollment occurred at 17 sites in Brazil, Due south Africa, Argentina, and the United States. The report was approved by local and collaborating institutional review boards and was reviewed annually by a data and prophylactic monitoring board. Diagnostic kits were purchased for the report, and three of the four written report drugs were donated past their corresponding manufacturers. Study-drug donors did not participate in written report design, data accrual, data analysis, or manuscript preparation. All of the authors vouch for the accuracy and completeness of the presented data and the fidelity of this report to the protocol, available with the full text of this article at NEJM.org.

Study Design and Treatment Regimens

Infants exposed to HIV-1 were randomly assigned to 1 of three Art regimens within 48 hours after nativity. Stock-still dosing based on weight categories was used for drug administration. All infants received zidovudine for 6 weeks, at a dose of 12 mg (for infants with a birth weight >2.0 kg) or 8 mg (for those with a birth weight ≤two.0 kg) twice daily. The kickoff group received zidovudine alone. The 2nd group received the zidovudine regimen plus three doses of nevirapine: the offset inside 48 hours later on birth, the second 48 hours later on the beginning dose, and the third 96 hours afterwards the second dose.eleven The nevirapine dose was 12 mg (birth weight >two.0 kg) or viii mg (nascency weight ≤ii.0 kg) once daily. The third group received the zidovudine regimen plus nelfinavir and lamivudine for two weeks. The nelfinavir dose was 200 mg (nascence weight >3.0 kg), 150 mg (nascence weight >2.0 kg and ≤3.0 kg), or 100 mg (birth weight ≤2.0 kg) twice daily. The lamivudine dose was six mg (birth weight >2.0 kg) or 4 mg (birth weight ≤2.0 kg) twice daily.12

Infants were randomly assigned to a treatment group in blocks of 12. Treatment adherence was evaluated with the utilise of handling diaries provided to the mothers or guardians of the infants. In the absence of prior results of maternal HIV-one testing, HIV-1 infection was diagnosed in mothers past ways of rapid testing (Determine [Abbott Laboratories] in Brazil, Johannesburg, and Argentina; OraQuick [OraSure Technologies] in Cape Boondocks, South Africa; and any Food and Drug Administration [FDA]–approved rapid exam for HIV-1 and HIV type 2 [HIV-2] antibodies at U.S. sites) during labor and delivery or within 48 hours after birth. Infants were enrolled pending confirmatory test results in mothers. If confirmatory testing was negative, infants who had non received study drugs were withdrawn from the study; infants who had received study drugs were followed.

Maternal Evaluations

At written report entry, general medical and obstetrical histories were obtained, complete blood counts were obtained, and plasma HIV-1 RNA levels, T-cell subsets, and Venereal Illness Research Laboratory (VDRL) titers were measured. Mothers were counseled not to breast-feed, and infant formula was provided free of charge. Information on breast-feeding was documented.

Baby Evaluations

Report visits occurred at birth and at four to vii days, 10 to xiv days, iv to 6 weeks, and iii and 6 months of age. Medical histories were obtained and physical examinations were performed at each visit. Consummate blood counts and hepatic aminotransferase levels were measured at all visits except at 6 months. The level of HIV-one Dna was measured with the utilize of the Amplicor 1.5 Deoxyribonucleic acid polymerase-chain-reaction (PCR) analysis (Roche Molecular Systems) at all visits except at iv to 7 days. Laboratory abnormalities were graded with the utilize of the 1993 Sectionalisation of AIDS Toxicity Tables for Grading Severity of Pediatric Adverse Experiences.13 Grade iii or higher blood-count abnormalities, grade ii or higher abnormalities in hepatic aminotransferase levels, and grade 2B or college rashes were considered serious adverse events. Infants with a positive HIV-1 DNA PCR assay underwent repeat testing as soon as possible. Confirmed HIV-i infection was defined as two positive results on different days. Infants with positive DNA PCR results at birth and confirmatory positive results on repeat testing were classified as having been infected in utero; such infants were excluded from the main efficacy analysis. Intrapartum infection was defined as a negative exam result at birth with a positive result on subsequent testing. In one case HIV-1 infection was confirmed, the written report ART prophylaxis was discontinued so that infants could brainstorm ART handling. All laboratory assays were performed by laboratories that were quality-assured after proficiency testing by the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Grouping.

Evaluation of genotypic antiretroviral resistance in batched specimens from infected infants was performed with the use of the ViroSeq HIV-1 Genotyping System. Specimens were chosen from a time earlier initiation of ART treatment (with 82% of specimens from the 3-month visit).

Statistical Analysis

The target sample size was 1731 infants (577 per written report group), with the assumption of a 6% rate of in utero transmission and a 5% loss to follow-up. Sample-size calculations were based on intrapartum transmission rates of 9.5% in the zidovudine-alone group,6 half dozen% in the two-drug grouping, and ii% in the 3-drug group, with fourscore% power at a 5% significance level for simultaneous pairwise comparisons between treatment groups. Deaths were considered to be censoring events.

The primary study end point was intrapartum HIV-1 transmission at iii months of historic period. The efficacy analysis used the Kaplan–Meier method for conclusion of manual rates in each treatment group; all infants with HIV-i test results were included. A ii-phase arroyo with an extension of the Mantel–Haenszel test was used for comparison of the three Kaplan–Meier curves, followed by a second-stage analysis comparing each pair of transmission rates with the utilize of two-sample Mantel–Haenszel tests. Hochberg'due south modified Bonferroni method was used to adjust the significance level for comparisons between groups.14 Because of lower-than-expected rates of HIV-1 manual, comparing of all possible pairs was supplemented by a comparing of monotherapy versus multidrug therapy.

Secondary end points included transmission at boosted time points, infant deaths, and gamble factors for HIV-1 transmission, including maternal HIV RNA level and CD4+ T-cell count at commitment, status with respect to maternal syphilis, demographic characteristics, obstetrical factors, and condition with respect to zidovudine receipt during labor. The evaluation of antiretroviral genotypic resistance in infected infants was descriptive.

Chi-square tests and logistic regression were used to place risk factors associated with HIV-ane transmission. Only infants with conclusive testify of HIV-1 status were included in these analyses. In add-on, all potential risk factors were tested for interactions with the study treatments. Covariates with a P value of less than 0.20 were entered into a multivariable logistic model. Backward elimination was then used to remove nonsignificant variables, resulting in the last model.

Results

Baseline Characteristics of Infants and Mothers

Tabular array 1. Table 1. Baseline Demographic and Clinical Characteristics of the Infants and Mothers.

From April 2004 through July 2010, a total of 1745 infants underwent randomization: 1224 (lxx.1%) from Brazil, 479 (27.iv%) from South Africa, 28 (ane.six%) from Argentine republic, and 14 (0.8%) from the Usa. Ten infants (0.half dozen%) did non receive written report drugs. Of the remaining 1735 infants, 51 (ii.ix%) had mothers who were HIV-1–negative on confirmatory tests; these infants, whose distribution did non differ significantly among study groups (Table one), were excluded from efficacy analyses but included in safety analyses. The primary efficacy analysis included 1684 infants.

At baseline, the median age of the mothers was 26 years; 76.iii% were black or of mixed race, 8.8% had used illegal substances during pregnancy, and 9.3% had syphilis coinfection (Table ane). The median log10 HIV RNA level was 4.2 copies per milliliter, and the CD4+ T-jail cell count was 459 per cubic millimeter at delivery. Despite non having received a diagnosis of HIV-1 infection, 62.six% of the mothers had received prenatal intendance, with 47.v% having had at least three prenatal visits. HIV-1 infection was diagnosed by means of rapid testing in 73.2% of women. A total of 41.0% of mothers received zidovudine during labor, 99.six% intravenously; zidovudine utilise during pregnancy was not associated with HIV-1 transmission (P=0.73). Cesarean delivery earlier labor or the rupture of membranes was performed for 23.five% of infants, with 535 (89.3%) of 599 cesarean deliveries performed in Brazil. There were no meaning differences (P>0.05) in maternal or infant characteristics amongst the written report groups. The median birth weight was iii.0 kg. Chest-feeding rates, which reflected the peripartum timing of the diagnosis of HIV-i infection in mothers, were 9.four% at birth, 1.v% at 4 to 7 days, and less than i.0% the age of 2 weeks or older, with similar rates in the three report groups.

HIV-i Infection in Infants

Overall, 140 (viii.3%) of 1684 infants had HIV-i infection. The HIV-one condition was unknown for 97 infants (5.viii%): 31 in the zidovudine-lonely grouping, 33 in the two-drug group, and 33 in the three-drug group. All 97 infants had blood specimens collected at birth and tested past PCR analysis for the presence of HIV-ane Deoxyribonucleic acid: 95 tested negative; 2 (i each in the zidovudine-alone and two-drug groups) had a positive DNA exam at nascency only with no subsequent samples bachelor for testing; 56 had no further specimens collected; 14 had samples between 10 days and 2 weeks (all negative), with no subsequent samples; and 27 had samples betwixt 4 and vi weeks (all negative), with no subsequent samples.

Figure ane. Figure 1. Intrapartum HIV-1 Transmission According to Treatment Group.

Kaplan–Meier curves for intrapartum transmission differed significantly (P=0.03 for the overall comparison). Transmission rates were highest in the zidovudine-alone group (3.4% at 4 to half dozen weeks vs. one.vi% in the two-drug group and i.four% in the three-drug group; 4.8% at 3 months vs. 2.2% in the 2-drug group and 2.4% in the three-drug group).

 Table 2. Table ii. Babe HIV-ane Infections According to Treatment Group.

HIV-1 infection rates by study group, based on Kaplan–Meier curves, are shown in Figure ane and Tabular array two. The Kaplan–Meier curves for intrapartum manual differed significantly among the groups (P=0.03 for the overall comparison). The overall rate of in utero transmission of HIV-i was 5.7%, ranging from 5.1% to 6.viii% across report groups; the charge per unit in the zidovudine-alone group did non differ significantly from the charge per unit in the ii-drug group or the charge per unit in the 3-drug group (P=0.24 for both comparisons). The overall rate of intrapartum transmission at three months was 3.2%; the rate in the zidovudine-lonely group (24 infants [four.8%]) was significantly higher than the rates in the two-drug group (11 infants [2.ii%]) and the three-drug group (12 infants [two.iv%]) (P=0.046 for both comparisons). The overall charge per unit of HIV-1 transmission was higher in the zidovudine-solitary grouping (61 infants [xi.0%]) than in the 2-drug group (39 infants [7.1%]) or the three-drug group (forty infants [7.four%]) (P=0.03 for both comparisons). These P values were adjusted for the comparing of the zidovudine-alone grouping with the ii multidrug groups. Adjusted P values for all possible comparisons were 0.07 for the zidovudine-alone group versus the two-drug grouping, 0.09 for the zidovudine-alone group versus the three-drug group, and 0.80 for the two-drug group versus the iii-drug group.

Bloodshed and Loss to Follow-upwardly

Forty-three infants (2.6%) died, with like mortality in the iii groups (11 deaths [one.9%] in the zidovudine-alone group, 15 [2.7%] in the two-drug group, and 17 [3.ane%] in the iii-drug group) (P=0.49 by the chi-square examination). No deaths were considered to exist related to the study drugs. There were 17 deaths in Brazil (i.four% of 1224 infants) versus 26 in Due south Africa (5.4% of 479 infants, P<0.001). Sixteen deaths (37%) occurred in HIV-1–infected infants, 6 (14%) in HIV-1–uninfected infants, and 21 (49%) in infants with undetermined HIV-i status (see Appendix 2 in the Supplementary Appendix, available at NEJM.org). Reasons for report discontinuation (97 infants) included expiry (21), withdrawal of consent (37), loss to follow-upward (32), relocation (half dozen), and other reasons (1). Participants attended 96% of the scheduled visits through 3 months; treatment adherence, as assessed on the footing of handling diaries completed by the mothers or guardians, exceeded 96% for all written report drugs.

Risk Factors for Perinatal Transmission

Table 3. Tabular array 3. Odds Ratios for Intrapartum HIV-i Infection According to Maternal Demographic and Clinical Characteristics.

Factors independently associated with an increased gamble of HIV-i manual included zidovudine monotherapy, a higher maternal HIV RNA level at delivery, and use of illegal substances during pregnancy (Tabular array 3).

Adverse Events

Neutropenia was the just grade 2 or higher laboratory abnormality that differed significantly amidst the groups, occurring in 27.5% of infants in the three-drug group versus 14.nine% in the 2-drug group and 16.4% in the zidovudine-lonely group (P<0.001 for both comparisons past the chi-square test) (Appendix three in the Supplementary Appendix). Elevated aminotransferase levels were uncommon (occurring in 2.5% of all the infants) and did not differ significantly among the groups. Serious adverse events were observed in twoscore.1% of infants: 38.7% of infants in the zidovudine-only group, 37.0% of those in the two-drug grouping, and 44.6% of those in the three-drug group (Appendix 4 in the Supplementary Appendix). Serious agin events possibly or probably related to study drugs, as determined past the medical officeholder of the study sponsor (the Eunice Kennedy Shriver National Institute of Child Wellness and Human Development [NICHD]), were observed in 8.4% and 3.four% of infants, respectively, with college rates in the three-drug group (12.2% and 4.9%) than in the zidovudine-alone group (six.nine% and 3.7%) or the two-drug grouping (6.2% and 1.eight%). Neutropenia and anemia accounted for the majority of serious adverse events. Only two skin-related serious adverse events, neither considered by the site investigators and the NICHD medical officer to be related to the study drugs, were reported (ane each in the 2- and three-drug groups).

Antiretroviral Drug Resistance

Table 4. Table 4. Viral Resistance According to Handling Group.

The results of genotypic antiretroviral resistance testing were available for 120 (85.vii%) of 140 HIV-infected infants (Table iv). Mutations conferring resistance to nucleoside analogue contrary-transcriptase inhibitors (NRTIs) were present in 3 infants (2 in the 3-drug grouping and 1 in the two-drug group), and mutations conferring resistance to protease inhibitors were present in 2 infants (both in the 3-drug group). Mutations conferring resistance to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) were nowadays in 12 infants: 3 (5.vii%) in the zidovudine-alone group, 6 (18.two%) in the two-drug grouping, and 3 (viii.8%) in the iii-drug group (P=0.15 for multiple comparisons). Most NNRTI mutations were detected in infants infected in utero; simply 3 infants with intrapartum infection had NNRTI mutations, i in each group. There were no significant differences in the distribution of resistance mutations among the groups.

Give-and-take

This report compared ART condom regimens in a solely formula-fed population of infants whose mothers had non received antenatal Fine art. On the basis of the results of the Pediatric AIDS Clinical Trials Group Protocol 076 study,15 the standard ART prophylactic regimen for infants built-in to HIV-1–infected mothers in high-income and middle-income countries has been a 6-week course of zidovudine.16,17 In our study, the overall transmission rate in the zidovudine-alone group (11%) was similar to rates in observational studies in which zidovudine was initiated within 48 hours after birth in postpartum-identified HIV-1–exposed infants.6,7,xviii Intrapartum transmissions were reduced by half in the two- and three-drug groups in our study, equally compared with the zidovudine-alone grouping. When we designed the study, we hypothesized that a protease-inhibitor–based three-drug ART regimen might confer a college level of protection confronting intrapartum HIV manual than would a two-drug regimen, given the high virologic efficacy of protease-inhibitor–based treatment regimens.19,20 However, intrapartum infection rates were like in the multidrug groups in our study.

Although intrapartum infection rates were about one-half equally high as anticipated, with consequent loss of power, we observed significant differences in infection rates. Although transmission rates were similar in the multidrug groups, ease of administration favors the zidovudine–nevirapine regimen (a liquid formulation of nevirapine is commercially available, whereas nelfinavir powder requires reconstitution before each dose). Moreover, different nevirapine,11 the absorption of nelfinavir in neonates is quite variable.12 Now, other protease inhibitors are not recommended in the neonatal period, given the adverse effects of lopinavir–ritonavir21 and FDA restrictions on its use in infants younger than xiv days of age. Neutropenia was significantly more than mutual with the three-drug regimen than with the other two regimens, a deviation that is probably related to the combined suppressive effects of zidovudine and lamivudine on os marrow production of blood cells.22-24

Although NNRTI resistance was observed more than frequently in the two-drug group, NNRTI resistance mutations were present in all three groups, most often among infants infected in utero. Baseline rates of primary NNRTI resistance of 4 to 11% accept been reported amid Brazilian patients, and transmission of resistant virus from mother to child could explain the presence of NNRTI resistance in all the groups in our written report.25-27 Maternal resistance testing to gain a improve agreement of the genesis of infant antiretroviral resistance is under style. Coadministration of zidovudine decreases NNRTI resistance after exposure to single-dose nevirapine.28 The clinical significance of NNRTI resistance in infants may be limited, considering protease-inhibitor–based therapy is highly effective in infants and is recommended in World Health Organization and U.S. guidelines for the treatment of pediatric HIV infection in infants exposed to NNRTI-based regimens for the prevention of mother-to-kid transmission of HIV.29,30

Factors independently associated with an increased rate of HIV-1 transmission included zidovudine monotherapy, a higher maternal HIV RNA level at delivery, and maternal utilise of illegal substances. The latter two take been associated with loftier rates of HIV manual in multiple studies.31-35 Although our study identified improved prophylactic alternatives for infants built-in to late-presenting HIV-1–infected mothers, the present approach does not substitute for the prevention and early identification of HIV-i infection in women, with prompt initiation of ART during pregnancy. Prenatal care was received past 63% of the mothers in our study, with 48% having had at least 3 visits; these findings bespeak that there were numerous missed opportunities to diagnose maternal HIV-ane infection and provide prophylaxis against mother-to-kid transmission. Provision of ART prophylaxis in infants volition not prevent in utero infection, which deemed for 70% or more of the residual infection in the two- and three-drug groups.

Like the findings in studies investigating rapid intrapartum and postpartum HIV-1 testing,36,37 our findings show that big-scale rapid HIV-1 testing during labor or the immediate postpartum period, followed by prompt initiation of ART in infants, is feasible, acceptable, and effective. The high level of acceptability of postexposure ART prophylaxis in infants is reflected by 96% adherence. In settings where zidovudine prophylaxis is the standard of care for HIV-exposed infants whose mothers have not received Fine art during pregnancy, our study shows that the administration of additional antiretroviral drugs significantly reduces the take chances of intrapartum acquisition of HIV, as compared with zidovudine alone. Our findings are pertinent to countries in which combination ART in mothers throughout pregnancy is standard and ongoing exposure to HIV-1 through breast-feeding does non occur. Our results support combination Art regimens instead of zidovudine lonely for prophylaxis in the infants of mothers who have not received antenatal ART. Ease of employ, reduced toxicity, availability, and low cost advise that zidovudine plus nevirapine is an attractive choice for prophylaxis in infants at high risk for perinatal HIV-1 infection.

Funding and Disclosures

Presented in part at the 18th Conference on Retroviruses and Opportunistic Infections, Boston, February 27–March ii, 2011.

Supported by the NICHD (HHSN267200800001C, N01-Hard disk-8-0001) and by a grant from the HIV Prevention Trials Network, which is funded by the National Establish of Allergy and Infectious Diseases (NIAID), to the Brazilian AIDS Prevention Trials International Network at the University of California, Los Angeles (U01 AI047986). Overall support for IMPAACT, which endorsed the study, was provided past grants from the NIAID (U01 AI068632), the NICHD, and the National Institute of Mental Health (AI068632).

The views expressed in this article are those of the authors and do non necessarily reflect the views of the National Institutes of Health or the Section of Health and Man Services.

Disclosure forms provided past the authors are available with the full text of this article at NEJM.org.

We thank the patients and their families who enrolled in this trial; and Marita McDonough and Lauren Petrella from Boehringer Ingelheim Pharmaceuticals and Helen Watson from GlaxoSmithKline (on behalf of ViiV Healthcare) for aid with the donation of study drugs from their respective companies for the conduct of the study.

Author Affiliations

The authors' affiliations are listed in the Appendix.

Accost reprint requests to Dr. Nielsen-Saines at the Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, MDCC 22-442 10833 LeConte Ave., Los Angeles, CA 90095, or at [email protected].

Members of the National Institute of Child Health and Man Development (NICHD) HIV-1 Prevention Trials Network (HPTN) 040/Pediatric AIDS Clinical Trials Group (PACTG) 1043 protocol team are listed in the Supplementary Appendix, available at NEJM.org.

Appendix

The authors' affiliations are as follows: David Geffen Schoolhouse of Medicine, Academy of California, Los Angeles, Los Angeles (K.N.-S., Y.J.B.); the Eunice Kennedy Shriver National Institute of Kid Wellness and Human being Evolution, National Institutes of Health, Bethesda (D.H.W., Thousand.S., J.M., L.G.1000.), and Westat, Rockville (J.B., M. Camarca, J.X.) — both in Maryland; the Laboratório de Pesquisa Clínica em DST e AIDS, Instituto de Pesquisa Clínica Evandro Chagas (5.One thousand.V., B.G.), the Laboratório de AIDS e Imunologia Molecular, Instituto Oswaldo Cruz (J.H.P., M.Thousand.M.), and the Laboratório de Informações em Saúde, Instituto de Informação Científica e Tecnológica em Saúde (R.I.One thousand., F.I.B.), Fundação Oswaldo Cruz (Fiocruz), the Hospital Federal dos Servidores practise Estado (E.C.J.), and the Hospital Geral de Nova Iguaçu (J.H.P.) — all in Rio de Janeiro; the Perinatal HIV Inquiry Unit, University of Witwatersrand and Chris Hani Baragwanath Hospital, Johannesburg (G.G.), and Stellenbosch University and Tygerberg Infirmary, Cape Town (Thou.T.) — both in South Africa; Hospital Conceicao (B.South.), Infirmary Femina (R.F.), and Irmandade da Santa Casa de Misericordia de Porto Alegre (R.Yard.), Porto Alegre, RS; Federal University of Minas Gerais, Belo Horizonte, MG (J.P.); Universidade de Sao Paulo, Ribeirao Preto, SP (G.M.M.-P.); and Universidade Federal de Sao Paulo, Sao Paulo, SP (D.Grand.) — all in Brazil; the Foundation for Maternal and Babe Wellness, Buenos Aires (K. Ceriotto); University of California, Davis, Davis (R.D.); and Boston University School of Medicine, Boston (M.M.).

Supplementary Material

References (37)

  1. 1. Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-one in Kampala, Republic of uganda: HIVNET 012 randomised trial. Lancet 1999;354:795-802

  2. ii. Taha TE, Kumwenda NI, Gibbons A, et al. Short postexposure prophylaxis in newborn babies to reduce mother-to-kid transmission of HIV-1: NVAZ randomised clinical trial. Lancet 2003;362:1171-1177

  3. 3. Taha TE, Kumwenda NI, Hoover DR, et al. Nevirapine and zidovudine at birth to reduce perinatal transmission of HIV in an African setting: a randomized controlled trial. JAMA 2004;292:202-209

  4. four. Chasela CS, Hudgens MG, Jamieson DJ, et al. Maternal or infant antiretroviral drugs to reduce HIV-one transmission. Northward Engl J Med 2010;362:2271-2281

  5. five. Gray GE, Urban M, Chersich MF, et al. A randomized trial of two postexposure prophylaxis regimens to reduce mother-to-kid HIV-1 transmission in infants of untreated mothers. AIDS 2005;19:1289-1297

  6. 6. Wade NA, Birkhead GS, Warren BL, et al. Abbreviated regimens of zidovudine prophylaxis and perinatal manual of the man immunodeficiency virus. N Engl J Med 1998;339:1409-1414

  7. 7. Veloso VG, Bastos FI, Portela M, et al. HIV rapid testing as a key strategy for prevention of mother-to-child transmission in Brazil. Rev Saude Publica 2010;44:803-811

  8. 8. Fiscus SA, Adimora AA, Schoenbach VJ, et al. Trends in human immunodeficiency virus (HIV) counseling, testing, and antiretroviral handling of HIV-infected women and perinatal manual in Due north Carolina. J Infect Dis 1999;180:99-105

  9. ix. McKeegan K, Rutstein R, Lowenthal E. Postnatal infant HIV prophylaxis: a survey of U.Southward. practice. AIDS Patient Care STDS 2011;25:1-iv

  10. x. Haile-Selassie H, Townsend C, Tookey P. Employ of neonatal mail service-exposure prophylaxis for prevention of mother-to-child HIV transmission in the United kingdom and Ireland, 2001-2008. HIV Med 2011;12:422-427

  11. xi. Mirochnick M, Nielsen-Saines M, Pilotto JH, et al. Nevirapine concentrations in newborns receiving an extended prophylactic regimen. J Acquir Immune Defic Syndr 2008;47:334-337

  12. 12. Mirochnick K, Nielsen-Saines K, Pilotto JH, et al. Nelfinavir and lamivudine pharmacokinetics during the start two weeks of life. Pediatr Infect Dis J 2011;30:769-772

  13. 13. Segmentation of AIDS (DAIDS) Regulatory Back up Middle. Table for grading severity of pediatric adverse experiences: less than three months of age. April 1994 (http://rsc.tech-res.com/safetyandpharmacovigilance/gradingtables.aspx).

  14. fourteen. Hochberg Y. A sharper Bonferroni process for multiple tests of significance. Biometrika 1988;75:800-802

  15. 15. Connor EM, Sperling RS, Gelbert R, et al. Reduction of maternal-babe transmission of human being immunodeficiency virus type ane with zidovudine handling. N Engl J Med 1994;331:1173-1180

  16. xvi. Panel on Treatment of HIV-Infected Meaning Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal wellness and interventions to reduce perinatal HIV transmission in the Usa. September xiv, 2011 (http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf).

  17. 17. Recommendations for the prevention of vertical transmission of HIV and antiretroviral handling for pregnant women, 2010. Brazil Ministry building of Health, 2010 (http://www.aids.gov.br/publicacao/consenso-recomendacoes-para-profilaxia-da-transmissao-vertical-do-hiv-eastward-terapia-antirretr). (In Spanish.)

  18. 18. Nogueira SA, Abreu T, Oliveira R, et al. Successful prevention of HIV manual from mother to babe in Brazil using a multidisciplinary team approach. Braz J Infect Dis 2001;5:78-86

  19. 19. Krogstad P, Wiznia A, Luzuriaga 1000, et al. Handling of human immunodeficiency virus ane-infected infants and children with the protease inhibitor nelfinavir mesylate. Clin Infect Dis 1999;28:1109-1118

  20. 20. Krogstad P, Lee Southward, Johnson 1000, et al. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human being immunodeficiency virus type i. Clin Infect Dis 2002;34:991-1001

  21. 21. Simon A, Warszawski J, Kariyawasam D, et al. Association of prenatal and postnatal exposure to lopinavir-ritonavir and adrenal dysfunction among uninfected infants of HIV-infected mothers. JAMA 2011;306:70-78

  22. 22. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudine-zidovudine combination for prevention of maternal-babe manual of HIV-1. JAMA 2001;285:2083-2093

  23. 23. El Beitune P, Duarte M. Antiretroviral agents during pregnancy: consequences on hematologic parameters in HIV-exposed, uninfected newborn infant. Eur J Obstet Gynecol Reprod Biol 2006;128:59-63

  24. 24. Lambert JS, Nogueira SA, Abreu T, et al. A pilot study to evaluate the safety and feasibility of the administration of AZT/3TC fixed dose combination to HIV infected pregnant women and their infants in Rio de Janeiro, Brazil. Sexual activity Transm Infect 2003;79:448-452

  25. 25. Pedroso C, Queiroz AT, Alcantara LC, et al. Loftier prevalence of primary antiretroviral resistance amongst HIV-i-infected adults and children in Bahia, a northeast land of Brazil. J Acquir Immune Defic Syndr 2007;45:251-253

  26. 26. Sprinz Eastward, Netto EM, Patelli M, et al. Main antiretroviral drug resistance among HIV blazon ane-infected individuals in Brazil. AIDS Res Hum Retroviruses 2009;25:861-867

  27. 27. Inocencio LA, Pereira AA, Sucupira MC, et al. Brazilian Network for HIV Drug Resistance Surveillance: a survey of individuals recently diagnosed with HIV. J Int AIDS Soc 2009;12:twenty-20

  28. 28. Eshleman SH, Hoover DR, Hudelson SE, et al. Development of nevirapine resistance in infants is reduced past use of infant-just unmarried-dose nevirapine plus zidovudine postexposure prophylaxis for the prevention of female parent-to-kid transmission of HIV-i. J Infect Dis 2006;193:479-481

  29. 29. Antiretroviral therapy for HIV infection in infants and children: towards universal admission: recommendations for a public health approach: 2010 revision. Geneva: World Health Organization, 2010 (http://whqlibdoc.who.int/publications/2010/9789241599801_eng.pdf).

  30. 30. Console on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. August 11, 2010 (http://aidsinfo.nih.gov/ContentFiles/PediatricGuidelines.pdf).

  31. 31. Sperling RS, Shapiro DE, Coombs RW, et al. Maternal viral load, zidovudine treatment and the risk of transmission of human immunodeficiency virus type ane from mother to infant. N Engl J Med 1996;335:1621-1629

  32. 32. Dickover RE, Garraty EM, Herman SA, et al. Identification of levels of maternal HIV-1 RNA associated with risk of perinatal transmission: consequence of maternal zidovudine treatment on viral load. JAMA 1996;275:599-605

  33. 33. Marazzi MC, Liotta G, Nielsen-Saines One thousand, et al. Extended antenatal antiretroviral employ correlates with improved infant outcomes throughout the first year of life. AIDS 2010;24:2819-2826

  34. 34. Purohit V, Rapaka RS, Shurtleff D. Female parent-to-kid transmission (MTCT) of HIV and drugs of abuse in post-highly active antiretroviral therapy (HAART) era. J Neuroimmune Pharmacol 2010;five:507-515

  35. 35. Ellis RJ, Childers ME, Cherner Thou, et al. Increased human immunodeficiency virus loads in agile methamphetamine users are explained by reduced effectiveness of antiretroviral therapy. J Infect Dis 2003;188:1820-1826

  36. 36. Bulterys M, Jamieson DJ, O'Sullivan MJ, et al. Rapid HIV-ane testing during labor: a multicenter study. JAMA 2004;292:219-223

  37. 37. Theron GB, Shapiro DE, Van Dyke R, et al. Rapid intrapartum or postpartum HIV testing at a midwife obstetric unit and a district infirmary in South Africa. Int J Gynaecol Obstet 2011;113:44-49

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