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Trial of Three Neonatal Antiretroviral Regimens for Prevention of Intrapartum HIV Transmission

NCT ID: NCT00099359

Last Updated: 2012-12-04

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

1735 participants

Study Classification

INTERVENTIONAL

Study Start Date

2004-02-29

Study Completion Date

2011-02-28

Brief Summary

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Giving anti-HIV medications to babies born of HIV positive mothers right after birth can lower the babies' risk of contracting HIV. This study will assess the safety and efficacy of two different combinations of anti-HIV medications compared to a one drug standard regimen in preventing mother to baby transmission. The one drug standard treatment and two combinations to be studied are: 1) zidovudine, 2) zidovudine/nevirapine and 3) zidovudine/lamivudine/nelfinavir.

Detailed Description

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Despite the notable reductions in perinatal transmission of HIV-1 with antiretroviral therapy and other interventions, perinatal transmission continues to occur at rates of 20-30% among pregnant women who are not identified as HIV-1-infected and/or are not provided with antiretroviral therapy. The optimum treatment strategy for prevention of transmission of HIV-1 to infants born to these women is unknown. No trials have evaluated the efficacy of neonatal antiretroviral therapy alone but observational data suggest benefit from zidovudine (ZDV) therapy given to the infant beginning within 48 hours of birth and continued for six weeks. This protocol will compare the safety and efficacy of three antiretroviral regimens administered in the neonatal period: Arm A- ZDV, Arm B- ZDV plus nevirapine (NVP), and Arm C- ZDV plus nelfinavir (NFV) and lamivudine (3TC). Two regimens were selected based on expected antiretroviral activity, pharmacokinetic data, and toxicity profiles. Standard of care (6 weeks of ZDV) alone will be compared to the 6 weeks of ZDV plus either 3 doses of NVP or 2 weeks of 3TC and NFV. Arm B (ZDV + NVP) is the regimen expected to provide the best profile when factors of efficacy, safety, cost, acceptability and convenience are considered. The comparison of Arms B and C is also of considerable interest since the 2-drug Arm B is easier to implement and less expensive than the triple drug Arm C. Although triple drug therapies have been recommended for post-exposure prophylaxis for needle-stick injuries in high-risk circumstances, it is unknown whether the triple drug arm will provide better efficacy than the 2-drug arm for post-exposure prophylaxis of the infant.

This open-label study is expected to accrue 1731 infants of women identified in labor as being HIV positive or who are HIV positive but have not received antiretroviral medication during the pregnancy. If eligible the infant will be randomized at birth to one of three aforementioned treatment arms. Medical history, social, demographic, physical exam, RNA and T- lymphocyte data are collected on the mother during the delivery visit. The infant will have a birth visit and then return for 1-week, 2-week, 4-week, 3-month and a final 6-month visit. Infant evaluations will include: a medical history and physical exam, DNA testing, CBC and liver function tests, cells for long-term storage and RNA/CD4/CD8 testing if HIV positive. The initial study drug doses will be given to the infant while in the hospital. Mothers will administer the infants' remaining treatment doses at home depending on ability.

Conditions

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Disease Transmission, Vertical Vertical Human Immunodeficiency Virus Transmission HIV Infections

Keywords

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HIV Perinatal Prevention Transmission Nevirapine Epivir Zidovudine Nelfinavir ZDV NVP 3TC NFV Viracept Viramune HIV Seronegativity Treatment Naive

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

NONE

Study Groups

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A

Standard of care ( Zidovudine only)

Group Type EXPERIMENTAL

Zidovudine

Intervention Type DRUG

Given for 6 weeks. 12mg PO BID if birthweight (BW) \> 2000 grams 8 mg PO BID if BW \< 2000 grams

B

Standard of care (Zidovudine) plus Nevirapine

Group Type EXPERIMENTAL

Nevirapine (NVP)

Intervention Type DRUG

Standard of Care (Zidovudine) plus

NVP, first dose initiated within 48 hrs of birth, second dose 48 hrs (+ 4 hours) after the first dose, and third dose 96 hours (+ 4 hours) after the second dose :

12 mg PO per dose if BW \> 2000 grams, 8 mg PO per dose if BW \< 2000 grams

C

Standard of Care (Zidovudine) plus 2 weeks of Epivir and Nelfinavir

Group Type EXPERIMENTAL

Epivir (3TC)

Intervention Type DRUG

Stand of care (Zidovudine) plus

3TC, given for 2 weeks: 6 mg po bid if BW \> 2000 grams 4 mg po bid if BW \< 2000 grams AND

NFV, given for 2 weeks:

200 mg po bid if BW \> 3000 grams 150 mg po bid if BW \> 2,000 - 3000 grams 100 mg PO BID if BW \< 2000 grams

Nelfinavir (NFV)

Intervention Type DRUG

200 mg BID if birth weight (BW) \> 3000 grams for 2 weeks;150 mg BID if BW \> 2000-3000 grams for 2 weeks; 100 mg BID BW \</= 2000 grams for 2 weeks

Interventions

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Zidovudine

Given for 6 weeks. 12mg PO BID if birthweight (BW) \> 2000 grams 8 mg PO BID if BW \< 2000 grams

Intervention Type DRUG

Nevirapine (NVP)

Standard of Care (Zidovudine) plus

NVP, first dose initiated within 48 hrs of birth, second dose 48 hrs (+ 4 hours) after the first dose, and third dose 96 hours (+ 4 hours) after the second dose :

12 mg PO per dose if BW \> 2000 grams, 8 mg PO per dose if BW \< 2000 grams

Intervention Type DRUG

Epivir (3TC)

Stand of care (Zidovudine) plus

3TC, given for 2 weeks: 6 mg po bid if BW \> 2000 grams 4 mg po bid if BW \< 2000 grams AND

NFV, given for 2 weeks:

200 mg po bid if BW \> 3000 grams 150 mg po bid if BW \> 2,000 - 3000 grams 100 mg PO BID if BW \< 2000 grams

Intervention Type DRUG

Nelfinavir (NFV)

200 mg BID if birth weight (BW) \> 3000 grams for 2 weeks;150 mg BID if BW \> 2000-3000 grams for 2 weeks; 100 mg BID BW \</= 2000 grams for 2 weeks

Intervention Type DRUG

Other Intervention Names

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Retrovir Viramune Lamivudine Viracept

Eligibility Criteria

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Inclusion Criteria

Infants who meet all of the following criteria are eligible for the study:

* Mother known to be HIV-1-infected prior to labor or identified at the time of labor or \<48 hours postpartum. HIV-1 infection for the purposes of enrollment into this study is defined as: (a) Single positive HIV-1 rapid test in mother or her infant; or (b) Historical documentation of a positive HIV-1 diagnostic test confirmed by repeat diagnostic testing for HIV-1 according to country guidelines in mother (written documentation of test results must be present in the medical record).
* Maternal written informed consent for study participation.
* Mother has not received any antiretroviral therapy during the current pregnancy prior to the onset of labor and delivery; women may have received intravenous or oral ZDV during labor. Women may have received any antiretroviral therapy in previous pregnancies for prevention of vertical HIV-1 transmission.
* Infant is \<48 hours old. Infant may have received up to 48 hours of ZDV as standard care before study enrollment.

Exclusion Criteria

Infants who meet any of the following criteria will be excluded from the study:

* Extreme prematurity (\< 32 weeks of gestation).
* Birth weight \<1500 grams.
* Presence of life-threatening conditions.
* Inability to take oral medication throughout the first 48 hours of life (must be able to receive oral medication by age 48 hours).
* Maternal inability to provide informed consent because of a lack of a conscious state, psychiatric conditions, or language barriers.
* Mother received any antiretroviral therapy during labor and delivery other than intravenous or oral ZDV.
Maximum Eligible Age

2 Days

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Karin Nielsen, MD

Role: STUDY_CHAIR

University of California, Los Angeles

Locations

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Miller Children's Hospital

Long Beach, California, United States

Site Status

University of FL

Gainesville, Florida, United States

Site Status

University of FL-HSC

Jacksonville, Florida, United States

Site Status

University Medical and Dental School of NJ-Newark Campus

Newark, New Jersey, United States

Site Status

Texas Childrens Hospital

Houston, Texas, United States

Site Status

Hospital I. G. A. Dr. Diego Paroissien

Buenos Aires, , Argentina

Site Status

Federal University of Minas Gerais (UFMG)

Belo Horizonte, Minas Gerais, Brazil

Site Status

Universidade de Sao Paulo (USP) , MD

São Paulo, Ribeirão Preto, Brazil

Site Status

Hospital Fêmina S.A. Unidade Perinatal de Transmissão Vertical

Porto Alegre, Rio Grande do Sul, Brazil

Site Status

Hospital Santa Casa (HSC)

Porto Alegre, Rio Grande do Sul, Brazil

Site Status

Hospital Nossa Senhora da Conceicao (GHC)

Porto Alegre, Rio Grande do Sul, Brazil

Site Status

Hospital dos Servidores do Estado (HSE)

Rio de Janeiro, , Brazil

Site Status

Hospital Geral de Novo Iguacu

Rio de Janeiro, , Brazil

Site Status

5088 - Universidade Federal de Sao Paulo (UFSP)

São Paulo, , Brazil

Site Status

San Juan Hospital

San Juan, , Puerto Rico

Site Status

Tygerberg Hospital

Cape Town, , South Africa

Site Status

Chris Hani Baragwanath Hospital

Johannesburg, , South Africa

Site Status

Countries

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United States Argentina Brazil Puerto Rico South Africa

References

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Mirochnick M, Nielsen-Saines K, Pilotto JH, Pinto J, Veloso VG, Rossi S, Moye J, Bryson Y, Mofenson L, Camarca M, Watts DH; NICHD HPTN 040/PACTG 1043 PROTOCOL Team. Nelfinavir and Lamivudine pharmacokinetics during the first two weeks of life. Pediatr Infect Dis J. 2011 Sep;30(9):769-72. doi: 10.1097/INF.0b013e3182242950.

Reference Type RESULT
PMID: 21666540 (View on PubMed)

Mirochnick M, Nielsen-Saines K, Pilotto JH, Pinto J, Jimenez E, Veloso VG, Parsons T, Watts DH, Moye J, Mofenson LM, Camarca M, Bryson Y; NICHD/HPTN 040/PACTG 1043 Protocol Team. Nevirapine concentrations in newborns receiving an extended prophylactic regimen. J Acquir Immune Defic Syndr. 2008 Mar 1;47(3):334-7.

Reference Type RESULT
PMID: 18398973 (View on PubMed)

Nielsen-Saines K, Watts DH, Veloso VG, Bryson YJ, Joao EC, Pilotto JH, Gray G, Theron G, Santos B, Fonseca R, Kreitchmann R, Pinto J, Mussi-Pinhata MM, Ceriotto M, Machado D, Bethel J, Morgado MG, Dickover R, Camarca M, Mirochnick M, Siberry G, Grinsztejn B, Moreira RI, Bastos FI, Xu J, Moye J, Mofenson LM; NICHD HPTN 040/PACTG 1043 Protocol Team. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med. 2012 Jun 21;366(25):2368-79. doi: 10.1056/NEJMoa1108275.

Reference Type RESULT
PMID: 22716975 (View on PubMed)

Adachi K, Xu J, Ank B, Watts DH, Camarca M, Mofenson LM, Pilotto JH, Joao E, Gray G, Theron G, Santos B, Fonseca R, Kreitchmann R, Pinto J, Mussi-Pinhata MM, Machado DM, Ceriotto M, Morgado MG, Bryson YJ, Veloso VG, Grinsztejn B, Mirochnick M, Moye J, Nielsen-Saines K; MPH for the NICHD HPTN 040 Study Team. Congenital Cytomegalovirus and HIV Perinatal Transmission. Pediatr Infect Dis J. 2018 Oct;37(10):1016-1021. doi: 10.1097/INF.0000000000001975.

Reference Type DERIVED
PMID: 30216294 (View on PubMed)

Yeganeh N, Watts DH, Xu J, Kerin T, Joao EC, Pilotto JH, Theron G, Gray G, Santos B, Fonseca R, Kreitchmann R, Pinto J, Mussi-Pinhata MM, Veloso V, Camarca M, Mofenson L, Moye J, Nielsen-Saines K. Infectious Morbidity, Mortality and Nutrition in HIV-exposed, Uninfected, Formula-fed Infants: Results From the HPTN 040/PACTG 1043 Trial. Pediatr Infect Dis J. 2018 Dec;37(12):1271-1278. doi: 10.1097/INF.0000000000002082.

Reference Type DERIVED
PMID: 29750766 (View on PubMed)

Adachi K, Xu J, Yeganeh N, Camarca M, Morgado MG, Watts DH, Mofenson LM, Veloso VG, Pilotto JH, Joao E, Gray G, Theron G, Santos B, Fonseca R, Kreitchmann R, Pinto J, Mussi-Pinhata MM, Ceriotto M, Machado DM, Bryson YJ, Grinsztejn B, Moye J, Klausner JD, Bristow CC, Dickover R, Mirochnick M, Nielsen-Saines K; NICHD HPTN 040 Study Team. Combined evaluation of sexually transmitted infections in HIV-infected pregnant women and infant HIV transmission. PLoS One. 2018 Jan 5;13(1):e0189851. doi: 10.1371/journal.pone.0189851. eCollection 2018.

Reference Type DERIVED
PMID: 29304083 (View on PubMed)

Adachi K, Xu J, Ank B, Watts DH, Mofenson LM, Pilotto JH, Joao E, Santos B, Fonseca R, Kreitchmann R, Pinto J, Mussi-Pinhata MM, Gray G, Theron G, Morgado MG, Bryson YJ, Veloso VG, Klausner JD, Moye J, Nielsen-Saines K; NICHD HPTN 040 Study Team. Cytomegalovirus Urinary Shedding in HIV-infected Pregnant Women and Congenital Cytomegalovirus Infection. Clin Infect Dis. 2017 Aug 1;65(3):405-413. doi: 10.1093/cid/cix222.

Reference Type DERIVED
PMID: 28369278 (View on PubMed)

Adachi K, Klausner JD, Bristow CC, Xu J, Ank B, Morgado MG, Watts DH, Weir F, Persing D, Mofenson LM, Veloso VG, Pilotto JH, Joao E, Nielsen-Saines K; NICHD HPTN 040 Study Team. Chlamydia and Gonorrhea in HIV-Infected Pregnant Women and Infant HIV Transmission. Sex Transm Dis. 2015 Oct;42(10):554-65. doi: 10.1097/OLQ.0000000000000340.

Reference Type DERIVED
PMID: 26372927 (View on PubMed)

Yeganeh N, Watts HD, Camarca M, Soares G, Joao E, Pilotto JH, Gray G, Theron G, Santos B, Fonseca R, Kreitchmann R, Pinto J, Mussi-Pinhata M, Ceriotto M, Machado DM, Grinzstejn B, Veloso VG, Morgado MG, Bryson Y, Mofenson LM, Nielsen-Saines K; NICHD HPTN 040P1043 Study Team. Syphilis in HIV-infected mothers and infants: results from the NICHD/HPTN 040 study. Pediatr Infect Dis J. 2015 Mar;34(3):e52-7. doi: 10.1097/INF.0000000000000578.

Reference Type DERIVED
PMID: 25742089 (View on PubMed)

Related Links

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http://www.nichd.nih.gov/

home page of the National Institute of Child Health and Human Development

Other Identifiers

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NICHD/HPTN 040 (P1043)

Identifier Type: -

Identifier Source: org_study_id