Combination Treatment With and Without Protease Inhibitors for Women Who Begin Therapy for HIV Infection During Pregnancy

Randomized Trial of Protease Inhibitor-Including vs. Protease Inhibitor-Sparing Regimens for Women Who Initiate Therapy of HIV Infection During Pregnancy

The best anti-HIV treatment regimen for pregnant women is not known. Protease inhibitors (PIs) are often used, but they have side effects that may be harmful for pregnant women. It is not known if treatment regimens that do not include PIs are as effective in pregnant women as those that include PIs. This trial will compare two anti-HIV treatment plans, one with and one without PIs, in women who start HIV treatment during pregnancy. The study will evaluate the effects of the anti-HIV drugs on the developing infant and prevention of mother-to-child HIV transmission during pregnancy.

Study Overview

• Status: Completed
• Conditions: HIV Infections; Pregnancy
• Intervention / Treatment: Drug: Nevirapine; Drug: Lamivudine; Drug: Zidovudine; Drug: Nelfinavir mesylate; Drug: Lamivudine/Zidovudine

Detailed Description

The optimal treatment strategy for women who initiate antiretroviral therapy during pregnancy is not known. Although PI-based antiretroviral regimens are prescribed with increasing frequency among pregnant women, the efficacy and safety of this approach is unknown. Pregnant women are at increased risk for glucose intolerance and insulin resistance; PIs are associated with glucose intolerance. Physiologic differences between pregnant women and nonpregnant adults may alter the pharmacokinetics of antiretroviral regimens. Fetal safety considerations and effects on perinatal HIV transmission must also be considered when selecting an antiretroviral regimen for pregnant women. This trial will compare PI-based and PI-sparing antiretroviral regimens for women initiating antiretroviral therapy in pregnancy.

Women will be stratified on the basis of viral load (50,000 or less copies/ml or greater than 50,000 copies/ml) and gestational age at entry (20 or less weeks or greater than 20 weeks) and then randomized to one of two treatment groups. Group A will receive the PI nelfinavir (NFV) with zidovudine (ZDV) and lamivudine (d4T); Group B will receive nevirapine (NVP) with ZDV and d4T. Women will have clinic visits for physical and obstetrical examinations at 2, 4, 6, and 8 weeks after entry and then every 4 weeks until delivery. After delivery, infants in both groups may receive ZDV until they are 6 weeks old. Infants are evaluated for safety and to test the infant's blood for HIV-1 at birth and at Weeks 2, 8, 16, and 24.

Women will continue on assigned antiretroviral therapy postpartum and will have 11 postpartum clinic visits over a period of 2 years. Blood samples from women will be evaluated for safety and for virologic, pharmacokinetic, and metabolic studies. The first 12 women randomized to Group A will undergo a 4-hour pharmacokinetic profile at 32 to 36 weeks gestation and at 8 weeks postpartum to determine the timing of the nelfinavir trough. The first 20 women randomized to Group B will undergo an 8-hour pharmacokinetic profile at either 16 to 24 weeks or 32 to 36 weeks gestation and then again at 8 weeks postpartum to characterize pharmacokinetics of nevirapine at steady state in pregnancy and in the postpartum period.

• Study Type: Interventional
• Enrollment: 440
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bahamas
  • Nassau, Bahamas
    • Princess Margaret Hosp. Bahamas NICHD CRS
• Brazil
  • Rio de Janeiro, Brazil, 20221-903
    • Hosp. dos Servidores Rio de Janeiro NICHD CRS
  • Rio de Janeiro, Brazil, 22261-161
    • Hosp. dos Servidores do Estado CRS
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil
      • SOM Federal University Minas Gerais Brazil NICHD CRS
• Puerto Rico
  • San Juan, Puerto Rico, 00936
    • San Juan City Hosp. PR NICHD CRS
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Usc La Nichd Crs
    • San Diego, California, United States, 92103
      • UCSD Mother-Child-Adolescent Program CRS
    • San Francisco, California, United States
      • UCSF Pediatric AIDS CRS
    • Torrance, California, United States, 90509
      • Harbor - UCLA Med. Ctr. - Dept. of Peds., Div. of Infectious Diseases
  • Connecticut
    • New Haven, Connecticut, United States, 06504
      • Yale Univ. School of Medicine - Dept. of Peds., Div. of Infectious Disease
  • District of Columbia
    • Washington, District of Columbia, United States, 20060
      • Howard Univ. Washington DC NICHD CRS
  • Florida
    • Miami, Florida, United States, 33161
      • Univ. of Miami Ped. Perinatal HIV/AIDS CRS
    • Miami, Florida, United States, 33136
      • Univ. of Miami Miller School of Medicine - Jackson Memorial Hosp.
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Med. College of Georgia School of Medicine, Dept. of Peds., Div. of Infectious Diseases
    • Columbus, Georgia, United States, 31901
      • Columbus Regional HealthCare System, The Med. Ctr.
  • Illinois
    • Chicago, Illinois, United States, 60608
      • Mt. Sinai Hosp. Med. Ctr. - Chicago, Womens & Childrens HIV Program
    • Chicago, Illinois, United States, 60637-1470
      • Univ. of Chicago - Dept. of Peds., Div. of Infectious Disease
  • Louisiana
    • New Orleans, Louisiana, United States, 70112-2699
      • Tulane/LSU Maternal/Child CRS
    • New Orleans, Louisiana, United States, 70112-2699
      • Tulane Univ. Health Science Ctr., Tulane Univ. Hosp. & Clinic
  • Maryland
    • Baltimore, Maryland, United States
      • Univ. of Maryland Med. Ctr., Div. of Ped. Immunology & Rheumatology
    • Baltimore, Maryland, United States, 21287-4933
      • Johns Hopkins Hosp. & Health System - Dept. of Peds., Div. of Infectious Diseases
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • HMS - Children's Hosp. Boston, Div. of Infectious Diseases
    • Boston, Massachusetts, United States, 02118
      • BMC, Div. of Ped Infectious Diseases
    • Boston, Massachusetts, United States, 02478
      • Brigham and Women's Hosp., Div. of Infectious Disease
    • Springfield, Massachusetts, United States, 01199
      • Baystate Health, Baystate Med. Ctr.
    • Worcester, Massachusetts, United States, 01655
      • WNE Maternal Pediatric Adolescent AIDS CRS
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan NICHD CRS
    • Jackson, Michigan, United States, 39213
      • Univ. of Mississippi Med. Ctr Children's Hosp.
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • Rutgers - New Jersey Medical School CRS
  • New York
    • Bronx, New York, United States, 10457
      • Bronx-Lebanon Hosp. IMPAACT CRS
    • Bronx, New York, United States, 19461
      • Montefiore Med. Ctr. - AECOM
    • New York, New York, United States, 10016
      • Nyu Ny Nichd Crs
    • New York, New York, United States, 10032
      • Columbia IMPAACT CRS
    • Rochester, New York, United States, 14642
      • Strong Memorial Hospital Rochester NY NICHD CRS
    • Stony Brook, New York, United States, 11794
      • SUNY Stony Brook NICHD CRS
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Med. Univ., Dept. of Peds.
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • DUMC Ped. CRS
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Univ. of Cincinnati CRS
    • Cleveland, Ohio, United States, 44109-1998
      • MetroHealth CRS
    • Cleveland, Ohio, United States, 44106
      • Case CRS
  • Oregon
    • Portland, Oregon, United States
      • Oregon Health & Science Univ. - Dept. of Peds., Div. of Infectious Disease
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude/UTHSC CRS
    • Memphis, Tennessee, United States, 38105
      • Regional Med. Ctr. at Memphis
    • Nashville, Tennessee, United States, 38105
      • Vanderbilt Univ. Med. Ctr., Div. of Ped. Infectious Diseases
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hosp. CRS
  • Washington
    • Seattle, Washington, United States
      • Seattle Children's Hospital CRS
    • Seattle, Washington, United States, 98105-0371
      • Univ. of Washington NICHD CRS
    • Seattle, Washington, United States, 98105-0371
      • UW Medicine - Harborview Med. Ctr., Northwest Family Ctr.
    • Seattle, Washington, United States, 98105-0371
      • UW School of Medicine - CHRMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• HIV infected
• 10 to 30 weeks pregnant
• Plan to continue pregnancy
• CD4 count less than 250 cells/mm3 within 30 days of study entry
• HIV RNA load greater than 1,000 copies/ml within 30 days of study entry
• Antiretroviral naive (except ZDV for 8 weeks or less, including prior pregnancy)
• Willing to follow study requirements and plan to continue receiving anti-HIV treatment for at least 2 years after delivery
• Understand that NFV will not be supplied by the study (except for the first 12 women in Group A)
• Understand the study drug NVP will not be supplied after 1 year following delivery and is reasonably certain that she can obtain NVP by prescription for the second year of the study
• Access to a participating site
• Willing to have infant followed until 24 weeks old
• Parent or guardian willing to provide informed consent, if applicable

Exclusion Criteria:

• Alcohol or drug abuse
• Chemotherapy for an active cancer
• Require certain medications
• AIDS-related opportunistic infection and/or serious bacterial infection or unstable or serious medical condition within 14 days of study entry
• Chronic malabsorption or diarrhea
• Diabetes, unless it only occurs during pregnancy
• Major fetal problem or abnormality
• Abnormal amniotic fluid volume
• Plan to breastfeed
• Acute hepatitis within 90 days of study entry
• Skin problems such as psoriasis or eczema that require systemic treatment
• Any serious disease that, in the opinion of the study official, would compromise study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Proportion of women in each treatment group who continue on original therapy with virologic suppression to less than 500 copies/ml at 34 weeks gestation (or the last viral load determination prior to delivery)
proportion of women in each treatment group who continue on original therapy with virologic suppression to less than 500 copies/ml at 48 weeks postpartum

Secondary Outcome Measures

Outcome Measure
Proportion of women in each treatment group who continue on original therapy with virologic suppression to less than 50 copies/ml at 34 weeks gestation (or the last viral load determination prior to delivery)
proportion of women in each treatment group who continue on original therapy with virologic suppression to less than 50 copies/ml at 48 weeks postpartum, and to less than 500 and 50 copies/ml at 104 weeks postpartum
study treatment adherence and health status by self-report, correlated with predose nelfinavir or nevirapine level at 34 weeks gestation and 8 weeks postpartum
difference between postpartum and pregnancy 12-hour area under the concentration curve (AUC) for nevirapine
time of trough levels in relation to the morning dose of nevirapine and nelfinavir at 34 weeks gestation and 8 weeks postpartum and correlation of trough levels with viral load
incidence of HIV viral resistance by genotype among women in each treatment group at the time of virologic failure
incidence of abnormal glucose tolerance, gestational diabetes, and abnormal lactate levels during pregnancy in each treatment group
incidence of impaired glucose tolerance, diabetes, hyperinsulinemia, and elevated cholesterol and triglycerides at 8 weeks postpartum in each treatment group
incidence of anemia, hypoglycemia, and abnormal liver function studies among infants born to women in each treatment group
incidence of prematurity (less than 37 weeks), extreme prematurity (less than 32 weeks), low birth weight (less than 2.5 kg), and very low birth weight (less than 1.5 kg) among infants born to women in each treatment group
perinatal HIV transmission among infants born to women in each treatment group

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Study Chair: Jane Hitti, MD, MPH, Department of Obstetrics/Gynecology, University of Washington Medical Center

Publications and helpful links

General Publications

• Moodley J, Moodley D. Management of human immunodeficiency virus infection in pregnancy. Best Pract Res Clin Obstet Gynaecol. 2005 Apr;19(2):169-83. doi: 10.1016/j.bpobgyn.2004.10.007. Epub 2004 Dec 15.
• Loutfy MR, Walmsley SL. Treatment of HIV infection in pregnant women: antiretroviral management options. Drugs. 2004;64(5):471-88. doi: 10.2165/00003495-200464050-00002.
• Capparelli EV, Aweeka F, Hitti J, Stek A, Hu C, Burchett SK, Best B, Smith E, Read JS, Watts H, Nachman S, Thorpe EM Jr, Spector SA, Jimenez E, Shearer WT, Foca M, Mirochnick M; PACTG 1026S Study Team; PACTG P1022 Study Team. Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics. HIV Med. 2008 Apr;9(4):214-20. doi: 10.1111/j.1468-1293.2008.00553.x.
• Hitti J, Frenkel LM, Stek AM, Nachman SA, Baker D, Gonzalez-Garcia A, Provisor A, Thorpe EM, Paul ME, Foca M, Gandia J, Huang S, Wei LJ, Stevens LM, Watts DH, McNamara J; PACTG 1022 Study Team. Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG 1022. J Acquir Immune Defic Syndr. 2004 Jul 1;36(3):772-6. doi: 10.1097/00126334-200407010-00002.

Study record dates

Study Major Dates

• Study Start: May 1, 2002
• Study Completion (Actual): March 1, 2006

Study Registration Dates

• First Submitted: June 8, 2001
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (Estimate): August 31, 2001

Study Record Updates

• Last Update Posted (Actual): November 1, 2021
• Last Update Submitted That Met QC Criteria: October 28, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Reverse Transcriptase Inhibitors; Anti-HIV Agents; Viral Load; HIV Protease Inhibitors; Treatment Naive; Pregnancy Complications, Infectious; Combivir
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; Slow Virus Diseases; HIV Infections; Infections; Communicable Diseases; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Protease Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Nevirapine; Lamivudine; Zidovudine; Nelfinavir; Lamivudine, zidovudine drug combination
• Other Study ID Numbers: P1022; 10192 (Registry Identifier: DAIDS ES); ACTG P1022; PACTG P1022