Comparison of Anti-HIV Drug Combinations to Prevent Mother-to-Child Transmission of HIV

A Phase III Randomized Trial of the Safety and Antiretroviral Effects of Zidovudine/Lamivudine/Abacavir Versus Zidovudine/Lamivudine/Lopinavir/Ritonavir in the Prevention of Perinatal Transmission of HIV

Pregnant women infected with HIV who take anti-HIV medications during pregnancy lower the risk of passing HIV to their infants. This study will compare how well two different combinations of anti-HIV medications control HIV in pregnancy, and whether these combinations of drugs are effective in preventing HIV from being transmitted from a pregnant woman to her baby. The two combinations are abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) and zidovudine/lamivudine (ZDV/3TC) plus lopinavir/ritonavir (LPV/RTV).

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Abacavir sulfate, lamivudine, and zidovudine; Drug: Lamivudine/zidovudine; Drug: Lopinavir/ritonavir

Detailed Description

Antiretroviral therapy (ART) in pregnancy has dramatically reduced the rates of perinatal HIV transmission. Many pregnant women infected with HIV may not meet the criteria for treatment as set forth by the Department of Health and Human Services' guidelines and would not be started on therapy if they were not pregnant. Pregnant women are prescribed a variety of treatment regimens; the optimum regimen for pregnant women who plan to discontinue therapy after delivery is unknown. An optimum regimen would account for the need for maximum viral suppression, minimal fetal toxicity, and preservation of future therapeutic options for the mother. This study will compare an all nucleoside reverse transcriptase inhibitor (NRTI) regimen of ABC/3TC/ZDV with a standard protease inhibitor (PI) regimen of LPV/RTV and 3TC/ZDV. This study was initially designed for women who plan to take antiretrovirals only while pregnant and do not meet the criteria for treatment initiation if not pregnant. However, pregnant women who have taken ART for 180 days or less or have taken ZDV monotherapy for a total of 8 weeks or less prior to entering this study are eligible for Version 2.0 of this study.

Women in this study will be randomly assigned to one of two groups. Women in Group A will receive one pill ABC/3TC/ZDV twice a day. Women in Group B will receive one pill 3TC/ZDV and 4 pills LPV/RTV twice a day. Women will take their assigned medications until they go into labor. Once in labor, women will be given zidovudine through intravenous (IV) infusion; they will stop taking oral zidovudine but will continue with their other medications. After delivery, all infants will be given zidovudine for six weeks.

Women will have study visits every 2 weeks for the first 8 weeks of treatment, and then every 4 weeks until Week 28. Depending on where a woman is in her pregnancy when she enrolls in the study, she will also have study visits at Weeks 20, 28, and 34 of her pregnancy. At each visit, women will have a medical interview, a physical exam, and an obstetrical exam; blood and urine collection will occur at these visits. Mothers will undergo a fetal ultrasound at Week 20. Adherence, health status, and behavior assessments will occur at selected visits prior to delivery.

After delivery, women will stop taking the study medications but will continue to have study visits at approximately 6, 12, 24, 36, 48, and 52 weeks after delivery. Medical history and a physical exam will occur at all visits for mothers postpartum. Blood collection will occur at every postpartum visit; urine collection will occur 12, 24, and 48 weeks postpartum; health status and behavior assessments will occur at most visits postpartum. Infants will have study visits at 2, 16, and 24 weeks after birth. A medical history, physical exam, and laboratory tests will be conducted at the infant study visits. Women will also be asked to enroll their infants in PACTG 219C, a long-term study that follows infants who are born to HIV infected mothers.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico
    • 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
  • Florida
    • Miami, Florida, United States, 33136
      • Univ. of Miami Ped. Perinatal HIV/AIDS CRS
  • Illinois
    • Chicago, Illinois, United States, 60608
      • Mt. Sinai Hosp. Med. Ctr. - Chicago, Womens & Childrens HIV Program
  • New York
    • Bronx, New York, United States, 10457
      • Bronx-Lebanon CRS
  • Tennessee
    • Memphis, Tennessee, United States, 38105-2794
      • Regional Med. Ctr. at Memphis
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hosp. CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Note: The pharmacokinetics testing portion of this study has been discontinued in Version 2.0 of this protocol.

Inclusion Criteria for Mothers:

• HIV infected
• Between the 12th and 30th week of pregnancy
• Intend to continue pregnancy
• Viral load less than 55,000 copies/ml within 30 days of study entry
• CD4 count greater than 350 cells/ml within 30 days of study entry
• Have not previously taken anti-HIV medications (women who have taken 8 weeks or fewer of zidovudine are still eligible) OR have taken anti-HIV medication but have been off treatment for more than 180 days
• Intend to stop taking anti-HIV medications after pregnancy
• Willing to have her infant tested for HIV
• Parent or guardian willing to provide informed consent, if applicable
• Have access to a participating site and are willing to be followed for the duration of the study

Exclusion Criteria for Mothers:

• Chemotherapy for active cancer
• Active opportunistic infection or severe medical condition within 14 days of study entry
• Chronic diarrhea within 1 month of study entry or unresolved acute diarrhea within 7 days of study entry
• Certain abnormal laboratory values
• Diabetes mellitus when not pregnant. Participants who have gestational diabetes are not excluded.
• Current alcohol or other substance abuse that, in the opinion of the investigator, may interfere with the study
• Acute hepatitis within 90 days of study entry
• Major birth defects in infant
• Severe skin disorder (e.g., eczema or psoriasis) requiring systemic treatment
• Require certain medications
• Medical condition that may, in the opinion of the investigator, interfere with the study
• Intend to breastfeed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; One pill of abacavir/lamivudine/zidovudine twice daily	Drug: Abacavir sulfate, lamivudine, and zidovudine; one pill twice daily
Experimental: B; One pill of zidovudine/lamivudine and four pills of lopinavir/ritonavir twice daily.	Drug: Lamivudine/zidovudine; one pill twice daily; Drug: Lopinavir/ritonavir; four pills twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of women in each treatment group with virologic suppression to less than 400 copies/ml at 34th week of pregnancy (or last viral load prior to delivery, if delivery occurs before 34th week of pregnancy) while continuing on assigned therapy	at Week 34 of pregnancy

Secondary Outcome Measures

Outcome Measure	Time Frame
Primary outcome, evaluating ART naive and ART experienced women	throughout study
HIV-related health status of women at delivery, determined by CD4 counts and plasma HIV-1 viral load in the two treatment groups and in ART naive and ART experienced women	throughout study
study treatment adherence and health status by self report	throughout study
HIV-related health status of women postpartum, determined by CD4 counts and plasma HIV-1 viral load	at Months 3, 6 and 12 postpartum and prior to ART treatment
development of HIV-1 genotypic resistance among women in each treatment group	at delivery, Months 3, 6, and 12 postpartum, and in all cases of treatment failure
incidence of abnormal glucose tolerance, gestational diabetes, and abnormal lactate levels during pregnancy in each treatment group	throughout study
incidence of anemia, hypoglycemia, abnormal liver function studies, prematurity, low birth weight, or perinatal HIV transmission among infants born to women in each treatment group	throughout study
predictive value, sensitivity, and specificity of polymorphisms in HLA-B57, HLA-DR7, and HLA-DQ3 in identifying pregnant women at risk for development of ABC hypersensitivity	throughout study
concentration of T cell receptor rearrangement excision DNA circles	at study entry, delivery and 6 weeks postpartum

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: Andrew D. Hull, MD, Department of Reproductive Medicine, Division of Perinatal Medicine, University of California, San Diego School of Medicine

Publications and helpful links

General Publications

• Thorne C, Newell ML. Mother-to-child transmission of HIV infection and its prevention. Curr HIV Res. 2003 Oct;1(4):447-62. doi: 10.2174/1570162033485140.
• Sullivan JL. Prevention of mother-to-child transmission of HIV--what next? J Acquir Immune Defic Syndr. 2003 Sep;34 Suppl 1:S67-72. doi: 10.1097/00126334-200309011-00010.
• Cooper ER, Charurat M, Mofenson L, Hanson IC, Pitt J, Diaz C, Hayani K, Handelsman E, Smeriglio V, Hoff R, Blattner W; Women and Infants' Transmission Study Group. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr. 2002 Apr 15;29(5):484-94. doi: 10.1097/00126334-200204150-00009.
• Scarlatti G. Mother-to-child transmission of HIV-1: advances and controversies of the twentieth centuries. AIDS Rev. 2004 Apr-Jun;6(2):67-78.
• Tuomala RE, Shapiro DE, Mofenson LM, Bryson Y, Culnane M, Hughes MD, O'Sullivan MJ, Scott G, Stek AM, Wara D, Bulterys M. Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med. 2002 Jun 13;346(24):1863-70. doi: 10.1056/NEJMoa991159.

Study record dates

Study Major Dates

• Study Start: July 1, 2004
• Study Completion (Actual): September 1, 2007

Study Registration Dates

• First Submitted: June 30, 2004
• First Submitted That Met QC Criteria: June 30, 2004
• First Posted (Estimate): July 1, 2004

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: Perinatal Transmission; MTCT; Mother-to-Child Transmission; Treatment Experienced; Treatment Naive
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; 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 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Lopinavir; Lamivudine; Zidovudine; Abacavir; Lamivudine, zidovudine drug combination
• Other Study ID Numbers: P1039; 10046 (Registry Identifier: DAIDS ES); PACTG P1039