Clinical trial NCT00017719: Combination Treatment With and Without Protease Inhibitors for Women Who Begin Therapy for HIV Infection During Pregnancy
Official title: Randomized Trial of Protease Inhibitor-Including vs. Protease Inhibitor-Sparing Regimens for Women Who Initiate Therapy of HIV Infection During Pregnancy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Pregnancy
Keywords: Pregnancy Complications, Infectious
HIV Protease Inhibitors
Reverse Transcriptase Inhibitors
Anti-HIV Agents
Viral Load
Combivir
Treatment Naive
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2001-08-31
Enrollment: 440
Sex: FEMALE
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
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)
measure: 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 outcomes:
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)
measure: 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
measure: study treatment adherence and health status by self-report, correlated with predose nelfinavir or nevirapine level at 34 weeks gestation and 8 weeks postpartum
measure: difference between postpartum and pregnancy 12-hour area under the concentration curve (AUC) for nevirapine
measure: 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
measure: incidence of HIV viral resistance by genotype among women in each treatment group at the time of virologic failure
measure: incidence of abnormal glucose tolerance, gestational diabetes, and abnormal lactate levels during pregnancy in each treatment group
measure: incidence of impaired glucose tolerance, diabetes, hyperinsulinemia, and elevated cholesterol and triglycerides at 8 weeks postpartum in each treatment group
measure: incidence of anemia, hypoglycemia, and abnormal liver function studies among infants born to women in each treatment group
measure: 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
measure: perinatal HIV transmission among infants born to women in each treatment group
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Usc La Nichd Crs
state: California
city: San Diego
country: United States
facility: UCSD Mother-Child-Adolescent Program CRS
state: California
city: San Francisco
country: United States
facility: UCSF Pediatric AIDS CRS
state: California
city: Torrance
country: United States
facility: Harbor - UCLA Med. Ctr. - Dept. of Peds., Div. of Infectious Diseases
state: California
city: New Haven
country: United States
facility: Yale Univ. School of Medicine - Dept. of Peds., Div. of Infectious Disease
state: Connecticut
city: Washington
country: United States
facility: Howard Univ. Washington DC NICHD CRS
state: District of Columbia
city: Miami
country: United States
facility: Univ. of Miami Miller School of Medicine - Jackson Memorial Hosp.
state: Florida
city: Miami
country: United States
facility: Univ. of Miami Ped. Perinatal HIV/AIDS CRS
state: Florida
city: Augusta
country: United States
facility: Med. College of Georgia School of Medicine, Dept. of Peds., Div. of Infectious Diseases
state: Georgia
city: Columbus
country: United States
facility: Columbus Regional HealthCare System, The Med. Ctr.
state: Georgia
city: Chicago
country: United States
facility: Mt. Sinai Hosp. Med. Ctr. - Chicago, Womens & Childrens HIV Program
state: Illinois
city: Chicago
country: United States
facility: Univ. of Chicago - Dept. of Peds., Div. of Infectious Disease
state: Illinois
city: New Orleans
country: United States
facility: Tulane Univ. Health Science Ctr., Tulane Univ. Hosp. & Clinic
state: Louisiana
city: New Orleans
country: United States
facility: Tulane/LSU Maternal/Child CRS
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Hosp. & Health System - Dept. of Peds., Div. of Infectious Diseases
state: Maryland
city: Baltimore
country: United States
facility: Univ. of Maryland Med. Ctr., Div. of Ped. Immunology & Rheumatology
state: Maryland
city: Boston
country: United States
facility: HMS - Children's Hosp. Boston, Div. of Infectious Diseases
state: Massachusetts
city: Boston
country: United States
facility: BMC, Div. of Ped Infectious Diseases
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp., Div. of Infectious Disease
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Health, Baystate Med. Ctr.
state: Massachusetts
city: Worcester
country: United States
facility: WNE Maternal Pediatric Adolescent AIDS CRS
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hospital of Michigan NICHD CRS
state: Michigan
city: Jackson
country: United States
facility: Univ. of Mississippi Med. Ctr Children's Hosp.
state: Michigan
city: Newark
country: United States
facility: Rutgers - New Jersey Medical School CRS
state: New Jersey
city: Bronx
country: United States
facility: Bronx-Lebanon Hosp. IMPAACT CRS
state: New York
city: Bronx
country: United States
facility: Montefiore Med. Ctr. - AECOM
state: New York
city: New York
country: United States
facility: Nyu Ny Nichd Crs
state: New York
city: New York
country: United States
facility: Columbia IMPAACT CRS
state: New York
city: Rochester
country: United States
facility: Strong Memorial Hospital Rochester NY NICHD CRS
state: New York
city: Stony Brook
country: United States
facility: SUNY Stony Brook NICHD CRS
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Med. Univ., Dept. of Peds.
state: New York
city: Durham
country: United States
facility: DUMC Ped. CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: Case CRS
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science Univ. - Dept. of Peds., Div. of Infectious Disease
state: Oregon
city: Memphis
country: United States
facility: Regional Med. Ctr. at Memphis
state: Tennessee
city: Memphis
country: United States
facility: St. Jude/UTHSC CRS
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Univ. Med. Ctr., Div. of Ped. Infectious Diseases
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hosp. CRS
state: Texas
city: Seattle
country: United States
facility: Univ. of Washington NICHD CRS
state: Washington
city: Seattle
country: United States
facility: UW Medicine - Harborview Med. Ctr., Northwest Family Ctr.
state: Washington
city: Seattle
country: United States
facility: UW School of Medicine - CHRMC
state: Washington
city: Seattle
country: United States
facility: Seattle Children's Hospital CRS
state: Washington
city: Nassau
country: Bahamas
facility: Princess Margaret Hosp. Bahamas NICHD CRS
city: Belo Horizonte
country: Brazil
facility: SOM Federal University Minas Gerais Brazil NICHD CRS
state: Minas Gerais
city: Rio de Janeiro
country: Brazil
facility: Hosp. dos Servidores Rio de Janeiro NICHD CRS
city: Rio de Janeiro
country: Brazil
facility: Hosp. dos Servidores do Estado CRS
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
Study officials:
affiliation: Department of Obstetrics/Gynecology, University of Washington Medical Center
name: Jane Hitti, MD, MPH
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.