Clinical Trials

MainTitle

Evaluating the Response to Two Antiretroviral Medication Regimens in HIV-Infected Pregnant Women, Who Begin Antiretroviral Therapy Between 20 and 36 Weeks of Pregnancy, for the Prevention of Mother-to-Child Transmission

This study has been completed
Sponsor
Westat

Collaborator
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Allergy and Infectious Diseases (NIAID)

Information provided by (Responsible Party)
Westat
ClinicalTrials.gov Identifier
NCT01618305

First received: June 6, 2012
Last updated: January 14, 2020
Last Verified: January 2020
History of Changes
Purpose

Purpose

HIV-infected pregnant women who begin taking antiretroviral (ARV) medications in the late stages of pregnancy need an effective medication regimen to reduce the risk of transmitting HIV to their children. This study examined the virologic response, safety, and tolerability of two different ARV medication regimens in HIV-infected pregnant women who were between 20 and 36 weeks pregnant when they entered the study.

Condition Intervention Phase
HIV Infections

Drug : Lamivudine/zidovudine
Drug : Efavirenz
Drug : Raltegravir
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Phase IV Randomized Trial to Evaluate the Virologic Response and Pharmacokinetics of Two Different Potent Regimens in HIV Infected Women Initiating Triple Antiretroviral Regimens Between 20 and 36 Weeks of Pregnancy for the Prevention of Mother-to-Child Transmission: NICHD P1081

Further study details as provided by Westat:

Primary Outcome Measures

  • Proportion of Women With Plasma HIV-1 RNA Viral Load Less Than 200 Copies/mL at Delivery [ Time Frame: Measured at participants' delivery visit (or last visit within three weeks prior to delivery) ]
    If there was no viral load measurement at the delivery visit, the last viral load within three weeks prior to delivery was considered.
  • Proportion of Participants Who Discontinued Randomized Study Drug Prior to Labor and Delivery. [ Time Frame: Measured from entry through participants' delivery visit (approximately 36 to 40 weeks gestation) ]
    Only women who initiated (i.e. received at least one dose of) their randomized treatment were eligible for this outcome measure. Women were considered to have discontinued study drug if they stopped receiving efavirenz or raltegravir (whichever was assigned) prior to labor and delivery for any reason, including loss to follow-up.
  • Proportion of Women Who Experienced at Least One New Adverse Event of Greater Than or Equal to Grade 3 as Defined in the Division of AIDS (DAIDS) Toxicity Table [ Time Frame: Measured from entry through participants' last study visit, approximately 24 weeks after delivery ]
    "New" adverse events were those with an onset date on or after randomization. Adverse events present at baseline would only be considered "New" if they increased in grade on or after randomization. All women who received at least one dose of study drug were eligible for this analysis.
  • Proportion of Infants Who Experienced at Least One Adverse Event of Greater Than or Equal to Grade 3. [ Time Frame: Measured from birth through infants' last study visit, approximately 24 weeks after delivery ]
    All infants who were live births on study were eligible for this analysis. Adverse event grades were defined based on the DAIDS toxicity table.
Secondary Outcome Measures:
  • Proportion of Women Who Achieved HIV-1 RNA Virologic Suppression Below the Lower Limit of Quantification of the Assay at Delivery [ Time Frame: Measured at participants' delivery visit (or last visit within three weeks prior to delivery) ]
    A successful outcome was defined as maternal HIV-1 RNA plasma viral load less than the lower limit of quantification (LLQ) for the testing assay, which could vary. Most (99%) women had their viral load measured using an assay with LLQ equal to 40 or 20 copies/mL. If the viral load at delivery was missing, the last observed viral load within 21 days prior to the delivery date was considered.
  • Proportion of Women With 1) Successful Viral Load (Plasma HIV-1 RNA VL) Decrease From Entry to Week 2 and VL Less Than 1,000 Copies/ml at All Time Points After 4 Weeks on Study Drugs, Until Delivery; and 2) Who Remain on the Assigned Study Regimen [ Time Frame: Measured from entry through delivery (approximately 36 to 40 weeks gestation). ]
    A successful viral load decrease was defined as follows: for women having HIV-1 RNA viral load greater than or equal to 10,000 copies/mL at entry, a viral load <200 copies/mL; for women with VL less than 10,000 copies/mL at entry, a Log10 viral load decrease of at least 2.0 from entry.
  • Log10 Change in Viral Load From Entry to Each Time Point Prior to Delivery [ Time Frame: Measured at antepartum Weeks 1, 2, 4, 6, 8, 10, 12, 14, and 16. ]
    Change in viral load from entry (or screening, if there was no entry viral load) to each study week prior to delivery, calculated on the log10 scale as log10(week X RNA) - log10(baseline RNA). For this analysis, HIV-1 RNA values that were censored below the lower limit of quantification (LLQ) were imputed to be equal to the LLQ - 1.
  • Proportion of Women With HIV-1 RNA Plasma Viral Load Less Than 200 Copies/mL at Weeks 4 and 6 From Treatment Initiation [ Time Frame: Measured at Weeks 4 and 6 from first dose of randomized treatment, prior to delivery ]
    The Week 4 and 6 participant viral loads were the viral load results obtained closest to (within four days of) the target date for that visit from initiation of treatment (for Week 4, day 24-32 after first dose; for Week 6, day 38-46 after first dose).
  • Proportion of Women With HIV-1 RNA Vaginal Viral Load Less Than 1200 Copies/mL at Weeks 4 and 6 From Treatment Initiation [ Time Frame: Measured at Weeks 4 and 6 from first dose of randomized treatment, prior to delivery ]
    The Week 4 and 6 participant viral loads were the viral load results obtained closest to (within four days of) the target date for that visit from initiation of treatment (for Week 4, day 24-32 after first dose; for Week 6, day 38-46 after first dose). Vaginal swabs produce much less testable sample volume than blood plasma draws. Each vaginal swab specimen had to be diluted, and this dilution factor raised the lower limit of quantification (LLQ). The most commonly observed LLQs were 300 and 1200. For consistency, the higher LLQ was considered the threshold for this outcome measure.
  • Infectivity of Plasma [ Time Frame: Measured on or after delivery up to participants' last postpartum study visit (approximately 26 weeks after delivery) ]
    The goal of this outcome measure was to address an objective relevant to protease inhibitors, one of which was originally included as a third arm in the Version 2.0 of the study. This outcome measure was included to assess how the infectivity of plasma changed over time among women receiving protease inhibitors, and whether this differed from other classes of antiretroviral drugs. However, the lopinavir/ritonavir arm was later dropped in Version 3.0, and only Version 2.0 women who received efavirenz or raltegravir were included in the study analyses. Therefore, because no women included in the study analyses received lopinavir/ritonavir, this outcome measure was not analyzed.
  • Proportion of Deliveries That Had an Outcome of a Stillbirth/Fetal Demise. [ Time Frame: Measured at delivery (approximately 36 to 40 weeks gestation) ]
    The unit of analysis was the mother-infant set. All sets where the woman received at least one dose of study treatment and remained on study through delivery were eligible. In the case of twins, the worst outcome (i.e. a stillbirth) was used.
  • Proportion of Deliveries That Were Premature (Less Than 37 Weeks Gestation) [ Time Frame: Measured at delivery (within 72 hours). ]
    The unit of analysis for this outcome measure was the mother-infant set. A mother-infant set was counted as having a premature delivery if any infant in the mother-infant set was delivered prior to 37 weeks gestation (i.e. in the case of twins, if either of the twins was delivered prior to 37 weeks gestation then this set would count as one premature delivery outcome). All mother-infant sets that delivered at least one live birth on study were eligible for this outcome.
  • Proportion of Deliveries That Were Extremely Premature (Less Than 34 Weeks Gestation). [ Time Frame: At delivery (within 72 hours). ]
    The unit of analysis for this outcome measure was the mother-infant set. A mother-infant set was counted as having an extremely premature delivery if any infant in the mother-infant set was delivered prior to 34 weeks gestation (i.e. in the case of twins, if either of the twins was delivered prior to 34 weeks gestation then this set would count as one extremely premature delivery outcome). Only women who enrolled prior to 34 weeks gestation were included in this analysis. Those that enrolled from 34 to less than 37 weeks gestation were excluded because they were already past the gestational age where this outcome could have occurred at entry.
  • Proportion of Deliveries With a Low Birth Weight (Less Than 2,500 Grams) [ Time Frame: Measured within 72 hours after delivery ]
    The unit of analysis was the mother-infant pair or set; in the case of multiple gestation, the worst outcome was considered in analysis (e.g. if two twins were delivered to one mother, one at 2,000 grams and one at 3,000 grams, this mother-infant set would count as one instance of low birth weight in analysis because at least one of the infants had the outcome).
  • Proportion of Deliveries With an Extremely Low Birth Weight (<1,500 Grams). [ Time Frame: Measured within 72 hours after delivery ]
    The unit of analysis was the mother-infant pair or set; in the case of multiple gestation, the worst outcome was considered in analysis (e.g. if two twins were delivered to one mother, one at 2,000 grams and one at 1,000 grams, this mother-infant set would count as one instance of extremely low birth weight in analysis because at least one of the infants had the outcome).
  • Infant HIV Infection Status (Per International Maternal Pediatric Adolescent AIDS Clinical Trials Group [IMPAACT] Definitions) [ Time Frame: Measured from birth through infants' last study visit at Week 24 ]
    Infants were considered infected if they had both a positive HIV nucleic acid test and a subsequent confirmatory test on a different sample. Uninfected infants were those that had no positive test results and negative test results obtained at two or more of the following visits: Week 6, Week 16, and/or Week 24 postpartum.
  • Proportion of HIV-infected Infants With Genotypic Resistance to Study Drugs [ Time Frame: Measured on or after confirmation of HIV-infection up to the infants' last study visit at Week 24 ]
    Genotypic resistance to each class of study drug (reverse transcriptase inhibitors and integrase inhibitors) was assessed separately among HIV infected infants.
  • Proportion of Women With HIV-1 Drug Resistance Mutations at Screening, 2-4 Weeks Postpartum in Women Who Stopped Antiretroviral Therapy, and at the Time of Inadequate Virologic Response Using Standard and Ultrasensitive Methods. [ Time Frame: Measured at screening and at the time of inadequate virologic response (from Week 2 antepartum through participants' last study visit 24 weeks after delivery). ]
    Consensus sequencing was performed on a sample from screening. Women were evaluated for integrase and reverse transcriptase resistance mutations separately. Additionally, consensus sequencing was performed among women who had an inadequate virologic response (defined in the protocol) on a sample taken at that time of inadequate virologic response. Genotypic resistance among women who stopped antiretroviral therapy was not assessed. Because World Health Organization guidelines have been updated to indicate all people living with HIV should remain on antiretroviral therapy, even postpartum women, no women stopped antiretroviral therapy after delivery. Therefore, this aspect of the outcome measure is no longer relevant and was not assessed.

Enrollment: 408
Study Start Date: September 5, 2013
Study Completion Date: December 11, 2018
Primary Completion Date: December 11, 2018 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: Arm A (Women)
Pregnant women received ZDV/3TC + EFV
Drug: Lamivudine/zidovudine
  • Participants received one lamivudine 150 mg/zidovudine 300 mg fixed-dose combination tablet twice a day from entry through delivery*.
  • * Participants may have received a locally supplied nucleoside reverse transcriptase inhibitor (NRTI) backbone in place of lamivudine/zidovudine with permission of the protocol team obtained prior to randomization.

Other Name: ZDV/3TC
Drug: Efavirenz

Participants received one 600 mg tablet of efavirenz each night from entry through delivery.

Other Name: EFV
Experimental: Arm B (Women)
Pregnant women received ZDV/3TC + RAL
Drug: Lamivudine/zidovudine
  • Participants received one lamivudine 150 mg/zidovudine 300 mg fixed-dose combination tablet twice a day from entry through delivery*.
  • * Participants may have received a locally supplied nucleoside reverse transcriptase inhibitor (NRTI) backbone in place of lamivudine/zidovudine with permission of the protocol team obtained prior to randomization.

Other Name: ZDV/3TC
Drug: Raltegravir

Participants received one 400 mg raltegravir tablet twice a day from entry through delivery.

Other Name: RAL
No Intervention: Arm A (Infants)
Infants born to women in Arm A; infants received no study intervention.
No Intervention: Arm B (Infants)
Infants born to women in Arm B; infants received no study intervention.

Detailed Description:

When initiating this study there were many ARV medications and combination regimens available to treat HIV-infected people. However, the number of ARV medications that had been studied in HIV-infected pregnant women for the prevention of mother-to-child transmission was limited. Although HIV-infected pregnant women who began taking ARV medications late in their pregnancies required effective therapy to reduce the risk of transmitting HIV to their children, there were no published data available that compared the effects of non-nucleoside reverse transcriptase inhibitors (NNRTI) and integrase inhibitors (which are two classes of ARV medications) in pregnant women. The purpose of this study was to compare the safety, tolerability, and virologic responses to two different medication regimens, each of which included an NNRTI or integrase inhibitor, in pregnant HIV-infected women who began ARV therapy late in their pregnancies (i.e., had gestational age between 20 and 36 weeks).
This study was originally opened under IMPAACT P1081, protocol version 2.0 (version 1.0 never opened to accrual) as a three arm study. However, IMPAACT P1081 was closed due to slow accrual, at which point NICHD took over the study, streamlined it to two arms, and reopened it as NICHD P1081 under protocol Version 3.0. Women who enrolled under IMPAACT P1081 (N=20) and were randomized to one of the two continuing arms (efavirenz- or raltegravir-based ART; N=14) were included in NICHD P1081, while IMPAACT P1081 women randomized to the dropped arm (lopinavir/ritonavir-based ART; N=6) were not eligible for inclusion in NICHD P1081.
In this study HIV-infected pregnant women were randomly assigned to one of two arms. Women in Arm A received lamivudine 150 mg/zidovudine 300 mg twice a day and efavirenz 600 mg each night. Women in Arm B received lamivudine 150 mg/zidovudine 300 mg twice a day and raltegravir 400 mg twice a day. All women were scheduled to receive their assigned medications from study entry through delivery. Antepartum study visits were scheduled at entry and Weeks 1, 2, and 4; and thereafter, every two weeks until labor and delivery. Study visits included a medical history review, physical examination, questionnaires, blood collection, and a vaginal swab procedure.
While women were in labor, they were scheduled to continue to receive their study medications. Some women may have received additional or alternate medications according to local standard of care/guidelines. Women had a physical examination and blood collection at the delivery visit. After delivery, some women continued to receive ARV medications according to the local guidelines, and could have received study ARV for up to eight weeks postpartum while they transitioned to the ARV regimen indicated per their local standard of care. Women were scheduled to attend study visits following delivery at Weeks 2, 6, 16, and 24, which included a medical history review, physical examination, and blood collection. Select visits were scheduled to include a vaginal swab procedure. Some women had vaginal specimens stored for future research.
Infants delivered on study were scheduled to receive ARV medications as prescribed by the babies' doctors per local standard of care/guidelines. Study visits for infants were scheduled at birth, and at Weeks 2, 6, 16, and 24. Each study visit included a medical history review, physical examination, and blood collection. Select visits included oral and nasopharyngeal swab collection.Some infants had oral and/or nasopharyngeal specimens stored for future research.

Eligibility

Eligibility

Ages Eligible for Study: 16 Years and older  
Sexes Eligible for Study: Female  
Accepts Healthy Volunteers: No  

Criteria

Inclusion Criteria:

  • Naive to antiretroviral therapy (ART) or have received ART with short course zidovudine (maximum of 8 weeks) for prevention of mother-to-child transmission in previous pregnancies
  • Willing and able to sign informed consent. Participant must be of an age to provide legal informed consent as defined by the country in which the participant resides. If not, the informed consent must be signed by a legal guardian/parent, as per country guidelines.
  • Documentation of HIV-1 infection defined as positive results from two samples collected at different time points. The same method may be used at both time points. All samples tested must be whole blood, serum, or plasma. Documentation may be abstracted from medical records to satisfy these criteria for infection. More information on this criterion can be found in the protocol.
  • Viable pregnancy with gestational age of greater than or equal to 20 weeks to less than or equal to 36 weeks based upon menstrual history and/or ultrasound. Note: If menstrual history is unknown or if there is a discrepancy between menstrual history and ultrasound, determination of gestational age should be based upon best available methodology at each site.
  • Intends to continue pregnancy
  • Willingness and intent to deliver at the participating clinical site and to be followed for the duration of the study at the site or associated outpatient facility
  • Willing to comply with the study regimen
  • Agrees to use two reliable methods of contraception after delivery if randomized to the efavirenz arm and is sexually active. A barrier method of contraception (condoms, diaphragm, or cervical cap) together with another reliable form of contraception must be used for 4 weeks after stopping efavirenz.


Exclusion Criteria:
  • Active labor defined as onset of regular contractions or cervical dilatation greater than 2 cm
  • Use of ART during current pregnancy
  • Chemotherapy for active malignancy
  • HIV genotypic resistance, as defined in the protocol, to efavirenz or raltegravir or to NRTIs that will be included in the ART regimen. Note: A lack of HIV drug resistance test results at the time of enrollment is not exclusionary.
  • Serious active opportunistic infection and/or serious bacterial infection including active tuberculosis (TB) or unstable or severe medical condition within 14 days of study entry
  • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
  • Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, would compromise the outcome of this study
  • Vomiting or inability to swallow medications due to an active, pre-existing condition that prevents adequate swallowing and absorption of study medication
  • Known allergy/sensitivity to any study drugs or their formulations or sulfonamide allergy
  • The following laboratory values (within 30 days of enrollment):
    1. Hemoglobin greater than or equal to Grade 3
    2. Absolute neutrophil count greater than or equal to Grade 2
    3. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than or equal to Grade 2
    4. Serum creatinine greater than or equal to Grade 1
    5. Platelet count greater than or equal to Grade 3
  • Evidence of pre-eclampsia (such as persistent diastolic blood pressure greater than 90 mm Hg)
  • Receipt of disallowed medications as described in the protocol

contacts and locations

Contacts and Locations

Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01618305

Locations

United States, Florida
South Flordia Childrens Diagnostic & Treatment Center
Fort Lauderdale, Florida, United States, 33316
United States, Louisiana
Tulane University
New Orleans, Louisiana, United States, 70118
United States, Tennessee
St Jude's Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Washington
University of Washington Medical Center
Seattle, Washington, United States, 98195
Argentina
Hosp. General de Agudos Buenos Aires Argentina NICHD CRS
Ciudad de Buenos Aires, Buenos Aires, Argentina, C1221ADC
Fundacion Huesped - Hospital Juan A Fernandez
Buenos Aires, Argentina
Brazil
SOM Federal University Minas Gerais Brazil NICHD CRS
Belo Horizonte, Minas Gerais, Brazil, 30.130-100
Univ. Caxias do Sul Brazil NICHD CRS
Caxias Do Sul, Rio Grande Do Sul, Brazil, 95070-560
Hospital Nossa Senhora da Conceicao NICHD CRS
Porto Alegre, Rio Grande Do Sul, Brazil, 91350-200
Hospital Federal dos Servidores do Estado NICHD CRS
Rio de Janeiro, Brazil, 20221-903
Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS
Rio de Janeiro, Brazil, 21941-612
Hosp. Geral De Nova Igaucu Brazil NICHD CRS
Rio de Janeiro, Brazil, 26030
Univ. of Sao Paulo Brazil NICHD CRS
Sao Paulo, Brazil, 14049-900
Puerto Rico
San Juan City Hosp. PR NICHD CRS
San Juan, Puerto Rico, 00936
South Africa
Perinatal HIV Research Unit-Chris Hani Baragwanath Hospital
Soweto, South Africa
Tanzania
Kilimanjaro Christian Medical Centre (KCMC)
Moshi, Tanzania
Thailand
Siriraj Hospital ,Mahidol University NICHD CRS
Bangkok, Bangkoknoi, Thailand, 10700
Bhumibol Adulyadej Hospital
Bangkok, Thailand, 10220
Chiangrai Prachanukroh Hospital NICHD CRS
Chiang Mai, Thailand, 50100

Sponsors and Collaborators

Westat
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

Study Chair: Esau Joao, M.D. Hospital Federal dos Servidores do Estado - RJ
Study Chair: Mark Mirochnick, M.D. Boston Medical Center
More Information

More Information

Additional Information:

The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014 (Corrected to Version 2.1, July 2017).

Additional Information:

The Division of AIDS Manual for the Expedited Reporting of Adverse Events, Version 2.0, January 2010.

Responsible Party: Westat  
ClinicalTrials.gov Identifier: NCT01618305   History of Changes  
Other Study ID Numbers: P1081  
  10770  
  NICHD P1081  
  HHSN2752018000011.  
  UM1AI068616  
Study First Received: June 6, 2012  
Last Updated: January 14, 2020  
Individual Participant Data    
Plan to Share IPD: Yes  

Additional relevant MeSH terms:
HIV Infections
Anti-Retroviral Agents
Lamivudine
Raltegravir Potassium
Efavirenz
Zidovudine
Lamivudine, zidovudine drug combination

ClinicalTrials.gov processed this data on March 27, 2020
This information is provided by ClinicalTrials.gov.