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

NCT ID: NCT01618305

Last Updated: 2020-01-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 408 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-09-05
• Study Completion Date: 2018-12-11

Brief Summary

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.

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.

Conditions

HIV Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Arm A (Women)

Pregnant women received ZDV/3TC + EFV

Group Type: EXPERIMENTAL

Lamivudine/zidovudine

Intervention Type: DRUG

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.

Efavirenz

Intervention Type: DRUG

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

Arm B (Women)

Pregnant women received ZDV/3TC + RAL

Group Type: EXPERIMENTAL

Lamivudine/zidovudine

Intervention Type: DRUG

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.

Raltegravir

Intervention Type: DRUG

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

Arm A (Infants)

Infants born to women in Arm A; infants received no study intervention.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Arm B (Infants)

Infants born to women in Arm B; infants received no study intervention.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

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.

Intervention Type: DRUG

Efavirenz

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

Intervention Type: DRUG

Raltegravir

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

Intervention Type: DRUG

Other Intervention Names

ZDV/3TC; EFV; RAL

Eligibility 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

• Minimum Eligible Age: 16 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

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

NIH

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Westat

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Esau Joao, M.D.

Role: STUDY_CHAIR

Hospital Federal dos Servidores do Estado - RJ

Mark Mirochnick, M.D.

Role: STUDY_CHAIR

Boston Medical Center

Locations

South Flordia Childrens Diagnostic & Treatment Center

Fort Lauderdale, Florida, United States

Tulane University

New Orleans, Louisiana, United States

St Jude's Children's Research Hospital

Memphis, Tennessee, United States

University of Washington Medical Center

Seattle, Washington, United States

Hosp. General de Agudos Buenos Aires Argentina NICHD CRS

Ciudad de Buenos Aires, Buenos Aires, Argentina

Fundacion Huesped - Hospital Juan A Fernandez

Buenos Aires, , Argentina

SOM Federal University Minas Gerais Brazil NICHD CRS

Belo Horizonte, Minas Gerais, Brazil

Univ. Caxias do Sul Brazil NICHD CRS

Caxias do Sul, Rio Grande do Sul, Brazil

Hospital Nossa Senhora da Conceicao NICHD CRS

Porto Alegre, Rio Grande do Sul, Brazil

Hospital Federal dos Servidores do Estado NICHD CRS

Rio de Janeiro, , Brazil

Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS

Rio de Janeiro, , Brazil

Hosp. Geral De Nova Igaucu Brazil NICHD CRS

Rio de Janeiro, , Brazil

Univ. of Sao Paulo Brazil NICHD CRS

São Paulo, , Brazil

San Juan City Hosp. PR NICHD CRS

San Juan, , Puerto Rico

Perinatal HIV Research Unit-Chris Hani Baragwanath Hospital

Soweto, , South Africa

Kilimanjaro Christian Medical Centre (KCMC)

Moshi, , Tanzania

Siriraj Hospital ,Mahidol University NICHD CRS

Bangkok, Bangkoknoi, Thailand

Bhumibol Adulyadej Hospital

Bangkok, , Thailand

Chiangrai Prachanukroh Hospital NICHD CRS

Chiang Mai, , Thailand

Countries

United States; Argentina; Brazil; Puerto Rico; South Africa; Tanzania; Thailand

References

Joao EC, Morrison RL, Shapiro DE, Chakhtoura N, Gouvea MIS, de Lourdes B Teixeira M, Fuller TL, Mmbaga BT, Ngocho JS, Njau BN, Violari A, Mathiba R, Essack Z, Pilotto JHS, Moreira LF, Rolon MJ, Cahn P, Prommas S, Cressey TR, Chokephaibulkit K, Werarak P, Laimon L, Hennessy R, Frenkel LM, Anthony P, Best BM, Siberry GK, Mirochnick M. Raltegravir versus efavirenz in antiretroviral-naive pregnant women living with HIV (NICHD P1081): an open-label, randomised, controlled, phase 4 trial. Lancet HIV. 2020 May;7(5):e322-e331. doi: 10.1016/S2352-3018(20)30038-2.

Reference Type: DERIVED

PMID: 32386720 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Related Links

https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables

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).

https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-reporting-adverse-events-daids

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

Other Identifiers

10770

Identifier Type: REGISTRY

Identifier Source: secondary_id

NICHD P1081

Identifier Type: -

Identifier Source: secondary_id

HHSN2752018000011.

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

UM1AI068616

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P1081

Identifier Type: -

Identifier Source: org_study_id