Clinical trial NCT01618305: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infections
Lead sponsor: Westat
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2012-06-13
Enrollment: 408
Sex: FEMALE
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Proportion of Women With Plasma HIV-1 RNA Viral Load Less Than 200 Copies/mL at Delivery
timeFrame: Measured at participants' delivery visit (or last visit within three weeks prior to delivery)
measure: Proportion of Participants Who Discontinued Randomized Study Drug Prior to Labor and Delivery.
timeFrame: Measured from entry through participants' delivery visit (approximately 36 to 40 weeks gestation)
measure: 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
timeFrame: Measured from entry through participants' last study visit, approximately 24 weeks after delivery
measure: Proportion of Infants Who Experienced at Least One Adverse Event of Greater Than or Equal to Grade 3.
timeFrame: Measured from birth through infants' last study visit, approximately 24 weeks after delivery
Secondary outcomes:
measure: Proportion of Women Who Achieved HIV-1 RNA Virologic Suppression Below the Lower Limit of Quantification of the Assay at Delivery
timeFrame: Measured at participants' delivery visit (or last visit within three weeks prior to delivery)
measure: 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
timeFrame: Measured from entry through delivery (approximately 36 to 40 weeks gestation).
measure: Log10 Change in Viral Load From Entry to Each Time Point Prior to Delivery
timeFrame: Measured at antepartum Weeks 1, 2, 4, 6, 8, 10, 12, 14, and 16.
measure: Proportion of Women With HIV-1 RNA Plasma Viral Load Less Than 200 Copies/mL at Weeks 4 and 6 From Treatment Initiation
timeFrame: Measured at Weeks 4 and 6 from first dose of randomized treatment, prior to delivery
measure: Proportion of Women With HIV-1 RNA Vaginal Viral Load Less Than 1200 Copies/mL at Weeks 4 and 6 From Treatment Initiation
timeFrame: Measured at Weeks 4 and 6 from first dose of randomized treatment, prior to delivery
measure: Infectivity of Plasma
timeFrame: Measured on or after delivery up to participants' last postpartum study visit (approximately 26 weeks after delivery)
measure: Proportion of Deliveries That Had an Outcome of a Stillbirth/Fetal Demise.
timeFrame: Measured at delivery (approximately 36 to 40 weeks gestation)
measure: Proportion of Deliveries That Were Premature (Less Than 37 Weeks Gestation)
timeFrame: Measured at delivery (within 72 hours).
measure: Proportion of Deliveries That Were Extremely Premature (Less Than 34 Weeks Gestation).
timeFrame: At delivery (within 72 hours).
measure: Proportion of Deliveries With a Low Birth Weight (Less Than 2,500 Grams)
timeFrame: Measured within 72 hours after delivery
measure: Proportion of Deliveries With an Extremely Low Birth Weight (<1,500 Grams).
timeFrame: Measured within 72 hours after delivery
measure: Infant HIV Infection Status (Per International Maternal Pediatric Adolescent AIDS Clinical Trials Group [IMPAACT] Definitions)
timeFrame: Measured from birth through infants' last study visit at Week 24
measure: Proportion of HIV-infected Infants With Genotypic Resistance to Study Drugs
timeFrame: Measured on or after confirmation of HIV-infection up to the infants' last study visit at Week 24
measure: 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.
timeFrame: Measured at screening and at the time of inadequate virologic response (from Week 2 antepartum through participants' last study visit 24 weeks after delivery).
Other outcomes:
Locations:
city: Fort Lauderdale
country: United States
facility: South Flordia Childrens Diagnostic & Treatment Center
state: Florida
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Memphis
country: United States
facility: St Jude's Children's Research Hospital
state: Tennessee
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Ciudad de Buenos Aires
country: Argentina
facility: Hosp. General de Agudos Buenos Aires Argentina NICHD CRS
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Fundacion Huesped - Hospital Juan A Fernandez
city: Belo Horizonte
country: Brazil
facility: SOM Federal University Minas Gerais Brazil NICHD CRS
state: Minas Gerais
city: Caxias Do Sul
country: Brazil
facility: Univ. Caxias do Sul Brazil NICHD CRS
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora da Conceicao NICHD CRS
state: Rio Grande Do Sul
city: Rio de Janeiro
country: Brazil
facility: Hospital Federal dos Servidores do Estado NICHD CRS
city: Rio de Janeiro
country: Brazil
facility: Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS
city: Rio de Janeiro
country: Brazil
facility: Hosp. Geral De Nova Igaucu Brazil NICHD CRS
city: Sao Paulo
country: Brazil
facility: Univ. of Sao Paulo Brazil NICHD CRS
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
city: Soweto
country: South Africa
facility: Perinatal HIV Research Unit-Chris Hani Baragwanath Hospital
city: Moshi
country: Tanzania
facility: Kilimanjaro Christian Medical Centre (KCMC)
city: Bangkok
country: Thailand
facility: Siriraj Hospital ,Mahidol University NICHD CRS
state: Bangkoknoi
city: Bangkok
country: Thailand
facility: Bhumibol Adulyadej Hospital
city: Chiang Mai
country: Thailand
facility: Chiangrai Prachanukroh Hospital NICHD CRS
Study officials:
affiliation: Hospital Federal dos Servidores do Estado - RJ
name: Esau Joao, M.D.
role: STUDY_CHAIR
affiliation: Boston Medical Center
name: Mark Mirochnick, M.D.
role: STUDY_CHAIR
References:
citation: 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.