Evaluating the Safety of Immediate Versus Deferred Isoniazid Preventive Therapy Among HIV-Infected Pregnant Women

NCT ID: NCT01494038

Last Updated: 2021-11-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 956 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-08-19
• Study Completion Date: 2017-09-06

Brief Summary

Tuberculosis (TB) is a leading cause of death among HIV-infected persons in low-income settings and can be a serious complication for HIV-infected pregnant women and their infants. Isoniazid (INH) preventive therapy (IPT) is effective in preventing TB infection in HIV-infected adults, but the safety of IPT in pregnant women is unknown. This study evaluated the safety of IPT among HIV-infected pregnant women.

Detailed Description

TB disease is the most common HIV-related opportunistic infection and is a leading cause of death among HIV-infected persons in low-income settings. When TB occurs during or soon after pregnancy, it can cause complications for the mother as well as infant TB or death. Infant TB is very difficult to diagnose, and up to half of infant TB cases are caused by maternal TB. It has been shown that treatment for active TB is safe and effective during pregnancy and that IPT is safe and effective in preventing TB infection in HIV-infected adults. However, the safety of IPT in HIV-infected pregnant women is not known, especially in regard to its combination with highly active retroviral therapy (HAART). This study evaluated the safety of immediate (antepartum, or before delivery) versus deferred (postpartum, or after delivery) IPT among HIV-infected pregnant women in high TB incidence settings.

HIV-infected pregnant women were randomly assigned (1:1) to one of two arms: Arm A (immediate/antepartum INH) and Arm B (deferred/postpartum INH group). Women in both arms received oral prenatal multivitamins and pyridoxine (vitamin B6) once daily from study entry through Week 40 postpartum.

Study visits for women occurred at screening, entry, every 4 weeks until labor and delivery, at labor and delivery, and every 4 weeks after delivery until 48 weeks postpartum. Visits consisted of giving a medical history and undergoing a physical exam and blood collection; all visits through the delivery visit also included an obstetrical exam. Presence of HIV infection was documented at screening and a tuberculin skin test (TST) was administered at the delivery visit and at the Week 44 postpartum visit. Study visits for infants occurred at birth and at several time points through Week 48. These visits included a medical history, physical exam, and blood collection. Intensive pharmacokinetic (PK) samples, that is, samples taken at many different time points within a 24-hour test period, were collected from a small subset of women, one test period at antepartum and one at postpartum. Sparse PK samples, that is, samples taken at fewer time points within the test period, were collected on all women, once each at antepartum and postpartum.

Conditions

HIV Infections; Tuberculosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

Arm A (Immediate INH Treatment)

Women in Arm A received immediate, or antepartum-initiated, INH treatment. Women received INH at study entry through Week 28, then switched to placebo for INH treatment through Week 40 postpartum.

Group Type: EXPERIMENTAL

Isoniazid (INH)

Intervention Type: DRUG

300-mg tablet once daily by mouth, either from entry through Week 28 antepartum (Arm A) or from Week 12 postpartum through Week 40 postpartum (Arm B)

Placebo for isoniazid (INH)

Intervention Type: DRUG

Placebo tablet once daily by mouth, either from Week 28 visit through Week 40 postpartum (Arm A) or from entry until Week 12 postpartum visit (Arm B)

Arm B (Deferred INH Treatment)

Women in Arm B received deferred, or postpartum-initiated, INH treatment. Women received placebo for INH at study entry through Week 12 postpartum, then switched to INH through Week 40 postpartum.

Group Type: EXPERIMENTAL

Isoniazid (INH)

Intervention Type: DRUG

300-mg tablet once daily by mouth, either from entry through Week 28 antepartum (Arm A) or from Week 12 postpartum through Week 40 postpartum (Arm B)

Placebo for isoniazid (INH)

Intervention Type: DRUG

Placebo tablet once daily by mouth, either from Week 28 visit through Week 40 postpartum (Arm A) or from entry until Week 12 postpartum visit (Arm B)

Interventions

Isoniazid (INH)

300-mg tablet once daily by mouth, either from entry through Week 28 antepartum (Arm A) or from Week 12 postpartum through Week 40 postpartum (Arm B)

Intervention Type: DRUG

Placebo for isoniazid (INH)

Placebo tablet once daily by mouth, either from Week 28 visit through Week 40 postpartum (Arm A) or from entry until Week 12 postpartum visit (Arm B)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Documented HIV-1 infection, defined as positive results from two samples collected at different time points. All samples tested must be whole blood, serum, or plasma. More information on this criterion can be found in the protocol.
• Documented HIV treatment, according to World Health Organization (WHO) guidelines, for prevention of mother-to-child transmission (PMTCT) and standard of care for HIV infection
• Pregnant females age 18 years or older
• Pregnant females between greater than or equal to 13 and less than 18 who are able and willing to provide signed informed consent under local law or pregnant females unable to consent under local law whose parents/legal guardians provide consent or "minimum age of consent according to locally applicable laws or regulations"
• Pregnancy gestational age confirmed by best available method at site to be greater than or equal to 14 weeks through less than or equal to 34 weeks (34 weeks, 6 days)
• Weight greater than or equal to 35 kg at screening
• The following laboratory values obtained within 30 days prior to study entry:

• Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm^3
• Hemoglobin greater than or equal to 7.5 g/dL
• Platelet count greater than or equal to 50,000/mm^3
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (ALT)/serum glutamic pyruvic transaminase (SGPT), and total bilirubin less than or equal to 1.25 times the upper limit of normal (ULN). (Note: If participant is taking atazanavir, direct bilirubin may be used to determine eligibility.)
• Intent to remain in current geographical area of residence for the duration of the study

Exclusion Criteria

• Any woman with a positive TB symptom screen per WHO guidelines, including any one or more of the following: any cough, fever, self-reported weight loss, or night sweats. Note: If a potential participant is found to be negative for TB upon further testing, the participant may be rescreened for the study.
• Any positive acid-fast bacillus (AFB) smear, Xpert, or any other rapid TB screening test or culture from any site within the past 12 weeks, or chest radiograph (x-ray) with findings suggestive of active TB, or clinician suspects active TB
• Known exposure to AFB smear-positive active TB case within past 12 weeks prior to study entry
• Reported INH exposure (more than 30 days) in the past year prior to study entry
• Receipt of any TB or atypical mycobacteria therapy for more than 30 days in the past year
• Evidence of acute hepatitis, such as jaundice, dark urine (not concentrated urine), and/or acholic stools sustained for more than 3 days within 90 days prior to entry. More information on this criterion can be found in the protocol.
• Grade 1 or higher peripheral neuropathy. More information on this criterion can be found in the protocol.
• History of acute systemic adverse reaction or allergy to INH
• Known current heavy alcohol use (more than 2 drinks per week) or alcohol exposure that, in the investigator's opinion, would compromise participation and the outcome of this study
• Presence of new AIDS-defining opportunistic infection that has been treated less than 30 days prior to study entry
• Receipt of an investigational agent or chemotherapy for active malignancy within 30 days prior to study entry
• 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 participation and the outcome of this study

• Minimum Eligible Age: 13 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Amita Gupta, MD, MHS

Role: STUDY_CHAIR

Johns Hopkins University

Locations

Gaborone CRS

Gaborone, , Botswana

Molepolole CRS

Gaborone, , Botswana

Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS

Port-au-Prince, , Haiti

Byramjee Jeejeebhoy Medical College (BJMC) CRS

Pune, Maharashtra, India

Soweto IMPAACT CRS

Johannesburg, Gauteng, South Africa

Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS

Cape Town, Western Cape, South Africa

Fam-Cru Crs

Cape Town, Western Cape, South Africa

Kilimanjaro Christian Medical Centre (KCMC)

Moshi, , Tanzania

Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS

Chiang Mai, , Thailand

MU-JHU Research Collaboration (MUJHU CARE LTD) CRS

Kampala, , Uganda

Seke North CRS

Chitungwiza, , Zimbabwe

St Mary's CRS

Chitungwiza, , Zimbabwe

Harare Family Care CRS

Harare, , Zimbabwe

Countries

Botswana; Haiti; India; South Africa; Tanzania; Thailand; Uganda; Zimbabwe

References

Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst Rev. 2010 Jan 20;2010(1):CD000171. doi: 10.1002/14651858.CD000171.pub3.

Reference Type: BACKGROUND

PMID: 20091503 (View on PubMed)

Zar HJ, Cotton MF, Strauss S, Karpakis J, Hussey G, Schaaf HS, Rabie H, Lombard CJ. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. BMJ. 2007 Jan 20;334(7585):136. doi: 10.1136/bmj.39000.486400.55. Epub 2006 Nov 3.

Reference Type: BACKGROUND

PMID: 17085459 (View on PubMed)

Cantwell MF, Snider DE Jr, Cauthen GM, Onorato IM. Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA. 1994 Aug 17;272(7):535-9.

Reference Type: BACKGROUND

PMID: 8046808 (View on PubMed)

Gupta A, Singh P, Aaron L, Montepiedra G, Chipato T, Stranix-Chibanda L, Chanaiwa V, Vhembo T, Mutambanengwe M, Masheto G, Raesi M, Bradford S, Golner A, Costello D, Kulkarni V, Shayo A, Kabugho E, Jean-Phillippe P, Chakhtoura N, Sterling TR, Theron G, Weinberg A; IMPAACT P1078 TB APPRISE Study Team. Timing of maternal isoniazid preventive therapy on tuberculosis infection among infants exposed to HIV in low-income and middle-income settings: a secondary analysis of the TB APPRISE trial. Lancet Child Adolesc Health. 2023 Oct;7(10):708-717. doi: 10.1016/S2352-4642(23)00174-8. Epub 2023 Aug 24.

Reference Type: DERIVED

PMID: 37634517 (View on PubMed)

Montepiedra G, Kim S, Weinberg A, Theron G, Sterling TR, LaCourse SM, Bradford S, Chakhtoura N, Jean-Philippe P, Evans S, Gupta A. Using a Composite Maternal-Infant Outcome Measure in Tuberculosis-Prevention Studies Among Pregnant Women. Clin Infect Dis. 2021 Aug 2;73(3):e587-e593. doi: 10.1093/cid/ciaa1674.

Reference Type: DERIVED

PMID: 33146706 (View on PubMed)

Gupta A, Montepiedra G, Aaron L, Theron G, McCarthy K, Bradford S, Chipato T, Vhembo T, Stranix-Chibanda L, Onyango-Makumbi C, Masheto GR, Violari A, Mmbaga BT, Aurpibul L, Bhosale R, Mave V, Rouzier V, Hesseling A, Shin K, Zimmer B, Costello D, Sterling TR, Chakhtoura N, Jean-Philippe P, Weinberg A; IMPAACT P1078 TB APPRISE Study Team. Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women. N Engl J Med. 2019 Oct 3;381(14):1333-1346. doi: 10.1056/NEJMoa1813060.

Reference Type: DERIVED

PMID: 31577875 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://rsc.tech-res.com/docs/default-source/safety/manual_for_expedited_reporting_aes_to_daids_v2.pdf?sfvrsn=12

Manual for Expedited Reporting of Adverse Events to Division of AIDS (DAIDS), Version 2.0, January 2010

http://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf?sfvrsn=6

Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004 (Clarification, August 2009)

Other Identifiers

10732

Identifier Type: REGISTRY

Identifier Source: secondary_id

IMPAACT P1078

Identifier Type: -

Identifier Source: secondary_id

P1078

Identifier Type: -

Identifier Source: org_study_id