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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase IV Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Safety of Immediate (Antepartum-Initiated) Versus Deferred (Postpartum-Initiated) Isoniazid Preventive Therapy Among HIV-Infected Women in High Tuberculosis (TB) Incidence Settings

Conditions
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HIV Infections, Tuberculosis

Intervention / Treatment
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* Drug: Isoniazid (INH)
* Drug: Placebo for isoniazid (INH)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Immediate INH Treatment)<br>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. | Drug: Isoniazid (INH)<br>* 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)<br>Drug: Placebo for isoniazid (INH)<br>* 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)<br>|
| Experimental: Arm B (Deferred INH Treatment)<br>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. | Drug: Isoniazid (INH)<br>* 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)<br>Drug: Placebo for isoniazid (INH)<br>* 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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rate of Combined Endpoint: Grade 3 or Higher Adverse Events (AEs) Related to Treatment, or AE Causing Discontinuation of Treatment | Incidence rate, calculated by Mantel-Haenszel (MH), weighted by gestational age strata 1) gestational age at entry less than 24 weeks or 2) gestational age at entry greater than or equal to 24 weeks. AE's include laboratory results, signs/symptoms, or diagnoses; graded as per Division of AIDS (DAIDS) or by protocol-defined hepatotoxicity measures. Related to treatment indicates possibly, probably, or definitely related to INH or Placebo for INH as judged by Independent Endpoint Review Committee. Discontinuation refers to permanent discontinuation of study treatment. | Measured from study entry through Week 48 after birth | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Mothers With a Fetal Death | Fetal deaths include both stillbirths and spontaneous abortions; in case of a multiple birth, mothers who had at least one fetal death | Measured from study entry through end of pregnancy | 
| Number of Mothers With a Fetus Small for Gestational Age | Small for gestational age was determined by physician at site | Measured at delivery | 
| Number of Mothers With an Infant Born Prematurely | Premature birth is defined as gestational age of < 37 weeks at delivery. | Measured at delivery | 
| Number of Mothers With a Low Birth-weight Infant | Low birth weight is defined as weight < 2500 mg | Measured on day of birth | 
| Number of Mothers With an Infant With a Congenital Anomaly | Includes congenital anomalies meeting the Metropolitan Atlanta Congenital Defects Program criteria. | Measured from study entry through Week 48 after birth | 
| Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly | In case of a multiple birth, mothers who had at least one adverse pregnancy outcome. Spontaneous abortion is intra-uterine fetal death prior to 20 weeks of gestational age; stillbirth, the same, >= 20 weeks; preterm delivery, < 37 weeks of gestational age; low birth weight, < 2,500 grams, and congenital anomalies meeting the Metropolitan Atlanta Congenital Defects Program criteria. | Measured from study entry through Week 48 after birth | 
| Number of Infants With Grade 3 or Higher Clinical or Laboratory AE | Laboratory, sign/symptom, or diagnoses graded as 3 or higher by DAIDS criteria. | Measured from study entry through Week 48 after birth | 
| Number of Infants With Grade 3 or Higher Clinical or Laboratory AE Related to Treatment | As before, but AE is judged to be possibly, probably, or definitely related to INH or Placebo for INH, by clinic medical staff | Measured from study entry through Week 48 after birth | 
| Number of Infants Which Are HIV-infected | HIV infection determined during follow-up period. Infection at birth or during breastfeeding | Measured from study entry through study Week 44 | 
| Number of Infants Hospitalized | Hospitalization due to reasons other than birth | Measured from study entry through Week 48 after birth | 
| Incidence Rate of TB Infection Among Mothers | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Probable or confirmed TB infection, as judged by Secondary Endpoint Review Committee | Measured from study entry to Week 48 after birth | 
| Incidence Rate of Tuberculosis (TB) Among Infants | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Probable or confirmed TB, or congenital TB as defined using the Cantwell criteria (see reference), judged by the Secondary Endpoint Review Committee. Includes an infant death due to unknown cause. | Measured from study entry through Week 48 after birth | 
| Incidence Rate of Infant Death | Incidence rate was calculated by Mantel-Haenszel, weighted by gestational age strata. | Measured from study entry through Week 48 after birth | 
| Incidence Rate of Maternal Deaths | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. | Measured from study entry through Week 48 postpartum | 
| Incidence Rate of Combined Endpoints: Maternal TB or Maternal Death | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. | Measured from study entry through Week 48 after birth | 
| Incidence Rate of Combined Endpoints: Infant TB or Infant Death | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. | Measured from study entry through Week 48 after birth | 
| Incidence Rate of Combined Endpoints: Maternal TB, Maternal Death, Infant TB, or Infant Death | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. | Measured from study entry through Week 48 after birth | 
| Incidence Rate of Combined Endpoint, Antepartum: Grade 3 or Higher AE Related to Treatment, or Discontinuation of Treatment Due to AE | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata | Measured from study entry through end of pregnancy | 
| Incidence Rate of Combined Endpoint, up to 12 Weeks Postpartum: Grade 3 or Higher AE Related to Treatment, or Discontinuation of Treatment Due to AE | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. | Measured from study entry through 12 weeks after birth | 
| Incidence Rate, Antepartum, of Grade 3 or Higher AE | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. | Measured from study entry through end of pregnancy | 
| Incidence Rate, up to 12 Weeks Postpartum, of Grade 3 or Higher AE | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. | Measured from study entry through 12 weeks postpartum | 
| Incidence Rate, Antepartum, of Hepatotoxicity, Defined by Protocol-specific Definition of Hepatotoxicity, Related to Treatment | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. Protocol-specific definition of hepatotoxicity: Any one of the following: 1) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 times the upper limit of normal (ULN), where ULN is specified by the clinic physician; 2) Total bilirubin > 3 X ULN; 3) ALT greater than 3 X ULN and total bilirubin greater than 2 X ULN; or 4) ALT > 3 X ULN and persistent symptomatic clinical hepatitis | Measured from study entry through delivery | 
| Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Related to Treatment | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata | Measured from study entry through 12 weeks postpartum | 
| Incidence Rate, Antepartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. | Measured from study entry through delivery | 
| Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. | Measured from study entry through 12 weeks postpartum | 
| Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Hepatotoxicity definition as defined by DAIDS AE grading criteria 1.0. | Measured from study entry through delivery | 
| Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata | Measured from study start through 12 weeks postpartum | 
| Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Any Cause | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. | Measured from study entry through delivery | 
| Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Any Cause | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. | Measured from study start through 12 weeks postpartum | 
| Number of Mothers With Tuberculosis Resistant to INH | Resistance to INH from isolates of Mycobacterium tuberculosis, as a percentage of mothers who develop culture-confirmed TB | Measured from study entry through Week 48 postpartum | 
| Number of Infants With Tuberculosis Resistant to INH | Resistance to INH from isolates of Mycobacterium tuberculosis, as a percentage of infants who develop culture-confirmed TB | Measured from study entry through Week 48 after birth | 
| Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH | Pharmacokinetic parameter was estimated from population PK modeling fitted to the intensive PK data. AUC0-24h was predicted using population pharmacokinetic model using the NONMEM software program. A 2-compartment model with first-order absorption with transit compartment and first-order elimination with well-stirred liver model to capture hepatic clearance and first-pass extraction with 1 parameter (hepatic intrinsic clearance) was used, | Measured at antepartum (third trimester and >= 2 weeks after starting study drug) and week 16 postpartum (+/-) 4 weeks) while on active INH; blood samples were drawn pre-dose and at 1, 2, 4, 6, 8, and 12 hours post-dosing. | 
| Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV | Pharmacokinetic parameter was estimated from population PK modeling fitted to the intensive PK data. AUC0-24h was predicted using population pharmacokinetic model using the NONMEM software program. A 2-compartment model with first-order absorption with transit compartment and first-order elimination with well-stirred liver model to capture hepatic clearance and first-pass extraction with 1 parameter (hepatic intrinsic clearance) was used, | Measured at antepartum (third trimester and >= 2 weeks after starting study drug) and week 16 postpartum (+/-) 4 weeks) while on active INH; blood samples were drawn pre-dose and at 1, 2, 4, 6, 8, and 12 hours post-dosing. | 
| Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery | IGRA done by Quantiferon Gold Test (QGIT). For women, TST is considered positive if greater than or equal to 5 mm | Measured at delivery | 
| Agreement Between IGRA and TST TB Test Results, Infant | The TST result was positive if greater than or equal to 10 mm in HIV-negative infants, or greater than or equal to 5 mm in HIV-positive infants. | Measured at week 44 after birth | 
| Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum | IGRA done by Quantiferon Gold Test (QGIT). For women, TST is considered positive if greater than or equal to 5 mm | Measured at Week 44 postpartum | 
| Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report | Adherence is the percentage of expected doses taken during the 28 week active treatment period, categorized as poor (<60%), reasonable (>= 60%, <80%), good (>=80%, <90%), or excellent (>= 90%). Measured by participant's self-report of doses taken within the last 3 days. | Adherence reported every 4 weeks during active treatment; study entry through week 28 for Arm A, week 12 postpartum through week 40 postpartum for Arm B | 
| Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count | Adherence is the percentage of expected doses taken during the 28 week active treatment period. Pill count: participants returned their prescription pill containers, and the remaining (unused) pills were counted. | Adherence reported every 4 weeks during active treatment; study entry through week 28 for Arm A, week 12 postpartum through week 40 postpartum for Arm B |