HIV Infections, Tuberculosis
Conditions
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.
Interventions
DRUGPlacebo 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)
DRUGIsoniazid (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)
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
FEMALE
Age
13 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Rate of Combined Endpoint: Grade 3 or Higher Adverse Events (AEs) Related to Treatment, or AE Causing Discontinuation of Treatment | Measured from study entry through Week 48 after birth | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Mothers With a Fetus Small for Gestational Age | Measured at delivery | Small for gestational age was determined by physician at site |
| Number of Mothers With an Infant Born Prematurely | Measured at delivery | Premature birth is defined as gestational age of \< 37 weeks at delivery. |
| Number of Mothers With a Low Birth-weight Infant | Measured on day of birth | Low birth weight is defined as weight \< 2500 mg |
| Number of Mothers With an Infant With a Congenital Anomaly | Measured from study entry through Week 48 after birth | Includes congenital anomalies meeting the Metropolitan Atlanta Congenital Defects Program criteria. |
| Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly | Measured from study entry through Week 48 after birth | 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. |
| Number of Infants With Grade 3 or Higher Clinical or Laboratory AE | Measured from study entry through Week 48 after birth | Laboratory, sign/symptom, or diagnoses graded as 3 or higher by DAIDS criteria. |
| Number of Infants With Grade 3 or Higher Clinical or Laboratory AE Related to Treatment | Measured from study entry through Week 48 after birth | As before, but AE is judged to be possibly, probably, or definitely related to INH or Placebo for INH, by clinic medical staff |
| Number of Infants Which Are HIV-infected | Measured from study entry through study Week 44 | HIV infection determined during follow-up period. Infection at birth or during breastfeeding |
| Number of Infants Hospitalized | Measured from study entry through Week 48 after birth | Hospitalization due to reasons other than birth |
| Incidence Rate of TB Infection Among Mothers | Measured from study entry to Week 48 after birth | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Probable or confirmed TB infection, as judged by Secondary Endpoint Review Committee |
| Incidence Rate of Tuberculosis (TB) Among Infants | Measured from study entry through Week 48 after birth | 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. |
| Incidence Rate of Infant Death | Measured from study entry through Week 48 after birth | Incidence rate was calculated by Mantel-Haenszel, weighted by gestational age strata. |
| Incidence Rate of Maternal Deaths | Measured from study entry through Week 48 postpartum | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. |
| Incidence Rate of Combined Endpoints: Maternal TB or Maternal Death | Measured from study entry through Week 48 after birth | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. |
| Incidence Rate of Combined Endpoints: Infant TB or Infant Death | Measured from study entry through Week 48 after birth | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. |
| Incidence Rate of Combined Endpoints: Maternal TB, Maternal Death, Infant TB, or Infant Death | Measured from study entry through Week 48 after birth | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. |
| Incidence Rate of Combined Endpoint, Antepartum: Grade 3 or Higher AE Related to Treatment, or Discontinuation of Treatment Due to AE | Measured from study entry through end of pregnancy | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata |
| 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 | Measured from study entry through 12 weeks after birth | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. |
| Number of Mothers With a Fetal Death | Measured from study entry through end of pregnancy | Fetal deaths include both stillbirths and spontaneous abortions; in case of a multiple birth, mothers who had at least one fetal death |
| Incidence Rate, up to 12 Weeks Postpartum, of Grade 3 or Higher AE | Measured from study entry through 12 weeks postpartum | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. |
| Incidence Rate, Antepartum, of Hepatotoxicity, Defined by Protocol-specific Definition of Hepatotoxicity, Related to Treatment | Measured from study entry through delivery | 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 |
| Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Related to Treatment | Measured from study entry through 12 weeks postpartum | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata |
| Incidence Rate, Antepartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause | Measured from study entry through delivery | Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata. |
| Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause | Measured from study entry through 12 weeks postpartum | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. |
| Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment | Measured from study entry through delivery | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. Hepatotoxicity definition as defined by DAIDS AE grading criteria 1.0. |
| Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment | Measured from study start through 12 weeks postpartum | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata |
| Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Any Cause | Measured from study entry through delivery | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. |
| Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Any Cause | Measured from study start through 12 weeks postpartum | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. |
| Number of Mothers With Tuberculosis Resistant to INH | Measured from study entry through Week 48 postpartum | Resistance to INH from isolates of Mycobacterium tuberculosis, as a percentage of mothers who develop culture-confirmed TB |
| Number of Infants With Tuberculosis Resistant to INH | Measured from study entry through Week 48 after birth | Resistance to INH from isolates of Mycobacterium tuberculosis, as a percentage of infants who develop culture-confirmed TB |
| Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH | 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 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, |
| Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV | 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 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, |
| Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery | Measured at delivery | IGRA done by Quantiferon Gold Test (QGIT). For women, TST is considered positive if greater than or equal to 5 mm |
| Agreement Between IGRA and TST TB Test Results, Infant | Measured at week 44 after birth | 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. |
| Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum | Measured at Week 44 postpartum | IGRA done by Quantiferon Gold Test (QGIT). For women, TST is considered positive if greater than or equal to 5 mm |
| Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report | 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 | 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. |
| Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count | 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 | 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. |
| Incidence Rate, Antepartum, of Grade 3 or Higher AE | Measured from study entry through end of pregnancy | Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata. |
Countries
Botswana, Haiti, India, South Africa, Tanzania, Thailand, Uganda, Zimbabwe
Participant flow
Recruitment details
HIV-infected pregnant women and their infants, gestational age greater than 14 but less than 34 weeks, who reside in a high TB prevalence area. Recruited at participating medical clinics in those areas, a total of 13 sites in Haiti, India, Thailand, and in 5 countries in central and southern Africa. Recruitment from August 2014 to April 2016.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Isoniazid (INH): 300-mg tablet once daily by mouth, from entry through Week 28 antepartum
Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from Week 28 visit through Week 40 postpartum | 477 |
| 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.
Isoniazid (INH): 300-mg tablet once daily by mouth, from Week 12 postpartum through Week 40 postpartum (Arm B)
Placebo for isoniazid (INH): Placebo tablet once daily by mouth, from entry until Week 12 postpartum visit (Arm B) | 479 |
| Total | 956 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 4 |
| Overall Study | Lost to Follow-up | 18 | 20 |
| Overall Study | Not able to get to clinic | 21 | 15 |
| Overall Study | Not willing to adhere to reqs | 2 | 9 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 44 | 34 |
Baseline characteristics
| Characteristic | Arm B (Deferred INH Treatment) | Total | Arm A (Immediate INH Treatment) |
|---|---|---|---|
| Age, Continuous | 29 years | 29 years | 29 years |
| CD4 Count 350 - <500 cells/mm^3 | 128 Participants | 257 Participants | 129 Participants |
| CD4 Count < 350 cells/mm^3 | 114 Participants | 232 Participants | 118 Participants |
| CD4 Count 500 - <650 cells/mm^3 | 105 Participants | 200 Participants | 95 Participants |
| CD4 Count >= 650 cells/mm^3 | 130 Participants | 263 Participants | 133 Participants |
| Efavirenz-containing anti-retroviral (ARV) regimen No | 70 Participants | 142 Participants | 72 Participants |
| Efavirenz-containing anti-retroviral (ARV) regimen Yes | 409 Participants | 814 Participants | 405 Participants |
| Gestational age at entry 14 - <24 weeks | 160 Participants | 321 Participants | 161 Participants |
| Gestational age at entry 24 - 34 weeks | 319 Participants | 635 Participants | 316 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 35 Participants | 67 Participants | 32 Participants |
| Race (NIH/OMB) Black or African American | 444 Participants | 889 Participants | 445 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Botswana | 60 participants | 120 participants | 60 participants |
| Region of Enrollment Haiti | 15 participants | 23 participants | 8 participants |
| Region of Enrollment India | 16 participants | 33 participants | 17 participants |
| Region of Enrollment South Africa | 91 participants | 182 participants | 91 participants |
| Region of Enrollment Tanzania | 39 participants | 80 participants | 41 participants |
| Region of Enrollment Thailand | 18 participants | 33 participants | 15 participants |
| Region of Enrollment Uganda | 83 participants | 166 participants | 83 participants |
| Region of Enrollment Zimbabwe | 157 participants | 319 participants | 162 participants |
| Sex: Female, Male Female | 479 Participants | 956 Participants | 477 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Tuberculosis (TB) test result by Interferon-Gamma Release Assay (IGRA) Indeterminate | 31 Participants | 61 Participants | 30 Participants |
| Tuberculosis (TB) test result by Interferon-Gamma Release Assay (IGRA) Negative | 297 Participants | 598 Participants | 301 Participants |
| Tuberculosis (TB) test result by Interferon-Gamma Release Assay (IGRA) Positive | 144 Participants | 283 Participants | 139 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 477 | 4 / 479 | 11 / 445 | 17 / 464 |
| other Total, other adverse events | 438 / 477 | 449 / 479 | 417 / 445 | 430 / 464 |
| serious Total, serious adverse events | 71 / 477 | 69 / 479 | 86 / 445 | 91 / 464 |
Outcome results
Primary
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.
Time frame: Measured from study entry through Week 48 after birth
Population: All women enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate of Combined Endpoint: Grade 3 or Higher Adverse Events (AEs) Related to Treatment, or AE Causing Discontinuation of Treatment | 15.03 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate of Combined Endpoint: Grade 3 or Higher Adverse Events (AEs) Related to Treatment, or AE Causing Discontinuation of Treatment | 14.93 events per 100 person-years |
95% CI: [-4.77, 4.98]
Secondary
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.
Time frame: Measured at week 44 after birth
Population: Infants with tuberculin tests performed at week 44 postpartum
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Immediate INH Treatment) | Agreement Between IGRA and TST TB Test Results, Infant | Positive tuberculin skin test | 8 Participants |
| Arm A (Immediate INH Treatment) | Agreement Between IGRA and TST TB Test Results, Infant | Negative tuberculin skin test | 34 Participants |
| Arm B (Deferred INH Treatment) | Agreement Between IGRA and TST TB Test Results, Infant | Positive tuberculin skin test | 45 Participants |
| Arm B (Deferred INH Treatment) | Agreement Between IGRA and TST TB Test Results, Infant | Negative tuberculin skin test | 597 Participants |
p-value: 0.22Chi-squared
95% CI: [0.001, 0.21]
Secondary
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
Time frame: Measured at Week 44 postpartum
Population: Women who were tested for tuberculosis infection at 44 weeks postpartum
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Immediate INH Treatment) | Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum | Positive tuberculin skin test | 100 Participants |
| Arm A (Immediate INH Treatment) | Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum | Negative tuberculin skin test | 127 Participants |
| Arm B (Deferred INH Treatment) | Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum | Positive tuberculin skin test | 20 Participants |
| Arm B (Deferred INH Treatment) | Agreement Between IGRA and TST TB Tests, Women at 44 Weeks Postpartum | Negative tuberculin skin test | 459 Participants |
p-value: <0.0001Chi-squared
95% CI: [0.39, 0.53]
Secondary
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
Time frame: Measured at delivery
Population: Women tested for tuberculosis infection at delivery
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Immediate INH Treatment) | Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery | Positive tuberculin skin test | 87 Participants |
| Arm A (Immediate INH Treatment) | Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery | Negative tuberculin skin test | 121 Participants |
| Arm B (Deferred INH Treatment) | Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery | Positive tuberculin skin test | 27 Participants |
| Arm B (Deferred INH Treatment) | Agreement Between Interferon-gamma Release Assay (IGRA) TB Test and Tuberculin Skin Test (TST) Results, Women at Delivery | Negative tuberculin skin test | 490 Participants |
p-value: <0.0001Chi-squared
95% CI: [0.35, 0.5]
Secondary
Incidence Rate, Antepartum, of Grade 3 or Higher AE
Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Time frame: Measured from study entry through end of pregnancy
Population: All women enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate, Antepartum, of Grade 3 or Higher AE | 56.36 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate, Antepartum, of Grade 3 or Higher AE | 50.88 events per 100 person-years |
95% CI: [-13.7, 24.68]
Secondary
Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Any Cause
Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Time frame: Measured from study entry through delivery
Population: All women
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Any Cause | 1.77 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Any Cause | 2.59 events per 100 person-years |
95% CI: [-4.63, 3]
Secondary
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.
Time frame: Measured from study entry through delivery
Population: All women.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment | 1.77 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate, Antepartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment | 2.59 events per 100 person-years |
95% CI: [-4.63, 3]
Secondary
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
Time frame: Measured from study entry through delivery
Population: All women enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate, Antepartum, of Hepatotoxicity, Defined by Protocol-specific Definition of Hepatotoxicity, Related to Treatment | 1.77 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate, Antepartum, of Hepatotoxicity, Defined by Protocol-specific Definition of Hepatotoxicity, Related to Treatment | 2.59 events per 100 person-years |
95% CI: [-4.63, 3]
Secondary
Incidence Rate, Antepartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause
Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Time frame: Measured from study entry through delivery
Population: All women enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate, Antepartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause | 1.77 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate, Antepartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause | 2.59 events per 100 person-years |
95% CI: [-4.63, 3]
Secondary
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
Time frame: Measured from study entry through end of pregnancy
Population: All women enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate of Combined Endpoint, Antepartum: Grade 3 or Higher AE Related to Treatment, or Discontinuation of Treatment Due to AE | 15.93 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate of Combined Endpoint, Antepartum: Grade 3 or Higher AE Related to Treatment, or Discontinuation of Treatment Due to AE | 13.79 events per 100 person-years |
95% CI: [-7.86, 12.13]
Secondary
Incidence Rate of Combined Endpoints: Infant TB or Infant Death
Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Time frame: Measured from study entry through Week 48 after birth
Population: Live-born infants of enrolled women
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate of Combined Endpoints: Infant TB or Infant Death | 2.99 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate of Combined Endpoints: Infant TB or Infant Death | 4.68 events per 100 person-years |
95% CI: [-4.48, 1.1]
Secondary
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.
Time frame: Measured from study entry through Week 48 after birth
Population: Number of mother-infant pairs with at least one infant live birth and in which mother did not have active TB at entry.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate of Combined Endpoints: Maternal TB, Maternal Death, Infant TB, or Infant Death | 3.42 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate of Combined Endpoints: Maternal TB, Maternal Death, Infant TB, or Infant Death | 4.72 events per 100 person-years |
95% CI: [-3.86, 1.25]
Secondary
Incidence Rate of Combined Endpoints: Maternal TB or Maternal Death
Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Time frame: Measured from study entry through Week 48 after birth
Population: All participants enrolled without active TB at entry.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate of Combined Endpoints: Maternal TB or Maternal Death | 1.00 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate of Combined Endpoints: Maternal TB or Maternal Death | 1.38 events per 100 person-years |
95% CI: [-1.72, 0.97]
Secondary
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.
Time frame: Measured from study entry through 12 weeks after birth
Population: All women enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | 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 | 16.98 events per 100 person-years |
| Arm B (Deferred INH Treatment) | 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 | 10.09 events per 100 person-years |
95% CI: [-0.08, 13.86]
Secondary
Incidence Rate of Infant Death
Incidence rate was calculated by Mantel-Haenszel, weighted by gestational age strata.
Time frame: Measured from study entry through Week 48 after birth
Population: Live-born infants of enrolled women
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate of Infant Death | 2.99 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate of Infant Death | 4.42 events per 100 person-years |
95% CI: [-4.17, 1.32]
Secondary
Incidence Rate of Maternal Deaths
Incidence rate calculated by Mantel-Haenszel, weighted by gestational age strata.
Time frame: Measured from study entry through Week 48 postpartum
Population: All participants enrolled without active TB at entry
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate of Maternal Deaths | 0.40 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate of Maternal Deaths | 0.78 events per 100 person-years |
95% CI: [-1.33, 0.56]
Secondary
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
Time frame: Measured from study entry to Week 48 after birth
Population: All participants enrolled without active TB at entry
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate of TB Infection Among Mothers | 0.60 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate of TB Infection Among Mothers | 0.59 events per 100 person-years |
95% CI: [-0.94, 0.96]
Secondary
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.
Time frame: Measured from study entry through Week 48 after birth
Population: Live-born infants of enrolled women
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate of Tuberculosis (TB) Among Infants | 0.54 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate of Tuberculosis (TB) Among Infants | 0.52 events per 100 person-years |
95% CI: [-1.02, 1.07]
Secondary
Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause
Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Time frame: Measured from study entry through 12 weeks postpartum
Population: All women enrolled
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause | 8.37 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Any Cause | 4.98 events per 100 person-years |
95% CI: [-1.46, 8.25]
Secondary
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
Time frame: Measured from study entry through 12 weeks postpartum
Population: All women enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Related to Treatment | 7.91 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate, to 12 Weeks Postpartum, of Hepatotoxicity, Protocol-specific Definition, Related to Treatment | 4.52 events per 100 person-years |
95% CI: [-1.31, 8.07]
Secondary
Incidence Rate, up to 12 Weeks Postpartum, of Grade 3 or Higher AE
Incidence rates calculated by Mantel-Haenszel, weighted by gestational age strata.
Time frame: Measured from study entry through 12 weeks postpartum
Population: All women enrolled.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate, up to 12 Weeks Postpartum, of Grade 3 or Higher AE | 56.48 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate, up to 12 Weeks Postpartum, of Grade 3 or Higher AE | 40.59 events per 100 person-years |
95% CI: [2.11, 29.65]
Secondary
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.
Time frame: Measured from study start through 12 weeks postpartum
Population: All women.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Any Cause | 8.37 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Any Cause | 4.98 events per 100 person-years |
95% CI: [-1.46, 8.25]
Secondary
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
Time frame: Measured from study start through 12 weeks postpartum
Population: All women
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment | 7.91 events per 100 person-years |
| Arm B (Deferred INH Treatment) | Incidence Rate, up to 12 Weeks Postpartum, of Hepatotoxicity, Defined by DAIDS, Related to Treatment | 4.52 events per 100 person-years |
95% CI: [-1.31, 8.07]
Secondary
Number of Infants Hospitalized
Hospitalization due to reasons other than birth
Time frame: Measured from study entry through Week 48 after birth
Population: Infants born alive
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Number of Infants Hospitalized | 73 Participants |
| Arm B (Deferred INH Treatment) | Number of Infants Hospitalized | 75 Participants |
p-value: 0.893Fisher Exact
Secondary
Number of Infants Which Are HIV-infected
HIV infection determined during follow-up period. Infection at birth or during breastfeeding
Time frame: Measured from study entry through study Week 44
Population: Infants born alive
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Immediate INH Treatment) | Number of Infants Which Are HIV-infected | Yes | 3 Participants |
| Arm A (Immediate INH Treatment) | Number of Infants Which Are HIV-infected | No | 436 Participants |
| Arm A (Immediate INH Treatment) | Number of Infants Which Are HIV-infected | Unknown | 6 Participants |
| Arm B (Deferred INH Treatment) | Number of Infants Which Are HIV-infected | Yes | 7 Participants |
| Arm B (Deferred INH Treatment) | Number of Infants Which Are HIV-infected | No | 451 Participants |
| Arm B (Deferred INH Treatment) | Number of Infants Which Are HIV-infected | Unknown | 6 Participants |
p-value: 0.279Fisher Exact
Secondary
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.
Time frame: Measured from study entry through Week 48 after birth
Population: Infants born alive
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Number of Infants With Grade 3 or Higher Clinical or Laboratory AE | 193 Participants |
| Arm B (Deferred INH Treatment) | Number of Infants With Grade 3 or Higher Clinical or Laboratory AE | 196 Participants |
Secondary
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
Time frame: Measured from study entry through Week 48 after birth
Population: Infants born alive
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Number of Infants With Grade 3 or Higher Clinical or Laboratory AE Related to Treatment | 5 Participants |
| Arm B (Deferred INH Treatment) | Number of Infants With Grade 3 or Higher Clinical or Laboratory AE Related to Treatment | 6 Participants |
Secondary
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
Time frame: Measured from study entry through Week 48 after birth
Population: No infants had culture-confirmed TB
Secondary
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
Time frame: Measured from study entry through end of pregnancy
Population: Mothers who had at least one live birth, stillbirth, or spontaneous abortion. One participant with outcome of induced abortion not included
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Number of Mothers With a Fetal Death | 17 Participants |
| Arm B (Deferred INH Treatment) | Number of Mothers With a Fetal Death | 9 Participants |
p-value: 0.093Fisher Exact
Secondary
Number of Mothers With a Fetus Small for Gestational Age
Small for gestational age was determined by physician at site
Time frame: Measured at delivery
Population: Measurement of small-for-gestational-age was deemed to be unreliable. Analysis not performed.
Secondary
Number of Mothers With a Low Birth-weight Infant
Low birth weight is defined as weight \< 2500 mg
Time frame: Measured on day of birth
Population: Mothers who had at least one live birth available to be weighed at time of delivery
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Immediate INH Treatment) | Number of Mothers With a Low Birth-weight Infant | Yes | 62 Participants |
| Arm A (Immediate INH Treatment) | Number of Mothers With a Low Birth-weight Infant | No | 368 Participants |
| Arm B (Deferred INH Treatment) | Number of Mothers With a Low Birth-weight Infant | Yes | 46 Participants |
| Arm B (Deferred INH Treatment) | Number of Mothers With a Low Birth-weight Infant | No | 400 Participants |
p-value: 0.073Fisher Exact
Secondary
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.
Time frame: Measured from study entry through Week 48 after birth
Population: Mothers who had at least one live birth, stillbirth, or spontaneous abortion; participant with induced abortion is omitted, and whose babies were available for examination after birth (if born alive)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Immediate INH Treatment) | Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly | Yes | 106 Participants |
| Arm A (Immediate INH Treatment) | Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly | No | 343 Participants |
| Arm B (Deferred INH Treatment) | Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly | Yes | 78 Participants |
| Arm B (Deferred INH Treatment) | Number of Mothers With an Adverse Pregnancy Outcome: Spontaneous Abortion, Stillbirth, Premature Birth, Low Birth Weight, or Congenital Anomaly | No | 382 Participants |
p-value: 0.012Fisher Exact
Secondary
Number of Mothers With an Infant Born Prematurely
Premature birth is defined as gestational age of \< 37 weeks at delivery.
Time frame: Measured at delivery
Population: Mothers who had at least one live birth
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Number of Mothers With an Infant Born Prematurely | 48 Participants |
| Arm B (Deferred INH Treatment) | Number of Mothers With an Infant Born Prematurely | 40 Participants |
p-value: 0.288Fisher Exact
Secondary
Number of Mothers With an Infant With a Congenital Anomaly
Includes congenital anomalies meeting the Metropolitan Atlanta Congenital Defects Program criteria.
Time frame: Measured from study entry through Week 48 after birth
Population: Mothers who had at least one live birth able to be assessed between birth and 48 weeks after birth
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Immediate INH Treatment) | Number of Mothers With an Infant With a Congenital Anomaly | Yes | 10 Participants |
| Arm A (Immediate INH Treatment) | Number of Mothers With an Infant With a Congenital Anomaly | No | 430 Participants |
| Arm B (Deferred INH Treatment) | Number of Mothers With an Infant With a Congenital Anomaly | Yes | 6 Participants |
| Arm B (Deferred INH Treatment) | Number of Mothers With an Infant With a Congenital Anomaly | No | 452 Participants |
p-value: 0.264Fisher Exact
Secondary
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
Time frame: Measured from study entry through Week 48 postpartum
Population: Mothers with culture-confirmed TB
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Immediate INH Treatment) | Number of Mothers With Tuberculosis Resistant to INH | 1 Participants |
| Arm B (Deferred INH Treatment) | Number of Mothers With Tuberculosis Resistant to INH | 0 Participants |
Secondary
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.
Time frame: 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
Population: All enrolled women
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Immediate INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count | Good adherence | 42 Participants |
| Arm A (Immediate INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count | Poor adherence | 5 Participants |
| Arm A (Immediate INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count | Reasonable adherence | 8 Participants |
| Arm A (Immediate INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count | Unknown | 14 Participants |
| Arm A (Immediate INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count | Excellent adherence | 408 Participants |
| Arm B (Deferred INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count | Unknown | 66 Participants |
| Arm B (Deferred INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count | Excellent adherence | 376 Participants |
| Arm B (Deferred INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count | Good adherence | 28 Participants |
| Arm B (Deferred INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count | Reasonable adherence | 6 Participants |
| Arm B (Deferred INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Pill Count | Poor adherence | 3 Participants |
Secondary
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.
Time frame: 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
Population: All women enrolled.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Immediate INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report | Good adherence | 47 Participants |
| Arm A (Immediate INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report | Poor adherence | 4 Participants |
| Arm A (Immediate INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report | Reasonable adherence | 15 Participants |
| Arm A (Immediate INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report | Unknown | 11 Participants |
| Arm A (Immediate INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report | Excellent adherence | 400 Participants |
| Arm B (Deferred INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report | Unknown | 66 Participants |
| Arm B (Deferred INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report | Excellent adherence | 363 Participants |
| Arm B (Deferred INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report | Good adherence | 35 Participants |
| Arm B (Deferred INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report | Reasonable adherence | 8 Participants |
| Arm B (Deferred INH Treatment) | Number of Women by Level of Adherence to Prescribed Regimen, as Assessed by Self-report | Poor adherence | 7 Participants |
Secondary
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,
Time frame: 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.
Population: Participants with intensive pharmacokinetic results while on active EFV and who were stabled on EFV-based ART.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Arm A (Immediate INH Treatment) | Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV | Third trimester of pregnancy | 38.5 hour*mg/L |
| Arm A (Immediate INH Treatment) | Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV | Week 16 postpartum | 46.9 hour*mg/L |
| Arm B (Deferred INH Treatment) | Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV | Third trimester of pregnancy | 62.5 hour*mg/L |
| Arm B (Deferred INH Treatment) | Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV | Week 16 postpartum | 76.2 hour*mg/L |
| Slow Metabolizers | Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV | Third trimester of pregnancy | 153.02 hour*mg/L |
| Slow Metabolizers | Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve (AUC24h), for EFV | Week 16 postpartum | 186 hour*mg/L |
Secondary
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,
Time frame: 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.
Population: Participants with intensive pharmacokinetic results while on active INH, who were established on INH.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Arm A (Immediate INH Treatment) | Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH | Third trimester of pregnancy | 3.63 hour*mg/L |
| Arm A (Immediate INH Treatment) | Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH | Week 16 postpartum | 4.25 hour*mg/L |
| Arm B (Deferred INH Treatment) | Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH | Third trimester of pregnancy | 6.55 hour*mg/L |
| Arm B (Deferred INH Treatment) | Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH | Week 16 postpartum | 7.67 hour*mg/L |
| Slow Metabolizers | Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH | Third trimester of pregnancy | 21.6 hour*mg/L |
| Slow Metabolizers | Pharmacokinetic (PK) Parameter: Adjusted Mean of Area Under the Curve of Plasma Concentration Versus Time (AUC24h), for INH | Week 16 postpartum | 25.3 hour*mg/L |