HIV Infection, Tuberculosis, Pneumocystis Jiroveci Pneumonia
Conditions
Keywords
Treatment Naive, INH Prophylaxis, HIV Seronegativity
Brief summary
Tuberculosis (TB) is highly endemic in sub-Saharan Africa. The increased burden of TB in settings with high prevalence of the Human Immunodeficiency Virus (HIV) is associated with high rates of transmission of Mycobacterium tuberculosis (M.tb) to both adults and children. Children infected with TB have a higher risk of developing severe disease than adults with TB. The purpose of this study was to determine if the antibiotic isoniazid (INH) prevented TB infection in infants born to HIV-infected mothers.
Detailed description
Tuberculosis (TB) and the Human Immunodeficiency Virus (HIV) are major public health problems in southern Africa, and the incidence of TB in South Africa is among the highest in the world. TB is caused by the highly contagious bacterium Mycobacterium tuberculosis. The use of Isoniazid (INH) prophylaxis in adults has been associated with reduced risk of TB disease in high-risk populations. Delay in initiating INH prophylaxis in children has resulted in more cases of childhood TB infection. This study evaluated the effectiveness of INH prophylaxis in preventing TB infection in infants born to HIV-infected mothers in southern Africa. Infants were randomly assigned to receive either INH or placebo by mouth daily, beginning between the 91st and 120th day of life, and at least 90 days after Bacille Calmette-Guerin (BCG) vaccination. At sites in South Africa, HIV-infected infants received daily trimethoprim/sulfamethoxazole (TMP/SMX) as Pneumocystis jiroveci pneumonia (PCP) prophylaxis until at least 1 year of age; HIV-uninfected infants received TMP/SMX until at least 6 months of age. The study was to follow participants for 192 weeks. Study visits occurred at study entry and every 12 weeks until week 192. A physical exam and blood collection occurred at each study visit. Infants were assessed for peripheral neuropathy every 12 weeks until week 96 and for TB at weeks 96, 144, and 192. The study also assessed medication adherence. As of November 12, 2008, follow-up was revised. All participants were permanently discontinued from study follow-up by February 28, 2009 and no later than May 31, 2009. Only clinical evaluations were performed for all participants. For HIV-infected participants, the study drug was stopped at the next scheduled visit. For HIV-uninfected subjects, the study drug was discontinued immediately.
Interventions
DRUGIsoniazid (INH)
Antibiotic for the prevention and treatment of TB
Antibiotic for the prevention and treatment of pneumocystis pneumonia (PCP)
DRUGIsoniazid Placebo (PL)
Isoniazid placebo and TMP/SMX
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Comprehensive International Program of Research on AIDS
Secure the Future Foundation
International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
91 Days to 120 Days
Healthy volunteers
Yes
Inclusion criteria
* Mother is HIV-infected. Hard copy documentation of the mother's HIV infection is unnecessary if a positive DNA PCR from her infant is available. * Received Bacille Calmette-Guerin (BCG) vaccine up to and including the 30th day of life and at least 90 days prior to study entry * Able to complete all study requirements * Physician assessment of age-appropriate neurodevelopment in which the chronological age is corrected for gestational age for prematurely born infants * Parent or legal guardian able and willing to provide signed informed consent * Plan to live in the study area for at least 4 years * For inclusion in HIV-infected stratum, infant must have a positive HIV-1 DNA PCR; for inclusion in HIV-uninfected stratum, infant must have a negative HIV-1 DNA PCR performed at \>= 4 weeks of age
Exclusion criteria
* Previous diagnosis of TB infection, TB disease or current treatment for TB infection or TB disease * Previous receipt of INH * Contact with a known acid fast bacilli (AFB) sputum smear or culture-positive case of TB before study entry * Current acute or recurrent (3 or more prior episodes) lower respiratory tract disease * Chronic persistent diarrhea * Failure to thrive * Contraindications for use of INH or TMP/SMX * Require certain medications * Known or suspected immune system diseases other than HIV * Current or previous diagnosis of or treatment for cancer * Current immunosuppressive therapy greater than 1 mg/kg/day of prednisone or equivalent * Anticipated long-term oral or intravenous corticosteroid therapy (greater than 3 weeks). Those receiving nonsteroidal anti-inflammatory agents and inhaled corticosteroids are not excluded. * Grade 3 or greater AST/SGOT, ALT/SGPT, ANC, hemoglobin, platelet count, rash, neuropathy, or myopathy at screening * Any Grade 4 clinical or laboratory toxicity within 14 days prior to study entry * Other acute or chronic conditions that, in the opinion of the investigator, may interfere with the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Development of Tuberculosis (TB) Disease or Death Among HIV-infected Children | Through to week 96 | Criteria for diagnosis with TB disease: Definite-isolation of Mycobacterium TB (M.tb) or +ve stain on cerebrospinal fluid (CSF); Probable- +ve acid fast bacilli (AFB) stain on fluids/tissues other than CSF and sufficient clinical criteria/radiographic evidence suggestive of TB; Possible-abnormal chest radiograph suggestive of pulmonary TB (PTB) and either a +ve tuberculin skin test (TST) or minimum score on algorithm for clinical TB. Records reviewed by Endpoint Review Group. Results report percent of participants reaching TB disease/death by week 96 calculated using the Kaplan-Meier method. |
| Time From Randomization to Development of TB Infection or Death Among Perinatally Exposed, HIV-uninfected Children | Through to week 96 | Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive tuberculin skin test (TST) based on a purified protein derivative (PPD) performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection or death by week 96 calculated using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to Development of TB Disease or Death Among Perinatally Exposed, HIV-uninfected Children | Through to week 96 | Criteria for diagnosis with TB disease were: Definite-isolation of M.tb or positive stain on CSF; Probable-positive AFB stain on fluids/tissues other than CSF and sufficient clinical criteria/radiographic evidence suggestive of TB; Possible-abnormal chest radiograph suggestive of PTB and either a +ve TST or minimum score on algorithm to diagnose clinical TB. All records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB disease. Results report percent of participants reaching TB disease/death by week 96 calculated using the Kaplan-Meier method. |
| Time From Randomization to Development of TB Disease Among HIV Infected and Perinatally Exposed, HIV-uninfected Children | Through to week 96 | Criteria for diagnosis with TB disease were: Definite-isolation of M.tb or positive stain on CSF; Probable-positive AFB stain on fluids/tissues other than CSF and sufficient clinical criteria/radiographic evidence suggestive of TB; Possible-abnormal chest radiograph suggestive of PTB and either a +ve TST or minimum score on algorithm to diagnose clinical TB. All records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB disease. Results report percent of participants reaching TB disease/death by week 96 calculated using the Kaplan-Meier method. |
| Time From Randomization to Development of TB Infection or Death Among HIV-infected Children | Through to week 96 | Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive TST based on a PPD performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection or death by week 96 calculated using the Kaplan-Meier method. |
| Time From Randomization to Death Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | Through to week 96 | Deaths from any cause were included. Results report percent of participants dying by week 96 calculated using the Kaplan-Meier method. |
| Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | Through to week 96 | Signs, symptoms and laboratory values were graded according to the Division of AIDS Adverse Event Grading System. Any event of grade 3 or higher not present at entry that occurred after randomization was classified as a new event. Results report percent of participants with a new event by week 96 calculated using the Kaplan-Meier method. |
| Time From Randomization to Development of TB Infection Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | Through to week 96 | Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive TST based on a PPD performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection by week 96 calculated using the Kaplan-Meier method. |
| Time From Randomization to HIV Disease Progression or Death Among HIV-infected Children | Through to week 96 | HIV disease progression was defined as any advancement in Centers for Disease Control (CDC) disease category from entry or death. If a participant was CDC disease category C at entry progression was defined as death. Results report percent of participants with HIV progression or death by week 96 calculated using the Kaplan-Meier method. |
Countries
Botswana, South Africa
Participant flow
Recruitment details
Study participants were recruited at four study sites, three in South Africa and one in Botswana, between December 13, 2004 and June 26, 2008
Pre-assignment details
Infants perinatally exposed to HIV 91-120 days with documented receipt of Bacille Calmette-Guerin (BCG) vaccine by 30 days (\>=90 days since receipt), no previous diagnosis or treatment of TB or contact with known TB case, stratified by HIV and randomized to receive blinded INH or INH placebo. 3 participants randomized but did not start treatment.
Participants by arm
| Arm | Count |
|---|---|
| HIVneg/INH Perinatally exposed, HIV-uninfected (HIVneg) children receiving Isoniazid (INH)10-20 mg/kg orally once a day for 96 weeks + Trimethoprim/Sulfamethoxazole (TMP/SMX) 5 mg/kg of TMP component orally once a day until HIV status is confirmed and child is no longer at risk of acquiring HIV through breastfeeding | 403 |
| HIVneg/PL Perinatally-exposed, HIV-uninfected (HIVneg) children receiving Isoniazid placebo (PL) orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until HIV status is confirmed and child is no longer at risk of acquiring HIV through breastfeeding | 401 |
| HIVpos/INH HIV-infected (HIVpos) children receiving Isoniazid (INH) 10-20 mg/kg orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until one year of age. TMP/SMX may have been continued after one year of age according to WHO guidelines. | 273 |
| HIVpos/PL HIV-infected (HIVpos) children receiving Isoniazid placebo (PL) orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until one year of age. TMP/SMX may have been continued after one year of age according to WHO guidelines. | 274 |
| Total | 1,351 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Consent withdrawn | 13 | 17 | 4 | 6 |
| Overall Study | Discontinued because of study closure | 0 | 0 | 130 | 141 |
| Overall Study | Lost to Follow-up | 16 | 19 | 19 | 14 |
| Overall Study | Unable to get to clinic | 24 | 24 | 7 | 1 |
| Overall Study | Unwilling to adhere to study requirement | 3 | 2 | 5 | 1 |
Baseline characteristics
| Characteristic | HIVneg/INH | Total | HIVpos/PL | HIVpos/INH | HIVneg/PL |
|---|---|---|---|---|---|
| Age at receipt of Bacille Calmette-Guerin (BCG) vaccination (days) <= 7 days | 395 participants | 1300 participants | 258 participants | 255 participants | 392 participants |
| Age at receipt of Bacille Calmette-Guerin (BCG) vaccination (days) 8-29 days | 8 participants | 51 participants | 16 participants | 18 participants | 9 participants |
| Age, Customized 101-110 days | 71 participants | 244 participants | 33 participants | 56 participants | 84 participants |
| Age, Customized 111-120 days | 74 participants | 233 participants | 49 participants | 46 participants | 64 participants |
| Age, Customized 91-100 days | 258 participants | 874 participants | 192 participants | 171 participants | 253 participants |
| Any smoker in household Missing | 1 participants | 3 participants | 2 participants | 0 participants | 0 participants |
| Any smoker in household No | 211 participants | 729 participants | 141 participants | 153 participants | 224 participants |
| Any smoker in household Yes | 191 participants | 619 participants | 131 participants | 120 participants | 177 participants |
| Birth weight (grams) <2500 grams | 49 participants | 222 participants | 56 participants | 68 participants | 49 participants |
| Birth weight (grams) >= 2500 grams | 354 participants | 1129 participants | 218 participants | 205 participants | 352 participants |
| Caregiver currently smokes No | 392 participants | 1289 participants | 264 participants | 257 participants | 376 participants |
| Caregiver currently smokes Yes | 11 participants | 62 participants | 10 participants | 16 participants | 25 participants |
| CD4% <20% | 0 participants | 111 participants | 55 participants | 56 participants | 0 participants |
| CD4% 20%-<25% | 0 participants | 86 participants | 46 participants | 40 participants | 0 participants |
| CD4% >= 25% | 0 participants | 319 participants | 157 participants | 162 participants | 0 participants |
| CD4% Missing | 0 participants | 27 participants | 13 participants | 14 participants | 0 participants |
| CD4% Not applicable | 403 participants | 808 participants | 3 participants | 1 participants | 401 participants |
| Centers for Disease Control (CDC) Disease Category Category B | 0 participants | 37 participants | 21 participants | 16 participants | 0 participants |
| Centers for Disease Control (CDC) Disease Category Category C | 0 participants | 5 participants | 3 participants | 2 participants | 0 participants |
| Centers for Disease Control (CDC) Disease Category Category N or A | 0 participants | 496 participants | 244 participants | 252 participants | 0 participants |
| Centers for Disease Control (CDC) Disease Category HIV-uninfected on repeat test | 0 participants | 4 participants | 3 participants | 1 participants | 0 participants |
| Centers for Disease Control (CDC) Disease Category Missing | 0 participants | 5 participants | 3 participants | 2 participants | 0 participants |
| Centers for Disease Control (CDC) Disease Category Not applicable (HIV-uninfected) | 403 participants | 804 participants | 0 participants | 0 participants | 401 participants |
| Ever breastfed No | 379 participants | 1230 participants | 238 participants | 236 participants | 377 participants |
| Ever breastfed Yes | 24 participants | 121 participants | 36 participants | 37 participants | 24 participants |
| History of tuberculosis (TB) in mother No | 370 participants | 1254 participants | 249 participants | 259 participants | 376 participants |
| History of tuberculosis (TB) in mother Yes | 33 participants | 97 participants | 25 participants | 14 participants | 25 participants |
| HIV-1 RNA (copies/ml) 20,000 - < 750,000 copies/ml | 0 participants | 177 participants | 86 participants | 91 participants | 0 participants |
| HIV-1 RNA (copies/ml) <= 400 copies/ml | 0 participants | 20 participants | 12 participants | 8 participants | 0 participants |
| HIV-1 RNA (copies/ml) 401 - <20,000 copies/ml | 0 participants | 87 participants | 51 participants | 36 participants | 0 participants |
| HIV-1 RNA (copies/ml) >= 750,000 copies/ml | 0 participants | 245 participants | 116 participants | 129 participants | 0 participants |
| HIV-1 RNA (copies/ml) Missing | 0 participants | 14 participants | 6 participants | 8 participants | 0 participants |
| HIV-1 RNA (copies/ml) Not applicable | 403 participants | 808 participants | 3 participants | 1 participants | 401 participants |
| Housing Formal (brick) house | 235 participants | 813 participants | 183 participants | 162 participants | 233 participants |
| Housing Hostel | 0 participants | 2 participants | 0 participants | 2 participants | 0 participants |
| Housing Informal (shack/wooden) | 168 participants | 534 participants | 89 participants | 109 participants | 168 participants |
| Housing Missing | 0 participants | 2 participants | 2 participants | 0 participants | 0 participants |
| On antiretrovirals at entry No | 0 participants | 372 participants | 178 participants | 194 participants | 0 participants |
| On antiretrovirals at entry Not applicable | 403 participants | 808 participants | 3 participants | 1 participants | 401 participants |
| On antiretrovirals at entry Yes | 0 participants | 171 participants | 93 participants | 78 participants | 0 participants |
| Race/Ethnicity, Customized Indigenous African | 389 participants | 1311 participants | 272 participants | 264 participants | 386 participants |
| Race/Ethnicity, Customized Mixed ancestry/other | 14 participants | 40 participants | 2 participants | 9 participants | 15 participants |
| Sex: Female, Male Female | 203 Participants | 703 Participants | 151 Participants | 159 Participants | 190 Participants |
| Sex: Female, Male Male | 200 Participants | 648 Participants | 123 Participants | 114 Participants | 211 Participants |
| Site of enrollment Cape Town, S Africa | 140 participants | 409 participants | 65 participants | 66 participants | 138 participants |
| Site of enrollment Durban, S Africa | 4 participants | 60 participants | 27 participants | 26 participants | 3 participants |
| Site of enrollment Gaborone, Botswana | 0 participants | 4 participants | 3 participants | 1 participants | 0 participants |
| Site of enrollment Johannesburg, S Africa | 259 participants | 878 participants | 179 participants | 180 participants | 260 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 353 / 403 | 368 / 401 | 264 / 273 | 268 / 274 |
| serious Total, serious adverse events | 25 / 403 | 18 / 401 | 55 / 273 | 42 / 274 |
Outcome results
Primary
Time From Randomization to Development of TB Infection or Death Among Perinatally Exposed, HIV-uninfected Children
Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive tuberculin skin test (TST) based on a purified protein derivative (PPD) performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection or death by week 96 calculated using the Kaplan-Meier method.
Time frame: Through to week 96
Population: HIVneg who started study treatment were included. Time from randomization to first of TB infection/death was calculated. Participants lost-to-follow-up before 96 wks were censored at the time of loss-to-follow-up. Participants in follow-up at 96 weeks (+12 week window) who were free of TB infection were censored at 96 weeks (+12 week window).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HIVpos/INH | Time From Randomization to Development of TB Infection or Death Among Perinatally Exposed, HIV-uninfected Children | 10.9 Percent of participants |
| HIVpos/PL | Time From Randomization to Development of TB Infection or Death Among Perinatally Exposed, HIV-uninfected Children | 12.6 Percent of participants |
p-value: 0.4395% CI: [0.55, 1.3]Log Rank
Primary
Time to Development of Tuberculosis (TB) Disease or Death Among HIV-infected Children
Criteria for diagnosis with TB disease: Definite-isolation of Mycobacterium TB (M.tb) or +ve stain on cerebrospinal fluid (CSF); Probable- +ve acid fast bacilli (AFB) stain on fluids/tissues other than CSF and sufficient clinical criteria/radiographic evidence suggestive of TB; Possible-abnormal chest radiograph suggestive of pulmonary TB (PTB) and either a +ve tuberculin skin test (TST) or minimum score on algorithm for clinical TB. Records reviewed by Endpoint Review Group. Results report percent of participants reaching TB disease/death by week 96 calculated using the Kaplan-Meier method.
Time frame: Through to week 96
Population: Includes HIVpos who started study treatment. Time from randomization to TB disease/death was calculated. Participants lost-to-follow-up (LTF) \<96 wks (+12wks) censored at the time of LTF. Participants in follow-up at 96 wks free of TB disease censored at 96 wks. Participants on study when study discontinued censored at discontinuation visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HIVpos/INH | Time to Development of Tuberculosis (TB) Disease or Death Among HIV-infected Children | 27.4 Percent of participants |
| HIVpos/PL | Time to Development of Tuberculosis (TB) Disease or Death Among HIV-infected Children | 28.9 Percent of participants |
p-value: 0.9395% CI: [0.67, 1.44]Log Rank
Secondary
Time From Randomization to Death Among HIV-infected and Perinatally Exposed, HIV-uninfected Children
Deaths from any cause were included. Results report percent of participants dying by week 96 calculated using the Kaplan-Meier method.
Time frame: Through to week 96
Population: Includes all starting study treatment. Time from randomization to death was calculated. Participants LTF \<96 weeks (+12 wks) censored at the time of LTF. Participants in follow-up at 96 wks (+12 wks) censored at 96 weeks. HIVpos on study when study was discontinued were censored at their discontinuation visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HIVpos/INH | Time From Randomization to Death Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | 0.8 Percent of participants |
| HIVpos/PL | Time From Randomization to Death Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | 0.8 Percent of participants |
| HIVpos/INH | Time From Randomization to Death Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | 11.6 Percent of participants |
| HIVpos/PL | Time From Randomization to Death Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | 7.2 Percent of participants |
Secondary
Time From Randomization to Development of TB Disease Among HIV Infected and Perinatally Exposed, HIV-uninfected Children
Criteria for diagnosis with TB disease were: Definite-isolation of M.tb or positive stain on CSF; Probable-positive AFB stain on fluids/tissues other than CSF and sufficient clinical criteria/radiographic evidence suggestive of TB; Possible-abnormal chest radiograph suggestive of PTB and either a +ve TST or minimum score on algorithm to diagnose clinical TB. All records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB disease. Results report percent of participants reaching TB disease/death by week 96 calculated using the Kaplan-Meier method.
Time frame: Through to week 96
Population: Includes all starting study treatment. Time from randomization to development of TB disease was calculated. Participants LTF \<96 wks (+12 wks) censored at time of LTF. Participants in follow-up at 96 wks free of TB disease censored at 96 wks. HIVpos on study when study discontinued were censored at their discontinuation visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HIVpos/INH | Time From Randomization to Development of TB Disease Among HIV Infected and Perinatally Exposed, HIV-uninfected Children | 7.8 Percent of participants |
| HIVpos/PL | Time From Randomization to Development of TB Disease Among HIV Infected and Perinatally Exposed, HIV-uninfected Children | 8.5 Percent of participants |
| HIVpos/INH | Time From Randomization to Development of TB Disease Among HIV Infected and Perinatally Exposed, HIV-uninfected Children | 20.3 Percent of participants |
| HIVpos/PL | Time From Randomization to Development of TB Disease Among HIV Infected and Perinatally Exposed, HIV-uninfected Children | 23.7 Percent of participants |
Secondary
Time From Randomization to Development of TB Disease or Death Among Perinatally Exposed, HIV-uninfected Children
Criteria for diagnosis with TB disease were: Definite-isolation of M.tb or positive stain on CSF; Probable-positive AFB stain on fluids/tissues other than CSF and sufficient clinical criteria/radiographic evidence suggestive of TB; Possible-abnormal chest radiograph suggestive of PTB and either a +ve TST or minimum score on algorithm to diagnose clinical TB. All records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB disease. Results report percent of participants reaching TB disease/death by week 96 calculated using the Kaplan-Meier method.
Time frame: Through to week 96
Population: Includes HIVneg who started study treatment. Time from randomization to the first of TB disease/death was calculated. Participants lost-to-follow-up before 96 weeks (+12 week window)were censored at the time of loss-to-follow-up. Participants in follow-up at 96 weeks who were free of TB disease were censored at 96 weeks (+12 week window).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HIVpos/INH | Time From Randomization to Development of TB Disease or Death Among Perinatally Exposed, HIV-uninfected Children | 8.3 Percent of participants |
| HIVpos/PL | Time From Randomization to Development of TB Disease or Death Among Perinatally Exposed, HIV-uninfected Children | 9.1 Percent of participants |
Secondary
Time From Randomization to Development of TB Infection Among HIV-infected and Perinatally Exposed, HIV-uninfected Children
Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive TST based on a PPD performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection by week 96 calculated using the Kaplan-Meier method.
Time frame: Through to week 96
Population: Includes all starting study treatment. Time from randomization to development of TB infection was calculated. Participants LTF \<96 weeks (+12 wks) censored at the time of LTF. Participants in follow-up at 96 wks free of TB infection were censored at 96 wks. HIVpos on study when study discontinued censored at their discontinuation visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HIVpos/INH | Time From Randomization to Development of TB Infection Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | 10.4 Percent of participants |
| HIVpos/PL | Time From Randomization to Development of TB Infection Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | 12.1 Percent of participants |
| HIVpos/INH | Time From Randomization to Development of TB Infection Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | 22.4 Percent of participants |
| HIVpos/PL | Time From Randomization to Development of TB Infection Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | 27.9 Percent of participants |
Secondary
Time From Randomization to Development of TB Infection or Death Among HIV-infected Children
Criteria for diagnosis with TB infection were outlined in the protocol. TB infection included TB disease (see primary outcome measure 1 for definition) and latent TB infection. Latent TB infection was diagnosed by a positive TST based on a PPD performed at week 96. Participant records were reviewed by an Endpoint Review Group to verify that participants had met the criteria for TB infection. Results report percent of participants reaching TB infection or death by week 96 calculated using the Kaplan-Meier method.
Time frame: Through to week 96
Population: HIVpos starting study treatment were included. Time from randomization to first of TB infection/death was calculated. Participants LTF \<96 weeks (+12 wk) censored at the time LTF. Participants in follow-up at 96 wks free of TB infection censored at 96 wks. Participants on study when study discontinued were censored at discontinuation visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HIVpos/INH | Time From Randomization to Development of TB Infection or Death Among HIV-infected Children | 29.4 Percent of participants |
| HIVpos/PL | Time From Randomization to Development of TB Infection or Death Among HIV-infected Children | 32.8 Percent of participants |
Secondary
Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children
Signs, symptoms and laboratory values were graded according to the Division of AIDS Adverse Event Grading System. Any event of grade 3 or higher not present at entry that occurred after randomization was classified as a new event. Results report percent of participants with a new event by week 96 calculated using the Kaplan-Meier method.
Time frame: Through to week 96
Population: Includes all starting treatment. Time from randomization to first new adverse event (AE) calculated. For lab toxicities, censored at visit following permanent discontinuation of study drugs. For signs/symptoms, participants in follow-up at 96 wks (+12) with no new grade \>=3 AE censored at 96 wks. Participants LTF \<96 wks censored at LTF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 platelets | 0.3 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 hemoglobin | 0.0 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 SGPT | 2.8 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >= grade 3 peripheral neuropathy | 1.1 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 lab abnormality | 4.9 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 SGOT | 1.0 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 ANC | 1.7 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 sign/symptom | 5.0 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >= grade 3 peripheral neuropathy | 0.3 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 SGOT | 2.8 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 SGPT | 4.4 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 sign/symptom | 4.2 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 ANC | 0.3 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 lab abnormality | 4.6 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 hemoglobin | 0.0 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 platelets | 0.0 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 lab abnormality | 11.3 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 ANC | 1.6 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 sign/symptom | 16.8 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 SGPT | 5.9 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 hemoglobin | 1.8 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >= grade 3 peripheral neuropathy | 2.4 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 platelets | 1.7 Percent of participants |
| HIVpos/INH | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 SGOT | 0.4 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 SGPT | 4.0 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 platelets | 0.9 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 sign/symptom | 11.7 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 lab abnormality | 10.1 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 hemoglobin | 1.2 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 ANC | 3.5 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >=grade 3 SGOT | 2.5 Percent of participants |
| HIVpos/PL | Time From Randomization to First New Grade 3 or Worse Adverse Event Among HIV-infected and Perinatally Exposed, HIV-uninfected Children | New >= grade 3 peripheral neuropathy | 0.8 Percent of participants |
Secondary
Time From Randomization to HIV Disease Progression or Death Among HIV-infected Children
HIV disease progression was defined as any advancement in Centers for Disease Control (CDC) disease category from entry or death. If a participant was CDC disease category C at entry progression was defined as death. Results report percent of participants with HIV progression or death by week 96 calculated using the Kaplan-Meier method.
Time frame: Through to week 96
Population: Includes HIVpos starting study treatment. Time from randomization to first of disease progression/death calculated. Censored if LTF \<96 wks, at 96 wks (if on study) or at discontinuation visit. Participants found to be HIVneg upon repeat testing could only progress by meeting a death endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HIVpos/INH | Time From Randomization to HIV Disease Progression or Death Among HIV-infected Children | 30.6 Percent of participants |
| HIVpos/PL | Time From Randomization to HIV Disease Progression or Death Among HIV-infected Children | 22.5 Percent of participants |