Tuberculosis Preventive Therapy Among Latent Tuberculosis Infection in HIV-infected Individuals

Phase 3

Active, not recruiting

• Conditions: HIV-infected Participants With Latent TB Infection in High TB Burden Country
• Interventions: Drug: Isoniazid/Rifapentine 12-weekly plus pyridoxine (vitamin B6); Drug: Isoniazid/Rifapentine daily (4 weeks) plus pyridoxine (vitamin B6)

• Registration Number: NCT03785106
• Lead Sponsor: The HIV Netherlands Australia Thailand Research Collaboration

Brief Summary

The investigators want to know if ultra-short, effective treatment for latent tuberculosis (TB) infection (LTBI) could dramatically reduce the global incidence of active TB or not. The investigators hypothesize that short-course (4-week) daily isoniazid/rifapentine (INH/RPT) (1HP) is not inferior to standard -course (12 weeks) INH/RPT weekly regimen (3HP) for the prevention of TB in human immunodeficiency virus (HIV)-infected individuals.

Detailed Description

This study is a multicenter, randomized, open-label, phase III clinical trial comparing a 4-week daily INH/RPT regimen (1HP) to a 12-weekly INH/RPT (3HP) for the treatment of LTBI in HIV-infected participants without evidence of active TB. The primary objective will be efficacy of active TB prevention. The study will also assess safety and tolerability of the regimens, adherence to the treatments, and patterns of antibiotic resistance among Mycobacterium tuberculosis (MTB) isolates in participants who fail on these prophylactic regimens.

Under this study, there is one substudy entitled, "Pharmacokinetic study of rifapentine, dolutegravir, and tenofovir alafenamide in HIV-infected individual with latent tubersulosis infection". There will be a subgroup of patients who will participate in this pharmacokinetic study of rifapentine and dolutegravir (DTG) / tenofovir alafenamide (TAF). Randomization is based on cluster of differentiation 4 (CD4) categories : \< 200, 200-350, \> 500 cells/mm3 and VL \<50 or \>50 copies/ml.

Study Timeline

• Study First Submitted: 2018-12-19
• Study First Submitted QC: 2018-12-21
• Study First Posted: 2018-12-24
• Study Start: 2019-08-15
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-14
• Last Update Posted: 2025-03-17
• Primary Completion: 2038-03
• Study Completion: 2038-03

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 2500

Inclusion Criteria

1. Documented HIV-1 infection by standard HIV test or plasma HIV-1 RNA viral load and received ART within 12 months. Participants received ART more than 12 months would be allowed if CD4 cell counts is less than 350 cells/mm3

2. 18 years and older

3. Evidence of latent TB infection, either by TST ≥5 mm or positive interferon gamma release assay (IGRA) or history of close contact with active pulmonary TB* within 3 months prior entry visit or residing in a high TB burden area** NOTE * close contact is referred to person living/sharing in the same room with active pulmonary TB participants for > 4 hours/day

   ** high TB burden areas are defined as areas with an estimated or reported TB prevalence of 100 to 300/100,000, according to the WHO. Thailand is included in high TB burden areas.

4. Laboratory values obtained within 30 days prior to entry

   • Absolute neutrophil count (ANC) >750 cells/mm3
   • Hemoglobin >7.4 g/dL
   • Platelet count >50,000/mm3
   • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) <3x upper limit of normal (ULN)
   • Total bilirubin <2.5 X ULN

5. Chest radiograph or chest computed tomography (CT) scan without evidence of active tuberculosis, unless one has been performed within 90 days prior to entry.

6. Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable non-hormonal form of contraceptive (i.e., condoms, IUD, diaphragm) during RPT treatment and contraception should be remain to 6 weeks post RPT NOTE Female participants who are not of reproductive potential or whose male partner(s) have undergone successful vasectomy with documented azoospermia or have documented azoospermia are eligible without requiring the use of contraceptives. Participant-reported history is acceptable documentation of menopause, hysterectomy, or bilateral oophorectomy or bilateral tubal ligation.

7. All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization) while receiving RPT and for 6 weeks after stopping this drug.

8. Body weight > 40 kg

9. Ability and willingness of participant to provide informed consent

Exclusion Criteria

1. Treatment for active or latent TB (pulmonary or extrapulmonary) within 2 years prior to study entry or presence of any confirmed or probable active TB at screening.
2. History of Isoniazid (INH) or Rifampicin (RIF)/Rifabutin (RFB) resistant TB at any time prior to study entry or known exposure to INH or RIF/RFB resistant TB (e.g., household member of a person with MDR or XDR TB) at any time prior to study entry.
3. Treatment for >14 consecutive days with a rifamycin or >30 consecutive days with INH at any time during the 2 years prior to enrollment.
4. Current or planned use of protease inhibitor-based ART.
5. Currently on a salvage ART regimen, defined as a regimen started due to confirmed HIV virologic failure on a prior ART regimen or due to known HIV drug resistance.
6. History of liver cirrhosis at any time prior to study entry.
7. Evidence of acute hepatitis, such as abdominal pain, jaundice, dark urine, and/or light stools within 90 days prior to entry.
8. Diagnosis of porphyria at any time prior to study entry.
9. Peripheral neuropathy ≥Grade 2 according to the Division of AIDS (DAIDS) Toxicity Table, within 90 days prior to study entry.
10. Known allergy/sensitivity or any hypersensitivity to components of study drug(s) or their formulation.
11. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
12. Acute or serious illness requiring systemic treatment and/or hospitalization within 30 days prior to entry.
13. Pregnancy or breastfeeding

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
3HP	Isoniazid/Rifapentine 12-weekly plus pyridoxine (vitamin B6)	12-weekly INH/RPT regimen, plus pyridoxine (vitamin B6)
1HP	Isoniazid/Rifapentine daily (4 weeks) plus pyridoxine (vitamin B6)	4-week daily regimen of weight-based RPT and INH, plus pyridoxine (vitamin B6)

Primary Outcome Measures

Name	Time	Method
tolerability to the regimens (proportion of participants that can complete the treatment course)	3 years	proportion of participants that can complete the treatment course
safety of the regimens (proportion of participants that do not have any side effects throughout the study period)	3 years	proportion of participants that do not have any side effects throughout the study period
efficacy in preventing active TB (proportion of participants that do not have active TB by the end of the study)	3 years	proportion of participants that do not have active TB by the end of the study
prevalence of drug resistance of MTB	3 years	proportion of participants with drug resistance to MTB

Secondary Outcome Measures

Name	Time	Method
time it takes for TB to be confirmed by IGRA	3 years	how much time does it take to confirm TB diagnosis via IGRA
consistency of taking LTBI treatment	3 years	proportion of pills missed during treatment period based on clinical assessment
CD4 count	3 years	CD4 count at baseline
when TB culture becomes positive	3 years	how much time does it take to have positive TB culture
level of total bilirubin	3 years	assess the level of total bilirubin
level of ALK	3 years	assess the level of ALK
death	3 years	time from randomization to death from any cause (TB and non TB events)
severity of the condition	3 years	proportion of participants that have side effects of grade more than or equal to 3 signs
level of CBC	3 years	assess the level of CBC
presence of symptoms	3 years	proportion of participants that have symptoms during the study period
level of ALT	3 years	assess the level of ALT
level of creatinine	3 years	assess the level of creatinine
when TB is confirmed by clinical examination	3 years	how much time does it take to have TB diagnosed via clinical examination
adherence to LTBI treatment	3 years	proportion of pills missed during treatment period based on self report
discontinuation of study due to adverse drug reactions	3 years	Proportion of participants that have discontinued the study because of adverse drug reactions
CD4 count to confirmed or probable TB	3 years	CD4 count at time from randomization to culture-confirmed or probable TB
level of AST	3 years	assess the level of AST
treatment discontinuation	3 years	proportion of participants with permanent LTBI treatment discontinuation due to all causes
TST result at baseline	day 0	TST result at day 0

Trial Locations

Locations (16)

Bhumibol Adulyadej Hospital; 🇹🇭 Bangkok, Thailand

King Chulalongkorn Memorial Hospital; 🇹🇭 Bangkok, Thailand

Sanpatong Hospital; 🇹🇭 Chiang Mai, Thailand

Buddhachinnaraj Hospital; 🇹🇭 Phitsanulok, Thailand

Hatyai Hospital; 🇹🇭 Songkhla, Thailand

Chiangrai Prachanukroh Hospital; 🇹🇭 Chiang Rai, Thailand

Pranangklao Hospital; 🇹🇭 Nonthaburi, Thailand

Klang Hospital; 🇹🇭 Bangkok, Thailand

Sisaket Hospital; 🇹🇭 Sisaket, Thailand

Police General Hospital; 🇹🇭 Bangkok, Thailand

HIV-NAT, Thai Red Cross AIDS Research Centre; 🇹🇭 Bangkok, Thailand

Taksin Hospital; 🇹🇭 Bangkok, Thailand

the Public Health Centre 28 Krung thon buri; 🇹🇭 Bangkok, Thailand

Queen Savang Vadhana Memorial Hospital; 🇹🇭 Chon Buri, Thailand

Srinagarind Hospital; 🇹🇭 Khon Kaen, Thailand

Maharat Nakhon Ratchasima Hospital; 🇹🇭 Nakhon Ratchasima, Thailand