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

Implementation for Tuberculosis Preventive Therapy Among Latent Tuberculosis Infection in HIV-infected Individuals Using Novel Regimen of Isoniazid/Rifapentine Daily (4 Weeks) Compared to Isoniazid/Rifapentine Weekly (12 Weeks)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: HIV-infected Participants With Latent TB Infection in High TB Burden Country
• Intervention / Treatment: Drug: Isoniazid/Rifapentine daily (4 weeks) plus pyridoxine (vitamin B6); Drug: Isoniazid/Rifapentine 12-weekly plus pyridoxine (vitamin B6)

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 Type: Interventional
• Enrollment (Actual): 2500
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anchalee Avihingsanon, MD, PhD; Phone Number: 026523040; Email: anchaleea2009@gmail.com
• Study Contact Backup: Name: June Ohata, BS; Phone Number: 026523040; Email: juneohata4@gmail.com

Study Locations

• Thailand
  • Bangkok, Thailand, 10330
    • King Chulalongkorn Memorial Hospital
  • Bangkok, Thailand, 10220
    • Bhumibol Adulyadej Hospital
  • Bangkok, Thailand, 10330
    • HIV-NAT, Thai Red Cross AIDS Research Centre
  • Bangkok, Thailand, 10330
    • Police General Hospital
  • Bangkok, Thailand, 10600
    • Taksin Hospital
  • Bangkok, Thailand, 10100
    • Klang Hospital
  • Bangkok, Thailand, 10600
    • the Public Health Centre 28 Krung thon buri
  • Chiang Mai, Thailand, 50120
    • Sanpatong Hospital
  • Chiang Rai, Thailand, 57000
    • Chiangrai Prachanukroh Hospital
  • Chon Buri, Thailand, 20110
    • Queen Savang Vadhana Memorial Hospital
  • Khon Kaen, Thailand, 40002
    • Srinagarind Hospital
  • Nakhon Ratchasima, Thailand, 30000
    • Maharat Nakhon Ratchasima Hospital
  • Nonthaburi, Thailand, 11000
    • Pranangklao Hospital
  • Phitsanulok, Thailand, 65000
    • Buddhachinnaraj Hospital
  • Sisaket, Thailand, 33000
    • Sisaket Hospital
  • Songkhla, Thailand, 90110
    • Hatyai Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1HP; 4-week daily regimen of weight-based RPT and INH, plus pyridoxine (vitamin B6)	Drug: Isoniazid/Rifapentine daily (4 weeks) plus pyridoxine (vitamin B6); Isoniazid/Rifapentine daily (4 weeks) plus pyridoxine (vitamin B6)
Active Comparator: 3HP; 12-weekly INH/RPT regimen, plus pyridoxine (vitamin B6)	Drug: Isoniazid/Rifapentine 12-weekly plus pyridoxine (vitamin B6); Isoniazid/Rifapentine 12-weekly plus pyridoxine (vitamin B6)

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: The HIV Netherlands Australia Thailand Research Collaboration
• Collaborators: King Chulalongkorn Memorial Hospital; Srinagarind Hospital, Khon Kaen University; Police General Hospital; Pranangklao Hospital; Taksin Hospital; Bhumibol Adulyadej Hospital; Klang Hospital; Chiang Rai Prachanukroh Hospital; Sanpatong Hospital; Queen Sawang Vadhana Memorial Hospital; Buddhachinnaraj Hospital; Maharat Nakhon Ratchasima Hospital; HatYai Hospital; Sisaket Hospital; The Public Health Centre 28 Krung thon buri
• Investigators: Principal Investigator: Anchalee Avihingsanon, MD, PhD, HIV-NAT, Thai Red Cross - AIDS Research Centre

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2019
• Primary Completion (Estimated): March 1, 2038
• Study Completion (Estimated): March 1, 2038

Study Registration Dates

• First Submitted: December 19, 2018
• First Submitted That Met QC Criteria: December 21, 2018
• First Posted (Actual): December 24, 2018

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 26, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: people living with HIV (PLHIV)
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Latent Infection; Infections; Communicable Diseases; Tuberculosis; Latent Tuberculosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Fatty Acid Synthesis Inhibitors; Rifapentine; Rifampin; Vitamins; Vitamin B Complex; Vitamin B 6; Pyridoxal; Pyridoxine; Isoniazid
• Other Study ID Numbers: HIV-NAT 255

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No