Pharmacogenetics-guided Isoniazid Dosing in TB-HIV

• Status: Not yet recruiting
• Trial end date: 2022-06-30
• Target enrollment: 0
• Participant gender: All

Summary

The current TB treatment as recommended by World Health Organization (WHO) although capable of achieving 85% cure rates, has limitations, in particular drug interactions, toxicities, and the long treatment duration which increases the possibility of nonadherence.

Sub-therapeutic isoniazid concentrations were demonstrated in several studies, including our previous work, carried out among patients with tuberculosis receiving the standard dose (5mg/kg) of isoniazid. The investigators found 78% of patients with HIV had isoniazid concentrations below the recommended threshold. Malabsorption, drug-drug interactions, poor adherence due to high pill burden may contribute to this. Pharmacogenetic variation may compound these factors; isoniazid displays inter-individual variation in serum concentrations and clearance due to differences in individual acetylator status.

While patients who metabolize isoniazid slowly (slow acetylators) are at a higher risk of high drug concentrations and toxicities, fast acetylators are more likely to have sub-therapeutic isoniazid concentrations.

In other studies, insufficient exposure with isoniazid, one of the cornerstone drugs for TB treatment, has been associated with delayed sputum clearance, development of drug resistance, and treatment failure.

Isoniazid is metabolized by the enzyme N-acetyl transferase, which in turn is controlled by the N-acetyl transferase-2 (NAT-2) gene. Polymorphisms in this gene are responsible for the N-acetylation phenotypes, with the distribution of NAT-2 fast, intermediate, and slow acetylators being highly variable especially among African populations.

Given that NAT2 acetylator status explains most of the variability in INH exposures, knowledge of NAT2 status may be a simpler way to select the right dose for individual patients. The investigators will therefore provide higher doses to fast acetylators and compare the isoniazid pharmacokinetics in these patients to slow acetylators who receive the standard dose, who are more likely to already be achieving target concentrations.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Makerere University
• Treatments: Isoniazid

Criteria

Inclusion Criteria:

• Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.

• Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

• Age of ≥18 years

• Bacteriologically confirmed pulmonary TB (determined by Xpert, culture, or microscopy)

• Confirmed HIV-1 infection.

• On TB treatment for ≤ 7 days at the time of enrolment (Within this time, the patient is still expected to have mycobacteria present in sputum and will provide enough time to conduct screening procedures)

Exclusion Criteria:

• TB infection of any organ/systems requiring TB treatment longer than 6 months

• Pregnancy

• Decompensated liver disease and/or aminotransferases >2.5 x ULN