Pharmacogenetics-guided Isoniazid Dosing in TB-HIV
Status:
Not yet recruiting
Trial end date:
2022-06-30
Target enrollment:
Participant gender:
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.