1. The central hypothesis of this study is that genetic polymorphisms in drug metabolising enzymes and regulators of enzyme expression may predispose to ATDH. We propose to evaluate the presence of genetic polymorphisms among TB patients in…
ID
Source
Brief title
Condition
- Other condition
- Mycobacterial infectious disorders
Synonym
Health condition
leverbijwerkingen van standaard tuberculosebehandeling
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Association between ATDH and genetic polymorphisms (single nucleotide
polymorphisms) in drug metabolising enzymes and regulators of enzyme
expression.
Enzymes: N-acetyltransferase 2, glutathione S-transferase, cytochrome P450 2E1.
Receptors: pregnane X-receptor (PXR), multidrug resistance gene 1 (MDR1).
Secondary outcome
Association between ATDH and other risk factors, including age, sex, weight and
length, underlying liver disease and HIV-status.
Background summary
Therapy adherence is crucial for curing patients with active tuberculosis (TB).
Incomplete treatment can result in remission of disease and contributes to
drug-resistance. Side effects significantly contribute to non-adherence.
Standard TB treatment contains isoniazid, rifampicin, pyrazinamide and
ethambutol. Anti-TB drug-induced hepatotoxicity (ATDH), one of the most serious
side effects, occurs in 2% to 28% of the patients. This rate depends on the
investigators* definition of hepatotoxicity as well as the population studied.
Previous described risk factors include advanced age, female sex, underlying
liver disease (hepatitis B/C), HIV infection, malnutrition and alcohol use.
Metabolism is important in the development of ATDH and reactive metabolites are
crucial. Genetic variation in biotransformation of TB drugs, caused by genetic
polymorphisms, may result in an increased formation or toxicity of reactive
metabolites which increases the risk on ATDH. Several genetic polymorphisms
have been associated with ATDH (N-acetyltransferase 2, glutathione
S-transferase, cytochrome P450 2E1).
In summary, genetic factors may predispose to the adverse effects of
anti-tuberculous drugs. They interact in a complex way and may explain why some
individuals develop ATDH. The relative importance of specific genetic
polymorphisms is unknown and their interplay has not been evaluated in detail.
Study objective
1. The central hypothesis of this study is that genetic polymorphisms in drug
metabolising enzymes and regulators of enzyme expression may predispose to
ATDH. We propose to evaluate the presence of genetic polymorphisms among TB
patients in different parts of the world. An association between specific
polymorphisms and the occurrence of ATDH will be sought.
2. Knowledge on the relevance of specific polymorphisms in the development of
ATDH may allow the identification of patients at risk of ATDH. They can
possibly be offered adjusted treatment regimens.
Study design
We will conduct a case-control study in three world regions with varying
incidences of ATDH and varying risk factor prevalence: the Netherlands and
United Kingdom, Indonesia and Tanzania. Cases are TB-patients with liver
toxicity during treatment and controls are TB-patients without ATDH.
Study burden and risks
We want to draw 10 ml venous blood of all cases and controls. The risk of
venous blood drawing is negligible.
Geert Grooteplein Zuid 8
6525 GA Nijmegen
Nederland
Geert Grooteplein Zuid 8
6525 GA Nijmegen
Nederland
Listed location countries
Age
Inclusion criteria
- Patient is treated for tuberculosis (pulmonary or extra-pulmonary) with standard treatment containing at least isoniazid, rifampicin and pyrazinamide.
- Age: above 18 years.
Exclusion criteria
- Patient receives treatment for multi-drug resistant tuberculosis.
- Patient also receives antiretroviral treatment and developed liver function disorders immediately after the start of ART.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL12524.091.06 |