Anti-tuberculosis (TB) Drug Levels and Correlation With Drug Induced Hepatotoxicity
Condition: Hepatitis; Tuberculosis
MeSH terms: Tuberculosis
Study type: Observational

Summary: 
      The purpose of the study is to estimate plasma drug levels ( free and total drug levels ) of
      rifampicin and other antituberculosis drugs and compare these drug levels in patients who
      develop drug induced hepatotoxicity versus those who do not .The study hypothesis is that the
      ATT drug induced hepatotoxicity is related to free drug levels of rifampicin and other
      antituberculosis drugs .
    

Detailed description: 
      Tuberculosis (TB) is a major health problem in both the developing and developed countries
      because of its resurgence in the immunosuppressed patients. World Health Organization (WHO)
      in 1993 declared tuberculosis to be a 'global emergency' with more than a third of the
      world's population infected. Globally 8.9 million new cases of tuberculosis occur annually,
      of which 1.8 million (20%) occur in India.

      Short-course chemotherapy containing isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA)
      has proved to be highly effective in the treatment of tuberculosis. One of its adverse
      effects is hepatotoxicity. It is the most common side effect leading to interruption of
      therapy. It is associated with mortality of 6-12% if these drugs are continued even after the
      onset of symptoms. Risk of hepatotoxicity is increased when these drugs are combined.

      The time interval between the start of anti-TB drugs and appearance of hepatotoxicity varies
      from 3 to 135 days. In most cases hepatitis is evident within three months of start of
      antituberculosis treatment (ATT).

      The pathogenesis of drug-induced hepatotoxicity (DIH) is still not entirely clear for most
      anti TB drugs including rifampicin. Hypersensitivity is a definite possibility. Rifampicin
      induced hepatitis has been postulated to occur as a part of systemic allergic reaction and
      due to unconjugated hyperbilirubinaemia as a result of competition with bilirubin for uptake
      at hepatocyte plasma membrane. DIH caused by rifampicin occurs earlier as compared to
      isoniazid. While a dose related toxicity may exist, a direct correlation between serum drug
      levels and hepatotoxicity has not been well reported. Thus the clinical relevance of
      therapeutic monitoring of serum rifampicin concentrations in managing DIH is still being
      explored. Rifampicin is highly protein bound and hypoalbuminemia is a known risk factor for
      DIH ,so free drug levels in plasma has more significance than total drug levels in plasma.

      Present study is done to estimate free and total drug levels of rifampicin and other
      antituberculosis drugs in patients on ATT and to compare it between patients who develop DIH
      vs those who do not and to assess the predicting ability of these drug levels in the
      subsequent development of drug induced hepatoxicity.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Subjects: Patients with diagnosis of pulmonary/extrapulmonary Tuberculosis attending the
        out-patient department of the All India Institute of Medical Sciences, New Delhi, will form
        the study population.

        Cases - those patients who develop DIH while on regular treatment with anti-TB drugs
        Controls - patients who do not develop DIH while on regular treatment with anti-TB drugs
      
Keywords: Plasma levels; isoniazid; rifampicin; pyrazinamide; hepatoxicity