Safety of 3 Different Reintroduction Regimens of Antituberculosis Drugs after Development of Antituberculosis Treatment–Induced Hepatotoxicity

Abstract

ClinicalTrials.gov identifier number: NCT00405301.

Acute liver failure due to antitubercular therapy: Strategy for antitubercular treatment before and after liver transplantation

“…The reintroduction of PZA and a full dose from day 1 of the treatment reintroduction are both risk factors. 32 However, these results were not confirmed in the randomized study of Sharma et al, 33 who included 175 patients with acute hepatitis due to ATT. In effect, regardless of the protocol for the reintroduction of ATT (the maximum dose of INH, RIF, and PZA from day 1 or the sequential reintroduction of increasing doses of INH, RIF, and PZA), the risk of recurrence of hepatotoxicity was the same.…”

An Update on Drug-induced Liver Injury

“…Given the questionable potency of the alternative second line drugs, rechallenge with the primary drugs with or without PZA either simultaneously or sequentially is the usual practise. 94,95 Tolerance to antituberculosis drugs could be a result of adaptation or a change in the environmental factors. 31,45 Various guidelines have been in place for monitoring of patients with anti-TB drugs.…”

Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: A systematic review

“…34 With statin cessation, liver chemistry elevations resolved within 2-8 weeks. Reactive metabolite 32 20-160 mg 26 Atorvastatin, simvastatin, lovastatin (n ¼ 10) 34 30% 34 Decreases mitochondrial membrane potential; inhibits fatty acid beta-oxidation 36 ; uncouples electron transport from phosphorylation 37 Atorvastatin electrophilic acyl glucuronide metabolite 35 20-80 mg 26 Isoniazid, rifampin, pyrazinamide (n ¼ 220) 6 Statin injury is predominantly hepatocellular. 33 The formation of electrophilic metabolites covalently binding to proteins is frequently implicated in immunebased hepatotoxicity; an electrophilic acyl glucuronide metabolite has been reported for atorvastatin.…”

“…Due to the high rate of liver injury associated with tuberculosis medications and their critical public health role in global tuberculosis control, two prospective controlled clinical trials have examined the clinical outcomes of rechallenging patients with active disease with tuberculosis medications. 6,7 One hundred seventy-five Indian patients, 93% of whom exhibited symptomatic hepatitis or jaundice on initial treatment with isoniazid, rifampin, and pyrazinamide, were observed until liver injury resolved and then randomized to rechallenge with tuberculosis medications, all restarted simultaneously or with each drug restarted sequentially. 6 Both treatment groups exhibited similar positive rechallenge rates with an overall 11% positive rechallenge rate and no fatalities.…”

“…3 However, risk factors for severe liver injury with rechallenge are poorly characterized. [1][2][3][4] Clinical outcomes following drug rechallenge appear to vary markedly by drug, 2,3,[5][6][7] suggesting that rechallenge risk may be related to drug-specific mechanisms of injury.…”