EPIDEMIOLOGY

The global rate of tuberculosis is growing at approximately 1.1% per year. India ranks first in the estimated number of tuberculosis cases, and approximates to 1761 (thousands) cases per 10, 49,549 population at the rate of 168 cases per 1,00,000 population [1,2]. India is considered the highest TB burden country accounting for one fifth of the global incidence (Global annual incidence estimate was 9.1 million cases out of which it was estimated that 1.9 million cases were from India). India was 17th among 22 High Burden Countries in terms of TB incidence rate.  The most effective anti –tuberculosis drugs comprise of Isoniazid, Rifampicin and Pyrazinamide all of which are hepatotoxic. ATT induced hepatitis can lead to treatment failure and further contribute to Multi Drug Resistant (MDR) tuberculosis as a result of sub-optimal TB treatment regimens. Worldwide, 3.7% of new cases and 20% of previously treated cases were estimated to have MDR-TB [3].

RNTCP-DOTS

In response to the tuberculosis epidemic and inadequate treatment strategies, a pilot project using the World Health Organization (WHO)–recommended strategy of directly observed treatment, short-course (DOTS), the Revised National Tuberculosis Control Program, was begun in 1993. The world adopted the DOTS strategy for TB control through the national TB control programs in different countries and was said to make good progress [4].

Diagnosis was primarily made by sputum microscopy, treatment was directly observed, and standardized regimens were used.⁸ It was gradually expanded to cover a population of 20 million by mid-1998. Rapid RNTCP expansion began in late 1998. By the end of 2002, 50% of country’s population was covered under RNTCP [5].

The country was fully covered by 23rd march 2006. Every day in India, under the RNTCP more than 5000 patients were examined for TB, free of charge. As a result of these examinations every day, more than 3200 patients were started on treatment and more than 2500 of them were cured. RNTCP was considered the largest and the fastest expanding programme in the world [6].

Under RNTCP, the doses of first line anti-TB drugs (Isoniazid, Rifampicin, Pyrazinamide, Streptomycin and Ethambutol) were standardized on the basis of body weight and were given in different regimens. All regimens had an initial intensive phase lasting 2-3 months, aimed to rapidly kill the TB bacilli, bring about sputum conversion and to afford symptomatic relief. This was followed by a continuation phase lasting 4-6 months, during which the remaining bacilli were eliminated so that relapse does not occur [7].

FDC DOTS

In 2014 the RNTCP recognised the need for daily dosing and announced a pilot in five states in December 2014. It was however very delayed. Three years later in 2017 the pilot was finally due to start. It was initiated in 5 states – Bihar, Himachal Pradesh, Kerala, Maharashtra and Sikkim covering 27 crore population of the country. By this time most private sector physicians were providing their patients with a daily TB drug regimen. In February 2017 the Supreme Court directed that after a period of nine months, all new patients should be administered a daily regimen of TB drugs. 

First line treatment of drug-sensitive TB consists of a two-months (8weeks) intensive phase with four drug FDCs followed by a continuation phase of four months (16 Weeks) with three drug FDCs. For new TB cases, the treatment in intensive phase (IP) consists of eight weeks of Isoniazid (INH), Rifampicin, Pyrazinamide and Ethambutol (HRZE) in daily doses as per four weight band categories and in continuation phase three drug FDCs- Rifampicin, Isoniazid, and Ethambutol (HRE) are continued for 16 weeks.

ADVERSE DRUG REACTION:

The WHO defined ADR as ‘A response to a drug that is noxious and unintended and occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease, or for modification of physiological function [8,9,10]. In India there were few ADR monitoring centres and a lot of effort is required in order to collect ADR data which may generate from safety surveillance of billions of therapeutically active substances either alone or in combinations. Anti tubercular drugs are considered as one of the most common drugs causing ADR [11].

ADR IN ANTI-TUBERCULAR DRUGS:

Adverse drug reactions to anti tuberculosis drugs occurred during treatment of tuberculosis and was expected in 10% of the patients treated for pulmonary tuberculosis [12]. However, they were more common and often severe in patients on second line drugs. In patients who received conventional therapy of long duration, many patients defaulted when their symptoms ameliorated, but some of them left treatment and became non-adherent due to adverse toxic reactions of drugs. The DOTS therapy based on powerful bactericidal drugs shortens the treatment duration and increase compliance and adherence with an additional advantage of lowering drug toxicity mainly because of fewer doses and less cumulative doses of drugs [12].

Anti-tubercular drugs, just like other drugs used in clinical practice, are not free from ADRs. The added problem is that combinations of drugs are always used for prolonged periods of time and therefore, it is likely that the adverse reactions of one drug may be potentiated by the companion drugs used. Moreover, the Adverse Drug Reactions (ADRs) to the drugs used is one of the major reasons for the patient default for treatment [6].

These adverse reactions or hepatitis caused by anti tubercular drugs cause significant morbidity and mortality. These side effects lead to modification or discontinuation of treatment and pose a challenge in controlling the reoccurrence of tuberculosis.

ADVERSE DRUG EFFECTS OF DRUGS USED FOR THE TREATMENT OF TUBERCULOSIS

• Rifampicin: GI side effects, abdominal pain, nausea, vomiting, hepatitis, cutaneous reaction, purpura, haemolytic anaemia, flu like syndrome, acute renal failure.

• Isoniazid: Peripheral neuropathy, skin rash, hepatitis, sleepiness and lethargy, convulsions, psychosis

• Pyrazinamide: Nausea, vomiting, hepatitis, arthralgia, cutaneous reactions Ethambutol – Optic neuritis, GI upset, hypersensitivity reactions, peripheral neuropathy, purpura

• Streptomycin: Loss of vestibular functions, deafness, renal toxicity, cutaneous hypersensitivity, deafness, renal toxicity, cutaneous hypersensitivity, circum oral numbness [13].

The occurrence, risk factors, morbidity, and mortality of adverse events from Isoniazid (INH), particularly hepatotoxicity, have been well defined [14,15,16]. Adverse reactions to Rifampin (RIF) and Ethambutol (EMB) have been well documented, [17,18,19] although causality of these drugs was less certain because they were seldom used alone. The incidence of major side effects associated with Pyrazinamide (PZA), was somewhat controversial. Authoritative treatment guidelines [20] have stated that "there did not appear to be a significant increase in hepatotoxicity when PZA was added to INH and RIF, based on results from large scale randomized trials" [21,22,23]. However, studies of patients treated for active disease, or receiving 2 months of RIF and PZA for latent infection, have reported serious adverse events attributable to PZA [24].

Drug induced Liver Injury has been described as ‘’PENALTY FOR PROGRESS”. By Popper and Colleagues about 50 years ago. Drug induced liver injury is the one of the major causes for the drawl of drugs prescribed for major illness treatment and is also for withdrawal of drug from the market. A few drugs have been withdrawn and banned due to major adverse events. Hepatotoxicity constitutes one of major adverse effects due to drugs. There is a unique susceptibility of certain individuals to DILI called as idiosyncratic DILI. DILI occurs mostly due to antimicrobials and ATT is one of the significant drugs, followed by Amoxicillin-clavulanic acid and flucloxacillin [25].

DEFINITION

The definition of DILI is as follows “Drug-induced liver injury (DILI) is defined as a liver injury caused by various medications, herbs, or other xenobiotic, leading to abnormalities in liver tests or liver dysfunction with the reasonable exclusion of other aetiologies”.

ATT and hepatotoxicity 

In a meta analysis done by S.K.Acharya et al it was concluded that the frequency of overt clinical hepatitis caused by Isoniazid, Rifampicin, or both together was 0.6%, 1.1%, and 2.6%, respectively [26].

Pathogenesis of drug-induced hepatotoxicity

Isoniazid

The pathogenesis of DIH caused by INH is not well understood. Histo-pathological evidence resembling viral hepatitis showing hepatocyte necrosis, ballooning degeneration and inflammatory infiltrates suggests dose related toxicity [27].

However, lack of direct correlation between serum drug levels and hepatotoxicity argues against a direct toxic effect [28]. Given the delayed onset of DIH, absence of symptoms usually associated with hypersensitivity such as rash, fever, arthralgia and eosinophilia, and no hepatotoxicity on re-challenge in most cases. Hypersensitivity is considered unlikely. But, presence of eosinophilic infiltrates on liver biopsy and recurrence of hepatotoxicity on re-challenge with the drug suggest hypersensitivity as a possible mechanism [29].

Altered profile of antioxidant enzymes with increased lipid per oxidation indicated that INH and RIF induced hepatotoxicity appeared to be mediated through oxidative stress [30].

Rifampicin

Compared with INH, DIH caused by RIF occurs earlier and produces a patchy cellular abnormality with marked periportal inflammation. Rif induced hepatitis has been postulated to occur as a part of systemic allergic reaction and due to unconjugated hyperbilirubinemia as a result of competition with bilirubin for uptake at hepatocyte plasma membrane [31].

Whether the hepatotoxicity is due to the additive effect of INH and RIF or due to their synergistic effect; whether the toxicity is due to their effect of drugs or is a hypersensitivity phenomenon is also being currently debated. The increased risk of hepatotoxicity with INH and RIF combination has been attributed to the interaction between the metabolism of INH and RIF. Acetyl-INH, the principal metabolite of INH, is converted to monoacetyl hydrazine. The microsomal p-450 enzymes convert monoacetyl hydrazine to other compounds resulting in hepatotoxicity. RIF is thought to enhance this effect by enzyme induction. The first human case of a proven hepatotoxic interaction between INH and RIF has recently been reported by Askgaard et al [32]. A 35 year old black Somalian patient with miliary tuberculosis developed hepatotoxicity after a few days of treatment with INH, RIF, Pyrazinamide and Ethambutol. On withdrawing all the drugs, the liver profile normalized and remained so after INH challenge. Hepatotoxicity recurred when RIF was added but it was well tolerated when RIF was re-introduced without INH.

Pyrazinamide

The exact pathogenetic mechanism for the DIH caused by Pyrazinamide has not been understood. In patients receiving a combination of INH, RIF and Pyrazinamide, two patterns of fulminant liver injury have been observed. Increase in serum transaminase activity which occurs late (usually after one month) has been attributed to Pyrazinamide induced hepatotoxicity while the early increase in trans-aminases (usually within first 15 days) has been attributed to RIF and INH induced hepatotoxicity [33].

Drug induced hepatotoxicity may occur in all currently recommended regimes for treatment of TB. Pyrazinamide, INH, followed by Rifampicin in order, are the most common drugs causing DILI. DILI is most common among first line ATT drugs. Pyrazinamide with Rifampicin appears more toxic than INH alone. A higher risk of hepatotoxicity has been reported in Indian patients than in their western counterparts.

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