Isoniazid is one of four drugs taken as part of the World Health Organisation recommended first-line treatment regimen for drug-susceptible TB. Isoniazid is the strongest medication available to treat TB. Patients that are resistant to both isoniazid and rifampicin have MDR TB. Isoniazid is also used to prevent latent TB from progressing to active TB. This use is called isoniazid preventative therapy (IPT). Isoniazid is used in South Africa as part of standard regimens to treat TB and as IPT to prevent TB infection in people living with HIV. ## Dosage * Adults: 4 – 6 mg/kg daily (max dose 300 mg) * Adults with liver damage - creatine clearance < 30 ml/min: 300 mg daily or 900 mg three times per week * Children: 4–6 mg/kg daily or 8–12 mg three times per week Isoniazid must be taken daily for six months, during the intensive and continuation phases of TB treatment. ## How it works Isoniazid is an organic compound that was synthesized in the early 20th century. Its activity against TB was discovered in the 1950s. It is a prodrug and must be activated by a bacterial enzyme. By a biochemical complex the isoniazid inhibits the synthesis of mycolic acid, which is required for the mycobacterial cell wall. It is bacteriacidal, which means it kills acgtive TB bacilli. It is also bacteriostatic, meaning that it stops TB from growing. ## Side effects Isoniazid may cause fevers, rashes and peripheral neuropathy. HIV positive patients are more likely to develop isoniazid related peripheral neuropathy. Isoniazid may cause neurotoxicity (damage to the nervous tissue) and hepatoxicity (damage to the liver). Neurotoxicity can be avoided with a low dose of pyridoxine (vitamin B6). Liver damage is usually reversible if isoniazid is stopped. Rare side effects include psychosis, jaundice and convulsions. ## Clinical evidence Isoniazid’s anti-tuberculosis activity was demonstrated in three independent laboratories in 1951. Following this three clinical trials were carried out showing the medicines effectiveness in humans. Researchers of the trials were not aware of others studies, but results were released in April 1952. Patient observations by the end of 1952 showed isoniazid to be more effective than streptomycin in treating TB. [^McDermott] Given the challenge of resistance, today TB is treated with a combination of four medicines including isoniazid. Patients that are resistant to isoniazid and rifampicin have drug resistant tuberculosis. However there is evidence that isoniazid in high doses can still be effective in treating drug resistant TB. In a randomised clinical trial, patients receiving high dose isoniazid as part of their standard MDR treatment became sputum smear negative 2.38 times more rapidly (95% CI 1·45–3·91; p=0·001) and were 2.37 times more likely (1·46–3·84, p=0·001) to achieve sputum smear conversion at 6 months than those who did not receive isoniazid. The studies sample size was too small to control for other predictors.[^2], [^3] Isoniazid can also be used to prevent TB. When isoniazid is used to prevent TB it is referred to as Isoniazid Preventative Therapy (IPT). In 1999, a Cochrane review of 11 trials using isoniazid for 6 to 12 months in people living with HIV showed that isoniazid could prevent TB in 66% of people. [^4] 2010, a trial in Botswana showed that 36 months of IPT is more effective than 6 months in reducing TB infections. The trial researchers concluded that : the benefit of 6 months of IPT was lost in less than 6 months after treatment completion; continuous IPT reduced TB incidence by 43% compared to 6 months of IPT; and, continuous IPT reduced TB incidence by 43% compared to 6 months of IPT. Worryingly, the trial showed that IPT can be harmful if given to people without latent TB. Mortality was significantly higher in people whose tuberculin skin test (TST) results were negative than those who were TST-postive (0.28 [p=0.06] vs 2.99 [p=0.01]). [^5] ## Pricing Prices are given per lowest unit, i.e. single tablet or injection. Key: Isoniazid = H Rifampicin = R * SA Public sector (Aug 2009 – July 2011 tender): - I (300mg): R0.73 - R (300 mg)/ H (150 mg): R0.71 - R (150 mg)/ H (75 mg): R0.48 - R (150 mg)/ E (275 mg)/ H (75 mg)/ P (400 mg): R0.57 * SA Private sector - H (300 mg): R0.66 * Private sector prices sourced on 26/07/11. Global Drug Facility prices converted to rands on 26/07/11. * Private and public sector prices may vary between suppliers. The lowest available prices are shown here. ## Advocacy issues * Affordable versions of isoniazid are available and the supply is secure. Isoniazid is available in fixed dose combinations. * IPT is provided in South Africa without providing the tuberculin skin test. There is evidence that IPT may be harmful to patients without latent TB. [^McDermott]: W McDermott. The story of INH. The Journal of Infectious Diseases Vol. 119, No. 6, Jun., 1969 [^2]: JA Caminero et al. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis. 2010 Sep;10(9):621-9. [^3]: SK Katiyar et al. A randomised controlled trial of high-dose isoniazid adjuvant therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2008; 12: 129 - 45 [^4]: M Smieja et al. Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database of Systematic Reviews 1999, Issue 1. Art. No.: CD001363. DOI: 10.1002/14651858.CD001363. [^5]: T Samandari et al. Randomized, placebo-controlled trial of 6 vs 36 months isoniazid TB preventive therapy for HIV-infected adults in Botswana. Oral abstract 104LB. 17th Conference on Retroviruses and Opportunistic Infections, 16-19 February 2010, San Francisco.