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Isoniazid Hepatitis
Decision to Use Isoniazid

Isoniazid (INH) chemoprophylaxis is preventive therapy for a subclinical tuberculous infection to prevent reactivation disease. Although the therapy of active pulmonary tuberculosis has improved considerably with highly effective short-course regimens, little progress has been made in INH preventive therapy.
Daily therapy with INH for 12 months has been the standard regimen for several decades. The major controversial issue concerns the recommendations of the American Thoracic Society and the Centers for Disease Control that all tuberculin skin test reactors between ages 21 and 35 years with no other risk factors should receive INH for 1 year. Using decision analysis, the authors concluded that young adults (ages 21 to 35 years) with a positive tuberculin skin test reaction and no additional risk factors should not take INH because the risk for INH-related hepatitis outweighs the benefits of preventive therapy. In the editorial that accompanied this report, Comstock concluded that the input values selected for decision analysis tipped the scales against INH prophylaxis. There is still a need for more data for this risk group.
An extensive controlled study involving almost 28,000 patients with positive Mantoux skin test reactions and fibrotic lesions detected by chest roentgenography was published in 1982 and provided important data on INH preventive therapy. In this study, patients were treated with either INH or placebo for 12, 24, or 52 weeks and were then followed for 5 years. Using data from this study to conduct a cost effectiveness analysis of the three treatment durations, Snider et al. (1986) concluded that a 24-week regimen was the most cost effective duration. A 12-week course of INH was felt to be inadequate, and the danger of a 24-week regimen was that patients might shorten their therapy even further. Other reports based on the application of decision-analysis techniques to the management of low-risk tuberculin reactors have failed to resolve the controversy.
A positive induration after testing with intermediate-strength (5 tuberculin units) purified protein derivative (PPD-S) stabilized with polysorbate 80 indicates recent or remote infection, usually with Mycobacterium tuberculosis (see Chapter 65). In the absence of evidence of active disease, a positive delayed-hypersensitivity reaction to tuberculosis means that the primary infection has been arrested by the host; thus, the tuberculin-positive person has viable tubercle bacilli that, although contained by acquired cellular immunity, may multiply in subsequent years with alterations in host-resistance factors. In fact, 92% of all new cases of active pulmonary tuberculosis represent reactivation disease in a small proportion (7%) of the tuberculin-positive population. The term INH chemoprophylaxis does not, in fact, indicate prophylaxis, but rather actual treatment of a subclinical infection to prevent the development of active tuberculosis. Single-drug therapy is effective because the number of organisms is small; thus, there is little chance of selecting out resistant mycobacteria.
INH was commercially released in 1952, and since then numerous controlled studies have shown that a 12-month course of INH therapy is effective in preventing reactivation of disease in tuberculin reactors. The risk for active disease in a placebo group was found to be as many as 61 times that in patients treated with INH. Eighty percent of the active cases in a placebo group occurred within the first year after diagnosis, but the onset of active disease in the placebo group might be delayed as long as 8 years. The protective effect of INH is more impressive for children than for adults. Compliance is the key to the effectiveness of INH, and success rates approach 100% when the drug is given under direct supervision. One year of treatment is effective for at least 19 years and probably for the life of the patient. In summary, there is no controversy that INH chemoprophylaxis is effective for symptomless tuberculin reactors, tuberculin-positive household contacts, and persons with positive skin test reactions and inactive fibrotic lesions revealed by chest roentgenography.
Isoniazid Hepatitis
The major disadvantage of INH is the risk for drug-induced hepatitis. The risk for hepatitis is age-related and is increased with daily alcohol consumption. This complication is extremely rare in a person under age 20 years but occurs in 2.1% to 4.3% of persons over the age of 50 years. Although the exact pathogenic mechanism of INH-associated hepatitis remains unknown, certain features are clear. Women may be at an increased risk for development of fatal INH hepatitis. Elevations in liver enzymes with or without symptoms develop in about 10% to 20% of those taking INH. In a small percentage (1%) of patients, jaundice and fatal hepatitis develop. The onset of the liver function abnormalities varies widely, from 1 week to 11 months after the start of treatment. Half the reactions occur within 2 months, mostly during the second month. Fatal hepatitis is more common in patients taking INH for at least 8 weeks than in those on therapy for a shorter period, and it often occurs in patients who continue therapy even after symptoms of hepatitis develop.
Symptoms of liver disease—anorexia, malaise, nausea, and vomiting—are low-sensitivity indicators of INH liver toxicity compared with liver function tests to detect INH hepatitis, and biochemical monitoring is required in patients over age 35 years. It is recommended that in subjects over age 35 years, determinations of transaminase levels and careful clinical assessments be performed at 1, 3, 6, and 9 months after the start of therapy. In persons under age 35 years, monthly evaluation of symptoms and signs of liver disease is adequate, and biochemical monitoring is not required unless adverse effects are detected by the clinical evaluation. In an asymptomatic person, a decision to discontinue INH should be made if the transaminase levels exceed five times the normal laboratory values. Only 7% of the patients in one large study had their INH treatments stopped because of symptoms or asymptomatic elevations of transaminase levels. Clinically, biochemically, and histologically, the liver injury is indistinguishable from viral hepatitis. Contrary to what was observed in earlier studies, the incidence is not increased in rapid acetylators. In fact, slow acetylators over age 35 years appear to be at an increased risk. The mechanism of the hepatitis appears to be conversion of INH to one or more toxic metabolites. The fatality rate is about 10% for icteric cases, and the illness is usually preceded by gastrointestinal symptoms. The majority of patients who have died of INH hepatitis continued to receive the drug despite clinical evidence of hepatitis.
Decision to Use Isoniazid
The decision to treat a tuberculin reactor with INH is not an easy one to make and should be individualized. Active tuberculosis must be excluded, because usually four drugs are required. The clinician must weigh the risk for development of active tuberculosis and the consequences of infection in each patient. Children less than 5 years old and adolescents tend to have more serious disease than do older persons. Patients of low body weight are also at increased risk for tuberculous disease. Finally, the younger a tuberculin reactor is, the greater the number of years there are in which reactivation disease may occur. In a patient who has coexisting illnesses or is taking drugs with which adverse interactions are possible, deferring INH therapy should always be considered. INH should be deferred in pregnancy until the postpartum period, although women may be particularly vulnerable during this period and must be monitored closely if given this agent.
Table 66-1 lists the indications for INH therapy in order of priority. All household contacts who are tuberculin-positive should receive INH unless active disease is documented, in which case two drugs are given. Children who are household contacts and are tuberculin-negative should be given INH for 3 months; a skin test is then repeated. If the test result remains negative and there is no further risk for exposure, INH can be discontinued. For tuberculin-negative adult household contacts, therapy with INH is optional, depending on the infectiousness of the source. Skin testing should be repeated after 3 months. Newly infected persons (documented to have a negative PPD skin test result within the past 2 years) should receive INH.

Table 66-1. Indications for isoniazid therapy

It is important to distinguish persons who are new, true tuberculin-positive reactors from those who are new positive reactors as a result of the booster phenomenon. The booster effect, which refers to an increase in the size of the tuberculin skin reaction as a consequence of serial tuberculin testing, can be demonstrated as early as 1 to 3 weeks after an initial tuberculin test. This diminished skin reactivity occurs more often in the elderly, and the repeated skin test can erroneously be interpreted as a new positive skin test reaction (conversion). Rather, the initial negative skin test reaction represents a false-negative result, and the result of the repeated test with an increase in size is positive but does not necessarily indicate a recent conversion.
The efficacy of INH is well documented in patients with a positive tuberculin skin test reaction and a fibrotic pulmonary lesion revealed by chest roentgenography. There are no studies supporting the efficacy of INH and the risk for disease in tuberculin reactors in the special clinical situations, and the recommendations are based on uncontrolled studies of tuberculosis in the various groups outlined (Table 66-1). Patients to be placed on either long-term prednisone or other cytotoxic drugs should undergo skin testing before starting the drugs to establish their tuberculin status before the immunosuppressive therapy.
Recommendations on the use of INH for immunosuppressed patients differ widely. Some authors advocate INH; others recommend deferring therapy because of the risk for hepatitis, such as that observed in renal transplant recipients. The duration of therapy for immunosuppressed patients is also unclear; some experts favor 1 year of therapy and others treatment for the duration of the immunosuppressed state. I favor using INH carefully for 1 year for the tuberculin-positive immunosuppressed patient. The greatest controversy concerns INH therapy in the tuberculin-positive adult (ages 21 to 35 years) with no other risk factors. Arguments on both sides of the issue have been clearly presented, and I favor chemoprophylaxis. An alternative approach to INH administration is careful observation of reactors and institution of therapy for active tuberculosis if it occurs. The benefits and risks of INH should be presented to the patient.
INH, the drug of choice for chemoprophylaxis, is given in a dose of 300 mg daily for adults and 10 mg/kg of body weight (up to 300 mg) in children. It is usually recommended for 6 to 12 months; however, 9 months of therapy is an acceptable duration for household contacts if the source case is being treated with a 9-month regimen. No more than a 1-month supply of INH should be given at any one time. In the recent trial of INH and placebo in Europe, patients randomly received 12, 24, or 52 weeks of treatment. There was a 93% reduction in tuberculosis for those with good compliance in the 52-week group. A 12-week treatment was too brief and eliminated fewer than one third of cases; 24 weeks of treatment eliminated 69% of the cases. INH for 1 year was particularly effective in patients with fibrotic lesions larger than 2 cm2. There were more cases of hepatitis (than in controls) in patients being treated for 1 year, but the test population had a median age of 50 years. Nearly half the cases of hepatitis were observed during the initial 3 months of therapy. This study also demonstrated the importance of compliance for successful therapy. Rifampin (10 mg/kg of body weight, up to 600 mg) is recommended for 1 year for contacts who have presumably been infected by a source shedding INH-resistant bacilli, although this form of therapy has not been studied and is expensive. Twice-weekly INH treatment in a high dose (15 mg/kg of body weight) for 1 year may be tried if compliance is a problem.
The optimal preventive regimen for persons exposed to a source patient infected with multidrug-resistant M. tuberculosis is unknown. Susceptibility test results of the source-infecting strain may be helpful to guide therapy. If the infecting strain is less than 100% resistant to INH or rifampin, these drugs can be used. Potential alternative regimens include a combination of pyrazinamide plus ethambutol, or pyrazinamide plus either ofloxacin or ciprofloxacin. Clinical data are lacking on preventive therapy regimens that do not include INH, as this is the only drug approved for chemoprophylaxis. Shortening the duration of therapy with other drug combinations, as well as developing other regimens for prevention, should be a goal of future investigations. (N.M.G.)
American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994;149:1359–1374.
Guidelines for screening and treatment. Persons with HIV infection should receive 12 months of INH preventive therapy. Children should be given 9 months of therapy.
American Thoracic Society, American Academy of Pediatrics, Centers for Disease Control, Infectious Disease Society of America. Control of tuberculosis in the United States. Am Rev Respir Dis 1992;146:1623.
Indications for INH prophylaxis.
Asch S, et al. Relationship of isoniazid resistance to human immunodeficiency virus infection in patients with tuberculosis. Am J Respir Crit Care Med 1996;153:1708–1710.
INH-resistant tuberculosis was not more frequent in HIV-infected patients.
Black M, et al. Isoniazid-associated hepatitis in 114 patients. Gastroenterology 1975; 69:289.
A review of the cases of 114 patients with INH hepatitis, who had a 12% fatality rate. The clinical picture is indistinguishable from that of viral hepatitis.
Byrd RB, Nelson R, Elliott RC. Toxic effects of isoniazid in tuberculosis chemoprophylaxis. JAMA 1979;241:1239.
Ten percent of patients were unable to complete therapy with INH.
Centers for Disease Control. Prevention and control of tuberculosis in facilities providing long-term care to the elderly: recommendations of the Advisory Committee for Elimination of Tuberculosis. MMWR Morb Mortal Wkly Rep 1990;39(RR10):7.
A positive tuberculin skin test reaction is defined as an increase of 10 mm or more for a person under age 35 years or an increase of 15 mm or more for someone age 35 years or older.
Centers for Disease Control. Management of persons exposed to multidrug-resistant tuberculosis. MMWR Morb Mortal Wkly Rep 1992;41(RR11):61.
An approach to a tuberculin-positive contact suspected of having acquired infection with multidrug-resistant M. tuberculosis. Preventive therapy consists of pyrazinamide plus ethambutol, or pyrazinamide plus a fluoroquinolone.
Centers for Disease Control. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR 1998;47 (No. RR-20):1–58.
Describes use of a two month regimen of rifampin or rifabutin combined with pyrazinamide to prevent tuberculosis in patients with HIV infection.
Colice GL. Decision analysis, public health policy, and isoniazid chemoprophylaxis for young adult tuberculin skin reactors. Arch Intern Med 1990;150:2517.
Supports the use of INH for tuberculin-positive persons under age 35 years with normal chest roentgenographic findings and no other risk factors.
Comstock GW, Baum C, Snider DE. Isoniazid prophylaxis among Alaskan Eskimos: a final report of the Bethel isoniazid studies. Am Rev Respir Dis 1979;119:827.
Documents INH effectiveness in preventing tuberculosis.
Comstock GW, Ferebee SH, Hammes LM. A controlled trial of community-wide isoniazid prophylaxis in Alaska. Am Rev Respir Dis 1967;95:935.
Documents INH effectiveness in preventing tuberculosis.
Curry FJ. Prophylactic effect of isoniazid in young tuberculin reactors. N Engl J Med 1967;277:562.
Documents INH effectiveness in preventing tuberculosis.
Dorken E, Grzybowski S, Enarson DA. Ten-year evaluation of a trial of chemoprophylaxis against tuberculosis in Frobisher Bay, Canada. Tubercle 1984;65:93.
A regimen of INH plus ethambutol three times twice a week for 18 months was effective.
Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis. A general review. Adv Tuber Res 1970;17:28.
Review of INH efficacy.
Glassroth J, et al. Why tuberculosis is not prevented. Am Rev Respir Dis 1990; 141:1236.
This report cites three reasons why tuberculosis is not prevented: (a) patients are not in the health care system until active tuberculosis occurs, (b) patients do not receive a tuberculin skin test or INH, or (c) patients fail to react to the skin test.
Gordon FM, et al. A controlled trial of isoniazid in persons with anergy and human immunodeficiency virus infection who are at high risk for tuberculosis. N Engl J Med 1997;337:315–320.
INH prophylaxis is not indicated for HIV-positive patients who are anergic unless they have been exposed to a patient with active tuberculosis.
Halsey NA, et al. Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection. Lancet 1998;351:786–792.
Twice-weekly isoniazid for 6 months or rifampin and pyrazinamide for 2 months were equally effective for chemoprophylaxis.
Hawken MP, et al. Isoniazid preventive therapy for tuberculosis in HIV-1-infected adults: results of a randomized controlled trial. AIDS 1997;11:875–882.
INH is not indicated for all HIV-infected persons.
Hong Kong Chest Service, Tuberculosis Research Centre, Madras, British Medical Research Council. A double-blind, placebo-controlled clinical trial of three anti-tuberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong. Am Rev Respir Dis 1992;145:36.
At 5 years, the rate of active tuberculosis was halved in patients with silicosis receiving chemoprophylaxis with rifampin for 3 months, INH and rifampin for 3 months, or INH for 6 months, compared with those given placebo.
Hsu KHK. Thirty years after isoniazid. JAMA 1984;251:1283.
No control group. Effectiveness of INH prophylaxis was best demonstrated in children infected before age 4 years.
International Union Against Tuberculosis Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: 5 years of follow-up in the IUAT trial. Bull World Health Organ 1982;60:555.
A 24-week regimen of INH was effective.
Israel HL, Gottlieb JE, Maddrey WC. Perspective: preventive isoniazid therapy and the liver. Chest 1992;101:1298.
INH hepatic toxicity is reviewed, and three cases of fatal INH hepatitis are reported.
Jordan TJ, Lewit EM, Reichman LB. Isoniazid preventive therapy for tuberculosis: decision analysis considering ethnicity and gender. Am Rev Respir Dis 1991;144:1357.
Black women over age 50 years are at higher risk for INH hepatotoxicity.
Jordan TJ, et al. Isoniazid as preventive therapy in HIV-infected intravenous drug abusers. JAMA 1991;265:2987.
Analysis supports the use of INH for all HIV-seropositive patients with a history of IV drug use except tuberculin-negative black women who are not anergic.
Livengood JR, et al. Isoniazid-resistant tuberculosis: a community outbreak and report of a rifampin prophylaxis failure. JAMA 1985;253:2847.
Three options are available for the management of contacts of persons with known INH-resistant tuberculosis: (a) INH, (b) rifampin alone or in combination with INH, or (c) no antituberculous therapy and close observation of the patient for development of active disease. A possible case of rifampin prophylaxis failure is presented.
Moreno S, et al. Isoniazid preventive therapy in human immunodeficiency virus-infected persons. Arch Intern Med 1997;157:1729–1734.
INH prophylaxis in HIV-positive patients decreased the incidence of active tuber-culosis and improved overall survival.
Moulding TS, Redeker AG, Kanal GC. Twenty isoniazid-associated deaths in one state. Am Rev Respir Dis 1989;140:700.
INH was used for prevention in 19 cases.
Nazar-Stewart V, Nolan CM. Results of a directly observed intermittent isoniazid preventive therapy program in a shelter for homeless men. Am Rev Respir Dis 1992; 146:57.
In a supervised program, INH could be given safely to the homeless in a dosage of 900 mg twice weekly.
Passannante M, Gallagher CT, Reichman LB. Preventive therapy for multidrug-resistant tuberculosis, MDRTB: a Delphi survey. Chest 1994;106:431–434.
No evidence that multidrug-resistant tuberculosis is more invasive than susceptible strains. Optimal therapy is unknown in this setting.
Salpeter S. Fatal isoniazid-induced hepatitis: its risk during chemoprophylaxis. West J Med 1993;159:560–564.
When liver function tests were monitored, the death rate from INH chemoprophylaxis for those over 35 years was 0.002% (1/43, 334).
Salpeter SR, et al. Monitored isoniazid prophylaxis for low-risk tuberculin reactors older than 35 years of age: a risk-benefit and cost effectiveness analysis. Ann Intern Med 1997;127:1051–1061.
Based on cost decision analysis, INH is indicated for all adults with a positive PPD skin test reaction over 35 years of age if liver function tests are monitored.
Snider DE Jr. Pyridoxine supplementation during isoniazid therapy. Tubercle 1980; 61:191.
Useful in the elderly, alcoholics, and pregnant women to prevent peripheral neuro-pathy.
Snider DE Jr, Caras GJ. Isoniazid-associated hepatitis deaths: a review of available information. Am Rev Respir Dis 1992;145:494.
Deaths reviewed. Women may be at an increased risk for fatal INH-related hepatitis.
Snider DE Jr, Caras GJ, Koplan JP. Preventive therapy with isoniazid: cost effectiveness of different durations of therapy. JAMA 1986;255:1579.
According to a cost effectiveness analysis, a 6-month course of INH had an advantage over a 1-year regimen.
Stead WW. Management of health care workers after inadvertent exposure to tuberculosis: a guide for the use of preventive therapy. Ann Intern Med 1995;122:906–912.
In a heavily exposed health care worker, start INH even if the tuberculin skin test reaction is negative. If the skin test reaction is still negative at 3 months, discontinue INH.
Stead WW, et al. Benefit-risk considerations in preventive treatment for tuberculosis in elderly persons. Ann Intern Med 1987;107:843.
Among the elderly, INH hepatic toxicity developed in 4.4% of persons.
Steiger Z, et al. Pulmonary tuberculosis after gastric resection. Am J Surg 1976; 131:668.
Tuberculosis is likely to be reactivated following a gastrectomy in patients with chest roentgenographic evidence of inactive tuberculosis who have not been previously treated.
Taylor WC, Aronson MD, Delbanco TL. Should young adults with a positive tuberculin test take isoniazid? Ann Intern Med 1981;94:808.
Study does not support the use of INH for those under age 35 years with no other risk factors.
Tsevat J, et al. Isoniazid for the tuberculin reactor: take it or leave it. Am Rev Respir Dis 1988;137:215.
Based on decision analysis, this study suggests that INH prophylaxis provides minimal benefit to the person under age 35 years with a positive tuberculin test, normal chest roentgenographic findings, and no risk factors.
Whalen CC, et al. A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. N Engl J Med 1997;337:801–808.
A 6-month course of INH in PPD-positive, HIV-infected adults was effective in reducing the risk for active tuberculosis. Also effective in reducing the risk for tuberculosis were INH and rifampin for 3 months and INH, rifampin, and pyrazinamide for 3 months.

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