Important note: Information in this article was accurate in January 2002. The state of the art may have changed since the publication date.
Treatment of Active Tuberculosis
At the Tuberculosis Workshop that preceded the IDSA meeting, Philip Hopewell, M.D., of the University of California, San Francisco discussed the revised tuberculosis treatment guidelines of the American Thoracic Society, Centers for Disease Control and Prevention, and the IDSA. The most recent treatment guidelines were published in 1994; the revised guidelines should be published in 2002. Some of the likely changes in the revised guidelines are discussed below.
The fundamental principals of the treatment of tuberculosis include the following:
The committee reviewed the literature regarding treatment of culture-positive pulmonary TB. They distinguished between HIV-negative and HIV-positive patients only because of differences in the quality of studies performed in these patients. There were no A1 guidelines (preferred and should be offered, based on at least one properly randomized trial with clinical endpoints) for HIV-infected patients because randomized trials of treatment have not been conducted. The regimen for HIV-infected adults that received an A2 rating (preferred and should be offered, based on data from clinical trials that were either not randomized, were conducted in other populations, or were based on data from uncontrolled trials) was two months of daily isoniazid, rifampin, pyrazinamide, and ethambutol followed by four months of daily or twice-weekly isoniazid plus rifampin. It is likely that the revised guidelines will recommend that the 4 month continuation phase of treatment be extended to 7 months if the initial chest x-ray shows cavities or if the sputum is culture positive after two months of treatment. This is based on data from U.S. Public Health Service Study 22 [Vernon A, et al., Am Resp J Crit Care Med 2000;161(3 part 2):A252].
Treatment of Latent Tuberculosis Infection
There were abstracts from several small studies evaluating the tolerability of the 2 month regimen of rifampin plus pyrazinamide for the treatment of latent tuberculosis infection. These studies are timely given the revised guidelines based on concerns about hepatotoxicity, including 6 deaths, as summarized in recent reports in MMWR [MMWR April 20, 2001 / Vol. 50 / No. 15:289-91; MMWR August 31, 2001 / Vol. 50 / No. 34;733-5]. Of note, the risk of death due to hepatoxicity associated with rifampin plus pyrazinamide is unknown because the number of persons receiving this regimen is unknown.
Jo Hoffmann and colleagues, from the Snohomish Health District in Everett, Washington, reported on 29 patients who initiated therapy with rifampin plus pyrazinamide [Abstract 340]. Of these 29, 26 completed a course of therapy (20 completed therapy without an adverse event, and 6 had adverse events but still completed therapy). Of these 6 adverse events, two were GI intolerance and four were hepatitis. Of the 4 patients who developed hepatitis, 2 completed treatment with rifampin/pyrazinamide, and 2 completed treatment with isoniazid. Of the 29 patients started on rifampin/pyrazinamide, 6 (21%) developed symptomatic hepatitis. None of these patients had predisposing factors for liver toxicity. The onset of hepatitis occurred 21-69 days after initiation of therapy. There were no hospitalizations or deaths, and transaminase elevations resolved within one to three weeks of discontinuation of therapy.
MD King from Emory University in Atlanta reported results of a randomized trial of two months of rifampin/pyrazinamide (2RZ) vs. six months of isoniazid (INH) for the treatment of latent TB infection in HIV-negative persons [Abstract 341]. These data represent a subset of a multi-center study (preliminary data presented previously by Jasmer and colleagues [Am J Resp Crit Care Med 2000;161:A524]). There were 115 patients enrolled in the study; 60 in the 2RZ arm and 55 in the INH arm. In a multivariate analysis controlling for age and sex, completion rates were higher in patients receiving 2RZ (33/60, 55%) than in the INH arm (18/55, 33%) (RR 2.68, 95% CI 1.21-5.92). Among patients with a follow-up liver transaminase determination, the risk of hepatitis (defined as AST >50) did not differ between the 2RZ (4/33, 12%) and the INH group (3/31, 10%). Data on drug discontinuation due to hepatitis were not presented. Drug discontinuation due to any adverse drug reaction occurred in 5/37 (14%) patients receiving 2RZ vs. 3/31 (10%) receiving INH.
A third study was presented by Cook from North Carolina [Abstract 342]. In this prospective non-randomized trial, 92 patients received 2RZ and 90 received INH. Hepatotoxicity (defined as transaminase elevation at least 4 times baseline level) occurred in 13/92 (14%) patients in the 2RZ arm vs. 4/90 (4%) in the INH arm (p <0.05); 64 of 92 (70%) patients receiving 2RZ completed therapy compared to 48 of 90 (53%) receiving INH. Data on drug discontinuation due to hepatotoxicity were not reported.
In summary, these three small studies suggest that compared to isoniazid, the regimen of rifampin plus pyrazinamide is associated with higher rates of both completion of therapy and hepatitis. However, data on the important comparison of rates of drug discontinuation due to hepatoxicity were not provided. Of note, no deaths due to hepatitis were reported in these three studies.
In an abstract by S. Blower, et al. [Abstract 321], a stochastic model of the effect of HIV on tuberculosis outbreaks was presented. This model demonstrated that an HIV epidemic can significantly increase the frequency and severity of tuberculosis outbreaks, but that the amplification effect of HIV on tuberculosis outbreaks is extremely sensitive to tuberculosis treatment rate. At moderate or low treatment rates (at the population level), even a fairly small HIV epidemic will cause the average size of tuberculosis outbreaks to double in comparison with what would be expected when HIV is absent from the population. However, the amplification effect of HIV can be substantially decreased if the treatment rate of tuberculosis is high. Their model also demonstrated that occasionally a strain of M. tuberculosis that is not highly virulent can generate a large outbreak. This suggests that large outbreaks can occur even with effective TB control, declining TB incidence rates, and low HIV prevalence. Such outbreaks occur due to chance.
In a study from Uganda and Case Western Reserve University, Jones et al. [Abstract 344] presented results of a study of immunoadjuvant therapy with prednisolone for HIV-associated tuberculosis. In this study, conducted between November 1998 and August 2000, 187 HIV- infected, smear-positive pulmonary TB cases with >200 CD4 cells/mm3 were randomized to receive 2.5 mg/kg of prednisolone or placebo for four weeks followed by a four week taper phase. All patients received short-course TB treatment (INH, rifampin, pyrazinamide, ethambutol for two months followed by INH plus rifampin for four months). At baseline, both treatment groups were similar in terms of age, CD4 count (mean >400 cells/mm3), HIV viral load, and severity of TB disease. At the completion of treatment there were no differences in CD4 count, viral load, or markers of immune activation. Adverse event rates did not differ between the two groups. Thus the intervention with prednisolone appeared to be safe, but the lack of beneficial effect on treatment outcome, led the authors to recommend that corticosteroids not be given to HIV- infected patients with pulmonary TB.
Other Issues in Tuberculosis and Nontuberculous Mycobacterial Infections
In a paper by Garder TJ and colleagues [Abstract 318] a follow-up report of a previously described outbreak among gay white HIV-positive men in Houston who "bar hop" was presented. In the current study, 1,806 individuals had culture-confirmed tuberculosis between October 1995 and December 2000; the patients in the original cohort (October 1, 1995 through May 31, 1997) were compared to a second cohort (June 1, 1997 through December 31, 2000). Each patient underwent an interview and had DNA fingerprinting performed on his M. tuberculosis isolate. A total of 68 patients had the outbreak strain, 45 of whom were identified during the second cohort period. Both cohorts were white gay men who were HIV positive and "bar hopped." There was substantial illicit drug use reported among both cohorts. The results of this study demonstrate that this M. tuberculosis isolate is still primarily found and transmitted among the social network of HIV-infected gay white men who frequent bars in Houston. Some dissemination beyond this social network occurred, but it was only to a very limited degree.
Two abstracts reported pseudo-outbreaks of M. fortuitum in hospitalized HIV-infected individuals [Gebo, KA, et al.; Abstract 201; Dunaway S, et al.; Abstract 202]. In the first report, 53 HIV-infected patients hospitalized at the Johns Hopkins hospital inpatient HIV unit had induced-sputum specimens positive for M. fortuitum. These patients were not thought to have clinical disease with M. fortuitum. Contamination of water sources, including an ice machine, was suspected. M. fortuitum was recovered from two samples of ice and four samples of water. The ice machine was disconnected and cleaned, and no further episodes of colonization or contamination were identified. Genotyping by pulsed field gel electrophoresis (PFGE) confirmed that the isolates from all 53 patients and the ice were identical. Only one of the 53 patients (2%) may have been infected with M. fortuitum. This patient was treated with ciprofloxacin and clarithromycin. All of the other patients were considered to be colonized and were not treated. In the second report, 30 patients from another inpatient HIV unit had cultures positive for M. fortuitum. A retrospective review revealed nine additional positive cultures. Of the 39 positive cultures, 33 were from sputum and six were from stool; all cultures were thought to represent colonization. None of the patients were thought to have clinical disease due to M. fortuitum. Environmental cultures of the airflow units and multiple water faucets in the unit were negative for M. fortuitum. However, the ice machine on the unit was heavily contaminated with M. fortuitum. PFGE linked the positive cultures from the patients and the ice machine. Once the ice machine was removed, no further positive culture results were obtained. Of note, attempts to eradicate the organism from the ice machine using a detergent containing phosphoric acid were unsuccessful. Both of the above reports illustrate the potential for ice machines to be a source of M. fortuitum, which could lead to the inappropriate diagnosis and treatment of patients for presumed M. fortuitum disease. Eradication of this organism from these machines can be difficult.
There will likely be a change in TB treatment guidelines next year that recommends that the duration of TB therapy should be extended among persons at high risk for TB relapse (regardless of HIV status). More data are still needed on the tolerability of a 2-month course of rifampin plus pyrazinamide for the treatment of latent TB infection; data presented at this meeting suggest that compared to standard isoniazid, this regimen is associated with higher rates of completion of therapy, but also hepatitis.
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