HIV/AIDS EDITORIAL COMMENTARY

Rifampin and Pyrazinamide for Latent Tuberculosis Infection: Clinical Trials and General Practice

Jussi Saukkonen Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts

(See the article by Gordin et al. on pages 561–5)

As the prevalence of active tuberculosis broad inclusion criteria; it enrolled sub- ommendations that limited RZ prescrip- decreases in the United States, the focus stantial numbers of injection drug users tion for treatment of LTBI. These rec- on treatment of latent tuberculous infec- who might have increased risks for hep- ommendations included provision of no tion (LTBI) has intensified. However, the atotoxicity, as well as individuals with more than 2-week supplies of RZ per visit, standard 6–9-month course of isoniazid baseline transaminase levels of up to 5 exclusion of patients with liver disease or has been burdened with suboptimal rates times the upper limit of normal. This history of significant isoniazid hepatotox- of therapy completion and concerns about study also reported equal efficacy for both icity, intensified monitoring of liver en- hepatotoxicity and infection with isonia- LTBI treatment regimens in HIV-infected zyme levels, and cautious use of RZ for zid-resistant organisms. These issues have individuals. Subsequently, RZ was rec- persons who were taking concomitant spurred interest in alternative, shorter reg- ommended for treatment of LTBI in HIV- hepatotoxic agents [7–9]. imens [1]. infected individuals, and the recommen- A retrospective surveillance study of pa- One of these LTBI regimens, a 2-month dation was extended to HIV-uninfected tients treated with 2-month courses of RZ course of rifampin with pyrazinamide individuals as an acceptable alternative was launched in response to these events. (RZ), has achieved considerable contro- regimen for isoniazid [1]. The study found hospitalization and mor- versy because of serious concerns about The ensuing experience with RZ in the tality rates of 3 hospitalizations and 0.9 its safety. Initially, randomized studies in- HIV-uninfected population raised serious deaths per 1000 treatment initiations [9]. volving HIV-infected individualsindicated concerns regarding the hepatotoxicity of These numbers are considerably higher that the regimen was safe, with no signif- the regimen. Jasmer et al. [5] found that than recent hospitalization and death rates individuals treated with a 2-month course for isoniazid of 0.1–0.2 hospitalizations icant differences in hepatotoxicity, com- of RZ developed significantly more ele- and 0–0.3 deaths per 1000 treated [9]. pared with a 6-month course of isoniazid vations in the alanine aminotransferase Eleven deaths were reported among pa- [2, 3]. Gordin et al. [4] found that hep- (ALT) level of grade III or higher (i.e., an tients treated with 2 months of RZ, in- atotoxicity that was potentially life-threat- ALT level of у250 U/L), compared with cluding the deaths of 2 HIV-infected in- ening or led to treatment discontinuation patients who were treated with a 6-months dividuals. Recommendations were revised was less common among patients treated course of isoniazid, and RZ recipients were to stipulate that RZ generally not be of- with RZ than among those treated with not more likely to complete the regimen. fered to patients for treatment of LTBI 12 months of isoniazid. This study had A nonrandomized trial reported signifi- and certainly not to individuals with un- cantly more elevations in the aspartate derlying liver disease or injury or who Received 28 April 2004; accepted 29 April 2004; у electronically published 30 July 2004. aminotransferase (AST) level of 160 U/ regularly ingest hepatotoxic agents. Mon- Reprints or correspondence: Dr. Jussi Saukkonen, L in patients who were treated with a 2- itoring of transaminase levels was recom- Pulmonary Center, Boston University School of Medicine, 80 month course of RZ [6]. There were case mended at 2-week intervals for persons E. Concord St., R-304, Boston, MA 02118 (jsaukkonen@ lung.bumc.bu.edu). reports to the Centers for Disease Control prescribed RZ for treatment of LTBI. Clinical Infectious Diseases 2004;39:566–8 and Prevention that eventually totaled 48 These recommendations were applied 2004 by the Infectious Diseases Society of America. All rights reserved. fatalities and hospitalizations associated equally to HIV-infected and HIV-unin- 1058-4838/2004/3904-0023$15.00 with RZ, which prompted revised rec- fected individuals [9], although the clinical

566 • CID 2004:39 (15 August) • HIV/AIDS trial experience suggested that the rate of differs from larger groups potentially eli- HIV-uninfected individuals [5, 6] is within RZ-associated hepatotoxicity was not sig- gible for the treatment studied. Further- the range that has been reported for treat- nificantly greater than the rate of isonia- more, particularly for interpreting serious ment of TB with multiple-drug regimens zid-associated hepatotoxicity for HIV- adverse events, it is important to consider [16–22]. More striking is the severity of infected individuals. how general clinical practice may differ hepatotoxicity, with resulting death and In this issue, Gordin et al. [10] provide from that under study conditions. Cofac- hospitalizations in both HIV-infected and additional data on hepatotoxicity from tors that may contribute to liver injury, HIV-uninfected individuals, associated their initial treatment trial comparing iso- such as preexisting liver disease, concom- with RZ in general clinical use, but not in niazid and RZ for treatment of LTBI in itant medications being used, alcohol clinical trials [2–6, 10]. In relation to iso- HIV-infected individuals. Their first re- consumption, and the coincidental oc- niazid for treatment of LTBI, RZ is more port was limited to the occurrence of currence of viral hepatitis, are not always hepatotoxic in the HIV-uninfected pop- life-threatening and treatment-limiting available to aid in the interpretation of ulation, but in clinical trials of HIV- hepatotoxicity, whereas the new report clinical trials. In general clinical practice, infected individuals, this does not appear provides objective data in the form of in- these hepatotoxicity cofactors may be to be the case. formation on grade III or higher eleva- more widespread and less appreciated. Given these aggregate findings, it seems tions in the AST level, as well as other The cause of the evident disparity in the prudent to restrict use of RZ for treatment measurements of hepatotoxicity. This new rates of clinically significant hepatotoxicity of LTBI to very specific instances in which data also allows for better comparisons in HIV-infected and HIV-uninfected in- the use of isoniazid is not feasible; the risks with other studies done in the field. Grade dividuals remains unclear. The pathogen- can be minimized and are not expected to III elevations of AST levels were no more esis of RZ-associated hepatotoxicity is not exceed the benefit of the treatment [10]. common in the RZ group than in the iso- understood, but one may speculate that Rifampin, with or without isoniazid, for niazid group, nor were other measure- immune-mediated injury could be atten- 4 months constitutes an often-used alter- ments of hepatotoxicity. Multiple regres- uated in persons with HIV infection, even native regimen [1]. A three-month regi- sion analysis showed that increases in the in the face of moderately high CD4 cell men of once-weekly isoniazid and rifa- AST level of у40 U/L were associated with counts [11], or with reduced bioavail- pentine is currently under investigation by older age, which was also previously iden- ability in patients with AIDS [12] might the TB Trials Consortium to determine tified as a risk factor for hepatotoxicity in be responsible. Some have hypothesized safety and efficacy for treatment of LTBI. the HIV-uninfected population [5]. The that RZ-associated high-grade hepatotox- There is clearly a need for shorter, safe, authors compare hepatotoxicity rates re- icity is more common when RZ is pre- and effective regimens for LTBI that can be used with relative ease in the general ported in studies of HIV-infected and scribed as treatment for LTBI, in contrast population. HIV-uninfected individuals and find sub- to that seen with RZ when prescribed as stantially higher rates among the latter. part of 4-drug therapy for active TB. This They conclude that, although 2-month might be related to relative immunodefi- Acknowledgment regimens of RZ are unsafe for general use ciency [13], although it is not clear that in the HIV-uninfected population, their such defects are relevant. Some have sug- Conflict of interest. J.S.: No conflict. data support use of this regimen for HIV- gested that isoniazid may exert a protec- infected individuals who are not likely to tive effect when given with RZ, perhaps References complete a longer regimen [10]. However, through decreased bioavailability of rif- 2 of the deaths associated with RZ therapy ampin [14]. However, the major offending 1. Center for Disease Control and American involved HIV-infected individuals. The agent has been believed to be pyrazin- Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. authors recommend adherence to the amide [5]. Rifampin has been implicated American Thoracic Society. MMWR Recomm most current updated recommendations in increasing the likelihood of liver injury Rep 2000; 49:1–51. regarding RZ, for use only under very spe- when used in combination with isoniazid 2. Halsey NA, Coberly JS, Desormeaux J, et al. Randomised trial of isoniazid versus rifam- cific conditions. or other antituberculous agents [15]. picin and pyrazinamide for prevention of tu- Several issues gnaw in the recent history Whether this is, in fact, the case with RZ berculosis in HIV-1 infection. Lancet 1998; of 2-month courses of RZ for treatment is unclear. Overall, it is difficult to precisely 351:786–92. 3. Mwinga A, Hosp M, Godfrey-Faussett P, et al. of LTBI. A common dilemma in inter- determine graded hepatotoxicities seen in Twice weekly tuberculosis preventive therapy preting the results of clinical trials is how active TB treatment trials, because such in HIV infection in Zambia. AIDS 1998; 12: far to generalize the findings of a study. data have often been vaguely reported or 2447–57. 4. Gordin F, Chaisson RE, Matts JP, et al. Rif- In making such an assessment, consider- include low-grade hepatotoxicity. Hepa- ampin and pyrazinamide vs. isoniazid for pre- ation is given to how a study population totoxicity of grade III or higher seen in vention of tuberculosis in HIV-infected per-

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