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Recurrent Tuberculosis in the United States and Canada

Relapse or Reinfection?

Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, and the Department of Medicine, University of California, San Francisco, California; Centers for Disease Control and Prevention, Atlanta, Georgia; University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas; Boston University School of Medicine, Boston, Massachusetts; Montreal Chest Institute and McGill University, Montreal, Canada; and Denver Public Health Department, Denver, Colorado

Correspondence and requests for reprints should be addressed to Robert M. Jasmer, M.D., Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, Room 5K-1, 1001 Potrero Avenue, San Francisco, CA 94110. E-mail: rjasmer{at}itsa.ucsf.edu

	ABSTRACT

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Recurrence of active tuberculosis after treatment can be due to relapse of infection with the same strain or reinfection with a new strain of Mycobacterium tuberculosis. The proportion of recurrent tuberculosis cases caused by reinfection has varied widely in previous studies. We evaluated cases of recurrent tuberculosis in two prospective clinical trials: a randomized study of two regimens for the last 4 months of treatment (n = 1,075) and a study of a twice-weekly rifabutin-containing regimen for human immunodeficiency virus–infected tuberculosis (n = 169). Isolates at diagnosis and from positive cultures after treatment completion underwent genotyping using IS6110 (with secondary genotyping for isolates with less than six copies of IS6110). Of 85 patients having a positive culture after completing treatment, 6 (7.1%) were classified as false-positive cultures by a review committee blinded to treatment assignment. Of the remaining 75 cases with recurrent tuberculosis and genotyping data available, 72 (96%; 95% confidence interval, 88.8–99.2%) paired isolates had the same genotype; only 3 (4%; 95% confidence interval, 0.8–11.2%) had a different genotype and were categorized as reinfection. We conclude that recurrent tuberculosis in the United States and Canada, countries with low rates of tuberculosis, is rarely due to reinfection with a new strain of M. tuberculosis.

Key Words: DNA fingerprinting • pulmonary tuberculosis • reinfection • relapse

Active tuberculosis recurs in 2 to 7% of patients with drug-susceptible isolates treated with contemporary short-course chemotherapy (1–3). With DNA fingerprinting, cases of recurrent tuberculosis can be categorized as being due to relapse of the original infecting strain or reinfection with a new strain of Mycobacterium tuberculosis. Although reinfection clearly occurs (4), the proportion of recurrent cases caused by reinfection has varied widely in previous studies (5–11). Factors that appear to affect the rate of recurrence are the rate of exposure to new strains of M. tuberculosis (the prevalence of active tuberculosis in the community) and the presence of a condition that increases the likelihood of progression to active disease after exposure to new strains (most commonly, advanced human immunodeficiency virus [HIV] disease). However, the small number of cases evaluated in previous studies limits the strength of these tentative conclusions about the pathogenesis of recurrent tuberculosis.

False-positive cultures caused by laboratory cross-contamination can also be identified by genotyping and are indicated by a subsequent nonmatching genotype that matches that of another isolate processed in the laboratory during a similar period of time (12–14). Therefore, genotyping, in combination with a review of clinical and radiographic data, allows an estimation of the incidence of relapse, reinfection, and laboratory cross-contamination. The results of two clinical studies conducted by the Tuberculosis Trials Consortium (TBTC) provide a large number of cases of recurrent tuberculosis for such an evaluation. Some of the results of this study have been previously reported in abstract form (15).

	METHODS

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Studies Included
We included patients treated in two prospective clinical trials in which treatment was given under direct observation. The TBTC study 22 enrolled adults with drug-susceptible pulmonary tuberculosis who had completed 2 months of standard four-drug therapy (16–17). Participants were then randomly allocated to receive treatment with either rifapentine and isoniazid once a week or rifampin and isoniazid twice per week to complete 6 months of therapy. Sputum cultures were obtained every 4 weeks during treatment and 3, 6, 9, 12, 18, and 24 months after treatment, as well as at the time of any symptoms of recurrent tuberculosis. Study 22 enrolled patients from 1995 to 1999, and the last follow-up for recurrent tuberculosis was completed in 2001. All patients in TBTC study 22 had HIV testing done, and 1,004 of 1,075 (93%) were HIV negative.

TBTC study 23 was a study of patients who were HIV infected with tuberculosis treated with isoniazid, rifabutin, ethambutol, and pyrazinamide for the first 2 months then with rifabutin and isoniazid twice weekly for at least 4 months (with 3 additional months for patients with a positive culture or a lack of a favorable clinical response after 2 months of treatment) (18). Sputum cultures were obtained monthly during treatment and 1.5, 3, 6, 12, 18, and 24 months after treatment completion and at the time of clinical evidence of recurrent tuberculosis. Patients in study 23 were enrolled between 1998 and 2002 and completed follow-up for recurrent tuberculosis in 2004.

Genotyping
Initial isolates of M. tuberculosis and from any cultures positive at or after 4 months of therapy underwent genotyping by IS6110-based restriction fragment length polymorphism analysis using the internationally standardized method (19). Isolates that had indistinguishable IS6110 restriction fragment length polymorphism patterns comprised of more than five hybridizing bands were considered as matched; those containing five or fewer hybridizing bands underwent secondary typing at the Veterans Administration Mycobacteriology Research Laboratory in Little Rock, Arkansas, using polymorphic guanine-cytosine–rich sequence–based restriction fragment length polymorphism analysis with the recombinant plasmid pTBN12. Isolates having fewer than five IS6110 bands were considered as matched if both the IS6110 and polymorphic guanine-cytosine–rich sequence genotypes were indistinguishable (20). Isolates from patients in TBTC study 23 underwent secondary genotyping using mycobacterial interspersed repeat units or spoligotyping (21).

Definitions and Data Analysis
The primary analysis dealt with positive cultures after completion of tuberculosis treatment. Laboratory cross-contamination was defined as the occurrence of a single positive culture in a patient who had converted to culture negative, whose subsequent genotype did not match that of the original isolate and who lacked any clinical or radiographic evidence of recurrent tuberculosis. Relapse was defined as the occurrence of a positive culture after both documented culture conversion and treatment completion in a patient with symptoms of recurrent tuberculosis, whose original and subsequent isolates had matching genotypes. Reinfection was defined as the occurrence of nonmatching genotypes of original and subsequent isolates in patients with a clinical course consistent with failure or relapse.

We also evaluated positive cultures that occurred at or after the fourth month but before treatment completion. Treatment failure was defined as the occurrence of a positive culture for M. tuberculosis after at least 4 months of treatment, in which the original and subsequent isolates had matching genotypes and when symptoms/signs consistent with unresponsive or recrudescent tuberculosis were present.

All cases were reviewed and classified by a clinical events committee that had access to clinical information and the results of genotyping but were blind to treatment assignment.

We calculated rates of relapse and reinfection as the number of cases per 100 patient-years of follow-up. Calculation of patient-years began at treatment completion and ended at the first of the following: relapse date or date of censoring or 2 years. Patients were censored at either the date of death or date of last study evaluation before move/loss to follow-up.

	RESULTS

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The two studies enrolled a total of 1,244 patients (1,075 in study 22 and 169 in study 23) who had culture-positive tuberculosis. Eighty-six percent of patients were followed for at least 12 months after treatment, and 78% were followed for 24 months. The vast majority, 1,142 (91.8%) had negative follow-up cultures without clinical evidence of treatment failure or relapse (Figure 1). Ninety-four patients had a positive culture after at least 4 months of treatment or during follow-up, 13 of whom met the criteria for treatment failure. Clinical and demographic characteristics of these 94 patients are described in Table 1. Six patients had positive cultures caused by laboratory cross-contamination (Figure 1 and Table 2), and two had recurrent tuberculosis with cultures that were negative or not obtainable.

View larger version (25K): [in this window] [in a new window]   Figure 1. Genotypic classification of culture-positive events. The figure shows the classification of patients in the study. Ninety-four patients had a positive culture after 4 months of treatment or during follow-up that was not due to laboratory cross-contamination. Of these, 15 were due to treatment failure, and 79 occurred after treatment had ended. Of these 79, 72 were classified as relapses, and 3 were classified as reinfections (see text for details). TB = tuberculosis.

An analysis of recurrent tuberculosis by time of occurrence after conclusion of treatment showed that for patients who were HIV negative over two-thirds of relapses (69.0%) occurred within 6 months of the conclusion of treatment, and the vast majority (89.7%) occurred within 12 months (Figure 2). For patients who were HIV positive, 78.6% of relapses occurred within 6 months of the conclusion of treatment. The occurrence of reinfection in either patients who were HIV negative or HIV infected did not follow a predictable time course (Figure 2).

View larger version (34K): [in this window] [in a new window]   Figure 2. Occurrence of recurrent tuberculosis by time after conclusion of therapy. Each histogram displays the number of patients who had relapse or reinfection in relation to the number of months after the conclusion of therapy. The upper histogram shows results for patients without human immunodeficiency virus (HIV) infection. The bottom histogram shows results for HIV-infected patients. In both groups of patients, the vast majority of relapses occurred within 12 months after treatment had ended.

	DISCUSSION

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In two tuberculosis treatment trials performed from 1995 to 2004 in the United States and Canada, nearly all cases of recurrent tuberculosis (96%) were due to relapse of the original infecting strain. The finding that nearly all recurrences were due to relapse was also true for the 240 patients who were HIV infected in the studies (93% of recurrences were relapse). To our knowledge, this is the largest study to date of recurrent tuberculosis, including 75 patients with paired isolates for which genotyping was performed. Another critical use of M. tuberculosis genotyping in clinical trials is to help detect false-positive cultures caused by laboratory cross-contamination. Without this tool, almost 6% of positive cultures after the completion of therapy in these studies might have been erroneously classified as recurrent tuberculosis.

As previously reported, independent risk factors for treatment failure or relapse among the patients who were HIV negative in TBTC study 22 (assessing the role of rifapentine in the continuation phase of treatment of tuberculosis) were sputum culture positive at 2 months of treatment, cavitation on chest radiograph, bilateral pulmonary involvement on chest radiograph, being underweight, and being a non-Hispanic white person (16). Only one patient who was HIV negative had relapse with acquired resistance to rifampin. Relapse with acquired monoresistance to rifamycin was increased in patients who were HIV negative in study 22 who received once-weekly rifapentine/isoniazid and in those who were younger, had a lower baseline CD-4 cell count, had extrapulmonary involvement, and received concomitant therapy with antifungal agents (17). For patients in TBTC study 23 (assessing the role of intermittent rifabutin in the treatment of tuberculosis in HIV-infected persons), low CD-4 cell count and use of twice weekly therapy during the first 2 months of tuberculosis treatment were independently associated with rifamycin-resistant treatment failure or relapse (18).

Patients enrolled in TBTC clinical trials have demographic and clinical characteristics that are very similar to those of all reported cases of active tuberculosis in the United States (data not shown), suggesting that the results of our analysis should be representative of recurrent tuberculosis in the United States and Canada. Because the case rates of active tuberculosis in the United States and Canada are low (< 6 per 100,000 per year) (22–24), the probability of both coming into contact with another tuberculosis strain and developing disease with that strain (i.e., reinfection) must be much lower than the probability of treatment failure or relapse with the same strain of M. tuberculosis. The rate of recurrent tuberculosis caused by reinfection we found was relatively high, likely reflecting patient's epidemiologic characteristics, which place them at increased risk of repeat exposure to tuberculosis followed by progression to clinical disease. However, because the number of reinfection cases was low, confidence intervals of the estimated rates are quite wide.

Rates of relapse and reinfection were comparable among patients who were HIV positive and HIV negative in our study. Whether the duration of treatment for HIV-related tuberculosis should be longer than that for patients who are HIV negative remains controversial. One large randomized trial showed lower rates of recurrent tuberculosis among patients who were HIV negative receiving prolonged therapy (12 months) but did not distinguish between relapse and reinfection (25); a second smaller study showed similar results from 6 and 9 months of treatment for HIV-related tuberculosis (26). Several cohort studies in which patients were treated with a standard, directly observed 6-month regimen showed comparable results among patients who were HIV positive and HIV negative (27, 28). Other cohorts have shown somewhat higher rates of recurrent tuberculosis, particularly among patients with advanced HIV disease (29, 30). The one cohort study that was able to distinguish relapse from reinfection showed that the increased rate of recurrent tuberculosis among HIV-infected gold miners was entirely due to an increased risk of reinfection (7). Clearly, additional studies are necessary to determine the optimal duration of therapy for HIV-related tuberculosis.

Studies from other areas of the world have shown that reinfection becomes an increasingly common cause of recurrent tuberculosis as tuberculosis case rates increase. In low- to moderate-incidence countries (i.e., tuberculosis case rates < 50 per 100,000), studies have found the percentage of reinfection ranging from 10% in Switzerland to 16% in Italy and 33% in Spain (11, 31, 32). In studies of high-burden countries (i.e., > 200 cases per 100,000 persons per year), reinfection was common, ranging from 23% in Uganda to 60% in a township in Cape Town, South Africa, having a remarkably high rate of tuberculosis (> 1,000 per 100,000 persons per year) (5, 6). Results of these studies suggest that reinfection occurs more often in high-incidence countries because of more frequent exposure to M. tuberculosis.

The frequency of HIV infection, an illness that accelerates progression from initial infection with tuberculosis to disease, also increased the risk of reinfection among persons working in gold mines of South Africa (7). Rates of reinfection were not significantly higher among the HIV-infected persons in our studies, probably because of the very low risk of re-exposure to infectious tuberculosis. In addition, most patients (> 80%) in TBTC study 23 were treated with potent antiretroviral therapy, and the resultant improvement in immune function may have further decreased the risk of recurrent disease, if reinfected.

The rate of laboratory cross-contamination in our study is similar to the rates in previous studies of M. tuberculosis cultures and was roughly twice as frequent as reinfection. Most population-based studies have found rates of 0.9 to 3.5% (12–14, 33–35). However, almost all of the cross-contamination events in these studies have been detected in initial isolates rather than in follow-up isolates of patients known to have tuberculosis. In our study, because of the requirement that patients have a previously positive culture, all of the cross-contamination events occurred in follow-up specimens. Clinicians should be cognizant that not all subsequently positive cultures in a patient previously or currently on tuberculosis treatment indicate treatment failure or relapse, and appropriate evaluation, including radiographic and clinical examinations, collection of additional sputum specimens, and genotyping, should be considered to distinguish among treatment failure/relapse, laboratory cross-contamination, and reinfection.

Our study has several limitations. First, it is a study of patients enrolled into two clinical trials from multiple sites, not a cohort of patients from a specific geographic area. It is possible that selection biases associated with enrollment into a clinical trial affected the risk of relapse versus reinfection. The period of follow-up after treatment completion in the two studies was 2 years, and the proportion of cases caused by reinfection may be higher among the unusual cases of recurrent tuberculosis occurring more than 2 years after treatment completion. Because two of the treatment regimens used (once-weekly rifapentine plus isoniazid and twice-weekly rifabutin and isoniazid) are not standard, the somewhat decreased potency of these regimens may have resulted in a modest overestimation of the proportion of cases caused by relapse. Finally, we did not make any attempt to detect infection with more than one strain of M. tuberculosis, either at the time of initial diagnosis or at the time of recurrent disease. Mixed infection could result in misclassification that recurrent tuberculosis was due to reinfection if a strain not detected initially was then the dominant strain at the time of recurrence. However, given the very small number of nonmatching genotypes in subsequent isolates, this possibility would not affect the conclusion that reinfection is rare in the United States and Canada.

In summary, this study shows that in addition to clinical and radiographic exam genotyping is an extremely useful technique to distinguish treatment failure or relapse from reinfection or laboratory cross-contamination in patients with tuberculosis with recurrently positive cultures. In patients from low-incidence regions such as most parts of North America, the vast majority (96%) of such cultures are due to treatment failure or relapse rather than reinfection.

	Acknowledgments

 
The authors acknowledge the efforts of Andrew Vernon for his thoughtful assistance in preparing this study and Charles Woodley, Suzanne Brim, David Temporado, Lois Diem, Sean Toney, David Sikes, Zhenhua Yang, and Zhen Yao for their expertise in genotyping.

Participating clinical sites (principal investigators and study coordinators) for TBTC Studies 22 and/or 23 were: Los Angeles County/University of Southern California Medical Center (Brenda Jones, Claudia Silva), University of California San Diego Medical Center (Antonino Catanzaro, Muppy Haigler, Sue Ann DiProfio Peach Francisco Philip Lobue, Diane Havlir), Emory University School of Medicine (C. Robert Horsburgh, Ben Barnett, Naomi Bock, Sue Ann Brenner, Edith Woodward-Aaron, Carlos Franco-Paredes), University of North Texas Health Science Center (Stephen Weis, Barbara King, Norma Shaffer, Lee Turk, Wanda Woods), Houston VA Medical Center (Christopher Lahart, Ruby Nickson, Terry Scott, Robert Awe), Maricopa Medical Center Research Foundation (Maricela Moffitt, Debra Smith, Wendi Attwood), Audie L. Murphy VA Hospital, San Antonio (Marc Weiner, Melissa Engle, Dorothy Phillips, Alma Quintero, David Leos, Karen Eley), Johns Hopkins University School of Medicine (Richard Chaisson, Tim Sterling, Kristina Moore, Walt Jones, Judith Hackman), Carolinas Medical Center (James Horton, Beth Quinn, Ann Boye), Nashville VA Medical Center (Douglas Kernodle, Anthony Chapdelaine, Guat-Siew McKee, Linda Reeves-Hammock), New Jersey Medical School National TB Center-University of Medicine & Dentistry of New Jersey (Lee B. Reichman, Bonita T. Mangura, Marilyn Owens, Cora Leus, Saundra Barnes, Marilyn Owens), Bellevue Hospital Center, New York University (Neil Schluger, William Rom, Rany Condos, Laurie Sandman), University of California at San Francisco Medical Center (Charles Daley, Llewellyn Stanton), University of British Columbia Health Center (Mark Fitzgerald, Eduardo Hernandez, Banafsheh Peyvandi), Harlem Hospital Center (Wafaa El-Sadr, Frantz Medard, Mary Klein, Waref Azmeh, Sandra Barnaby), Denver Health and Hospitals (Randall Reves, William Burman, Jan Tapy), McClellan VA Hospital, Little Rock (Rebecca Edge Martin, Katherine Hayden), Chicago VA Medical Center-Westside (David Pitrak, Mary Jo Werhane, Marilyn Szenkendi), Chicago VA Medical Center-Lakeside (Mondira Bhattacharya, Julie Fabre), University of Manitoba (Earl Hershfield, Gerry Izon), VA Greater Los Angeles Healthcare System (Matthew Goetz, Felicitas Lorenzo), San Francisco VA Medical Center (Peter Jensen, Llewellyn Stanton), Columbia University College of Physicians and Surgeons and the New York City Department of Health (Neil Schluger, Joseph Burzinski, Sonal Munsiff, Vilma Lozano), Hines VA Medical Center and Suburban Cook County TB District, Illinois (Constance Pachuki, Mary Samuel, James Gallai, ), Seattle King County Health Department (Charles Nolan, Stefan Goldberg, Marcia Stone, Debra Schwartz), Veterans Affairs Medical Center-Washington DC (Fred Gordin, Debra Benator, Donna Sepulveda Conwell, Thomas Walsh, Margaret Lankford, Charlotte Quinlan-Mauzy), and Duke University Medical Center and Durham VA Medical Center (Carol Dukes Hamilton, Ann Mosher), Chicago Department of Public Health (William Paul, Rosalie Cyrier), Miami VA Medical Center (Gordon Dickinson, Mattie Jackson, Michael Picou), New York VA Medical Center (Michael Simberkoff, Yvonne Francis), Mount Sinai Medical Center (Burt Meyers, Nenette Shlasko), Bronx VA Medical Center (Jeffrey Jacobson, Betzaida Ruiz), Beth Israel Medical Center-New York (David Perlman, Nadim Salomon, Ron Farinella, Cassandra Diggs).

	FOOTNOTES

 
Supported by a Chercheur-Boursier Clinicien career award from the Fonds de Recherche en Santé du Québec (K.S.).

Conflict of Interest Statement: R.M.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; L.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.D.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.J.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; B.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; W.J.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form August 19, 2004; accepted in final form September 27, 2004

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