Tuberculosis Recurrence and Mortality after Successful Treatment: Impact of Drug Resistance

Background: The DOTS (directly observed treatment short-course) strategy for tuberculosis (TB) control is recommended by the World Health Organization globally. However, there are few studies of long-term TB treatment outcomes from DOTS programs in high-burden settings and particularly settings of high drug resistance. A DOTS program was implemented progressively in Karakalpakstan, Uzbekistan starting in 1998. The total case notification rate in 2003 was 462/100,000, and a drug resistance survey found multidrug-resistant (MDR) Mycobacterium tuberculosis strains among 13% of new and 40% of previously treated patients. A retrospective, observational study was conducted to assess the capacity of standardized short-course chemotherapy to effectively cure patients with TB in this setting. Methods and Findings: Using routine data sources, 213 patients who were sputum smear-positive for TB, included in the drug resistance survey and diagnosed consecutively in 2001–2002 from four districts, were followed up to a median of 22 months from diagnosis, to determine mortality and subsequent TB rediagnosis. Valid follow-up data were obtained for 197 (92%) of these patients. Mortality was high, with an average of 15% (95% confidence interval, 11% to 19%) dying per year after diagnosis (6% of 73 pansusceptible cases and 43% of 55 MDR TB cases also died per year). While 73 (74%) of the 99 new cases were “successfully” treated, 25 (34%) of these patients were subsequently rediagnosed with recurrent TB (13 were smear-positive on rediagnosis). Recurrence ranged from ten (23%) of 43 new, pansusceptible cases to six (60%) of ten previously treated MDR TB cases. MDR M. tuberculosis infection and previous TB treatment predicted unsuccessful DOTS treatment, while initial drug resistance contributed substantially to both mortality and disease recurrence after successful DOTS treatment. Conclusions: These results suggest that specific treatment of drug-resistant TB is needed in similar settings of high drug resistance. High disease recurrence after successful treatment, even for drug-susceptible cases, suggests that at least in this setting, end-of-treatment outcomes may not reflect the longer-term status of patients, with consequent negative impacts for patients and for TB control. A retrospective, observational study was conducted to assess the effectiveness of a "DOTS" tuberculosis control program in Uzbekistan. High rates of disease recurrence were found among patients whose treatment had been initially successful. Background.: Throughout history, tuberculosis (TB) has been a leading infectious cause of death—it kills about 2 million people every year. Until the 1940s, there was no effective treatment for TB, a chronic bacterial infection, usually of the lungs. Then, antibiotics active against the bacteria that cause TB—Mycobacterium tuberculosis—were introduced, and its incidence (the annual number of new cases) declined rapidly, particularly in developed countries. However, in the 1980s, there was a resurgence of TB, much of it driven by the HIV/AIDS epidemic—people with damaged immune systems are very susceptible to TB—and the emergence of drug-resistant M. tuberculosis. In 1995, the World Health Organization instigated what it called “DOTS,” an international strategy for global TB control. Central to DOTS is directly observed standardized short-course drug treatment. To prevent relapse and the emergence of drug-resistant bacteria, TB patients have to take antibiotics regularly for six months, even if they feel better sooner. The DOTS approach ensures that they do this by having trained observers watch them swallow their medications. Why Was This Study Done?: DOTS aims to detect 70% of new cases of sputum smear-positive TB (sputum is mucus coughed up from the lungs) and to treat 85% of these patients successfully. Both a cure—a negative smear at the end of treatment—and completion of treatment are recorded as “treatment successes.” There is no requirement in DOTS to check for TB recurrence, and few studies have investigated the long-term outcomes of treatment, particularly in areas with a high TB burden or where there is a problem with multidrug-resistant TB. Such data are needed to indicate whether DOTS can deliver global TB control. In this study, the researchers asked how often TB recurred in patients treated in a DOTS program in Karakalpakstan, Uzbekistan, an area with one of the highest incidences of multidrug-resistant TB. What Did the Researchers Do and Find?: The researchers identified about 200 sputum smear-positive TB patients who were treated consecutively in the Karakalpakstan DOTS program in 2001–2002. For most of the patients, follow-up data were available for an average of 22 months, a legacy of the pre-DOTS TB treatment system in Uzbekistan. The researchers found that, although three-quarters of new cases were “successfully” treated (i.e., close to the DOTS goal), a third of these “successes” were later re-diagnosed with TB. Recurrence of TB was particularly common among patients whose initial disease was multidrug resistant. Previous TB treatment was also associated with an increased risk of disease recurrence. Overall, nearly a quarter of the study patients died from TB during the follow-up period. Again, patients initially infected with multidrug-resistant TB fared particularly badly. Finally, only 65% of successfully treated patients were still alive and had not been re-diagnosed with TB 18 months after completion of their treatment. What Do These Findings Mean?: These high rates of disease recurrence and mortality suggest that DOTS might not be sufficient to control TB in areas like Karakalpakstan where the disease burden is high and multidrug-resistant infections are common. These poor long-term outcomes, note the researchers, are not hinted at by the end-of-treatment outcomes reported by the DOTS program. Limitations in the present study mean, however, that further studies are needed before these findings can be extrapolated to other settings. For example, the study used historical data so the researchers could not determine whether inadequate adherence to the DOTS program had contributed to the poor long-term outcome or whether disease recurrence was due to a relapse of the initial infection (which might indicate poor treatment adherence) or a new infection. Nevertheless, the current results warn against relying on end-of-treatment outcomes to judge the potential effectiveness of DOTS in controlling TB, and suggest that the expansion of DOTS-Plus, a supplement to DOTS for use where multidrug resistant TB is common, should be made a priority. Additional Information.: Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030384.