Tuberculosis Treatment Interruptions ---Ivanovo Oblast, Russian Federation, 1999

In the Russian Federation, the number of tuberculosis (TB) cases increased from 45,000 (34 per 100,000 population) in 1991 to 124,000 (85 per 100,000 population) in 1999 (1). In 1995, the World Health Organization (WHO) implemented a pilot TB control project in the Ivanovo oblast of the Russian Federation (1995 population: 1.3 million), located 175 miles northeast of Moscow. The project is based on the following five elements of the WHO directly observed treatment, short-course (DOTS) strategy for controlling TB: government commitment, laboratory-based diagnosis, a reliable supply of anti-TB medications, direct supervision of standardized treatment, and a recording and reporting system that permits evaluation of treatment outcomes. In most settings, implementing this strategy has resulted in cure rates of >85% (2,3); however, little improvement occurred in cure rates in Ivanovo after implementation of this strategy in 1995 (4,5). Although 17% of these poor outcomes were attributed to primary multidrug-resistant TB (MDR TB) (i.e., TB resistant to at least isoniazid and rifampin) (4), other factors that may have contributed to poor outcomes, such as treatment delay and interruption, were not quantified. To determine the extent of treatment interruption as a potential cause of poor outcomes among TB patients in Ivanovo, CDC reviewed TB treatment records for all newly diagnosed, never-treated pulmonary TB patients registered in Ivanovo from April through June 1999. This report summarizes the results of that analysis and indicates that approximately one fourth of highly infectious TB patients interrupted treatment for 2--8 weeks and nearly one fourth interrupted treatment for more than 8 weeks. On the basis of these results, TB project staff have increased efforts to reduce treatment interruption through use of incentives.

For each patient, the frequency and duration of treatment interruptions and treatment outcomes were recorded. The analysis was limited to new patients whose sputum smears were positive for acid-fast bacilli (AFB). TB treatment requires a minimum of 6 months of anti-TB medications: the first 2 months involve taking four anti-TB medications (i.e., intensive phase), and the following 4 months involve taking two anti-TB medications (i.e., continuation phase). Patients who discontinued medication for 2--8 consecutive weeks but eventually restarted treatment were considered to have interrupted treatment. Standard WHO definitions were used to assign mutually exclusive treatment outcomes for each patient; these definitions were dichotomized further into successful treatment versus poor outcome (5). Patients were considered to have had a successful treatment outcome if they completed 6 months of prescribed medication within 1 year of starting treatment. Patients were considered to have had a poor outcome if treatment failed (i.e., patient remained or again became AFB smear-positive following >5 months of treatment), they defaulted (i.e., interrupted treatment for >8 consecutive weeks), or they died for any reason during the course of TB treatment.

During April--June, 115 newly diagnosed, never-treated pulmonary TB patients were registered; 54 (47%) were AFB smear-positive. The median age of the smear-positive patients was 43 years (range: 17--85 years), and 34 (63%) were male. No patients were documented to have MDR TB by subsequent culture and susceptibility testing. Successful treatment outcomes were documented for 31 (57%) smear-positive patients. Of the remaining 23 with poor outcomes, treatment failed in six (26%) patients, 12 (52%) defaulted, and five (22%) died. Of the patients who died, three died within 1 month of starting treatment and two died in the second and third months of treatment, respectively.

Treatment interruption of 2--8 weeks occurred among 15 (28%) patients. Of patients who interrupted treatment, 13 (87%) were male, and 10 (67%) were aged <50 years. The median number of interruptions per patient was two (range: one--six). Among patients who interrupted treatment, three (20%) interrupted during the intensive phase, 10 (67%) during the continuation phase, and two (13%) during both phases of treatment. The median duration of all interruptions was 3 weeks (range: 2--8 weeks); of 30 interruptions, 20 (67%) were 2--3 weeks and 10 (33%) were 4--8 weeks.

Of the 31 AFB smear-positive patients who completed treatment, the median duration of treatment was 10 months (range: 6--18 months). Sixteen (52%) completed 6 months of prescribed medication within 6--9 months, eight (26%) within 10--12 months, and seven (23%) within 13--18 months.

Reported by: I Danilova, L Mitunina, M Urastova, M Stoyunin, Ivanovo TB Dispensary; V Shapkin, Oblast TB Hospital, Ivanovo; G Oswald, N Afanasiev, U.S. Agency for International Development; V Erokhin, V Punga, I Vassilieva, Central TB Research Institute, Moscow, Russia. M Grzemska, W Jakubowiak, H Kluge, World Health Organization, Geneva, Switzerland. International Activity, Div of TB Elimination, National Center for HIV, STD, and TB Prevention; and an EIS Officer, CDC.

Editorial Note:

The incidence of adult TB cases in Ivanovo remained stable from 1996 to 1998 at approximately 45 per 100,000 annually (WHO, unpublished data, 1998). However, primary MDR TB more than doubled from 3.8% in 1996 to 9.4% in 1998 (4). Patients who default are at high risk for developing drug resistance or disease progression (6,7). However, interruptions of shorter duration also are of concern because patient adherence is important for treatment success (8) and to prevent transmission (9).

In Ivanovo, the rates of treatment default and interruption were high. Approximately one third interrupted treatment during the intensive phase, when patients with a high bacillary load are at greatest risk for developing drug resistance and for spreading untreated disease in the community. Half of the patients interrupted treatment more than once, and the median duration of interruption was long, resulting in considerable delays in treatment completion and increasing the workload of staff responsible for tracking patients who interrupted or defaulted. Reasons for treatment interruption included both patient and program factors such as cost of transportation and length of hospital stay required for treatment.

The findings in this report are subject to at least three limitations. First, the sample size of the population was small, limiting statistical power to detect significant differences in outcomes among groups. Second, other risk factors (e.g., human immunodeficiency virus infection and excessive alcohol consumtion) that may have affected the likelihood of both treatment interruption and poor outcomes could not be assessed in the treatment record review. Finally, not all patients were evaluated following treatment completion, and their final treatment outcome was not available.

On the basis of this study and another study examining reasons for treatment interruption (10), the TB project staff were encouraged to concentrate human and financial resources on treatment completion. To improve patient adherence and reduce treatment interruption, patients are now receiving food supplements or free transportation to the clinic. Aggressive efforts are being made to locate and restart treatment in patients who interrupt before completion. Vehicles, fuel, and public transportation passes have been provided to the TB project staff to enable them to find patients who interrupt treatment. Finally, health-care providers are receiving performance-based rewards if their patients complete treatment.

References

1. Shilova MV. Tuberculosis in Russia in 1999. Moscow, Russia: Ministry of Health of Russia, Sechenov Moscow Medical Academy, Scientific-Research Institute of Phthysiopulmonology, 2000.
2. China Tuberculosis Control Collaboration. Results of directly observed short-course chemotherapy in 112,842 Chinese patients with smear-positive tuberculosis. Lancet 1996; 347:358--62.
3. Kumaresan JA, Ahsan Ali AK, Parkkali LM. Tuberculosis control in Bangladesh: success of the DOTS strategy. Int J Tuberc Lung Dis 1998;2:992--8.
4. CDC. Primary multidrug-resistant tuberculosis---Ivanovo oblast, Russia, 1999. MMWR 1999;48:661--4.
5. World Health Organization. Treatment of tuberculosis: guidelines for national programmes. Geneva, Switzerland: World Health Organization, 1997.
6. Mitchison DA. How drug resistance emerges as a result of poor compliance during short course chemotherapy for tuberculosis. Int J Tuberc Lung Dis 1998;2:10--5.
7. Laserson KF, Osorio L, Sheppard JD, et al. Clinical and programmatic mismanagement rather than community outbreak as the cause of chronic, drug-resistant tuberculosis in Buenaventura, Colombia, 1998. Int J Tuberc Lung Dis 2000;4:673--83.
8. Addington WW. Patient compliance: the most serious remaining problem in control of tuberculosis in the US. Chest 1979;76:741--3.
9. PablosMendez A, Knirsch CA, Barr RG, Lerner BH, Frieden TR. Nonadherence in tuberculosis treatment: predictors and consequences in New York City. Am J Med 1997;102:164--70.
10. Larson JL, Danilova ID, Caudill C, et al. Factors associated with tuberculosis treatment delay and interruption, Ivanovo, Russia---1999 [Abstract]. Presented at the EIS Conference, Atlanta, Georgia, April 2000.

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