Primary Multidrug-Resistant Tuberculosis -- Ivanovo Oblast, Russia, 1999

The incidence of tuberculosis (TB) in the Russian Federation has increased steadily from 34 per 100,000 population in 1991 to 78 per 100,000 in 1998 (Central Tuberculosis Research Institute, unpublished data, 1999). To reverse this trend, in 1995, federal and local governments, with assistance from the World Health Organization (WHO), implemented a pilot project using the WHO TB-control strategy of directly observed therapy, short-course (DOTS)* in Ivanovo oblast (1998 population: approximately 1.3 million), a district 165 miles (280 km) northeast of Moscow. This report documents a substantial increase in primary multidrug-resistant TB (P-MDRTB) in the civilian population of Ivanovo from January 1996 through October 1998 and a high prevalence of alcoholism, previous incarceration, unemployment, and history of homelessness among persons infected with both drug-susceptible and drug-resistant Mycobacterium tuberculosis strains.

Despite implementation of DOTS in Ivanovo in October 1995, as of October 1998, approximately 30% of 514 never-treated (defined as less than 1 month of previous treatment), smear-positive TB patients had poor treatment outcomes (i.e., relapse, treatment failure, or death). P-MDRTB, defined as M. tuberculosis isolates resistant to at least isoniazid and rifampin in never-treated TB patients, was suspected to be a major contributing factor to these poor outcomes. WHO requested CDC's assistance to investigate trends in P-MDRTB, identify epidemiologic risk factors for P-MDRTB, and examine outcomes for persons with P-MDRTB.

The Ivanovo TB laboratory performed drug-susceptibility testing on all 514 M. tuberculosis isolates; 26 (5%) had primary multidrug resistance. The percentage of P-MDRTB cases more than doubled after program implementation, from 3.8% (seven of 186) in 1996 to 9.4% (11 of 117) during the first 9 months of 1998 (chi-square for linear trend; p less than 0.05).

To identify risk factors for P-MDRTB, a case-control study was conducted in February 1999 of never-treated, smear- and culture-positive pulmonary TB patients reported during October 1995-October 1998. A case of P-MDRTB was defined as culture-confirmed MDRTB in a patient; controls were patients with culture-confirmed drug-susceptible TB. Controls were frequency-matched to cases by quarter-year of report; three controls per case were chosen randomly. Risk factor data, drug susceptibility results, and clinical outcomes were obtained from the WHO project database, a detailed local TB database, and medical chart reviews.

Twenty-six P-MDRTB case-patients and 76 frequency-matched controls were enrolled in the study. The mean ages of both case-patients and controls were similar (44 years versus 46 years; range: 15-76 years); 92% of case-patients and 84% of controls were male. None of the case-patients or controls were infected with human immunodeficiency virus. Case-patients were more likely than controls to have been hospitalized previously (46% versus 25%; odds ratio [OR]=1.9; 95% confidence interval [CI]=0.8-4.3), incarcerated previously (44% versus 29%; OR=1.6; 95% CI=0.7-3.6), unemployed at time of diagnosis (58% versus 55%; OR=1.3; 95% CI=0.6-3.0), or to have a history of alcoholism (65% versus 61%; OR=1.3; 95% CI=0.6-2.9), but the differences were not statistically significant. However, compared with controls, case-patients were significantly more likely to have a history of homelessness (23% versus 5%; OR=3.1; 95% CI=1.1-8.8; p=0.04).

During October 1995-October 1998, 5% (one of 19) of case-patients compared with 77% (43 of 56) of controls were cured (i.e., negative sputum smear at treatment completion and on at least one previous occasion [3]) by the standardized 6-month DOTS treatment regimen (p less than 0.001). Furthermore, 27% (six of 22) of case-patients, compared with 8% (six of 75) of controls, died of TB (hazard ratio for death associated with TB among case-patients=2.2; p=0.17, Cox proportional hazard analysis).

Reported by: I Danilova, M Stoyunin, E Repina, M Vorobiov, O Adreevna, Ivanovo Oblast TB Dispensary, Ivanovo; A Khomenko, V Puzanov, L Kapkov, V Punga, Central TB Research Institute, Moscow; G Oswald, N Afanasiev, C Carrino, United States Agency for International Development, Moscow, Russia. GB Migliori, M Ambrosetti, World Health Organization, Geneva, Switzerland; FS Maugeri, Tradate, Italy. M Grzemska, M Espinal, M Raviglione, World Health Organization, Geneva, Switzerland. A Goldfarb, Public Health Research Institute, New York City. A Slutsky, Massachusetts State Laboratory, Boston, Massachusetts. International Activity and Field Services Br, Div of TB Elimination, National Center for HIV, STD, and TB Prevention, CDC.

Editorial Note:

Worldwide, approximately 8 million TB cases and 2 million TB deaths occur annually (4). MDRTB is present on five continents and is increasing (5). The four-drug regimen used as part of the WHO DOTS strategy results in high cure rates in areas with low levels of resistance. However, in communities such as Ivanovo that have high levels of drug resistance, additional strategies are needed for patients with drug-resistant TB, including rapid assessment of drug susceptibilities and use of alternative, "second-line" TB drugs (5,6).

In the Russian Federation, the incidence of all TB and of drug-resistant TB is increasing in the civilian and the prison populations (7,8). The findings in this report identify a significant increase in P-MDRTB in the civilian population of Ivanovo from January 1996 through October 1998 and a high prevalence of alcoholism, previous incarceration, unemployment, and history of homelessness among persons infected with drug-resistant and drug-susceptible M. tuberculosis strains. Drug resistance contributed to 17% of the poor treatment outcomes observed in Ivanovo; however, most of these poor outcomes probably were associated with delayed diagnosis, treatment interruption, failure to ensure patient adherence, and other program-related factors (5). Analysis of the impact of these factors on treatment outcome among the patients in Ivanovo is under way.

The findings in this report are subject to at least three limitations. First, details about previous prison and hospitalization history were not available for all study participants. This limited the ability to identify specific high-risk exposures in the community. Second, the relatively small sample size limited the power to detect statistically significant differences between cases and controls. Third, case-patients and controls described in this report are limited to Ivanovo and may not be representative of TB patients in other geographic regions within Russia.

On the basis of these findings, CDC made two recommendations to improve the outcomes of TB-control activities in Ivanovo. First, to prevent further spread of drug-resistant and drug-susceptible TB, TB-control efforts must target high-risk populations for active case finding and assurance of completion of therapy. Second, rapid drug-susceptibility testing and the use of appropriate second-line TB drug regimens for patients with demonstrated MDRTB should be implemented to improve treatment outcomes in active TB patients and to reduce the widespread emergence of MDRTB in this community. Until second-line drug susceptibility testing is widely available, one or more second-line treatment regimens will need to be used empirically (based on knowledge of drug-resistance profiles in the community) for these patients. Expansion of rapid drug susceptibility testing and a reliable drug supply will facilitate the design of more individualized treatment regimens in patients with drug-resistant TB, improve the likelihood of cure, prevent the transmission of drug-resistant TB, and avert premature deaths attributable to MDRTB.

References

1. 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.
2. 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.
3. World Health Organization. Global tuberculosis control: WHO report 1999. Geneva, Switzerland: World Health Organization, 1999; report no. WHO/CDS/CPC/TB/99.259.
4. World Health Organization. World health report 1999: making a difference. Geneva, Switzerland: World Health Organization, 1999.
5. World Health Organization. Anti-tuberculosis drug resistance in the world: the WHO/IUATLD global project on anti-tuberculosis drug resistance surveillance, 1994-1997. Geneva, Switzerland: WHO Global Tuberculosis Program, 1997; report no. WHO/TB/97.229.
6. Crofton J, Chaulet P, Maher D. Guidelines for the management of drug-resistant tuberculosis. Geneva, Switzerland: World Health Organization, 1997; report no. WHO/TB/96.210 (rev. 1).
7. Coninx R, Mathieu C, Debacker M, et al. First-line tuberculosis therapy and drug-resistant Mycobacterium tuberculosis in prisons. Lancet 1999;353:969-73.
8. Kimerling ME, Kluge H, Vezhina N, et al. Inadequacy of the current WHO re-treatment in a central Siberian prison: treatment failure and MDR-TB. Int J Tuberc Lung Dis 1999;3:451-3.

* DOTS consists of 1) government commitment to sustained TB control; 2) a bacteriologically confirmed diagnosis; 3) a standardized short-course multidrug regimen for treatment of active TB, provided under direct observation; 4) a regular, uninterrupted supply of drugs and diagnostic materials; and 5) the systematic monitoring and evaluation of program activities. In other countries, DOTS programs have resulted in successful completion of therapy for greater than or equal to 80% of patients (1-3).

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