INT J TUBERC LUNG DIS 3(5):451–453 © 1999 IUATLD
SHORT COMMUNICATION
Inadequacy of the current WHO re-treatment regimen in a central Siberian prison: treatment failure and MDR-TB M. E. Kimerling,* H. Kluge,† N. Vezhnina,‡ T. Iacovazzi,† T. Demeulenaere,† F. Portaels,§ F. Matthys† * Department of Medicine, School of Medicine, University of Alabama at Birmingham, USA, † Médecins Sans Frontières, Brussels, Belgium, ‡ Colony 33 Medical Department, Mariinsk, Russia, § Department of Microbiology, Institute of Tropical Medicine, Antwerp, Belgium SUMMARY
Multidrug-resistant tuberculosis (MDR-TB) threatens the progress of global control efforts. Prisons represent a high risk setting for development and transmission of MDR-TB. In a Siberian TB referral prison (Kemerovo region), the treatment failure rate is 35% (June 1996– March 1997), despite implementation of a strict DOTS program and use of the World Health Organization Category 2 re-treatment regimen for all new cases. Among
164 patients (December 1997–March 1998), initial resistance to isoniazid and rifampin is 22.6%. Such a rate is a warning call to reconsider prison control strategies, and importantly, to address the treatment regimens necessary to combat an institutional epidemic of MDR-TB. K E Y W O R D S : tuberculosis; multidrug resistance; prisons
THE ISSUE of multidrug-resistant tuberculosis (MDRTB) has emerged as a threat to global control efforts. Recently, the World Health Organization (WHO) published its first surveillance report on global drug susceptibility.1 It represents the first international collaborative effort capable of assessing the magnitude of the MDR problem. The current WHO re-treatment regimen for persons who have failed an initial regimen of four drugs {isoniazid (H), rifampin (R), ethambutol (E) and pyrazinamide (Z)} includes the addition of a single agent, streptomycin (S), and is given for 8 months.2 Beyond drug surveillance data is program information regarding the impact of drug resistance on the ability to cure patients, thereby preventing the development of ‘chronic’ patients excreting MDR-TB in communities. If a regimen is not able to do so in persons who have previously received treatment, then the adequacy of the treatment regimen must be questioned. Until now, no one has defined on a population basis what level the prevalence of MDR disease must reach before considering a change in treatment and/or re-treatment strategies. This question is crucial when considering high-risk environments such as prisons where transmission is intense and multiple risk factors co-exist.
of treatment regimen adequacy. Kemerovo has approximately 30 000 prisoners and a single TB colony/hospital that has implemented the WHO DOTS (directlyobserved treatment, short-course) program. The colony has 750 beds with over 1300 patients, supported by the international medical organization Médecins Sans Frontières (MSF-Belgium) since December 1995. As it serves the northern part of the region, patients are transferred to Colony 33 from 15 regional prisons and two pre-detention centers (jails). All prisoners are initially incarcerated in jails while their cases are investigated. Convicted persons are sent to regional prisons; those not convicted are released. Their stay in such a center ranges from several months to three years, with an average of one year; they reside in overcrowded cells containing 30 to 50 persons each. Legally, TB suspects in jails may not be moved to the TB colony unless convicted, so they are kept together next to cells with non-sick persons and no outside ventilation. These jails have no sputum examination capacity and few medical staff. Convicted TB suspects may be transferred to Colony 33 from the other colonies only when a bed becomes available and only if they are not due for release during the next several months. Consequently, the majority of those transferred (79%) receive prior non-standardized Russian-based therapy with one to four anti-tuberculosis drugs given for intermittent periods of time, depending upon drug availability and
POOR TREATMENT OUTCOMES IN COLONY 33 Data from Colony 33, a TB referral prison in central Siberia (Mariinsk, Kemerovo region), raises the issue
Correspondence to: Dr Kimerling, Department of Epidemiology and International Health, UAB School of Public Health, 217 Ryals Building, 1665 University Boulevard, Birmingham, AL 35294-0022, USA. Tel: (205) 934-1732. Fax: (205) 975-3329. e-mail:
[email protected] Article submitted 3 June 1998. Final version accepted 11 December 1998.
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symptoms. Due to this situation, MSF/Colony 33 medical policy is to start all newly admitted patients on WHO Category 2 therapy (2EHRZS/1EHRZ/ 5EHR) under a strict system of direct observation using only imported medicines. Treatment outcomes, based on sputum examination and using standard definitions,2 are available for 210 initially smear-positive patients placed on Category 2 therapy from June 1996 through March 1997: cured 46%, completed therapy 6%, treatment failure 35%, death 4%, transfer out 6%, default 0%. There were no results available on 2.4% of patients (n 5). In light of these poor results, drug susceptibility testing (DST) was performed (December 1997–March 1998) for new DOTS patients to evaluate the level of initial resistance among this population as an explanation for poor treatment outcomes. We report our findings on 164 consecutive patients.
METHODS All cultures are performed on initial sputum specimens collected at 7 am by prison health staff. Under supervision, prisoners must rinse their mouths with water prior to collection. Culture on solid media (Löwenstein-Jensen) and drug susceptibility testing, using the proportion method,3 are performed by the Mariinsk laboratory. Quality control is done at the WHO reference laboratory in Antwerp, and resistance determined by standard procedure.4 Forty-nine samples were received for quality control, including all rifampin-resistant strains.
RESULTS Although treatment outcomes are not available, DST results for 164 patients (culture confirmed, smear positive and negative) are known (Table). Results for ethambutol (EMB) were excluded due to discordance between the prison and reference laboratories (50%). However, on a sample of 18 initial cultures from new patients evaluated in Antwerp in December 1996, EMB resistance was 22%. There-
Table Drug Susceptibility Test (DST) results (any combination) from Mariinsk for smear positive and negative patients started on Category 2 therapy (n 164)* Drug H R S HS RS HRS Sensitive to all drugs
Number
Percentage
10 1 13 61 1 37 41
6.1% 0.6% 7.9% 37.2% 0.6% 22.6% 25.0%
* DST concordance results from the Antwerp reference laboratory: H (94%), R (84%), S (86%). H isoniazid; R rifampin; S streptomycin.
fore, RMP monotherapy is likely occurring in the continuation phase but to an uncertain degree. The initial MDR rate (H R) is 22.6%, defined by the prevalence of rifampin resistance. Resistance to isoniazid is significantly worse, at 66%. Only 25% of patients were sensitive to all drugs tested. In another small sample (n 18) of initially smear-positive patients who remained smear-positive after a prolonged initial treatment phase, 94% were resistant to both H and R.
DISCUSSION The Colony 33 data show low cure rates and high initial rates of MDR-TB. While these results were obtained from separate cohorts, treatment with the standard WHO Category 2 regimen was used in both groups following strict DOT procedures. That there are no defaulters is explained by the support of the internal prison hierarchy. Consequently, non-compliance cannot explain our findings. As all drugs are imported from Europe, drug quality is a remote issue. We are thus left to conclude that an inadequate regimen is the reason for treatment failures. The results are not surprising as the Category 2 regimen is not designed for patients with prior exposure and resistance to rifampin or resistance to multiple first-line drugs in combination. Such a reality now exists and requires urgent consideration of current re-treatment regimens, especially in intense transmission settings. Since inadequate Russian-based therapy is given in prisons, it cannot be overlooked as a great source of drug resistance. This underlines the urgent need to expand DOTS to the very periphery of the incarceration system, especially given the length of time detainees spend in jails where TB exposure is high. However, given the initial DST results documented, creation of additional resistance is also likely with Category 2 therapy. High initial MDR rates mean that uncured, persistent excreters of TB organisms will rejoin their communities. With over 100 ‘chronic’ patients isolated within Colony 33 and nearly 300 released, communities are already directly threatened. Since a regimen which adds only a single drug to a failing one is considered inadequate,5,6 the WHO, the International Union Against Tuberculosis and Lung Disease and other policy makers must take the initiative to address an expanding problem that will ultimately affect distant communities and populations. Our results add to a growing literature concerned with the issue of drug resistance in prisons, particularly in Russia.7,8 While we do not include information from the civilian sector, prisoners come from communities and return to their families upon release. The recent announcement by the Russian government of its plan to give amnesty to 100 000 prisoners further highlights this immediate threat.
MDR-TB in a Russian prison
Acknowledgements We thank all of the MSF teams that have worked in Colony 33 since the initiation of the project. Special appreciation is extended to Dr Vera Golubeva, head of the Colony 33 mycobacteriology laboratory, and to Dr Nena Tihonova, head of the microscopy laboratory.
References 1 World Health Organization. Anti-tuberculosis drug resistance in the world: the WHO/IUATLD global project on anti-tuberculosis drug resistance surveillance 1994–1997. Geneva: WHO Global Tuberculosis Program, 1997. 2 World Health Organization. Treatment of tuberculosis: guidelines for national programmes. Geneva: WHO Global Tuberculosis Program, 1997. 3 Canetti G, Fox W, Khomenko A, et al. Advances in techniques of testing mycobacterial drug sensitivity tests in tuberculosis
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control programmes. Bull World Health Organ 1969; 41: 24– 43. Inderlied CB, Nash K. Antimycobacterial agents: in vitro susceptibility testing, spectra of activity, mechanisms of action and resistance, and assays for activity in biologic fluids. In: Lorian V. ed. Antibiotics in laboratory medicine. 4th ed. Baltimore; Williams and Wilkins 1996: pp 127–75. World Health Organization. Guidelines for the management of drug-resistant tuberculosis. Geneva: WHO Global Tuberculosis Program, 1997. Iseman M D. Treatment of multidrug-resistant tuberculosis. N Engl J Med 1993; 329: 784–791. Drobniewski F, Tayler E, Ignatenko N, et al. Tuberculosis in Siberia: I. An epidemiological and microbiological assessment. Tubercle Lung Dis 1996; 77: 199–206. Coninx R, Pfyffer G E, Mathieu C, et al. Drug resistant tuberculosis in prisons in Azerbaijan: case study. BMJ 1998; 316: 1423–1425.
RÉSUMÉ
La tuberculose à germes multirésistants (MDR-TB) menace les efforts de lutte mondiale contre la tuberculose. Les prisons représentent un site à haut risque pour le développement et la transmission de la MDR-TB. Dans un centre sibérien de référence de tuberculose carcérale (région de Kemerovo), le taux d’échec du traitement est de 35% (juin 1996–mars 1997), malgré la mise en oeuvre d’un programme sévère de traitement directement supervisé (DOTS) et l’utilisation du régime
de retraitement catégorie 2 de l’OMS pour tous les nouveaux cas. Parmi 164 patients (décembre 1997–mars 1998), le taux de résistance initiale à l’isoniazide et à la rifampicine est de 22,6%. Un pareil taux est un avertissement poussant à reconsidérer les stratégies de lutte contre la tuberculose carcérale et à prendre surtout en considération les régimes de traitement nécessaires pour combattre une épidémie institutionnelle de tuberculose à germes multirésistants. RESUMEN
La tuberculosis multirresistente (MDR-TB) frena los esfuerzos para el control mundial de la tuberculosis. Las prisiones representan sitios de alto riesgo para el desarrollo y la transmisión de la MDR-TB. En una prisión de referencia en Siberia (región Kemerovo) la tasa de fracaso del tratamiento es del 35% (junio 1996–marzo 1997), a pesar de la implementación de un programa DOTS estricto y el empleo del esquema de retratamiento
Categoría 2 de la Organización Mundial de la Salud para todos los casos nuevos. Sobre 164 pacientes (diciembre 1997–marzo 1998) la resistencia inicial a la isoniacida y a la rifampicina fue del 22,6%. Esta tasa es un llamado de atención para reconsiderar la estrategia del control en las prisiones y además aplicar los esquemas necesarios para combatir una epidemia institucional de MDRTB.
