LESSONS FROM THE FIELD
Eliminating the category II retreatment regimen from National Tuberculosis Programme guidelines: the Georgian experience
Eliminación de las pautas de repetición del tratamiento de categoría II de las directrices del Programa Nacional Contra la Tuberculosis: el caso de Georgia
Suppression du schéma de retraitement de catégorie II des directives thérapeutiques nationales du Programme de Lutte Contre la Tuberculose: l'expérience géorgienne
Jennifer FurinI,*; Medea GegiaII; Carole MitnickIII; Michael RichIV; Sonya ShinV; Mercedes BecerraIII; Peter DrobacIV; Paul FarmerIV; Rocio HurtadoVI; J Keith JosephIV; Salmaan KeshavjeeV; Iagor KalandadzeII
ISchool of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, United States of America (USA)
IINational Centre for Tuberculosis and Lung Disease, Tbilisi, Georgia
IIIHarvard Medical School, Boston, USA
IVPartners In Health, Boston, USA
VBrigham and Women's Hospital, Boston, USA
VIMassachusetts General Hospital, Boston, USA
ABSTRACT
PROBLEM: The category II retreatment regimen for management of tuberculosis in previously treated patients was first introduced in the early 1990s. It consists of 8 months of total therapy with the addition of streptomycin to standard first-line medications. A review of 6500 patients on category II therapy in Georgia showed poor outcomes and high rates of streptomycin resistance.
APPROACH: The National Tuberculosis Program used an evidence-based analysis of national data to convince policy-makers that category II therapy should be eliminated from national guidelines in Georgia.
LOCAL SETTING: The World Health Organization tuberculosis case-notification rate in Georgia is 102 per 100 000 population. All patients receive culture and drug susceptibility testing as a standard part of tuberculosis diagnosis. In 2009, routine surveillance found multidrug-resistant tuberculosis in 10.6% of newly diagnosed patients and 32.5% of previously treated cases.
RELEVANT CHANGES: Category II retreatment regimen is no longer used in Georgia. Treatment is guided by results of drug susceptibility testing - using rapid, molecular tests where possible - for all previously treated tuberculosis patients.
LESSONS LEARNT: There was little resistance to policy change because the review was initiated and led by the National Tuberculosis Program. This experience can serve as a successful model for other countries to make informed decisions about the use of category II therapy.
RESUMEN
SITUACIÓN: A principios de la década de los 90 se introdujeron las pautas de repetición del tratamiento de categoría II para la gestión de la tuberculosis en pacientes previamente tratados. Consiste en un tratamiento total de 8 meses de duración en el que se añade estreptomicina a los fármacos de primera línea. Un examen de 6500 pacientes en tratamiento de categoría II en Georgia ofreció unos resultados deficientes y unas tasas elevadas de resistencia a la estreptomicina.
ENFOQUE: El Programa Nacional contra la Tuberculosis empleó un análisis de los datos nacionales basado en la evidencia para convencer a los responsables de que la categoría II del tratamiento debería ser eliminada de las directrices nacionales en Georgia.
MARCO REGIONAL: La tasa de notificación de casos de tuberculosis de la Organización Mundial de la Salud en Georgia es de 102 por cada 100 000 personas. A todos los pacientes se les realiza un análisis de cultivo y una prueba de sensibilidad a los medicamentos como parte del procedimiento habitual de diagnóstico de la tuberculosis. En 2009, una vigilancia rutinaria detectó tuberculosis multirresistente en un 10,6% de los pacientes diagnosticados recientemente y en un 32,5% de los casos tratados previamente.
CAMBIOS IMPORTANTES: Las pautas de repetición del tratamiento de categoría II han dejado de emplearse en Georgia. El tratamiento se guía por los resultados de la prueba de sensibilidad a los medicamentos (siempre que es posible se emplean pruebas moleculares, muy rápidas) para todos los pacientes tratados previamente contra la tuberculosis.
LECCIONES APRENDIDAS: Se observó poca resistencia al cambio de estrategia porque fue el Programa Nacional contra la Tuberculosis quien inició y dirigió el examen. La presente experiencia puede servir como modelo de éxito para otros países a la hora de tomar decisiones bien informadas acerca del uso del tratamiento de categoría II.
RÉSUMÉ
PROBLÈME: Le schéma de retraitement de catégorie II dans le cadre de la prise en charge de la tuberculose chez des patients ayant déjà suivi un traitement a été initié au début des années 1990. Il consiste en 8 mois de traitement complet, avec l'ajout de streptomycine aux médicaments de première intention standard. Une étude portant sur 6 500 patients sous traitement de catégorie II en Géorgie a révélé de mauvais résultats, ainsi que des taux élevés de résistance à la streptomycine.
APPROCHE: Le programme national de lutte contre la tuberculose a recouru à une analyse factuelle des données nationales pour convaincre les responsables politiques qu'il convenait de supprimer le traitement de catégorie II des directives thérapeutiques nationales géorgiennes.
CONFIGURATION LOCALE: Le taux de notification des cas de tuberculose à l'Organisation mondiale de la Santé en Géorgie est de 102 pour 100 000 habitants. Tous les patients se soumettent à des prélèvements d'expectoration et à des tests de sensibilité aux antituberculeux, conformément aux diagnostics standard de la tuberculose. En 2009, un contrôle de routine constatait une tuberculose multi-résistante dans 10,6% des nouveaux cas diagnostiqués et dans 32,5% des cas traités antérieurement.
CHANGEMENTS SIGNIFICATIFS: Le schéma de retraitement de catégorie II n'est plus utilisé en Géorgie. Le traitement est désormais orienté en fonction des tests de sensibilité aux antituberculeux avec, si possible, l'utilisation de tests moléculaires rapides, chez tous les patients précédemment traités contre la tuberculose.
LEÇONS TIRÉES: Le changement de politique a rencontré peu de résistance, car l'étude a été engagée et menée par le programme national de lutte contre la tuberculose. Cette expérience peut servir de modèle réussi pour permettre à d'autres pays de prendre des décisions éclairées sur le recours au traitement de catégorie II.
Introduction
Management of patients who have been previously treated for tuberculosis (TB) has been a cause of much debate.1 In 1991, the World Health Organization (WHO) recommended the use of the "category II retreatment regimen" for all patients with a prior history of TB treatment.2, 3 The category II regimen added streptomycin to the first-line agents and extended treatment to 8 months. Multiple observational studies have examined outcomes among individuals receiving category II treatment and shown mixed results. Overall success rates are in the 60-80% range,4, 5 with notably worse outcomes seen among patients who failed or relapsed after their initial treatment episode.6, 7
WHO TB treatment guidelines published in 2010 recommend treatment guided by drug susceptibility testing - using rapid, molecular tests where possible - for all previously treated patients.3 The category II regimen, however, is still recommended for certain patients who return after default or relapse in settings with low risk of multidrug-resistant TB (MDR-TB). There is little documentation concerning implementation of these guidelines and category II remains the standard of care for patients requiring retreatment in most settings in the world. This paper presents the experience of Georgia - a country with a substantial population of previously treated patients and high rates of MDR-TB - in eliminating category II therapy from its National TB Program (NTP) guidelines.
Local setting
Georgia is a country of 4.4 million people located in the South Caucasus region. The WHO TB case notification rate is 102 per 100 000 population.8 All Georgian TB patients receive culture and drug susceptibility testing as a standard part of diagnosis. In 2009, routine surveillance found MDR-TB in 10.6% of newly diagnosed patients and 32.5% of previously treated cases.9 Programmatic management of drug-resistance TB in Georgia was started in 2006 and in 2009 the country achieved universal access to MDR-TB treatment.
Approach
An operational assessment of the utility of category II in Georgia was done in July and August 2010, led by members of the Georgian NTP with a WHO-recruited consultant. The steps taken were: (i) programme review, (ii) consensus building, and (iii) implementation planning (Table 1).
Programme review
Outcomes of patients treated with category II were assessed in addition to the local epidemiology and programme resources in Georgia. More than 6500 patients received category II therapy between 2007 and 2009 and their outcomes are shown in Table 2.
Georgia has a high burden of TB, particularly drug-resistant TB. Prevalence of HIV in the country is low (< 1%). Culture of the Mycobacterium tuberculosis and drug susceptibility testing is done for all patients diagnosed with TB and Georgia has the resources (human and financial) to continue to do this. It also has a national programme for managing drug-resistant TB. Patients with documented resistance are given treatment regimens based on drug susceptibility test results.
Consensus building
Following this review, the NTP decided to no longer recommend category II treatment in Georgia because of: (i) poor outcomes among patients on category II therapy; (ii) high rates of streptomycin resistance among previously treated patients; (iii) lack of evidence to support category II; and (iv) widespread access to both drug susceptibility testing and treatment for drug-resistant TB. The NTP concluded that patients with documented resistance, including those with mono-resistance, would receive a regimen based on drug susceptibility test results. Those with a history of previous treatment who had pan-susceptible disease would receive HREZ (first-line drugs).
Consensus building was initiated and led by the Georgian NTP; as such, there was strong political will. It held a series of meetings with TB care providers to review and discuss the decision openly. Most of the NTP staff in Georgia are actively involved in TB patient care, and ongoing provider relationships allowed for rapid consensus building. The NTP also used an evidence-based analysis to support its decision. There were some concerns that previously treated patients with pan-susceptible disease still needed a "stronger" regimen but, upon further review, there was little evidence to support this claim. There was little resistance to this policy change so, once internal consensus was reached, the NTP applied for regulatory changes and category II was removed from recommendations for TB treatment.
Implementation
Following the elimination of category II treatment, the programme has committed time and resources to expanding access to rapid, molecular-based drug susceptibility testing. Georgia will also continue its commitment to universal management of all forms of drug-resistant TB and monitor resistance and patient outcomes. Operational research on the discontinuation of category II treatment - including cost implications and provider and patient experiences - will be carried out as funding permits.
Lessons learnt
The experience from Georgia is an important example of how category II treatment can be successfully removed from NTP guidelines in settings where it is of limited utility. Georgia used an operational assessment of its national data to reach consensus on the use of category II within its specific context. There was little resistance to policy change in the country because the review was initiated and led by the NTP. Although it may not be possible to generalize this experience to all settings, the review was done retrospectively and outcome data are pending, the Georgian experience may serve as a roadmap for other countries.
The operational assessment concluded that there were no patients in Georgia for whom category II treatment was appropriate. Patients with a history of previous treatment who have pan-susceptible disease are now treated with first-line drugs. Patients with mono- or poly-resistance are treated with appropriate regimens. Patients with MDR-TB are treated with second-line therapy.
Georgia is a unique setting but other countries with different profiles may be able to use this model to determine whether they should use category II. Each country will need to do its own programme review of category II outcomes. They can then use these data to prioritize whether they will continue to use category II or invest in improved diagnostics and drug-resistant TB treatment or both. This paper presents an important example of putting WHO recommendations into action. It is hoped the experience from Georgia can inspire other TB programmes to assess the utility of category II regimens - and other programmatic TB recommendations - in their settings (Box 1). 
Competing interests: None declared.
References
1. Treatment of tuberculosis: guidelines for national programmes, 2nd edition. Geneva: World Health Organization;1997.
2. Rouillon A. The Mutual Assistance Programme of the IUATLD. Development, contribution and significance. Bull Int Union Tuberc Lung Dis 1991;66:159-72. PMID: 1687508
3. Treatment of tuberculosis: guidelines for national programmes, 4th edition. Geneva: World Health Organization;2010.
4. Matthys F, Rigouts L, Sizaire V, Vezhnina N, Lecoq M, Golubeva V et al. Outcomes after chemotherapy with WHO category II regimen in a population with high prevalence of drug resistant tuberculosis. PLoS ONE 2009;4:e7954. doi: 10.1371/journal.pone.0007954 PMID: 19956770
5. Ottmani SE, Zignol M, Bencheikh N, Laâsri L, Chaouki N, Mahjour J. Results of cohort analysis by category of tuberculosis retreatment cases in Morocco from 1996 to 2003. Int J Tuberc Lung Dis 2006;10:1367-72. PMID: 17167954
6. Mehra RK, Dhingra VK, Nish A, Vashist RP. Study of relapse and failure cases of CAT I retreated with CAT II under RNTCP-an eleven year follow up. Indian J Tuberc 2008;55:188-91. PMID: 19295105
7. Saravia JC, Appleton SC, Rich ML, Sarria M, Bayona J, Becerra MC. Retreatment management strategies when first-line tuberculosis therapy fails. Int J Tuberc Lung Dis 2005;9:421-9. PMID: 15830748
8. Anti-tuberculosis drug resistance in the world, report no. 4. Geneva: World Health Organization; 2008. Available from: http://www.who.int/tb/publications/2008/drs_report4_26feb08.pdf [accessed 21 November 2011]
9. Tuberculosis control plan for Georgia 2007-2011. Tblisi: National Center for Tuberculosis and Lung Diseases; 2011. Available from: http://www.tbgeo.ge/index.php?a=page&lang=en&pid=154 [accessed 21 November 2011].
Submitted: 16 June 2011
Revised version received: 6 September 2011
Accepted: 21 September 2011
Published online: 24 November 2011
* Correspondence to Jennifer Furin (e-mail: jenniferfurin@gmail.com).