Efficacy and outcomes of clarithromycin treatment for pulmonary MAC disease

Transcription

1 INT J TUBERC LUNG DIS 9(11): The Union Efficacy and outcomes of clarithromycin treatment for pulmonary MAC disease T. Fujikane, S. Fujiuchi, Y. Yamazaki, M. Sato, Y. Yamamoto, A. Takeda, Y. Nishigaki, Y. Fujita, T. Shimizu Department of Respiratory Medicine, Dohoku National Hospital, Asahikawa, Japan SUMMARY SETTING: Retrospective review of patients with pulmonary Mycobacterium avium complex (MAC) disease treated with clarithromycin. OBJECTIVES: To investigate whether the short-term response to treatment predicts long-term outcomes, and to analyse what explanatory variables are associated with the efficacy and outcome of treatment. DESIGN: Sputum conversion rates in short- and longterm outcomes were evaluated for 111 patients. Respectively 9 and 10 explanatory variables were analysed for their association with both response and outcomes. RESULTS: Eighty-four patients (75.7%) showed good short-term response and 94 (82.0%) showed good longterm outcomes. Women and patients with satisfactory nutrition status showed good short-term response. Patients with small lesions and those treated for 12 months after sputum conversion showed good longterm outcomes. Patients who showed good short-term response, in the group with large lesions, showed significantly good long-term outcomes (P ). CONCLUSION: There were differences between prognostic factors reflecting short-term response and longterm outcomes. The short-term response predicts longterm outcomes in certain groups divided by prognostic factor. To establish standard treatment for pulmonary MAC disease, it is important to determine a standardised method of evaluation of treatment taking such factors into consideration. KEY WORDS: MAC; pulmonary disease; treatment; efficacy; outcomes; clarithromycin THERE ARE MANY REPORTS on the treatment of pulmonary Mycobacterium avium complex (MAC) disease. 1,2 However, the efficacy of treatment varies, and no standard regimen has been established. In 1997, the American Thoracic Society (ATS) recommended a four-drug regimen including clarithromycin (CLM). 3 In 1998, the Japanese Society for Tuberculosis (JST) reported that a three-drug regimen consisting of rifampicin (RMP), ethambutol (EMB) and an initial aminoglycoside (AG) should be standard treatment for pulmonary MAC disease. 4 In addition, the JST reported a study of the efficacy of CLM (600 mg/day) in addition to the three-drug regimen. 5 The CLM-containing regimen has been used widely as the virtual standard, and several reports have been published on its efficacy. 6,7 However, the efficacy of this regimen for the treatment of pulmonary MAC disease has never been confirmed by a randomised clinical trial. In addition, as several reports stated that RMP reduces the serum concentration of CLM in patients receiving both drugs, 8,9 the British Thoracic Society (BTS) did not recommend the CLMcontaining regimen. 10 The regimen was tested including other macrolides 11 and different administration methods for CLM. 12 To establish a standard treatment regimen, randomised clinical trials are necessary to confirm the efficacy of the regimen. Rational evaluation of its efficacy is also important. Several randomised trials for the treatment of disseminated MAC infection in patients with human immunodeficiency virus (HIV) have been reported In these trials, the MAC colony count was evaluated in serum. However, few randomised trials for the treatment of pulmonary MAC disease in HIV-negative patients have been reported. 17 In these trials, the failure of treatment/relapse rates was evaluated, and very long periods were needed for the study. In many non-randomised trials, the sputum conversion rate was evaluated. 6,7,18 21 Pulmonary MAC disease presents various clinical courses and shows a high degree of relapse. The time periods and responses that are necessary to evaluate treatment efficacy are an important problem. As survival takes a long time to evaluate, it would be useful to know whether short-term response predicts long-term outcome. For the randomised trial, it would also be useful to know Correspondence to: Toshiaki Fujikane, Department of Respiratory Medicine, Dohoku National Hospital, 7-Hanasaki, Asahikawa Japan. Tel: ( 81) Fax: ( 81) fujikane@douhoku.hosp.go.jp Article submitted 19 August Final version accepted 5 April 2005.

2 1282 The International Journal of Tuberculosis and Lung Disease what explanatory variables should be considered to randomise the subjects. The first aim of this study was to investigate whether short-term response predicts long-term outcomes. The second aim was to analyse what explanatory variables are associated with short-term response and long-term outcomes. In this study, we reviewed consecutive patients with pulmonary MAC disease who were treated with the CLM-containing regimen. We evaluated the short-term response by sputum conversion at 4 6 months after treatment, and evaluated the long-term outcomes by patient status (whether treatment was completed and whether the patient remained culture-negative) using the most recent information available. SUBJECTS AND METHODS Patients in whom pulmonary MAC disease was diagnosed using ATS criteria 3 and treated at Dohoku National Hospital were reviewed from January 1997 to December The subjects of this study were consecutive patients receiving initial treatment with a three- or four-drug regimen containing CLM for 6 months, who were followed up for 2 years. The three-drug regimen consisted of RMP 450 mg/day, EMB 750 mg/day and CLM 600 mg/day (weight 50 kg) or 400 mg/day (weight 50 kg). The fourdrug regimen consisted of streptomycin (SM) 1 g twice a week for the initial 6 months in addition to the three-drug regimen. Treatment efficacy was evaluated by short-term response, sputum conversion rate and long-term outcomes. Short-term response was evaluated at 6 months after the start of treatment. Patients who converted to culture-negative at 4 6 months after beginning treatment were regarded as having a good short-term response. In 31 patients who stopped producing sputum during treatment, sputum was induced by inhalation with hypertonic saline. The sputum conversion rate was estimated using two methods: 1) the initial conversion rate after treatment, and 2) the cumulative conversion rate, which reflected relapse. Long-term outcomes were based on the most recent information available for the patients after an observation period of more than 2 years. Patients who completed treatment and remained culture-negative were regarded as having a good long-term outcome. Patients who died due to pulmonary MAC disease were regarded as having a poor long-term outcome. Patients who died for other reasons were evaluated on the basis of the last information available. Sputum conversion was defined as three consecutive negative sputum cultures over a 6- month period, with the time of conversion the date of the first negative culture. Cases whose sputum culture converted back to positive within 6 months were defined as persistent culture-positive. Sputum relapse was defined as two consecutive positive cultures after sputum conversion. Nine explanatory variables were analysed for their association with short-term response and the initial conversion rate after treatment: 1) sex (male vs. female), 2) previous tuberculosis treatment (yes vs. no), 3) underlying respiratory disease (yes vs. no), 4) body mass index (BMI) ( 18 vs. 18), 5) serum albumin concentration ( 3.5 vs. 3.5 g/dl), 6) extent of lesion (small vs. large), 7) cavity on chest X-ray (yes vs. no), 8) CLM dosage ( 12 vs. 12 mg/kg), and 9) use of AG (yes vs. no). In addition to the above, 10) the period of treatment after sputum conversion ( 12 months vs. 12 months) was analysed for its association with long-term outcomes and the cumulative conversion rate. Fisher s exact test was used to compare the proportion of patients who showed good responses or outcomes. Variables were analysed for their association with short-term response and long-term outcomes, using simple regression. After excluding variables that had a mutually significant relation, the remaining variables were analysed using multiple regression. Fisher s exact test was used to analyse the relation between variables. Sputum conversion rates were estimated using the Kaplan-Meier method. Variables were analysed for their association with both rates using Cox s proportional hazards model. Results were considered statistically significant with P value RESULTS From January 1997 to December 2001, 137 patients were diagnosed with pulmonary MAC disease and were treated with three- or four-drug regimens containing CLM. Twenty-six patients were excluded from this study: seven failed to complete 6 months of treatment; two died within 2 years due to pulmonary MAC disease and six died from other diseases; and 11 patients were lost to follow-up. The remaining 111 patients were eligible. All patients were Japanese, and 38 were male. Median age was 66 years (range years). Twenty-nine patients (26.1%) were smokers, and 36 (32.4%) had underlying pulmonary disease. Seventy-three patients (65.8%) were treated with the four-drug regimen, including an AG. The median observation period from the day of starting initial treatment was 45.6 months (range months); the median treatment period was 20.4 months (6 60 months). Twenty-five patients changed regimens due to side effects. Of these, 23 stopped one or more drugs, and two changed from SM to kanamycin. There was no addition of a new drug. Table 1 presents the characteristics and outcomes of the 111 patients. Three patients remained persistent culture-positive; two patients were alive at 60 and 29.9 months, respectively; one patient died due to malignant lymphoma at 34.0 months. There were

3 Treatment for MAC pulmonary disease 1283 Table 1 Characteristics and outcomes of 111 patients n (%) Bacteriology Remained culture-positive 3 (2.7) Converted to culture-negative 108 (97.3) Converted and then relapsed 25 (23.1) Relapsed and remained culture-positive 7 (6.3) Relapsed then reconverted to culturenegative 18 (16.2) Converted and remained culture-negative 83 (74.8) Conversion rate at time of writing 101/111 (91.0) Treatment Underwent retreatment 25/111 (22.5) Prognosis Died (all cases) 8/111 (7.2) Died due to MAC 1/111 (0.9) Short-term response Good* 84/111 (75.7) Long-term outcomes Good 91/111 (82.0) * Converted to culture-negative 4 6 months after treatment. Completed treatment and remained culture-negative on the basis of the last information. MAC Mycobacterium avium complex. no particular distinguishing characteristics in these patients. Twenty-five patients converted and then relapsed. Among these, seven remained culture-positive. The conversion rate at the time of writing was 91.0% (101/111). Twenty-five patients (22.5%) underwent a second course of treatment. Of these, 22 received a CLM-containing regimen, two received a levofloxacin-containing regimen, and one received an isoniazid (INH) containing regimen. Eight patients (7.2%) died. Among these, one (0.9%) died due to pulmonary MAC disease. Eighty-four patients (75.7%) showed a good short-term response, and 91 (82.0%) showed good long-term outcomes. Seventy-two patients (85.7%) who showed a good short-term response showed good long-term outcomes. On the other hand, 19 patients (70.4%) who showed a poor short-term response showed good long-term outcomes. There was no significant relationship between short-term response and long-term outcomes (P ). Table 2 presents the results of analysis of variables regarding short-term response. Simple regression analysis showed that serum albumin concentration 3.5 g/dl, female sex, and no cavity on chest X-ray were significantly favourable factors. Serum albumin concentration had a significant relation with cavity on chest X-ray (P ), BMI (P ), underlying respiratory disease (P ), and extent of lesion (P ). Multiple regression analysis excluding these variables showed that serum albumin concentration (P ) and sex (P ) were significant prognostic factors. Table 3 presents the results of analysis of variables regarding long-term outcomes. Simple regression analysis showed that small lesion, serum albumin concentration 3.5 g/dl, and BMI 18 were significantly favourable factors. Extent of lesion had a significant relation with serum albumin concentration (P ), BMI (P ), and underlying respiratory disease (P ). Multiple regression analysis excluding these variables showed that extent of lesion (P ) and period of treatment after sputum conversion (P ) were significant prognostic factors. The Figure shows the sputum conversion rates. The initial conversion rates after treatment were 82.9% and 92.8% at 6 months and 2 years, respectively. The cumulative conversion rate, which reflects relapse, was 63.1% and 76.6% at 6 months and 2 years, respectively. Table 4 presents the results of analysis of variables regarding the sputum conversion rate using Cox s proportional hazards model. Serum albumin concentration 3.5 g/dl and female sex were significantly favourable factors for the initial conversion rate, while small lesion was a significantly favourable factor for the cumulative conversion rate. In consideration of these results, 111 patients were divided into two groups by extent of lesion. In the large lesion group, 75.6% of the patients who showed a good short-term response showed good long-term outcomes, and 41.7% of the patients who showed a poor short-term response showed good long-term outcomes. In this group, there was a significant relation- Table 2 Results of simple and multiple regression analysis of variables regarding short-term response Response Simple regression Multiple regression Variables Favourable factor Good % Coefficient (95%CI) P Coefficient (95%CI) P Serum albumin concentration 3.5 g/dl (n 98) ( ) ( ) Sex Female (n 73) ( ) ( ) Cavity on chest X-ray No (n 88) ( ) Previous TB treatment No (n 91) ( ) ( ) CLM dose 12 mg/kg (n 51) ( ) ( ) Body mass index 18 (n 85) ( ) Use of AG Yes (n 72) ( ) ( ) Respiratory disease No (n 75) ( ) Extent of lesion Large* (n 53) ( ) * Lesion wider than the area of the upper part of the collarbone. CI confidence interval; TB tuberculosis; CLM clarithromycin; AG aminoglycoside.

4 1284 The International Journal of Tuberculosis and Lung Disease Table 3 Results of simple and multiple regression analysis of variables regarding long-term outcomes Favorable Outcomes Simple regression Multiple regression Variables factor Good % Coefficient (95%CI) P Coefficient (95%CI) P Extent of lesion Small* (n 58) ( ) ( ) Serum albumin concentration 3.5 g/dl (n 98) ( ) Body mass index 18 (n 85) ( ) CLM dose 12 mg/kg (n 60) ( ) ( ) Period of treatment 12 months (n 80) ( ) ( ) Use of AG No (n 39) ( ) ( ) Cavity on chest X-ray No (n 88) ( ) ( ) Sex Male (n 38) ( ) ( ) Respiratory disease No (n 75) ( ) Previous TB treatment No (n 91) ( ) ( ) * Lesion narrower than the area of the upper part of the collarbone. Period of treatment after sputum conversion. CI confidence interval; CLM clarithromycin; AG aminoglycoside; TB tuberculosis. ship between short-term response and long-term outcomes (P ). In the small lesion group, longterm outcome was almost always good. DISCUSSION Figure Sputum conversion rate: the initial conversion rate after treatment, and the cumulative conversion rate which reflects relapse. Both rates were estimated using the Kaplan- Meier method. We evaluated the efficacy of the CLM-containing regimen for 111 patients with pulmonary MAC disease. At 4 6 months after treatment, 84 patients (75.7%) converted to culture-negative. After 2 years of observation, 91 patients (82.0%) had ended treatment and remained culture-negative. Compared to the results of Wallace et al., 20 our results are poor in the shortterm but are better in the long-term. The reports of Wallace et al. 20 and Dautzenberg et al. 19 became the basis of the ATS recommendation. 3 These results were considered to be better in efficacy than results reported previously. 1,2 However, the methods of evaluation, such as definition of sputum conversion, differ between the reports. Kobashi et al. reported significant improvements in sputum conversion rate as a result of the increased use of CLM. 22 Although it was a historic review, the report evaluated efficacy in the same manner. The report suggests the efficacy of CLM, but there were no significant differences in sputum relapse rate, and whether CLM improves longterm outcomes is unclear. It is important to define the standardised method of evaluation of treatment for pulmonary MAC disease. In most reports, 7,20,21 sputum conversion was defined as three consecutive negative sputum cultures over a certain period. Because there are often sporadic positive cultures, we defined it more severely as three consecutive negative sputum cultures over a 6- month period. In most reports, 6,7,20 as in our study, sputum relapse was defined as two consecutive positive cultures after sputum conversion. Efficacy of treatment is evaluated as sputum conversion rate at a certain period after treatment. However, the time of evaluation is not established, such as 3 months after treatment, months after treatment, 7,21 and undefined. 20 In this study, we evaluated short-term response at 4 6 months after treatment, as did Kobashi et al. 7 The response rate was 75.7%. We also estimated the sputum conversion rates using the Kaplan- Meier method; the rate was 82.9% at 6 months after treatment. There are few reports regarding the long-term outcomes of pulmonary MAC disease, 17 and there is no standardised method of evaluation. In addition to sputum conversion, symptom subscale, 15 clinical improvement, 22 and radiological findings 22,23 were evaluated as an indicator of efficacy. Pulmonary MAC disease presents with various clinical signs 2,23 25 and shows a high degree of relapse. 17 The BTS Research Committee reported that 31% of patients treated with a regimen containing RMP EMB or RMP EMB INH were alive and cured 5 years after treatment. 17 Sakatani et al. reported that 80% of patients treated with a CLM-containing regimen remained culture-negative for at least 2 years. 26 In this study, we

5 Treatment for MAC pulmonary disease 1285 Table 4 Results of multivariate analysis by Cox s proportional hazards model Favourable Initial sputum conversion rate Cumulative sputum conversion rate Variables factor Hazard ratio (95%CI) P Hazard ratio (95%CI) P Serum albumin concentration 3.5 g/dl (n 98) ( ) ( ) Sex Female (n 73) ( ) ( ) Cavity on chest X-ray No (n 88) ( ) ( ) CLM dose 12 mg/kg (n 51) ( ) ( ) Previous TB treatment No (n 91) ( ) ( ) Respiratory disease Yes (n 36) ( ) ( ) Extent of lesion Small* (n 58) ( ) ( ) Use of AG Yes (n 72) ( ) ( ) Body mass index 18 (n 85) ( ) ( ) Period of treatment 12 months (n 80) ( ) * Lesion narrower than the area of the upper part of the collarbone. Period of treatment after sputum conversion. CI confidence interval; CLM clarithromycin; TB tuberculosis, AG aminoglycoside. evaluated the long-term outcomes based on the most recent information available for patients after more than 2 years of observation; 82.0% of the patients had completed treatment and remained culture-negative. We also estimated the cumulative conversion rate, which sums up relapse, using the Kaplan-Meier method; the rate was 76.6% 2 years after treatment. As patients with pulmonary MAC disease are often difficult to follow up for long periods, 2 the estimation of the sputum conversion rate using the Kaplan-Meier method is effective, especially for comparing the efficacy of different treatment regimens. 6 There are no reports on whether short-term response predicts long-term outcomes. In this study, most patients who showed a good short-term response showed good long-term outcomes. However, this was not statistically significant. The difference between the prognostic factors reflecting short-term response and longterm outcomes is conceivable as a reason. Women and patients with good nutritional status showed a good short-term response. On the other hand, patients with small lesions and those treated for 12 months after sputum conversion showed good long-term outcomes. A good short-term response, such as sputum conversion, did not predict cure. When patients were divided into two groups by prognostic factor, those who showed a good short-term response in the large lesion group showed significantly good long-term outcomes. To establish standard treatment for pulmonary MAC disease, randomised clinical trials are necessary, and very long periods are needed for evaluation of long-term outcomes. Short-term response, which rationally predicts long-term outcomes, is therefore needed. This study revealed that short-term response predicts long-term outcomes in groups divided by prognostic factor. These factors should be considered for randomisation of subjects in clinical trials. It is also important to determine the standardised methods of evaluation of treatment for pulmonary MAC disease. The definition of sputum conversion and sputum relapse, the time of evaluation and the indicator of long-term outcomes should be determined. This study showed that significantly favourable factors analysed using Cox s proportional hazards model were the same as significant prognostic factors analysed with multiple regression in both short-term responses and long-term outcomes. Therefore, the cumulative conversion rate which reflects relapse using the Kaplan-Meier method is conceivable as a useful indicator. References 1 Hunter A M, Campbell I A, Jenkins P A, Smith A P. Treatment of pulmonary infections caused by mycobacteria of the Mycobacterium avium-intracellulare complex. Thorax 1981; 36: Ahn C H, Ahn S S, Anderson R A, Murphy D T, Mammo A. A four-drug regimen for initial treatment of cavitary disease caused by Mycobacterium avium complex. Am Rev Respir Dis 1986; 134: American Thoracic Society. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am J Respir Crit Care Med 1997; 156: S1 S25. 4 Japanese Society for Tuberculosis. Opinion on therapy of atypical mycobacterial infections Kekkaku 1998; 73: Yamamoto M, Kuze F, Sakatani M, et al. The clinical study of clarithromycin for pulmonary Mycobacterium avium-intracellulare complex infection. Kekkaku 1997; 72: Tanaka E, Kimoto T, Tsuyuguchi K, et al. Effect of clarithromycin regimen for Mycobacterium avium complex pulmonary disease. Am J Respir Crit Care Med 1999; 160: Kobashi Y, Matsushima T. The effect of combined therapy according to the guidelines for the treatment of Mycobacterium avium complex pulmonary disease. Intern Med 2003; 42: Wallace R J Jr, Brown B A, Griffith D E, Girard W, Tanaka K. Reduced serum levels of clarithromycin in patients treated with multidrug regimens including rifampin or rifabutin for Mycobacterium avium-mycobacterium intracellulare infection. J Infect Dis 1995; 171: Peloquin C A, Berning S E. Evaluation of the drug interaction between clarithromycin and rifampin. J Infect Dis Pharmacother 1996; 2: Subcommittee of the Joint Tuberculosis Committee of the British Thoracic Society. Management of opportunist mycobacte-

6 1286 The International Journal of Tuberculosis and Lung Disease rial infections: Joint Tuberculosis Committee guidelines Thorax 2000; 55: Field S K, Cowie R L. Treatment of Mycobacterium aviumintracellulare complex lung disease with a macrolide, ethambutol, and clofazimine. Chest 2003; 124: Griffith D E, Brown B A, Cegielski P, Murphy D T, Wallace R J Jr. Early results (at 6 months) with intermittent clarithromycin including regimens for lung disease due to Mycobacterium avium complex. Clin Infect Dis 2000; 30: Chaisson R E, Benson C A, Dube M P, et al. Clarithromycin therapy for bacteremic Mycobacterium avium complex disease: a randomized, double-blind, dose-ranging study in patients with AIDS. Ann Intern Med 1994; 121: Dunne M, Fessel J, Kumar P, et al. A randomized, double-blind trial comparing azithromycin and clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with human immunodeficiency virus. Clin Infect Dis 2000; 31: Singer J, Thorne A, Khorasheh S, et al. Symptomatic and health status outcomes in the Canadian randomized MAC treatment trial (CTN010). Int J ATD AIDS 2000; 11: Benson C A, Williams P L, Currier J S. A prospective, randomized trials examining the efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons with acquired immunodeficiency syndrome. Clin Infect Dis 2003; 37: Research committee of the British Thoracic Society. First randomized trial of treatments for pulmonary disease caused by M. avium intracellulare, M. malmoense, and M. xenopi in HIV negative patients: rifampicin, ethambutol and isoniazid versus rifampicin and ethambutol. Thorax 2001; 56: Wallace R J Jr, Brown B A, Griffith D E, et al. Initial clarithromycin monotherapy for Mycobacterium avium-intracellulare complex lung disease. Am J Respir Crit Care Med 1994; 149: Dautzenberg B, Piperno D, Diot P, Truffot-Pernot C, Chauvin J-P, the Clarithromycin Study Group of France. Clarithromycin in the treatment of Mycobacterium avium lung infections in patients without AIDS. Chest 1995; 107: Wallace R J Jr, Brown B A, Griffith D E, Girard W M, Murphy D T. Clarithromycin regimens for Mycobacterium avium complex: the first 50 patients. Am J Respir Crit Care Med 1996; 153: Griffith D E, Brown B A, Girard W M, Murphy D T, Wallace R J Jr. Azithromycin activity against Mycobacterium avium complex lung disease in patients who were not infected with human immunodeficiency virus. Clin Infect Dis 1996; 23: Kobashi Y, Matsushima T. Comparison of clinical features in patients with pulmonary Mycobacterium avium complex (MAC) disease treated before and after proposal for guidelines. J Infect Chemother 2004; 10: Fujiuchi S, Matsumoto H, Yamazaki Y, et al. Analysis of chest CT in patients with Mycobacterium avium complex pulmonary disease. Respir 2003; 70: Huang J H, Kao P N, Adi V, Ruoss S J. Mycobacterium avium intracellulare pulmonary infection in HIV-negative patients without pre-existing lung disease. Chest 1999; 115: Prince D S, Peterson D D, Steiner R M, et al. Infection with Mycobacterium avium complex in patients without predisposing conditions. New Engl J Med 1989; 321: Sakatani M. Nontuberculous mycobacteriosis; the present status of epidemiology and clinical studies. Kekkaku 1999; 74: RÉSUMÉ CONTEXTE : Etude rétrospective des patients atteints de maladies pulmonaires dues au complexe Mycobacterium avium (MAC) et traitées par un régime contenant le clarithromycine. OBJECTIF : Investiguer dans quelle mesure la réponse à court terme au traitement permet de prédire les résultats à long terme, et analyser quelles variables explicatives sont en association avec l efficacité et les résultats finaux du traitement. SCHÉMA : On a évalué chez 111 patients le taux de négativation des expectorations à court et à long terme. Respectivement neuf et 10 variables explicatives ont été analysées en ce qui concerne leur association à la fois avec la réponse précoce et les résultats finaux. RÉSULTATS : Une bonne réponse à court terme a été observée chez 84 patients (75,7%) et les résultats finaux à long terme ont été bons chez 94 patients (82%). Les réponses favorables à court terme ont été observées chez les femmes et les patients en bonne condition nutritionnelle. Les patients dont les lésions sont limitées et ceux traités pendant 12 mois après la négativation des expectorations ont de bons résultats finaux à long terme. Dans le groupe de lésions étendues chez les patients dont la réponse à court terme était bonne, les bons résultats à long terme sont significatifs (P 0,0382). CONCLUSION : Les facteurs de pronostic concernant les réponses à court terme et les résultats finaux à long terme sont différents. La réponse à court terme permet de prédire des résultats finaux à long terme dans certains groupes délimités par les facteurs pronostiques. Pour l établissement d un traitement standard de maladies pulmonaires dues au MAC, il est important de déterminer le standard d évaluation du traitement en prenant ces facteurs en considération. RESUMEN MARCO DE REFERENCIA : Estudio retrospectivo de pacientes con micobacteriosis pulmonar por el complejo Mycobacterium avium (MAC), tratados con claritromicina. OBJETIVO : Investigar si la respuesta a corto plazo durante el tratamiento predice los resultados a largo plazo, y analizar las variables predictoras de eficacia y predictoras del desenlace del tratamiento. MÉTODO : Se evaluó la tasa de conversión del esputo a corto plazo y el desenlace a largo plazo en 111 pacientes. Se estudió la asociación de nueve y 10 variables predictoras con la respuesta y además de estas, una más con el desenlace. RESULTADOS : Ochenta y cuatro pacientes (75,7%) tuvieron una buena respuesta a corto plazo y 94 pacientes (82,0%) presentaron buen resultado a largo plazo. Las

7 Treatment for MAC pulmonary disease 1287 mujeres y los pacientes en buen estado nutricional tuvieron buena respuesta a corto plazo. Los pacientes con lesiones pequeñas y aquellos tratados durante 12 meses, tras la conversión del esputo, presentaron buenos resultados a largo plazo. Los pacientes con lesiones extensas, que presentaron una buena respuesta a corto plazo, tuvieron buenos resultados a largo plazo (P 0,0382). CONCLUSIÓN : Se observó una diferencia entre los factores pronósticos de la respuesta a corto plazo y del resultado a largo plazo. La respuesta a corto plazo predijo el resultado a largo plazo, en un grupo de pacientes determinado por los factores pronósticos. Para formular un tratamiento normalizado de la micobacteriosis pulmonar por el MAC, es importante definir criterios estándar de evaluación de este tratamiento, teniendo en cuenta los factores pronósticos mencionados.