Risk factors for active tuberculosis following antiretroviral treatment initiation in Abidjan

Transcription

1 Risk factors for active tuberculosis following antiretroviral treatment initiation in Abidjan Catherine Seyler, Siaka Toure, Eugène Messou, Dominique Bonard, Delphine Gabillard, Xavier Anglaret Online Data Supplement

2 1. Additional details on methods Patients and follow-up Since 1996, 723 HIV-infected adults have been followed up in Abidjan in the Cotrame ANRS 1203 cohort, which procedures have been described previously (E1,E2). In summary: written informed consent; standardized questionnaire at inclusion and at every monthly scheduled visit; CD4+ cell count at inclusion and every six months; cotrimoxazole prophylaxis in patients with CD4+ cell count under 500/mm 3 ; standardized algorithms of investigation and treatment; morbidity labeled by an event documentation committee; free-of-charge care; and systematic investigation of vital status for subjects who do not keep scheduled appointments (E3) ; Since 1998, patients from the cohort who had less than 200 CD4 per cubic millimeter and/or AIDS defining diseases were delivered antiretroviral drugs in one of the UNAIDS/Côte d Ivoire initiative pharmacy, but continued to be followed monthly and to receive all other care and drugs in the Cotrame cohort center (E2). Patients described here are all patients from the Cotrame cohort who have started HAART. Baseline was the day of HAART initiation. The study ended on July 31, The protocol of the Cotrame study has been approved by the ethics committee of the Ivoirian Ministry of Health and the Institutional Review Board of the French Agence Nationale de Recherche sur le SIDA (ANRS). Diagnosis and treatment of tuberculosis Before admission to the cohort In Côte d Ivoire, patients with symptoms evocative of TB are routinely referred to one of the centres of the national TB program. In this program, patients are considered for treatment in the presence of acid-fast mycobacteria and/or positive cultures. On admission to the program, patients receive a registration card, on which all details on TB documentation, date of treatment initiation and treatment regimen are recorded. The first line antituberculosis

3 curative regimen is 2ERHZ/4RH for all TB location and all HIV serostatus. At the end of the sixth month, microbiological and radiological controls are performed, and patients are considered as cured when both controls are negative. This conclusion is reported on the registration card. On admission to the Cotrame cohort, patients reporting a history of TB were asked to return the national program registration card, and the following data were recorded on the Cotrame inclusion form: history of TB (yes/no), localization (pulmonary, extrapulmonary or both), date of treatment initiation, treatment regimen(s) delivered, date of treatment termination, and conclusion of the TB program. During follow-up in the cohort On admission and during follow-up in the cohort, including before HAART and after HAART was started patients with symptoms consistent with TB were investigated with at least three sputum direct examinations and cultures and one chest X-ray. Other systematic investigations depended on signs and symptoms, as reported previously (E4). When an episode of active TB was diagnosed by the Cotrame study team, the treatment was given according to the national TB program recommendations, as described above. Definition of TB The following criteria were required for the diagnosis of active TB. Definitive TB: (i) consistent clinical picture, and (ii) positive culture for Mycobacterium tuberculosis of sputum sample or bronchoalveolar lavage ( pulmonary TB) or from normally sterile body fluid or tissue from a site other than lungs ( extra-pulmonary TB); Presumptive pulmonary TB: (i) Consistent clinical picture > 30 days, (ii) positive smear for acid-fast bacilli on sputum sample or bronchoalveolar lavage and/or non-microbiological evidence of pneumonia due to any other known pathogen, (iii) unsuccessful response to standard antibiotic therapy and (iv) successful response to standard antituberculous therapy; Presumptive extra-pulmonary TB:

4 (i) Consistent clinical picture > 30 days, (ii) positive smear for acid-fast bacilli on normally sterile body fluid or tissue from a site other than lungs and/or no other microbiological explanation, and (iii) successful response to standard antituberculous therapy. Definition of prior tuberculosis For each episode of TB which occurred before admission to the Cotrame cohort, the date of the episode was the date of treatment initiation in the national TB program centre. For each episode which occurred after admission to the Cotrame cohort, the date of the episode was the date of the first symptoms recorded in the Cotrame centre medical record. Patients were considered to have: (i) a past history of active TB at HAART initiation if they reported a history of TB on admission to the Cotrame cohort and/or if they had an episode of active TB which was considered to be cured between their admission to the Cotrame cohort and HAART initiation; (ii) a prevalent episode of active TB if they had an episode of active TB which was under treatment on HAART initiation, or if an episode of active TB was documented after HAART initiation and the date of the first symptoms recorded in the Cotrame centre medical record preceded the date of HAART initiation; (iii) an incident episode of active TB if TB was documented after HAART initiation and the date of the first symptoms was posterior to HAART initiation. Laboratory tools Blood cultures for mycobacteria were performed by means of the BACTEC radiometric system (BACTEC 13A vials, Becton Dickinson). Samples other than blood were processed with acid fast bacilli smear (AFB) after auramine staining and then cultured on a BACTEC Middlebrook medium (BACTEC 12B) and on Loweinsten-Jensen (LJ) agar (E5). Positive BACTEC vials were subcultured on LJ agar. Confirmed cultures were separated into the tuberculous group and mycobacteria other than tuberculosis (MOTT) group by means of

5 morphological examination and the radiometric NAP (p-nitro-alpha-acetylamino-betahydroxypropiophenone) inhibition test (Becton Dickinson) (E6). Statistical analyses The incidence rate of tuberculosis was defined as the number of patients with incident active tuberculosis per 100 patient-years (/100 P-Y) of at-risk follow-up. The at-risk period began on ART initiation and continued to the date of study termination, death, default or the date of the first episode of active tuberculosis. Default was the date of the last contact with the cohort team for all patients whose last contact was prior to the date of study termination and who were not found to be deceased prior to this date when investigating their vital status. Incident tuberculosis-free survival times were estimated using the Kaplan-Meier method. Univariate Cox proportional hazard regression models for first events were used to study the association between incident tuberculosis and baseline characteristics (E7). A multivariate model was then used to study the association between incident tuberculosis and all characteristics associated with tuberculosis with a p<0.25 in a univariate analysis. We decided a priori that the baseline CD4 count and the past history of TB would be included in the multivariate model even if not associated with tuberculosis with a p<0.25 in a univariate analysis, because of the existence of evidence of a likely association of these variables with the occurrence of TB. Incidence rates, hazard ratios and survival probabilities were given with their 95% confidence intervals (95% CI). Analyses were done with SAS statistical software version 8.02 (SAS Institute, Inc., Cary, North Carolina). 2. Additional details on results Table E1 shows the results of the univariate analyses.

6 References E1. Anglaret X, Messou E, Ouassa T, Toure S, Dakoury-Dogbo N, Combe P, Mahassadi A, Seyler C, N'Dri-Yoman T, Salamon R. Pattern of bacterial diseases in a cohort of HIV-1 infected adults receiving cotrimoxazole prophylaxis in Abidjan, Cote d'ivoire. AIDS 2003;17: E2. Seyler C, Anglaret X, Dakoury-Dogbo N, Messou E, Toure S, Danel C, Diakite N, Daudie A, Inwoley A, Maurice C, et al. Medium-term survival, morbidity and immunovirological evolution in HIV-infected adults receiving antiretroviral therapy, Abidjan, Cote d'ivoire. Antivir Ther 2003;8: E3. Anglaret X, Toure S, Gourvellec G, Tchehy A, Zio L, Zaho M, Kassi M, Lehou J, Coulibaly H, Seyler C, et al. Impact of vital status investigation procedures on estimates of survival in cohorts of HIV-infected patients from sub-saharan Africa. J Acquir Immune Defic Syndr 2004;35: E4. Anglaret X, Dakoury-Dogbo N, Bonard D, Toure S, Combe P, Ouassa T, Menan H, N'Dri-Yoman T, Dabis F, Salamon R. Causes and empirical treatment of fever in HIVinfected adult outpatients, Abidjan, Cote d'ivoire. AIDS 2002;16: E5. Kirihara JM, Hillier SL, Coyle MB. Improved detection times for Mycobacterium avium complex and Mycobacterium tuberculosis with the BACTEC radiometric system. J Clin Microbiol 1985;22: E6. Bonard D, Messou E, Seyler C, Vincent V, Gabillard D, Anglaret X. High incidence of atypical mycobacteriosis in African HIV-infected adults with low CD4 cell counts: a 6-year cohort study in Cote d'ivoire. AIDS 2004;18: E7. Cox D. Regression models and life-tables. J R Statist Soc. B; 34:

7 Table E1 : Factors associated with the occurrence of active tuberculosis after HAART initiation: univariate analysis * continuous variable, by 50/mm 3 ; ** continuous variable, by 5 years; *** continuous variable, by 1 kg/m 2