A pilot study of antituberculosis combinations comparing rifabutin with rifampicin in the treatment of HIV-1 associated tuberculosis. A single-blind randomized evaluation in Ugandan patients with HIV-1 infection and pulmonary tuberculosis

This pilot study was conducted at the Joint Clinical Research Centre (JCRC) in Kampala, Uganda, where tuberculosis (TB) is an epidemic health problem aggravated by the HIV-1 pandemic. To evaluate the feasibility of a larger phase III trial utilizing
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  Tubercle and Lung isease (1995) 76, 210-218 © 1995 Pearson Professional Ltd Tubercle and Lung isease A pilot study of antituberculosis combinations comparing rifabutin with rifampicin in the treatment of HIV-1 associated tuberculosis A single-blind randomized evaluation in Ugandan patients with I-IIV-1 infection and pulmonary tuberculosis S. Schwander*, S. Rtisch-Gerdes*, A. Mateega*, T. Lutalo *, S. Tugume*, C. Kityo*, R. Rubaramira*, P. Mugyenyi*, A. Okwera ~, R. Mugerwa ~, T. Aisu**, R. Moser t, K. Ochen**, B. M'Bonye*, M. Dietrich* *Clinical Department Bernhard Nocht Institute for Tropical Medicine, Hamburg, fForschungsinstitut Borstel, Borstel, Germany, Cooint Clinical Research Centre, Kampala, §Mulago University Hospital, Kampala, ** Uganda TB Investigation Centre, Bacteriological Unit, Kampala, ttRubaga Hospital, Kampala, fCCCMbuya Hospital, Kampala, Uganda S U M M A R Y. Setting: This pilot study was conducted at the Joint Clinical Research Centre (JCRC) in Kampala, Uganda, where tuberculosis (TB) is an epidemic health problem aggravated by the HIV-1 pandemic. Objective: To evaluate the feasibility of a larger phase III trial utilizing rifabutin as a substitute for rifampicin in short-course therapy for pulmonary TB. Design: Single-blind randomized trial in 50 patients with new onset smear- and culture-positive pulmonary tuberculosis and HIV-1 infection. Comparison of daily, intermittently supervised 6-month treatment regimens of rifabutin versus rifampicin, together with isoniazid, ethambntol and pyrazinamide. Results: Rifabutin- and rifampicin-containing regimens had comparable efficiency. However, rifabutin- treated patients had significantly more rapid clearance of acid-fast bacilli from sputum at 2 months (P < 0.05, Fisher exact test) and over the entire study period (P < 0.05, logrank test) than rifampicin-treated patients. The presence of eavitary disease was associated with a longer sputum conversion time for patients treated with either regimen. No major adverse events requiring dosage reduction or withdrawal of any study medica- tion were seen in either treatment group. Mean absolute peripheral blood CD4 T lymphocyte counts increased by 28% from week 0 to week 12 in all subjects (33 A. ~27/[tl, respectively). An unexpected finding was the isolation of Mycobacterium africanum from 49% of the sputum cultures. This is the first report indicating a high prevalence of M. africanum in human TB in Uganda. Conclusion: Short-course antituberculosis regimens containing rifabutin or rifampicin are both safe and efficacious in the treatment of HIV-1 associated tuberculosis. Rifabutin-containing regimens were associated with earlier sputum smear and culture conversion. R 1~ S U M 1~. Cadre: La pr~sente 6tude pilote a 6t6 men6e au Centre de Recherches Cliniques Collectives (JCRC), ~ Kampala, Ouganda, oh la tuberculose (TB) est un probl~me de sant6 end6mique, aggrav6 par la pand6mie de l'infection au VH-I-1. Objet: Evaluer la faisabilit6 d'une 6tude plus 6tendue de phase HI, remplagant la rifampicine par la rifabutine dans les r6gimes antituberculeux de courte dur6e. Schdma: Essai randomis6 en simple aveugle portant sur 50 sujets atteints d'une tuberculose pulmonaire r6cente frottis positif et positive ~ la culture, associ6e ~ une infection an VIH-1. Ont 6t6 compares des r6gimes d'une duroc de six tools, quotidiens, de surveillance intermittente, et contenant rifabutine ou rifampicine, et isoniazide, 6thambutol et pyrazinamide. Rdsultats: Les r6gimes contenant de la rifabutine ou de la rifampicine ont montr6 une efficacit6 comparable. N6anmoins les malades recevant de la rifabutine ont eu une disparition des bacilles acido-alcoolo-r6sistants dans leurs crachats significativement plus rapide ~ deux mois (P < 0,05, test exact de Fisher) et pour l'6tnde Correspondence o: Dr Stephan Schwander, Case Western Reserve University, Department of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106--4984, USA. Paper received 2 May 1994. Final version accepted 13 December 1994. 210  Treatment of HIV-assoeiated pulmonary uberculosis with rifabutin 211 enti~re (P < 0,05, test log-rank) par comparaison aux malades recevant de la rifampicine. La pg~sence de cavernes ~tait associ~e in une p~riode de conversion plus longue pour les malades dans les deux r~gimes. Aucune r~action adverse majeure n~cessitant une diminution des dosages ou l'interruption du traitement antituberculeux n'a ~t~ observ~e dans les deux groupes de traitement. Les comptages moyens absolus des lymphocytes CD4 T darts le sang p~riph~rique~nt augrnent~ de 28 entre la semaine 0 et la semaine 12 chez tous les malades (334/~ h 427/Ixi, respectivement). Une observation inattendue ~tait risolation ¢~e Mycobacte rium africanum ~ partir de 49 des cultures de crachats. Ceci constitue la premiere notification d'une prevalence ~lev~e de M. africanum dans la tuberculose humaine en Ouganda. Conclusion: Des rdgimes antituberculeux de courte dur~e et contenant de la rifabutine ou de la rifampicine sont stirs et efficaces dans le traitement de la tuberculose associ~e au VIH-1. Les r~gimes contenant de la rifabutine ont ~t~ associ~s h une conversion plus pr~coce des frottis et des cultures. R E S U M E N. Marco de referencia: Este estudio piloto fue realizado en el Joint Clinical Research Centre (JCRC) en Kampala, Uganda. La tuberculosis (TB) es un problema de salud end~mico en Uganda, el cual ha sido agravado por la pandemia de VIH-1. Objetivo: Evaluar la factibilidad de un estudio mils amplio, en fase HI, utilizando rifabutina como substituto de la rifampicina en la quimioterapia de corta duraci6n de la TB pulmonar. Mdtodo: Estudio en simple ciego, aleatorio, en 50 pacientes recientemente diagnosticados, con tuberculosis pulmonar con bacfloscopia y cultivo positivos e infecci6n VIH-1. Comparaci6n de esquemas terap~uticos diarios, de 6 meses supervisados en forma intermitente, los cuales contenian isoniacida, etambutol y pirazinamida, asociados ya sea con rifabutina o con rifampicina. Resultados: Los esquemas que contenian rifampicina tenian una eficacia comparable a aquellos que contenian rifabutina. Sin embargo, los pacientes tratados con rifabutina tenian una negativizaci6n significativamente mils rhpida de bacflos ficido-resistentes en el esputo a los dos meses (P < 0,05, test exacto de Fisher) y en el periodo completo de estudio (P < 0,05, test logrank), comparados con los pacientes tratados con rifampicina. La presencia de enfermedad cavitaria estaba asociada a un tiempo de negativizaci6n mils largo en los pacientes tratados con ambos esquemas. En ningdn grupo de tratamiento se observ6 efectos adversos que hubieran requerido la reducci6n de ias dosis o ia suspensi6n de algdn medicamento. El promedio absoluto del recuento de linfocitos T CD4 en la sangre perif~rica aument6 en 28 desde la semana 0 a la semana 12 en todos los sujetos (334/~tl a 427/p1, respectivamente). Un hallazgo inesperado fue el aislamiento Mycobacterium africanum en el 49 de los cultivos de expectoraci6n. Este es el primer informe que muestra una alta prevalencia de de M. africanum en el hombre en Uganda. Conclusidn: Los esquemas antituberculosos de corta duraci6n que contienen rifabutina y rifampicina son, ambos, inofensivos y eficaces para el tratamiento de la tuberculosis asociada a infecci6n VIH-1. Los esquemas que contienen rifabutina presentaron una negativizaci6n mds rfipida de la bacfloscopia y del cultivo de expectoraci6n. INTRODUCTION Tuberculosis (TB) and HIV-1 infection are major health problems in Uganda. Between 1985 and 1989 the number of admissions of patients with TB doubled at Mulago Hospital, the principal tertiary care teaching hospital in Kampala, Uganda? In 1992, 25 000 new tuberculosis cases were reported to the National Tuber- culosis and Leprosy Programme in Uganda, reflecting a 47 increase in cases from 1990. 2 At the National TB Treatment Centre in Kampala the prevalence of HIV-1 co-infection in individuals with new pulmonary tuber- culosis (FIB) was found to be 66 . 3 Possible reasons for this increase in TB in Uganda include a breakdown of the health infrastructure following repeated civil unrest, poor socio-economic conditions and the HIV-1 epidemic? At autopsy, active tuberculosis was present in 25 of adult Ugandan AIDS patients. 4 Increases in HIV-TB have been reported from many other African countries. 5-s Between 1990 and 2005 it is estimated that the inci- dence of TB in Africa may increase by 10 additional cases per 100 000 population per year, primarily due to the HIV epidemic. By the year 2000 it is estimated that one-seventh of all deaths due to TB will occur in HIV-infected individuals. 9 Although published sys- tematic surveys of drug susceptibility data are rare there is concern about the emergence of multidrug-resistant TB (MDRTB) in Africa. The circumstances for the emergence of MDRTB are present, especially in coun- tries with TB-control programmes which cannot assure a full course of effective therapy. Identification and rapid, effective treatment of smear-positive pulmonary TB cases continues to be the principal goal of TB control programmes in developing nations. Short-course regimens are indispensable elements of such control strategies because of improved patient adherence, con- venient application and lower rates of adverse drug reactions. Rifabutin has lower minimum inhibitory concentra- tion (MIC) values than fifampicin, ~°.u has shown some in vitro activity against Mycobacterium tuberculosis strains with low level rifampiein resistance, u demon- strates better tissue penetration L2 and better antituberculosis  212 Tubercle and Lung Disease activity in in vitro macrophage models than rifampicin, ~3 has shown some activity in the treatment of rifampicin- resistant tuberculosis, ~4.~s and is a potential candidate for lifelong preventive therapy against M. tuberculosis.16 We conducted a pilot study comparing the safety and efficacy of short-course regimens containing either rifabutin or rifampicin for the treatment of TB in HIV-1 seropositive patients in Uganda. PATIENTS AND METHODS Location of the study The study was conducted at the Joint Clinical Research Centre (JCRC) in Kampala, Uganda. JCRC is a joint venture of the Ministry of Health, the Ministry of Defence and the Department of Medicine of Makerere Medical School in Kampala. The study protocol was approved by the Ugandan AIDS Commission and the Ugandan National Council of Science and Technology. Screening procedure and eligibility Identification of appropriate study subjects with new onset (initial episodes) of acid-fast bacilli (AFB)-sputum smear-positive mycobacterial disease and HIV-1 infec- tion took place in the out-patient departments and wards of Mulago, Rubaga and Mbuya hospitals in Kampala. Pretest counselling for HIV-1 antibody testing was done by highly trained Ugandan counsellors at the JCRC or in the hospitals where patients were admitted. Informed consent was obtained from all study subjects before testing. Study candidates received written infor- mation about their HIV-1 antibody test results and re- ceived post-test counselling from trained counsellors. Information about HIV-I and TB transmission and counselling concerning means of preventing infection and further spread of HIV-1 and TB infection were given in individual or group meetings. Study candidates with positive HIV-1 antibody tests were given additional information about the aims of the TB treatment study, the implications of participation in the study, and their right to withdraw from study participation at any time. Study candidates were eligible for the study if they gave written informed consent and if they met the inclusion and exclusion criteria shown in Table 1. Study design, randomization and medication The study was designed as a single-blind, randomized, comparative treatment trial. All study data and labora- tory specimens were identified only by patient initials and a unique study patient identification number. Ran- dom assignment to study treatment regimens was per- formed by the JCRC dispenser by pulling consecutively numbered opaque envelopes containing randomly gen- erated treatment orders. Study patients received drugs corresponding to regimen 1 or regimen 2, as determined by the treatment orders, throughout the study period. Study nurses and physicians were not involved in the randomization process, were advised not to request in- formation about medication from patients and remained blind to treatment throughout the study. The dispenser and her deputy were the only persons not blind to the treatment regimen. Patients were able to determine differences in the shape of rifampicin tablets and rifabutin capsules, but were not informed about their content. The treatment consisted of daily morning intake of either rifabutin (RFB), isoniazid (H), ethambutol (E) and pyrazinamide (Z), labelled regimen 1, or of rifampicin (RMP), H, E and Z, labelled regimen 2 (Table 2). E and Z were given only for the first 2 months, RFB or RMP and H were given for 6 months. Treatment regimens were adapted and modified according to the World Health Organisation (WHO) guidelines for TB treatment in adults) 7 Dosage adjustments were made if patients gained or lost weight. Study drugs were taken daily in the morning hours. Therapy was intermittently supervised. Each patient was directly observed ingesting the study medications by the dispenser twice weekly during the first 8 weeks and once weekly during the subsequent 4 months of study therapy. Study medication was handed out to patients in prepacked dosages for each day until the next supervision day. Five patients who were hospitalized at study entry and 3 patients hospitalized during the study received daily directly observed therapy in the hospital. Study drugs were given in prepacked dosages to attending nurses and were administered under direct supervision daily on the wards. Clinical and laboratory examinations were continued as scheduled by the proto- col in all hospitalized study patients throughout the period of hospitalization. Table 1. Study eligibility criteria Inclusion criteria Exclusion criteria Chest X-ray suggestive for PTB AFB-positive sputum HIV-1 seropositive age ~> 15 years of age use of approved contraceptive method resident of Kampala Ugandan srcin signed informed consent uric acid > 24 mg/dl (men), > 18 mg/dl (women) ALT > 78 U/L total bilirubin > 2.5 mg/dl creatinine > 1.5 mg/dl alcohol abuse pregnancy/lactation PTB = pulmonary tuberculosis; AFB = acid-fast bacilli. Evaluation of study patients Clinical and laboratory evaluations were performed as shown in Table 3. Posterior-anterior chest X-ray films were assessed for either pathological features or normal appearance in the upper, middle and lower regions of each lung. Pre-therapy chest X-rays at study entry were used to assess radiological deterioration, stability or improvement of follow-up chest X-ray during study therapy. The radiographic extent of disease was graded as normal, minimal, moderately advanced or far advanced  Treatment of HIV-associated pulmonary tuberculosis with rifabutin 213 Table 2. Study medication in both regimens during initiation and continuation phase Initiation phase dosage (mg/d) Continuation phase dosage (mg/d) Body weight < 50 kg ~> 50 kg < 50 kg ~> 50 kg Rifabutin (RI *) 150 300 150 300 Rifampicin (R2t) 450 600 450 600 Ethambutol 800 1200 Pyrazinamide 1500 2000 Isoniazid 300 300 300 300 * RI = regimen 1, consists of daily rifabutin, ethambutol, pyrazinamide and isoniazid for 2 months followed by daily dfabutin and isoniazid for 4 months; * R2 = regimen 2, consists of daily rifampicin, ethambutol, pyrazinamide and isoniazid for 2 months followed by daily rifampicin and isoniazid for 4 months. Table 3. Schedule of examinations during the study week month Physical examination 0, 2, 4, 6, 8 3, 4, 5, 6 ESR, WBC, RBC, Hgb 0, 2, 4, 6, 8 3, 4, 5, 6 CD4, CD8 count 0 3 Creatinine, uric acid 0, 2, 4, 6, 8 3, 4, 5, 6 ALT, bilirubin 0, 2, 4, 6, 8 3, 4, 5, 6 Chest X-ray 0, 4, 8 3, 4, 6 Tuberculin skin test 0 3, 6 Medical history, vital signs 0, 1, 2, 3, 4, 5, 6, 7, 8 and every 2 weeks until month 6 Karnofsky Performance Score 0, 1, 2, 3, 4, 5, 6, 7, 8 and every 2 weeks until month 6 Adverse events assessment 0, 1, 2, 3, 4, 5, 6, 7, 8 and every 2 weeks until month 6 Sputum smears for AFB 0, 2, 4, 6, 8 until three consecutive negative smears Sputum culture 0 and at timepoint of sputum smear conversion ESR = erythrocyte sedimentation rates; WBC = white blood ceils; RBC = red blood cells; ALT = alanine aminotransferase; AFB = acid-fast bacilli. using criteria established by the National Tuberculosis and Respiratory Disease Association, USA. j8 Chest X-rays were classified as 'typical' tuberculosis if upper lung field infiltrates or cavities were present with or without lower lung field infiltrates or pleural effusions. Chest X-rays were classified as 'atypical' tuberculosis if infiltrates including cavities were present predominantly in the lower lung fields or if there was prominent hilar or mediastinal adenopathy. Early morning sputum samples were collected for AFB smear, culture speciation and substrain analysis and drug susceptibility testing prior to initiation of therapy and at the timepoint of three consecutive nega- tive sputum smears for AFB after initiation of therapy. Following identification of the first negative sputum smear result for a particular patient, subsequent sputum samples were immediately obtained from the patient. The date of the first of three consecutive AFB-negative sputum smears and cultures or a negative sputum smear followed by absence of sputum production was defined as the date of sputum conversion. Time to sputum con- version was calculated as the number of days from therapy initiation to the date of sputum conversion. Collection of sputum samples ended after completion of 6 months of therapy. Further follow-up sputum examinations were not performed due to the design of this pilot study. Patient adherence Adherence of patients was assessed by measuring their reliability in keeping appointment dates, by interviewing the patients and by random urine INH metabolite tests with niacin test strips (Difco). Study drugs were provided twice weekly during the first 8 weeks and weekly from week 9 to week 24. On each appointment date for the reception of study medication, patients were required to take that day's dose under supervision of JCRC personnel. Good compliance was defined as keep- ing more than 85 of the appointment dates, and posi- tive urine tests in more than 85 of the examinations. Patients falling to keep an appointment were traced by home visiting nurses within 48 hours and received additional counselling. Haematology Automated counting of white blood cells (WBC), red blood cells (RBC) and platelets was performed with a Coulter Counter T 540. Differential WBC counts and red cell morphology were assessed manually by oil immersion microscopy (x 1000). Erythrocyte sedimenta- tion rates (ESR) were measured by the Westergren method. Clinical chemistry Serum creatinine, uric acid, alanine aminotransferase (ALT) and total bilirubin concentrations were deter- mined using dry chemistry test strips (Reflotron, Boehringer Mannheim).  214 Tubercle and Lung Disease Determination of CD4 and CD8 lymphocyte subpopulations CD4 and CD8 T lymphocyte subsets were determined by flow cytometry (Becton Dickinson FACScan Model 1990). Absolute lymphocyte counts as determined by the Coulter T540 counter were then used to calculate absolute CD4 and CD8 T lymphocyte counts. All veni- punctures throughout the study were done between 9:00 and 11:00. Quality control of lymphocyte sub- population estimations was performed monthly by run- ning paired specimens on the FACScan at JCRC and a Coulter Epics IV flow cytometer at the Makerere Case Western Reserve Laboratory at Mulago Hospital. Sputum decontamination and cultures Sputum samples were digested and decontaminated with 1 N-acetyl-L-cysteine-sodium hydoxide. The samples were then cultured using both Ltwenstein-Jensen media slopes and a liquid culture system (MB check Base Medium, Roche) with solid agar-containing slides (MB check Slide E, Roche). Sputum cultures from initial sputum samples on Ltwenstein-Jensen slopes were sent to the German Reference Centre for Mycobacteria, Institute for Experimental Medicine and Biology, Forschungsinstitut Borstel, for substrain analysis and drug susceptibility testing. Biotech) was used for the detection of HIV-1 antibodies. All positive results were confirmed by HIV-1 Western immuno-blotting (Novapath a, BIO-RAD). Statistics All data were collected using standardized questionaires and later entered into a computer data base using EPI Info 5 software (Centers for Disease Control [CDC]). Tests of normality of the data at baseline was performed using the Kolmogorov-Smirnov statistic (P<0.05). Differences in means of the parameters of interest were investigated using the two sample t-test (for normally distributed data) and the nonparametric Kruskal-Wallis test for those that failed the test of normality. Subjects with information missing for any parameter analysed were excluded from that particular analysis. Deter- minations of statistical significance between mean values of laboratory parameters at week 0 and subse- quent weeks (2, 4, 6, 8, 12, 16, 20 and 24) were made for each regimen and for the entire patient group. The cumulative proportion of sputum conversion was estimated using the Kaplan-Meier method and differ- ences between regimen 1 and regimen 2 tested using the logrank test. Factors associated with the time to sputum conversion were determined using Cox proportional hazards regression analysis. Mycobacterial substrain analysis and sensitivity testing Mycobacterial speciation between M. tuberculosis and M. africanum was done at the German Reference Centre for Mycobacteria, Institute for Experimental Medicine and Biology, Borstel, Germany using previ- ously published methods? 9'2° Briefly, mycobacteria were determined to be M. africanum if the organisms grew slowly in dysgonic colonies, did not change the colour of bromcresol purple medium, formed a niveau in depth in Lebeck-medium, and gave negative niacin results and weakly positive reactions in nitrate reductase tests, weakly split urea, nicotin and pyrazinamide in amldase testing, had low (< 1 mm) catalase activity and were avirulent in rabbits. Drug susceptibility testing was performed by the indirect proportion method on L0wenstein-Jensen media and radiometric methods (Bactec 460 Tb). Tuberculin skin test Ten I.U. (0.1 ml) of PPD (Tuberkulin GT 10, Behring) were intradermally injected into the left forearm by the Mantoux technique and the largest diameter of the induration was noted after 72 hours. 21 HIV-1 serology An enzyme immuno-assay (Recombigen, Cambridge RESULTS Patient characteristics Out of 153 individuals with clinical signs and symp- toms of PTB screened between October 8, 1992 and December 20, 1992, 16 females (32 ) and 34 males (68 ) with HIV-1 infection and previously untreated PTB fulfilled the entry criteria and were enrolled into the study. Age, sex, BCG scar presence and other clinical and laboratory parameters were comparable between the two study groups at enrolment (Table 4). 37 (74 ) of the patients were civilians, 10 (20 ) were soldiers of the Ugandan National Resistance Army and 3 (6 ) were spouses of military personnel. C~mc~ ou~ome Study outcomes are summarized in Table 5. Three pa- tients (6 ) were dropped because of protocol violation. One of them was discovered to be receiving a second antituberculosis therapy regimen, and the other two patients defaulted. 41 (82 ) patients completed the six-month treatment course and improved. Six (12 ) patients died (4 on regimen 1, 2 on regimen 2) during the study period with a mean survival time in the study of 74 + 55 days (range 10-158 days). Only one autopsy could be obtained and revealed disseminated crypto- coccosis. Four other patients died with clinical diag- noses of cryptococcal meningitis, rapidly progressive
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