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1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 2011;365:

2 Supplementary appendix Integration of Antiretroviral Therapy with Tuberculosis Treatment Salim S. Abdool Karim 1,2,3, MBChB, PhD; Kogieleum Naidoo 1, MBChB; Anneke Grobler 1, MSc; Nesri Padayatchi 1,2, MBChB; Cheryl Baxter 1, MSc; Andrew L. Gray 2, MSc(Pharm); Tanuja Gengiah 1, MClin Pharm, MS (Epi); Santhanalakshmi Gengiah 1 MA(Res Psych); Anushka Naidoo 1, MMedSci(Pharm); Niraksha Jithoo 1, MBChB; Gonasagrie Nair 1, MBChB, MPH; Wafaa M. El-Sadr 3,4, MD, MPH; Gerald Friedland 5, MD; Quarraisha Abdool Karim 1,2,3, PhD Table of contents: Page METHODS SUPPLEMENT 1 Study Design and Procedures 1 Statistical methods 2 RESULTS SUPPLEMENT 2 Retention 2 Cause of death 2 IRIS-related deaths 2 Table 1: 3 Mortality, AIDS defining illness or mortality and immune reconstitution inflammatory syndrome rates in the three study groups at 18 months of follow-up in the SAPiT trial Table 2: 4 Clinical Outcomes of Tuberculosis and Antiretroviral Therapy after 18 months of follow up in the three groups in the SAPiT trial Table 3: 5 Grade 3 and 4 adverse events after 18 months of follow-up in the three groups in the SAPiT trial REFERENCES 8

3 METHODS SUPPLEMENT The study was conducted from 28 June 2005 to 4 July 2010 at the CAPRISA ethekwini HIV-tuberculosis clinic that adjoins one of the largest out-patient tuberculosis facilities in South Africa, the Prince Cyril Zulu Communicable Disease Centre (PCZCDC) in Durban. Patients were offered community or clinic based directly observed therapy (DOT). All patients received a standard package of care which included adherence counseling and cotrimoxazole prophylaxis. Additionally, female patients were required to use contraception while receiving efavirenz. Study Design and Procedures This was a prospective, open-label, randomized trial with three groups as follows: Early integrated-therapy group - antiretroviral therapy to be initiated within 4 weeks of starting tuberculosis treatment, Late integrated-therapy group - antiretroviral therapy to be initiated within 4 weeks of completing the intensive phase of tuberculosis treatment, and Sequential-therapy group - antiretroviral therapy to be initiated within 4 weeks after completing tuberculosis treatment. Following a review on 1 September 2008, the Safety Monitoring Committee recommended, based on superior survival in the combined integrated-therapy groups 1, that all participants in the sequential-therapy group be initiated on antiretroviral therapy as soon as possible and the two integrated-therapy groups continue follow-up with no changes. This analysis comprises complete follow-up data on the early integratedtherapy group and the late integrated-therapy group. Data on the sequential-therapy group as at 1 September 2008 are available elsewhere 1. Data on 18 month follow-up of all three study groups are presented in tables 4-6 below. Follow-up visits for clinical assessment and laboratory monitoring were scheduled monthly for 24 months. CD4+ count was measured using the FACS Calibur flow cytometer (Becton Dickinson, Franklin Lakes NJ, USA) and viral load by HIV RNA PCR (Roche Cobas Amplicor HIV-1 Monitor v1.5). IRIS was defined as the occurrence of new onset or worsening symptoms, signs or radiographic features temporally related to treatment initiation; together with a CD4 increase, viral load decrease and upon exclusion of confirmed TB or ART treatment failure, toxicity, non-compliance, or new concurrent opportunistic infections. All cases of IRIS identified during the trial were retrospectively assessed and were found to meet the 2008 IRIS definition of one major or two minor clinical criteria 2. 1

4 Statistical Methods Eligible HIV-tuberculosis co-infected patients were randomized without stratification to one of three treatment groups in a 1:1:1 ratio in permuted blocks of six or nine using sealed envelopes. The target sample size of 216 in each of the 3 groups was selected for 80% power to detect a 60% difference between two treatment arms if the predicted event rate is 10% in the least favorable group, adjusted for anticipated loss to follow-up. RESULTS SUPPLEMENT Retention The overall retention rates (proportion of all live patients in active follow-up) were 76.9% and 71.5% in the early and late integrated-therapy groups respectively. In the early integrated-therapy group, 15 (7.0%) patients died, 20 (9.3%) withdrew before study completion, 26 (12.1%) were lost to follow-up and 153 completed study follow-up. In the late integrated-therapy group, 15 (7.0%) patients died, 23 (10.7%) withdrew before study completion, 34 (15.8%) were lost to follow-up and 143 completed study follow-up (Figure 1). At 18 months, 15 of the 26 and 21 of the 34 patients lost to follow-up in the early and late integrated-therapy group respectively were known to be alive, and the clinical status of the remaining 24 patients was unknown. Causes of death Information on the 30 deaths was based on hospital chart notes for 10 participants, a death certificate for one participant and two independent oral reports of death for 19 participants. On the basis of the chart notes and death certificate, causes of death in the early integrated-therapy group (n=5) were: meningitis, respiratory distress, pneumonia, dehydration secondary to diarrhea, and motor vehicle accident, while the causes of death in the late integrated-therapy group (n=6) were: respiratory distress, pneumonia, lung abscess, HIV associated cardio-myopathy, metabolic acidosis and the cause of death was unclear in the chart notes of one participant. Based on two independent oral reports of death, available causes of death in the early integrated-therapy group (n= 5) were: respiratory distress, pneumonia, disseminated tuberculosis, thrombocytopaenia, and suicide. Available causes of deaths in the late integrated-therapy group (n=8) were respiratory distress for 2 participants, gastroenteritis for 3 participants, and tuberculosis, multi-drug resistant tuberculosis, motor vehicle accident for 1 participants each. The cause of death was not known for the remaining six participants. IRIS-related deaths Four participants who had been diagnosed with IRIS died; two of these deaths were attributed to IRIS. Both deaths, one due to pneumonia and one to severe respiratory distress, were in low CD4+ count patients in the early integrated-therapy group. 2

5 Table 1: Mortality, AIDS defining illness or mortality and immune reconstitution inflammatory syndrome rates in the three study groups at 18 months of follow-up in the SAPiT trial Early integrated therapy group Late integrated therapy group Sequential Therapy group Event Rate per 100 No of events/ No. of Event Rate per 100 No of events/ No. Person-Years (95% CI) Person-Years Person-Years (95% CI) of Person-Years No of events/ No. of Person-Years Event Rate per 100 Person-Years (95% CI) Mortality 15/ ( ) 15/ ( ) 35/ ( ) AIDS defining illness (by study definition) or death AIDS defining illness (by updated WHO criteria 3 ) or death Immune Reconstitution Inflammatory Syndrome 18/ ( ) 19/ ( ) 39/ ( ) 28/ ( ) 26/ ( ) 47/ ( ) 43/ ( ) 18/ ( ) 20/ ( ) 3

6 Table 2: Clinical Outcomes of Tuberculosis and Antiretroviral Therapy after 18 months of follow up in the three groups in the SAPiT trial. Early integrated therapy group N=214 Tuberculosis treatment outcomes Late integrated therapy group N=215 Sequential therapy group N=213 Tuberculosis cured 131 (61.2%) 138 (64.2%) 131 (61.5%) Tuberculosis treatment 40 (18.7%) 38 (17.7%) 31 (14.6%) successfully completed Treatment success 171 (79.9%) 176 (81.9%) 162 (76.1%) Died prior to tuberculosis treatment completion 14 (6.5%) 11 (5.1%) 19 (8.9%) Treatment interruption 5 (2.3%) 4 (1.9%) 12 (5.6%) Failure on first line regimen 6 (2.8%) 2 (0.9%) 4 (1.9%) Loss to follow-up prior to tuberculosis treatment outcome Transferred to other clinics - tuberculosis treatment outcome not known 13 (6.1%) 16 (7.4%) 12 (5.6%) 5 (2.3%) 6 (2.8%) 4 (1.9%) Early integrated therapy group n/n Percent (95% CI) HIV treatment outcomes Late integrated therapy group n/n Percent (95% CI) Sequential therapy group n/n Percent (95% CI) Viral load <400 copies/ml 144/ / /126 Mean CD4+ count increase from baseline cells/mm3 94.1% (88.8; 97.1) 94.4% (88.9; 97.4) 84.1% (76.3; 89.8) Mean (IQR) Mean (IQR) Mean (IQR) (192; 243, n=152) (150; 194, n=142) (126; 182, n=126) Tuberculosis cure was defined in accordance with the 2004 South African National tuberculosis Control Program Guideline, which states that "a patient who is smear-negative at, or one month prior to, the completion of treatment and on at least one previous occasion." Most study patients were unable to produce sputum after the first few months of tuberculosis treatment, making demonstration of a cure difficult. Successful completion of therapy was defined as the use of more than 85% of the prescribed medication. Treatment success is defined as Tuberculosis cure and successful tuberculosis treatment completion Therapy failure was defined as the presence of a positive smear or culture for Mycobacterium tuberculosis obtained at least 5 months after the initiation of tuberculosis therapy. 4

7 Table 3: Grade 3 and 4 adverse events after 18 months of follow-up in the three groups in the SAPiT trial Adverse Event Category Early Integrated-therapy Group (N=214) # of Gr 3/4 adverse events (# of serious adverse events) Late Integrated-therapy Group (N=215) # of Gr 3/4 adverse events (# of serious adverse events) Sequential therapy Group (N=213) # of adverse events (# of serious adverse events) Person years of follow-up Death Elective hospitalization 10 (10) 6 (6) 7 (7) Extrapulmonary tuberculosis 4 (3) 1 (1) 0 (0) Skin and subcutaneous tissue disorders Rash 2 (1) 2 (1) 5 (1) Cellulitis 1 (1) 0 (0) 0 (0) Incision site abscess 1 (1) 0 (0) 0 (0) Herpes Zoster virus 2 (0) 2 (0) 6 (0) Molluscum contagiosum 0 (0) 1 (0) 0 (0) Blood and lymphatic system disorders Lymphadenopathy 12 (3) 1 (1) 0 (0) Pancytopaenia 0 (0) 1 (1) 0 (0) Thrombocytopaenia 2 (2) 1 (1) 1 (0) Leukopaenia 1 (1) 1 (1) 0 (0) Neutropaenia 0 (0) 1 (1) 2 (1) Anaemia 2 (2) 4 (1) 2 (2) Post procedural haematoma 1 (1) 0 (0) 0 (0) Gastrointestinal and hepatobiliary system disorders Gastrointestinal abnormalities 7 (2) 14 (7) 13 (4) Liver abnormalities 32 (13) 26 (17) 13 (7) Central nervous system Meningitis: cryptococcal 4 (3) 4 (4) 3 (3) Meningitis Tuberculosis 3 (3) 2 (2) 1 (1) Meningitis unspecified 0 (0) 1 (1) 4 (4) 5

8 Peripheral Neuropathy 3 (0) 4 (0) 1 (0) Neuropsychiatric 4 (2) 3 (2) 4 (3) Other central nervous system 7 (5) 5 (5) 6 (5) Respiratory system disorders Pneumocystis jiroveci pneumonia 1 (0) 1 (1) 6 (4) Bacterial pneumonia 0 (0) 0 (0) 1 (0) Pneumonia unspecified 23 (11) 13 (8) 12 (6) Tuberculosis 9 (0) 6 (5) 12 (11) Other respiratory 25 (7) 12 (9) 11 (4) Cardiac disorders Pericardial Effusion 0 (0) 1 (1) 0 (0) Cardiac arrhythmias 1 (1) 1 (1) 0 (0) Congestive cardiac failure 1 (0) 0 (0) 0 (0) Cardiomyopathy 0 (0) 1 (1) 0 (0) Genital urinary system disorders Cervical dysplasia 1 (1) 1 (1) 3 (2) Genital Abscess 0 (0) 0 (0) 1 (1) Anogenital Warts 0 (0) 0 (0) 1 (1) Haematuria 0 (0) 0 (0) 1 (0) Renal Failure 2 (2) 1 (1) 1 (1) Metrorrhagia 5 (0) 2 (0) 3 (0) Urine retention 1 (0) 0 (0) 0 (0) Electrolyte and fluid volume abnormalities Hyperuricaemia 0 (0) 0 (0) 1 (0) Hyperglycaemia 0 (0) 1 (0) 1 (0) Hypoglycaemia 0 (0) 0 (0) 1 (0) Blood Increased creatinine 1 (1) 0 (0) 0 (0) Hyponatraemia 1 (1) 0 (0) 1 (1) Hypoalbuminaemia 1 (0) 0 (0) 0 (0) Hypomagnesaemia 0 (0) 1 (1) 0 (0) Hypocalcaemia 0 (0) 1 (1) 0 (1) 6

9 Muscular skeletal disorders Muscular weakness 0 (0) 1 (0) 0 (0) Chest Pain 0 (0) 1 (1) 0 (0) Fractures 1 (1) 2 (2) 1 (1) Road traffic accident 1 (1) 1 (1) 2 (2) Wasting 2 (1) 2 (2) 0 (0) Gynecomastia 0 (0) 0 (0) 1 (0) Neoplasms Carcinoma Cervix 0 (0) 0 (0) 2 (1) Kaposi s sarcoma 1 (0) 0 (0) 0 (0) Uterine Leiomyoma 0 (0) 1 (1) 0 (0) Glioma 0 (0) 0 (0) 1 (1) B Cell Lymphoma 0 (0) 0 (0) 1 (1) Eye abnormalities Cataract 0 (0) 1 (1) 0 (0) Unilateral blindness 1 (1) 0 (0) 1 (0) CMV Chorioretinitis 0 (0) 1 (0) 0 (0) Vascular system disorders Deep Vein Thrombosis 2 (2) 0 (0) 0 (0) Epistaxis 0 (0) 0 (0) 1 (0) Infections and infestations not elsewhere specified Schistosomiasis 1 (0) 0(0) 0 (0) Chronic Otitis media 0 (0) 0 (0) 1 (1) Metabolism and nutrition disorders Diabetes Mellitis 1 (0) 0 (0) 1 (1) Dehydration 1 (1) 2 (2) 0 (0) Total 181 (84) 134 (92) 137 (78) 7

10 References 1. Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010;362: Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008;8: WHO. WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV-related disease in adults and children. Geneva, Switzerland: World Health Organisation;

Co-treatment of HIV and tuberculosis is associated with. Original Research

Co-treatment of HIV and tuberculosis is associated with. Original Research Annals of Internal Medicine Original Research The Immune Reconstitution Inflammatory Syndrome After Antiretroviral Therapy Initiation in Patients With Tuberculosis: Findings From the SAPiT Trial Kogieleum