Timing of Initiation of Antiretroviral drugs during Tuberculosis Therapy Salim S Abdool Karim et al Published on 25 th February 2010 Speaker : Dr Anzar T

Introduction TB HIV Co-infection  Tuberculosis is the most common opportunistic infection in HIV infected persons  Tuberculosis the most common cause of death in patient with HIV in developing countries  HIV and TB epidemiology strongly influence each other  HIV – immune deficiency – newly acquiring TB  HIV promotes progression of latent TB into active TB and relapse in previously treated patients  Diagnostic issue of TB in HIV patients  TB - infects earlier than other opportunistic infections  TB – Only major AIDS related opportunistic infection with risk to others WHO

Introduction TB or HIV to be treated first? Tuberculosis must be treated to contain the source of infection WHO

Introduction Issues in TB HIV Co-infection treatment 1)Drug interactions  Rifampicin – inducer of cytochrome P450, decreases the level of Protease inhibitors and NNRTIs  PI and NNRTIs can enhance or inhibit enzyme system leads to decreased level of Rifampicin and ATT failure  Abacavir and INH combination – decreased level of Abacavir and increased level of INH WHO

Introduction Issues in TB HIV Co-infection treatment 2) Overlapping adverse reactions  Peripheral neuropathy ADR of NsRTIs(Didanosine, Zalcitabine and Stavudine etc)  Toxicity may be added if combined with INH WHO

Introduction Issues in TB HIV Co-infection treatment 3) Immune Reconstitution Inflammatory Syndrome(IRIS) ART Suppress viral replication Partial restoration of the immune system Immune reconstitution and inflammatory reactions fever, new/increase lymphadenopathy, new or worsening of pulmonary infiltrates, respiratory failure, pleuritis, pericarditis, skin lesions, epididymitis, hepato- splenomegaly, skin abscess Low baseline CD4 count, short interval between ATT and ART, disseminated TB, greated CD4 count, greater reduction in viral load Associated with MTB, NTM, leshmaniasis, fungal/viral infections Tuberculosis 2 nd Edition, Dr S K Sharma

Introduction The optimum time to start ART is unknown! Issues in TB HIV Co-infection treatment 4) Timing of ART ? HIV + TB CD4 <200CD CD4 >350 ART started as soon as ATT is tolerated, 2wks - 2 months ART started after intensive phase of ATT, 2 months Monitor CD4, Start ART when indicated WHO CD4 not available Start ART after 2wks - 2 months of ATT initiation

Introduction Current guidelines are based on Observational studies and expert opinions Despite guidelines the ART is differed till completion of ATT because of concern about potential issues Issues in TB HIV Co-infection treatment 4) Timing of ART ? NEJM

Salim S Abdool Karim et al Published on 25 th February 2010 Timing of Initiation of Antiretroviral drugs during Tuberculosis Therapy

The optimum time to start ART in HIV - TB Co-infection is unknown! Back ground

 Open labeled  Randomized Control Trial  conducted at eThekwini Tuberculosis clinic in Durban, South Africa  Patients recruited from 28 June 2005 to 11 July 2008 Methods Study

 at least 18 years of Age  Confirmed HIV infection (on the basis of two rapid HIV tests) and  Tuberculosis smear positivity for acid fast bacilli (Auramine/ZN staining)  CD 4 cell count of <500 at screening  Absence of clinical contraindication to start antiretroviral therapy  Female patients required to use contraception while on Efavirenz Patients Methods

ATT ( intensive) ATT(continuation)Post ATT Early integrated Late integrated Sequential Study procedures Methods  Informed consent  Confirmed TB and HIV co-infection randomly assigned in 1:1:1 ratio in sealed envelops  Study groups of Early Integrated, Late Integrated, Sequential therapy group  Anti retroviral drugs started within 4 weeks of the specified time in ATT  Adherence counseling to all patients  Prophylaxis with Trimethoprim-Sulphamethoxazole for opportunistic infection in HIV

Study procedures Methods  ATT according to Guidelines of South African National Tuberculosis control program  First Episode of TB to be treated with 2 Months intensive phase of Rifampin, INH, Ethambutol and Pyrazinamide  Thereafter continuation treatment with INH and Rifampin. Dose determined according to body weight.  Patient with a history of Tuberculosis 3 months intensive regimen, including addition Streptomycin in the first 2 months  Directly observed drug therapy  Monitoring of Radiographic changes and sputum conversion at screening, at the end of intensive phase, 1 month before the end of ATT and whenever clinically indicated. Anti Tubercular Treatment

Study procedures Methods  Three drug Anti retroviral therapy  Didanosine (250mg if body weight 60kg)  Lamivudine (300mg), Efavirenz (600mg)  Adherence to treatment assessed monthly according to pill count  Regardless of the study-group, patient could be started on Anti retro viral treatment at anytime by clinicians at Communicable disease centre/physicians at their discretion  Follow-up visits for safety and clinical status monthly for 2years  Adverse events graded with use of Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events version 1.0  CD4 Counts, HIV RNA performed at screening, randomization and every 6 months Anti Retroviral Treatment

End points Methods Primary End points Secondary End points Death from any cause Discontinuation Side effects / toxic effects HIV RNA Levels, Tuberculosis outcome Immune reconstitution inflammatory syndrome Toxic effects asses by Clinical check list, Hemogram, LFT, RFT etc

Interim monitoring Methods 1 st September 2008, safety monitoring committee recommended to start Antiretroviral therapy for all patients in the sequential therapy group, but remain in follow up Integrated therapy group - no change Data up to 1 st September 2008 used to compare the two groups viz. Integrated and Sequential therapy groups

Statistical analysis Methods Duration of the study - calculated - time from randomization to death/withdraw from the study/cut of date of 1 st September 2008 All analysis performed according to Intention to treat principle Primary outcome by Kaplan Meier Curves and LogRank test Poisson approximation used to calculate confidence interval for death rate Proportional hazards regression model to adjust confounding variables Fisher’s exact test - categorical data analysis Unpaired t-test / wilcoxon two sample test for continuous data analysis

Results 642 patients with HIV and TB co-infection Patients 429 Integrated therapy group 213 Sequential therapy group At baseline two groups similar in demographic, clinical characteristic( CD4, HIV RNA) Mean follow-up in the study 12.1 months Lost to follow-up - 4 months without a visit

Results

Initiation of ART Results Integrated therapy (350)Sequential therapy(100) 70± 7.2 days260± 71 days 190 days later then integrated therapy group Initiation of ATT Median duration of ATT was similar in patients who completed such therapy

Primary end point Results Integrated therapy group  25 deaths  Death rate of 5.4 per 100 personal years  Hazard ratio 0.44, (95% CI, 0.25 to 0.79P 0.003)  After adjusting to Status of HIV infection, CD4, Age, Sex, history of TB, extra pulmonary TB, HIV RNA level Hazard ratio is 0.43, (95%CI, 0.25 to 0.77 p=0.004)  Cause of death – Tuberculosis (2) including TBM, Respiratory distress / P.jiroveci (6), metabolic acidosis(1), cardio myopathy(1), Road traffic accident (1) Sequential therapy group  27 death  Death rate of 12.1 per 100 person year  Cause of death – Tuberculosis (6) including TBM, Respiratory distress / P.jiroveci (3), non tubercular menigitis(1), gastro enteritis(1), renal failure(1), hepatic failure(1), glioma(1) Source: Hospital chart notes, death certificate, Oral reports of death. Cause of death could not gather for all cases

Primary end point Results Integrated therapy group  Over all mortality reduced by 56%(95% CI, 21 to 75)  CD4 <200 death rate 46% lower (p=0.04)  CD trend towards lower mortality Sequential therapy group  Death rate increased from 5.4 to 12.1 per 100 person year when delayed till completion of ATT

Results

Primary end point Results CD4 Counts: Independently predicted mortality in both groups. Mortality was lower in Integrated therapy group in all CD4 counts No interaction between CD4 count and study groups(P 0.57)

Treatment outcome Results Treatment adherence Integrated therapy group: 97.2% Sequential therapy group: 97.6 % ATT outcome Similar in two study group, whether first episode or repeated episode of therapy

Treatment outcome Results ART outcome (Suppression o f HIV RNA)  12 m of randomization: higher in integrated group (90.0 vs. 77.8%, p 0.006)  6 m after ART: similar in two groups

Adverse events Results Integrated therapy group  Immune reconstitution and inflammatory syndrome  53 / 429 (12.5%) p=<0.001  5 needed to use corticosteroids  No need to change in therapy  No death attributed  Other adverse events  140 / 429 (30 / 100 person year, p= 0.69) Sequential therapy group  Immune reconstitution and inflammatory syndrome  8 / 213 (3.8%), p=<0.001  1 needed to use corticosteroids  No need to change in therapy  No death attributed  Other adverse events  71 / 213 (32 / 100 person year, p= 0.69)

Limitations of the study Discussion  Not able to obtain cause of death in all cases  only death from any cause considered  Could not estimate death resulting from HIV/TB  Results may not be generalized to all forms and severity level of TB  May be applicable to Extra pulmonary tuberculosis  Sputum Smear Negative TB may be applicable, need confirmation  Timing of initiation of Anti retroviral therapy  Non study care providers took precedence over protocol timing  Delay in initiation of Anti retroviral therapy due  Clinical issues: elevated liver enzymes

Conclusion Discussion  Integrated therapy reduced mortality by 56%  Death rate rose from 5.4 to 12.1 % per 100 person year when the treatment is delayed in sequential therapy group  Once ART is started death similar viral suppression in both the groups  Major concern are the issues related to early ART  Immune reconstitution and inflammatory reaction  Expected finding though higher in integrated therapy group  Rarely fatal, successfully managed with Steroids