timing of initiation of antiretroviral drugs during tuberculosis therapy salim s abdool karim et al...
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Timing of Initiation of Antiretroviral drugs during Tuberculosis Therapy
Salim S Abdool Karim et al Published on 25th 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 countriesHIV 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 othersWHO
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
reactionsfever, 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 2nd 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 <200CD4 200 -
350CD4 >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 25th 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 labeledRandomized 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 AgeConfirmed HIV infection (on the basis of two rapid HIV tests) andTuberculosis smear positivity for acid fast bacilli (Auramine/ZN staining)CD 4 cell count of <500 at screeningAbsence of clinical contraindication to start antiretroviral therapyFemale 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 consentConfirmed TB and HIV co-infection randomly assigned in 1:1:1 ratio in sealed envelopsStudy groups of Early Integrated, Late Integrated, Sequential therapy groupAnti retroviral drugs started within 4 weeks of the specified time in ATTAdherence counseling to all patientsProphylaxis with Trimethoprim-Sulphamethoxazole for opportunistic infection in HIV
Study procedures
Methods
ATT according to Guidelines of South African National Tuberculosis control programFirst Episode of TB to be treated with 2 Months intensive phase of Rifampin, INH, Ethambutol and PyrazinamideThereafter 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 monthsDirectly observed drug therapyMonitoring 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 therapyDidanosine (250mg if body weight <60kg, 400mg if body weight >60kg)Lamivudine (300mg), Efavirenz (600mg)Adherence to treatment assessed monthly according to pill countRegardless of the study-group, patient could be started on Anti retro viral treatment at anytime by clinicians at Communicable disease centre/physicians at their discretionFollow-up visits for safety and clinical status monthly for 2yearsAdverse events graded with use of Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse Events version 1.0CD4 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
DiscontinuationSide effects / toxic effectsHIV RNA Levels, Tuberculosis outcomeImmune reconstitution inflammatory
syndrome
Toxic effects asses by Clinical check list, Hemogram, LFT, RFT etc
Interim monitoring
Methods
1st 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 1st 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 1st September 2008All analysis performed according to Intention to treat principlePrimary outcome by Kaplan Meier Curves and LogRank testPoisson approximation used to calculate confidence interval for death rateProportional hazards regression model to adjust confounding variablesFisher’s exact test - categorical data analysisUnpaired 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
Results
Initiation of ART
Results
Integrated therapy (350)
Sequential therapy(100)
70± 7.2 days
260± 71 days
190 days later then integrated therapy groupInitiation of
ATT
Median duration of ATT was similar in patients who completed such therapy
Primary end point
Results
Integrated therapy group
25 deathsDeath rate of 5.4 per 100 personal yearsHazard 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 deathDeath 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 groupOver all mortality reduced by 56%(95% CI, 21 to 75)CD4 <200 death rate 46% lower (p=0.04)CD4 200 - 500 trend towards lower mortality
Sequential therapy groupDeath 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 countsNo interaction between CD4 count and study groups(P 0.57)
Treatment outcome
Results
Treatment adherenceIntegrated therapy group: 97.2%Sequential therapy group: 97.6 %ATT outcomeSimilar 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 groupImmune 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 groupImmune 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 groupOnce ART is started death similar viral suppression in both the groupsMajor concern are the issues related to early ARTImmune reconstitution and inflammatory reaction
Expected finding though higher in integrated therapy group
Rarely fatal, successfully managed with Steroids