HIV/TB Co

Infection

Timing of Initiation of
ART During TB Therapy

Niamh Barry
Niamh.barry85@gmail.
com
 Background
TB/HIV Co – Infection
• 33 million persons living with HIV
• 2 billion infected with TB
• 9.4 million people were newly diagnosed with TB
• 1.8 million people died from TB in 2008, including 500
000 people with HIV - equal to 4500 deaths a day
• The two diseases are closely intertwined, with TB as
the most common OI and one of the most common
cause of death for PLWHA in developing countries

WHO STOP TB update,2009

Background on Initiation of ART During
TB Therapy
• Concerns about co treatment
– Increased risk of the immune reconstitution
inflammatory syndrome (IRIS)
– Drugs toxicities
– Potential ART and TB drug interactions
– High pill burden
– Adherence issues
– Programmatic concerns
 Unresolved Questions on Co
Treatment
• Acceptability of co treatment among patients
• ARV/TB drug-associated toxicities.
• The effect of immediate versus deferred ART on
patient outcome.
• The effect of immediate vs. deferred ART on CD4
restoration and viral load
• The effect of co treatment on adherence/LTFU
• Effect of co treatment on IRIS
PREVIOUS STUDIES ON INITIATION
OF ART IN TB THERAPY
Previous studies on initiating ART in TB
Therapy
• Meta-analysis of COMESEM cohort Madrid N=313
• N=140 started ART during TB therapy < 2months
• N=173 delayed ART until > 3 months of TB therapy
• Primary outcome: From 1996-2000 ,9.3% ART+TB
therapy died compared with 19.7% for those who
delayed ART
• HR: 0.38; 95% CI 0.20 to 0.72, P = 0.003
• Simultaneous ART+TB therapy is associated with an
improvement in survival

Velasco M, JAIDS 2009;50:148-52.

Previous studies on initiating ART in TB
Therapy
• Meta-analysis of the Thailand TB Active Surveillance
Network
• Total N=1269. ART+TB (N=626) and TB only (N=643)
• Primary outcome: From 2004-2006 ,11% ART+TB therapy
died compared with 46% for those who delayed ART until
TB treatment completion
• RR: 0.24, 95% CI: 0.19 to 0.30
• Patients with very low CD4, 21% patients receiving ART
died compared with 81% patients not receiving ART during
TB therapy (RR 0.26, 95% CI: 0.16 to 0.44)
Sanguanwongse N,JAIDS 2008;48:181–189
WHO GUIDELINES

TUBERCULOSIS
CARE WITH TB-
HIV CO-
MANAGEMENT,
2007
When CD4 is <200
When CD4 is between 200 and 350
When CD4 is >350
Starting ART at Three Points in TB Trial
(SAPIT)
Study Goal

To determine the optimal time to initiate

antiretroviral therapy in patients with HIV and
tuberculosis co infection who were receiving
tuberculosis therapy.
 Study Design/Process
• Durban, South Africa from June 05 –July 08
(Follow up still ongoing)
• Patients: Adults, HIV positive (CD4<500), AFB
smear positive
• N=642
• Randomized into 3 arms:
1) Early integrated therapy group
2) Late integrated-therapy group
3) Sequential-therapy group
 Three Arms
Early integrated
group Continuation Phase
Combined

ART
N=429

Late integrated Continuation Phase

group
ART

Continuation Phase
Sequential group
N=213
ART
 SA TB Treatment Guidelines
• First episode of TB
– 2-month intensive regime (Rifampin, isoniazid,
ethambutol, and pyrazinamide)
– 4-month continuation regimen (Isoniazid and
rifampin)
• Recurrent episode of TB
– 3-month intensive regimen (Rifampin, isoniazid,
ethambutol, and pyrazinamide, addition of
streptomycin for the first 2 months)
– 5-month continuation regimen (Isoniazid and
rifampin)
 Study Procedure
• All patients received:
– Adherence counseling
– Prophylaxis with septrin
– once-daily three-drug ART regimen, consisting of D4T,
3CT and efavirenz.
• Regardless of the study-group assignment,
patients could be started on ART at any time by
clinicians at their discretion.
• Monthly follow-up visits for the monitoring of
safety and clinical status
 1,970 excluded
3301 794 HIV –
627 Declined Testing
Assessed for eligibility
349 never returned
200 other reasons

689 excluded
130 never returned
1331 201 came after enrollment
screened window was closed
91 no + smear
55 CD4>500
44 declined participation
16 declined ART
13 receiving ART
642 10 Died
Randomized 12 No sputum test
6 not receiving TB
treatment
3 Pregnant
108 other reasons
429 213
79 Did not initiate ART Integrated group Sequential group
53 not completed 24m 113 Did not initiate ART
FU 24 died
16 died 19 LTFU
19 LTFU 56 awaiting ART
18 Withdrawn 100 Initiated 14 withdrawn
350 initiated ART
ART
 Study End Points
• Primary end point:
– Death from any cause
• Secondary end points included
discontinuation due to:
– Side effects
– Drug toxicities
– Viral load
– Occurrence of IRIS
RESULTS
Baseline Characteristics of Patients
 Initiation of ART
210 days

Integrated TB Treatment
ART Treatment

70 days

207 days
Sequential TB Treatment 260 days
ART
Treatment

20 40 60 80 100 120 140 160 180 200 220 240 260 280

Number of Days
 Primary End Point
• Total of 52 deaths
• Integrated group:
– 25 (5.8%)
– death rate of 5.4 per 100 person-years
– Pre ART N=9
– During/post ART N=16
• Sequential group:
– 27 (12.6%)
– Death rate of 12.1 per 100 person-years
– Pre ART N=24
– During/post ART N=3
 Causes of Death
Integrated Group n=11 Sequential Group n=14
TB (2) TB (6)
Respiratory distress(6) Respiratory distress (3)
Metabolic acidosis (1) Non TB meningitis (1)
Cardiomyopathy, (1) Gastroenteritis (1)
Motor vehicle accident (1) Glioma (1)
Hepatic failure, (1)
Renal failure (1)

•Based on chart notes on 29 patients.

•4 charts were unreadable
•2 independent oral reports for 23 patients – Oral reports were
not reported
Death Rates and Hazard Ratios, Stratified by CD4
Count
Clinical Outcomes of HIV Therapy
 Adverse Events
• Among grade 3 or 4 adverse events:
• 206 (48%) occurred in the integrated-therapy
group
• 92 (43%) occurred in the sequential-therapy
group
Adverse Event Categories Integrated N= 429 Sequential N= 213
Skin and subcutaneous tissue 8 (1.8%) 6 (2.1%)
disorders
Blood & lymphatic system 21 (4.8%) 3 (1.4%)
disorders (SD)
Gastrointestinal & 44 (10.2%) 11 ( 5.1%)
hepatobiliary SD
Central nervous system 30 ( 6.9%) 15 ( 7%)
Respiratory SD 50 (11.6%) 27 (12.6%)
Cardiac disorders 3 (0.6%) 0
Genital Urinary SD 6 (1.3%) 4 (1.8%)
Electrolyte & fluid volume 5 (0.2%) 1 (0.4%)
abnormalities
Muscular skeletal disorder 7 (1.6%) 2 (0.9%)
Neoplasm 1 (0.2%) 2 (0.9%)
Eye abnormalities 1 (0.2%) 1 (0.4%)

Vascular SD 2 (0.4%) 1 (0.4%)

Infections not specified 1 (0.2%) 1 (0.4%)
Metabolism/nutrition 3 (0.6%) 0
 IRIS
• In this study IRIS was defined as:
A paradoxical deterioration in clinical status or
laboratory findings after the initiation
of antiretroviral or antituberculosis therapy without
another attributable cause.

• IRIS diagnosed in:

– 53 patients (12.4%, 95% CI, 9.5 to 15.9) in integrated
group
– 8 patients (3.8%; 95% CI, 1.8 to 7.5) in sequential
group
 Summary of Findings
• Death rate rose from 5.4 per 100 person years
to 12.1 per 100 person-years when initiation
of ART was delayed
• Once ART was initiated, it was associated with
high levels of viral suppression in both arms
• Among patients with CD4 < 200, the rate of
death was 46% lower in the integrated group
(P = 0.04).
 Summary of Findings
• Number of deaths was small in patients
(CD4>200) but was a trend toward lower
mortality in the integrated group
• Similar rates of grade 3 and 4 AEs in the two
arms
• Incidence IRIS was significantly higher in the
integrated group
 Limitations
• Use of death from any cause as the primary
end point might underestimate the potential
effect of integrated HIV/TB treatment
• Early initiation of ART in some patients in the
sequential group and delayed initiation in
some patients in the integrated group.
• Question of when exactly ART should be
initiated during TB therapy awaits completion
of the study.
DISCUSSION
 Discussion
• Did not use cultures so excluding XDR,MDR and
smear negative patients (i.e. the sicker
population)
• Older ART regime was used – D4T
• Possibility of misdiagnosis of IRIS as MDR was not
tested for
• Integrated arm patients may be sicker due to co-
treatment which may reduce the benefits of
starting co treatment earlier in public health
programs