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 TBHIV COMANAGEMENT, 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
ART

Combined

N=429 Late integrated group

Continuation Phase ART

Sequential group N=213

Continuation Phase 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

3301 Assessed for eligibility

1,970 excluded 794 HIV – 627 Declined Testing 349 never returned 200 other reasons 689 excluded 130 never returned 201 came after enrollment window was closed 91 no + smear 55 CD4>500 44 declined participation 16 declined ART 13 receiving ART 10 Died 12 No sputum test 6 not receiving TB treatment 3 Pregnant 108 other reasons

1331 screened

642

Randomized

429
79 Did not initiate ART 53 not completed 24m FU 16 died 19 LTFU 18 Withdrawn

213 Sequential group
113 Did not initiate ART 24 died 19 LTFU 56 awaiting ART 14 withdrawn

Integrated group

350 initiated ART

100 Initiated 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 TB (2) Respiratory distress(6) Metabolic acidosis (1) Cardiomyopathy, (1) Motor vehicle accident (1) Sequential Group n=14 TB (6) Respiratory distress (3) Non TB meningitis (1) Gastroenteritis (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 Skin and subcutaneous tissue disorders Blood & lymphatic system disorders (SD) Gastrointestinal & hepatobiliary SD Central nervous system Respiratory SD Cardiac disorders

Integrated N= 429 8 (1.8%) 21 (4.8%) 44 (10.2%) 30 ( 6.9%) 50 (11.6%) 3 (0.6%)

Sequential N= 213 6 (2.1%) 3 (1.4%) 11 ( 5.1%) 15 ( 7%) 27 (12.6%) 0

Genital Urinary SD Electrolyte & fluid volume abnormalities
Muscular skeletal disorder Neoplasm Eye abnormalities

6 (1.3%) 5 (0.2%)
7 (1.6%) 1 (0.2%) 1 (0.2%)

4 (1.8%) 1 (0.4%)
2 (0.9%) 2 (0.9%) 1 (0.4%)

Vascular SD Infections not specified
Metabolism/nutrition

2 (0.4%) 1 (0.2%)
3 (0.6%)

1 (0.4%) 1 (0.4%)
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 cotreatment which may reduce the benefits of starting co treatment earlier in public health programs

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