1. Management of HIV/TB Co-infection
Dr.G.Manoharan
Medical Director,
International Training and Education Center for Health India
Clinical Associate Professor, DGH,UW.

2. Topics to be discussed
When to start ART in HIV associated Tuberculosis
Duration of TB treatment
Intermittent Vs Daily TB treatment
Drugs used in the TB Treatment
Recurrent TB/Relapse/Re-infection
Role of steroids

3. Case study 35 yrs. male HIV +VE
Hospitalized for weight loss, fever, and cough with expectoration
Diagnosed as sputum negative pulmonary TB, oral candidiasis and HIV wasting.
CD4 cell count- 70 cells & 18.3%
Chest x-ray : 29th May, 04.

4. Case study OI s managed appropriately
Managed with ATT ( 2HREZ and 4RH), ART ( ddI,3TC and EFV) along with CTZ and Vitamins
Followed up regularly for almost an year

5. Chest x-ray : 29th May, 04.
Chest x-ray : 20th Sept, 04.

6. Chest x-ray : Feb 05.
Chest x-ray : June, 05.

7. TB therapy in patients with HIV-TB Co-infection
Aims of TB therapy are to
Achieve cure and prevent death
Prevent relapse
Render patients non-infectious as rapidly as possible
Prevent the emergence of drug resistance.

8. TB therapy in patients with HIV-TB Co-infection
So to achieve our aim, we need to
kill the actively metabolizing TB bacilli (Isoniazid)
destroy less actively replicating bacilli in the acidic and anoxic closed lesions(Pyrazinamide)
kill near-dormant bacilli that might otherwise cause a relapse of the disease (Rifampin)

9. TB therapy in patients with HIV-TB Co-infection
So the Anti TB drugs are given as
Initial Intensive phase
followed by a
Continuous Phase

10. TB therapy in patients with HIV-TB Co-infection
1. When will you start ART in patients with HIV-TB Co infection?
2. Do you give 6 months therapy or 9 months therapy?
3.Do you treat with intermittent regimen or daily Regimen?
4. What drugs do you use? Rifampin throughout the therapy?
5.What to do after the completion of ATT?

11. 1 .When to Start Antiretroviral Therapy in HIV- TB co-infection
Early ART
IRIS
Drug Toxicity
Drug interactions
High pill burden
Delayed ART
AIDS related Illness
Mortality

12. Studies: Early Vs Late initiation of ART
The Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPIT) trial
The AIDS Clinical Trials Group Study A5221
The Cambodian Early versus Late Introduction of Antiretrovirals (CAMELIA) study
N Engl J Med 365;16 october 20, 2011

13. SAPiT Trial: Main Findings
Integrated therapy associated with 56% reduction in risk of death Vs sequential therapy
Outcome
Integrated Therapy (n = 429)
Sequential Therapy (n = 213)
HR (95% CI)
P Value
All patients
Death rate per 100 person-yrs
Deaths, n
5.4 25
12.1 27
0.44 ( )
.003
CD4+ cell count ≤ 200 cells/mm3
8.2 23
15.3 21
0.54 ( )
.04
CD4+ cell count > 200 cells/mm3
1.1 2
7.0 6
0.16 ( )
.02
Integrated therapy independently associated with reduced risk of death (HR: 0.43; 95% CI: ; P = .004)

14. SAPiT: Increased survival with concurrent HIV and TB treatment
Abdool Karim SS, et al. CROI Abstract 36a.
0.70
0.75
0.80
0.85
0.90
0.95
1.00
Survival
Months Postrandomization 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Intensive phase of TB treatment
Post-TB treatment
Continuation phase of TB treatment
Early ART
Sequential ART

15. CAMELIA trial
N Engl J Med, Vol 365;1No 6 ; october 20, 2011; Pages

16. At wk 50, the median gain in the CD4 count was 118 in the earlier-ART group and 112 in the later-ART group (P = 0.22).
whereas Viral load was undetectable in 96.5% of pts, with no difference between the two study groups (P = 0.82),

17. CAMELIA trial : Early initiation of ART (2 weeks after the start of tuberculosis therapy) significantly increases survival among HIV infected adults with newly diagnosed tuberculosis and CD4+ T-cell counts of 200 per cubic millimeter or lower.
This is of particular relevance in resource-limited settings where tuberculosis is the leading cause of death in HIV-infected patients

18. Duration of TB treatment
2. TB therapy in patients with HIV-TB Co infection
Duration of TB treatment
6 Months Vs 9 Months or longer…..

19. 6 months supervised intermittent TB therapy in patients with and without HIV- Haiti
Short-course, thrice-weekly therapy highly efficacious in HIV positive and HIV negative patients
427 Patients ; 177 HIV +VE
Outcome
HIV Positive
HIV Negative
Cure
81%
89%
Relapse
5.4%
2.8%
Death 9% 1%
Ref: Chaisson RE, Clermont HC, Holt EA, Cantave M, Johnson MP, Atkinson J, Davis H, Boulos R, Quinn TC, Halsey NA. Six-month supervised intermittent tuberculosis therapy in Haitian patients with and without HIV. Am J Respir Crit Care Med 1996;154:1034–1038.

20. Successful Treatment rate 34-100% 91-99%
Ref: El-Sadr WM, Perlman DC, Denning E, et al. A review of efficacy studies of 6-month short-course therapy for tuberculosis among patients infected with human immunodeficiency virus: differences in study outcomes. Clin Infect Dis 2001; 32: 623–632.
TB Outcome
HIV Infected
HIV Un infected
Cure Rate
59-97%
62-88%
Successful Treatment rate
34-100%
91-99%
Relapse Rates
0-10%
0-3%

21. Outcome of 6 Vs 9 Months anti-TB treatment in HIV-associated tuberculosis (without ART)
Antiretroviral treatment–naïve, HIV-Positive patients with TB, a 9-month regimen resulted in a similar outcome at the end of treatment but a significantly lower bacteriological recurrence rate compared with a 6-month thrice-weekly regimen. ARR was high with these intermittent regimens and neither mortality nor ARR was altered by lengthening TB treatment.
ARR > Acquired Rifamycin Resistance
Reference: Am J Respir Crit Care Med Vol 181. pp 743–751, 2010

22. (2EHRZ3/4RH3) Vs (2EHRZ3/7RH3)
Sputum culture negativity in months

23. Kaplan-Meier plot showing time to death for patients in the 6-month regimen(blue line) and in the 9-month regimen (green line); P = 0.17 (not significant)..

24. Time to bacteriological recurrence up to 36 months for patients in the 6-month and 9-month regimen
9 Months Regimen
P = 0.03
6 Months Regimen

25. 6 Months Vs 9 Months Therapy
A retrospective review from the US showed no treatment failures in HIV-1 infected patients administered a 6 month standard rifampicin-based regimen but relapse rates were four-times higher in those treated for 6 months compared to those treated for longer.
Nahid P, Gonzalez LC, Rudoy I, et al. Treatment outcomes of
patients with HIV and tuberculosis. Am J Respir Crit Care Med
2007; 175: 1199–1206.

26. Duration of TB therapy
Overall most studies concur that standard TB treatment should be given to HIV-1 infected patients whenever possible .
A 6-month treatment regimen that includes rifampicin and INH throughout should be given for drug-sensitive TB (outside of the central nervous system). This is usually a regimen of four drugs for 2 months, followed by INH and rifampicin for a further 4 months. .

27. Duration of ATT
Current recommendations: Standard 6-month regimens and the extension of therapy to 9 months for patients with extra pulmonary disease or a delayed response.
NACO guideline: Recommended to follow RNTCP guideline.
Guidelines for Prevention and Management of Common Opportunistic Infections/Malignancies among HIV-Infected Adult and Adolescent, May 2007; NACO.
The Journal of Infectious Diseases 2007; 196 : S35-45 ; BHIVA treatment guidelines for TB/HIV infection, February 2005.

28. Intermittent Dosing /Therapy Vs
3. TB therapy in patients with HIV-TB Co infection
Intermittent Dosing /Therapy Vs
Continuous therapy

29. Contraindicated Once weekly INH and Rifapentine
Twice weekly Rifampin- or Rifabutin- based regimens

30. Pooled estimates of outcomes stratified by schedule of treatment administration during the initial intensive phase ( first 8 weeks)
Outcome
Treatment Schedule
No of events/subjects
Pooled event rate(95% C1), %
Failure
Daily
74/2531
2.5( )
3 Times weekly
12/163
5.3( )
Relapse
142/1241
6.7( )
18/65
28.1(0-69.5)
Death during Treatment
430/2957
11.9( )
31/194
14.3( )

31. Intermittent Dosing ( ATT)
Current recommendations: In patients who have advanced immunodeficiency daily or three times weekly treatment for at least the first two months of intensive therapy.
NACO guideline: Recommend intermittent ( three times weekly ) regimen( as per RNTCP guideline) for all patients
The Journal of Infectious Diseases 2007; 196 : S35-45

32. What drugs do you use? Rifampin throughout the therapy?
4. TB therapy in patients with HIV-TB Co infection
What drugs?
What drugs do you use? Rifampin throughout the therapy?

33. Randomized controlled Trial of two 8-month regimens- a non inferiority study
Ref: Results at 30 months of a randomized trial of two 8-month regimens for the treatment of tuberculosis: A.J. Nunn et al, Int J Tuberc Lung 15(6): , 2011

34. Status at 30 months by treatment arm and HIV status
Ref: Results at 30 months of a randomized trial of two 8-month regimens for the treatment of tuberculosis: A.J. Nunn et al, Int J Tuberc Lung 15(6): , 2011

35. Treatment of Active Tuberculosis in HIV-TB Coinfected Patients: A systematic Review and Meta-Analysis.
Outcome
Duration of Rifamycin
No of events/subjects
Pooled event rate(95% C1), %
Failure
2 Months
27/872
2.9 ( )
6 Months
45/1377
2.6 ( )
>8 Months
14/441
1.9(0-4.0)
Relapse
40/258
10.8(0-25.1)
100/730
9.8(0-19.8)
20/314
3.3(0-9.0)
Death during Treatment
205/1077
16.6( )
196/1573
10.5( )
60/501
11.7( )

36. Recurrence / relapse after the completion of Anti TB Therapy
The role post treatment INH

37. 5. TB therapy in patients with HIV-TB Co infection Recurrence / Re-infection
In Brazil, TB recurrence rates were high in HIV-1 infected persons but if there was completion of initial TB therapy, use of ART and subsequent increases in CD4 cell counts then recurrence rates were low, suggesting re-infection may have been the reason for recurrence .
Ref: Golub JE, Durovni B, King BS, et al. Recurrent tuberculosis in HIV-infected patients in Rio de Janeiro, Brazil. AIDS 2008; 22: 2527–2533.

38. Recurrence of TB after completing Rx
Rates of recurrence per 100 person – year of observation
HIV+
HIV-
Zaire
18.1 6
Kenya
16.7
0.5
Zambia 22
Malawi
18.2
1.7
S. India
15.0
3.0

40. Strategies to Reduce Recurrence Rates
80% recurrences in HIV+: Re-infection
90% recurrences in HIV-: Reactivation
Extending treatment (RH2 up to 12 months ↓ recurrence to 1.9% compared to 9%.
Post-treatment isoniazid prophylaxis for one year ↓ recurrence (1.4%/year) vs placebo (7.8%/ year)
HAART
Ref: Sonnenberg Lancet 2001; Penneris NEJM 1995;Fitzgerald DW Lancet 2000

41. 233 patients treated for TB
Recurrence rate of TB in HIV+ and HIV- after therapy and Effect of Post-treatment Isoniazid
233 patients treated for TB
Randomized
HIV+ (142)
HIV- (91)
Placebo (74)
Isoniazid
(68)
Placebo (40)
Isoniazid (51)
Recurrent TB 12 2 1
Recurrence rate
per 100 persons-years (95% CI)
7.8 ( )
1.4 ( )
0.0 ( )
0.7 ( )
Ref: Fitzgerald D, Desvarieux M, Sévère P, Joseph P, Johnson WD Jr, Pape J.W. The Lancet :

43. Effect of Post Treatment Isoniazid Prophylaxis on TB Recurrence Among HIV+ Patients Kaplan-Meier estimate of proportion of patients with recurrent tuberculosis among HIV-1-positive individuals

44. Additional Slides

45. Am J Respir Crit Care Med Vol 167. pp 603–662, 2003

46. Benefit of Cotrimoxazole therapy in HIV-TB co infected patients
Studies in Coˆ te d’Ivoire & Malawi >> significant decrease in mortality and the number of hospital admissions & improved survival
In a large study in Uganda >> The effect on mortality was seen only among patients with CD4 cell counts < 200 cells/mm3 or with WHO stage 3 or 4 HIV disease, but the reductions in morbidity were seen among all HIV-infected patients
In a placebo-controlled study performed in Coˆ te d’Ivoire , 771 HIV-infected patients with TB were treated with daily cotrimoxazole, which resulted in a significant decrease in mortality and the number of hospital admissions.
In a subsequent study performed in Malawi , among 717 patients with TB, the overall CFR fell from 37% to 29%—that
is, for every 12.5 patients with TB treated, 1 death was averted. CFRs were unchanged over a period of 2 years among HIVuninfected patients but fell among HIV-infected patients, from 43% to 24%. Improved survival became apparent after the first 2 months and was maintained beyond the end of treatment.
In a large study in Uganda , an area with high rates of bacterial resistance to cotrimoxazole, the effect of such prophylaxis on morbidity, mortality, CD4 cell count, and viral load was evaluated among people with HIV infection. Cotrimoxazole prophylaxis was associated with a 46% reduction in mortality (hazard ratio, 0.54 [95% CI, 0.35–0.84]; Pp.006) and the number of hospital admissions (hazard ratio, 0.69 [95% CI, 0.48–0.98]; Pp.04). The annual rate of decline in CD4 cell count was lower during prophylaxis than before prophylaxis (77 vs. 203 cells/mm3; P ! .0001), and the annual rate of increase in viral load was lower (0.08 vs log10 copies/mL; Pp .01). The effect on mortality was seen only among patients with CD4 cell counts !200 cells/mm3 or with WHO stage 3 or 4 HIV disease, but the reductions in morbidity were seen among all HIV-infected patients.
Additional studies corroborated these findings and the feasibility of implementing cotrimoxazole therapy within a TB control program .
(1) Wiktor SZ et al ; Lancet 1999; 353:1469–75. (2) Mwaungulu FB et al. Bull World Health Organ 2004; 82:354–63. (3) Mermin J, et al, Lancet 2004; 64:1428–34.

47. Adjunctive Therapy
Immunomodulators including corticosteroids, therapeutic vaccines, and other drugs and biologics—have the potential to shorten TB treatment by modulating the host response and helping the immune system to eliminate persistent organisms.
(1) Imperiali FG et al ; Clin Exp Immunol; 2001; 123:435–42. (2) Ehlers S et al ; J Rheumatol Suppl 2005; 74:35–9. (3) Keane J et al ; Rheumatology 2005; 44:714–20. (4) Wallis RS et al ; J Infect Dis 1996; 174:727–33. (5) Wallis RS et al ; AIDS 2004; 18:257–64. (6) Bekker LG et al ; J Infect Dis 2000; 181:954–65. (7) Smego RA et al ; Int J Tuberc Lung Dis 2003; 7:208–13.

48. Role of Steroids in the management of HIV-TB co infection
In HIV-1-infected adults with pulmonary or pleural TB, corticosteroids do not improve survival or reduce TB recurrence [1-3].
A sub study of HIV-1 infected persons within a randomised controlled trial of dexamethasone for TBM in Vietnam showed a trend towards increased survival in the dexamethasone arm [4].
Most physicians, therefore, give steroids to patients with TB meningitis and use dexamethasone 12–16 mg?day-1 intravenously until the patient begins taking medicines orally.
An alternative is prednisolone 1.5 mg?kg-1?day-1 for 3 weeks and tapered over the next 3 weeks [5].
A randomised controlled trial of adjunctive prednisolone in HIV-1-infected patients with effusive tuberculous pericarditis demonstrated reduction in mortality among patients who received prednisolone despite the relatively small sample size (n558) [3].
1 Mayanja-Kizza H, Jones-Lopez E, Okwera A, et al. Immunoadjuvant prednisolone therapy for HIV-associated tuberculosis: a phase 2 clinical trial in Uganda. J Infect Dis 2005; 191: 856–865.
2 Elliott AM, Luzze H, Quigley MA, et al. A randomized, doubleblind, placebo-controlled trial of the use of prednisolone as an adjunct to treatment in HIV-1-associated pleural tuberculosis. J Infect Dis 2004; 190: 869–878.
3 Hakim JG, Ternouth I, Mushangi E, et al. Double blind randomised placebo controlled trial of adjunctive prednisolone in the treatment of effusive tuberculous pericarditis in HIV seropositive patients. Heart 2000; 84: 183–188.
4 Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004; 351: 1741–1751.
5 Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008; 1: CD

49. Thank you
ITECH India/Arogyaan express our gratitude and thanks to Lucie Kroschel and Alex McGee for their logistic support.