Management of HIV/TB Co-infection

Dr.G.ManoharanMedical Director,

International Training and Education Center for Health India

Clinical Associate Professor, DGH,UW.

Topics to be discussed

o When to start ART in HIV associated Tuberculosis

o Duration of TB treatmento Intermittent Vs Daily TB treatmento Drugs used in the TB Treatment o Recurrent TB/Relapse/Re-infection o Role of steroids

Case studyo 35 yrs. male HIV +VE

o Hospitalized for weight loss, fever, and cough with expectoration

o Diagnosed as sputum negative pulmonary TB, oral candidiasis and HIV wasting.

o CD4 cell count- 70 cells & 18.3%

Chest x-ray : 29th May, 04.

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

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

Chest x-ray : June, 05.

Chest x-ray : Feb 05.

TB therapy in patients with HIV-TB Co-infection

Aims of TB therapy are too Achieve cure and prevent death o Prevent relapse o Render patients non-infectious as rapidly as

possible o Prevent the emergence of drug resistance.

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)

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

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?

1 .When to Start Antiretroviral Therapy in HIV- TB co-infection

AIDS related IllnessMortality

IRISDrug ToxicityDrug interactions High pill burden

Delayed ART

Early ART

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

SAPiT Trial: Main Findings• Integrated therapy associated with 56% reduction in

risk of death Vs sequential therapy

OutcomeIntegrated Therapy(n = 429)

Sequential Therapy(n = 213)

HR (95% CI) P Value

All patients Death rate per 100 person-yrs Deaths, n

5.425

12.127

0.44 (0.25-0.79) .003

CD4+ cell count ≤ 200 cells/mm3

Death rate per 100 person-yrs Deaths, n

8.223

15.321

0.54 (0.30-0.98) .04

CD4+ cell count > 200 cells/mm3

Death rate per 100 person-yrs Deaths, n

1.12

7.06

0.16 (0.03-0.79) .02

Integrated therapy independently associated with reduced risk of death (HR: 0.43; 95% CI: 0.25-0.77; P = .004)

SAPiT: Increased survival with concurrent HIV and TB treatment

Abdool Karim SS, et al. CROI 2009. Abstract 36a.

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Surv

ival

Months Postrandomization0 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 treatmentContinuationphase of TB treatment

Early ARTSequential ART

CAMELIA trial

N Engl J Med, Vol 365;1No 6 ; october 20, 2011; Pages 1471-1481

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),

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

Duration of TB treatment

6 Months Vs 9 Months or longer…..

2. TB therapy in patients with HIV-TB Co infection

6 months supervised intermittent TB therapy in patients with and without HIV- Haiti

• 427 Patients ; 177 HIV +VE

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.

Short-course, thrice-weekly therapy highly efficacious in HIV positive and HIV negative patients

Outcome HIV Positive HIV Negative

Cure 81% 89%

Relapse 5.4% 2.8%

Death 9% 1%

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%

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 ResistanceReference: Am J Respir Crit Care Med Vol 181. pp 743–751, 2010

22

(2EHRZ3/4RH3) Vs (2EHRZ3/7RH3)

0

10

20

30

40

50

60

70

80

90

100

0M 1m 2M 3M 4M 5M 6M 7M 8M 9M

reg 6M

reg 9M

Sputum culture negativity in months

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)..

Time to bacteriological recurrenceup to 36 months for patients in the 6-month and 9-month regimen

9 Months Regimen

6 Months Regimen

P = 0.03

6 Months Vs 9 Months TherapyA 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 ofpatients with HIV and tuberculosis. Am J Respir Crit Care Med2007; 175: 1199–1206.

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.

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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.

Intermittent Dosing /Therapy

Vs

Continuous therapy

3. TB therapy in patients with HIV-TB Co infection

Contraindicated

• Once weekly INH and Rifapentine

• Twice weekly Rifampin- or Rifabutin- based regimens

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(1.5-3.5)3 Times weekly 12/163 5.3(0.4-10.2)

RelapseDaily 142/1241 6.7(0.6-12.8)3 Times weekly 18/65 28.1(0-69.5)

Death during Treatment

Daily 430/2957 11.9(8.5-15.3)3 Times weekly 31/194 14.3(4.8-23.9)

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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

What drugs?

What drugs do you use? Rifampin throughout the therapy?

4. TB therapy in patients with HIV-TB Co infection

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):741-745, 2011

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):741-745, 2011

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 (1.0-4.8)6 Months 45/1377 2.6 (1.1-4.1)>8 Months 14/441 1.9(0-4.0)

Relapse 2 Months 40/258 10.8(0-25.1)

6 Months 100/730 9.8(0-19.8)>8 Months 20/314 3.3(0-9.0)

Death during Treatment

2 Months 205/1077 16.6(10.2-22.9)

6 Months 196/1573 10.5(6.8-14.3)>8 Months 60/501 11.7(5.9-18.4)

Recurrence / relapse after the completion of Anti TB Therapy

The role post treatment INH

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.

Recurrence of TB after completing RxRates of recurrence per 100 person – year of

observationHIV+ HIV-

Zaire 18.1 6

Kenya 16.7 0.5

Zambia 22 6

Malawi 18.2 1.7

S. India 15.0 3.0

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

Recurrence rate of TB in HIV+ and HIV- after therapy and Effect of Post-treatment Isoniazid

233 patients treated for TB

Randomized

HIV- (91)HIV+ (142)

Isoniazid (51)Placebo (40)

Isoniazid (68)

Placebo (74)

• Recurrent TB 12 2 0 1• Recurrence rate

1.4 (0.0-3.4) 0.0 (0.0-4.0) 0.7 (0.0-3.9)

Ref: Fitzgerald D, Desvarieux M, Sévère P, Joseph P, Johnson WD Jr, Pape J.W. The Lancet 2000 356 : 1470-74

per 100 persons-years (95% CI)

7.8 (4.1-13.3)

Effect of Post Treatment Isoniazid Prophylaxis on TB Recurrence Among HIV+ Patients

Kaplan-Meier estimate of proportion of patients withrecurrent tuberculosis among HIV-1-positive individuals

Additional Slides

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

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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

(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.

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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.

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].

Thank you

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