1. TB-H V Co-infection by Dr. Ker Hong Bee 11

2. LEARNING OBJECTIVES To know & understand about TB-HIV co- infection in relation to:- – interaction & prevalence – diagnosis & treatment – Isoniazid Prophylaxis Therapy (IPT) – Highly Active Antiretroviral Therapy (HAART) – Immune Reconstitution Inflammatory Syndrome (IRIS) – Co-trimoxazole (CTX) Prophylaxis 2

3. TB & HIV: A DEADLY HUMAN SYNDEMIC 3 TB is one of the leading causes of death among HIV patients

4. TB-H V INTERACTION 4 HIV infection accelerates the development of TB from infection to advanced disease TB depletes the CD4 count & intensifying the immunodepressant effect of HIV

5. TB-H V INTERACTION 5 HIV-positive patients have more than 2x risk of primary MDR-TB. 1,2 Risk of mortality is 2.6x higher in HIV-positive patients who develop TB compared to those who do not. 3 1 Conaty SJ et al., Epidemiol Infect, 2004 2 Suchindran S et al., PLoS ONE, 2009 3 Straetemans et al., PLoS ONE, 2010

6. At least one-third of HIV-positive persons worldwide are infected with MTB. 8 - 10% of them develop clinical disease every year 1 1 Swaminathan S et al, Clin Infect Dis. 2010 PREVALENCE OF TB-H V CO-INFECTION 6

7. TB- H V INTERACTION 7 Both PTB & EPTB (2.7 - 3.0%) PTB (44.0 - 79.5%) EPTB (14.0 - 18.8%) Zhou J et al., BMC Infect Dis, 2009

8. DIAGNOSTIC CHALLENGES Many HIV-TB co-infected patients: Have no cough & negative sputum AFB smears Have lower AFB { } in sputum – AFB density in sputum decreases with decreasing CD4 Have normal CXR even in culture- confirmed PTB Have less cavitary disease on initial CXR 8

9. TB CULTURES Sputum/BAL TB cultures should be obtained in all TB suspects with a normal CXR, particularly HIV-positive persons. 1 Any biopsy specimen from extrapulmonary sites should be sent for TB culture. 9 1 Pepper T et al., Int J Tuberc Lung Dis, 2008

10. DIAGNOSTIC TESTS 10

11. ANTITB FOR TB-H V CO-INFECTION Require prompt initiation of TB treatment 1 Treatment complicated by higher rate of TB relapse & increased mortality rate during treatment 11 1 Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services.

12. ANTITB FOR TB-H V CO-INFECTION 6 month regimen consisting of 1,2 – 2EHRZ /4 HR when the disease is caused by organisms that are known or presumed to be susceptible to the first-line drugs 12 1 CDC. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: 2 Blumberg HM et al,,Am J Respir Crit Care Med, 2003

13. ANTITB FOR TB-H V CO-INFECTION Prolong the continuation phase if:- – there is a slow or suboptimal response (e.g. cultures are still positive after 2 months of therapy) – patients with EPTB All HIV patients should receive DAILY TB treatment in maintenance phase. 13

14. TREATMENT REGIMEN FOR TB-H V CO-INFECTION 14

15. RIFAMYCIN & ANTIRETROVIRAL (ARV) DRUGS Includes rifampin (rifampicin) & rifabutin Regimens in which rifampin is only used for the first 2 months  higher rates of Rx failure & relapse 1 Recommend to include rifamycin for the full course of TB treatment unless- the Mycobacterium is resistant to rifamycin the patient has a severe side effect that is clearly due to the rifamycin 15 1 Jindani A et al., Lancet, 2004

16. RIFAMYCIN & ARV DRUGS Rifampicin: – the most potent inducer of CYP450 system – significant interactions with most ARVs including all protease inhibitors (PIs) Rifabutin* – has much less effect on drugs metabolism through the CYP3A system – as effective as rifampicin 1 16 *Not registered in Malaysia 1 Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1- infected adults and adolescents. Department of Health and Human Services

17. *Not registered in Malaysia RIFAMYCIN & ARV DRUGS 17

18. ISONIAZID PROPHYLAXIS THERAPY (IPT) FOR H V INFECTED PATIENTS HIV infection significantly increases the risk of progression from latent to active TB 18

19. Latent TB Active TB Risk of TB reactivation Lifetime risk 5 - 10% Annual risk of TB reactivation 5 - 10% 1 1 Narain JP et al., Tuber Lung Dis, 1992 CONCERN OF TB REACTIVATION 19

20. IPT FOR H V INFECTED PATIENTS 20

21. Isoniazide 5mg/kg OD (max 300 mg) + Pyridoxine 50 mg OD for 6 months 21

22. ANTITB + HAART = SURVIVAL Highly Active Antiretroviral Therapy (HAART) during TB treatment 1 o protective against mortality o result in earlier conversion of sputum & cultures to negative 22 1 Nahid P et al., Am J Respir Crit Care Med, 2007

23. TIMING TO INITIATE HAART Initiation of earlier-HAART in patients with CD4 <50/cubic ml improves survival. 1 In HIV-associated TB meningitis, immediate HAART is associated with an increase in grade 4 adverse events  safer to defer HAART. 2 23 1 Abdool Karim SS et al., N Engl J Med.2011 2 Torok ME et al., Clin Infect Dis2011

24. TIMING OF HAART 24 CD4 count (cells/µl) Timing of HAART initiation <502 weeks after starting intensive phase of antiTB treatment >50 but <350 After completion of intensive phase of antiTB treatment >350Continue antiTB treatment & monitor CD4. Commence HAART if CD4 drops <350 cells/µl.

25. Antiretroviral drugsInteractions with rifampicin NRTIsNo clinically significant interaction NNRTIsEfavirenz: the preferred NNRTI Nevirapine:  can be continued if already on a nevirapine-based HAART with close monitoring of LFT;  if need to start, please d/w ID physician PIsReferral to an ID Physician if patient already on PI-based regimen ARV REGIME 25

26. 26 HAART IN H V-TB CO-INFECTION

27. 27 DRUG INTERACTIONS BETWEEN HAART & ANTITB REGIMEN

28. IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS) An augmented inflammatory response that occurs in patients started on HAART & antiTB Usually occurs within 3 months of TB treatment o typically within 2 to 12 weeks after the initiation of HAART 28

29. IRIS The major manifestations of IRIS are fever & lymphadenitis. 1 HAART & antiTB treatment should not be stopped while managing IRIS. 29 1 Dibyendu D et al., Braz J Infect Dis2011

30. CO-TRIMOXAZOLE (CTX) PROPHYLAXIS IN TB-H V CO-INFECTION A RCT showed that CTX prophylaxis in TB-HIV co-infected adults was associated with a 21% reduction in all cause mortality. 1 CTX is generally safe & well-tolerated. 1,2 CTX should be initiated as soon as possible & given throughout TB treatment. 3 30 1 Nunn AJ et al., BMJ, 2008 2 Boeree MJ et al., Trop Med Int Health, 2005 3 WHO, 2010

31. TAKE HOME MESSAGES 1.Active TB should be ruled out in all HIV-positive patients. 2.Sputum TB culture should be done regardless of CXR/smear AFB status in TB-HIV suspect. 3.AntiTB regimen offered to HIV +ve adults should be the same as for HIV -ve individual. o Caution on drug interaction with HAART o Daily maintenance phase 31

32. TAKE HOME MESSAGES 4.IPT for 6 months should be offered to all HIV patients with LTBI after ruling out active TB. 4.For patients with CD4 <50 cells/μl, initiate HAART 2 weeks after starting antiTB treatment. 4.CTX prophylaxis should be given to HIV patients on antiTB treatment. 32

33. 33 THANK YOU  kerhb@hotmail.com kerhb@hotmail.com