TB & HIV Infection: Treatment

1. TB & HIV Infection: Treatment Your name Institution/organization Meeting Date International Standards 8, 15, 16

2. TB/HIV: Treatment Objectives: At the end of this presentation, participants will be able to: • List the major drug interactions and possible first-line combinations for concomitant TB and antiretroviral therapy (ART) • Describe the effect of ART, cotrimoxazole preventive therapy (CPT), and isoniazid preventive therapy (IPT) on TB/HIV outcomes • Describe the circumstances when immune reconstitution inflammatory syndrome (IRIS) may present • List ways that TB/HIV co-infection may negatively impact adherence

3. TB/HIV: Treatment Overview: • TB regimens in TB/HIV • Antiretroviral therapy (ART) and TB treatment • Cotrimoxazole preventive therapy (CPT) • Isoniazid preventive therapy (IPT) • Overlapping toxicities • Immune reconstitution inflammatory syndrome (IRIS) • Adherence issues International Standards 8, 15, 16

4. Treatment of HIV-associated TB

5. TB/HIV: Treatment Outcomes In HIV-positive patients: • TB treatment regimens are the same in HIV-positive and HIV-negative patients • HIV is associated with increased mortality during TB treatment • Patients with smear-negative TB have a higher mortality than those with smear-positive TB

6. TB/HIV: Treatment Outcomes HIV and MDR/XDR TB: “Perfect Storm” • Poor treatment outcomes and exceptionally high mortality rates • Rapid disease progression • Delayed diagnosis • Inadequate initial treatment • KwaZulu Natal outbreak: 52 of 53 (HIV + XDR TB) died within median 16 days of diagnosis

7. ART Improves Outcomes Antiretroviral Therapy (ART) significantly reduces TB incidence Decrease in TB incidence after starting ART in resource-limited, high-burden area Lawn SD, et al, Am J Respir Crit Care Med, 2008;177:680-685

8. Standard 8: Treatment* (1 of 2) • All patients who have not been previously treated should receive an internationally accepted treatment regimen of known bioavailability: • Initial phase: 2 months INH, RIF, PZA, EMB • Continuation phase: 4 months INH and RIF * Abbreviated version

9. Standard 8: Treatment (2 of 2) • The doses of anti-TB drugs used should conform to international recommendations • Fixed-dose combinations (FDCs) of two (INH, RIF), three (INH, RIF, PZA), and four (INH, RIF, PZA, EMB) drugs are highly recommended

10. TB/HIV: Treatment TB/HIV issues to consider: • Drug-drug interactions • Role of antiretroviral therapy (ART) • Overlapping drug toxicities • Immune-reconstitution inflammatory syndrome (IRIS) • Adherence issues

11. TB/HIV Treatment: Rifamycins Drug interactions: • Rifamycins induce hepatic cytochrome P450 (CYP3A4) enzymes, accelerating metabolism of: • Protease inhibitors (PIs) • Some non-nucleoside reverse transcriptase inhibitors (NNRTIs) • Nucleosides (NRTIs) are not effected • Rifampicin >> Rifabutin

12. TB/HIV Treatment: Rifamycins • Evidence for development of acquired rifamycin resistance with intermittent therapy • Advanced HIV and /or diarrhea: concern for poor drug absorption • Intermittent therapy not recommended during initial phase of TB treatment in patients with HIV infection • No twice-weekly continuation phase with advanced immunosuppression

13. TB/HIV Treatment: RIF • Rifampicin (RIF) - based regimens remain first choice for TB treatment. Use of RIF straightforward in cases: • Not on antiretroviral therapy • For whom PIs or NNRTIs are not recommended • RIF may be used with some NNRTIs (and limited PIs), but requires caution

14. TB/HIV Treatment: RIF Alternative • For patients receiving PIs or NNRTIs, the substitution of rifabutin (for rifampin) is recommended if available • Alternative non-rifamycin regimen: • INH, EMB, PZA, and streptomycin (but not generally recommended)

15. Antiretroviral Therapy with TB

16. Standard 15: TB/HIV (1 of 3) • All patients with TB and HIV infections should be evaluated todetermine if antiretroviral therapy is indicatedduring the course of treatment for TB. • Appropriate arrangements for access to antiretroviral drugs should be made for patients who meet indications for treatment.

17. Standard 15: TB/HIV (2 of 3) • However, initiation of treatment for tuberculosis should not be delayed. ISTC Training Modules 2008

18. TB and Antiretroviral Therapy • Indications for ART in TB/HIV patients depend upon: • Status of HIV disease (CD4 level) • Success of current TB treatment regimen • Adherence and toxicity issues • If not on ART at time of TB diagnosis, use assessment of these issues to decide when to start ART

19. TB Care: If Already on ART  Key point: Start TB treatment immediately

20. When to Start Antiretrovirals HIV-infected TB patients not yet on ART should be evaluated for ART immediately

21. When to Start Antiretrovirals If CD4 count not available:

22. ART and RIF-based TB Rx Recommended ART regimen: • Efavirenz plus two nucleosides (EFV + two NRTIs) • Use efavirenz for adults and children >3 years old • Avoid 1st trimester of pregnancy • Efavirenz dose 600mg (or 800mg)

23. NNRTIs and Rifampicin Rifampicin decreases blood levels of NVP and EFV

24. ART and RIF-based TB Rx Choice of nucleosides (NRTIs) to combine with efavirenz: • Usual adult first-line therapy (may also be used in children >3): • Zidovudine + lamivudine (AZT/3TC) • Alternative in case of anemia: Stavudine + lamivudine (d4T/3TC)

25. PIs and RIF: Not Recommended Rifampicin decreases blood levels of all PIs

26. ART Options: RIF-based TB Rx More options (consider expert consultation): • Triple NRTI: abacavir or tenofovir* + 2 NRTIs • Not as potent, but no drug interactions • WHO first-line for children >3 • Nevirapine + 2 NRTIs • Some successful clinical experience • Concern for low blood levels, toxicity overlap (hepatitis, rash), and hypersensitivity reactions • Preferred WHO alternative in children < 3 *Tenofovir not recommended in pregnancy

27. ART Options: RIF-based TB Rx • Ritonavir boosting of other PIscan achieve adequate blood levels but significant hepatotoxicity risk • Can be used in children (<3) • Lopinavir/ritonavir (Kaletra) usual dose 400/100 mg twice a day PLUS an extra ritonavir 300 mg twice a day (adult dose)

28. Other Issues in TB/HIV Treatment

29. Standard 15: TB/HIV (3 of 3) • Patients with TB and HIV infection should also receivecotrimoxazoleas prophylaxis for other infections. Pneumocystis jiroveci pneumonia

30. Cotrimoxazole Preventive Therapy • Reduces the risk of • Pneumocystis jiroveci pneumonia (PCP) • Toxoplasma • Bacterial infections • Reduces deaths and hospitalizations • Also effective against: • Pneumococcus, salmonella, nocardia and malaria

31. Cotrimoxazole Preventive Therapy • All HIV-positive TB patients should receive Cotrimoxazole Preventive Therapy regardless of the CD4 count, for at least the duration of anti-TB treatment. • CPT is recommended for all patients with CD4 cell count less than 200 cells/mm3

32. Standard 16: Isoniazid Preventive Therapy Persons with HIV infection who, after careful evaluation, do not have active tuberculosis should be treated for presumed latent tuberculosis infection with isoniazid for 6-9 months

33. TB Risk with HIV Infection • Exceptionally high rate of reactivation of latent infection (7-10% per year) • Rapid progression to TB following new infection • Increased risk begins soon after HIV infection and increases as immunosuppression increases • Increased risk is reduced but not eliminated by antiretroviral treatment • Increased potential for reinfection after successful treatment for TB

34. Overlapping Side Effects * May also see rash with cotrimoxazole Burman et al, Am J Respir Crit Care Med 2001

35. Overlapping Side Effects Burman et al, Am J Respir Crit Care Med 2001

36. Progression on TB/HIV Treatment What could be happening here? HIV+ case with TB dx; TB treatment begun • After 2 mo. TB treatment, • begins ART • 6 wks. later symptoms and CXR worsen  

37. IRIS Immune Reconstitution Inflammatory Syndrome (IRIS) • Clinical worsening in the setting of an adequate response to ART • “Paradoxical” worsening of previously known treated (completed or ongoing) opportunistic pathogen • “Unmasking” of subclinical opportunistic pathogen

38. IRIS • Risk factors • Disseminated TB • Shorter delay between onset of TB and ART drugs • Low baseline CD4, higher baseline viral load • Greater CD4 or viral load response to ART • Timing of onset • Usually within first 6 weeks of ART (often 2–3 weeks, but can be months after ART started)

39. IRIS Clinical presentation: • Fever • Nodal enlargement • Worsening pulmonary infiltrates (with or without respiratory symptoms) • Local worsening in extrapulmonary sites

40. IRIS Differential Diagnosis Differential diagnosis of IRIS: • TB treatment failure • Drug-resistant TB • Other opportunistic (or non-opportunistic) infections • Lymphoma, Kaposi’s sarcoma • Hypersensitivity drug reactions • ART failure (if symptoms occur late in the course of ART therapy)

41. IRIS Evaluation and Treatment • TB treatment should be continued • Exclude TB treatment failure • Adequate treatment and adherence? • Drug resistance? • Exclude additional/new diagnosis • Continue ART (unless life-threatening) • Consider NSAIDS, steroids • Drainage of lesions

42. TB/HIV: Adherence Increased difficulties for adherence: • Higher pill burden • Greater number of potential drug side effects • Dual social stigma • Additional illness (opportunistic infections) • Difficult medical access, drug-supply interruptions

43. Example: Co-treatment Regimen Source: Tuberculosis Care with TB-HIV Co-management, IMAI

44. Improving Adherence • DOTS • Patient-centered care • Incentives, enablers • Patient education and counseling • Collaboration between TB and HIV providers • Joint TB and HIV medication dispensaries • Patient support groups

45. Infection Control Infection Control: Important in facilities providing services for patients with TB, especially in high HIV prevalence areas • Establish an infection control plan • Maximize natural ventilation of patient care and waiting areas • Identify and separate coughing patients • Ensure rapid sputum smear results (24 hours) • Consolidate TB services in time and place

46. Summary: TB/HIV Treatment Summary: • Standard TB treatment usually cures TB in TB/HIV co-infection • Despite successful TB treatment, mortality among TB/HIV patients remains high • Cotrimoxazole prophylaxis (CPT) improves survival and should be used in all TB/HIV patients • Latent TB infection should be treated with isoniazid (IPT) in HIV-infected patients

47. Summary: TB/HIV Treatment Summary (continued): • ART for eligible patients greatly improves survival • Different ART regimens may be required because of drug interactions with rifampicin • Coordination between the TB and HIV programs is needed to improve treatment of both conditions and will reduce disease and death

48. Summary: ISTC Standards Covered* Standard 8: • All patients who have not been previously treated should receive an internationally accepted treatment regimen. • Initial phase: 2 months INH, RIF, PZA, EMB. • Continuation phase: 4 months INH and RIF. • EMB may be omitted in the initial phase for non-HIV smear-negative cases without severe disease. • The doses of anti-TB drugs used should conform to international recommendations. Fixed-dose combinations are highly recommended. * Abbreviated versions

49. Summary: ISTC Standards Covered* Standard 15: • All TB/HIV patients should be evaluated to determine if ART is indicated during the course of TB treatment. • Appropriate arrangements for access to ART should be made. • However, initiation of treatment for tuberculosis should not be delayed. • TB/HIV patients should also receivecotrimoxazolepreventative therapy. * Abbreviated versions

50. Summary: ISTC Standards Covered Standard 16: • Persons with HIV infection who, after careful evaluation, do not have active tuberculosis should be treated for presumed latent tuberculosis infection with isoniazid for 6-9 months