1. TB & HIV Infection: Treatment Your name Institution/organization Meeting Date International Standard 8, 13 TB & HIV Infection: Treatment Your name Institution/organization Meeting Date International Standards 8, 15, 16

2. ISTC TB Training Modules 2009 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 TB/HIV: Treatment

3. ISTC TB Training Modules 2009 International Standards 8, 15, 16 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

4. ISTC TB Training Modules 2009 Treatment of HIV-associated TB

5. ISTC TB Training Modules 2009 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 TB/HIV: Treatment Outcomes

6. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 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 ART Improves Outcomes

8. ISTC TB Training Modules 2009 * Abbreviated version Initial phase: 2 months INH, RIF, PZA, EMB Continuation phase: 4 months INH and RIF Standard 8: Treatment* All patients who have not been previously treated should receive an internationally accepted treatment regimen of known bioavailability: (1 of 2)

9. ISTC TB Training Modules 2009 Standard 8: Treatment 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 (2 of 2)

10. ISTC TB Training Modules 2009 TB/HIV issues to consider: Drug-drug interactions Role of antiretroviral therapy (ART) Overlapping drug toxicities Immune-reconstitution inflammatory syndrome (IRIS) Adherence issues TB/HIV: Treatment

11. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 Antiretroviral Therapy with TB

16. ISTC TB Training Modules 2009 Standard 15: TB/HIV All patients with TB and HIV infections should be evaluated to determine if antiretroviral therapy is indicated during the course of treatment for TB. Appropriate arrangements for access to antiretroviral drugs should be made for patients who meet indications for treatment. (1 of 3)

17. ISTC TB Training Modules 2009 Standard 15: TB/HIV However, initiation of treatment for tuberculosis should not be delayed. (2 of 3) ISTC Training Modules 2008

18. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 If TB develops…Then Within 6 months of starting ART Start first-line TB rx and change ART regimen if necessary After 6 months of starting ART evidence of clinical immunological failure Consider ART failure and change to second- line ART Key point: Start TB treatment immediately TB Care: If Already on ART

20. ISTC TB Training Modules 2009 CD4Consider starting ART <200 2–8 weeks after start of TB rx >200 and <3508 weeks after start of TB rx >350 Defer ART (re-evaluate at 8 weeks and end of TB rx) HIV-infected TB patients not yet on ART should be evaluated for ART immediately When to Start Antiretrovirals

21. ISTC TB Training Modules 2009 When to Start Antiretrovirals If CD4 count not available: Clinical PresentationART Any pulmonary TB and signs of advanced HIV, or no clinical improvement; extrapulmonary TB Start ART as soon as TB rx tolerated Smear-negative pulmonary TB, gaining weight on rx, no other signs/sx of advanced HIV Start ART after the intensive phase of TB rx Smear-positive pulmonary TB, gaining weight on rx, no other signs/sx of advanced HIV Defer ART until TB rx done

22. ISTC TB Training Modules 2009 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) ART and RIF-based TB Rx

23. ISTC TB Training Modules 2009 Rifampicin decreases blood levels of NVP and EFV NNRTIEffect of Rifampicin Nevirapine 37–58% Efavirenz 22% NNRTIs and Rifampicin

24. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 Protease InhibitorEffect of Rifampicin Saquinavir by 84% Ritonavir by 35% Indinavir by 89% Nelfinavir by 82% Amprenavir by 81% Lopinavir/ritonavir by 75% Rifampicin decreases blood levels of all PIs PIs and RIF: Not Recommended

26. ISTC TB Training Modules 2009 *Tenofovir not recommended in pregnancy 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

27. ISTC TB Training Modules 2009 ART Options: RIF-based TB Rx Ritonavir boosting of other PIs can 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. ISTC TB Training Modules 2009 Other Issues in TB/HIV Treatment

29. ISTC TB Training Modules 2009 Standard 15: TB/HIV Patients with TB and HIV infection should also receive cotrimoxazole as prophylaxis for other infections. Patients with TB and HIV infection should also receive cotrimoxazole as prophylaxis for other infections. Pneumocystis jiroveci pneumonia (3 of 3)

30. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 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 Cotrimoxazole Preventive Therapy

32. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 Overlapping Side Effects Side EffectTB DrugARV Skin rash*PZA, RIF, INH Nevirapine Efavirenz Abacavir Nausea, vomiting PZA, RIF, INH Zidovudine Ritonavir Amprenavir Indinavir Burman et al, Am J Respir Crit Care Med 2001 * May also see rash with cotrimoxazole

35. ISTC TB Training Modules 2009 Side EffectTB DrugARV HepatitisPZA, RIF, INH Nevirapine Protease inhibitors IRIS (with chronic hepatitis) Leukopenia, anemia RIF Zidovudine Overlapping Side Effects Burman et al, Am J Respir Crit Care Med 2001

36. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 IRIS Clinical presentation: Fever Nodal enlargement Worsening pulmonary infiltrates (with or without respiratory symptoms) Local worsening in extrapulmonary sites

40. ISTC TB Training Modules 2009 IRIS Differential Diagnosis Differential diagnosis of IRIS: TB treatment failure Drug-resistant TB Other opportunistic (or non-opportunistic) infections Lymphoma, Kaposis sarcoma Hypersensitivity drug reactions ART failure (if symptoms occur late in the course of ART therapy)

41. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 Source: Tuberculosis Care with TB-HIV Co-management, IMAI Example: Co-treatment Regimen

44. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 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. ISTC TB Training Modules 2009 * Abbreviated versions 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.

49. ISTC TB Training Modules 2009 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 receive cotrimoxazole preventative therapy. * Abbreviated versions

50. ISTC TB Training Modules 2009 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

51. ISTC TB Training Modules 2009 Alternate Slides

52. ISTC TB Training Modules 2009 WHO HIV Clinical Stage 1 Asymptomatic Persistent generalized lymphadenopathy (WHO clinical stage 1 conditions are not HIV specific)

53. ISTC TB Training Modules 2009 WHO HIV Clinical Stage 2 Moderate unexplained weight loss (<10%) Recurrent respiratory tract infections Herpes zoster Angular cheilitis Recurrent oral ulceration Papular pruritic eruptions Seborrhoeic dermatitis Fungal nail infections

54. ISTC TB Training Modules 2009 WHO HIV Clinical Stage 3 Unexplained severe weight loss >10% Unexplained chronic diarrhea > 1 month Unexplained persistent fever > 1 month Persistent oral candidiasis Oral hairy leukoplakia Pulmonary tuberculosis

55. ISTC TB Training Modules 2009 WHO HIV Clinical Stage 3 Severe bacterial infections Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis Unexplained: Anemia <8 g/dl Neutropenia < 0.5 x 109/l Chronic thrombocytopenia <50 x 109 /l

56. ISTC TB Training Modules 2009 WHO HIV Clinical Stage 4 HIV wasting syndrome Pneumocystis pneumonia Recurrent severe bacterial pneumonia Chronic herpes simplex infection Esophageal candidiasis Extrapulmonary tuberculosis Kaposis sarcoma Cytomegalovirus infection

57. ISTC TB Training Modules 2009 WHO HIV Clinical Stage 4 Central nervous system toxoplasmosis HIV encephalopathy Extrapulmonary cryptococcosis, including meningitis Disseminated non-tuberculous mycobacterial infection Progressive multifocal leukoencephalopathy Chronic cryptosporidiosis

58. ISTC TB Training Modules 2009 WHO HIV Clinical Stage 4 Chronic isosporiasis Disseminated mycosis Recurrent septicemia Lymphoma (cerebral or B cell non-Hodgkin) Invasive cervical carcinoma Atypical disseminated leishmaniasis Symptomatic HIV-associated nephropathy or HIV-associated cardiomyopathy

59. ISTC TB Training Modules 2009 Purpose of ISTC

60. ISTC TB Training Modules 2009 ISTC: Key Points 21 Standards (revised/renumbered in 2009) Differ from existing guidelines: standards present what should be done, whereas, guidelines describe how the action is to be accomplished Evidence-based, living document Developed in tandem with Patients Charter for Tuberculosis Care Handbook for using the International Standards for Tuberculosis Care

61. ISTC TB Training Modules 2009 Audience: all health care practitioners, public and private Scope: diagnosis, treatment, and public health responsibilities; intended to complement local and national guidelines Rationale: sound tuberculosis control requires the effective engagement of all providers in providing high quality care and in collaborating with TB control programs ISTC: Key Points

62. ISTC TB Training Modules 2009 Questions

63. ISTC TB Training Modules 2009 TB/HIV: Treatment 1.A 45 year-old man with AIDS had documented clinical improvement after two months of standard TB treatment and subsequently began ART. After one month of combined TB treatment and ART, symptoms of cough with new infiltrates on chest radiograph are discovered. Which of the following need to be considered in the differential diagnosis at this time: A.TB treatment failure B.New opportunistic respiratory infection C.Immune reconstitution inflammatory syndrome D.All of the above

64. ISTC TB Training Modules 2009 TB/HIV: Treatment 2. The antiretroviral therapy regimen of choice for a patient on first-line TB treatment with isoniazid, rifampicin, ethambutol, and pyrazinamide would be: A.A triple nucleoside (NRTI) regimen B.Ritonavir super-boosted protease inhibitor (PI) regimen C.A dual protease inhibitor (PI) regimen D.Efavirenz plus two nucleosides (NRTIs) if not pregnant

65. ISTC TB Training Modules 2009 TB/HIV: Treatment 3.A 50 year-old woman with sputum smear-positive TB and new HIV infection is started on both a standard four-drug TB regimen and a three-drug ART regimen at the same time. The patients adherence is spotty and one week later she complains of severe nausea and vomiting. All of the following statements are correct except: A.Nausea and vomiting can be side effects seen with either TB or ART drugs B.The initial high pill burden may be contributing to the patients poor adherence C.Starting both TB and HIV treatments together has made the job of finding the cause of the symptoms more complicated D.Prioritizing the start of ART first, with a delay in TB treatment would have been the recommended sequence