1. Challenges of treating two infections (HIV and TB): the ART of HIV/TB management William Burman MD Denver Public Health University of Colorado

2. Case 1 27 y/o man from Ethiopia, admitted with cough, fevers, and 20 lb. weight loss over one month Sputum - rare AFB HIV-positive, CD4 - 18, viral load > 1,000,000 Dramatic initial improvement with IRZE

3. Case 1 1.Should antiretroviral therapy be started during TB treatment? 2.When during TB therapy should antiretroviral therapy be started? 3.What regimens can be used for co-treatment of HIV and TB therapy?

4. Survival of persons with HIV-related TB in the pre-HAART era – San Francisco N Engl J Med 1991; 324: 289-94

5. Complicating factors: antiretroviral therapy during TB therapy Need for coordination between TB and HIV treatment programs Challenge of adherence to multidrug therapy for both diseases Overlapping drug toxicity profiles Drug interactions Immune reconstitution (paradoxical) reactions

6. SAPiT: Starting Antiretroviral therapy (ART) in three Points in TB Primary Objective: To determine the optimal time to initiate ARVs in TB patients Inclusion Criteria: Smear pulmonary TB HIV positive with CD4 count < 500 cells/mm 3 Effective contraception (efavirenz) Endpoint 1 0 – all-cause mortality Karim S, et al. N Engl J Med. 2010;362:697-706

7. Initiation of ART during vs. after TB treatment: SAPIT Abdool Karim S, et al. New Engl J Med 2010; 362: 697-706

8. Effects of timing of ART on mortality, by baseline CD4 cell count: SAPIT Abdool Karim S, et al. New Engl J Med 2010; 362: 697-706 2/186 6/86 22/281 21/137

9. Effects of timing of ART on mortality, by baseline CD4 cell count: SAPIT Abdool Karim S, et al. New Engl J Med 2010; 362: 697-706 2/186 6/86 22/281 21/137 All patients with HIV-TB should receive ART during TB treatment

10. Competing risks in the timing of ART during TB treatment Immediate (< 2 wks) Benefits: ↓ risk of other OIs Risks: ↑ adverse effects ↑ incidence of IRD Early (2 months) Benefiits: ↓ risk of IRD Risks: ↑ incidence of OIs feasibility Mortality

11. TB treatment ART Study week 8 0 24 HIV+ TB Primary endpoint General schema for CAMELIA, STRIDE, and integrated arms of SAPIT “Immediate ART” (within 2 weeks) “Early ART” (2-3 months)

12. Key characteristics of trials of timing of ART during TB treatment StudySettingKey enrollment criteria Median CD4 (IQR) Primary endpoint CAMELIACambodiaSmear +, CD4 < 200 25 (10 - 56)Death STRIDEMulti- national Clinical TB, CD4 < 250 77 (36 – 145)AIDS or death SAPITSouth Africa Smear +, CD4 < 500 150 (77 – 254) AIDS or death N Engl J Med 365; 2011; 1471-1501

13. Effect of ART timing on death (CAMELIA) or death/AIDS (STRIDE, SAPIT) 34% ↓ p=0.004 19% ↓ p=0.45 11% ↓ p=0.73 N Engl J Med 2011; 1471-1501

14. Relationship between median baseline CD4 count and the effect of immediate ART on death (CAMELIA) or death/AIDS (STRIDE, SAPIT) N Engl J Med 2011; 1471-1501 P = 0.004 P = 0.45 P = 0.73

15. Effects of ART timing on outcomes in CAMELIA and patients with CD4 < 50 in STRIDE and SAPIT 34% ↓ p=0.004 42% ↓ p=0.02 68% ↓ p=0.06 N Engl J Med 2011; 1471-1501

16. Effects of ART timing on death/AIDS among patients with CD4 > 50 in STRIDE and SAPIT p=0.67 p=0.34 N Engl J Med 2011; 1471-1501

17. Effects of ART timing on Immune Reconstitution Disease among patients with CD4 > 50 in STRIDE and SAPIT p=0.009 p=0.02 N Engl J Med 2011; 1471-1501

18. Effect of ART timing on survival of patients with TB meningitis Median CD4 ~ 40 (16 – 100) 60% + CSF culture KM survival estimates at 9 months 35.2% in immediate arm 40.3% in deferred arm Similar in per protocol analysis Török et al, 41 st Union World Conference on Lung Health, Berlin Nov 2010 Early ART Immediate ART Hazard ratio 1.1 (95% CI 0.8 – 1.6), p = 0.52

19. Effect of ART timing on risk of adverse events in patients with TB meningitis Török et al, 41 st Union World Conference on Lung Health, Berlin Nov 2010 p = 0.04

20. Timing of ART in patients with TB Advanced AIDS (CD4 < 50): immediate ART (within 2 weeks) improves survival Markedly increased risk of IRIS, including fatal IRIS events Overall survival benefit despite IRIS CD4 > 50: early ART (~ 2 months) provides good balance of competing risks of death/AIDS vs. IRIS Caveats CNS involvement – no benefit to immediate therapy, and there may be increased risk (Clin Infect Dis. 2011;52:1374-83) Programmatic complexities of early ART

21. Programmatic challenges of immediate ART during TB treatment Rapid HIV diagnosis Rapid provisional diagnosis of TB Rapid way to identify those in need of immediate ART: CD4 cell count, BMI, clinical status ART available in settings where TB is diagnosed (hospital or clinic) Training in diagnosis and management of IRD events

22. Adverse events during treatment of HIV-TB 54% (99/167) had adverse events, 34% interrupted TB or HIV therapy Common adverse events Peripheral neuropathy (21%) - more common with use of stavudine Skin rash (17%) - TB drugs (16), co-trimoxazole (7), nevirapine (2), other drugs (4) hepatitis (6%) - TB drugs (6), unknown (5) AIDS 2002;16:75-83

23. Example of drug-drug interactions in HIV- TB care: atazanavir with rifampin HIV Medicine 2007;8:131-4

24. Effect of rifampin on exposure (AUC) of NNRTIs

25. Effect of EFV dose (600 vs. 800 mg) on mid-dose levels, patients on RIF AIDS 2005;19:1481-6, AIDS 2006;20:131-2 Outcomes at 48 wks On EFV 600 mg – 81% 800 mg – 74% VL < 50 600 mg – 91% 800 mg – 87%

26. Virological failure of efavirenz-based ART, among patients with and without rifampin for TB JAMA 2008; 300: 530-9

27. Case #2 - Intubated in the ED 38 year old man sent from jail – 1 wk of fevers, cough, dyspnea BP – 85/36 P – 100 T – 38.8 ABG – pH – 7.21, PCO 2 – 29, PO 2 - 38 Intubated for CV instability, acidosis, hypoxia PMH – Meds – trim/sulfa, azithro, acyclovir AIDS CD4 – 2, VL – 10,200 Crack cocaine abuse, frequent incarcerations PPD negative 3 mos. prior

28. Hospital course Initial treatment – trim/sulfa and prednisone Sputum DFA – negative for PCP Sputum AFB – strongly positive Started on parenteral INH, RIF, levo, amikacin Extubated, switched to oral IRZE Culture – susceptible M. tuberculosis

29. In the ID Clinic 3 weeks into TB treatment – first ID Clinic visit since TB diagnosis Current TB treatment - IRZE 5 days/wk by DOT Living situation – SRO provided by TB program Drug use – clean and sober Interested in ART, but very worried about side effects and being experimented on

30. ART history 6 years ago – brief multidrug regimen, no records, patient unable to identify meds 18 months ago – tenofovir / 3TC / EFV Initial suppression to < 50 copies/ml CD4 from 4 to 24 Subsequent virological and immunological failure 2 o nonadherence Genotype: L100I, K103N (EFV), M184V (3TC)

31. Patients who cannot be treated with EFV-based ART Efavirenz intolerance Resistance to efavirenz (other 1 st -generation NNRTIs) Pregnancy (at least for the first 1-2 trimesters) Very young children (< 3 years)

32. Comparison of the effects of RIF vs. RBT on trough concentrations of boosted PIs AAC 2204;48:1553-60, AAC 2006; 50:3336-42, AAC 2010;54:4440-5, AAC 2008;52:534-8, ND

33. Effect of protease inhibitors on serum concentrations (AUC) of rifamycins RifabutinRifampinPI Ritonavir Indinavir Nelfinavir Amprenavir Lopinavir/ritonavir Atazanavir  400%  270%  200%  400%  300%  250% unchanged NR Clin Infect Dis 1999; 28: 419-30

34. Clinical relevance of increased rifabutin concentrations due to ritonavir Adverse effect % of patients on ritonavir + rifabutin % of patients on ritonavir Arthralgia Joint stiffness Uveitis Leukopenia 9.2 4.1 4.7 38 0.6 0 0.6 19 11th International Conference on AIDS; abstract Mo.B171

35. Rifabutin PK with lopinavir/R in TB patients (n = 16) PK parameterRBT 300 mg/day RBT 150 mg QOD + LPV/r RBT 150 mg/day+ LPV/r Median AUC (exposure) 302623075010 Median Cmax (peak) 297168311 Naiker S, et al. 2011 CROI, abstract 650

36. Rifabutin and TB therapy Rifabutin is as active as rifampin No dose adjustments of ART needed for commonly-used drugs (ATZ, lopinavir/R) Decrease RBT from 300 mg daily to 150 mg daily when given with boosted PIs Give remainder of TB drugs daily Caution – RBT dose would be inadequate if patient stopped PI

37. HIV, TB drug interaction - summary Drug interactions in HIV-TB are regrettably complex, but should not prevent HIV-TB co- treatment Co-treatment regimen of choice: rifampin- based TB treatment + efavirenz-based (standard dose) ART Drug interactions should be managed, not avoided – use a rifamycin-based regimen New drug interaction guidelines at http://www.cdc.gov/tb/TB_HIV_Drugs

38. Case 1 – Chest x-ray response to therapy Diagnosis 2 months

39. Case 3 – Chest x-ray response to therapy - II 3 months Started antiretroviral therapy at 8 weeks of TB therapy Developed fever, cough, left pleuritic chest pain 10 days after starting HAART

40. Types of immune reconstitution inflammatory syndrome (IRIS) events in HIV-TB Hectic fever New or worsening adenitis - peripheral or central nodes New or worsening pulmonary infiltrates, including respiratory failure New or worsening pleuritis, pericarditis, or ascites Intracranial tuberculomas, worsening meningitis Disseminated skin lesions Epididymitis, hepatosplenomegaly, soft tissue abscesses

41. Association between timing of ART and risk of IRIS event (SAPIT) Ann Intern Med 2012; 157:313-24 42% hospitalized 22% hospitalized 5% hospitalized

42. Association between timing of ART and risk of IRIS event (SAPIT) Ann Intern Med 2012; 157:313-24 Median duration - 71 days Median duration - 34 days Median duration – 24 days

43. IRIS in the CAMELIA study (median CD4 of 25) Immediate ART increased risk of IRIS (33% vs. 14% for early ART) Similar timing of IRIS events (14 vs. 16 days after starting ART 6 deaths, all in the immediate arm, were attributed to IRIS events However, immediate ART was associated with a lower risk of death (8% vs. 14%) N Engl J Med 2011; 365: 1471-81

44. IRIS events - implications for use of antiretroviral therapy (ART) Those who need ART the most (patients with low CD4 cell counts) have higher risk for an IRIS event and for a serious IRIS event Delaying ART decreases risk of severe paradoxical reactions, but increases risk of another OI or death Anticipate IRIS events – discuss beforehand with patient and other care providers Schedule early follow-up after starting ARV - detect and manage IRIS events

45. Management of IRIS Anticipate IRIS events – warn patients and other care providers Rule out other possible causes – bacterial infections, a 2 nd OI, inadequate Rx for OI, drug- resistant pathogen For relatively severe manifestations, prednisone is reasonable 1 mg/kg (1.5 mg/kg with rifampin), tapering over 4-6 weeks

46. What’s happening in the clinic? Starting ART in TB patients in London, 1998-2007) British recommendations (at that time) CD4 < 100 – at 2 weeks CD4 100-200 – at 2 months CD4 > 200 – after TB treatment 83 patients eligible to start ART 20 patients (24%) started ART at the recommended point in TB treatment Thorax 2008;63:935

47. Reasons for the delay in starting ART among patients with CD4 < 100 Patient-related reasons: Refused to start Fear of side effects of ART Poor adherence Physician-related reasons: Serious side effect of TB treatment Concern about ART side effects / IRIS Presence of another illness Seriousness of the manifestations of TB 7 (21%) 2 (6%) 3 (9%) 8 (24%) 6 (18%) 4 (12%) 5 (15%) Thorax 2008;63:935

48. Starting ART during TB treatment – summary of the steps required Start TB therapy, deal with initial side effects Help patient deal with the diagnosis of two stigmatizing diseases Start cotrimoxazole, deal with initial side effects Assess readiness for HAART Coordinate start of ART (~ 2 weeks for CD4 50) Use DOT visits to  adherence with HAART Anticipate and manage immune reconstitution events

49. Summary – treatment of HIV-related TB: issues with antiretroviral therapy Should antiretroviral therapy be used during TB treatment? Yes, for all patients What regimens can be used for co-treatment of HIV and TB? Preferred: efavirenz-based HAART + rifampin-based TB treatment Alternative: PI-based HAART + rifabutin-based TB treatment When should HAART be started? 2 weeks (CD4 < 50 to 2 months after starting TB treatment

50. Two infections; one patient GLOBAL PARTNERSHIP TO STOP TB