MANAGEMENT OF TUBERCULOSIS IN PATIENTS WITH HIV INFECTION

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1 MANAGEMENT OF TUBERCULOSIS IN PATIENTS WITH HIV INFECTION Outline Presentation of Case Challenges in treatment of TB in HIV-infected patients Immune reconstitution inflammatory syndrome Duration of anti-tb treatment Timing of combination of antiretroviral therapy Relapse vs. re-infection

Present illness-(1) 2010/04/20 Admitted due to inguinal hernia 2010/08/26 Productive cough with intermittent fever for 20 days HIV infection diagnosed Pneumocystosis 2008/10/8 Lost to

2 Present illness-(1) 2010/04/20 Admitted due to inguinal hernia 2010/08/26 Productive cough with intermittent fever for 20 days HIV infection diagnosed Pneumocystosis 2008/10/8 Lost to follow-up Date / / / / / /27 CD Viral load > < Kivexa 1#QD Kaletra 3#BID 2007/11/06 2 # BID

Laboratory investigations Bacterial Fungal Mycobacterial

Chlamydiae Antigen(-) Mycoplasma pneumoniae IgM(-) Legionella

3 Laboratory investigations Bacterial Fungal Mycobacterial Atypical S/C: K. pneumoniae 1+ B/C(-) (II/II) U/C(-) Aspergillus antigen(-) Cryptococcal antigen(-) Sputum AFS(-) (III/III) Blood AFS(-) Chlamydiae Antigen(-) Mycoplasma pneumoniae IgM(-) Legionella urinary antigen(-) Influenza A+B rapid test(-) S/C: sputum culture; B/C: blood culture; U/C: urine culture AFS: acid-fast stain

Poor response to antibiotics On 2010/09/08, he underwent video-assisted thoracoscopic surgery (VATS) of the nodules at the right lower lobe nodules

4 Poor response to antibiotics On 2010/09/08, he underwent video-assisted thoracoscopic surgery (VATS) of the nodules at the right lower lobe nodules and lymphadenopathies. Some papule-like lesions over lung surface One 2.5*2.5 cm, yellowish, necrotic tumor Some over whitish RLL nodules over pleura

Massive whitish pus from subcarinal lymph nodes Examinations of surgical specimens Pathology of the biopsy: mycobacterial infection Extensive

5 Massive whitish pus from subcarinal lymph nodes Examinations of surgical specimens Pathology of the biopsy: mycobacterial infection Extensive caseating necrotizing granulomatous inflammation Acid-fast smear (AFS) of the sub-carinal lymph nodes: 3+ AFS of the right lower lung (RLL) lesion: 3+

6 Caseating necrotizing granulomatous inflammation AFS

7 Results of mycobacterial cultures Sputum (2010/08/26, 2010/08/30, 2010/09/09) Blood (2010/08/30) Lung mass (2010/09/09) Sub-carinal lymph nodes (2010/09/09) AFS(-) (IV/IV) M/C: Mycobacterium tuberculosis (IV/IV) (2010/10/01) AFS(-) M/C: Mycobacterium tuberculosis (2010/10/06) AFS(3+) (2010/09/10) M/C: Mycobacterium tuberculosis (2010/10/01) AFS(3+) (2010/09/10) M/C: Mycobacterium tuberculosis (2010/10/01) M/C: mycobacterial culture Susceptibility of the M. tuberculosis isolate Antibiotic tested INH1: INH 0.2 INH2: INH 1.0 RIF: RIF 1.0 EMB1: EMB 5.0 EMB2: EMB 10.0 SM1: SM 2.0 SM2: SM 10.0 EA: Ethionamide PAS: p-aminosalicylic OFX: Ofloxacin Ri: Rifabutin S S S S S S S S S S S INH: isoniazid; RIF: rifampin; EMB: ethambutol; SM: streptomycin

8 Discharged and transferred to DOTS 9/9 9/16 9/29 10/15 10/26 11/2 11/16 12/14 12/28 1/11 2/10 3/10 3/24 NA NA NA NA INH RIF EMB PZA /26 8/30 9/9 11/14 11/15 11/16 12/30 1/23 1/24 2/10 S/C -/TB*2 -/TB -/TB -/- +/- -/- +/- -/- -/- -/- Ascending numbness of bilateral feet after taking anti-tb drugs NCV : compatible with motor and sensory polyneuropathy DC isoniazid 2011/4/21 lost to follow-up on DOTs2011/4/ /4/21CDC Challenges in diagnosis of TB in HIV-infected patients Symptoms/signs More systemic symptoms/signs Multiple organ involvement Chest radiography Patterns of primary TB in patients with a depleted CD4 count Microbiology Less smear-positive More mycobacteremia

9 Present illness-(2) 2011/ /08/ /09/05 Right inguinal redness, swelling, local heat and pain Accompanied by fever and chills Mild productive cough with whitish sputum No diarrhea, no abdominal pain, no dysuria OPD of surgery Cephalexin for cellulitis Progression with pus formation ED of NTUH WBC (K/μL) RBC (M/μL) HB (g/dl) HCT (%) MCV (fl) MCHC (g/dl) PLT (K/μL) Band (%) Seg (%) Eos. (%) Baso. (%) Mono. (%) Lym. (%) Aty.Lym. (%) UN (mg/dl) CRE (mg/dl) Na (mmole/l) K (mmole/l) T-BIL (mg/dl) AST (U/L) CRP (mg/dl) HIV viral load (copies/ml) CD4 count (/μl) 1,530, Ferritin (ng/ml) Iron (μg/dl) TIBC (μg/dl) Fe/TIBC (%) %

10 Multiple nodular lesions with central low density Right common iliac region right pelvic sidewall right inguinal region Suspected necrotic lymphadenopathy or abscess

11 Results of laboratory investigations 9/5 9/6 9/9 Sputum AFS(-) Blood B/C(-)(II/II) Others U/A: no pyuria Right inguinal pus: AFS (2+) Lymph node aspiration: AFS (-), TB PCR (+) B/C: bacterial culture; U/A: urine analysis; PCR: polymerase chain reaction BT WBC CRP ALP Repeated sputum AFS (-) (II/II) Unasyn ERZ+S+Mox E: ethambutol; R: rifampin; Z: pyrazinamide; S: streptomycin; Mox: moxifloxacin

12 Unasyn ERZ+S+Mox BT WBC CRP ALP Unasyn ERZ+S+Mox EFV+(ABC+3TC) D14 after anti-tb EFV: efavirenz; ABC: abacavir; 3TC: lamivudine BT WBC CRP ALP

13 BT WBC CRP ALP Unasyn ERZ+S+Mox EFV+(ABC+3TC) 9/26 New onset fever and chills Septic workup for breakthrough fever Differential diagnosis Progression of the initial tuberculosis Antimicrobial resistance Nonadherence Drug interaction Drug malabsorption Chronic diarrhea Wasting syndrome Drug hypersensitivity Development of a new opportunistic infection Immune reconstitution inflammatory syndrome (IRIS)

14 Drug-drug interaction? MICROMEDEX 2.0 Drug-drug interactions Concurrent use of efavirenz and rifampin may result in decreased serum efavirenz concentrations Efavirenz 26%

15 Drug hypersensitivity? Usual causes: Cotrimoxazole Rifampin Abacavir Nevirapine Tuberculosis: a comprehensive clinical reference. Edited by H. Simon Schaaf, Saunders, 2009

16 Results of laboratory investigations Sputu m Blood 9/16 9/26 (Breakthrough fever) 10/2 (Repeated septic workup for persistent fever) AFS(-) (II/II) No sputum No sputum B/C(-)(II/II) AFS(-) F/C(-) B/C(-)(II/II) AFS(-) F/C(-) 10/12 (Right inguinal abscess rupture with pus discharge) Others U/A: no pyuria U/A: no pyuria Pus of right inguinal wound: B/C(-) Pus of RLQ abdomen: B/C(-) Differential diagnosis Progression of the initial tuberculosis Antimicrobial resistance Nonadherence Drug interaction Drug malabsorption Chronic diarrhea Wasting syndrome Drug hypersensitivity Development of a new opportunistic infection Immune reconstitution inflammatory syndrome

17 Unasyn ERZ+S+Mox EFV+(ABC+3TC) Wound TB culture(9/6): Mycobacterium tuberculosis Sensitivity: pending BT WBC CRP ALP Unasyn ERZ+S+Mox EFV+(ABC+3TC) EFV+TDF+3TC Gastrointestinal upset (nausea/vomiting) TDF: tenofovir disoproxil fumarate BT WBC CRP ALP

18 Unasyn ERZ+S+Mox EFV+(ABC+3TC) EFV+TDF+3TC 10/2 Repeated septic workup for persistent fever BT WBC CRP ALP CXR 2011/10/ /09/27

19 BT WBC CRP ALP Unasyn ERZ+S+Mox EFV+(ABC+3TC) 10/06 Abdominal sonography EFV+TDF+3TC Spleen index: 6.2 x 5.3 cm Several hypoechoic lesions scattered inside the spleen The sizes were around 0.3~0.9 cm in diameter

20 Results of laboratory investigations 9/16 9/26 (Breakthrough fever) 10/2 (Repeated septic workup for persistent fever) Sputum AFS(-) (II/II) No sputum No sputum 10/12 (Right inguinal abscess rupture with pus discharge) Blood B/C(-)(II/II) AFS(-) F/C(-) B/C(-)(II/II) AFS(-) F/C(-) Others U/A: no pyuria Aspergillus Ag (serum)(-) Cryptococcus Ag (serum)(-) U/A: no pyuria Pus of right inguinal wound: B/C(-) Pus of RLQ abdomen: B/C(-) BT WBC CRP ALP Unasyn ERZ+S+Mox EFV+(ABC+3TC) Regular acetaminophen EFV+TDF+3TC

21 BT WBC CRP ALP Unasyn ERZ+S+Mox EFV+(ABC+3TC) Regular acetaminophen Blood culture (9/9): M. tuberculosis EFV+TDF+3TC Susceptibility of M. tuberculosis isolate (9/6 pus specimen from the right inguinal region) Antibiotic tested INH1: INH 0.2 INH2: INH 1.0 RIF: RIF 1.0 EMB1: EMB 5.0 EMB2: EMB 10.0 SM1: SM 2.0 SM2: SM 10.0 EA: Ethionamide PAS: p-aminosalicylic OFX: Ofloxacin Ri: Rifabutin S S S S S S S S S S S

22 Unasyn ERZ+S+Mox HERZ EFV+(ABC+3TC) EFV+TDF+3TC 10/12 Abdominal CT H: isoniazid BT WBC CRP ALP Regular acetaminophen

23 Unasyn ERZ+S+Mox HERZ EFV+(ABC+3TC) EFV+TDF+3TC 10/12 Right inguinal abscess rupture with pus discharge BT WBC CRP ALP Regular acetaminophen

Results of laboratory investigations Sputu m Blood 9/16 9/26 (Breakthrough fever) 10/2 (Repeated septic workup for persistent fever) AFS(-) (II/II) No sputum No sputum B/C(-)(II/II) AFS(-) F/C(-)

24 Results of laboratory investigations Sputu m Blood 9/16 9/26 (Breakthrough fever) 10/2 (Repeated septic workup for persistent fever) AFS(-) (II/II) No sputum No sputum B/C(-)(II/II) AFS(-) F/C(-) B/C(-)(II/II) AFS(-) F/C(-) 10/12 (Right inguinal abscess rupture with pus discharge) Others U/A: no pyuria Aspergillus Ag (serum)(-) Cryptococcus Ag (serum)(-) U/A: no pyuria Pus of right inguinal wound: B/C(-) Pus of RLQ abdomen: B/C(-) RLQ: right lower quadrant

25 Unasyn ERZ+S+Mox HERZ EFV+(ABC+3TC) EFV+TDF+3TC Acetaminophen PRN PRN: pro re nata BT WBC CRP ALP Regular acetaminophen Unasyn ERZ+S+Mox HERZ EFV+(ABC+3TC) EFV+TDF+3TC BT WBC CRP ALP Acetaminophen PRN Regular acetaminophen

26 Sputum AFS(-) M/C(-) Results of laboratory investigations 9/5 9/6 9/9 Blood B/C(-)(II/II) AFS(-), M. tuberculosis Others U/A: no pyuria OI: opportunistic infection Right inguinal pus: AFS(2+), M. tuberculosis F/C(-) Lymph node aspiration: B/C(-) AFS(-), TB PCR(+) M. tuberculosis F/C(-) OI survey: negative Results of laboratory investigations 9/16 9/26 10/2 10/12 (Breakthrough fever) (Repeated septic workup for persistent fever) (Right inguinal abscess rupture with pus discharge) Sputum AFS(-) (II/II) M. tuberculosis (I/II) No sputum No sputum Blood B/C(-)(II/II) AFS(-) F/C(-) B/C(-)(II/II) AFS(-) F/C(-) Others U/A: no pyuria Aspergillus Ag (serum)(-) Cryptococcus Ag (serum)(-) U/A: no pyuria Pus of right inguinal wound: B/C(-) Pus of RLQ abdomen: B/C(-)

27 TUBERCULOSIS-RELATED IRIS Unasyn ERZ+S+Mox HERZ EFV+(ABC+3TC) EFV+TDF+3TC Steroids BT WBC CRP ALP Acetaminophen PRN Regular acetaminophen

28 BT WBC CRP ALP Unasyn ERZ+S+Mox EFV+(ABC+3TC) Regular acetaminophen Good virologic response 10/24 PVL: copies/ml CD4: /μL HERZ EFV+TDF+3TC Acetaminophen PRN Steroids BT WBC CRP ALP Unasyn ERZ+S+Mox EFV+(ABC+3TC) Regular acetaminophen HERZ EFV+TDF+3TC Acetaminophen PRN Steroids 10/26 Worsening fever with chills Repeated septic work up

CXR 2011/10/26 2011/10/02 Results of laboratory investigations 9/16 9/26 (Breakthrough fever) 10/2 (Repeated septic workup for persistent fever) 10/12 (Right inguinal abscess rupture with pus

29 CXR 2011/10/ /10/02 Results of laboratory investigations 9/16 9/26 (Breakthrough fever) 10/2 (Repeated septic workup for persistent fever) 10/12 (Right inguinal abscess rupture with pus discharge) 10/26 Sputum AFS(-) (II/II) M. tuberculosis (I/II) No sputum No sputum No sputum Blood B/C(-)(II/II) AFS(-), M/C(-) F/C(-) B/C(-)(II/II) AFS(-), M/C(-) F/C(-) B/C(-)(I/I) Others U/A: no pyuria Aspergillus Ag (serum)(-) Cryptococcus Ag (serum)(-) U/A: no pyuria Pus of right inguinal wound: B/C(-) Pus of RLQ abdomen: B/C(-)

30 Unasyn ERZ+S+Mox HERZ EFV+(ABC+3TC) EFV+TDF+3TC Steroid BT WBC CRP ALP Acetaminophen PRN Regular acetaminophen Unasyn ERZ+S+Mox HERZ EFV+(ABC+3TC) EFV+TDF+3TC Steroids BT WBC CRP ALP Acetaminophen PRN Regular acetaminophen

31 Unasyn ERZ+S+Mox HERZ EFV+(ABC+3TC) EFV+TDF+3TC Steroids BT WBC CRP ALP Acetaminophen PRN Regular acetaminophen Unasyn ERZ+S+Mox HERZ EFV+(ABC+3TC) EFV+TDF+3TC Steroids BT WBC CRP ALP Acetaminophen PRN Regular acetaminophen

32 Final diagnosis Recurrent disseminated tuberculosis, suspected replase, with lung, blood, lymph nodes, and suspected liver and spleen involvement Human immunodeficiency virus infection with acquired immunodeficiency syndrome, on highly active antiretroviral therapy TB-related immune reconstitution inflammatory syndrome with inguinal and pelvic lymphadenitis, resulting in skin rupture and pus formation Challenges in treatment of TB in HIV-infected patients HIV infection increases both risk and recurrence of tuberculosis Appropriate duration of anti-tb therapy Antiretroviral therapy prevent tuberculosis and its recurrence in HIV-infected patients Appropriate timing of combination antiretroviral therapy Diagnosis and management of IRIS

33 TB can occur at any stage of HIV infection Impact of HIV on risk of TB JAMA 2008;300:

34 HIV increases TB risk by reactivation of a latent tuberculosis infection rapid evolution to active tuberculosis in those with recent acquisition of M. tuberculosis Tuberculosis and Nontuberculosis Mycobacterial Infections, 6th ed. Edited by David Schlossberg, 2011 CART prevent TB in HIV-infected patients Antiretroviral therapy (ART) reduces TB incidence by 67% (95% CI 61 73%) Antiretroviral therapy (ART) reduces TB recurrence rates by about 50% Lancet Infect Dis 2010;10: AIDS 2008;22:

35 Declined incidence of TB with widespread use of antiretroviral therapy Lawn SD, et al. AJRCCM 2008;177: ART prevent TB in HIV-infected Lancet Infect Dis 2010;10:

36 Decrease of TB incidence by antiretroviral therapy among HIV-positive patients in high-income countries HIV-CAUSAL Collaboration Clin Infect Dis 2012;54: TB<3 m since cart TB>3 m since cart PCP<3 m since cart PCP>3 m since cart PCP>3 m since cart PCP<3 m since cart TB>3 m since cart TB<3 m since cart

37 WHEN TO START ANTI-RETROVIRAL THERAPY FOR HIV-INFECTED PATIENTS WITH TB TB detected in patients not on highly active antiretroviral therapy (HAART) TB detected in patients already on highly active antiretroviral therapy HAART in TB-HIV: Early or late? START TB TREATMENT AND HAART SIMULTANEOUSLY PROS HIV disease progression or death in advanced patients (CD4 <50 cells/mm 3 ) CONS Overlapping side effects PK interactions Higher pill burden Risk of IRIS START TB TREATMENT FIRST AND DELAY HAART PROS Avoid overlapping side effects Avoid PK interactions Lower pill burden Lower risk of IRIS CONS Higher risk of HIV disease progression or death in advanced patients (CD4 < 50 cells/mm 3 ) IRIS: immune reconstitution inflmmatory syndrome Adapted from J Acquir Immune Defic Syndr 2007; 46: S9-S18.

38 When to start antiretroviral therapy in patients with active tuberculosis? DHHS Guidelines, 29 January, 2008 Among patients already on HAART Start anti-tb therapy after careful selection of regimens (pk consideration) Among patients not on HAART CD4<100, delay HAART by 2 weeks CD4, , delay HAART by 8 weeks CD4, , delay HAART by 8 weeks CD4>350, anti-tb therapy only 642 Randomization 492 Integrated therapy 213 Sequential therapy 350 Initiated ART 100 Initiated ART 94 completed 24 mo f/u 203 continued in f/u 38 completed 24 mo f/u 55 continued in f/u Abdool Karim SS, et al. N Engl J Med 2010;362:

39 Timing of initiation of antiretroviral drugs during tuberculosis therapy Abdool Karim SS, et al. N Engl J Med : Death Rates and Hazard Ratios, Stratified According to CD4+ Cell Count CD4 Integrated No. P-Y Death Rate Sequential No. P-Y Death Rate Hazard ratio P value All ( ) < ( ) 0.04 > ( ) 0.02 Abdool Karim SS, et al. N Engl J Med 2010;362:

40 Criticisms Prolonged deferral in HIV+ patients with CD4 <200, unethical Systematic review: IRIS incidence 15.7% in patients receiving HERZ & ART of whom 3.2% died Approx. 1 in 200 patients receiving HERZ and ART die from or with this complication In this study: IRIS Integrated Sequential P-value IRIS 53/429 (12.4%) 8/213 (3.8%) <0.001 ( ) ( ) INTEGRATION OF ANTIRETROVIRAL THERAPY WITH TUBERCULOSIS TREATMENT ABDOOL KARIM SS, ET AL. N ENGL J MED 2011;365:

41 Integration of antiretroviral therapy with tuberculosis treatment Abdool Karim SS, et al. N Engl J Med 2011;365: CAMELIA strategy Switch D4T to AZT ANRS 1295/ CIPRA KH001/10425 study

42 CAMELIA Gender Male Female Early arm (N=332) Late arm (N=329) p 215 (64.8) 117 (35.2) 210 (63.8) 119 (36.2) Age, years Median (IQR) 35 (30 41) 36 (30 42) BMI, kg/m 2 Median (IQR) 16.7 ( ) 16.8 ( ) Karnofsky score Patient characteristics at enrollment 43 (13.0) 259 (78.0) 30 (9.0) 44 (13.4) 251 (76.3) 34 (10.3) CD4, cells/mm 3 Median (IQR) 25 (11 56) 25 (10 55) Viral load, log copies/ml Median (IQR) 5.60 ( ) 5.66 ( ) 0.25 ANRS 1295/ CIPRA KH001/10425 study

43 Characteristics of tuberculosis Early arm (N=320) Late arm (N=325) p Location of TB Pulmonary Pulmonary & extra-pulmonary Extra-pulmonary 221 (69.1) 71 (22.2) 28 (8.7) 222 (68.3) 73 (22.5) 30 (9.2) 0.97 Drug resistance None Isoniazid (INH) monoresistance Streptomycin monoresistance Rifampin monoresistance INH polydrug resistance Multidrug resistant (MDR) No DST Missing 217 (67.8) 23 (7.2) 17 (5.3) 3 (0.9) 16 (5.0) 6 (1.9) 37 (11.6) 1 (0.3) 240 (73.8) 10 (3.1) 10 (3.1) 4 (1.2) 24 (7.4) 7 (2.2) 30 (9.2) CAMELIA

44 SIGNIFICANT REDUCTION OF MORTALITY IN THE EARLY ARM N Deaths Follow-up time* Mortality rate** (95% CI) p Early arm ( ) Late arm ( ) * expressed in person-years ** per 100 person-years 12 patients (1.8%) lost to follow-up. 8,955 protocol visits, <2% missed visits. ANRS 1295/ CIPRA KH001/10425 study Immunologic and virologic responses to ART in Cambodian patients with TB

45 IRIS significantly more frequent in the early arm N PR/IRIS Follow-up time* Incidence** (95% CI) p Early arm ( ) Late arm ( ) < * expressed in person-months ** per 100 person-months Time Time aftre after TB TB treatment initiation (weeks) Early arm Late arm TIMING OF ANTIRETROVIRAL THERAPY FOR HIV-1 INFECTION AND TUBERCULOSIS HAVLIER D, ET AL. N ENGL J MED 2011;365:

46 Study flow of ACTG A5221 Significant difference in combined outcome in patients with CD4<50 CD4<50: (p=0.02) Earlier- vs. later-art, 15.5% vs. 26.6%

47 CD4 50 CD TUBERCULOSIS-RELATED IRIS

48 Tuberculosis-related IRIS TB-IRIS (8-43%) Meintjes G et al. Lancet Infect Dis 2008;8:

49 Case definition for paradoxical TB-IRIS Three components of the case definition A. Antecedent requirements B. Clinical criteria C. Alternative explanations for clinical deterioration must be excluded if possible Meintjes G et al. Lancet Infect Dis 2008;8: Antecedent Requirements Both of two following requirements must be met: A. Diagnosis of tuberculosis Meintjes G et al. Lancet Infect Dis 2008;8: The tuberculosis diagnosis was made before starting ART and this should fulfill WHO criteria for diagnosis of smear-positive pulmonary tuberculosis, smear-negative pulmonary tuberculosis, or extra-pulmonary tuberculosis B. Initial response to tuberculosis treatment The patient s condition should have stabilized or improved on appropriate tuberculosis treatment before ART initiation

50 Clinical Criteria (1) The onset of tuberculosis-associated IRIS manifestations should be within 3 months of ART initiation, re-initiation, or regimen change because of treatment failure Meintjes G et al. Lancet Infect Dis 2008;8: Clinical Criteria (2) At least one major criterion or two minor criteria: 1. Major criteria New or enlarging lymph nodes, cold abscesses, or other focal involvement New or worsening radiological features of tuberculosis New or worsening CNS tuberculosis New or worsening serositis 2. Minor criteria New or worsening constitutional symptoms New or worsening respiratory symptoms New or worsening abdominal pain with peritonitis, hepatomegaly, splenomegaly, or abdominal adenopathy

51 Alternative explanations for clinical deteriorations are excluded 1. Failure of tuberculosis treatment because of anti-tuberculosis drug resistance 2. Poor adherence to tuberculosis treatment 3. Another opportunistic infection or neoplasm 4. Drug toxicity or reaction Meintjes G et al. Lancet Infect Dis 2008;8: TB-associated IRIS: incidence, risk factors, and impact on an ART service in SA Lawn SD, et al. AIDS 2007;21: Retrospective study 12% (19/160) IRD Median time, 2 wk ( ) Multivariate analysis Low baseline CD4 Shorter interval between anti-tb and ART IRD (+), 40 days vs. IRD (-), 107 days

52 Pathogenesis Restoration of tuberculosis-specific immune responses resulting in inflammation at disease sites of tuberculosis wherein antigen persists despite antitubercular treatment. Recommended management: Glucocorticoids Unmasked TB and TB-IRIS: a disease spectrum after initiation of antiretroviral therapy Manabe YC, et al. J Infect Dis 2009;199:

53 Relationship between CD4 cell counts and mycobacterial burden Manabe YC, et al. J Infect Dis 2009;199: Glucocorticoids for Paradoxical TB-IRIS Pros Cons Theoretical Clinical Evidence? risk of herpes zoster risk of Kaposi s sarcoma Possible drug-resistant M. tuberculosis

54 Time to Initiate Open-label Prednisolone The First 4 weeks Deteriorating symptoms Concerning steroid A/E All in placebo group (3) HBV flare up (1) HSV esophagitis (1) Pancreatitis (1) Later 4 weeks Relapsing TB-IRIS Median duration of open-label prednisolone: 84 days (IQR, ) (DOT)

FOR HOW LONG ANTI-TB THERAPY SHOULD BE CONTINUED FOR HIV- INFECTED PATIENTS WITH TB? Treatment of active tuberculosis in HIV-coinfected patients: a systematic review and meta-analysis Conclusions 1.

55 FOR HOW LONG ANTI-TB THERAPY SHOULD BE CONTINUED FOR HIV- INFECTED PATIENTS WITH TB? Treatment of active tuberculosis in HIV-coinfected patients: a systematic review and meta-analysis Conclusions 1. at least 8 months duration of rifamycin therapy, 2. initial daily dosing 3. concurrent antiretroviral therapy might be associated with better outcomes Khan FA, et al. Clin Infect Dis 2010:50:

56 A retrospective cohort study in San Francisco Am J Respir Crit Care Med 2007;175: A randomized controlled clinical trial in India 9 months 6 months P = 0.03 Am J Respir Crit Care Med 2010;181:

Immune Reconstitution Inflammatory Syndrome. Dr. Lesego Mawela

Immune Reconstitution Inflammatory Syndrome Dr. Lesego Mawela TOPICS FOR DISCUSSION IRIS Case Epidermiology Pathogenesis of IRIS Risk factors for IRIS Epidemiology of IRIS Health system burden of IRIS