Tuberculosis in AIDS Patients. Chien-Ching Hung Division of Infectious Diseases Department of Internal Medicine National Taiwan University Hospital

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1 Tuberculosis in AIDS Patients Chien-Ching Hung Division of Infectious Diseases Department of Internal Medicine National Taiwan University Hospital

2 Topics Epidemiology of TB in the era of HIV epidemic Impact of highly active antiretroviral therapy (HAART) Diagnosis of TB in HIV-infected patients Latent TB infection (LTBI) Active TB Clinical manifestations of TB among HIVinfected patients Treatment of TB among HIV-infected patients Combination of anti-tb and HAART Immune reconstitution inflammatory syndrome (IRIS) Outcome of TB among HIV-infected patients Prevention of TB among HIV-infected patients

3 Abbreviations HAART: highly active antiretroviral therapy Containing 3 antiretroviral agents 2 Nucleoside reverse transcriptase inhibitors plus 1 non-nucleoside RTI; or plus protease inhibitor(s) TB, tuberculosis

4 TB can occur at any stage of HIV infection

5 Epidemiologic model of TB Uninfected Infected Diseased died Incidence and prevalence of TB Genetic; Nutrition; BCG vaccination; Co-morbidity; HIV infection; Immunocompromised; Treatment for LTBI; Treatment for HIV infection Diagnosis Anti-TB susceptibility Treatment for TB Treatment for HIV infection

6 Co-infection with HIV and TB in Asia Epidemiologic synergy between HIV and TB Vermund SH, et al. Tuberculosis 2007:87:S Mutually detrimental effects between TB and HIV Once infection occurs, CD4 cells are essential to keeping TB bacilli inside the granulomas through activating macrophages by production of cytokines. Risk of developing TB diseases, 5-15% annually in HIV-coinfected persons. cf. 5-10% lifetime risk in persons without HIV infection TB enhances HIV replication and HIV disease progression Contribute to 1/3 of deaths due to AIDS

7 Overlapping epidemiology of HIV infection and tuberculosis Nat Rev Immunol 2005;5:

8 TB in Sub-Saharan Africa: opportunities, challenges, and change in the era of ART Corbett E, et al. Lancet 2006;367:

9 TB in Sub-Saharan Africa: opportunities, challenges, and change in the era of ART Corbett E, et al. Lancet 2006;367:

10 Impact of HIV infection on the epidemiology of tuberculosis in a peri-urban community in South Africa: the need for age-specific interventions Lawn SD, et al. Clin Infect Dis 2006;42:

11 HIV prevalence in adults, and TB notification rates, for Kisumu, Kenya

12 Impact of combination antiretroviral therapy on the risk of tuberculosis among persons with HIV infection Girardi E, et al. AIDS 2000;14:

13 Impact of antiretroviral therapy on the incidence of TB: the Brazilian experience, PLoS ONE 2008;2:e826.

14 Tuberculosis among HIV-infected patients receiving HAART: long term incidence and risk factors in a South African cohort Lawn SD, et al. AIDS 2005;19:

15 Immune reconstitution and unmasking of TB during antiretroviral therapy Lawn SD, et al. AJRCCM 2008;177:680-5.

16 Quantitative impact of HIV on TB dynamics DeRiemer K, et al. AJRCCM 2007;176: HIV-infected patients HIV-uninfected patients

17 Epidemiology of HIV infection in Taiwan 台灣地區本國籍感染人類免疫缺乏病毒者趨勢圖 1984 年至 2007 年 12 月 ( 依診斷日分析 ) 4000 感染者 發病者 人數 Male-to-female: 13653:1358 (10.0) Age groups (20-49 years): 88.8% Risk groups: MSM: 35.6%; heterosexual: 23.8%; IDU: 38.54% 西元

18 TB-HIV co-infection in Taiwan % % 2.00% % 1.13% 0.95% 1.01% 1.00% 0.76% 0.73% 0.53% 0.56% 0.45% 0.45% 0.36% 0.50% 0.25% % HIV(+) TB cases new diagnosed TB cases HIV prevalence in new TB cases(%) y/o HIV prevalence in new TB cases(%)

19 Summary HIV infection increase susceptibility to TB reactivation or acceleration of progression to active TB once infected with M. tuberculosis. TB is the leading cause of death among HIVinfected patients in resource-limited countries. HAART significantly reduces risk for active TB, both in low- and high-income countries. The impact of HIV on TB remains to be seen in Taiwan HIV testing in all patients with TB?

20 Tuberculosis and HIV infection Clinical manifestations and outcome are related to degree of immunosuppression. More likely to be anergic to TST (tuberculin skin test) In patients with lower CD4 counts, more extra-pulmonary TB; miliary TB; patterns of primary TB; M. tuberculosis bacteremia More likely to be smear-negative TB (?) Higher mortality rate

21 TB as a common opportunistic infection in HIV-infected patients in Taiwan 14.3% (198) of HIV-infected persons sought medical attention because of active TB. 117 (60.0%) culture-confirmed sputum and lymph node 77.2% with CD4<100 cells/μl at presentation 50% extrapulmonary; 6 mycobacteremia Hung CC, et al. J AIDS 2000 Hung CC, et al. AIDS 2003 Sun HY, et al. Jpn J Infect Dis 2006

22 TB in Sub-Saharan Africa: opportunities, challenges, and change in the era of ART Corbett E, et al. Lancet 2006;367: More likely to be smear-negative TB (?)

23 Improved outcomes of HIV-1-infected adults with tuberculosis in the era of HAART Hung CC, et al. AIDS 2003 Pre-HAART era Post-HAART Era The virologic and immunlogic responses to HAART were similar between antiretroviral-naïve HIV-infected persons (N=46) with TB and persons without TB (270).

24 Factors associated with mortality of patients with TB/HIV co-infection Timely and appropriate institution of anti-tb therapy Regimens of anti-tb therapy Anti-TB resistance Duration of anti-tb therapy Status of immunosuppression Highly active antiretroviral therapy Nutrition Concurrent diseases Extent of tuberculosis

25 Treatment Outcomes of Patients with HIV and Tuberculosis Nahid P, et al. Am J Resp Crit Care Med 2007; 175: patients, 264 (38%) were HIV infected Mean duration of treatment: 10.2 months for HIV-infected vs 8.4 months for uninfected/unknown (p<0.001). Relapse rate among HIV-infected, 9.3 per 100 PY vs 1.0 per 100 PY in HIV-uninfected/unknown (p<0.001). HIV-infected individuals receiving a standard 6-month rifamycin-based regimen were more likely to relapse than those treated longer (adjusted hazard ratio, 4.33; p= 0.02). HIV-infected individuals who received intermittent therapy were also more likely to relapse than those treated on daily basis (adjusted hazard ratio, 4.12; p= 0.04).

26 Treatment of tuberculosis in HIV-infected persons in the era of HAART Dean GL, et al. AIDS 2002;16: HAART Decrease of viral load, AIDS-defining illness and mortality Drug-drug interactions between anti-hiv therapy and rifamycins (rifampin, rifabutin) Adverse drug effects are common (54%; 99/183): 21% neuropathy; 17% skin rashes A high proportion of patients had to interrupt or change anti-tb regimens

27 US CDC. Managing Drug Interactions in the Treatment of HIV-related Tuberculosis MMWR 2008 Rifabutin (RFT)-containing anti-tb plus Indinavir (1000 mg q8h) plus 2 NRTIs (RFT, 150 mg qd) Atazanavir (200 mg qd) plus 2 NRTIs (RFT, 150 mg qod) Kaletra (800/200 mg) plus 2 NRTIs (RFT, 150 mg qod) Efavirenz ( mg hs) plus 2 NRTIs (RFT, 450 mg qd) Nevirapine (200 mg bid) plus 2 NRTIs (RFT, 300 mg qd) Rifampin-containing anti-tb plus Ritonavir/saquinavir (400/400 mg) plus 2 NRTIs Kaletra (200/100 mg)/300 mg Ritonavir plus 2 NRTIs Kaletra (1600/400 mg) plus 2 NRTIs Efavirenz ( mg) plus 2 NRTIs Nevirapine ( mg bid) plus 2 NRTIs

28 Treatment of tuberculosis in persons with HIV infection Regimens of anti-tuberculous therapy Anti-TB susceptibility tests Clinical responses to anti-tb therapy? Toxicity? Duration of anti-tb therapy? Risk of TB recurrence? When to start ART? good or bad? What to start with? Survival benefit of HAART?

29 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

30 Summary Same anti-tb regimens for HIV-infected and HIV-uninfected individuals with TB At least thrice-weekly rifamycins-containing anti-tb therapy in HIV-infected patients Longer duration (>6 mo; preferably 9 mo pr greater) may be needed for HIV-infected patients HAART commenced in HIV-infected patients with CD4 counts<200 cells/μl Appropriate combinations Appropriate timing of adding HAART to anti-tb therapy (clinical trials, ongoing)

31 Impact of drug-resistant tuberculosis on the survival of HIV-infected patients Sungkarnuparph S, et al. Int J Tuberc Lung Dis 2007;11: HIV-TB patients: mean age, 35.8 years; 72.4% were male. The median CD4 cell count, 44 cells/mm3. 60% extra-pulmonary TB 63 (28%) infected with MTB resistant to at least one drug; 16.4%, 9.3%, 5.3% and 12.9% resistant to isoniazid (INH), rifampicin (RMP), ethambutol and streptomycin, respectively, and 14 (6.2%) being MDR-TB MDR-TB (hazard ratio [HR] 11.7; 95% CI ), not receiving antiretroviral therapy (ART) (HR 7.9; 95% CI ) and ExPTB (HR 5.1; 95% CI ) were significant risk factors for death.

32 Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa Gandhi NR, et al. Lancet 2007;368: Time: Jan 2005-March sputum specimens 542 culture-confirmed TB 221 MDR-TB 53 XDR-TB 44 XDR-TB were HIV-infected; 15 (34% received HAART) 45% had been previously treated for TB. 67% had a recent hospital admission (nosocomial transmission?) 52/53 died, with a median survival of 16 days (6-37 d), of 42 confirmed dates of death

33 Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa Gandhi NR, et al. Lancet 2007;368:

34 Comparison of resistance for M. tuberculosis isolates between 75 HIV-infected and 429 HIV-uninfected patients 2000 to 2006 (modified proportional method) Agent (conc [µg/ml] tested) HIV-infected (n=75) Non-HIV-infected (n=429) Isoniazid (0.2) 13 (17.3) 53 (12.4) Isoniazid (1.0) 9 (12) 23 (5.3) Rifampin (1) 5 (6.7) 17 (4.0) Ethambutol (5) 3 (4.0) 11 (2.5) Streptomycin (2) 5 (6.7) 39 (9.1) Streptomycin (10) 2 (2.7) 24 (5.6) Any drug resistant 19 (25.3) 76 (17.7) Multidrug resistant 2 (2.7) 14 (3.3) (Courtesy of Prof. PR Hsueh)

35 Trend of resistance to isoniazid (0.2 µg/ml), ethambutol, and rifampin (NTUH) (Courtesy of Prof. PR Hsueh)

36 TB recurrence in HIV-infected patients receiving rifamycins 16/431 (3.7%) TB recurrences; 9/109 (8.3%) HIV positives vs 7/322 (2.2%) HIV-negative/unknown (RR = 2.3; p = 0.007). Relapse was only associated with low median initial CD4 count (51/mm 3 vs 137/mm 3 ; p = 0.02) and not with the rifamycin used. HAART? Not mentioned Nettles R, et al. Clin Infect Dis % of 98 TB/HIV patients followed for >2 years had TB relapse. Dean GL, et al. AIDS (5.6%) developed 8 cases of culture-proven TB recurrences (2.54 per 100 PY [95% CI, ]). The median interval from TB diagnosis to the date TB recurrences was 1,065 days. Hung CC, et al. JAIDS 2003

37 Factors associated with TB recurrence Anti-TB therapy containing rifamycins or not Background TB prevalence and incidence Reinfection vs. recurrence HIV infection Initiation of HAART in HIV-infected patients

38 Paradoxical response to anti-tb therapy and HAART

39 TB lymphadentitis due to paradoxical responses

40 Immune reconstitution inflammatory syndrome complications of antiretroviral therapy in TB patients McIlleron H, et al. J Infect Dis 2007;196:S No standard, sensitive/specific case definitions Mechanisms Dys-regulated delayed-type hypersensitivity response Granulomatous and necrotizing inflammation directed at mycobacterial antigen Two distinct circumstances Paradoxical worsening or recurrent symptoms after initial improvement Unmasking of sub-clinical or un-recognized TB when HAART is commenced.

41 TB-associated Immune reconstitution inflammatory syndrome Lawn SD, et al. AIDS 2007;21: No standard, sensitive/specific case definitions Paradoxical worsening Risk factors for IRIS Disseminated TB; shorter delay between commencing anti-tb and HAART; a low baseline CD4; a higher baseline PVL; a greater reduction of viral load; a greater increase of CD4 or in CD4/CD8 ratio Prevalent TB Initial symptomatic improvement during anti-tb therapy Deterioration of symptoms after initiation of ART Exclusion of other OI, ADR, ineffective anti-tb therapy or drug-resistant TB

42 Immune reconstitution and unmasking of TB during antiretroviral therapy Lawn SD, et al. AJRCCM 2008;177: Interactions between mycobacterial load and immune recovery Sub-clinical TB, unmasking after initiation of HAART

43 Explosion of tuberculin-specific Th1-responses induces IRIS in TB and HIV co-infected patients Bourgarit A, et al. AIDS 2006;20:F1-7. SFC, 2970 SFC, 430 ELISpot IFN-γassays IRIS (+) patients IRIS (-) patients

44 Immune reconstitution inflammatory syndrome complications of antiretroviral therapy in TB patients McIlleron H, et al. J Infect Dis 2007;196:S Clinical manifestations Incidence: 8-43% Interval between HAART and IRIS (mean or median), days Median duration of symptoms, 57 days Longer in lymphadenopathy Exacerbation of existing disease manifestations Development of new manifestations Rare fatality Treatment NSAIDs Corticosteroids

45 TB-associated IRD: incidence, risk factors, and impact on an ART service in South Africa 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

46 Epidemiologic model of TB Treatment of LTBI Diagnosis and treatment of TB Uninfected Infected Diseased died Incidence and prevalence of TB Genetic; Nutrition; BCG vaccination; Co-morbidity; HIV infection; Immunocompromed; Treatment for LTBI; Treatment for HIV infection Diagnosis Anti-TB susceptibility Treatment for TB Treatment for HIV infection

47 TB preventive therapy in the era of HIV infection Efficacy of TB preventive therapy compared with placebo Churchyard GV, et al. J Infect Dis 2007;196:S Secondary INH TB preventive therapy Primary INH TB preventive therapy

48 Effect of tuberculosis preventive therapy on HIV disease progression and survival in HIV-infected adults (Uganda) Lim HJ, et al. HIV Cin Trials 2006; 7: a randomized placebo-controlled trial in Kampala, Uganda, 2,736 PPD (+) and anergic HIV-infected adults INH for 6 months (n = 536) [anergic] INH plus rifampicin for 3 months (556) INH plus rifampicin plus pyrazinamide for 3 months (462) placebo for 6 months (464) [anergic] Results Survival was greater in the PPD-positive cohort compared to the anergic cohort (p =.0001). Preventive therapies reduced TB incidence, but not for AIDS progression or survival.

49 Summary Epidemiology of TB in the era of HIV epidemic Surveillance of TB among HIV-infected persons and HIV infection among TB persons are urgently needed in Taiwan. Clinical manifestations of TB among HIV-infected patients More extrapulmonary, more smear-negative (??), more relapse Treatment of TB among HIV-infected patients Efavirenz-containing HAART plus rifampin or rifabutincontaining anti-tb therapy Ritonavir-boosted or atazanavir-containing HAART plus rifabutin-containing anti-tb therapy Outcome of TB among HIV-infected patients Improved with HAART, appropriate TB/HIV program Paradoxical responses How to reduce risk for relapse?