1/18/2011. Handling TB and HIV. Fargo, North Dakota September 15-16, Treatment of TB in the HIV Co-Infected Patient

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1 1/18/2011 Handling TB and HIV Co-Infection Fargo, North Dakota September 15-16, 2010 Treatment of TB in the HIV Co-Infected Patient Dean Tsukayama, MD September 15,

2 Co-infection with TB and HIV Dean T. Tsukayama Hennepin County Public Health Clinic Hennepin County Medical Center Minneapolis, Minnesota

3 Something old, something new Prevalence (millions) Incidence (millions) Mortality (millions) TB HIV

4 Tuberculosis and HIV Co-infection Co-infected: 11 million In some countries the prevalence of HIV in newly diagnosed TB is 80% TB is the most common cause of death among HIV patients People living with HIV are 50X more likely to develop active TB 8% of all HIV-related deaths caused by TB (457K in 2007) Between , the incidence of TB increased by 7% per year in countries where the prevalence of HIV among adults is greater than 5%.

5 Co-infection in the US MMWR 58:1103, % of TB patients were HIV-positive Greatest risk for HIV among TB patients in drug users, homeless persons, non-hispanic blacks, prison inmates, alcohol abusers Routine HIV testing in TB patients encouraged

6 Effect of HIV on TB Increased worldwide incidence of tuberculosis Increased risk of: active disease after infection smear-negative pulmonary disease atypical pulmonary presentation, including normal CXR extrapulmonary and disseminated disease death from disease re-infection after treatment infection with drug-resistant tuberculosis

7 Effect of HIV on TB Changes in management of disease need longer duration of therapy unable to use intermittent therapy with antiretroviral medications cannot use rifampin with some regimens increased risk of adverse drug effects immune reconstitution inflammatory syndrome (IRIS)

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9 Effect of immunosuppression Clinical Aaron Microbiology et al. Clin and Infection, Microbiol Volume Infect 10 10:388, Number 5, 2004 May 2004

10 Natural History of Tuberculosis Exposure Infection Latent Infection Transmission Disease Resolution Treatment Death

11 Effect of HIV on TB Exposure? Infection Latent Infection Transmission Disease Resolution Treatment Affected by HIV Death

12 Risk of active disease Exposure 1 Infection 2 Latent Infection 1. In general, 70-80% of household contacts do not acquire infection, 3 4 Disease 2. Usually 25-40% in household contacts. 3. Increased risk of 6-8X in HIV patients 4. General risk of 10-15% over lifetime. In HIV, risk is 10% per year

13 Risk of TB disease after exposure Daley et al. NEJM 326:231, 1992 At risk Hx or Initial TST + TST Conversion TB disease Residents Staff Exposure in HIV residential facility 37% developed active TB after exposure

14 Immunodeficiency Granuloma formation* AFB * CD4 Lymphocyte recruitment Macrophage number and differentiation Langhans giant cell formation Caseous necrosis

15 Estimated HIV prevalence in new TB cases, 2005 HIV prevalence in TB cases, years (%) No estimate or more The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO All rights reserved

16 Trends in TB Incidence Rates Incidence rate (/ / yr) World Established Market Economies Change in incidence rate (%/yr) Africa -countries with low HIV prevalence Africa - countries with high HIV prevalence South-East Asia Eastern Europe

17 Risk of pulmonary TB with HIV infection Sonnenberg et al. JID191:150, 2005 South African miners (23,874) TB incidence per 100 patient-years HIV HIV seroconverted during study TB incidence doubled within 1st year of HIV infection

18 TB is undiagnosed in HIV patients Wood et al. AJRCCM 175:87, 2007 Active case finding for TB and HIV in high prevalence area for both infections Undiagnosed TB ( per 100,000) 762 patients tested for TB (smear and culture), HIV and symptoms 23% found to be HIV+ HIV- 175 No cough, night sweats, loss of appetite, weight loss in 67% of those with previously undiagnosed TB HIV+ 2837

19 Abnormal CXR in HIV patients without respiratory symptoms At Bellevue Hospital (NY), TB (26%) was most common diagnosis Other diagnoses were NTM (23%) and Kaposi s sarcoma (12%), other malignancies. Common CXR findings in TB patients were nodular infiltrates and adenopathy Only 2 of 11 patients with TB were diagnosed by sputum Gold et al. Chest 121:1472, 2005

20 Atypical CXR associated with CD4 count Kelper et al. Chest 107:74, 1995 CD4 Typical Atypical < Typical: Atypical: Unilateral or bilateral apical opacity Diffuse and lower lobe opacities, pleural effusion, mediastinal adenopathy, interstitial nodules, normal chest radiograph

21 Change in Clinical Presentation Lack of cavitation on chest radiograph More disease with smear-negative sputum Mediastinal adenopathy common CNS TB with increase in mass lesions Overall increased extrapulmonary disease

22 Pulmonary Complications of AIDS Bacterial Pneumococcal Hemophilus Pseudomonas Staphylococcus Mycobacterium Rhodococcus Protozoan Toxoplasma Parasite Strongyloides Fungal Pneumocystis HIstoplasmosis Cryptococcus Penicillium Aspergillus Non-infectious Lung cancer Kaposi sarcoma Lymphoma Pulmonary hypertension Lymphoid interstitial pneumonia Viral CMV Non-infectious Lung cancer Kaposi sarcoma Lymphoma Pulmonary hypertension Lymphoid interstitial pneumonia

23 TB Mortality (%) with HIV HIV Control S Africa NYC/MDR S Africa/XDR South Africa: TB w/wo HIV. AJRCCM 159:733, 1999 NYC: MDR w/wo HIV. Median survival of HIV patients- 14 months. AJRCCM 153:317, 1996 South Africa (KZN): 53 cases, 52 deaths. All tested for HIV (44) were positive. Median survival of 16 days. Lancet 368:1575, 2006

24 Increased mortality of TB with AIDS Frieden et al. NEJM 328:521, 1993

25 Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR 2000; 49:

26 Antiretroviral Medications NRTI Abacavir! Didanosine! Emtricitabine Lamivudine Stavudine! Tenofovir Zidovudine!! NNRTI Delavirdine! Efavirenz Etravirine! PI Atazanavir Darunavir Fosamprenavir! Indinavir! Lopinavir Nelfinavir Ritonavir! Saquinavir Tipranavir!! Fusion Inhibitor Enfuvirtide!! CCR5 Antagonist Maraviroc!! Integrase Inhibitor Raltegravir

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29 Dosing rifabutin with ART

30 Recurrence of TB after treatment Incidence per 100 patient-years Due to: HIV- HIV+ Reinfection Relapse South African miners Overall recurrence: 10.3 HIV+: 16.0 HIV-: 6.4 Sonnenberg et al. Lancet 358:1687, 2001

31 Need longer treatment? Relapse Rate (per 100 patient-years) Other studies have shown no difference in relapse rate Relapse also associated with intermittent therapy HAART with TB therapy improved survival. 0 nhiv/6m HIV/6M HIV/6M+ Nahid et al. AJRCCM 175:1199, 2007

32 Treatment regimens With and without HIV

33 Intermittent regimens not recommended Once or twice weekly treatment regimens associated with increased rate of relapse and rifampin resistance Rifapentine not recommended for HIV patients Relapse was more common with regimens using 2 months rifamycin than with regimens using rifamycins for at least 8 months. Compared with daily therapy in the initial phase, thrice-weekly therapy was associated with higher rates of failure and relapse. There were trends toward higher ffelapse rates if rifamycins were used for only 6 months, compared with 8 months, or if antiretroviral therapy was not used. Khan et al. Clinical Infectious Diseases 50:1288, 2010

34 Drug interactions Rifampin should not be used with most protease inhibitors (CYP 3A) Substitute rifabutin at reduced dose when using PI-based regimens Rifampin can be used with efavirenz-based regimens

35 Low TB drug levels in HIV patients Some studies show reduced levels of isoniazid, rifampin, and ethambutol in HIV patients May have reduced absorption of drug However most HIV patients respond well to daily dose TB therapy Relapse with intermittent therapy may be due to reduced drug levels.

36 HIV as a risk factor for MDR Risk Factor Risk Previous treatment HIV 3.52 Age < Foreign-born 2.46 Previous treatment most important risk factor HIV associated with outbreaks HIV associated with rifamycin resistance Not clear that MDR-TB is less virulent than pansensitive TB Faustini et al. Thorax 61:158, 2006

37 Risk of disease with MDR-TB Previous treatment 2.7 No previous treatment AIDS 2.3 HIV 2.0 NYC 1991 Possible explanations for higher rate of disease in HIV patients More exposure Greater infection rate More progression to disease Frieden et al. NEJM 328:521, 1993

38 Impact of HIV therapy on TB Year 1 Year 5 TB Incidence/100 patient-years Years after starting ART Risk also associated with CD4 Stage of disease Lawn et al. AIDS 19:2109, 2005

39 HAART improves outcome of TB Risk of death without HAART CD4>200 1 CD CD< Comparison of patients treated pre-haart era and after. Risk seen in death and AIDS events High event risk of AIDS event in first 2 months of TB therapy with CD4<100 Dheda et al. JID 190:1670, 2004

40 TB accelerates HIV course OI (PPM) Survive one year (%) No TB TB Retrospective cohort study TB associated with overall risk of opportunistic infection (RR 1.42) and death (OR 2.17) TB may act as cofactor to accelerate clinical course of HIV infection Whalen et al. AJRCCM 151:129, 1995

41 Overlapping adverse effects of TB and HIV medication Dermatologic Nausea Hepatitis Anemia/Leukopenia/Thrombocytopenia Nephrotoxicity Neuropathy May need to consider other causes of symptoms: -HIV disease -other opportunistic infections

42 Immune Reconstitution Inflammatory Syndrome (IRIS) Initial presentation or worsening of opportunistic infections associated with starting anti-retroviral therapy (ART) Can occur within days to months after starting ART Most episodes are mild, but IRIS can be lifethreatening Patients with lowest CD4 counts at highest risk

43 IRIS and TB Manifestations include fever, adenopathy, increased pulmonary infiltrates, serositis, rash, abscesses Similar to paradoxical reactions that can occur in immunocompetent TB patients Differential diagnosis includes other opportunistic infections, adverse drug effects, failure of TB therapy Higher incidence if ART given early after starting TB treatment, in the presence of a high mycobacterial antigen burden

44 IRIS and TB Risk factors for developing IRIS lower CD4 count higher viral load at the start of therapy rapidity of viral load decline large bacterial burden (e.g., disseminated disease) starting ART close the start of TB therapy

45 Management of IRIS Exclude progression of infection, drug toxicity, other opportunistic infections CNS or mediastinal disease can cause compression of vital structures Can treat with steroids (or NSAIDS)

46 When should ART be started in patients being treated for TB? Improved survival with ART, especially in those with low CD4 Combined HIV and TB therapy risks: increased drug adverse effects restricted options of TB regimen IRIS

47 When should ART be started in patients being treated for TB? NO official recommendations, but: no ART required if CD4>500 wait until 2 months of TB therapy completed if CD4>100 Start ART after stable TB regimen established if CD4 100

48 Conclusion Co-infection with TB and HIV changes the natural history of both infections Co-infection has contributed to an increase in TB cases and drug-resistant TB world-wide Need to treat HIV complicates the management of TB (increased side effects, modification of TB regimen, IRIS) Current TB control strategies are inadequate in resourcepoor countries with high rates of TB and HIV. Gobal implications of this failing policy are unclear.

49 Case 1 41 yo man admitted with hypotension, tachypnea, and tachycardia. Abnormal CXR on admission History of treatment for pulmonary tuberculosis 4 years prior Lives in residential shelter for alcoholics which had a recent case of tuberculosis diagnosed in another resident. Diagnosed with HIV infection and CD4-86 during admission Diagnosis: Pulmonary tuberculosis, smear-positive Genotype shows re-infection with new strain identical to the other recently diagnosed case and different from his previous strain

50 Case 2 28 yo man presents to ED with one month of L-axillary swelling and pain. Found to have draining abscess. Taken to surgery. Diagnosis: tuberculosis,started on standard 4 drug therapy, found to have pansensitive strain Also diagnosed with HIV (CD4-259, HLA-B5701+), LFTs normal Patient develops rash (felt to be due to isoniazid and rifampin) and elevated LFTs. Now found to be HCV antibody positive. Hold TB meds for one month, but LFTs still elevated. Adenopathy now starting to increase. Patient admitted to hospital to start liver-sparing TB regimen of amikacin, ethambutol, ethionamide, and moxifloxacin. Has Port-A-Cath placed. After 2 months of stable TB regimen, HAART started- atazanavir, ritonavir, and Truvada. Adenopathy responding to therapy, LFTs remain normal. High rate of adverse drug reactions in HIV, can be complicated by co-infection with HBV, HCV Often difficult to distinguish side effects of TB v. HIV meds, also need to consider drug interactions.

51 Case 3 24 yo man hospitalized for abdominal pain, weight loss, and fatigue. Diagnosed as abdominal and pulmonary TB. Also HIV+ (CD4-102). Started on 4-drug TB regimen. Started on HAART 6 weeks after starting TB medication. Regimen is Kaletra, Viread, Emtriva. Rifampin changed to rifabutin. Develops left knee arthralgia without swelling, persists after stopping pyrazinamide. Knee xray normal.some, but not total, relief with NSAIDS. One month after onset of symptoms, develops large knee effusion. Knee xray now shows lucency in tibial plateau not present 6 weeks earlier. Abnormality confirmed on MRI which also shows pathological fracture. Knee aspiration shows yellow,cloudy fluid, WBC-10K, PMN-88%. AFB culture negative, Fungal culture- Coccidioides immitis Patient treated with itraconazole, surgical debridement and bone grafting.

52 Case 4 38 yo man, recently arrived refugee from Africa, known HIV (for 3 years) and TB treated 3 months ago. Has peripheral neuropathy of legs. Initial work-up shows no respiratory symptoms, CXR shows bilateral fibronodular scarring. CD4-24, VL-300K. AFB smears negative, culture performed. Started on PCP prophylaxis AFB culture returns as MTB. Started on 4-drug TB therapy and initiation of anti-retrovirals is delayed. Sensitivity of MTB shows resistance to INH and RIF. Sensitive to PZA and ETB. Therapy changed to amikacin, moxifloxacin, ethambutol, pyrazinamide, ethionamide. Starts Kaletra and Truvada 2 months after starting 2nd line TB medication. Has possible side effects of medication including hearing difficulty, dizziness, and Achilles tendon pain. Eventually amikacin and moxifloxacin are discontinued.

53 Case 5 29 year old man presents with nausea/vomiting for 3 days, was started on HAART two weeks ago. Has developed painful inguinal adenopathy. Also had diarrhea, high fever on admission to hospital HIV for 12 years, CD4-30. Recently agreed to restart ART- Trizivir and atazanavir. FNA of lymph node showed chronic abscess, AFB stain with many AFB Lymph node: Mycobacterium tuberculosis, Mycobacterium avium-intracellulare Stool: Mycobacterium tuberculosis Started on 4-drug TB regimen with substitution of rifabutin for rifampin, and azithromycin added. ART discontinued. Antiretroviral meds restarted one month after TB meds. Immune reconstitution inflammatory syndrome (IRIS)