TB Intensive San Antonio, Texas May 7-10, 2013

TB Intensive San Antonio, Texas May 7-10, 2013 TB in the HIV Patient Lisa Armitige, MD, PhD May 09, 2013 Lisa Armitige, MD, PhD has the following disclosures to make: No conflict of interests No relevant financial relationships with any commercial companies pertaining to this educational activity 1

Tuberculosis in the HIV Patient Lisa Y. Armitige, MD, PhD Medical Consultant Heartland TB Center Associate Professor of Medicine/Pediatrics University of Texas HSC at Tyler Effect of HIV on Tuberculosis Epidemiology 2

Estimated Incidence of TB per 100,000 Population in African Countries in 1990 and 2005 Chaisson R and Martinson N. N Engl J Med 2008;358:1089-1092 Newly reported cases of tuberculosis per 100 000 persons by year in the United States, 1980 to 1995 Snider, G. L. Ann Intern Med 1997;126:237-243 3

% Coinfection Estimated HIV Coinfection in Persons Reported with TB, United States, 1993 2010* 30 25 20 15 10 5 0 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Aged 25-44 All Ages *Updated as of July 21, 2011 Note: Minimum estimates based on reported HIV-positive status among all TB cases in the age group Outcomes of Exposure to M. tuberculosis Inhalation of Droplet Nuclei Regional replication in lungs, dissemination ~90% ~5% ~5% Killing, clearance of organisms Latent disease Active disease 4

Outcomes of Exposure to M. tuberculosis in HIV-negative and HIV-positive patients Inhalation of Droplet Nuclei Regional replication in lungs, dissemination ~90% 10% reactivation ~5% reactivation per year lifetime Up to 36% active disease ~5% Killing, clearance of organisms Latent disease Active disease Signs & Symptoms - Pulmonary TB Pulmonary Symptoms: Productive, prolonged cough of over 3 weeks duration Chest pain Hemoptysis Systemic Symptoms: Fever Chills Night sweats Appetite loss Weight loss Easy fatigability 5

An Algorithm for Tuberculosis Screening and Diagnosis in People with HIV N Engl J Med 2010;362:707-16 An Algorithm for Tuberculosis Screening and Diagnosis in People with HIV N Engl J Med 2010;362:707-16 6

Clinical Presentation HIV-positive vs. HIV-negative patients Driven mostly by degree of immunity HIV-positive patients are more likely to have: Isolated extrapulmonary localization (53-63% in some studies) Primary infection Pulmonary basilar involvement Tuberculous pneumonia Hilar or mediastinal lymphadenopathies Miliary or disseminated TB Normal CXR (8-20% in some studies) Clinical Microbiology and Infection, Volume 10 Number 5, May 2004 Testing for TB Infection -TST The tuberculin skin test (TST) may help differentiate infected from uninfected people with signs and symptoms A negative TST does not exclude the diagnosis of TB (especially for patient s with severe TB illness or infection with HIV) 7

Classifying the Tuberculin Reaction 5 mm is classified as positive in HIV-positive persons Recent contacts of TB case Persons with fibrotic changes on chest radiograph consistent with old healed TB Patients with organ transplants and other immunosuppressed patients Diagnosis * * Clinical Microbiology and Infection, Volume 10 Number 5, May 2004 8

IFN-γ (gamma) release assays (IGRAs) www.cellestis.com Antigens for Gamma-Release Assays www.cellestis.com 9

FDA-approved IGRAs Quantiferon-Gold In-Tube (IT) T-SPOT.TB Quantiferon Gold In-Tube 10

ELISPOT S. A. Clark et al. 2007. Clinical and Experimental Immunology Poor concordance between interferon-γ release assays and tuberculin skin tests in diagnosis of latent tuberculosis infection among HIV-infected individuals BMC Infectious Diseases 2009, 9:15 Cross sectional study in 2 HIV clinics in Atlanta, Georgia (n= 336), 85% black, 65% male, 91% US-born, 69% on HAART, 60% with a history of an OI. Median CD4 = 334, median viral load 400 copies/ml Conclusion: We found a low prevalence of LTBI and poor concordance between all 3 diagnostic tests (TST, QF-IT, T-SPOT.TB). 11

Role of Interferon Gamma Release Assay in Active TB Diagnosis among HIV Infected Individuals PLoS ONE May 2009. vol 4(5) 105 HIV/TB patients in India 50% were culture positive 31% were TST positive Sensitivity decreased with declining CD4 count 65% were positive by Quantiferon-IT More indeterminate results with CD4 <200 Role of interferon-gamma release assays in the diagnosis of pulmonary tuberculosis in patients with advanced HIV infection Cattamanchi et al. BMC Infectious Diseases 2010, 10:75 ** 12

CXR HIV infected persons In HIV-infected persons almost any abnormality on CXR may indicate TB May cause infiltrates without cavities in any lung zone May cause mediastinal or hilar lymphadenopathy with or without infiltrates or cavities Clinical Presentation HIV-positive vs. HIV-negative patients Driven mostly by degree of immunity HIV-positive patients are more likely to have: Isolated extrapulmonary localization (53-63% in some studies) Primary infection Pulmonary basilar involvement Tuberculous pneumonia Hilar or mediastinal lymphadenopathies Miliary or disseminated TB Normal CXR (8-20% in some studies) Clinical Microbiology and Infection, Volume 10 Number 5, May 2004 13

Primary Tuberculosis 14

Miliary Tuberculosis 15

Tuberculosis and HIV 16

CXR Special Situations Pregnant women who are highly suspicious and being evaluated for active disease should undergo a CXR without delay, even during the first trimester Patients suspected of extrapulmonary TB should have a CXR to rule out pulmonary TB Bacteriologic or histologic exam Sputum Three (8-24 hours apart, at least one first thing in the morning) Tissue Lymph node biopsy Bone marrow biopsy Other specimens Urine CSF Peritoneal fluid Pleural fluid (pleural biopsy) 17

Diagnosis * * * Clinical Microbiology and Infection, Volume 10 Number 5, May 2004 An Algorithm for Tuberculosis Screening and Diagnosis in People with HIV N Engl J Med 2010;362:707-16. 18

Diagnosis Summary Must have a high index of suspicion Must utilize many pieces of information in making the diagnosis TB can present very differently in HIVinfected patients when compared to HIVnegative patients Case Scenario #1 A 35 year old HIV+ man (A.G.) is referred to you for a TST measuring 12 mm. On questioning, the patient states he was skin tested because one of his roommates was diagnosed with pulmonary cavitary TB. How should you approach this patient? 19

Classifying the Tuberculin Reaction 5 mm is classified as positive in HIV-positive persons Recent contacts of TB case Persons with fibrotic changes on chest radiograph consistent with old healed TB Patients with organ transplants and other immunosuppressed patients Case Scenario # 1 (cont) A.G. reveals his TST 3 years ago was negative. He currently takes Atripla (efavirenz-based treatment), his CD4 count is 453 and his viral load is <40. He has HCV and hypertension managed with HCTZ. 20

Case Scenario #1 (cont) He has 2 other roommates who will see you later this week. They are also HIV+ but were TST-negative. How would you evaluate these individuals? Case Scenario #1 (cont) Roommate #1 only recently moved into the home. He has a CD4 count of 638, takes no meds, has no significant health issues and denies any current symptoms. Roommate #2 was recently diagnosed with HIV and is not currently on medications. His CD4 count is 45 and he has a cough he attributes to post-nasal drip. He feels well, denies weight loss or other suggestive symptoms. 21

Testing for TB Infection - Principles Individuals who have a + TST result, a + IGRA result or symptoms suggestive of TB (regardless of TST/IGRA results) should be evaluated with an chest x-ray Patients with HIV who may not react to testing by TST or IGRA should have a chest x-ray if TB is suspected or if exposed to an active TB case If abnormalities are noted, or the client has symptoms suggestive of extrapulmonary TB, additional diagnostic tests should be conducted CXR HIV infected persons In HIV-infected persons almost any abnormality on CXR may indicate TB May cause infiltrates without cavities in any lung zone May cause mediastinal or hilar lymphadenopathy with or without infiltrates or cavities 22

Case Scenario #1 (cont) Assuming a negative CXR in all three, how would you approach each patient? A.G. (TST 12 mm, CD4 453, HCV, denies symptoms) Roommate #1 (TST 0mm, CD4 638, no symptoms) Roommate #2 (TST 0mm, CD4 45, cough, no symptoms) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, MMWR 2009 HIV-infected persons, regardless of age, should be treated for LTBI if they have no evidence of active TB and exhibit the following characteristics: 1) a positive diagnostic test for LTBI and no prior history of treatment for active or latent TB (AI); 2) a negative diagnostic test for LTBI but are close contacts of persons with infectious pulmonary TB (AII); and 3) a history of untreated or inadequately treated healed TB (i.e., old fibrotic lesions on chest radiography) regardless of diagnostic tests for LTBI (AII) 23

Risk reduction by treatment of Latent TB Infection (LTBI) in HIV-infected patients Churchyard et al. JID 2007:196 (Suppl 1) S52 Initiating Treatment for LTBI Before initiating treatment for LTBI Rule out TB disease i.e. wait for culture results if specimen obtained Determine prior history of treatment for LTBI or TB disease Assess risks and benefits of treatment Determine current and previous drug therapy 24

Isoniazid Regimens for LTBI 9-month regimen of isoniazid (INH) is the preferred regimen 6-month regimen is less effective but may be used if unable to complete 9 months May be given daily or intermittently (twice weekly) Use directly observed therapy (DOT) for intermittent regimen Persons with the following conditions need special precautions while on isoniazid a. Age 35 years and over b. Taking other medications on a long term basis c. Alcohol abusers d. History of previous discontinuation of isoniazid because of toxicity/adverse reactions e. Chronic liver disease f. Peripheral neuropathy g. Pregnancy 25

Rifampin Regimens for LTBI Rifampin (RIF) given daily for 4 months is an acceptable alternative when treatment with INH is not feasible. In situations where RIF cannot be used (e.g., HIV-infected persons receiving protease inhibitors), rifabutin may be substituted. RIF and PZA for 2 months should generally not be offered due to risk of severe adverse events 6 6 MMWR August 8, 2003; 52 (31): 735-739 LTBI treatment MMWR August 8, 2003 / Vol. 52 / No. 31 26

3HP Regimen and HIV patients 12 week regimen of INH and Rifapentine dosed once a week Contraindicated in patients on ANY antiretrovirals Acceptable if not on HIV medications Case Scenario #1 (cont) Assuming a negative CXR in all three, how would you approach each patient? A.G. (TST 12 mm, CD4 453, HCV, denies symptoms) Roommate #1 (TST 0mm, CD4 638, no symptoms) Roommate #2 (TST 0mm, CD4 45, cough, no symptoms) 27

Case Scenario #2 A 28 year old Latino male with HIV presents with a 2 ½ month history of productive cough, night sweats, fevers, fatigue and 30 lb weight loss. The patient has been under the care of an ID physician for his HIV and has been stable on a protease inhibitor (PI)- containing regimen. The patient has been working construction out of state and has not been able to visit his doctor until now. He has been compliant with his HIV meds and his current laboratory studies show a CD4 count of 281 and viral load <50. Two of 3 sputums collected on consecutive days are positive for AFB Which anti-tb regimen do you start him on? What do you do with his HIV meds? Anti-Tuberculosis drugs (ATS/CDC/IDSA) First-Line drugs Isoniazid Rifampin Rifapentine Rifabutin* Ethambutol Pyrazinamide *Not FDA approved for TB Second-Line Drugs Cylcoserine Ethionamide Levofloxacin* Moxifloxacin* PAS Streptomycin Amikacin/Kanamycin Capreomycin 28

Purpose 1 5. Recommended Treatment Regimens 36 What s New In this Document 1 CONTENTS OF 6. Practical Aspects of Treatment 42 Summary 1 THE 80 Page 7. Drug Interactions 45 1. Introduction and Background 13 Document 8. Treatment in Special Situations 50 2. Organization and Supervision of Treatment 15 9. Management of Relapse, Treatment Failure, and 66 Drug Resistance 3. Drugs in Current Use 19 10. Treatment of Tuberculosis in Low Income Countries: Recommendations and Guidelines of the WHO and the IUATLD 72 4. Principles of Antituberculosis Chemotherapy 32 11. Research Agenda for Tuberculosis Treatment 74 Updates and Changes in Therapy Changes in dosing schedules: HIV + individuals with low CD4 counts should NOT be given twice weekly therapy Daily therapy can be 7 days per week OR can be 5 days per week IF given by DOT and the Mtb is drug susceptible 29

Role of New Agents Rifabutin (RBT): May be used as a primary drug for patients (especially HIV+) receiving medications having unacceptable interactions with rifampin (e.g. Protease Inhibitors, methadone) Fluoroquinolones: May be used when first line drugs are not tolerated or the organism is resistant Moxifloxacin is rapidly becoming the agent of choice ATS recommendations for treatment of tuberculosis * * Morbidity and Mortality Weekly Report June 20, 2003 / Vol. 52 / No. RR 11 30

Rifamycins Have significant interaction with all ARVs except nucleoside analogues (other than AZT) and enfuvirtide Once or twice weekly regimens show high rate of rifampin resistance in HIV patients with CD4 cell count <100 Most common locus of interaction is the cytochrome P450 system As inducers, rifampin > rifapentine > rifabutin Effect of efavirenz dosing with rifampin on treatment outcomes Manosuthi et al AIDS 2005, 19:1481 1486 Manosuthi et al AIDS 2006, Vol 20 No 1 31

Rifampin and PIs Note: Decrease in serum protease inhibitor level is NOT overcome by low dose ritonavir Clinical Microbiology and Infection, Volume 10 Number 5, May 2004 Rifabutin Has much less effect than rifampin on drugs metabolized by CYP3A Requires dosage adjustment due to effects by many other drugs (such as ritonavir). PIs (especially if boosted with ritonavir) cause a marked increase in serum rifabutin serum concentrations and toxicity Rifabutin dose should be decreased when using PI-based regimens. Concerns regarding adequate dosing if patient is not compliant with PI medication 32

Rifabutin Good virological and immunological outcomes when administered with PI-based HAART Treatment of choice when pt cannot tolerate NNRTIbased treatment (though no head-to-head studies) Expensive 33

http://aidsinfo.nih.gov/guidelines Commonly used HIV medications and rifamycins Efavirenz (Sustiva/Atripla) Rifampin (no change) Rifabutin 450-600 mg Protease Inhibitors Rifampin contraindicated Rifabutin 150 mg daily or 300 mg TIW 34

Treatment - Summary Every effort should be made to treat within the CDC guidelines to increase the chances of treatment success, decrease the chances of relapse and minimize the length of time with toxicities. Rifamycins can be safely added to almost any regimen. TB treatment regimens that do not contain rifampin have an unacceptably high failure rate Overall Treatment Outcomes * * Ronan. A. M. JID 2006:193 (15 May) 1439 35

When should treatment be started when patient is being treated for TB? Considerations Treatment of HIV improves outcomes in patients with TB Decreased death or relapse Multiple medications with multiple potential toxicities that are overlapping 36

Initiation of ART in patients with HIV/TB In patients with CD4 counts <50 cells/mm 3, ART should be initiated within 2 weeks of starting TB treatment (AI) In patients with CD4 counts 50 cells/mm 3 who present with clinical disease of major severity as indicated by clinical evaluation, ART should be initiated within 2 to 4 weeks of starting TB treatment. The strength of this recommendation varies on the basis of CD4 cell count: CD4 count 50 to 200 cells/mm3 (BI) CD4 count >200 cells/mm3 (BIII) In patients with CD4 counts 50 cells/mm 3 who do not have severe clinical disease, ART can be delayed beyond 2 to 4 weeks of starting TB therapy but should be started within 8 to 12 weeks of TB therapy initiation. The strength of this recommendation also varies on the basis of CD4 cell count: CD4 count 50 to 500 cells/mm3 (AI) CD4 count >500 cells/mm3 (BIII) http://www.aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/ Additional recommendations for patients with HIV/TB Despite pharmacokinetic drug interactions, a rifamycin (rifampin or rifabutin) should be included in TB regimens for patients receiving ART, with dosage adjustment if necessary (AII). Rifapentine (RPT) is NOT recommended in HIV-infected patients receiving ART for treatment of latent TB infection (LTBI) or active TB, unless in the context of a clinical trial (AIII). Immune reconstitution inflammatory syndrome (IRIS) may occur after initiation of ART. Both ART and TB treatment should be continued while managing IRIS (AIII). Treatment support, which can include directly observed therapy (DOT) of TB treatment, is strongly recommended for HIV-infected patients with active TB disease (AII). http://www.aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/ 37

Case Scenario #3 A 30 year old black woman presents with fever, chills, night sweats and a 20 lb weight loss over the past month. She has large anterior cervical lymph nodes and a left lower lobe infiltrate. Biopsy of one of the lymph nodes reveals granulomas and AFB which are probe positive for Mtb. After further testing, the patient is found to be HIV positive with a CD4 count of 80. The patient is started on 4 drug therapy and, once stable on anti-tb drugs, is started on HAART with efavirenz. Two months into treatment, the patient has worsening cough, a return of fevers, night sweats and worsening LAD. How do you proceed with this patient? IRIS Meintjes et al. 2008. Lancet ID 8: 516-23. 38

IRIS Meintjes et al. 2008. Lancet ID 8: 516-23. IRIS Meintjes et al. 2008. Lancet ID 8: 516-23. 39

One more thing Co-trimoxazole prophylaxis Nunn et al. BMJ 2008;337;a257 40

THEY ALWAYS COME BACK Do It Right The First Time! Barbara Seaworth Thanks!! Questions? Lisa.Armitige@dshs.state.tx.us Heartland National Tuberculosis Center 1-800-TEX-LUNG 41