Tuberculosis Treatment Symposia - The CRUDEM Foundation

Tuberculosis Treatment Greg Schumaker, MD Assistant Professor of Medicine Pulmonary, Critical Care & Sleep Division Tufts Medical Center

Outline Epidemiology Latent TB Active TB Special Treatment Situations Extra-pulmonary TB MDR & XDR TB

Global Impact About 2 billion people thought to have latent TB About 9 million new cases annually (new case every 17 sec) - incidence is decreasing last 5 years, as is mortality Causes more deaths than any other infectious disease (about 1.5 million deaths) Major health problem in developing countries Leading killer of youth and young adults Leading cause of death for women of childbearing age 10 million children orphaned by TB World Health Organization

Current Anti-TB Drugs Four first-line drugs considered standard treatment: Isoniazid (INH) Rifampin (RIF) Pyrazinamide (PZA) Ethambutol (EMB) Rifabutin and rifapentine also considered first-line drugs in some circumstances Streptomycin (SM) formerly first-line drug, but now less useful owing to increased SM resistance

Sites of TB Disease Location Frequency Pulmonary TB Lungs Most TB cases are pulmonary Extrapulmonary TB Larynx Lymph nodes Pleura Brain Kidneys Bones and joints Peritoneum Pericardium Found more often in: HIV-infected or other immunosuppressed individuals Young children Miliary TB Carried to all parts of body, through bloodstream Rare

Progression to TB Disease People Exposed to TB Not TB Infected Latent TB Infection (LTBI) Not Infectious Positive TST or QFT-G test result Latent TB Infection May go on to develop TB disease Not Infectious Negative TST or QFT-G test result No TB Infection

LTBI vs. TB Disease Latent TB Infection (LTBI) TB Disease (in the lungs) Inactive , contained tubercle bacilli in the body Active , multiplying tubercle bacilli in the body TST or blood test results usually positive TST or blood test results usually positive Chest x-ray usually normal Chest x-ray usually abnormal Sputum smears and cultures negative Sputum smears and cultures may be positive No symptoms Symptoms such as cough, fever, weight loss Not infectious Often infectious before treatment Not a case of TB A case of TB

Who should be tested? Targeted Testing High-risk groups can be divided into two categories: People who are at high risk for becoming infected with M. tuberculosis People who are at high risk for developing TB disease once infected with M. tuberculosis Centers for Disease Control and Prevention, Division of Tuberculosis Elimination (DTBE)

Close Contacts of people with infectious TB People from areas where TB is common Populations defined locally as having increased incidence of LTBI/TB People who live or work in high risk settings Healthcare workers Infants, children, and adolescents exposed to adults in high-risk groups High Risk for TB Infection

Infection with HIV Chest x-ray findings suggestive of previous TB Substance abuse Recent TB infection Prolonged therapy with corticosteroids and other immunosuppressive therapy, such as prednisone and tumor necrosis factor-alpha [TNF- α ] antagonists Organ transplant Silicosis Diabetes mellitus Severe kidney disease Certain types of cancer Certain intestinal conditions Low body weight Progression to TB Disease

Diagnosis of LTBI Mantoux tuberculin skin test (TST) Interferon-gamma release assays (IGRAs): QuantiFERON®-TB Gold test (QFT-G) QuantiFERON®-TB Gold In-Tube (QFT-GIT) T-SPOT

0.1 ml of 5 tuberculin units of liquid tuberculin are injected between the layers of skin on forearm Mantoux Tuberculin Skin Test HCW administering Mantoux TST CDC

Mantoux Tuberculin Skin Test Forearm should be examined within 48 - 72 hours by HCW Reaction is an area of induration (swelling) around injection site Induration is measured in millimeters Erythema (redness) is not measured Only the induration is measured CDC

Induration of > 5 mm is considered positive for: People living with HIV Recent close contacts of people with infectious TB People with chest x-ray findings suggestive of previous TB disease People with organ transplants Other immunosuppressed patients Interpreting the Reaction

Interpreting the Reaction Induration of > 10 mm is considered a positive reaction for: People who have recently come from areas where TB is common People who inject drugs People who live or work in high-risk congregate settings Mycobacteriology laboratory workers

Induration of > 10 mm is considered a positive reaction for: People with certain medical conditions that increase risk for TB Children younger than 4 years old Infants, children, or adolescents exposed to adults in high-risk categories Interpreting the Reaction

Induration of > 15 mm is considered a positive reaction for people who have no known risk factors for TB Interpreting the Reaction

Infection with nontuberculous mycobacteria BCG vaccination Administration of incorrect antigen Incorrect measuring or interpretation of TST reaction False-Positive Reaction

Anergy Recent TB infection (within past 8 – 10 weeks) Younger than 6 months of age Recent live-virus (e.g., measles or smallpox) vaccination Incorrect method of giving the TST Incorrect measuring or interpretation of TST reaction False-Negative Reaction

Interferon-Gamma Release Assays (IGRAs) Measure person’s T-cell reactivity to M. tuberculosis Blood samples are mixed with antigens and incubated for 16 - 24 hours If infected with M. tuberculosis, T cells will recognize antigens and release interferon gamma (IFN-γ) in response Test results are based on IFN-γ concentrations

Requires single patient visit to conduct test Results can be available in 24 hours Less likely to have incorrect reading of results as compared to TST BCG vaccination does not affect results More specific to Mycobacterium Tuberculosis Does not cause booster phenomenon IGRA Advantages MMWR/CDC June 25, 2010 / Vol. 59 / No. RR-5

Blood samples must be processed within 12 hours for some IGRAs Limited data on its use in certain populations Limited data on its use to determine who is at risk for developing TB disease IGRA Disadvantages and Limitations

Patient Medical Evaluation Exclude possibility of TB disease Determine whether patient has ever been treated for LTBI or TB disease Find out if patient has any medical conditions that may complicate therapy Current medications Patients should be offered HIV testing

LTBI Treatment Regimens MMWR/CDC 2003; 52 (No. 31) RIF/ PZA RIF and PZA combinations generally should not be offered for treatment of LTBI

Special Considerations for LTBI Retest Close Contacts in 8-10 wks if initial TST/IGRA is negative Close Contacts at high risk of developing TB disease (children under 5, HIV, immunocompromised) should be treated even if initial testing is negative, then reevaluate at 8-10 wks. Severely immunocompromised Contacts might be treated for the full duration regardless of the results of 8-10 wks testing. Retreatment for patients with positive TST and documented completed treatment, in patients at high risk for reinfection or progression to TB disease Centers for Disease Control and Prevention, Division of Tuberculosis Elimination (DTBE)

Special Considerations for LTBI Contacts of patients with MDR TB should be evaluated for the risk of developing TB disease. They can be either treated with alternative regimen for 6-12 ms, OR observed for symptoms of disease for a 2 year period without treatment In Pregnant Women, LTBI treatment can be delayed till after delivery, Unless, immunocompromised, HIV, or recent TB contact. Prefered regimen is INH x 9ms with B6 supplement Breast feeding women can take INH with B6 supplement. INH in breast milk is not enough to treat infant Centers for Disease Control and Prevention, Division of Tuberculosis Elimination (DTBE)

Patient Monitoring Patients need to be evaluated at least monthly during therapy for: Adherence to prescribed regimen Signs and symptoms of active TB disease Adverse reactions Liver function tests should be done before starting INH LTBI treatment and every month during therapy: People living with HIV People with history of liver disease People who use alcohol regularly Women who are pregnant or just had a baby People taking medications that may increase risk of hepatitis Centers for Disease Control and Prevention, Division of Tuberculosis Elimination (DTBE)

Goals of Treatment Cure active disease Prevent reactivation of LTBI Prevent transmission Avoid resistance by ensuring adherence Minimize toxicity

General Rules Treatment must contain multiple drugs to which organisms are susceptible INH & RIF are the pillars of TB therapy Never add a single drug to a failing regimen Patients should take their medicines regularly under DOT Patients should take ALL their medicines If there is a possible adverse drug reaction, stop drugs altogether, and evaluate. Regimens can be given daily or 2 or 3 x/week

Treatment Outcomes Cured – smear negative at end of tx and 1 other previous smear negative Completed – finished full course Successful – either cured or completed Failed – remained smear + Defaulted - ≥ 2 consecutive months of tx interruption

Directly Observed Therapy (DOT) Health care worker watches patient swallow each dose DOT is preferred management strategy for all patients Can reduce acquired drug resistance, treatment failure, and relapse Nearly all regimens can be intermittent if given as DOT DOT reduces total number of doses and encounters For drug-resistant TB, use daily regimen and DOT

Isoniazid Rifampin Pyrazinamide Ethambutol Rifabutin Rifapentine Anti-tuberculosis Drugs Streptomycin Cycloserine p-Aminosalicylic acid Ethionamide Amikacin or kanamycin Capreomycin Levofloxacin Moxifloxacin Gatifloxacin First-Line Drugs Second-Line Drugs

Treatment of Susceptible TB Initial phase – 2 months - Start with 4 drugs pending cx results - INH, RIF, PZA, EMB - Can d/c EMB if sensitive to INH & RIF Continuation phase from 4 to 7 months

Regimens 4 basic treatment regimens All have same 4 drugs initially Difference is in number of doses/week and in duration of continuation phase

Regimens (cont) Use 7 months continuation if: - Cavitary TB with still + sputum - Initial tx did not include PZA at 2 mo - Once-weekly INH and RPT used but culture was + at end of initiation

Regimen 1 Initial Phase – 2 months - INH, RIF, PZA, EMB (5 or 7 d/week) Continuation Phase – 4 months - INH, RIF daily (5 or 7 d/week) or - INH, RIF intermittent (2d/week) or - INH, Rifapentine (RPT) - (1d/week)

Regimen 2 Initial Phase – 2 months - 4 drugs 5 or 7d/week for 2 weeks - then 2 d/week for 6 weeks Continuation Phase – 4 months - INH, RIF 2d/week or - INH, RPT 1d/week

Regimen 3 Initial Phase – 2 months - INH, RIF,PZA,EMB for 3d/week Continuation Phase - INH, RIF for 3d/week

Regimen 4 Initial Phase – 2 months - INH, RIF, EMB for 5 or 7 d/week Continuation Phase – 7 months - INH, RIF daily (5 or 7 d/week) or - INH, RIF 2 d/week

Is specimen collected at end of initial phase (2 months) culture positive? NO YES Place patient on initial-phase regimen: INH, RIF, EMB, PZA for 2 months Give continuation-phase treatment of INH/RIF daily or twice weekly for 4 months Culture-Positive TB Patients CDC High clinical suspicion for active TB

Give continuation-phase treatment of INH/RIF daily or twice weekly for 7 months Give continuation- phase treatment of INH/RIF daily or twice weekly for 4 months NO YES Was there cavitation on initial CXR? NO YES Is the patient HIV positive? Culture-Positive TB Patients (Continued) Give continuation- phase treatment of INH/RIF daily for 7 months CDC

Culture-Negative TB High clinical suspicion for active TB despite negative smears based on: Abnormal chest x-ray Clinical symptoms No other diagnosis Positive tuberculin skin test Patient placed on initial phase regimen: INH, RIF, EMB, PZA for 2 months CDC

Culture-Negative TB (Continued) Give continuation- phase treatment of INH/RIF daily or twice weekly for 2 months NO YES Was there symptomatic or chest x-ray improvement after 2 months of treatment? NO YES Is initial culture positive? Continue treatment for culture-positive TB Discontinue treatment Patient presumed to have LTBI Treatment completed CDC

Treatment Interruption Can be due to drug toxicity Can be due to patient non-adherence Most important to try to achieve continuous treatment in initial phase - lessens chance of resistance

Treatment Interruption – Initial Phase Interruption ≥ 14 days - Restart at beginning of initial phase Interruption < 14 days - continue to completion Important to get all initial phase doses done within 3 months

Interruption – Continuation Phase 80% or more of doses given - if initial smear negative, may stop tx - if initial smear +, continue therapy

Interruption – Continuation Phase Less than 80% of doses given - if possible repeat smear & culture - if interruption < 3 mos, continue tx - if interruption > 3mos, restart from initial phase - if repeat culture +, use 4 drugs until susceptibility returns

Treatment Monitoring Monthly sputum until 2 consecutive cultures negative Drug-susceptibility tests if culture-positive after 3 months of Rx Monthly visits to assess adherence and adverse reactions - LFT’s, CBC, Vision Repeat chest x-ray: -At completion of initial treatment phase for patients with initial negative cultures -At end of treatment for patients with culture-negative TB -Generally not necessary for patients with culture positive TB

Treatment Monitoring Renal function, AST, ALT, bilirubin, and platelet count if abnormalities at baseline Visual acuity and color vision monthly if EMB used > 2 months or doses > 15-20 mg/kg

Common Adverse Reactions to Drug Treatment (1) Caused by Adverse Reaction Signs and Symptoms Any drug Allergy Skin rash Ethambutol Eye damage Blurred or changed vision Changed color vision Isoniazid, Pyrazinamide, or Rifampin Hepatitis Abdominal pain Abnormal liver function test results Fatigue Lack of appetite Nausea Vomiting Yellowish skin or eyes Dark urine

Common Adverse Reactions to Drug Treatment (2) Caused by Adverse Reaction Signs and Symptoms Isoniazid Peripheral neuropathy Tingling sensation in hands and feet Pyrazinamide Gastrointestinal intolerance Arthralgia Arthritis Upset stomach, vomiting, lack of appetite Joint aches Increased Uric Acid, Gout (rare) Streptomycin Ear damage Kidney damage Balance problems Hearing loss Ringing in the ears Abnormal kidney function test results

Common Adverse Reactions to Drug Treatment (3) Caused by Adverse Reaction Signs and Symptoms Rifamycins Rifabutin Rifapentine Rifampin Thrombocytopenia Gastrointestinal intolerance Drug interactions Orange discoloration Photosensitivity Easy bruising Slow blood clotting Upset stomach Interferes with certain medications, such as methadone, and HIV protease inhibitors Urine, sweat, tears, contact lenses

Toxicity Related Interruption - Hepatic Stop all drugs if: - Clinical evidence of hepatitis not due to other causes - LFT’s > 3X ULN with symptoms - LFT’s > 5X ULN without symptoms

Toxicity Related Interruption - Hepatic If severe TB, continue treatment with aminoglycoside, quinolone, EMB Otherwise, when sx’s/labs improve - Add RIF +/- EMB - if tolerates, then add INH - if tolerates and toxicity was not severe can add PZA

Toxicity Related Interruption – Rash or Fever Exclude other causes Stop all drugs If severe TB, alternative tx as in hepatic Once rash or fever better, restart 1 drug every 3 days

HIV/AIDS Treatment for HIV-positive patients same as for HIV-negative patients, except Once-weekly INH-rifapentine in continuation phase is contraindicated in HIV-positive patients Twice-weekly INH-RIF or INH-rifabutin should not be used in patients with CD4+ counts < 100 Every effort should be made to use a rifamycin-based regimen for the entire course of therapy (unless patient is on a protease inhibitor) Rifabutin has interaction than RIF Centers for Disease Control and Prevention, Division of Tuberculosis Elimination (DTBE)

HIV/AIDS When to start anti-HIV and anti-TB Risk of immune reconstitution syndrome Generally start TB therapy first Anti-HIV can be started 2-8 weeks later

HIV/AIDS CAMELIA – CD4 < 200 - 2 vs 8 weeks post starting TB therapy - Early group mortality 18% vs. 27% ACTG A5221 – CD4 < 250 - 2 vs. 8-12 weeks post starting TB rx - Subgroup with CD4 < 50 had lower mortality and less new AIDS illness NEJM, October 20, 2011

HIV/AIDS SAPIT – CD4 < 500 - 4 weeks post start of TB therapy vs. week 8-12 - CD4 <50 had mortality benefit with early ART (but with > IRIS)

Children and Adolescents Use DOT Treat young children (<5 years old) with three (rather than four) drugs in initial phase (i.e., INH, RIF, and PZA) EMB not recommended unless increased likelihood of INH resistance or diagnosis of adult-like TB Thrice-weekly therapy not recommended Centers for Disease Control and Prevention, Division of Tuberculosis Elimination (DTBE)

Extrapulmonary TB Similar treatment regimen for pulmonary TB, except for TB of the CNS, bone or joint; length of therapy is 9-12 months Corticosteroids used as adjunctive therapy for patients with TB meningitis and pericarditis If PZA cannot be used in the initial phase, continuation phase must be increased to 7 months Centers for Disease Control and Prevention, Division of Tuberculosis Elimination (DTBE)

Pregnancy and Breastfeeding Initial phase treatment regimen should consist of INH, RIF, and EMB SM contraindicated & PZA teratogenicity unknown so not recommended for pregnant women If PZA not used, use 6 month continuation phase Add pyridoxine if using INH Centers for Disease Control and Prevention, Division of Tuberculosis Elimination (DTBE)

Renal Insufficiency and End-Stage Renal Disease Dosage should not be decreased because peak serum concentrations may be too low; smaller doses may decrease drug efficacy Dosing interval of drugs could be increased Most drugs can be given 3 times weekly after hemodialysis; for some drugs, dose must be adjusted Centers for Disease Control and Prevention, Division of Tuberculosis Elimination (DTBE)

Hepatic Disease Recommended regimens: Treatment without PZA Initial phase (2 months): INH, RIF, and EMB Continuation phase (7 months): INH and RIF Treatment without INH Initial phase (2 months): RIF, PZA, and EMB Continuation phase (4 months): RIF, PZA and EMB Centers for Disease Control and Prevention, Division of Tuberculosis Elimination (DTBE)

Hepatic Disease Recommended regimens: (continued) Regimens with only one potentially hepatotoxic drug RIF should be retained Duration of treatment is 12-18 months Regimens with no potentially hepatotoxic drugs Duration of treatment is 18-24 months Centers for Disease Control and Prevention, Division of Tuberculosis Elimination (DTBE)

MDR TB Resistant to INH and RIF ~ 5% of TB cases in 2010 Haiti had 41 new MDR cases in 2010 per WHO Drugs that can be used are less effective and are more likely to cause adverse reactions Treatment can last 2 years or more Surgery is sometimes use to remove infected site Centers for Disease Control and Prevention, Division of Tuberculosis Elimination (DTBE) &WHO

MDR TB Risk Factors No response to appropriate therapy Patient previously treated for TB Close contact of patient with MDR TB Pt treated w/ multiple course of quinolones for CAP found to be TB Patient from high endemic areas

MDR TB Treatment If possible, should be guided by cultures Empiric therapy if suspect MDR - Standard 4 agents plus ≥ 2 other meds When get susceptibilities, stop resistant meds and add aminoglycoside and quinolone to remaining drugs Need to treat with 4 effective agents Treat for at least 18-24 months

MDR TB Surgery considered if: - Localized pulmonary TB - Lack of improvement with drugs - Highly resistant strain Give meds for 1 to 3 months pre-op Continue meds for 18 months post-op

XDR TB XDR TB is resistant to INH, RIF, all fluoroquinolones, and at least one injectable second-line drug (e.g., amikacin, kanamycin, or capreomycin) XDR TB patients have less effective treatment options XDR TB is very difficult to treat Consult with an expert

XDR TB Agents Cycloserine or other serine analogues Thionamides Para-aminosalicylic acid Capreomycin Amikacin, kanamycin Linezolid Amoxicillin-clavulanate Clarithromycin Meropenem Clofazimine

References CDC, division of TB elimination, www.cdc.gov/tb Infectious Diseases Society of America American Thoracic Society: http:// www.thoracic.org/adobe/statements/treattb.pdf CDC’s Morbidity and Mortality Weekly Report: http:// www.cdc.gov/mmwr WHO: Treatment of Tuberculosis Guidelines – 4 th edition 2010

Tuberculosis Treatment Symposia - The CRUDEM Foundation

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Tuberculosis Treatment Symposia - The CRUDEM Foundation