Moving Past the Basics of Tuberculosis Phoenix, Arizona May 8-10, 2012 LTBI and TB Disease Treatment Cara Christ, MD, MS May 8, 2012 Cara Christ, MD, MS has the following disclosures to make: No conflict of interests No relevant financial relationships with any commercial companies pertaining to this educational activity 1
LTBI and TB Treatment Cara Christ, MD MS Chief Medical Officer, Division of Public Health Tuberculosis Control Officer Bureau Chief and Medical Director, Epidemiology and Disease Control Arizona Department of Health Services Objectives List 1 treatment option for LTBI Common and alternative regimens Monitoring for side effects and drug drug interactions New treatment options List 1 treatment option for TB disease Basic treatment for TB disease Management and monitoring during therapy 2
Antituberculosis Medications First line drugs Isoniazid Rifampin Rifapentine Rifabutin* Ethambutol Pyrazinamide * Not FDA approved for TB Second line drugs Cycloserine Ethionamide Levofloxacin* Moxifloxacin* PAS Streptomycin Amikacin/Kanamycin Capreomycin Antituberculosis Medications INH (Isoniazid) Majority of early bactericidal activity of multi drug TB regimens Excellent absorption and tissue penetration RIF (Rifampin) Bactericidal (highest sterilizing activity) Activity against rapidly dividing and semi dormant bacteria Cornerstone of short course therapy Well absorbed, good tissue levels 3
Antituberculosis Medications EMB (Ethambutol) Included in first line treatment to prevent emergence of RIF resistance PZA (Pyrazinamide) Bacteriostatic/sterilizing agent Greatest activity against dormant or semi dormant (slow growing) organisms within macrophages or caseous foci (acidic environment) Necessary for 6 month treatment Antituberculosis Medication Fluoroquinolones Preferred oral agents for treating drug resistant TB that is susceptible to this class of drugs, or for patients intolerant of first line drugs Activity against MTB: Moxifloxacin > levofloxacin > ofloxacin/ciprofloxacin Cross resistance 4
LTBI Treatment Why should you treat LTBI? Prevent progression of infection to disease Interrupt transmission of disease Evidence that this works? 1953: 52.6 cases/100,000 US Population 2010: 3.6 cases/100,000 US Population 5
Who should be treated for LTBI? A decision to test is a decision to treat! Tests should only be placed on persons who would benefit from treatment Occasional tests can be placed for administrative reasons These individuals should be evaluated on a case by case basis regarding initiation of treatment CDC Recommended LTBI Treatment How do you decide what to use? Efficacy, Duration, Cost Regimen Duration of therapy Cost INH (daily, 2x weekly DOT) 9 months (270 doses) $30* INH (daily, 2x weekly DOT) 6 months (180 doses) $20* Rifampin (600mg daily) 4 months (120 doses) $110 INH + RPT (once weekly DOT) 12 weeks (12 doses) $250* The longer the duration/more doses, the less likely your patient is to complete Rx! Fewer than 60% complete 9 months of INH! Medication costs *DOT cost not included 6
INH LTBI Therapy Regimen Duration of therapy Cost INH (daily, 2x weekly DOT) 9 months (270 doses) $30* INH (daily, 2x weekly DOT) 6 months (180 doses) $20* INH LTBI Therapy The standard treatment regimen for LTBI is nine months of daily INH. The regimen is very effective and is the preferred regimen for HIV infected people taking antiretroviral therapy, and children aged 2-11 years. CDC. November 2011. 7
Special Precautions While on INH Age 35 years and older Taking other medications on a long term basis Alcohol abuse History of incomplete INH treatment due to toxicity or adverse reactions Chronic liver disease Peripheral neuropathy Pregnancy INH Side Effects Hepatotoxicity Migraine Headaches Gastrointestinal Nausea, Diarrhea, Constipation Rash Peripheral Neuropathy Pyridoxine 50mg daily can prevent this 8
INH Hepatotoxicity Asymptomatic elevation of aminotransferases: 20% of patients Clinical hepatitis: 0.6% of patients Fulminant hepatitis (hepatic failure) Approximately 4/100,000 persons completing therapy (continued INH with symptoms of hepatitis, prior INH hepatotoxicity, malnutrition). INH Toxicity Monitoring The critical element for INH toxicity monitoring is CLINICAL MONITORING. Recommendations: Only prescribe 30 day supply at a time/no refills Emphasize to patients that INH treatment should be stopped immediately upon the earliest onset of symptoms Communicate with patient every 30 days Ask about Nausea, vomiting, Abdominal pain, Jaundice Document a note about this communication Only refill INH if the patient is OK Stop INH and/or check LFTs if not OK 9
Rifampin LTBI Therapy Regimen Duration of therapy Cost Rifampin (600mg daily) 4 months (120 doses) $110 Rifampin vs INH for Treatment of LTBI 4 month Rifampin regimen vs 9 months INH regimen Menzies et al AJRCCM 2004, 170; 445 Completion of therapy significantly better with rifampin with fewer side effects than INH Lardizabal et al Chest 2006, 130; 1712 Patients receiving rifampin were significantly more likely to complete therapy than those receiving INH Menzies et al Ann Int Med 2008, 149; 689 Significantly higher rate of treatment completion with fewer serious adverse events 10
Rifampin Treatment of LTBI Pros: Higher Completion Rates Less Side Effects Less Hepatotoxicty Cons: Drug Interactions Hormonal Contraceptives Warfarin Prednisone HIV Antiretrovirals Look up all drugs for interactions Orange Body Fluids Other Side Effects: Rash Thrombocytopenia Anemia Leukopenia Allergic Interstitial Nephritis INH/Rifapentine LTBI Treatment Regimen Duration of therapy Cost INH + RPT (once weekly DOT) 12 weeks (12 doses) $250* 11
INH/Rifapentine LTBI Therapy The 12 dose regimen of INH and RPT does not replace other recommended LTBI treatment regimens. Effective regimen option for otherwise healthy patients aged 12 years who have a predictive factor for greater likelihood of TB developing including: Recent TB contacts TST/IGRA Converters Radiographic findings of healed pulmonary TB CDC. November 2011. INH + RPT is NOT recommended for: Children under 2 yo HIV infected on Antiretroviral Therapy Drug interactions have not been established Presumed INH or Rifampin Resistance Pregnancy Safety in pregnancy has not been evaluated 12
Who should prescribe INH + RPT? Health Departments with established DOT programs Ideal candidates for the regimen are healthy LTBI patient discovered in contact investigation of active TB cases. If you choose to prescribe INH + RPT Emphasize to patients to seek medical attention upon the earliest onset of symptoms Baseline labs (LFTs) + monitoring for those at risk Elderly, certain conditions, risk of liver disease, abn. tests Monthly interview and physical examination Ask about Nausea, vomiting, Abdominal pain, Jaundice Look for drug hypersensitivity (hypotension, thrombocytopenia) Discontinue if LFTs >=5 times the upper limit Or >=3 times upper limit if patient is symptomatic CDC. November 2011. 13
If you choose to prescribe INH + RPT The regimen MUST be administered via DOT Be vigilant about Rifamycin drug interactions: Coumadin Hormonal contraception HIV Antiretrovirals Treatment of Active TB 14
Strategies Stressed in Guidelines Identification of patients at increased risk of relapse Obtain sputum smear and culture at end of initial phase of treatment (2months) Extended therapy (7 months) for patients with drugsusceptible pulmonary TB Who have cavitation on initial CXR and Who have a positive sputum culture at 2 months Counting Doses Define treatment completion by number of doses taken as well as duration of treatment Strategies Stressed in Guidelines 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 (Levofloxacin or Moxifloxacin) may be used when first line drugs are not tolerated or the organism is resistant 15
Treatment of Culture Positive Drug Susceptible Pulmonary TB General conclusions from the literature 6 mo (26 wk) is the MINIMUM duration of RX 6 mo regimens require rifampin and INH throughout and PZA for the first 2 months 6 mo regimens are effective without INH if PZA given throughout Intermittent regimens (2 3x/wk): DOT ONLY Drug susceptible isolate Treatment of Culture Positive Drug Susceptible Pulmonary TB General conclusions from the literature: Without PZA minimum duration is 9 months Without rifampin minimum duration is 12 months (up to 18 months) Streptomycin and ethambutol (EMB) are approximately equivalent in effect Because of high incidence of Streptomycin resistance ethambutol is preferred for initial therapy Use streptomycin only if isolate is proven susceptible 16
Treatment Regimens for TB Disease Initiation phase of therapy 8 weeks INH, Rifampin and PZA +/ EMB Continuation phase of therapy (At least)18 weeks INH and Rifampin USPHS/IDSA Evidenced based Rating Scale Strength of the Recommendation A = Preferred B = Acceptable alternative C = Offer when unable to give A or B D = Should generally NOT be offered E = Should NEVER be offered Graded Quality of Supporting Evidence I = Randomized clinical trial II = Clinical trial, not randomized III = Expert opinion 17
Treatment of Culture Positive Pulmonary Tuberculosis Regimens Rated A I (HIV Uninfected) INITIAL PHASE 2 mo I,R,Z,E daily (56 doses, 8wks) or 2 mo I,R,Z,E 5x/wk (40 doses, 8wks) then CONTINUATION PHASE 4 mo I,R daily (126 doses, 18 wks) or 4 mo I,R 5x/wk (90 doses, 18 wks) or 4 mo I,R, 2x/wk (36 doses, 18 wks) Treatment of Culture Positive Pulmonary Tuberculosis Regimens Rated A II (HIV Uninfected) INITIAL PHASE 2weeks I,R,Z,E daily (14 doses) then 6 weeks I,R,Z,E twice weekly (12 doses) CONTINUATION PHASE (DOT only) 4mo I,R Twice weekly (36 doses, 18 weeks) 18
Treatment of Culture Positive Pulmonary Tuberculosis Regimens Rated B I (HIV Uninfected) Thrice weekly Hong Kong Regimen INITIAL PHASE 2mo I,R,Z,E 3x/week (24 doses, 8weeks) CONTINUATION PHASE 4mo I,R 3x/wk (54 doses, 18 weeks) Monthly clinical visit Case Management check response to therapy, evaluate for toxicity: hepatitis, visual acuity, Ishihara Plates repeat education (document) Monthly laboratory to check liver enzymes, CBC Pt educated regarding: signs/symptoms of visual and liver toxicity & the need to report these to provider Document susceptibility of isolate prior to stopping ethambutol For pulmonary TB Monthly sputum until two consecutive cultures are negative 2 month sputum is crucial 80% should convert by 2 months, 95% by 3 months 19
Drug Susceptibility Tests The Arizona State Laboratory will test for INH, Rifampin, and Ethambutol for each initial isolate and for requests processed by the State TB Program Isolates from a positive culture should be sent to the State Lab for DST Do not wait for culture to grow on solid media Prolongation of Continuation Phase Continuation phase increased to 7 months if initial CXR is cavitary & culture is positive at 2 months Rational for Extending Therapy Continuation of PZA for an additional 2 months was not helpful in drug susceptible disease Prolongation of continuation phase by 2 months decreased relapses in silico tuberculosis from 20% to 2% 20
Relapse Circumstance in which a patient becomes and remains culture negative while receiving antituberculosis drugs but at some point after completion of therapy, either becomes culture positive again or experiences clinical and radiographic deterioration consistent with active tuberculosis Confirm relapse bacteriologically Use DNA fingerprinting to identify new infection causing the disease versus relapse Identify drug susceptibility pattern of isolate Relapsed Tuberculosis Most relapses occur within the first 6 12 months after stopping therapy but some occur 5 or more years later Nearly all drug susceptible patients who were treated with a rifamycin and received DOT will relapse with drug susceptible organisms Treat with standard RIPE regimen 21
Relapsed Tuberculosis Management Strategies Suspect drug resistance if Patients treated with self administered therapy Patient was poorly adherent Patient deteriorates clinically or radiographically during initial weeks of treatment Consider expanded regimen, especially if immune suppressed RIPE plus a fluoroquinolone and an injectable Contact the ADHS Tuberculosis Program for assistance with further testing, if drug resistance is suspected Medical Factors Associated With Relapse Cavitary TB Extensive disease on CXR; bilateral infiltrates Positive 2 month culture Associated medical conditions Diabetes HIV Malabsorption of TB drugs Tuberculous lymphadenitis Underweight at diagnosis and failure to gain Drug resistant disease Prior treatment for tuberculosis 22
Factors Used to Prevent Relapse of Tuberculosis DOT Adherence Dosing intensity (Dose itself) Duration of therapy Intensive phase Continuation phase Both Rifampin containing regimen Importance of the Initiation Phase Evidence suggests Effect of dosing schedules on treatment efficacy is best harnessed in the initial phase Evidence has existed in vitro for several decades that: the more rapid the anti bacterial effect the less likely is the emergence of persisters and the lower is the risk of relapse. 23
Treatment in Special Situations TB With INH Resistance (2 studies) Dosing intermittency reduces TB treatment efficacy as shown by: Higher risk of treatment failure, relapse or acquired drug resistance Level of evidence 1+ Grade of evidence: A Avoid dosing intermittency, especially in the initial phase in the presence of INH resistance Chang; Thorax December, 2010 24
Treatment of INH Resistant TB Duration of treatment and # drugs in regimen depend on patient s immune system and the extent of disease Normal host and minimal to moderate disease Rifampin, PZA, Ethambutol for 6 9 months Daily therapy preferred, no < three times weekly Impaired host or extensive, cavitary disease Add quinolone at least first 2 months Daily therapy Nine months Active TB During Pregnancy Diagnosis may be difficult Respiratory symptoms common in late pregnancy Reluctance to do a CXR Extra pulmonary disease is even more difficult Outcomes for BOTH mom and baby are improved with treatment during pregnancy Infection control is important at time of delivery if mom is still infectious 25
Treatment: Active TB During Pregnancy INH, Rifampin, Ethambutol x 9 months Stop ethambutol if susceptible to INH and rifampin PZA only if drug resistance is present PZA regarded as safe by most countries in world Follow carefully for hepatotoxicity risk is increased During pregnancy Three months postpartum Delayed Response Culture Positive at 3 Months Consider repeat susceptibility studies on last positive culture at 3 months Assess patient adherence Consider serum drug levels Evaluate response to therapy Clinically and radiographically 26
Treatment Failure Culture Positive at 4 Months Repeat susceptibility studies On last positive culture And request on a new sputum culture now Serum drug levels if not previously done Clinical evaluation Augment therapy Add at least two and preferably three new drugs to which the isolate is likely to be susceptible Even if no clinical or radiographic evidence of failure MMWR Treatment of Tuberculosis 2003; 52 Tuberculosis Drug Serum Level Monitoring Recommended Delayed response to therapy Advanced AIDS with evidence of malabsorption Seriously ill patient to maximize therapy Toxicity evaluation Use of second line drugs Acquired drug resistance Relapse Potential for drug drug interactions Renal and hepatic insufficiency 27
Culture Negative TB TB suspect with positive TST or IGRA Risk factors for TB Abnormal CXR Usually clinical symptoms All cultures are negative Classify based on clinical and/or radiograph response to treatment at 2 months Clinical or CXR improvement Culture Negative TB Treat for 4 months (children and HIV + 6 months) RIPE for 2 months, then RIE +/ PZA dependent on INH resistance Summary There are several acceptable regimens for treating LTBI and TB Careful monitoring of the patient during treatment is essential Follow treatment recommendations in MMWR Treatment of Tuberculosis 2003 Contact the State TB Program or Heartland with any treatment questions 28
Where to Get More Information Arizona Department of Health Services Tuberculosis Control Program Heartland National TB Center 1 800 TEX LUNG: Medical Consultation and Technical Assistance Line Future training courses CDC Division of Tuberculosis Elimination TB Educate TBresources.com 29