Pediatric TB Intensive San Antonio, Texas October 14, 2013

Pediatric TB Intensive San Antonio, Texas October 14, 2013 Treatment of Tuberculosis in Children Jeffrey R. Starke, M.D. Professor of Pediatrics October 14, 2013 Jeffrey R. Starke, M.D. has the following disclosures to make: Is a current member of the Data Safety Monitoring Board at Otsuka Pharmaceuticals & Roach. No relevant financial relationships with any commercial companies pertaining to this educational activity 1

DIRECTLY OBSERVED THERAPY FOR TUBERCULOSIS means a dispassionate 3rd party is actually present when medications are taken with every dose standard of care in U.S. for treating tuberculosis disease desirable for high risk infections - newborns and infants, household contacts, HIV - infected or immune compromised 2

DRUG RESISTANCE IN TUBERCULOSIS The development of drug resistance in M. tuberculosis is the result of a conspiracy among the organism, the patient, the doctor and the healthcare system! DRUG RESISTANCE IN MYCOBACTERIUM TUBERCULOSIS genetic loci for resistance on chromosome, unlinked resistance of drugs independent frequency of mutations at loci is known more likely to have mutations when mycobacterial population is larger : infection vs. disease primary - resistance present when infection acquired secondary - resistance develops while on therapy 3

Preventing Drug Resistance in TB Cavity 10*9 organisms 10*3 R-INH 10*2 R-RIF All organisms R-RIF killed 10*3 organisms R-INH survive and grow Cavity 10*9 organisms All R-INH 10*2 R-RIF I INH R-INH: 10*-6 R-RIF: 10*-7 R-INH+RIF: 10*-13 Preventing Drug Resistance in TB Cavity 10*9 organisms RIF kills R-INH organisms 10*3 R-INH 10*2 R-RIF CURE! INH kills R-RIF organisms I INH + RIF R-INH: 10*-6 R-RIF: 10*-7 R-INH+RIF: 10*-13 4

Preventing Drug Resistance in TB Granulomas Granulomas 10*4-5 organisms? any R-INH? any R-RIF? Cure INH R-INH: 10*-6 R-RIF: 10*-7 R-INH+RIF: 10*-13 Treatment of Tuberculosis More bugs More drugs! 5

Roles of Specific TB Drugs in Regimens Isoniazid Bactericidal Prevents emergence of resistance to other drugs Rifampin Bactericidal Prevents emergence of resistance to other drugs Ethambutol Bacteriostatic at lower doses Prevents emergence of resistance to other drugs Pyrazinamide Allows for shorter durations of therapy Points To Ponder What is the real difference between TB infection and TB disease in children? The organism is present in both cases We can sometimes culture the organism from children with recent infection but no clinical disease We treat infection with 1 drug, disease with 3-4 drugs The functional difference is the burden of organisms Infection and disease are on a continuum when does infection turn into disease? The convention is that it is disease when we can see it with our eyes or feel it with our fingers 6

Susceptible TRANSITIONS IN TUBERCULOSIS Exposed Prevent Infection Infected Diseased Prevent Disease Sick Diagnosed Treated Curative Therapy Cured TUBERCULOSIS IN CHILDREN TREATING EXPOSED CHILDREN So-called window prophylaxis Very high rate of infection w/o treatment Takes up to 3 months for the skin test to turn positive U.S. studies 10% to 20% of childhood TB cases can be prevented if children exposed in a household receive isoniazid WHO standards children <5 years old in a TB household should be treated 7

Major Issues With Current Treatment Regimens for LTBI Acceptance Adherence and completion Self: 49% ESAT: 75% DOT: 98% Duration even 3 months is long Adverse events hepatotoxicity, hypersensitivity reactions Cost [beyond isoniazid] Drug-Drug interactions [esp. rifamycins] Misdiagnosis early TB disease Treatment of [Latent]Tuberculosis Infection Established therapies include: Isoniazid for 9 months Isoniazid for 6 months Rifampin for 4 months Isoniazid and rifampin for 3 months RIPE for 2 months [2 RZ] Isoniazid and rifapentine once weekly for 12 weeks [under directly observed therapy] 8

Sterling et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011;365:2155. Rifapentine [15 mg/kg/dose] is a rifamycin with a long halflife and greater potency against M. tuberculosis A CDC-funded clinical trials group conducted an open label randomized non-inferiority trial (2001 2008) comparing 3 months of once-weekly rifapentine [900 mg max.] plus isoniazid [900 mg max.] under DOT with 9 months of daily self-administered isoniazid [300 mg max.] in subjects at high risk for TB [case contacts or recent TST conversion] For initial enrollment, persons > 12 years of age Later enrollment of children 2 11 years of age Subjects followed for 33 months after enrollment Sterling et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011;365:2155. 7731 enrolled and eligible subjects 87% of subjects completed 33 months f/u [mean 30] TB developed in 0.19% of subjects receiving combination therapy and 0.43% of isoniazid only subjects Among subjects who completed 100% of the doses, 5/3376 in the combination group and 6/2792 in the isoniazid group developed TB Treatment completion was higher in the combination [82%] than the isoniazid [69%] group Main adverse reaction: Combination: hypersensitivity Isoniazid: hepatitis 9

Sterling et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011;365:2155. Sterling et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med 2011;365:2155. Jereb et al. MMWR 2011 (Dec.);60:1650 CDC recommends 12 weeks of once weekly DOT INH-RPT in otherwise healthy patients > 12 yrs of age who are at high risk for developing disease Children 2-11 yrs of age: Efficacy not adequately studied and safety and tolerability data not yet assessed The preferred regimen for children aged 2-11 years is 9 months of isoniazid. However, INH-RPT can be considered on a case-by-case basis when both 1) the circumstances make the completion of 9 months of isoniazid unlikely and 2) the likelihood or hazard of TB is great 10

Limitations and Advantages of the INH-RFP 12 Week, Once Weekly Regimen Limitations Lack of data in children < 12 years of age Must be given under DOT health departments to decide if, how and when they can gear-up No cost-benefit analysis Shortage of rifapentine Advantages 3 months vs. 9 months higher adherence, esp. in transient groups and individuals Less hepatitis high risk persons Perhaps more effective PEARLS OF WISDOM FOR TREATING LTBI IN CHILDREN Use INH suspension only in children 5 kg Use DOPT for: recent contacts, infants, immune compromised When children aren t tolerating INH, the problem is more often with the parent than the child Route LFTs only for: other liver toxic drugs, liver disease, signs or symptoms of hepatitis Pyridoxine needed only for breast-feeding infants, pregnancy, poor diets 11

Considerations for Pediatric TB Treatment Regimens Very few true RCTs have been performed for intrathoracic TB, almost none for extrapulmonary TB Regimens that work in adults tend to work in children; may define the maximum treatment children require However, adult data do not necessarily define the minimum treatment required by children Children generally tolerate existing drugs and drug regimens better than adults Therapy for TB Disease Start 4-drug therapy - RIPE INH, rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB); INH/RIF are the backbone of therapy Use PZA only during 1 st 2 months for susceptible TB This is your shortening agent : consolidate from 9 to 6 months of therapy Stop EMB once culture results known, if have pan-susceptible TB This is your insurance in case you have drug-resistant TB Anticipate minimum 6 month therapy, and we often extend it to longer periods, especially for extrapulmonary disease Always administered by directly observed therapy (DOT) 12

Ethambutol Metabolized faster by children than adults Same mg/kg dose results in lower serum levels in children Consequently, risk of optic neuritis is very low You can feel very comfortable using ethambutol even in the pre-verbal child in whom visual acuity screening is challenging! Remember, however, that it crosses the bloodbrain barrier poorly and should not be used for meningitis Regimen 1 for Treatment of Pulmonary, Drug-Susceptible TB 6 month standard regimen Initial phase INH, RIF, PZA, EMB daily (7 or 5 days/week) for 8 weeks Continuation phase options 1) INH, RIF daily (7 or 5 days/week) for 18 weeks 2) INH, RIF intermittently (2 days/week or 1 day/week for INH, RPT) for 18 weeks 13

Regimen 2 for Treatment of Pulmonary, Drug-Susceptible TB 6 month daily +intermittent options Initial phase INH, RIF, PZA, EMB daily (7 or 5 days/week) for 2 weeks, then 2 days/week for 6 weeks Continuation phase INH, RIF intermittently (2 days/week) for 18 weeks Regimen 3 for Treatment of Pulmonary, Drug-Susceptible TB 6 month intermittent dosing options Initial phase INH, RIF, PZA, EMB intermittently (3 days/week) for 8 weeks Continuation phase INH, RIF intermittently (3 days/week) for 18 weeks 14

Regimen 4 for Treatment of Pulmonary, Drug-Susceptible TB 9 month without pyrazinamide options Initial phase INH, RIF, EMB daily (7 or 5 days/week) for 8 weeks Continuation phase options 1) INH, RIF daily (7 or 5 days/week) for 31 weeks 2) INH, RIF intermittently (2 days/week) for 31 weeks WHO Rapid Advice 2010 Pulmonary and Lymph Node TB in Children Standard therapy is 2HRZE + 4HR Where prevalence of HIV and INH resistance are low, therapy can be 2HRZ+4HR In HIV uninfected children with fully drug-susceptible TB, thrice weekly regimens can be used in the continuation phase with well established DOT [Weak recommendation, very low-quality evidence] Children with HIV infection should not receive intermittent regimens [Strong recommendation, lowto-moderate quality evidence] 15

WHO Rapid Advice 2010 Meningeal and Osteoarticular TB Children with suspected or confirmed tuberculous meningitis should be treated with HRZE for 2 months, followed by HR for 10 months, the total duration of therapy being 12 months. Standard doses should be used. [Strong recommendation, low-quality evidence] Children with suspected or confirmed osteoarticular tuberculosis should be treated with HRZE for 2 months followed by HR for 10 months, the total duration of therapy being 12 months. Standard doses should be used. [Strong recommendation, low-quality evidence] Notes on TB Drugs Drug Side Effects Other notes INH RIF PZA EMB Peripheral neuropathy; seizures in overdose; hepatotoxicity Orange discoloration of secretions; inactivates oral contraceptives; many drug interactions; hepatotoxicity Can increase uric acid gout symptoms; rash; pruritis; hepatotoxicity Optic neuritis, red-green color blindness B6 helps prevent neuropathy and is only treatment for INH seizures, but doesn t prevent hepatotoxicity Please warn of orange urine! Of 1 st -line drugs, greatest association with hepatotoxicity Despite side effects, has very poor CNS penetrance and not used for meningitis 16

Medication Tolerance Pediatrics: 5% risk of side effects in children Most minor abdominal pain without elevation in LFTs 3.3% incidence of elevated LFTs with INH and Rifampin (usually asymptomatic) Peripheral neuropathy quite rare before adolescence Adults: Hepatotoxicity: 3-4% with INH alone Up to 5% with INH and Rifampin Peripheral neuropathy: 4% Bone marrow suppression: 2% Medication Administration INH suspension only to child not taking any solid/pureed foods Warn parents about rifampin and urine color Make sure child can tolerate all medication doses prior to discharge (for some young babies, doses may need to be divided in the course of the day) 17

FOLLOW-UP EVALUATIONS FOR CHILDREN WITH TUBERCULOSIS skin test stays positive forever frequent chest xrays unnecessary - at diagnosis, 1-2 months, end of therapy follow growth & development closely adequate nutrition routine liver enzyme monitoring not necessary routine vitamin B 6 not necessary except breastfeeding, pregnant adolescents, poor diet CORTICOSTEROIDS IN PEDIATRIC TUBERCULOSIS Useful when host inflammatory response is contributing to tissue damage or dysfunction meningitis endobronchial miliary with alveolar block pericardial with constriction vertebral with spinal root irritation Can use prednisone or dexamethasone 18

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Treatment of Drug Resistant TB in Children INH mono-resistance: well-treated with 6-9 months of rifampin, pyrazinamide and ethambutol MDR- TB: treatment must be individualized depending on Exact drug susceptibility profile Anatomic location of disease Extent of disease Tolerance of medications Requires 4-6 drugs to which the organism is susceptible, at least 2 being bactericidal Recommended Monitoring While on Treatment Major obstacles to treating pediatric MDR TB is keeping children on numerous medications for a prolonged period. Many of these medications have side effects that need to be closely monitored. Close monitoring of side effects, and treating those side effects or changing medications when necessary can greatly improve adherence. Recent studies have shown that children often tolerate MDR-TB regimens better than adults. 40 20

All Children Baseline Month Ongoing HIV status X 1 2 3 4 5 6 9 1 2 Toxicity symptoms X X X X X X X X X X X X Height and weight X X X X X X X X X X X X Audiology (while on injectable) X X X X X X X Color vision testing (if on ethambutol) Recommended Drug Monitoring Schedule Chest X-ray (if lung involvement) X X X X X X X X X X X X X X X TB culture and DST X X X X X X X X X X X Creatinine and potassium X X X X X X X TSH/T4 (If on prothionamide, ethionamide, or PAS) X X X X X X X X 1 5 1 8 Blood count with diff (If HIV positive or on linezolid) X X X X X X X X X X HIV-infected children LFT s, cholesterol (if on ART) X X X X Adverse Event Hepatotoxicity Likely Culprit Drugs INH, RIF, PZA, ethionamide, PAS, clofazimine Adverse Effects Identification Tender liver, visible jaundice Management Stop all drugs; Wait for liver function to return to normal; Reintroduce drugs one-byone, every 2 days with monitoring of liver function before next drug Visual Problems EMB, ethionamide, PAS, linezolid Regular testing Stop EMB or substitute alternative drug; offer B6 with ethionamide Hearing Problems Amikacin, capreomycin, kanamycin Identification through audiometry or problems in communication Consider stopping injectable drug, substituting alternative drug, reducing dose or increasing dosing interval 21

Adverse Event Likely Culprit Drugs Adverse Events Identification Management Thyroid dysfunction Ethionamide, PAS Regular blood testing, clinical hypothyroidism or goiter Consider thyroxine supplementation (0.5g daily) if clinical hypothyroidism or raised TSH and decreased ft4 If raised TSH or decreased ft4 repeat test in one month Renal impairment Amikacin, capreomycin, kanamycin Regular blood testing, symptoms of high potassium If creatinine rises or if potassium is high, stop injectable, substitute for alternative drug, dose 3 times per week or reduce dose Severe Rash Any drug, skin discoloration (clofazimine), cycloserine, linezolid, EMB, STM Severe rash, peeling mucous membranes, child unwell Stop all drugs; Wait until clinical condition improves; Reintroduce drugs one by one, every 2 days, monitor closely Adverse Events Adverse Event Likely Culprit Drugs Identification Management Nausea and vomiting INH, RIF, EMB, PAS, ethionamide, PZA, clofazimine Clinically Considering separating the dosing of THA from the other drugs, by giving it in the evening; Consider reducing the dose of THA and building the dose back up to full dose over 2 weeks Diarrhea PAS Clinically Split dose of granules to give small doses throughout the day, Reduce dose, Consider loperamide Peripheral neuropathy INH, ethionamide, fluoroquinolones, linezolid, EMB, cycloserine, injectables Clinically Give or increase pyridoxine; If persistent or sever, stop INH 22

Adverse Event Likely Culprit Drugs Adverse Events Identification Management Neuropsychiatric problems INH, ethionamide, fluoroquinolones, terizidone, cycloserine Seizures, headache, behavior changes, sleep disturbances Verify correct dosing; Stop likely culprit drug; If symptoms persist, reintroduce and stop next most likely dose Less with terizidone than cycloserine Joint problems PZA, ofloxacin, levofloxacin, moxifloxacin Clinically Verify correct dosing; Consider reducing dose or stopping possible culprit drug; Consider trial of allopurinol Painful injection sites Amikacin, capreomycin, kanamycin Clinically Add local anesthetic to drug in equal volumes; Vary site of injection on a daily basis, If severe, consider splitting dose and giving half into two different sites Warm packs to skin Adverse Events Adverse Event Bone marrow suppression Likely Culprit Drugs PAS, rifampin, cycloserine (anemia), linezolid Identification Regular blood testing, ecchymoses Management PAS: B12 supplementation Cycloserine: folate supplementation Severe cases: G-CSF Arrhythmia Fluoroquinolones Baseline EKG Correct hypokalemia, hypomagnesemia; beware use of quinolones with other medications which can prolong the QTc 23

Potential Drug Interactions Drug 1 Drug 2 Symptom Management Ethionamid e Cycloserin e Increase seizure risk Consider checking levels Ethionamid e INH Increased seizure risk Pyridoxine Clofazimine INH INH increases clofazimine serum and decreases skin concentration Unclear clinical significance Clofazimine RIF Clofazimine results in decreased rifampin concentrations Unclear clinical significance PAS RIF Decreased RIF concentrations Unclear clinical significance Strategies to Lessen AEs Separate medication over time Provide potential nausea-inducing medicine (e.g., ethionamide) separately from other medications Provide medication to children with food Educate caregivers on what side effects are seen with medications, as well as what symptoms would not be consistent with a medication AE 24