LTBI in Special Populations John Nava, MD October 5, 2010

Understanding and Managing Latent TB Infection Arnold, Missouri October 5, 2010 LTBI in Special Populations John Nava, MD October 5, 2010 2 Treatment of Latent TB Infection in Special Populations John J. Nava, MD City Chest Clinic San Antonio, TX Missouri Dept. of Health and Senior Services October 5, 2010 1

Objectives (1) Latent TB Infection (LTBI) List high priority groups to receive treatment for LTBI Describe treatment regimen for LTBI List common adverse reactions to drugs used against LTBI Describe patient monitoring, both clinical and laboratory for LTBI patients 3 Objectives (2) Latent TB Infection (LTBI) Describe TB treatment adherence strategies and their effects on development of drug resistance Describe pediatrics, pregnancy, HIV coinfection, substance abuse, and methadone treatment issues in case management Describe treatment of LTBI in contacts to MDR-TB 4 2

Meeting the Challenge of TB Prevention 5 For every patient Assess TB risk factors If risk is present, perform TST or IGRA If TST or IGRA is positive, rule out active TB disease If active TB disease is ruled out, initiate treatment for LTBI If treatment is initiated, ensure completion 6 Identifying Risk Factors That Lead to Development of TB Disease 3

7 Persons at Risk for Developing TB Disease Persons at high risk for developing TB disease fall into 2 categories Those who have been recently infected Those with clinical conditions that increase their risk of progressing from LTBI to TB disease Recent Infection as a Risk Factor (1) 8 Persons more likely to have been recently infected include Close contacts to person with infectious TB Skin test converters (within past 2 years) Recent immigrants from TB-endemic regions of the world (within 5 years of arrival to the U.S.) 4

Recent Infection as a Risk Factor (2) 9 Children 5 years with a positive TST (Always DOPT to ensure compliance!) Residents and employees of high-risk congregate settings (e.g., correctional facilities, homeless shelters, health care facilities) Increased Risk for Progression to TB Disease (1) 10 Persons more likely to progress from LTBI to TB disease include HIV-infected persons Those with a history of prior, untreated TB or fibrotic lesions on chest radiograph (including recent immigrants with no documentation of prior TB regimen) 5

Increased Risk for Progression to TB Disease (2) 11 Underweight or malnourished persons Injection drug users Those receiving TNF-α antagonists for treatment of rheumatoid arthritis, psoriasis, or Crohn s disease Increased Risk for Progression to TB Disease (3) 12 Persons with certain medical conditions such as Silicosis Diabetes mellitus Chronic renal failure or on hemodialysis Solid organ transplantation (e.g., heart, kidney) Carcinoma of head or neck Gastrectomy or jejunoilial bypass 6

13 HIV Status and Risk of Progression to Active TB HIV negative - after exposure, 5% progress to active TB, and another 5% LTBI with lifetime risk if untreated HIV positive after exposure, up to 30% progress to active TB, and the TB infected have 10% reactivation risk EACH YEAR Clinical Presentation of Active TB in HIV-infected Patients 14 More likely to have: Isolated extrapulmonary location Pulmonary infection Pulmonary basilar involvement Tuberculous pneumonia Hilar or mediastinal lymphadenopathy Miliary or disseminated TB Normal CXR ( 8 to 20 percent in some studies) 7

15 Pediatric LTBI Age at exposure related to severity of disease and risk of rapid progression Window prophylaxis until BIC screening completed Reliability of screening method? Half of children less than 12 years old not symptomatic, even with active disease, so R/O carefully. 16 Pregnancy and LTBI Pregnancy does not alter diagnostic work-up No need for window prophylaxis until BIC screening completed Radiation risk to fetus not a concern PZA usually not used in the US, but may be required for treating contact to MDR case. 8

Referrals from Drug Rehab Centers 17 Clearance vs. LTBI Treatment Two strikes and you are OUT! Undiagnosed Hep C and other risks for hepatotoxicity polypharmacy, alcohol abuse, comorbid conditions, psychiatric issues INH does not interact with methadone, but RIF does. Candidates for Treatment for LTBI by TBST Result 18 Give LTBI Treatment to Highest risk groups Immunocompromised Recent contacts X-ray indicates previous TB If M. tuberculosis Test Result Is 5 mm Other high-risk groups 10 mm Patients with no risks 15 mm The frequency of TB testing for HCWs will be determined by the risk classification for the setting. 9

Recommendations for TB Skin Testing Emphasis on targeting persons at high risk 5-mm induration cutoff level for organ transplant recipients and other immunosuppressed patients being treated with prednisone or TNF-α antagonists Skin-test conversion defined as increase of 10 mm of induration within a 2-year period, regardless of age 19 MMWR August 61, 2004; 53(33): 683-686 Factors That May Cause False-Negative TST Reactions (1) Live-virus vaccination For example, measles or smallpox Can temporarily suppress TST reactivity Overwhelming TB disease Poor TST administration technique For example, TST injection too shallow or too deep, or wheal is too small 20 10

Factors That May Cause False-Negative TST Reactions (2) 21 Recent TB infection Defined as 2 to 10 weeks after exposure Very young age Newborns Initiating Treatment 22 Before initiating treatment for LTBI Rule out TB disease (i.e., wait for culture result 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 11

23 LTBI Treatment Regimens 24 Treatment Regiments for LTBI Drugs Months of Duration Interval Minimum Doses INH 9* Daily 2x wkly 270 76 INH 6 Daily 2x wkly 180 52 RIF 4 (adults) 6 (children) Daily 120 180 *Preferred INH=isoniazid; RIF=rifampin 12

25 Rifamycin Regimens (1) Rifampin (RIF) given daily for 4 months is an acceptable alternative when treatment with INH is not feasible (remember, 6 months for children). In situations where RIF cannot be used (e.g., HIV-infected persons receiving protease inhibitors), rifabutin may be substituted. Coumadin or methadone doses may need adjustments. 26 Rifamycin Regimens (2) Rifampin (RIF) should not be used with PI s (protease inhibitors), due to decreased level of the PI and unknown effects on RIF level. Rifabutin has less effect on PI level, and may approach toxic levels especially when boosted with ritonavir. Cytochrome P450 inducers RIF>RPT>RBT Newer drugs have substantial interactions. 13

27 Completion of Therapy Completion of therapy is based on the total number of doses administered, not on duration alone. 28 Treatment of LTBI Recommendations HIV-negative persons INH for 9 months preferred regimen HIV-positive persons and those with fibrotic lesions on chest x-ray (consistent with previous TB) INH should be given for 9 months For all adult patients RIF for 4 months is an option 14

29 Clinical Monitoring for LTBI (1) Instruct patient to report signs or symptoms of adverse drug reactions Rash Anorexia, nausea, vomiting, or abdominal pain in right upper quadrant Fatigue or weakness Dark urine Persistent numbness in hands or feet 30 Clinical Monitoring for LTBI (2) Monthly visits should include a brief physical exam and a review of Rationale for treatment Adherence with therapy Symptoms of adverse drug reactions Plans to continue treatment- Are parents of child or referring clinician supportive? 15

Clinical Monitoring for LTBI (3) 31 Incidence of hepatitis in persons taking INH is lower than previously thought (0.1 to 0.15%) Hepatitis risk increases with age Uncommon in persons < 20 years old Nearly 2% in persons 50 to 64 years old Risk increased with underlying liver disease or heavy alcohol consumption 32 Laboratory Monitoring for LTBI (1) Baseline liver function tests (e.g., AST, ALT, and bilirubin) are not necessary except for patients with the following risk factors: HIV infection History of liver disease, possible hepatotoxic medications Alcoholism Pregnancy or in early postpartum period 16

33 Laboratory Monitoring for LTBI (2) Repeat laboratory monitoring if patient has Abnormal baseline results Current or recent pregnancy (up to three months postpartum) High risk for adverse reactions Symptoms of adverse reaction Liver enlargement or tenderness during examination Laboratory Monitoring for LTBI (3) 34 Asymptomatic elevation of hepatic enzymes seen in 10%-20% of people taking INH Levels usually return to normal after completion of treatment Some experts recommend withholding INH if transaminase level exceeds 3 times the upper limit of normal if patient has symptoms of hepatotoxicity, and 5 times the upper limit of normal if patient is asymptomatic MMWR June 9, 2000; 49(No. RR-6): 39 17

35 Adverse Drug Reactions 36 Hepatitis Meds on hold while assessment is being done! Early signs fatigue, rash, poor appetite, nausea, bloating Later signs vomiting, abdominal pain (RUQ), jaundice, dark urine, light stools, neurologic problems ANY first line antituberculous medications, except EMB, can cause hepatitis. 18

37 Dealing with Hepatotoxicity Meds on hold while assessment is being done! If confirmed by lab results, repeat periodically every one to four weeks. LFT s may continue to rise despite suspending medication administration. Once LFT s have returned to < 2X ULN, consider rechallenge with same regimen or more liver friendly combination. Reinforce avoidance of other hepatotoxic substances! 38 Isoniazid (INH) Most likely toxicity is hepatitis, but also: peripheral neuropathy, especially after early adolescence prevented and treated by Vitamin B6 50 mg. to 100 mg.+ CNS neuropathy HA, insomnia, loss of concentration, memory loss, personality changes, seizures rarely rarely marrow suppression, rash, drug fever, alopecia GI upset and some CNS effects resolve if continued 19

39 Rifampin (RIF) Most likely toxicity is hepatitis, but also: marrow suppression, especially low platelets and low WBC easy bruising and inability to fight infection visual toxicity less likely color vision and acuity Rifabutin (RBT) uveitis eye pain, redness, blurred vision consider drug interaction with HIV meds, perhaps intermittent dosing GI upset and rash possible 40 Pyrazinamide (PZA) Most likely toxicity is hepatitis, maybe more than INH and RIF: gouty arthritis and arthralgias try NSAID before stopping drug, but if necessary to stop, extend treatment to nine months renal function impairment, especially with preexisting chronic renal insufficiency GI upset and rash possible 20

41 Ethambutol (EMB) Most likely toxicity is optic nerve inflammation: decreased visual acuity and color vision possibly rash, less likely stomach upset consider lower dose (range 15 to 25 mg./kg.) for children or prolonged duration of therapy beyond two months (induction phase) Consider intermittent dosing with renal disease 42 Fluoroquinolones (FQ) Ciprofloxacin, Gatifloxacin, Levofloxacin, Moxifloxacin GI upset tendonitis, including tendon rupture QTc prolongation Possible hepatotoxicity with moxifloxacin 21

43 Treatment Adherence Strategies and Prevention of Acquired Drug Resistance TB Management Questions to Ask (1) Compliance by DOT Are they where they are supposed to be at the agreed upon time? Are they vomiting after medication administration? Are they cheeking the meds and spitting them out? Are they concerned they will have to take meds longer if they experience missed doses? 44 22

TB Management Questions to Ask (2) Compliance by DOT Is their favorite pastime impacted by their diagnosis and DOT requirement? Are they intending to work together with staff to complete recommended therapy until cured? 45 46 TB Management Errors Associated with Acquired Drug Resistance Mahmoudi A, Iseman MD, JAMA 1993; 270:65-68 INH monotherapy for misdiagnosed LTBI Addition of single drug to failing regimen Inadequate initial regimen Failure to identify drug resistance and modify regimen based on drug susceptibility testing (DST) Failure to identify/remedy non-adherence 23

TB Management Errors Can Be Prevented (1) For every patient Don t treat active TB with monotherapy! Add two or more drugs to a failing regimen! Always take a good history! Don t let a good clinical response justify continuing an inadequate regimen! OR They get better for a little while before they get worse! If they don t improve, they may be spitting out the meds! 47 TB Management Errors Can Be Prevented (2) Try to collect an adequate bacteriologic specimen before initiating therapy by: Confirm induced sputum collection on three different days is done before lifting respiratory isolation precautions Dead mycobacteria do not grow, so order AFB studies on fresh, not fixed, gross surgical specimens Excisional lymph node biopsies are better than FNA s. 48 24

TB Management Errors Can Be Prevented (3) For respiratory specimens; Induced sputa are better than natural, unless the natural is already positive. If induced sputa are negative smear, bronchoscopy may be indicated. Tracheal aspirates can be collected from intubated patients. Pediatric cases can be admitted for early AM gastric aspirates on three successive days. 49 TB Management Errors Can Be Prevented (4) For every patient Confirm a good specimen collection before starting therapy, so drug susceptibility testing can guide therapy. Elicit a good antibiotic history for three months before the suspicious symptom onset, especially for quinolones. 50 25

51 Suspect MDR or XDR TB (1) Patient history: Prior treatment for TB, known contact to drug-resistant case or noncompliant person Current noncompliance Treatment failure in past Birth in country with high incidence of TB Recent immigration (even if > 5 years) 52 Suspect MDR or XDR TB (2) Patient response: Clinical deterioration after 2-3 weeks of therapy with presumed effective regimen Radiographic deterioration after 2-3 weeks of therapy with presumed effective regimen 26

Management of Contacts to MDR-TB (1) 53 Options for selection of LTBI regimen: Choose two drugs that source case has documented sensitivity to Choose fluoroquinolone as monotherapy Choose INH or Rifampin, as contact may be prior TBST converter after contact to pansensitive isolate Choose to hold treatment and monitor clinically Management of Contacts to MDR-TB (2) 54 Duration of treatment of LTBI using two drugs with documented effectiveness: Usually six months In cases of HIV positive contacts, recommend twelve months If INH selected, nine months If RIF selected, four to six months 27

Management of Contacts to MDR-TB (3) 55 Recommended follow-up of all contacts: Regardless of LTBI regimen selected CXR and clinical evaluation every six months Duration for two years 56 Guidelines Available Online CDC s Morbidity and Mortality Weekly Report http://www.cdc.gov/mmwr American Thoracic Society http://www.thoracic.org/statements/ 28

57 Additional Resources For additional information on TB, visit the CDC Division of Tuberculosis Elimination Website at http://www.cdc.gov/tb 29