Lisa Armitige, MD, PhD October 22, Comprehensive Care of Patients with Tuberculosis and Their Contacts October 19 22, 2015 Wichita, KS

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1 Complicating Issues Related to TB Diagnosis and Treatment Lisa Armitige, MD, PhD October 22, 2015 Comprehensive Care of Patients with Tuberculosis and Their Contacts October 19 22, 2015 Wichita, KS EXCELLENCE EXPERTISE INNOVATION 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

2 Diagnosis and Management of TB Disease Complicated by Co Morbidities Barbara J Seaworth M.D. October 22, 2015 EXCELLENCE EXPERTISE INNOVATION Objectives Describe diagnosis and management of TB complicated by medical co morbidity Hepatitis C Chronic kidney Disease and Dialysis HIV Diabetes 2

3 Case Study What Would You Do? 34 yr. old U.S. born woman in battered women s shelter hospitalized due to markedly reactive TST No known TB exposure Normal CXR, no cough, SOB or chest pain Abdominal pain, difficult to characterize, 20 pound weight loss in last 3 6 months Obvious history of significant stress TB AND CHRONIC KIDNEY DISEASE 3

4 Case Study 84 yr. old military man, lived in SAT x past 20 years, no report of prior + TST Prior multiple prolonged assignments to SE Asia 6 month history of cough, weight loss and fatigue Abnormal CXR; BAL/BX smear/culture + MTB 5 days into RX at 1 st clinic visit elevated creatinine, vision abnormal, nausea/vomiting after TB medications but LFTs normal How Should This Elderly Man Be Managed? Baseline creatinine (c/w CKD), now 2.1 Watch for worsening of renal function ~ 40+ % decrease in kidney function Consider need for ethambutol Patient is color blind and vision 20/70 bilaterally Xpert shows rifampin is susceptible so perhaps can add moxifloxacin and avoid ethambutol Change dose of ethambutol and PZA Watch liver as elderly may have more PZA toxicity 4

5 TB in Persons with Chronic Kidney Disease Increased risk of progression from latent to active TB with chronic kidney disease (CKD) Diagnosis & treatment of TB is more difficult in dialysis patients Symptoms can be mistaken for complications of dialysis Cough (congestive heart failure, fluid overload), fever (bacterial infection) Atypical presentation Extrapulmonary TB TB Presentation in Dialysis Patient Pulmonary Atypical presentation Fever most common sign! Low or high grade Weight Loss Anorexia Cough (may not be present) TB Disease must be considered in ANY patient with recurrent pneumonia pneumonia not improved within 2 weeks of antibiotics 5

6 CXR Findings in Persons with TB and CKD CXR may be normal or atypical Infiltrates in lower lobes, diffuse, miliary, resembling pulmonary edema, pleural effusions; these are more common with late disease Cavitations, typical nodules and upper lobe infiltrates; these are less common in late stage CKD TB Presentation in Dialysis patients Extra pulmonary TB More common in dialysis patients Pleural and lymph node most common Peritoneal/Abdominal» Can be indistinguishable from typical bacterial peritonitis» Peritoneal BX may show caseating granulomas Any site (Bone, Brain, Pericardium, etc.) Don t forget to do SPUTUMS!! even if CXR is normal 6

7 Treatment of TB in End Stage CKD Standard treatment applies BUT Dosing of ethambutol and PZA needs adjustment Ethambutol 15 25mg/kg p.o. 3 x weekly PZA 25 35mg/kg po thrice weekly No change in dose of INH or Rifampin; give daily in initiation phase of treatment INH 300mg po daily or 900 mg thrice weekly Rifampin 600mg po daily or thrice weekly Levofloxacin x /week Rifabutin 300 mg 3 x /week All doses should be given AFTER DIALYSIS ART is Recommended in all HIV Infected Persons with TB Person already on ART, start TB treatment immediately Treatment should be with a rifamycin (very rare exceptions) Adjust ART to reduce risk of drug drug interactions ART naïve patients CD4 count is <50 cells/mm3, Start ART within 2 weeks of starting TB therapy CD4 count >50 cells/mm3, Start ART by 8 to 12 weeks» Guidelines for the Use of Antiretroviral Agents in HIV 1 Infected Adults and Adolescents, August

8 Effects of HIV on TB TB is an AIDS defining illness HIV infection accelerates progression of TB TB risk increases at lower CD4 count HIV increases incidence of sputum smear negative TB TB is more difficult to diagnose in HIV+ patients HIV increases risk of extra pulmonary/disseminated TB Neil A. Martinson; Proc Am Thorac Soc Vol 8. pp , 2011 Effect of TB on HIV TB have a negative impact on HIV disease TB increases the risk of death TB increases plasma HIV viremia TB Increases expression of the HIV co receptors CCR5 and CXCR4 in HIV infected patients Badri M, Association between tuberculosis and HIV disease progression Int J Tuberc Lung Dis. 2001;5(3):225. 8

9 Clinical Presentation of TB in HIV Early Stage HIV Late Stage HIV Clinical picture Often resembles postprimary pulmonary TB often resembles primary pulmonary TB Sputum Smear Often positive More likely to be negative Chest x ray Upper lobe infiltrates with or without cavitation Infiltrates any lung zone, no cavitation, military; normal Immune Reaction Inflammatory Syndrome (IRIS) and TB Unmasking IRIS initial clinical manifestations of active TB; occurs soon after ART is started Paradoxical TB IRIS Worsening TB clinical symptoms after ART is started in patients receiving TB treatment. Fever, enlarging lymph nodes and worsening CXR Diagnosis of exclusion Incidence: 8 40% of pts starting ART after TB DX Guidelines for the Use of Antiretroviral Agents in HIV 1 Infected Adults and Adolescents, Nov 13,

10 Risk Factors for Paradoxical TB IRIS CD4 count <100 cells/mm 3 Severe TB disease, disseminated, extra pulmonary Less than 30 day interval between initiation of TB and HIV treatment Most IRIS in HIV/TB disease occurs within 3 months of the start of TB treatment» Guidelines for the Use of Antiretroviral Agents in HIV 1 Infected Adults and Adolescents, August 2015 Management IRIS and TB Significant morbidity and mortality may occur Continue ART and TB treatment Treat with NSAIDS/ steroids Consult HIV TB expert» Guidelines for the Use of Antiretroviral Agents in HIV 1 Infected Adults and Adolescents, Nov 13,

11 Rifamycins and TB Treatment Rifampin has many drug drug interactions with ART Rifabutin can be substituted for rifampin to decrease impact of the drug drug interaction Prior to prescribing a rifamycin base regimen, drug interactions and dose adjustments should be checked» guidelines/html/4/adult and adolescent oi prevention and treatmentguidelines/0 TB pts. have a higher infection rate of HIV HIV positive TB pts. have a higher rate of HCV infection HIV, HBV and HCV are risk factors for the development of abnormal LFTs. HIV, HBV and HCV are risk factors for mortality during anti TB treatment. IJID Vol. 28, Nov 2014,

12 TB Treatment in Patients with Advanced Liver Disease Likelihood of drug induced hepatitis may be higher Implications of drug induced hepatitis in pts with marginal hepatic reserve are potentially serious. TB may involve the liver, and hepatic abnormalities may improve with TB treatment.» Treatment of Tuberculosis : MMWR, June 20, 2003 TB Treatment without PZA in Persons with Hepatic Disease PZA can cause severe and prolonged liver injury Treat with INH, rifampin and ethambutol for 2 months follow by a continuation phase with INH and rifampin for 7 months» Treatment of Tuberculosis : MMWR, June 20,

13 TB Regimen Recommended for Persons with Advanced Liver Disease Treat with only one potentially hepatotoxic drug Rifampin should be retained Additional agents include ethambutol, fluoroquinolones, linezolid and cycloserine Injectable drugs not liver toxic but kidneys may be harmed with severe liver disease, be careful Treatment duration with such regimens should be months, depending on the extent and disease response these pts have functional MDR TB Obtain TB expert consultation; use MDR regimen Treatment of Tuberculosis : MMWR, June 20, 2003 Case Studies What Should I Do? 64 yr. old IVDU starting on methadone Screening abnormal CXR and sputum smear + Susceptibility pending Baseline LFTs 2.5 x nl Positive HCV, never RX Reports some N/V after 5 days of RIPE 54 yr. old with long hx of serious ETOH abuse To ER for detox Hospital day #3 noted to be coughing, H/H 7/27 ABN CXR extensive cavitary disease, 4+ AFB Susceptibility pending History of GI bleed, esohageal varices Baseline line LFTs 3 x nl 13

14 WHO 2009 People with a weak immune system, as a result of chronic diseases such as diabetes, are at a higher risk of progressing from latent to active TB People with diabetes have a 2-3 times higher risk of TB compared to people without diabetes About 10% of TB cases globally are linked to diabetes 14

15 The Link Between Diabetes and TB Tuberculosis and diabetes mellitus: convergence of two epidemics; Dooley K; Lancet Infect Dis December; 9(12): A link between diabetes and TB has been recognized for centuries Diabetics have increased risk of progression to disease, Diabetics are at increased risk of poor treatment outcomes The Impact of Diabetes on Tuberculosis Treatment Outcomes: A systematic Review of 33 studies: Diabetes is associated with an increased risk of death 4.95 greater in the studies that adjusted for age and other potential confounding factors. Diabetes is associated with an increased risk of relapse 3.89 greater» Baker et al. Bio Med Central, Medicine,

16 Does Diabetes Impact TB Treatment Outcomes? Previously thought not to affect treatment outcomes Four new studies from Baltimore, Texas, Taiwan and Indonesia reveal: Delayed culture conversion Higher mortality Dooly, 2009; Restrepo 2008; Wang 2008; Alisahlanda,2007 Presentation of TB in Diabetics Various reports of more severe disease Varying findings as to the radiographic presentation? More cavities? Isolated lower lung involvement 16

17 Response to Treatment Relapse may be more frequent Recent Shanghai study 203 diabetics with TB followed for 2 years after standard treatment 20% relapse rate in patients with DM (most Type 2) 5% relapse rate in patients without DM Zhang et al. Jpn J Infect Dis, 2009 Impact of Diabetes on Tuberculosis Treatment Outcomes A Systematic Review of 33 studies: Diabetes is associated with an increased risk of failure and death during TB treatment. Diabetes is associated with an increased risk of death 4.95 greater in the studies that adjusted for age and other potential confounding factors. Diabetes is associated with an increased risk of relapse (RR 3.89)» Baker et al. Bio Med Central, Medicine,

18 Should Treatment of Diabetics with TB be Different? No data to make comprehensive recommendations on diabetics But we should treat aggressively and monitor carefully Case by case decision: Intensity of dosing, many should have daily dosing Duration of therapy Monitoring during treatment Drug levels if slow to convert Recommendations for TB Management in Persons with DM Diabetes is associated with poor TB medication absorption Consider drug levels Consider extending treatment to 9 months if slow culture conversion or slow clinical response Adjust the frequency of pyrazinamide and ethambutol if diabetic nephropathy is present Administer B6 to prevent INH induced peripheral neuropathy Observe closely for TB treatment failure Manage the many interactions between rifampin and DM meds 18

19 TB and Diabetes Treatment Issues Diabetic neuropathy at baseline complicates therapy due to risk of INH related neuropathy Baseline assessment of neuropathy Vitamin B 6 to all diabetics on INH or ethionamide Gastroparesis Vomiting and slow emptying could prevent good drug levels Renal insufficiency is associated with diabetes, especially long standing or poorly controlled DM Adjust dose and dosing interval of EMB & PZA (Crt Cl < 30) TB and Diabetes Treatment Issues Diabetics have an increased risk of hepatotoxicity Multiple medications Fatty liver Monitoring and education are very important Baseline and monthly liver enzymes Educate regarding risk of liver toxicity, symptoms to watch for, and what to do should these occur Contact provider Hold TB medications until liver injury excluded 19

20 Case Study How Would You Manage? 56 yr. old Pilipino with history of RX for LTBI as child; + TST at U.S. entry > 20 yrs. Ago > 3 month hx of dry cough, fatigue, fever sweats Poor adherence with DM medications and diet Glucose > 500, HbA1C > 10% CXR cavitary infiltrate Sputum AFB +, Xpert no rifampin resistance Case History part 2 MDDR no mutation for INH or FQN Culture shows low level INH resistance Moxifloxacin 750 mg added to treatment Notes medication too strong after she goes to primary provider and restarts DM medications at 2 months of TB treatment Denies she ever had TB and wants to stop all treatment Cultures negative by week 6 CXR completely normal by month Notes itching all over for 2 weeks and reports rash Medications held and clinic visit scheduled next day With INH resistance, cavitary disease, and uncontrolled DM how long should we treat? 20

21 Rash is raised, reddish pin or salmon colored Begins on trunk and spreads to arms and legs Drug rash Typical maculopapular rash Cellulitis due to Candida Satellite lesion 21

22 Diabetic Skin Rashes Diabetics have more vulnerability to skin infections Yeast infections Bacterial infections such as cellulitis Encourage patients to examine the feet to look for fungus (athlete s foot), small cuts that may get infected and fungus that may be growing around the nails. Stress that because of diabetic neuropathy they may not feel pain Cellulitis Bacterial Infection 22

23 Shingles Herpes Zoster Infection Blistering rash in a dermatomal distribution Impetigo Infection Due to Streptococcus or Staphylococcus 23

24 Case Study What Should We Consider? 50 yr old HCW diagnosed with pulmonary TB as part of screening for travel out of U.S. to Canada for continuing education Abnormal CXR, + IGRA, negative smear Completely asymptomatic BAL, negative smear but positive culture Week #2 puritic rash, maculopapular Notes mild nausea, decreased appetite with meds x several hours after dose for past week, no nausea TB and Smoking 24

25 Global lung health: the colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD van Zyl Smit et al, EurRespirJ 2010, 35; 27 In 2006 approximately 5.8 trillion cigarettes were manufactured; an average of 2.4/day for all 6.5 billion inhabitants of earth Current estimates of tobacco smoking rates are 49% males, 8% females in low and middle income countries (37% and 21% respectively in high income countries) In 2004, COPD was the 4 th leading cause of death worldwide (5.1% of total deaths) By 2030, COPD will be the 3 rd leading cause of death globally, eclipsing deaths by TB and HIV Association between Tobacco Smoking and Active Tuberculosis in Taiwan Hsien Ho et al AJRCCM 2009, 180; 475 Prospective cohort study in Taiwan: 17,699 participants, Current smoking associated with two fold increased risk of active TB Association stronger for patients < 65 years Significant dose response relations Cigarettes per day Years of smoking Pack years 25

26 Smoking, drinking and incident tuberculosis in rural India: population based case control study Gajalakshmi et al Int J Epidemiol 2009, 38; 1018 Case control study from India: 1839 males, 870 females NO WOMEN SMOKED or DRANK ALCOHOL! 82% TB cases vs 55% of controls smoked RR 2.2 (for alcohol consumption RR 1.5) Conclusion: increased incidence of pulmonary TB among those who smoke and among those who drink Association between Tobacco Smoking and Active Tuberculosis in Taiwan Hsien Ho et al AJRCCM 2009, 180; 475 The finding that smoking increased the risk of tuberculosis suggests that tobacco control be considered as an important component in the global effort to eliminate tuberculosis. policy makers and public health personnel should consider addressing tobacco cessation as part of TB control. 26

27 Systematic Reviews and Meta analyses evaluating tuberculosis and cigarette smoking Approximately 13% of the TB cases in the world each year may be attributable to tobacco exposure. Tobacco cessation must become an integral part of all TB control programmes. Tobacco and Treatment Delay 605 TB patients 271 (44.8%) current smokers, 33 (5.5%) ex smokers, 301 (49.8%) never smokers. Median total delay in seeking treatment was 103 days (current smokers 133 days, ex smoker 103 days and never smokers 80 days). Longer delay was more common among current smokers (aor 2.03, 95%CI ). Covariates with significantly more delay were female sex, lower levels of education and higher degrees of sputum smear positivity. 27

28 Tobacco and Culture Conversion 714 patients in Brazil, screened for Phase 2 trial, Dec 2002 August months daily HRZE then 2 or 4 months daily HR, all evaluated after 2 months Excluded if co morbid conditions: DM, asthma, rheum dz, HIV Patients who smoked had three fold greater odds of remaining sputum culture positive after 2 months of treatment than non smokers *Alcohol consumption did not affect culture conversion Alcohol 28

29 Isoniazid Alcohol and TBI treatment Alcohol consumption appeared to more than double the rate of probable isoniazid hepatitis Abnormal results were associated with alcohol use, but not with race, age, chronic hepatitis B infection, or HIV infection A study in Spain found that only excessive alcohol consumption and a high baseline ALT concentration were independently associated with isoniazid hepatotoxicity Rifampin Hong Kong Chest Service study showed none of 49 individuals, 20% of whom used alcohol and 8% of whom used injection drugs, treated with rifampin for 6 months had symptomatic liver injury Isoniazid Drug Toxicities Increased toxicity when administered with INH due to increased serum levels Phenytoin valproic acid Carbamazepine disulfiram (Antabuse) Serotonergic antidepressants acetaminophen 29

30 Isoniazid Toxicity Central Nervous System Effects irritability, seizures, dysphoria, inability to concentrate GI reactions (nausea, anorexia, abdominal pain) Peripheral Neurotoxicity Dose Related Uncommon (< 0.2%) at conventional doses Increased risk with other conditions associated with neuropathy: malnutrition, diabetes, HIV, renal failure, alcohol Pyridoxine 25 mg/kg (vitamin B6) recommended patients with above conditions Alcohol and TBI treatment For those with.. chronic alcohol consumption, or severe liver disease manifested by low albumin and coagulopathy or encephalopathy, the risks of LTBI may outweigh benefits If LTBI treatment is undertaken, close monitoring is indicated The decision to treat LTBI, or more likely defer, should be carefully made on a case by case basis, weighing the risk of progression to TB disease against the risk of INH or rifampin related DILI. 30

31 Alcohol and TB Disease Pulmonary Disease 92.3% vs 61.1% Smear positive 74% vs 57.6% IV drug use 4.2% vs 0.8% Fiske et al Journal of Infection (2009) 58, Alcohol and Hepatotoxicity in the Treatment of TB Disease Pande Thorax 1996;51:

32 Rifampin and Opioids Methadone Rifampin lowers the serum concentration of methadone by 33 66% Administration of rifampin to patients on methadone has led to opioid withdrawal in patients on methadone replacement therapy Need to increase methadone dose and monitor carefully to prevent withdrawal with co administration of rifampin and methadone Niemi et al. Clin Pharmacokinet (9): Rifampin and Opioids Codeine Administration with rifampin leads to decreased biotransformation to morphine (which is responsible for most of the analgesic effects) Decreased serum concentration with rifampin Morphine 28 % decrease in serum levels when given with rifampin Loss of analgesic effect Niemi et al. Clin Pharmacokinet (9):

33 Rifampin and Benzodiazepines Diazapam Reduction of half life by 76% Enhanced total body clearance by 300% May require a 2 3 fold increase in dose for effect Midazolam and Triazolam Decreased serum concentration to 2 4% of controls Ineffective during co administration with rifampin Niemi et al. Clin Pharmacokinet (9): Rifampin and Benzodiazepines Niemi et al. Clin Pharmacokinet (9):

34 Rifampin Drug Toxicities Significant decrease in serum levels Phenytoin valproic acid Carbamazepine Serotonergic antidepressants Rifampin Drug Interactions It is imperative to be aware of all medications a patient is taking when that patient is placed on rifampin. 34

35 Rifabutin A substitute for rifampin for patients who are receiving drugs, especially antiretroviral drugs, that have unacceptable interactions with rifampin. Adverse effects: Less severe induction of hepatic microsomal enzymes, therefore, less effect on the metabolism of other drugs Thanks!! Questions? TEX LUNG 35