RECENT ADVANCES OF TUBERCULOSIS MANAGEMENT. Qais Abdulmajeed Haddad Consultant ID & IC Security Forces Hospital Program Riyadh - Saudi Arabia

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1 RECENT ADVANCES OF TUBERCULOSIS MANAGEMENT Qais Abdulmajeed Haddad Consultant ID & IC Security Forces Hospital Program Riyadh - Saudi Arabia

2 RECENT ADVANCES OF TUBERCULOSIS MANAGEMENT History Epidemiology Latent Tuberculosis Diagnosis Therapy Vaccine Infection Control Future Trends

3 1.5 m/year = 4110/day

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5 Pulmoary Tuberculosis Extrapulmoary Tuberculosis TB Pleural effusion Tuberculous meningitis CNS Tuberculoma Milliary tuberculosis Renal & urogenital tuberculosis Bone & joint tuberculosis GIT tuberculosis TB Peritonitis Ileocecal TB Colonic TB Hepatic TB TB retinitis

6 Tuberculosis History Spinal TB After 1850 Laennec Neolithic skeleton (stone age) Pre-Columbian skeleton Early Egyptian remains Pulmonary & Extrapulmonary tuberculosis is one disease 1865 F. Villemin Tuberculosis transmitted to guinea pig by injecting diseased tissue 1882 Koch AFB & its pathogenicity

7 TB History Timeline 1993: TB cases decline due to increased funding and enhanced TB control efforts 1865: Jean-Antoine Villemin proved TB is contagious 1884: First TB sanatorium established in U.S. 1943: Streptomycin (SM) a drug used to treat TB is discovered Mid-1970s: Most TB sanatoriums in U.S. closed : Robert Koch discovers M. tuberculosis : Two more drugs are discovered to treat TB: INH and PAS Mid-1980s: Unexpected rise in TB cases Rifampicin introduced 1967

8 M. tuberculosis causes most TB cases in the world Mycobacteria that cause TB: M. tuberculosis M. bovis M. africanum M. microti M. canetti Types of Mycobacteria Mycobacteria that do not cause TB (NTM) e.g., M. avium complex, M. chelonae

9 TB TRANSMISSION Dots in air represent droplet nuclei containing M. tuberculosis

10 TB Transmission Probability that TB will be transmitted depends on: Infectiousness of person with TB disease Environment in which exposure occurred Length of exposure Virulence (strength) of the tubercle bacilli The best way to stop transmission is to: Isolate infectious persons Provide effective treatment to infectious persons as soon as possible

11 WHO Global TB Report 2014 Incidence: 9 million (2013) 95% occurs in low- and middle-income countries Alarming increase in the number of patients with MDR-TB and XDR-TB has been noted (East Europe & Africa) Globally, 45% drop in mortality between 1990 & 2012 Mortality: 1.5 million / year 0.5 million are children HIV co-infection with TB: 360,000 deaths / year 13% of total active TB infections

12 RR-TB (Rifampicin Resistant) MDR-TB (INH+Rifampicin Resistant)

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14 Latent Tuberculosis

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

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17 PPD VS IGRA Latent TB infection (LTBI) diagnosis remained to be dependent on PPD (Mantoux test) which was first described by Robert Koch in 1890 PPD needs two patient visits and liable for observer error in reading Interferon-Gamma Release Assays (IGRAs) are whole-blood tests that can aid in diagnosing LTBI with one patient visit

18 Initial Process QFT-TB Gold T-Spot Process whole blood within 16 hours Process peripheral blood mononuclear cells (PBMCs) within 8 hours, or if T-Cell Xtend is used, within 30 hours M. Tuberculosis Antigen Single mixture of synthetic peptides representing ESAT-6, CFP-10 & TB7.7. Separate mixtures of synthetic peptides representing ESAT-6 & CFP-10 Measurement IFN-g concentration Number of IFN-g producing cells (spots) Possible Results Positive, negative, indeterminate Positive, negative, indeterminate, borderline

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21 Isoniazid VS Isoniazid + Rifapentine Rates of Treatment completion Isoniazid only Isoniazid + Rifapentine P Value 69% 82% <0.001 Drug Discontinuation 3.7% 4.9% Doses

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23 1148 patients had a median age of 30 years and a median CD4 cell count of 484/ml This was an open-label, randomized trial of LTBI in HIV patients (PPD 5mm or more) Divided in 4 blocks 2:2:2:1 rifapentine (900 mg) plus isoniazid (900 mg) once weekly for 12 weeks Rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks Isoniazid (300 mg) daily for duration of the study ( 6 yrs) Control regimen of isoniazid (300 mg) daily for 6 months

24 Conclusions The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment completion rate Neither a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid

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26 A Trial of Mass Isoniazid Preventive Therapy for Tuberculosis Control In the intervention clusters, 27,126 miners (66.2%) underwent screening. Of these miners, 23,659 (87.2%) started taking isoniazid for 9 months If active tuberculosis was diagnosed, they were referred for treatment Conclusions: Mass screening and treatment for latent tuberculosis had no significant effect on tuberculosis control in South African gold miners, despite the successful use of isoniazid in preventing tuberculosis during treatment

27 Laboratory Diagnosis of Tuberculosis AFB smear by ZN stain and culture remain the gold standard in diagnosis

28 Detecting AFB by fluorochrome stain using fluorescence microscopy The smear may be stained by auramine-o dye. In this method the TB bacilli are stained yellow against dark background & easily visualized using florescent microscope Advantages: - More sensitive - Rapid Disadvantages: - Hazards of dye toxicity - more expensive - must be confirmed by Z-N stain

29 Cultures on L J media Lowenstein Jensen medium is an egg based media with addition of salts, 5 % glycerol, Malachite green & penicillin Advantages: - Specificity about 99 % - More sensitive (need lower no. of bacilli / ml) - Can differentiate between TB complex & NTM using biochemical reactions - Sensitivity tests for antituberculous drugs ( St, INH, Rif., E) Disadvantages: Slowly growing ( up to 8 weeks )

30 Rapid Radiometric Culture System BACTEC specimens are cultured in a liquid medium (Middle brook7h9 broth base ) containing C 14 labelled palmitic acid & PANTA antibiotic mixture Growing mycobacteria utilize the acid, releasing radioactive CO 2 which is measured as growth index (GI) in the BACTEC instrument The daily increase in GI output is directly proportional to the rate & amount of growth in the medium

31 Microscopic-Observation Drug-Susceptibility Assay for the Diagnosis of TB A single MODS culture of a sputum sample offers more rapid and sensitive detection of tuberculosis and multidrug-resistant tuberculosis than the existing gold-standard methods used Moore DA et al, N Engl J Med 2006;355:

32 Nucleic Acid Amplification (NAP) Test. A new molecular diagnostic test called Xpert MTB/RIF assay detects M. tuberculosis complex within 2 hours, with an assay sensitivity that is much higher than that of smear microscopy

33 Treatment of Tuberculosis

34 TB Drug Resistance Mono-resistance MDR-TB: Resistance to isoniazid and rifampicin XDR-TB: FLD: SLD: TDR: Resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the 3 2 nd line injectables (amikacin, capreomycin & kanamycin) CDC, Mortal Wkly Rep 2006; 55: Resistance to all first-line anti-tb drugs Resistance to second-line anti-tb drugs cohort of 15 patients in Iran was reported which were resistant to all anti-tb drugs tested Velayati AA et al, Chest 2009; 136: 420-5)

35 Major Problems in Treatment OF TB MDR-TB Paradoxical expansion of TB lesions (brain) Chronic Liver Disease Raised ALT Raised bilirubin Chronic Renal Disease Mild renal impairment ESRD

36 Group Anti-TB Drugs Group 1: First line Oral agents Anti-TB Drugs Isoniazid, Rifampicin, Pyrazinamide, ethambutol, Rifabutin, Rifapentin Group 2: Injectable agents Kanamycin, Amikacin, Capreomycin, Streptomycin Group 3: Fluoroquinolones Levofloxacin, Moxifloxacin, Ofloxacin Group 4: Oral Bacteriostatic Second Line Agents Group 5: Agents with an unclear role in the Rx of drug resistant TB Para aminosalicylic acid, Cycloserine, Terizidone, Ethionamide, Prothionamide, viomycin Clofazimine, Linezolid, Amoxicillin/clavulanate, Thioacetazone, Imipenem/cilastatin, high dose Isoniazid, Clarithromycin

37 CLINICAL TRIALS OF RECOMMENDED CHEMOTHERAPY REGIMENS 9 MONTHS DURATION REGIMENS Study Regimen PATIENTS ASSESSED Comp. N Failures N (%) Relapses N (%) 1 st BTA S(E)HR/7HR ND BTA EHR/7HR (1.5) 1 ST French EHR/7HR (2.4) 2 nd French E(S)HR/6HR (3.8) Arkansas HR/8H 2 R (2.8) 15 (2.1) San Francisco 88 2HRE/7HR (1.5) 4 (2)

38 CLINICAL TRIALS OF RECOMMENDED CHEMOTHERAPY REGIMENS FOR TUBERCULOSIS 6 MONTHS DURATION REGIMENS PATIENTS ASSESSED Study Regimen Comp. N Failures N (%) Relapses N (%) East Africa BMRC 2HRSZ/4HR (Z) (1.3) 1983 Singapore BMRC 2(H)HR(S)Z/HR (.3) 3 (1) 1985 Singapore BMRC 2HRSZ/4HR(Z) (1.9) nd BTA HRS(E)Z/4HR (1.6) Poland HRSZ/4HR Algeria EHRZ/2HR (3) Hongkong/BMRC 6HRZ(S) (E) (1.4) 1987 Germany HRSZ 95 2 (2.1) 0

39 BACTERIOLOGIC RELAPSE RATES IN SMEAR-POSITIVE & CULTURE POSITIVE DISEASE: HIGHLY EFFECTIVE SIX-MONTH REGIMENS WITH ISONIAZID & RIFAMPIN Study Regimen mo Follow-up mo Patients Assessed US Public Health Service study 20 Second East African-BMRC study East African- BMRC study Singapore- BMRC study Second BTA study Bacteriologic Relapses (%) HR (9) HR (7) 2 SHR/HRZ 2SHRZ/HR 2 SHRZ/HRZ 2 SHRZ/HR (2) (2) (2) 2 SHRZ/HR (1)

40 USPHS TUBERCULOSIS SHORT COURSE (1990) THERAPY TRIAL 21, RANDOMIZED, MULTI-CNTRE TRIAL Myco. tuberculosis, positive sputum culture All susceptible 617 pts. HRZ (2) / HR (4) 445 pts. HR (9) 6 months 9 months Sputum conversion (16 wks) 95% 90% Non-compliance Relapse (22 months) Completed therapy 61 51

41 TREATMENT ALTERNATIVES WITH SUSPECTED INITIAL DRUG RESISTANCE Beginning Regimens Continuing Regimens INH ( R ) OR INH ( R ) and SM (R) SM ( R ) (1) HRE (2) RE (10) HR (7) (2) HRZS (2) RE (10) HR (7) (3) HRZE (2) RE (10) HR (7)

42 SHORT COURSE FOR EXTRAPULMONARY TUBERCULOSIS 350 pts 402 sites Pleural (119), Disseminated (51), GU (51) Lymphatic (56), Bone/joints (26), Vertebral (21) Abdominal (21), Meningeal (18), Pericardial (12) Laryngeal (13), Misc (14) HR (1) daily/ HR (8) TW H (300mg), R (600mg) H (900mg), R (600mg) Mortality 5/297 = 1.7% Treatment failure 6/297 = 2.0% Late relapse 2/297 = 0.7% Ann Int. Med 1986 ASIM DUTT

43 Four-Month Moxifloxacin or Gatifloxacin Based Regimens for Drug-Sensitive TB Gillespie S et al, NEJM 2014 Merle CS et al, NEJM 2014 Fouad M, Ann Pharmacother 2011 Conde MB et al, Lancet 2009 Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown

44 THE IMPACT OF DOT ON EPIDEMIOLOGY The WHO-recommended Stop TB Strategy provides the framework for treating and caring for those who are sick and controlling the epidemic of drugsusceptible and drug-resistant disease The DOTS approach, which underpins the Stop TB Strategy, calls for political commitment to national programs designed to control disease by means of early diagnosis with the use of bacteriologic testing, standardized treatment with supervision and patient support, and provision and management of the drugs used in treatment

45 Where might new anti-tb drugs come from Repurposing of existing drugs used for other infections: Fluoroquinolnes, linezolid, clofazimine Improved use of existing TB drugs: Rifamycins Development of new chemical entities: Bedaquiline (TMC207) (Diaryquinoline) Delamanid (OPC67683) and Petomanid (Nitroimidazole) Sutezolid and AZD5847 (Oxazolidinone) SQ109 (Ethylene diamine)

46 FDA NEWS RELEASE For Immediate Release: Dec. 31, 2012 Media Inquiries: Sandy Walsh, , Consumer Inquiries: 888-INFO-FDA On Dec. 28, the U.S. Food and Drug Administration approved Sirturo (bedaquiline) as part of combination therapy to treat adults with multi-drug resistant pulmonary tuberculosis (TB) when other alternatives are not available.

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48 BEDAQUILINE Bedaquiline fumarate is an oral diarylquinoline; it was approved by the United States Food and Drug Administration (FDA) in 2012 for treatment of multidrugresistant tuberculosis (MDR-TB) Provisional Centers for Disease Control and Prevention (CDC) guidelines have been issued for both approved and unapproved uses The World Health Organization (WHO) has also published recommendations on the use of bedaquiline

49 BEDAQUILINE Toxicity The FDA issued a black box warning to alert healthcare practitioners regarding an increased rate of death due to QT prolongation has been observed among patients treated with bedaquiline compared with patients treated with placebo (11.4 percent versus 2.5 percent, respectively). Bedaquiline may also result in increases in liver function tests

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51 Delamanid (OPC-67683) Delamanid (OPC-67683), a new agent derived from the nitro-dihydroimidazooxazole class of compounds Inhibits mycolic acid synthesis, Has shown potent in vitro and in vivo activity Against both drug-susceptible and drug-resistant Administered at doses of 200 and 300 mg daily resulted in a decrease in the sputum M. tuberculosis burden that was similar to that of the potent antituberculosis drug rifampicin in previous studies of early bactericidal activity

52 TB Recurrences: Relapse vs Reinfection In a population based study in northern Malawi, tuberculosis patients diagnosed from were actively followed after the end of treatment Whole genome sequencing with approximately 100X coverage was carried out on all available cultures IS6110 Restriction Fragment Length Polymorphism (RFLP) was available on cultures up to 2008 a single nucleotide polymorphism (SNP) difference of: 10 SNPs was used to define relapse >100 SNPs for reinfection Guerra Assunção1 JA et al, J Infect Dis 2014

53 TB Recurrences: Relapse vs Reinfection Of 1471 patients 139 had laboratory-confirmed recurrences: 55 had relapse 20 had reinfection 64 type of recurrence was unclassified Almost all relapses occurred in the first 2 years HIV infection was associated with reinfection but not relapse Relapses were associated with: Isoniazid resistance Treatment before 2007 Lineage-3 strains Guerra Assunção1 JA et al, J Infect Dis 2014

54 TB Vaccine - BCG The protection conferred by the BCG vaccine is significantly greater when the vaccine is administered to neonates or school children and for miliary or meningeal TB Protection against pulmonary TB, which accounts for the majority of TB mortality and morbidity worldwide, is age dependent In children,protection against pulmonary TB can reach up to 80% [5]; however, only 50% of adults are protected, and some studies have reported no real preventive effects Previous exposure to environmental mycobacteria appears to be an important limiting factor for the BCG vaccine Subjects with latent TB infection are less protected and the vaccine efficacy has been shown N. Principi; Tuberculosis 2014 (in press)

55 N. Principi; Tuberculosis 2014 (in press)

56 TB Infection Control Negative pressure room Wear N95 mask Hand Hygiene Limit patient movement (put mask if patient moved to radiology, surgery, etc ) Investigate family contacts and close contacts No need for special hospital or sanatorium

57 WHO Ambitious Target Reducing TB incidence to 10 per 10 5 by year 2035 Aim at eliminating TB as a public health problem by 2050 (reducing TB incidence to 1 per 10 5 )

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