Tuberculosis_Pathology,_Diagnosis_and_Treatment-Slides.pdf

Tuberculosis: Pathogen, Pathology & Treatment Dr Wilber Sabiiti (ws31) MD3001, 15th Nov 2023 Learning Outcomes • Appreciate the global burden of tuberculosis as a major Public Health problem • Understand how Mycobacterium tuberculosis causes infection and disease • Consider the strengths and limit...

Tuberculosis: Pathogen, Pathology & Treatment Dr Wilber Sabiiti (ws31) MD3001, 15th Nov 2023 Learning Outcomes • Appreciate the global burden of tuberculosis as a major Public Health problem • Understand how Mycobacterium tuberculosis causes infection and disease • Consider the strengths and limitations of current diagnostic methods for tuberculosis • Describe current approaches to treatment of tuberculosis • Describe the mechanism of action of different anti-TB drugs The cause tuberculosis (TB) Mycobacterium tuberculosis Tuberculosis & me A disease of the past? , TB.deaths.per.100,000 1000 London Stockholm Hamburg 800 Discovery.of. MTB 600 Discovery.of. BCG Discovery.of. Streptomycin 400 200 0 1750 1800 1850 1900 1950 Year Grigg%ERN.%Am%Rev%Tuberc%Pulm%Dis%1958:78:151=72%(%c/o%Hans%Rieder) However… World Health Organisation (WHO) produced annual report per reflecting the state of TB in the previous year. State of the epidemic 2016 WHO Global TB Report 2017 State of the epidemic 2018 WHO Global TB Report 2019 State of the epidemic 2019 Estimated TB incidence, 2019 WHO Global TB Report 2020 State of the epidemic 2019 Countries with incidence of 100000 and above in 2019 WHO Global TB Report 2020 State of the epidemic 2020 Estimated TB incidence, 2020 WHO Global TB Report 2021 State of the epidemic 2020 Countries with incidence of 100000 and above in 2020 WHO Global TB Report 2021 State of the epidemic 2021 Estimated TB incidence, 2021 WHO Global TB Report 2022 State of the epidemic 2021 Countries with incidence of 100000 and above in 2021 WHO Global TB Report 2022 State of the epidemic 2021 Percentage of the new cases diagnosed by WHO approved rapid test in 2021 WHO Global TB Report 2022 Target to end TB by 2035 WHO Global TB Report 2019 How were the 2020 targets achieved? • Most were unmet WHO Global TB Report 2021 Impact of COVID-19 on Global TB control • Increased stigma to TB symptoms such as cough • Resources diverted and focused on managing COVID-19 • Reduced access to diagnosis and treatment services • Reduction in TB notifications to as low as 40% in some countries • Loss of employment and livelihoods aggravating poverty, a major risk for TB • Shrinking global economy putting a strain on the money available for TB response • Excess deaths which would otherwise be prevented. WHO Global TB Report 2020 Impact of COVID-19 on Global TB control Sharp drop in TB case notifications in 2020 WHO Global TB Report 2021 Why have we failed? 1. Poverty 2. Health systems p<2e-16 R2=0.549 9 3. HIV Someone dies from TB every twenty seconds Mycobacterium tuberculosis Form a clotting factor as the cells stayed joined together • “Fungus-like bacterium” • Waxy (mycolic acid rich) cell wall • Gram positive • Acid-Fast • Slow generation time (~17h) • Complex metabolic responses in latent/persistent state Cluster (clump) of mycobacterial cells Cell wall Cell membrane id p li r la ll u ce a tr n I es i d o b ©Dr Wilber Sabiiti Pathogenesis of tuberculosis Transmission Primary Infection Latent Infection HIV TNFα IFNγ Vitamin D Immune immaturity/ senescence Active Disease Transmission 108 organisms/ mL sputum Droplet nuclei < 5µm Each with ~ 6 bacilli Deposited at alveolar level (not cleared by muco-ciliary action in larger airways) 100 million baccilli needed to cause infection Factors influencing infection Clinical Tuberculosis 2nd Edition. Edited by Crofton, Home and Miller Timetable of tuberculosis primary infection re-infection infection DEATH BIRTH non- infectious primary disease Infectious – especially if smear positive Secondary disease due to endogenous re-activation Secondary disease due to exogenous re-infection Slide c/o Prof Bertie Squire, Liverpool School of Tropical Medicine Diagnosing tuberculosis infection Tuberculin Skin Test (TST) Someone if injected with some TB antigen and expects ten to mount an antibody process Interferon Gamma Release Assays (IGRA) If there is a strong response of interforn gamma most likely to be infected Pulmonary Tuberculosis (PTB) disease • 85% of clinical TB cases are PTB • “Sputum smear positive” PTB patients are believed to cause the majority of community transmission • Typical symptoms include • Cough of ≥ 2-3 weeks, not responding to antibiotics • Sputum production (± haemoptysis) • Fever • Night sweats • Weight loss Sputum smear microscopy Yellow rods show baccilli Sputum culture • Solid vs Liquid • Additional 20-30% diagnostic yield • Susceptibility testing • Expensive • Slow • Biohazard! Molecular Tests - “GeneXpert” Learn this Boehme et al NEJM 2010 363(11): 1005-15 Molecular Tests - “Tuberculosis Molecular Bacterial Load Assay – TB-MBLA)” Research Use Only at this stage Sabiiti et al 2019 EASci TB-MBLA – Treatment response monitoring Research Use Only at this stage Sabiiti et al 2019 EASci X-ray appearances: Primary TB Small (often calcified) focus of pulmonary infection Ghon complex Associated lymphadenopathy Miiary TB X-ray appearances: Secondary TB Cavitation: Almost always secondary disease Miliary TB: Can be primary or post-primary disease Extra-pulmonary Tuberculosis Treatment of Tuberculosis Streptomycin Resistance Mitchison Thorax 1950 5: 144-61 Current first-line anti-TB drugs: Rifampicin • • • • • Highly bactericidal vs. rapidly replicating & non-replicating bacteria Is crucial to “short course” chemotherapy Action: Inhibits bacterial DNA-dependent RNA polymerase Current single daily oral dose (10mg/kg) may be too low Toxicity includes • Hepatitis • Itch, rash, GI upset • Discolouration of urine, tears, sweat, • Induces liver enzymes (CYP450) increasing clearance of other drugs • Warfarin, OCP, Anti-retroviral therapy interactions Current first-line anti-TB drugs: Isoniazid • • • • • Highly bactericidal vs. rapidly replicating bacteria Is a pro-drug, activated by KatG enzyme Action: Inhibits mycolic acid biosynthesis in cell wall (amongst others) Easily tolerated orally in single daily dose (5mg/kg) Toxicity includes • Hepatitis • Peripheral neuropathy – minimized by using pyridoxine (vitamin B6) • Resistance – overall 10%, varies by population Current first-line anti-TB drugs: Pyrazinamide • Bacteriostatic, but bactericidal at acid pH (e.g. inside cells) • Action: Exact mechanism unknown • Inhibits fatty acid synthetase I • In combination therapy accelerates sterilizing effect of isoniazid and • rifampicin allowing 6 month treatment • Once daily dose (15-35 mg/kg/day) • Toxicity includes • Hepatitis • Hyperuricemia (lab test); can exacerbate gout Current first-line anti-TB drugs: Ethambutol • Bacteriostatic • Action: Poorly understood • Inhibits arabinosyn transferase • Single daily dose (15mg/kg) • Usually well tolerated • Toxicity • Optic neuritis (uncommon at < 15 mg/kg) • Mainly added to regimen to help prevent resistance to other drugs Intensive phase Current First Line TB treatment Hepatotoxicity Drug interactions 2 months Rifampicin (R) Isoniazid (H) Pyrazinamide (Z) Ethambutol (E) o Steroids (inc. OCP) o Opiates (inc. methadone) Hepatotoxicity Peripheral neuropathy Hepatotoxicity Joint pain (↑ urate) Continuation phase Ocular toxicity 4 months Rifampicin (R) Isoniazid (H) Could we shorten to less than 6 months? Less than 6 months? 4th East African Collaborative Study 4th East African Collaborative Study Bacterial subpopulations hypothesis Recent clinical trials in tuberculosis REMoxTB Trial (Gillespie et al) All three major trials published on 2014 All attempted to use 8-methoxyfluoroquinolones to reduce treatment duration All failed because of high rates of post-treatment relapse in experimental arms How does antibiotic resistance develop? Naturally occurring M tuberculosis mutations • 1:107 cells with INH resistance Resistant organisms selected by • 1:109 cells RIF resistance antibiotic therapy RESISTANCE TO ISONIAZID USUALLY PRECEDES RESISTANCE TO RIFAMPICIN katG mutations account for 50-90% of ISONIAZID RESISTANT TB strains inhA mutations account for ~31% of ISONIAZID RESISTANT TB strains rpoB mutations account for 96% of RIFAMPICIN RESISTANT TB strains Growing burden of drug-resistant TB MDR-TB: Resistant to RIFAMPICIN & ISONIAZID 250,000 new cases in 2009 480,000 new cases in 2015 Pre-XDR-TB: Additional second line drug resistance to: any INJECTABLE SECOND LINE DRUG or FLUOROQUINOLONE XDR-TB: Additional second line drug resistance to: INJECTABLE & FLUOROQUINOLONE Cases notified in ~100 countries ~10% of MDR-TB may be XDR Global distribution of MDR-TB 30 high burden countries defined in 2015 http://www.who.int/tb/publications/global_report/high_tb_burdencountrylists2016-2020.pdf 45% of global total of MDR-TB cases originate in India, China & Russian Federation Highest incidence per 100,000 in Eastern Europe & Central Asia UK MDR-TB data • ~50-90 per year • 1.6% of total TB cases • ~90% acquired overseas Current principles of MDR-TB Follow international guidelines and take advice from those experienced in MDR-TB management http://forums.brit-thoracic.org.uk http://www.tbdrugmonographs.co.uk Challenges of MDR-TB Treatment duration in months 0 2 6 8 20 First-line treatment for ”drug sensitive” TB Intensive phase 4 drugs All oral Continuation phase 2 drugs All oral Regimen is standardised internationally Strong clinical trial evidence Moderate toxicity Second-line treatment for ”multi-drug resistant” TB Intensive phase At least 5 drugs (May include injectable) Continuation phase At least 4 drugs All oral Second line-drugs are: • Less effective – patients are infectious for longer, and cured more slowly • More toxic – patients have more side-effects and may require several regimen changes during therapy • Not well studied - the best doses and combinations are incompletely understood Could we give something shorter? ‘4-month treatment regimen for DS-TB’ In 2022 WHO recommended a new shorter all oral regimen for treatment of drug susceptible TB (DS-TB) 4 months *Rifapentine Isoniazid Pyrazinamide *Moxifloxacin *Rifampetine replaces Rifampicin while Moxifloxacin replaces Ethanmbtol in the old standard-ofcare regimen. Highlights • TBTC study • Tolerable as the Standard of care • Rifapentine not readily available in Europe, Asia and Africa OptiRimox study (trialing rifampicin instead of rifapentine). • High dose Rifampicin • Moxifloxacin • Gabon • Malawi • Tanzania • Mozambique https://iris.who.int/bitstream/handle/10665/341729/9789240028678-eng.pdf?sequence=1 Could we give something shorter? ‘The Bangladesh Regimen’ Serial adapted multi-drug MDR-TB regimens from 1997-2004 Final regimen reported 89% relapse-free cure1 4 months (intensive phase)*: Kanamycin (500-1000mg) Prothionamide (500-1000mg) High dose isoniazid (400-600mg) Gatifloxacin (400-800mg) Clofazimine (50-100mg) Pyrazinamide (800-2000mg) Ethambutol (800-1200mg) 5 months (continuation phase): Gatifloxacin (400-800mg) Clofazimine (50-100mg) Pyrazinamide (800-2000mg) Ethambutol (800-1200mg) *Intensive phase extended until sputum smear conversion if not smear negative at 4 months Highlights • Use of clofazimine & high dose 4th generation fluoroquinolone • Follow-up under routine conditions • Low cost - €200 (US$218) per patient Additional data from • Uzbekistan • Swaziland • Cameroon • Niger • Other subSaharan African countries Van Deun et al AJRCCM 2010, 182: 684-92 Current status of 9-12 month MDR-TB Regimen Data: Resistance pattern Treatment success, n/N (%) All cases 108/1116 (90.3%) Fluoroquinolone resistant 31/43 (72%) Provisional Recommendation: In patients… who have not been previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9-12 months may be used instead of a conventional regimen (conditional recommendation, very low certainty in the evidence) STREAM Trial, Phase I: • • • • ‘WHO-standard’ MDR-TB therapy vs. ’Bangladesh-style’ regimen Gatifloxacin replaced by moxifloxacin in ‘trial’ regimen Completed in Ethiopia, Mongolia, South Africa, Viet Nam Final Results: Show non-inferiority to the conventional regimen New drugs Ongoing studies with the new drugs: Nix-TB Data from first 61 patients All in South Africa (reported Feb 2017) 49% HIV-infected 79% with XDR-TB 21% MDR-TB 6 month regimen: Bedaquiline Linezolid (1200mg od) Pretomanid Learning Outcomes • Appreciate the global burden of tuberculosis as a major Public Health problem • Understand how Mycobacterium tuberculosis causes infection and disease • Consider the strengths and limitations of current diagnostic methods for tuberculosis • Describe current approaches to treatment of tuberculosis