Drug Resistant (DR) TB (Back to Basics) 9th International TB and HIV Management course Nesri Padayatchi MBChB PhD Deputy Director CAPRISA Presented on 5th August 2016 at University of Pretoria

OUTLINE Terminology Grouping of Drugs Epidemiology Management

Definitions Type of TB Definition Treatment Drug Sensitive MTB sensitive to Group 1 drugs RHZE- 2 M RH - 4 M RR TB MTB Resistant to Rifampicin +/ - resistance to other TB medicines MDR Treatment + INH INH Mono-resistant Resistance to INH only RHZE for 6-9 month MDR TB MTB Resistant to Rif & INH, with/without resistance to other 1st line anti-TB drugs MDR TB Treatment XDR TB Extensive Drug Resistant TB MTB Resistant to Rifampicin, INH, the Fluoroquinolones AND to at least one 2nd line Injectable drugs (CM,KM,AM) Treatment +/ - INH + New drugs

Definitions Type of TB Definition Treatment R H Z E Drug Sensitive MTB sensitive to standard TB drugs R H Z E

Definitions Type of TB Definition Treatment R H Z E Drug Sensitive MTB sensitive to standard TB drugs R H Z E INH Mono-resistant Resistance to INH only

Definitions Type of TB Definition Treatment R H Z E Drug Sensitive MTB sensitive to standard TB drugs R H Z E INH Mono-resistant Resistance to INH only RR TB MTB Resistant to Rifampicin +/ - resistance to other TB medicines R H Z E (treat as MDRTB) The prevalence of PZA resistance is strongly correlated with resistance to rifampicin and increases with additional resistance in MDR and XDR-TB strains. The presence of rifampicin-resistance could then be considered as an indicator to perform DST to PZA. Consideration should also be given when defining the role of PZA in future TB treatment regimens.

Definitions Type of TB Definition Treatment R H Z E Drug Sensitive MTB sensitive to standard TB drugs R H Z E INH Mono-resistant Resistance to INH only RR TB MTB Resistant to Rifampicin +/ - resistance to other TB medicines R H Z E (treat as MDRTB) MDR-TB MTB Resistant to Rifampicin & INH, with/without resistance to other first line anti-TB drugs Quinolone Injectable, other Core drugs

Definitions Type of TB Definition Treatment R H Z E Drug Sensitive MTB sensitive to standard TB drugs R H Z E INH Mono-resistant Resistance to INH only RR TB MTB Resistant to Rifampicin +/ - resistance to other TB medicines R H Z E (treat as MDRTB) MDR-TB MTB Resistant to Rifampicin & INH, with/without resistance to other first line anti-TB drugs Quinolone Injectable, other Core drugs XDR TB Extensive Drug Resistant MTB Resistant to Rifampicin, INH, the Quinolones AND at least one 2nd line Injectable drugs Individualised regimen

Definitions Type of TB Definition Treatment R H Z E Drug Sensitive MTB sensitive to standard TB drugs R H Z E INH Mono-resistant Resistance to INH only RR TB MTB Resistant to Rifampicin +/ - resistance to other TB medicines R H Z E (treat as MDRTB) MDR-TB MTB Resistant to Rifampicin & INH, with/without resistance to other first line anti-TB drugs Quinolone Injectable, other Core drugs XDR TB Extensive Drug Resistant MTB Resistant to Rifampicin, INH, the Quinolones AND at least one 2nd line Injectable drugs Individualised regimen Pre-XDR TB MTB Resistant to Rifampicin, INH, the Quinolones OR at least one 2nd line Injectable drug

Source: WHO Global Tuberculosis Report 2014

Resistance in previously treated (acquired drug resistance) is the result of Inadequate Incomplete poor treatment quality that allows the selection of mutant resistant strains

Global MDR-TB Epidemiology In 2013, more than 50% of New cases of MDR-TB were among people never before treated for TB, highlighting the importance of Transmission and the lack of appropriate Infection Control Measures, particularly at Community level WHO. Drug-Resistant TB. Supplement Global TB Report 2014

23 studies met the inclusion criteria. Median estimates of delay: patient: 18.4 days diagnostic: 31.0 days treatment: 2.5 days Median total delay: 55.3 days 48% of all patients first consulted private providers; an average of 2.7 health care providers were consulted before diagnosis

Even for countries with unlimited resources, the time to generate a MDR-TB case is less than the time required to cure it

TB Diagnostic Testing Gene Xpert Line Probe Assay (LPA) HAIN Test Screens for MTB and Rif resistance Done directly on sputum- more sensitive than smear with higher yield Point of care test - Result in hours Line Probe Assay (LPA) HAIN Test Tests for Rif & INH resistance Results in days Line Probe Assay (LPA) SL second line Tests for Kana/Amik & Moxi

Back to basics Early bactericidal activity (EBA) The ability of a drug to kill tubercle bacilli in the first few days of treatment e.g INH Sterilizing activity The ability to remove so-called persisters –these are bacilli that have low metabolic activity and replicate slowly Prevention of resistance to the companion drug The ability of a drug to prevent selection of mutants resistant to the companion drug

Drugs recommended for RR, M(X)DRTB Group Name Drugs A Fluoroquinolones (Core drugs) Levofloxacin/ Moxifloxacin B Second-line Injectable Drugs Amikacin/ Capreomycin/ Kanamycin C Other core 2nd-line agents Ethionamide / Terizidone/ Cycloserine Linezolid / Clofazamine D Add-on-agents (Not part of the core MDRTB Regimen) D1 Pyrazinamide (Z) / Ethambutol (E) High Dose Isoniazid (H) D2 Bedaquiline / Delamanid D3 Para-Aminosalicylic Acid (PAS) Imipenem- cilastatin Meropenem / Augmentin Carbapenems and amoxicillin –clavulanate must be used together WHO treatment guidelines for MDR-TB 2016 update

Definitions Type of TB Definition Treatment R H Z E 2 mo RH 4 mo Drug Sensitive MTB sensitive to standard TB drugs R H Z E 2 mo RH 4 mo INH Mono-resistant Resistance to INH only R H Z E 6-9 mo

Treatment of INH mono resistance Continue RHZE for 6-9 months based on symptom response Minimum of 6 months after culture conversion Could omit INH (H) but easier to use FDC’s If poor response, consult MDR TB specialist unit

Definitions Type of TB Definition Treatment R H Z E Drug Sensitive MTB sensitive to standard TB drugs R H Z E INH Mono-resistant Resistance to INH only Rif Mono-resistance RR TB MTB Resistant to Rifampicin +/ - resistance to other TB medicines R H Z E (treat as MDRTB) The prevalence of PZA resistance is strongly correlated with resistance to rifampicin and increases with additional resistance in MDR and XDR-TB strains. The presence of rifampicin-resistance could then be considered as an indicator to perform DST to PZA. Consideration should also be given when defining the role of PZA in future TB treatment regimens.

MDR-TB and RR-TB detected, compared with cases enrolled on MDR-TB treatment, 2009-2012 Falzon et al

Definitions Type of TB Definition Treatment R H Z E Drug Sensitive MTB sensitive to standard TB drugs R H Z E INH Mono-resistant Resistance to INH only RR TB MTB Resistant to Rifampicin +/ - resistance to other TB medicines R H Z E (treat as MDRTB) MDR-TB MTB Resistant to Rifampicin & INH, with/without resistance to other first line anti-TB drugs Quinolone Injectable, other Core drugs

Case study A 41 year old female was referred to the clinic in November 2015 with a positive Xpert MTB/RIF result She complained of cough, loss of weight and night sweats. On examination, she was ambulant, wasted, but not distressed; with bilateral basal crackles. CXR showed bilateral disease She was cured of Drug Sensitive TB in 2001 In Feb 2012 she was diagnosed with HIV and started on Atroiza. Her baseline CD4 was 85c/ml

Symptoms of DR- TB Same symptoms as Drug Sensitive TB Diagnosis of DR TB is microbiological Persistent cough Chest pain Dyspnoea Haemoptysis LOA / LOW Night sweats and chills Fever Tiredness/malaise

37 studies were included. Inappropriate treatment regimens were prescribed in 67% of studies. The percentage of patients receiving inappropriate regimens varied between 0.4% and 100%. In 19 studies the quality of treatment regimen reporting was low

Principles of treatment of MDR-TB Minimum of 4 effective drugs 2 core drugs (Fluoroquinolones and Injectables) 2 supporting drugs Use Injectable agents for a minimum of 6 months (ideally 4 months after culture conversion) Don’t rely on drugs to which: Resistance is suspected or To which the patient has been previously exposed Include 1st line drugs the infecting strain is susceptible to (but do not count them if patient has been previously exposed)

Standard MDR treatment Intensive phase (KMETZI) Kanamycin or Amikacin (6 months) Moxifloxacin Ethionamide Terizidone PZA May add INH if no katG mutation Continuation Phase (min 18 months) Moxifloxacin / Ethionamide / Terizidone / PZA (+/- INH)

Interpreting LPA Results Mutation Confers resistance to Able to use InhA INH- Low level Ethionamide High Dose INH KatG High dose INH Ethionamide InhA and KatG PAS

In the Western Cape and Eastern Cape Provinces, the percentage of isolates exhibiting inhA promoter mutations increased significantly from respectively 48.4% and 62.4% in MDR-TB isolates to 85.5% and 91.9% in XDR isolates. Data from the Western Cape revealed that significantly more XDR-TB isolates showed mutations in the inhA promoter than in katG (85.5% vs. 60.9%, P < 0.01), while the respective proportions were equal for INH-resistant non-MDR-TB isolates (~30%). inhA promoter mutations are strongly associated with XDR-TB in South Africa

10 Commandments of managing MDR TB If a person infected with a strain, initially resistant to a specific medicine is treated with that medicine plus a new additional medicine, then there is a risk of developing resistance to the additional medicine Step-wise additions of drugs may eventually lead to more severe patterns of drug resistance and

10 Commandments of managing MDR TB

10 Commandments of managing MDR TB DO NOT ADD A SINGLE DRUG TO A FAILING REGIMEN

10 Commandments of managing MDR TB DO NOT ADD A SINGLE DRUG TO A FAILING REGIMEN Commandment 2-10:

10 Commandments of managing MDR TB DO NOT ADD A SINGLE DRUG TO A FAILING REGIMEN Commandment 2-10:

10 Commandments of managing MDR TB DO NOT ADD A SINGLE DRUG TO A FAILING REGIMEN Commandment 2-10: Step-wise additions of drugs may eventually lead to more severe patterns of drug resistance

One final remark, even considering the clear evidence that the prognosis of TB patients worsens when the pattern of resistance increases, it should never be accepted that a TB case is incurable. All TB patients, even those with XDR-TB or beyond XDR-TB, should always have a chance to be treated using the available clinical and programmatic management strategies.

The first priority to fight against MDR/XDR-TB is to strengthen the NTP with good management of susceptible TB cases

Assuming adherence to national DR-TB management guidelines, the per patient cost of XDR-TB was $26,392, four times greater than MDR-TB ($6772), and 103 times greater than drug-sensitive TB ($257). Despite DR-TB comprising only 2.2% of the case burden, it consumed, 32% of the total estimated 2011 national TB budget of US $218 million. 45% and 25% of the DR-TB costs were attributed to anti-TB drugs and hospitalization, respectively. A decentralized XDR-TB treatment programme could potentially reduce costs by $6930 (26%) per case and reduce the total amount spent on DR-TB by ,7%.

Conclusion MDR/XDR-TB is a global threat With adequate clinical and operational management, all TB cases have a chance to be cured, even those with very extensive pattern of resistance The first priority to fight against MDR/XDR-TB is to strengthen the NTP with good management of susceptible TB cases However, it is necessary to increase the rate of detection and cure of all DR-TB

Acknowledgments DR-TB Guidelines Doctors and staff of KDHC Dr Jose Caminero