Tuberculosis Management 2016

Department of Pharmacology

SVMC, Tirupati.

• TB Burden in India• Incidence of MDR & XDR TB • Anti TB drugs• TB Management• OLD vs New regimens• Mono/Poly-drug Resistant TB Mx• MDR TB Mx• XDR TB Mx

• Bedaquiline• Weight bands – What? How? Why?• Paediatric TB management• Mx of other special conditions• The End TB Strategy• References...

TB Burden in India• Annually, 1/4th of Global TB Incidence.• WHO Global TB report – 2.2 million cases.

• 58% reduction in TB mortality rate; 55% reduction in TB prevalence rate by 2014 as compared to 1990 level

• The TB incidence is on declining trend.

Incidence of MDR & XDR-TB• Over 480 000 cases of multidrug-resistant (MDR) tuberculosis (TB)

occur every year globally

• 9% of them being affected by extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. 

• In India (2014), an estimated 2.2% of new cases (95% CI: 1.9–2.6%) and 15% of previously treated cases (95%CI: 11–19%) have MDR-TB.

More than half of the global burden of MDR-TB is in three countries

• India• China• Russia

In 2013, the average proportion of MDR-TB cases with XDR-TB was 9.0%.

MDR-TB & HIV+TB Incidence

TB burden Percentage Number (millions)

MDR-TB in Notified PTB 0.071

MDR-TB in New Notified PTB 2.2% 0.024

MDR-TB in Re-Rx PTB 15% 0.047

HIV in Incident TB cases 5%

Anti TB Drugs

New Anti TB drugs• Bedaquiline• Delamanid• Pretomanid• NC-002, NC-003• Sutezolid• SQ 109• Benzothiazinones

Repurposed Anti TB drugs• Linezolid• Clofazamine• Imipenem/ Meropenem• Amoxicillin – Clavulanate• Thioacetazone• Clarithromycin

TB Management

CasesMicrobiologically

confirmed TB CaseClinically diagnosed

TB case

Anatomical site TB Rx History Drug resistance

Pulmonary TB

Extra Pulmonary TB

New case

Previously treated

Transferred in

MR

PDR

MDR

XDR

RR

Recurrent Rx after Failure

Rx after loss to follow up

Others

Miliary TB

Old vs New (2016) Regimens

Rx of Drug sensitive TB:Till 2015 2016

Thrice weekly regimen Once daily for all Paediatric & PLHIV cases – 104 districts

Individual drug doses based on 3 weight bands for MDR TB Rx

FDCs based on weight bands (4 in adult, & in child) for TB Rx

Continuation of IP for 1 month if sputum positive

IP need not be continued

CP is with HR CP includes Ethambutol (HRE)For EP Tb cases, CP is for 7 mo For EP TB cases, CP is extended for

12-24 wks (3-6mo)

For TBM cases Inj SM added in IP No change in IP

104 districts in 5 states• Maharashtra• Bihar• Kerala • Sikkim • Himachal Pradesh

Mono/Poly-drug Resistant TB Mx• IP can be extended for maximum 3mo.

RR/MDR TB MxDrugs given are -• Kanamycin• Levofloxacin• Ethionamide• Pyrazinamide• Ethambutol• Cycloserine

• For MDR TB cases, IP can be extended for 3mo maximum

• For all MDR TB cases with additional resistance, IP can be extended for maximum 6mo.

In case of additional resistance,• Resistance to E – Omit E• Resistance to P – Omit P• Res to P&E – Add PAS in IP & CP• Res to Lfx/Mfx – use PAS + the sensitive one among them• Res to Lfx&Mfx – Clfz, Lz, PAS in IP&CP(6-12mo)• Res to any SLI – use the sensitive one• Res to all SLI - Clfz, Lz, PAS in IP&CP(6-12mo)

Cure: Completed treatment but consistently culture -ve (with at least 5 consecutive negative results in the last 12 to 15 months). If one follow-up +ve culture is reported during the last three quarters, patient will still be considered cured provided this positive culture is followed by at least 3 consecutive negative cultures, taken at least 30 days apart, provided that there is clinical evidence of improvement.

Treatment completed: A patient who has completed treatment according to guidelines but does not meet the definition for cure or treatment failure due to lack of bacteriological results.

Treatment failure: If >2 of 5 cultures recorded in the final 12-15 months are +ve, or if any of the final three cultures are +ve.

Treatment default: A patient whose treatment was interrupted for 2 or >2 consecutive months for any reasons.

XDR TB MxDrugs given are – • Capreomycin• Moxifloxacin• Linezolid• PAS• Clofazamine• Amoxi/Clav• High Dose INH

Management Guidelines for Patie nts with Documentedor Strongly Suspecte d Extensively Drug-Resista ntTuberculo sis (XDR-TB)1. Use pyrazinamide and any first-line oral agents that may be

effective.2. Use an injectable agent to which the strain is susceptible, and

consideran extended duration of use (12 months or possibly the whole

treatmentperiod). If the strain is resistant to all injectable agents, use of onethat the patient has not previously received is recommended.a3. Use a later-generation fluoroquinolone, such as moxifloxacin,

high-doselevofloxacin, or possibly gatifloxacin.b4. Use all second-line oral bacteriostatic agents (para-aminosalicylic

acid,cycloserine, and ethionamide or prothionamide) that have not beenused extensively in a previous regimen or any such agents that are

likelyto be effective.

5. Add bedaquiline or delamanid and one or more of the following drugsc:

clofazimine, linezolid, amoxicillin/clavulanic acid, clarithromycin, and carbapenems

such as imipenem/cilastatin and meropenem.6. The simultaneous use of bedaquiline and delamanid is not

recommendedat the moment in view of the current lack of information on the

potentialof adverse reactions when these drugs are administered together.7. Consider treatment with high-dose isoniazid if low-level

resistance to thisdrug is documented.8. Consider adjuvant surgery if there is localized disease.9. Enforce strong infection-control measures.10. Implement strict directly observed therapy and full adherence

support aswell as comprehensive bacteriologic and clinical monitoring.

TDR TB

• No specific management guidelines mentioned by WHO/ RNTCP.

Mixed resistance TB

Bedaquiline (BDQ)• New class of drug - Diarylquinone.• Specifically targets Mycobacterial ATP Synthase.• Strong Bactericidal and sterilizing activity.

• June 2013 – WHO published Interim policy guidance for use of BDQ in conjunction with WHO recommended MDR-TB STRs.

• 2016 – RNTCP is introducing BDQ through conditional access programme at 6 sites in India.

Criteria to receive BDQ (Apex Committee):

• Adults >18y with PTB

• Non pregnant females using non-hormonal birth control methods.

• Absence of arrhythmias or Controlled stable arrhythmias.

Weight bands... What? How? Why?• Recommendation of drug doses according to weight have been

made since 2010 itself.• New (2016) guidelines by Govt of India Central TB Division provides

number of FDCs according to weight bands.• 4 weight bands for Adults, 7 for children.• This is to prevent further drug resistance and assured bioavailability

by increasing drug compliance.

Paediatric TB Mx

• Children represent about 10-11% of all TB cases.

• In 2014, 81 000 children died of TB, and there were an additional 55 000 TB deaths among children who were HIV-positive.

• TB in children can be treated. Most children tolerate treatment very well.

• Preventive therapy is highly effective in children exposed to TB.

• Simple, child-friendly fixed-dose formulations are easy to administer and match WHO dosage recommendations for first line treatment.

• STRs to drug sensitive and MDR TB for paediatric age group are similar to adult, with dose changes.

• INH Preventive therapy for <6y age children who are – Close contacts of TB– Excluded to have active TB

• Irrespective of BCG and nutritional status.• INH 10mg/kg for 6mo given.

Mx of Other Special conditions

TB in Pregnancy

TB in seizure pts• Prophylactic Pyridoxine (Vit B6):

– On INH – 10-25mg/d– On Cycloserine – 25mg/250mg cycloserine.

• In DR TB cases with H/O seizures, avoid– Cycloserine– Ethionamide– Fluoroquinolones

TB in Psychosis pts• Psychosis Rx, Individual counselling, Group therapy, along with TB

management are essential.

• Avoid Ethionamide & FQs.

• No absolute C/I for Cycloserine, though it may cause severe psychosis and depression.Only temporary suspension advised.

• Prophylactic Pyridoxine is helpful.

TB with Liver disorders

• Usual STRs for– Past h/o active hepatitis– H/o alcohol intake– Hepatitis virus carriage– No evidence of chronic liver disease

• LFTs to be done at treatment initiation for patients with unstable or advanced liver disease.

If serum alanine aminotransferase is 3 times more than that at treatment initiation,

DR TB in Liver disease pts:

• PZA, PAS & Ethionamide – Potentially hepatotoxic.

• Most of second line drugs are safer than first line drugs in mild hepatic impairment.

• Avoid P & E.

• If hepatic reactions occur even to second line drugs, consider & evaluate other causes.

End TB Strategy

• WHO’s End TB Strategy

The strategy aims to end the global TB epidemic, with targets to reduce TB deaths by 95% and to cut new cases by 90%

between 2015 and 2035, and to ensure that no family 100% is burdened with catastrophic expenses due to TB.

References

• http://tbcindia.nic.in Central Tuberculosis Division, Govt Of India.• WHO website http://www.who.int/tb/en/• Goodman & Gilman, The Pharmacological basis of Therapeutics

12th Ed.• K.D. Tripathi, Essentials of Medical Pharmacology, 7th Ed.• Harrison’s Principles of Internal Medicine 19th Ed.