Rational Use of Drugs for Management of Drug-Resistant TB

Askar Edilbaev, MD, MPH Partners in Health Antalya, Turkey 10-13 December 2013

DR-TB Treatment

• MDR-TB treatment is long (20 months and more)

• It consists of up to 5 or 6 drugs • More than 80% of patients

experience adverse reactions • High cost of therapy prevents

access to high-quality treatment • On average, 60% of patients have

a favorable treatment outcome • MDR-TB treatment approaches

have not been finalized/regulated

DR-TB Drug Management Cycle

• Selection of high-quality drugs • Estimating quantity of the required

drugs • Procurement management • Distribution • Drug quality assurance • Rational use of drugs

Rational Use of Second-Line Drugs (SLDs)

«Доступ к противотуберкулезным препаратам второго ряда всегда должен сопровождаться обязательными мерами для обеспечения гарантии рационального использования лекарственных препаратов. Ошибки в использовании лекарственных противотуберкулезных препаратов могут привести к потере чувствительности к препаратам второго ряда и дальнейшему распространению лекарственно-устойчивых форм туберкулеза, возможности для лечения которых ограничено в современных условиях»

Cycle of Anti-TB Medicine Use in TB Facilities

• Appropriate prescription of therapy (DST results, close contact)

• Appropriate choice of drugs taking into account their efficacy, safety, and cost

• Appropriate dose, frequency of administration, duration of therapy • Taking into account contraindications to therapy and risk of adverse reactions • Proper distribution of drugs, including provision of

information to the patients on the prescribed chemotherapy scheme

• Adherence to treatment (patient and health care worker)

SLD Prescription (1)

• National protocol adopted in the country – Regulates prescription and prevents use of ineffective

drugs – Allows for the rational use of financial resources

allocated for the drugs • Prescription – a dynamic process that is not limited to

the prescription of the treatment regimen before the start of chemotherapy – Monitoring time of sputum conversion (S, C) after 2-3

months of treatment – Strengthening chemotherapy regimen during post-

surgery period, in case of sputum smear reversion, etc. – Chemotherapy efficacy control

• The first cohort of MDR-TB patients (244) 09/2000 – 09/2002: – Civil sector: 134, penitentiary sector: 110

• Mean age: 34.4 years • Male: 211 (86%), female: 33 (14%)

– Total duration of therapy: 19.2 months – Duration of the intensive phase: 9.9 months – Average number of drugs in the treatment regimens: 6 (4-7)

KM Cap AM OFL Cyc PAS Eth Z E99 139 3 240 243 209 175 173 65

40,6% 57,0% 1,2% 98,4% 99,6% 85,7% 71,7% 70,9% 26,6%

SLD Prescription (2)

TOTAL 401 401 401 401 401 401 401 400 400 316 367 401 401% 100 100 92 100 98.4 39 10 7 0 5 51 45 85

Inappropriate Prescription of SLD

37 observational studies investigated prescription of SLDs:

– Inappropriate prescription of drugs was found in 67% of cases

– Proportion of patients on the inappropriate treatment regimen was 0.4-100%

Inappropriate Prescription of Anti-TB Drugs

• Inappropriate prescription of anti-TB drugs (choice of treatment regimen) results in the development/ amplification of drug resistance.

• Risk of MDR-TB in patients on an inappropriate treatment regimen was 27 times as high as in patients on a proper therapy.

Forest plot and meta-analysis of the two included studies

Selection of Drugs

• National protocol should regulate TB treatment regimens based on drug-resistance patterns (mono-, PDR-TB, MDR-TB, XDR-TB) and include the entire list of drugs for treatment of DR-TB.

• WHO Essential Drugs List: • Km, Am, Cm, Ofx, Lfx, Eto, Cs, PAS • Mfx, 5th group drugs, new drugs are not always included

in the list of anti-TB drugs • Earlier generations of fluoroquinolones (ciprofloxacin,

lomefloxacin, sparfloxacin)

XDR-TB Treatment

Main Goals of Chemotherapy

• To kill major part of actively multiplying population of mycobacteria

• To prevent development of drug-resistant strains

• To achieve sterilizing effect of the chemotherapy

• To manage MDR-TB, aggressive treatment is the only approach

Anti-TB Drugs Doses Based on Body Weight during DR-TB Treatment

Aggressive DR-TB Treatment

Adverse Reactions

0

10

20

30

40

50

60

70

80

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Arthral

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Diarrhe

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Hypok

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Hypoth

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Hepato

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Ototox

icity

Psych

osis

Seizure

Nephro

toxicit

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Depres

sion

Neurop

athy

Adverse Event

% o

f pat

ient

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Adverse Reactions Monitoring

Time of Adverse Reactions During the Course of MDR-TB Treatment

0,0

75,0

150,0

225,0

300,0

0,0 7,5 15,0 22,5 30,0

Histogram of month_all

month_all

Coun

t

65% of ARs are registered within the first 6.18 months of treatment

Main Adverse Reactions During Treatment of MDR-TB

Nausea, vomitting, heartburn 180 (76.9) 14 (7.8)Diarrhea 110 (47.0) 10 (9.1)Artralgia 114 (46.7) 7 (6.1)Myodinia 25 (10.7) 1 (4.0)

Metabolic processes Hypokalemia 91 (38.9) 6 (6.6)Skin itch 61 (26.1) 4 (6.6)Skin eruption 39 (16.7) 4 (10.3)Elevated transaminase level 41 (17.5) 3 (7.6)Drug-induced hepatitis 4 (1.7) 4 (25)Tinnitis 38 (16.2) 6 (15.7)Hearing loss 37 (15.8) 7 (18.9)

Endocrine system Hypotheriosis 35 (15.0) 2 (5.7)Epileptoid seizures 28 (12.0) 3 (10.8)Psychosis 27 (11.5) 4 (14.8)Depression 19 (8.1) 3 (15.8)

PNS Peripheral neuropathy 10 (4.3) 0 (0.0)Cardiovascular system Hypotonic states 19 (8.1) 0 (0.0)Kidneys Nephrotoxicity 14 (6.0) 0 (0.0)Allergy Anaphylaxis reactions 3 (1.3) 3 (100.0)

Organ of hearing

CNS

GIT

Locomotor system

Skin

Liver

Pharmacovigilance

• The science and activities relating to the detection, assessment, understanding, and prevention of adverse effects of the administered therapy

• The goal is to get the best outcome from the treatment with medicines

• Facilitates assessment of benefit, harm, efficacy, and risks of use of medicines, encouraging rational and effective use

Correlation Between the % of Doses Taken Within the First 6 Months of Treatment and Treatment Outcomes (N = 635) Percentage of missed

doses Cured Failure Death Default

< 2% 85.5% 5.5% 2.4% 6.7%

2% - 7% 74.8% 5.8% 5.0% 14.4%

7% - 16% 64.2% 9.2% 5.2% 21.4%

> 16% 44.3% 11.4% 7.0% 37.3%

DOT Monitoring and Compliance

Project Sputnik

Main Issues of Rational Use of SLDs • Poor diagnostics and adherence to diagnostic algorithms

(detection of progressed cases, lack of access to molecular diagnostics of DR)

• Selection of an inappropriate treatment regimen (inadequate, not corresponding to the DST results, lack of capability to strengthen the treatment regimen, lack of a national protocol, TDR-TB and XDR-TB treatment approaches)

• Duration of DR-TB treatment, adverse reactions, lack of ways to motivate and to improve adherence to treatment

• Weakness of the distribution system within the country/region (drug use monitoring)

Strategies for Improving Rational Use of SLDs • Develop and implement a national protocol on the

programmatic and clinical management of DR-TB • Intensify staff training on all aspects of the

programmatic and clinical management of DR-TB • Develop auxiliary materials for doctors,

paramedical personnel, and DOT providers • Conduct regular programmatic and clinical

monitoring • Conduct programmatic activities aimed at

improvement of adherence to treatment

Thank you for your attention!