MDR TB – threat or challenge?

Prof. I. Vasilyeva Chief TB specialist of RF Central TB Research Institute of RAMS TB incidence and TB mortality rates in RF The proportion of MDR TB among new TB cases

MDR-TB among pulmonary TB patients with DST results. Resident population

MDR-TB among pulmonary TB patients with DST results, all population, including a prison sector

MDR-TB among respiratory TB patients, resident population

2012 MDR TB among relapse cases of pulmonary TB *

*% of DS-tested relapse cases The incidence of tuberculosis in the Federal districts of the Russian Federation in 2012 (per 100 000 population) Mortality from tuberculosis in Federal districts of the Russian Federation in 2012 (per 100 000 population) MDR TB among new TB cases in the North- Western Federal district in 2012 MDR TB among relapses in the North- Western Federal district in 2012 Portion of smear and culture positive cases among new TB cases in 2012

Ratio of s+/cv+ in 2012 0,7 0,7 0,8 Main reasons for an increase in MDR TB cases

. Accumulation of MDR TB reservoir as a result of social- economic crisis in the 90-th . Migration . HIV . Shortcomings in treatment management and supervision . Insufficient infection control . Failure to comply with treatment standards . Late diagnostics of drug resistance

Improving quality of bacteriology testing – increasing detection of MDR-TB

2011: coverage by drug susceptibility testing (DST) – 93.4% of all sputum positive cases

DR patterns of M. tuberculosis among new and retreatment cases in the region supervised by CTRI RAMS DR patterns of M. tuberculosis among new and retreatment MDR-TB cases in the region supervised by CTRI RAMS Range of mutations in rpoB gene responsible for RIF resistance (n=1510) Range of mutations in katG, inhA, ahpC genes responsible for INH resistance (n=1510)

RFLP IS6110 typing was performed for M. tuberculosis strains from Central, Southern, Privolzhsky, Siberian Districts

Nizhny Novgorod Oblast

Vladimir Oblast Republic

Moscow oblast

Karachai- Central Cherkess Privolzhsky Southern Tomsk Siberian Oblast North Ossetia

Daghestan Oblast Republic Federal districts of RFLP IS6110 Mari El Republic

Ivanovo Oblast Nizhny

Moscow oblast

Tomsk Oblast

Central

Privolzhsky Siberian

Southern FD Tuva Republic

RFLP-typing revealed increasing proportion of W - strains from the west to the east of Russia The prevalence of W-strains ranged from 22 to 72%

Analysis of MDR/sensitive strains

 49% of MDR strains belonged to W- family  24% of sensitive strains belonged to W- family

W AI KY Other clusters 001

MDR strains Sensitive strains Improving TB activities in the Russian Federation

Developed :

• Concept of etiologic diagnosis of TB and drug resistant TB • Concept of chemotherapy of TB and MDR/XDR TB • Guidelines for monitoring MDR-TB prevalence in RF • Infection control guidelines • MDR-TB registration and reporting

Draft concept of TB and DR TB etiological diagnostics

• TB case detection by molecular-genetic and bacteriological methods.

• DST for all TB patients: new and previously treated.

• Implementation of molecular-genetic and rapid methods for culturing on liquid media in all regional laboratories.

• Priority application of molecular-genetic methods for the diagnostics of DR among TB patients with high risk of MDR TB . ВАСТЕС MGIT: 103 instruments were installed in 82 TB Dispensaries

1 1 1 1 1 1 1 1 1 1 11 1 1 6 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 1 1 1 1 1 1 151 devices for molecular-genetic detection of MDR were installed

Gx Gx Gx Gx Gx МГМ Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx GxGx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx Gx

PCR-laboratory molecular-genetic Gx GeneX-pert MTB\Rif detection of multi-drug resistance in 85 civil lab in 44 Lab In 22 penitenciary lab North Western Federal district: BACTEC MGIT (16), GX (8), MGM (7)

В БИОЧИП

Biochip

GX

В

GX

В PCR GX MDR GX GX HAIN HAIN В GX GX test test В PCR 8-В Biochio MDR В В В В GX Implementation of rapid DST

• TB- Biochip (HR Fq): 24hours • Gene Xpert MTB/RIF (R): 90 min • Multiplex PCR (Sintol) (HR Fq): 5,5 hours • DNA – strip Hain Lifescience ( HRE Fq Am/Сm): 5 hours

Promotion of technologies aimed to reduce working hours • The CTRI implemented the automated station and developed a programme to extract DNA from TB patients’ sputum and include it into amplification mix for subsequent PCR. Draft concept of TB chemotherapу

• Based on the WHO recommendations, 2011

Additions:

• Principal regimen design is based on the DST results • Chemotherapy algorithms are based on molecular-genetic DST • Algorithms for chemotherapy correction are based on the DST results • Treatment regimen for XDR/TB • Duration of chemotherapy for МDR/XDR TB patients before and after surgery • Monitoring, prevention and reduction of adverse events during MDR/XDR TB treatment • Principles of treatment management and supervision • Treatment in special situations

Development of treatment regimen based on results of molecular-genetic techniques

Prescribing and modification of a chemotherapy regimen is carried out in two stages:

1. On the basis of individual DST results received with molecular-genetic techniques.

2. On the basis of DST results to 1st and 2nd lines drugs using liquid or solid media techniques. Arkhangelsk region of the Russian Federation  Area: 578,000 square km

 Population: 1, 117, 096 people

 24 municipal districts

 13000 in penal system

Andrey Maryandyshev, Elena Nikishova TB Incidence in RF and Arkhangelsk Region 1991-2011 гг.

Andrey Maryandyshev, Elena Nikishova Drug resistance among new TB cases in 2001- 2012 (%)

Andrey Maryandyshev, Elena Nikishova TB service of the area

27 municipal tuberculosis ambulatory

Arkhangelsk Clinical TB Dispensary Reference laboratory and 3 in-patient departments for 130 patients: Sensitive TB SS+ 50 MDR/XDR TB SS+ 50 Sensitive, MDR TB SS- 30 Out-patients department

Regional hospital of penitentiary TB Colony system - bacteriological laboratory for continuation and 2 in-patient departments treatment for 140 patients (sensitive and MDR) Rapid Drug Susceptibility Tests implemented

• BacTAlert– 2004-2009 • LPA (Hain Test) in 2009 – DST for 1 and 2 line drugs • Bactec MGIT - DST for first line drugs -2010 DST for second line drugs - 2011 • Gene Xpert - 2011 • Admission of TB patients to hospital is determined only by epidemiologic indications

• The duration of inpatient treatment is not more than 2-3 months

• The priority form of treatment is outpatient – more comfortable for patients and reduced risk of cross- resistance

Social and psychological support of patients

• 2001 – social workers • 2003 – “TB school” • 2003 – food parcels during outpatient treatment • 2005 – psychologists, a psychiatrist • 2008 – a department of medical and social support and rehabilitation of TB patients

Social rehabilitation Psychological rehabilitation Nursing Health education Training of medical workers Rehabilitation of drug addicts

Andrey Maryandyshev, Elena Nikishova The pilot project “Harmony” started at the outpatient department of Arkhangelsk Clinical TB Dispensary on June 1, 2011.

The goal of the project was to promote treatment adherence and treatment completion among patients, who did not comply with conventional forms of treatment.

Andrey Maryandyshev, Elena Nikishova Results of treatment all registered (566) TB cases in civil sector in 2011

• Сured new cases – 81,8% (381/465) • Cured relapses –70,9% (66/93) • Cured treatment loss to follow up – 60,0% (3/5) • Cured treatment failure –100% (3/3) • Total cured TB registered patients in 2011 – 80,0% (453/566)

Andrey Maryandyshev, Elena Nikishova New TB cases in 2001-2012 (absolute numbers)

Andrey Maryandyshev, Elena Nikishova TB relapses in 2001-2012 (absolute numbers)

Andrey Maryandyshev, Elena Nikishova TB Incidence including penitentiary system (new cases and relapses ) and mortality in Arkhangelsk Region 2001-2012 (per 100 000 population)

Andrey Maryandyshev, Elena Nikishova Thank you