Multidrug-resistant Tuberculosis - World, Europe, Switzerland

Multidrug-resistant Tuberculosis - World, Europe, Switzerland Magglingen March 23, 2017 peter.helbling@bag.admin.ch

Topics Definitions Epidemiology of TB and MDR-TB worldwide Treatment outcome results for MDR-TB in Europe MDR-TB in Switzerland - Epidemiological data - Treatment outcomes MDR-TB - Clusters and transmission - Somali MDR cluster 2016

Definition of MDR-TB Multidrug resistance (MDR) = resistance to isoniazid and rifampicin (with or without additional resistances to other drugs) Extensively drug-resistant tuberculosis (XDR) = a subgroup of MDR-TB with additional resistances to: - fluoroquinolones AND - at least one of the injectable drugs amikacin, kanamycin or capreomycin

Clinician with a patient 1. «Think TB» 2. Does this patient have TB? Symptoms Geographic origin History Decision support tool in 32 languages: www.tb-screen.ch

Estimated TB incidence rates in 2015 per 100,000 pop. WHO/HTM/TB/2016.13

Does the patient with TB have MDR-TB? Prior knowledge of: - geographic origin - history of previous treatment for tuberculosis or just rely on result of Xpert MTB/RIF?

% MDR in TB patients never treated before WHO/HTM/TB/2016.13

% MDR in TB patients having had treatment before WHO/HTM/TB/2016.13 WHO/HTM/TB/2016.13

Does the patient with TB have MDR-TB? Just rely on Xpert MTB/RIF result? Positive predictive value depends on proportion of MDR among the TB cases <-> Prior knowledge on: - geographic origin - history of previous treatment for tuberculosis

Predictive value of a "rifampicin resistant" result with Xpert MTB / RIF, given prevalence of rifampicin resistance 1.0 Predicitve value of a positive test 0.8 0.6 0.4 0.2 Operating characteristics based on Boehme papers: Sensitivity: Specificity: 0.95824 0.98113 0.0 0.00 0.05 0.10 0.15 0.20 0.25 0.30 Prevalence of rifampicin resistance Courtesy Hans Rieder Boehme CC, et al. N Engl J Med 2010;363:1005-15 Boehme CC, et al. Lancet 2011;377:1495-1505

Estimated MDR-TB incidence per 100,000 pop., 2015 Republic of Moldova 96 Kyrgyzstan 84 Swaziland 69 Lesotho 52 Kazakhstan 50 Ukraine 49 Namibia 45 Russian Federation 42 Belarus 37 South Africa 37 Kiribati 36 Uzbekistan 33 Somalia 29 Calculated from www.who.int/tb/country/data/download/en/

Treatment outcomes in WHO European Region Source: WHO Global Tuberculosis Report 2016

Treatment success MDR, WHO Europe High-Priority x Source: ECDC Tuberculosis Surveillance and Monitoring Report 2016

Origins of notified cases of Tuberculosis (all cases) Switzerland 1996-2016 800 700 600 500 400 300 200 100 0 Total Foreign Swiss Unknown origin

TB cases among asylum seekers / refugees vs. total n Switzerland 1996-2016 800 700 600 500 400 300 200 100 0 Total number of cases Asylum seekers / refugees

70 MDR-TB in Switzerland 1997-2016 3.5% 60 MDR cases (N) % MDR of all strains 3.0% 50 2.5% 40 2.0% 30 1.5% 20 1.0% 10 0.5% 0 1997-2001 2002-2006 2007-2011 2012-2016 0.0% 16

Outcomes of MDR treatments (at 24 months) Switzerland 2003-2013 51 MDR cases 2003-2010 (Swiss Med Wkly. 2014;144:w14053): 76% success 24% unsatisfactory (loss to follow-up > stop due to side effects > deaths) 32 MDR cases 2011-2013 (unpublished data collected by the Swiss Lung Association): 81% success (26/32) [2 lost to follow-up, 2 deaths (not due to TB), 1 treatment continued abroad and no information, 1 still being treated]

Definition of XDR Multidrug resistance (MDR) = resistance to isoniazid and rifampicin (with or without additional resistances to other drugs) Extensively drug-resistant tuberculosis (XDR) = a subgroup of MDR-TB with additional resistances to: - fluoroquinolones AND - at least one of the injectable drugs amikacin, kanamycin or capreomycin

«XDR-TB» in Switzerland 1997-2016 MDR cases (N) 4 XDR 65 1 XDR 37 38 28 1997-2001 2002-2006 2007-2011 2012-2016 19

Origin of MDR-TB cases, Switzerland 2012-2016 Region Country N (Total=65) Asia «China» (all with Tibetan names) 14 India 1 Horn of Africa Somalia 10 Eritrea 5 Ethiopia 3 Former Soviet Union Georgia 6 Ukraine 3 Uzbekistan 2 Belarus, Moldova, Azerbaijan 3 Europe Switzerland 7 Germany 2 Hungary, Italy, Turkey 3 Various Morocco, Cameroon, Angola, DR Congo, Brazil, unknown 6

TB and MDR-TB cases among Somalis and Eritreans Switzerland 1996-2016 90 80 70 60 50 40 30 20 10 0 Somali MDR Eritrean MDR Somali tested Eritrean tested 1 2 2 2 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 10 0 2 10 01 2

Xpert MTB / RIF High negative predictive value for rifampicin resistance (hardly any false-negative)

MDR clusters in Switzerland? Routine surveillance since 1995/96: Drug susceptibilities for the 4 standard drugs to be notified Rifampicin-resistant strains sent to National Reference Lab for Mycobacteria, University of Zurich: - extensive drug susceptibility testing - molecular analyses to identify links between patients Eur Respir J. 2000;16(2):200

Clustered MDR cases in Switzerland 2006-2015 2006-2012 (n=49): 4 transmissions among immigrants with close contact Euro Surveill. 2014;19(11):pii=20736 2013-2015: (n=39) 2 transmissions within families Annual reports NRLM -> Transmission is rare and occurs among close social contacts.

Drug resistances in 8 MDR cases from Horn of Africa (Switzerland 2016) Isoniazid (3 mg/l) & rifampicin Pyrazinamide Capreomycin (5 or 25 mg/l) MDR [. «Pre-XDR»: MDR with resistance either to fluoroquinolones OR an injectable second-line drug.]

Somali cluster of MDR-TB in 2016 25 identical strains in Whole Genome Sequencing Germany: 13 cases Switzerland: 8 cases Austria: 2 cases Sweden: 1 case Finland: 1 case Data as of 22 March 2017

Somali cluster of MDR-TB in 2016 (Switzerland) 6 Somali, 1 Somali-speaking Ethiopian, 1 Eritrean Males, age 15 to 19 years Asylum request between Dec 2015 and Jun 2016 Start of TB treatment between Feb and Sep 2016 6 pulmonary, 1 pleural, 1 intrathoracic lymph nodes Preliminary information on 11 cases in Germany All Somali, age 15-25, males except one Registered for asylum in Germany Dec 2015 - Aug 2016 Notified Mar 2016 - Nov 2016

Migration route of clustered cases to Switzerland 7 patient interviews, 1 refusal Start of journeys: Jan through Dec 2015 (1 in 2013) Duration (Somalia-Chiasso): 5 months (2), 6, 10 (2), 11; 29 6 through Ethiopia (5 Addis Abeba), All through Sudan All through Libya (5/7 through Bani Waleed) All through Italy (Sicily, Sardinia) All through Chiasso Preliminary information on migration routes of 8 cases to Germany: all through Sudan, Libya, Italy Bern Inselspital, 9 Feb 2017 29

Locations en route mentioned by cases 30

Migratory routes in North Africa 31

Time of diagnosis in relation to entry to Switzerland Delay screen to start treatment (d) Delay screen to first positive sample taken (d) Screen score 7 6 10 5 1 13 68 15 10 Screening details "Weight loss, family history of TB" "Weight loss, cough >3 weeks" "Cough <3 weeks", "sick". Bronchial sample mic-, PCR-; culture+ 112 111 14 Productive cough <3 wks, weight loss, sick ; Normal chest x-ray 42 8 9 159 154 8 "All normal" 168 155 9 "Weight loss" 153 150 4 Cough <3 weeks "Cough <3 weeks"; chest pain (after screen). Sputum mic-, PCR-; culture+

Start of symptoms (interview and screening) Recurrent cough, bloody cough, fever and thorax pain for the last ~2-3 years Cough with bloody sputum in Somalia in 2014, but not since then Father had TB in Somalia a year ago before he migrated. They lived together. Cough and fever in the weeks before arrival. Sick, including a cough, for a period of 3 months in early 2015 when working on a farm in Libya, and again on arrival in Italy 2 months later 3 cases: Cough <3 weeks before arrival. One had a cousin who died of hemoptysis before embarking in Libya to Italy. Pleural case: symptoms only after arrival in CH. Brother had TB in Somalia. Bern Inselspital, 9 Feb 2017 33

Preliminary conclusions Origin of this cluster probably lies in Somalia. Some transmission along the migration route likely At least one hotspot for transmission in Libya Transmission in Switzerland: unlikely, but not impossible No more cases in Germany and Switzerland since November 2016 At least some more cases are to be expected. 34

Acknowledgements All MDs and laboratories notifying the cases Ekkehardt Altpeter, Simone Graf, Daniela Beeli, Domenica Perissinotto, Nathalie Vicari () Dr. Peter Keller, National Ref Lab for Mycobacteria University of Zurich Astrid Knoblauch, PhD Kompetenzzentrum für Epidemiol. Ausbruchsuntersuchungen Swiss Tropical and Public Health Institute Jean-Marie Egger, Swiss Lung Association Magglingen, 23 Mar 2017 35