Multidrug-Resistant Tuberculosis in Lisbon: Unfavourable Treatment and Associated Factors, 2000–2014

INT J TUBERC LUNG DIS 23(10):1075–1081 Q 2019 The Union http://dx.doi.org/10.5588/ijtld.18.0596

Multidrug-resistant tuberculosis in Lisbon: unfavourable treatment and associated factors, 2000–2014

M. Bhering,1,2 A. Kritski,1,2 C. Nunes,3 R. Duarte4,5 1School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, 2Brazilian Tuberculosis Network, Rio de Janeiro, Rio de Janeiro, Brazil; 3National School of Public Health at the Nova University Lisbon, Lisbon, 4Pulmonology Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, Lisbon, 5Public Health Science and Medical Education Department, School of Medicine, University of Porto, Porto, Portugal

SUMMARY

SETTING: The incidence of tuberculosis (TB) has been was 30.5%. These were associated mostly with being decreasing in Portugal. Lisbon concentrates the largest male, foreign-born and resistant to kanamycin. Death number of cases of multidrug-resistant (MDR) TB in the was associated with being human immunodeficiency country. This study aims at identifying clinical and virus-positive and resistant to kanamycin. Being foreign- demographic factors associated with unfavourable born had a 4.46-fold higher odds of a LTFU outcome treatment results of patients with MDR-TB in the city. than did being Portuguese-born. The foreign-born METHOD: The data on 265 MDR-TB cases, notified patients were mostly African immigrants. from 2000 to 2014 in the District of Lisbon, were collected CONCLUSION: The main finding in this study is that from the Tuberculosis Surveillance System. Unfavourable foreign-born patients are associated with a higher cases were classified as failure, loss to follow-up (LTFU) probability of unfavourable outcomes than Portuguese- and death. Bivariate and multivariate logistic regressions born patients. Therefore, foreign-born patients need were undertaken to estimate the factors associated with more careful monitoring in the control of MDR-TB. unfavourable outcomes, LTFU and death. KEY WORDS: tuberculosis; migration; Portugal; treat- RESULTS: The proportion of unfavourable outcomes ment outcomes; surveillance

THE RESISTANCE OF Mycobacterium tuberculosis ic factors associated with the unfavourable outcome to drugs is a major public health threat, and one of the in MDR-TB patients, in the District of Lisbon. LTFU challenges for disease control since treatment of drug- and death will also be analysed as specific outcomes. resistant tuberculosis (TB) requires the use of more expensive, more toxic, and less effective drugs than METHODS the first-line regimen.1 Multidrug-resistant (MDR) TB is defined as TB Data with resistance to at least rifampicin and isoniazid. The data were taken from the Tuberculosis Surveil- Extensively drug-resistant TB (XDR-TB) is defined as lance System of Portugal (SVIG-TB). MDR-TB cases MDR-TB with resistance to one or more quinolones notified from 2000 to 2014 in the District of Lisbon and to at least one of the three injectable drugs used in were included in the sample. Treatment outcomes the treatment of TB (capreomycin [CPM], kanamycin were classified according to World Health Organiza- [KM], and amikacin).2 tion (WHO) definitions.4 Outcomes were considered In Portugal, the majority of TB cases occur in unfavourable if the patient’s outcome was classified Lisbon and Oporto, which account for 57.3% of as ‘death’, ‘failure’ or ‘loss to follow-up (LTFU)’. reported TB cases. Cases of MDR-TB are also ‘LTFU’ was defined as patients whose treatment was concentrated in these areas.3 discontinued for 2 consecutive months or more; An important fact to note is the increase in recent ‘death’ referred to patients who died for any reason years in TB cases among the foreign-born population. during the course of the treatment. Patients who In 2017 the estimated incidence was 83.7 per 100 000 transferred out of Portugal during treatment, classi- inhabitants, which is 5.4 times greater than the fied as ‘transfer out or emigration’, were excluded estimates for the country.3 from the analysis. Our study aims to identify clinical and demograph- Individuals who were born in Portugal and had

Correspondence to: Marcela Bhering, Faculdade de Medicina da Universidade Federal do Rio de Janeiro, Centro de Pesquisa em Tuberculose, Cidade Universita´ria, Rua Prof Rodolpho Paulo Rocco, 255/68 andar, 21941-913 Rio de Janeiro, RJ, Brazil. e-mail: [email protected] Article submitted 27 August 2018. Final version accepted 4 December 2018. 1076 The International Journal of Tuberculosis and Lung Disease

Portuguese citizenship were considered Portuguese. foreign-born patients (25.2% vs. 21.0% respectively, Individuals whose country of origin was not Portugal P ¼ 0.476), was the most common risk factor among were considered foreign-born, regardless of their the latter. The use of injectable drugs was the only risk length of stay in the country or whether they had factor associated with significant differences between Portuguese citizenship. There is no information about the groups, being the most prevalent among Portu- asylum seekers among the patients. guese patients (29.2% vs. 12.5% respectively, P ¼ As this study used surveillance data, with no 0.004). possibility of linking patient records to patient Regarding patients’ occupation, 17 (6.4%) were personal data, ethical approval was considered health care workers (of whom 12 were Portuguese, unnecessary. and 5 were foreign-born [7.0% and 5.4% respectively, P ¼ 0.612]). There was, however, no information Statistical methods about whether the transmission was nosocomial or According to the nature of the variable, number related to work in the health area. (frequency) and median (range) were used to describe In terms of resistance categories, 176 (66.4%) were the general characteristics of the patients and MDR-TB and 89 (33.6%) were XDR-TB, with more specifically their Portuguese or foreign-born status. cases of XDR-TB among Portuguese patients than The relationship between treatment outcomes among foreign-born patients (37.8% vs. 25.8%, (unfavourable, LTFU and death) and possible predic- respectively). tive categorical variables was evaluated through Overall, 59.2% of the patients had no previous binary logistic regressions. Odds ratios (ORs) and history of TB treatment, 117 (66.4%) between MDR- 95% confidence intervals (95%CIs) were estimated. TB and 40 (44.9%) among XDR-TB. Portuguese The final multivariate logistic regression model was patients had a higher percentage of cases with run for each event, including variables that were primary XDR-TB infection than foreign-born pa- 0.20 significant in the bivariate analyses. Variables tients, 44.9% and 33.3%, respectively. associated with outcomes with 0.10 significance in Supplementary Table S1 shows the resistance to the adjusted model were reported. Statistical analyses first- and second-line tested drugs. Among the were performed using STATA v.13.1 (StataCorp, patients first-line tested, 199 (75.1%) were resistant College Station, TX, USA). to streptomycin and 185 (75.1%) were resistant to pyrazinamide. Among the second-line tested drugs, KM and CPM appeared with 80 (48.2%) cases each. RESULTS Overall, the unfavourable outcome rate was 30.6%. Descriptive analysis The LTFU rate was much higher among foreign-born Between 2000 and 2014, 275 MDR-TB cases were patients than among Portuguese patients (18% vs. reported in the District of Lisbon, 10 of which were 4.6% respectively; P , 0.001). Supplementary Table excluded because they were classified as ‘transfer out S2 shows treatment outcomes by origin and resistance or emigration’. Of the total, 93 (35.1%) patients were type. foreign-born. Table 1 shows the general clinical and demographic characteristics of all patients and Factors associated with treatment outcomes differences between the Portuguese-born and for- The bivariate relations reported in Table 2 indicate eign-born patients. that the dependent variable ‘unfavourable outcome’ There were 180 (67.9%) male patients. Among the was associated with the following factors: being male 93 foreign-born patients, 76 (81.7%) were born in (OR 2.00, 95%CI 1.09–3.66, P ¼ 0.024), being African countries. The largest number, 25 (26.9%), foreign-born (OR 1.78, 95%CI 1.04–3.05, P ¼ were from Angola, followed by 23 (24.7%) from 0.035), being HIV-positive (OR 2.13, 95%CI 1.22– Cape Verde and 14 (15%) from Guinea Bissau. For 3.71, P ¼ 0.007), being an intravenous drug user (OR the 48 cases for whom there was information about 2.17, 95%CI 1.15–4.07, P ¼ 0.015), being unem- the time elapsed between their entry in Portugal and ployed (OR 1.77, 95%CI 0.95–3.29, P ¼ 0.071), date of MDR-TB diagnosis, the median time was having previous treatment for TB (OR 2.03, 95%CI 3.474 days. 0.87–4.73, P ¼0.097) and being resistant to KM (OR Of 249 patients with known serology for the 2.02, 95%CI 1.05–3.88, P ¼ 0.034). human immunodeficiency virus (HIV), 99 (39.8%) LTFU was associated with being foreign-born (OR were positive, with a larger percentage among the 4.58, 95%CI 1.89–11.09, P ¼ 0.001) and being born foreign-born patients (43% vs. 38% respectively, P ¼ in Africa (OR 5.04, 95% CI 2.03–12.48, P , 0.001). 0.445). Portuguese patients exhibited double the The variable ‘region of origin’ was not included in the percentage of registered comorbidities (excluding multivariate regressions because it is highly co-linear diabetes and HIV) than foreign-born patients with ‘country of origin’. (33.6% vs. 15.1% respectively, P ¼ 0.466). Alcohol Death was associated with HIV-positive status dependence, high among both the Portuguese and the (OR 2.56, 95% CI 1.34–4.87, P ¼ 0.004), intrave- MDR-TB in Lisbon, Portugal 1077

Table 1 Demographic and clinical characteristics of patients with MDR-TB (n ¼ 265: 172 Portuguese and 93 foreign-born)

Patients Portuguese Foreign-born (n ¼ 265) (n ¼ 172) (n ¼ 93) Characteristics n (%) n (%) n (%) P value* Sex 0.963 Female 85 (32.1) 55 (32.0) 30 (32.3) Male 180 (67.9) 117 (68.0) 63 (67.7) Age, years, median [range] 39 [10–81] 41 [10–81] 38 [16–68] 0.038 Age group, years 10–24 28 (10.6) 16 (9.3) 12 (12.9) 0.261 25–44 145 (54.7) 92 (53.5) 53 (57.0) 45–64 73 (27.5) 48 (27.9) 25 (26.9) 65 19 (7.17) 16 (9.3) 3 (3.2) HIV status (n ¼ 249) Negative 150 (60.2) 101 (62.0) 49 (57.0) Positive 99 (39.8) 62 (38.0) 37 (43.0) 0.445 Risk factors Diabetes 8 (3.0) 5 (2.9) 3 (3.2) 0.885 Comorbidities† 46 (17.4) 89 (52.7) 14 (15.1) 0.466 Alcohol abuse (n ¼ 232) 55 (23.7) 38 (25.2) 17 (21.0) 0.476 Intravenous drug use (n ¼ 234) 55 (23.5) 45 (29.2) 10 (12.5) 0.004 Prisoner (n ¼ 223) 19 (8.5) 15 (10.3) 4 (5.1) 0.183 Unemployed 54 (20.4) 36 (20.9) 18 (19.4) 0.761 Homeless (n ¼ 223) 5 (2.2) 3 (2.1) 2 (2.6) 0.812 Community residence 14 (6.3) 11 (7.6) 3 (3.9) 0.282 Healthcare worker (n ¼ 222) 17 (6.4) 12 (7.0) 5 (5.4) 0.612 Treatment history for TB 0.813 Never treated 157 (59.2) 101 (58.7) 56 (60.2) Previously treated 108 (40.8) 71 (41.3) 37 (39.8) Site of disease 0.961 Pulmonary 240 (90.6) 155 (90.1) 85 (91.4) Others 25 (9.4) 17 (9.9) 8 (8.6) Chest radiography (n ¼ 233) 0.799 Cavitation 125 (53.6) 86 (54.8) 39 (51.3) No cavitation 88 (37.8) 57 (36.3) 31 (40.8) Normal 20 (8.6) 14 (8.9) 6 (7.9) Categories of drug resistance 0.049 MDR-TB 176 (66.4) 107 (62.2) 69 (74.2) XDR-TB 89 (33.6) 65 (37.8) 24 (25.8) Duration of therapy, days, median (range) 671 (33–2659) 670 (33–2659) 677 (88–2148) 0.303 Time between onset of symptoms and diagnosis, days, median (range) 73 (2–2230) 72 (4–750) 75 (2–2230) 0.089

* Comparison between Portuguese and foreign-born patients. † Except diabetes and HIV. MDR-TB ¼ multidrug-resistant TB; IQR ¼ interquartile range; HIV ¼ human immunodeficiency virus; TB ¼ tuberculosis; XDR-TB ¼ extensively drug-resistant TB. nous drug use (OR 3.57, 95% CI 1.76–7.26, P , 4.46, 95%CI 1.81–10.98, P ¼ 0.001) was associated 0.001), unemployment (OR 2.19, 95%CI 1.09– with LTFU. Being male (OR 4.47, 95%CI 0.83– 4.36, P ¼ 0.026), living in a community residence 23.95, P ¼ 0.080), HIV-positive (OR 3.08, 95%CI (OR 3.57, 95% CI 1.11–11.43, P ¼ 0.032) and 0.88–10.72, P ¼ 0.076) and resistant to KM (OR resistance to KM (OR 2.19, 95% CI 0.99–4.82, P ¼ 4.01, 95%CI 1.21–13.29, P ¼ 0.023) were associated 0.050) (Table 2). with death. Finally, those independent variables found to have a P value 0.20 in bivariate regressions were DISCUSSION included on the right-hand side of multivariate logistic regression equations. Variables with a P value This study of 265 cases found a therapeutic success 0.10 were considered significant. The odds ratio rate of 69.4% (71.0% among MDR-TB cases and reported in Table 3 indicates that being male (OR 66.3% among XDR-TB cases). The overall percent- 2.43, 95%CI 0.93–6.37, P ¼ 0.069), being foreign- age is higher than that reported in studies conducted born (OR 3.00, 95%CI 1.28–7.03, P ¼ 0.011) and in Europe, where success rates among MDR-TB and being resistant to KM (OR 2.73, 95%CI 1.18–6.33, P XDR-TB patients were respectively 54% and ¼ 0.019) were significantly associated with unfav- 40%.5–7 This figure is also higher than the success ourable treatment outcome. Being foreign-born (OR rates described in a recent systematic review and 1078 The International Journal of Tuberculosis and Lung Disease

Table 2 Bivariate analysis: Predictors of unsuccessful, loss to follow-up and death among 265 patients with MDR-TB

Unsuccessful outcomes Loss to follow-up Death (n ¼ 265) (n ¼ 215) (n ¼ 265) Predictors OR (95% CI) P value OR (95% CI) P value OR (95% CI) P value Sex Female 1.0 0.024 1.0 0.181 1.0 Male 2.00 (1.09–3.66) 0.821 2.0 (0.72–5.52) 0.096 1.62 (0.80–3.30) 0.177 Age, years 0.99 (0.97–1.01) 0.035 0.97 (0.94–1.0) 0.001 1.01 (0.99–1.03) 0.239 Country of origin Born in Portugal 1.0 1.0 1.0 Foreign-born 1.78 (1.04–3.05) 4.58 (1.89–11.09) 0.94 (0.49–1.80) 0.857 Region of origin Portugal 1.0 1.0 1.0 Africa 2.05 (1.16–3.62) 0.013 5.04 (2.03–12.48) ,0.001 1.12 (0.57–2.19) 0.743 East Europe 1.25 (0.36–4.27) 0.717 3.72 (0.70–19.70) 0.122 0.35 (0.44–2.79) 0.323 HIV status (n ¼ 249) Negative 1.0 1.0 1.0 Positive 2.13 (1.22–3.71) 0.007 1.15 (0.46–2.44) 0.762 2.56 (1.34–4.87) 0.004 Risk factors (reference ¼ no) Diabetes 1.37 (0.32–5.90) 0.667 — 2.68 (0.61–11.61) 0.187 Comorbidities* 0.49 (0.22–1.08) 0.079 0.45 (0.13–1.60) 0.233 1.05 (0.47–2.35) 0.894 Intravenous drug use (n ¼ 234) 2.17 (1.15–4.07) 0.015 1.02 (0.36–2.87) 0.961 3.57 (1.76–7.26) ,0.001 Prison inmate (n ¼ 223) 1.25 (0.45–3.45) 0.666 1.08 (0.23–5.02) 0.920 1.54 (0.48–4.97) 0.465 Unemployed 1.77 (0.95–3.29) 0.071 0.97 (0.34–2.72) 0.961 2.19 (1.09–4.36) 0.026 Homeless (n ¼ 223) 1.83 (0.29–11.28) 0.510 — 4.02 (0.64–25.04) 0.136 Community residence (n ¼ 222) 1.54 (0.49–4.81) 0.453 — 3.57 (1.11–11.43) 0.032 Healthcare worker 0.28 (0.63–1.27 0.101 — 0.25 (0.03–1.96) 0.189 Treatment history Never treated for TB 1.0 1.0 1.0 Previously treated for TB 2.03 (0.87–4.73) 0.097 1.97 (0.86–4.53) 0.108 1.06 (0.57–1.98) 0.842 Site of disease Others 1.0 1.0 1.0 Pulmonary 1.43 (0.55–3.75) 0.456 0.74 (0.20–2.67) 0.646 1.78 (0.51–6.21) 0.362 Categories of drug resistance MDR-TB 1.0 1.0 1.0 XDR-TB 1.24 (0.72–2.15) 0.430 1.12 (0.47–2.65) 0.788 1.14 (0.59–2.17) 0.688 Resistance to kanamycin No 1.0 1.0 1.0 Yes 2.02 (1.05–3.88) 0.034 1.22 (0.46–3.18) 0.681 2.19 (0.99–4.82) 0.050 Resistance to ofloxacin No 1.0 1.0 1.0 Yes 0.59 (0.30–1.15) 0.126 0.62 (0.22–1.77) 0.379 0.64 (0.28–1.45) 0.291 Resistance to ethambutol No 1.0 1.0 1.0 Yes 0.87 (0.51–1.48) 0.615 0.96 (0.42–2.21) 0.930 0.73 (0.39–1.39) 0.346 Resistance to pyrazinamide No 1.0 1.0 1.0 Yes 1.37 (0.73–2.56) 0.314 1.81 (0.72–4.52) 0.202 1.15 (0.55–2.41) 0.695

* Except diabetes and HIV. MDR-TB ¼ multidrug-resistant TB; OR ¼ odds ratio; CI ¼ confidence interval; HIV ¼ human immunodeficiency virus; TB ¼ tuberculosis; XDR-TB ¼ extensively drug- resistant TB. meta-analysis (60% for MDR-TB and 26% for XDR- with MDR-TB and XDR-TB in Lisbon are designated TB).8 Lisbon3 and Q1. The Lisbon3 cluster was originally Of the total number of MDR-TB cases analysed, 89 described in the 1990s and was highly associated with (33.6%) were XDR-TB, which were more frequent the original outbreak of MDR-TB in the region and among Portuguese patients than among foreign-born currently with XDR-TB. The Q1 cluster, described patients (37.8% vs. 25.8%, respectively). This for the first time from strains recovered in 2003, is proportion is higher than that of countries considered genetically very close to the original Lisbon family to have a high percentage of XDR-TB among MDR- and contains XDR-TB strains, although it has lower TB cases, such as Belarus (29.3% in 2014) and mutational diversity than the Lisbon3 cluster.10 Lithuania (24.7% in 2013).9 Currently, this drug resistance is almost entirely In Lisbon, the high rates of multidrug resistance are due to the endemic circulation of the Q1 strains and caused mainly by a particular group of lineages: the Lisbon3 phylogenetic clades, which may explain why, Lisbon family. The main genetic groups associated in the sample studied, 157 (59.2%) patients did not MDR-TB in Lisbon, Portugal 1079

Table 3 Multivariate analysis: predictors of unsuccessful outcomes, i.e., loss to follow-up and death among patients with MDR-TB (n ¼ 265) Unsuccessful outcomes Loss to follow-up Death (n ¼ 265) (n ¼ 215) (n ¼ 265) Predictors aOR (95% CI) P value aOR (95% CI) P value aOR (95% CI) P value Sex 0.069 0.080 Female 1.0 1.0 Male 2.43 (0.93–6.37) 4.47 (0.83–23.95) Country of origin 0.011 0.001 Portugal-born 1.0 1.0 Foreign-born 3.00 (1.28–7.03) 4.46 (1.81–10.98) HIV status 0.076 Negative 1.0 Positive 3.08 (0.88–10.72) Resistance to kanamycin 0.019 0.023 No 1.0 1.0 Yes 2.73 (1.18–6.33) 4 01 (1.21–13.29)

MDR-TB ¼ multidrug-resistant tuberculosis; aOR ¼ adjusted odds ratio; CI ¼ confidence interval; HIV ¼ human immunodeficiency virus.

have a previous history of TB treatment, indicating a born occurs predominantly within their communities, predominance of primary infection.10 there is a risk of transmission by both foreign-born The high prevalence of XDR-TB in Portugal led to patients and those who are Portuguese born.14 the creation of the national reference centres for In the multivariable regression models, being male MDR-TB in 2008. Since then, a decrease in the was associated with unfavourable treatment out- number of prevalent cases has been observed.11 come. The unfavourable outcome rate among men Alongside TB, HIV infection continues to be an was significantly higher than that among women important public health problem in Portugal. In (35.0% vs. 21.2%, respectively, P ¼ 0.023). A study 2015, the incidence per 100 000 inhabitants, was of TB in European countries showed that the failure 9.5 cases, higher than the average of 6.3 cases found rate was due mainly to a higher proportion of deaths, in European Union (EU) countries. Most of the cases failed, and LTFU in men compared to women. Other are in large cities, of which 41.1% were in Lisbon, studies also reported that the failure rate was higher 18.5% in Oporto and 11.3% in Setubal. This is among men due to a higher occurrence of LTFU and reflected in the TB-HIV coinfection rate, which is the treatment failure. Behavioral components, such as highest among Western European countries. In 2015, alcohol and drug abuse, more frequent among men, of the 88.2% TB patients with known HIV serology, are associated with poor outcomes.15 11.8% were positive.12 The regression output showed an association Although HIV is the most important risk factor for between resistance to KM and unfavourable outcome the development of active TB, there is no consensus (OR 2.53, 95%CI 1.08–5.90, P ¼ 0.031) and death on whether available data clearly demonstrate the (OR 3.73, 95%CI 1.11–12.51, P¼0.033). Amikacin, relationship between levels of HIV infection and KM, and CPM are the main injectable drugs for the MDR-TB in the population.9. Some studies have treatment of MDR-TB. Of the 166 patients tested for shown a moderate association between primary KM, 80 (48.2%) had resistance. Among the Portu- MDR-TB and HIV, as well as the risk of a higher guese patients, 50% of those tested were resistant, primary infection.13 In the present study of 99 cases and among the foreign-born patients, 44% were of HIV-positive patients, 38 (35.85%) were among resistant. Meta-analysis performed with XDR-TB patients with primary MDR-TB. patients showed that those resistant to both CPM The foreign-born patients exhibit a higher rate of and KM, and amikacin had unfavorable outcomes, HIV coinfection than Portuguese cases (43% vs. 38% even when susceptible to several other drugs, respectively, P¼0.045). This can also be explained by suggesting the importance of these injectable drugs the fact that among the 93 foreign-born patients in in the therapeutic arsenal.16 Nowadays the use of KM the sample, 81.7% came from Africa, the region with and CPM for lengthy MDR-TB treatments is no the highest global incidence of HIV associated with longer recommended by the World Health Organiza- TB.2 tion, due to an increasing risk of treatment failure and Even though there is a downward trend in the rate relapse associated with the use of these substances.17 of MDR-TB in both groups, as shown in Supplemen- Being foreign-born was associated with unfavour- tary Table S3, the average rate among foreign-born able treatment outcome and was the only indepen- patents in 2000–2014 was 7.6 times higher than dent variable significantly associated with LTFU. The among the Portuguese born. While there is evidence foreign-born patients were younger than the average that TB transmission among those who are foreign- age observed in the Portuguese population, and were 1080 The International Journal of Tuberculosis and Lung Disease concentrated in urban and coastal regions. There is a CONCLUSION greater risk of LTFU in urban and tourist regions of Portugal has an inclusive policy for the country’s Portugal than elsewhere.18 foreign-born population. All treatment for TB and Moreover, some studies show that foreign-born MDR/XDR-TB is provided by the government free of patients exhibit a greater chance of therapeutic failure charge, and is never dependent on the legal status of when associated with socioeconomic vulnerabili- the patient. However, it is still necessary for the 19 ties. The foreign-born population live in worse country to develop new strategies that improve economic and social conditions and had less access to adherence among foreign-born patients. This is 20 the use of health services in their original countries. particularly true for patients from Africa, who need Another study on foreign-born population more careful monitoring of MDR/XDR-TB. Portugal showed that those who lived in Portugal for ,2 needs to undertake additional actions involving these years and those who were single, divorced, or communities, and to expand social protection to widowed were less likely to have a family doctor. substantially reduce LTFU. Finally, studies on the These factors had an association with reports of adherence of foreign-born patients to MDR-TB barriers to access the health system. The main treatment are scarce.24 These elements point to the obstacles reported were the difficulty of understand- need for qualitative analyses of the factors that ing how a doctor might be assigned, not being sure impact LTFU, especially among foreign-born pa- about their rights to medical care, and the long tients. waiting period for an appointment. The survey also showed that anyone who had a family doctor was Acknowledgements more likely to use health services.21 The authors would like to thank the local public health authorities Although treatment is free, TB-related costs are an in Portugal involved in TB surveillance for their continuous effort to follow up TB cases. important barrier to treatment. They include direct Conflicts of interest: none declared. and indirect medical expenses, such as transporta- tion, food, access to services, loss of income due to References work leave, etc. A study on MDR-TB patients showed that adoption of social protection measures was 1 Samuel J P, Sood A, Campbell J R, Khan F A, Johnston J C. Comorbidities and treatment outcomes in multidrug resistant associated with a lower risk of incurring total costs by tuberculosis: a systematic review and meta-analysis. Sci Rep 20% of family income and of impoverishment. It 2018; 8: 4980. should be noted that due to the long duration of 2 World Health Organization. Global tuberculosis report, treatment, affected households are especially vulner- 2017. Geneva, Switzerland: WHO, 2017. WHO/HTM/TB/ able to TB-related costs.22 2017.23. http://apps.who.int/iris/bitstream/10665/259366/ 1/9789241565516-eng.pdf?ua¼1 Accessed June 2019. Despite the fact that our study did not evaluate 3 Programa Nacional para Tuberculose. Tuberculose em access to health services, there was no significant Portugal—desafios e estrategias.´ Lisbon, Portugal: Dire¸ca˜o- difference between the time of the onset of symptoms Geral da Saude,´ 2018. https://www.dgs.pt/documentos-e- and diagnosis, which was 72 days among Portuguese publicacoes/tuberculose-em-portugal-desafios-e-estrategias- 2018-.aspx Accessed June 2019. patients and 75 among foreign-born patients, which 4 Laserson K F, Thorpe L E, Leimane V, et al. Speaking the same may indicate that there is no difference in accessing language: treatment outcome definitions for multidrug- the health system among Portuguese and foreign- resistant tuberculosis. Int J Tuberc Lung Dis 2005; 9: 640–645. born populations. While there is no difference 5Gunther¨ G, van Leth F, Alexandru S, et al. Multidrug-resistant tuberculosis in Europe, 2010–2011. Emerg Infect Dis 2015; 21: between both groups, the delay in diagnosis is very 409–416. long, which may contribute to the increase in primary 6 Ahuja S D, Ashkin D, Avendano M, et al. Multidrug resistant MDR-TB and XDR-TB cases. pulmonary tuberculosis treatment regimens and patient Death was also associated with a positive HIV outcomes: an individual patient data meta-analysis of 9,153 status. Poor outcomes and higher mortality rates are patients. PLOS Med 2012; 9: e1001300. 7 van der Werf M J, Kodmon C, Hollo V, Sandgren A, Zucs P. expected among HIV-positive patients. 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RE´ SUME´

CONTEXTE : L’incidence de la tuberculose (TB) a et´´ e de 30,5%. Ceux-ci ontet´ ´ e associés surtout au sexe diminué au Portugal. Lisbonne concentre le plus grand masculin, au fait d’être néàl’étranger etalar´ ` esistancea ` nombre de cas de TB multirésistante (MDR-TB) du la kanamycine. Le décès aet´ ´ e associé au fait d’être positif pays. Cetteetude ´ visea ` identifier les facteurs cliniques et au virus de l’immunodéficience humaine et résistantala ` démographiques associésal’´ ` echec du traitement des kanamycine. Etre néàl’étranger a entraˆıné un risque patients atteints de MDR-TB dans cette ville. 4,46 fois supérieur d’abandon du traitement qu’être ME´ THODE : Les données de 265 cas de MDR-TB, portugais. Les patients nésal’´ ` etranger sont surtout des notifiés de 2000a ` 2014 dans le district de Lisbonne immigrants africains. ontet´ ´ e recueilliesa ` partir du système de surveillance de CONCLUSION : Le résultat principal est que les patients la TB. Les cas défavorables ontet´ ´ e classés enechec, ´ nésal’´ ` etranger ont une probabilité pluselev´ ´ ee de abandon ou décès. Des régressions logistiques résultats défavorables que les patients nés en Portugal. bivariables et multivariables ont permis d’estimer les C’est pourquoi les personnes néesal’´ ` etranger requièrent facteurs associésaunr´ ` esultat défavorable, abandon et un suivi plusetroit ´ dans le cadre de la lutte contre la décès. MDR-TB. RE´ SULTATS : La proportion des résultats défavorables a

RESUMEN

MARCO DE REFERENCIA: La incidencia de tuberculosis desfavorables fue 30,5%. Estos desenlaces se asociaron (TB) se ha ido reduciendo en Portugal. Lisboa concentra sobre todo con el sexo masculino, el hecho de haber el mayor numero ´ de casos de TB multirresistente (MDR- nacido en el extranjero y la resistencia a kanamicina. La TB) del pa´ıs. El proposito ´ del presente estudio fue mortalidad se asocio ´ con la positividad frente al virus de reconocer los factores cl´ınicos y demogra´ficos asociados la inmunodeficiencia humana y la resistencia a con un desenlace terap´eutico desfavorable de los kanamicina. Los pacientes nacidos en el extranjero pacientes con MDR-TB en esta ciudad. presentaban una probabilidad 4,46 veces mayor de ME´ TODO: Se recogieron datos sobre 265 casos de abandonar el tratamiento que los pacientes portugueses. MDR-TB notificados del 2000 al 2014 en el Distrito La mayor´ıa de las personas nacidas en el extranjero eran de Lisboa, a partir del Sistema de Vigilancia de inmigrantes de Africa.´ Tuberculosis. Los casos desfavorables se clasificaron CONCLUSIO´ N: La principal conclusion ´ del estudio es como fracaso, abandono y muerte. Se aplicaron modelos que los pacientes nacidos en el extranjero tienen una de regresion ´ log´ıstica bivariante y multivariante con el mayor probabilidad de desenlaces desfavorables que los fin de determinar los factores asociados con los pacientes portugueses. En consecuencia, este grupo de la desenlaces desfavorables, el abandono y la muerte. poblacion ´ precisa una supervision ´ ma´s estrecha en el RESULTADOS: La proporcion ´ de desenlaces marco del control de la MDR-TB.