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 Table of Contents  
ARTICLE
Year : 2012  |  Volume : 1  |  Issue : 3  |  Page : 131-136

Multidrug and extensively drug-resistant tuberculosis in Lisbon and Vale do Tejo, Portugal, from 2008 to 2010


1 Programa Nacional de Luta Contra a Tuberculose, Direcção-Geral da Saúde; Centro de Patogénese Molecular, URIA, Faculdade de Farmácia, Universidade de Lisboa, Portugal
2 Programa Nacional de Luta Contra a Tuberculose, Direcção-Geral da Saúde, Portugal
3 Centro de Patogénese Molecular, URIA, Faculdade de Farmácia, Universidade de Lisboa, Portugal

Date of Web Publication28-Feb-2017

Correspondence Address:
I Portugal
Centro de Patogénese Molecular, URIA, Faculdade de Farmácia, Universidade de Lisboa, Av., Prof. Gama Pinto, 1649-003 Lisboa
Portugal
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Source of Support: None, Conflict of Interest: None


DOI: 10.1016/j.ijmyco.2012.07.001

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  Abstract 


Tuberculosis (TB) was explicitly recognized as a major global public health problem in the early 1990s and, if it is to be eliminated, it is essential that every country organize control activities in line with its own epidemiological situation.
Portugal still remains among the countries with intermediate incidence, with 2756 cases of TB diagnosed in 2009. The incidence of multidrug-resistant (MDR) TB has been decreasing, representing an average of 1.7% of the total number of TB cases, with about 25% of extensively drug-resistant (XDR) TB, and with more than two thirds residing in the region of Lisbon and Vale do Tejo (LVT).
The aim of this study is to evaluate risk factors and treatment outcomes associated with MDR and XDR-TB in LVT during the time period of 2008–2010. In 50 (2.4%) out of 2093 culture-positive TB cases from patients diagnosed in the LVT region, Mycobacterium tuberculosis (MTB) isolates were identified as MDR-TB; 12 (24%) met the criteria for XDR-TB. It was noted that HIV-positive status and retreatment cases are still closely associated with drug-resistant TB. Although the WHO target of about 75% treatment success rates for MDR-TB was not yet achieved, extensive drug susceptibility testing and the availability of second- and third-line drugs under strictly supervised treatment conditions permitted relatively good treatment success rates in MDR and XDR-TB cases in Lisbon.

Keywords: Epidemiology, Tuberculosis, Drug-resistance, Risk factors


How to cite this article:
Macedo R, Antunes A F, Villar M, Portugal I. Multidrug and extensively drug-resistant tuberculosis in Lisbon and Vale do Tejo, Portugal, from 2008 to 2010. Int J Mycobacteriol 2012;1:131-6

How to cite this URL:
Macedo R, Antunes A F, Villar M, Portugal I. Multidrug and extensively drug-resistant tuberculosis in Lisbon and Vale do Tejo, Portugal, from 2008 to 2010. Int J Mycobacteriol [serial online] 2012 [cited 2020 Apr 5];1:131-6. Available from: http://www.ijmyco.org/text.asp?2012/1/3/131/201237




  Introduction Top


Tuberculosis (TB) is a serious bacterial disease, which most commonly affects the lungs, and it is the leading cause of death from a curable infectious disease.

In the European Union (EU), TB incidence rates are among the lowest in the world. However, the epidemiological pattern varies considerably from country to country, with some countries showing steady progress towards eliminating the disease, while others still face unacceptably high incidence rates. In all countries, control efforts have to deal with the challenges of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, co-infection with human immunodeficiency virus (HIV) infection, and the concentration of cases in vulnerable groups.

In 2009, there were approximately 9.4 million TB cases in the whole world, i.e., 139 new cases per 100,000 inhabitants, with a mortality of 1.3 million people (20/100,000). Most cases (85%) still occur in Asia (50%) and Africa (30%). In the EU, 79,665 TB cases—new and retreatment cases—were reported, giving an overall notification rate of 15.8 per 100,000 population and showing an annual decrease of 3.8% [1]. Although great progress has been made in the last 15 years since the implementation of the Directly Observed Treatment, Short-course (DOTS) strategy, the emergence of MDR-TB, defined as TB with resistance to, at least, both isoniazid and rifampicin, poses a serious challenge for TB control; 23 out of 30 countries of the European Economic Area (EEA) reported MDR-TB cases, with the Baltic States, Spain, Romania and Italy reporting 50 or more cases. The overall proportion of MDR-TB amongst new and retreatment cases was 5.3% (ranging from 0% to over 50% in Lithuania or Estonia) [1],[2],[3]. XDR-TB was reported in 15 European countries. In 2009, 66 XDR-TB cases (MDR-TB with additional resistance to a fluoroquinolone and one or more of the second-line injectable drugs) were reported, with an increase from 6.1% to 7.0% since 2007 [1], and are supposedly associated with worse treatment outcomes than those with MDR-TB [4],[5],[6],[7].

In 2009, in Portugal, 2756 TB cases were diagnosed, including 2565 new cases, i.e., 24.1/100,000 population. Although it still remains among the countries with intermediate incidence—the only one in Western Europe—this represents a reduction of 8% compared with the incidence rate in 2008, which is a higher reduction than the median in the EU, and which continues the evolution towards a consistent decrease since 2002 [3]. The incidence of MDR-TB has also been decreasing, representing an average of 1.7% of the total number of TB cases in 2009 (1.2% in new cases and 7.5% in retreatments). It is comparable to the median in the EU and is virtually confined to the metropolitan areas of Porto (the second largest city of Portugal) and, mainly, Lisbon. The fact that it takes longer to treat raises the number of prevalent cases: in December 2009, the prevalence of MDR-TB was 63 cases, 24% of which were also XDR, and more than two thirds (68%) of the cases resided in LVT [3].

HIV-positive status is the major risk factor associated with TB. It is an important programmatic objective that HIV testing is performed on all TB patients, and there has been a progressive increase of its coverage. In 2009, the test covered 87% of the TB cases, confirming the prevalence of infection in 15% of cases (391 cases) which represents a decrease of 45% in the last 10 years. However, Portugal has the highest prevalence of TB-HIV throughout the EU, with an average of 2.3% of the cases, most of them (81%) concentrated in the metropolitan areas of Lisbon and Porto [1],[3].

Since 2000, TB surveillance data for Portugal is reported annually to the National TB Programme (NTP) through its Intrinsic Surveillance System, SVIG-TB; however, the intention of this research is to assess the prevalence and risk factors associated with MDR and XDR-TB.


  Materials and methods Top


Study design and data collection

All TB cases diagnosed in LVT between 2008 and 2010 were analysed. TB patient's data was collected on a standardized form by the physician [8],[9] and reported to SVIG-TB. The records included various information on each patient, including age, gender and country of origin, HIV-seropositivity status, history of previous treatment, Mycobacterium tuberculosis drug-resistance profile, treatment regimen and outcomes.

Laboratory drug susceptibility testing

Drug susceptibility testing (DST) for first-line anti-TB drugs (isoniazid, rifampicin, ethambutol, pyrazinamide and streptomycin) and for second-line drugs (ethionamide, amikacin, capreomycin, p-aminosalicylic acid, cycloserine and fluoroquinolones–ofloxacin and ciprofloxacin for the study period) or third-line drugs (linezolid) was performed by quality-assured laboratories. The BACTEC MGIT 960 (Becton Dickinson Diagnostic Systems, Sparks, MD, USA) was used for DST of first-line drugs and BACTEC MGIT 960 or the proportion method on Lowenstein–Jensen medium, or both, were used for DST of second- and third-line drugs.

Definitions

MDR-TB was defined as resistance to at least both isoniazid and rifampicin; XDR TB was defined as MDR-TB with additional resistance to a fluoroquinolone, and at least one of the injectable drugs capreomycin, kanamycin, or amikacin [10],[11]. Only cases with DST performed before initiating treatment or before 1 month of treatment were considered.

A new TB case was defined as a patient who had never had treatment for TB or who had received anti-tuberculosis drugs for less than 1month (excluding prophylactic purposes); and retreatment cases were defined as patients who had a prior history of treatment with anti-tuberculosis drugs for more than 1month (curative purposes) [12].

For the outcomes evaluation, the cohort with 24 months' treatment duration, i.e., the 2008 MDR-TB cases, was considered. A patient was classified as “cured” when he or she had completed treatment according to the country protocol and had been consistently culture-negative (with at least five results) for the last 12 months of treatment; “treatment completed” when he or she had completed treatment according to the country protocol, but did not meet the definition for cure or treatment failure or bacteriologic results were missing (i.e., <5 cultures were performed in the final 12 months of therapy) [13].

Statistical analysis

In the statistical analysis, demographic, socio-behavioural and clinical characteristics of the patients were included. Univariable analysis was performed to assess risk factors for MDR-/XDR-TB. Statistical parameters were compared by using fisher exact test or qui-squared test for categorical data and t-test for numeric data, whenever appropriate. A p-value <0.05 was defined as statistically significant.


  Results Top


Among 2093 culture-confirmed TB cases in the LVT region in the 3-year period 2008–2010, 50 (2.4%) M. tuberculosis isolates were resistant in vitro to at least isoniazid and rifampicin. Of these cases, 12 (24%) were also XDR-TB. Demographic and clinical characteristics of the studied population are described in [Table 1] and [Table 2].
Table 1: Demographic, socio-behavioural and clinical characteristics of the TB patients in the LVT region from 2008 to 2010.

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Table 2: Demographic, socio-behavioural and clinical characteristics of the XDR-TB patients in the LVT region from 2008 to 2010.

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Most of the MDR and XDR-TB patients were young adults (median age 44 ± 17 and 42 ± 16 years old, respectively) and male (78.0% and 83.3%, respectively). Almost half of the MDR-TB patients were foreign born (44%) and 40% had associated social risk factors (alcoholism being the most prevalent in 12 cases). HIV testing was reported in 37 (74%) patients—16 patients with MDR-TB (32%) and four patients with XDR-TB (33.3%) tested positive. This report found statistical relevance for MDR-TB/HIV positive co-infection (p = 0.050), but no significant differences between patients with XDR and non-XDR-TB (p = 1,000). Being foreign born was also associated with the development of MDR-TB (p = 0.015).

The majority of the MDR-TB cases were new cases (70%); however, the total proportion of MDR-TB cases from 2008 to 2010 was 2.4%, with an incidence of 1.8% amongst new cases and 9.3% amongst previously treated cases. In fact, retreatment cases were found to be a risk factor for MDR-TB (p ≤ 0.0001). Half of the XDR-TB patients were retreatment cases.

Of the 50 study patients with MDR-TB, an analysis was performed on the first- and second-line drug resistance patterns. As shown in [Table 3], the first-line drugs streptomycin (n = 39, 78%) and pyrazinamide (n = 35, 70%) and the second-line drugs fluoroquinolones (n = 13, 26%) and ethionamide (n = 19, 38%) were those with the higher resistance levels. No resistance to linezolid was found.
Table 3: First- and second-line drug resistance of the MDR-TB (n = 50) patients in the LVT region from 2008 to 2010.

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In [Table 4] the treatment outcomes of the 2008 MDR-TB cohort after 24 months of treatment are described. The overall treatment success for patients with MDR-TB was 54.6% and for patients with XDR-TB, 57.1%. After 24 months, 27.3% and 14.3% of the MDR and XDR-TB cases, respectively, were classified as “still on treatment”. However, the “still on treatment” cases should be re-classified as “lost to follow-up”, since the surveillance system sorts them as such by default if the information is not updated by the clinician at the end of the treatment.
Table 4: Outcomes for the 2008 MDR-TB cohort after 24 months of treatment.

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  Discussion Top


MDR-TB is an increasing global problem, with most cases arising from a mixture of physician error and patient non-compliance during treatment of susceptible TB. The extent and burden of MDR-TB varies significantly from country to country and region to region. Recent surveillance data, including data from Portugal, has revealed that the prevalence of these drug-resistant cases has risen to the highest rates ever recorded in its history, and previous drug treatment is the largest single risk factor for the presence of MDR-TB. Thus, drug-resistant TB reflects a failure in the implementation of an effective TB control programme [1],[2].

Proper implementation of the DOTS strategy should achieve a high cure rate for disease and curtail the development of drug resistance. Innovations in the expansion of this strategy should further facilitate its delivery and enhance its effectiveness. However, established MDR-TB is notoriously difficult to treat, and it needs the use of alternative specific anti-tuberculosis chemotherapy regimens. These regimens comprise a combination use of second-line drugs that are generally more costly and toxic and have to be given for longer periods. The technical key components for a successful drug-resistant TB programme comprise three major points: (1) more accurate and rapid diagnostic methods implementation, including molecular tests, and regular drug susceptibility testing; (2) reliable supply of quality treatment regimens under directly observed settings; and (3) infection control programmes. The effectiveness of these major points is evaluated with a specific reporting system for MDR-TB cases that allow the monitoring of the individual treatment outcome of the patient and the overall performance of the TB control programme.

In Portugal, the incidence of MDR-TB appears to have been decreasing, representing an average of 1.5% of the total number of TB cases in 2009 (1% among new cases and 5.2% in retreatments). It is comparable to the median of the EU and is largely confined to the metropolitan areas of Porto and, mainly, Lisbon. The fact that it is harder to cure and has a much longer treatment course does increase the number of prevalent cases. However, in 2007, a national network for the management of the MDR-TB cases was created [3], and it may be one of the reasons why these cases have started to decline steadily. In December 2010, the prevalence of MDR-TB was 53 cases, 32% of which met the criteria for XDR, and more than two thirds reside in the LVT region.

Here, this research presented the results of a national surveillance database on clinical, demographic and social-behavioural parameters associated with MDR and XDR-TB in the population of the LVT region between 2008 and 2010. The number of MDR-TB cases decreased significantly during this period: 23 cases in 2008, 16 in 2009 and 11 in 2010. This accentuated decline is corroborated by the DST coverage target, which remains above 80%, pointed out by WHO for representativeness to the data [14]. Although the level of multidrug resistance is not high, MDR-TB is proving to be endemic, without being restricted to any risk factor, occurs in adults and children, and in most cases does not have any epidemiological link to other cases ([Table 1] and [Table 2]). In fact, its endemic character is reflected by the proportion of MDR-TB in new cases—more than 70% of the cases are not related to previous treatment (of the 50 MDR-TB patients diagnosed, only 30% had been previously treated for TB). However, the prevalence amongst retreatment cases—9.3% amongst culture-positive TB patients—still makes previous treatment one of the major risk factors known to be associated with the development of resistance. As shown in [Table 1], MDR-TB is closely related with retreatment cases (p ≤ 0.0001), HIV positive status (p = 0.050) and being foreign-born (p = 0.015).

In this cohort, strains of M. tuberculosis in 12 (24%) out of 50 patients with MDR-TB also met the case definition for XDR-TB. Opposing to most of the alarming reports on the spread of XDR-TB among HIV-seropositive persons [15], this research found that HIV co-infection was not related with XDR-TB (p = 1.00). Also not related with XDR-TB was being foreign-born (p = 0.512). Previous treatment (p = 0.084) and incarceration (p = 0.054) were the demographic characteristics more statistically associated with developing XDR-TB.

This endemic character and the realization that, in many cases, the therapeutic options are extremely limited have led to the undertaking of an analysis of the prevalence of resistance to the various first- and second-line drugs ([Table 3]). The major point of this study is the possible definition of treatment regimens to be applied in patients with high suspicion of MDR-TB or whose MDR-TB was detected using molecular testing without the complete pattern of resistance. In fact, national guidelines that propose standardized regimens to be applied on each of the cases were recently published by the NTP [16],[17].

It is known that patients with XDR-TB have a higher risk for treatment failure or even death than those with MDR-TB [18],[19]. In infections with MDR-TB, drug resistance to additional first-line drugs other than isoniazid and rifampicin is related to negative treatment outcomes [20]. Resistance to a fluoroquinolone and injectable second-line drugs also increases the risk for treatment failure and death in these cases [21],[22] as XDR-TB defining drugs are those considered essential to achieving successful outcomes in MDR-TB cases [23],[24],[25]. The WHO 2011 report defines as a target over 75% of treatment success for MDR-TB [14]. As shown in [Table 4] for the 2008 cohort, which has already completed 24 months of treatment, success rates of 54.6% of the MDR-TB cases and 57.1% of the XDR-TB cases were achieved. Although it is still some distance away from the target defined by WHO, it can be considered relatively good rates compared with some of the recent published studies [18],[20],[25]. These success rates may be as a result of the use of linezolid, a third-line anti-TB drug, to which no resistance was yet reported in the LVT region. Although it is toxic, it is established that its efficacy and tolerability suggest that a linezolid-containing combination treatment might be an effective option against MDR and XDR-TB cases [24],[26]. For this purpose, drug-susceptibility testing for linezolid is now included in the laboratory routine. However, to support this fact—that linezolid has a major role in the treatment of MDR and XDR-TB—other clinical and surveillance studies should be conducted.

In conclusion, it was found that the endemic character of MDR- and XDR-TB cases may be threatening TB control, and the major risk factor associated with the increased risk of developing MDR-TB was, as expected, a previous treatment. More resources and aggressive TB control efforts are required; largely through more accurate and rapid drug susceptibility testing implementation and regular drug-resistance surveillance.


  Conflict of interest statement Top


None declared.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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