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Effective Tuberculosis Control in the Setting of High Level Anti-Tuberculosis Drug Resistance

 Rediger
  Published: 15.12.09 Updated: 16.12.2009 15:40:55

V. Riekstina, I. Sture, V. Leimane, J. Leimans
State Agency of Tuberculosis and Lung Diseases, Riga, Latvia

Citation: Riekstina V., Sture I., Leimane V., Leimans J. Effective tuberculosis control in the setting of high level anti-tuberculosis drug resistance.EpiNorth,2009;10(3):128-135.

Abstract
Latvia adopted the directly observed therapy short-course (DOTS) strategy in 1996 and subsequently introduced MDR TB management in 1998. Data from the National Tuberculosis Registry and MDR TB database were used for the descriptive analysis performed in this study.
The rate of newly diagnosed patients decreased from 74 to 49 per 100,000 population from 1998 until 2007. A similar tendency was registered for patients diagnosed with MDR TB; 335 and 108 patients in 1997 and 2007, respectively. The proportion of MDR TB among previously treated cases started to decline in 2003 and among new cases in 2007. HIV prevalence among new cases increased from 0.5% in 2000 to 4.6% in 2007. Treatment success for MDR TB cases is lower than treatment success for new cases in DOTS program (68% and 76%, respectively) due to higher default and failure rates. Cure rates for new TB cases including MDR TB increased to 84%. The prevalence of extensively drug-resistant (XDR) TB cases in the MDR TB cohort increased from 2.5% in 2001 to 9% in 2007.
The establishment of sound TB control including DOTS as well as MDR TB management has led to an improvement in the TB epidemiological situation over the past 8 years in Latvia. Challenges for the TB program are management of TB/HIV cases and MDR TB treatment defaulters and failure cases.

Introduction
Multidrug resistant tuberculosis (MDR TB) is increasing in many parts of the world (1). MDR TB poses challenges to national TB control programs (NTP) due to longer duration of treatment, higher level of mortality, lower cure rates and increased financial resources needed to administer second-line drugs. The Baltic countries present the highest rates of TB and MDR TB in the European Union (2). Latvia adopted the DOTS in 1996 and subsequently introduced countrywide MDR TB management in 1998. Several previous studies by Latvian NTP report the effectiveness of TB and MDR TB management (3,4). The aim of this study was to present epidemiological trends of TB in Latvia during the last ten years and to document how NTP can control TB by implementing a countrywide integrated approach to TB and MDR TB.

Methods
Descriptive analysis was performed using data from the National Tuberculosis Registry and MDR TB database. The National Tuberculosis Registry database includes all TB cases including the prison sector diagnosed in Latvia since 1996. Individual data including drug sensitivity testing results are collected. The database for MDR TB registration and outcome analysis was developed in 2000.
Sputum specimens from all patients are subjected to Mycobacterium tuberculosis culture and drug susceptibility testing at the time of diagnosis. Rapid diagnostic methods (BACTEC, Hain test) are used for patients at high risk for MDR TB. The laboratory reports all drug susceptibility tests to the registry. All MDR TB cases diagnosed in laboratory are discussed with clinicians and validated before entering in registry. A centralized system for monitoring and supervision has been established.

Results
Registered tuberculosis cases
Since independence from the former Soviet Union in 1991, Latvia has experienced an increase in TB morbidity together with the appearance of drug resistant and multidrug resistant tuberculosis. In 1991, the incidence of TB was 29 cases per 100,000 population, increasing to 74 cases per 100,000 in 1998 and then declining to reach 49 per 100,000 in 2007 (Figure 1). Patients diagnosed with MDR TB for the first time present a similar tendency: 47, 335 and 108 MDR TB cases were registered in 1994, 1997 and 2007, respectively.
Half of the registered new cases present with at least one social risk factor and many patients have overlapping factors. Among the cases registered in 2007, 43% were unemployed, 31% were alcohol abusers, 9% had a history of incarceration and 27% of all cases had contacts with known TB cases.

Figure 1. Incidence of TB and number of MDR TB in Latvia, 1991 – 2007

Figure 1. Incidence of TB and number of MDR TB in Latvia, 1991 – 2007

 

 

 

 

 

 

 

 

 

 

 



A similar tendency in incidence was registered among all age groups; adults, adolescents (15 – 17 years) and children (0 – 14 years). The highest incidence was registered among the economically productive age groups (25 – 54 years old). The incidence per 100,000 was 28.4 among women and 69.1 among men in 2007, i.e. 2.4 times higher among men then women (Figure 2).

Figure 2. Incidence of TB by age group and gender, Latvia, 2007

Figure 2. Incidence of TB by age group and gender, Latvia, 2007

 

 

 

 

 

 

 

 

 

 


Tuberculosis in children
TB cases among children constituted 5 – 9% out of all new cases during 1998 – 2007 (Table 1). The first MDR case among children was diagnosed in 2000 and 1 – 5 cases were diagnosed each year during 2002 – 2006.

Table 1. Reported TB cases in children, Latvia, 1998 - 2007

  

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

Registered cases among children (0 – 14)/ зарегистрированные случаи ТБ у детей (0 – 14 лет)

125

129

144

162

111

110

110

66

84

57

% out of all TB cases / % от всех случаев ТБ

6.9

7.7

8.4

9.4

7.2

7.4

8.0

5.3

7.3

5.3

MDRTB (cases) / МЛУ ТБ (количество случаев)

0

0

1

0

5

4

4

1

3

0

Treatment outcomes
Treatment outcome cohort analysis was introduced in 1996. The outcome “MDR TB” was applied to MDR TB cases diagnosed at treatment initiation (Figure 3) and these cases were consequently registered to category IV. The WHO goal to cure 85% of patients through the DOTS program in settings with high levels of MDR TB is difficult to achieve. However, by including the results of the MDR TB treatment in the comprehensive results, the overall treatment success rate increased from 75/78% to 84% (5).

Figure 3. Treatment outcomes of confirmed pulmonary TB cases, 1998 – 2006

Figure 3. Treatment outcomes of confirmed pulmonary TB cases, 1998 – 2006

 

 

 

 

 

 

 

 

 

 


Retreatment cases
In addition to existing categories “New” and “Relapse” cases, categories “Treatment after failure” and “Treatment after default” were implemented in 1998. 14 - 16% of all registered cases were retreatment cases (relapses, retreatment after default and retreatment after failure) during 1998 – 2007 (Figure 4).

Figure 4. Number of registered TB cases, Latvia, 1998 – 2007

Figure 4. Number of registered TB cases, Latvia, 1998 – 2007

 

 

 

 

 

 

 

 

 

 

 


 

Extrapulmonary tuberculosis

Extrapulmonary tuberculosis was diagnosed among 11 – 18% out of all new cases during 1998 – 2007 (Table 2). There were 137 cases registered in 2007 and the infection sites included intrathoracic lymph nodes (53 cases), pleura (47), bone and joint TB (15), urogenital tract (9), skin (6), peripheral lymph nodes (4), meningitis (2) and other (1). 51 (37%) cases were confirmed by culture and 2 were MDR TB cases (one pleuritis and one spondylitis).

Table 2. Prevalence of extrapulmonary tuberculosis, Latvia, 1998 – 2007

 

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

No./ количество

295

278

285

312

224

183

205

148

124

137

% ofallTBcases /

 % от всех случаев ТБ

16.2

16.6

16.6

18.0

14.6

12.4

14.9

12.0

10.8

12.7

 

 

 

 

 

Tuberculosis and HIV co-infection
Since the first patient was registered with TB/HIV co-infection in 1994, the number of patients diagnosed with both infections continues to increase each year (Figure 5). HIV prevalence among new cases increased from 0.5% in 2000 to 4.6% in 2007. Between 1994 and 2007, 312 cases of TB/HIV coinfection were registered and 23 of these persons had 2 episodes of tuberculosis. Among TB/HIV cases 18% were diagnosed with MDR TB.

Figure 5. Number of TB cases with HIV co-infection, Latvia, 1994 - 2007

Figure 5. Number of TB cases with HIV co-infection, Latvia, 1994 - 2007

 

 

 

 

 

 

 

 

 

 

 


MDR TB
All MDR TB cases (resistance to at least rifampicin and isoniazid) detected in the laboratory have been registered in the MDR TB database since 2001. 232 cases were registered in 2001 and number declined thereafter to 108 cases in 2007 (Table 3). Regarding the MDR TB epidemiological situation, it is important to evaluate not only number of cases registered during the given year, but also the point prevalence. The number of MDR TB prevalent cases has decreased each year since 2001.

Table 3. Number of registered MDR TB cases, Latvia, 2001 – 2007

Year / год

Total

TB cases (extra-pulmonary and pulmonary) / общеечислослучаевТБ

(внелегоч-ного и легочного)

Extra - pulmonary TB / внелегоч-ныйТБ

Pulmonary TB / легочный ТБ

Prevalence

(numberofcases)* / Распростра-

ненность

(число случаев) *

Total

pulmonaryTB / общее число случаев легочного ТБ

Nevertreated / Не проходили лечение

Previouslytreated / Ранее проходили лечение

2001

232

3

229

97

132

539

2002

212

5

207

83

124

481

2003

163

4

159

79

80

439

2004

187

6

181

105

76  

425

2005

153

4

149

95

54

359

2006

143

6

137

81

56

303

2007

108

2

106

66

40

244

* Number of patients at the end of the year including cases diagnosed during previous years, but still having active disease (receiving treatment, defaulters and failure cases).

The proportion of MDR TB among previously treated cases started to decline after the implementation of the DOTS programme. The proportion of MDR TB among new cases was stable for 5 years, but starting declining in 2007 (Table 4).

Table 4. Proportion of MDR TB (pulmonary and extrapulmonary TB) in relation to previous treatment status, Latvia, 2003 – 2007

Year / год

Never treated  

(MDR Cases / Total) / не получали

 лечение

(случаи МЛУ / общее число)

Previously treated

(MDR Cases / Total) / ранее получали лечение

(случаи МЛУ/ общее число)  

2003

8.3%

(80 / 962)

42.5%

(96 / 226)

2004

12.5%

(112 / 896)

40.2%

(84 / 209)

2005

10.6%

(91 / 860)

35.7%

(65 / 182)

2006

10.7%

(85 / 796)

33.3%

(57 / 171)

2007

7.2%

(58 / 810)

24.2%

(40 / 165)

All MDR TB patients start treatment at category IV using ofloxacin, moxifloxacin, p-aminosalicylic acid, protionamide, cycloserine, terizidone, thioacetazone, kanamycin, capreomycin, amikacin, clarithromycin, amoxicillin. In addition, patients who have already been treated with second line drugs (8 – 12% out of all cases in the cohort) are started on MDR TB treatment again known as MDR retreatment (Table 5).  The prevalence of XDR TB cases (MDR TB + resistance to fluorquinolone and injectable drugs) in the cohort increased from 2.5% in 2001 (6 cases) to 9% in 2007 (10 cases). Treatment success in MDR TB cases was lower than in cases susceptible to treatment (66 – 71%) due to higher default and failure rates (Figure 6).

Table 5. XDR TB among MDR TB treatment cohorts, Latvia, 2001 – 2007

 

2001

2002

2003

2004

2005

2006

2007

TB cases in cohort / случаи ТБ в когорте

245

205

165

208

155

136

117

Of  which MDR TB retreatment cases / из них случаи повторного лечения МЛУ ТБ

22 (9%)

16 (8%)

22 (13%)

26 (13%)

19 (12%)

19 (14%)

18 (15%)

Of which XDR TB / из них ШЛУ ТБ

6 (2.5%)

11 (5%)

8 (5%)

19 (9%)

12 (8%)

12 (9%)

10 (8.5%)


Figure 6. MDR TB treatment outcomes, Latvia, 2000 – 2005

Figure 6. MDR TB treatment outcomes, Latvia, 2000 – 2005

 

 

 

 

 

 

 

 

 

 

 


 

Discussion

Our results demonstrate that individualized MDR TB treatment using an integrated countrywide approach to TB and MDR TB management can effectively reduce the MDR TB incidence and prevalence. The establishment of sound TB control including appropriate TB treatment using DOTS and infection control has led to a rapid downward trend of acquired MDR tuberculosis in Latvia. The high and stable proportion of primary MDR TB suggests that MDR TB transmission will be sustained for a long time in our society. The 9 – 14% failure rate among MDR TB patients is one reason for transmission. Failure cases have incurable disease and these patients need palliative care and infection control measures.

The early diagnosis of MDR TB and timely start of category IV treatment reduces MDR TB transmission. The availability of rapid diagnostic methods and access to second-line drugs in countries with a high level of MDR TB is important.  MDR TB management can be scaled-up through access to Global Fund support and high quality second-line drugs through the WHO Green Light Committee mechanism. The Green Light Committee made it possible for Latvia to obtain full coverage of MDR TB treatment during 2000-2001.

The proportion of XDR among MDR TB cases increased from 5% in 2001 to 9% in 2007 partly due to the number of MDR TB patients who had received several courses of MDR TB treatment. The absolute number of XDR TB cases is small and did not have a significant impact on the overall MDR TB situation. Despite well organized MDR TB treatment, additional resistance can develop for patients with advanced TB disease due to ineffective treatment with second line drugs, side effects and other concomitant conditions. The development of new effective TB drugs may safeguard these patients from treatment failure and death, as well as shorten the duration of treatment and improve adherence. The default rate among MDR TB patients was 2 times higher than among sensitive TB patients despite social support provided to patients during treatment. One area of especial concern for TB management in Latvia is the growing HIV epidemic. However, we do not see a growing proportion of MDR TB among HIV-positive persons, apparently due to the decrease of the total number of MDR TB cases and proper management.

Our experience indicates that for countries with a high level of MDR TB it is valuable to evaluate the final cohort analysis, including results of MDR TB treatment, 2 years after case registration, as well as the total number of MDR TB cases (prevalence). These data support NTP management and planning.

Lastly, the provision of treatment with high quality second line drugs for all MDR TB cases is most important for effective control.

Conclusions
The establishment of sound TB control including DOTS and MDR TB management has resulted in an improvement of the TB epidemiological situation over last 8 years in Latvia. We observed a decline in registered TB cases (including prisons) and MDR TB cases. Challenges for the TB program are proper management of TB/HIV cases and MDR TB treatment defaulters and failure cases. Rapid diagnosic methods and new drugs are essential to prevent the spread of MDR and XDR TB infection.

References

  1. World Health Organization. Global Tuberculosis Control, 2009. Epidemiology, Strategy, Financing. WHO/HTM/TB/2009.411.
  2. Tuberculosis surveillance in Europe, 2007. European Centre for Disease Prevention and Control, 2009.
  3. Leimane V, Riekstina V, Holtz T.H., et al. Clinical outcome of individualised treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study. Lancet.2005;365:318-26.
  4. Leimane V. Leimans J. Tuberculosis control in Latvia: integrated DOTS and DOTS – plus programmes. Euro Surveill. 2006;11:29-33.
  5. Riekstina V, Leimane V, T.H.Holtz T.H., et al. Treatment outcome cohort analysis in an integrated DOTS and DOTS-Plus TB program in Latvia. Int J Tuberc Lung Dis. 2007;11:585-7.

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