Treatment Outcome of Multidrug/Extensively Drug-resistant Tuberculosis in
Latvia, 2000–2004
Online Data Supplement
Methods:
Latvia is a newly independent country of 2.5 million people on the
eastern side of the Baltic Sea. The treatment cohort consisted of all cases
that began individualized treatment for MDR-TB and XDR-TB with anti-TB
SLDs between January 1, 2000 and December 31, 2004. SLD drug
susceptibility testing (DST) was begun on all MDR-TB cases starting in 2000.
Treatment for TB is not available in the private sector. Incarcerated cases
diagnosed and treated from 2001 were also included in the treatment cohort.
Definitions
We defined time to culture conversion as the time between starting
treatment and the first of two consecutive negative cultures taken 30 days apart.1
Low body-mass index for both men and women was defined as a BMI less than
18.5.2
MDR-TB cases were stratified into four drug resistance groups: 1)
resistance to at least one injectable and a fluoroquinolone (XDR-TB), 2)
resistance to a fluoroquinolone but not an injectable, 3) resistance to at least one
injectable but not a fluoroquinolone, and 4) all others.
We combined treatment cure and completion as treatment outcome
success, and death (from any cause) and failure as poor outcomes. Treatment
1
effectiveness was determined as the proportion of all cases with a successful
outcome.
Laboratory testing
Culture colony counts were not reported for cultures performed using
BACTEC. DST for pyrazinamide, ofloxacin, and capreomycin was done using
BACTEC.3 The quality of FLD susceptibility testing was assured by the
Swedish Institute for Infectious Disease Control, the World Health
Organisation-designated supranational reference laboratory for the Baltic
region. Quality control of FLD DST has been previously described. 4 External
quality assessment of SLD DST is performed by the Belgian Tropical Disease
Institute in Antwerp, Belgium. Drug susceptibility tests for second-line drugs
were done using the following concentrations: kanamycin (30.0 ug/mL),
capreomycin (40.0 ug/mL on L-J, 2.5 ug/mL on BACTEC), ofloxacin (2.0
ug/mL ), cycloserine (30.0 ug/mL), prothionamide (30.0 ug/mL), and paraaminosalicylic acid (0.5 ug/mL).
Treatment
Treatment of MDR TB follows national guidelines for the treatment of MDR
TB that were first written in 1999. Injectables are the cornerstone of MDR TB
management in Latvia. Because kanamycin had been used for many years in the
former Soviet Union, kanamycin was used before capreomycin if the case’s
isolate was susceptible to kanamycin or to both drugs, or if the patient had no
history of kanamycin use. Regimens were individually modified when results of
SLD drug susceptibility testing were received in order to treat the person with at
2
least 4 oral drugs to which his/her isolate was susceptible. If the results of drug
susceptibility testing were discrepant, the susceptibility result showing less
resistance was used to tailor a regimen. Drugs that showed susceptibility at least
once were included in the treatment regimen. Drugs with a resistant DST result
were included in the regimen if the regimen did not contain at least three drugs to
which the isolate was susceptible.
Adherence was measured by weeks of interrupted treatment. Heavy
alcohol use was diagnosed (not quantified) by the treating clinician. Adjunctive
resectional lung surgery was used for patients that met criteria: extensive
cavitation with or without culture conversion; failure of medical treatment to
affect culture conversion; or significant pulmonary hemorrhage.5
Data collection
We collected baseline demographic and risk factor information including
age, sex, household location and size, employment status, alcohol use, current or
past history of imprisonment, height and weight, human immunodeficiency virus
(HIV) status, previous treatment for TB and MDR-TB, prior contact with an MDRTB case, TB surgical history, the number of anti-TB drugs to which the case’s M.
tuberculosis strain was resistant at treatment initiation, anti-TB drugs used for 3
months or more (regimen drug), susceptible anti-TB drugs used, treatment
duration, drug side effects, and adherence to treatment. Data for sputum smear
and culture conversion and final treatment outcome were also extracted.
Statistical analysis
3
Continuous variables were reported as means if they had a normal
distribution, and non-normal continuous variables were presented as medians.
All statistical tests were two-sided, and no multiple comparison adjustments were
made.
To evaluate the effects of demographic, clinical and treatment variables on
poor outcome, we checked the proportionality of the Cox proportional-hazards
model by observing a constant vertical difference for plotted curves of the log
cumulative hazard for each significant variable. When proportionality was not
satisfied, we performed a time-dependent analysis (by time to culture conversion).
The second episode for thirty-two cases retreated during the cohort period was
excluded from the multivariable analysis to eliminate patient duplication. Cases
were censored if they did not reach a poor treatment outcome of death or failure
at the end of the cohort period.
Results of screening
Between 2000–2004, 1,180 pulmonary MDR-TB cases were diagnosed
and registered in Latvia. Of these, 141 (11.9%) never initiated treatment due to
death before treatment or diagnosis, refusal of treatment, or drug intolerance that
prevented the use of second-line drugs. Pretreatment deaths were not
statistically more likely to have XDR-TB. Five cases began treatment the year
after their cohort registration period (2000–2004) in 2005. Twenty-three cases
that started treatment during 2000–2004 were registered the year before or the
year after 2000–2004 and were added to the cohort. Thirty prisoners who began
4
treatment during 2000 were excluded from the analysis because outcome data
were not available. 1 case on treatment was excluded from the outcome analysis.
During the cohort period two XDR-TB cases relapsed, twenty-eight MDRTB cases were treated for two distinct episodes, and one was retreated twice
(different DST pattern).
References
1. Laserson KF, Thorpe LE, Leimane V, et al. Speaking the same language:
treatment outcome definitions for multidrug-resistant tuberculosis. Int J TB Lung
Ds 2005;9(6):640-645.
2. Bailey KV, Ferro-Luzzi A. Use of body mass index of adults in assessing
individual and community health status. Bull WHO 1995;73(5):673-80.
3. World Health Organization. Use of liquid tuberculosis culture and drug
susceptibility testing (DST) in low and medium income settings: Summary report
of the expert group meeting on the use of liquid culture media. Geneva,
Switzerland: WHO, 26 March 2007.
4. Leimane V, Riekstina V, Holtz TH, et al. Clinical outcome of individualised
treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort
study. Lancet 2005;365:318-326.
5. Dravniece G, Cain KP, Holtz TH, Riekstina V, Leimane V, Zaleskis R.
Resectional lung surgery for extensively drug-resistant tuberculosis. European
Respiratory Journal 2009;34(1):180-183.
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Appendix Table 1. Variables Associated with Poor Treatment Outcome among 881 MDR-TB Cases, Univariate Analysis, Latvia,
2000-2004*
Characteristic
Age
Under 45 years
Over 45 years
BMI low
Yes
No
Existing co-morbidities
Any
None
HIV status
Infected
Uninfected
Category of MDR-TB
Previously treated for MDR-TB
Previously treated for tuberculosis
Never treated for TB
Site of MDR-TB
Pulmonary and extrapulmonary
Pulmonary
Radiological findings at onset
Bilateral cavitary
Unilateral cavitary
Number with
poor outcome
#
Percent with
poor
outcome
%
Univariate
unadjusted risk ratio,
95% CI
#
98/493
86/388
19.9
22.2
0.90 (0.69-1.16)
--
0.41
45/174
134/688
25.9
19.5
1.33 (0.99-1.78)
--
0.06
82/413
19.8
P value
-4/22
179/855
18.2
20.9
0.87 (0.35-2.13)
--
0.75
48/100
96/450
40/331
48.0
21.3
12.1
3.97 (2.78-5.66)
1.77 (1.26-2.48)
--
<0.001
<0.001
5/49
179/832
10.2
21.5
0.47 (0.20-1.10)
--
0.06
72/192
80/405
37.5
19.8
3.33 (2.29-4.84)
1.75 (1.20-2.57)
<0.001
0.003
6
Non-cavitary
Sex
Male
Female
Location
Riga city
Other
Birthplace
Latvia
Other
Housing
Renter
Own one’s home
Employment
Pensioner/retired/student
Unemployed
Employed
Living situation
With 2 or more
With 1 person
Alone
Started treatment in prison
Yes
No
History of incarceration
Any
None
Past/current heavy alcohol use
Ever
None
32/284
11.3
--
153/664
31/217
23.0
14.3
1.61 (1.13-2.30)
--
0.006
55/302
129/579
18.2
22.3
0.82 (0.62-1.09)
--
0.16
156/770
28/111
20.3
25.2
0.80 (0.57-1.14)
--
0.23
48/191
136/690
25.1
19.7
1.28 (0.96-1.70)
--
0.10
75/263
99/470
10/148
28.5
21.1
6.7
4.22 (2.25-7.91)
3.12 (1.67-5.82)
--
0.001
<0.001
58/332
51/265
42/181
17.5
19.3
23.2
0.75 (0.53-1.07)
0.83 (0.58-1.19)
--
0.12
0.31
17/61
167/820
27.9
20.4
1.37 (0.89-2.09)
--
0.16
78/260
105/620
30.0
16.9
1.77 (1.37-2.29)
--
<0.001
122/479
62/402
25.5
15.4
1.65 (1.25-2.18)
--
0.001
7
Injection drug use ever
Yes
No
Treatment Characteristic
Smear positive at treatment onset
Yes
No
Culture positive at treatment onset
Yes
No
Colony count of initial culture, if +
3-4
1-2
MDR/XDR-TB resistance pattern
Resistant to FQ and 1 injectable
[Resistant to FQ & both injectables]
Resistant to FQ but not injectables
Resistant to injectables but not FQ
All other MDR-TB patients
Number of drugs to which MTB was
resistant
>7 drugs
5-6 drugs
2-4 drugs
Number of sensitive drugs used for 3
months or more
0-3
4
>5
3/36
173/820
8.3
21.1
0.39 (0.13-1.18)
--
0.06
122/144
55/428
84.7
12.9
6.59 (5.10-8.52)
--
<0.001
171/705
13/175
24.3
7.4
3.27 (1.90-5.60)
--
<0.001
115/372
55/324
30.9
16.9
1.82 (1.37-2.42)
--
<0.001
27/45
[14/19]
4/18
87/390
66/428
60.0
73.7
22.2
22.3
15.4
3.89 (2.81-5.39)
4.78 (3.37-6.77)
1.44 (0.59-3.52)
1.45 (1.08-1.93)
--
<0.001
<0.001
0.43
0.01
77/276
77/361
30/244
27.9
21.3
12.3
2.27 (1.54-3.33)
1.73 (1.18-2.56)
--
0.001
0.004
43/103
38/148
103/630
41.8
25.7
16.4
2.55 (1.91-3.41)
1.57 (1.13-2.18)
--
<0.001
0.008
8
Number of resistant drugs used for 3
months or more
0
1
>2
Adjuvant surgical management
Yes
No
Culture conversion
Conversion after 62 days
Conversion before 62 days
Started negative
Interruption of treatment
For 5 weeks or more
Less than 5 weeks
Patients experiencing adverse events
during treatment
Any
None
100/607
41/152
43/122
16.5
27.0
35.3
0.47 (0.35-0.63)
0.77 (0.54-1.09)
--
<0.001
0.14
15/77
169/804
19.5
21.0
0.93 (0.58-1.49)
--
0.75
153/416
18/289
13/176
36.8
6.2
7.4
4.98 (2.91-8.53)
0.84 (0.42-1.68)
--
<0.001
0.63
79/402
105/479
19.7
21.9
0.90 (0.69-1.16)
--
0.41
37/169
147/712
21.9
20.6
1.06 (0.77-1.46)
--
0.72
*146 defaulters and one case still on treatment excluded from analysis
9