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UDC 616.24-002.5-078-053.2
Efficacy of Complex Therapy and Possible Adverse Reactions of
Respiratory Apparatus Multi-Drug Resistance Tuberculosis Treatment
M. V. Pavlova1, A. A. Starshinova1, N.V. Sapozhnikova1,
I. V. Chernokhayeva1, A. A. Yakovchuk1, L.I. Archakova 1,2, P. K.
Yablonsky1,2
1
FSBI «Saint-Petersburg Phthisiopulmonology Research Instituteе »
of the Ministry of Healthcare of the Russian Federation
2
Saint-Petersburg State University,
Saint-Petersburg, Russia
Introduction
By the latest estimates of the WHO, multi-drug resistance and extensive
resistance (MDR and XDR respectively) tuberculosis makes about 9.0 % of the
newly detected cases and 20 % of previously treated cases in the world. Almost
60 % of MDR TB cases in the world are detected in India, China, Russian
Federation and South Africa [25, 29, and 30].
Stabilization of the epidemic process in the Russian Federation is noted
over the last years [10]. However, this trend is not persistent and this is related to
increasing
prevalence
of
multi-drug
resistant
(MDR)
Mycobacterium
tuberculosis (MTB) [16, 17, 19, and 23]. Share of patients infected with the
MDR-TB among the newly detected cases of microbiologically proven
respiratory apparatus tuberculosis has doubled in the Russian Federation for the
period from 2002 to 2012 year.
Low efficacy of the current MDR-MTB therapy which is below 48.7% in
the RF and in the world [16, 26, 27, 28] is also associated with high incidence of
adverse reactions concurrent with administration of the required drug combination
[4, 6, 11, 4, 15].
Incidence of adverse drug reactions reaches 62-65 % [2], which is first of
all explained with toxicity of the second-line drugs [1, 8, 9, and 28]. Development
of the adverse reactions due to chemical therapy of tuberculosis requires
prevention, monitoring and correction thereof and thus may require further
decrease of the drug dosage and complete withdrawal of the drug in particular
cases. Certainly it's all significantly decrease treatment efficacy for the tuberculosis
cases [4, 5, 6, 20], restricts possibility of complete and continuous chemical
treatment course and afterwards affects level of the tuberculosis-suffering patient
disability[1, 22].
Development of new anti-tuberculosis drugs to which the MTB has no
resistance yet is one of the ways to solve the problem. Perchlozone® was
registered (Russia, Pharmasyntez OJSC, marketing authorization No. ЛП-001899
dated 09.11.12) in 2012 in the Russian Federation when clinical trials of 4thioreidoiminomethylpiridiny within the frames of II/III phases was completed.
Perchlozone® has a clear selective inhibitory effect on viability of the
mycobacterium tuberculosis. It has an apparent anti-tuberculosis effect on drugsusceptible and drug-resistant strains of mycobacterium and it is recommended for
use to treat MDR-MBT tuberculosis [13, 15]. At that, the results of the clinical
trials’ third phase showed significant number of adverse reactions that have not
been noted for standard regimens of the tuberculosis treatment.
Therefore, it is very timely and urgent to conduct studies of combined
therapy efficacy, incidence and severity of adverse reactions during the treatment
of multi-drug resistant tuberculosis with thioureido-iminomethyl pyridium
(perchlozone) and without it.
The study objectives are to determine efficacy and safety of therapy in
case of inclusion of thioureido-iminomethyl pyridium (perchlozone) into the
treatment regimen for respiratory apparatus tuberculosis with multi-drug resistant
causative agent.
Materials and Methods
During the period from the beginning of 2013 to June 2014 49 patients
were examined and treated at the facilities of a therapeutics department of the
FSBI "SPbNIIF (St. Petersburg Phthisiopulmonology Research Institution)" of
the Russian Federation Ministry of Healthcare. They were 19 males and 30
females aged from 18 to 70 years who were receiving a complex therapy with
regards to infiltrative pulmonary tuberculosis (14,3%; 7), infiltrative pulmonary
tuberculosis in exsolved and dissemination phase (55,1%; 27), disseminated
(12,2%; 6), cavernous (6,1%; 3) and fibrotic-cavernous tuberculosis (12,2%; 6)
with multi-drug resistance of the causative agent which was ascertained by
molecular genetic methods of analysis (MGA). As per biological analysis data
all the patients had resistance to rifampicin and isoniazid that was confirmed by
the results of microbiological tests. Almost all the patients had resistance to
streptomycin (81.6%; 40), most had resistance to ethambutol (59.1%; 29),
quarter of all had resistance to ethionamide (22.4%; 11) and prothionamide
(10.2%; 5), ofloxacin (8.1%; 4), kanamycin (10.2%; 5), capreomycin (8.1%; 4).
Resistance to pyrazinamide also took place (6.1%; 3). Overwhelming majority
was represented by newly detected cases (93.8, 46). The patients were
randomized using random number generator (version 14.0) and distribution 1:1
into two comparable groups on the basis of clinical roentgenological and
laboratory parameters. The main group (I) (n=25) received combination of 6
anti-tuberculosis drugs including perchlozone, the comparison group (II) (n=24)
received similar combination of 6 anti-tuberculosis drugs including levofloxacin
or ofloxacin as per the guidance documents [7]. All the cases were newly
detected.
Duration of treatment with 6 anti-tuberculosis drugs (fluoroquinolone
(levofloxacin
or
ofloxacin)/perchlozone,
pyrazinamide,
capreomycin,
cycloserine/terizidone and PAS, ethambutol/prothionamide/ethionamide) was 6
months. Average daily dosage of perchlozone was 10 to 12 mg/kg. 6-months
duration of perchlozone regimen is based on the results of non-clinical studies
[13]. The patients did not undergo surgical treatment.
Criteria of inclusion were: age from 18 to 70 years; newly detected
microbiologically proven tuberculosis of respiratory apparatus, presence of
MDR-MTB determined using molecular genetic methods of analysis (MGA),
and mutations associated with resistance at least to R or R and H.
Criteria of exclusion were: tumours in the history; severe or chronic
somatic disease in decompensation stage: availability of data on any DR not
coming within MDR definition including concurrent resistance of MBT to
aminoglycosides or fluoroquinolones (extensive drug resistance); HIV infection;
intolerance to the drugs included in the treatment regimen in history;
tuberculosis of other locations including generalized forms.
A complex examination including assessment of clinical symptoms and
respiratory manifestation intensity, severity of roentgenological changes, sputum
analysis for presence of MBT and evaluation of drug susceptibility. Complex
roentgenological examination was performed using spiral computed tomography
of a thoracic cage («Aquilion-32», a multi-detector row CT scanner). Complex
laboratory examination included luminescent bacterioscopy, inoculation of
diagnostic materials into solid and liquid nutrient medium, determination of
MBT DNA using analysis of real-time polymerase chain reaction (PCR) by
GeneXpert. Status of liver, kidneys and body systemic reactions was checked
every 2 weeks through biochemical and clinical parameters of blood.
Basic criteria of the therapy short-term efficacy were relief of clinical
manifestations of the disease and respiratory symptoms, microbiological
improvement and roentgenological dynamics as per a developed rating scale and
the guidance documents [7, 12]. Analysis of results was performed in the month
3 and the month 6 from the beginning of the therapy.
As per the WHO definition, adverse drug reaction is “a response to a drug
which is noxious and unintended and which occurs at doses normally used for
prophylaxis, diagnosis, or therapy of diseases". A term of "side effect” is
introduced in the Russian Federation. It means a body response occurred due to
administration of a drug at doses recommended for prophylaxis, diagnosis, therapy
of a disease or rehabilitation from the disease in an application instruction of the
drug (Federal Law of the Russian Federation dated April 12, 2010. № 61-ФЗ "On
Drug Circulation").
Adverse reactions are classified according to types recommended by the
WHO and applied for monitoring of adverse drug reactions (ADR) as follows: type
A (dose-related or ADR associated with pharmacodynamics of the drug, toxic
effect thereof; type B (allergic ADR); type C (effects of prolonged administration
with associated drug dependence) and type D (delayed ADR) [2]. Monitoring and
assessment of the adverse reactions were performed using globally adopted 5grade scale of Common Terminology Criteria for Adverse Events (CTCAE),
version 3.0 [24]. Relief of adverse reactions was provided as per the
methodological recommendations and research data [2, 9, and 18].
Statistical processing of the data was performed using "Statistica"version
6.0 and SPSS® version 16.0 software. Quantitative data ware assessed as М±SD,
where M is an arithmetic mean and SD is a standard deviation. An analysis of
differences was performed and the parameters considered significant at level of
р<0.05. Parameters of relative risk (RR) and odds ratio (OR) were also
calculated [3].
Results and Discussion
Efficacy of the chemical therapy was analyzed by the month 3 and the
month 6 at the end of the intensive phase in both groups. Relief of the
intoxication symptoms was already statistically more significant in the group I
by the month 1 of the therapy: 60% (15) versus 33.3 % (7), χ2 = 4.71, p<0.05. By
the month 3 relief of respiratory symptoms and intoxication were observed in
80% (20) of cases in the main group whereas the same in the comparison group
was observed only in half of the cases (66.7% (16)).
Microbiologically negative results were achieved at the main group (I)
by the month 3 which were statistically more significant than in group II: 172.0% (18) versus 2 – 37.5% (9), χ2 = 4.08, p<0,05. By the month 6 of the
therapy the microbiological analysis showed negative results with statistical
significance for almost all of the main group patients (I): 96.0% (24) versus
58.3% (14), χ2=9.97, р<0.01 (Figure 1).
Positive roentgenological dynamics in lungs (resorption of infiltrative
changes, regression of destruction cavities and closure thereof (40.0% (10)
versus 25.0% (6), χ2=7.01, р<0.01) had statistically more significant results in
the main group: 80% (20) versus - 50% (12), χ2= 4.86; р<0.05. By the month 6
of the treatment the destruction cavities' closure was observed in 100% (25) of
cases in the main group and in 87.5% (21) of cases in the comparison group
(Fig.2).
The data obtained clearly demonstrate high efficacy of the treatment
regimen including perchlozone in combination with 5 anti-tuberculosis drugs in
comparison with similar regimen with levofloxacin/ofloxacin.
Monitoring of the adverse reactions in the groups showed that incidence
thereof is comparable (group I – 76.0 % (Cl 95% 56.0-4.0; RR=0.7; OR=3.16);
group II – 70.8% (Cl 95% 62.5-4.0; RR=0.7; OR=2.4). At that risk (RR) of
adverse reactions is the same in both groups with a scant margin of OR value in
the group I. As per assessment of adverse reaction according to CTCAE scale
almost all of the reactions both in the main and in the comparison groups were
correspondent to the 1st or 2nd severity grade which are mild (1) adverse
reactions (with symptoms relieved without symptomatic treatment) and
moderate (2) adverse reactions (symptoms relieved after correspondent
management). One patient of the main group had the 3rd severity grade adverse
events. There were no adverse reactions of the 4th and 5th severity grades
observed in the groups.
Almost all of the adverse reactions were correspondent to type A
reactions which are associated with pharmacokinetics or toxicity of the
formulation: 72.0% (I) versus 70.8% (II). Type B adverse reactions (pyretic
fever) took place in 16.0 % (4) of cases of the main group; type C reactions
(effects of prolonged administration associated with drug dependence
development) was in 36.0 % (9) of cases (after the month 3 of the therapy).
There were no similar reactions observed in the group II.
The results of the adverse reaction monitoring by systems are presented
in Table 1
Gastrointestinal adverse reactions were observed in 56.0 % (14) of cases
in the group I and were manifested as diarrhoea (the 1st severity grade in 85.7 %
and the 2nd severity grade in 14.2%), nausea (the 1st severity grade in 85.7 %,
the 2nd severity grade in 7.1 % and the 3rd severity grade in 7.1 %), vomiting
(the 1st severity grade in 85.7 % and the 2nd severity grade in 14.2 %). These
reactions were observed in 62.5 % (15) of cases in the comparison group i.e.
more often than in the group I; the only observations were diarrhoea and
vomiting of the 1st severity grade. Risk of these adverse reactions in the both
groups was comparable; OR of the group II was slightly higher in the group II
(Table 2).
Relief of the adverse reactions was achieved through changes of drug
administration mode i.e. after meals or during the meals, by enzymatic drugs, by
proton pump inhibitors. Some cases required prescription of probiotics.
Metoclopramide (cerucal) was prescribed to prevent nausea at dose 10 mg 3 to 4
times a day 30 minutes prior to the anti-tuberculosis drug administration.
Vomiting and diarrhoea of the 2nd severity grade was managed by correction of
the water-electrolytic balance with parenteral saline administration [2].
There were no hepatobiliary dysfunctions characterized by cholecystitis
development, liver dysfunctions (jaundice, tremor, and hepatic coma), and
functional changes of pancreas and pancreatitis development observed in the
groups. There were metabolic disorders, which were observed more often in the
group II (44.0 % (I) versus 60.0 % (II)) and were characterized by increase of
ALT, AST and bilirubin levels.
Risk of metabolic reactions development (OR) and odds ratio (RR) in
the group II was significantly higher. Severity of these disorders in the group I
was as follows: the 1st grade (ALT, AST levels increase by 2.5 times, bilirubin
level increase by 1.5 times higher than the accepted limit) in 81.8 % (9) of cases,
the 2nd grade (ALT, AST levels increase by 2.5 to 5.0 times, bilirubin level
increase by 1.5 to 3.0 times higher than the accepted limit) in 18.2 % (2) of cases.
In the group II the severity of the above disorders was as follows: the 1st grade
in 83.3 % (10) of cases and the 2nd grade in 16.7 % (2) of cases. A significant
difference was not obtained.
Metabolic disorders of the cases were managed by symptomatic therapy
(remaxol, mafusol, reamberin, essentiale forte, phosphogliv, heptral etc.) [18].
The drug administration was continued in case of the 1st severity grade toxicity,
In case of the 2nd severity grade the therapy was suspended until the decrease of
the parameter values. Decrease of the parameter values more often (80 %) took
place by the day 5 or 6 of the treatment and normalization was achieved by the
day 10.
Neurological reactions (drowsiness, vertigo) were observed in 28 % (7)
of cases in the group I and in 33.0 % (8) of cases in the group II. Vitamins of B
group, glycine and glutamic acid were included in the main therapy in order to
relieve neurotoxic effect of the anti-tuberculosis drugs [2, 9]. Two patients of the
group II suffered disorientation of the 1st grade.
Dermatological adverse reactions were observed in 32.0 % (8) of cases
in the main group (I) and in 20.8 % (5) in the comparison group (II): A
significant difference was not obtained. There were rash with desquamation,
pruritus, acneiform rash, urticaria observed. The changes was of the 1st severity
grade in 80 % of cases excluding 3 patients from group I and 2 patients from
group II with the 2nd severity grade, whose cutaneous eruption required
symptomatic therapy. Antihistamines [9] were added into the therapy in order to
relieve the cutaneous adverse reactions, at that no drug withdrawal including
perchlozone required.
General cardiotoxic changes took place with similar incidence in the first
(28.0 % (7)) and in the second (16.7 % (4)) groups. All the changes were
detected through ECG and were referred to the 1st severity grade. The above
disorders did not require additional therapy. Monitoring of cases was performed.
Endocrine adverse reactions (changes in blood glucose level in case of
diabetes
in
history
(2);
oedema,
drowsiness,
hypotony
along
with
hypothyroidism (6)) were noted in 18.4 % (9) of cases in the group I with
statistically significance. It should be noted that the above changes did not
depend on sex and were observed in males (44 % (n=4)) and females (56 %
(n=5)) to the same extent and did not lead to any difficulties in everyday
activities
but
required
correcting
therapy
under
surveillance
of
an
endocrinologist and were referred to the 2nd severity grade.
In case of the drug hypothyroidism the patients underwent thyroid gland
function evaluation and an endocrinologist consulting with the following
prescription of levothyroxine sodium at daily dose 25-150 μg 30 minutes prior to
the breakfast [9], at that no withdrawal of perchlozone required. Hormonal
therapy provided relief of the hypothyroidism clinical manifestations within 2
weeks from the beginning of the levothyroxine sodium administration and
improvement of laboratory manifestations within 2 months.
Allergic adverse reactions (combination of transient rash and fever) also
took place with statistic significance in 8.2 % (4) of cases in the main group I,
which were accompanied by fever higher than 38oC and were referred to the 2nd
severity grade. Hyperthermia was relieved only by non-steroidal antiinflammatory drugs (NSAID) prescribed (diclofenac, ketorol etc.) [9],
administration of analgin is contraindicated [13].
Thus, the therapeutic regimen including perchlozone proved high
efficacy in treatment of the respiratory apparatus tuberculosis and proved to be
comparable with the standard therapeutic regimen including 6 anti-tuberculosis
drugs in number of the adverse reactions not exceeding the 1st and 2nd severity
grades, therefore this therapeutic regimen is considered less toxic in view of
higher efficacy. The data obtained are to be analysed further when the
continuation phase is completed and delayed results of the therapy by the months
12-18 are obtained.
CONCLUSION
Use of thioureido-iminomethyl pyridium (perchlozone) in complex
therapy of the respiratory apparatus tuberculosis with multi-drug resistant MBT
during the intensive phase of the therapy (6 months) showed high efficacy as per
the basic criteria: negative results of microbiological tests and positive
roentgenological dynamics.
Number of adverse reactions as per the “Common Terminology Criteria
for Adverse Events, version 3.0” international program showed no statistically
significant differences in groups excluding endocrine and allergic reactions. All
the reactions were referred to mild or moderate severity grade and were relieved
with symptomatic and hormonal therapy.
Thus, the gastrointestinal adverse reactions were relieved through standard
management. In case of the increased functional parameters of liver and the
metabolic adverse reactions a symptomatic therapy was prescribed along with
continued anti-tuberculosis therapy in case of mild severity reactions and
suspension of the therapy until the parameters' normalization in case of moderate
severity reactions. Development of the drug hypothyroidism is possible by the
month 3 of the therapy by perchlozone and requires levothyroxine prescription and
surveillance of an endocrinologist. Hyperthermia development requires prescription
of non-steroidal anti-inflammatory drugs only since analgin is contraindicated. Mild
adverse reactions developing during perchlozone administration do not require
withdrawal thereof. Well-timed correction of the adverse events does not affect the
therapy
efficacy.
Pavlova Maria Vasilievna, head of Pulmonary Tuberculosis Therapy Department,
professor, M.D., FSBI «Saint-Petersburg Phtisiopulmonology Research Institute»
of the Russian Federation Ministry of Healthcare, 191036, Saint-Petersburg,
Ligovsky av., 2—4, tel.: 8(812) 5792501, e-mail: [email protected]
* - р 0.05-statistically significant difference between the groups
** - р 0.001-statistically significant difference between the groups
Fig. 1. Parameters of microbiological tests results of the patients suffering
pulmonary tuberculosis with multi-drug resistant causative agent
** - р 0.01-statistically significant difference between the groups
Fig. 2. Roentgenological dynamics in comparison group during the therapy
Table 1.
Adverse reactions in the main and control groups as per the “Common
Terminology Criteria for Adverse Events, version 3.0” program
Main Group
(n=25)
%
n
Gastrointestinal tract 56.0
14
Metabolic reactions 44.0
11
Neurological
28.0
7
reactions
Control Group
(n=24)
%
n
62.5
15
60.0
15
33.0
8
x2
p
0.08
1.68
0.16
>0.1
>0.1
>0.1
Endocrine reactions
18.4
9
0
0
10.58
<0.01
Cutaneous reactions
Cardiotoxic
disorders
Allergic adverse
reactions
32.0
28.0
8
7
20.8
16.7
5
4
0.78
0.9
>0.5
>0.1
8.2
4
0
0
4.18
<0.05
Table 2.
Development risk and odds ratio of the adverse events
Adverse events
Main group
Comparsion group
RR
ОR
RR
ОR
0.5
1.3
0.6
1.6
Metabolic reactions
0.4
0.8
0.6
1.6
Neurological
0.3
0.4
0.3
0.5
Endocrine reactions
0.4
0.5
0
0
Dermatological
0.3
0.5
0.2
0.5
0.3
0.4
0.2
0.2
0.16
0.2
0
0
Gastrointestinal
tract
reactions
reactions
Cardiotoxic
disorders
Allergic reactions
Summary
Efficacy of Complex Therapy and Possible Adverse Reactions of
Respiratory Apparatus Multi-Drug Resistance Tuberculosis Treatment
M. V. Pavlova, A. A. Starshinova, N.V. Sapozhnikova,
I. V. Chernokhayeva, A. A. Yakovchuk, L.I. Archakova, P. K. Yablonsky
Treatment of tuberculosis with multi-drug resistant causative agent
(MDR) is a complex problem. Use of thioureido-iminomethyl pyridium
(perchlozone) in a complex therapy of the pulmonary tuberculosis with multidrug resistant causative agent significantly increased efficacy of the therapy
within 6 months as per the basic criteria i. e. negative results of microbiological
tests and positive roentgenological dynamics.
Monitoring and evaluation of the adverse reactions did not show
statistically significant differences in number of the adverse reactions excluding
endocrine and allergic disorders during the perchlozone administration in
combination with the other drugs. All the adverse reactions were referred to mild
and moderate severity grade and were corrected symptomatically according to
the gastrointestinal, allergic and neurological adverse reactions. Possible
development of the hypothyroidism after the month 3 of the therapy requires
hormonal therapy and endocrinologist surveillance. Mild adverse reactions
developing during perchlozone administration do not require withdrawal thereof.
Well-timed relief of the adverse reactions during the period of the antituberculosis drug administration including regimen with thioureido-iminomethyl
pyridium (perchlozone) as well does not affect efficacy of the respiratory
apparatus tuberculosis treatment with multi-drug resistant causative agent during
6 months.
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Information on the Authors
1. Pavlova Maria Vasilievna, head of Pulmonary Tuberculosis Therapy
Department, professor, M.D., FSBI «Saint-Petersburg Phtisiopulmonology
Research Institute» of the Russian Federation Ministry of Healthcare, 191036,
Saint-Petersburg, Ligovsky av., 2—4, tel.: 8(812) 5792501, e-mail:
[email protected]
2. Starshinova Anna Andreyevna, head of Phtisiopulmonology Department,
professor, M.D., FSBI « Saint-Petersburg Phtisiopulmonology Research Institute»
of the Russian Federation Ministry of Healthcare, 191036, Saint-Petersburg,
Ligovsky av., 2—4, tel.: 8(812) 5792501, e-mail: [email protected]
3. Yablonsky Piotr Kazimirovich, director of FSBI « Saint-Petersburg
Phtisiopulmonology Research Institute» of the Russian Federation Ministry of
Healthcare, M.D., 191036, Saint-Petersburg, Ligovsky av., 2—4, tel.: 8(812)
5792501, e-mail: [email protected]
4. Sapozhnikova Nadezhda Valentinovna, senior staff scientist of Pulmonary
Tuberculosis Therapy Department, Candidate of Medicine, FSBI « SaintPetersburg Phtisiopulmonology Research Institute» of the Russian Federation
Ministry of Healthcare, 191036, Saint-Petersburg, Ligovsky av., 2—4, tel.: 8(812)
5792501, e-mail: : [email protected]
5. Chernokhaeva Irina Vladislavovna, doctor in charge of Pulmonary Tuberculosis
Therapy Department, FSBI « Saint-Petersburg Phtisiopulmonology Research
Institute» of the Russian Federation Ministry of Healthcare, 191036, SaintPetersburg, Ligovsky av., 2—4, tel.: 8(812) 5792501, e-mail: [email protected]
6. Archakova Ludmila Ivanovna, M.D., manager of Pulmonary Tuberculosis
Therapy Department, FSBI «Saint-Petersburg Research Institute of
Phtisiopulmonology» of the Russian Federation Ministry of Healthcare, 191036,
Saint-Petersburg, Ligovsky av., 2—4, tel.: 8(812) 5792501, e-mail: spbniif
[email protected]
Captions
Fig. 1 Parameters of microbiological tests results of the patients suffering
pulmonary tuberculosis with multi-drug resistant causative agent
Fig. 2. Roentgenological dynamics in comparison group during the therapy.