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Adjuvant immunotherapy of extensively drug-resistant tuberculosis (XDR-TB) in Ukraine

Nathalia D. Prihoda1, Olga V. Arjanova1, Larisa V. Yurchenko1, Nina I. Sokolenko1, Lyudmila A. Vihrova2, Volodymyr S. Pylypchuk3, Valéry M. Frolov4, Galyna A. Kutsyna4 1Lisichansk Regional Tuberculosis Dispensary, Lisichansk, Ukraine, 2Lisichansk Regional Hospital, Lisichansk, Ukraine; 3Ekomed LLC, Prospect Pravdy 80-A, Kiev, Ukraine; 4Luhansk State Medical University, Luhansk, Ukraine

Abstract

Conventional TB chemotherapy success rates are low in patients with extensively drug- resistant tuberculosis (XDR-TB). We treated twelve XDR-TB individuals, seven of which in addition to standard anti-TB therapy (ATT) received Immunoxel (Dzherelo), Svitanok and Lisorm - over-the-counter herbal immunomodulators. All seven patients who received adjunct immunotherapy improved clinically and radiologically and were discharged after 3.7±0.8 months, with average/median time to mycobacterial clearance 28/25 days. None of five patients on TB drugs alone improved after 9 months and one had died. Patients on immune intervention gained 9.6 kg (P=0.0001) while those on ATT lost 1.4 kg. The levels of total bilirubin had decreased from 15.6 to 10.7 umol/L. Similarly, the values of alanine transaminase (ALT) have declined from abnormally high 42.6 IU/L to normal levels 22. IU/L (P=0.23). Patients on ATT had unchanged levels of bilirubin, but their ALT declined from 29.6 to 12 IU/L (P=0.02). The levels of hemoglobin had risen from 104.1 to 118 g/L (P=0.07), whereas leukocyte counts descended to normal levels from 8.9 to 7.3 * 10 cells/L (P=0.18). Conversely, in patients on ATT leukocyte counts had risen from 8.7 to 13.8 * 109 cells/L (P=0.21), whereas hemoglobin declined to below normal levels from 116.4 to 96.6 g/L (P=0.18). These results show that immune-modulating interventions can favorably influence the effect of TB drugs. The difference between two treatment outcomes was highly significant (Mantel Haenszel odds ratio=11; P=0.0009 at 95% CI). Thus, adjunct herbal immunotherapy is safe, shortens dramatically treatment duration, and can overcome drug resistance even in patients with XDR-TB.

Keywords: Immunomodulator; MDR-TB; XDR-TB; phytoconcentrates; Mycobacterium
Running title: Immunotherapy of XDR-TB

"Corresponding author:
Ms. Galyna Kutsyna
Tel: +380508093822
Fax: +3806454347106
E-mail: kutsyna@list.ru

Introduction

The extensively resistant TB (XDR-TB) is diagnosed when M. tuberculosis bacilli in addition to lack of sensitivity to isoniazid (H) and rifampicin (R), two most commonly-used, first-line TB drugs, are also resistant to any one of fluoroquinolones, and at least one of second-line injectable drugs, e.g., capreomycin, kanamycin, and amikacin (Migliori et al., 2008). This emerging form of TB caused worldwide concern after outbreak in Kwazulu Natal province of South Africa where 52 of 53 patients with XDR tuberculosis and HIV co-infection had died within 2 weeks from the time of diagnosis (Gandhi et al., 2006). Success rates in treating XDR-TB are significantly lower than among drug-sensitive cases ranging between 29% and 67%. In addition it takes much longer (18-24 months) to achieve a cure and concerns over adverse effects of drugs became more prominent since second-line drugs are more toxic. The cost is another factor as the deployment of second-line drugs increases treatment cost by about hundred-fold. Clearly there is an urgent need to find additional therapeutic interventions that could overcome these problems. Lisichansk TB Dispensary is within Luhansk administrative region of the eastern. Ukraine with total population 2.5 million. Approximate population of registered TB patients in this region is 2 thousand. Lisichansk TB dispensary has turnover of about 600-800 patients per year. The dispensary has six medical doctors and approximately 15 medical nurses and lab technicians who care for hospitalized patients and perform the lab work. Immunomodulators Immunoxel (Dzherelo), Svitanok and Lizorm are made from a proprietary combination of medicinal plants and are commonly used in Ukraine for the management of TB and HIV infections, including patients with dual infection (Arjanova et al., 2009; Chkhetiany et al., 2007; Melnik et al., 1999; Nikolaeva et al., 2008; Prihoda et al., 2007; Zaitzeva 2008). They have been approved in 1997 by the Ministry of Health of Ukraine as functional supplements with therapeutic indications. In 1999 Dzherelo and Svitanok were specifically recommended as immune adjuvants to the therapy of pulmonary tuberculosis (Melnik et al., 1999). So far, the phytoconcentrates we have decided to use in this study have been taken safely by several hundred thousand individuals for various indications including chronic bacterial and viral infections such as TB and HIV, autoimmune diseases, and malignancy (Chkhetiany et al., 2007). In this retrospective study, conducted at Lisichansk TB Dispensary, we have compared the adjunct effect of herbal immunomodulators to outcome of treatment with conventional TB therapy.

Materials and Methods
Patients

Twelve patients with pulmonary XDR-TB were identified retrospectively, five of which received individualized TB drugs regimen and seven who received in addition to ATT an immunomodulating phytopreparations Dzherelo, Svitanok and Lizorm. All patients were males with age range between 25 and 67 years. Five presented with first-diagnosed TB and the rest were previously treated, relapsed cases of TB. All study patients presented with acute symptoms of pulmonary TB that required hospitalization. Most common symptoms were prolonged heavy cough, pain in the chest, high fever, profuse night sweats, fatigue, and loss of weight and appetite. Active pulmonary tuberculosis was certified by a medical history and clinical findings compatible with tuberculosis, a chest X-ray showing lung involvement, and positive sputum smear for acid-fast bacilli (AFB) and the culture of M. tuberculosis. The conduct of the study was approved by the internal review board (IRB) of Lisichansk TB dispensary in accordance with the Helsinki Declaration.

Treatment regimen All anti-TB drugs were procured free-of-charge through centralized national supply system of Ukraine. The over-the-counter phytoconcentrates, Dzherelo, Lizorm and Svitanok were generously supplied by Ekomed LLC. Individualized, first- and second-line anti-TB drugs were administered to all hospitalized patients based on physician's decision prior to or after results of drug susceptibility tests. In the immunotherapy group, in addition to ATT, patients
received a daily dose of Dzherelo which was given as 30 drops diluted in a half-glass of water 30 minutes before breakfast. Some patients received Immunoxel - slightly modified form of Dzherelo. The same dose, 30 drops, of Lizorm and Svitanok were given before lunch and supper respectively. The exact formula of phytoconcentrates has been described by us earlier (Prihoda et al., 2008). Sputum smear and culture examinations for AFB were performed at monthly intervals. The decision to discharge was based on at least twice- repeated negative culture outcome and satisfactory clinical and radiological findings.

TB drug resistance testing

The drug resistance to first- and second-line TB drugs was tested with commercially supplied kit (Tulip Diagnostics, Goa, India). The cultures of M. tuberculosis derived from sputum of each patient were inoculated into ready-to-use tubes containing TB drugs incorporated at manufacturer-predetermined concentrations into standard Lowenstein-Jensen agar slants. The cultures were incubated at 37° C and checked periodically until appearance of colonies in control tubes without drugs. The calculation of the proportion of resistant bacilli was done by comparing counts on drug free and drug-containing Lowenstein-Jensen medium.

Statistical analysis

The obtained results were analyzed with available online statistical software (GraphPad Software, Inc., La Jolla, CA). All statistical analyses were done on intent-to-treat basis, involving the total number of patients without subgrouping them into responders and non-responders. The stratification analysis of patients was conducted to reveal the difference between distinct treatment categories. Parametric baseline values relative to the end of study values were evaluated by paired or unpaired Student t-test. The categorical test was done by Mantel Haenszel's odds ratio calculation. The probability values were considered as significant at P<0.05 cut-off value.

Results and Discussion

None of five patients on conventional TB drugs regimen had positive outcome after 9 months of treatment and one patient died after 9.5 months. The duration of treatment in immunotherapy group ranged between 10.6-20.4 weeks with average/median 15.7/16.7 weeks (Table 1). The treatment lasted until patients were discharged from the dispensary upon twice-repeated negative culture findings and clinical and radiological improvements. The time to negative culture conversion ranged between 20-37 days with mean/median 28/25 days. Mycobacterial clearance was confirmed by repeated cultures at monthly intervals. There appears to be no difference between first-diagnosed TB cases versus chronic, previously treated TB in terms of median days to discharge, i.e., 117 vs. 105.6 or days to mycobacterial clearance, 23 vs. 30. However sample size was too small to reveal statistically significant difference.

At the end of study every patient had gained substantial lean body mass, ranging between 6 and 13 kg. The average accrual in lean body mass was 9.6 kg, which was
statistically highly significant as evidenced by a paired Student's t-test (P=0.0001) - an effect that was evident early as one month from initiation of the therapy. In contrast, patients on ATT had lost on average 1.4 kg (P=0.4).

The potential hepatotoxicity of ATT combination with herbal preparations was monitored by quantitative liver function tests. Surprisingly, despite intensive chemotherapy patients have shown signs of better liver function. The level of total bilirubin had decreased from mean 15.6 to 10.7 umol/L - a favorable change that was not statistically significant (P=0.16). Similarly, the values of alanine transaminase (ALT), another marker of liver damage, have declined from abnormally high (42.6 IU/L) to normal levels (22. IU/L) - a change that was not statistically significant (P=0.23). Patients on ATT had same levels of bilirubin but their ALT declined from 29.6 to 12 IU/L (P=0.02).

Another phenomenon observed during therapy is a reversal of baseline anemic state and pro-inflammatory condition - symptoms very common in TB. Most patients at study entry displayed signs of anemia and had abnormally elevated leukocyte counts. At the end of treatment these parameters were improved in a statistically significant manner. The levels of hemoglobin had risen from 104.1 to 118 g/L (P=0.07), whereas leukocyte counts descended to quasi-normal levels from 8.9 to 7.3 * 109 cells/L (P=0.003). In patients on ATT the reverse trend was observed. Leukocyte counts had risen from 8.7 to 13.8 * 109 cells/L (P=0.21). Whereas hemoglobin declined to below normal levels from 116.4 to 96.6 g/L (P=0.18). These results show that immune-modulating interventions can favorably influence the efficacy of TB drugs (Arjanova et al., 2009; Chkhetiany et al., 2007; Nikolaeva et al., 2008; Prihoda et al., 2007; Zaitzeva 2008). All seven patients who received ATT and immunotherapy improved clinically and radiologically and were discharged after 3.7±0.8 months, with average/median time to mycobacterial clearance 28/25 days. None of five patients on TB drugs alone improved and one had died. The difference between two treatment outcomes was statistically significant (Mantel Haenszel odds ratio=11; P=0.0009 at 95% CI).

Our results compare favorably to XDR-TB chemotherapy outcomes reported in several
recent papers. According to study by Kim et al., (2008) only 29.3% of those with XDR-TB were cured. TB therapy success rate in Russian patients with XDR-TB as reported by Keshavjee et al., (2008) was 48.3%. Earlier reported cure rates in Europe, USA, Peru and Korea were between 37.5%-67% indicating that XDR-TB poses serious clinical challenge (Edward et al., 2008; Kwon et al., 2008; Migliori et al., 2008; Mitnick et al., 2008). In conclusion, adjunct herbal immunotherapy is safe, enhances significantly treatment outcome, and can overcome drug resistance even in patients with extremely poor prognosis. Further studies are needed to confirm our findings.

Acknowledgements

We thank all participants who volunteered in this study. The support of clinical staff and technicians who contributed to this study has been of tremendous help to us. We are grateful to other colleagues who shared their insight and provided helpful suggestions based on their own experience with phytoconcentrates used in present study.

References

Arjanova OV, Prihoda ND, Sokolenko Nl, Yurchenko LV, Vihrova LA, Pylypchuk VS, Frolov VM, Kutsyna GA. Impact of adjunct immunotherapy with multi-herbal supplement Dzherelo (Immunoxel) on treatment outcomes in end-stage TB/HIV patients. 2009 (in press J Appl Res Clin Exp Ther. Chechitiany R, Pylypchuk V, Argzanova O, Prihoda N, Vichrova L, Zagaydanova E, Kutsyna G. Comparative effect of an immunomodulator Immunoxel (Dzherelo) when used alone or in combination with antiretroviral therapy in drug-naive HIV infected individuals. Intl J Biotechnol 2007;9:267-276. Edward D. Chan ED, Strand MJ, Iseman MD. Treatment outcomes in extensively resistant tuberculosis. New Engl J Med 2008;359:657-9. Keshavjee S, Gelmanova IY, Farmer PE, Mishustin SP, Strelis AK, Andreev YG, Pasechnikov AD, Atwood S, Mukherjee JS, Rich ML, Furin JJ, Nardell EA, Kim JY, Shin SS. Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 2008;372:1403-9. Kim DH, Kim HJ, Park SK, Kong SJ, Kim YS, Kim TH, Kim EK, Lee KM, Lee SS, Park JS, Koh WJ, Lee CH, Kim JY, Shim TS. Treatment outcomes and long-term survival in patients with extensively drug-resistant tuberculosis. Am J Respir Crit Care Med 2008;178:1075-1082. Kwon YS, Kim YH, Suh GY, Chung MP, Kim H, Kwon OJ, Choi YS, Kim K, Kim J, Shim YM, Koh WJ. Treatment outcomes for HIV-uninfected patients with multidrug-resistant and extensively drug-resistant tuberculosis. Clin Infect Dis 2008;47:496-502. Melnik VP, Panasyuk OV, Pylypchuk VS, Moshich OP, Procenko NM, Leonenko OM. Deployment of herbal preparations Dzherelo and Svitanok for combination therapy of pulmonary tuberculosis. Medical Institute of Ukrainian Association of People's Medicine. Information Bulletin of the Ministry of Health of Autonomous Republic of Crimea. UDK:616.24-002.5-085-038:615.017. 1999. Kiev, Ukraine. Migliori GB, Lange C, Centis R, Sotgiu G, Mütterlein R, Hoffmann H, Kliiman K, De laco G, Lauria FN, Richardson MD, Spanevello A, Cirillo DM, TBNET Study Group. Resistance to second-line injectables and treatment outcomes in multidrug-resistant and extensively drug-resistant tuberculosis cases. Eur Respir J 2008;31:1155-9. Mitnick CD, Shin SS, Seung KJ, Rich ML, Atwood SS, Furin JJ, Fitzmaurice GM, Alcantara Viru FA, Appleton SC, Bayona JN, Bonilla CA, Chalco K, Choi S, Franke MF, Fräser HS, Guerra D, Hurtado RM, Jazayeri D, Joseph K, Llaro K, Mestanza L, Mukherjee JS, Muñoz M, Palacios E, Sanchez E, Sloutsky A, Becerra MC. Comprehensive treatment of extensively drug-resistant tuberculosis. New Engl J Med 2008;359:563-74. Nikolaeva LG, Maystat TV, Pylypchuk VS, Volyanskii YuL, Masyuk LA, Kutsyna GA. Effect of oral immunomodulator Dzherelo (Immunoxel) in TB/HIV co-infected patients receiving anti-tuberculosis therapy under DOTS. Intl Immunopharmacol 2008;8:845-851. Prihoda ND, Arjanova OV, Yurchenko LV, Sokolenko Nl, Vihrova LA, Pylypchuk VS, Kutsyna GA. Open label trial of adjuvant immunotherapy with Dzherelo, Svitanok and Lizorm, in MDR-TB, XDR-TB and TB/HIV co-infected patients receiving anti-tuberculosis therapy under DOT. J Med Plant Res 2007;1:117-122. Prihoda ND, Arjanova OV, Yurchenko LV, Sokolenko Nl, Vihrova LA, Pylypchuk VS, Kutsyna GA. Adjuvant immunotherapy of tuberculosis in drug-resistant TB and TB/HIV co-infected patients. Intl J Biomed Pharm Sei 2008;2:59-64. Shah NS, Pratt R, Armstrong L, Robison V, Castro KG, Cegielski JP. Extensively drug- resistant tuberculosis in the United States, 1993-2007. JAMA 2008;300:2153-60. Zaitzeva SI, Matveeva SL, Gerasimova TG, Pashkov YuN, Butov DA, Pylypchuk VS, Frolov VM, Kutsyna GA. Efficacy and safety of phytoconcentrate Dzherelo (Immunoxel) in treatment of patients with multi-drug resistant TB (MDR-TB) in comparison to standard chemotherapy. In press Res J Med Sei. 2008.
Conclusions
  • Immunoxel is safe and reverses hepatotoxicity of TB drugs
  • Favorably affects anemia: increases hemoglobin levels
  • Has clear anti-inflammatory property: reduces high leukocyte counts
  • Helps to gain weight: mean gain 9.6 kg
  • Reduces time to negative culture conversion: median 25 days
  • Time to complete cure: 4 months
  • Success rate in our study is 100%
  • Standard TB therapy is not effective against XDR-TB: no result after 9 months. Further studies are required to confirm our findings

Baseline and outcome characteristics of XDR-TB patients treated with TB drugs without or in combination with Dzherelo, Lizorm and Svitanok

No.

Sex

Age

Type of
TB
infection
at
baseline
Resis
tance
to
TB
drugs3

Prescribed
TB drugs
regimen

Days
until
dischar
ge
Days
to
negative
culture
Weight
change
kg
Leukocyte
x 109L
Hb
g/L
Total
bilirubin
umol/L
ALT
IU/L

before

after

before

after

before

after

before

after

before

after

1

M

47

Relapse

H/R/S/K/
L

H/R/Z/S/E
Proth

Died
after
9.5
Months

No
conversion

67

55

8.9

4.0

115

90

10

12

37

12

2

M

52

Relapse

H/R/Z/S/
K/O

H/R/Z/S/E
PAS/L/A/
Cs
Still
treated
12 Mo

No
conversion

66

68

10.9

21

100

101

10

11

12

12

3

M

32

Relapse

H/R/Z/S/
K/L

H/R/Z/S/E
PAS/A

Still
treated
10 Mo

No
conversion

70

68

8,5

13.4

162

102

13

14

37

12

4

M

46

Relapse

H/R/Z/E/
S/K/L
H/R/Z/S/E/
PAS/Cs/
RFB
Still
treated
9 Mo
No
conversion

65

63

10.5

11.4

119

95

14

14

37

12

5

M

67

Relapse

H/R/E/
K/L
H/R/Z/S/E
Proth/PAS/
RFB
Still
treated
9 Mo
No
conversion

73

75

4.8

19.4

86

95

18

14

25

12



48.8
±12.
6






68.2
±3.3

66.8
±7.4

8.7
±2.4

13.8
±6.8

116.4
±28.6

96.6
±4.9

13.0
±3.3

13.0
±1.4

29.6
±11.1

12.0
±0









Mean loss
=1.4 kg
P=0.40
Mean gain
=5.1 x 109L
P=0.21
Mean loss
=19.8 g/L
P=0.18
Mean loss
=0 umol/L
P=1.0
Mean loss
=17.6 IU/L
P=0.02

6

M

42

First Rx

H/R/E/
K/O/PAS
H/R/Z/S/E/
Eth/RFB
+Dzh/Sv/Li

74

23

59

68

11.6

8.1

122

114

10.5

11.7

25

50

7

M

44

First Rx

H/R/K/L/
Eth/PAS
H/R/Z/S/E/
Eth
+Dzh/Sv/Li

143

34

63

69

4.5

6.8

120

118

18.6

10.5

12

50

8

M

35

First Rx

H/R/K/
A/C/P
H/R/Z/S/E/
Proth
+Dzh/Sv/Li

93

20

50

63

9

10

88

118

32.4

10.5

25

12

9

M

47

First Rx

H/R/S/
K/L/P
H/R/Z/S/E/
Proth/PAS
+Dzh/Sv/Li

133

22

52

62

9.1

9.1

108

116

11.7

10.7

62

12

10

M

25

Relapse

H/R/Z/O/
K/A/PAS
H/R/Z/S/E/
Proth/RFB
+Dzh/Sv/Li

89

25

65

78

8.2

6

109

120

10.5

10.5

62

12

11

M

52

First Rx

H/R/A/
P/PAS
H/R/Z/S/E/
Proth
+Dzh/Sv/Li

117

37

64

74

11

6

100

118

11.7

10.4

75

12

12

M

48

Relapse

H/R/K/O
A/PAS
H/R/Z/S/E/
Proth/RFB
+Dzh/Sv/Li

122

35

72

78

8.8

5.3

82

122

14

10.5

37

12



41.9
±9.2




110.1
±25.3
28
±7.1
60.7
±7.7
70.3
±6.6
8.9
±2.3
7.3
±1.8
104.1
±15.1

118.0
±2.6

15.6
±7.9

10.7
±0.5

42.6
±23.8

22.9
±18.5








Mean gain
=9.6 kg
P=0.0001
Mean loss
=1.6 x 109L
P=0.18
Mean gain
=13.9 g/L
P=0.07
Mean loss
=4.9 umol/L
P=0.16
Mean loss
=19.7 IU/L
P=0.23
aCriteria for definition of XDR are as per the WHO recommendations. TB drugs are
abbreviated as follows: Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E), Streptomycin (S), Levofloxacin (L), Ofloxacin (O), Ciprofloxacin (C), Pefloxacin (P), Kanamycin (K), Amikacin (A), Cs (Cycloserine), Para-aminosalicylic acid (PAS), Ethionamide (Eth), Prothionamide (Proth), Rifabutin (RFB), Dzh (Dzherelo), Sv (Svitanok), Li (Lizorm).

 

 

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