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Adjuvant Immunotherapy of Extensively Drug-Resistant Tuberculosis (XDR-TB) in Ukraine

'NafhaliaD. Prihoda, 'Olga V. Arjanova, 'Larisa V. Yurchenko, 'Nina I. Sokolenko, 2Lyudmila A. Vihrova, 3Volodymyr S. Pylypchuk, 4Valery M. Frolov and4GalynaA. Kutsyna 'Lisichansk 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 very 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 - ove - 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 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 uM L-1, similarly the values of alanine transaminase (ALT) have declined from abnormally high 42.6 IU L"1 to normal levels 22. IU L"1 (p = 0.23). Patients on ATT had unchanged levels of bilirubin, but their ALT declined from 29.6 to 12 IU L"1 (p = 0.02). The levels of hemoglobin had risen from 104.1 to 118 g L-1 (p = 0.07), whereas, leukocyte counts descended to normal levels from 8.9 to 7.3x10s cells L-1 (p = 0.003). Conversely, inpatients on ATT leukocyte counts had risen from 8.7 to 13.8x10s cells L-1 (p = 0.21), whereas, hemoglobin declined to below normal levels from 116.4 to 96.6 g L-1 (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 treatment duration and can overcome drug resistance even in patients with XDR-TB.

Key words: Immunomodulator, MDR-TB, XDR-TB, phytoconcentrates, Mycobacterium

INTRODUCTION
The extensively resistant TB (XDR-TB) is diagnosed whenM 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 a!., 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 a!., 2006). Success rates in treating XDR-TB are significantly lower than among drugsensitive cases ranging between 29 and 67%. In additionit 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.
 

Immunomodulators Immunoxel (Dzherelo)Svitanok and Lisorm are made from aproprietary 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 a!., 2009; Chkhetiany et a!., 2007; Melnik et al., 1999; Nikolaeva et al., 2008; Prihoda et al., 2007; Zaitzeva et al., 2008). They have been approved in 1997 by the Ministry of Health of Ukraine as functional supplements with therapeutic indications. Dzhereloand 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
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. 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 Lisorm. 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, DzhereloLisorm 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 min before breakfast. Some patients received Immunoxel-slightly modified form of Dzherelo. The same dose, 30 drops, of Lisorm and Svitanok were given before lunch and supper, respectively. The exact formula of phytoconcentrates has been described by 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 ofM 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 analysis 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 uM L-1 -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-1) to normal levels (22. IU L-1) -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"1 (p = 0.02).Another phenomenon observed during therapy is a reversal of baseline anemic state and proinflammatory 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-1 (p = 0.07), whereas leukocyte counts descended to quasi-normal levels from 8.9 to 7.3x10s cells L 1 (p = 0.003). Inpatients on ATT the reverse trend was observed. Leukocyte counts had risen from 8.7 to 13.8x10s cells L-1 (p =0.21) whereas hemoglobin declined to below normal levels from 116.4 to 96.6 g L"1 (p = 0.18).  
Table1: Baseline and outcome characteristics of XDR-TB patients treated with TB drugs without or in combination with Dzherelo (Immunoxel)Svitanok and Lisorm    
   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 ah, 2008; Prihoda et ah, 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).
Present 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; Mitnicke/o/., 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 present findings.
ACKNOWLEDGMENTS     
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.
Kwon, Y.S., Y.H. Kim, G.Y. Suh, M.P. Chung and H. Kim et a!., 2008. Treatment outcomes for HlV-uninfected patients with multidrug-resistant and extensively drug-resistant tuberculosis. Clin. Infect. Dis.,47: 496-502.
Melnik, V.P., O.V. Panasyuk, V.S. Pylypchuk, O.P. Moshich, N.M. Procenko and O.M. Leonenko,1999. Deployment of herbal preparations Dzherelo and Svitanok for combination therapy of pulmonary tuberculosis. Medical Institute of UkrainianAssociation 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, G.B., C. Lange, R. Centis, G. Sotgiu and R. Mutterlein et al., 2008. TBNET Study Group. Resistance to second-line injectables and treatment outcomes in multidrug-resistant and extensively drug-resistant tuberculosis cases. Eur. Respir. J., 31: 1155-1159.
Mitnick, CD., S.S. Shin, K.J. Seung, M.L. Rich and S.S. Atwood et al., 2008. Comprehensive treatment of extensively drug-resistant tuberculosis. New Engl. J. Med., 563: 563-574.
Nikolaeva, L.G., T.V. Maystat, V.S. Pylypchuk, Y.L. Volyanskii, L.A. Masyuk and G.A. Kutsyna, 2008. Effect of oral immunomodulator Dzherelo (Immunoxel) in TB/HIV co-infected patients receiving anti-tuberculosis therapy under DOTS. Intl. Immunopharmacol., 8: 845-851.
Prihoda, N.D., O.V. Arjanova, L.V. Yurchenko, N.I. Sokolenko, L.A. Vihrova, V.S. Pylypchuk and G.A. Kutsyna, 2007. Open label trial of adjuvant immunotherapy with DzhereloSvitanok and Lisorm, in MDR-TB, XDR-TB and TB/HIV co-infected patients receiving anti-tuberculosis therapy under DOT. J. Med. Plant Res., 1: 117-122. Prihoda, N.D., O.V. Arjanova, L.V. Yurchenko, N.I. Sokolenko, L.A. Vihrova, V.S. Pylypchuk and GA. Kutsyna, 2008. Adjuvant immunotherapy of tuberculosis in drug-resistant TB and TB/HIV co-infected patients. Int. J. Biomed. Pharm. Sci., 2: 59-64.
Zaitzeva, S.I., S.L. Matveeva, T.G. Gerasimova, Y.N. Pashkov, D.A. Butov, V.S. Pylypchuk V.M. Frolov and G.A. Kutsyna, 2008. Efficacy and safety of phytoconcentrate Dzherelo (Immunoxel) in treatment of patients with multi-drug resistant TB (MDR-TB) in comparison to standard chemotherapy. Res. J. Med. Sci.      

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