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Effect of solid formulation of Immunoxel (Dzherelo)

Effect of solid formulation of Immunoxel (Dzherelo) as an adjuvant immunotherapy in treatment of ТВ and ТВ/HIV co-infected patients

Olga V. Arjanova -1, Nathalia D. Prihoda -1, Larisa V. Yurchenko -1, Nina I. Sokolenko -1, Lyudmila A. Vihrova - 2, Volodymyr S. Pylypchuk - 3, Valery M. Frolov - 4, Galyna A. Kutsyna - 4*
1-Lisichansk Tuberculosis Dispensary, Lisichansk, Ukraine; 2-Lisichansk Regional Hospital, Lisichansk, Ukraine; 3-Ekomed LLC, Kyiv, Ukraine; *4-Luhansk Regional AIDS Center and Luhansk State Medical University, Luhansk, Ukraine

ТВ and ТВ/HIV co-infected patients received either first-line anti-TB therapy (ATT; Arm A; N=20) or ATT + Immunoxel (Arm B; N=19) - an oral immunomodulator used as an adjunct therapy. In previous studies Immunoxel was formulated as alcohol-water solution of medicinal herbs. In this study a new solid, sublingual formulation of Immunoxel was tested to determine whether it will be as effective as liquid formula. At the end of one-month of follow-up, 17 (89.5%) versus 2 (10.5%) patients on Dzherelo cleared Mycobacterium tuberculosis in sputum samples, whereas only 7 (35%) vs 13 (65%) had conversion (p=0.0006). In ATT arm the body weight at baseline was 62.6±8.3 kg, after one month they have gained 1.1 kg (P=0.03). The mean starting weight in Immunoxel arm В was 54.1±7.5 kg, the immunotherapeutic intervention helped them to gain 2.8kg (p=0.0000004). The blood analysis revealed that hemoglobin (Hb) had increased from 116.1 to 119 (+2.95; P=0.03) in arm A, whereas in those who received Immunoxel Hb rose from 117.3 to 127.7 (+10.4; P=0.00007). Erythrocyte sedimentation rate in arms A and В decreased from 19.1 to 13.1 (P=0.00001) and 20.5 to 10.5 (P=0.0003). The leukocyte count decreased from 10.8 to 9 (P=0.0007) and 9.5 to 5.8 (P=0.00005). Clinical improvement was seen in 7 out 20 and 18 out 19 in arms A and В respectively. In each arm one patient died at the end of follow-up. The arm A and arm В had 7 and 2 patients co-infected with HIV who seemed to respond to therapy at the same rate as ТВ patients. These findings indicate that solid formulation of Dzherelo is equally effective as liquid formulation and contributes positively to the clinical efficacy of tuberculosis drugs.

INTRODUCTION

 
We and our clinical collaborators in Ukraine have worked on immunotherapy of ТВ over past 10 years.
 
We have used locally-produced, plant-derived immunomodulator Dzherelo (Immunoxel) and have reported encouraging results and published the data in a dozen of Russian- and English-language medical journals [1-7].
However, in previous studies Immunoxel - an oral immunomodulator used as an adjunct to ТВ therapy - was formulated as alcohol-water extract of medicinal herbs.
 
In this study a solid, sublingual, sugar-based formulation of Immunoxel was tested to determine whether it will be as effective as liquid formula.

MATERIALS AND METHODS

 
The study was conducted at the Lisichansk Regional ТВ Dispensary which administers the anti-TB therapy to 600-800 inpatients annually.
The main criteria for the eligibility were an informed consent and positive sputum smear.
Patients were randomly selected among those who were admitted to a special ward in which difficuIt-to-treat cases are managed.

 

Over half of patients in this facility require individualized treatment rather than WHO-recommended standard ATT regimen.
 
All patients were bed-ridden and had fever, cough and other common ТВ symptoms such as chest pain, dyspnea, hemoptysis, weight loss and anorexia.
 
The patients' age, gender, body weight, severity and form of the disease were matched in order to minimize the statistical bias due to population heterogeneity.
 
The anti-TB drugs were procured free-of-charge from the national supply system administered by the Ministry of Health of Ukraine.
 
The supplies of Immunoxel and placebo pills were provided by Ekomed company.
 
Standard ТВ therapy consisted of daily doses of Isoniazid (H) 300 mg; Rifampicin (R) 600 mg; Pyrazinamide (Z) 2,000 mg; Streptomycin (S) 1,000 mg; and Ethambutol (E) 1,200 mg. Individualized therapy comprised first- and second-line anti-TB drugs as decided by a physician prior to or after results of drug susceptibility tests.
 
The study lasted one month and primary end-point sputum conversion was evaluated at the end of study.
 

RESULTS

 
At the end of one-month of follow-up, 2 (10.5%) vs 17 (89.5%) patients had cleared M. tuberculosis in sputum samples and 7 (35%) vs 13 (65%) had culture conversion (P=0.0006) in arms A and В respectively.
 
In ATT arm the body weight at baseline was 62.6±8.3 kg, after one month the average gain was 1.1 kg (P=0.03).
 
The mean starting weight in Immunoxel arm was 54.1 ±7.5 kg, the immunotherapeutic intervention helped them to gain 2.8 kg (P=0.0000004).
 
The hemoglobin (Hb) had increased by 2.95 g/L from 116.1 to 119 (P=0.03) in arm A, whereas those who received Immunoxel had Hb risen by 10.4 g/L from 117.3 to 127.7 (P=0.00007). 
Erythrocyte sedimentation rate in arms A and В decreased
from 19.1 to 13.1 (P=0.00001) and 20.5 to 10.5 (P=0.0003)
respectively.  The leukocyte count decreased from
 
10.8 to 9 x109 (P=0.0007) and 9.5 to 5.8 x109 (P=0.00005).
 
Clinical improvement was seen in 7 out 20 and 18 out 19 patients in arms A and B. In each arm one patient died at the end of follow-up.
 
The arms A and В had 7 and 2 patients co-infected with HIV who seemed to respond to therapy at the same rate as ТВ patients.
 
Other solid formulations of Immunoxel are now being tested and results will be available in near future.

CONCLUSIONS                                                                       

 
  One pill of Immunoxel given once-per-day is safe; has not produced any adverse effects.
 
 Administration of Immunoxel with 1st- or 2nd-line ТВ drugs resulted in clearance of M. tuberculosis in sputum smears of 89.5% patients vs. 10.5% among placebo recipients.
 
*  Sputum conversion occurred very fast - only 1 month treatment was needed.
No difference was seen when 1st diagnosed ТВ was compared to re-treated ТВ, MDR-TB or HIV-TB - the proportion of converted patients and time to conversion were identical.
 
* Immunoxel reversed ТВ-associated wasting; average weight gain was 2.8 kg vs. 1.1 kg in placebo.
 
* Immunoxel eliminated ТВ-associated fever.
* Immunoxel demonstrated anti-inflammatory effect. Erythrocyte sedimentation rate and leukocyte counts reverted back to normal.
* Immunoxel is affordable; easy to administer; stable at room temperature, without need for cold-chains; and is made from readily available natural source.

REFERENCES

 
1 Prihoda N.D., Arjanova O.V., Yurchenko L.V, Sokolenko N.I., Vihrova L.A., Pylypchuk VS., Kutsyna G.A.: Open label trial of adjuvant immunotherapy with Dzherelo, Svitanok and Lizorm, in MDR-TB, XDR-TB and ТВ/HIV co-infected patients receiving anti-tuberculosis therapy under DOT. J. Med. Plant Res. 1, 117-122 (2007).
 
 
2.  Nikolaeva L.G., MaystatT.V, Pylypchuk VS., Volyanskii Yu.L., Masyuk L.A., Kutsyna G.A.: Effect of oral immunomodulator Dzherelo (Immunoxel) in TBI HIV co-infected patients receiving anti-tuberculosis therapy under DOTS. Intl. Immunopharmacol. 8, 845-851 (2008).
 
3.    Prihoda N.D., Arjanova O.V., Yurchenko L.V, Sokolenko N.I.,
Vihrova L.A., Pylypchuk VS., Kutsyna G.A.: Adjuvant immunotherapy of tuberculosis in drug-resistant ТВ
 and ТВ/HIV co-infected patients. Intl. J. Biomed. Pharm. Sci. 2, 59-64 (2008).
 
4. Arjanova O.V, Prihoda N.D., Yurchenko L.V,
Sokolenko N.I., Vihrova L.A., Pylypchuk VS., Frolov V.M.,
 
 
 
 
Kutsyna G.A.: Enhancement of efficacy of tuberculosis drugs with Immunoxel (Dzherelo) in HIV-infected patients with active pulmonary tuberculosis. Immunotherapy 1, 549-556 (2009).
 
 
5.  Zaitzeva S.I., Matveeva S.L., Gerasimova T.G., Pashkov Yu.N.,
Butov D.A., Pylypchuk VS., Frolov V.M., Kutsyna G.A.: Efficacy and safety of phytoconcentrate Dzherelo (Immunoxel) in treatment of patients with multi-drug resistant 
ТВ (MDR-TB) in comparison to standard chemotherapy. Res. J. Med. Sci. 3, 36-41 (2009).
 
 
6. Zaitzeva S.I., Matveeva S.L, Gerasimova T.G., Pashkov Yu.N., Butov D.A., Pylypchuk VS., Frolov V.M., Kutsyna G.A.: Treatment of cavitary and infiltrating pulmonary tuberculosis with and without the immunomodulator Dzherelo. Clin. Microbiol. Infect. 15, 1154-1162 (2009).
 
 
7.  Arjanova O.V, Prihoda N.D., Sokolenko N.I., Yurchenko L.V,
Vihrova L.A., Pylypchuk VS., Frolov V.M., Kutsyna G.A.: Impact of adjunct immunotherapy with multi-herbal supplement Dzherelo (Immunoxel) on treatment outcomes in end-stage 
ТВ/HIV patients. J. Antivir. Antiretrovir. 1, 86-88 (2009).
 
 
8.  Prihoda N.D, Arjanova O.V, Yurchenko L.V, Sokolenko N.I., Vihrova L.A., Pylypchuk VS., Frolov V.M., Kutsyna G.A.: Adjuvant immunotherapy of extensively drug-resistant tuberculosis (XDR-TB) in Ukraine. Curr. Res. ТВ 1,1-6 (2009).

ACKNOWLEDGEMENTS

 
This ongoing study is supported by grant No. UKB1-9017-LK-09 from the U.S. Civilian Research & Development Foundation (CRDF) - a non-profit organization authorized by the U.S. Congress and established in 1995 by the National Science Foundation.
 
The authors have obtained the Institutional Review Board approval of Lisichansk ТВ Dispensary and have followed the principles of the Declaration of Helsinki for all human or animal experimental investigations.
 
This study is registered with the Clinical Trials.gov under identifier NCT01061593.

Comparative efficacy of tableted form of Immunoxel vs. control on sputum conversion rate (%) after 1 month of treatment

Immunoxel
80,3
87,5
100
89,5

Poster

Second International

Workshop

on HIV and    Hepatitis                          

Co-infection           

Amsterdam,

12-14 January 20

New therapeutic option  for decreasing ART-related toxicity in HIV/HCV    co-infected  atients. 

 

                                                             

            

V Frolov. V.Pylypchuk. G.Kutsyna. R. Chehiliany. L Vihrova. E. Zagaydaiova O. Ofdzanova. L. Urchenko State Medical University. Luhansk . Ukraine Regional AIDS- center. Luhansk , Ukraine

 

MORE INFORMATION:

Galina Kulsyna

e-mail:galina@krem.Ig.ua

 htth-y/www.ekomed.com.ua e-mail: ekomed@itpak.com

 

 

 

 

 

Background

Hepatic toxicity greatly complicates the manage­ment of HIV treatment - experienced patients. In several large trials of HIV/HCV co-infected pa­tients, more participants stopped their assigned therapy due to toxicity than virological failure. In the Ukraine, most HIV -infected patients have few antiretroviral options due to limited resources. Significant metabolic disorders and underlying hepatic injury caused by chronic alcohol, drug ad­diction and hepatitis co-infection are common. Preliminary results of the immunomodulating agent dzherelo suggested hepatic anti-inflamma­tory activity. We hypothesized that the addition of dzherelo may attenuate hepatic toxicity in pa­tients receiving antiretroviral therapy (ART).
Freaquently meet features in the HIV/HCV -infected individuals in east Ukraine:
- drug addiction and alcohol dependency
- poor diet
- bad conditions of life
- financial limited for HCV therapies(interferon and antiviral).

Method

Now we report the 32 - week results of an ongo­ing study initiated March 2005. 35 HIV/HCV co-infected patients suffering from alcohol abuse or/and drug addict were enrolled. ART including AZT/3TC/NVP was initiated. Dzherelo was added to the therapy a median of 8-10 weeks after start­ing ART. ART- related hepatotoxicity was defined as an increase in ALT/AST levels up to five times the upper limit of normal, or 3,5 fold increase if baseline level was abnormal.

Summary of patients characteristic at base­line intention to treat population.

 Result

Evaluation of IFT under AZT/3TC/NVP ther­apy regime in continue first 8 weeks.
mean                                     mean values
baseline values                    at week 8
ALT-62 U/L             <=>            109 U/L
AST- 49 U/L           =>             47 U/L
ART- related hepatotoxicity
In continuer first 8 week therapy 6/35 (18 %) pa­tients was with protocol-defined ART related hepatotoxicity. Among them:
-3 died
-2 need ART interrupted
-1 refused from ART due to side effect (fatigue, vomiting, gastrointestinal disorders).
What therapy strategies need in this situation ?
Exist in study cohort of significant metabolic disorders and underlying myltifactorial liver injury caused by chronic alcohol, drug addiction and not antiviral treated hepatitis co-infection not give the optimism that new (change) therapy regime will be successful.


Preliminary results of the immunomodulating agent dzherelo suggested hepatic anti-inflammatory activity. We hypothesized that the addition of dzherelo may at­tenuate hepatic toxicity in patients receiving antiretro­viral therapy.
Immunomodulator Dzherelo was added to the therapy a median of 8-10 weeks after starting ART
  • For prevention further elevating of LFT under ART
  • For facilitate of immune responses to HIV/HCV- inf.:
 - recruitment of immune cells
- induct of potent cytokines secretion (INFs, lis)
                                                    
 acceleration the phase immune control under HCV infection

Change the LFT under two consecutive therapy regimes

No new cases of hepatotoxicity were reported after starting dzhere­lo, and no clinical signs ot hepatic inflammation were seen.

Repopulation of the CD4 cells count was corre­lated with normalization of LFT.

 Hypothetical mechanism of decreasing the baseline evaluate ALT in HIV/HCV infected individuals after added dzherelo to ART

 Hypothetical mechanism of decreasing the ART-related evaluate ALT in HIV/HCV infec­tion under AZT/3TC/NVP +dzherelo therapy regime 
• HCV- infection associate with increasing toxicity of HAART 
• Shown decreasing ALT values to normal range can caused the suppression of HCV replication
    inflammatory process in liver
the basis for decreasing hepatotoxicity of HAART

Conclution

This and previous clinical trials results suggest a beneficial effect of dzherlo as a potential immu-noenhancer in HIV infected patients. Also Dzherelo appeared to attenuate hepatotoxicity from ART ther­apy (NRTI + NNRTI) in population with underlying liver pathology. This may lead to improved hepato­toxicity and reduced toxicity related therapy inter­ruptions.
The new options for successful HIV Regimes -using immunomodulate agent dzherelo In Combination with ART for: 
• Decreasing ART- related toxicity in HIV/HCV co-infected patients 
• Restoring weak and transient Immune Responses to HIV/HCV in chronic HIV/HCV co-infection 
• Accelerating CD4 Reconstitution under ART - Restoring CD4 cell numbers in failures of immune reconstitution with ART -CD4 reconstitution in late AIDS
• Decrease  the risk of prevalence immune resto­
ration disease after ART

Reference

1. Lyahovaya T. Influence of Immunomodulate agenl of dzherelo lo the synthesis of serum interferon in the patients with chronical HCV-infection. )// Problems of ecological and medical genetics and clinical immunology. - 2005. -1* 5(68) - P.74-81. 
2.KutsinaG.A.. Chetiani R.8.. ZagaidanovaY G Effects of immuno­modulator  Dzhereloon Immune signs among HIV-infectedlndinlduals // Problems of ecological and medical genetics and immunology- 2003. -1*7(53) -P.51-60.
3.Chhetianl R.B.. Influence of plant derivative drug Dzherelo on circu­lating immune complexes and their molecular content among patients with chronical persistant infection of mixed genesis (Epstain-Barr and herpetic)// Problems of ecological and medical genetics and clinical im­munology. - 2004. - № 61. - P.130-134.

 

Comparative effect of an immunomodulator Immunoxel (Dzherelo™) when used alone or in combination with antiretroviral therapy in drug-naive HIV-infected individuals.

 Revaz Chkhetiany                                                           
Regional AIDS Center, Luhansk, Ukraine                   
 Vladimir Pylipchuk                                                             
EKOMED Company Ltd., Kiev, Ukraine                                  
 Olga Argzanova and Nathalia Prihoda
Tuberculosis Hospital, Lisichansk, Ukraine
 Ludmila Vihrova
Regional Hospital, Lisichansk, Ukraine
 Elena Zagaynova and Galina Kutsyna*
Luhansk Regional AIDS Center, 50-years of Defense of Luhansk Street, Luhansk 91045, Ukraine Fax: +00380-6454-347-106
Corresponding author

Abstract: Immunomodulating agent Immunoxel (Dzherelo) has been evaluated in 70 HIV-positive individuals divided into three arms: first, control arm, received standard antiretroviral therapy zidovudine/lamivudine/efavirenz (AZT/3TC/EFV); second-AZT/3TC/EFV+Immunoxel and third, Immunoxel alone, given orally, twice daily. At 32 weeks of follow-up CD4 cell counts increased in all arms, reaching + 102, +190 and +175 cells/mm', respectively. The proportion of patients who experienced adverse events attributable to study medication was 65%, 24% and 5%. Immunoxel attenuated hepatic toxicity in patients receiving ART as determined by liver function test. Baseline values for ALT aminotransferase were 36, 62 and 72 U/L, which at study conclusion have Copyright © XXXX Inderscience Enterprises Ltd. R. Chechitiany et al. risen to 78 U/L in arm A, but declined to 38 and 31 U/L in arms B and C. Immunoxel also reversed AIDS-associated wasting. The average weight gain was 1.4, 6.9 and 5.1kg. The results indicate that Immunoxel is safe and exerts beneficial effect in AIDS patients.

Keywords: Author please provide keywords.

Reference to this paper should be made as follows: Chkhetiany, R., Pylipchuk, V., Argzanova, O., Prihoda, N., Vihrova, L., Zagaynova, E. and Kutsyna, G. (XXXX) 'Comparative effect of an immunomodulator Immunoxel (Dzherelo™) when used alone or in combination with antiretroviral therapy in drug-naive HIV-infected individuals', Int. J. Biotechnology, Vol. X, No. Y, pp.XXX-XXX.

Biographical notes: Revaz Chkhetiany is the Head of the Regional AIDS Center, Luhansk, Ukraine, his area of expertise is viral diseases.
Vladimir Pylipchuk, PhD is the Head of Scientific Board of EKOMED, Kiev, Ukraine, his area of expertise is molecular biology, he is the author of exclusive technology relating to fluid crystal structures from organic molecules.
Olga Argzanova is the Chief of the Lungs and Tuberculosis Department at the Tuberculosis Hospital, Lisichansk, Ukraine.
Nathalia Prihoda is the Head of the Tuberculosis Hospital, Lisichansk, Ukraine.
Ludmila Vihrova is the Principal Epidemiologist of the Regional Hospital, Lisichansk.
Elena Zagaynova is a Specialist in HIV infection transmissions. Regional AIDS Center, Luhansk, Ukraine.
Galina Kutsyna is with the State Medical University and AIDS Regional Center, Luhansk, her area of expertise is immunopathogenesis of HIV infection, she has more than 40 publications to her credit, which were published in Ukraine and EU.

  1.   Introduction

The antiretroviral drug resistance, drug toxicity and adherence are major concerns in clinical management of HIV infection. On the other hand, the immune activation caused by immune reaction to HIV, is now recognised as a major cause of depletion of CD4 T-cells and resulting immunodeficiency (Appay et al., 2005). In fact, African monkeys, the natural hosts of simian immunodeficiency virus have adapted to this retrovirus by blocking immune activation and thus remaining healthy. These problems are driving force for research on new therapies that can provide an answer. Most optimal therapeutic solution is an effective and safe immunotherapy that could regulate the immune response in a manner favourable to a host.
Immunoxel is an oral immunomodulating agent produced in Ukraine by Ekomed company. It contains concentrated extracts from medicinal plants. In vitro studies on cultured thymocytes and epithelial thymic cells have shown that Immunoxel can induce synthesis of serum thymic factor and other substances with thymus like activity (Grinevich, 2001). Experiments on laboratory animals demonstrated the restoration of endocrine function and increase of thymus weight after partial thymectomia (Grinevich, 2001). It has been successfully used in the past for the therapy of various infectious diseases of viral origin such as herpes and Epstein-Barr viruses. The choice of the given immunomodulator for our study was made on the basis of the analysis of prior evidence indicating the tendency to restore suppressed immunity characteristic to chronic bacterial infections and malignant diseases (Barabai et al., 2004; Chechitiany, 2003, 2004; Grinevich, 2001; Shapovalovi, 2004; Zeleniy, 2003). Furthermore, Immunoxel has shown the efficacy in treatment of autoimmune diseases (Bodnar et al., 2002).

Preliminary data from pilot trials conducted by us in HIV-infected individuals have been very encouraging (Kutsyna et al., 2003, 2004, 2005). The results have shown that Immunoxel is safe, can increase the total and CD4 lymphocyte counts and reduce the incidence of Opportunistic Infections (OI). In addition it appeared to have favourable effect in diminishing the hepatoxicity of antiretroviral drugs. In #order to further evaluate the clinical benefit of Immunoxel in comparison to standard ART we initiated the multicentre trial conducted at four regional hospitals in Ukraine. Here we present data from 32-week, open label, three-arm trial in 70 HIV-infected individuals who were treated either with zidovudine (AZT), lamividine (3TC) and efavirenz (EFV), (AZT/3TC/EFV) in combination with Immunoxel or Immunoxel alone, assigned to arms A, B and C, respectively.

 2.   Materials and methods

 2.2   Treatment regimen

After initial screening, qualifying patients were randomly divided in three arms: arm A was prescribed: zidovudine (AZT) in 300 mg doses twice-daily; lamividine (3TC) 150 mg tablets twice-daily and efavirenz (EFV) 600mg once daily. The arm B received the same ART plus Immunoxel given as 50 drops added to a glass of water, twice-daily. The arm C received immunomodulator Immunoxel monotherapy in same 50 drops twice-daily dose. Immunoxel (Dzherelo) was provided by Ekomed company, Kiev, Ukraine. It contains aqueous alcohol extract of elecampane rhizome (Inula helenium); fennel fruit (Foenkulum vulgare); juniper berry (Juniperus communis); licorice root
(Glycyrrhiza glabra); oregano herb (Oreganum majorana): marigold flowers (Calendula officinalis); rose hips (Rosa canina) and thyme (Thymus serpyllum). These herbs are considered by the FDA as Generally Regarded As Safe (GRAS) substances. Immunoxel (Dzherelo) has been approved in 1997 by the Ministry of Health of Ukraine as a dietary, immunomodulating supplement.

2.3     Evaluation

Parameters such as CD4 cell counts, AIDS defining events, relapse and new events of Opportunistic Infection (01), adverse events and laboratory parameters were assessed at baseline and at weeks 12, 20, 32. For patients with clinical signs of adverse events laboratory tests were performed every two weeks. Baseline values for CD4 cells counts were defined as the average of the last screening and last baseline values. Adherence to treatment was assessed at each visit. Adverse events were graded by intensity and their relationship to the study medications. AIDS defining adverse events (as per 1993 Center for Disease Control definitions of AIDS) were recoded in the same way as all other adverse events.

 2.4     Statistical analysis

The primary outcome measure was CD4 cells count. The secondary endpoints were levels of adherence, incidence of HIV related events, adverse events, laboratory abnormalities, liver function test, incidence of opportunistic infections or coinfections, clinical improvement and changes in body weight. The trial was designed to compare arm A with arm B and C at weeks 12, 20, 32 and 48, using the proportion of patients. All statistical tests were performed as on the Intent-To-Treat (ITT) population, which included all patients who took at least one dose of study medications; patients who discontinued for any reason were considered as treatment failures. Tests were performed on the On-Treatment (OT) population, which included only those patients with available evaluation at that time point. The safety evaluation included all patients who had at least one post-baseline safety assessment.

 2.7   Patients' population

In this trial 70 male or female adults with HIV/AIDS were enrolled. Most of them were hepatitis virus C (HCV) coinfected, with significant proportion of them suffering from alcohol abuse or/and drug addiction. Significant metabolic disorders and underlying hepatic injury caused by chronic alcohol, drug addiction and hepatitis coinfection were common for study cohort. At study initiation 21% had active OI and 71% had grade three or more laboratory or clinical abnormalities. Patients were divided into three arms, their baseline characteristics were comparable. All participants were antiretroviral drug nai've. Each participant provided an informed consent and was free to withdraw from the study at any time. All patients were given symptomatic therapy for OI if required. The trial is designed to continue until the last enrolled patient reaches 48 weeks on therapy.

3.   Results

3.1   Change in CD4 cell counts

Significant increases from baseline were seen in all three arms at every assessed time point. By the end of first 12 weeks of treatment, CD4 cell counts changed as follows: in arm A reaching +122 cells/mm3; in arm B decreasing but not significantly -10 cells/mm' and in arm C increasing +36 cells/mm3 but not in a significant manner. On the follow-up CD4 counts increased progressively in all arms, reaching +108, +85 and +103 cells/mm' by 20 weeks and +102, +190 and +175 cells/mm'by 32 weeks, for arms A, B and C, respectively (OT analysis).
There was a significant difference between arm A compared with arms B and C in terms of change in CD4 counts from baseline to week 12. In arm A CD4 cell counts increased significantly compared with arm B, in which cell counts decreased
(A versus B; P < 0.04) and with arm C, where increasing CD4 count was not significant from baseline level (A versus C; P < 0.05).
The first statistically significant increase in CD4 counts from baseline was observed in groups B and C at week 20. By week 32 progressive increase in CD4 cells in these two groups was higher than in arm A (B versus A; P < 0.05 and C versus A; P < 0.05).
The arm C had three patients in terminal stage of AIDS and who had very low levels of CD4 cells count at baseline 65, 64 and 128 cells/mm'. After treatment initiation CD4 cells have ris.en, reaching +15,+111 and +194 cells/mm'by 12 weeks and +85, +103 and +1171 cells/mm'by 20 weeks. In parallel with rising CD4 cell counts these patients experienced progressive clinical improvement (Table 1).

3.2  Adverse events

Over 32 weeks of treatment significant differences were observed between arm A as compared with arms B and C in terms of overall incidents of adverse events. At least one adverse event, which possibly and probably was related to the study medications, was reported in 65, 24 and 5% of patients in arms A, B and C, respectively. Most clinical adverse events were mild - gastrointestinal symptoms were the most frequently reported adverse events. Over 32 weeks period, the most common adverse events considered as possibly related to study medication as well as those of moderate or severe intensity are shown in Table 2. There were clear differences between arms in a pattern or incidence of adverse events: the levels of diarrhoea and nausea were significantly higher in arm.
A compared with arm B. In contrast in arm C gastrointestinal symptoms were not observed throughout the study period. Occurrences of headache and fatigue were also significantly higher in arm A when compared with arm B and these symptoms were not observed in arm C. Seven patients (35%) in arm A experienced serious adverse events, which were considered to be possibly or probably related to study medication. In this arm 1(5%) patient refused further therapy and 6(30%) patients needed replacement therapy due to progressive fatigue, vomiting and gastrointestinal disorders and/or hepatotoxicity. In arms B and C no incidents of interruption or changing therapy were observed. There were also significant differences between three arms in respect to laboratory findings (Table 2).

 

*Defined as a fall from 1000-1500/mm1 to <5000/mm'or from >1500/mm'to <749/mm\ **Defined as a rise from 1.25-2.5 ULN to >10 ULN or from 1.25 ULN to >5 ULN. ***Defined as a rise from 1.25-2.5 ULN to >10 ULN or from 1.25 ULN to >5 ULN. **** Defined as a reduction from normal levels < 9.0 g/dl.

*****Defined as a rise from normal levels >6.3 mmol/1.

3.3  Opportunistic or coinfection defined events

During 32-week reporting period, 01 were observed in all three arms under therapy. 01 were observed in 6 (30%), 4 (13%) and 4(20%) patients for A, B and C arms, respectively (Table 3). There was a clear distinction between treatment arms in terms of frequency OI and co-infection events. These events were significantly higher in arm A compared with arms B or C.

Among most frequently reported relapses of OI and coinfection were oral or oesophageal candidiasis 4(20%), 2(7%) and 2(10%), herpetic infections 4(20%), 4(13%) and 3(15%) patients in the arms A, B and C, respectively. Acute tuberculosis was observed in 2(10%), 2(7%) patients in arms A and B, respectively. Similarly, the relapses of hepatitis C were observed only in arms A and B, 2(10%) and 1(3%), respectively.

 3.4  Effect on liver function

Most patients enrolled in study had underlying liver pathology. Signs of progressing chronic inflammatory process in liver caused by persistent viral infection, toxicity and alcohol were registered as mean values of standard Liver Function Test (LFT). Baseline ALT or/and AST were elevated in 7/20 (30%), 13/30 (43%), 11/20 (55%) patients in arms A, B and C, respectively. Mean baseline values for ALT were 36, 62 and 72 ULN, respectively. The median cumulative change from baseline ALT values were + 22, +18 and -16ULN at 12 weeks, +30, -36 and -34ULN by week 20 and + 42, -24, -41 ULN by week 32 for arms A, B and C, respectively. At week 32 ALT values have increased to a mean 78ULN in arm A and declined to 38 and 31 ULN in arms B and C, respectively. The difference between arms B and C compared with arm A in terms of ALT values (B versus A; P < 0.05, C versus A; P < 0.03). In arm C ALT values were decreasing progressively under therapy and became significant lower than baseline levels (P < 0.01). Similar trends were observed with AST marker. The mean baseline values of AST were 42, 49, 58ULN for arms A, B and C, respectively. At week 32 AST values increased to a mean 68ULN in arm A and decreased to 42, 26 ULN in arms B and C, respectively. The number of patients with ART related hepatotoxicity was 6(30%), 2(10%) patients in arm A and B, respectively. In arm C no cases of drug-related hepatotoxicity were noted.
3.5  Effect on body weight
Mean values for baseline body weight were 64.2 ± 8.9; 68.9 ± 7.6; 67.3 ± 8.4 kg for arms A, B and C. Among arms A, B and C 7(35%), 11(33%), 6(30%) patients had cachexia. The body mass steadily increased during therapy, gaining additional 1.4; 6.9 and 5.1 kg at week 32 for arms A, B and C, respectively. Weight gain varied for every patient ranging from 0.5-2 kg up to 6-9 kg during the therapy period. At the end of study, the mean weight values were 65.6 ± 7.3; 75.8 ± 6.9; 72.4 ± 8.6 kg for arms A, B and C respectively.

 4.  Discussion

AIDS is a significant threat to the mankind and the search for effective anti-HIV therapies is of paramount importance. Several chemical anti-HIV agents have been developed. However, besides the high cost, there are adverse effects and^toxicity associated with use of chemotherapy. The herbal medicines have frequently been used as alternative or adjunct means of therapy by HIV positive individuals and AIDS patients. Except few instances, there is insufficient evidence to support the benefit of plant-derived medicines (Liu et al., 2005). Potential beneficial effects of medicinal plants need to be confirmed by rigorous clinical trials, preferably by comparing them to standard ART.
In this study we compared the safety and efficacy of immunomodulator Immunoxel with standard ART AZT/3TC/EFV or combination of AZT/3TC7EFV with Immunoxel using as the primary endpoint the change in CD4 lymphocyte counts. The increase from baseline in CD4 cells was seen in all three arms at every assessed time point, except for arm B at 12 weeks. However, patients on standard ART therapy gained lowest number of cells when compared to B and C arms, that is, +102, +190 and +175 cells/mm3.
Additional parameters under consideration were the incidence of adverse events, frequency of opportunistic infections and coinfections, liver function test and effect on body weight. The incidence of adverse events which possibly and probably were related to the study medications was lowest in Immunoxel arm (5%) when compared to standard AZT/3TC/EFV tri-therapy (65%). Interestingly, patients in arm B who were treated with AZT/3TC/EFV and Immunoxel had significantly lower incidence (24%) of adverse events and hepatotoxicity despite exposure to the same ART dose as in arm A.
Immunoxel seems to normalise elevated liver enzyme levels. At treatment initiation baseline values for ALT were 36, 62 and 72 ULN but at week 32 AST values have increased to a mean 78 ULN in arm A but declined to 38 and 31 ULN in B and C arms. These properties of Immunoxel are of major consequence to management of ART toxicity. In addition to iatrogenic hepatotoxicity that ranges from mild hepatitis to liver failure there is a significant threat in form of chronic viral hepatitis, that is, HCV and HBV with higher risk of morbidity and mortality. Almost half of patients participating in this trial had confirmed HCV infection. However, despite the lack of hepatitis-specific treatment, patients who were given Immunoxel, experienced normalisation of initially high ALT and AST levels without a single incident of relapse. In contrast patients on AZT/3TC/EFV had higher incidence of hepatitis relapses. The patients on the same ART regimen supplemented with Immunoxel had lower number of outbreaks and normalised liver function test. These observations suggest that Immunoxel possesses anti-inflammatory activity.                                   
AIDS-associated wasting is the major factor that contributes to morbidity and mortality. Currently, there is no standard treatment for this condition, which remains poorly treatable even in countries with advanced medical care. Some of nutritional regimens did yield positive results, however their success was unpredictable. Weight gain observed with Immunoxel was significantly higher when compared to such supplements or ART therapy. This weight-correcting property alone represents a significant achievement that greatly augments the choice of available treatment options.
Obtained findings support our earlier open-label trials conducted on more than 200 patients. In prior studies we have observed significant increase in body weight, reduced anemia and leucopenia processes and the increase of total lymphocytes and their CD4+ subpopulation (Kutsyna et al., 2003, 2004, 2005). These data taken together with present findings indicate that Immunoxel is safe and effective for clinical management of HIV infection.
At this stage we are not certain as to what is the precise mechanism of Immunoxel action. It is possible that Immunoxel may affect directly viral replication. However, this has not been verified by in vitro studies. The broad-spectrum antiviral, antimicrobial and anti-tumor activities shown in the clinical setting also preclude such a conclusion. Preliminary results suggest that Immunoxel can correct autoimmune disorders in a variety of diseases (Barabai et al., 2004; Bodnar et al., 2002;
Chechitiany, 2003, 2004; Grinevich, 2001; Shapovalovi, 2004; Zeleniy, 2003). If we consider that the immunopathogenesis of HIV-infection is inherently an autoimmune process, then the role of Immunoxel as a modulator of HIV-caused self-destructive immunity makes a sense (Appay et al., 2005; Bourinbaiar et al., 2006).
Currently, several immunotherapeutic approaches are available, which operate on the premise that AIDS is an autoimmune disease. So far most of these therapies are in the domain of so-called therapeutic vaccines and related immunotherapies (Bourinbaiar et al., 2006). Very few validated, immune-based interventions are available when it comes to products of plant origin. Most studies in this area concern Oriental medicinal plants some of which were used for treatment of autoimmune disorders such as habitual abortion (Chen et al., 2003). However, we are not aware of any examples of application of autoimmunity-regulating herbs in infectious diseases, especially HIV infection. Not every herbal preparation can possess the right property suitable for such an indication. Indeed, some herbal supplements were shown to exacerbate autoimmunity - a property contrary to the intended action of Immunoxel (Lee and Werth, 2004). On the other hand it will be a mistake to classify Immunoxel as an immunosuppressant. The decrease in the frequency of opportunistic infections and absence of new episodes of OI as demonstrated in this trial support our prior observations, indicating that Immunoxel does not compromise the native immunity. These considerations are intriguing not only from the immunological point-of-view but are also important in finding effective therapeutic solutions for diseases which so far have been refractory to existing choices of treatment.
In conclusion, Immunoxel displays a broad-spectrum clinical activity that has far-reaching implications. It reduces drug toxicity and improves ART efficacy when used in combination with standard ART. Further studies are required to identify the mechanism of action and additional benefits associated with its use.
Acknowledgements
We thank all patients who participated in this study. The assistance of Ekomed in generously providing Immunoxel is very much appreciated.
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