Vol.1, No.2, 50-55 (2011)
opyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/OJI/
Open Journal of Immunology
One-month immunotherapy trial in treatment-failed TB
Olga V. Arjanova1, Dmitry A. Butov2, Natalia D. Prihoda1,Svetlana I. Zaitzeva2,
Larisa V. Yurchenko1, Nina I. Sokolenko1, Anna L. Stepanenko2, Tatyana S. Butova2,
Elena A. Grinishina3, Olga A. Maksimenko4, Vichai Jirathitikal5, Aldar S. Bourinbaiar6,
Valery M. Frolov7, Galyna A. Kutsyna7*
1Lisichansk Regional Tuberculosis Dispensary, Lisichan sk, Ukraine;
2Department of Phtysiatry and Pulmonology, Kharkov National Medical University; Kharkov, Ukraine;
3Zmeev Regional Tuberculosis Dispensary, Zmeev, Ukraine;
4Izyum Regional Tuberculosis Dispensary, Izyum, Ukraine;
5Immunitor Thailand Co., LLC, Bangpakong Industrial Park, Chachoengsao, Thailand;
6Immunitor USA Inc., College Park, USA;
7Luhansk State Medical University, Luhansk, Ukraine; *kutsynagalyna@yahoo.com.
Received 17 August 2011; revised 1 September 2011; accepted 9 September 2011.
Treatment failed TB patients have very limited
chances of s urv ival. Open label trial of daily oral
pill of V-5 Immunitor (V5) was conducted in 48
treatment-failed TB patie nts on palliative support
consisting of isoniazid (H) and rifampicin (R).
The subjects had the following forms of TB;
cavit ary : disseminated: MDR-TB: DR-TB: TB/HIV
at 35:13:7:4:1 ratio. After 1 month 62.5% of V5-
treated patients experienced negative sputum
smear conversion (P < 0.0001), comprising 11
out of 12 (91.7%) converted among those who
had drug-resistant TB an d TB/HIV. TB-associated
inflammation was downregulated as evidenced
by normalization of leukocy tosis 7.4 vs. 6.7 x 109
L (P = 0.01) and decr eas e d erythrocyte sedimen-
tation rate 20.5 vs. 14.9 mm/h (P < 0.0001). The
mean body temperature normalized from 37.25˚
± 0.6˚ to 36.98˚ ± 0.4˚ (P = 0.0002). The average
body weight gain and body mass index (BMI)
increased by 0.8 ± 0.7 kg and from 18.9 to 19.6
kg/m2 respectively (P < 0.0001). Two patients
(4.2%) died from illicit drug- and alcohol-abuse
related causes. No adverse effects or reactiva-
tion of disease due to im mune interv ention were
seen at any time. V5 is safe and in combination
with a simple two-drug regimen was highly
effective as an immune adjunct to produce
favorable outcome among treatment-failed and/
or drug-resis tant TB patients.
Keywords: Biomarker; HIV; Inflammat ion; MDR-TB;
Mycobacterium; Survival; Treatment Failure; Vaccine;
Mycobacterium tuberculosis is responsible for the
largest number of deaths attributable to a single micro-
organism. Nearly 9 million people develop TB each year
and 2 million die from the disease [1]. Currently avail-
able chemotherapies for treatment of TB are not ideal -
they require multiple tuberculosis drugs to be taken for
long periods of time. The length of therapy, co upled with
side effects, often results in poor patient adherence,
treatment failure, and the emergence of drug resistance
[2]. Current so-called directly observed short-course
(DOTS) chemotherapy requires 6 months; with isoniazid,
rifampicin, pyrazinamide and ethambutol during first 2
months of intensive phase and isoniazid and rifampicin
for continuation phase. The WHO global target for suc-
cessful DOTS is set at 85% or higher, however the
worsening epidemic of drug resistant TB converging
with HIV reduces the likelihood of attaining this goal.
Patients who failed treatment have very few therapeutic
options and mortality and morbidity in this category is
extremely high. If left untreated one year fatality esti-
mate is 70% for smear-positive and 20% for culture-
positive but smear-negative tuberculosis [2]. In a study
involving patients resistant to isoniazid and rifampicin
65% became culture negative but treatment failure, de-
fined as the inability of chemotherapy to sterilize cul-
tures, occurred in almost half of patients (46%) [3]. The
idea that immunotherapy might improve TB treatment
outcomes started gaining consensus in recent years [4].
O. V. Arjanova et al. / Open Journal of Immunology 1 (2011) 50-55
Copyright © 2011 SciRes. Openl y accessible at http://www.scirp.org/journal/OJI/
Oral therapeutic vaccine V5 Immunitor was originally
developed for the management of chronic hepatitis B and
C [5-7]. The preparation is derived from pooled blood of
HBV- and HCV-positive donors, which following chemi-
cal- and heat inactivation was formulated into an oral pill
according to the proprietary technology developed by us
[7]. During clinical trial in 20 patients with hepatitis C,
who happened to have pulmonary TB with HIV
co-infection, V5 produced mycobacterial clearance in
sputum smears of 94.4% of patients within one month [8].
Due to this surprising outcome a placebo-controlled, ran-
domized phase 2b trial was initiated. Two preliminary
reports from this trial involving initial 88 patients were
already published, confir ming that V5 was safe and con-
sistently enhanced the efficacy of TB drugs [9,10].
In these trials we had a couple of patients who have
repeatedly failed all available therapies and were on
so-called palliative support consisting of isoniazid and
rifampicin only [10]. Despite treatment failure and
seemingly ineffective two-drug combination these pa-
tients became sputum smear negative within one month.
In the present study we expanded this observation by
recruiting 48 treatment-failure patients who received
palliative HR in combination with V5 for one month.
2.1. V5 Immunitor
V5 is derived from the pooled blood of donors with
HBV and HCV, which after heat- and chemical inactiva-
tion was formulated into an oral pill [5-7]. It is well
known that one third of people carry M. tuberculosis
without showing symptoms of the disease—latent TB.
Therefore, V5 inherently comprises circulating antigens
of M. tuberculosis. As we had not known prior to this
accidental discovery that V5 may affect TB we have no
much information regarding the exact content of M. tu-
berculosis antigens. V5 was approved in 2008 by the
Ministry of Health of Ukraine as an immunomodulating
supplement for the management of chronic hepatitis.
2.2. Patients
The conduct of the trial was approved by the internal
review board of th e Lisich ansk TB Disp ensary a nd has a
ClinicalTrials.gov identifier: NCT01222338. The study
involved 48 patients all of whom were treatment failures
and were placed on so-called palliative support consist-
ing of daily isoniazid (H) and rifampicin (R) (Table 1
and Figure 1). This regimen is assigned to very limited
number of patients by the regional h ealth authorities as a
result of case-by-case evaluation of medical and treat-
ment adherence history by specially appointed ethics
committee. Usually these are patients who had repeat-
edly failed to convert after multiple treatment options
had been tried unsuccessfully for an average/median (6
years ± 3.3 years /5 years (range 2 years - 19 years).
Drug and alcohol abuse combined with poor compliance
are common among these patients. The participation in
this study was voluntary and patients were eligible to
enroll only after signing the written consent. The group
had 4 females (8.3%) and 44 males between ages 23 - 68
with mean ± SD (median) age 38.4 years ± 10.9(35.5)
Male FemaleTB/HIVDR-TBMDR-TBMiliaryCavitary
% of patients
Figure 1. The proportion of patients at baseline ac-
cording to their gender and diagnosis .
Table 1. Summary of baseline data and treatment outcome in 48 treatment-failed TB patients treated with isoniazid and rifampicin in
combination with V5 for one month.
weight(kg) Body mass
temperture(˚C) Hemoglo-
bin(g/L) ESR(mm/h) Leukocytes
(×109L) Sputumsmear
F/M Age Diagnosis
before after before afterbeforeafterbeforeafterbeforeafter before after beforeafter
±10.8 58.6
±10.7 18.9
±3 19.7
±3 37.25
±0.6 36.98
±0.4 118.8
±15 118.5
±14.3 20.5
±14.9 14.9
±11.2 7.4
±3.4 6.7
±2.9 48/0 18/30
Miliary TB = 13
Cavitary TB =
MDR-TBa = 7
DR-TBb = 4
TB/HIV = 1 P < 0.0001 P < 0.0001 P = 0.0002 P = 0.78 P < 0.0001 P = 0.013 P < 0.0001
O. V. Arjanova et al. / Open Journal of Immunology 1 (2011) 50-55
Copyright © 2011 SciRes. Openl y accessible at http://www.scirp.org/journal/OJI/
years. Almost half of patients were underweight (47.9%
with BMI less than 18.5 kg/m2), the baseline body
weight and body mass index (BMI) ranged between 38
kg - 86 kg and 14 - 26.5 with mean ± SD (median) 57.8
kg ± 10.8 (56.5) kg and 18.9 kg/m2 ± 3 (18.6) kg/m2.
This group had one confirmed HIV infection and 7
MDR-TB. Four additional patients had confirmed drug
resistance other than MDR-TB (Table 1). For the re-
maining patients drug resistance profile was unavailable.
Thirteen patients had disseminated or miliary form of
TB (27.1%) and the rest had cavitary disease (72.9%).
Most patients, 29 out of 48 (60.4%), had normal body
temperature at study initiation with overall mean ±
SD/median 37.3˚C ± 0.6˚C/36.8˚C.
2.3. Laboratory Evaluation
The sputum microscopy on acid-fast bacilli (AFB)
smears was conducted in a blinded fashion at baseline
and one month later. TB drug resistance was deter mined
by commercially available kit (Tulip Diagnostics, Goa,
India) in one third of patients. The failure to test every
patient for drug resistance was due to lack of funds for
laboratory services. MDR-TB status was assigned when
resistance to both isoniazid and rifampicin, with or
without resistance to other drugs, was present. DR-TB
was assigned when resistance to drugs other than those
in MDR-TB category was found. The hematology pa-
rameters were evaluated by standard routine techniques at
baseline and repeated one month later.
2.4. Statistical Analysis
The obtained results were analyzed with commercially
available statistical software (GraphPad Software Inc, La
Jolla, CA, USA). The paired Student t-test was used to
compare before-after means by assuming that the distribu-
tion of the differences was in accord with Gaussian dis-
tribution. The Wilcoxon test was used to compare paired
before-after nonparametric values such as conversion
rates arranged in “yes” or “no” binary manner. Fisher’s
exact two-tailed test was employed for analysis of data
arranged in a contingency table. All statistical analyses
were done on intent-to-treat basis, involving all initially
enrolled patients including fatalities. The resulting prob-
ability values were considered as significant at P 0.05.
3.1. Lack of Adverse Reactions
During the entire duration of follow-up no adverse
reactions or reactivation of TB attributable to V5 were
identified. Quite contrary patients who were receiving
chemotherapy along with V5 fared much better. Due to
alcohol and narcotic drugs’ overdose two patients in the
V5 group died during the study but they were not ex-
cluded from the statistical analysis of data, so that the
intent-to-treat design was not compromised. The quanti-
tative endpoints detailed below indicate that the addition
of V5 to anti-tuberculosis therapy (ATT) has resulted in
better clinical outcome.
3.2. Effect On Axillary Body Temperature
The average ± SD (median) body temperature values
were relatively low, i.e., 37.3˚C ± 0.6 (36.8) ˚C. The
proportion of patients with low grade fever was also
small, i.e., 39.6%. At study initiation the proportion of
patients who had normal body temperature of 36.8˚C
was 60.4% which one month later increased to 83.3%
(Figure 2).The overall mean temperature drop was
0.3˚C, i.e., from 37.25˚C ± 0.6˚C to 36.98˚C ± 0.4˚C (P
= 0.0002).
3.3 Effect on Hematology Parameters
The effect of V5 on white blood cells and hematology
parameters are shown in Tab l e 1 and Figure 2. Patients
displayed following positive changes, which resulted
from V5 intervention. Elevated leukocyte counts, tradi-
tionally associated with inflammation, were reduced in
V5-treated group from 7.4 to 6.7 x109/L (P = 0.013). The
decrease was observed in 31 (64.6%) patients, increase
in 10 (20.8%), and in remaining 7 (14.6%) no changes
relative to baseline were seen. Another marker of in-
flammation, the erythrocyte sedimentation rate (ESR),
declined from 20.5 to 14.9 mm/h (P < 0.0001). The fa-
vorable response was seen in 37 (77.1%) individuals and
in remaining 11 patients ESR increased. The content of
hemoglobin has not changed, i.e., 118.8 g/L ± 15 g/L vs.
118.5 g/L ± 14.3 g/L (P = 0.78). Among these 39.6% of
patients had favorable response, one (2.1%) had un-
changed level, and in remaining 28 (58.3%) patients the
hemoglobin content had decreased.
Sam e
Sam e
Sam e
Weight/BMI TemperatureHBESRLeukocytes
% of patien ts
Figure 2. Proportion of patients with three types of outcome in
relation to the weight/body mass index, body temperature,
hemoglobin content (HB), erythrocyte sedimentation rate
(ESR), and leukocyte counts.
O. V. Arjanova et al. / Open Journal of Immunology 1 (2011) 50-55
Copyright © 2011 SciRes. Openl y accessible at http://www.scirp.org/journal/OJI/
3.4. Effect On Weight and Body Mass Index
Enrolled patients had underweight problem. Accord-
ing to BMI almost half of enrolled patients (47.9%) had
entry level values below normal 18.5 kg/m2; two (4 .2%)
patients were overweight, and the rest were in the nor-
mal range between 18.6 kg/m2 - 25 kg/m2. The mean/
median baseline weight and body mass index were 57.8
kg ± 10.8/56.5 kg and 18.9 kg/m2 ± 3/18.6 kg/m2 respec-
tively. After one month one patient (2.1%) lost 1 kg, 16
patients (33.3%) retained the same weight and in re-
maining 31 (64.6%) patients the increase in body mass
ranged between 1 kg - 2 kg, with average (median) body
weight accrual equal to 0.8 kg ± 0.7 (1.0) kg (P <
0.0001). Changes in body mass index were identical to
variations in the absolute bodyweight (Figure 2). After
the month one patient lost 0.3 kg/m2, 16 patients (33.3%)
retained same BMI, and in remaining 31 (64.6%) pa-
tients the increase ranged b etween 0.2 kg/m2 - 0.9 kg/m2,
with average (median) gain equal to 0.27 kg/m2 ± 0.26
(0.3) kg/m2 reaching values considered to be in the nor-
mal range, i.e., 19.7 ± 3 (19.6) (P < 0.0001).
3.5. Effect on Mycobacterial Clearance
Bacterial clearance was scored in a blinded fashion on
AFB-stained sputum smears as negative/positive scores.
At the end of first month thirty (62.5%) of V5-treated
patients became sputum negative, which was highly sig-
nificant by paired Wilcoxon ranking test (P < 0.0001).
The majority of conver ted patients, 37 out of 48 (70.3%)
had cavitary TB, and remaining converters had dissemi-
nated TB. Eleven out of 12 (91.7%) patients with
MDR-TB, DR-TB and single TB/HIV had converted
after one month. It is of interest that when treat-
ment-failure patients have been stratified according to
the duration of their disease, those who had longer TB
history were converted more readily (Figure 3).
The results of this one-month immunotherapy study in
treatment-failed TB patients on palliative support, con-
sisting of isoniazid and rifampicin, revealed high nega-
tive sputum conversion rate. These results combined
with additional benefit of enhanced body mass gain,
fever normalization, and potent anti-inflammatory effect
are in line with previously reported favorable responses
due to V5 intervention [8-10]. The fact that we have seen
negative conversion in patients who were unsuccessfully
treated with first- and second-line chemotherapy for 6
years on average and w ere as a consequence giv en up is
perhaps the most impressive outcome of this study.
As new TB drugs are still in pipeline, one of priorities
in TB managem ent i s to find opt im al combinati on am ong
0 255075
No. of patients in each y ear
P ercenta ge
Success Failure
Figure 3. Proportion of V5-treated patients at study conclusion
with negative (success) or positive (failure) sputum smear in
relation to the year of TB diagnosis (Y axis).
existing drugs [1,11]. Isoniazid and rifampicin tandem
regimen, introduced in 1970’s, is perhaps best effective
and least toxic combination. However, when resistance
to both drugs arises, treatment is complicated, prolonged,
costly, and outcome is poor. TB treatment failure is
strongly predictive of active MDR-TB and success rates
are rarely better than 65% even when multiple 1st and 2nd
line TB drugs are employed for as long as 12 months -
24 months [3,12,13]. Recently reported DOTS success
rate in former Soviet Union countries in TB patients,
some of whom had MDR-TB and HIV, was 68.1% [14].
However, not every patient enrolled in our study had lab
results from drug-resistance testing. We had 7 and 4
confirmed MDR-TB and DR-TB respectively including
one single patient with HIV; out of these 12 individuals
11 became sputum negative. Even if it may appear at
first sight that we are obtaining similar proportion of
conversion as in literature, our results are not compara-
ble to prior studies since we were able to obtain such a
conversion rate after one month instead of conventional
6 months - 24 months. This implies that immune-based
therapy can contribute to faster favorable response even
when the least-potent combination of TB drugs is em-
ployed, since by definition MDR-TB is refractor y to this
very same H and R combination. It is also of interest th at
all treatment-failure patients who had history of chronic
TB longer than 10 years had converted. Due to small
sample size the latter findings could have been a random
event. Specially tailored, larger, longitudinal studies are
required to determine the extent of the clinical benefit of
V5, which according to our experience spanning over
the last 4 years appears to be equally effective against
treatment-refractory TB and drug-sensitive cases.
The weight accrual during TB therapy has been iden-
tified as a reliable anthropomorphic biomarker of favor-
able treatment outcome that could be readily utilized in
O. V. Arjanova et al. / Open Journal of Immunology 1 (2011) 50-55
Copyright © 2011 SciRes. Openl y accessible at http://www.scirp.org/journal/OJI/
resource-limited settings [15]. Bernabe-Ortiz et al., [ 16]
have shown that after adjustment for baseline differences,
patients with good outcome gained, after the first month
of treatment, mean 0.9 kg (P < 0.001), whereas those
with poor outcome lost 1.9 kg (P = 0.003). Present re-
sults with V5 closely match findings from Peru study
suggesting that the trend in bodyweight can predict suc-
cess of tuberculosis therapy. The correlation between
body weight and BMI was not surprising either. Body
mass index is equally reflective of severity of disease
and is a risk factor closer associated with death than
even MDR-TB diagnosis. Its improvement in parallel
with weight gain indicates that the benefit of V5 therapy
can be predicted by both categories of wasting meas-
urement. Alcohol and substance abuse have been associ-
ated with poor TB outcome in many studies [17,18] and
was the cause of death in two patients during this study.
We suspect that practically every patient in our group
had this problem but the exact extent of abuse is not
known since most patients were reluctant to disclose
their addictions.
Leukocytosis and high erythrocyte sedimentation rate
are common during active pulmonary TB [19]. These
biomarkers of tuberculosis which reflect the inflamma-
tory response have been predictable of outcome of V5
immunotherapy in this and prior studies. In our patient
population favorable responses were seen when values
of both markers declined. These results are further sup-
ported by the effect of V5 on defervescence. In contrast,
the hemoglobin content, which does not seem to be re-
lated to inflammation, has not been affected by V5.
It has been commonly argued that immunotherapy can
boost TB drugs’ activity and shorten treatment duration
[4,20-23]. As conventional TB drugs have been of little
value in failure cases are there immune-based intervene-
tions that were successful in such a situation? The search
of the medical literature failed to produce any notewor-
thy evidence except our own published study in which
40 end-stage patients with TB and HIV were treated with
multi-herbal immunomodulator, Dzherelo (Immunoxel)
[24]. This intervention resulted in 65% negative sputum
conversion r ate as opposed to 5% in the contro l. Despite
best possible care 6 patients had died in Immunoxel arm.
Remaining 14 patients experienced clinical improve-
ments and one patient was discharged due to full recov-
ery. Among 20 matched subjects on conventional TB
regimen, 12 died and only one had shown some clinical
improvement (P = 0.001; OR 2.6 at 95% CI 1.5 - 4.7).
While patient population in th at study was not compara-
ble to ours and sample sizes were small, we and our col-
laborators in Uk raine h ave work ed o n immuno th erapy o f
TB and HIV over the past 10 years, which resulted in a
dozen published trials involving about 1,200 individuals
[25]. This extensive experience is summarized as fol-
lows. Typical sputum conversion rate among MDR,
XDR and TB/HIV patients after 2 months - 4 months of
herbal immunotherapy was in 85% - 100% range, while
in chemotherapy controls it took 6 months - 24 months
to reach 48% - 85%. What is remarkable is that very
same clinical manifestations, i.e., inflammation, fever,
and wasting improved in a manner strikingly similar to
V5. This suggests to us that a successful immunotherapy
of any kind ought to produce clinical response that dis-
plays similar, if not identical trend, with these endpoints.
This conclusion is supported by results of numerous
trials of Mycobacterium vaccae, the WH O recommende d
immunotherapy for TB [4], in which sputum conversion
was invariably accompanied by weight gain and de-
creased ESR [26].
Despite many limitations of this study it is clear that
the combination of V5 with stripped-down TB regimen,
consisting of isoniazid and rifampicin only, produces
favorable outcome in treatment-failed TB including
drug-resistant TB and TB/HIV. V5 was safe; no reactiva-
tion of TB was seen at any time, which perhaps is due to
potent anti-inflammatory activity. Immune intervention
such as V5 needs to be tried independently by investiga-
tors in other countries so that simple and safe treatment
for TB is available sooner, especially to those who have
exhausted all treatment options.
We thank all volunteers who participated in this study. The whole-
hearted support of clinicians, nurses and lab personnel who contributed
their effort made this study possible. Our gratitude is expressed to
too-many-to-list experts in TB who kindly shared with us their opin-
ions and critique s prior to and after this study was completed.
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