Adjunct oral immunotherapy in patients with re-treated, multidrug-resistant or HIV-coinfected TB.

Abstract

This Phase IIb, placebo-controlled study involved 55 TB patients treated with anti-TB therapy. They were divided into two groups, matched by age, gender, baseline bodyweight and clinical manifestations: one group (n = 27) received a once-daily V-5 Immunitor (V5) immunotherapy pill and the other (n = 28) received placebo. Only one (3.7%) and three (10.7%) subjects in V5 and placebo arms, respectively had first-diagnosed, drug-sensitive TB; the remaining patients had re-treated TB, multidrug-resistant TB or HIV-TB coinfection. After 1 month, 26 out of 27 patients (96.3%) became sputum smear negative in the V5 group (p < 0.0000001), whereas seven out of 28 (25%) in the placebo group had converted (p = 0.005). V5 contributed to the downregulation of TB-associated inflammation, as shown by normalization of high leukocyte counts, erythrocyte sedimentation rate and faster defervescence than controls. Patients in both arms experienced an increase in the levels of hemoglobin corresponding to 128.9 ± 17.6 versus 133.1 ± 14.7 g/l (p = 0.03) and 112.6 ± 14 versus 117 ± 11.7 g/l (p = 0.03) in V5 and placebo arms, respectively. In total, 19 out of 28 placebo patients (67.9%) gained, on average, 1.07 kg (59.1 ± 10 vs 60.1 ± 10.4 kg; p = 0.003). By contrast, all patients in the V5 group gained weight with mean 3.4 kg (59.7 ± 8 vs 63.1 ± 9 kg; p = 5.7E-007). Clinical symptoms improved among all patients in V5 arm, while 28.6% of patients on placebo reported satisfactory results (p = 0.007). No adverse or side effects attributable to V5 were seen at any time. Further studies are needed to gauge the extent of the benefits of V5 as safe and effective adjunct immunotherapy for TB.

Full text

Page 1

This Phase IIb, placebo-controlled study involved 55 TB patients treated with anti-TB therapy. They were
divided into two groups, matched by age, gender, baseline bodyweight and clinical manifestations: one
group (n = 27) received a once-daily V-5 Immunitor (V5) immunotherapy pill and the other (n = 28) received
placebo. Only one (3.7%) and three (10.7%) subjects in V5 and placebo arms, respectively had first-
diagnosed, drug-sensitive TB; the remaining patients had re-treated TB, multidrug-resistant TB or HIV–TB
coinfection. After 1 month, 26 out of 27 patients (96.3%) became sputum smear negative in the V5 group
(p < 0.0000001), whereas seven out of 28 (25%) in the placebo group had converted (p = 0.005). V5
contributed to the downregulation of TB-associated inflammation, as shown by normalization of high
leukocyte counts, erythrocyte sedimentation rate and faster defervescence than controls. Patients in both
arms experienced an increase in the levels of hemoglobin corresponding to 128.9 ± 17.6 versus 133.1 ± 14.7
g/l (p = 0.03) and 112.6 ± 14 versus 117 ± 11.7 g/l (p = 0.03) in V5 and placebo arms, respectively. In total,
19 out of 28 placebo patients (67.9%) gained, on average, 1.07 kg (59.1 ± 10 vs 60.1 ± 10.4 kg; p = 0.003).
By contrast, all patients in the V5 group gained weight with mean 3.4 kg (59.7 ± 8 vs 63.1 ± 9 kg; p = 5.7E-
007). Clinical symptoms improved among all patients in V5 arm, while 28.6% of patients on placebo
reported satisfactory results (p = 0.007). No adverse or side effects attributable to V5 were seen at any
time. Further studies are needed to gauge the extent of the benefits of V5 as safe and effective adjunct
immunotherapy for TB.

Author Proof
ATT requires the deployment of second‑line TB
drugs. This represents a significant challenge,
particularly in resource‑poor countries, since the
cost of the therapy increases 100‑fold.
The incidence of TB in Ukraine prior to 1992
was approximately 40 cases per 100,000 people.
A decade later, TB cases increased to over 80
per 100,000 people, with mortality doubling
from 10.2 per 100,000 to 21.6 per 100,000 [2].
Drug‑resistant TB is now common in Ukraine.
Isoniazid and rifampicin resistance, which
defines MDR‑TB, has been found in 44 and
32.9% of TB isolates, respectively [3]. The first
Ukrainian case of HIV was reported in 1987 [4].
Currently, Ukraine has the highest HIV rate in this study. The aim of the present study was to





ReseaRch aRticle
ISSN 1750-743X
DOI: 10.2217/IMT.10.96 © 2011 Future Medicine Ltd
Immunotherapy (2011) 3(2), (Epub ahead of print)
Adjunct oral immunotherapy in patients
with re‑treated, multidrug‑resistant or
HIV‑coinfected TB
First‑diagnosed Mycobacterium tuberculosis
infection is curable with the first line of anti‑
TB therapy (ATT) in over 85% of cases within
6 months [1]. However, when TB presents with
HIV or there is a relapsing TB or drug‑resistant
form of TB, such as multidrug‑ resistant (MDR)
or extensively drug‑resistant TB, the currently
available drugs are less effective, and it takes as
long as 12–24 months to treat a patient. The
treatment of TB refractory to conventional
Eastern Europe, with an increasing proportion of
dual infection. For example, in 2002, the preva‑
lence of TB and HIV coinfection was 6.3% but,
in 2006, at least 15.5 % of TB patients had HIV
coinfection [6].
It is clear that alternative and improved
treatment options are needed. If such an inter‑
vention is found, the impact on healthcare and
clinical management of treatment‑refractory
TB and HIV–TB patients will be tremendous.
Significant efforts are directed at finding new
drugs and vaccines against TB [7]. Immune‑
based interventions are actively sought as an
adjunct therapy to conventional ATT [8].
Immunitor V‑5 (V5) is an immuno modulating
preparation derived from the blood of hepatitis B
and C donors, which, following chemical and
heat inactivation, was formulated into an oral
tablet [9–11]. In our previous study, we acciden‑
tally observed that, when V5 was administered
to patients with chronic hepatitis C and HIV–TB
together with TB drugs, it resulted in negative
sputum conversion in 94.4% of patients within
1 month [12]. This startling finding had prompted
KEYWORDS: DOT n extensively drug resistant n immunomodulator n HIV–TB
n multidrug-resistant TB n Mycobacterium n therapeutic vaccination
Olga V Arjanova1,
Nathalia D Prihoda1,
Larisa V Yurchenko1,
Nina I Sokolenko1,
Valery M Frolov2,
Marina G
Tarakanovskaya3,
Dendev Batdelger4,
Vichai Jirathitikal5
& Aldar S Bourinbaiar†
1Lisichansk Regional Tuberculosis
Dispensary, Lisichansk, Ukraine
2Luhansk State Medical University,
Luhansk, Ukraine
3Ekomed LLC, Ulaanbaatar, Mongolia
4National Research Center for
Infectious Diseases (NRCID),
Ulaanbaatar, Mongolia
5Immunitor Thailand Co., LLC,
Bangpakong Industrial Park,
Chachoengsao, Thailand
†Author for correspondence:
Immunitor USA Inc., College Park,
MD 20740, USA
Tel.: +1 301 476 0930
Fax: +1 775 640 6636
info@immunitor.com

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Author Proof



treat cases are managed. Over half of patients
in this facility require individualized treatment
rather than WHO‑recommended standard ATT
regimen; the proportion of such patients was 15
out of 27 (55.6%) and 19 out of 28 (67.9%) in
the V5 and placebo arms, respectively (Figure 1).
Altogether, 27 patients were recruited into the
ATT + V5 arm and 28 subjects received ATT
along with identically appearing placebo pills.
All patients were bedridden, and had fever,
cough and other common TB symptoms, such
as chest pain, dyspnea, hemoptysis, weight
loss and anorexia. The patients’ age, gender,
bodyweight, severity and form of disease were
matched in order to minimize the statistical bias
owing to population heterogeneity. In the V5
and placebo arms, the female:male ratio were
3:24 (11.1%) and 5:23 (17.9%), respectively,
and the median/mean age was 36/38.1 ± 10 and
35.5/38.3 ± 12 years, respectively (Tables 1 & 2).
The number of patients with first‑diagnosed TB,


ReseaRch aRticle
Arjanova, Prihoda, Yurchenko et al.
Immunotherapy (2011) 3(2)
future science group
DOI: 10.2217/IMT.10.96
compare the clinical benefit of TB therapy in
combination with V5 versus combination of pla‑
cebo with ATT in a representative population
of patients who are poorly manageable owing to
relapsing TB, MDR‑TB or HIV–TB coinfection.
Materials & methods
n Patients & clinical setting
The study was conducted at the Lisichansk
Regional TB Dispensary (Ukraine), which
administers ATT to 600–800 in ‑patients annu‑
ally. The conduct of the study was approved
by the internal review board of the hospital in
accordance with the Helsinki Declaration. The
main criteria for the eligibility were informed
consent and a positive sputum smear. Patients
were randomly selected among those who were
admitted to a special ward in which difficult‑to‑
re‑treated TB, MDR‑TB and HIV–TB coinfec‑
tion were 5:18:5:7 and 4:19:4:10 in the placebo
and V5 arms, respectively. Figure 1 shows this
distribution in percentage figures. Nevertheless,
only one out of four patients in V5 arm and three
out of five patients in placebo could be catego‑
rized as first‑diagnosed and drug‑sensitive cases,
since the remaining first‑diagnosed patients were
HIV positive and considered to be less amenable
to standard TB drugs (Tables 1 & 2).
n Treatment regimen
The ATT drugs were procured free‑of‑charge
from the national supply system administered
by the Ministry of Health of Ukraine. The sup‑
plies of V5 and placebo pills were provided by
Immunitor. Standard TB therapy consisted of
daily doses of isoniazid (H) 300 mg, rifampi‑
cin (R) 600 mg, pyrazinamide (Z) 2000 mg,
streptomycin (S) 1000 mg and ethambutol (E)
1200 mg. Individualized therapy comprised
first‑ and second‑line ATT, as decided by a phy‑
sician prior to or after results of drug‑susceptibil‑
ity tests (Tables 1 & 2). Our dispensary has access
to several classes of second‑line drugs: amino‑
glycosides, such as kanamycin (K) and amikacin
(A), thioamides (e.g., ethionamide [T]), fluoro‑
quinolones (e.g., levofloxacin [L]), sparfloxacin
(F) and gatifloxacin [G]), cycloserine (Cs),
para‑aminosalicylic acid (P) and clofazimine
(C). The category of individualized therapy
includes patients who had complete treatment
failure and received ‘palliative’ regimen consist‑
ing of life‑long H and R. This regimen should
not be confused with the WHO‑recommended
2HREZ/4HR regimen, which calls for 2 months
of intensive phase on HRZE followed by thrice‑
weekly H and R for 4 months. In the immu‑
notherapy group, in addition to ATT, patients
received a daily tablet of V5, which was admin‑
istered 30 min before or after breakfast. In the
control group, patients received placebo pills,
which had the same appearance and excepients,
but without the biologically active ingredient.
No other immuno modulators or anti‑infective
drugs, beside ATT, were used during this study.
n Immunitor V-5
Immunitor V‑5 is derived from the pooled blood
of hepatitis B and C carriers by employing pro‑
prietary technology, which requires heat and
chemical inactivation and formulation into a
tablet. The process of manufacturing is described
in detail earlier [11]. The principle for production
of V5 is very different from established principles
with old‑fashioned killed vaccines (e.g., hepatitis
First
diagnosed
Drug
sensitive
Re-treatedMDR-TB HIV–TBIndividualized
therapy
Proportion of patients (%)
0
20
40
60
80
V5Placebo
Figure 1. Distribution of patients at baseline according to their diagnosis
and treatment regimens.
MDR: Multidrug-resistant; V5: Immunitor V-5.

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1
4
12
2
4
9
2
1
1
87


+
+

8
8

6.1
8.1

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28
Immunotherapy of TB ReseaRch aRticle
ReseaRch aRticle
www.futuremedicine.com
future science group
DOI: 10.2217/IMT.10.96
Table 1. Baseline and outcome characteristics of TB patients receiving Immunitor V-5 in combination with anti-TB therapy for 1 month.
No. Sex
Age
(years)
TB form
Months treated
with ATT prior
to V5
Therapy
regimen
Hemoglobin
(g/l)
ERS (mm/h)
Leukocyte
count × 109 l-1
Smear
positive
Axillary temp.
(oC)
Bodyweight
(kg)
Before
After
Before After
Before After
Before After
Before
After
Before After
1
Male
37
Re-treated
HKLCP
140
155
16
30
8.7
7.2
+
-
38
36.8
58
60
2
Male
33
Re-treated†
HAFTC
138
136
15
11
6.7
4.1
+
38.3
36.8
60
61
3
Male
33
Re-treated
HKFCP
150
151
6
4
5.2
4.8
-
37.8
36.8
65
70
4
Male
24
MDR-TB
HAGCP
110
122
15
9
11
+
-
38
36.8
55
57
5
Male
35
MDR-TB†
HAFCP
149
150
7
8
9
+
-
37.6
36.8
60
61
6
Male
47
Re-treated
HKLCP
121
97
5
13
11.3
3.7
+
-
37.8
36.8
55
57
7
Male
26
MDR-TB
HZKFC
146
142
17
5
6.4
+
-
38
36.8
42
45
8
Male
59
Re-treated
HREAP
131
137
43
17
7.8
+
-
37.3
36.8
57
59
9
Male
35
Re-treated
ZKCFTP
152
150
3
12.4
10.8
+
-
37.4
36.8
63
65
10
Male
45
Re-treated
HKFCP
119
115
31
7.9
11.3
+
-
37.9
36.8
50
51
11
Female 28
Re-treated†
HRZES
124
122
20
8
7.1
5.1
+
-
36.8
36.8
53
58
12
Male
32
Re-treated†
HR
140
138
21
11
14
6
+
-
36.8
36.8
63
68
13
Female 42
Re-treated†
6
HKLCP
113
128
10
8
6.9
6.1
+
-
38
36.8
50
55
14
Male
56
1stDx
4
HRZES
120
128
21
9
5.9
5.3
+
-
38.3
36.8
48
50
15
Male
40
Re-treated
3
HRZES
124
126
28
4
12.2
7.4
+
-
37.1
36.8
65
66
16
Male
33
Re-treated
3
HRZES
150
142
6
8
5.2
5.6
+
-
37.1
36.8
65
66
17
Male
34
Re-treated
2
HRZES
145
143
6
7
16.7
6.3
+
-
37.8
36.8
58
60
18
Male
55
Re-treated
2
HRZES
142
145
48
11
11.5
7
+
-
37.4
36.8
67
69
19
Male
45
Re-treated
4
HR
124
143
18
4
9
5.9
+
-
36.8
36.8
77
79
20
Male
41
Re-treated
11
HKFCP
136
138
23
9
7.7
5
+
-
37.8
36.8
73
78
21
Male
54
Re-treated
3
HRZES
117
125
21
11
12.8
8.1
+
-
36.8
36.8
50
55
22
Male
32
1stDx†
2
HRZES
114
122
42
18
6.3
7.1
+
-
37.4
36.8
59
63
23
Male
36
MDR-TB
4
HKFCT
142
148
12
8
7.8
7.2
+
-
38
36.8
67
71
24
Male
23
1stDx†
3
HRZES
145
148
24
8
8.6
4
+
-
37.3
36.8
69
73
25
Female 24
1stDx†
4
HRZES
101
118
58
9
11.6
4.3
+
-
38
36.8
62
75
26
Male
42
Re-treated†
1
HRZES
104
118
28
10
18
4
+
-
38
36.8
66
75
27
Male
37
Re-treated†
1
HRZES
84
108
47
11
11.6
9.2
+
-
38
37.2
56
58
3/24
Mean: 38.1 Median: 36
Mean: 4 ± 3
Median: 3
–
128.9 ± 17.6
133.1
± 14.7
21.9 ± 14.8
10.5
± 6.4
9.6 ± 3.4
6.5 ± 2
0/27
26/1
4/23 37.6
27/0 36.8
59.7
± 8
63.1
± 8.6
p = 0.03
p = 0.0003
p = 0.0002
p <0.0001
p = 2.6E-009
p = 5.7E-007
With the exception of HRZES standardized drug combination, other combinations of drugs are individualized treatment regimens.
†HIV-positive status.
1stDx: First diagnosed; A: Amikacin; ATT: Anti-TB therapy; C: Clofazimine; E: Ethambutol; ESR: Erythrocyte sedimentation rate; F: Sparfloxacin; G: Gatifloxacin; H: Isoniazid; K: Kanamycin; L: Levofloxacin; MDR: Multidrug
resistant; P: Para-aminosalicylic acid; R: Rifampicin; S: Streptomycin; T: Ethionamide; Z: Pyrazinamide.

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used to determine the association between treat‑
ments and negative sputum conversion. The
probability values were considered as significant
at a cutoff at p ≤ 0.05.



respectively (Tables 1 & 2). Drug resistance to
first‑ and second‑line TB drugs was tested with
a commercially supplied kit (Tulip Diagnostics,
Goa, India) with ready‑to‑use tubes contain‑
ing TB drugs incorporated at manufacturer‑
predetermined concentrations into standard
Löwenstein–Jensen agar slants. MDR‑TB was
diagnosed when resistance to both I and R, with
or without resistance to other drugs, was present.


ReseaRch aRticle
Arjanova, Prihoda, Yurchenko et al.
Immunotherapy (2011) 3(2)
future science group
DOI: 10.2217/IMT.10.96
B vaccine made from pooled plasma). V5 is
currently approved in Ukraine as an immuno‑
modulating supplement. V5 is presented as an
850‑mg coated pill, ten of which are sealed in
a ‘blister’ pallet, with 30 pills per pack. The
recom mended dose is one to two pills per day.
The preparation is stable at ambient temperature
for 5 years.
n Microbiological assays
A standard microbiology examination of sputum
smear staining, by the Ziehl–Neelsen method,
was conducted prior to study entry and at day 30
post‑treatment. All patients were acid‑fast stain‑
ing positive prior to the study initiation, despite
the fact that the median/average duration of
ATT prior to immunotherapy was 3/4 ± 3 and
3/3.4 ± 2.7 months for the V5 and placebo arms,
n Statistical analysis
The obtained results were analyzed with sta‑
tistical software available online (GraphPad
Software, Inc., CA, USA). All statistical analy‑
ses were carried out an on intent‑to‑treat basis,
involving the total number of patients without
subgrouping them into responders and nonre‑
sponders. Parametric baseline values relative to
the end of study results were evaluated by the
student t‑test. The comparisons of categorical
values were performed with Fisher’s exact two‑
tailed test, odds ratio calculation and McNemar
test. Spearman rank correlation analysis was
Results
This study involved 55 TB patients, over half of
whom were refractory to the conventional ATT
and required individualized TB drugs regimen
(Figure 1). Only one (3.7%) and three (10.7%) sub‑
jects in the V5 and placebo arms had first‑diag‑
nosed, drug‑sensitive TB; the remaining patients
had re‑treated TB, MDR‑TB or HIV–TB (Table
1 & 2). They were equally divided into treatment
(n = 27) and placebo (n = 28) arms, matched by
age, gender, baseline bodyweight and clinical
manifestations. With the exception of hemo‑
globin, the study entry parameters of patients
in both groups were almost identical, indicat‑
ing that observed disparities in outcome were
not owing to patients’ heterogeneity prior to the
study initiation.
n Lack of adverse reactions
No adverse reactions or side effects attribut‑
able to V5 were seen during the entire dura‑
tion of the follow‑up. No reactivations of TB,
malaise, intolerance or allergic reactions were
evident at any time. After 1 month, self‑reported
and physician‑observed clinical symptoms had
improved greatly among all patients in V5 arm,
while the proportion of patients on placebo
who reported satisfactory results was consid‑
erably smaller (28.6%). The baseline clinical
symptoms of TB, such as night sweats, nausea,
fatigue, anorexia and general malaise started to
reverse after the first few days of treatment. By
the end of the first week, most patients in the
V5 arm were clearly benefiting from the ther‑
apy. The improvement in quality of life among
patients on placebo was not common, and the
differences in outcome were highly significant,
with p = 0.007 by Fisher’s exact test. Owing
to the subjective nature of clinical symptoms
and difficulty of measuring them in an objective
manner, these effects have not been elaborated
in detail in this study (Figure 2). However, this
subjective impression is supported by quanti‑
tative end points, such as an effect on weight
gain, fever reduction, erythrocyte sedimentation
rate (ESR), leukocyte counts and hemoglobin
content as detailed later.
n Effect on mycobacterial clearance
The 26 out of 27 patients (96.3%) became
sputum negative in the V5 group, which was
highly significant by nonparametric Fisher’s
two‑tailed exact test (p < 0.0000001) (Table 1 &
Figure 2). In the placebo group, only seven out
of 28 patients (25%) converted (p = 0.005).
McNemar’s test comparing outcomes between
the V5 and placebo arms indicates statistically
significant differ ence at p = 0.0007, with an
odds ratio of 5.5 (range: 2.6–13.5) at 95% CI.
In the V5 arm, nine out of ten patients with
HIV–TB coinfection had a negative sputum
smear after 1 month, compared with two out of
seven HIV‑positive individuals in the placebo
arm. This difference was, again, significant by
McNemar’s test, with p = 0.015 and an odds
ratio of 4.7 (range: 1.3–25.3) at 95% CI. The

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99

149

11 10
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DOI: 10.2217/IMT.10.96
Table 2. Baseline and outcome characteristics of TB patients receiving placebo in combination with anti-TB therapy for 1 month.
No.
Sex
Age
(years)
TB form
Months treated
with ATT prior
to placebo
Therapy
regimen
Hemoglobin
(g/l)
ESR (mm/h)
Leukocyte
count × 109 l-1
Smear
positive
Axillary temp.
(°C)
Bodyweight
(kg)
Before
After
Before
After
Before
After
Before After
Before
After
Before
After
1
Male
29
Re-treated†8
HR
102
104
23
20
17
17
+
+
38
37.8
60
60
2
Male
35
Re-treated†6
HKLCP
126
130
13
11
11
8
+
-
38.3
36.8
68
70
3
Male
44
Re-treated
2
HRZES
108
112
14
10
9
8
+
+
37.8
37.4
61
62
4
Male
35
Re-treated
2
HAFCP
118
120
18
15
12
11
+
+
38
37.5
69
70
5
Male
28
MDR-TB
4
HZKLC
120
132
32
11
12
+
-
37.6
36.8
68
72
6
Male
24
Re-treated
1
HR
115
117
22
18
8
+
+
37.8
37.6
70
71
7
Male
22
Re-treated
1
HRZES
121
122
28
24
11
+
+
38
37.4
67
67
8
Male
44
MDR-TB
3
HAFTP
128
130
16
9
8
+
+
37.3
36.8
72
73
9
Female 78
1stDx
3
HRZES
116
124
14
9
8
8
+
-
37.4
36.8
52
54
10
Male
28
MDR-TB
3
HKLCP
128
122
16
13
9
+
+
37.9
36.8
60
61
11
Female 41
1stDx
3
HRZES
113
122
21
12
8
+
-
36.8
36.8
47
50
12
Male
41
1stDx
3
HRZES
120
132
14
8
9
5
+
-
36.8
36.8
78
81
13
Male
47
Re-treated
4
HRZES
126
132
24
10
11
6
+
-
38
36.8
72
77
14
Male
44
Re-treated†4
HRZES
118
128
18
9
13
8
+
-
38.3
36.8
61
63
15
Male
33
Re-treated†3
ZEAFC
100
103
22
16
11
10
+
+
37.1
37.7
57
57
16
Female 21
MDR-TB
4
HKLCT
102
100
14
11
9
8
+
+
37.1
37.2
47
48
17
Male
24
MDR-TB
10
HEACF
110
112
15
10
11
9
+
+
37.8
37.5
55
55
18
Male
30
1stDx†
1
HRZES
112
110
26
22
7
9
+
+
37.4
38
63
63
19
Male
33
Re-treated†2
HZKCF
116
108
15
12
11
10
+
+
36.8
37.4
60
55
20
Male
31
1stDx†
3
HRZES
122
120
17
15
8
8
+
+
37.8
37.4
65
65
21
Female 50
Re-treated
4
HKFCP
130
118
10
18
7.8
7.5
+
+
37.3
37.5
55
56
22
Female 42
Re-treated
1
HALTC
83
90
38
35
7.7
8
+
+
37.5
36.8
35
36
23
Male
51
Re-treated
12
HZEAP
65
96
47
21
9.4
9.2
+
+
38
36.8
58
60
24
Male
52
Re-treated
1
AFCTP
110
112
26
20
5.5
6
+
+
38
37.5
55
55
25
Male
53
Re-treated
1
HKLCP
119
120
35
28
11.2
12.3
+
+
37.3
37.1
40
41
26
Male
45
Re-treated
1
KLTCP
117
115
18
9
11.5
9
+
+
37.5
37
55
55
27
Male
36
Re-treated
1
HAFTC
108
110
15
11
16.4
12
+
+
38
37.3
49
50
28
Male
31
Re-treated
4
HKLTP
100
135
21
27
5.1
7.8
+
+
37.5
37.1
55
57
–
5/23
Mean:
38.3
Median:
35.5
–
Mean: 3.4 ± 2.7 Median: 3
–
112.6 ± 14
117 ± 11.7
21.1 ± 8.6
15.4 ± 7
10.3 ± 2.9
9 ± 2.3
0/28
7/21
3/25 37.6
11/1737.2
59.1 ± 9.9
60.1
±
10.4
p = 0.03
p = 7.9E-005
p = 0.002
p = 0.01
p = 0.0005
p = 0.003
With the exception of HRZES standardized drug combination, other combinations of drugs are individualized treatment regimens.
†HIV-positive status.
1stDx: First diagnosed; A: Amikacin; ATT: Anti-TB therapy; C: Clofazimine; E: Ethambutol; ESR: Erythrocyte sedimentation rate; F: Sparfloxacin; G: Gatifloxacin; H: Isoniazid; K: Kanamycin; L: Levofloxacin; MDR: Multidrug-
resistant; P: Para-aminosalicylic acid; R: Rifampicin; S: Streptomycin; T: Ethionamide; TB: Tuberculosis; Z: Pyrazinamide.

Page 6

Author Proof
outcomes differed by over threefold disparity in
mean weight accrual and proportion of patients
who gained weight (67.9 vs 100%; Fisher’s exact
two‑tailed test: p = 0.002), the latter value was
also significant by McNemar analysis (p = 0.03;
odds ratio: 1.9; range: 1.1–3.5 at 95% CI). These
findings indicate that V5 had more pronounced
benefit on weight gain than ATT alone.



negative smear conversion does not appear to be
dependent on the choice of TB drugs. Spearman
rank correlation analysis failed to reveal any
signifi cant association between negative conver‑
sion and more intense individualized therapy in
the placebo group, with p = 0.14, or in V5 group,
with p = 0.31. However, the same correlation
analysis, which takes into account V5 as thera‑
peutic inter vention, was highly significant, with
p < 0.0000001.


ReseaRch aRticle
Arjanova, Prihoda, Yurchenko et al.
Immunotherapy (2011) 3(2)
future science group
DOI: 10.2217/IMT.10.96
n Effect on bodyweight
After 1 month, the average bodyweight among
placebo recipients had risen by 1.07 kg from base‑
line (i.e., 59.07 ± 9.9 vs 60.14 ± 10.4 kg; p = 0.003
by paired t‑test). The proportion of patients who
gained weight was 19 out of 28 (67.9%). By con‑
trast, among those who received V5, the average
weight gain was 3.4 kg (59.7 ± 8 vs 63.1 ± 8.8 kg;
p = 5.7E‑007) in 100% of treated patients. The
mean body mass of patients in both groups
prior to enrollment was not statistically differ‑
ent (p = 0.78 by unpaired t‑test), but treatment
n Effect on axillary body temperature
The average body temperature among placebo
recipients dropped by 0.4°C from a mean of 37.6
to 37.2°C (p = 0.0005 by paired t‑test). While
this remained above the normal range, the pro‑
portion of patients with normalized temp erature
after 1 month was 11 out of 28 (39.3%; Fisher’s
exact two‑tailed test: p = 0.01). In the V5
group, body temperature became normal in all
27 patients (100%; Fisher’s exact two‑tailed test:
p < 000001) descending from the mean 37.6
to normal 36.8°C (p = 7.5E‑008). McNemar’s
test, which was used to compare the difference
in defervescence outcome between placebo and
V5 groups, has revealed statistically significant
discrepancy (p < 0.0001), with odds ratio equal
to 4.0 (range: 2–8.6) at 95% CI.
n Effect on inflammation indices
In addition to persisting fever, TB patients are
known to have an elevated ESR and leuko‑
cyte counts, both of which are indicative of
TB‑associated inflammation. Adjunctive
use of V5 halved ESR from 21.9 ± 14.8 to
10.5 ± 6.4 mm/h (p = 0.0003), whereas, in the
placebo arm, the ESR was reduced by 27.4%,
from a mean of 21.1 ± 8.7 to 15.4 ± 7%, a decrease
that was, nevertheless, highly signifi cant (p = 7.9
E‑005), even though ESR at 15.4 mm/h is still
above the normal threshold. In the V5 arm, leu‑
kocytes decreased from a mean of 9.6 ± 3.4 × 109
cells/l to normal levels 6.5 ± 1.9 × 109 cells/l
(p = 0.0002), while those who received pla‑
cebo along with ATT have not seen the com‑
plete normalization of white cell counts, but
there was a definitive decrease as demon strated
by paired t‑test (from 10.3 ± 2.9 × 109 to
8.96 ± 2.3 × 109 cells/l; p = 0.002).
n Effect on anemia
Most TB patients are characterized by low hemo‑
globin content, which is usually associated with
poor prognosis. Patients in both treatment regi‑
mens experienced an equally significant increase
in levels of hemoglobin from 128.9 ± 17.6 to
133.1 ± 14.7 g/l (p = 0.03), and from 112.6 ± 14
to 117 ± 11.7 g/l (p = 0.03), in the V5 and pla‑
cebo arms, respectively. This occurred despite
the fact that, for an unknown reason, the base‑
line levels of hemoglobin differed significantly
between two populations (128.9 vs 112.6 g/l;
p = 0.0004 by unpaired t‑test).
Discussion
The results of this placebo‑controlled, matched‑
case study, in a representative group of TB
patients refractory to conventional ATT, indi‑
cate that when TB drugs are combined with V5,
this combination can produce superior clinical
response and clearance of M. tuberculosis in
the sputum smear at a rate higher than among
patients on ATT and placebo. These findings
Response rate (%)
0
20
40
60
120
V5Placebo
100
80
Fever
reduction
ESRLeukocyte
count
Hb Weight
gain
Life
quality
Sputum
conversion
Figure 2. Proportion of anti-TB-treated patients in Immunitor V-5 (V5) and
placebo arms who benefited from the therapy according to the measured
end points.
ESR: Erythrocyte sedimentation rate; Hb: Hemoglobin.

Page 7

patients, the conversion rate was very similar (i.e.,
94.4%) [12]. This response rate occurred within
such a short period of time, which was excep‑
tional and has been seldom seen in TB chemo‑
therapy trials. The usual rate of mycobacterial
clearance of drug‑sensitive TB after 1 month
on ATT does not exceed 40–50% [13]. Among
patients refractory to TB drugs, as in the case of
re‑treated TB, MDR‑TB or HIV–TB, this rate is
even lower, and is comparable with the outcome
in the placebo arm [14–18].
There were earlier indications that V5 exhib‑
its anti‑inflammatory properties [9–12]. This
notion is further supported by the findings of
this study. The decline of elevated body tempera‑
ture to normal levels occurred in all V5‑treated
patients. This effect was also observed in the pre‑
vious study, where TB‑associated fever subsided
within a mean/median of 4.1/3 days. By contrast,
the mean temperature among placebo recipients
failed to reach normal levels and the proportion
of patients with normalized temp erature was
only 39.3%. As fever is an independent risk fac‑
tor associated with an aggressive form of TB, an
intervention that can produce fast and reliable
defervescence ought to be considered as beneficial
to patients. Elevated numbers of leukocytes are
known to associate with active pulmonary TB
[19]. The restoration of normal leukocyte counts
was seen in both arms, indicating that both V5
and ATT have a favorable anti‑ inflammatory
effect. V5 also reduced the ESR – another
marker of TB‑associated inflammation – much
more efficiently than in the ATT alone group [20].
Anemia is a common manifestation of pulmo‑
nary TB. The precise mechanism of anemia in
pulmonary TB is not clear, but inflammation, as
well as iron deficiency, is thought to be the main
causative factors [21]. As our patients were not
receiving iron supplementation, we believe that
the increase in hemoglobin content is also related
to anti‑inflammatory properties of V5 and ATT.
TB is a wasting disease, which is poorly man‑
ageable and is one of the leading factors contrib‑
uting to higher morbidity and mortality [22,23].
The remarkable aspect of our therapy is a more
than threefold weight gain, which occurred in

Author Proof
than chemotherapy alone. For example, negative
sputum conversion seen in MDR‑TB patients
after 3 months was 43%, while among those who
received chemotherapy it was 21% [29]. M. vaccae
appeared to produce a measurable improvement
in some geographical regions, but not in oth‑
ers, suggesting that different environmental
and immunological experiences of the treated
host can contribute to this inconsistency [28].
Recently, a therapeutic vaccine, RUTI® contain‑
ing detoxified cellular fragments of M. tubercu-
losis was reported but no data regarding its effi‑
cacy in humans are available yet [30]. In addition
to these two preparations, there are few other
Mycobacterium‑derived immune therapies that





Immunotherapy of TB ReseaRch aRticle
www.futuremedicine.com
future science group
DOI: 10.2217/IMT.10.96
support our previous open‑label study that was
initially set out to treat chronic hepatitis C
patients with concurrent TB and HIV infections
and unexpectedly revealed the clinical potential
against TB [12].
In this study, 96.3% of V5 recipients became
sputum negative after 30 days, whereas, in the
placebo group, only 25% had converted. In the
previous 1‑month study involving 20 HIV–TB
all of the V5‑treated patients, compared with
the modest effect among a smaller proportion of
patients on placebo. In the prior study, the mean
weight gain was 7.7 kg [12]. We do not know the
reason for this discrepancy or how V5 reverses
the weight loss. In general, based on our prior
experience with unrelated TB immunothera‑
pies, we believe that there is a strong relation‑
ship between reversal of cachexia and efficacy of
immunotherapy [13,14].
How do our results compare with previ‑
ously tried immunotherapeutic interventions?
Back in 1890, Robert Koch, the discoverer of
M. tuberculosis, announced that the injection of
tuberculin can cure the disease. However, the
subsequent clinical trial, involving nearly 1700
patients, revealed that only 2% benefited from
this approach [24]. The Bacillus Calmette–Guérin
(BCG) vaccine was introduced in 1921, and
has been predominantly used as a prophylactic
modality. There are, however, reports of BCG
use as an adjunct to TB therapy. In the Chinese
study involving 360 volunteers, the negative spu‑
tum conversion rate in BCG recipients was 98.3
and 97.2% in chemotherapy control. While this
was not significant, the recurrence of TB after
5 years in the BCG group was 2.3%, but 6.9%
in the control group [25]. By contrast, when ther‑
apeutic vaccination with BCG was attempted
in a mouse model, it resulted in exacerbation of
the disease – a phenomenon first observed by
Koch [26]. However, other investigators noted
that, while the potential risk of inducing Koch‑
like reaction is low, extreme caution is still
needed as post exposure vaccines progress into
the initial phases of clinical testing [27].
More promising immunotherapy is a killed
Mycobacterium vaccae preparation, discovered by
Stanford et al. in the 1970s [28]. This immuno‑
therapy has been tested in many countries world‑
wide, and usually resulted in a better outcome

Page 8

Author Proof
to us is that inflammation, fever, wasting, ane‑
mia and other TB symptoms were improved by
Dzherelo in a manner that was almost identical
to what we have observed with V5.
What is the mechanism of V5 action? The
onset of TB disease is generally attributed to
the failure of cellular immunity [24]. Every pro‑
phylactic vaccine that has entered clinical trial
stage is designed to boost immune reaction
against M. tuberculosis [40,41]. In our opinion,
this approach is not appropriate in designing
therapeutic vaccines. TB is a disease whereby
pulmonary or other tissues harboring myco‑
bacteria are constantly assaulted by the host’s
immune system, creating chronic inflammation



51.9% became sputum negative.
Other immune intervention, such as inhaled
IFN‑g, corticosteroids, and various cytokine or
anticytokine regimens showed some improve‑
ments, but results were inconsistent and occa‑
sionally associated with deleterious side effects,
such as high fever, malaise, edema and even the
death of the host [8]. In view of the current status
of TB immunotherapy, it is clear that safer and
better solutions need to be found [33]. Prior to
this study, we have been working on Ukrainian‑
made herbal immunomodulator Dzherelo
(Immunoxel) as a means to treat TB, drug‑
resistant TB and HIV–TB. From approximately
12 clinical studies, involving nearly 1200 indi‑
viduals in whom different end points were
investigated, we can conclude that Dzherelo is
safe, although not as effective as V5 [13,14,34–39].
Sputum conversion among MDR‑TB and
HIV–TB patients after 2 months of treatment
was in the region of 85–100%, while in controls
on ATT alone, it took 6–24 months to reach the
48–85% range. However, what was of interest


ReseaRch aRticle
Arjanova, Prihoda, Yurchenko et al.
Immunotherapy (2011) 3(2)
future science group
DOI: 10.2217/IMT.10.96
are commercially available and have been used in
TB patients. A recent review from China, report‑
ing Mycobacterium phlei as adjunctive therapy for
drug‑resistant TB, summarizes six clinical trials
in which sputum conversion data were avail‑
able. Out of 212 patients who received M. phlei
injection, 169 (79.7%) became sputum negative
versus 104 out of 212 (49.1%) in controls [31]. In
India, a vaccine preparation of Mycobacterium w
(Immuvac, Cadila Pharmaceuticals, Ahmedabad,
India), originally developed for leprosy, has been
tried in so‑called category II TB patients, which
approximately corresponds to our re‑treated TB
population [32]. Patel et al., who conducted the
study, have obtained practically same results
as Chinese investigators; 75.5% patients, who
received twice‑per‑month injection of Immuvac
for 2 months, had converted, while in control,
and ensuing tissue damage [20]. Thus, in order
to treat TB, one needs to induce the immune
tolerance instead of vexing self‑directed immune
response. Our vaccine is derived from pooled
blood of hepatitis C‑ and B‑positive donors.
As a third of people harbor latent M. tubercu-
losis, this means that V5 preparation comprises
TB bacterium inherently present in the donors’
blood. Therefore, we surmise that the adminis‑
tration of V5 triggers the immune response not
only to hepatitis viruses (as intended originally)
but also to tubercle bacilli. It is well known that
when a low dose of an antigen is administered
orally, it produces mucosal tolerance rather than
the immune activation [42]. The same rationale
applies to the other oral vaccines that we have
developed for unrelated indications and, so far,
none have failed, and the clinical benefit was far
beyond our expectations. Oral delivery of vac‑
cines, thus, makes sense and should, in theory,
perform no worse than injectable preparations, as
has been demon strated recently by Dlugovitzky
et al. in their clinical trial of M. vaccae [43]. In our
view, TB is just another autoimmune disease that
can be managed by tolerance induction. This
obviously needs to be verified in further studies
addressing the immune mechanism of V5 action.
Conclusion
In developing countries, TB is out of control
owing to increasing poverty, drug‑resistant TB
and HIV coinfection [44]. The improved under‑
standing of the immunopathogenesis of TB will
result in the development of effective and safe
immunotherapies [45]. Despite many limitations
of this study, we believe that V5 has a potential
to improve treatment outcome in patients with
refractory TB, including those with drug‑resis‑
tant TB and HIV–TB. V5 is safe and capable
of producing better quality of life in treated
patients. No reactivation of TB was seen at any
time, which is not surprising considering the
potent anti‑inflammatory property of V5. We
do not know whether or how downregulation of
inflammation relates to bacterial clearance, since
the mechanism of action of V5 is unknown and,
at this time, we can only speculate as to its mode
of action. In a mouse model, the concurrent
administration of TB drugs, except when pyra‑
zinamide was used alone, with anti‑ inflammatory
drugs (e.g., aspirin) has not produced clear‑cut
benefits [46,47]. By contrast, the combination of
V5 with ATT drastically shortens the duration
of treatment and produces higher response rate
than ATT alone. Immune interventions, such as
V5, must be validated through rigorous scientific

Page 9

lator, Dzherelo, the clinical effects we observed
were strikingly similar to V5. Despite encour‑
aging results, and the publication of data in 12
Russian and English language medical journals,
we have not seen any meaningful follow‑up either
inside or outside of Ukraine. There has been
no genuine interest in trying Dzherelo in TB
patients. In relation to this, it is of interest that
it took more than 30 years for another immu‑
nomodulator, heat‑killed M. vaccae preparation,
to advance to a Phase III trial [45]. This suggests
that it takes time to overcome the inertia. We do
not know whether V5 will have a different fate.
It is true that V5 produces faster and higher pro‑
portion of sputum conversion than Dzherelo or
M. vaccae, but this is besides the point. The pub‑
lic and doctors have to be ready to embrace new
treatment paradigms. It takes time and money
to do so. Even mediocre treatments can thrive
if spun out properly with the right amount of
cash and political backing. Thus, the success of
a product, in addition to its scientific merit, also
depends on proper connections in the medical
business and savvy marketing strategies. We can‑
not predict whether, in the next 5 years, V5 will
be used widely as an adjunct immune therapy for
TB or will linger outside of the mainstream with‑
out adequate funding or interest. Unless we are
naive and do not know better, we believe this is
the future perspective for V5 and for TB immu‑
notherapy in general. However, the emergence of
drug‑resistant TB and HIV–TB coinfection has

Author Proof
Executive summary





Immunotherapy of TB ReseaRch aRticle
www.futuremedicine.com
future science group
DOI: 10.2217/IMT.10.96
and clinical research to facilitate their integra‑
tion into modern medical practice, so treatment
options for TB are expanded as a result.
Future perspective
We and our clinical collaborators in the Ukraine
have worked on immunotherapy of TB over the
past 10 years [13,14,34–39]. While we have used the
locally produced, plant‑derived immunomodu‑
become of greater concern to TB caregivers and
policymakers. If this trend continues, we may see
changes that will be constructive and may result
in tangible action. If this happens, then the future
could mean improved therapy for TB patients,
and that is our hope.
“Things do not change; we change.”
– Henry David Thoreau
Acknowledgements
We dedicate our work to volunteers who participated in this
study. The wholehearted support of our medical staff and
lab personnel who contributed their efforts made this study
possible. We are also grateful to our colleagues abroad who
shared their experiences relating to the present study.
Financial & competing interests disclosure
This study was conducted under auspices of the regional
health authorities of Ukraine as a part of the routine clinical
care at the TB Dispensary. The assistance of Immunitor
company for providing free supplies of V-5 Immunitor (V5)
is appreciated. Vichai Jirathitikal and Aldar S Bourinbaiar
are officers and owners of Immunitor company – the sponsor
of this trial. The authors have no other relevant affiliations
or financial involvement with any organization or entity
with a financial interest in or financial conflict with the
subject matter or materials discussed in the manuscript
apart from those disclosed.
No writing assistance was utilized in the production of
this manuscript.
Ethical conduct of research
The authors have obtained the Institutional Review
Board approval of Lisichansk TB Dispensary and have
followed the principles of the Declaration of Helsinki for
all human or animal experimental investigations. The
participants in the trial have had the informed consent,
participated in this study voluntarily, and were free to
withdraw from this study at any time. This study is reg-
istered with the ClinicalTrials.gov under identifier
NCT01222338.
ƒ Concurrent administration of Immunitor V-5 (V5) with first- or second-line TB drugs resulted in clearance of Mycobacterium tuberculosis
in sputum smears of 96.3% patients versus 25% among placebo recipients.
ƒ Sputum conversion occurred very fast – only 1 month of treatment was needed.
ƒ No difference was seen when first-diagnosed TB was compared with re-treated TB, multidrug-resistant TB or HIV–TB coinfection– the
proportion of converted patients and time to conversion were identical.
ƒ One pill of V5 administered once per day produced other statistically significant clinical benefits.
ƒ V5 reversed TB-associated wasting; average weight gain was 3.4 kg in 100% of patients versus 1.07 kg in 67.9% in placebo.
ƒ V5 eliminated TB-associated fever in 100% of patients versus 39.3% of patients on placebo.
ƒ V5 demonstrated marked anti-inflammatory effect. Erythrocyte sedimentation rate and leukocyte counts reverted back to normal.
However, patients on TB drugs alone also experienced reduced inflammation.
ƒ The relationship between anti-inflammatory property of V5 and bacterial clearance needs to be investigated.
ƒ V5 is affordable, easy to administer, stable at room temperature (without need for cold chains), and is made from a readily
available source.
ƒ V5 is safe, and has not produced any adverse effects or reactivation of TB.

Page 10

Bazhora Y, Servetsky S: Increasing trends in
HIV and TB rates in Odessa and the
Ukraine. Int. J. STD AIDS 16, 374–378
(2005).

Author Proof
therapeutic hepatitis B vaccine V‑5
Immunitor (V5) delivered by oral route.
Lett. Drug Design Discovery 4, 540–544
(2007).
of stronger immune response as means to
overcome active TB is questioned.





patients with multidrug‑resistant
tuberculosis. Am. J. Respir. Crit. Care Med.
169, 1103–1109 (2004).
ReseaRch aRticle
Arjanova, Prihoda, Yurchenko et al.
Immunotherapy (2011) 3(2)
future science group
DOI: 10.2217/IMT.10.96
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