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Influence of Treg cells and HBV genotype on sustained response and drug resistance in the treatment with nucleoside drugs.

Introduction

It is known that antiviral efficacy and drug resistance are related to chronic hepatitis B virus (HBV). The host's immune state, the selection of nucleoside drugs and the virus' genotype could be major factors in antiviral efficacy and drug resistance in patients (1,2). Recent studies have indicated that regulatory T cells (Tregs) inhibited effector Tcells in the HBV infection process, and consequently the virus was not completely eliminated (3). [CD4.sup.+] [CD25.sup.+] and [CD8.sup.+] [CD28.sup.-] are Treg subgroups that have mostly been studied recently. Stoop et al. (4) found that PB [CD4.sup.+] [CD25.sup.+] Treg proportion in patients with chronic HBV was obviously increased compared to healthy control patients and healed patients, and the proportion of patients with positive hepatitis B E antigen (HBeAg) was higher than patients with negative HBeAg. Franzese et al. (5) evaluated Tregs levels among patients that carried asymptomatic viruses, patients at the chronic infection stage, patients with previous infections, and healthy controls, and found no significant difference. This was independent of HBeAg status, HBV load and different antiviral therapies. However, Zhang et al. (6) reported that the proportion of PB [CD4.sup.+] [CD25.sup.+] was significantly reduced after HBV DNA was inhibited by entecavir, and the immune function of patients was recovered. In addition, other studies found that the high expression of [CD8.sup.+] [CD28.sup.-] was a marker for decreased T cell function, which may go against the clearance of HBV (7,8). However, there are no studies that determined whether or not [CD4.sup.+] [CD25.sup.+] and [CD8.sup.+] [CD28.sup.-] levels have an influence on antiviral efficacy and drug resistance to nucleoside drugs.

The HBV genotype is divided into nine types from A to I. In general, patients with HBV infection have mostly types A and B, while Chinese patients with HBV infection have mostly types B and C (9). Studies have reported that the virological response to lamivudine therapy was more likely to occur in patients with genotype B than in patients with genotype C, which present with more severe conditions and poor drug efficacy (10). To date, no studies exist with respect to the relationship between virus genotypes and early virological responses to nucleoside drug treatment (lamivudine and entecavir).

Therefore, this study aimed to investigate the influence of Treg cells at baseline and virus genotype on early virological response and drug resistance to nucleoside drugs.

Patients and Methods

Patients

This study included a total of 137 inpatients and outpatients with chronic HBV infection from May 2010 to April 2014. Among these patients, 95 were males and 42 were females with age ranging between 24-70 years (mean age: 46.8 years). The Guidelines for the Prevention and Treatment of Chronic HBV Infection, established by the Chinese Society of Hepatology and the Society of Infectious Diseases, was used as the diagnostic criteria (11). Based on these guidelines, study participants were classified as 88 patients with chronic HBV, 49 patients with cirrhosis, 54 HBeAg-positive patients, and 83 HBeAg-negative patients (demographic data are reported in Table 1). Inclusion criteria were as follows: 1) patients with positive HBsAg for more than 6 months, and HBV DNA [greater than or equal to] [10.sup.4] cps/mL in two examinations (reference value: <1 x [10.sup.3] cps/mL); 2) patients with alanine aminotrasferase (ALT) levels [greater than or equal to] 1.5 ULN; 3) patients treatment-naive for lamivudine and entecavir.

Exclusion criteria were as follows: patients with hepatitis C, hepatitis D, HIV infection, primary liver cancer and hepatic failure.

Methods

Among the 137 patients with chronic HBV infection, 84 were administered 100 mg/day of lamivudine po (GlaxoSmithKline Medical, China), and 53 patients were administered 0.5 mg/day of entecavir (Chiatai Tianqing Pharmaceutical, China) po for treatment, according to the time sequence of hospitalization. Biochemical tests, HBV DNA burden, HBV serum level, HBV genotype, [CD3.sup.+], [CD4.sup.+], [CD8.sup.+], [CD4.sup.+] [CD25.sup.+]/[CD3.sup.+] and [CD8.sup.+][CD28.sup.-]/[CD3.sup.+] percentages were measured before treatment; biochemical tests and HBV DNA load were rechecked at the 4th, 12th and 24th week of treatment. During lamivudine therapy, if HBV DNA load rebounded, drug resistance was determined. Biochemical examination was performed using an automatic biochemical analyzer in The First People's Hospital of Lanzhou City, and the reagent for HBV DNA load was provided by Hunan Sansure Biotech Reagent Co., Ltd., China, with a lower limit of 500 IU/mL. HBV genotype and the test for drug resistance to lamivudine were performed using real-time PCR, and assisted by Xi'an KingMed Diagnostics, China. [CD3.sup.+], [CD4.sup.+], [CD8.sup.+], [CD4.sup.+] [CD25.sup.+]/[CD3.sup.+] and [CD8.sup.+] [CD28.sup.-]/[CD3.sup.+] were detected using flow cytometry, and assisted by Xi'an KingMed Diagnostics.

Flow cytometry detection method was as follows: Elbow venous blood was collected early in the morning on an empty stomach, and was kept in sodium citrate anticoagulation tubes. Empty tubes were coded, and 20 [micro]L of CD25-PE, [CD28.sup.-]PC7, CD8-FITC, CD4-PC5 and CD3ECD monoclonal antibodies were added. Then, 100 [micro]L of whole blood with anticoagulant was added and gently mixed. Afterwards, the tubes were placed at room temperature for 15 min, and BD general hemolysin was added and left for 10 min until complete specimen hemolysis. Then, the solution was centrifuged at 500 g for 5 min at 18-22[degrees]C. The supernatant was removed, calf serum washing liquid was added for rinsing, and centrifuged at 500 g for 5 min at 18-22[degrees]C. The supernatant was removed and fixed liquid was added to re-suspend cells for detection using a computer. A flow cytometry instrument (Beckman Coulter, model: FC500 MCL, USA) was used for detection, the reagent was provided by Beckman Coulter, and the CXP analysis software (USA) was used for data analysis.

Grouping criteria

Patients were divided into two groups: the response group and the suboptimal response group, based on whether or not HBV DNA load was detected at the end of the 4th week of lamivudine or entecavir treatment. The comparison was performed between groups in terms of [CD3.sup.+], [CD4.sup.+], [CD8.sup.+], [CD4.sup.+][CD25.sup.+]/[CD3.sup.+] and [CD8.sup.+] [CD28.sup.-]/[CD3.sup.+] levels at baseline and the constituent ratio of the virus genotype. Patients in the lamivudine treatment group received treatment continuously for 96 weeks. Patients of this group were categorized into two groups, the resistance group and the non-resistance group, based on whether the patient was resistant to the drug during treatment or not. The resistance group was compared to the non-resistance group in terms of [CD3.sup.+], [CD4.sup.+], [CD8.sup.+], [CD4.sup.+] [CD25.sup.+]/[CD3.sup.+] and [CD8.sup.+] [CD28.sup.-]/[CD3.sup.+] levels, as well as the constituent ratio of virus genotype.

Statistical analysis

SPSS 19.0 (IBM, USA) software package was used for data processing. Data are reported as means [+ or -] SD. The comparison of means between groups was performed using the Student's t-test, and the comparison of the constituent ratio was carried out using the [X.sup.2] test. P<0.05 was considered to be statistically significant.

Results

Correlation between [CD3.sup.+], [CD4.sup.+], [CD8.sup.+], [CD4.sup.+][CD25.sup.+], [CD8.sup.+] [CD28.sup.-] levels and virological response to lamivudine therapy at the 4th week

Table 2 shows that, in the response group, the [CD4.sup.+] [CD25.sup.+] level was higher than the suboptimal response group, and the difference was statistically significant (t=4.372, P=0.046). However, the [CD8.sup.+] [CD28.sup.-] level was lower than in the suboptimal response group, and the difference was not significant (t=2.290, P=0.151). The differences between groups for [CD3.sup.+], [CD4.sup.+] and [CD8.sup.+] levels were not significant (P>0.05).

Correlation between [CD3.sup.+], [CD4.sup.+], [CD8.sup.+], [CD4.sup.+][CD25.sup.+], [CD8.sup.+] [CD28.sup.-] levels and the incidence of drug resistance to lamivudine therapy at the 96th week

Table 3 shows that the levels of [CD4.sup.+] [CD25.sup.+] and [CD8.sup.+] [CD28.sup.-] were significantly different (t=7.262, P=0.017; t=5.527, P=0.037, respectively). The levels of [CD3.sup.+], [CD4.sup.+] and [CD8.sup.+] were not significantly different (P>0.05).

Correlation between HBV genotype and virological response to lamivudine at the 4th week of treatment

As reported in Table 4, the proportions of HBV genotype C in the response and suboptimal response groups were 69.2 and 72.4%, respectively; the proportions of HBV genotype B in both groups were 19.2 and 20.0%, respectively; and the proportions of HBV genotype D in both groups were 7.7 and 5.2%, respectively. The constituent ratios of virus genotypes in both groups were compared, and the difference was not significant ([X.sup.2]=0.226, P=0.973). HBV DNA burden (to obtain the Lg value) in the response group was lower than that in the suboptimal response group, and the difference was significant (t=2.164, P=0.038). HBeAg-positive rate in the response group was reduced compared with the suboptimal response group, and the difference was significant ([X.sup.2]=4.239, P=0.040). The difference of ALT level in both groups was not significant.

Correlation between HBV genotype and the incidence of drug resistance at the 96th week of lamivudine treatment

As reported in Table 5, the proportions of HBV genotype C in non-resistance and resistance groups were 60 and 79.5%, respectively; 30 and 2.3% for genotype B, respectively; and 7.5 and 2.3% for genotype D, respectively. The constituent ratios of virus genotypes in both groups were compared, and the difference was statistically significant ([X.sup.2]=59.714, P=0.000). In the nonresistance group, HBV DNA burden (to obtain the Lg value) and HBeAg-positive rate were lower than in the resistance group, and the differences were statistically significant (t=2.015, P=0.044; [X.sup.2]=16.2, P=0.000, respectively).

Correlation between [CD3.sup.+], [CD4.sup.+], [CD8.sup.+], [CD4.sup.+][CD25.sup.+], [CD8.sup.+] [CD28.sup.-] levels and virological response to entecavir treatment at the 4th week

Table 6 indicates that [CD8.sup.+][CD28.sup.-]/[CD3.sup.+] level in the response group was lower than the suboptimal response group, and the difference was statistically significant (t=6.283, P=0.036). The differences in [CD3.sup.+], [CD4.sup.+], [CD8.sup.+] and [CD4.sup.+][CD25.sup.+]/[CD3.sup.+] levels between both groups were not significant (P>0.05).

Correlation between HBV genotype and virological response to entecavir at the 4th week of treatment

As reported in Table 7, the proportions of HBV in the response and suboptimal response groups were 65.8 and 66.7% for genotype C, respectively; 26.3 and 26.7.3% for genotype B, respectively, and 2.6 and 0% for genotype D, respectively. Comparisons were performed in terms of HBV DNA loads (to obtain the Lg value), HBeAg positive rate, ALT level and the constituent ratio of virus genotypes, and the differences were not significant (P>0.05).

Discussion

Recent international and local studies have indicated that early virological response could predict drug resistance to nucleoside analogues in the future (12). In the current study, HBeAg positive rate and HBV DNA load in the virological response group and non-resistance group were lower than in the suboptimal response group and drug resistance group at the 4th week of lamivudine therapy. This indicates that negative HBeAg and low viral replication are advantage factors for the four-week virological response to lamivudine therapy and non-drug resistance at the 96th week of treatment. Virological response is more likely to occur in patients with HBV infection and negative HBeAg, which may be related to immune statuses that are different from patients with positive HBeAg, in addition to low viral replication. The results of this study revealed that patients with virus genotype C were more prone to drug resistance following lamivudine therapy, which was similar to the results of studies performed by other Chinese scholars (13). This indicates that the efficacy of lamivudine was greatly influenced by the baseline factors of patients, which is a disadvantage of lamivudine treatment. However, the virological response of patients in the entecavir treatment group was in general not affected by liver function, HBV DNA load, HBeAg status, virus genotypes and other baseline factors, indicating the advantages of entecavir treatment.

A study was further performed on the relationship among [CD3.sup.+], [CD4.sup.+], [CD8.sup.+], [CD4.sup.+] [CD25.sup.+] and [CD8.sup.+] [CD28.sup.-] frequency and virological response, as well as drug resistance, in both nucleoside therapy groups. The results indicated that the [CD4.sup.+][CD25.sup.+] levels in the 4-week virological response group and in the 2-year nonresistance of the lamivudine treatment group were higher than in the suboptimal response group and drug resistance group. This was in contrast with the opinion of many scholars that the immune suppression of [CD4.sup.+] [CD25.sup.+] has a negative effect on the clearance of viruses (14-16). This analysis indicated that such results may be related to antiviral actions of partially activated effector T cells included in [CD4.sup.+] [CD25.sup.+] (17). Therefore, recent international and local studies have considered that specific T cells containing CTLA-4, GITR, OX-40 and FoxP3, as well as other surface markers, were more suitable for the features of Treg cells (18). Hence, some scholars considered that highly expressed FoxP3[CD4.sup.+] [CD25.sup.+] T was a specific marker for Treg cells (4). No significant difference was found in [CD4.sup.+] [CD25.sup.+] T level between the virological response group and suboptimal response group in the entecavir treatment group. However, [CD8.sup.+] [CD28.sup.-] level in the response group was significantly lower than in the suboptimal response group. In addition, [CD8.sup.+] [CD28.sup.-] level in the non-resistance group with lamivudine treatment was significantly lower than that in the resistance group. This indicated that increased [CD8.sup.+] [CD28.sup.-] levels reduced the clearance capacity of viruses and increased drug resistance risk. International scholars (19,20) have demonstrated that [CD8.sup.+] [CD28.sup.-] could induce a specific T cell subgroup of tolerant APC, and result in no reactivity of helper T cell (Th) by triggering inhibitory signal circuits. This indicates that the immunosuppressive action of [CD8.sup.+] [CD28.sup.-] is stronger and more extensive than that of [CD4.sup.+] [CD25.sup.+]. Accordingly, our study found that [CD8.sup.+][CD28.sup.-] percentage can more accurately reflect immune suppression on the clearance of HBV. Boni et al. (15) indicated that for patients who responded to nucleoside therapy effectively, [CD4.sup.+] [CD8.sup.+] level remained lower than healthy people, and immune response in the patients with chronic HBV was weaker than in healthy people. These data indicate that partial actions of HBV-specific T lymphocytes were recovered, but without returning to normal levels.

doi: 10.1590/1414-431X20165796

Acknowledgments

This research was supported by the Natural Science Funding of Gansu province (No. 1308RJZA296).

References

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Y.R. Zhang [1], B. Li [2], C.X. Wang [3], N. Zhou [1], W. Qi [1], X.L. Li [1], L.Y. Wu [1], S.F. Wei [1] and Y.D. Zhang [1]

[1] Department of Infectious Diseases, The First People's Hospital of Lanzhou, Gansu, China

[2] Department of Thoracic Surgery, Gansu Province Tumor Hospital, Gansu, China

[3] Department of Geriatrics, The First People's Hospital of Lanzhou, Gansu, China

Correspondence: Y.R. Zhang: <yrzhangdoc@163.com>

Received August 28, 2016 | Accepted November 9, 2016
Table 1. Demographic data of patients.

                      n (%)      Lamivudine    Entecavir
                                    group        group

Patients (n)        137          84            53
Male                95 (69.3)    56            39
Female              42 (30.7)    28            14
Age (mean)          46.8         46.1          47.7
Hepatitis B         88 (64.2)    57            31
Cirrhosis           49 (35.8)    27            22
HBeAg positive      54 (39.4)    26            28
HBeAg negative      83 (60.6)    58            25
HBV Genotype
  C                 95 (69.3)    60            35
  B                 30 (21.9)    16            14
  D                 6 (4.4)      5             1
  Mix               6 (4.4)      3             3

Table 2. Correlation between [CD3.sup.+], [CD4.sup.+], [CD8.sup.+],
[CD4.sup.+] [CD25.sup.+], [CD8.sup.+] [CD28.sup.-] levels and
virological response to lamivudine treatment at the 4th week.

                               [CD3.sup.+]

Response group (n=26)      78.5 [+ or -] 13.6
Suboptimal response        75.1 [+ or -] 12.6
  group (n=58)
t value                           0.736
P value                           0.429

                               [CD4.sup.+]            [CD8.sup.+]

Response group (n=26)      38.9 [+ or -] 14.4      36.7 [+ or -] 5.1
Suboptimal response        35.6 [+ or -] 16.7      32.7 [+ or -] 8.4
  group (n=58)
t value                           0.311                  1.046
P value                           0.771                  0.152

                              [CD4.sup.+]             [CD8.sup.+]
                             [CD25.sup.+]/           [CD28.sup.-]/
                              [CD3.sup.+]             [CD3.sup.+]

Response group (n=26)      1.85 [+ or -] 0.91      16.3 [+ or -] 6.9
Suboptimal response        1.27 [+ or -] 0.43     18.2 [+ or -] 11.6
  group (n=58)
t value                          4.372                   2.290
P value                          0.046                   0.151

Data are reported as means [+ or -] SD (Student's t-test).

Table 3. Correlation between [CD3.sup.+], [CD4.sup.+], [CD8.sup.+],
[CD4.sup.+] [CD25.sup.+] and [CD8.sup.+] [CD28.sup.-] levels and
the incidence of drug resistance to lamivudine treatment at the
96th week.

                                     [CD3.sup.+]

Non-resistance group (n=40)       77.9 [+ or -] 12.3
Resistance group (n=44)           75.4 [+ or -] 11.6
t value                                 1.236
P value                                 0.125

                                     [CD4.sup.+]

Non-resistance group (n=40)       37.9 [+ or -] 13.4
Resistance group (n=44)           36.6 [+ or -] 15.2
t value                                 0.475
P value                                 0.198

                                     [CD8.sup.+]

Non-resistance group (n=40)       36.7 [+ or -] 5.1
Resistance group (n=44)           34.3 [+ or -] 6.7
t value                                 1.796
P value                                 0.246

                                     [CD4.sup.+]
                                    [CD25.sup.+]/
                                     [CD3.sup.+]

Non-resistance group (n=40)       1.98 [+ or -] 1.11
Resistance group (n=44)           1.31 [+ or -] 0.50
t value                                 7.262
P value                                 0.017

                                      [CD8.sup.+]
                                     [CD28.sup.-]/
                                      [CD3.sup.+]

Non-resistance group (n=40)       16.17 [+ or -] 6.39
Resistance group (n=44)           20.37 [+ or -] 10.35
t value                                  5.527
P value                                  0.037

Data are reported as means [+ or -] SD (Student's t-test).

Table 4. Correlation between hepatitis B virus (HBV) genotype
and virological response to lamivudine on the 4th week of treatment.

                              ALT (U/L)             HBV DNA
                                                  (Lg value)

Response group (n=26)      103 [+ or -] 35     5.1 [+ or -] 0.49
Suboptimal response        96 [+ or -] 38      6.7 [+ or -]0.67
  group (n=58)
t, [X.sup.2]                    1.312                2.164
P                               0.436                0.038

                                                Proportion of HBV
                                                   genotype (%)
                          HBeAg positive
                             rate (%)         C (%)         B (%)

Response group (n=26)       8/26 (30.8)     18 (69.2)     5 (19.2)
Suboptimal response        27/58 (46.6)     42 (72.4)     11 (20.0)
  group (n=58)
t, [X.sup.2]                   4.239          0.226
P                              0.040          0.973

                              Proportion of HBV
                                genotype (%)

                           D (%)     Mixed type
                                     (C/D) (%)

Response group (n=26)     2 (7.7)     1 (3.8)
Suboptimal response       3 (5.2)     2 (3.4)
  group (n=58)
t, [X.sup.2]
P

Data are reported as means [+ or -] SD, unless otherwise
specified (Student's t-test and [X.sup.2] test). ALT:
alanine aminotransferase.

Table 5. Correlation between hepatitis B virus (HBV) genotype and
the incidence of drug resistance at the 96th week of lamivudine
treatment.

                                        ALT
                                     (U/L unit)

Non-resistance group (n=40)      80.3 [+ or -] 21.4
Resistance group (n=44)          76.7 [+ or -] 26.2
t, [X.sup.2]                           1.236
P                                      0.527

                                      HBV DNA         HBeAg positive
                                    (Lg value)           rate (%)

Non-resistance group (n=40)      5.3 [+ or -] 0.60      7/40 (17.5)
Resistance group (n=44)          6.4 [+ or -] 0.54     28/44 (63.6)
t, [X.sup.2]                           2.015               16.2
P                                      0.044               0.000

                                Proportion of HBV genotype (%)

                                  C (%)       B (%)      D (%)

Non-resistance group (n=40)      24 (60)     12 (30)    3 (7.5)
Resistance group (n=44)         35 (79.5)    1 (2.3)    1 (2.3)
t, [X.sup.2]                      59.714
P                                 0.000

                              Proportion of HBV
                                 genotype (%)

                                Mixed type
                                 (C/D) (%)

Non-resistance group (n=40)       1 (2.5)
Resistance group (n=44)          7 (15.9)
t, [X.sup.2]
P

Data are reported as means [+ or -] SD, unless otherwise specified
(Student's t-test and [X.sup.2] test). ALT: alanine aminotrasferase.

Table 6. Correlation between [CD3.sup.+], [CD4.sup.+], [CD8.sup.+],
[CD4.sup.+] [CD25.sup.+], [CD8.sup.+] [CD28.sup.-] levels and
virological response to entecavir treatment at the 4th week.

                               [CD3.sup.+]            [CD4.sup.+]

Response group (n=38)       78.1 [+ or -] 11.8     37.9 [+ or -] 13.2
Suboptimal response         76.3 [+ or -] 12.4     36.2 [+ or -] 15.6
  group (n=15)
t                                 0.389                  0.647
P                                 0.825                  0.583

                               [CD8.sup.+]           [CD4.sup.+]
                                                    [CD25.sup.+]/
                                                     [CD3.sup.+]

Response group (n=38)       36.3 [+ or -] 7.2     2.01 [+ or -] 0.84
Suboptimal response         34.5 [+ or -] 6.1     1.92 [+ or -] 0.86
  group (n=15)
t                                 0.904                 1.173
P                                 0.247                 0.648

                                [CD8.sup.+]
                               [CD28.sup.-]/
                                [CD3.sup.+]

Response group (n=38)       15.57 [+ or -] 6.3
Suboptimal response         25.26 [+ or -] 7.02
  group (n=15)
t                                  6.283
P                                  0.036

Data are reported as means [+ or -] SD (Student's t-test).

Table 7. Correlation between HBV genotype and virological response
to entecavir at the 4th week of treatment.

                                ALT               HBV DNA
                                                (Lg value)

Response group (n=38)     85 [+ or -] 34     5.7 [+ or -] 0.54
Suboptimal response       93 [+ or -] 32     6.3 [+ or -] 0.47
  group (n=15)
t, [X.sup.2]                   1.428               0.793
P                              0.536               0.425

                          HBeAg positive     Proportion of HBV
                             rate (%)           genotype (%)

                                              C (%)       B (%)

Response group (n=38)      20/38 (52.6)     25 (65.8)   10 (26.3)
Suboptimal response         8/15 (53.3)     10 (66.7)    4 (26.6)
  group (n=15)
t, [X.sup.2]                   0.002          0.451
P                              1.000          1.270

                            Proportion of HBV
                               genotype (%)

                           D (%)     Mixed type
                                      (C/D) (%)

Response group (n=38)     1 (2.6)      2 (5.3)
Suboptimal response          0         1 (6.6)
  group (n=15)
t, [X.sup.2]
P

Data are reported as means [+ or -] SD (Student's t-test).
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Author:Zhang, Y.R.; Li, B.; Wang, C.X.; Zhou, N.; Qi, W.; Li, X.L.; Wu, L.Y.; Wei, S.F.; Zhang, Y.D.
Publication:Brazilian Journal of Medical and Biological Research
Article Type:Report
Date:Mar 1, 2017
Words:4506
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