Treatment medication patterns and follow-up evaluation on clinical, biochemical, and laboratory parameters in patients with hepatitis B virus infection

DOI 10.17480/psk.2018.62.2.135

Treatment medication patterns and follow-up evaluation on clinical, biochemical, and laboratory parameters in patients with hepatitis B virus infection

Young-Mo Yang

, Sun Hee Park

, In Choe

, and Eun Joo Choi

*

Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, South Korea

**

Department of Pharmacy, Chosun University Hospital, Gwangju, South Korea (Received March 7, 2018; Revised April 20, 2018; Accepted April 24, 2018)

Abstract — The aims of this study were to compare the efficacy between tenofovir (TDF) and entecavir (ETV) mono- therapy for 24 months and to assess the gender differences in the clinical prognosis in Korean patients with chronic hepatitis B (CHB). This study was retrospectively conducted with hepatitis B virus (HBV)-infected patients taking TDF or ETV between July 2012 and June 2016 in Chosun University Hospital, Gwangju, South Korea. Data were collected through the review of Electronic Medical Records. Among 1,450 patients during the study period, 130 were selected based on inclusion and exclusion criteria. At baseline, the rate of hepatitis B envelope antigen (HBeAg)-positivity in TDF was higher than that of HBeAg-positivity in ETV, showing a significant difference (84.4% vs. 57.8%, p = 0.0020). However, these rates in both TDF and ETV became similar at 3 months, and this tendency had continued after 3 months. There were no significant dif- ferences in the changes of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels during the follow- up period between TDF and ETV. However, these levels were almost normalized within 3 months, and the normal levels had also been kept after 3 months. Men tended to have more liver cirrhosis or hepatocellular carcinoma than women. ALT levels had been continuously higher in men than in women, showing significant differences at 3, 6, 12, and 24 months. TDF is more likely than ETV to be a potent option for CHB patients with severe liver diseases, especially men, because TDF tended to decrease the parameters related with HBV infection (e.g., ALT, AST, and HBV DNA level) more rapidly within 3 months than ETV.

Keywords chronic hepatitis B, hepatitis B virus, tenofovir, entecavir, efficacy, gender

Approximately 257 million people worldwide have hepatitis B virus (HBV) infection that is characterized by the presence of hepatitis B surface antigen (HBsAg); this infection can result in the development of complications such as cirrhosis and hepatocellular carcinoma (HCC), which may result in death.

This can be almost completely prevented by using cur- rently available vaccines. Since vaccines against HBV were commercialized, the infection rate has gradually decreased;

however, according to a report from the Korean Ministry of Health and Welfare in 2012, the rate of hepatitis B envelope antigen (HBeAg)-positivity was 3.4% in males and 2.6% in

females, which indicated that approximately 3.0% of the total Korean population were infected with HBV.

Viral suppression through oral antiviral therapy with nucleot(s)ide analogs (NAs) has prevented disease progres- sion in patients with chronic hepatitis B (CHB), leading to a reduction in the development of hepatic decompensation, cir- rhosis, and HCC.

However, antiviral resistance, which usu- ally occurs in long-term therapy, and the failure of complete viral suppression contribute to a reduction in therapeutic bene- fits.

The currently available NAs for the treatment of CHB in Korea include lamivudine (LAM), telbivudine (TEL), clevu- dine (CLV), adefovir (ADV), entecavir (ETV), and tenofovir (TDF).

NAs with high genetic barriers to resistance, such as TDF and ETV, are strongly recommended by the current clinical practice guidelines as the first-line agents for the treat- ment of CHB;

specifically, either TDF or ETV is recom- mended for patients aged ≥ 12 years and ETV is recommended for patients aged between 2 and 11 years.

#

Corresponding Author Eun Joo Choi

Department of Pharmacy, College of Pharmacy, Chosun Univer- sity, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Korea

Tel.: 062-230-6382 Fax.: 062-222-5414 E-mail: [email protected]

†

Joint first authors and contributed equally to this work.

Short Report

TDF is a potent nucleotide analog used to treat HBV infec- tion.

It exhibited sustained antiviral efficacy in treatment- naïve patients with CHB and it was effective in patients with CHB with an altered response to NAs.

TDF demon- strated a similar efficacy in patients with LAM failure as that in NA-naïve patients with CHB, independent of the presence of antiviral resistance conferred by mutations.

In addition, TDF exhibited excellent and long-term efficacy, even in patients with CHB who experienced NA treatment failure.

However, TDF had lower efficacy in patients with CHB and previous ADV exposure than in NA-naïve patients with CHB.

ETV is another potent nucleoside for the treatment of HBV-infected patients.

HBV resistance to ETV is not common in NA- naïve patients with CHB; furthermore, long-term ETV ther- apy in these patients led to the reversal of fibrosis/cirrhosis and sustained histological improvement.

However, ETV resistance during therapy was noted in NA-experienced patients with CHB and suboptimal viral suppression was also reported in NA-naïve patients with CHB owing to poor adher- ence and individual genetic variation.

Although several studies of the efficacy of TDF or ETV have been conducted in Korean patients with CHB, long-term follow-up data are still lacking.

In addition, among HBV-infected patients, men are more likely than women to have an increased risk for the development of severe liver dis- eases

, but studies focusing on differences between men and women in the prognostic values of HBV infection have been scarce in Korea. Therefore, the aims of this study were to

compare the efficacy of TDF and ETV monotherapy for 24 months and to evaluate the sex-based differences in the clini- cal prognosis of Korean patients with CHB.

Methods

The Institutional Review Board of Chosun University Hospi- tal granted ethical approval for the study (IRB No 2016-11- 021). The requirement for informed consent from the study patients was waived because their data were de-identified and encoded anonymously prior to analysis. This retrospective study included NA-naïve and NA-experienced patients with HBV infection who were administered TDF or ETV between July 2012 and June 2016 at Chosun University Hospital, Gwangju, South Korea. The follow-up period was 24 months.

The following exclusion criteria were applied: patients aged <

18 years, patients with alcoholic or autoimmune liver disease, patients who had taken antiviral drugs for < 12 weeks, or patients for whom insufficient information on demographics and clinical factors was available.

Through a retrospective chart review of the electronic medi- cal records (EMRs) of selected patients, a trained hospital pharmacist collected the following information by using paper case report forms: demographic characteristics (e.g., sex, age, body mass index [BMI], height, and weight), family history of HBV, alcohol consumption, previous treatment for HBV, comor- bidities, prescribed medications for HBV, and laboratory values (e.g., HBeAg positivity, HBV DNA level, aspartate aminotrans-

Fig. 1 − Flow diagram of steps in the selection of study subjects. CHB, chronic hepatitis B.

ferase [AST], alanine aminotransferase [ALT], total bilirubin, albumin, and serum creatinine).

All statistical analyses were computed by using SAS, ver- sion 9.3 (SAS Institute Inc., Cary, NC, USA). The demo- graphic variables and clinical characteristics of patients selected in this study were examined by using descriptive sta- tistics. The mean and standard deviation were utilized to present continuous variables, whereas frequencies (n) and percentages (%) were used for the presentation of categorical variables. The Chi-square test or Fisher’s exact test was used to compare cat- egorical data and the independent t-test was utilized for contin- uous data. Logistic regression analysis was used to identify the predictive factors of adequate HBV DNA suppression (HBV DNA < 50 IU/mL). The results were presented as odds ratios (ORs) with their 95% confidence intervals (CIs). Values were considered statistically significant for p < 0.05.

Results

During the study period, 1,450 patients were diagnosed with HBV infection; among these patients, 130 who met the inclu- sion criteria and did not meet the exclusion criteria were

included for the analysis (Figure 1). The baseline characteris- tics of the patients are presented in Tables I and II and arranged by sex and treatment drug. The mean patient age was 53.8±12.2 years; 83.1% of patients were younger than 65 years. Most patients were men (69.2%) and HBeAg-positive (73.4%). The mean HBV DNA level was 5.9±1.6 log

IU/mL.

The mean ALT was 125.7±281.1 IU/L. Tenofovir and enteca- vir were used in 61.5% and 38.5% patients, respectively. A large percentage of patients were treatment-experienced. The rate of HBeAg-positivity was significantly higher in patients receiving tenofovir than in those receiving entecavir (p = 0.0020). However, the rate of previous treatment for HBV was significantly higher in patients receiving entecavir than in those receiving tenofovir (p = 0.0056).

The changes in serological, virological, and biochemical fac- tors at baseline, 3, 6, 12, and 24 months are presented in Table 3, according to sex. At baseline and during the follow-up period, there were no statistically significant differences in the rate of HBeAg-positivity between men and women. At base- line, the HBV DNA level was higher in women (6.4±1.4 log

IU/mL) than in men (5.6±1.7 log

IU/mL); this difference was statistically significant (p = 0.0336). However, during the fol- low-up period, significant differences in the HBV DNA level Prior treatment for

HBV, n (%)

Yes 85 (65.4) 54 (60) 31 (77.5)

0.0529

No 45 (34.6) 36 (40) 9 (22.5)

Family history of HBV, n (%)

Yes 27 (26.2) 14 (20.6) 13 (37.1)

0.0704 No 76 (73.8) 54 (79.4) 22 (62.9)

Alcohol consump- tion, n (%)

Yes 17 (16.5) 17 (24.3) 0 (0.0)

0.0011 No 86 (83.5) 53 (75.7) 33 (100.0)

Comorbidities, n (%)

Liver cirrhosis 60 (46.2) 41 (45.6) 19 (47.5) 0.8374 Hepatocellular

carcinoma 17 (13.1) 11 (12.2) 6 (15.0) 0.6646

DM 11 (8.5) 10 (11.1) 1 (2.5) 0.1710

HTN 15 (11.5) 12 (13.3) 3 (7.5) 0.3921 Continuous variable: mean±standard deviation (SD); Categorical variable: n (%)

HBeAg-positive, hepatitis B envelope antigen-positive; HBV DNA, hepatitis B virus deoxyribonucleic acid; ALT, alanine aminotransferase; BUN, blood urea nitrogen; DM, diabetes mellitus; HTN, hypertension.

Table I − Baseline characteristics of the patients according to gender

Variables Overall Men Women p - value

Age (years) 53.8±12.2 53.4±12.13 54.7±12.3 0.5930 ≥ 65, n (%) 22 (16.9) 12 (13.3) 10 (25.0)

0.1016 < 65, n (%) 108 (83.1) 78 (86.7) 30 (75.0)

HBeAg-positive, n

(%) 80 (73.4) 58 (74.4) 22 (71) 0.7178

HBV DNA level

(log

IU/mL) 5.9±1.6 5.6±1.7 6.4±1.4 0.0336 Undetectable HBV

DNA, n (%) 14 (11.5) 8 (9.3) 6 (16.7) 0.2444 ALT (IU/L) 125.7±281.1141.4±329.4 90.4±108.7 0.3417 Total bilirubin

(mg/dL) 1.2±1.5 1.3±1.6 1.0±1.1 0.2532

Albumin (g/dL) 4.1±0.6 4.0±0.6 4.1±0.6 0.4253 Creatinine (mg/dL) 1.0±0.2 1.1±0.2 0.8±0.1 < 0.0001 Creatinine ≥ 1.4

mg/dL, n (%) 7 (5.4) 7 (7.9) 0 (0.0) 0.0983 BUN (mmol/L) 14.0±4.2 14.7±4.3 12.5±3.5 0.0042 HBV Treatment

drug, n (%)

Tenofovir 80 (61.5) 56 (62.2) 24 (60.0)

0.8100

Entecavir 50 (38.5) 34 (37.8) 16 (40.0)

were not observed between men and women. Overall, the ALT level was higher in men than in women at baseline and Table II − Baseline characteristics of the patients according to

treatment drugs

Variables Overall Tenofovir Entecavir p - value Age (years) 53.8±12.2 52.2±12.3 56.3±11.6 0.0610

≥ 65, n (%) 22 (16.9) 12 (15.0) 10 (20.0)

0.4595 < 65, n (%) 108 (83.1) 68 (85.0) 40 (80.0)

Sex, n (%)

Men 90 (69.2) 56 (70.0) 34 (68.0)

0.8100 Women 40 (30.8) 24 (30.0) 16 (32.0)

HBeAg-positive, n

(%) 80 (73.4) 54 (84.4) 26 (57.8) 0.0020 HBV DNA level

(log

IU/mL) 5.9±1.6 6.0±1.7 5.6±1.5 0.1367 Undetectable HBV

DNA, n (%) 14 (11.5) 7 (9.5) 7 (14.6) 0.3857 ALT (IU/L) 125.7±281.1 141.6±340.3 100.2±142.2 0.4160 Total bilirubin

(mg/dL) 1.2±1.5 1.3±1.7 1.2±1.2 0.7677

Albumin (g/dL) 4.1±0.6 4.1±0.5 4.1±0.7 0.9646 Creatinine (mg/dL) 1.0±0.2 1.0±0.2 1.0±0.2 0.3507 Creatinine ≥ 1.4 mg/

dL, n (%) 7 (5.4) 3 (3.8) 4 (8.0) 0.4291 BUN (mmol/L) 14.0±4.2 13.9±3.8 14.3±4.7 0.5212 Prior treatment for

HBV, n (%)

Yes 85 (65.4) 45 (56.3) 40 (80.0)

0.0056 No 45 (34.6) 35 (43.8) 10 (20.0)

Family history of HBV, n (%)

Yes 27 (26.2) 13 (20.6) 14 (35.0)

0.1062 No 76 (73.8) 50 (79.4) 26 (65.0)

Alcohol

consumption, n (%)

Yes 17 (16.5) 8 (12.9) 9 (22.0)

0.2260 No 86 (83.5) 54 (87.1) 32 (78.0)

Comorbidities, n (%)

Liver cirrhosis 60 (46.2) 37 (46.3) 23 (46.0) 0.9778 Hepatocellular

carcinoma 17 (13.1) 5 (6.3) 12 (24.0) 0.0035

DM 11 (8.5) 5 (6.3) 6 (12.0) 0.2518

HTN 15 (11.5) 8 (10.0) 7 (14.0) 0.4874 Continuous variable: mean±standard deviation (SD); Categorical variable: n (%)

HBeAg-positive, hepatitis B envelope antigen-positive; HBV DNA, hepatitis B virus deoxyribonucleic acid; ALT, alanine aminotransferase; BUN, blood urea nitrogen; DM, diabetes mellitus; HTN, hypertension.

Table III − Changes in serological, virological, and biochemical factors at baseline, 12, and 24 months by gender

Variables Men Women p - value

HBeAg positive, n (%)

0 month 58 (74.4) 22 (71.0) 0.7178

3 month 36 (78.3) 12 (66.7) 0.3355

6 month 39 (79.6) 13 (68.4) 0.3298

12 months 38 (80.9) 13 (72.2) 0.4489

24 months 25 (78.1) 13 (81.3) 1.0000

HBV DNA level (log

IU/mL)

0 month 5.6±1.7 6.4±1.4 0.0336

3 month 3.1±1.0 3.0±1.3 0.8155

6 month 2.9±0.9 2.0±0.4 0.1086

12 months 2.8±1.0 2.2±0.7 0.3506

24 months 2.8±1.0 2.2±0.7 0.3506

Undetectable HBV DNA, n (%)

0 month 78 (90.7) 30 (83.3) 0.2444

3 month 25 (41.7) 12 (60.0) 0.1544

6 month 15 (24.6) 3 (12.5) 0.2561

12 months 12 (20.3) 4 (14.3) 0.5680

24 months 4 (8.5) 1 (4.5) 1.0000

AST (IU/L)

0 month 110.8±230.9 71.1±64.4 0.2878

3 month 41.2±22.6 36.4±18.4 0.2998

6 month 36.6±16.3 32.6±11.3 0.2244

12 months 34.7±17.8 28.6±10.7 0.0774

24 months 35.4±43.7 25.5±7.6 0.2488

ALT (IU/L)

0 month 141.4±329.4 90.4±108.7 0.3417

3 month 44.1±28.3 30.0±12.8 0.0097

6 month 36.0±20.5 23.3±9.0 0.0023

12 months 32.7±19.0 22.1±6.7 0.0025

24 months 28.8±15.1 21.0±9.6 0.0180

Total bilirubin (mg/dL)

0 month 1.3±1.6 1.0 ± 1.1 0.2532

3 month 1.1±1.8 0.9±1.3 0.5725

6 month 1.1±1.4 0.7±0.3 0.2044

12 months 1.0±0.5 0.9±1.1 0.8541

24 months 1.0±0.7 1.0±1.3 0.8190

Albumin (g/dL)

0 month 4.0±0.6 4.1±0.6 0.4253

3 month 4.2±0.5 4.1±0.6 0.4834

6 month 4.3±0.5 4.1±0.5 0.0799

12 months 4.3±0.4 4.2±0.5 0.1602

24 months 4.3±0.4 4.2±0.7 0.4813

during the follow-up period. After 3 months, the ALT level was almost normalized in both men and women and its level remained stable during the remaining follow-up period. The changes in serological, virological, and biochemical factors at baseline, 3, 6, 12, and 24 months are presented in Table 4,

according to treatment drugs. At baseline, the rate of HBeAg- positivity was significantly higher in patients treated with TDF (84.4%) than in those treated with ETV (57.8%) (p = 0.0020).

However, no significant differences in the rate of HBeAg-posi- tivity were noted between both groups during the follow-up period. At baseline, the HBV DNA level was higher in patients treated with TDF (6.0±1.7 log

IU/mL) than in those treated with ETV (5.6±1.5 log

IU/mL). However, HBV DNA levels were lower in the TDF group than in the ETV group during the entire follow-up period. The ALT level was higher in the TDF group than in the ETV group at baseline, but similar in both groups throughout the whole follow-up period.

Univariate analyses were performed to assess the factors associated with a complete virologic response (CVR) 12 and 24 months after the initiation of treatment. No factors were asso- ciated with CVR. Two multivariate analyses were performed:

Creatinine (mg/dL)

0 month 1.1±0.2 0.8±0.1 < 0.0001

3 month 1.1±0.2 0.8±0.1 < 0.0001

6 month 1.1±0.1 0.9±0.1 < 0.0001

12 months 1.1±0.2 0.9±0.1 < 0.0001

24 months 1.1±0.2 0.8±0.2 < 0.0001

Continuous variable: mean±standard deviation (SD); Categorical variable: n (%)

HBeAg-positive, hepatitis B envelope antigen-positive; HBV DNA, hepatitis B virus deoxyribonucleic acid; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

ALT (IU/L)

0 month 141.6±340.3 100.2±142.2 0.4160

3 month 41.7 ± 29.4 37.7±17.8 0.4280

6 month 34.5±21.2 28.2±12.3 0.1154

12 months 28.7±18.4 29.9±13.7 0.7234

24 months 26.4±14.8 25.8±12.9 0.8583

Total bilirubin (mg/dL)

0 month 1.3±1.7 1.2±1.2 0.7677

3 month 0.9±0.9 1.3±2.5 0.2068

6 month 0.8±0.4 1.3±2.0 0.1016

12 months 0.9±0.9 1.0±0.5 0.6836

24 months 1.0±1.0 1.1±0.8 0.8247

Albumin (g/dL)

0 month 4.1±0.5 4.1±0.7 0.9646

3 month 4.2±0.4 4.1±0.7 0.3208

6 month 4.3±0.4 4.1±0.6 0.1481

12 months 4.3±0.3 4.1±0.6 0.0087

24 months 4.4±0.2 4.2±0.7 0.2968

Creatinine (mg/dL)

0 month 1.0±0.2 1.0±0.2 0.3507

3 month 1.0±0.2 1.1±0.2 0.8324

6 month 1.1±0.2 1.0±0.2 0.4282

12 months 1.0±0.2 1.1±0.2 0.5020

24 months 1.0±0.2 1.0±0.2 0.7374

Continuous variable: mean±standard deviation (SD); Categorical variable: n (%)

HBeAg-positive, hepatitis B envelope antigen-positive; HBV DNA, hepatitis B virus deoxyribonucleic acid; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

Table IV − Changes in serological, virological, and biochemical factors at baseline, 12, and 24 months by treatment drugs Variables Tenofovir Entecavir p - value HBeAg-positive, n (%)

0 month 54 (84.4) 26 (57.8) 0.0020

3 month 35 (76.1) 13 (72.2) 0.7482

6 month 37 (78.7) 15 (71.4) 0.5123

12 months 35 (79.5) 16 (76.2) 0.7583

24 months 25 (78.1) 13 (81.3) 1.0000

HBV DNA level (log

IU/mL)

0 month 6.0±1.7 5.6±1.5 0.1367

3 month 2.7±0.8 3.6±1.2 0.0150

6 month 2.5±0.4 3.6±1.4 0.0184

12 months 2.1±0.4 3.1±1.2 0.0431

24 months 2.1±0.4 3.1±1.2 0.0431

Undetectable HBV DNA, n (%)

0 month 67 (90.5) 41 (85.4) 0.3857

3 month 19 (37.3) 18 (62.1) 0.0324

6 month 13 (21.7) 5 (20.0) 0.8639

12 months 8 (14.3) 8 (25.8) 0.1840

24 months 1 (2.6) 4 (13.3) 0.1590

AST (IU/L)

0 month 111.5±239.3 78.1±89.7 0.3469

3 month 39.0±19.6 41.4±24.8 0.5722

6 month 35.7±16.2 34.8± 2.6 0.7815

12 months 30.0±11.8 37.0±20.5 0.0352

24 months 36.4±46.8 26.2±8.1 0.2145

the first included HBeAg positivity, baseline HBV DNA, and the presence of liver cirrhosis as confounding factors and sex as an independent variable; the second one included HBeAg positivity, baseline HBV DNA, and the presence of liver cirrho- sis as confounding factors and treatment drug as an indepen- dent variable. Only treatment drug was associated with CVR at 24 months (OR, 17.96; 95% confidence interval [CI], 1.48–

218.32; p = 0.0235) (Table V).

Discussion

TDF and ETV, which have high genetic barriers against resistance, are currently the most potent antiviral agents for the treatment of HBV infection; therefore, it is important to pay close attention to their use as a long-term treatment with-

out the loss of their potency in patients with CHB.

The present study compared the efficacy of TDF and ETV and evaluated the sex-based disparities in the clinical characteris- tics and prognosis of Korean HBV-infected patients. Based on the results of this study, TDF and ETV were likely to have at least similar efficacy for the treatment of HBV infection and the clinical characteristics and prognosis between men and women with HBV infection treated with TDF or ETV might also be similar.

In this study, the efficacy of TDF and ETV was compared based on the changes in serological, virological, and biochemi- cal factors over 24 months. At baseline, the rate of HBeAg- positivity in patients treated with TDF was higher than that in patients treated with ETV, showing a significant difference (84.4% vs. 57.8%, p = 0.0020). However, this rate was similar Table V − Univariate and multivariate analyses of factors related with complete virologic response

Variables Univariate analysis Multivariate analysis

Model 1

Model 2

OR (95% CI) p - value OR (95% CI) p - value OR (95% CI) p - value Month 12

Age, years (≥ 65 vs. < 65) 1.06 (0.26-4.26) 0.9297

Sex (Men vs. Women) 0.66 (0.20-2.24) 0.4983 0.88 (0.22-3.70) 0.8660 HBeAg-positive (positive vs. negative) 0.14 (0.02-1.20) 0.0727

Baseline HBV DNA, log

IU/mL 0.80 (0.54-1.16) 0.2333

Baseline ALT, IU/L 1.00 (1.00-1.00) 0.4929

Treatment drug (tenofovir vs. entecavir) 2.08 (0.70-6.26) 0.1894 3.24 (0.90-11.56) 0.0712 Prior treatment for HBV (experienced vs.

naïve) 0.48 (0.16-1.44) 0.1894

Presence of liver cirrhosis (Yes vs. No) 3.08 (0.90-10.48) 0.0711 Month 24

Age, years (≥ 65 vs. < 65) 0.92 (0.10-9.02) 0.9451

Sex (Men vs. Women) 0.52 (0.06-4.86) 0.5601 0.86 (0.08-10.42) 0.9030 HBeAg-positive (positive vs. negative) 0.00 (0.00-0.00) 0.9547

Baseline HBV DNA, log

IU/mL 1.10 (0.62-1.96) 0.7568

Baseline ALT, IU/L 1.02 (0.98-1.04) 0.3451

Treatment drug (tenofovir vs. entecavir) 5.84 (0.62-55.32) 0.1236 17.96 (1.48-218.32) 0.0235 Prior treatment for HBV (experienced vs.

naïve) 0.74 (0.12-4.72) 0.7434

Presence of liver cirrhosis (Yes vs. No) 1.82 (0.28-11.58) 0.5307 OR, Odds ratio; CI, confidence interval

HBeAg-positive, hepatitis B envelope antigen-positive; HBV DNA, hepatitis B virus deoxyribonucleic acid; ALT, alanine aminotransferase.

Complete virologic response: undetected serum HBV DNA by real-time polymerase chain reaction (PCR)

a

Both analyses were adjusted for HBeAg positivity, baseline HBV DNA level, and presence of cirrhosis.

b

Model 1 used gender as an independent variable.

c

Model 2 used treatment as an independent variable.

in both TDF and ETV after 3 months and this continued throughout the remaining follow-up period. No significant dif- ferences were found between TDF and ETV in the changes of AST and ALT levels during the follow-up period. However, these levels were almost normalized within 3 months and the normal levels were maintained for the remainder of the follow- up period. The combined results of HBeAg-positivity and AST/

ALT normalization suggest that TDF was more potent at the beginning of treatment than ETV, but achieved similar efficacy for long-term treatment. This was supported by the results from a meta-analysis conducted by Han and colleagues,

which reported that for the viral suppression and improve- ment of liver function, TDF was more effective than ETV during a treatment period of 3 months, but that TDF and ETV might have no significant difference in efficacy during long- term treatment.

In addition, according to a retrospective study conducted with treatment-naïve patients with CHB in Korea, both TDF and ETV suppressed similar HBV DNA lev- els during a follow-up period of 12 months (TDF vs. ETV; - 5.22 vs. -5.01 log

IU/mL, p = 0.559) and no differences in serologic, biochemical, and virologic responses were observed between TDF and ETV at 12 months.

The sex-based differences in characteristics and prognosis in patients with HBV infection treated with TDF or ETV were evaluated in this study. Chronic HBV infection was more likely to lead to severe liver diseases more rapidly in men than in women.

HBV-associated liver diseases, such as end-stage liver disease, HCC, and death by liver disease, occurred more frequently in men than in women, specifically, 1.5 to 7.6 times more often.

According to the clinical study conducted on HBsAg carriers in Italy, the man:woman ratios for liver dis- eases were 1.3, 2.8, 3.6, and 6.8 in patients with normal ALT, chronic hepatitis, liver cirrhosis, and HCC, respectively.

This suggested that the increase in the sex-based ratio was linearly associated with the severity of liver diseases.

In this study, a higher proportion of men than that of women tended to have liver cirrhosis or HCC, although the linear increase in the sex ratio (liver cirrhosis, 2.2; HCC, 1.8) was not observed; this was probably a result of the small sample size compared with that used in the previous study.

In addition, large decrease in ALT levels occurred within 3 months in both men and women owing to the use of antivirals (i.e., TDF or ETV), as men- tioned above. However, ALT levels were continuously higher

in men than in women during the follow-up period; moreover, there were significant differences between men and women at 3, 6, 12, and 24 months. This might be associated with the higher proportions of liver cirrhosis, HCC, and alcohol con- sumption in men than in women.

Two multivariate logistic regression models were utilized to identify the independent predictor significantly associated with CVR at 12 and 24 months; however, only treatment drug was associated with CVR at 24 months. The CVR of TDF was approximately 17.96 times higher than that of ETV at 24 months after the initiation of treatment. However, the wide 95% CI, which ranged from 1.48 to 218.32, should be consid- ered for the correct interpretation of this result. The wide CI indicates that the sample size was too small because of patients lost to follow-up and is unlikely to provide precise information about the efficacy comparison of TDF and ETV for the long-term treatment of patients with CHB. Therefore, a similar analysis should be conducted with a larger sample size to confirm this result. A retrospective study conducted with treatment-naïve patients with CHB in Turkey reported that the CVR of patients with TDF was 1.66 (95% CI 1.21–2.33; p = 0.010) times greater than that ETV at 30 months.

Interest- ingly, the initial virologic response at 3 months (IVR-3), defined as HBV DNA level < 3.3 log

IU/mL at 3 months after treatment, could be used as the good predictor for the short- and long-term CVR.

The CVR at 12 and 36 months for patients that achieved IVR-3 was 6.214 (95% CI 2.500–

15.443; p < 0.001) and 3.403 (95% CI 1.977–5.859; p < 0.001) times higher than those that did not achieve IVR-3, respec- tively.

However, this result was derived from one retrospec- tive study conducted with treatment-naïve patients with CHB;

therefore, it should be cautious to extrapolate it to other CHB patients’ groups. In addition, baseline ALT and HBV DNA lev- els and HBeAg status are associated with CVR.

Comprehen- sively, other baseline factors of patients as well as IVR-3 should be considered in order to predict prognosis and to eval- uate whether to maintain or change initial therapy for CHB.

This study has some limitations that should be considered.

First, all necessary data for the analysis in this study were col-

lected retrospectively through the review of patients with

EMRs. During the study period, the sample size continuously

decreased owing to patients lost to follow-up. Consequently, a

substantial number of patients could not be followed up, espe-

cially at 24 months. To compensate for this shortcoming, a pro- spective and randomized study with a substantial sample size should be conducted in the near future. Second, the effect of each NA used for prior treatment on CVR could not be esti- mated owing to the lack of records in most patients. Third, it may be difficult to generalize the results from this study to other races because only Korean (Asian) patients with CHB were included.

Conclusion

TDF was more potent than ETV in the first 3 months after treatment was started, but both had comparable efficacy for long-term treatment. Although the ratio of men and women was positively related with the severity of liver diseases in patients with CHB

, we did not observe this tendency in our study. However, a higher proportion of men than that of women had liver cirrhosis or HCC. Patients with CHB and severe liver diseases, especially men, should be carefully mon- itored; furthermore, TDF is more likely than ETV to be an effective option for these patients because TDF tended to decrease the parameters related to HBV infection (e.g., ALT, AST, and HBV DNA level) more rapidly in the first 3 months of treatment compared with ETV.

Acknowledgements

This work was supported by the National Research Founda- tion of Korea grant funded by the Korea government (NRF- 2016R1C1B1015938).

Conflicts of interest

There is no conflict of interest for the present communica- tion.

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