Hepatitis B virus (HBV) is a major global health problem, with an estimated number of 240 million chronically infected HBV patients worldwide [
High HBV DNA levels correlate with increased risk of HCC in chronic hepatitis B (CHB). Recently, the main treatment goal for (CHB) is to significantly suppress viral replication with the goal of preventing severe liver complications such as fibrosis and cirrhosis, liver failure, and development of hepatocellular carcinoma [
TDF is an oral prodrug of the nucleotide analogue tenofovir and it is a potent and selective inhibitor of HBV DNA polymerase/reverse transcriptase (pol/RT) in vitro [
TDF was more effective than ADV in viral suppression and alleviating histologic inflammation, which has been showed in two international, multicenter, randomized, double-blind phase 3 studies comparing once-daily TDF and once-daily adefovir dipivoxil (ADV) [
However, there is still limited data to show whether TDF is effective for the NA-experienced and NA-naïve CHB patients in China. Here, we report the efficacy, safety, and resistance results of patients between these two groups of CHB treated patients through a follow-up study in our hospital.
All the selected patients in our follow-up study group were from the 3rd Affiliated Hospital, Sun Yat-sen University. The study was conducted in accordance with the guidelines of the Declaration of Helsinki and was approved by the 3rd Affiliated Hospital Ethical Committee at SYSU. The study design and manuscript preparation fully followed the guideline from the STROBE statement [
From June 1, 2012, to December 31, 2015, 102 CHB were enrolled in this study, including 36 in the NA-naïve treatment group and 66 NA-experienced treatment group. Parameters such as age, height, weight, serum alanine, aminotransferase (ALT) and HBV DNA levels at baseline, gender, alcohol use, and smoking status were recorded for each patient prior to treatment. All the patients were followed up once at least every 3 months in order to collect the serum testing. All the patients corresponded to the guideline of prevention and treatment for chronic hepatitis B, which was implemented by guidelines for prevention and treatment of chronic hepatitis B (2010 edition). The demographics of the patients are shown in Table
Baseline of patients with CHB in NA-naïve and NA-experienced group, respectively.
TDF NA-naïve | TDF NA-experienced | Statistics | | |
---|---|---|---|---|
( | ( | |||
Age (years) | 35 (26–61) | 34.0 (24–61) | | 0.128 |
Sex (male, %) | 72.2 (26/36) | 71.2 (47/66) | | 0.914 |
Body mass index (kg/m2) | 22.63 ± 2.73 | 23.85 ± 2.86 | | 0.723 |
Follow-up time (weeks) | 42.0 (25.0–109.0) | 55.5 (24.0–110.0) | | 0.199 |
The proportion of alcohol history (%) | 22.2 (8/36) | 25.8 (17/66) | | 0.692 |
The proportion of smoking history (%) | 38.9 (14/36) | 21.2 (14/66) | | 0.056 |
Family history of hepatitis B (%) | 58.3 (21/36) | 48.5 (32/66) | | 0.341 |
ALT baseline (U/L) | 136.0 (56–597) | 80 (10–1231) | | 0.786 |
HBV DNA baseline (log10 IU/ml) | 6.50 ± 0.69 | 5.78 ± 1.49 | | 0.054 |
NA-experienced (%) previously | N/A | LMV (%) | 6.06 (4/66) | |
ADV (%) | 1.51 (1/66) | |||
LdT (%) | 9.09 (6/66) | |||
ETV (%) | 10.6 (7/66) | |||
Complicated# (%) | 72.7 (48/66) | |||
Rate of hepatitis B e antigen positive (%) | 50.0 (18/36) | 53.0 (35/66) | | 0.770 |
ALT: alanine aminotransferase; TDF: tenofovir disoproxil fumarate; NA: nucleos(t)ide analogue. N/A: not applicable. LMV: lamivudine, LdT: telbivudine, ADV: adefovir dipivoxil, and ETV: entecavir.
#Complicated experience means at least two or more than two different NAs before switching to TDF.
The flow chart of the patients enrolled.
All the patients received daily TDF (300 mg) (Viread, GSK Co.) monotherapy. They participated in our follow-up study under their own consent. Liver and kidney functions were tested using Hitachi 7180 (Hitachi, Ltd., Tokyo, Japan) and Olympus 64 (Olympus Co., Tokyo, Japan). Normal range of ALT value is 5–35 U/L. The lower limit of serum HBV DNA detection was 100 IU/ml (Da an Genetics). The following HBV infection parameters were assessed: HBeAg and anti-HBe status, serum ALT and HBV DNA levels during 4, 12, 24, 36, 48, 60, 72, and 96 weeks of treatment, time to ALT normalization, time to undetectable HBV DNA level, and HBeAg seroconversion and total duration of follow-up. Definitions: complete viral suppression was defined as undetectable serum HBV DNA (<100 IU/mL, or below the lower limit of quantification of the PCR assay). Virological breakthrough was defined as a >1 log10 IU/mL increase in serum HBV DNA levels from nadir in two consecutive measurements. ALT ≤ 40 U/L was considered as normal.
The SPSS 13.0 software (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. Categorical variables were defined as proportion (%) and compared by Chi-square or Fisher’s exact test. Continuous variables are mean ± standard deviation (SD) and were assessed by Student’s
A total of 102 patients were included in this study, comprising 36 and 66 cases in NA-naïve group and NA-experienced group, respectively. Their average ages were 35 (26–61) years in the NA-naïve group and 34.0 (24–61) years in the NA-experienced group. There were no statistically significant differences in age, gender, height, weight, smoking and drinking history, HBV family history, baseline ALT levels, and HBV DNA levels between two groups’ patients (Table
The ALT levels progressively decreased to normal following administration of antiviral drugs treatment in both groups. ALT levels dropped from 183.0 ± 50.0 U/L at week 0 to 26.3 ± 13.0 U/L at week 72 in the NA-naïve group and from 156.8 ± 66.0 U/L at week 0 to 30.3 ± 19.0 U/L at week 72 in NA-experienced group (
ALT levels changes (a) and the rates of ALT normalizations (b) during antivirus therapy in each group. There was no significant difference in NA-naïve and NA-experienced group neither in ALT levels changes nor in ALT normalization rates. However, ALT level decreased significantly from week 0 to week 12 in both NA-naïve and NA-experienced group. ALT: Alanine aminotransferase; TDF: tenofovir disoproxil fumarate; NA: nucleos(t)ide analogue (all
HBV DNA levels in NA-naïve and NA-experienced groups were both decreased significantly for 72 weeks (
HBV DNA level (a) decreased and HBV DNA undetectable rates (b) increased during the antivirus therapy. In addition, undetectable HBV DNA cumulative undetectable rates (c) also increased but neither had significant difference in the two groups. TDF: tenofovir disoproxil fumarate; NA: nucleos(t)ide analogue.
In addition, Kaplan-Meier survival analysis revealed no significant differences in HBV DNA cumulative undetectable rates between the two groups (Figure
Multivariate Cox regression analysis in HBV DNA negative time.
B | SE | Wald | df | | |
---|---|---|---|---|---|
Sex | 0.159 | 0.277 | 0.328 | 1.0 | 0.567 |
BMI | | 0.038 | 0.367 | 1.0 | 0.545 |
Age | | 0.012 | 0.856 | 1.0 | 0.355 |
Antivirus history (NA-naïve or NA-experienced) | | 0.249 | 0.119 | 1.0 | 0.730 |
HBV DNA baseline level | | | | | |
Gene Type | 0.671 | 0.412 | 1.546 | 1.0 | 0.106 |
ALT baseline level | 0.000 | 0.001 | 0.019 | 1.0 | 0.892 |
HBeAg statue | | 0.227 | 0.042 | 1.0 | 0.838 |
Alcohol history | | 0.288 | 0.013 | 1.0 | 0.909 |
Smoking history | | 0.432 | 1.746 | 1.0 | 0.186 |
Family history of hepatitis B | | 0.428 | 2.720 | 1.0 | 0.099 |
ALT: alanine aminotransferase; TDF: tenofovir disoproxil fumarate; NA: nucleos(t)ide analogue. HBeAg: hepatitis B e antigen, BMI: Body mass index.
After treatment with TDF in NA-naïve and NA-experienced groups, 27.8% (5/18) and 11.4% (4/35) achieved HBeAg seroconversion at the end of the follow-up, respectively (
The rates of HBeAg seroconversion at the end of follow-up. There was no significant difference in HBeAg seroconversion rates in every time point in the NA-naïve and NA-experienced groups. TDF: tenofovir disoproxil fumarate; NA: nucleos(t)ide analogue.
Three patients in NA-experienced group (Case numbers T0038, 22535, and 18457) and 1 patient in the NA-naïve group (Case number L160) developed viral breakthrough. The three cases in the NA-experienced group all had undetectable levels of HBV DNA after 3–6 months of antiviral therapy, but following breakthrough the patients’ viral loads were even increased. However, a reduction in viral DNA levels to below the limit of detection was observed for all of these patients following an additional 6–12 months of therapy. The only one case of viral breakthrough in NA-naive group had high baseline level of 8.48 log10 IU/ml. HBV DNA was undetectable for this patient at week 24 but could be detected up to 3.94 log10 IU/ml at week 60. The patient’s HBV DNA levels finally became undetectable again at week 72. No genotypic resistance to TDF was observed for any of these patients over the course of this study.
All the enrolled patients tolerated treatment well during the entire course of therapy of TDF and none reported serious clinical adverse reactions. Serum creatinine was normal for both groups. Serum phosphorus was 0.73 mmol/L, a little lower than normal range (0.85–1.51 mmol/L) in one of the patients in the NA-experienced group, but it could be recovered to normal (1.09 mmol/L) after another half-year follow-up with continuous TDF administration. Serum phosphorous levels were normal for all NA-naive patients through the end of follow-up.
Recently, TDF has been ranked as one of first-line antiviral NAs therapies all around the world [
In this study, TDF exhibited potent antiviral effects on NA-naïve and NA-experienced patients without a significant difference in magnitude of effect between the two groups. The HBV DNA levels in two groups showed a two-phase decline pattern: a rapid decrease before week 24 followed by a slowing and final plateau. The HBV DNA levels in most patients decreased to 2 log10 IU/mL (lower detection limit) until 24 weeks. Therefore, TDF in the treatment of NA-naïve and NA-experienced groups showed potent antiviral effects and consistently inhibited virus to below the lower detection limit. Although a previous report indicated that the HBV DNA levels after treatment with TDF for 48 weeks in the HBeAg (+) naïve CHB patients was 2.46 log10 IU/ml and in the HBeAg (−) patients was 2.31 log10 IU/ml (the detection limit was 2.6 log10 IU/ml) [
The HBV DNA undetectable rate is an important indicator commonly used to reflect the ability of viral suppression and is a primary goal of therapy for CHB. In this study, HBV DNA undetectable rates were increased with antiviral drug treatment equivalently for both NA-naive and NA-treatment groups, with consistency between the groups observed throughout the study. Jung et al. [
HBeAg seroconversion is another important measure of TDF efficacy during the therapy, which means loss of HBeAg and development of antibodies to HBeAg (anti-HBe). HBeAg seroconversion is closely associated with a sustained reduction in HBV DNA levels during therapy [
Serum ALT level reflects the host immune response to the hepatitis B virus. ALT normalization often accompanies complete virological response, indicating liver damage recovery [
Regarding adverse events, TDF showed good tolerability in both NA-naïve and NA-experienced groups in our study, which was consistent with previous reports [
Due to the constraints of a retrospective study, there may be some limitations in our study. First, our population size was small and follow-up time was short. As TDF was first approved by Chinese FDA just 2 years ago, very limited data can be obtained from the follow-up patients. Secondly, most results in this study showed good consistency with other studies around the world [
In conclusion, TDF monotherapy was effective for CHB treatment regardless of previous NA treatment and was well tolerated in CHB patients in China. Baseline serum HBV DNA was the only independent predictive factor of a HBV DNA negative time in TDF monotherapy.
The authors declare no conflicts of interest.
Yutian Chong and Mingxing Huang conceived and designed the experiments; Mingixng Huang, Guoli Lin, Hong Shi, Yuankai Wu, and Yusheng Jie performed the experiments; Mingxing Huang and Guoli Lin analyzed the data; Yusheng Jie and Zhe Zhu contributed patients analysis tools; Mingxing Huang and Guoli Lin wrote the paper. Yutian Chong edited the paper and checked up the final edition. Mingxing Huang and Guoli Lin are equal contributors to this article. Dr. Guoli Lin is co-first author.
This project was supported by the 11th Five-Year National Science and Technology Major Project (no. 2009ZX10001-018).