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Hepatitis B virus (HBV), a major cause of liver disease, has infected approximately 2 billion people worldwide, and more than 350 million are chronically infected [
1]. Persistent viral replication increases the risk of progression to liver cirrhosis, development of hepatocellular carcinoma (HCC) and liver-related death [
2-
4]. Therefore, the goals of antiviral therapy are to improve quality of life and survival by preventing progression of the disease to cirrhosis, HCC and death [
5,
6]. These goals can be achieved if HBV replication can be suppressed completely. Recent clinical studies showed that long-term suppression of HBV replication using anti-viral agents in patients with CHB can prevent progression to liver cirrhosis, hepatic failure and the development of HCC [
2-
5,
7-
9].
Lamivudine (LAM), adefovir dipivoxil (ADV), telbivudine (Ltd), entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are available nucleos(t)ide analogues (NAs) for treating CHB patients worldwide. However, long-term treatment with NAs other than ETV and TDF increase the risk of drug resistance up to 80% because of low antiviral efficacy and low genetic barrier [
10-
14], Therefore, most guidelines recommend peg-interferon, ETV, or TDF in treatment-naïve patients [
5,
15].
ADV add-on therapy has been widely used as a rescue therapy for patients with LAM-resistant CHB before TDF was not available [
6,
16]. However, suboptimal response has been commonly observed in patients receiving ADV-based therapy [
17-
19].
TDF, one of very potent antiviral agent with a high genetic barrier, showed excellent virologic response (VR), defined as serum HBV DNA level undetectably by sensitive PCR method, in NAs-naïve [
20,
21] and NAs-resistant patients [
22-
26]. Clinical efficacies of TDF therapy in NA-naïve and experienced patients are summarized in
Table 1. In NA naïve patients, a significantly higher proportion of patients receiving TDF than of those receiving ADV had reached VR at 48 weeks (
Table 1). Almost all patients who received TDF therapy showed VR without any evidence of resistance at seven year [
14]. In patients with LAM-resistant patients receiving TDF or TDF/emtricitabine (FTC), VR achieved in 89.4% and 86.3% at 96 weeks of therapy, respectively [
24], without any evidence of TDF resistance during 5 years of follow-up [
27]. TDF also showed high rate of VR in patients with ETV resistance [
26]. In a randomized controlled trial conducted by Lim et al. [
26] the proportion of patients with HBV DNA <15 IU/mL was high in patients who received TDF and TDF+ETV groups (71% vs. 73%;
P=0.99). In patients with ADV-resistant patients with prior LAM resistance, the proportion of patients with HBV DNA <15 IU/mL was not significantly different between the TDF-TDF and TDF/ETV-TDF groups at weeks 48 (62% vs. 63.5%;
P=0.88) and 96 (64% vs. 63.5%;
P=0.96), suggesting that TDF monotherapy or combination therapy is effective even in patients with NAs-resistant patients.
There are several studies to evaluate the antiviral efficacy of TDF monotherapy or combination in patients with suboptimal response to ADV with or without prior resistance to LAM [
23,
28,
29]. Berg, et al. conducted a randomized controlled trial to compare the anti-viral efficacy of TDF-based therapy for patients with CHB who had a suboptimal response to ADV (73% of the patients had received prior LAM therapy). A TDF monotherapy and TDF+FTC combination therapy showed similar VR at 48 week (81% vs. 81%) [
23]. Cho et al. reported that the rate of VR was about 86.5 % through TDF monotherapy or TDF-based combination therapy in CHB patients with suboptimal responses to ADV plus LAM combination therapy [
28]. Park et al. reported that the rate of VR was significantly higher in patients receiving TDV+ETV than in those receiving ADV+ETV for 12 months (84.8% vs. 26.7%,
P<0.001) [
29]. However, little randomized controlled trials are available to compare between to switch into TDF-based therapy or to continue ADV-based therapy in CHB patients with suboptimal response to ADV-based therapy.
In the current issue, Lee et al. [
30] conducted a randomized controlled trial to compare the antiviral efficacy comparing between switching to TDF+NAs therapy and continuing current ADV+NA therapy in patients with suboptimal response to ADV-based therapy. They clearly showed that TDF+NAs therapy provide better VR compared to continue ADV+ NA who showed suboptimal response to ADV-based therapy (87.5% vs. 37.5% at 48 weeks,
P=0.002).
However, there are several limitations of the study. First, even though the study was designed as a randomized controlled trial, the sample size was very small to conclude the results. Second, in this study, there was no TDF monotherapy group because TDF monotherapy and TDF+NAs combination therapy did not show any difference in VR in NA-experienced patients (
Table 1). In addition, Yang et al. [
31] compared the antiviral efficacy between switching to TDF monotherapy and continuing ADV+LAM combination therapy in patients with suboptimal response to ADV+LAM (prior LAM resistance patients) therapy. TDF monotherapy showed higher VR compared with continuing ADV+LAM combination therapy (96.43% vs. 29.0%;
P<0.001). ADV monotherapy in patients with LAM resistance increase the risk of drug resistance [
17-
19]. Therefore, there is a concern about selective pressure on pre-existing resistant mutant viruses [
32]. However, clonal analysis revealed that there is no significant selective pressure on pre-existing ADV or LAM resistant strains in during NA monotherpay patients with CHB and suboptimal response to ADV therapy who receiving TDF or TDF+FTC combination therapy [
33].
In conclusion, considering the result from current study [
30] and previous studies [
23-
26,
31], TDF with or without NAs might be very effective to treat the patient with suboptimal response to ADV-based therapy.
FOOTNOTES
-
Conflicts of Interest: The author has no conflicts to disclose.
Table 1.Summary of randomized controlled trials to evaluate the anti-viral efficacy of tenofovir-based therapy in patients with NAs-naïve or experienced patients
Table 1.
|
Authors |
Study populations |
Intervention |
Primary efficacy end point |
Virologic response |
|
Marcellin et al. (2008) [20] |
NAs-naïve |
TDF vs. ADV |
HBV DNA level <69 IU/mL at 48 week |
76% vs. 13% in HBeAg (+) patients |
|
HBeAg (+) (n=266) |
96.8% vs. 71.2% in HBeAg (-) patients |
|
HBeAg (-) (n=375) |
|
Fung et al. (2014) [24] |
LAM -resistant |
TDF (n=141) vs. TDF/FTC (n=139) |
HBV DNA level <69 IU/mL at 96 week |
89.4% vs. 86.3 % (P=0.43) |
|
Lim et al. (2016) [25] |
ADV-resistant (100% LAM-resistant) |
TDF (n=50) vs. TDF/ETV (n=52) |
HBV DNA level <15 IU/mL at 48 week |
62% vs. 63.5% (P=0.88) |
|
Lim et al. (2016) [26] |
ETV-resistant |
TDF (n=45) vs. TDF/ETV (n=5) |
HBV DNA level <15 IU/mL at 48 week |
71% vs. 73% (P=0.99) |
|
Berg et al. (2010) [23] |
Suboptimal response to ADV (73% of the patients had received prior LAM therapy) |
TDF (n=53) vs. TDF/FTC (n=52) |
HBV DNA level <69 IU/mL at 48 week |
81% vs. 81% (P=ns) |
|
Yang et al. (2015) [31] |
Suboptimal response to ADV/LAM (prior LAM resistance patients) |
TDF (n=28) vs. continue ADV/LAM (n=31) |
HBV DNA level <200 IU/mL at 48 week |
96.43% vs. 29.0% (P<0.001) |
|
Lee et al. (2016) [30] |
Suboptimal response to ADV-based combination therapy due to NA resistance (LAM-resistant 9, Ldt-resistant 14, ETV-resistant 9) |
TDF +NA (n=16) vs. continue ADV+NA (n=16) |
HBV DNA level < 60 IU/mL at 48 week |
81.3% vs. 56.3% (P<0.001) |
Abbreviations
tenofovir disoproxil fumarate
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