Published online Jun 21, 2014. doi: 10.3748/wjg.v20.i23.7169
Revised: November 20, 2013
Accepted: January 2, 2014
Published online: June 21, 2014
Processing time: 248 Days and 18.6 Hours
Results from phase III clinical trials clearly demonstrate the efficacy and safety of entecavir and tenofovir in the controlled environment of randomized clinical studies. There are several studies with both drugs performed in clinical practice (also called “real life studies”). Despite the pros and cons, studies performed in real life conditions represent everyday practice and add important information about long term treatment effectiveness and safety in this clinical setting. This review shows that patients treated with first line nucleos(t)ide analogs at referral centres, with good clinical follow-up and adherence to international guidelines, can achieve high treatment response rates with a very low rate of adverse events.
Core tip: Patients treated with entecavir or tenofovir in routine clinical practice at referral centres, with good clinical follow-up and adherence to international guidelines, can achieve high treatment response rates with a very low rate of adverse events.
- Citation: Ridruejo E. Treatment of chronic hepatitis B in clinical practice with entecavir or tenofovir. World J Gastroenterol 2014; 20(23): 7169-7180
- URL: https://www.wjgnet.com/1007-9327/full/v20/i23/7169.htm
- DOI: https://dx.doi.org/10.3748/wjg.v20.i23.7169
The hepatitis B virus (HBV) is estimated to have infected more than 2 billion people worldwide, of whom 400 million are chronically infected today and are at an increased risk of liver-related complications, including cirrhosis, liver failure, hepatocellular carcinoma (HCC) and death[1,2]. In most regions of America, HBV prevalence is relatively low, with hepatitis B surface antigen (HBsAg) positivity ranging from < 2% to 7% compared with Asia, Africa and the Middle East, where chronic hepatitis B (CHB) prevalence rates reach 5%-20% of the general population[2,3]. Indications for treatment have been established by several international guidelines[3,4]. Treatment end-points are complete viral suppression (undetectable levels of HBV DNA replication), hepatitis B e antigen (HBeAg) clearance and seroconversion in HBeAg-positive patients, and if possible HBsAg clearance and development of antiHBs antibody[3,4]. Patients achieving these serologic end-points may discontinue treatment after an additional 6-12 mo period of consolidation therapy according to the cited guidelines. The goal of HBV treatment is to improve survival by preventing disease progression to decompensated cirrhosis and HCC[3,4].
Treatment induced suppression of HBV DNA to undetectable levels reduce the risk of disease progression improving liver fibrosis, and can result in fibrosis and cirrhosis regression[5,6]. Also, HBV DNA clearance is associated with increased rates of HBeAg and HBsAg seroconversion, the ultimate goal of HBV therapy. Since HBV DNA is integrated in the host genome, HBV persists in the covalently closed circular DNA form in the hepatocyte even if HBV DNA is not detectable in the serum. This HBV persistence may result in reactivation and hepatocarcinogenesis. Long-term treatment nucleos(t)ide analogs (NUC) is required in HBeAg negative and positive patients who cannot maintain off-treatment virologic suppression.
Pegylated interferon alpha (PEG-IFN alpha), entecavir (ETV) and tenofovir disoproxil fumarate (TDF) had been selected as the first-line therapy to initiate treatment in naïve CHB infected patients[3,4]. Other NUCs like lamivudine (LAM), adefovir (ADV) and telbivudine (LdT), are no longer recommended as first-line therapy since long-term therapy success with these drugs has been reduced with the emergence of drug-resistant mutants[3,4]. ETV and TDF were approved by different regulatory agencies in most countries between 2005 and 2009 on the basis of phase III clinical trials results. Since their approval, observational studies have been performed in everyday clinical practice (also known as “real life studies”), with their long term use adding valuable information to the efficacy and safety profiles of these two drugs. The aim of this review is to analyze the currently available data of long term ETV and TDF use in clinical practice as first-line treatments for NUC naïve chronic HBeAg positive and negative HBV patients.
Results from phase III clinical trials (CT) are critical for the approval of new drugs. Their main objective is to demonstrate the efficacy and safety of the drug being evaluated in comparison with the current standard of care, in a controlled setting. These trials are conducted on large patients groups under standardized conditions. “Ideal” young patients without comorbidities are included, and usually, patients with advanced liver disease are excluded. These strict inclusion/exclusion criteria are developed to facilitate analyzing the results and getting the new drug approved for its use in clinical practice. Also, patients treated within CT are strictly monitored and assist more frequently to clinical consultation and to laboratory monitoring than in routine clinical practice. Once approved, treating physicians use the same drug in “real life” patients, some of whom would have been excluded from these trials.
Entecavir is a potent inhibitor of HBV replication, which has been commercially available since 2005. In phase III randomized clinical trials (RCT) ETV showed increased virologic, biochemical and histologic response rates when compared with LAM. ETV at a dose of 0.5 mg/d in treatment-naïve patients suppressed HBV DNA to undetectable levels by year 1 in 67% of HBeAg-positive and in 90% of HBeAg-negative patients compared with 36% and 72% in the LAM arms, respectively[7,8]. Recent reports showed that when administered for 2 to 5 years, ETV resulted in better HBV DNA suppression and higher HBeAg seroconversion rates[9-11]. ETV treatment for 3 years in HBeAg-negative and for 5 years in HBeAg-positive patients resulted in 95% and 94% HBV DNA undetectable levels, respectively[10,11]. In HBeAg-positive patients, treatment for 96 wk resulted in 31% HBeAg seroconversion rates[9]. In the ETV-901 study, continuing treatment in those patients who remained HBeAg positive at week 96 resulted in 23% HBeAg seroconversion rates and 1.4% HBsAg loss[11].
ETV has a high genetic barrier to resistance and a strong resistance profile, and has a very favorable safety profile. Recently reported results of more than 6 years of therapy showed that in NUC naïve patients the cumulative probability of genotypic resistance to entecavir was very low (1.2%) and that treatment was well tolerated[12,13]. Also, analysis of liver biopsies from the two phase III entecavir studies (ETV-022 and ETV-027) and the open-label rollover study (ETV-901) have shown that ETV treatment can improve fibrosis of the liver and can cause fibrosis and cirrhosis regression[5]. Patients receiving treatment for at least 3 years had ≥ 2 point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score in 96% of the cases, and ≥ 1-point improvement in the Ishak fibrosis score in 88% of the cases[5]. Reversal of advanced fibrosis/biopsy-proven cirrhosis was demonstrated in nine of 10 patients with baseline Ishak fibrosis scores of 4-6 who underwent serial liver biopsies up to year 6.
TDF is also a potent inhibitor of HBV replication, which has been commercially available since 2008. In phase III RCT TDF showed increased virologic and biochemical response rates when compared with ADV. TDF at a dose of 300 mg/d in treatment-naive patients suppressed HBV DNA to undetectable levels by year 1 in 76% of HBeAg-positive and in 93% of HBeAg-negative patients compared with 13% and 63% in the ADV arms, respectively[14]. As previously shown with ETV, extending treatment with TDF is associated with increasing HBV DNA suppression and higher HBeAg seroconversion rates[15-17]. After 4 years of treatment, 96% of HBeAg positive and 99% of HBeAg negative patients achieved undetectable HBV DNA levels[15-17]. In HBeAg positive patients, HBeAg loss occurred in 41% of patients and HBeAg seroconversion in 29%; the cumulative probability of HBsAg loss was 11%[15,16]. Longer treatment with TDF is associated with higher HBV DNA negativization rates (98%-99%), and higher HBeAg and HBsAg negativization and seroconversion rates[18].
As with ETV, long-term treatment with TDF has been associated with histologic improvement. Sustained viral suppression with TDF treatment over 5 years was associated with histological improvement in 87% of patients and 51% fibrosis regression; 74% of patients with cirrhosis (Ishak score 5 or 6) at baseline no longer had cirrhosis[6]. TDF was well tolerated over this treatment period[15-18], and no resistance with long term treatment has been reported to date[19,20].
Results from phase III RCT clearly demonstrate the efficacy and safety of ETV and TDF in the controlled environment of randomized clinical studies. There are several studies with both drugs performed in clinical practice (also called “real life studies”). Some had been published in full text in peer review journals, and some had been only presented at the liver meetings organized by the American Association for the Study of Liver Diseases and the European Association for the Study of Liver. These studies contain a heterogeneous mixture of patients treated for different periods of time who are differentiated from those in clinical trials as based on a number of criteria and may, therefore, be more reflective of the treatment population and the real efficacy and safety of the drug (Table 1)[21]. Results from these studies are discussed in the following section and summarized in Table 2.
| Characteristic, n (%)1 | ETV-022 | ETV-027 | Oriente | Virgil | King’s College Cohort | Italian cohort | Argentineancohort | Hong Kongcohort | Japan cohort | China cohort | China cohort 2 | Taiwan cohort | Taiwan cohort 2 | United States cohort | United States cohort 2 | Australia |
| Ref. | [7] | [8] | [22] | [23] | [24] | [25[ | [29] | [32] | [33] | [34] | [35] | [36] | [37] | [38] | [39] | [40] |
| n | 354 | 325 | 190 | 243 | 154 | 418 | 169 | 222 | 474 | 230 | 1768 | 98 | 248 | 169 | 136 | 163 |
| Age, yr (mean ± SD or range) | 35 ± 132 | 44 ± 112 | 44 (35-54)3 | 43 ± 142 | 423 | 58 (18-82)4 | 51 ± 132 | 47 (21-77)4 | 47 (17-82)4 | 42 ± 122 | 36 (16-70)4 | 48 ± 132 | 39 (17-77)4 | 39 ± 122 | 39 ± 122 | 52 (24-86)4 |
| Male | 274 (77) | 248 (76) | 139 (73) | 177 (73) | 122 (79) | 316 (76) | 113 (77) | 157 (71) | 321 (67) | 196 (85) | 1414 (80) | 67 (68) | 172 (69) | 100 (59) | 83 (61) | 113 (69) |
| Race | NR | NR | NR | NR | NR | NR | NR | |||||||||
| White | 140 (40) | 193 (59) | 60 (84) | 114 (47) | 143 (85) | 7(4) | 10 (7) | |||||||||
| Asian | 204 (58) | 122 (38) | 18 (9) | 70 (29) | 26 (15) | 1768 (100) | 162 (96) | 126 (93) | ||||||||
| Other | 2 (< 1) | 2 (< 1) | 6 (3) | 59 (24) | ||||||||||||
| Region | Europe 24%, North America 13%, South America 14%, Australia and Asia 49% | Europe 48%, North America 9%, South America 11%, Australia and Asia 33% | Europe | Europe | Europe | Europe | South America | Asia | Asia | Asia | Asia | Asia | North America | North America | Oceania | |
| Genotype | NR | NR | NR | NR | NR | NR | NR | NR | ||||||||
| A | 94 (27) | 33 (10) | 40 (22) | 12 (3) | 0 | |||||||||||
| B | 68 (19) | 46 (14) | 14 (8) | 67 (16) | -61 | -57 | ||||||||||
| C | 111 (31) | 57 (18) | 25 (14) | 336 (81) | -39 | -41 | ||||||||||
| D | 37 (10) | 157 (48) | 91 (50) | 84 (90) | 0 (0) | 0 | ||||||||||
| HBeAg negative | 6 (3) | 322 (99) | 133 (70) | 157 (65) | 106 (69) | 347 (83) | 65 (39) | 132 (59) | 252 (53) | 117 (51) | 602 (34) | 57 (58) | 0 (0) | 0 (0) | 0 (0) | 10 (6.1) |
| HBV DNA, log10 IU/mL1 | 9.62 (2.01)25 | 7.6 (1.8)25 | 5.94 (4.64-7.39)3 | 6.2 ± 1.73 | 4.6 (0.2)6 | 6.0 (1.5–9)4 | 6.88 (1.81)2 | 7.1 (4.0-> 8.8)4 | 6.7 (2.6-> 9.0)4 | 6.3 ± 1.43 | 6.74 (1.04-9.69)4 | 6.0 ± 1.53 | 7.6 (2.2-13.1)4 | 7.58 (3.77-9.70)4 | 7.48 (3.8-9.9)4 | NR |
| ALT, IU/L1 | 140.5 (114.3)2 | 141 (114.7)2 | 71.5 (44-108)3 | NR | NR | 92 (11-2241)4 | 139 (231)2 | 92 (17-2168)4 | 70 (8-2121)4 | 68(3-2631)4 | NR | 138 (21-4190)4 | 201 (27-2415)4 | 62 (14-839)4 | 67 (14-1077)4 | NR |
| Cirrhosis | 26/329 (8) | 15/303 (5) | 07 | 57 (24) | 52 (34) | 202 (49) | 38 (23) | 0 | 102 (22) | 74 (32) | NR | 13 (14) | 39 (16) | NR | NR | 26(16) |
| Study | Median follow-up (range) | Patients(n) | Cut-off (assaylimit) (IU/mL) | HBV DNA undetectable1 | HBeAg seroconversion12 | HBsAg loss1 |
| ORIENTE[22] | 52 wk (46-53 wk) | 190 | 50 | 115 (82) | 12 (21) | 2 (1) |
| VIRGIL[23] | 19 mo (3-45 mo) | 243 | 80 | 126 (74) | 13 (15) | 3 (1) |
| King’s College cohort[24] | 28 mo (NR) | 154 | 12 | NR | NR | NR |
| Italian cohort[25] | 58 mo (2-80 mo) | 418 | 12 | 93 (99) | 527 (31 patients) | 337 (15 patients) |
| Argentinean cohort[29] | 181 wk (108-248 wk) | 169 | 6 | 34 (100) | 71 (68) | 23 (14) |
| Hong Kong cohort[32] | 3 yr (12-60 mo) | 222 | 12 | 51 (90) | 16 (53) | 1 (0.5)3 |
| Japan cohort[33] | 2.37 yr (0.5-7.2 yr) | 473 | 12 | 70 (96) | 93 (42) | 1 (0.2) |
| China cohort[34] | 27.5 mo (3-73 mo) | 230 | 100 | NR | 17 (15) | 1 (0.4) |
| China cohort 2[35] | 191 wk (1-233 wk) | 1768 | 50 | 1327 (83) | NR | NR |
| Taiwan cohort[36] | 144 wk | 98 | NR | 93 (95) | 5 (12) | 0 |
| Taiwan cohort 2[37] | 25.3 mo (12-69 mo) | 248 | 6 | 33 (82) | 64 (28) | NR |
| United States cohort[38] | 25 mo (6-68 mo) | 169 | 100 | 75 (44) | 12 (8) | NR |
| United States cohort 2[39] | 36 mo | 136 | 100 | 115 (85) | 41 (30) | 0 |
| Australia cohort[40] | 26 mo (3-46) | 163 | 12 | 134 (82) | 66 (43) | 1 (0.6) |
There are several studies of ETV treatment in clinical practice from different regions of the world. Most of them are from Europe and Asia, and a minority from America and Oceania. The Oriente study analyzed the results from 190 NUC-naïve patients treated for a year in 25 centres in Spain. The cohort was 73% male, 84% Caucasian, 30% HBeAg positive and 34% of the patients who underwent biopsy had advanced fibrosis/cirrhosis. At week 48, 83% of the patients (61% HBeAg-positive; 92% HBeAg negative) achieved a virological response, 26% of the HBeAg-positive patients lost HBeAg and 22% achieved seroconversion to antiHBe and 2% showed HBsAg clearance[22]. The European network of excellence for vigilance against viral resistance (VIRGIL) performed a multicentre cohort study at over 10 European referral centres between 2005 and 2010 including 243 NUC-naïve patients[23]. At week 144, 90% of HBeAg positive patients and 99% of HBeAg negative patients achieved a virologic response, and 34% of the HBeAg-positive patients lost HBeAg. In a single-centre cohort study from the King’s College in the United Kingdom 3 treatment strategies were compared. One hundred and fifty four patients were treated with ETV monotherapy for a median of 28 mo: 76% of patients achieved HBV DNA undetectable levels, 8% of the HBeAg positive patients cleared HBeAg and 1% cleared HBsAg[24].
A retrospective/prospective, multicentre study was conducted at 19 Italian centres and included 418 consecutive NUC-naïve patients treated with ETV[25]. In their last evaluation, 100% of HBeAg positive patients and 99% of HBeAg negative patients achieved HBV DNA undetectable levels after 60 mo of treatment. In HBeAg positive patients, HBeAg seroconversion occurred in 31 patients (cumulative rate of 55%) and HBsAg loss in 15 patients (cumulative rate of 34%). One patient developed resistance to ETV (L180M, M204V, S202G) over the treatment period and was successfully treated with TDF[25].
A single centre study from Italy included 100 patients, 85 of whom were NUC-naïve treated with ETV for 36 mo. Overall, 94% of the patients achieved HBV DNA negativization, 33% of HBeAg positive patients cleared HBeAg and 15% cleared HBsAg[26]. Another multicentre study from Italy included 300 patients, 287 being NUC-naïve treated for 24 mo. At the end of follow up, cumulative rates of undetectable HBV DNA was 89%, 39 patients were HBeAg positive and 17 achieved negative HBeAg with antiHBe seroconversion in 15 cases (38.4%), and HBsAg loss was observed in 5 patients[27]. Unfortunately, both studies presented their overall results, including both NUC-naïve and NUC-experienced patients.
The results from a previously reported multicentre study performed in Argentina were recently updated[21,28]. One hundred and sixty nine consecutive patients were treated with ETV for a median 181 wk. Overall, 156 (92%) patients became HBV DNA undetectable, 92 (88%) of HBeAg positive and 64 (98%) of HBeAg negative patients. Cumulative clearance of HBV DNA by week 192 and 240 was 100% in both HBeAg positive and negative patients. Seventy four (71%) patients cleared HBeAg, 23 (14%) patients cleared HBsAg (19 HBeAg positive and 4 HBeAg negative, P = 0.025), and 22 (13%) patients developed protective titers of antiHBs. One patient developed virological breakthrough due to ETV resistance (M204V, S202G) over the treatment period[29]. In a follow up study, post-treatment outcomes of patient from this study were evaluated in clinical practice[30]. Thirty-five patients (20%) discontinued ETV treatment due to sustained virological response; 33 of these patients developed HBeAg seroconversion and 18 HBsAg seroconversion. Nine patients (26%), all HBeAg positive at baseline, developed virological relapse after a median 48 wk off treatment, 3 of them showed HBeAg reversion and 4 lost antiHBe. No patient with HBsAg seroconversion relapsed[30]. These results confirmed that ETV, after 12 mo consolidation therapy, can be discontinued in real life. Patients have to be followed since there is still a risk of virological relapse.
A single-centre prospectively followed cohort from Hong Kong analyzed 222 NUC-naïve patients receiving ETV (0.5 mg daily) for up to 4 years[31,32]. The cumulative rate of patients achieving HBV DNA undetectable levels was 90% by year 4. HBeAg seroconversion occurred in 53% of HBeAg positive patients, and of HBsAg positive patients seroconversion developed only in one patient (0.5%). Only one case of resistance (rt180M, rt204V, and rt184S/C/G/A) was reported in this cohort, representing a 0.6% cumulative resistance rate up to year 4[32]. This low rate, by comparison with previously mentioned results, probably evidences the less frequent occurrence of HBsAg loss (mainly if not exclusively reported in HBeAg positive patients) in genotypes B and C (the most frequent in Asia) compared with genotypes A and D (the most frequent in Europe)[21].
A retrospective analysis from Japan included 474 patients who received ETV treatment for up to 4 years[33]. The cumulative rate of patients achieving HBV DNA undetectable levels was 96% by year 4. HBeAg seroconversion occurred in 42% of HBeAg positive patients, and of HBsAg patients seroconversion developed only in one patient (0.2%). In this cohort, 5 patients showed virological breakthrough during the treatment period, including 2 patients who developed ETV-resistant mutations[33]. Two hundred and thirty NUC-naïve patients treated for up to 5 years were retrospectively evaluated in China[34]. Incremental increases were observed in undetectable HBV DNA rates, with 100% being undetectable at 5 years of treatment. Fifteen percent achieved HBeAg/antiHBe seroconversion, and only one patient cleared HBsAg (0.4%). Only one patient developed ETV resistance mutations (rtL180M + rtT184A + rtM204V), and was subsequently treated with ETV+ADV combination therapy[34].
In a sub-study of the randomized, observational study of entecavir to assess long-term [(REALM) outcomes associated with nucleoside/nucleotide monotherapy for patients with chronic HBV infection] trial, 1768 NUC-naïve patients were treated with ETV in a ‘real-world’ clinical practice setting in China[35]. The preliminary results of the virologic efficacy and limited safety data were recently presented. At week 144, 84% of ETV-treated patients had HBV DNA undetectable levels. Unfortunately HBeAg and HBsAg clearance rates were not reported. Importantly, in this large cohort of patients prospectively followed, ETV demonstrated to be very safe with no serious adverse events reported. In Taiwan 98 patients were treated with ETV, in a study comparing its efficacy with LdT[36]. Short term treatment, up to 48 wk, showed HBV DNA was undetectable in 95% of patients and the HBeAg seroconversion rate was 27%. None of the patients achieved HBsAg clearance. No resistance was reported. In the real-world study “Taiwan Retrospective study of Entecavir Treatment: a Multi-center E Antigen positive Treatment-Naïve Trial of Chronic Hepatitis B” (TREATMENTCHB), 248 HBeAg positive patients were treated with ETV[37]. Undetectable serum HBV DNA levels were achieved in 52% (111/213), 79% (101/128), and 82% (33/40) of patients at 1, 2, and 3 years of treatment, respectively. Of 248 patients, 99 (40%) achieved HBeAg loss at the time of data analysis. The rate of HBeAg seroconversion was 28% (64/231; 17 missing data of antiHBe antibody). The cumulative rates of HBeAg loss were 20%, 38%, and 49% at years 1, 2, and 3 of treatment, respectively. HBsAg loss rate were not reported[37].
A retrospective cohort study was performed including 333 consecutive treatment-naïve HBeAg positive patients treated with oral NUC monotherapy with LAM, ADV, ETV, or TDF for up to 12 mo at three gastroenterology clinics in the United States, where 96% of the cohort were Asians[38]. One hundred and sixty nine of them received treatment with ETV. At the time of evaluation 44% achieved HBV DNA undetectable levels and the HBeAg seroconversion rate was only 8%. In the entire cohort, a total of 118 patients switched therapy during the course of treatment: 38 switched to combination therapy and 80 switched to alternative monotherapy. The HBeAg seroconversion rates improved with time, being 21% at year 2, 28% at year 3, 38% at year 4, and 38% at year 5. There is no data about ETV patients treated outcome. A subgroup of this study, those receiving only ETV was reported[39]. One and hundred thirty six patients received treatment for up to 36 mo. Complete viral suppression rates at months 24 and 36 were 66% and 85%, respectively. The cumulative HBeAg seroconversion rates were 20% at month 24 and 30% at month 36. No patients achieved HBsAg loss or HBsAg seroconversion in this study. The results from this study suggest that, unlike the majority of the studies reported, achieving HBeAg seroconversion in real-life settings appears to be much more difficult than in registration trial settings. In this case, it might be related to lower ALT levels. Also, the low rate of HBsAg loss in this predominately Asian cohort may be associated with the predominance of HBV genotypes B and C as previously mentioned.
A study from Australia included 163 NUC-naïve patients treated with ETV for up to 36 mo[40]. It showed that 134 patients (82%) achieved complete virological suppression (HBV DNA levels < 12 IU/mL). Authors reported that the annual HBeAg positive to negative seroconversion rate was 14%; after 36 mo 66 patients (43%) achieved this serologic endpoint. In this cohort only one patient (HBeAg negative) cleared HBsAg. A recent review also from Australia showed similar results: 81%-89% HBV DNA suppression rates[41]. Unfortunately they do not report HBeAg and HBsAg clearance rates.
Results from these 13 studies, including 4434 patients, showed that ETV is as effective in clinical practice as in clinical trials. Extending treatment duration is associated with increasing rates of HBV DNA complete suppression, HBeAg seroconversion and HBsAg loss. Different response rates between studies, mainly regarding serological response, may be associated with particular virological and host factors of each geographic region.
There are fewer studies published with TDF than with ETV. Also, the population included in these studies tended to be heterogeneous, patients were treated for different periods of time (generally for shorter periods of time than with ETV) (Table 3), and may also be more reflective of the treatment population and the real efficacy and safety of the drug[22]. Results from these studies are discussed in the following section and summarized in Table 4.
| Characteristic1 | Study 103 | Study 102 | King’s College Cohort | United States cohort | European cohort | German cohort |
| Reference | [14] | 14 | [24] | [38] | [42] | [43] |
| n | 176 | 250 | 60 | 28 | 302 | 184 |
| Age, yr (mean ± SD or range) | 34 ± 112 | 44 ± 112 | 403 | 36 ± 92 | 55 (19-80) | 44 ± 142 |
| Male | 119 (68) | 193 (77) | 30 (50) | 16 (58) | 222 (74) | 127 (69) |
| Race | NR | NR | ||||
| White | 92 (52) | 161 (64) | 1 (4) | 140 (76) | ||
| Asian | 64 (36) | 63 (25) | 27 (96) | |||
| Other | 20 (11) | 26 (10) | ||||
| Region | Europe 55%, North America 27%, Australia and Asia 18% | Europe 63%, North America 21%, Australia and Asia 16%4 | Europe | North America | Europe | Europe |
| Genotype | NR | NR | NR | |||
| A | 94 (27) | 33 (10) | ||||
| B | 68 (19) | 46 (14) | 18 (65) | |||
| C | 111 (31) | 57 (18) | 10 (35) | |||
| D | 55/173 (32) | 156/243 (64) | ||||
| HBeAg negative | 0 (0) | 250 (100) | 46 (77) | 0 (0) | 241 (80) | 127 (69) |
| HBV DNA, log10 IU/mL1 | 8.64 (1.076)25 | 6.86 (1.31)25 | 4.2 (0.3)6 | 7.74 (3.34-8.66)3 | 5.9 (1.4 -> 9)3 | 6.9 |
| ALT, IU/L1 | 142 (102.81)2 | 127.5 (101.21)2 | NR | 52.5 (8-468)3 | 88 (11-3733)3 | |
| Cirrhosis | 34/172 (20) | 47/250 (19) | 14 (23) | NR | 105 (35) | 20 (11) |
| Study | Median follow-up (range) | Patients(n) | Cut-off (assay limit) (IU/mL) | HBV DNA undetectable1 | HBeAg seroconversion12 | HBsAg loss1 |
| King’s College cohort[24] | 12 mo | 60 | 12 | 33 (76) | 2 (7) | 0 |
| United States cohort[38] | 12 mo (6-23 mo) | 28 | 100 | 23 (82) | 7 (5) | 0 |
| European cohort[42] | 33 mo (0-66 mo) | 302 | 12 | 91 (97) | 18 (36)3 | 8 (13) |
| German cohort[43] | 24 mo | 184 | 69 | 170 (92) | NR | NR |
The King’s College Cohort from London (already discussed in the ETV section) included 60 patients receiving first-line TDF treatment[24]. Since TDF was approved after ETV, these patients received a shorter duration of treatment at the time of the analysis (9 mo compared with 28 mo). At 12 mo of treatment, 76% of TDF treated patients cleared HBV DNA, 7% achieved HBeAg seroconversion and no patient cleared HBsAg. In another previously mentioned study, 333 consecutive treatment-naïve CHB patients treated with oral NUC monotherapy with LAM, ADV, ETV, or TDF for up to 12 mo were evaluated at three gastroenterology clinics in the United States[38]. Twenty eight of them received treatment with TDF. At 12 mo of treatment, 82% of TDF treated patients cleared HBV DNA, 5% achieved HBeAg seroconversion and no patient cleared HBsAg.
Two large studies evaluating TDF use in clinical practice were recently reported[42,43]. A multicentre cohort study conducted at 19 European centres retrospectively and prospectively monitored 302 NUC-naïve patients followed for a median of 33 mo and the 3 years follow up study was presented[42]. Virological response rates increased over time from 84% at year 1 to 95% at year 3 in the overall population, from 66% to 86% in HBeAg positive patients and from 74% to 98% in HBeAg negative ones. The cumulative probability of HBeAg seroconversion steadily increased to 36% at year 3, with 8 patients (13%) clearing HBsAg, and 5 of these stopping TDF successfully. Virologic breakthrough was reported in 2% of patients, with no potentially resistance-associated mutations identified to date. A prospective observational study including 400 TDF-naïve patients was performed in Germany and the 2 year data is available (GEMINIS study)[43,44]. Forty-six percent of the patients (n = 184) were NUC-naïve. At the time of evaluation, overall 92% of NUC-naïve patients achieved HBV DNA undetectable levels, 81% of HBeAg positive and 91% of HBeAg negative patients; 20% achieved HBeAg seroconversion, and there was 5% loss in HBsAg in HBeAg positive patients. No virologic breakthrough and no resistance have been reported to date.
ETV should be administered on an empty stomach (at least 2 h after a meal and 2 h before the next meal) and is generally well tolerated. The most commonly reported treatment related adverse events in phase III clinical trials were headache, fatigue, dizziness, and nausea at comparable rates to LAM[7,8]. In the ETV-901 rollover study 1051 patients were enrolled from 10 prior Phase II/III studies and were treated with ETV for at least a 5 year period[13]. Most of the reported adverse events (AEs) were mild to moderate, 19% were grade 3-4 events, with only 4% of them possibly related to ETV. These grade 3-4 AEs were myalgias (5%), neuropathy (hypoparesthesia and hyperparesthesia, polyneuropathy) (4%), increased lipase (2%), increased serum creatinine (< 1%), increased serum lactate or decreased serum bicarbonate (< 1%), hypophosphatemia (< 1%), muscular weakness (< 1%), pancreatitis (< 1%) and creatinine phosphokinase elevation (< 1%)[45,46]. It was reported an overall discontinuation rate due to AEs was extremely low (< 1%).
Are these results from phase III trials applicable to treatment in real life settings? After reviewing the experience from these studies (including 4434 patients), it seems that the ETV Safety profile in clinical practice is consistent with those of Phase III studies, in that no major safety issues or serious side effects have been reported to date[21-25,29-40,44]. As a controlled trial, patients have been carefully selected in order to be able to be included. Excluded patients usually have advanced liver diseases or comorbidities. The latter commonly require administration of concomitant medications. The addition of different medications may have an important impact upon study drug pharmacokinetics, efficacy and safety. The strict inclusion criteria of these studies did not allow testing unexpected adverse events due to drug to drug interactions, nor potential toxicity in patients with advance liver disease. For this reason, studies reporting results in “real life” are necessary to add information to controlled clinical trials reports[44].
There are some safety concerns when using the newer NUCs in CHB cirrhotic patients. Lactic acidosis (LA) with ETV was first reported in 2009. Five of 16 HBV cirrhotic patients treated with EVT developed lactic acidosis. One of the patients died, and the other 4 recovered after treatment discontinuation. A significant correlation between the MELD score and the development of lactic acidosis was observed (P = 0.002). The single components of the MELD score - bilirubin, INR, and creatinine - also correlated with the development of lactic acidosis (P = 0.003, P = 0.003, and P = 0.008, respectively). LA developed in patients with more severe liver dysfunction (MELD score > 20)[45]. There were no cases of LA reported in the ETV 901 study or in the clinical practice studies, considering that 8% to 49% of patients included were cirrhotics[22-26,30-41]. A recent study using ETV and/or TDF in compensated or decompensated HBV cirrhotic patients in real-life clinical practice demonstrated that both drugs can be safely used in this subgroup of high risk patients[46]. Safety of ETV in decompensated HBV cirrhotic patients was confirmed in an open label study[47]. This data suggested that ETV can be used, but should be applied cautiously, in patients with severe decompensated liver disease. As per reported NUCs preclinical data, a usual concern with the long term administration is their potential carcinogenicity. After a 5 year period of ETV administration, only 3 cases of the novo non liver neoplasms were identified: two gastric and one pancreatic adenocarcinoma[13,44]. However, to date, there is no evidence for the occurrence of cancers as a result of ETV treatment in patients. A global phase IV study (the REALM study), preliminary results of which were discussed above[35], is continuing to address this safety concern in patients treated with ETV during a 10-year follow-up period.
In phase III trials the overall incidence of AEs was comparable in patients receiving TDF vs ADV[14]. The most common AEs in both studies included headache, nasopharyngitis, back pain, nausea, and fatigue. Nephrotoxicity may be a potential concern with TDF, based on evidence from post-marketing surveillance of patients receiving TDF for HIV infection, but so far the problem appears to be less evident in patients with HBV infection[22,43]. Results from the long term follow up of phase III studies have been recently presented[20]. At year 6, less than 2% of patients discontinued TDF due to an adverse event, and less than 1.5% experienced a confirmed renal event (≥ 0.5 mg/dL increase in serum creatinine from baseline, phosphorus < 2 mg/dL, or CrCL < 50 mL/min)[21]. The use of tenofovir has been associated with greater loss of bone mineral density during the early months of therapy in HIV monoinfected patients, although no HBV monoinfected patient experienced bone fractures in these studies[16-20]. Bone mineral density (BMD) remained stable from year 4 through year 6, for both hip and lumbar spine[20]. Recent data suggests that in HBV monoinfected patients, bone mineral loss might be related to vitamin D deficiency and no to TDF treatment[48]. Nevertheless, BMD should be periodically evaluated in HBV patients taking TDF[44]. Safety data collected from the European cohort study concerning TDF were generally consistent with the long term clinical study safety data[42].
Median serum creatinine, eGFR and phosphorus blood levels remained unchanged over time. Approximately 2% of the patients showed > 0.5 mg/dL increase of serum creatinine or < 2 mg/dL phosphorus or proteinuria. The proportion of patients with eGFR < 50 mL/min by MDRD increased from 3% at baseline to 6% at the end of the study. TmPO4/GFR ratio, a marker of urinary phosphate reabsorption, was reduced in nearly 20% of the patients at baseline and in nearly 30% during follow-up. TDF doses were reduced to 300 mg/48 h in 10 patients (3%, decline of eGFR in all) and discontinued in an additional 9 patients (3%, renal-related events in 2 cases). Overall, 5% stopped TDF (HBsAg loss in 5, adverse events in the remaining 11)[42]. In the GEMINIS study serum creatinine clearance and phosphorous levels remained stable. No frequent AEs were reported. Four renal events were detected, all in NUC-experienced patients (prior long-term LAM +/− ADV therapy) with comorbidities: diabetes (2 patients), renal insufficiency (2 patients), and cirrhosis (1 patient)[43].
A French multicentre prospective cohort (Vireal study) evaluated the tolerance of TDF treatment in a real life cohort, including elderly patients with comorbidities[49]. Unfortunately, 58% of the 441 HBV patients treated were NUC-experienced or resistant and were not included in the review of the virological response discussed above. The 2-year data reported no major safety issues. Forty-eight elderly patients were subsequently analyzed: mean age 71 ± 6 years, 73% male, 87% HBeAg-negative, 58% advanced fibrosis and 79% treatment experienced. Although 82% of elderly had prior GFR < 90 mL/min (estimated by CKD-EPI formula), GFR remained stable or improved in 91%. The mean GFR was 73, 69 and 70 mL/min at baseline, 1 and 2 years. This study showed that TDF safety and tolerance were similar in elderly and younger patients[49]. Also, TDF can be safely used in patients with mild renal impairment. A prospective, randomized, double-blind trial of TDF vs emtricitabine (FTC)/TDF combination in LAM-resistant patients compared mild renal impairment (MRI; CrCL 50 ≤ 80 mL/min by Cockroft-Gault) patients (74/280; 26%) and normal renal function (NRF; CrCL ≥ 80 mL/min) patients (206/280; 74%)[50]. No patients had a confirmed increase in serum creatinine of ≥ 0.5 mg/dL, and 1% (2-NRF) had transient phosphorus < 2 mg/dL. Nine MRI patients had CrCL < 50 mL/min (pre-treatment range: 49-61 mL/min) that stabilized with dose adjustment. No differences were observed in percentage change in spine or hip BMD over 96 wk, and no clinically relevant bone loss was noted in either group. The safety of patients with MRI receiving TDF was similar to NRF patients; in MRI patients there was no evidence of increased risk for renal- or bone-related complications[50]. In TDF treated patients serum chemistries, including creatinine and phosphorus, should be monitored every 6 mo. Monitoring may be more frequent in patients with impaired baseline renal function or other medical conditions that increase the risk of renal failure[51].
TDF was also used in HBV patients with decompensated liver disease in a phase II double-blind randomized study[52]. TDF, alone or in combination with FTC, was demonstrated to be safe in this population. As previously mentioned, TDF was safe when used in this group of patients in real-life clinical practice[46].
The factors that determine the likelihood of achieving a virological and/or serological response are called predictors of response. They can be classified as viral or host related, or as baseline or on-treatment depending on the time point of evaluation. Many viral and host factors affect treatment response, and not achieving the desired response might be related to a combination of them. Before initiating treatment, it is useful for patients and physicians to know the likelihood of achieving a response, so that they can decide whether treatment benefits outweigh its costs and its risks. Also, predictors may be helpful to guide the continuation of antiviral therapy[4].
In CHB therapy, some baseline and on-treatment predictors of subsequent response have been identified. These factors are stronger predictors of treatment outcomes and are more useful for IFN/PegIFN based than for NUCs based therapies[4]. Predictors of response for the existing NUCs at various time points vary for different agents. In HBeAg positive patients, baseline factors predictive of antiHBe seroconversion are low viral load (HBV DNA below 2 × 108 IU/mL), high serum ALT levels, and high activity scores on liver biopsy[4]. HBV genotype does not influence the virological response to any of the available NUCs[4,53]. Virological response (undetectable HBV DNA) at 24 wk during treatment with LAM or LdT and at 48 wk during treatment with ADV is associated with a lower incidence of resistance, i.e. an improved chance of maintained virological response in both HBeAg positive and HBeAg negative patients and with a higher chance of antiHBe seroconversion in HBeAg positive patients[4]. A decline of HBsAg, HBeAg and HBV DNA levels during NUC treatment in HBeAg positive patients may identify cases with subsequent HBeAg or HBsAg loss[4,54-56].
Evaluation of predictors of response tends to be difficult in real world studies since patients’ characteristics are heterogeneous and treatment duration and parameters evaluated may vary between studies. But there are some data reported with ETV treatment in the studies cited above, and unfortunately none of the TDF studies reported predictors of response. In the ORIENTE study, virological response in the HBeAg positive patients at week 12 correlated significantly with antiHBe seroconversion rate at week 48: odds ratio for this correlation at week 12 was 8 (95%CI: 1.17-54.5, P < 0.05). This correlation was also observed at weeks 24, 36 and 48 (P = 0.003, 0.002 and 0.017, respectively)[22]. In the single centre study from Italy, the presence of cirrhosis (OR = 1.730, 95%CI: 1.082-2.766, P = 0.022) and absence of HBeAg at baseline (OR = 0.479, 95%CI: 0.273-0.842, P = 0.011) were independent predictors of earlier clearance of serum HBV DNA[26].
In our study from Argentina, baseline HBV DNA ≥ 7 log10 IU/mL (HR = 9.40, 95%CI: 3.46-25.54, P < 0.001) and Metavir A score ≥ 2 (HR = 2.48, 95%CI: 1.39-4.40, P = 0.002) predicted HBeAg clearance in ETV treated patients[29]. Being HBeAg positive at baseline (HR = 11.1, 95%CI: 0.96-128, P = 0.053) and HBV DNA clearance before week 48 (HR = 7.76, 95%CI: 0.96-62.4, P = 0.054) tended to predict HBsAg seroclearance, but they were not statistically significant[29]. In the Hong Kong cohort baseline HBV DNA levels ≥ 8 logs10 copies/mL and undetectable HBV DNA levels at week 24 were associated the higher possibilities of achieving undetectable HBV DNA at year 3 of ETV treatment[31]. In the Japan cohort, HBV DNA levels < 7.6 log10 copies/ml (OR = 15.8, 95%CI: 43.1-79.9, P = 0.001) predicted HBV DNA undetectable levels after 3 years of ETV treatment[33]. Serum albumin < 3.5 g/dL (RR = 2.0, 95%CI: 1.1-3.6, P = 0.019) was the only significant determinant of HBeAg seroconversion[33]. In the Chinese study, high baseline HBV DNA levels (OR = 0.532, 95%CI: 0.315-0.896, P = 0.018) and virological non-response at week 24 (OR = 6.093, 95%CI: 2.099-17.685, P = 0.001) to ETV monotherapy were the independent risk factors for a partial virologic response at 1 year[34]. In the TREATMENT CHB study form Taiwan, baseline ALT > 5-times ULN (HR = 1.810, 95%CI: 1.062-3.085, P = 0.001) and baseline HBV-DNA level (HR = 0.812, 95%CI: 0.700-0.942, P = 0.014) were independent factors associated with HBeAg loss in ETV treated patients[37]. In the Australian cohort, patients with baseline DNA levels < 108 log10 IU/mL vs > 108 log10 IU/mL (P = 0.001) and HBeAg negative patients (P = 0.001) achieved more rapidly complete virological suppression[40].
In summary, baseline HBV DNA levels and HBeAg status appeared to predict HBV DNA clearance and HBeAg clearance/seroconversion in clinical practice. There is little information about predictors of HBsAg clearance/seroconversion. There is no information about how HBsAg and/or HBeAg baseline and on-treatment levels impact on treatment response in real life.
Is ETV or TDF treatment effective in clinical practice? Can the results observed in CT be extrapolated to clinical practice? Efficacy is the ability of a drug or intervention to produce an effect under optimal conditions, whereas effectiveness is its usefulness in routine practice[57]. Clinical trials differ in many ways from clinical practice, and many patients treated in clinical practice would have been excluded from these trials. This is the main reason why studies performed in routine clinical practice provide useful information for the treating physician. This review shows that ETV and TDF used in clinical practice have similar response rates when compared with CT, with low rates of resistance and favorable safety profiles.
Studies performed in clinical practice have some limitations when compared with CT. They are, in most cases, retrospective; the treatment protocol is not standardized; adverse events may be under-reported since there is no strict register of safety parameters; and they include a variable number of patients. These treatments were conducted at referral centres by highly trained specialists with experience in the field who have participated in CT. This ensures treatment effectiveness, but tends to exclude less experienced investigation centres. Another concern is that patient compliance to these long term treatment regimens may be poorer and less controlled than compliance to short term strictly monitored treatments in CT. Most of the studies reviewed show a low rate of patients lost to follow up and a low rate of non-adherence[58]. Even if adherence is not strictly evaluated in these types of studies, it can be assumed that if there is a low rate of virological breakthroughs and resistance, adherence has to be good to maintain treatment responses.
Despite the pros and cons, studies performed in real life conditions represent everyday practice and add important information about long term treatment effectiveness and safety in this clinical setting. This review shows that patients treated with first line NUCs at referral centres, with good clinical follow-up and adherence to international guidelines, can achieve high treatment response rates with a very low rate of adverse events.
P- Reviewers: Ong HT, Rodriguez-Frias F S- Editor: Cui XM L- Editor: O’Neill M E- Editor: Liu XM
| 1. | Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11:97-107. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1734] [Cited by in F6Publishing: 1711] [Article Influence: 85.6] [Reference Citation Analysis (0)] |
| 2. | World Health Organization. Hepatitis B Fact Sheet No. 204, Revised September 2013. Available from: http://www.who.int/mediacentre/factsheets/fs204/en/. [Cited in This Article: ] |
| 3. | Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-662. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 2125] [Cited by in F6Publishing: 2120] [Article Influence: 141.3] [Reference Citation Analysis (0)] |
| 4. | European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167-185. [PubMed] [Cited in This Article: ] |
| 5. | Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, Safadi R, Lee SS, Halota W, Goodman Z. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010;52:886-893. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 721] [Cited by in F6Publishing: 738] [Article Influence: 52.7] [Reference Citation Analysis (0)] |
| 6. | Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, Washington MK, Germanidis G, Flaherty JF, Schall RA. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381:468-475. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1228] [Cited by in F6Publishing: 1286] [Article Influence: 116.9] [Reference Citation Analysis (0)] |
| 7. | Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001-1010. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1107] [Cited by in F6Publishing: 1032] [Article Influence: 57.3] [Reference Citation Analysis (0)] |
| 8. | Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011-1020. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 915] [Cited by in F6Publishing: 867] [Article Influence: 48.2] [Reference Citation Analysis (0)] |
| 9. | Gish RG, Lok AS, Chang TT, de Man RA, Gadano A, Sollano J, Han KH, Chao YC, Lee SD, Harris M. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology. 2007;133:1437-1444. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 274] [Cited by in F6Publishing: 256] [Article Influence: 15.1] [Reference Citation Analysis (0)] |
| 10. | Shouval D, Lai CL, Chang TT, Gadano A, Shun-Sheng W, Halota W, Sievert W. Three years of entecavir re-treatment of HBeAg (-) entecavir patients who previously discontinued entecavir therapy: results from study ETV-901. Hepatology. 2008;48 Suppl 1:Abstract 927. [Cited in This Article: ] |
| 11. | Chang TT, Lai CL, Kew Yoon S, Lee SS, Coelho HS, Carrilho FJ, Poordad F, Halota W, Horsmans Y, Tsai N. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2010;51:422-430. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 447] [Cited by in F6Publishing: 478] [Article Influence: 34.1] [Reference Citation Analysis (0)] |
| 12. | Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, Wichroski MJ, Xu D, Yang J, Wilber RB. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy. Hepatology. 2009;49:1503-1514. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 615] [Cited by in F6Publishing: 600] [Article Influence: 40.0] [Reference Citation Analysis (0)] |
| 13. | Manns MP, Akarca US, Chang TT, Sievert W, Yoon SK, Tsai N, Min A, Pangerl A, Beebe S, Yu M, Wongcharatrawee S. Long-term safety and tolerability of entecavir in patients with chronic hepatitis B in the rollover study ETV-901. Expert Opin Drug Saf. 2012;11:361-368. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 47] [Cited by in F6Publishing: 49] [Article Influence: 4.1] [Reference Citation Analysis (0)] |
| 14. | Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442-2455. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 890] [Cited by in F6Publishing: 863] [Article Influence: 53.9] [Reference Citation Analysis (0)] |
| 15. | Heathcote EJ, Marcellin P, Buti M, Gane E, De Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology. 2011;140:132-143. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 348] [Cited by in F6Publishing: 352] [Article Influence: 27.1] [Reference Citation Analysis (0)] |
| 16. | Heathcote EJ, Gane EJ, de Man RA, Chan S, George J, Tsai N, Marcellin P. Long-term (4 year) efficacy and safety of tenofovir disoproxil fumarate (TDF) treatment in HBeAg positive patients with chronic hepatitis B (study 103). Hepatology. 2010;52 Suppl 1:Abstract 477. [Cited in This Article: ] |
| 17. | Marcellin P, Buti M, Krastev Z, Gurel S, Di Bisceglie AM, Odin JA, Dusheiko GM. Continued efficacy and safety through 4 years of tenofovir disoproxil fumarate (TDF) treatment in HBeAg-negative patients with chronic hepatitis B (study 102). Hepatology. 2010;52 Suppl 1:Abstract 476. [Cited in This Article: ] |
| 18. | Gordon SC, Krastev Z, Horban A, Petersen J, Sperl J, Dinh P, Martins EB, Yee LJ, Flaherty JF, Kitrinos KM. Efficacy of tenofovir disoproxil fumarate at 240 weeks in patients with chronic hepatitis B with high baseline viral load. Hepatology. 2013;58:505-513. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 84] [Cited by in F6Publishing: 87] [Article Influence: 7.9] [Reference Citation Analysis (0)] |
| 19. | Snow-Lampart A, Kitrinos K, Chappell B, Myrick F, Schawalder J, Heathcote EJ, Marcellin . No resistance to tenofovir disoproxil fumarate (TDF) detected following up to 192 weeks of treatment in subjects monoinfected with chronic hepatitis B virus. Hepatology. 2010;52 Suppl 1:Abstract 1365. [Cited in This Article: ] |
| 20. | Marcellin P, Buti M, Gane E, Tsai N, Sievert W, Jacobson IM, Germanidis G. Six Years of Treatment With Tenofovir Disoproxil Fumarate for Chronic Hepatitis B Virus Infection Is Safe and Well Tolerated and Associated With Sustained Virological, Biochemical, and Serological Responses With No Detectable Resistance. Hepatology. 2012;56 Suppl 1:Abstract 374. [Cited in This Article: ] |
| 21. | Pol S, Lampertico P. First-line treatment of chronic hepatitis B with entecavir or tenofovir in ‘real-life’ settings: from clinical trials to clinical practice. J Viral Hepat. 2012;19:377-386. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 94] [Cited by in F6Publishing: 90] [Article Influence: 7.5] [Reference Citation Analysis (0)] |
| 22. | Buti M, Morillas RM, Prieto M, Diago M, Pérez J, Solà R, Bonet L, Palau A, Testillano M, García-Samaniego J. Efficacy and safety of entecavir in clinical practice in treatment-naive Caucasian chronic hepatitis B patients. Eur J Gastroenterol Hepatol. 2012;24:535-542. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 23] [Cited by in F6Publishing: 19] [Article Influence: 1.6] [Reference Citation Analysis (0)] |
| 23. | Zoutendijk R, Reijnders JG, Brown A, Zoulim F, Mutimer D, Deterding K, Petersen J, Hofmann WP, Buti M, Santantonio T. Entecavir treatment for chronic hepatitis B: adaptation is not needed for the majority of naïve patients with a partial virological response. Hepatology. 2011;54:443-451. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 134] [Cited by in F6Publishing: 140] [Article Influence: 10.8] [Reference Citation Analysis (0)] |
| 24. | Carey I, Nguyen HL, Joe D, Al-Freah MA, Knighton S, Suddle A, Harrison PM. De-novo antiviral therapy with nucleos(t)ide analogues in “real-life” patients with chronic hepatitis B infection: comparison of virological responses between lamivudine adefovir, entecavir vs. tenofovir therapy. Hepatology. 2011;54 Suppl 1:Abstract 1396. [Cited in This Article: ] |
| 25. | Lampertico P, Soffredini R, Vigano M, Minola E, Cologni G, Rizzi M, Zaltron S. 5-year entecavir treatment in NUC-naive, field-practice patients with chronic hepatitis B showed excellent viral suppression and safety profile but no prevention of HCC in cirrhotics. J Hepatol. 2013;58 Suppl 1:Abstract 755. [Cited in This Article: ] |
| 26. | Marengo A, Bitetto D, D’Avolio A, Ciancio A, Fabris C, Marietti M, Toniutto P, Di Perri G, Rizzetto M, Marzano A. Clinical and virological response to entecavir in HBV-related chronic hepatitis or cirrhosis: data from the clinical practice in a single-centre cohort. Antivir Ther. 2013;18:87-94. [PubMed] [Cited in This Article: ] |
| 27. | Giuberti T, Fasano M, Brancaccio G, Santantonio T, Grasso T, Marzano A, Bronte F. Entecavir effectiveness in daily clinical practice, interim analysis of the Italian Master-Entas cohort study of patients with chronic hepatitis B. J Hepatol. 2013;58 Suppl 1:Abstract 764. [Cited in This Article: ] |
| 28. | Ridruejo E, Adrover R, Cocozzella D, Reggiardo MV, Estepo C, Schroder T, Paz S, Mendizábal M, Fainboim H, Mandó OG. Effectiveness of entecavir in chronic hepatitis B NUC-naive patients in routine clinical practice. Int J Clin Pract. 2011;65:866-870. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 18] [Cited by in F6Publishing: 18] [Article Influence: 1.4] [Reference Citation Analysis (0)] |
| 29. | Ridruejo E, Marciano S, Galdame O, Reggiardo MV, Muñoz AE, Adrover R, Cocozzella D. Efficacy and safety of long term entecavir in Chronic Hepatitis B NUC naïve patients in clinical practice. Hepatology. 2013;58 Suppl 1:Abstract 901. [Cited in This Article: ] |
| 30. | Ridruejo E, Marciano S, Galdame O, Reggiardo MV, Mu AE, Adrover R, Cocozzella D. Relapse rates in chronic hepatitis B patients after discontinuation of anti-viral therapy with entecavir. J Viral Hepat. 2013;In press. [DOI] [Cited in This Article: ] [Cited by in Crossref: 21] [Cited by in F6Publishing: 15] [Article Influence: 1.5] [Reference Citation Analysis (0)] |
| 31. | Yuen MF, Seto WK, Fung J, Wong DK, Yuen JC, Lai CL. Three years of continuous entecavir therapy in treatment-naïve chronic hepatitis B patients: VIRAL suppression, viral resistance, and clinical safety. Am J Gastroenterol. 2011;106:1264-1271. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 118] [Cited by in F6Publishing: 120] [Article Influence: 9.2] [Reference Citation Analysis (0)] |
| 32. | Seto WK, Lai CL, Fung J, Yuen JC, Wong DK, Yuen MF. Outcome of 4-year treatment of entecavir for treatment-na? chronic hepatitis B. J Hepatol. 2011;54 Suppl 1:Abstract 748. [Cited in This Article: ] |
| 33. | Ono A, Suzuki F, Kawamura Y, Sezaki H, Hosaka T, Akuta N, Kobayashi M, Suzuki Y, Saitou S, Arase Y. Long-term continuous entecavir therapy in nucleos(t)ide-naïve chronic hepatitis B patients. J Hepatol. 2012;57:508-514. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 121] [Cited by in F6Publishing: 126] [Article Influence: 10.5] [Reference Citation Analysis (0)] |
| 34. | Luo J, Li X, Wu Y, Lin G, Pang Y, Zhang X, Ao Y, Du Z, Zhao Z, Chong Y. Efficacy of entecavir treatment for up to 5 years in nucleos(t)ide-naïve chronic hepatitis B patients in real life. Int J Med Sci. 2013;10:427-433. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 45] [Cited by in F6Publishing: 46] [Article Influence: 4.2] [Reference Citation Analysis (0)] |
| 35. | Hou JL, Jia JD, Wei L, Ren H, Xie JD, Gao L, Zhao H. Randomized, observational study of long-term entecavir treatment versus other standard of care nucleos(t)ide analog therapy in nucleos(t)ide-na? patients with chronic hepatitis B from a ‘real-world’ clinical practice setting in China. Hepatology. 2012;56 Suppl 1:Abstract 392. [Cited in This Article: ] |
| 36. | Tsai MC, Lee CM, Chiu KW, Hung CH, Tung WC, Chen CH, Tseng PL, Chang KC, Wang JH, Lu SN. A comparison of telbivudine and entecavir for chronic hepatitis B in real-world clinical practice. J Antimicrob Chemother. 2012;67:696-699. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 24] [Cited by in F6Publishing: 26] [Article Influence: 2.0] [Reference Citation Analysis (0)] |
| 37. | Wang CC, Tseng KC, Peng CY, Hsieh TY, Lin CL, Su TH, Tseng TC, Hsu CS, Lin HH, Kao JH. Viral load and alanine aminotransferase correlate with serologic response in chronic hepatitis B patients treated with entecavir. J Gastroenterol Hepatol. 2013;28:46-50. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 21] [Cited by in F6Publishing: 18] [Article Influence: 1.6] [Reference Citation Analysis (0)] |
| 38. | Lin B, Ha NB, Liu A, Trinh HN, Nguyen HA, Nguyen KK, Ahmed A, Keeffe EB, Garcia RT, Garcia G. Low incidence of hepatitis B e antigen seroconversion in patients treated with oral nucleos(t)ides in routine practice. J Gastroenterol Hepatol. 2013;28:855-860. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 21] [Cited by in F6Publishing: 19] [Article Influence: 1.7] [Reference Citation Analysis (0)] |
| 39. | Liu A, Ha NB, Lin B, Yip B, Trinh HN, Nguyen HA, Nguyen KK, Ahmed A, Garcia G, Nguyen MH. Low hepatitis B envelope antigen seroconversion rate in chronic hepatitis B patients on long-term entecavir 0.5 mg daily in routine clinical practice. Eur J Gastroenterol Hepatol. 2013;25:338-343. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 15] [Cited by in F6Publishing: 15] [Article Influence: 1.4] [Reference Citation Analysis (0)] |
| 40. | Fahrtash-Bahin F, Kariyawasam VC, Gray T, Byth K, George J, Douglas MW. Australian tertiary care outcomes of entecavir monotherapy in treatment naive patients with chronic hepatitis B. World J Gastroenterol. 2013;19:721-726. [PubMed] [DOI] [Cited in This Article: ] [Cited by in CrossRef: 2] [Cited by in F6Publishing: 2] [Article Influence: 0.2] [Reference Citation Analysis (0)] |
| 41. | Ratnam D, Angus P. Global Perspectives: Australia – Real World Experience with HBV Antiviral Therapy. Curr Hepatitis Rep. 2012;11:213-220. [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 1] [Reference Citation Analysis (0)] |
| 42. | Lampertico P, Soffredini R, Facchetti F, Invernizzi F, Colombo M, Vigan M, Yurdaydin C. Tenofovir monotherapy suppressed viral suppression in most field practice, treatment-na? patients with chronic hepatitis B followed for 3 years in a multicenter European study. Hepatology. 2012;56 Suppl 1:Abstract 401. [Cited in This Article: ] |
| 43. | Petersen J, Heyne R, Mauss S, Schlaak J, Schiffelholz W, Eisenbach C, Hartmann H. Effectiveness of tenofovir for chronic hepatitis B in field practice–2 year interim results from the prospective German multicenter non-interventional study (GEMINIS). J Hepatol. 2013;58 Suppl 1:Abstract 768. [Cited in This Article: ] |
| 44. | Ridruejo E, Silva MO. Safety of long-term nucleos(t)ide treatment in chronic hepatitis B. Expert Opin Drug Saf. 2012;11:357-360. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 22] [Cited by in F6Publishing: 26] [Article Influence: 2.2] [Reference Citation Analysis (0)] |
| 45. | Lange CM, Bojunga J, Hofmann WP, Wunder K, Mihm U, Zeuzem S, Sarrazin C. Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology. 2009;50:2001-2006. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 207] [Cited by in F6Publishing: 187] [Article Influence: 12.5] [Reference Citation Analysis (0)] |
| 46. | Miquel M, Núñez Ó, Trapero-Marugán M, Díaz-Sánchez A, Jiménez M, Arenas J, Canós AP. Efficacy and safety of entecavir and/or tenofovir in hepatitis B compensated and decompensated cirrhotic patients in clinical practice. Ann Hepatol. 2013;12:205-212. [PubMed] [Cited in This Article: ] |
| 47. | Liaw YF, Raptopoulou-Gigi M, Cheinquer H, Sarin SK, Tanwandee T, Leung N, Peng CY, Myers RP, Brown RS, Jeffers L. Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: a randomized, open-label study. Hepatology. 2011;54:91-100. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 155] [Cited by in F6Publishing: 147] [Article Influence: 11.3] [Reference Citation Analysis (0)] |
| 48. | Gill U, Al-Shamma S, Burke KB, Ross V, Marley R, Kooner P, Foster GR, Kennedy PT. Bone mineral density loss in tenofovir treated chronic hepatitis B virus (HBV) patients is a consequence of vitamin D deficiency and not tenofovir therapy. Hepatology. 2011;54 Suppl 1:Abstract 1376. [Cited in This Article: ] |
| 49. | Hezode C, Causse X, Larrey D, Ouzan D, Pageaux GP, Truchi R, Pauwels A, Guyader D, De L▽edinghen V, Zoulim F, Zarski JP, Cadranel JF, Tilliet V, Libert1 O, Stern C, Marcellin P, Vireal Group. Virological response and tolerance of tenofovir DF (TDF) in the elderly is similar to younger patients in real life practice. J Hepatol. 2013;58 Suppl 1:Abstract 748. [Cited in This Article: ] |
| 50. | Fung S, Kwan P, Horban A, Pelemis M, Husa P, Hann HW, Flaherty J, Massetto B, Dinh P, Custodio J. Tenofovir DF (TDF) is safe and well tolerated in chronic hepatitis B (CHB) patients with pre-existing mild renal impairment. J Hepatol. 2013;58 Suppl 1:Abstract 744. [Cited in This Article: ] |
| 51. | Lok AS. Drug therapy: tenofovir. Hepatology. 2010;52:743-747. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 12] [Cited by in F6Publishing: 13] [Article Influence: 0.9] [Reference Citation Analysis (0)] |
| 52. | Liaw YF, Sheen IS, Lee CM, Akarca US, Papatheodoridis GV, Suet-Hing Wong F, Chang TT, Horban A, Wang C, Kwan P, Buti M, Prieto M, Berg T, Kitrinos K, Peschell K, Mondou E, Frederick D, Rousseau F, Schiff ER. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology. 2011;53:62-72. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 235] [Cited by in F6Publishing: 252] [Article Influence: 19.4] [Reference Citation Analysis (0)] |
| 53. | Kim BK, Revill PA, Ahn SH. HBV genotypes: relevance to natural history, pathogenesis and treatment of chronic hepatitis B. Antivir Ther. 2011;16:1169-1186. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 119] [Cited by in F6Publishing: 115] [Article Influence: 9.6] [Reference Citation Analysis (0)] |
| 54. | Lee JM, Ahn SH, Kim HS, Park H, Chang HY, Kim do Y, Hwang SG, Rim KS, Chon CY, Han KH. Quantitative hepatitis B surface antigen and hepatitis B e antigen titers in prediction of treatment response to entecavir. Hepatology. 2011;53:1486-1493. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 107] [Cited by in F6Publishing: 112] [Article Influence: 8.6] [Reference Citation Analysis (0)] |
| 55. | Shin JW, Jung SW, Park BR, Kim CJ, Eum JB, Kim BG, Jeong ID, Bang SJ, Lee SH, Kim SR. Prediction of response to entecavir therapy in patients with HBeAg-positive chronic hepatitis B based on on-treatment HBsAg, HBeAg and HBV DNA levels. J Viral Hepat. 2012;19:724-731. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 22] [Cited by in F6Publishing: 21] [Article Influence: 1.8] [Reference Citation Analysis (0)] |
| 56. | Marcellin P, Heathcote EJ, Buti M, Krastev Z, Jacobson I, de Man RA, Dusheiko G, Zeuzem S, Barnes C, Ng C. HBsAg kinetics in patients with chronic hepatitis B (CHB) treated with tenofovir disoproxil fumarate (TDF) for up to 4 years. J Hepatol. 2011;54 Suppl 1:Abstract 740. [Cited in This Article: ] |
| 57. | Scaglione SJ, Lok AS. Effectiveness of hepatitis B treatment in clinical practice. Gastroenterology. 2012;142:1360-1368.e1. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 102] [Cited by in F6Publishing: 112] [Article Influence: 9.3] [Reference Citation Analysis (0)] |
| 58. | Chotiyaputta W, Hongthanakorn C, Oberhelman K, Fontana RJ, Licari T, Lok AS. Adherence to nucleos(t)ide analogues for chronic hepatitis B in clinical practice and correlation with virological breakthroughs. J Viral Hepat. 2012;19:205-212. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 43] [Cited by in F6Publishing: 50] [Article Influence: 4.2] [Reference Citation Analysis (0)] |