Chronic hepatitis B virus (HBV) infection is a serious clinical problem worldwide because of the potentially adverse sequelae, such as hepatic decompensation and the development of cirrhosis or hepatocellular carcinoma (HCC) . Studies have shown that active HBV replication is the key driving force of the HBV-related immune clearance events that determine clinical outcome [1, 2]. Thus, the primary aim of therapy is to eliminate or permanently suppress HBV, to reduce the activity of hepatitis and slow or limit the progression of liver disease. The ultimate long-term goal is to achieve a sustained viral response (SVR), to clear the HBsAg thus preventing or reducing the development of hepatic decompensation, cirrhosis or HCC and prolonging survival . At present, conventional interferon α (IFN), pegylated interferon (PEG- IFN), lamivudine (LAM), adefovir dipivoxil (ADV), entecavir (ETV), telbivudine (LdT) and tenofovir disoproxil fumarate (TDF) have been approved for the treatment of chronic HBV infection and have made it possible to achieve the goals of therapy . Evidence has shown that anti-HBV therapy can improve both the short-term and long-term outcome of chronic HBV infection.
Chronic hepatitis B virus (HBV) infection is a dynamic state in which HBV replication is the key driving force of disease progression, resulting in the development of hepatic decompensation, cirrhosis and hepatocellular carcinoma (HCC). The primary aim of therapy is to eliminate or suppress HBV to reduce the activity of hepatitis thus reducing the risk of or slowing the progression of liver disease. Treatment with nucleos(t)ide analogues (Nuc) may result in rapid suppression of HBV replication with normalization of serum transaminases and restore liver function thus increasing survival in patients with hepatic decompensation. The long-term benefits of a finite course of interferon α (IFN) therapy include a sustained and cumulative response, as well as a reduction in the progression of fibrosis and in the development of cirrhosis and/or HCC. Long-term Nuc therapy may also result in histological improvement or reversal of advanced fibrosis and reduction in disease progression including the development of HCC. Hepatitis B surface antigen (HBsAg) seroclearance, a status close to a “cure”, may also occur in patients with a sustained or maintained viral response, especially in those with IFN-based therapy. Pegylated IFN (PEG-IFN) and newer Nucs may have even better long-term outcomes because of improved efficacy and/or a low risk of drug resistance. However, treatment outcomes are still far from satisfactory. The development of more effective and safe but affordable anti-HBV agents/strategies is needed to further improve outcomes.
hepatitis B virus
sustained viral response
tenofovir disoproxil fumarate
Short-term impact of antiviral therapy
Short-term studies have shown that IFN-based therapy is modestly effective in inducing HBeAg loss or seroconversion (30–40%) in HBeAg-positive patients [5, 6] and sustained HBV DNA suppression (<20 000 copies/ml) in up to 40% of HBeAg-negative patients [7-10]. Therapy with direct antiviral nucleos(t)ide analogues (Nuc) may result in rapid and profound suppression of HBV replication in both HBeAg-positive and negative patients. Although the serological response is lower than that of IFN-based therapy, the virological response to Nuc may reach > 90% in 1–2 years. Effective therapy is associated with alanine aminotransferase (ALT) normalization and contributes to significant improvement in liver disease, including the regression of fibrosis [6, 10-15].
Rescue hepatic decompensation
Hepatic decompensation is a serious clinical complication in hepatitis B patients with severe hepatitis flares or cirrhosis. Before antiviral therapy, hepatic decompensation was associated with a high mortality and could require emergency liver transplantation. Interferon-based therapy is contraindicated in patients with hepatic decompensation, whereas currently available Nucs are well-tolerated and can restore liver function and survival, especially if the drug is begun early enough . As such, certain waiting list patients who are receiving antiviral therapy may be withdrawn from the transplantation list. Since Nuc was first used in this population, the number of candidates on the liver transplantation waiting list for HBV-related decompensated liver disease has decreased significantly in the United States .
Long-term impact of antiviral therapy
Long-term follow-up studies after a 4- to 6-month course of conventional IFN therapy in HBeAg-positive patients showed a reduction in the progression of fibrosis, especially in patients with sustained HBeAg seroconversion. A large study comparing 233 IFN-treated HBeAg-positive patients with 233 well-matched (age, gender, ALT, HBeAg status, histology and length of follow-up) untreated patients showed a reduced cumulative incidence of cirrhosis (17.8% vs 33.7% in the controls; P = 0.041) after a median follow-up of 6.8 (1.1-15.5) years . Studies have also shown that sustained elimination of HBeAg is associated with a significant increase in survival and a reduction in severe cirrhotic complications and the need for liver transplantation [5, 19]. An earlier randomized control study showed that IFN therapy reduced the incidence of HCC in patients with HBeAg-positive active chronic hepatitis , which was confirmed in the previously mentioned recent matched-control study (2.7% vs 12.5% in the controls; P = 0.011) .
HBeAg-negative European patients treated with IFN for 6-24 months who achieved a sustained response also showed a decrease in the progression of the Ishak fibrosis score or a decreased risk of cirrhosis. The long-term outcome was also significantly improved in sustained responders with fewer severe cirrhosis-related complications, a reduced incidence of HCC (1.8% vs 10.5% in relapsers; P = 0.027 and 7.7% in untreated; P = 0.048), less need for liver transplantation and lower mortality, although the sustained response rate in HBeAg-negative patients was usually < 30% [7, 8, 20]. HBsAg clearance occurred more frequently in IFN-treated patients with a sustained response [6-9] and was associated with a lower rate of hepatic decompensation, HCC and with longer survival .
Interferon-based therapy has been shown to be safe and even more effective in patients with compensated cirrhosis than in patients without cirrhosis [21, 22]. This suggests that HCC may be reduced in IFN-treated patients with cirrhosis after a longer follow-up. A subgroup analysis in a long-term follow-up study showed that the incidence of HCC was significantly reduced in patients with cirrhosis treated with IFN . A meta-analysis including 12 trials (1292 IFN-treated and 1450 untreated patients) showed a significant reduction in the risk of HCC (34% reduction [risk ratio (RR): 0.66, 95% confidence interval (CI): 0.48–0.89; P = 0.006] after treatment with IFN and even more (47% reduction; RR 0.53, 95% CI: 0.36–0.78; P = 0.001) in patients with cirrhosis . Another meta-analysis including 11 trials showed that IFN therapy reduced cirrhosis and HCC . The pooled estimation in another meta-analysis of two randomized control trials and five non-RCT trials (553 IFN-treated vs 750 no treatment) showed that IFN therapy significantly prevented the development of HCC especially in HBeAg-positive patients, Asian patients or in populations with a high incidence of HCC .
Direct antiviral therapy
Impact on liver fibrosis
Long-term (>3 years) LAM or ADV therapy resulted in the improvement of fibrosis or the reversal of advanced fibrosis [11, 12, 26]. There was a significantly lower cumulative rate of cirrhosis and/or development of HCC (P = 0.005) with long-term LAM therapy (median 89.9 months; range 26.5–128.3 months) in 142 HBeAg-positive, non-cirrhotic patients from Hong Kong compared to 124 HBeAg-positive untreated controls . Long-term therapy with ETV or TDF results in maintained undetectable serum HBV DNA in >90% of the patients and a very low incidence of drug resistance [28, 29]. Fibrosis improved (≥1 point of Ishak fibrosis score) in 57% and 88% of patients treated with ETV for 3 and 6 years respectively [30, 31]. A significant regression of fibrosis or cirrhosis was also observed in 44 and 76%, respectively, of patients treated with TDF for 5 years  [Table 1].
|Nucleos(t)ide||No.||HBeAg||Duration (years)||Regression of fibrosis||Reference|
|Entecavir||21||+ or −||3||57%|||
|Entecavir||57||+ or –||6b||88%|||
|Tenofovir||348 (96a)||+ or −||5||51% (74%a)|||
Impact on liver disease progression
A double-blind, randomized-controlled trial showed that maintenance LAM therapy for a median of 32.4 months in 436 patients with advanced fibrosis or cirrhosis (Ishak fibrosis score ≥4) significantly reduced overall disease progression (17.7% vs 7.8%; P = 0.001), compared to 215 untreated controls . The recent VIRGIL study also showed that a virological response (serum HBV-DNA < 80 IU/ml) to ETV after a median of 20 (11–32) months was associated with a 71% reduction in the probability of developing decompensation, HCC or death . Of note, long-term therapy with NUC which has a low genetic barrier to resistance such as LAM was associated with a high rate of drug-resistant mutations. Patients with drug resistance were more likely to experience disease progression and die from causes related to the worsening of liver function, especially patients with advanced fibrosis or cirrhosis [32, 34].
Impact on the development of HCC
In the above mentioned randomized control trial, the incidence of HCC was also significantly reduced in patients with advanced fibrosis or cirrhosis treated with LAM (3.9%, vs 7.4% in the placebo group, P = 0.047) . A study of 377 Japanese patients (51% HBeAg-negative, 17% with cirrhosis) treated with LAM for up to 96 (23.1 ± 19.0) months also showed a marked reduction in the incidence of HCC compared with a historical control group matched for age, sex, liver fibrosis score, albumin level and platelet count (0.4% vs 2.5% per year; P < 0.001) . A retrospective multicentre study including 656 HBeAg-negative patients (353 with chronic hepatitis, 303 with cirrhosis) treated with LAM for 1–66 months (median, 22 months) showed that HBV suppression reduced the development of HCC even in patients with cirrhosis, but that the chance of developing HCC was significantly higher in patients with a virological breakthrough than in those with maintained viral suppression . An earlier meta-analysis including 1267 LAM treated and 1022 untreated patients showed that HCC was reduced by 78% (RR: 0.22, 95% CI: 0.10–0.50; P = 0.0003) during maintained LAM therapy with more benefit in patients with cirrhosis and HBeAg-positive patients . In the most recent review of 21 studies (starting with LAM in 19 studies) including 3881 Nuc treated and 534 untreated patients, HCC developed less frequently in Nuc treated patients (2.8% vs 6.4%; P < 0.003) . A Korean study showed a reduced incidence of HCC in patients with compensated cirrhosis who achieved a SVR with LAM compared to untreated patients or patients treated with LAM who had a viral breakthrough or a suboptimal response. This beneficial effect was not observed in patients with chronic hepatitis B without cirrhosis or in those with decompensated cirrhosis . However, a European study on long-term (median 4.7 years) Nuc therapy starting with LAM showed that maintained viral suppression in HBeAg-negative patients with cirrhosis did not significantly reduce the incidence of HCC, compared with patients who failed to achieve a virological remission during initial LAM mono-therapy . In contrast, only one of 144 patients treated with ETV for up to 5 years developed HCC at week 51 of treatment , and only three of 372 patients (47% HBeAg positive, 98 with cirrhosis) treated with ETV developed HCC in the VIRGIL study, suggesting that the incidence of HCC is significantly reduced in patients with a SVR, even those with cirrhosis . Longer HBV suppression may be necessary to clearly show the beneficial effect of Nuc therapy on the development of HCC in patients with cirrhosis.
Overall long-term impact
These results confirm that suppression of HBV reduces the risk of or slows the progression of liver disease, and that the disease may again progress if HBV replication recurs. It is important to start therapy with a Nuc with a high genetic barrier to resistance such as ETV or TDF as first-line therapy [3, 39, 40].
HBsAg seroclearance as an ideal outcome
HBsAg seroclearance is the closest that can be achieved to a ‘cure’ of chronic HBV infection  and, therefore, the ideal outcome of antiviral therapy. Long-term follow-up studies have shown that IFN-based therapy increases HBsAg seroclearance over time. A 3-year (mean) follow-up study in 172 HBeAg-positive patients treated with PEG-IFNα 2b showed that HBsAg seroclearance was achieved in 11 and 30% of overall patients and initial responders respectively . The HBsAg seroclearance rate in 230 HBeAg-negative patients increased from 5% at 1-year to 12% (or 35% in initial responders) 5-years after treatment with PEG-IFN α 2a . However, the HBsAg seroclearance rate was much lower in Asian patients . HBsAg seroclearance is less common (2–3% in 3 years) in patients treated with Nuc than with IFN-based therapy, and is the highest (8% after 3 years) in HBeAg-positive patients treated with TDF, all in non-Asians infected by genotype A, D and F HBV .
Summary and perspectives
Overall long-term data show that IFN-based therapy in HBeAg-positive patients results in cumulative HBeAg seroconversion, an increase in HBsAg seroclearance and a reduction in fibrosis/cirrhosis and/or the development of HCC, especially in patients with a SVR. In HBeAg-negative patients, those with a SVR and those who lose HBsAg have better outcomes. As PEG-IFN is more effective than conventional IFN in the treatment of chronic hepatitis B and may result in a sustained and delayed response, long-term follow-up studies will probably show that PEG-IFN has similar or even better effects.
Studies have also shown that timely use of Nuc may improve liver function and increase survival in patients with hepatic decompensation. Maintained suppression of HBV replication with Nuc therapy may limit the worsening of liver fibrosis, reverse advanced fibrosis, reduce the development of cirrhosis and prevent further disease progression including HCC in patients with advanced fibrosis or cirrhosis. Because of the high rate of maintained HBV suppression, long-term studies will probably confirm that ETV or TDF is better in reducing disease progression than LAM therapy.
However, current therapies only reduce the risk of or slow disease progression, they do not prevent all adverse sequellae. HCC must be monitored using ultrasound and α-Foetoprotein assays to improve outcomes by increasing early detection and the chance of curative treatment . Developing safe and affordable agents as well as management strategies to improve sustained or maintained HBV suppression should be the ultimate goal in the management of chronic HBV infection.
The author thanks the long-term grant support provided by Chang Gung Medical Research Fund (SMRPG1005, BMRPG380061) and the Prosperous Foundation, Taipei, Taiwan; and the excellent assistance of Ms Su-Chiung Chu.