Current and future antiviral agents for chronic hepatitis B

Man-Fung Yuen and Ching-Lung Lai*

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China

Keywords: antivirals, hepatitis, HBV

Effective antiviral therapy for chronic hepatitis B virus (HBV) infection is important since ~400 million people are affected globally. Loss of hepatitis B e antigen (HBeAg) with or without seroconversion to antibody against HBeAg (anti-HBe), normalization of alanine aminotransferase (ALT) and improvement in liver histology are the usual short-term endpoints of therapy.1 To determine whether the ultimate treatment target, i.e. prevention of cirrhosis-related complications and hepatocellular carcinoma (HCC), is achieved requires more long-term follow-up of treated patients.1

The two established agents for the treatment of chronic hepatitis B are interferon (IFN)-{alpha} and lamivudine. Adefovir dipivoxil has also been licensed recently in the USA and in Europe. Their main modes of action are immunomodulation and direct suppression of viral replication. IFN-{alpha} induces HBeAg seroconversion in ~20–30% of patients. The proportion achieving HBeAg seroconversion is lower in Asian patients, who mostly acquire the infection at birth or early in life and consequently have a long period of immunotolerance. More importantly, IFN-{alpha} treatment in Asian patients does not prevent the occurrence of cirrhosis-related complications and HCC.2 The substantial side effects during treatment and the possibility of causing hepatic decompensation in patients with pre-existing cirrhosis also limit the use of IFN-{alpha}.

The rest of the review will concentrate on lamivudine and other more novel nucleoside analogues. The structures of various nucleoside analogues are illustrated in Figure 1.



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Figure 1. Biochemical structures of nucleoside analogues mentioned in this review.

 

    Lamivudine
 Top
 Lamivudine
 Adefovir dipivoxil
 Tenofovir
 Entecavir
 ß-l-2'-Deoxythymidine...
 Emtricitabine
 1-ß-2,6-Diaminopurine...
 2'-Fluoro-5-methyl-ß-l...
 Famciclovir
 Combination therapy
 References
 
Lamivudine, the (–) enantiomer of the deoxycytidine analogue 2'-deoxy-3'-thiacytidine, exerts its antiviral effect mainly by inhibiting reverse transcription during the replication cycle of HBV. Another postulated site of action is the inhibition of the completion of the double-stranded DNA. The formation of covalently closed circular (ccc) DNA (the template for HBV replication) may therefore be reduced. The efficacy of lamivudine is the same for both Asian and Caucasian patients, since the mode of action is through viral suppression rather than through immunomodulatory effect. Phase 3 randomized placebo-controlled studies in Asian and Caucasian patients show that the rate of HBeAg seroconversion after 1 year of treatment is 16–32%.3,4 Normalization of ALT occurs in 41–72% of patients. More importantly, lamivudine can reduce the severity of necroinflammation and decrease the rate of progression of fibrosis. In one study, lamivudine has been shown to halt or reverse the process of cirrhosis.5 In patients who have been treated with lamivudine for 5 years, the HBeAg seroconversion rate increases to 50% [77% for patients with baseline ALT level greater than twice the upper limit of normal (ULN)]. According to a study in Korea,6 relapse after HBeAg seroconversion is common when lamivudine is stopped (37.5% for the first year, 49.2% for the second year). However, the high relapse rate is likely to be related to the early cessation of lamivudine treatment after HBeAg seroconversion (within 2–4 months). Therefore, it is now recommended that lamivudine should be continued for 6–9 months after HBeAg seroconversion. The drug is remarkably free of side effects. In addition, lamivudine treatment is safe even in patients with decompensated cirrhosis.

Lamivudine has also been shown to have beneficial effects on two subgroups of patients with chronic hepatitis B. In HBeAg-negative patients, complete biochemical and virological responses can be achieved in two-thirds of the patients after a treatment period of 12–26 months.7,8 There is also improvement in the necroinflammatory activities in the liver in these patients; however, relapse rates are high after cessation of lamivudine treatment. The second subgroup of patients are patients with decompensated liver disease. In these patients, lamivudine is effective in inducing HBV DNA suppression, biochemical remission, HBeAg seroconversion and improvement in liver performance status as reflected by the Child–Pugh score.911 Importantly, lamivudine therapy is associated with a better survival for decompensated patients.11

The major drawback of lamivudine treatment is the development of drug-resistant HBV after 6–9 months of therapy. Resistance is due to the mutation of the catalytic domain of the HBV polymerase gene [reverse transcriptase (rt) position 204] with the methionine of the YMDD (tyrosine–methionine–aspartate–aspartate) motif being substituted by either isoleucine (YIDD or rtM204I) or valine (YVDD or rtM204V). There may be a concomitant mutation at the B domain of the HBV polymerase gene at rt180, with the leucine being substituted by methionine (rtL180M). Using a PCR assay that detects down to 500 copies/mL of the lamivudine-resistant HBV, the incidences of resistance are: 15–32%, 38%, 56% and 67% at the end of the first, second, third and fourth year of treatment, respectively. HBV DNA breakthrough with lamivudine-resistant HBV is more commonly seen in patients with higher pre-treatment ALT and HBV DNA levels.12 Patients with HBV DNA levels of >1000 copies/mL at the sixth month of treatment have a >60% chance of developing lamivudine-resistant HBV within 29 months of follow-up.12 Laboratory studies have shown that the lamivudine-resistant HBV has less replication competence compared with the wild-type.13,14 Clinically, the median HBV DNA and ALT levels after the emergence of lamivudine-resistant HBV are lower than the levels at baseline. Furthermore, there is continued improvement of the necroinflammation and bridging fibrosis in patients with lamivudine-resistant HBV. HBeAg seroconversion at the end of 5 years of treatment can occur in up to 48% of patients with lamivudine-resistant HBV with baseline ALT levels >2 x ULN. However, hepatitis flares due to the emergence of lamivudine-resistant HBV may occur. These hepatitis flares may be associated with HBeAg seroconversion, and may also be severe. According to one study, such flares may even be more dangerous in HBeAg-negative patients.15


    Adefovir dipivoxil
 Top
 Lamivudine
 Adefovir dipivoxil
 Tenofovir
 Entecavir
 ß-l-2'-Deoxythymidine...
 Emtricitabine
 1-ß-2,6-Diaminopurine...
 2'-Fluoro-5-methyl-ß-l...
 Famciclovir
 Combination therapy
 References
 
Adefovir is an acyclic analogue of deoxyadenosine monophosphate (dAMP), which has just been approved by the Food and Drug Administration (FDA) for use in chronic hepatitis B. Adefovir has been shown to inhibit the amplification of cccDNA although the de novo formation of cccDNA cannot be prevented in duck HBV-infected hepatocytes.

In Phase I/II studies, treatment with adefovir results in significant reduction of HBV DNA within 1–2 weeks. In a Phase III placebo-controlled trial, adefovir 10 mg daily given for 48 weeks in 171 patients was associated with significantly better histological improvement, a higher rate of HBeAg seroconversion, a three logarithmic reduction of HBV DNA levels and a higher chance of normalization of ALT levels when compared with 167 patients receiving placebo.16 Importantly, adefovir is also active against lamivudine-resistant YMDD mutants.

There were no adefovir-resistant mutations observed up to 135 weeks of treatment. The lack of resistance to adefovir may be related to the close resemblance of adefovir to its natural substrate and/or the flexible acyclic structure of the adefovir molecule allowing multiple binding modes. Both these conditions may subvert the steric hindrance between the mutant amino acid side chain and agents like lamivudine that account for drug resistance.17

Severe renal toxicity has been observed in patients receiving higher doses (60–120 mg daily) of adefovir in trials for patients infected with human immunodeficiency virus (HIV). The renal toxicity is mediated through the human renal organic anion transporter 1 (hOAT1) and may result in proximal renal tubular dysfunction. To date, no clinical renal toxicity has been observed with the 10 mg daily dose.


    Tenofovir
 Top
 Lamivudine
 Adefovir dipivoxil
 Tenofovir
 Entecavir
 ß-l-2'-Deoxythymidine...
 Emtricitabine
 1-ß-2,6-Diaminopurine...
 2'-Fluoro-5-methyl-ß-l...
 Famciclovir
 Combination therapy
 References
 
Tenofovir disoproxil fumarate, another acyclic nucleoside analogue similar to adefovir, has been approved for the treatment of HIV. In vitro studies show that this drug is also effective in suppressing replication of lamivudine-resistant HBV.18 In HIV patients co-infected with lamivudine-resistant HBV, it causes HBV DNA reduction by 4.5 log.19 However, to date, no studies have been reported in patients with HBV infection alone.


    Entecavir
 Top
 Lamivudine
 Adefovir dipivoxil
 Tenofovir
 Entecavir
 ß-l-2'-Deoxythymidine...
 Emtricitabine
 1-ß-2,6-Diaminopurine...
 2'-Fluoro-5-methyl-ß-l...
 Famciclovir
 Combination therapy
 References
 
Entecavir is a carbocyclic deoxyguanosine analogue. It is highly effective in inhibiting the priming of the HBV polymerase by guanosine triphosphate during the initiation of HBV replication. Entecavir has been shown to reduce the viral antigens and cccDNA levels in liver samples of HBV-infected woodchucks. No entecavir-resistant mutants have been detected in animal studies even after 3 years of entecavir administration.20

A Phase II trial involving 180 patients with chronic hepatitis B shows a dose-proportional antiviral response, with a 0.5 mg daily dose of entecavir being superior to 0.01 and 0.1 mg doses. In addition, 6 months of 0.1 and 0.5 mg entecavir are both significantly more potent than 100 mg lamivudine (>4 log reduction of HBV DNA levels with either dose of entecavir versus 3 log reduction with lamivudine).21 Phase III trials of 0.5 mg entecavir versus lamivudine are being conducted.

Entecavir is also effective against lamivudine-resistant HBV although a higher dose of 1 mg daily may be required.


    ß-L-2'-Deoxythymidine (telbivudine)
 Top
 Lamivudine
 Adefovir dipivoxil
 Tenofovir
 Entecavir
 ß-l-2'-Deoxythymidine...
 Emtricitabine
 1-ß-2,6-Diaminopurine...
 2'-Fluoro-5-methyl-ß-l...
 Famciclovir
 Combination therapy
 References
 
ß-L-2'-Deoxythymidine is one of three L-nucleosides that specifically inhibit HBV replication. The other two members are ß-L-2'-deoxycytidine and ß-L-2'-deoxyadenosine.22 The anti-HBV activities are conferred by the common hydroxyl group in the 3'-position of the ß-L-2'-deoxyribose sugar of the molecules. Eight logarithmic reduction of viral DNA levels has been demonstrated in the woodchuck model with ß-L-2'-deoxythymidine. In Phase I/II clinical trials, ß-L-2'-deoxythymidine shows marked dose-proportional antiviral activities with 4 weeks of the 800 mg daily dose causing a 4 log reduction in median HBV DNA levels. No side effects have been observed. The lack of side effects may be related to the L-configuration of the molecule.23 A Phase IIb trial of 400 and 600 mg ß-L-2'-deoxythymidine with or without lamivudine is currently being conducted.


    Emtricitabine
 Top
 Lamivudine
 Adefovir dipivoxil
 Tenofovir
 Entecavir
 ß-l-2'-Deoxythymidine...
 Emtricitabine
 1-ß-2,6-Diaminopurine...
 2'-Fluoro-5-methyl-ß-l...
 Famciclovir
 Combination therapy
 References
 
Emtricitabine [(–)-ß-2',3'-dideoxy-5-fluoro-3'-thiacytidine] has a similar molecular structure as well as antiviral potency and selectivity to lamivudine in the woodchuck model. It has rapid antiviral activities with a daily dose of 100 mg or greater. Because of the similarity to lamivudine, it is not effective in suppressing lamivudine-resistant HBV virus.


    1-ß-2,6-Diaminopurine dioxalane (DAPD, amdoxovir)
 Top
 Lamivudine
 Adefovir dipivoxil
 Tenofovir
 Entecavir
 ß-l-2'-Deoxythymidine...
 Emtricitabine
 1-ß-2,6-Diaminopurine...
 2'-Fluoro-5-methyl-ß-l...
 Famciclovir
 Combination therapy
 References
 
DAPD is the prodrug of viral replication inhibitor dioxalane guanosine. This drug is now being investigated by Phase II clinical trials. Preliminary studies show that it is effective against lamivudine-resistant virus.


    2'-Fluoro-5-methyl-ß-L-arabinofuranosyluridine (L-FMAU, clevudine)
 Top
 Lamivudine
 Adefovir dipivoxil
 Tenofovir
 Entecavir
 ß-l-2'-Deoxythymidine...
 Emtricitabine
 1-ß-2,6-Diaminopurine...
 2'-Fluoro-5-methyl-ß-l...
 Famciclovir
 Combination therapy
 References
 
Clevudine, a pyrimidine analogue, is a potent anti-HBV and anti-Epstein–Barr virus agent. A pre-clinical pharmacological study shows that clevudine has good bioavailability and no apparent toxicity in mice and woodchucks.24 It is active against woodchuck hepatitis virus and, unlike most other nucleoside analogues, has no significant rebound in DNA levels after cessation of treatment.24 However, preliminary studies show that it is probably not effective against lamivudine-resistant virus, particularly in the presence of concomitant L528M mutation.


    Famciclovir
 Top
 Lamivudine
 Adefovir dipivoxil
 Tenofovir
 Entecavir
 ß-l-2'-Deoxythymidine...
 Emtricitabine
 1-ß-2,6-Diaminopurine...
 2'-Fluoro-5-methyl-ß-l...
 Famciclovir
 Combination therapy
 References
 
Famciclovir, the active derivative being penciclovir, is a potent nucleoside analogue against the herpes simplex virus. It also has some activities against HBV. A synergic antiviral effect has been observed when famciclovir is combined with lamivudine in the duck model and in man.25 The anti-viral effect of famciclovir monotherapy has been shown to be modest.26 According to a 12 week direct comparison study, only 8% of the famciclovir-treated patients have >2 log reductions of HBV DNA levels compared with 82% of the lamivudine-treated patients (P < 0.001).27 Further trials of famciclovir for HBV patients have been abandoned.


    Combination therapy
 Top
 Lamivudine
 Adefovir dipivoxil
 Tenofovir
 Entecavir
 ß-l-2'-Deoxythymidine...
 Emtricitabine
 1-ß-2,6-Diaminopurine...
 2'-Fluoro-5-methyl-ß-l...
 Famciclovir
 Combination therapy
 References
 
To date, monotherapy for the treatment of HBV is still far from ideal, mainly because of the emergence of drug-resistant viruses. The future probably lies in combination therapy. There are at least three beneficial effects of using combination therapy. Different agents acting at different sites of the viral replication cycle may have additive or even synergic effects. The side effects of individual agents may be lessened if a lower dose can be used when combined with other agents. Finally, more effective viral suppression should minimize the risk of viral mutations.

The first approach to combination therapy is the combination of immunomodulation with viral suppression. The combination of IFN-{alpha} and lamivudine has been investigated in two multicentre trials for treatment-naive patients and for non-responders to previous IFN-{alpha} treatment.28,29 The treatment regime for both trials is an 8 week course of lamivudine followed by 16 weeks of lamivudine and IFN-{alpha}. However, the efficacy of this form of combination therapy is not significantly better than monotherapy with either agent alone. Current studies on this combination are attempting to optimize the timing of the combination and to prolong the duration of IFN-{alpha} treatment. Since pegylated IFN has been shown to be more efficacious than traditional IFN for hepatitis C, studies combining longer duration of pegylated IFN with lamivudine are currently being conducted. Other trials are investigating the combination of lamivudine with newer immunomodulatory agents such as therapeutic vaccines.

Another possible combination of immunomodulation and viral suppression is to utilize the immune rebound occurring after the cessation of a short course of steroid. A pilot study of 3 weeks of prednisolone followed by 9 months of lamivudine results in a significantly higher HBeAg seroconversion rate in patients with ALT rebound following steroid withdrawal compared with patients without ALT rebound (60% versus 10%, respectively; P < 0.002).30 However, it is important to note that steroid withdrawal can occasionally lead to severe or even fatal HBV reactivations. Steroid priming as a form of therapy is not recommended.

The second approach to combination therapy is the combination of two or more nucleoside analogues as in the treatment of HIV. The ideal combination should be of two or more highly potent nucleoside analogues acting on different sites of the HBV replication cycle to achieve maximal viral suppression and to ensure effectiveness against any pre-existing drug-resistant mutant HBV.


    Footnotes
 
* Corresponding author. Tel: +852-2855-4252; Fax: +852-2816-2863; E-mail: hrmelcl{at}hkucc.hku.hk Back


    References
 Top
 Lamivudine
 Adefovir dipivoxil
 Tenofovir
 Entecavir
 ß-l-2'-Deoxythymidine...
 Emtricitabine
 1-ß-2,6-Diaminopurine...
 2'-Fluoro-5-methyl-ß-l...
 Famciclovir
 Combination therapy
 References
 
1 . Yuen, M. F. & Lai, C. L. (2001). Treatment of chronic hepatitis B. Lancet Infectious Diseases 1, 232–41.[CrossRef][Medline]

2 . Yuen, M. F., Hui, C. K., Cheng, C. C., Wu, C. H., Lai, Y. P. & Lai, C. L. (2001). Long-term follow-up of interferon-alpha treatment in Chinese patients with chronic hepatitis B infection: the effect on HBeAg seroconversion and the development of cirrhosis-related complications. Hepatology 34, 139–45.[ISI][Medline]

3 . Lai, C. L., Chien, R. N., Leung, N. W. Y., Chang, T. T., Guan, R., Tai, D. I. et al. (1998). A one-year trial of lamivudine for chronic hepatitis B. New England Journal of Medicine 339, 61–8.[Abstract/Free Full Text]

4 . Dienstag, J. L., Schiff, E. R., Wright, T. L., Perrillo, R. P., Hann, H. W. L., Goodman, Z. et al. (1999). Lamivudine as initial treatment for chronic hepatitis B in the United States. New England Journal of Medicine 341, 1256–63.[Abstract/Free Full Text]

5 . Schiff, E. R., Heathcote, J., Dienstag, J. L., Hann, H. W. L., Woessner, M., Brown, N. et al. (2000). Improvement in liver histology and cirrhosis with extended lamivudine therapy. Hepatology 32, 296A.

6 . Song, B. C., Suh, D. J., Lee, H. C., Chung, Y. H. & Lee, Y. S. (2000). Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea. Hepatology 32, 803–6.[ISI][Medline]

7 . Santantonio, T., Mazzola, M., Iacovazzi, T., Miglietta, A., Guastadisegni, A. & Pastore, G. (2000). Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine. Journal of Hepatology 32, 300–6.[CrossRef][ISI][Medline]

8 . Hadziyannis, S. J., Papatheodoridis, G. V., Dimou, E., Laras, A. & Papaioannou, C. (2000). Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B. Hepatology 32, 847–51.[ISI][Medline]

9 . Yao, F. Y. & Bass, N. M. (2000). Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. Journal of Hepatology 33, 301–7.[CrossRef][ISI][Medline]

10 . Kapoor, D., Guptan, R. C., Wakil, S. M., Kazim, S. N., Kaul, R., Agarwal, S. R. et al. (2000). Beneficial effects of lamivudine in hepatitis B virus-related decompensated cirrhosis. Journal of Hepatology 33, 308–12.[CrossRef][ISI][Medline]

11 . Yao, F. Y., Terrault, N. A., Freise, C., Maslow, L. & Bass, N. M. (2001). Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort. Hepatology 34, 411–6.[CrossRef][ISI][Medline]

12 . Yuen, M. F., Sablon, E., Hui, C. K., Yuan, H. J., Decraemer, H. & Lai, C. L. (2001). Factors predicting hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology 34, 785–91.[ISI][Medline]

13 . Melegari, M,, Scaglioni, P. P. & Wands, J. R. (1998). Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective. Hepatology 27, 628–33.[ISI][Medline]

14 . Ono-Nita, S. K., Kato, N., Shiratori, Y., Masaki, T., Lan, K. H., Carrilho, F. J. et al. (1999). YMDD motif in hepatitis B virus DNA polymerase influences on replication and lamivudine resistance: a study by in vitro full-length viral DNA transfection. Hepatology 29, 939–45.[ISI][Medline]

15 . Hadziyannis, S. J., Papatheodoridis, G. V., Dimou, E., Laras, A. & Papaioannou, C. (2000). Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B. Hepatology 32, 847–51.[ISI][Medline]

16 . Marcellin, P., Goodman, Z., Chang, T. T., Lim, S. G., Tong, M. R., Sievert, W. et al. (2002). Histological improvement in HBeAg positive chronic hepatitis B patients treated with adefovir dipivoxil. Journal of Hepatology 36, Suppl. 1, 8A.

17 . Das, K., Xiong, X., Yang, H., Westland, C. E., Gibbs, C. S., Sarafianos, S. G. et al. (2001). Molecular modeling and biochemical characterization reveal the mechanism of hepatitis B virus polymerase resistance to lamivudine (3TC) and emtricitabine (FTC). Journal of Virology 75, 4771–9.[Abstract/Free Full Text]

18 . Ying, C., De Clercq, E., Nicholson, W., Furman, P. & Neyts, J. (2000). Inhibition of the replication of the DNA polymerase M550V mutation variant of human hepatitis B virus by adefovir, tenofovir, L-FMAU, DAPD, penciclovir and lobucavir. Journal of Viral Hepatitis 7, 161–5.[CrossRef][ISI][Medline]

19 . van Bömmel, F., Wünsche, T., Schürmann, D. & Berg, T. (2002). Tenofovir treatment in patients with lamivudine-resistant hepatitis B mutants strongly affects viral replication. Hepatology 36, 507.[CrossRef][ISI][Medline]

20 . Colonno, R. J., Genovesi, E. V., Medina, I., Lamb, L., Durhan, S. K., Huang, M. L. et al. (2001). Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection. Journal of Infectious Diseases 184, 1236–45.[CrossRef][ISI][Medline]

21 . Lai, C. L., Rosmawati, M., Lao, J., Vlierberghe, H. V., Anderson, F. H., Thomas, N. et al. (2002). Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection. Gastroenterology 123, 1831–8.[CrossRef][ISI][Medline]

22 . Bryant, M. L., Bridges, E. G., Placidi, L., Faraj, A., Loi, A. G., Pierra, C. et al. (2001). Antiviral L-nucleosides specific for hepatitis B virus infection. Antimicrobial Agents and Chemotherapy 45, 229–35.[Abstract/Free Full Text]

23 . Lai, C. L., Lim, S. G., Yuen, M. F., Pow, D. M. & Myers, M. W. (2002). L-DT: an ongoing phase I/II dose escalation trial in patients with chronic HBV infection (NV-02B-001). Journal of Hepatology 34, Suppl. 1, 139A.

24 . Chu, C. K., Boundinot, F. D., Peek, S. F., Hong, J. H., Choi, Y., Korba, B. E. et al. (1998). Preclinical investigation of L-FMAU as an anti-hepatitis B virus agent. Antiviral Therapy 3, Suppl. 3, 113–21.[ISI][Medline]

25 . Colledge, D., Locarnini, S. A. & Shaw, T. (1997). Synergistic inhibition of hepadnaviral replication by lamivudine in combination with penciclovir in vitro. Hepatology 26, 234–7.[ISI][Medline]

26 . De Man, R. A., Marcellin, P., Habal, F., Desmond, P., Wright, T., Rose, T. et al. (2000). The famciclovir hepatitis B study group. A randomized, placebo-controlled study to evaluate the efficacy of 12-month famciclovir treatment in patients with chronic hepatitis B e antigen-positive hepatitis B. Hepatology 32, 413–7.[ISI][Medline]

27 . Lai, C. L., Yuen, M. F., Hui, C. K., Garrido-Lestache, S., Cheng, C. T. K. & Lai, Y. P. (2002). A comparison of the efficacy of lamivudine and famciclovir in Asian patients with chronic hepatitis B: results of 24 weeks of therapy. Journal of Medical Virology 67, 334–8.[CrossRef][ISI][Medline]

28 . Schalm, S. W., Heathcote, J., Cianciara, J., Farrell, G., Sherman, M., Williams, B. et al. (2000). Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut 46, 562–8.[Abstract/Free Full Text]

29 . Schiff, E., Karayalcin, S., Grimm, I., Perrillo, R., Dienstag, J., Husa, P. et al. (1998). A placebo controlled study of lamivudine and interferon alpha-2b in patients with chronic hepatitis B who previously failed interferon therapy. Hepatology 28S, 388A.

30 . Liaw, Y. F., Tsai, S. L., Chien, R. N., Yeh, C. T. & Chu, C. M. (2000). Prednisolone priming enhances Th 1 response and efficacy of subsequent lamivudine therapy in patients with chronic hepatitis B. Hepatology 32, 604–9.[CrossRef][ISI][Medline]





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