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)- 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-
induces HBeAg seroconversion in
2030% 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-
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-
.
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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Lamivudine |
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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 1226 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 ChildPugh 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 69 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 (tyrosinemethionineaspartateaspartate) 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: 1532%, 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
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Adefovir dipivoxil |
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In Phase I/II studies, treatment with adefovir results in significant reduction of HBV DNA within 12 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 (60120 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.
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Tenofovir |
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Entecavir |
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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.
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ß-L-2'-Deoxythymidine (telbivudine) |
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Emtricitabine |
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1-ß-2,6-Diaminopurine dioxalane (DAPD, amdoxovir) |
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2'-Fluoro-5-methyl-ß-L-arabinofuranosyluridine (L-FMAU, clevudine) |
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Famciclovir |
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Combination therapy |
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The first approach to combination therapy is the combination of immunomodulation with viral suppression. The combination of IFN- and lamivudine has been investigated in two multicentre trials for treatment-naive patients and for non-responders to previous IFN-
treatment.28,29 The treatment regime for both trials is an 8 week course of lamivudine followed by 16 weeks of lamivudine and IFN-
. 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-
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.
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Footnotes |
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References |
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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, 13945.[ISI][Medline]
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.
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, 618.
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.
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, 125663.
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, 8036.[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, 3006.[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, 84751.[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, 3017.[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, 30812.[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, 4116.[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, 78591.[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, 62833.[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, 93945.[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, 84751.[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.
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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, 47719.
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, 1615.[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, 123645.[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, 18318.[CrossRef][ISI][Medline]
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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, 22935.
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, 11321.[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, 2347.[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, 4137.[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, 3348.[CrossRef][ISI][Medline]
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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, 5628.
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, 6049.[CrossRef][ISI][Medline]
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