Tram T. Tran, MD   

Hepatitis B

New therapies for the treatment of hepatitis B have emerged over the past several years, demonstrating excellent therapeutic results in viral suppression and leading to improvement in liver injury from chronic hepatitis B infection. There are 6 therapies currently approved by the US Food and Drug Administration (FDA) for the treatment of hepatitis B in adults: interferon alfa-2b; lamivudine; adefovir dipivoxil; entecavir; pegylated interferon alfa-2a; and the oral antiviral agent telbivudine, which received approval just last month. Research presented at this year's meeting of the American Association for the Study of Liver Diseases (AASLD) focused on these therapeutic options as well as on new strategies in applying these agents, including the utility of early viral suppression as a determinant of response to therapy.

Lamivudine

Lamivudine is a potent nucleoside analog and was the first oral therapy approved for the treatment of hepatitis B. Unfortunately, high rates of viral resistance, manifesting as the YMDD mutation, emerged after even short periods of lamivudine therapy (24% resistance at 1 year, increasing up to 70% by 4 years of therapy).^[1] However, despite this high rate of viral resistance, due to its relatively low cost and ready availability, lamivudine remains widely used worldwide.

Yuen and colleagues^[2] examined the long-term impact of rapid early viral suppression at week 12 of lamivudine therapy on seroconversion rates, viral resistance, and alanine aminotransferase (ALT) normalization in 74 patients with chronic hepatitis B. As defined by the study, using hepatitis B virus [HBV] DNA of 4 logs as a cut-off level for good response, if patients achieved viral suppression to < 4 logs, they were able to attain higher rates of seroconversion (90% vs 20%), ALT normalization (100% vs 51%), and lower resistance (63% vs 0%) compared with patients with HBV DNA > 4 logs, after 5 years of therapy. The sensitivity and specificity of using this cut-off level for determination of good response was 50% and 100%, respectively, in this small study.

Rapid and profound suppression of viral replication may be a good predictor of long-term outcomes and resistance, but larger studies are needed to determine true negative and positive predictive values and the most clinically relevant time points.

Adefovir

Adefovir is a nucleotide analog with effective antiviral activity against the lamivudine-resistant YMDD viral strain. Previously, once resistance had developed to lamivudine, therapy was initiated with adefovir and lamivudine was often discontinued after some period of overlap. However, recent data have suggested that the addition of adefovir to lamivudine, instead of the switch from lamivudine to adefovir monotherapy, may be more effective in preventing the development of adefovir resistance.^[3] Marzano and colleagues^[4] studied the impact of add-on vs switch therapy with adefovir on HBV viral suppression in a group of 52 patients with clinical or genotypic lamivudine resistance. Patients were randomly assigned to adefovir alone or lamivudine plus adefovir (ie, adefovir combined with ongoing lamivudine). The investigators reported that overall viral response to adefovir monotherapy vs combined adefovir + lamivudine therapy was similar in patients with lower viral levels, confirming previous findings.^[5] However, patients with high viral loads (HBV DNA > 5 log copies/mL) were less likely to achieve viral suppression with a shift to adefovir monotherapy, and were at higher risk for the development of adefovir resistance. Thus, combination therapy, either as a rescue strategy after development of resistance or as therapy in the naive patient, may be beneficial for the prevention of resistance; additional, larger studies are warranted.

The current treatment paradigm for patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B is continued, indefinite viral suppression because of the high relapse rates once suppressive antiviral therapy is discontinued. Hadziyannis and colleagues^[6] assessed relapse in HBeAg-negative patients who had been on long-term adefovir therapy. The study involved patients on adefovir therapy for 4-5 years who had achieved and maintained biochemical remission (ALT normalization), had viral suppression (HBV DNA < 1000 copies/mL), and had no detectable adefovir resistance mutations; antiviral therapy was discontinued and subjects were monitored for relapse. Results showed that although all patients had some evidence of viral rebound (≤ 50,000 copies/mL), 67% were able to maintain normalized serum ALT. Patients with biochemical relapse were successfully re-treated with resumption of therapy. Thus, on the basis of these study findings, discontinuation of antiviral therapy in the difficult-to-manage HBeAg-negative chronic hepatitis B patient population may be feasible, although all patients experience virologic relapse and the possibility of biochemical flare.

Entecavir

Entecavir was approved for the treatment of hepatitis B in 2005, and data continue to be reported on the long-term outcomes of patients. The phase 3 randomized study comparing entecavir with lamivudine in the treatment of nucleoside-naive HBeAg-positive patients was continued for a total of 96 weeks. Thereafter, patients who had achieved virologic suppression (HBV DNA < 0.7 Meq/mL), but had not yet lost HBeAg or seroconverted, were allowed to enter into the follow-up roll-over study for continued monitoring.^[7] A total of 122 patients were enrolled into this follow-up study, and endpoints included HBeAg loss or seroconversion, normalization of serum ALT, and viral suppression to HBV DNA < 300 copies/mL. Of note, these patients were given a higher dose of entecavir than that used in the original study (1.0 mg entecavir vs 0.5 mg) due to the roll-over study design. Results showed that by week 144, 90% of patients who continued entecavir treatment achieved complete viral suppression, 80% normalized ALT, and an additional 33% lost HBeAg; 16% had seroconversion in the third year on therapy (cumulative seroconversion rate was not reported). Safety profile was similar to that reported in previous studies, with no major changes to the entecavir safety profile. Thus, continued entecavir treatment to 3 years in the nucleoside-naive HBeAg-positive patient appears to result in high rates of viral suppression and normalization of serum ALT, along with improved chances of HBeAg seroconversion.

Long-term treatment with any antiviral therapy leads to concerns regarding the potential development of viral resistance mutations, the loss of efficacy, and histologic and biochemical rebound. As mentioned previously, lamivudine resistance, with the development of the YMDD mutation, has been well established at high rates approaching 70% at 4 years^[1]; adefovir resistance is now reported at 29% with 5 years of therapy.^[8] Colonno and colleagues^[9] reported the 3-year resistance data for patients treated with entecavir during this year's AASLD meeting. All patients with detectable HBV DNA (> 300 copies/mL) and any patient experiencing a viral rebound of > 1 log during entecavir therapy were analyzed for genotypic mutations conferring entecavir resistance. The authors reported entecavir resistance to be less than 1% in each of the 3 years on therapy for nucleoside-naive patients receiving treatment. Cumulatively, genotypic mutations to entecavir occurred in 6%, 14%, and 29% of patients with baseline lamivudine resistance prior to entecavir therapy for years 1, 2, and 3 of entecavir treatment. Thus, entecavir appears to have an excellent 3-year resistance profile in nucleoside-naive patients, with resistance rates of < 1% per year on therapy. Patients with previous lamivudine resistance are at higher risk of developing entecavir resistance.

Telbivudine

Telbivudine is the most recent FDA-approved therapy for the treatment of chronic HBV infection, and is a nucleoside analogue that inhibits the HBV polymerase. The 2-year results from the phase 3 trial comparing telbivudine with lamivudine in chronic hepatitis B (GLOBE) were presented by Lai and colleagues^[10] during AASLD 2006. Patients (n = 1367) were randomized to telbivudine 600 mg orally once daily or lamivudine 100 mg once daily, with the usual inclusion criteria (ALT > 1.3-10 X upper limit of normal; HBV DNA > 6 log₁₀ copies/mL; compensated liver disease). Results showed superior efficacy for telbivudine vs lamivudine by week 104 in HBeAg-negative chronic hepatitis B patients with regard to HBV DNA suppression (HBV DNA undetectable: 82% vs 57%). In the HBeAg-positive cohort, telbivudine was also more effective than lamivudine with respect to HBV DNA suppression to undetectable levels and normalization of serum ALT; seroconversion was achieved in 30% of patients by week 104 in the telbivudine group (vs 25% in the lamivudine group; NS). Resistance occurred in patients receiving both therapies, with rates of 8.1% (HBeAg-negative) and 21% (HBeAg-positive) observed in the telbivudine arms. It is interesting to note that analysis of patients who achieved rapid viral suppression at week 24 was predictive of lower resistance rates for telbivudine (2% for the HBeAg-negative cohort; 4% for the HBeAg-positive cohort).

Bzowej and colleagues^[11] presented findings from a study assessing the efficacy of telbivudine vs adefovir in 135 patients with HBeAg-positive chronic hepatitis B. Patients were randomized initially to treatment with telbivudine or adefovir for 24 weeks, and then a secondary randomization at 24 weeks took place in those patients receiving adefovir, to either continue adefovir therapy or switch to telbivudine. Telbivudine demonstrated significantly greater efficacy in viral suppression in the first 24 weeks compared with adefovir (38% vs 12% undetectable HBV DNA); this trend continued into the 52-week data, with better virologic response rates seen in those patients either on (or switched to) telbivudine compared with those who remained on adefovir.

Thus, telbivudine demonstrates better efficacy than lamivudine for most clinical endpoints of treatment. Virologic breakthrough due to resistance was statistically lower in the telbivudine-treated patients than in those treated with of lamivudine, and some prediction of resistance may be possible on the basis of early viral response at week 24. In addition, telbivudine appears to have better viral suppression than adefovir at 24 and 52 weeks, although rates of HBeAg seroconversion and ALT normalization were not significantly different.

Pegylated Interferon

Pegylated interferon is indicated for the treatment of chronic hepatitis B, but due to issues of cost and associated side effects, is not as widely used as the oral antiviral therapies. However, a finite duration of treatment and the lack of concern for viral resistance still make interferon-based therapy a viable option for some patients.

Marcellin and colleagues^[12] reported follow-up data from a large trial of HBeAg-negative chronic hepatitis B patients previously treated with pegylated interferon with or without lamivudine vs lamivudine alone for a total of 48 weeks. Data from the initial 48 weeks of therapy have been previously reported, and revealed that no additional benefit was associated with combined pegylated interferon plus lamivudine compared with pegylated interferon alone.^[13] The current study^[12] evaluated the durability of response to pegylated interferon with or without lamivudine for up to 2 years post treatment. They found that in the pegylated interferon monotherapy group, at 24 months post treatment, 28% of patients were able to maintain HBV DNA levels < 10,000 copies/mL and 32% were able to maintain normal ALT levels. Data also confirmed that the addition of lamivudine to pegylated interferon did not provide any benefit with regard to virologic or biochemical sustained response.

Patients with HBeAg-negative chronic hepatitis B represent a more difficult-to-treat population due to the high relapse rates post therapy. Immunomodulation with interferon for 1 year appears to have some positive benefit in 28% of patients, even 24 months after therapy.

Hepatitis C

Pegylated Interferon

The mainstay of treatment for patients with hepatitis C has been combination therapy with pegylated interferon and ribavirin, which overall yields sustained response rates in approximately 50% of patients treated. Few options are available for those patients who do not respond to therapy, are unable to tolerate the side effects of the interferon or ribavirin, or who relapse after discontinuation of the medications.

More information has been accumulated in the past several years on early predictors of nonresponse to therapy, whereby the lack of at least a 2-log drop in the baseline viral load at week 12 was able to identify those patients who had little chance of responding to therapy (early viral response [EVR] rule). Clinicians, using this EVR rule, were able to discontinue therapy in patients earlier, sparing them significant side effects and associated costs. More recently, a positive 4-week hepatitis C virus (HCV) RNA level has been shown to be predictive of higher rates of relapse post therapy, and the use of this so-called rapid viral response (RVR) is now gaining clinical applicability.

Shiffman and colleagues^[14] reported results from the ACCELERATE trial involving 1463 patients infected with HCV genotype 2 or 3 who were treated with pegylated interferon alfa-2a plus ribavirin for either 16* or 24 weeks. Currently, the standard of care is treatment for 24 weeks for patients with HCV genotype 2 or 3. Results showed that, overall, patients who received 24 weeks of therapy had a 90% sustained virologic response (SVR) rate compared with 82% of patients treated for 16 weeks. RVR and EVR rule were both highly predictive of achieving SVR. Thus, RVR (HCV RNA undetectable at week 4 by polymerase chain reaction [PCR]) and EVR are both highly predictive of response to therapy in patients infected with HCV genotypes 2/3. Decreasing duration of therapy to 16 weeks may be reasonable in patients who achieve an RVR and have significant difficulty or side effects with treatment.

Pearlman and colleagues^[15] examined the effect of longer duration of therapy using pegylated interferon alfa-2b plus weight-based ribavirin dosing in patients infected with HCV genotype 1 who, despite meeting the criteria for EVR (> 2-log drop in baseline HCV RNA by PCR), were still HCV RNA PCR detectable until week 24 of therapy. This group of "slower viral responders" was then treated for either the usual 48 weeks or was extended to 72 weeks* of therapy. Results showed a 39% SVR in the 72-week arm compared with 18% SVR in the 48-week arm; treatment extension did not seem to result in an increase in dose reductions or discontinuations. Thus, treatment of hepatitis C has now evolved to a more individualized regimen, using weight-based dosing of ribavirin and an adjusted duration of therapy, depending on how rapidly patients respond to therapy. Longer duration of therapy may improve sustained response rates in patients with slower viral suppression.

Agents on the Horizon

Although great advances have been made with interferon and ribavirin-based therapy, the most exciting new development on the horizon for hepatitis C is the use of therapies that specifically target steps in the cycle of hepatitis C replication as opposed to general immunomodulators or antivirals. VX-950* is an oral HCV protease inhibitor that has been shown to dramatically reduce HCV viral loads to undetectable levels within 2-4 weeks in phase 2 trials.^[16] However, some viral variants emerged with this therapy. During this year's AASLD meeting, Kieffer and colleagues^[17] reported a detailed analysis of these variants; data were presented on 16 patients treated with VX-950 750 mg 3 times daily (n = 8) vs VX-950 750 mg 3 times daily plus pegylated interferon (n = 8) for 14 days. HCV RNA was isolated after the treatment period for variants in the NS3 protease domain. Six of 8 patients treated with VX-950 monotherapy had detectable mutations by the end of the 14 days, whereas 4 of 8 of patients receiving combination pegylated interferon plus VX-950 also had detectable virus (resistant or wild-type) at day 8. After the 14 days of therapy, 15 of 16 patients were treated with the standard pegylated interferon plus ribavirin and all responded with complete viral suppression by week 24. This suggests that although there may be some viral resistance due to mutations with the use of the protease inhibitor, viral suppression occurs successfully with the addition of pegylated interferon and ribavirin.

In a late-breaking abstract presented by Roberts and colleagues,^[18] another target-specific HCV therapy, R1626*, a nucleoside analog oral polymerase inhibitor, was administered in a phase 1b trial involving 47 treatment-naive patients infected with HCV genotype 1. Patients were given R1626 at doses of 500, 1500, 3000, and 4500 mg twice daily vs placebo for 14 days. The authors found that a dose-dependent viral suppression occurred, with 5 of 9 patients in the 4500-mg treatment arm having undetectable HCV RNA at day 15. Anemia occurred in some patients; headache and gastrointestinal side effects were noted at the highest dose.

New therapies targeting specific sites in the HCV replication cycle, such as these protease or polymerase inhibitors, show early promise, although viral resistance and side effects need further study in larger, phase 2 trials.

Consensus Interferon

One of the most difficult clinical issues in liver transplantation is the recurrence of hepatitis C after transplantation. Recurrence is nearly universal, and studies have shown a more aggressive course of HCV progression after transplant, with up to 20% of patients developing cirrhosis by 5 years.^[19] Treating the cirrhotic patient before liver transplant may reduce the likelihood of recurrence; however, treatment is limited by constitutional side effects, anemia, thrombocytopenia, and neutropenia in this patient population.

Bacon and colleagues^[20] presented their results from the DIRECT (Daily-dose consensus Interferon and Ribavirin Efficacy of Combined Therapy) trial using consensus interferon* plus ribavirin in patients who previously failed to respond to pegylated interferon + ribavirin therapy. Of note, 29% of patients in this study were cirrhotic by liver biopsy and more than 50% had bridging fibrosis. Patients received consensus interferon at a dose of 9 micrograms (mcg)/day or 15 mcg/day in combination with ribavirin vs no treatment. Preliminary analysis at the end of treatment revealed a 29% end-of-treatment response in patients with greater than 80% compliance with the 15-mcg/day consensus interferon + ribavirin regimen. The lower dose of consensus interferon demonstrated lower response rates (15%), and patients with cirrhosis had very low response rates (< 8%). The most common side effects were neutropenia and fatigue, with an overall 10% to 17% discontinuation rate.

Consensus interferon has demonstrated some moderate success in the very difficult-to-treat group of patients who have nonresponse to combination pegylated interferon plus ribavirin. Early treatment of HCV infection offers more benefit, as the more advanced the histologic disease, the lower the chance of success with any therapy thus far.

Conclusion

Exciting new advances were presented in viral hepatitis at this year's AASLD meeting. Our therapeutic armamentarium for hepatitis B now includes several oral antiviral therapies, as well as immunomodulatory agents. The major issues of viral resistance and predictors of response and resistance are now under active study.

Hepatitis C is entering a new era of drug development with specifically targeted therapies, although these strategies remain very early in clinical development. Again, issues of safety and viral resistance will come to the forefront in this arena. Individualized therapy with the current standard of care, pegylated interferon plus ribavirin, is key to optimizing patient outcomes.

References

1. Lai CL, Dienstag J, Schiff E, et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis. 2003;36:687-696.
2. Yuen M-F, Wong D, Fung J, et al. Predictive value of HBV DNA levels at frequent time points during early and maintenance phase of 5-year lamivudine and mutational profiles of reverse transcriptase and surface genes. Hepatology. 2006;44:557A. [Abstract 991]
3. Lampertico P, Marzano A, Battista G, et al. A multicenter Italian study of rescue adefovir dipivoxil therapy in lamivudine resistant patients: a 2-year analysis of 604 patients. Hepatology. 2005;42:591A. [Abstract 1003]
4. Marzano A, Gaia S, Barbon V, et al. Therapy with adefovir alone or combined with lamivudine in patients with lamivudine-resistant chronic hepatitis B: clinical and virological aspects. Hepatology. 2006;44:231A. [Abstract 113]
5. Peters MG, Hann HW, Martin P, et al, for the GS-00-461 Study Group. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2004;126:91-101.
6. Hadziyannis S, Sevastianos V, Rapti I, et al. Sustained biochemical and virological remission after discontinuation of 4 to 5 years of adefovir dipivoxil treatment in HBeAg-negative chronic hepatitis B. Hepatology. 2006;44:231A. [Abstract 114]
7. Chang TT, Chao YC, Kaymakoglu S, et al. Entecavir maintained virological suppression through 3 years of treatment in antiviral naive HBeAg+ patients. Hepatology. 2006;44:229A. [Abstract 109]
8. Borroto-Esoda K, Arterburn S, Snow A, et al. Final analysis of virological outcomes and resistance during 5 years of adefovir dipivoxil monotherapy in HBeAg-negative patients. Gastroenterology. 2006;130:A-765. [Abstract 477]
9. Colonno RJ, Rose RE, Pokornowski K, et al. Assessment at three years shows high barrier to resistance is maintained in entecavir-treated nucleoside naïve patients while resistance emergence increases over time in lamivudine refractory patients. Hepatology. 2006;44:229A. [Abstract 110]
10. Lai CL, Gane E, Hsu CW, et al. Two-year results from the GLOBE trial in patients with hepatitis B: greater clinical and antiviral efficacy for telbivudine vs lamivudine. Hepatology. 2006;44:222A. [Abstract 91]
11. Bzowej N, Chan H, Lai CL, et al. A randomized trial of telbivudine vs adefovir for HBeAg-positive chronic hepatitis B: week 52 results. Hepatology. 2006;44:563A. [Abstract 1005]
12. Marcellin P, Bonino F, Lau GK, et al. Suppression of HBV DNA in patients with HBeAg-negative CHB treated with peginterferon alfa-2a (40 kd) ± lamivudine: 2 year follow-up results. Hepatology. 2006;44:550A. [Abstract 972]
13. Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351:1206-1217.
14. Shiffman M, Pappas S, Bacon B, et al. Utility of virological response at weeks 4 and 12 in the prediction of SVR rates in genotype 2/3 patients treated with peginterferon alfa-2a (40 kd) plus ribavirin: findings from ACCELERATE. Hepatology. 2006;44:316A. [Abstract 340]
15. Pearlman B, Ehleben C, Saifee S. Improved virologic response rates with treatment extension to 72 weeks of peginterferon alfa-2b plus weight-based ribavirin in a difficult-to-treat population of genotype-1 infected slow responders. Hepatology. 2006;44:318A. [Abstract 343]
16. Lawitz E, Rodriguez-Torres M, Muir A, et al. 28 days of the hepatitis C protease inhibitor VX-950, in combination with peg-interferon-alfa-2a and ribavirin, is well-tolerated and demonstrates robust antiviral effects. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. [Late-breaking abstract 686f]
17. Kieffer T, Sarrazin C, Miller J, et al. Combination of telaprevir (VX-950) and PEG-IFN-alfa suppressed both wild-type virus and resistance variants in HCV genotype 1-infected patients in a 14-day phase 1B study. Hepatology. 2006;44:222A. [Abstract 92]
18. Roberts S, Cooksley G, Dore G, et al. Results of a phase 1B multiple dose study of R1626 a novel nucleoside analog targeting HCV polymerase in chronic HCV genotype 1 patients. Hepatology. 2006;44:692A. [Late-breaking abstract 2]
19. Gane EJ, Portmann BC, Naoumouv NV, et al. Long-term outcome of hepatitis C infection after liver transplantation. N Engl J Med. 1996;334:821-827.
20. Bacon B, Regev A, Ghalib R, et al. Use of daily interferon alfacon-1 (integren, CIFN) plus ribavirin in patients infected with hepatitis C who are nonresponders to previous pegylated interferon plus RBV therapy: 24-week data from the DIRECT trial. Hepatology. 2006;44:698A. [Late-breaking abstract 18]