Anna S. F. Lok, MD
University of Michigan
Ann Arbor, Michigan
This section focuses on new treatments in development for chronic hepatitis B. After a brief discussion of treatment goals and the efficacy of currently approved medications, new therapeutic agents and combination therapies that are now in clinical trials will be reviewed.
The goals of treatment in chronic hepatitis B are to 1) achieve sustained suppression of viral replication; 2) induce remission of liver disease (ie, reduce hepatic necroinflammation and fibrosis); and 3) prevent progression to cirrhosis, liver failure, and hepatocellular carcinoma.
Currently, there are three approved treatments: interferon, lamivudine, and adefovir. Table 1 summarizes the efficacy of these drugs in achieving HBeAg seroconversion (in HBeAg-positive patients) or viral suppression (in HBeAgnegative patients).
Clinical studies have shown that, after a finite course of interferon or a year of lamivudine or adefovir, responses are achieved in approximately 10% to 20% of HBeAg-positive patients and 50% to 70% of HBeAg-negative patients. But when posttreatment relapses are taken into account, <15% of HBeAg-positive patients (50% to 80% of initial responders) and <10% of HBeAg-negative patients achieve a sustained response with lamivudine or adefovir. The percentage of interferontreated patients achieving a sustained response appears to be somewhat higher, but is still <20%.1,2
Interferon is usually given for 4 to 6 months in HBeAg-positive patients, and 12 to 24 months in HBeAg-negative patients, while lamivudine and adefovir are usually administered for several years or indefinitely in order to forestall posttreatment relapse.
Other limitations of current therapy are summarized in Table 2. Interferon has to be administered parenterally, is associated with many side effects, is contraindicated in patients with decompensated liver disease, and is expensive. Lamivudine has few side effects, but is associated with a high rate of drug resistant mutations-as high as 14% to 32% after one year,1 and up to 70% after 5 years of treatment.1,3
Adefovir is associated with a small risk of nephrotoxicity and drug resistant mutations, although not observed during the first year of treatment, and occurs in 3% of patients after 2 years, and in about 6% after 3 years of continuous treatment.4
Thus, while there has been much progress in hepatitis B treatment during the past decade, current treatments remain unsatisfactory. Sustained viral suppression is achieved in only a small percentage of patients. Long or indefinite treatment is often required to maintain viral suppression, leading to an increasing risk of drug resistance and adverse effects, as well as escalating costs. Therefore, new treatments are needed. Table 3 lists some of the new antiviral agents that are currently being evaluated in clinical trials. Furthest along is entecavir (ETV), a synthetic nucleoside analog with in vitro and in vivo activity against both wild-type and lamivudine-resistant hepatitis B virus (HBV). Clinical trials suggest that it has a safety profile similar to that of lamivudine, and is more potent than lamivudine in suppressing HBV replication.5 So far there have been no reports of ETV-resistant mutations in nucleoside-naïve patients; however, two cases have been reported in patients with prior lamivudine resistance who had received ETV for >1 year. These mutations differ from those associated with lamivudine or adefovir resistance.6
Figure 1 illustrates results of a phase 2 trial of ETV (0.01 mg/day, 0.1 mg/day, or 0.5 mg/day) versus lamivudine (100 mg/day) in 169 nucleoside-naïve patients. The two higher ETV doses were significantly more potent than lamivudine in decreasing serum HBV DNA levels.5
Figure 2 shows results of a clinical trial of ETV (0.1, 0.5, or 1.0 mg/day) versus continued lamivudine (100 mg/day) in 181 patients who had previously failed lamivudine therapy. Mutations in the YMDD motif were detected in 87% of the patients. All three ETV doses were significantly more effective than lamivudine in suppressing HBV DNA. The two higher ETV doses decreased HBV DNA levels by 4 to 5 logs after 48 weeks of treatment.7
Another new antiviral is emtricitabine (FTC), a synthetic nucleoside analog that was recently approved for HIV treatment. It also has potent activity against HBV. FTC is structurally related to lamivudine, and like lamivudine, it selects for mutations in the YMDD motif. However, in a 96-week clinical trial, these mutations occurred at a lower rate (19% after 2 years), while the HBeAg seroconversion rate was similar (29% after 2 years) to that with lamivudine. FTC was well tolerated at the optimally-effective dose of 200 mg/day.8 Phase 3 trials in hepatitis B are ongoing.
Telbivudine (LdT) is a natural, HBV-specific nucleoside. In animal experiments (woodchucks), LdT produced marked viral load reduction (8 to 10 logs). In a phase 2 clinical trial, LdT was more potent than lamivudine in suppressing HBV replication, but the combination of LdT and lamivudine was not superior to LdT alone. The results of that trial are summarized in Table 4. Patients who received LdT (either alone or in combination with lamivudine) had a 6.1-log decrease in HBV DNA, compared to a 4.6-log decrease in the group that received only lamivudine-a statistically significant difference. The LdT-only group also had a significantly higher rate of ALT normalization than the lamivudine-only group. However, more potent viral suppression did not translate into a higher rate of HBeAg loss. YMDD mutations occurred in all three groups, with the lowest rate in the LdT-only group (5%, compared to 16% with lamivudine only). All three treatments had similar side effect profiles.9
Clevudine (CLV or L-FMAU) is a nucleoside analog which is unique in having a very long half-life (>40 hours). Figure 3 shows the results of a phase 2 clinical trial, evaluating 4 different doses of CLV (10, 50, 100, and 200 mg/day). After 4 weeks of treatment, all 4 doses produced HBV DNA decreases, ranging from 2.5 logs (with the 10 mg dose) to 3 logs (with the 100 mg dose). When treatment was stopped, HBV DNA remained suppressed for up to 6 months.10
This sustained effect suggests that a short course of CLV may produce long-term suppression. However, the optimal dose, dosing interval, and treatment duration have not yet been determined.
Tenofovir, a nucleotide analog similar to adefovir, has been approved for HIV treatment. It has in vitro and in vivo activity against both wild-type and lamivudine- resistant HBV, but has not been thoroughly evaluated as a therapy for hepatitis B. Limited clinical evidence suggests that TFV (300 mg/day) decreases serum HBV DNA levels by a mean of 4.5 logs (range, 3.4 to 7.3 logs)11-a greater degree of suppression than that observed with adefovir (10 mg/day). It also appears to have less potential for nephrotoxicity than adefovir. TFV therefore deserves further study as a hepatitis B treatment.
In a much earlier stage of development are two new antiviral agents, LB 80380 and ACH-126,433 (Beta-L-FD4C). LB 80380 is a nucleoside phosphonate prodrug with in vitro activity against wild-type and lamivudine-resistant HBV. In vitro studies also suggest that it is less nephrotoxic than adefovir. Preliminary data are available from a phase 2A dose-finding trial. After 4 weeks of treatment, the higher doses of LB 80380 produced a 3- to 4-log decrease in serum HBV DNA, and were well tolerated.12
ACH-126,443 has been shown to have in vitro activity against wild-type and lamivudine-resistant HBV. Preliminary data from a phase 2A clinical trial were recently presented. Three different doses (5, 20, and 50 mg/day) were evaluated. After 12 weeks of therapy, pooled data from all patients showed an approximately 3-log decrease in serum HBV DNA.13 However, there are concerns about bone marrow toxicity at the higher doses.
Many new antiviral agents are on the horizon. Of the new agents discussed, ETV and LdT (particularly entecavir) appear to produce the most potent viral suppression and the least drug resistance compared to lamivudine. Comparative data with adefovir are not available.
LdT, FTC, and CLV are cross-resistant with lamivudine. Entecavir, LB 80380, and ACH-126,433 have in vitro activity against lamivudine-resistant HBV, but in vivo activity has been confirmed only for entecavir.
For many years, a need for combination therapy has been recognized; however, the promise of combination therapy has not yet been fulfilled. For example, in one study the combination of LdT and lamivudine appeared to be less effective than LdT alone, suggesting a possible antagonistic effect between the two drugs. However, further research may yet discover combinations that will improve the rate of sustained viral suppression in chronic hepatitis B patients.