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发表于 2002-11-24 01:08
53rd American Association for the Study of Liver(AASLD)
Diseases Annual Meeting
November 1-5, 2002, Boston MA
By Mack C. Mitchell, MD
Introduction
The last 5 years represent an exciting period in the understanding and treatment of chronic hepatitis B infection. In this time, the efficacy of treatment of chronic hepatitis B infection has increased dramatically.
Nucleoside analogues and interferon-Alfa are both effective in treatment of HBV. The lower side effect profile of the nucleoside analogues has made them preferred agents for first-line therapy, although concerns about resistance developing during monotherapy has tempered enthusiasm somewhat.
At this year’s meeting of the 53rd AASLD, there were several reports on newer nucleoside analogues including Hepsera (adefovir dipivoxil), entecavir, Coviracil (emtricitabine; FTC) and telbivudine (formerly LdT), and a report on Pegasys (pegylated interferon-alfa 2a) as well as follow-up studies on the use of Epivir-HBV (lamivudine; 3TC).
Phase III Trial of Hepsera (Adefovir Dipivoxil) in Treatment of Lamivudine-Resistant HBV (Abstract 831)
Epivir HBV (lamivudine) is currently the standard of care for pre- and post-transplant treatment of advanced chronic hepatitis B infection. Treatment with lamivudine is effective in preventing hepatic decompensation in most patients pre-transplant. The combination of lamivudine and treatment with HBIG is highly effective in preventing recurrence of hepatitis B after liver transplantation. The main drawback to lamivudine monotherapy is development of resistance (YMDD) in a significant percentage of patients.
Dr. Schiff and colleagues reported experience in an open-label, non-randomized trial of adefovir dipivoxil for treatment of patients who had developed resistance to lamivudine. ALT normalization was achieved in 60% of both pre- and post-transplant patients.
Undetectable levels of HBV DNA (< 400 copies/ml) were achieved in up to 50% of patients after 48 weeks and up to 70% after 96 weeks.
The median reduction in DNA levels was 4.1 logs after 48 weeks. Serum creatinine elevations were noted in a proportion of patients, most of whom also had multiple risk factors for renal damage such as concomitant use of nephrotoxic immunosuppressants. Overall 2% discontinued treatment due to renal toxicity.
These findings indicate that adefovir is effective in treatment of patients with lamivudine resistance, but remind us of the need to monitor carefully for nephrotoxicity during therapy.
Effects of Adefovir on Liver Histology and Viral Suppression at 48 Weeks (Abstract 840 and 841)
Analysis of the first year of the phase III trial of adefovir in patients with HBeAg + CHB was presented by Dr. Goodman and colleagues. Primary endpoints in the trial included a two-point reduction in the inflammatory component of the Knodell HAI score. This was achieved in 53% (p = NS) of patients treated with adefovir 10 mg daily and 59% (p < .0001) of those treated with 30 mg daily compared to 25% of placebo treated patients.
Improvement in the 6-point Ishak fibrosis score was also evaluated. Improvement of > 1 stage was seen in 35% of those treated with 10 mg daily and 41% of those treated with 30 mg daily. Significant improvements in the overall fibrosis scores (2.20 pre to 1.95 post-treatment) were seen in the 10 mg daily group. In addition, fewer patients treated with adefovir (11%) showed evidence of worsening compared with those on placebo (22%).
After 48 weeks, the HBeAg seroconversion rate was 12% for the 10 mg daily group compared to 6% of those on placebo. Seroconversion increased to 20% after 72 weeks. HBeAg loss was much higher—24% at 48 weeks and up to 40% at 72 weeks. ALT normalization was observed in 48% of the 10 mg daily group compared to 16% of placebo recipients. HBV DNA was < 400 copies/ml in 21% of patients on adefovir and an additional 21% of 71 patients who continued therapy beyond 48 weeks had undetectable levels of HBV DNA.
Of note, no resistance to adefovir was observed in any patients during the entire duration of the study, which is a distinct difference from the results reported previously for lamivudine monotherapy.
The Roche Amplicor assay is much more sensitive than the Abbot hybridization assay used in the original lamivudine studies which makes direct comparison of the results of those trials with this one problematic. In the lamivudine trials, the 52-week seroconversion rates were somewhat higher (15-16%) in the treated group with a similar rate of seroconversion (4-5%) in the placebo group.
Direct comparison between lamivudine and adefovir was not included and it is hard to know whether the study populations were comparable. Since seroconversion rates are highly dependent on pre-treatment ALT levels, the differences may not be clinically important.
Eradication of cccDNA from the Liver in Patients on Adefovir (Abstract 534)
Complete eradication of HBV has proven to be a difficult problem despite the availability of several anti-viral agents that are potent inhibitors of viral replication. In part, HBV is difficult to eradicate because of the persistence of the covalently closed circular DNA (cccDNA) which serves as the template for viral replication. Measurement of this pool of HBV requires liver biopsy since the cccDNA does not circulate in the plasma. In general, very little is known about how this pool of virus is affected by antiviral therapy.
During the phase III trial of adefovir dipivoxil, cccDNA was measured in liver biopsy specimens obtained at baseline and after 48 weeks of therapy with adefovir. Interestingly, those patients who seroconverted had lower baseline levels of cccDNA (median 0.62 copies/cell) than those who did not seroconvert (1.66 copies/cell). Treatment with adefovir lowered cccDNA to a similar extent in both groups (93% vs 83%). Final levels of cccDNA as well as the baseline levels were lower in the seroconverters than in those who had persistent HBeAg. At this time, it is unclear whether cccDNA levels must be lowered below a particular range to achieve a sustained response, but the results are intriguing.
Entecavir for Treatment of Lamivudine-resistant Chronic HBV (Abstract 550)
Entecavir is another one of the next generation of nucleoside analogues with potent, anti-HBV activity now in clinical trials for treatment of chronic HBV infection. This report is from an international, multicenter trial of entecavir in patients who failed therapy with lamivudine based on either the presence of YMDD mutation OR with persistently positive serum HBV DNA (> 10 mEq/ml on the Quantiplex bDNA test) AND persistent elevation of ALT after at least 24 weeks of treatment with lamivudine.
181 patients were divided into 4 groups (.1, .5 and 1.0 mg entecavir daily or continued treatment with lamivudine 100 mg daily) for 48 weeks of treatment. Results are summarized in the table below:
Drug ALT Normal HBV DNA log decrease HBV DNA negative
Entecavir 1 mg 43%* 2.78* 4%
Entecavir .5 mg 59%* 4.46* 26%*
Entecavir 1.0 mg 68%* 5.11* 26%*
Lamivudine 100 mg 4% 1.41 4%
p < .05
These findings suggest that entecavir is effective in treatment of patients who have developed YMDD resistance to lamivudine. Results of seroconversion are not yet analyzed, but will be presented within the next few months, perhaps at EASL. Within the time of study, no patients developed evidence of resistance to entecavir.
Side effects were similar in all groups and included headache, abdominal pain and fatigue.
Emtricitabine Follow-on Study for Treatment of Chronic HBV for 96 weeks (Abstract 838)
Emtricitabine; FTC (Coviracil) is a nucleoside analogue that is structurally similar to lamivudine. Results of an open label follow-on study for an additional period (96 weeks) were reported at this year’s meeting. The original phase III RCT was conducted for 48 weeks. During the first year, 50% of patients lost HBeAg, 23% seroconverted to HBeAb and HBV DNA decreased by a median of 2.92 log and was undetectable (< 4700 copies/ml) in 55%. Resistance to emtricitabine developed in 6% of those treated. Because of the structural similarity of emtricitabine, it is unlikely to be effective in treatment of YMDD-lamivudine resistant HBV.
Sustained virologic responses were observed in 41% of patients with 19% resistance after 96 weeks of therapy. Favorable serological responses including a seroconversion rate of 29% and HBeAg loss of 51% were also reported. Unfortunately, the study design allowed inclusion of a significant number (64 pts) who had not previously been treated with a nucleoside analogue. Those patients who developed resistance experienced an increase in ALT, but had a favorable evolution.
The rate of seroconversion observed in the randomized controlled trial makes this nucleoside an interesting possible addition to the therapeutic options for treatment of chronic HBV. However, longer experience will be needed to determine whether the rate of resistance increases further with prolonged therapy.
Telbivudine for Treatment of Chronic HBV (Abstract 554)
Telbivudine (LdT), a small nucleoside analogue, is a potent inhibitor of HBV polymerase in vitro. The results of a phase II dose escalation study indicated that 400-600 mg/day rapidly reduced HBV DNA levels by 3-4 logs from baseline values. 104 HBeAg positive patients with elevated ALT were enrolled in a phase IIb trial to receive LdT 400 or 600 mg daily alone or with lamivudine 100 mg daily for 24 weeks.
3T LdT400 LdT600 LdT400 + Lam LdT600 + Lam
Median log10 drop 4.67 6.08 6.11 6.21 6.15
HBV neg by PCR 16% 41% 23% 29% 35%
As shown in the table above, Telbivudine resulted in a dramatic decrease in the HBV DNA levels within a relatively short time. ALT normalized in 70-80% of all groups over the same 24 week interval. Previous data have suggested that rapid decrease in HBV DNA leads to a much lower rate of development of resistance and may also translate into a higher rate of seroconversion. The follow-up from this study is not yet long enough to determine rates of HBeAg seroconversion or to know about the pattern of resistance that may or may not develop. However, the rapid decrease in HBV DNA is an exciting observation.
Treatment of HBeAg Negative, HBV DNA positive Chronic HBV with Lamivudine (Abstract 835)
In some patients with chronic HBV, active viral replication continues after HBeAg seroconversion. Active viral replication in this group usually indicates the presence of the pre-core or core promoter mutation, which allows the intact virus to be made without expressing the E antigen. Since these patients can have progressive liver disease, treatment may be warranted.
This study reported experience in treating HBeAg negative, HBeAb positive, HBV DNA positive chronic hepatitis B. Lamivudine (100 mg) was given daily for an average of 24 months. 421/443 patients had an initial virologic response, which was 88% at 1 year and decreased to 66.2% at 2 years, 51.5% at 3 years and 42.5% at 4 years. During therapy YMDD resistance developed in 31.4% of patients. In 34/139 patients a flare in hepatitis (elevated ALT) occurred.
The outcome of these flares in ALT depended on the baseline histology and clinical status of patients. In those with only chronic hepatitis, there were no cases of hepatic decompensation, but in those with Childs A cirrhosis, 6/15 (40%) developed decompensation and 2/15 (13%) died. Even worse outcomes were seen in those with more advanced disease, 4/5 patients with Childs B/C cirrhosis decompensated and 3/5 died. Hepatocellular carcinoma developed in 4.6% of those without YMDD and in 10.7% of those with YMDD mutations (results were not statistically significant).
These observations highlight the importance of the extent of liver disease at baseline in determining the ultimate outcome of HBV with or without treatment. Other studies have shown clearly that lamivudine can improve clinical status (decrease Childs-Pugh scores) and reduce fibrosis. However, this study sounds a cautionary note for physicians who are following patients with advanced stages of HBV. Any evidence of elevation of ALT should be monitored carefully and alternative therapy such as adefovir should be considered if there are signs of hepatic decompensation.
Lamivudine for the Treatment of Fulminant Hepatitis B Infection (Abstract 848)
Fulminant hepatitis B is a rare (1%) complication of acute hepatitis B infection. The mortality rate for fulminant hepatitis B is approximately 50% without liver transplantation. Lamivudine has been shown to be very effective in treatment of chronic hepatitis B infection, including those patients with advanced liver disease, but has generally not been used for treating acute hepatitis B, which is usually a self-limited illness.
Tillman and colleagues reported that lamivudine treatment significantly reduced the length of stay in the ICU (5.4 ± 5.9 days for lamivudine vs 21.2 ± 28.8 days for standard therapy) and the need for liver transplantation (16/21 with standard therapy vs 1/8 lamivudine treated). Although the study was not randomized, the differences between the groups were both statistically significant and impressive. These findings justify a randomized controlled trial of lamivudine or other antiviral agents given the shortage of donor organs for transplantation which is needed in many patients with fulminant hepatitis B infection.
Prevention of Reactivation of Hepatitis B in Patients Treated with Chemotherapy (Abstract 836)
The immune system plays an important role in suppressing replication of hepatitis B in patients, who remain HBsAg positive, with chronic hepatitis B. Previous studies have reported relapse of clinical hepatitis in patients who have been treated with anti-neoplastic chemotherapy or other immunosuppressive regimens. Viral replication is reactivated during the time of immunosuppression and when discontinued, the larger amount of virus present stimulates an exaggerated immune response that can lead to severe exacerbations in chronic hepatitis. Since lamivudine is effective in suppressing viral replication, the investigators reasoned that pre-treatment with lamivudine before administration of chemotherapy might prevent serious relapses following chemotherapy.
Patients were treated either with lamivudine before beginning chemotherapy or at the time of diagnosis of reactivation of hepatitis B infection. One of the 11 patients pre-treated with lamivudine had evidence of clinical hepatitis, whereas 5/11 not pre-treated developed reactivation hepatitis that was severe in 3 patients with a fulminant course in 1/3. On the basis of this observation, the authors concluded that lamivudine pre-treatment was preferable to waiting for evidence of reactivation in patients with chronic HBV undergoing chemotherapy.
Pegylated (40 kDa) Interferon-alfa 2a (Pegasys) for Chronic HBV Infection (Abstract 846)
Although much of the recent attention has been focused on nucleoside analogues for treatment of CHB, interferon remains an alternative therapy. Patients and physicians have generally resisted use of interferons because of expense, side effects and the fact that it must be administered by injection. Furthermore, standard interferon dosing regimens were not very effective in producing HBeAg seroconversion in patients with low ALT and high HBV DNA levels.
The advent of pegylated interferons has simplified treatment to a once weekly injection regimen that appears to have somewhat fewer side effects than the high dose (5 MU) daily injections of α-interferon.
Cooksley and his colleagues reported on the use of 40 kDa pegylated α-interferon 2a (Pegasys) for treatment of HBeAg positive CHB. Patients were given weekly injections of 90, 180 or 270 μg of Pegasys or 4.5 million units three of interferon α2a, three times weekly for a total of 24 weeks.
At the end of an additional follow-up period of 24 weeks, 24% of patients treated with Pegasys had lost HBeAg, normalized ALT and suppressed HBV DNA to < 500,000 copies/ml (Roche Amplicor assay) compared with 12% of those treated with standard α-interferon 2a (p < .05).
Subset analysis indicated that patients with ALT > 5 x ULN had the highest rates of HBeAg loss, suppression of HBV DNA and normalization of ALT (29%), with similar results for both Pegasys and interferon alfa-2a. However, patients with ALT 2-5 x ULN and < 2 x ULN derived more benefit when treated with Pegasys compared with the standard interferon.
The combined response of HBeAg loss, HBV DNA suppression and normalization of ALT occurred in 27% vs 11% for ALT < 2 x ULN and 22% vs 7% for ALT 2-5 x ULN for Pegasys-treated patients. A similar observation of improved efficacy was noted in those patients with high DNA levels.
Several points are worth noting about these findings.
Although statistical significance was not achieved in the subset analyses because of relatively small numbers, the results are intriguing. There is a clear suggestion that those patients who are traditionally most resistant to treatment (high DNA levels and low ALT) are the ones who will benefit the most from pegylated interferon. This is an important observation if it holds up since there are many patients who fall into this category and were previously not believed to be good candidates for lamivudine or standard interferon dosing because of lack of efficacy.
Although seroconversion to HBeAb was not reported, the loss of HBeAg and ALT normalization was relatively high (comparable to nucleoside analogues). Presumably, as reported with other studies of interferon treatment in CHB, seroconversion to HBeAb may be delayed for up to 1 year after completion of therapy.
It was somewhat surprising that suppression of HBV DNA to < 500,000 copies was used as an endpoint, since most recent studies of adefovir and other nucleoside analogues have used detection limits of < 400 copies/ml as an endpoint.
Conclusions
In 2002, we finally have several options for the treatment of chronic hepatitis B infection. Two nucleoside analogues (lamivudine and adefovir dipivoxil) and interferon alfa-2b (PEG-Intron) are FDA-approved for therapy. The nucleoside analogues can be taken orally and have fewer short-term side effects than interferon, but require a longer course of treatment to achieve HBeAg to HBeAb seroconversion.
Patients on lamivudine (Epivir-HBV) monotherapy develop resistance with courses of treatment more than 6-12 months, with rates approaching 60% after 4-5 years of therapy. However, seroconversion can occur after development of resistance.
Resistance to adefovir has not yet been reported, but the rate of seroconversion is somewhat lower than for lamivudine. The potential for adefovir-associated nephrotoxicity requires cautious use in patients with pre-existing renal disease or who are at high risk for developing kidney problems. Other patients tolerate the approved dose of 10 mg daily with relatively few side effects.
The course of interferon is shorter (4-6 months) with seroconversion rates similar to 1 year on nucleoside analogues (15-20%), but short-term side effects of fatigue, arthralgias, headache, fever, etc make some patients reluctant to complete therapy.
While side effects of the pegylated interferons are similar, the seroconversion rates may be higher, particularly for the high HBV DNA, low ALT subgroup. The highest response rates for all drugs are seen in those patients with ALT > 2 x ULN and active inflammation on liver biopsy. Because of the risk of progression of disease in this group, strong consideration should be given to treatment with one of the 3 available drugs or inclusion in a clinical trial of newer agents.
References
AASLD 2002 all rights resrved
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