- 现金
- 3700 元
- 精华
- 16
- 帖子
- 1790
- 注册时间
- 2002-12-9
- 最后登录
- 2021-4-14
|
2楼
发表于 2004-4-8 10:04
Lamivudine
LdT 400
LdT 600
LdT 400 + Lam
LdT 600 + 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
Unless otherwise stated, all references are to the Program and Abstracts of the 53 Annual Meeting of the American Association of the study of Liver Diseases. November 1-5, 2002. Boston, MA. Published in Hepatology Vol 36, No 4, Part 2 of 2. October 2002.
Schiff, E; Lai, C; Neuhaus, P; et al. Adefovir dipivoxil (ADV) for the treatment of chronic hepatitis B in patients pre-and post-liver transplantation (OLT) with lamivudine-resistant (LAM-R) hepatitis B virus (HBV) patients. Abstract 831.
Marcellin, P; Chang, T; Lim, S; et al. Adefovir dipivoxil (ADV) 10 mg for the treatment of patients with HBEAG+ chronic hepatitis B: Continued efficacy beyond 48 weeks. Abstract 840.
Goodman, Z; Marcellin, P; Chang, T; et al. 48 weeks of adefovir dipivoxil (ADV) results in improvement in fibrosis and decreased progression of fibrosis in a double-blind, randomized, placebo-controlled study for the treatment of patients with HBEAG+ chronic hepatitis B. Abstract 841.
Werle, B; Wursthorn, K; Bowden, S et al. Quantitative analyses of hepatic HBV CCC DNA during the natural history of chronic hepatitis B and adefovir dipivoxil therapy: An international, multicenter study. Abstract 534.
Chang, T; Hadziyannis, S; Cianciara, J et al. Sustained viral load and ALT reduction following 48 weeks of entecavir treatment in subjects with chronic hepatitis B who have failed lamivudine. Abstract 550.
Gish, R; Leung, N; Wang, C et al. Antiviral activity, safety, and incidence of resistance in chronically infected hepatitis B patients (CHB) given once daily emtricitabine for 2 years. Abstract 838.
Lai, C; Leung, N; Teo, E et al. International multicenter trial of LDT (telbivudine), alone and in combination with lamivudine, for chronic hepatitis B: An interim analysis. Abstract 554.
Di Marco, V; Lampertico, P; Marzano, A et al. Long term lamivudine in patients with anti-HBE/HBV- DNA positive liver disease. Abstract 835.
Tillmann, H; Wedemeyer, H; Hadem, J et al. Early lamivudine therapy may prevent liver failure in patients with fulminant hepatitis B. Abstract 848.
Lau, G; Ngan, R; He, M et al. A randomized study of lamivudine for prevention of HBV reactivation in HBSAG positive patients undergoing cytotoxic chemotherapy. Abstract 836.
Cooksley, W.G.; Lai, M; Piratvisuth, T et al. HBEAG-positive chronic hepatitis B (CHB) patients with difficult-to-treat disease: Improved response rates with Peginterferon Alfa-2A (40KD) (PEGASYS®) Compared with conventional Interferon Alfa-2A. Abstract 846.
|
|