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发表于 2002-2-7 01:16
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Selected Highlights from
Drug Development for Antiretroviral Therapies 2001 (Hep DART 2001)
December 16-20, 2001, Maui, Hawaii
By Mark Nelson
Dr Nelson is Lead Clinician for HIV inpatient services at Chelsea & Westminster Hospital in London and Deputy Director of the Research Department at the hospital.
Introduction
The majority of antiviral research thus far has been performed on individuals infected with HIV.?However, it is clear that there are many more individuals infected with the hepatitis viruses compared with those with HIV.?Worldwide, 370 million individuals have hepatitis B virus (HBV) infection; 180 million are infected with hepatitis C virus (HCV) infection, compared with 30 million with HIV.?The deaths per year are similar between HBV and HIV at approximately one million a year, and around 250,000 individuals will die yearly due to complications from HCV.
Hep DART 2001 Focus and Program Highlights
Sponsored by Northwestern University Medical School, HEP DART 2001 assembled clinicians, researchers and basic scientists together to advance? knowledge of ongoing drug development processes in the treatment of hepatitis B and hepatitis C.
The conference program included sessions covering the following topics:
Pathogenesis and Immunology of the Hepatitis Viruses
Epidemiology and Emerging Viral Issues
Viral and Cell Dynamics Quasispecies and Quantitation of Hepatitis Viruses
Public Health and Outreach Efforts
Next Generation of Hepatitis Inhibitors
Cell Cultures and Animal Models for Hepatitis B and C
Impact of Drug Resistance
Optimizing Outcome of Therapeutics for Hepatitis Infections and Pediatric Issues
Therapeutic Modalities in Patients Co-Infected with Hepatitis and Other Viruses
Improved Therapeutic Modalities for Hepatitis Infections and Vaccines
Liver Damage, Fibrosis and Hepatocellular Carcinoma
Treatment of Hepatitis B and C
As eradication of HBV is difficult, the goal of HBV treatment has been the suppression of viral replication with improvements in hepatic necroinflammatory disease and the reduction of long-term sequelae. Currently, there are only 2 approved treatments for hepatitis B: Intron-A (interferon alfa-2b) and Epivir-HBV (lamivudine, 3TC).
Epivir-HBV may also be of use in individuals with hepatic fibrosis with 67% of individuals showing improvement in fibrosis score when YMDD resistance has not developed, but only 40% where the YMDD resistant mutation is present. However 4% of individuals without the YMMD change developed further fibrosis, whilst 19% with the YMDD change had increases in their fibrosis score.
Two additional potentials uses of Epivir-HBV were discussed. Firstly, in the prevention of perinatal infection and secondly the possibility of using it to prevent nosocomial spread of HBV. [Abstract 037].
Mothers with high levels of HBV, despite standard hepatitis B immunoglobulin and vaccination of the child, may still transmit HBV in up to 25% of cases. A group from Rotterdam has presented data on three such mothers who were treated with Epivir-HBV from week 36 of pregnancy, followed by standard vaccination with hepatitis B immunoglobulin and hepatitis B vaccination of the infant. In the 3 infants at 12 months of follow up, none were HBsAg (hepatitis B surface antigen) positive compared with 4 out of 4 in a historical group.
Emergence of drug resistant virus in HBV-infected individuals treated with Epivir-HBV is well documented. This commonly occurs as a M552V/I mutation with resistance further enhanced by a further mutation at L528M in the hepatitis B viral polymerase. The 552 mutation is analogous to the M184V/I which occurs in HIV reverse transcriptase when it is exposed to this drug. Further mutations in the HBV polymerase are now described.
In one study [Abstract 032] 31 individuals with chronic HBV who completed at least 104 weeks of Epivir-HBV therapy were investigated. Resistant virus was detected in 7 of the individuals between 9 and 18 months of therapy. Of the 7 patients, 6 were HbeAg (hepatitis B e antigen) positive at baseline, and 4 had a double mutation consisting of RTM204V and RTL108M. Two had a RTM204I switch. In one patient two base substitutions at RTM204 leading to a methionine to serine change were detected as a novel DNA mutation at month 18. This new variant indicates new codon changes conferring Epivir-HBV resistance in vivo.
The gold standard therapy for HCV is interferon in combination with weight adjusted ribavirin. Individuals with genotype I should receive therapy for 48 weeks, however, interferon and ribavirin for genotype 2 and 4 showed similar viral response at both 24 and 48 weeks. Pegylated interferon appears more effective than interferon with improved compliance due to the once daily dosing and possible reductions in toxicity
Acute Hepatitis C Virus Infection
Although most acute infections with HCV are asymptomatic approximately 25% of individuals will develop symptoms, commonly flu-like with arthralgia and malaise and occasionally jaundice. The outcome of acute HCV infection is that approximately 80% will develop chronic infection with the remaining 20% making a spontaneous recovery. Of those individuals who go on to develop chronic infection, there is a high probability of developing hepatitis with possible progression to cirrhosis and hepatocellular carcinoma. Individuals who develop a symptomatic infection may be more likely to spontaneously recover, than those who remain asymptomatic. The treatment of those individuals who are found to have acute hepatitis C has been unclear.
Manns and colleagues reported the results of a German multicentre study of interferon for acute HCV infection. The premise behind treatment is that early control of viral replication will prevent depletion or loss of virus specific cytotoxic T cell responses, and also prevent diversification of HCV viral epitopes. In addition, the lessons learnt from HIV, would suggest that early treatment of infection may lead to sustained control of viral replication. 44 individuals were recruited to this study. They received 5 million units of Intron-A (interferon alfa-2b) daily for 4 weeks, and then 5 million units three times a week for 24 weeks.
Follow up to 48 weeks was reported. Of the 44 individuals, 21% were intravenous drugs users, 23% were infected sexually, 16% from medical procedures, and 32% from a needle stick injury. In 9% of individuals the source of hepatitis C was unknown 43% were male, and 68% of patients developed jaundice. The mean age was 36.7 years. HCV genotype 1 was the present in 61% of the patients. The viral load was 418,000IU/L at the time of initiation of therapy. Individuals were treated at a mean of 87 days post infection. Virological response at 24 weeks was 100% with a 98% response rate at 48 weeks. Treatment with interferon therefore was recommended by the authors for individuals with acute symptomatic hepatitis C infection. Although there was no control cohort, if compared with the results of another study from Bari in individuals with acute hepatitis C who were not treated, the natural course of infection showed that only 30% (12 of 40) of individuals spontaneously cleared 24 weeks post diagnosis.
The real problem at the present time is to try and find which individuals will spontaneously clear, and which ones will not. This treatment used interferon alone, but it should be noted that this was a potentially highly compliant group being made up of mainly non-IVDU individuals. A new study with pegylated interferon has commenced to try to examine whether there can be any better results although as the presenter pointed out this is difficult with 98% of individuals responding.
Other Viral Infections
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