2001年世界肝炎大会: 回顾和重点-->可可转移

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(顺便贴过来, 大家有时间可以一同翻译探讨) 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 Hepatitis GB (aka Hepatitis G) It appears that the whole alphabet will soon be involved with new hepatitis viruses. Hepatitis A to E are well recognized, although hepatitis F appears to have been a false alarm. Hepatitis GB, which is synonymous with hepatitis G virus, was first isolated from a surgeon who developed hepatitis (with the initials GB in the 1950's). This agent is parentally transmitted and can result in a persistent infection. In controlled studies of transfusion and community acquired hepatitis, hepatitis G appears to have no specific association with clinical hepatitis and no influence on co-existent hepatitis C virus infection. Therefore this virus's designation as a hepatitis virus appears to be a misnomer. In recent months there has been great excitement over the fact that individuals infected with HIV who remain chronically infected with hepatitis G, have an improved survival compared with those individuals who are hepatitis G antigen negative. Two studies have recently shown this and have shown not only an improved overall survival, but also a reduction in the development of AIDS, and survival in the post HAART era. The reasons why this is the case are unclear, although in vitro cells pre-infected with hepatitis G fail to support replication of HIV. TTV Another virus recently studied by Japanese investigators, TTV, is a small non-enveloped circular virus of the circoviridiae family. TTV is found in approximately 7 to 12% of blood donors, although it may be more prevalent in certain geographical areas, especially Japan. The clinical significance of this agent is unclear. The incidence of new TTV infection in cases of non- A-E hepatitis does not differ in incidence in transfused individuals who did not develop hepatitis compared with those that do. In addition, TTV has no impact on both severity and persistence of co-existent HCV infection. Therefore at present, there is no known disease association for TTV. SENV A sub virus of TTV, SENV, may be associated with hepatic disease. There are at least 8 members of the SENV family, with major variation between them (approximately a 25% difference in nucleotide sequence). SENV-H and SENV-D have shown a close association with post transfusion hepatitis, although both are found in low prevalence in volunteer donor populations (around 2%). In studies prospectively following patients having undergone open heart surgery, SENV was found in 30.1% of transfused individuals compared to only 3.1% of identically followed surgical patients who were not transfused. This was highly significant (p < 0.001). A positive donor could be identified in 70% of cases and donor recipient transmission was proven by sequence homology. SENV has also been found in a high proportion (up to 60% of individuals) with established parental exposure. New SENV infections have been found in 92% of individuals with transfusion associated non A-E hepatitis compared to 24% of those who did not develop hepatitis. Clinical disease in such cases has been mild but 18% developed chronic hepatitis. The majority of individuals cleared this infection within one year. SENV has also been reported to occur as an acute co-infection in 41% of individuals developing hepatitis C, although the presence of this agent did not appear to affect the severity or persistence of hepatitis C. Pre-Core Mutants The presence in some individuals of pre-core mutants is well described, with these individuals being HbeAg negative but continuing to have evidence of viral replication when tested by double-stranded DNA. The commonest mutation in the pre-core region to cause this is G1896A acting as a stop codon. Changes may also occur at codons 1762 and 1764 giving similar laboratory results. These pre-core mutants may be associated with differing immunological changes compared with standard HbeAg-positive chronic HBV with increased CD8+ T cell activity to hepatitis B epitopes. The major problem with pre-core mutants is definition of end of therapy. A recent study of individuals with the pre-core mutant treated with standard doses of interferon showed at 12 months 25% had lost HBsAg, with 27% HBV DNA negative and 28% a normal ALT. A similar study with Epivir-HBV at 12 months in HBeAg negative individuals showed 70% had an HBV DNA below the level of detectability; however on stopping treatment a large percentage of these rebounded suggesting the importance of long-term therapy. However, it is known with extended therapy with Epivir-HBV that there is considerable development of resistance to Epivir-HBV and although initial benefits in histology have been shown, with the development of resistance there is an association with increased levels of DNA and worsening of liver histology. Interferon Non-Responders Despite the advances associated with pegylated interferon in the treatment of hepatitis C there are still a large numbers of individuals who either do not respond to treatment or who have a viral relapse once therapy is discontinued. Various factors may be associated with this failure and it may be due to viral, drug, host or environmental factors. Factors so far identified have included a poor response in genotype 1, high initial HCV viral load, increasing age, male sex and the presence of fibrosis. In addition, in studies with interferon alone, but not interferon/ribavirin, African - American race has been a poor prognostic factor. Increasingly the importance of adherence has been realized and in one study with pegylated interferon adherence of less than 80% with therapy was associated with a reduction in efficacy. HALT-C Study The HALT-C study examines individuals who have failed treatment with interferon either alone or with ribavirin, and aims to examine reduction in progression of hepatitis to cirrhosis, hepatocellular carcinoma and liver failure, in individuals who receive pegylated interferon (Pegasys) and ribavirin. To be eligible for the study, patients need to be HCV positive, have bridging fibrosis or cirrhosis present on liver biopsy and have been non respondent to at least 12 weeks of interferon therapy. Patients receive pegylated interferon and ribavirin and at week 20 a PCR is performed. If the PCR is negative patients continue therapy to 48 weeks, and if positive patients are randomized to cessation of therapy or maintenance therapy with pegylated interferon. So far 268 patients have been recruited with a mean age of 50. 72% are male and 88% Caucasian. Mean HCV viral load is 3.52 x 106 IU/mL, 84% of patients have genotype 1 and 41% are cirrhotic. 253 patients have reached week 20 with 15 patients having withdrawn. PCR is negative in 107 at 20 weeks (42.3% OT) Factors associated with poor response have been prior therapy with interferon and ribavirin compared with interferon alone, fibrosis and genotype non-2B/3A. 59 patients required dose reduction of interferon, ribavirin or both. Fibrosis The major consequence of the continued inflammation secondary to viral hepatitis is the development of fibrosis. This seems to be secondary to stellate cell activation leading to production of type I collagen resulting in progressive accumulation of extra cellular matrix in the liver parenchyma. Approaches to therapy for fibrosis include removal of the fibrotic stimulus, inhibition of stellate cell activation, the treatment of the consequences of the stellate cell activation, and the induction of apoptosis of hepatic stellate cells. The removal of the stimuli for hepatitis fibrosis has mixed results. In hepatitis B there is conflicting data over the ability of Epivir-HBV and interferon either alone or in combination to reduce fibrosis. However, in one study fibrosis worsened in only 2% of Epivir-HBV treated individuals versus 12% of a placebo group (p < 0.05). A recent trial of adefovir has demonstrated significant reduction of fibrosis progression versus placebo. A meta analysis of several studies of interferon +/- ribavirin or pegylated interferon/ribavirin for hepatitis C showed fibrosis worsening in ranges from 23% in patients treated with interferon alone for 24 weeks to 8% in patients receiving optimized pegylated interferon/ribavirin. All regimens significantly reduced fibrosis progression rates in comparison to the rates before treatment. In addition a reversal of cirrhosis was observed in 75 of 153 patients with baseline cirrhosis. 6 factors were independently associated with the absence of significant fibrosis after treatment. These were baseline fibrosis stage, sustained viral response, age younger than 40, a low body mass index, no or minimal baseline activity and viral load lower than 3.5 million copies. Hepatic stellate cell activation is associated with production of the cytokine TGF beta which inhibits intracellular matrix degradation and also activates hepatic stellate cells. Several TGF beta inhibitors have been isolated including comostat, mesylate, decorin and antibodies to both TGF beta and its receptor. These are presently being studied in animal models. As TGF beta is induced by the renin-angiotensin pathway, ACE II inhibitors have also been examined. These are known to reduce renal and cardiac fibrosis, and in animal models block hepatic fibrosis. Another group of agents that may be useful are anti-oxidants which protect hepatocytes from damage and also inhibit Kupffer and stellate cell activation. These include vitamin E, respiritol, quercetine, and salymarin (which is the active ingredient in milk thistle) and TJ9 which is an herbal preparation from Japan. Studies with these agents have shown no effect in alcoholic cirrhosis although a pilot study with vitamin E showed improvement in fibrosis in hepatitis C infected individuals as did a pilot study with glyceyrizine. In a large recent cohort analysis no definite effect of these alternative therapies was shown. Both gamma interferon and alpha interferon inhibit hepatic stellate cell activation. Gamma interferon has been shown to reduce fibrosis in animal models, and interferon alpha in multiple studies has shown a reduction of fibrosis in hepatitis C patients independent of virological response. As activated hepatic cells have low levels of PPAR gamma; antagonists of PPAR gamma are also under study as are endothelium antagonists. Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is now the fourth commonest GI tumor found in the United States. It appears to be especially common in black males. The rise in HCC has been linked to an increased incidence of both hepatitis C and hepatitis B. HBsAg positivity has a relative risk of 63 for developing HCC, and in high prevalent areas hepatitis C is associated with 60% of hepatocellular carcinomas. The HCV core protein appears to play an important role. Although HCV is not integrated within the liver, the core protein appears to be involved in stimulating large amounts of regeneration and remodeling of the liver. In HCV cirrhotics, the risk of development of HCC is 1-4% per year, although 43% of patients developing HCC will not have cirrhosis in the adjacent liver. Other risk factors for HCC include alcohol, metabolic diseases such as hemochromotosis and the use of estrogens and anabolic steroids. Treatment and prognosis for HCC continues to remain poor. In those patients not receiving therapy, 1 year survival is 54% and 3 year survival only 28%. In patients who are able to undergo surgical resection, i.e., those patients with small lesions, prognosis improved to 81% at one year and 44% at 3 years. However, less than 5% of individuals are suitable for surgical techniques. An alternative treatment is by ethanol injection which shows similar rates of prognosis (82% and 38%) as those undergoing surgical resection. Other local techniques would include local ablative therapies with agents such as TCA, and chemo-embolization and cryotherapy. The best survival is seen those individuals undergoing transplantation with survival rates of 84% and 74%. However, once more the number of patients suitable is small (those with a single tumor less than 5cm or three tumors each less than 3 cm in diameter). Indications for Epivir-HBV and interferon treatment are HBeAg positive with a raised ALT and a positive HBV DNA, or in the pre-core mutant, which is HBeAg negative, raised ALT and positive HBV DNA. There appears to be an increased therapeutic response in individuals with higher ALT levels, and recent guidelines have suggested individuals who have an ALT less than 2 times normal should not receive treatment as they are much less likely to respond. Treatment with either interferon for between 12 and 24 weeks, or treatment with Epivir-HBV for 52 weeks both lead to a loss of HBeAg in approximately 1/3 of individuals, with normalization of ALT occurring at a much higher rate than in controls. Recent studies have suggested that a longer than standard four month treatment with interferon therapy may lead to significant increases in the number of individuals who respond. Epivir-HBV is the treatment of choice in individuals with decompensated cirrhosis where interferon may be associated with further decompensation, bacterial peritonitis and sepsis. Whilst interferon has well known associated toxicity, the major drawback to therapy with Epivir-HBV is the development of resistance due to YMDD variants. These may occur in up to 66% of individuals at 4 years However, the emergence of YMDD variant does not always indicate the development of clinical antiviral resistance with some individuals continuing to sero-convert despite the development of resistance mutations. Recent guidelines suggest that treatment with Epivir-HBV should be stopped after seroconversion with loss of HBV DNA on two occasions at least 6 months apart. In individuals developing the YMDD variants the cessation of therapy should occur based on the clinical picture and increases in ALT and hepatitis B viral load. New Drugs for Hepatitis B and C Although there have been recent advances in the treatment of both hepatitis B and C new agents with increased efficacy and reduced toxicity are urgently needed. Several promising new agents were reported both in animal models and early clinical studies. Hepatic C protease inhibitors Similar to HIV, hepatitis C has a protease which is essential for viral replication. This protease differs from the HIV protease in that it is a serine protease which in hepatitis C has been ascribed to the NSV3 protein in concert with the NSV4 a co-factor. Several agents have been developed with activity against this protease which is a chemotrysin like serine protease with a shallow substrate binding region. The most likely inhibitor to enter clinical studies in the future is the Boehringer Ingelheim compound 8, which has been tested in cell cultures with an EC50 of between 76 and 440 nanograms depending on the system used. This compound has a low potential for drug interactions having low inhibition of P450, but is heavily protein bound (97.6%). In studies in the rat model, an oral dose has shown a plasma bio-availability of only 5%. Due to the high plasma protein binding the volume of distribution is low. New analogues of ribavirin Two new analogues of ribavirin were discussed. First of these levovirin is the L enantiomer of ribavirin which has a similar immunomodulatory activity as ribavirin, but without the associated toxicity. This drug has entered a phase I study at doses of between 200 and 1200mg and is well tolerated and orally absorbed. The other compound viramidine is a prodrug of ribavirin, which is converted to the active drug by adenosine deaminase within the liver. Viramidine itself has no anti-HCV inhibitor but when converted to ribavirin shows similar antiviral activity against DNA and RNA viruses. Within a monkey model a dose of 600mg per kg had no significant hematological toxicity in males although it was associated with 10% reduction in red blood cells in the female. This compares with ribavirin which showed an 11-14% loss of red blood cells in males and 23-25% in females. Calculation showed that the therapeutic index for this drug was 6 times better than for ribavirin. Ribozymes Ribozymes are catalytic RNA binders entailing a catalytic core with two binding arms which cleave target sequence allowing cell nucleases to destroy the viral RNA. Two ribozymes, one with activity against hepatitis B and one against hepatitis C were reported. Hep B zyme is targeted against the pregenomic RNA at the 31 terminus of the major transcript of hepatitis B. In cell systems their use led to a reduction in production of HBsAg and HBeAg. In a transgenic mouse model, doses of this ribozyme at between 30 and 300mg gave a viral load reduction of approximately 1.6-2.4 log compared with 3TC giving a reduction of approximately 2 log within this system. Ribozymes against hepatitis C are associated with significant reduction in HCV RNA production in vitro, and have a synergistic effect with interferon with a dose response effect of the ribozyme. In addition, they allowed a 12% reduction of interferon without loss of efficacy suggesting that this drug is useful in allowing dose reduction of interferon. In the mouse model, delivery by the sub-cutaneous route led to active levels of ribozyme with little toxicity apart from injecting site reactions and basophilia, probably secondary to an accumulation of the ribozyme in renal tubular cells and lymph nodes. A phase I study has commenced with individuals receiving doses of between 3 and 90mg for up to 28 days. So far the drug has been well tolerated with no abnormalities in laboratory parameters and no major patient toxicity. MCC478 MCC478 is a nucleotide analogue which has entered phase I studies, and shown comparable efficacy to Epivir-HBV. In cell cultures it appears more potent than adefovir and up to 100 times more potent than Epivir-HBV. In mice, MCC478 was less efficacious than adefovir which may have been related to problems of exposure to the drug, although in infected ducks MCC478 had similar efficacy to Epivir-HBV and adefovir. L nucleoside analogues The L nucleoside analogues are unnatural antiviral compounds which include Epivir-HBV. Other L nucleoside analogues have now been formulated including LdT, LdC and LdA, all of which are selective specific inhibitors of hepatitis B activity. They appear to be low in both mitochondrial and cellular toxicity and have good intracellular phosphorylation and activity in the wood chuck model. Pharmacokinetic studies of all these analogues would favor once daily therapy. LdC is not well absorbed and is presently being studied as a divaline ester. Antiviral activity of LdT in adults with chronic hepatitis B has been investigated in a dose escalation study. Patients received either 25, 50, 100, 200 or 400mg of LdT, and had serum HBV DNA levels monitored weekly. After 4 weeks of treatment the mean reduction of HBV DNA was 2.4, 2.7, 3.1, 2.9 and 3.63 log10 copies/mL respectively. The HBV DNA levels were subjected to an analysis of first phase (during week 1) and second phase (during weeks 2-4) clearance. All doses of LdT were associated with similar falls in HBV DNA during the first week, but in the second phase of HBV clearance exhibited a dose associated effect. In addition, when therapy was stopped there was a quicker return to baseline in those individuals receiving lower doses of therapy. Adefovir Adefovir has completed several studies showing anti-hepatitis B activity in individuals naïve to therapy and also in individuals who have previously been exposed to Epivir-HBV. Further data from study 437 was reported. This study evaluated the safety and efficacy of adefovir at two drug dose levels - 10mg and 30mg compared to placebo. A total of 515 individuals were randomized, 172 to adefovir 10mg daily, 173 to the 30mg arm daily and 170 to placebo. At week 48, 53% of the adefovir 10mg patients exhibited significant improvements in liver histology, with sero-conversion in 12% compared to 6% in the placebo arm. The median reduction serum HBV DNA in the 10mg arm was 3.52 log10 copies/mL compared with only 0.55 log10 copies/mL in the placebo arm. Reduction in ALT was also greater in the adefovir arms. Although the 30mg arm had greater antiviral efficacy, this arm showed increased toxicity with dose reduction necessary in 25% of individuals compared with 3% in the 10mg arm. In addition, a greater than 0.5 g/dL rise in creatinine occurred in 8% of individuals in the 30mg arm. Interestingly there was no evidence of resistance in those failing adefovir, although it is unclear why indeed these patients did fail. Adefovir clearly has activity against hepatitis B and an expanded access program was reported to be starting by Gilead in the first quarter of 2002. Entecavir Entecavir is a cyclopentile guanosine nucleoside analogue with selective activity against hepatitis B viral DNA polymerase. It is orally bioavailable, and due to a long terminal elimination half life of approximately 110 hours is clearly suitable for once daily therapy. Study 005 treated individuals who had active hepatitis B, both HBeAg positive and HbeAg negative, with well compensated liver disease. 136 individuals were randomized to receive entecavir at either 0.01, 0.1 or 0.5mg once daily, and a further group of 41 individuals received 3TC at the standard dose of 100mg daily. Over 50% of individuals in both groups were Asian. The median reduction in serum HBV DNA were 2.4, 4.3 and 4.7 log10 copies/mL with the 0.01, 0.1 and 0.5 mg doses, respectively, and a 3.4 log10 copy/mL drop with Epivir-HBV. The 0.1 and 0.5mg groups were significantly better in antiviral activity than the 0.01mg and the Epivir-HBV group. The 0.5mg arm performed significantly better than the 0.1mg arm. The other results of the study are summarized below. Study 014 is on going, with results available at 24 weeks. It studied individuals who had received and failed either greater than 24 weeks of Epivir-HBV or had the presence of the YMMD mutation. Individuals could be HBeAg positive or negative with compensated liver disease. Results of this study are summarized below. Phase III studies are presently recruiting, and clearly entecavir offers an important advance in therapeutic options for individuals with hepatitis B. Coviracil Coviracil (FTC, emtricitabine) is an L nucleoside with potent selective activity against both HBV and HIV. In some studies, it appeared to have greater potency in vitro than Epivir-HBV. Study 101 was a dose ranging study of hepatitis B infected individuals who received Coviracil at a dose of 25mg, 50mg, 100mg, 200mg or 300mg once daily for eight weeks. The antiviral activity was greater in all other arms compared with the 25mg arm. A second study, 102, examined individuals, 88% of whom were Asian, who were randomized to receive Coviracil at a dose of 25mg, 100mg or 200mg for 48 weeks. Mean viral load at baseline ranged between 7.42 and 7.68 log10 copies/mL. Individuals could be HBeAg positive or negative with active viral replication. Individuals were stratified in this study by viral load and previous exposure to Coviracil in study 101. The results of this study are summarized below. Only 3 patients discontinued the study due to adverse events, one of whom developed Hoenoch-Schonlein purpura. Grade 3 and 4 toxicity was low, being 9% in the 25mg arm, 3% in the 100mg arm and 6% in the 200mg arm. Clevudine Clevudine is biochemically similar to DFIAU, but does not appear to have the associated problems of mitochondrial toxicity and lactic acidosis production, at least in vitro. Experiments in the infected woodchuck model have shown this drug to be highly active at a dose of 10mg per kg once daily, producing a 9 log decrease in viral load with a dose dependent delay in the time to viral recrudescence. An open label phase I / II dose escalation study is underway, with patients receiving either 10mg, 50mg or 100mg once daily for 28 days. 24 of 25 individuals have completed the study protocol Median DNA reduction at day 28 was 2.48, 2.74 and 2.95 log10 copies/mL respectively. Interestingly, 5 months after the end of treatment the median decrease in HBV DNA was 1.91 log10 copies/mL in the 10mg arm, and 2.07 log10 copies/mL among individuals receiving 50mg of clevudine. In individuals who received 100mg once daily, data was only available to week 8 (one month post therapy cessation) with 5 available patients demonstrating a continued HBV DNA fall greater than 3 log10 copies/mL. ACH126443 ACH126443 is an L nucleoside analogue which is highly potent against both HIV and hepatitis B. In vitro there is no mitochondrial toxicity. Due to its susceptibility to stomach acid, it must be dosed with an antacid, although an enteric coated preparation is now available. Due to the high levels of drug that may be potentiality achieved, it may be active against Epivir-resistant HBV and HIV. Early results of a phase I b/ II clinical study are available, although it is important to realize that there are still placebo patients in each of the 3 arms therefore giving potential dilution of efficacy results. Results are available at day 14, and showed a drop in HBV DNA of 0.68, 1.43 and 1.74 log10 copies/mL in those receiving 1, 5 or 10mg, respectively. Clearly this drug does have activity against HBV, although much greater data needs to be made available before the manufacturers claims that this drug is "best in class" for both HIV and hepatitis B can be proven. Figure 1: Annual Infection and Death Rates for HBV, HCV and HIV HBV HCV HIV Worldwide Chronic infection x10⁶ 370 180 30 Deaths per year x 10⁶ 1.1 0.25 1 USA Chronic x 10⁶ 1.25 2.7 0.8 New 80 x 10^{3[sup] 35 x 10[sup]3} 40 x 10³ Deaths 5,000 8,000 18,000 Figure 2: Incidence of YMMD Variant with Continuing 3TC Year % 1 24% 2 38% 3 49% 4 66% Figure 3: Factors in Progression of Hepatitis Hep B Hep C Infant/Young child Age > 40 at the age of infection Immune deterioration Immune deterioration Male Male Alcohol Alcohol Co-infection Co-infection Figure 4: FTC Study 102 25mg 100mg 200mg BDNA < 4.7k 38% 42% 61% Loss of HBeAg 32% 38% 50% Seroconversion to HBeAb+ 23% 24% 23% Resistant mutations 12% 12% 6% Grade 3/4 toxicity 9% 3% 6% Figure 5: Entecavir Study 005 at Week 22 Dose Ent 0.01mg Ent0.1mg Ent 0.5mg 3TC 100mg Undetectable < 700K ml -1 23% 62% 84% 58% < 400 copies/ml 2% 27% 26% 18% Loss of HBeAg 0% 14% 0% 6% AE ?any 70% 69% 65% 73% AE grade ?o> 6% 11% 0% 10%