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| New Data on Viral Hepatitis and Related
Complications Source: CCO Independent Conference Coverage of the Digestive Disease Week 2006* *CCO is an independent medical education company that provides state-of-the- Overview The Digestive Disease Week (DDW) 2006 conference took place May 20-25, 2006, in Los Angeles, California. The conference, which presents the latest research in the field of gastroenterology and digestive diseases, is a collaborative effort between the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT). This report highlights the faculty members’ selection of the most important and clinically relevant new data related to hepatitis C, hepatitis B, and fatty liver disease presented at the meeting. Each presentation is briefly summarized, followed by commentary from the faculty on its implications. The following topics are discussed in this report: Hepatitis C a.. Data from the WIN-R Trial b.. Peginterferon Alfa-2a Retreatment in Previous Nonresponders c.. High-Dose Albumin Interferon in Prior Nonresponders d.. VX-950 Plus Peginterferon/ e.. Dose-Ranging Study of the Polymerase Inhibitor HCV-796 Response to HCV Therapy in Hispanic Patients f.. Peginterferon Plus Ribavirin in Adolescents with Genotype 4 HCV g.. Treating Hepatitis C in Patients With Thalassemia and Sickle Cell Disease h.. Eltrombopag for HCV-Associated Thrombocytopenia Hepatitis B a.. Entecavir Response at 96 Weeks in Lamivudine-Refracto b.. Histologic Improvement With Entecavir c.. Telbivudine vs Adefovir in HBeAg-Positive Patients d.. HBV Viral Breakthrough and ALT Flares e.. Treating Multidrug-Resistant HBV Fatty Liver Disease a.. Noninvasive Markers for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) Data from the WIN-R Trial Summary: At the DDW meeting, there were several presentations of data from WIN‑R, a large community‑based HCV treatment trial, which included 4913 treatment-naive patients at 225 US sites. Subjects were randomly assigned to receive 1.5 μg/kg/week of peginterferon alfa-2b plus either 800 mg/day of fixed-dose ribavirin or weight-based ribavirin doses ranging from 800-1400 mg/day. Afdhal and colleagues[1] presented data from an analysis of fibrosis and cirrhosis as predictors of sustained virologic response (SVR) in the WIN-R study; 4223 patients weighing > 65 kg were included. Liver biopsies showed that 654 patients had stage 0 fibrosis (15.5%), 1460 had stage 1 (34.6%), 1324 had stage 2 (31.3%), 975 had stage 3 (23.1%), and 500 had stage 4 (11.8%). Weight-based and fixed-dose ribavirin performed equally well among patients with fibrosis stages 0-2 (SVR, 45% vs 42%, respectively) Nezam H. Afdhal, MD: In this particular analysis, the goal was to look at fibrosis stages across all treatment groups and correlate fibrosis level with SVR rates using both univariate and multivariate logistic regression. The data showed that cirrhosis—or stage F4—was the predominant independent negative predictor of SVR. The results suggest that this relationship was as strong as the relationship between HCV RNA level and SVR. In particular, in multivariate analysis, one of the key findings was that cirrhotic patients with high baseline viral load were 1.58 times less likely to achieve SVR when compared with noncirrhotic patients with low baseline viral load (< 600,000 IU/mL). This is important to know because we often consider shortening treatment duration in patients with low viral load. Overall, the data emphasize the importance of knowing a patient’s clinical stage prior to treatment for HCV. Cirrhotic patients require optimal therapy, including the use of weight-based ribavirin. Summary: Another analysis from the WIN-R trial, presented by Brown and colleagues[2] Kris V. Kowdley, MD: The SVR rates in this analysis of genotype 2 and 3 patients were similar for the weight‑based and fixed‑dose ribavirin groups. While SVR rates were somewhat higher in the 24- vs 48-week group, it was determined that this was primarily due to missing data and a higher drop‑out rate during the second 6 months of therapy. In comparison with genotype 1 patients, weight‑based ribavirin dosing offers less of an advantage over fixed dosing in patients with genotypes 2 or 3. An interesting aspect of this analysis is the observation that compared with genotype 2 patients, those with genotype 3 had a lower SVR rate and a higher relapse rate; a previous study found that HCV genotype 3 patients with high viral load may also not respond as well as genotype 2 patients.[3] The authors speculate that we therefore may be better off using weight‑based ribavirin dosing for genotype 3 patients and possibly considering 48 vs 24 weeks of therapy. Nezam H. Afdhal, MD: Studies of this size have an advantage in that they allow us to evaluate predictors of response in genotypes 2 and 3 patients independently. The key point from this analysis is that genotype 3 does not appear to be identical to genotype 2. Perhaps we should think of genotype 1 as hard to treat, genotype 2 as easy to treat, and genotype 3 as intermediately difficult to treat. As we start to see data from larger studies, we may be able to tease out other subtle differences that were not apparent in smaller trials. Summary: In a third WIN-R analysis presented by Jacobson and colleagues,[ Nezam H. Afdhal, MD: This analysis looked at the effect of pretreatment viral load—using the sensitive TaqMan PCR assay—on SVR rates. By way of background, high HCV RNA level has traditionally been defined as an HCV RNA level of > 2 million copies/mL, or 600,000 IU/mL, without significant amounts of data supporting this cutoff point. In this study, the researchers compared patients using the traditional definitions of high viral load (> 2 million copies) or low viral load (< 2 million copies). Overall, they found the lower the viral load, the better the SVR. Because of the large study size, they were able to break down the patients with high viral load into several categories and better evaluate the relationship between viral load and response. The interesting finding was that, on the whole, once the HCV RNA level was above 2 million, patients had a poor SVR rate; it made no difference whether the HCV RNA was 2-5 million or more than 30 million. This is an important point to share with our patients because they are often concerned about specific numbers regarding their viral load. Kris V. Kowdley, MD: I do not know of other studies stratifying viral load in this manner and evaluating the relationship between viral load and SVR. This analysis is powerful, in that such a large study allows stratification on such a sensitive scale, and allows us to evaluate this type of question. I think it is interesting that viral load made such little difference once that threshold was reached. When the standard error numbers were evaluated, you can see that the SVR rates across groups were quite even. Peginterferon Alfa-2a Retreatment in Previous Nonresponders Summary: Gitlin and colleagues[5] presented data from the REPEAT trial, which assessed the safety and efficacy of peginterferon alfa-2a plus ribavirin in 950 prior nonresponders to treatment with 12 or more weeks of peginterferon alfa-2b plus ribavirin. Patients were randomized to receive 1000-1200 mg/day of ribavirin plus one of the following: a.. standard therapy with 180 μg/week peginterferon alfa-2a for 48 or 72 weeks; or a.. peginterferon alfa-2a 360 μg/week for a 12-week induction period followed by 180 μg/week for 36 or 60 weeks In the current analysis, the data were evaluated with regard to standard dosing vs induction dosing, regardless of treatment duration. In a planned interim analysis after 12 weeks, more patients with advanced fibrosis or cirrhosis achieved early virologic response (EVR), defined as an undetectable (< 50 IU/mL) HCV RNA or a ≥ 2-log10 decrease in HCV RNA, in the induction group compared with the standard therapy group (50% vs 38%, respectively) Kris V. Kowdley, MD: The concept in this study was to determine whether prior nonresponders could achieve superior results when retreated with higher peginterferon doses. This was an interim analysis, so these are on-treatment results for EVR. There was no difference in response rates between patients from Europe or Brazil and patients from the United States or Canada in the standard therapy groups, but the European and Brazilian patients did appear to have a higher response rate when compared to US or Canadian patients given 360 μg/week of peginterferon. However, all groups had somewhat higher EVR rates in the high-dose induction group. There was no significant difference in terms of safety or rates of serious adverse events between the standard-dose and high-dose group. Dose reductions occurred in fewer patients receiving the standard dose (16% vs 25%), which is not surprising. But, in terms of treatment discontinuation, only 2% of patients receiving the standard dose and 4% receiving the induction dose discontinued for safety reasons. In addition, the incidence of adverse events among patients with advanced fibrosis or cirrhosis was similar to that of the overall study population. This study is promising because it suggests that if nonresponders are retreated with higher doses of peginterferon plus standard or weight‑based doses of ribavirin, they may be able to achieve EVR. Even in cirrhotic patients, the EVR rates may approach 50%. This study bears watching, and we hope that these EVR numbers will translate into high rates of SVR. Nezam H. Afdhal, MD: The key here is that if one pushes up the dose of interferon, as has been done in the REPEAT trial and some consensus interferon trials, more patients have EVR and become HCV RNA negative. But we need to get some SVR data to make sure that we are not just converting this group of patients into relapsers. The answer to that question will be apparent at the final analysis. High-Dose Albumin Interferon in Prior Nonresponders Summary: Nelson and colleagues[6] presented data from a phase II dose-ranging study evaluating the safety and efficacy of high-dose albumin interferon in a group of patients who failed to respond to treatment with interferon-based therapy; nonresponse was defined as failure to achieve ≥ 2 log10 decrease or undetectable HCV RNA after 12 weeks of therapy. Patients received albumin interferon at doses of 900 μg or 1200 μg once every 2 weeks or 1200 μg once every 4 weeks by subcutaneous injection, in combination with 1000-1200 mg daily ribavirin. After safety data for these groups were evaluated, 2 higher-dose cohorts were enrolled, receiving 1500 or 1800 μg once every 2 weeks. In the current analysis, 48-week data were available for the 3 lower-dose groups, 24-week data for the 1500-μg group, and 12-week data for the 1800-μg group. After 12 weeks, virologic response was greatest in the 1800-μg cohort (median HCV RNA decrease, 3.7 log10 IU/mL), despite this group having a significantly larger proportion of prior peginterferon/ Nezam H. Afdhal, MD: Researchers are continually trying to develop novel ways to administer interferon in an attempt to improve efficacy and safety profiles as compared with standard formulations. Albumin interferon is composed of interferon alfa‑2b fused with human albumin using recombinant technology. The goal with this formulation is to produce a longer half‑life with a compound that is not immunogenic and potentially has greater ability to stimulate interferon receptors and downstream genes. In this current interim analysis, Nelson and colleagues[6] evaluated EVR and HCV RNA undetectability at Weeks 12 and 24, but the key endpoints will be the final analysis evaluating SVR. The safety profile for albumin interferon was excellent. It was impressive to see that the greatest response was among a group having the highest proportion of nonresponders to peginterferon/ The remaining question however, is: Who are the responders? If they are peginterferon/ Kris V. Kowdley, MD: We will eagerly await the 48-week results for the 2 high-dose arms, in particular, because the EVR rates appear to be dramatically higher in the groups receiving the highest doses. Early on in the study of albumin interferon, there was some excitement over the prospect that this agent might be dosed as seldom as once every 3 or 4 weeks. However, the data from the every 4 weeks dosage group in this study clearly are not as exciting as the results for the every 2 weeks group. Dosing once every 4 weeks, as previously hoped, likely will not be sufficient with this agent. The much larger phase II trial with treatment-naive patients (presented at the European Association for the Study of the Liver [EASL])[7] found the best results with every 2 week dosing strategies (Capsule Summary), so I anticipate that we will use this dosing strategy if this drug is approved. VX-950 Plus Peginterferon/ Summary: Lawitz and colleagues[8] presented data on VX-950, a HCV NS3-4A protease inhibitor, used in combination with peginterferon and ribavirin. In the open-label study, 12 treatment-naive patients with genotype 1 HCV received 750 mg of VX-950 every 8 hours plus standard-dose peginterferon and weight-based ribavirin. After 28 days, the triple combination was well tolerated, with no serious adverse events and no treatment discontinuations. All subjects demonstrated virologic response; 2 patients achieved undetectable (< 10 IU/mL) HCV RNA levels within 8 days after starting therapy, and all 12 were HCV RNA negative at the end of the 28-day dosing period. All subjects showed evidence of continually declining HCV RNA throughout the dosing period with no cases of virologic breakthrough. Samples obtained on Day 2 (the only point at which some patients had sufficient levels of HCV RNA to sequence) demonstrated only wild-type virus. Nezam H. Afdhal, MD: In a previous study,[9] VX-950 reduced HCV RNA levels by approximately 4 logs when used as monotherapy, and 5.5 logs in combination with peginterferon (Capsule Summary). This is the first reported data on VX-950 plus both peginterferon and ribavirin. In addition to evaluating the pharmacokinetics, safety, and efficacy of the triple combination, the goal was also to investigate the viral genetic sequences and virologic breakthrough rates at each time point during the treatment period. Samples were taken at 8, 15, 22, and 28 days, and there was sequential reduction in HCV RNA levels. The importance of this study is that it demonstrated the safety of the combination of peginterferon, ribavirin, and VX‑950. Also, the rapid virologic response data at 28 days were impressive, with all patients becoming HCV RNA negative. There was no evidence of breakthrough in any patient nor was there evidence of the development of any resistant HCV isolates. To follow-up on these results, a much larger phase II trial will commence in the United States shortly. With each new agent in development, the first step is to show that they can be combined with current agents and that resistance can be prevented. The second step is then to show that they produce high rates of sustained response. The third step will be to look at potentially reducing the necessary doses of other drugs, such as interferon and ribavirin, which would reduce adverse events associated with HCV therapy. Kris V. Kowdley, MD: I would broadly classify the new agents currently being studied for HCV as immunomodulators, protease inhibitors, or polymerase inhibitors. The major points of concern with new agents are long‑term toxicity and antiviral efficacy. The data so far indicate to me that it is unlikely that any of these classes of agents, even immunomodulators, will be effective as monotherapy. I think it is likely that they will have to be used as part of dual, if not triple, combination therapy to achieve the best results. In situations where there is severe disease, such as decompensated cirrhosis, viral suppression alone may be an acceptable endpoint. But for treatment of most patients, we are aiming for SVR and a finite duration of therapy, followed by discontinuation of medications. This study demonstrates that early results with VX-950 show that it has solid potential as a component of combination therapy. Dose-Ranging Study of the Polymerase Inhibitor HCV-796 Summary: Villano and colleagues[10] presented data on HCV-796, an oral inhibitor of HCV RNA-dependent RNA polymerase. In a randomized, double-blind, placebo-controlled trial, treatment-naive participants (72% with genotype 1; all with HCV RNA ≥ 10,000 IU/mL) were enrolled into sequential ascending-dose cohorts of up to 16 patients (12 HCV-796, 4 placebo). Subjects received 50, 100, 250, 500, 1000, or 1500 mg of HCV-796 monotherapy or placebo twice daily for 14 days. Pharmacokinetic exposure was less than dose proportional with increasing dose and appeared to reach a plateau at the 1000 mg twice-daily dose. The area under the curve for this dose cohort was 20,046 ng/hour/mL. HCV-796 reduced HCV RNA by a mean of 0.3-1.4 logs (50% to 97%), depending on dose, with peak antiviral activity at Day 4. In the 1000-mg cohort, the mean reduction in HCV RNA was 1.4 logs on Day 4, 1.3 logs on Day 7, and 0.7 logs on Day 14. On Day 4, 83% of patients had HCV RNA reductions from baseline of more than 1 log, 33% had reductions greater than 1.5 logs, and 25% had reductions greater than 2 logs; 17% of patients had HCV RNA reductions greater than 2.0 logs at Day 14. Kris V. Kowdley, MD: This was a phase Ib trial, so this agent is early in development. All dose groups experienced a reduction in HCV RNA, but at somewhat modest levels. In the 1000-mg cohort, which is likely the dose that will be used for further studies, the mean reduction in HCV RNA decreased from 1.4 logs on Day 4 to 0.7 logs on Day 14, suggesting that there may be a loss of efficacy after a certain point or that there were few patients who still had detectable virus; this is something we need to explore further to determine if, indeed, there is a reduction in efficacy over time. The data did not demonstrate any differences in antiviral activity based on genotype. In summary, these data suggest that HCV‑796 demonstrates antiviral activity in HCV infection—though not a remarkably potent degree of antiviral activity as a monotherapy. It is reassuring to note that the agent was safe and well tolerated when given for 14 days, with mild to moderate headache reported most commonly and no evident of dose-limiting toxicities. I think the data support further studies of HCV‑796 as long‑term HCV therapy using 1000 mg every 12 hours. Nezam H. Afdhal, MD: I agree with Dr. Kowdley that it is worth highlighting that there was an unusual event in this study. Unlike the other 2 HCV polymerase inhibitors in clinical development—valopicitabine (NM 283) and R1626—HCV-796 actually produced the maximal viral suppression at Day 4, and then there was a gradual rebound of HCV RNA from Day 5 through Day 14. In the 1000-mg cohort, the maximal effect was observed quickly, followed by a slow increase, so that by Day 14 the viral load reduction from baseline was only 0.7 logs. This clearly indicates that this agent will have to be used as part of combination therapy to provide maximal efficacy and prevention of resistance, not as monotherapy. Response to HCV Therapy in Hispanic Patients Summary: Douglass and colleagues[11] presented data on response to HCV treatment in Hispanic patients. Previous studies have suggested that Hispanic individuals may have higher treatment discontinuation rates and lower response rates compared with white patients. The researchers conducted a retrospective review of medical records from 116 Hispanic and 148 white hepatitis C patients treated with peginterferon plus ribavirin at the University of New Mexico Hospital and the Albuquerque Veterans Administration Hospital. Demographic characteristics were similar in the 2 groups, as were baseline viral load and laboratory values. Proportions with genotype 1 or 4 HCV were also similar (65% among Hispanics, 58% among whites). The overall SVR rates in the Hispanic and white groups were 36.5% and 47.3%, respectively (P = .10); corresponding SVR rates were 33.0% vs 30.0% (P = not significant) for Hispanic vs white patients with genotypes 1 or 4, and 42.5% vs 71.0% (P = .007) for those with genotypes 2 or 3. Treatment discontinuation rates were similar in both ethnic groups (33% vs 24%). After excluding patients who prematurely discontinued treatment, Hispanic ethnicity remained an independent predictor of lower SVR among patients with genotype 2 or 3 when compared with whites (59% vs 86%; P = .01). Nezam H. Afdhal, MD: In this study, Hispanic patients with genotype 2 or 3 had a significantly lower SVR rate vs whites with the same genotypes (42.5% vs 71.0%, respectively) Kris V. Kowdley, MD: Body mass index was not significantly different in Hispanic and non‑Hispanic patients in this study (27.5 vs 28 kg/m2). Therefore, I suspect that one explanation for this finding could be that there is a higher prevalence of insulin resistance among Hispanics vs whites in the general population.[ Peginterferon Plus Ribavirin in Adolescents with Genotype 4 HCV Summary: Hasan and colleagues[15] reported on HCV treatment in adolescents in the Middle East, where genotype 4 accounts for the majority of cases. In an uncontrolled open-label pilot study, 12 adolescents (age, 14-17 years) with biopsy proven hepatitis, but no cirrhosis were treated with 1.5 mg/kg once weekly peginterferon alfa-2b plus 15 mg/kg daily ribavirin for 48 weeks. Sustained virologic response was observed in 9 patients (75%). The most frequent adverse effect was flulike illness, reported by all patients. A majority of patients (67%) developed leukopenia, but only one required adjunct therapy with a growth factor; 4 patients developed anemia requiring ribavirin dose reduction, and 1 patient developed hypothyroidism. Kris V. Kowdley, MD: The goal of this study was to look at the safety, efficacy, and tolerability of this treatment regimen in adolescents with genotype 4 HCV. I think this is a proof‑of‑principle study that shows that patients with genotype 4 can have good treatment outcomes, and that adolescents—if given the right support and treated by physicians with the appropriate expertise—can achieve a high rate of successful treatment completion. Treating Hepatitis C in Patients with Thalassemia and Sickle Cell Disease Summary: Ancel and colleagues[16] reported on the treatment of HCV in patients with congenital hemolytic anemia, among whom hepatic complications due to posttransfusion viral hepatitis, and iron overload are a major cause of death. Thus, the study included 10 patients (8 with genotypes 1 or 4), 5 of whom had sickle cell disease and 5 of whom had thalassemic syndrome; 5 were nonresponders after prior HCV therapy. Four thalassemic patients had a Metavir fibrosis score of F4, while the remaining patients had scores of 2 or smaller. Eight patients were treated with peginterferon plus ribavirin and 2 thalassemic patients received interferon monotherapy. Patients received either 24 or 48 weeks of treatment. End-of-treatment response was observed in 9 patients (90%), and 6 (60%) achieved SVR (5 with combination therapy). The patients who had a sustained response did not experience hepatic complication during follow-up. The mean increase in transfusion requirements during treatment of the thalassemic patients was 22% (growth factors were not used). The hemoglobin level at the end of treatment was higher than the baseline value among 4 sickle cell patients. Kris V. Kowdley, MD: Historically, we have not treated patients with anemia for HCV. These authors demonstrated that the treated sickle cell patients did not need blood transfusions during or after the treatment period; in the thalassemic patients, there was a slight increase in transfusion requirements during treatment. This pilot study shows that having thalassemia or sickle cell disease does not automatically exclude treatment of HCV. Nezam H. Afdhal, MD: These results are important because thalassemia and sickle cell disease are widely believed to be absolute contraindications to HCV therapy. This study showed that in carefully controlled situations, if these patients are followed by a physician with the appropriate expertise, not only can they be treated, but they can also have a high rate of response. Eltrombopag for HCV-Associated Thrombocytopenia Summary: McHutchison and colleagues[17] presented data on eltrombopag, an oral thrombopoietin- Nezam H. Afdhal, MD: One of the major problems with chronic liver disease is the development of portal hypertension, which is associated with the development of thrombocytopenia; HCV patients also have an increased prevalence of idiopathic thrombocytopenia related to HCV infection itself. We would like to treat HCV in these patients but are often worried about starting them on therapy because their platelet counts are too low. In this study, the researchers observed that patients who were treated with eltrombopag experienced a dose‑dependent increase in platelet counts. After 28 weeks, 67% of patients in the 30-mg group, 78% in the 50-mg group, and 90% in the 75-mg group had median platelet counts well above 100,000 cells/µL—quite a dramatic increase. There are 2 points to be made about this research. One is that we always try to aggressively treat HCV in patients with advanced liver disease. Eltrombopag could be a growth factor for platelets that will help us achieve this goal by allowing treatment in a group of patients for whom therapy is generally contraindicated. Second, as we deal with more patients with cirrhosis and advanced liver disease, low platelet count can become a major problem, for example when performing procedures, such as dental extractions. Here, too, an agent like eltrombopag could enable us to pretreat these patients prior to standard surgical procedures. Currently, the only growth factor we use for platelets is IL‑11, which has a fair amount of toxicity, particularly for patients with cirrhosis, as it can cause fluid retention. So these early results with eltrombopag show promise in that they provide the potential for growth-factor treatment, which is more tolerable than currently available regimens. Kris V. Kowdley, MD: I think the key question is: what is the real need for a therapy such as this? By and large, patients with cirrhosis who have platelet counts above 50,000 cells/µL generally will tolerate bleeding well. If they have somewhat higher platelet counts, they will tolerate interferon well. I am not sure whether there is a major need for long-term growth factors in these patients, because they generally tolerate treatment well. Where eltrombopag could have a significant impact as short-term therapy is for patients with portal hypertension who present with bleeding or for those undergoing elective procedures. If nothing else, this would reassure the patients that we can prevent bleeding. Entecavir in HBeAg-Negative Patients Summary: Poordad and colleagues[18] presented 96-week data on the use of entecavir in HBeAg-negative individuals with chronic HBV infection (N = 638). Patients received either 0.5 mg/day of entecavir or 100 mg/day of lamivudine. After 48 weeks, 85% of subjects in the entecavir group had achieved both HBV DNA levels below 0.7 MEq/mL (as measured by branched DNA assay) and ALT below 1.25 times the upper limit of normal (ULN) vs 78% in the lamivudine group. While this group of patients stopped therapy, patients who achieved virologic suppression but still had elevated ALT continued therapy through 96 weeks. Among those continuing treatment, 96% in the entecavir group and 64% in the lamivudine group maintained virologic response (HBV DNA < 300 copies/mL by PCR). In a cumulative analysis of data through 96 weeks, 94% in the entecavir group, and 77% receiving lamivudine had HBV DNA < 300 copies/mL (P < .001), and 89% and 84%, respectively, had ALT ≤ 1.25 x ULN (not significant) Kris V. Kowdley, MD: These data show that the percentage of patients who achieved a virologic response was significantly higher in the group that received entecavir compared with those who received lamivudine. The other goal of this analysis was to evaluate off-treatment responses in patients who had both a virologic and a histologic response at Week 48 and stopped therapy at that point. Twenty-four weeks after stopping treatment, 42% of patients in the entecavir group had ALT < 1 x ULN compared with 25% of patients in the lamivudine group. The proportion of patients who remained HBV DNA negative was < 5% for both groups. This suggests that continued therapy is likely to result in more effective HBV DNA suppression that may be more sustained and that these effects quickly diminish if antiviral therapy is stopped. The 2-year entecavir data show that with extended duration of treatment we can achieve HBV DNA undetectability in the overwhelming majority of patients. Given that no resistance is observed at 2 years in treatment-naive patients, I look forward to seeing the data with treatment out for 3-5 years of therapy. Histologic Improvement with Entecavir Summary: Shiffman and colleagues[19] presented additional data on entecavir from a prospective trial in which patients with lamivudine-refracto Nezam H. Afdhal, MD: As you would expect, entecavir was associated with a much better improvement in HBV DNA levels when compared with lamivudine in a group of patients with lamivudine-resistan Kris V. Kowdley, MD: In this study, even the patients who had higher levels of HBV DNA at baseline had quite effective virologic suppression during treatment with entecavir. However, high baseline viral load in lamivudine-refracto Telbivudine vs Adefovir in HBeAg-Positive Patients Summary: Heathcote and colleagues[20] presented data from a randomized trial of telbivudine vs adefovir in 133 HBeAg-positive patients. Enrolled patients had HBV DNA levels of more than 6 log10 copies/mL, ALT levels ranging from 1.3-10 x ULN, and compensated liver disease. Patients received 10 mg/day of adefovir or 600 mg/day telbivudine, and at Week 24, half the adefovir group was assigned randomly to switch to telbivudine. In an intent-to-treat analysis after 24 weeks, HBV DNA decreased by 6.37 log10 copies/mL in the telbivudine group and 5.11 log10 copies/mL in the adefovir group (P < .01). In the telbivudine group, 38.6% achieved undetectable HBV DNA vs 12.4% of adefovir patients (P < .01). ALT normalization occurred at similar rates in both groups (61.4% vs 62.9%, respectively) Kris V. Kowdley, MD: After 24 weeks, telbivudine was associated with greater suppression of viral replication and a higher proportion of patients achieving undetectable HBV DNA. We need to follow up these patients to see what happens over the long term. As we know, adefovir has a cumulative benefit over time (Capsule Summary),[21] and patients are increasingly likely to achieve undetectable viral load if they continue treatment. We do not yet know whether this will also occur with telbivudine. Thus, the 1-year telbivudine- Nezam H. Afdhal, MD: This study shows that telbivudine is a highly effective oral agent—more so than adefovir—in terms of its ability to suppress HBV during the first 24 weeks of therapy. However, during the next period of the study, the key endpoints to follow will be development of resistance and HBeAg seroconversion. HBV Viral Breakthrough and ALT Flares Summary: Chae and Hann[22] presented a retrospective analysis of factors associated with HBV virologic breakthrough during treatment with lamivudine. The study included 88 Asian American patients with chronic HBV infection who received lamivudine for more than 1 year (median duration: 25 months) and had baseline HBV DNA ≥ 3 logs; 39 were HBeAg-positive and 45 were HBeAg-negative at baseline. After 1 year, the mean reduction in HBV DNA was 4.1 log10 copies/mL. After 2 years this decreased to 2.7 log10 copies/mL due to virologic breakthrough in some patients (≥ 1-log increase in HBV DNA following suppression) In a second retrospective study, Murata and colleagues[23] evaluated factors predicting HBV exacerbation (ALT > 10 x ULN) after discontinuation of oral anti-HBV therapy in 40 HBeAg-negative patients with chronic HBV infection. Participants were part of a registration trial (Study 438) comparing 10 mg/day adefovir vs placebo. After stopping therapy, 13 patients experienced ALT flares, usually within 13 weeks of adefovir discontinuation; most of these patients never attained HBV DNA below 400 copies/mL during therapy. In a logistic regression analysis evaluating a variety of demographic and disease-related factors, only baseline HBV DNA was a significant predictor of hepatitis exacerbation. Multivariate analysis determined that duration of HBV DNA suppression was highly predictive of ALT flares and that baseline HBV DNA was only marginally correlated. Nezam H. Afdhal, MD: About 20% of patients per year develop lamivudine resistance or breakthrough during treatment. Chae and colleagues[22] were able to show that the major predictor of breakthrough was baseline HBV DNA. We know that to avoid breakthrough during treatment with any drug, viral replication must be suppressed as much as possible. The higher the initial HBV DNA, the more difficult it is to suppress virus to undetectable levels. Lamivudine produces an average HBV DNA reduction of 4.0-4.5 log10 copies/mL and is not powerful enough to suppress virus to undetectable levels in many patients with high pretreatment viral load. The researchers suggest that some patients with low baseline viral load may benefit from lamivudine. This may be true, but development of resistance is such an important issue that if there are affordable alternatives, we should use more potent therapies first. The second study looked at stopping therapy in HBeAg-negative patients. With treatment discontinuation, hepatitis flares are always a concern. Murata and colleagues[23] evaluated a small number of patients, but 13 developed flares after stopping adefovir. Only 1 flare was associated with elevated bilirubin and none with liver failure. The study showed that posttreatment hepatitis flares were most likely to occur if HBV DNA could not be suppressed during therapy: 12 of the 13 patients who experienced a flare never achieved HBV DNA levels below 400 copies/mL while receiving adefovir. We are often asked when HBeAg-negative patients can stop treatment. Although we do not have a definitive answer, and one possibility is that therapy can never be stopped without risk for a flare, alternatively these data might suggest that therapy can safely be stopped after patients have a prolonged period of persistent HBV DNA negativity; in fact, it shows that the longer one is negative, the better. Mathematical models based on viral kinetics suggest that HBV replication must be suppressed for 14 years to eliminate covalently closed circular HBV DNA. The longer we can suppress virus to undetectable levels, the lower the risk for hepatitis flares after stopping treatment. Today, most people are no longer switching from one anti-HBV drug to another. Instead, if there is a suboptimal response to one drug, most physicians will add a second drug. This lowers the incidence of hepatitis flares and also reduces the risk of developing resistance to the new drug. Kris V. Kowdley, MD: We are developing a better understanding about the shortcomings of first-line monotherapy with a drug such as lamivudine that not only promotes the development of resistance to itself, but can also confer resistance to a whole class of drugs. It is important to recognize that there are still many patients receiving lamivudine as first-line therapy for financial reasons, including mandates by insurance plans. At the very least, we want to identify patients for whom lamivudine is unlikely to work. We need to try to avoid treating these patients because not only do they have a reduced likelihood of response, but use of lamivudine could result in resistance that could affect their responses to other drugs, thus limiting future therapeutic options and reducing the likelihood of subsequent treatment success. It may be that we do not have to treat HBeAg-negative patients indefinitely, but further study is needed to determine the optimal length of treatment. Treating Multidrug-Resistant HBV Summary: Yim and colleagues[24] presented data on multidrug-resistant HBV. The researchers cloned HBV from serum samples taken from 6 patients with resistance to 2 antiviral drugs. Mutations conferring resistance to both agents were present on the same genome in 163 (84%) of 195 clones derived from 10 samples from patients with dual resistance to lamivudine/adefovir Kris V. Kowdley, MD: During monotherapy with any agent, HBV mutations resistant to that drug will be selected. When we then put the patient on a different drug, a new population of viruses may evolve that are resistant to the second agent. This study shows that mutations conferring resistance to multiple antiviral agents can be present in the same genome—as opposed to there being coexisting populations of viruses each of which is resistant to a single drug. This suggests that if one particular viral isolate is resistant to several drugs, combination therapy may not work. That is, combination therapy directed against HBV mutants resistant to each particular therapy may not adequately suppress dual-resistant HBV. Essentially, optimal therapy would include a drug or combination of drugs that can reduce HBV replication as quickly as possible and maintain enough pressure to prevent the development of resistance. Nezam H. Afdhal, MD: This study adds further evidence supporting the idea that rather than using sequential antiviral monotherapies in patients with resistant HBV, it would be better to initially use the drug that most potently suppress viral replication, in hopes of preventing resistance development. Then, if any resistance develops, a combination of therapies should be used to prevent sequential resistance development. Noninvasive Markers for NAFLD and NASH Summary: Wieckowska and colleagues[25] presented data on a study of caspase activity as a noninvasive marker for NAFLD. The aim of this study was to validate a serum marker for hepatocyte apoptosis in patients with NAFLD; currently, liver biopsy is the only reliable method for differentiating simple steatosis from NASH and determining the stage and grade of disease. Caspase 3 activation and hepatocyte apoptosis are prominent pathologic features of NAFLD and correlate with disease severity.[26] The researchers analyzed data from 41 consecutive patients undergoing liver biopsy for suspected NAFLD. Caspase 3-generated cytokeratin- Kelleher and colleagues[27] presented results of a second study evaluated the use of liver stiffness (using FibroScan) as a predictor of NASH-related fibrosis. The study enrolled 129 patients with NASH and in logistic regression analysis age, diabetes, AST/ALT ratio, and hepatic stiffness were predictive of fibrosis. In a stepwise multivariate analysis, only age and liver stiffness remained as predictors. Hepatic stiffness measurement with a cutoff of 10 Kpa had a sensitivity of 88% and a specificity of 72% for significant fibrosis (≥ stage F2). Obesity was not a contraindication to elastography. Nezam H. Afdhal, MD: Fatty liver appears to be a serious factor in liver disease in the United States, and one that is likely to become increasingly important. Given that we have 35 million people with metabolic syndrome and an increasing incidence of diabetes, we are likely to see more and more fatty liver disease in the clinic. As clinicians, it is difficult to differentiate patients with simple steatosis or simple fatty liver from those with the more severe form of NAFLD known as NASH. Both of these studies investigated ways of detecting steatohepatitis. The first pilot study focused on serum markers of hepatocyte apoptosis, a clinical feature of steatohepatitis observed in liver biopsy samples. These investigators showed that there was a sequential increase in cytokeratin- The second study looked at another feature associated with NASH, development of fibrosis. Patients with simple steatosis do not have liver fibrosis, whereas NASH patients develop fibrosis that eventually progresses to cirrhosis. FibroScan is a novel technology for measuring liver stiffness in patients with steatohepatitis and varying degrees of fibrosis; a Food and Drug Administration registration trial is currently underway. The researchers showed that there was a strong correlation between liver stiffness and the development of fibrosis in patients with NASH. The exciting component of this study is that the investigations were able to use FibroScan in patients with body mass index up to 47 kg/m2—that is, they were able to successful measure liver stiffness in morbidly obese patients. Both studies are aimed at addressing the issue of how to better screen at-risk populations to determine which patients need further evaluation with liver biopsy and consideration for some of the new therapeutic trials for NASH. In the future, FibroScan may be used like we now use ultrasound or an echographic examination of the liver. The technology is advantageous in that it is small, portable, and highly efficient. A technician could perform the test in 5-7 minutes. Kris V. Kowdley, MD: This is an important area of research. We recognize that NASH is common, but we are also beginning to understand that the subset of patients who are at risk for decompensated liver disease and premature mortality related to cirrhosis is probably a lot smaller than previously thought. Thus, it is simply not realistic to biopsy every individual with an echogenic liver. Caspase activity is emerging as an interesting candidate as a marker for NASH. We have the ability in the NASH Clinical Research Network to evaluate hundreds, if not more than a thousand patients, which will allow us to validate these findings. The FibroScan data are encouraging, and I am hopeful that we will be able to use FibroScan clinically in a range of liver disease, including NASH, for which we do not yet have validated biochemical or serologic markers. References 1. Afdhal N, Jacobson IM, Brown RS, et al. The effect of liver fibrosis and cirrhosis on SVR in 4913 patients with hepatitis C: results from the WIN-R trial. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract 655. 2. Brown RS, Jacobson IM, Afdhal N, et al. Differences in treatment outcome to antiviral therapy based on genotype and viral load in hepatitis C genotypes 2 and 3 in the WIN-R trial. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract 523. 3. von Wagner M, Huber M, Berg T, et al. Peginterferon-α 4. Jacobson IM, Brown RS, Freilich B, et al. Stratification of high viral load: impact on sustained virologic response in the WIN-R trial. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract T1806. 5. Gitlin N, Di Bisceglie A, Marcellin P, et al. Peginterferon alfa-2a (40KD) (Pegasys) plus ribavirin (RBV) (Copegus) in pegylated interferon alfa-2b (12KD)/ribavirin non-responders with cirrhosis/advanced fibrosis: interim analysis of the REPEAT study. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract T1808. 6. Nelson D, Rustgi V, Balan V, et al. Week 12 and beyond antiviral activity of higher doses of albuferon combined with ribavirin in non-responders to prior interferon based therapy for chronic hepatitis C infection. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract 196. 7. Zeuzem S, Benhamou Y, Shouval D, et al. Interim (Week 12) phase 2B virological efficacy and safety results of albumin interferon alfa-2b combined with ribavirin in genotype 1 chronic hepatitis C infection. Program and abstracts of the 41st Annual Meeting of the European Association for the Study of the Liver; April 26-30, 2006; Vienna, Austria. Abstract 733. (Capsule Summary) 8. Lawitz EJ, Rodriguez-Torres M, Muir A, et al. 28 days of the hepatitis C protease inhibitor VX-950, in combination with peg-interferon- 9. Reesink HW, Forestier N, Weegink CJ, et al. Initial results of a 14-day study of the hepatitis C virus inhibitor VX-950, in combination with peginterferon- 10. Chandra P, Raible D, Harper D, Speth J, Villano S, Bichier G. Antiviral activity of the non-nucleoside polymerase inhibitor, HCV-796, in patients with chronic hepatitis C virus: preliminary results from a randomized, double-blind, placebo-controlled, ascending multiple dose study. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract 1. 11. Douglass J, Qualls C, Wiggins C, Dunkelberg J, Arora S. Hispanic patients with genotype 2 or 3 chronic hepatitis C have lower rates of sustained virologic response to treatment with pegylated interferon and ribavirin. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract 653. 12. Reddy KR, Hoofnagle J, Tong M, et al. Racial differences in responses to therapy with interferon in chronic hepatitis C. Hepatology. 1999;30:787- 13. McHutchison JG, Poynard T, Pianko S, et al. The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. Gastroenterology. 2000;119:1317- 14. Haffner SM, D'Agostino R, Saad MF, et al. Increased insulin resistance and insulin secretion in nondiabetic African-Americans and Hispanics compared with non-Hispanic whites: The Insulin Resistance Atherosclerosis Study. Diabetes. 1996;45:742- 15. Hasan F, Alsarraf K, Qabandi W. Pegylated interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4 in adolescents: a pilot study. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract T1819. 16. Ancel DB, Chaslin-Ferbus D, Amiot XJ, et al. Treatment of chronic hepatitis C in thalassemic and sickle cell disease patients with interferon alfa-2b (IFN) and ribavirin (RBV). Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract 198. 17. McHutchison JG, Afdhal N, Shiffman ML, et al. Efficacy and safety of eltrombopag, an oral platelet growth factor, in subjects with HCV associated thrombocytopenia: preliminary results from a phase II multicenter, randomised, placebo controlled, double-blind, dose-ranging study. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract 338. 18. Poordad F, Dieterich DT, Min AD, et al. Continued virologic improvement through 96 weeks of entecavir treatment in HBeAg(-) chronic hepatitis B patients (Study ETV-027). Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract T1851. 19. Shiffman ML, Goodman Z, Paul PJ, et al. Entecavir (ETV) is associated with an improvement in liver histology and a reduction in HBV in patients with lamivudine-refracto 20. Heathcote E, Chan HL, Cho M, et al. A randomized trial of telbivudine (LdT) vs. adefovir for HBeAg-positive chronic hepatitis B: results of the primary Week 24 analysis. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract 479. 21. Hadziyannis S, Tassopoulos N, Chang TT, et al. Long-term adefovir dipivoxil treatment induces regression of liver fibrosis in patients with HBeAg-negative chronic hepatitis B: results after 5 years of therapy. Program and abstracts of the 56th Annual Meeting of the American Association for the Study of Liver Diseases; November 11-15, 2005; San Francisco, California. Abstract LB14. (Capsule Summary) 22. Chae H, Hann H. Baseline HBV DNA level > 6 log is the most important factor associated with viral breakthrough (BT) during lamivudine (LAM) therapy for chronic hepatitis B (CHB). Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract T1840. 23. Murata Y, Arterburn S, Pang C, Mondou E, Rousseau F. Predictive factors for exacerbation of hepatitis B after discontinuation of oral therapy in HBeAg-negative patients. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract 481. 24. Yim H, Hussain, Wong S, Liu Y, Fung SK, Lok AS. Evolution of multi-drug resistant HBV: implications on rescue therapy. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract 5. 25. Wieckowska A, Zein N, Yerian L, Lopez AR, Feldstein AE. Detection of caspase activity in the blood of patients with nonalcoholic fatty liver disease as a novel biomarker of disease severity. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract 6. 26. Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology. 2003;125:437- 27. Kelleher TB, MacFarlane C, de Ledinghen V, et al. Risk factors and hepatic elastography (Fibroscan) in the prediction of hepatic fibrosis in non alcoholic steatohepatitis. Program and abstracts of Digestive Disease Week 2006; May 20-25, 2006; Los Angeles, California. Abstract 546. http://clinicalopti |