LIVER MEETING 2011

SAN FRANCISCO – Older and newer oral antiviral agents are similarly effective at preventing hepatocellular carcinoma in patients with chronic hepatitis B, according to a systematic review of 45 studies involving 9,330 patients.

The rate of hepatocellular carcinoma (HCC) was almost identical in patients given older drugs (lamivudine or adefovir) and patients given newer ones (entecavir, telbivudine, or tenofovir), ranging from just 0.012 to 0.017 per person-year of follow-up, Dr. Ashwani K. Singal reported at the annual meeting of the American Association for the Study of Liver Diseases.

"This is a surprising finding, that it doesn’t make a difference," he commented in an interview. "Whatever medication you use, the occurrence is similar – it’s low but it’s similar."

The surprise stems from the fact that the newer agents have a low rate of drug resistance and achieve continued suppression of hepatitis B virus DNA during prolonged therapy, Dr. Singal explained. And indeed, undetectable DNA at last follow-up was associated with a lower risk of HCC in the study.

He speculated that the apparent nonsuperiority of the newer agents in terms of this outcome may be related to the relatively small number of patients treated with them thus far. "Now that we have newer antiviral agents, maybe we need more larger studies done in a prospective fashion to see whether one is better than the other," he commented.

In addition to patients having detectable viral DNA at last follow-up, patients aged 50 years or older and patients having cirrhosis at the start of antiviral therapy had higher rates of HCC than did their respective counterparts. The take-home message is that "these populations should be more carefully followed up, even on treatment," maintained Dr. Singal, a gastroenterologist with the Mayo Clinic in Rochester, Minn.

The investigators conducted the systematic review because at least 10 additional studies, several involving the newer antivirals, have been published since the last large meta-analysis looking at this issue in 2010.

They identified studies of oral antiviral therapy among patients with chronic hepatitis B that were published in full in English, regardless of whether patients had cirrhosis or not, and were treatment naive or treatment experienced. But the studies had to have had a treatment duration of at least 12 months and a follow-up duration of at least 2 years. Patients coinfected with HIV or hepatitis C were excluded.

In contrast to the previous meta-analysis, the review used a statistical method that took into account the greater likelihood of detecting HCC with longer follow-up, Dr. Singal noted.

Overall, 42% of the patients had received lamivudine (Epivir), 32% had received adefovir (Hepsera), 10% had received tenofovir (Viread), 9% had received telbivudine (Tyzeka), and 7% had received entecavir (Baraclude).

Results of the review showed that the rate of HCC did not differ significantly with older vs. newer antiviral agents: It was at 0.013 per person-year of follow-up with lamivudine in controlled studies, 0.017 with lamivudine in uncontrolled studies, 0.015 with adefovir with or without lamivudine, and 0.012 with entecavir, telbivudine, or tenofovir.

But the rate was significantly higher in patients having detectable vs. undetectable viral DNA at last follow-up (0.019 vs. 0.01 per person-year of follow-up), patients aged 50 years or older vs. younger at the start of therapy (0.02 vs. 0.009), and patients with vs. without cirrhosis at the start of therapy (0.03 vs. 0.003).

Among those with cirrhosis, there was no difference according to whether the cirrhosis was compensated or decompensated. "The way I can explain that is before they get HCC, there are other things that kill these people: liver failure, bleeding, infections, those kind of things," commented Dr. Singal.

In the six studies having untreated control groups, all of which evaluated lamivudine, there was a significant 56% reduction in the risk of HCC for treated patients as compared with their untreated counterparts, confirming the marked benefit of antiviral therapy in general for reducing this outcome, he said.

"People say there are so many good drugs available now, the research on hepatitis B has almost come to a dead end," Dr. Singal concluded. "But I think there is still scope for doing research. For example ... most of the prospective studies on newer drugs are looking at 1-year outcomes of e antigen loss or surface antigen loss, but I think there should be ... longer follow-up and specifically aiming to look at whether newer drugs are different from older drugs when comparing hepatocellular carcinoma. That will have to be ... at least 5 or 7 years."

Dr. Singal reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Older and newer oral antiviral agents are similarly effective at preventing hepatocellular carcinoma in patients with chronic hepatitis B, according to a systematic review of 45 studies involving 9,330 patients.

The rate of hepatocellular carcinoma (HCC) was almost identical in patients given older drugs (lamivudine or adefovir) and patients given newer ones (entecavir, telbivudine, or tenofovir), ranging from just 0.012 to 0.017 per person-year of follow-up, Dr. Ashwani K. Singal reported at the annual meeting of the American Association for the Study of Liver Diseases.

"This is a surprising finding, that it doesn’t make a difference," he commented in an interview. "Whatever medication you use, the occurrence is similar – it’s low but it’s similar."

The surprise stems from the fact that the newer agents have a low rate of drug resistance and achieve continued suppression of hepatitis B virus DNA during prolonged therapy, Dr. Singal explained. And indeed, undetectable DNA at last follow-up was associated with a lower risk of HCC in the study.

He speculated that the apparent nonsuperiority of the newer agents in terms of this outcome may be related to the relatively small number of patients treated with them thus far. "Now that we have newer antiviral agents, maybe we need more larger studies done in a prospective fashion to see whether one is better than the other," he commented.

In addition to patients having detectable viral DNA at last follow-up, patients aged 50 years or older and patients having cirrhosis at the start of antiviral therapy had higher rates of HCC than did their respective counterparts. The take-home message is that "these populations should be more carefully followed up, even on treatment," maintained Dr. Singal, a gastroenterologist with the Mayo Clinic in Rochester, Minn.

The investigators conducted the systematic review because at least 10 additional studies, several involving the newer antivirals, have been published since the last large meta-analysis looking at this issue in 2010.

They identified studies of oral antiviral therapy among patients with chronic hepatitis B that were published in full in English, regardless of whether patients had cirrhosis or not, and were treatment naive or treatment experienced. But the studies had to have had a treatment duration of at least 12 months and a follow-up duration of at least 2 years. Patients coinfected with HIV or hepatitis C were excluded.

In contrast to the previous meta-analysis, the review used a statistical method that took into account the greater likelihood of detecting HCC with longer follow-up, Dr. Singal noted.

Overall, 42% of the patients had received lamivudine (Epivir), 32% had received adefovir (Hepsera), 10% had received tenofovir (Viread), 9% had received telbivudine (Tyzeka), and 7% had received entecavir (Baraclude).

Results of the review showed that the rate of HCC did not differ significantly with older vs. newer antiviral agents: It was at 0.013 per person-year of follow-up with lamivudine in controlled studies, 0.017 with lamivudine in uncontrolled studies, 0.015 with adefovir with or without lamivudine, and 0.012 with entecavir, telbivudine, or tenofovir.

But the rate was significantly higher in patients having detectable vs. undetectable viral DNA at last follow-up (0.019 vs. 0.01 per person-year of follow-up), patients aged 50 years or older vs. younger at the start of therapy (0.02 vs. 0.009), and patients with vs. without cirrhosis at the start of therapy (0.03 vs. 0.003).

Among those with cirrhosis, there was no difference according to whether the cirrhosis was compensated or decompensated. "The way I can explain that is before they get HCC, there are other things that kill these people: liver failure, bleeding, infections, those kind of things," commented Dr. Singal.

In the six studies having untreated control groups, all of which evaluated lamivudine, there was a significant 56% reduction in the risk of HCC for treated patients as compared with their untreated counterparts, confirming the marked benefit of antiviral therapy in general for reducing this outcome, he said.

"People say there are so many good drugs available now, the research on hepatitis B has almost come to a dead end," Dr. Singal concluded. "But I think there is still scope for doing research. For example ... most of the prospective studies on newer drugs are looking at 1-year outcomes of e antigen loss or surface antigen loss, but I think there should be ... longer follow-up and specifically aiming to look at whether newer drugs are different from older drugs when comparing hepatocellular carcinoma. That will have to be ... at least 5 or 7 years."

Dr. Singal reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Older and newer oral antiviral agents are similarly effective at preventing hepatocellular carcinoma in patients with chronic hepatitis B, according to a systematic review of 45 studies involving 9,330 patients.

The rate of hepatocellular carcinoma (HCC) was almost identical in patients given older drugs (lamivudine or adefovir) and patients given newer ones (entecavir, telbivudine, or tenofovir), ranging from just 0.012 to 0.017 per person-year of follow-up, Dr. Ashwani K. Singal reported at the annual meeting of the American Association for the Study of Liver Diseases.

"This is a surprising finding, that it doesn’t make a difference," he commented in an interview. "Whatever medication you use, the occurrence is similar – it’s low but it’s similar."

The surprise stems from the fact that the newer agents have a low rate of drug resistance and achieve continued suppression of hepatitis B virus DNA during prolonged therapy, Dr. Singal explained. And indeed, undetectable DNA at last follow-up was associated with a lower risk of HCC in the study.

He speculated that the apparent nonsuperiority of the newer agents in terms of this outcome may be related to the relatively small number of patients treated with them thus far. "Now that we have newer antiviral agents, maybe we need more larger studies done in a prospective fashion to see whether one is better than the other," he commented.

In addition to patients having detectable viral DNA at last follow-up, patients aged 50 years or older and patients having cirrhosis at the start of antiviral therapy had higher rates of HCC than did their respective counterparts. The take-home message is that "these populations should be more carefully followed up, even on treatment," maintained Dr. Singal, a gastroenterologist with the Mayo Clinic in Rochester, Minn.

The investigators conducted the systematic review because at least 10 additional studies, several involving the newer antivirals, have been published since the last large meta-analysis looking at this issue in 2010.

They identified studies of oral antiviral therapy among patients with chronic hepatitis B that were published in full in English, regardless of whether patients had cirrhosis or not, and were treatment naive or treatment experienced. But the studies had to have had a treatment duration of at least 12 months and a follow-up duration of at least 2 years. Patients coinfected with HIV or hepatitis C were excluded.

In contrast to the previous meta-analysis, the review used a statistical method that took into account the greater likelihood of detecting HCC with longer follow-up, Dr. Singal noted.

Overall, 42% of the patients had received lamivudine (Epivir), 32% had received adefovir (Hepsera), 10% had received tenofovir (Viread), 9% had received telbivudine (Tyzeka), and 7% had received entecavir (Baraclude).

Results of the review showed that the rate of HCC did not differ significantly with older vs. newer antiviral agents: It was at 0.013 per person-year of follow-up with lamivudine in controlled studies, 0.017 with lamivudine in uncontrolled studies, 0.015 with adefovir with or without lamivudine, and 0.012 with entecavir, telbivudine, or tenofovir.

But the rate was significantly higher in patients having detectable vs. undetectable viral DNA at last follow-up (0.019 vs. 0.01 per person-year of follow-up), patients aged 50 years or older vs. younger at the start of therapy (0.02 vs. 0.009), and patients with vs. without cirrhosis at the start of therapy (0.03 vs. 0.003).

Among those with cirrhosis, there was no difference according to whether the cirrhosis was compensated or decompensated. "The way I can explain that is before they get HCC, there are other things that kill these people: liver failure, bleeding, infections, those kind of things," commented Dr. Singal.

In the six studies having untreated control groups, all of which evaluated lamivudine, there was a significant 56% reduction in the risk of HCC for treated patients as compared with their untreated counterparts, confirming the marked benefit of antiviral therapy in general for reducing this outcome, he said.

"People say there are so many good drugs available now, the research on hepatitis B has almost come to a dead end," Dr. Singal concluded. "But I think there is still scope for doing research. For example ... most of the prospective studies on newer drugs are looking at 1-year outcomes of e antigen loss or surface antigen loss, but I think there should be ... longer follow-up and specifically aiming to look at whether newer drugs are different from older drugs when comparing hepatocellular carcinoma. That will have to be ... at least 5 or 7 years."

Dr. Singal reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Both donor and recipient interleukin 28B genotype affect the risk of recurrence of hepatitis C after liver transplantation, but they do so in opposite directions.

Investigators led by Dr. Andres Duarte-Rojo of the Mayo Clinic in Rochester, Minn., studied a cohort of more than 200 patients with hepatitis C who underwent liver transplantation, finding that 32% had a histologic recurrence 1 year later.

The risk of such recurrence was reduced by more than half when the recipient had the interleukin 28B (IL28B) CC genotype, as compared with the CT or TT genotype, according to results reported at the annual meeting of the American Association for the Study of Liver Diseases. In sharp contrast, the risk was almost tripled if the donor had the CC genotype for IL28B instead of one of the others.

"Variations in the phenotypic expression of IL28B genotype occur in relation to its source, either the recipient or the donor. This paradoxical effect suggests variation in the activation of the adaptive immune system according to hepatic and nonhepatic IL28B genotype," Dr. Duarte-Rojo commented.

Other research by his group suggests that donor and recipient CC genotype have a synergistic effect in promoting sustained virologic response after transplantation. "However, according to current results, allocation of a CC allograft to hepatitis C patients may predispose to a more severe disease in those untreated or not achieving a sustained virologic response," he said.

IL28 is a cytokine playing a role in antiviral defenses. The genotype for the B isoform "affects hepatitis C virus eradication, whether spontaneous or therapy driven," Dr. Duarte-Rojo noted. "It is important to study the associations of IL28B in the posttransplant setting to unravel mechanisms driving viral-host interactions and help the understanding of this polymorphism in hepatitis C pathobiology."

The investigators studied 241 consecutive patients with hepatitis C virus infection who underwent liver transplantation between 1995 and 2010. Average age was 52 years and the mean Model for End-Stage Liver Disease (MELD) score was 15.

IL28B genotype of recipient and donor was assessed from liver biopsies done at the time of transplantation, and serial biopsies of the liver graft were done after transplantation to assess virologic and histologic measures of recurrence.

Only 31% of the recipients had the IL28B CC genotype, compared with 52% of the donors, Dr. Duarte-Rojo reported.

The time to virologic recurrence after transplantation was longer when the recipient had the CC genotype vs. a non-CC genotype (4.6 vs. 4.1 months), whereas it was nonsignificantly shorter when the donor had the CC vs. a non-CC genotype.

Similarly, the proportion of patients that developed histologic recurrence as defined by stage 2 or greater fibrosis 1 year post transplantation was lower when the recipient had the CC vs. a non-CC genotype (19% vs. 38%). In contrast, recurrence rate was higher when the donor had the CC vs. a non-CC genotype (43% vs. 23%).

And there was also an interaction, whereby the proportion with recurrence ranged from a low of 17% with a CC recipient and non-CC donor, to a high of 52% with a non-CC recipient and a CC donor.

In a multivariate analysis that included factors such as alanine aminotransferase level, MELD score, viral genotype, surgical and biliary complications, cytomegalovirus infection, and diabetes, the risk of recurrence was still markedly decreased when the recipient had the CC genotype (odds ratio, 0.40) and markedly increased when the donor had the CC genotype (OR, 2.71).

The results were essentially the same after exclusion of patients who received antiviral therapy, according to Dr. Duarte-Rojo.

He noted that the recipient and donor IL28B genotypes also had opposite effects on alanine aminotransferase levels, viral loads, and rates of acute cellular rejection during follow-up.

Dr. Duarte-Rojo reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Both donor and recipient interleukin 28B genotype affect the risk of recurrence of hepatitis C after liver transplantation, but they do so in opposite directions.

Investigators led by Dr. Andres Duarte-Rojo of the Mayo Clinic in Rochester, Minn., studied a cohort of more than 200 patients with hepatitis C who underwent liver transplantation, finding that 32% had a histologic recurrence 1 year later.

The risk of such recurrence was reduced by more than half when the recipient had the interleukin 28B (IL28B) CC genotype, as compared with the CT or TT genotype, according to results reported at the annual meeting of the American Association for the Study of Liver Diseases. In sharp contrast, the risk was almost tripled if the donor had the CC genotype for IL28B instead of one of the others.

"Variations in the phenotypic expression of IL28B genotype occur in relation to its source, either the recipient or the donor. This paradoxical effect suggests variation in the activation of the adaptive immune system according to hepatic and nonhepatic IL28B genotype," Dr. Duarte-Rojo commented.

Other research by his group suggests that donor and recipient CC genotype have a synergistic effect in promoting sustained virologic response after transplantation. "However, according to current results, allocation of a CC allograft to hepatitis C patients may predispose to a more severe disease in those untreated or not achieving a sustained virologic response," he said.

IL28 is a cytokine playing a role in antiviral defenses. The genotype for the B isoform "affects hepatitis C virus eradication, whether spontaneous or therapy driven," Dr. Duarte-Rojo noted. "It is important to study the associations of IL28B in the posttransplant setting to unravel mechanisms driving viral-host interactions and help the understanding of this polymorphism in hepatitis C pathobiology."

The investigators studied 241 consecutive patients with hepatitis C virus infection who underwent liver transplantation between 1995 and 2010. Average age was 52 years and the mean Model for End-Stage Liver Disease (MELD) score was 15.

IL28B genotype of recipient and donor was assessed from liver biopsies done at the time of transplantation, and serial biopsies of the liver graft were done after transplantation to assess virologic and histologic measures of recurrence.

Only 31% of the recipients had the IL28B CC genotype, compared with 52% of the donors, Dr. Duarte-Rojo reported.

The time to virologic recurrence after transplantation was longer when the recipient had the CC genotype vs. a non-CC genotype (4.6 vs. 4.1 months), whereas it was nonsignificantly shorter when the donor had the CC vs. a non-CC genotype.

Similarly, the proportion of patients that developed histologic recurrence as defined by stage 2 or greater fibrosis 1 year post transplantation was lower when the recipient had the CC vs. a non-CC genotype (19% vs. 38%). In contrast, recurrence rate was higher when the donor had the CC vs. a non-CC genotype (43% vs. 23%).

And there was also an interaction, whereby the proportion with recurrence ranged from a low of 17% with a CC recipient and non-CC donor, to a high of 52% with a non-CC recipient and a CC donor.

In a multivariate analysis that included factors such as alanine aminotransferase level, MELD score, viral genotype, surgical and biliary complications, cytomegalovirus infection, and diabetes, the risk of recurrence was still markedly decreased when the recipient had the CC genotype (odds ratio, 0.40) and markedly increased when the donor had the CC genotype (OR, 2.71).

The results were essentially the same after exclusion of patients who received antiviral therapy, according to Dr. Duarte-Rojo.

He noted that the recipient and donor IL28B genotypes also had opposite effects on alanine aminotransferase levels, viral loads, and rates of acute cellular rejection during follow-up.

Dr. Duarte-Rojo reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Both donor and recipient interleukin 28B genotype affect the risk of recurrence of hepatitis C after liver transplantation, but they do so in opposite directions.

Investigators led by Dr. Andres Duarte-Rojo of the Mayo Clinic in Rochester, Minn., studied a cohort of more than 200 patients with hepatitis C who underwent liver transplantation, finding that 32% had a histologic recurrence 1 year later.

The risk of such recurrence was reduced by more than half when the recipient had the interleukin 28B (IL28B) CC genotype, as compared with the CT or TT genotype, according to results reported at the annual meeting of the American Association for the Study of Liver Diseases. In sharp contrast, the risk was almost tripled if the donor had the CC genotype for IL28B instead of one of the others.

"Variations in the phenotypic expression of IL28B genotype occur in relation to its source, either the recipient or the donor. This paradoxical effect suggests variation in the activation of the adaptive immune system according to hepatic and nonhepatic IL28B genotype," Dr. Duarte-Rojo commented.

Other research by his group suggests that donor and recipient CC genotype have a synergistic effect in promoting sustained virologic response after transplantation. "However, according to current results, allocation of a CC allograft to hepatitis C patients may predispose to a more severe disease in those untreated or not achieving a sustained virologic response," he said.

IL28 is a cytokine playing a role in antiviral defenses. The genotype for the B isoform "affects hepatitis C virus eradication, whether spontaneous or therapy driven," Dr. Duarte-Rojo noted. "It is important to study the associations of IL28B in the posttransplant setting to unravel mechanisms driving viral-host interactions and help the understanding of this polymorphism in hepatitis C pathobiology."

The investigators studied 241 consecutive patients with hepatitis C virus infection who underwent liver transplantation between 1995 and 2010. Average age was 52 years and the mean Model for End-Stage Liver Disease (MELD) score was 15.

IL28B genotype of recipient and donor was assessed from liver biopsies done at the time of transplantation, and serial biopsies of the liver graft were done after transplantation to assess virologic and histologic measures of recurrence.

Only 31% of the recipients had the IL28B CC genotype, compared with 52% of the donors, Dr. Duarte-Rojo reported.

The time to virologic recurrence after transplantation was longer when the recipient had the CC genotype vs. a non-CC genotype (4.6 vs. 4.1 months), whereas it was nonsignificantly shorter when the donor had the CC vs. a non-CC genotype.

Similarly, the proportion of patients that developed histologic recurrence as defined by stage 2 or greater fibrosis 1 year post transplantation was lower when the recipient had the CC vs. a non-CC genotype (19% vs. 38%). In contrast, recurrence rate was higher when the donor had the CC vs. a non-CC genotype (43% vs. 23%).

And there was also an interaction, whereby the proportion with recurrence ranged from a low of 17% with a CC recipient and non-CC donor, to a high of 52% with a non-CC recipient and a CC donor.

In a multivariate analysis that included factors such as alanine aminotransferase level, MELD score, viral genotype, surgical and biliary complications, cytomegalovirus infection, and diabetes, the risk of recurrence was still markedly decreased when the recipient had the CC genotype (odds ratio, 0.40) and markedly increased when the donor had the CC genotype (OR, 2.71).

The results were essentially the same after exclusion of patients who received antiviral therapy, according to Dr. Duarte-Rojo.

He noted that the recipient and donor IL28B genotypes also had opposite effects on alanine aminotransferase levels, viral loads, and rates of acute cellular rejection during follow-up.

Dr. Duarte-Rojo reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Use of the oral thrombopoietin receptor agonist eltrombopag allows most thrombocytopenic patients with chronic hepatitis C to receive antiviral therapy and improves their odds of achieving a sustained virologic response, according to final results of the ENABLE 1 trial.

In the phase III randomized trial, 95% of 716 patients given eltrombopag were able to start antiviral therapy with pegylated interferon alfa-2a and ribavirin, lead investigator Dr. Nezam H. Afdhal reported at the annual meeting of the American Association for the Study of Liver Diseases.

After starting antiviral therapy, patients who continued on eltrombopag were less likely than their counterparts switched to placebo to have to stop the hepatitis C therapy and more likely to achieve a sustained virologic response (SVR), although the rate was still fairly low (23% vs. 14%).

Eltrombopag also had a good safety profile, with no increase in the rate of thromboembolic events, compared with placebo (2% in each group).

"The results from ENABLE 1 show that eltrombopag treatment in thrombocytopenic patients with HCV [hepatitis C virus] and advanced fibrosis enabled the introduction of antiviral therapy in 95% of patients who would otherwise be marginal candidates for treatment," commented Dr. Afdhal, an associate professor of medicine at Harvard Medical School and director of hepatology at the Beth Israel Deaconess Medical Center, both in Boston.

"We saw a statistically significant and meaningful improvement in SVR vs. placebo in this population that is difficult to treat," Dr. Afdhal noted.

"The SVR rates are obviously low in comparison to some of the dynamic numbers we have seen at this meeting," he added. "And this is because these patients are constrained by lack of interferon efficacy in patients with advanced disease."

Dr. Afdhal also presented some late-breaking data from the ENABLE 2 trial, which has an identical design except that it uses pegylated interferon alfa-2b instead of alfa-2a. Findings among the 758 patients here were essentially the same for SVR, favoring eltrombopag over placebo (19% vs. 13%), but there was a hint of an increased rate of thromboembolic events with the drug in this case (4% vs. less than 1%). "ENABLE 2 results are truly preliminary and under full evaluation, and we will hopefully be presenting them at a subsequent meeting," he commented.

Thrombocytopenia is a problematic complication of chronic liver disease in patients with viral hepatitis, Dr. Afdhal noted. "Up until now, these patients have typically been ineligible for antiviral treatment and have been excluded from nearly all of the clinical trials that we see," he pointed out. Additionally, dose reduction and treatment discontinuation are recommended for patients on antiviral therapy who develop thrombocytopenia, which may reduce their chances of achieving SVR.

Patients were eligible for the ENABLE 1 trial if they had chronic hepatitis C and a platelet count less than 75,000 per mcL.

In the first part of the trial, all were treated on an open-label basis with increasing doses of eltrombopag (Promacta), up to 100 mg/day, until they achieved a platelet count of at least 90,000 per mcL and could start antiviral therapy. (Eltrombopag is currently approved only for treating thrombocytopenia in patients with chronic immune [idiopathic] thrombocytopenic purpura.)

In the second part of the trial, patients were randomized 2:1 to double-blind treatment with eltrombopag or placebo, along with antiviral therapy (pegylated interferon alfa-2a and ribavirin). Therapy was planned to continue for up to 24-48 weeks, depending on viral genotype.

The interferon was reduced or discontinued if a patient’s platelet count fell below 50,000 per mcL. Growth factors were allowed to manage anemia and neutropenia.

Results showed that fully 95% of enrolled patients were able to achieve the platelet count required to start antiviral therapy and proceed to randomization. The randomized patients had a median age of 52 years. The majority had viral genotype 1. More than two-thirds were interferon naive.

Compared with the placebo group, the eltrombopag group had a higher rate of SVR at 24 weeks after the end of antiviral therapy (23% vs. 14%, P = .006), Dr. Afdhal reported. Results were much the same in subgroups stratified by viral genotype, baseline platelet count, and baseline viral load.

Median platelet counts in the eltrombopag group never fell below the threshold for reducing the dose of antiviral therapy, but they were below this threshold the majority of time in the placebo group. The proportion of patients not needing any interferon dose reduction was about twice as high in the former group (57% vs. 30%).

The rate, type, and severity of adverse events were generally similar between treatment groups. "What we see are the standard side effects that we see in the majority of patients on interferon-ribavirin therapy," Dr. Afdhal commented.

Patients in the eltrombopag group had a higher rate of events suggestive of progressive liver disease, 13% vs. 8%. However, "the majority of these events are those that are typical of patients with chronic liver disease," he noted. "In addition, what we did see is that there was no change throughout the study in either arm in MELD [Model for End-stage Liver Disease] score, Child-Pugh score, albumin, bilirubin, INR [international normalized ratio], or any of the standard parameters."

Patients in the trial were rigorously monitored for portal vein thrombosis with serial ultrasound and Doppler imaging, according to Dr. Afdhal. The rare thromboses detected were evident only on ultrasound, except for a single clinical thrombosis in a patient in the placebo group who had a tumor invading the portal vein.

"Unlike what we have previously presented, where there was a significant correlation between the elevation of thrombocytes and portal vein thrombosis, there is no easily apparent association here," he noted. "Many of these events took place in patients with platelet counts of less than 50,000, and many of these took place after the study was over."

Dr. Afdhal reported that he receives research support from Merck, Novartis, GlaxoSmithKline, Echosens, Vertex, Gilead, Quest, Pharmasset, and Abbott, and is an adviser to Gilead, Echosens, Biogen, Vertex, Novartis, Idera Pharmaceuticals, Boehringer Ingelheim, Human Genome Sciences, Biolex, FibroGen, Ligand, Spring Bank, Synexis, and GlaxoSmithKline, which manufactures Promacta.

SAN FRANCISCO – Use of the oral thrombopoietin receptor agonist eltrombopag allows most thrombocytopenic patients with chronic hepatitis C to receive antiviral therapy and improves their odds of achieving a sustained virologic response, according to final results of the ENABLE 1 trial.

In the phase III randomized trial, 95% of 716 patients given eltrombopag were able to start antiviral therapy with pegylated interferon alfa-2a and ribavirin, lead investigator Dr. Nezam H. Afdhal reported at the annual meeting of the American Association for the Study of Liver Diseases.

After starting antiviral therapy, patients who continued on eltrombopag were less likely than their counterparts switched to placebo to have to stop the hepatitis C therapy and more likely to achieve a sustained virologic response (SVR), although the rate was still fairly low (23% vs. 14%).

Eltrombopag also had a good safety profile, with no increase in the rate of thromboembolic events, compared with placebo (2% in each group).

"The results from ENABLE 1 show that eltrombopag treatment in thrombocytopenic patients with HCV [hepatitis C virus] and advanced fibrosis enabled the introduction of antiviral therapy in 95% of patients who would otherwise be marginal candidates for treatment," commented Dr. Afdhal, an associate professor of medicine at Harvard Medical School and director of hepatology at the Beth Israel Deaconess Medical Center, both in Boston.

"We saw a statistically significant and meaningful improvement in SVR vs. placebo in this population that is difficult to treat," Dr. Afdhal noted.

"The SVR rates are obviously low in comparison to some of the dynamic numbers we have seen at this meeting," he added. "And this is because these patients are constrained by lack of interferon efficacy in patients with advanced disease."

Dr. Afdhal also presented some late-breaking data from the ENABLE 2 trial, which has an identical design except that it uses pegylated interferon alfa-2b instead of alfa-2a. Findings among the 758 patients here were essentially the same for SVR, favoring eltrombopag over placebo (19% vs. 13%), but there was a hint of an increased rate of thromboembolic events with the drug in this case (4% vs. less than 1%). "ENABLE 2 results are truly preliminary and under full evaluation, and we will hopefully be presenting them at a subsequent meeting," he commented.

Thrombocytopenia is a problematic complication of chronic liver disease in patients with viral hepatitis, Dr. Afdhal noted. "Up until now, these patients have typically been ineligible for antiviral treatment and have been excluded from nearly all of the clinical trials that we see," he pointed out. Additionally, dose reduction and treatment discontinuation are recommended for patients on antiviral therapy who develop thrombocytopenia, which may reduce their chances of achieving SVR.

Patients were eligible for the ENABLE 1 trial if they had chronic hepatitis C and a platelet count less than 75,000 per mcL.

In the first part of the trial, all were treated on an open-label basis with increasing doses of eltrombopag (Promacta), up to 100 mg/day, until they achieved a platelet count of at least 90,000 per mcL and could start antiviral therapy. (Eltrombopag is currently approved only for treating thrombocytopenia in patients with chronic immune [idiopathic] thrombocytopenic purpura.)

In the second part of the trial, patients were randomized 2:1 to double-blind treatment with eltrombopag or placebo, along with antiviral therapy (pegylated interferon alfa-2a and ribavirin). Therapy was planned to continue for up to 24-48 weeks, depending on viral genotype.

The interferon was reduced or discontinued if a patient’s platelet count fell below 50,000 per mcL. Growth factors were allowed to manage anemia and neutropenia.

Results showed that fully 95% of enrolled patients were able to achieve the platelet count required to start antiviral therapy and proceed to randomization. The randomized patients had a median age of 52 years. The majority had viral genotype 1. More than two-thirds were interferon naive.

Compared with the placebo group, the eltrombopag group had a higher rate of SVR at 24 weeks after the end of antiviral therapy (23% vs. 14%, P = .006), Dr. Afdhal reported. Results were much the same in subgroups stratified by viral genotype, baseline platelet count, and baseline viral load.

Median platelet counts in the eltrombopag group never fell below the threshold for reducing the dose of antiviral therapy, but they were below this threshold the majority of time in the placebo group. The proportion of patients not needing any interferon dose reduction was about twice as high in the former group (57% vs. 30%).

The rate, type, and severity of adverse events were generally similar between treatment groups. "What we see are the standard side effects that we see in the majority of patients on interferon-ribavirin therapy," Dr. Afdhal commented.

Patients in the eltrombopag group had a higher rate of events suggestive of progressive liver disease, 13% vs. 8%. However, "the majority of these events are those that are typical of patients with chronic liver disease," he noted. "In addition, what we did see is that there was no change throughout the study in either arm in MELD [Model for End-stage Liver Disease] score, Child-Pugh score, albumin, bilirubin, INR [international normalized ratio], or any of the standard parameters."

Patients in the trial were rigorously monitored for portal vein thrombosis with serial ultrasound and Doppler imaging, according to Dr. Afdhal. The rare thromboses detected were evident only on ultrasound, except for a single clinical thrombosis in a patient in the placebo group who had a tumor invading the portal vein.

"Unlike what we have previously presented, where there was a significant correlation between the elevation of thrombocytes and portal vein thrombosis, there is no easily apparent association here," he noted. "Many of these events took place in patients with platelet counts of less than 50,000, and many of these took place after the study was over."

Dr. Afdhal reported that he receives research support from Merck, Novartis, GlaxoSmithKline, Echosens, Vertex, Gilead, Quest, Pharmasset, and Abbott, and is an adviser to Gilead, Echosens, Biogen, Vertex, Novartis, Idera Pharmaceuticals, Boehringer Ingelheim, Human Genome Sciences, Biolex, FibroGen, Ligand, Spring Bank, Synexis, and GlaxoSmithKline, which manufactures Promacta.

SAN FRANCISCO – Use of the oral thrombopoietin receptor agonist eltrombopag allows most thrombocytopenic patients with chronic hepatitis C to receive antiviral therapy and improves their odds of achieving a sustained virologic response, according to final results of the ENABLE 1 trial.

In the phase III randomized trial, 95% of 716 patients given eltrombopag were able to start antiviral therapy with pegylated interferon alfa-2a and ribavirin, lead investigator Dr. Nezam H. Afdhal reported at the annual meeting of the American Association for the Study of Liver Diseases.

After starting antiviral therapy, patients who continued on eltrombopag were less likely than their counterparts switched to placebo to have to stop the hepatitis C therapy and more likely to achieve a sustained virologic response (SVR), although the rate was still fairly low (23% vs. 14%).

Eltrombopag also had a good safety profile, with no increase in the rate of thromboembolic events, compared with placebo (2% in each group).

"The results from ENABLE 1 show that eltrombopag treatment in thrombocytopenic patients with HCV [hepatitis C virus] and advanced fibrosis enabled the introduction of antiviral therapy in 95% of patients who would otherwise be marginal candidates for treatment," commented Dr. Afdhal, an associate professor of medicine at Harvard Medical School and director of hepatology at the Beth Israel Deaconess Medical Center, both in Boston.

"We saw a statistically significant and meaningful improvement in SVR vs. placebo in this population that is difficult to treat," Dr. Afdhal noted.

"The SVR rates are obviously low in comparison to some of the dynamic numbers we have seen at this meeting," he added. "And this is because these patients are constrained by lack of interferon efficacy in patients with advanced disease."

Dr. Afdhal also presented some late-breaking data from the ENABLE 2 trial, which has an identical design except that it uses pegylated interferon alfa-2b instead of alfa-2a. Findings among the 758 patients here were essentially the same for SVR, favoring eltrombopag over placebo (19% vs. 13%), but there was a hint of an increased rate of thromboembolic events with the drug in this case (4% vs. less than 1%). "ENABLE 2 results are truly preliminary and under full evaluation, and we will hopefully be presenting them at a subsequent meeting," he commented.

Thrombocytopenia is a problematic complication of chronic liver disease in patients with viral hepatitis, Dr. Afdhal noted. "Up until now, these patients have typically been ineligible for antiviral treatment and have been excluded from nearly all of the clinical trials that we see," he pointed out. Additionally, dose reduction and treatment discontinuation are recommended for patients on antiviral therapy who develop thrombocytopenia, which may reduce their chances of achieving SVR.

Patients were eligible for the ENABLE 1 trial if they had chronic hepatitis C and a platelet count less than 75,000 per mcL.

In the first part of the trial, all were treated on an open-label basis with increasing doses of eltrombopag (Promacta), up to 100 mg/day, until they achieved a platelet count of at least 90,000 per mcL and could start antiviral therapy. (Eltrombopag is currently approved only for treating thrombocytopenia in patients with chronic immune [idiopathic] thrombocytopenic purpura.)

In the second part of the trial, patients were randomized 2:1 to double-blind treatment with eltrombopag or placebo, along with antiviral therapy (pegylated interferon alfa-2a and ribavirin). Therapy was planned to continue for up to 24-48 weeks, depending on viral genotype.

The interferon was reduced or discontinued if a patient’s platelet count fell below 50,000 per mcL. Growth factors were allowed to manage anemia and neutropenia.

Results showed that fully 95% of enrolled patients were able to achieve the platelet count required to start antiviral therapy and proceed to randomization. The randomized patients had a median age of 52 years. The majority had viral genotype 1. More than two-thirds were interferon naive.

Compared with the placebo group, the eltrombopag group had a higher rate of SVR at 24 weeks after the end of antiviral therapy (23% vs. 14%, P = .006), Dr. Afdhal reported. Results were much the same in subgroups stratified by viral genotype, baseline platelet count, and baseline viral load.

Median platelet counts in the eltrombopag group never fell below the threshold for reducing the dose of antiviral therapy, but they were below this threshold the majority of time in the placebo group. The proportion of patients not needing any interferon dose reduction was about twice as high in the former group (57% vs. 30%).

The rate, type, and severity of adverse events were generally similar between treatment groups. "What we see are the standard side effects that we see in the majority of patients on interferon-ribavirin therapy," Dr. Afdhal commented.

Patients in the eltrombopag group had a higher rate of events suggestive of progressive liver disease, 13% vs. 8%. However, "the majority of these events are those that are typical of patients with chronic liver disease," he noted. "In addition, what we did see is that there was no change throughout the study in either arm in MELD [Model for End-stage Liver Disease] score, Child-Pugh score, albumin, bilirubin, INR [international normalized ratio], or any of the standard parameters."

Patients in the trial were rigorously monitored for portal vein thrombosis with serial ultrasound and Doppler imaging, according to Dr. Afdhal. The rare thromboses detected were evident only on ultrasound, except for a single clinical thrombosis in a patient in the placebo group who had a tumor invading the portal vein.

"Unlike what we have previously presented, where there was a significant correlation between the elevation of thrombocytes and portal vein thrombosis, there is no easily apparent association here," he noted. "Many of these events took place in patients with platelet counts of less than 50,000, and many of these took place after the study was over."

Dr. Afdhal reported that he receives research support from Merck, Novartis, GlaxoSmithKline, Echosens, Vertex, Gilead, Quest, Pharmasset, and Abbott, and is an adviser to Gilead, Echosens, Biogen, Vertex, Novartis, Idera Pharmaceuticals, Boehringer Ingelheim, Human Genome Sciences, Biolex, FibroGen, Ligand, Spring Bank, Synexis, and GlaxoSmithKline, which manufactures Promacta.

SAN FRANCISCO – Both sorafenib and transcatheter arterial chemoembolization/radiofrequency ablation can extend the lives of patients with infiltrative hepatocellular carcinoma, according to a retrospective review of 155 patients.

The radiologic-based therapy gave patients a median of 3 additional months of life; sorafenib (Nexavar) gave them a median of 4.5 months. The difference between treatments was not statistically significant.

Little research has been done on infiltrative hepatocellular carcinoma (HCC), including whether it responds to treatment. "Often [patients] are deemed not to be treatment candidates. I think we’ve shown that if you treat these patients, they have a significantly lengthened life. It’s not a huge difference, but it can be decent," said lead investigator Dr. Neil Mehta, a gastroenterology fellow at the University of California, San Francisco.

Perhaps 10% of hepatocellular carcinomas are infiltrative; these tumors are usually larger, with poor definition and vascular invasion.

"I think we’ve shown that if you treat these patients, they have a significantly lengthened life."

Just 30% of the 155 patients were treated for their tumors, including the 22 treated with transcatheter arterial chemoembolization/radiofrequency ablation (TACE/RFA) and the 11 treated with sorafenib.

These low treatment rates are not unusual. Patients might be too sick, or may opt out of treatment, Dr. Mehta said. Sometimes it’s thought that the tumor won’t respond, he added.

Treatment did appear to make a difference at UCSF, however. Eleven (50%) of the TACE/RFA patients were alive at 6 months and 4 (18%) were living at 12 months; their median survival was 6 months. Eight (73%) of the sorafenib patients were alive at 6 months, with 4 (36%) alive at 12 months; their median survival was 7.5 months. Only 17% of the untreated patients were alive at 6 months, and 2% at 12 months; their median survival was 3 months.

"Tumor-directed therapy confers a significant survival benefit even after adjusting for factors that may affect treatment eligibility," the researchers concluded. Treatment approaches in the study included liver resection, transplant, and other chemotherapy regimens.

Besides lack of treatment, predictors of death within 6 months were advanced liver disease (Child-Pugh class B or C), alpha-fetoprotein greater than 1,000 ng/mL, large tumor size, and female gender.

Patients ranged in age from 22 to 89 years, and almost 80% were men. Seventy-one percent had stage C disease in the BCLC (Barcelona Clinic Liver Cancer) classification system, whereas 23% had stage D disease, and the rest had stage A or B.

The baseline median alpha-fetoprotein was 347 ng/mL and the median MELD (Model for End-Stage Liver Disease) score was 13. The median maximal tumor diameter was 11.9 cm; 48% of patients had extrahepatic metastases, and 26% had biliary dilation. Hepatitis C was thought to be the cause of liver disease in well over half of patients, followed by hepatitis B, alcoholism, and fatty liver disease.

Dr. Mehta said he had no disclosures. Coauthor Dr. Nicholas Fidelman disclosed grant/research support from Bayer Inc., maker of sorafenib, and Nordion Inc., maker of TheraSphere, a radioembolization product for unresectable HCC.

SAN FRANCISCO – Both sorafenib and transcatheter arterial chemoembolization/radiofrequency ablation can extend the lives of patients with infiltrative hepatocellular carcinoma, according to a retrospective review of 155 patients.

The radiologic-based therapy gave patients a median of 3 additional months of life; sorafenib (Nexavar) gave them a median of 4.5 months. The difference between treatments was not statistically significant.

Little research has been done on infiltrative hepatocellular carcinoma (HCC), including whether it responds to treatment. "Often [patients] are deemed not to be treatment candidates. I think we’ve shown that if you treat these patients, they have a significantly lengthened life. It’s not a huge difference, but it can be decent," said lead investigator Dr. Neil Mehta, a gastroenterology fellow at the University of California, San Francisco.

Perhaps 10% of hepatocellular carcinomas are infiltrative; these tumors are usually larger, with poor definition and vascular invasion.

"I think we’ve shown that if you treat these patients, they have a significantly lengthened life."

Just 30% of the 155 patients were treated for their tumors, including the 22 treated with transcatheter arterial chemoembolization/radiofrequency ablation (TACE/RFA) and the 11 treated with sorafenib.

These low treatment rates are not unusual. Patients might be too sick, or may opt out of treatment, Dr. Mehta said. Sometimes it’s thought that the tumor won’t respond, he added.

Treatment did appear to make a difference at UCSF, however. Eleven (50%) of the TACE/RFA patients were alive at 6 months and 4 (18%) were living at 12 months; their median survival was 6 months. Eight (73%) of the sorafenib patients were alive at 6 months, with 4 (36%) alive at 12 months; their median survival was 7.5 months. Only 17% of the untreated patients were alive at 6 months, and 2% at 12 months; their median survival was 3 months.

"Tumor-directed therapy confers a significant survival benefit even after adjusting for factors that may affect treatment eligibility," the researchers concluded. Treatment approaches in the study included liver resection, transplant, and other chemotherapy regimens.

Besides lack of treatment, predictors of death within 6 months were advanced liver disease (Child-Pugh class B or C), alpha-fetoprotein greater than 1,000 ng/mL, large tumor size, and female gender.

Patients ranged in age from 22 to 89 years, and almost 80% were men. Seventy-one percent had stage C disease in the BCLC (Barcelona Clinic Liver Cancer) classification system, whereas 23% had stage D disease, and the rest had stage A or B.

The baseline median alpha-fetoprotein was 347 ng/mL and the median MELD (Model for End-Stage Liver Disease) score was 13. The median maximal tumor diameter was 11.9 cm; 48% of patients had extrahepatic metastases, and 26% had biliary dilation. Hepatitis C was thought to be the cause of liver disease in well over half of patients, followed by hepatitis B, alcoholism, and fatty liver disease.

Dr. Mehta said he had no disclosures. Coauthor Dr. Nicholas Fidelman disclosed grant/research support from Bayer Inc., maker of sorafenib, and Nordion Inc., maker of TheraSphere, a radioembolization product for unresectable HCC.

SAN FRANCISCO – Both sorafenib and transcatheter arterial chemoembolization/radiofrequency ablation can extend the lives of patients with infiltrative hepatocellular carcinoma, according to a retrospective review of 155 patients.

The radiologic-based therapy gave patients a median of 3 additional months of life; sorafenib (Nexavar) gave them a median of 4.5 months. The difference between treatments was not statistically significant.

Little research has been done on infiltrative hepatocellular carcinoma (HCC), including whether it responds to treatment. "Often [patients] are deemed not to be treatment candidates. I think we’ve shown that if you treat these patients, they have a significantly lengthened life. It’s not a huge difference, but it can be decent," said lead investigator Dr. Neil Mehta, a gastroenterology fellow at the University of California, San Francisco.

Perhaps 10% of hepatocellular carcinomas are infiltrative; these tumors are usually larger, with poor definition and vascular invasion.

"I think we’ve shown that if you treat these patients, they have a significantly lengthened life."

Just 30% of the 155 patients were treated for their tumors, including the 22 treated with transcatheter arterial chemoembolization/radiofrequency ablation (TACE/RFA) and the 11 treated with sorafenib.

These low treatment rates are not unusual. Patients might be too sick, or may opt out of treatment, Dr. Mehta said. Sometimes it’s thought that the tumor won’t respond, he added.

Treatment did appear to make a difference at UCSF, however. Eleven (50%) of the TACE/RFA patients were alive at 6 months and 4 (18%) were living at 12 months; their median survival was 6 months. Eight (73%) of the sorafenib patients were alive at 6 months, with 4 (36%) alive at 12 months; their median survival was 7.5 months. Only 17% of the untreated patients were alive at 6 months, and 2% at 12 months; their median survival was 3 months.

"Tumor-directed therapy confers a significant survival benefit even after adjusting for factors that may affect treatment eligibility," the researchers concluded. Treatment approaches in the study included liver resection, transplant, and other chemotherapy regimens.

Besides lack of treatment, predictors of death within 6 months were advanced liver disease (Child-Pugh class B or C), alpha-fetoprotein greater than 1,000 ng/mL, large tumor size, and female gender.

Patients ranged in age from 22 to 89 years, and almost 80% were men. Seventy-one percent had stage C disease in the BCLC (Barcelona Clinic Liver Cancer) classification system, whereas 23% had stage D disease, and the rest had stage A or B.

The baseline median alpha-fetoprotein was 347 ng/mL and the median MELD (Model for End-Stage Liver Disease) score was 13. The median maximal tumor diameter was 11.9 cm; 48% of patients had extrahepatic metastases, and 26% had biliary dilation. Hepatitis C was thought to be the cause of liver disease in well over half of patients, followed by hepatitis B, alcoholism, and fatty liver disease.

Dr. Mehta said he had no disclosures. Coauthor Dr. Nicholas Fidelman disclosed grant/research support from Bayer Inc., maker of sorafenib, and Nordion Inc., maker of TheraSphere, a radioembolization product for unresectable HCC.

SAN FRANCISCO – Health care providers should be aware that adult patients with diabetes have a sharply increased risk for chronic liver disease and should be counseled accordingly, advised investigators with the Centers for Disease Control and Prevention.

In a U.S. population-based study reported at the annual meeting of the American Association for the Study of Liver Diseases, the investigators found that diabetic adults had four times the rate of hospitalizations related to chronic liver disease, compared with their nondiabetic counterparts. Hepatitis C and "chronic hepatitis and cirrhosis" accounted for most of these hospitalizations in the diabetic group.

"The bottom line is that people with diabetes have associated liver disease, and this is something that providers should be aware of and they should take some sort of preventive measures toward that, [things like] vaccinating against hepatitis B or counseling about decreasing alcohol intake," lead investigator Dr. Kathy K. Byrd of the CDC’s Division of Viral Hepatitis said in an interview.

In fact, the study results provided some of the impetus behind the new recommendation from the Advisory Committee on Immunization Practices that calls for hepatitis B vaccination among diabetic adults aged younger than 60 years, she said.

Dr. Byrd and her colleagues used the Nationwide Inpatient Sample (a nationally representative survey of hospital discharge data) to assess rates of hospitalization related to chronic liver disease for the years 2001-2008. The sample captured information on roughly 7.5-8.2 million hospital discharges per year.

For each hospitalization, the investigators checked for the presence of diagnostic codes for hepatitis B; hepatitis C; chronic hepatitis and cirrhosis; malignancy of the liver or bile ducts; and alcoholic liver disease. They used National Health and Nutrition Examination Survey data to obtain population denominators for adults with and without diabetes.

Study results, reported in a poster session at the meeting, showed that the age-adjusted rate of chronic liver disease–related hospitalization during the entire study period was 1,546 per 100,000 for diabetic adults in the population, roughly fourfold higher than the rate of 398 per 100,000 for nondiabetic adults. For each of the five diagnostic codes, hospitalization rates in diabetic adults were two- to sixfold higher than those in their nondiabetic peers.

Hepatitis C, as well as chronic hepatitis and cirrhosis, were by far the two most common diagnoses within the diabetic group, each seen in about 40% of the hospitalizations, according to Dr. Byrd. Results also showed a temporal trend whereby the rate of chronic liver disease–related hospitalization increased by 34% among diabetic adults between 2001 and 2008 (P = .002). When analyzed by specific diagnosis, there was a 55% increase in the rate for chronic hepatitis and cirrhosis, a 44% increase in the rate for malignancy of the liver and bile ducts, and a 34% increase in the rate for hepatitis C.

The rate of chronic liver disease–related hospitalization was consistently higher for men with diabetes than for women with diabetes. This hospitalization rate also increased by a greater extent during the study period among men with diabetes (by 46%; P = .001) than among women with diabetes (by 24%; P = .058).

Dr. Byrd reported that she had no relevant conflicts of interest.

SAN FRANCISCO – Health care providers should be aware that adult patients with diabetes have a sharply increased risk for chronic liver disease and should be counseled accordingly, advised investigators with the Centers for Disease Control and Prevention.

In a U.S. population-based study reported at the annual meeting of the American Association for the Study of Liver Diseases, the investigators found that diabetic adults had four times the rate of hospitalizations related to chronic liver disease, compared with their nondiabetic counterparts. Hepatitis C and "chronic hepatitis and cirrhosis" accounted for most of these hospitalizations in the diabetic group.

"The bottom line is that people with diabetes have associated liver disease, and this is something that providers should be aware of and they should take some sort of preventive measures toward that, [things like] vaccinating against hepatitis B or counseling about decreasing alcohol intake," lead investigator Dr. Kathy K. Byrd of the CDC’s Division of Viral Hepatitis said in an interview.

In fact, the study results provided some of the impetus behind the new recommendation from the Advisory Committee on Immunization Practices that calls for hepatitis B vaccination among diabetic adults aged younger than 60 years, she said.

Dr. Byrd and her colleagues used the Nationwide Inpatient Sample (a nationally representative survey of hospital discharge data) to assess rates of hospitalization related to chronic liver disease for the years 2001-2008. The sample captured information on roughly 7.5-8.2 million hospital discharges per year.

For each hospitalization, the investigators checked for the presence of diagnostic codes for hepatitis B; hepatitis C; chronic hepatitis and cirrhosis; malignancy of the liver or bile ducts; and alcoholic liver disease. They used National Health and Nutrition Examination Survey data to obtain population denominators for adults with and without diabetes.

Study results, reported in a poster session at the meeting, showed that the age-adjusted rate of chronic liver disease–related hospitalization during the entire study period was 1,546 per 100,000 for diabetic adults in the population, roughly fourfold higher than the rate of 398 per 100,000 for nondiabetic adults. For each of the five diagnostic codes, hospitalization rates in diabetic adults were two- to sixfold higher than those in their nondiabetic peers.

Hepatitis C, as well as chronic hepatitis and cirrhosis, were by far the two most common diagnoses within the diabetic group, each seen in about 40% of the hospitalizations, according to Dr. Byrd. Results also showed a temporal trend whereby the rate of chronic liver disease–related hospitalization increased by 34% among diabetic adults between 2001 and 2008 (P = .002). When analyzed by specific diagnosis, there was a 55% increase in the rate for chronic hepatitis and cirrhosis, a 44% increase in the rate for malignancy of the liver and bile ducts, and a 34% increase in the rate for hepatitis C.

The rate of chronic liver disease–related hospitalization was consistently higher for men with diabetes than for women with diabetes. This hospitalization rate also increased by a greater extent during the study period among men with diabetes (by 46%; P = .001) than among women with diabetes (by 24%; P = .058).

Dr. Byrd reported that she had no relevant conflicts of interest.

SAN FRANCISCO – Health care providers should be aware that adult patients with diabetes have a sharply increased risk for chronic liver disease and should be counseled accordingly, advised investigators with the Centers for Disease Control and Prevention.

In a U.S. population-based study reported at the annual meeting of the American Association for the Study of Liver Diseases, the investigators found that diabetic adults had four times the rate of hospitalizations related to chronic liver disease, compared with their nondiabetic counterparts. Hepatitis C and "chronic hepatitis and cirrhosis" accounted for most of these hospitalizations in the diabetic group.

"The bottom line is that people with diabetes have associated liver disease, and this is something that providers should be aware of and they should take some sort of preventive measures toward that, [things like] vaccinating against hepatitis B or counseling about decreasing alcohol intake," lead investigator Dr. Kathy K. Byrd of the CDC’s Division of Viral Hepatitis said in an interview.

In fact, the study results provided some of the impetus behind the new recommendation from the Advisory Committee on Immunization Practices that calls for hepatitis B vaccination among diabetic adults aged younger than 60 years, she said.

Dr. Byrd and her colleagues used the Nationwide Inpatient Sample (a nationally representative survey of hospital discharge data) to assess rates of hospitalization related to chronic liver disease for the years 2001-2008. The sample captured information on roughly 7.5-8.2 million hospital discharges per year.

For each hospitalization, the investigators checked for the presence of diagnostic codes for hepatitis B; hepatitis C; chronic hepatitis and cirrhosis; malignancy of the liver or bile ducts; and alcoholic liver disease. They used National Health and Nutrition Examination Survey data to obtain population denominators for adults with and without diabetes.

Study results, reported in a poster session at the meeting, showed that the age-adjusted rate of chronic liver disease–related hospitalization during the entire study period was 1,546 per 100,000 for diabetic adults in the population, roughly fourfold higher than the rate of 398 per 100,000 for nondiabetic adults. For each of the five diagnostic codes, hospitalization rates in diabetic adults were two- to sixfold higher than those in their nondiabetic peers.

Hepatitis C, as well as chronic hepatitis and cirrhosis, were by far the two most common diagnoses within the diabetic group, each seen in about 40% of the hospitalizations, according to Dr. Byrd. Results also showed a temporal trend whereby the rate of chronic liver disease–related hospitalization increased by 34% among diabetic adults between 2001 and 2008 (P = .002). When analyzed by specific diagnosis, there was a 55% increase in the rate for chronic hepatitis and cirrhosis, a 44% increase in the rate for malignancy of the liver and bile ducts, and a 34% increase in the rate for hepatitis C.

The rate of chronic liver disease–related hospitalization was consistently higher for men with diabetes than for women with diabetes. This hospitalization rate also increased by a greater extent during the study period among men with diabetes (by 46%; P = .001) than among women with diabetes (by 24%; P = .058).

Dr. Byrd reported that she had no relevant conflicts of interest.

SAN FRANCISCO – Oral silymarin, an extract of milk thistle, is well tolerated but not efficacious for treating chronic hepatitis C virus infection, according to results from a randomized phase II trial reported at the annual meeting of the American Association for the Study of Liver Diseases.

After 24 weeks, patients taking high doses of the botanical agent – which is known to have anti-inflammatory, immunomodulatory, and antiviral activity in vitro – did not show improvement in serum levels of alanine aminotransferase (ALT) compared with their counterparts taking placebo.

© M. Schuppich - Fotolia.com

There were also no significant differences between groups in a variety of measures of symptoms and quality of life.

"We must conclude that oral silymarin used at higher-than-customary doses did not significantly alter biochemical or virological markers of disease activity in hepatitis C patients previously treated with interferon-based regimens," said first author Dr. Michael W. Fried, director of hepatology at the University of North Carolina at Chapel Hill. But he added that "this was a fairly difficult group – these were nonresponders [to conventional therapy] – they were older."

The study is noteworthy for its many strengths, such as its use of a well characterized silymarin product, prolonged treatment, excellent adherence, and focus on a specific liver disease, he said.

Recent studies finding a benefit of silymarin in treating HCV infection used a different, intravenous formulation, according to Dr. Fried. That formulation contains a succinate moiety that may be important and likely achieves blood levels of silybin A, a major active component, higher than can be achieved with the oral formulation.

The oral doses used in the trial were probably not sufficient to inhibit the virus’ replicative enzymes, but giving higher doses was not practical. "We had to balance that with the pill burden: These were five capsules given three times a day, so we were not able to push the dose currently," he explained. "There may be attempts to try higher[-dose] formulations. There is also some way, interestingly, that’s being investigated to try to boost the silymarin levels with other botanical products ... because of their interactions on metabolism."

Dr. T. Jake Liang, president of the AASLD and chief of the liver diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md., noted that the market for herbal and related products "is a big business in this country, about $30 billion, and it’s really not that well regulated, and there are a lot of unsubstantiated claims."

He pointed out that the trial focused on a more modest disease outcome. "The goal was not so much to see whether silymarin can eradicate the hepatitis C virus; the goal was really to see whether it could improve the damage to the liver," he explained in a press conference.

"I think this study clearly shows that the use of milk thistle is not effective in treating patients with hepatitis C. It’s a very important negative study – I think that’s key. We really want to make sure that we prevent any unwarranted use of herbal products despite the [health claims]," Dr. Liang concluded.

The trial, known as SyNCH and funded by the National Institutes of Health, enrolled 154 adult patients from four U.S. centers with chronic HCV who had not had a sustained virologic response to prior interferon-based therapy, had quantifiable HCV RNA, and had an ALT level of at least 65 IU/L.

Patients who had decompensated cirrhosis or moderate to severe steatosis or steatohepatitis were excluded, as were those who were positive for HIV or hepatitis B surface antigen, or who had used silymarin in the past month.

The patients were assigned to double-blind treatment in three groups: silymarin 420 mg three times daily, silymarin 700 mg three times daily, or matching placebo three times daily. The silymarin product used was a standardized preparation (Legalon, manufactured and supplied by Rottapharm Madaus in Monza, Italy, and Cologne, Germany) that is approved as a prescription drug in some European and Asian countries. Doses three- to fivefold higher than the customary one were chosen to achieve the highest likelihood of finding a benefit, according to Dr. Fried.

The patients studied were about 55 years old, on average, and three-fourths were white. Their mean ALT was 125 IU/L. Forty-four percent had used silymarin previously.

"Adherence throughout the treatment trial was quite excellent," he reported; across groups, 92%-98% of participants took more than 80% of planned doses. And random testing confirmed that patients in the silymarin group had silybin A in plasma while those in the placebo group did not.

However, final intent-to-treat analyses showed no significant difference between groups at 24 weeks in the primary end point, defined as achievement of a serum ALT level of 45 IU/L or lower (approximately the upper limit of normal) or a drop in serum ALT level of at least 50% to less than 65 IU/L (approximately 1.5 times the upper limit of normal).

Just 3.8% of patients in the placebo group met this end point, as did 4% in the silymarin 420-mg group and 3.8% in the silymarin 700-mg group.

"We really looked at many different subpopulations, and we could not find any signal at all," Dr. Fried said; additionally, the findings were much the same in per-protocol analyses.

The treatment groups were also statistically indistinguishable with respect to the changes from baseline in ALT levels and in HCV RNA levels, and with respect to changes from baseline in scores on questionnaires assessing depression, physical and mental health, and quality of life specific to chronic liver disease.

"Silymarin was well tolerated with an adverse event profile similar to placebo," Dr. Fried said. The three treatment groups did not differ significantly with respect to rates of adverse events (most of which were mild or moderate) or serious adverse events.

Dr. Fried reported that he is a consultant to Genentech, Tibotec, Vertex, Merck, Abbott, and Pharmasset; receives grant or research support from Genentech, Tibotec, Vertex, Merck, Anadys, Abbott, and Bristol-Myers Squibb; is an adviser or reviewer for GlaxoSmithKline; and has stock in Pharmasset. Dr. Liang reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Oral silymarin, an extract of milk thistle, is well tolerated but not efficacious for treating chronic hepatitis C virus infection, according to results from a randomized phase II trial reported at the annual meeting of the American Association for the Study of Liver Diseases.

After 24 weeks, patients taking high doses of the botanical agent – which is known to have anti-inflammatory, immunomodulatory, and antiviral activity in vitro – did not show improvement in serum levels of alanine aminotransferase (ALT) compared with their counterparts taking placebo.

© M. Schuppich - Fotolia.com

There were also no significant differences between groups in a variety of measures of symptoms and quality of life.

"We must conclude that oral silymarin used at higher-than-customary doses did not significantly alter biochemical or virological markers of disease activity in hepatitis C patients previously treated with interferon-based regimens," said first author Dr. Michael W. Fried, director of hepatology at the University of North Carolina at Chapel Hill. But he added that "this was a fairly difficult group – these were nonresponders [to conventional therapy] – they were older."

The study is noteworthy for its many strengths, such as its use of a well characterized silymarin product, prolonged treatment, excellent adherence, and focus on a specific liver disease, he said.

Recent studies finding a benefit of silymarin in treating HCV infection used a different, intravenous formulation, according to Dr. Fried. That formulation contains a succinate moiety that may be important and likely achieves blood levels of silybin A, a major active component, higher than can be achieved with the oral formulation.

The oral doses used in the trial were probably not sufficient to inhibit the virus’ replicative enzymes, but giving higher doses was not practical. "We had to balance that with the pill burden: These were five capsules given three times a day, so we were not able to push the dose currently," he explained. "There may be attempts to try higher[-dose] formulations. There is also some way, interestingly, that’s being investigated to try to boost the silymarin levels with other botanical products ... because of their interactions on metabolism."

Dr. T. Jake Liang, president of the AASLD and chief of the liver diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md., noted that the market for herbal and related products "is a big business in this country, about $30 billion, and it’s really not that well regulated, and there are a lot of unsubstantiated claims."

He pointed out that the trial focused on a more modest disease outcome. "The goal was not so much to see whether silymarin can eradicate the hepatitis C virus; the goal was really to see whether it could improve the damage to the liver," he explained in a press conference.

"I think this study clearly shows that the use of milk thistle is not effective in treating patients with hepatitis C. It’s a very important negative study – I think that’s key. We really want to make sure that we prevent any unwarranted use of herbal products despite the [health claims]," Dr. Liang concluded.

The trial, known as SyNCH and funded by the National Institutes of Health, enrolled 154 adult patients from four U.S. centers with chronic HCV who had not had a sustained virologic response to prior interferon-based therapy, had quantifiable HCV RNA, and had an ALT level of at least 65 IU/L.

Patients who had decompensated cirrhosis or moderate to severe steatosis or steatohepatitis were excluded, as were those who were positive for HIV or hepatitis B surface antigen, or who had used silymarin in the past month.

The patients were assigned to double-blind treatment in three groups: silymarin 420 mg three times daily, silymarin 700 mg three times daily, or matching placebo three times daily. The silymarin product used was a standardized preparation (Legalon, manufactured and supplied by Rottapharm Madaus in Monza, Italy, and Cologne, Germany) that is approved as a prescription drug in some European and Asian countries. Doses three- to fivefold higher than the customary one were chosen to achieve the highest likelihood of finding a benefit, according to Dr. Fried.

The patients studied were about 55 years old, on average, and three-fourths were white. Their mean ALT was 125 IU/L. Forty-four percent had used silymarin previously.

"Adherence throughout the treatment trial was quite excellent," he reported; across groups, 92%-98% of participants took more than 80% of planned doses. And random testing confirmed that patients in the silymarin group had silybin A in plasma while those in the placebo group did not.

However, final intent-to-treat analyses showed no significant difference between groups at 24 weeks in the primary end point, defined as achievement of a serum ALT level of 45 IU/L or lower (approximately the upper limit of normal) or a drop in serum ALT level of at least 50% to less than 65 IU/L (approximately 1.5 times the upper limit of normal).

Just 3.8% of patients in the placebo group met this end point, as did 4% in the silymarin 420-mg group and 3.8% in the silymarin 700-mg group.

"We really looked at many different subpopulations, and we could not find any signal at all," Dr. Fried said; additionally, the findings were much the same in per-protocol analyses.

The treatment groups were also statistically indistinguishable with respect to the changes from baseline in ALT levels and in HCV RNA levels, and with respect to changes from baseline in scores on questionnaires assessing depression, physical and mental health, and quality of life specific to chronic liver disease.

"Silymarin was well tolerated with an adverse event profile similar to placebo," Dr. Fried said. The three treatment groups did not differ significantly with respect to rates of adverse events (most of which were mild or moderate) or serious adverse events.

Dr. Fried reported that he is a consultant to Genentech, Tibotec, Vertex, Merck, Abbott, and Pharmasset; receives grant or research support from Genentech, Tibotec, Vertex, Merck, Anadys, Abbott, and Bristol-Myers Squibb; is an adviser or reviewer for GlaxoSmithKline; and has stock in Pharmasset. Dr. Liang reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Oral silymarin, an extract of milk thistle, is well tolerated but not efficacious for treating chronic hepatitis C virus infection, according to results from a randomized phase II trial reported at the annual meeting of the American Association for the Study of Liver Diseases.

After 24 weeks, patients taking high doses of the botanical agent – which is known to have anti-inflammatory, immunomodulatory, and antiviral activity in vitro – did not show improvement in serum levels of alanine aminotransferase (ALT) compared with their counterparts taking placebo.

© M. Schuppich - Fotolia.com

There were also no significant differences between groups in a variety of measures of symptoms and quality of life.

"We must conclude that oral silymarin used at higher-than-customary doses did not significantly alter biochemical or virological markers of disease activity in hepatitis C patients previously treated with interferon-based regimens," said first author Dr. Michael W. Fried, director of hepatology at the University of North Carolina at Chapel Hill. But he added that "this was a fairly difficult group – these were nonresponders [to conventional therapy] – they were older."

The study is noteworthy for its many strengths, such as its use of a well characterized silymarin product, prolonged treatment, excellent adherence, and focus on a specific liver disease, he said.

Recent studies finding a benefit of silymarin in treating HCV infection used a different, intravenous formulation, according to Dr. Fried. That formulation contains a succinate moiety that may be important and likely achieves blood levels of silybin A, a major active component, higher than can be achieved with the oral formulation.

The oral doses used in the trial were probably not sufficient to inhibit the virus’ replicative enzymes, but giving higher doses was not practical. "We had to balance that with the pill burden: These were five capsules given three times a day, so we were not able to push the dose currently," he explained. "There may be attempts to try higher[-dose] formulations. There is also some way, interestingly, that’s being investigated to try to boost the silymarin levels with other botanical products ... because of their interactions on metabolism."

Dr. T. Jake Liang, president of the AASLD and chief of the liver diseases branch at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md., noted that the market for herbal and related products "is a big business in this country, about $30 billion, and it’s really not that well regulated, and there are a lot of unsubstantiated claims."

He pointed out that the trial focused on a more modest disease outcome. "The goal was not so much to see whether silymarin can eradicate the hepatitis C virus; the goal was really to see whether it could improve the damage to the liver," he explained in a press conference.

"I think this study clearly shows that the use of milk thistle is not effective in treating patients with hepatitis C. It’s a very important negative study – I think that’s key. We really want to make sure that we prevent any unwarranted use of herbal products despite the [health claims]," Dr. Liang concluded.

The trial, known as SyNCH and funded by the National Institutes of Health, enrolled 154 adult patients from four U.S. centers with chronic HCV who had not had a sustained virologic response to prior interferon-based therapy, had quantifiable HCV RNA, and had an ALT level of at least 65 IU/L.

Patients who had decompensated cirrhosis or moderate to severe steatosis or steatohepatitis were excluded, as were those who were positive for HIV or hepatitis B surface antigen, or who had used silymarin in the past month.

The patients were assigned to double-blind treatment in three groups: silymarin 420 mg three times daily, silymarin 700 mg three times daily, or matching placebo three times daily. The silymarin product used was a standardized preparation (Legalon, manufactured and supplied by Rottapharm Madaus in Monza, Italy, and Cologne, Germany) that is approved as a prescription drug in some European and Asian countries. Doses three- to fivefold higher than the customary one were chosen to achieve the highest likelihood of finding a benefit, according to Dr. Fried.

The patients studied were about 55 years old, on average, and three-fourths were white. Their mean ALT was 125 IU/L. Forty-four percent had used silymarin previously.

"Adherence throughout the treatment trial was quite excellent," he reported; across groups, 92%-98% of participants took more than 80% of planned doses. And random testing confirmed that patients in the silymarin group had silybin A in plasma while those in the placebo group did not.

However, final intent-to-treat analyses showed no significant difference between groups at 24 weeks in the primary end point, defined as achievement of a serum ALT level of 45 IU/L or lower (approximately the upper limit of normal) or a drop in serum ALT level of at least 50% to less than 65 IU/L (approximately 1.5 times the upper limit of normal).

Just 3.8% of patients in the placebo group met this end point, as did 4% in the silymarin 420-mg group and 3.8% in the silymarin 700-mg group.

"We really looked at many different subpopulations, and we could not find any signal at all," Dr. Fried said; additionally, the findings were much the same in per-protocol analyses.

The treatment groups were also statistically indistinguishable with respect to the changes from baseline in ALT levels and in HCV RNA levels, and with respect to changes from baseline in scores on questionnaires assessing depression, physical and mental health, and quality of life specific to chronic liver disease.

"Silymarin was well tolerated with an adverse event profile similar to placebo," Dr. Fried said. The three treatment groups did not differ significantly with respect to rates of adverse events (most of which were mild or moderate) or serious adverse events.

Dr. Fried reported that he is a consultant to Genentech, Tibotec, Vertex, Merck, Abbott, and Pharmasset; receives grant or research support from Genentech, Tibotec, Vertex, Merck, Anadys, Abbott, and Bristol-Myers Squibb; is an adviser or reviewer for GlaxoSmithKline; and has stock in Pharmasset. Dr. Liang reported that he had no relevant conflicts of interest.

SAN FRANCISCO – When treating patients with chronic hepatitis B, two antiviral agents are not necessarily better than one, according to the results of an international randomized trial called BE-LOW.

About 80% of patients achieved viral suppression regardless of whether they received entecavir alone or entecavir combined with tenofovir, with no significant difference between groups, Dr. Anna S. Lok reported at the annual meeting of the American Association for the Study of Liver Diseases.

"The combination did not provide an overall benefit compared to the entecavir monotherapy; however, it may provide incremental benefit in HBeAg-positive patients with a baseline viral load of more than 10⁸ IU/mL."

However, combined therapy was more efficacious than monotherapy among the subset of patients who were hepatitis B e antigen (HBeAg) positive and had a high viral load at baseline.

"The combination did not provide an overall benefit compared to the entecavir monotherapy; however, it may provide incremental benefit in HBeAg-positive patients with a baseline viral load of more than 10⁸ IU/mL," she commented. "It is possible that there may be some clinical settings in patients with high viral load in which rapid viral decline is important, where combination therapy may have a role."

An attendee asked whether the better response with the combination in those HBeAg-positive patients might have been due to the tenofovir alone. "Obviously, the limitation of this study was that there was no tenofovir monotherapy group, so we don’t know," Dr. Lok replied. "Maybe this would be just because of tenofovir and we don’t need the combination."

The trial tested combination therapy for several reasons. "Entecavir and tenofovir are both potent antiviral agents with nonoverlapping resistance profiles, and they are also generally very well tolerated. Combination therapy may provide additive or synergistic antiviral activity and reduce the risk of resistance development," she explained. "But this potential benefit has not yet been confirmed, and the safety of the combination also needs to be established."

Patients were eligible for the phase IIIb trial if they were aged 16 years or older, had been hepatitis B surface antigen (HBsAg) positive for at least 24 weeks, and had not previously received a nucleoside or nucleotide analogue.

"Because one of the purposes was to determine if combination therapy might have a preferential advantage in patients with high baseline hepatitis B virus (HBV) DNA, the study was designed to cap the number of HBeAg-negative patients at 30% to enrich for patients with high baseline viral load," noted Dr. Lok, who is director of clinical hepatology at the University of Michigan, Ann Arbor.

In all, 384 patients were randomized in balanced fashion to open-label treatment with entecavir (Baraclude) alone or entecavir at the same dose combined with tenofovir (Viread).

The patients had a mean age of 39 years. Roughly half of the patients were white and the other half were Asian. Seventy percent were HBeAg positive.

About 7% of patients in the monotherapy group and 12% of patients in the combination therapy group discontinued treatment before 96 weeks. "In the majority of the patients who came off treatment, it was because of loss to follow-up. There were some patients who discontinued because of adverse events, but those adverse events were not related to renal side effects or anything significant – they were more sort-of constitutional symptoms," Dr. Lok said.

In a modified intention-to-treat analysis, in which patients lost to follow-up were considered not to have achieved suppression, the 96-week rate of viral suppression (HBV DNA less than 50 IU/mL), was 76.4% with entecavir alone and 83.2% with entecavir plus tenofovir, not a statistically significant difference. The results were essentially the same in a per-protocol analysis.

However, in the HBeAg-positive subset of patients, the rate was higher with the combination therapy (80.4% vs. 69.8%, P = .046), and further analysis showed that this difference was solely due to a higher rate among those who had a high viral load at baseline, with an HBV DNA of at least 10⁸ IU/mL (78.8% vs. 62.0%).

For other end points in the trial population overall, there were numerical trends actually favoring monotherapy when it came to rates of alanine aminotransferase normalization, HBeAg loss, and HBeAg seroconversion.

The rate of virologic breakthrough was 1.0% with the monotherapy and 3.6% with the combination therapy. There were no cases of genotypic resistance specific for the study drugs in either group.

"Safety was also very comparable between the two groups," Dr. Lok reported, with similar rates of serious adverse events.

Three patients in the monotherapy group developed hepatocellular carcinoma, compared with none in the combination therapy group. In all three cases, HBV DNA was undetectable at the time of the cancer diagnosis.

Dr. Lok reported that she is an adviser or reviewer for Bristol-Myers Squibb, Gilead, Merck, Roche, Abbott, Bayer, and GlaxoSmithKline, and that she receives research or grant support from Bristol-Myers Squibb, Gilead, Merck, Roche, and GlaxoSmithKline.

SAN FRANCISCO – When treating patients with chronic hepatitis B, two antiviral agents are not necessarily better than one, according to the results of an international randomized trial called BE-LOW.

About 80% of patients achieved viral suppression regardless of whether they received entecavir alone or entecavir combined with tenofovir, with no significant difference between groups, Dr. Anna S. Lok reported at the annual meeting of the American Association for the Study of Liver Diseases.

"The combination did not provide an overall benefit compared to the entecavir monotherapy; however, it may provide incremental benefit in HBeAg-positive patients with a baseline viral load of more than 10⁸ IU/mL."

However, combined therapy was more efficacious than monotherapy among the subset of patients who were hepatitis B e antigen (HBeAg) positive and had a high viral load at baseline.

"The combination did not provide an overall benefit compared to the entecavir monotherapy; however, it may provide incremental benefit in HBeAg-positive patients with a baseline viral load of more than 10⁸ IU/mL," she commented. "It is possible that there may be some clinical settings in patients with high viral load in which rapid viral decline is important, where combination therapy may have a role."

An attendee asked whether the better response with the combination in those HBeAg-positive patients might have been due to the tenofovir alone. "Obviously, the limitation of this study was that there was no tenofovir monotherapy group, so we don’t know," Dr. Lok replied. "Maybe this would be just because of tenofovir and we don’t need the combination."

The trial tested combination therapy for several reasons. "Entecavir and tenofovir are both potent antiviral agents with nonoverlapping resistance profiles, and they are also generally very well tolerated. Combination therapy may provide additive or synergistic antiviral activity and reduce the risk of resistance development," she explained. "But this potential benefit has not yet been confirmed, and the safety of the combination also needs to be established."

Patients were eligible for the phase IIIb trial if they were aged 16 years or older, had been hepatitis B surface antigen (HBsAg) positive for at least 24 weeks, and had not previously received a nucleoside or nucleotide analogue.

"Because one of the purposes was to determine if combination therapy might have a preferential advantage in patients with high baseline hepatitis B virus (HBV) DNA, the study was designed to cap the number of HBeAg-negative patients at 30% to enrich for patients with high baseline viral load," noted Dr. Lok, who is director of clinical hepatology at the University of Michigan, Ann Arbor.

In all, 384 patients were randomized in balanced fashion to open-label treatment with entecavir (Baraclude) alone or entecavir at the same dose combined with tenofovir (Viread).

The patients had a mean age of 39 years. Roughly half of the patients were white and the other half were Asian. Seventy percent were HBeAg positive.

About 7% of patients in the monotherapy group and 12% of patients in the combination therapy group discontinued treatment before 96 weeks. "In the majority of the patients who came off treatment, it was because of loss to follow-up. There were some patients who discontinued because of adverse events, but those adverse events were not related to renal side effects or anything significant – they were more sort-of constitutional symptoms," Dr. Lok said.

In a modified intention-to-treat analysis, in which patients lost to follow-up were considered not to have achieved suppression, the 96-week rate of viral suppression (HBV DNA less than 50 IU/mL), was 76.4% with entecavir alone and 83.2% with entecavir plus tenofovir, not a statistically significant difference. The results were essentially the same in a per-protocol analysis.

However, in the HBeAg-positive subset of patients, the rate was higher with the combination therapy (80.4% vs. 69.8%, P = .046), and further analysis showed that this difference was solely due to a higher rate among those who had a high viral load at baseline, with an HBV DNA of at least 10⁸ IU/mL (78.8% vs. 62.0%).

For other end points in the trial population overall, there were numerical trends actually favoring monotherapy when it came to rates of alanine aminotransferase normalization, HBeAg loss, and HBeAg seroconversion.

The rate of virologic breakthrough was 1.0% with the monotherapy and 3.6% with the combination therapy. There were no cases of genotypic resistance specific for the study drugs in either group.

"Safety was also very comparable between the two groups," Dr. Lok reported, with similar rates of serious adverse events.

Three patients in the monotherapy group developed hepatocellular carcinoma, compared with none in the combination therapy group. In all three cases, HBV DNA was undetectable at the time of the cancer diagnosis.

Dr. Lok reported that she is an adviser or reviewer for Bristol-Myers Squibb, Gilead, Merck, Roche, Abbott, Bayer, and GlaxoSmithKline, and that she receives research or grant support from Bristol-Myers Squibb, Gilead, Merck, Roche, and GlaxoSmithKline.

SAN FRANCISCO – When treating patients with chronic hepatitis B, two antiviral agents are not necessarily better than one, according to the results of an international randomized trial called BE-LOW.

About 80% of patients achieved viral suppression regardless of whether they received entecavir alone or entecavir combined with tenofovir, with no significant difference between groups, Dr. Anna S. Lok reported at the annual meeting of the American Association for the Study of Liver Diseases.

"The combination did not provide an overall benefit compared to the entecavir monotherapy; however, it may provide incremental benefit in HBeAg-positive patients with a baseline viral load of more than 10⁸ IU/mL."

However, combined therapy was more efficacious than monotherapy among the subset of patients who were hepatitis B e antigen (HBeAg) positive and had a high viral load at baseline.

"The combination did not provide an overall benefit compared to the entecavir monotherapy; however, it may provide incremental benefit in HBeAg-positive patients with a baseline viral load of more than 10⁸ IU/mL," she commented. "It is possible that there may be some clinical settings in patients with high viral load in which rapid viral decline is important, where combination therapy may have a role."

An attendee asked whether the better response with the combination in those HBeAg-positive patients might have been due to the tenofovir alone. "Obviously, the limitation of this study was that there was no tenofovir monotherapy group, so we don’t know," Dr. Lok replied. "Maybe this would be just because of tenofovir and we don’t need the combination."

The trial tested combination therapy for several reasons. "Entecavir and tenofovir are both potent antiviral agents with nonoverlapping resistance profiles, and they are also generally very well tolerated. Combination therapy may provide additive or synergistic antiviral activity and reduce the risk of resistance development," she explained. "But this potential benefit has not yet been confirmed, and the safety of the combination also needs to be established."

Patients were eligible for the phase IIIb trial if they were aged 16 years or older, had been hepatitis B surface antigen (HBsAg) positive for at least 24 weeks, and had not previously received a nucleoside or nucleotide analogue.

"Because one of the purposes was to determine if combination therapy might have a preferential advantage in patients with high baseline hepatitis B virus (HBV) DNA, the study was designed to cap the number of HBeAg-negative patients at 30% to enrich for patients with high baseline viral load," noted Dr. Lok, who is director of clinical hepatology at the University of Michigan, Ann Arbor.

In all, 384 patients were randomized in balanced fashion to open-label treatment with entecavir (Baraclude) alone or entecavir at the same dose combined with tenofovir (Viread).

The patients had a mean age of 39 years. Roughly half of the patients were white and the other half were Asian. Seventy percent were HBeAg positive.

About 7% of patients in the monotherapy group and 12% of patients in the combination therapy group discontinued treatment before 96 weeks. "In the majority of the patients who came off treatment, it was because of loss to follow-up. There were some patients who discontinued because of adverse events, but those adverse events were not related to renal side effects or anything significant – they were more sort-of constitutional symptoms," Dr. Lok said.

In a modified intention-to-treat analysis, in which patients lost to follow-up were considered not to have achieved suppression, the 96-week rate of viral suppression (HBV DNA less than 50 IU/mL), was 76.4% with entecavir alone and 83.2% with entecavir plus tenofovir, not a statistically significant difference. The results were essentially the same in a per-protocol analysis.

However, in the HBeAg-positive subset of patients, the rate was higher with the combination therapy (80.4% vs. 69.8%, P = .046), and further analysis showed that this difference was solely due to a higher rate among those who had a high viral load at baseline, with an HBV DNA of at least 10⁸ IU/mL (78.8% vs. 62.0%).

For other end points in the trial population overall, there were numerical trends actually favoring monotherapy when it came to rates of alanine aminotransferase normalization, HBeAg loss, and HBeAg seroconversion.

The rate of virologic breakthrough was 1.0% with the monotherapy and 3.6% with the combination therapy. There were no cases of genotypic resistance specific for the study drugs in either group.

"Safety was also very comparable between the two groups," Dr. Lok reported, with similar rates of serious adverse events.

Three patients in the monotherapy group developed hepatocellular carcinoma, compared with none in the combination therapy group. In all three cases, HBV DNA was undetectable at the time of the cancer diagnosis.

Dr. Lok reported that she is an adviser or reviewer for Bristol-Myers Squibb, Gilead, Merck, Roche, Abbott, Bayer, and GlaxoSmithKline, and that she receives research or grant support from Bristol-Myers Squibb, Gilead, Merck, Roche, and GlaxoSmithKline.

SAN FRANCISCO – Factors that can be measured in the first few years of life can predict whether a child will develop nonalcoholic fatty liver disease (NAFLD) by adolescence, suggests a study presented at the annual meeting of the American Association for the Study of Liver Diseases.

Investigators in Australia led by Dr. Oyekoya T. Ayonrinde prospectively followed more than 1,000 children from birth to adolescence, by which time one in eight had developed NAFLD, now the most common chronic liver disorder in pediatric and adult populations in many countries. The data showed distinctly different trajectories for measures of adiposity and systolic blood pressure between the children who did and did not develop NAFLD.

Additionally, greater values for measures of adiposity at various ages in the first decade of life were among the independent positive predictors of NAFLD, whereas longer duration of breastfeeding and, among girls, larger head circumference were among the independent negative predictors.

"There seems to be a potential protective role of breastfeeding on NAFLD, which needs to be explored further," Dr. Ayonrinde commented. "There [are] some data to show that breastfeeding is associated with lower insulin release and also less-rapid weight gain. And it has also been associated with larger head circumference as well, so that probably ties in to some degree."

The study’s findings have implications for pediatric health assessments, he maintained. "Routine recording of childhood anthropometrics is recommended. The trajectory of systolic blood pressure and any adiposity measure during childhood identifies those at particular risk of NAFLD and associated metabolic disorders, who may benefit from further targeted assessment."

Explaining the study’s rationale, Dr. Ayonrinde noted that little is known about the natural history of NAFLD, and the disease is underdiagnosed. "So it makes sense to consider that the identification of children at risk of NAFLD through longitudinal studies may provide improved understanding of the natural history and potential opportunities for prevention and therapy of NAFLD," he said.

The investigators followed 1,170 children who were participating in the Raine Study, a birth cohort study conducted in western Australia. The children had serial anthropometric measurements between birth and the age of 17 years.

Liver ultrasound was performed when the participants were aged 17 years. Boys consuming at least two alcoholic drinks per day and girls consuming at least one alcoholic drink per day were excluded from the study to reduce that possible source of confounding, he noted.

Study results showed that by the age of 17 years, fully 13% of the children – 16% of girls and 10% of boys – had developed NAFLD, according to Dr. Ayonrinde, a gastroenterologist at the University of Western Australia in Perth.

A case-control analysis of the children who did and did not develop NAFLD showed that none of the anthropometric factors assessed at birth were associated with NAFLD, nor was weight gain in the first year of life. But breastfeeding was highly protective: Infants breastfed for more than 6 months were less than half as likely to have NAFLD as adolescents.

The earliest anthropometric measure to show an association with NAFLD was smaller head circumference (at the age of 1 year in girls), and the strongest predictor overall was suprailiac skinfold thickness, Dr. Ayonrinde reported.

In addition, the children who did and did not develop NAFLD had significantly different trajectories throughout childhood when it came to head circumference (in girls only), body weight, body mass index, various skinfold thicknesses, and systolic blood pressure.

In a multivariate analysis, boys were more likely to develop NAFLD if they had a greater suprailiac skinfold thickness at age 3 years, a greater chest circumference at age 5 years, a greater body mass index at age 8 years, or a greater suprailiac skinfold thickness at age 10 years (odds ratios ranged from 1.11 to 1.37). Boys were less likely to develop NAFLD if they were breastfed for longer as infants (OR, 0.91).

Girls were more likely to develop NAFLD if they had a higher body weight at age 3 years, a greater suprailiac skinfold thickness or chest circumference at age 5 years, a greater chest circumference at age 8 years, or a larger suprailiac skinfold thickness at age 10 years (OR, 1.08-1.44). Girls were less likely to develop NAFLD if they were breastfed for longer as infants or if they had a larger head circumference at age 3, 5, or 8 years (OR, 0.62-0.90).

Data on maternal factors, such as obesity and diabetes, and on socioeconomic factors, are available in the dataset but have not yet been analyzed, according to Dr. Ayonrinde.

Dr. Ayonrinde reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Factors that can be measured in the first few years of life can predict whether a child will develop nonalcoholic fatty liver disease (NAFLD) by adolescence, suggests a study presented at the annual meeting of the American Association for the Study of Liver Diseases.

Investigators in Australia led by Dr. Oyekoya T. Ayonrinde prospectively followed more than 1,000 children from birth to adolescence, by which time one in eight had developed NAFLD, now the most common chronic liver disorder in pediatric and adult populations in many countries. The data showed distinctly different trajectories for measures of adiposity and systolic blood pressure between the children who did and did not develop NAFLD.

Additionally, greater values for measures of adiposity at various ages in the first decade of life were among the independent positive predictors of NAFLD, whereas longer duration of breastfeeding and, among girls, larger head circumference were among the independent negative predictors.

"There seems to be a potential protective role of breastfeeding on NAFLD, which needs to be explored further," Dr. Ayonrinde commented. "There [are] some data to show that breastfeeding is associated with lower insulin release and also less-rapid weight gain. And it has also been associated with larger head circumference as well, so that probably ties in to some degree."

The study’s findings have implications for pediatric health assessments, he maintained. "Routine recording of childhood anthropometrics is recommended. The trajectory of systolic blood pressure and any adiposity measure during childhood identifies those at particular risk of NAFLD and associated metabolic disorders, who may benefit from further targeted assessment."

Explaining the study’s rationale, Dr. Ayonrinde noted that little is known about the natural history of NAFLD, and the disease is underdiagnosed. "So it makes sense to consider that the identification of children at risk of NAFLD through longitudinal studies may provide improved understanding of the natural history and potential opportunities for prevention and therapy of NAFLD," he said.

The investigators followed 1,170 children who were participating in the Raine Study, a birth cohort study conducted in western Australia. The children had serial anthropometric measurements between birth and the age of 17 years.

Liver ultrasound was performed when the participants were aged 17 years. Boys consuming at least two alcoholic drinks per day and girls consuming at least one alcoholic drink per day were excluded from the study to reduce that possible source of confounding, he noted.

Study results showed that by the age of 17 years, fully 13% of the children – 16% of girls and 10% of boys – had developed NAFLD, according to Dr. Ayonrinde, a gastroenterologist at the University of Western Australia in Perth.

A case-control analysis of the children who did and did not develop NAFLD showed that none of the anthropometric factors assessed at birth were associated with NAFLD, nor was weight gain in the first year of life. But breastfeeding was highly protective: Infants breastfed for more than 6 months were less than half as likely to have NAFLD as adolescents.

The earliest anthropometric measure to show an association with NAFLD was smaller head circumference (at the age of 1 year in girls), and the strongest predictor overall was suprailiac skinfold thickness, Dr. Ayonrinde reported.

In addition, the children who did and did not develop NAFLD had significantly different trajectories throughout childhood when it came to head circumference (in girls only), body weight, body mass index, various skinfold thicknesses, and systolic blood pressure.

In a multivariate analysis, boys were more likely to develop NAFLD if they had a greater suprailiac skinfold thickness at age 3 years, a greater chest circumference at age 5 years, a greater body mass index at age 8 years, or a greater suprailiac skinfold thickness at age 10 years (odds ratios ranged from 1.11 to 1.37). Boys were less likely to develop NAFLD if they were breastfed for longer as infants (OR, 0.91).

Girls were more likely to develop NAFLD if they had a higher body weight at age 3 years, a greater suprailiac skinfold thickness or chest circumference at age 5 years, a greater chest circumference at age 8 years, or a larger suprailiac skinfold thickness at age 10 years (OR, 1.08-1.44). Girls were less likely to develop NAFLD if they were breastfed for longer as infants or if they had a larger head circumference at age 3, 5, or 8 years (OR, 0.62-0.90).

Data on maternal factors, such as obesity and diabetes, and on socioeconomic factors, are available in the dataset but have not yet been analyzed, according to Dr. Ayonrinde.

Dr. Ayonrinde reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Factors that can be measured in the first few years of life can predict whether a child will develop nonalcoholic fatty liver disease (NAFLD) by adolescence, suggests a study presented at the annual meeting of the American Association for the Study of Liver Diseases.

Investigators in Australia led by Dr. Oyekoya T. Ayonrinde prospectively followed more than 1,000 children from birth to adolescence, by which time one in eight had developed NAFLD, now the most common chronic liver disorder in pediatric and adult populations in many countries. The data showed distinctly different trajectories for measures of adiposity and systolic blood pressure between the children who did and did not develop NAFLD.

Additionally, greater values for measures of adiposity at various ages in the first decade of life were among the independent positive predictors of NAFLD, whereas longer duration of breastfeeding and, among girls, larger head circumference were among the independent negative predictors.

"There seems to be a potential protective role of breastfeeding on NAFLD, which needs to be explored further," Dr. Ayonrinde commented. "There [are] some data to show that breastfeeding is associated with lower insulin release and also less-rapid weight gain. And it has also been associated with larger head circumference as well, so that probably ties in to some degree."

The study’s findings have implications for pediatric health assessments, he maintained. "Routine recording of childhood anthropometrics is recommended. The trajectory of systolic blood pressure and any adiposity measure during childhood identifies those at particular risk of NAFLD and associated metabolic disorders, who may benefit from further targeted assessment."

Explaining the study’s rationale, Dr. Ayonrinde noted that little is known about the natural history of NAFLD, and the disease is underdiagnosed. "So it makes sense to consider that the identification of children at risk of NAFLD through longitudinal studies may provide improved understanding of the natural history and potential opportunities for prevention and therapy of NAFLD," he said.

The investigators followed 1,170 children who were participating in the Raine Study, a birth cohort study conducted in western Australia. The children had serial anthropometric measurements between birth and the age of 17 years.

Liver ultrasound was performed when the participants were aged 17 years. Boys consuming at least two alcoholic drinks per day and girls consuming at least one alcoholic drink per day were excluded from the study to reduce that possible source of confounding, he noted.

Study results showed that by the age of 17 years, fully 13% of the children – 16% of girls and 10% of boys – had developed NAFLD, according to Dr. Ayonrinde, a gastroenterologist at the University of Western Australia in Perth.

A case-control analysis of the children who did and did not develop NAFLD showed that none of the anthropometric factors assessed at birth were associated with NAFLD, nor was weight gain in the first year of life. But breastfeeding was highly protective: Infants breastfed for more than 6 months were less than half as likely to have NAFLD as adolescents.

The earliest anthropometric measure to show an association with NAFLD was smaller head circumference (at the age of 1 year in girls), and the strongest predictor overall was suprailiac skinfold thickness, Dr. Ayonrinde reported.

In addition, the children who did and did not develop NAFLD had significantly different trajectories throughout childhood when it came to head circumference (in girls only), body weight, body mass index, various skinfold thicknesses, and systolic blood pressure.

In a multivariate analysis, boys were more likely to develop NAFLD if they had a greater suprailiac skinfold thickness at age 3 years, a greater chest circumference at age 5 years, a greater body mass index at age 8 years, or a greater suprailiac skinfold thickness at age 10 years (odds ratios ranged from 1.11 to 1.37). Boys were less likely to develop NAFLD if they were breastfed for longer as infants (OR, 0.91).

Girls were more likely to develop NAFLD if they had a higher body weight at age 3 years, a greater suprailiac skinfold thickness or chest circumference at age 5 years, a greater chest circumference at age 8 years, or a larger suprailiac skinfold thickness at age 10 years (OR, 1.08-1.44). Girls were less likely to develop NAFLD if they were breastfed for longer as infants or if they had a larger head circumference at age 3, 5, or 8 years (OR, 0.62-0.90).

Data on maternal factors, such as obesity and diabetes, and on socioeconomic factors, are available in the dataset but have not yet been analyzed, according to Dr. Ayonrinde.

Dr. Ayonrinde reported that he had no relevant conflicts of interest.

SAN FRANCISCO – Hepatitis E is an uncommon but often serious infection in immunosuppressed heart transplant recipients that warrants routine screening, according to investigators at Erasmus University Medical Center in Rotterdam, the Netherlands.

In a study of 263 recipients, 3% were found to have become infected with hepatitis E, most with symptomatic chronic disease. The infections ranged in severity from mild, transient viremia to severe and possibly progressive hepatitis with marked steatosis on liver biopsy.

"Chronic hepatitis E virus infection can have serious consequences in this group of patients," Dr. Annemiek A. van der Eijk said in presenting the findings at the annual meeting of the American Association for the Study of Liver Diseases (AASLD). "We advise systematic hepatitis E virus RNA screening in solid organ transplant recipients. In cases in which liver enzymes are increased, additional hepatitis E virus screening should be implemented."

"Chronic hepatitis E virus infection ... is a treatable disease," she added. Some patients were able to clear the virus when their immunosuppressants were tapered, but doing so also sometimes triggered rejection, which necessitated a resumption of therapy. "In our center, we are now treating patients with ribavirin (Copegus, Rebetol), but there are no large, randomized, controlled trials about the dose and duration of therapy."

"We advise systematic hepatitis E virus RNA screening in solid organ transplant recipients."

Importantly, she stressed, physicians should include hepatitis E infection in the differential diagnosis when transplant recipients have signs and symptoms of liver dysfunction, as it could be mistaken for a variety of other conditions having distinctly different treatments.

Chronicity "is not something we often associate with hepatitis E; it really doesn’t cause chronic infection like hepatitis B or C. But in this kind of immunosuppressed situation, it could," commented Dr. T. Jake Liang, president of the AASLD and chief of the Liver Diseases Branch at the National Institute of Diabetes and Digestive and Kidney Diseases.

"This [study] makes us aware of another cause of chronic liver disease, especially in people who are immunosuppressed, or receiving chemotherapy, or undergoing transplantation with lifelong immunosuppression," he said in a press conference.

Hepatitis E is transmitted mainly by the fecal-oral route (especially through contaminated water) but it can also be acquired by consuming raw or undercooked meat, through parenteral and vertical transmission, and – rarely – by person-to-person contact.

Swine are known to carry the virus. "In the Netherlands, more than 50% of the pig population is infected with hepatitis E virus, and 7% of the livers sold in supermarkets are hepatitis E virus RNA positive," Dr. van der Eijk noted.

Infection is especially worrisome in immunocompromised patients, as they can develop persistent elevation of liver enzymes and chronic hepatitis, with some reports also suggesting the possibility of rapid progression to cirrhosis.

In a cross-sectional study, the investigators tested serum samples from orthotopic heart transplant recipients at the center who were alive in 2010 and 2011 and had banked serum. The patients were receiving tacrolimus (Prograf)- and prednisolone-based immunosuppression.

Samples were tested by both polymerase chain reaction (PCR) for viral RNA – which was used to define infection – and serologic assays for antibodies to the virus. "We decided to screen all of our patients with PCR because we know serology outcomes differ greatly between the different tests used," Dr. van der Eijk explained.

Overall, 7 of the 263 patients studied were found to be infected with hepatitis E virus, for a point prevalence of 3%, and six of them had chronic infection (defined as PCR positivity for more than 6 months). The six men and one woman had a median age of 53 years. Retrospective serum testing showed that the time between transplantation and infection was a median of 8 years, but it ranged widely, from 1 to 20 years.

Viral genotyping showed that all of the patients were infected with genotype 3, which is associated with sporadic cases of hepatitis E in Western countries unrelated to travel and is likely of swine origin. Phylogenetic testing showed no evidence that the infections shared a common source or were acquired nosocomially.

Only two patients had virus-specific IgM antibodies at the time of initial PCR-detected infection and, on average, the PCR became positive 143 days before IgM antibodies were detectable. Thus, "PCR is superior [to serology] to detect infection in immunocompromised patients," Dr. van der Eijk commented.

The patients with chronic infection had elevations to varying extents of alanine aminotransferase levels, gamma-glutamyl transferase levels, or both. On liver biopsy, their Histologic Activity Index scores also ranged considerably, but three patients had scores of 10, indicating moderate disease, with features such as hepatocyte degeneration and fibrosis.

Although all of the patients with chronic hepatitis E had fecal shedding of the virus, none of their spouses was found to be infected on either serologic or PCR testing.

Dr. van der Eijk and Dr. Liang reported that they had no relevant conflicts of interest.

SAN FRANCISCO – Hepatitis E is an uncommon but often serious infection in immunosuppressed heart transplant recipients that warrants routine screening, according to investigators at Erasmus University Medical Center in Rotterdam, the Netherlands.

In a study of 263 recipients, 3% were found to have become infected with hepatitis E, most with symptomatic chronic disease. The infections ranged in severity from mild, transient viremia to severe and possibly progressive hepatitis with marked steatosis on liver biopsy.

"Chronic hepatitis E virus infection can have serious consequences in this group of patients," Dr. Annemiek A. van der Eijk said in presenting the findings at the annual meeting of the American Association for the Study of Liver Diseases (AASLD). "We advise systematic hepatitis E virus RNA screening in solid organ transplant recipients. In cases in which liver enzymes are increased, additional hepatitis E virus screening should be implemented."

"Chronic hepatitis E virus infection ... is a treatable disease," she added. Some patients were able to clear the virus when their immunosuppressants were tapered, but doing so also sometimes triggered rejection, which necessitated a resumption of therapy. "In our center, we are now treating patients with ribavirin (Copegus, Rebetol), but there are no large, randomized, controlled trials about the dose and duration of therapy."

"We advise systematic hepatitis E virus RNA screening in solid organ transplant recipients."

Importantly, she stressed, physicians should include hepatitis E infection in the differential diagnosis when transplant recipients have signs and symptoms of liver dysfunction, as it could be mistaken for a variety of other conditions having distinctly different treatments.

Chronicity "is not something we often associate with hepatitis E; it really doesn’t cause chronic infection like hepatitis B or C. But in this kind of immunosuppressed situation, it could," commented Dr. T. Jake Liang, president of the AASLD and chief of the Liver Diseases Branch at the National Institute of Diabetes and Digestive and Kidney Diseases.

"This [study] makes us aware of another cause of chronic liver disease, especially in people who are immunosuppressed, or receiving chemotherapy, or undergoing transplantation with lifelong immunosuppression," he said in a press conference.

Hepatitis E is transmitted mainly by the fecal-oral route (especially through contaminated water) but it can also be acquired by consuming raw or undercooked meat, through parenteral and vertical transmission, and – rarely – by person-to-person contact.

Swine are known to carry the virus. "In the Netherlands, more than 50% of the pig population is infected with hepatitis E virus, and 7% of the livers sold in supermarkets are hepatitis E virus RNA positive," Dr. van der Eijk noted.

Infection is especially worrisome in immunocompromised patients, as they can develop persistent elevation of liver enzymes and chronic hepatitis, with some reports also suggesting the possibility of rapid progression to cirrhosis.

In a cross-sectional study, the investigators tested serum samples from orthotopic heart transplant recipients at the center who were alive in 2010 and 2011 and had banked serum. The patients were receiving tacrolimus (Prograf)- and prednisolone-based immunosuppression.

Samples were tested by both polymerase chain reaction (PCR) for viral RNA – which was used to define infection – and serologic assays for antibodies to the virus. "We decided to screen all of our patients with PCR because we know serology outcomes differ greatly between the different tests used," Dr. van der Eijk explained.

Overall, 7 of the 263 patients studied were found to be infected with hepatitis E virus, for a point prevalence of 3%, and six of them had chronic infection (defined as PCR positivity for more than 6 months). The six men and one woman had a median age of 53 years. Retrospective serum testing showed that the time between transplantation and infection was a median of 8 years, but it ranged widely, from 1 to 20 years.

Viral genotyping showed that all of the patients were infected with genotype 3, which is associated with sporadic cases of hepatitis E in Western countries unrelated to travel and is likely of swine origin. Phylogenetic testing showed no evidence that the infections shared a common source or were acquired nosocomially.

Only two patients had virus-specific IgM antibodies at the time of initial PCR-detected infection and, on average, the PCR became positive 143 days before IgM antibodies were detectable. Thus, "PCR is superior [to serology] to detect infection in immunocompromised patients," Dr. van der Eijk commented.

The patients with chronic infection had elevations to varying extents of alanine aminotransferase levels, gamma-glutamyl transferase levels, or both. On liver biopsy, their Histologic Activity Index scores also ranged considerably, but three patients had scores of 10, indicating moderate disease, with features such as hepatocyte degeneration and fibrosis.

Although all of the patients with chronic hepatitis E had fecal shedding of the virus, none of their spouses was found to be infected on either serologic or PCR testing.

Dr. van der Eijk and Dr. Liang reported that they had no relevant conflicts of interest.

SAN FRANCISCO – Hepatitis E is an uncommon but often serious infection in immunosuppressed heart transplant recipients that warrants routine screening, according to investigators at Erasmus University Medical Center in Rotterdam, the Netherlands.

In a study of 263 recipients, 3% were found to have become infected with hepatitis E, most with symptomatic chronic disease. The infections ranged in severity from mild, transient viremia to severe and possibly progressive hepatitis with marked steatosis on liver biopsy.

"Chronic hepatitis E virus infection can have serious consequences in this group of patients," Dr. Annemiek A. van der Eijk said in presenting the findings at the annual meeting of the American Association for the Study of Liver Diseases (AASLD). "We advise systematic hepatitis E virus RNA screening in solid organ transplant recipients. In cases in which liver enzymes are increased, additional hepatitis E virus screening should be implemented."

"Chronic hepatitis E virus infection ... is a treatable disease," she added. Some patients were able to clear the virus when their immunosuppressants were tapered, but doing so also sometimes triggered rejection, which necessitated a resumption of therapy. "In our center, we are now treating patients with ribavirin (Copegus, Rebetol), but there are no large, randomized, controlled trials about the dose and duration of therapy."

"We advise systematic hepatitis E virus RNA screening in solid organ transplant recipients."

Importantly, she stressed, physicians should include hepatitis E infection in the differential diagnosis when transplant recipients have signs and symptoms of liver dysfunction, as it could be mistaken for a variety of other conditions having distinctly different treatments.

Chronicity "is not something we often associate with hepatitis E; it really doesn’t cause chronic infection like hepatitis B or C. But in this kind of immunosuppressed situation, it could," commented Dr. T. Jake Liang, president of the AASLD and chief of the Liver Diseases Branch at the National Institute of Diabetes and Digestive and Kidney Diseases.

"This [study] makes us aware of another cause of chronic liver disease, especially in people who are immunosuppressed, or receiving chemotherapy, or undergoing transplantation with lifelong immunosuppression," he said in a press conference.

Hepatitis E is transmitted mainly by the fecal-oral route (especially through contaminated water) but it can also be acquired by consuming raw or undercooked meat, through parenteral and vertical transmission, and – rarely – by person-to-person contact.

Swine are known to carry the virus. "In the Netherlands, more than 50% of the pig population is infected with hepatitis E virus, and 7% of the livers sold in supermarkets are hepatitis E virus RNA positive," Dr. van der Eijk noted.

Infection is especially worrisome in immunocompromised patients, as they can develop persistent elevation of liver enzymes and chronic hepatitis, with some reports also suggesting the possibility of rapid progression to cirrhosis.

In a cross-sectional study, the investigators tested serum samples from orthotopic heart transplant recipients at the center who were alive in 2010 and 2011 and had banked serum. The patients were receiving tacrolimus (Prograf)- and prednisolone-based immunosuppression.

Samples were tested by both polymerase chain reaction (PCR) for viral RNA – which was used to define infection – and serologic assays for antibodies to the virus. "We decided to screen all of our patients with PCR because we know serology outcomes differ greatly between the different tests used," Dr. van der Eijk explained.

Overall, 7 of the 263 patients studied were found to be infected with hepatitis E virus, for a point prevalence of 3%, and six of them had chronic infection (defined as PCR positivity for more than 6 months). The six men and one woman had a median age of 53 years. Retrospective serum testing showed that the time between transplantation and infection was a median of 8 years, but it ranged widely, from 1 to 20 years.

Viral genotyping showed that all of the patients were infected with genotype 3, which is associated with sporadic cases of hepatitis E in Western countries unrelated to travel and is likely of swine origin. Phylogenetic testing showed no evidence that the infections shared a common source or were acquired nosocomially.

Only two patients had virus-specific IgM antibodies at the time of initial PCR-detected infection and, on average, the PCR became positive 143 days before IgM antibodies were detectable. Thus, "PCR is superior [to serology] to detect infection in immunocompromised patients," Dr. van der Eijk commented.

The patients with chronic infection had elevations to varying extents of alanine aminotransferase levels, gamma-glutamyl transferase levels, or both. On liver biopsy, their Histologic Activity Index scores also ranged considerably, but three patients had scores of 10, indicating moderate disease, with features such as hepatocyte degeneration and fibrosis.

Although all of the patients with chronic hepatitis E had fecal shedding of the virus, none of their spouses was found to be infected on either serologic or PCR testing.

Dr. van der Eijk and Dr. Liang reported that they had no relevant conflicts of interest.

SAN FRANCISCO – Nonalcoholic fatty liver disease is common in adolescent girls with polycystic ovaries, and its presence coincides with worse metabolic derangements, according to Australian researchers.

Because of that, it makes sense when doing an ultrasound study of women with polycystic ovary syndrome (PCOS) to check the liver, as well, for signs of nonalcoholic fatty liver disease (NAFLD), including increased echogenicity and bile duct or blood vessel blurring, said lead investigator Dr. Oyekoya Ayonrinde.

"If we see a girl or woman who has PCOS, we should look for the presence of fatty liver. It just adds maybe another 5 or 10 minutes to the [ultrasound] study," said Dr. Ayonrinde at the annual meeting of the American Association for the Study of Liver Diseases.

That’s important because PCOS, and perhaps even more so when combined with NAFLD, predisposes women to diabetes and cardiovascular disease, among other problems. The combination might also increase the risk of nonalcoholic steatohepatitis.

Dr. Ayonrinde, a clinical gastroenterology lecturer at the University of Western Australia in Perth, and his colleagues came to their conclusions after analyzing 244 girls aged 14-17 years in the Western Australian Pregnancy Cohort (Raine) Study, plus 578 girls and 592 boys, all 17 years old, in a separate NAFLD study. In all, 201 girls had both ovarian and liver ultrasounds, which were used to diagnose both PCOS and NAFLD.

In all, 43% of the girls with PCOS had concomitant NAFLD.

The researchers also found that suprailiac skinfold thickness (odds ratio, 1.16; 95% CI, 1.08-1.24; P less than .001) and the presence of PCOS (OR 3.87; 95% CI, 1.09-13.76; P = .04) were independent predictors of NAFLD in the Raine cohort; free testosterone levels were not predictors after obesity was controlled for.

Obesity in girls with PCOS coincided with a greater prevalence of NAFLD. Girls with both conditions had a mean suprailiac skin fold thickness of 29.6 mm; girls with PCOS alone had a mean thickness of 15.4 mm.

Girls with both conditions, compared to those with PCOS alone, also had higher serum leptin and triglyceride levels, lower serum adiponectin levels, higher body mass indexes, and more subcutaneous fat.

They "approach what we find in boys" with NAFLD, who tend to have more severe disease, Dr. Ayonrinde said.

Boys with NAFLD and girls with PCOS and NAFLD had similar body weights, waist circumferences, waist/hip ratios, body mass indexes, subcutaneous and visceral fat thicknesses, and glucose tolerance test results, as well as similar serum glucose, insulin, triglyceride, cholesterol, and adiponectin levels.

Dr. Ayonrinde said he has no disclosures. Coauthors disclosed research support from Hoffmann-La Roche and Merck – both of whom are developing NAFLD therapies – and other companies.

SAN FRANCISCO – Nonalcoholic fatty liver disease is common in adolescent girls with polycystic ovaries, and its presence coincides with worse metabolic derangements, according to Australian researchers.

Because of that, it makes sense when doing an ultrasound study of women with polycystic ovary syndrome (PCOS) to check the liver, as well, for signs of nonalcoholic fatty liver disease (NAFLD), including increased echogenicity and bile duct or blood vessel blurring, said lead investigator Dr. Oyekoya Ayonrinde.

"If we see a girl or woman who has PCOS, we should look for the presence of fatty liver. It just adds maybe another 5 or 10 minutes to the [ultrasound] study," said Dr. Ayonrinde at the annual meeting of the American Association for the Study of Liver Diseases.

That’s important because PCOS, and perhaps even more so when combined with NAFLD, predisposes women to diabetes and cardiovascular disease, among other problems. The combination might also increase the risk of nonalcoholic steatohepatitis.

Dr. Ayonrinde, a clinical gastroenterology lecturer at the University of Western Australia in Perth, and his colleagues came to their conclusions after analyzing 244 girls aged 14-17 years in the Western Australian Pregnancy Cohort (Raine) Study, plus 578 girls and 592 boys, all 17 years old, in a separate NAFLD study. In all, 201 girls had both ovarian and liver ultrasounds, which were used to diagnose both PCOS and NAFLD.

In all, 43% of the girls with PCOS had concomitant NAFLD.

The researchers also found that suprailiac skinfold thickness (odds ratio, 1.16; 95% CI, 1.08-1.24; P less than .001) and the presence of PCOS (OR 3.87; 95% CI, 1.09-13.76; P = .04) were independent predictors of NAFLD in the Raine cohort; free testosterone levels were not predictors after obesity was controlled for.

Obesity in girls with PCOS coincided with a greater prevalence of NAFLD. Girls with both conditions had a mean suprailiac skin fold thickness of 29.6 mm; girls with PCOS alone had a mean thickness of 15.4 mm.

Girls with both conditions, compared to those with PCOS alone, also had higher serum leptin and triglyceride levels, lower serum adiponectin levels, higher body mass indexes, and more subcutaneous fat.

They "approach what we find in boys" with NAFLD, who tend to have more severe disease, Dr. Ayonrinde said.

Boys with NAFLD and girls with PCOS and NAFLD had similar body weights, waist circumferences, waist/hip ratios, body mass indexes, subcutaneous and visceral fat thicknesses, and glucose tolerance test results, as well as similar serum glucose, insulin, triglyceride, cholesterol, and adiponectin levels.

Dr. Ayonrinde said he has no disclosures. Coauthors disclosed research support from Hoffmann-La Roche and Merck – both of whom are developing NAFLD therapies – and other companies.

SAN FRANCISCO – Nonalcoholic fatty liver disease is common in adolescent girls with polycystic ovaries, and its presence coincides with worse metabolic derangements, according to Australian researchers.

Because of that, it makes sense when doing an ultrasound study of women with polycystic ovary syndrome (PCOS) to check the liver, as well, for signs of nonalcoholic fatty liver disease (NAFLD), including increased echogenicity and bile duct or blood vessel blurring, said lead investigator Dr. Oyekoya Ayonrinde.

"If we see a girl or woman who has PCOS, we should look for the presence of fatty liver. It just adds maybe another 5 or 10 minutes to the [ultrasound] study," said Dr. Ayonrinde at the annual meeting of the American Association for the Study of Liver Diseases.

That’s important because PCOS, and perhaps even more so when combined with NAFLD, predisposes women to diabetes and cardiovascular disease, among other problems. The combination might also increase the risk of nonalcoholic steatohepatitis.

Dr. Ayonrinde, a clinical gastroenterology lecturer at the University of Western Australia in Perth, and his colleagues came to their conclusions after analyzing 244 girls aged 14-17 years in the Western Australian Pregnancy Cohort (Raine) Study, plus 578 girls and 592 boys, all 17 years old, in a separate NAFLD study. In all, 201 girls had both ovarian and liver ultrasounds, which were used to diagnose both PCOS and NAFLD.

In all, 43% of the girls with PCOS had concomitant NAFLD.

The researchers also found that suprailiac skinfold thickness (odds ratio, 1.16; 95% CI, 1.08-1.24; P less than .001) and the presence of PCOS (OR 3.87; 95% CI, 1.09-13.76; P = .04) were independent predictors of NAFLD in the Raine cohort; free testosterone levels were not predictors after obesity was controlled for.

Obesity in girls with PCOS coincided with a greater prevalence of NAFLD. Girls with both conditions had a mean suprailiac skin fold thickness of 29.6 mm; girls with PCOS alone had a mean thickness of 15.4 mm.

Girls with both conditions, compared to those with PCOS alone, also had higher serum leptin and triglyceride levels, lower serum adiponectin levels, higher body mass indexes, and more subcutaneous fat.

They "approach what we find in boys" with NAFLD, who tend to have more severe disease, Dr. Ayonrinde said.

Boys with NAFLD and girls with PCOS and NAFLD had similar body weights, waist circumferences, waist/hip ratios, body mass indexes, subcutaneous and visceral fat thicknesses, and glucose tolerance test results, as well as similar serum glucose, insulin, triglyceride, cholesterol, and adiponectin levels.

Dr. Ayonrinde said he has no disclosures. Coauthors disclosed research support from Hoffmann-La Roche and Merck – both of whom are developing NAFLD therapies – and other companies.