Liver Disease

ORLANDO – The investigational protease inhibitor simeprevir was associated with high levels of sustained virologic response in patients with both treatment-naive and relapsed hepatitis C viral infections, reported investigators at the annual Digestive Disease Week.

In the QUEST-2 phase III trial, 81.3% of previously untreated patients with hepatitis C (HCV) genotype 1 infections randomized to simeprevir (TMC435) and pegylated interferon-alfa (pegIFN/RBV) had a sustained virologic response following 12 weeks of therapy (SVR12, the primary endpoint), compared with 50% of those assigned to pegIFN/RBV and placebo (P less than .001), reported Dr. Fred Poordad from the University of Texas Health Science Center in San Antonio.

In the phase III PROMISE trial, 79.2% of patients with HCV genotype 1 infections who had a relapse following prior therapy with an interferon-based regimen had an SVR12 when treated with simeprevir, compared with 36.8% of patients treated with pegIFN/RBV and placebo (P less than .001), said Dr. Eric Lawitz, also from the University of Texas in San Antonio.

"Safety and tolerability appear to be comparable to placebo, and patient-reported outcomes support both the efficacy and the safety profiles of simeprevir," Dr. Poordad said.

QUEST-2

Simeprevir is a once-daily oral inhibitor of the HCV NS3/4A protease with demonstrated antiviral activity against HCV genotypes 1, 2, 4, 5, and 6.

In QUEST-2, 391 patients were randomized on a 2:1 basis to receive either simeprevir 150 mg daily plus pegIFN/RBV or placebo plus pegIFN/RBV for 12 weeks, followed by an additional 12 or 36 weeks of pegIFN/RBV depending on response-guided therapy criteria. If patients had HCV RNA less than 25 IU/mL at week 4 and undetectable at week 12, they received an additional 12 weeks of pegIFN/RBV. Patients outside of the response-guided criteria received a total of 36 additional weeks of pegIFN/RBV. In both treatment arms, patients were followed for an additional 24 months, for a total of 72 months.

A total of 235 of the 257 patients assigned to simeprevir (91.4%) met the response-guided criteria by week 24, completed therapy, and were then followed until study end. Of this group, 86% (202 patients) achieved SVR12.

Simeprevir was statistically significantly superior to placebo regardless of IL28B polymorphism genotype or METAVIR (fibrosis and inflammation) scores.

On-treatment failures, defined as a confirmed detectable HCV RNA level at the actual end of treatment, occurred in 7% of patients on simeprevir and 32.1% of controls. Relapses, defined as detectable HCV RNA on one or more follow-up visits following undetectable end-of-treatment levels, occurred in 12.7% and 23.9%, respectively (P values not shown).

Of the simeprevir-treated patients who did not achieve an SVR, 97.6% had emerging mutations in the NS3 protease domain at the time of treatment failure, Dr. Poordad said.

PROMISE

In the PROMISE trial, 393 patients who had experienced a relapse following interferon-based therapy were randomized to response guided therapy as described in the QUEST-2 study.

As noted before, 79.2% of patients assigned to simeprevir/pegIFN/RBV met the primary endpoint of SVR12, compared with 36.8% of patients assigned to placebo/pegIFN/RBV (P less than .001).

In this trial, simeprevir was significantly better than placebo in patients with both HCV genotypes 1a and 1b, and as in QUEST-2 was superior to placebo regardless of IL28B genotype or METAVIR score.

On-treatment failures occurred in 3.1% of simeprevir-treated patients and 27.1% of those on placebo and pegIFN/RBV. The respective relapse rates were 18.5% and 48.4%. As in QUEST-2, the large majority (92.3%) of simeprevir-treated patients who did not have an SVR had emerging mutations in the NS3 protease domain.

Safety

In QUEST-2, patients on simeprevir had more cases of rash, 27% vs. 20%, and photosensitivity, 4% vs. 1%. Anemia occurred in 13.6% and 15.7%, respectively. The incidences of other adverse events were similar between the groups.

In PROMISE, the most common adverse events were fatigue, influenzalike illness, pruritus, and headache. Anemia occurred in 17% of patients on the active drug plus pegIFN/RBV, compared with 20% for those on placebo/pegIFN/RBV. Neutropenia occurred in 18% and 22%, respectively. Rates of pruritus and rash were comparable between simeprevir and placebo.

The Food and Drug Administration has granted priority review status to simeprevir for the treatment of chronic HCV genotype 1.

The studies were funded by Janssen. Dr. Poordad and Dr. Lawitz have received grants and/or research support from the company, and several of their coauthors are employees of Janssen or its parent company Johnson & Johnson.

ORLANDO – The investigational protease inhibitor simeprevir was associated with high levels of sustained virologic response in patients with both treatment-naive and relapsed hepatitis C viral infections, reported investigators at the annual Digestive Disease Week.

In the QUEST-2 phase III trial, 81.3% of previously untreated patients with hepatitis C (HCV) genotype 1 infections randomized to simeprevir (TMC435) and pegylated interferon-alfa (pegIFN/RBV) had a sustained virologic response following 12 weeks of therapy (SVR12, the primary endpoint), compared with 50% of those assigned to pegIFN/RBV and placebo (P less than .001), reported Dr. Fred Poordad from the University of Texas Health Science Center in San Antonio.

In the phase III PROMISE trial, 79.2% of patients with HCV genotype 1 infections who had a relapse following prior therapy with an interferon-based regimen had an SVR12 when treated with simeprevir, compared with 36.8% of patients treated with pegIFN/RBV and placebo (P less than .001), said Dr. Eric Lawitz, also from the University of Texas in San Antonio.

"Safety and tolerability appear to be comparable to placebo, and patient-reported outcomes support both the efficacy and the safety profiles of simeprevir," Dr. Poordad said.

QUEST-2

Simeprevir is a once-daily oral inhibitor of the HCV NS3/4A protease with demonstrated antiviral activity against HCV genotypes 1, 2, 4, 5, and 6.

In QUEST-2, 391 patients were randomized on a 2:1 basis to receive either simeprevir 150 mg daily plus pegIFN/RBV or placebo plus pegIFN/RBV for 12 weeks, followed by an additional 12 or 36 weeks of pegIFN/RBV depending on response-guided therapy criteria. If patients had HCV RNA less than 25 IU/mL at week 4 and undetectable at week 12, they received an additional 12 weeks of pegIFN/RBV. Patients outside of the response-guided criteria received a total of 36 additional weeks of pegIFN/RBV. In both treatment arms, patients were followed for an additional 24 months, for a total of 72 months.

A total of 235 of the 257 patients assigned to simeprevir (91.4%) met the response-guided criteria by week 24, completed therapy, and were then followed until study end. Of this group, 86% (202 patients) achieved SVR12.

Simeprevir was statistically significantly superior to placebo regardless of IL28B polymorphism genotype or METAVIR (fibrosis and inflammation) scores.

On-treatment failures, defined as a confirmed detectable HCV RNA level at the actual end of treatment, occurred in 7% of patients on simeprevir and 32.1% of controls. Relapses, defined as detectable HCV RNA on one or more follow-up visits following undetectable end-of-treatment levels, occurred in 12.7% and 23.9%, respectively (P values not shown).

Of the simeprevir-treated patients who did not achieve an SVR, 97.6% had emerging mutations in the NS3 protease domain at the time of treatment failure, Dr. Poordad said.

PROMISE

In the PROMISE trial, 393 patients who had experienced a relapse following interferon-based therapy were randomized to response guided therapy as described in the QUEST-2 study.

As noted before, 79.2% of patients assigned to simeprevir/pegIFN/RBV met the primary endpoint of SVR12, compared with 36.8% of patients assigned to placebo/pegIFN/RBV (P less than .001).

In this trial, simeprevir was significantly better than placebo in patients with both HCV genotypes 1a and 1b, and as in QUEST-2 was superior to placebo regardless of IL28B genotype or METAVIR score.

On-treatment failures occurred in 3.1% of simeprevir-treated patients and 27.1% of those on placebo and pegIFN/RBV. The respective relapse rates were 18.5% and 48.4%. As in QUEST-2, the large majority (92.3%) of simeprevir-treated patients who did not have an SVR had emerging mutations in the NS3 protease domain.

Safety

In QUEST-2, patients on simeprevir had more cases of rash, 27% vs. 20%, and photosensitivity, 4% vs. 1%. Anemia occurred in 13.6% and 15.7%, respectively. The incidences of other adverse events were similar between the groups.

In PROMISE, the most common adverse events were fatigue, influenzalike illness, pruritus, and headache. Anemia occurred in 17% of patients on the active drug plus pegIFN/RBV, compared with 20% for those on placebo/pegIFN/RBV. Neutropenia occurred in 18% and 22%, respectively. Rates of pruritus and rash were comparable between simeprevir and placebo.

The Food and Drug Administration has granted priority review status to simeprevir for the treatment of chronic HCV genotype 1.

The studies were funded by Janssen. Dr. Poordad and Dr. Lawitz have received grants and/or research support from the company, and several of their coauthors are employees of Janssen or its parent company Johnson & Johnson.

ORLANDO – The investigational protease inhibitor simeprevir was associated with high levels of sustained virologic response in patients with both treatment-naive and relapsed hepatitis C viral infections, reported investigators at the annual Digestive Disease Week.

In the QUEST-2 phase III trial, 81.3% of previously untreated patients with hepatitis C (HCV) genotype 1 infections randomized to simeprevir (TMC435) and pegylated interferon-alfa (pegIFN/RBV) had a sustained virologic response following 12 weeks of therapy (SVR12, the primary endpoint), compared with 50% of those assigned to pegIFN/RBV and placebo (P less than .001), reported Dr. Fred Poordad from the University of Texas Health Science Center in San Antonio.

In the phase III PROMISE trial, 79.2% of patients with HCV genotype 1 infections who had a relapse following prior therapy with an interferon-based regimen had an SVR12 when treated with simeprevir, compared with 36.8% of patients treated with pegIFN/RBV and placebo (P less than .001), said Dr. Eric Lawitz, also from the University of Texas in San Antonio.

"Safety and tolerability appear to be comparable to placebo, and patient-reported outcomes support both the efficacy and the safety profiles of simeprevir," Dr. Poordad said.

QUEST-2

Simeprevir is a once-daily oral inhibitor of the HCV NS3/4A protease with demonstrated antiviral activity against HCV genotypes 1, 2, 4, 5, and 6.

In QUEST-2, 391 patients were randomized on a 2:1 basis to receive either simeprevir 150 mg daily plus pegIFN/RBV or placebo plus pegIFN/RBV for 12 weeks, followed by an additional 12 or 36 weeks of pegIFN/RBV depending on response-guided therapy criteria. If patients had HCV RNA less than 25 IU/mL at week 4 and undetectable at week 12, they received an additional 12 weeks of pegIFN/RBV. Patients outside of the response-guided criteria received a total of 36 additional weeks of pegIFN/RBV. In both treatment arms, patients were followed for an additional 24 months, for a total of 72 months.

A total of 235 of the 257 patients assigned to simeprevir (91.4%) met the response-guided criteria by week 24, completed therapy, and were then followed until study end. Of this group, 86% (202 patients) achieved SVR12.

Simeprevir was statistically significantly superior to placebo regardless of IL28B polymorphism genotype or METAVIR (fibrosis and inflammation) scores.

On-treatment failures, defined as a confirmed detectable HCV RNA level at the actual end of treatment, occurred in 7% of patients on simeprevir and 32.1% of controls. Relapses, defined as detectable HCV RNA on one or more follow-up visits following undetectable end-of-treatment levels, occurred in 12.7% and 23.9%, respectively (P values not shown).

Of the simeprevir-treated patients who did not achieve an SVR, 97.6% had emerging mutations in the NS3 protease domain at the time of treatment failure, Dr. Poordad said.

PROMISE

In the PROMISE trial, 393 patients who had experienced a relapse following interferon-based therapy were randomized to response guided therapy as described in the QUEST-2 study.

As noted before, 79.2% of patients assigned to simeprevir/pegIFN/RBV met the primary endpoint of SVR12, compared with 36.8% of patients assigned to placebo/pegIFN/RBV (P less than .001).

In this trial, simeprevir was significantly better than placebo in patients with both HCV genotypes 1a and 1b, and as in QUEST-2 was superior to placebo regardless of IL28B genotype or METAVIR score.

On-treatment failures occurred in 3.1% of simeprevir-treated patients and 27.1% of those on placebo and pegIFN/RBV. The respective relapse rates were 18.5% and 48.4%. As in QUEST-2, the large majority (92.3%) of simeprevir-treated patients who did not have an SVR had emerging mutations in the NS3 protease domain.

Safety

In QUEST-2, patients on simeprevir had more cases of rash, 27% vs. 20%, and photosensitivity, 4% vs. 1%. Anemia occurred in 13.6% and 15.7%, respectively. The incidences of other adverse events were similar between the groups.

In PROMISE, the most common adverse events were fatigue, influenzalike illness, pruritus, and headache. Anemia occurred in 17% of patients on the active drug plus pegIFN/RBV, compared with 20% for those on placebo/pegIFN/RBV. Neutropenia occurred in 18% and 22%, respectively. Rates of pruritus and rash were comparable between simeprevir and placebo.

The Food and Drug Administration has granted priority review status to simeprevir for the treatment of chronic HCV genotype 1.

The studies were funded by Janssen. Dr. Poordad and Dr. Lawitz have received grants and/or research support from the company, and several of their coauthors are employees of Janssen or its parent company Johnson & Johnson.

ORLANDO – Adding a protease inhibitor to pegylated interferon and ribavirin increased the rate of sustained virologic responses in patients with chronic hepatitis C infections for whom prior interferon/ribavirin therapy had failed, an investigator reported at the annual Digestive Disease Week.

Among patients with hepatitis C virus (HCV) infections who received only pegylated interferon and ribavirin (peg-IFN/RBV) in the control arms of phase II and III studies of boceprevir (Victrelis), more than 90% of those who had relapsed had a sustained virologic response for at least 24 weeks after therapy (SVR24) with combined boceprevir and peg-IFN/RBV, reported Dr. John Vierling, chief of hepatology at Baylor College of Medicine in Houston.

"Overall, the data from this final analysis lead to the conclusion that boceprevir combined with pegylated interferon/ribavirin therapy is efficacious in subjects with all three categories of nonresponse: relapsers, partial responders, and most importantly, null responders," Dr. Vierling said.

The PROVIDE study Included 168 patients (mean age, 52 years) in an intention-to-treat analysis whose peg-IFN/RBV therapy was considered a failure. The cohort included treatment-experienced patients with detectable HCV RNA after 12 weeks of peg-IFN/RBV and treatment-naive patients after 24 weeks of therapy, as well as those who had experienced virological breakthrough or relapse after having an end-of-treatment response.

Patients who had completed peg-IFN/RBV therapy within the previous 2 weeks were enrolled for 44 weeks. Those patients who had completed peg-IFN/RBV more than 2 weeks earlier were assigned to a 4-week lead-in phase with peg-IFN/RBV prior to starting on the study combination.

All participants were given boceprevir 800 mg orally three times daily with food, pegylated interferon-alpha-2b (Intron A) 1.5 mcg/kg subcutaneously once weekly, and weight-based ribavirin 600-1,400 mg daily divided into two oral doses.

Four patients dropped out of the study during the lead-in phase and thus did not receive any boceprevir, leaving 164 for a prespecified full-analysis set. A total of 60 patients discontinued therapy (including the 4 who dropped out in the lead-in phase). Of these patients, 14 stopped due to adverse events, 33 had treatment failure, and 13 dropped out for nonmedical reasons.

In the full analysis set, 27 of 28 (96%) patients who had had a relapse after prior peg-IFN/RBV had an SVR24, the primary endpoint, as did 57 of 85 (67%) prior partial responders and 20 of 49 (41%) prior null responders. Overall, 65% of patients in the full-analysis population and 63% of those in an intention-to-treat population had an SVR24.

In a breakdown by baseline characteristics of patients who had an SVR24, the authors found that SVR occurred more frequently in men than in women, in nonblack vs. black patients, among those with a viral load of 800,000 copies/mL or fewer, HCV genotype 1a vs. 1b (except among those with prior relapse), and patients with platelet counts of 200,000/mcL.

The most frequently reported adverse events were anemia in 45% of patients, dysgeusia in 35%, and neutropenia in 23%. The safety profile was similar to that reported for the combination in phase II and III studies, Dr. Vierling said.

The study was sponsored by Merck. Dr. Vierling disclosed serving in an advisory capacity and receiving grants and research support from the company. Three of his coauthors are employees of Merck, and one is a board member.

ORLANDO – Adding a protease inhibitor to pegylated interferon and ribavirin increased the rate of sustained virologic responses in patients with chronic hepatitis C infections for whom prior interferon/ribavirin therapy had failed, an investigator reported at the annual Digestive Disease Week.

Among patients with hepatitis C virus (HCV) infections who received only pegylated interferon and ribavirin (peg-IFN/RBV) in the control arms of phase II and III studies of boceprevir (Victrelis), more than 90% of those who had relapsed had a sustained virologic response for at least 24 weeks after therapy (SVR24) with combined boceprevir and peg-IFN/RBV, reported Dr. John Vierling, chief of hepatology at Baylor College of Medicine in Houston.

"Overall, the data from this final analysis lead to the conclusion that boceprevir combined with pegylated interferon/ribavirin therapy is efficacious in subjects with all three categories of nonresponse: relapsers, partial responders, and most importantly, null responders," Dr. Vierling said.

The PROVIDE study Included 168 patients (mean age, 52 years) in an intention-to-treat analysis whose peg-IFN/RBV therapy was considered a failure. The cohort included treatment-experienced patients with detectable HCV RNA after 12 weeks of peg-IFN/RBV and treatment-naive patients after 24 weeks of therapy, as well as those who had experienced virological breakthrough or relapse after having an end-of-treatment response.

Patients who had completed peg-IFN/RBV therapy within the previous 2 weeks were enrolled for 44 weeks. Those patients who had completed peg-IFN/RBV more than 2 weeks earlier were assigned to a 4-week lead-in phase with peg-IFN/RBV prior to starting on the study combination.

All participants were given boceprevir 800 mg orally three times daily with food, pegylated interferon-alpha-2b (Intron A) 1.5 mcg/kg subcutaneously once weekly, and weight-based ribavirin 600-1,400 mg daily divided into two oral doses.

Four patients dropped out of the study during the lead-in phase and thus did not receive any boceprevir, leaving 164 for a prespecified full-analysis set. A total of 60 patients discontinued therapy (including the 4 who dropped out in the lead-in phase). Of these patients, 14 stopped due to adverse events, 33 had treatment failure, and 13 dropped out for nonmedical reasons.

In the full analysis set, 27 of 28 (96%) patients who had had a relapse after prior peg-IFN/RBV had an SVR24, the primary endpoint, as did 57 of 85 (67%) prior partial responders and 20 of 49 (41%) prior null responders. Overall, 65% of patients in the full-analysis population and 63% of those in an intention-to-treat population had an SVR24.

In a breakdown by baseline characteristics of patients who had an SVR24, the authors found that SVR occurred more frequently in men than in women, in nonblack vs. black patients, among those with a viral load of 800,000 copies/mL or fewer, HCV genotype 1a vs. 1b (except among those with prior relapse), and patients with platelet counts of 200,000/mcL.

The most frequently reported adverse events were anemia in 45% of patients, dysgeusia in 35%, and neutropenia in 23%. The safety profile was similar to that reported for the combination in phase II and III studies, Dr. Vierling said.

The study was sponsored by Merck. Dr. Vierling disclosed serving in an advisory capacity and receiving grants and research support from the company. Three of his coauthors are employees of Merck, and one is a board member.

ORLANDO – Adding a protease inhibitor to pegylated interferon and ribavirin increased the rate of sustained virologic responses in patients with chronic hepatitis C infections for whom prior interferon/ribavirin therapy had failed, an investigator reported at the annual Digestive Disease Week.

Among patients with hepatitis C virus (HCV) infections who received only pegylated interferon and ribavirin (peg-IFN/RBV) in the control arms of phase II and III studies of boceprevir (Victrelis), more than 90% of those who had relapsed had a sustained virologic response for at least 24 weeks after therapy (SVR24) with combined boceprevir and peg-IFN/RBV, reported Dr. John Vierling, chief of hepatology at Baylor College of Medicine in Houston.

"Overall, the data from this final analysis lead to the conclusion that boceprevir combined with pegylated interferon/ribavirin therapy is efficacious in subjects with all three categories of nonresponse: relapsers, partial responders, and most importantly, null responders," Dr. Vierling said.

The PROVIDE study Included 168 patients (mean age, 52 years) in an intention-to-treat analysis whose peg-IFN/RBV therapy was considered a failure. The cohort included treatment-experienced patients with detectable HCV RNA after 12 weeks of peg-IFN/RBV and treatment-naive patients after 24 weeks of therapy, as well as those who had experienced virological breakthrough or relapse after having an end-of-treatment response.

Patients who had completed peg-IFN/RBV therapy within the previous 2 weeks were enrolled for 44 weeks. Those patients who had completed peg-IFN/RBV more than 2 weeks earlier were assigned to a 4-week lead-in phase with peg-IFN/RBV prior to starting on the study combination.

All participants were given boceprevir 800 mg orally three times daily with food, pegylated interferon-alpha-2b (Intron A) 1.5 mcg/kg subcutaneously once weekly, and weight-based ribavirin 600-1,400 mg daily divided into two oral doses.

Four patients dropped out of the study during the lead-in phase and thus did not receive any boceprevir, leaving 164 for a prespecified full-analysis set. A total of 60 patients discontinued therapy (including the 4 who dropped out in the lead-in phase). Of these patients, 14 stopped due to adverse events, 33 had treatment failure, and 13 dropped out for nonmedical reasons.

In the full analysis set, 27 of 28 (96%) patients who had had a relapse after prior peg-IFN/RBV had an SVR24, the primary endpoint, as did 57 of 85 (67%) prior partial responders and 20 of 49 (41%) prior null responders. Overall, 65% of patients in the full-analysis population and 63% of those in an intention-to-treat population had an SVR24.

In a breakdown by baseline characteristics of patients who had an SVR24, the authors found that SVR occurred more frequently in men than in women, in nonblack vs. black patients, among those with a viral load of 800,000 copies/mL or fewer, HCV genotype 1a vs. 1b (except among those with prior relapse), and patients with platelet counts of 200,000/mcL.

The most frequently reported adverse events were anemia in 45% of patients, dysgeusia in 35%, and neutropenia in 23%. The safety profile was similar to that reported for the combination in phase II and III studies, Dr. Vierling said.

The study was sponsored by Merck. Dr. Vierling disclosed serving in an advisory capacity and receiving grants and research support from the company. Three of his coauthors are employees of Merck, and one is a board member.

Several different blood tests can be useful for identifying clinically significant fibrosis and cirrhosis in patients infected with hepatitis C virus, now that liver biopsy is no longer recommended for that purpose, according to a report published online June 3 in Annals of Internal Medicine.

Liver biopsy used to be recommended before antiviral therapy was initiated for HCV because the treatment was used primarily in patients at highest risk for disease progression. But "the increased effectiveness of antiviral treatments has resulted in broadening of treatment indications to encompass patients at lower risk for disease progression, calling into question the need to obtain detailed pretreatment prognostic information with an invasive test," said Dr. Roger Chou and Ngoc Wasson of Oregon Health & Science University, Portland.

Moreover, biopsy is avoided because it is subject to sampling error; inconsistency in the interpretation of the results; and complications including bleeding, severe pain, and infection. "However, given the adverse effects and costs associated with current antiviral therapies, knowing the degree of liver fibrosis can still provide important information and allow for more informed treatment decisions," the investigators said.

They assessed the accuracy of less invasive alternatives to liver biopsy – specifically, blood tests that aim to identify fibrosis and cirrhosis – in a review of the literature commissioned by the Agency for Healthcare Research and Quality.

The researchers selected 172 English-language studies of HCV-infected patients, excluding posttransplant patients, those coinfected with HIV or hepatitis B virus, patients receiving hemodialysis, and children. "We did not pool results because of differences across studies in populations evaluated, differences in how fibrosis and cirrhosis were defined, and methodological limitations in the studies," Dr. Chou and Ms. Wasson said.

Many of the 30 blood tests included in the analysis were found to be "moderately useful at commonly used cutoffs" in identifying fibrosis and cirrhosis. These included simple platelet counts, the age-platelet index, the aspartate aminotransferase/platelet ratio index (APRI), the FibroIndex, the FibroTest, and the Forns index.

The GUCI (Göteborg University Cirrhosis Index) and the Lok index were slightly less useful, but still more accurate than the remaining 20-odd tests assessed, they noted (Ann. Intern. Med. 2013 June 3 [10.7326/0003-4819-158-11-201306040-00005]).

More complicated indexes that incorporate the results of a variety of tests, particularly indexes that rely on tests that are not routine, were no more accurate at predicting fibrosis or cirrhosis than many of the simpler, more readily available blood tests, the investigators said.

Their findings remained robust in sensitivity analyses that categorized the data according to the quality of the study, type of methodology, and characteristics of the study population.

This study was supported by the Agency for Healthcare Research and Quality.

Several different blood tests can be useful for identifying clinically significant fibrosis and cirrhosis in patients infected with hepatitis C virus, now that liver biopsy is no longer recommended for that purpose, according to a report published online June 3 in Annals of Internal Medicine.

Liver biopsy used to be recommended before antiviral therapy was initiated for HCV because the treatment was used primarily in patients at highest risk for disease progression. But "the increased effectiveness of antiviral treatments has resulted in broadening of treatment indications to encompass patients at lower risk for disease progression, calling into question the need to obtain detailed pretreatment prognostic information with an invasive test," said Dr. Roger Chou and Ngoc Wasson of Oregon Health & Science University, Portland.

Moreover, biopsy is avoided because it is subject to sampling error; inconsistency in the interpretation of the results; and complications including bleeding, severe pain, and infection. "However, given the adverse effects and costs associated with current antiviral therapies, knowing the degree of liver fibrosis can still provide important information and allow for more informed treatment decisions," the investigators said.

They assessed the accuracy of less invasive alternatives to liver biopsy – specifically, blood tests that aim to identify fibrosis and cirrhosis – in a review of the literature commissioned by the Agency for Healthcare Research and Quality.

The researchers selected 172 English-language studies of HCV-infected patients, excluding posttransplant patients, those coinfected with HIV or hepatitis B virus, patients receiving hemodialysis, and children. "We did not pool results because of differences across studies in populations evaluated, differences in how fibrosis and cirrhosis were defined, and methodological limitations in the studies," Dr. Chou and Ms. Wasson said.

Many of the 30 blood tests included in the analysis were found to be "moderately useful at commonly used cutoffs" in identifying fibrosis and cirrhosis. These included simple platelet counts, the age-platelet index, the aspartate aminotransferase/platelet ratio index (APRI), the FibroIndex, the FibroTest, and the Forns index.

The GUCI (Göteborg University Cirrhosis Index) and the Lok index were slightly less useful, but still more accurate than the remaining 20-odd tests assessed, they noted (Ann. Intern. Med. 2013 June 3 [10.7326/0003-4819-158-11-201306040-00005]).

More complicated indexes that incorporate the results of a variety of tests, particularly indexes that rely on tests that are not routine, were no more accurate at predicting fibrosis or cirrhosis than many of the simpler, more readily available blood tests, the investigators said.

Their findings remained robust in sensitivity analyses that categorized the data according to the quality of the study, type of methodology, and characteristics of the study population.

This study was supported by the Agency for Healthcare Research and Quality.

Several different blood tests can be useful for identifying clinically significant fibrosis and cirrhosis in patients infected with hepatitis C virus, now that liver biopsy is no longer recommended for that purpose, according to a report published online June 3 in Annals of Internal Medicine.

Liver biopsy used to be recommended before antiviral therapy was initiated for HCV because the treatment was used primarily in patients at highest risk for disease progression. But "the increased effectiveness of antiviral treatments has resulted in broadening of treatment indications to encompass patients at lower risk for disease progression, calling into question the need to obtain detailed pretreatment prognostic information with an invasive test," said Dr. Roger Chou and Ngoc Wasson of Oregon Health & Science University, Portland.

Moreover, biopsy is avoided because it is subject to sampling error; inconsistency in the interpretation of the results; and complications including bleeding, severe pain, and infection. "However, given the adverse effects and costs associated with current antiviral therapies, knowing the degree of liver fibrosis can still provide important information and allow for more informed treatment decisions," the investigators said.

They assessed the accuracy of less invasive alternatives to liver biopsy – specifically, blood tests that aim to identify fibrosis and cirrhosis – in a review of the literature commissioned by the Agency for Healthcare Research and Quality.

The researchers selected 172 English-language studies of HCV-infected patients, excluding posttransplant patients, those coinfected with HIV or hepatitis B virus, patients receiving hemodialysis, and children. "We did not pool results because of differences across studies in populations evaluated, differences in how fibrosis and cirrhosis were defined, and methodological limitations in the studies," Dr. Chou and Ms. Wasson said.

Many of the 30 blood tests included in the analysis were found to be "moderately useful at commonly used cutoffs" in identifying fibrosis and cirrhosis. These included simple platelet counts, the age-platelet index, the aspartate aminotransferase/platelet ratio index (APRI), the FibroIndex, the FibroTest, and the Forns index.

The GUCI (Göteborg University Cirrhosis Index) and the Lok index were slightly less useful, but still more accurate than the remaining 20-odd tests assessed, they noted (Ann. Intern. Med. 2013 June 3 [10.7326/0003-4819-158-11-201306040-00005]).

More complicated indexes that incorporate the results of a variety of tests, particularly indexes that rely on tests that are not routine, were no more accurate at predicting fibrosis or cirrhosis than many of the simpler, more readily available blood tests, the investigators said.

Their findings remained robust in sensitivity analyses that categorized the data according to the quality of the study, type of methodology, and characteristics of the study population.

This study was supported by the Agency for Healthcare Research and Quality.

An attempt to define and classify acute-on-chronic liver failure showed that the syndrome carries a 28-day mortality rate that is 15 times greater than in cirrhosis patients who do not have the syndrome.

Moreover, the syndrome is extremely common, and may be found in nearly one-third of acutely decompensated cirrhosis patients, wrote Dr. Richard Moreau and colleagues. The study was published in the June issue of Gastroenterology.

Source: American Gastroenterological Association

"A universally accepted and used definition of acute-on-chronic liver failure (ACLF) is still lacking," said Dr. Moreau of Université Paris Diderot, Paris.

"Defining ACLF is not only a matter of nosology, but also is of great importance because it would allow early identification of patients at high risk for end-organ failure–related death, requiring specific treatments and/or intensive management," he added.

To that end, Dr. Moreau looked at 1,343 adult patients hospitalized for at least 1 day who had an acute decompensation of cirrhosis as defined by the acute development of large ascites, hepatic encephalopathy, gastrointestinal hemorrhage, bacterial infection, or any combination of the above.

Patients who were admitted for a scheduled procedure or treatment were excluded from the analysis, as were patients with severe chronic extrahepatic disease and patients with HIV infection.

The study subjects were then divided into four groups. The first group, which was judged not to have ACLF, had no organ failure, a serum creatinine less than 1.5 mg/dL, and no hepatic encephalopathy. This group made up 1,040 of the 1,343 enrolled patients (77.4%), and had 28-day and 90-day mortality rates of 4.7% and 14%, respectively.

The next cohort, called ACLF grade 1, comprised patients with a single coagulation, circulatory or respiratory failure; a serum creatinine between 1.5 and 1.9 mg/dL; and/or mild to moderate hepatic encephalopathy. The 148 patients in this class (11.0%) had 28- and 90-day mortality rates of 22.1% and 40.7%, respectively.

ACLF grade 2 was more severe, with two organ failures; 108 patients (8%) had this at enrollment, and exhibited 28- and 90-day mortality rates of 32.0% and 40.7%, respectively.

The most severely ill patients were classed as having ACLF grade 3, with three organ failures or more. A total of 47 patients (3.5%) fell into this category, and they had 28- and 90-day mortality rates of 76.7% and 79.1%, respectively.

Overall, according to the investigators, patients with ACLF were younger (mean age 56 years versus 58 years in patients without ACLF; P = .02), had a lower mean arterial blood pressure on admittance to the hospital (79 mm Hg versus 85 mm Hg in non-ACLF patients; P less than .001) and more frequently were actively alcoholic.

They also found that patients with ACLF had a significantly higher white cell count (9.7 x 109 compared with 6.6 x 109/L; P less than .001) and plasma C-reactive protein level (40.3 versus 24.9 mg/L; P less than .001) than the group without ACLF.

And finally, in what they called an "outstanding observation," the authors determined that up to 43.6% of patients with ACLF had no precipitating event leading to their acute decompensation, including gastrointestinal hemorrhage, bacterial infection, or active alcoholism.

The authors concluded that their novel diagnostic criteria show that ACLF is "distinct from ‘mere’ AD."

They conceded that their study was not designed to assess ideal management for these patients. "Whether patients with ACLF should be admitted or not to the intensive care unit is controversial," they wrote. "Nevertheless, our results can serve as a resource for designing studies aimed to investigate the appropriate site of hospitalization for patients with ACLF."

The authors disclosed that pharmaceutical companies provided funding for a chronic liver failure consortium, which provided the initiative for this study; several other investigators also disclosed ties with pharmaceutical companies.

An attempt to define and classify acute-on-chronic liver failure showed that the syndrome carries a 28-day mortality rate that is 15 times greater than in cirrhosis patients who do not have the syndrome.

Moreover, the syndrome is extremely common, and may be found in nearly one-third of acutely decompensated cirrhosis patients, wrote Dr. Richard Moreau and colleagues. The study was published in the June issue of Gastroenterology.

Source: American Gastroenterological Association

"A universally accepted and used definition of acute-on-chronic liver failure (ACLF) is still lacking," said Dr. Moreau of Université Paris Diderot, Paris.

"Defining ACLF is not only a matter of nosology, but also is of great importance because it would allow early identification of patients at high risk for end-organ failure–related death, requiring specific treatments and/or intensive management," he added.

To that end, Dr. Moreau looked at 1,343 adult patients hospitalized for at least 1 day who had an acute decompensation of cirrhosis as defined by the acute development of large ascites, hepatic encephalopathy, gastrointestinal hemorrhage, bacterial infection, or any combination of the above.

Patients who were admitted for a scheduled procedure or treatment were excluded from the analysis, as were patients with severe chronic extrahepatic disease and patients with HIV infection.

The study subjects were then divided into four groups. The first group, which was judged not to have ACLF, had no organ failure, a serum creatinine less than 1.5 mg/dL, and no hepatic encephalopathy. This group made up 1,040 of the 1,343 enrolled patients (77.4%), and had 28-day and 90-day mortality rates of 4.7% and 14%, respectively.

The next cohort, called ACLF grade 1, comprised patients with a single coagulation, circulatory or respiratory failure; a serum creatinine between 1.5 and 1.9 mg/dL; and/or mild to moderate hepatic encephalopathy. The 148 patients in this class (11.0%) had 28- and 90-day mortality rates of 22.1% and 40.7%, respectively.

ACLF grade 2 was more severe, with two organ failures; 108 patients (8%) had this at enrollment, and exhibited 28- and 90-day mortality rates of 32.0% and 40.7%, respectively.

The most severely ill patients were classed as having ACLF grade 3, with three organ failures or more. A total of 47 patients (3.5%) fell into this category, and they had 28- and 90-day mortality rates of 76.7% and 79.1%, respectively.

Overall, according to the investigators, patients with ACLF were younger (mean age 56 years versus 58 years in patients without ACLF; P = .02), had a lower mean arterial blood pressure on admittance to the hospital (79 mm Hg versus 85 mm Hg in non-ACLF patients; P less than .001) and more frequently were actively alcoholic.

They also found that patients with ACLF had a significantly higher white cell count (9.7 x 109 compared with 6.6 x 109/L; P less than .001) and plasma C-reactive protein level (40.3 versus 24.9 mg/L; P less than .001) than the group without ACLF.

And finally, in what they called an "outstanding observation," the authors determined that up to 43.6% of patients with ACLF had no precipitating event leading to their acute decompensation, including gastrointestinal hemorrhage, bacterial infection, or active alcoholism.

The authors concluded that their novel diagnostic criteria show that ACLF is "distinct from ‘mere’ AD."

They conceded that their study was not designed to assess ideal management for these patients. "Whether patients with ACLF should be admitted or not to the intensive care unit is controversial," they wrote. "Nevertheless, our results can serve as a resource for designing studies aimed to investigate the appropriate site of hospitalization for patients with ACLF."

The authors disclosed that pharmaceutical companies provided funding for a chronic liver failure consortium, which provided the initiative for this study; several other investigators also disclosed ties with pharmaceutical companies.

An attempt to define and classify acute-on-chronic liver failure showed that the syndrome carries a 28-day mortality rate that is 15 times greater than in cirrhosis patients who do not have the syndrome.

Moreover, the syndrome is extremely common, and may be found in nearly one-third of acutely decompensated cirrhosis patients, wrote Dr. Richard Moreau and colleagues. The study was published in the June issue of Gastroenterology.

Source: American Gastroenterological Association

"A universally accepted and used definition of acute-on-chronic liver failure (ACLF) is still lacking," said Dr. Moreau of Université Paris Diderot, Paris.

"Defining ACLF is not only a matter of nosology, but also is of great importance because it would allow early identification of patients at high risk for end-organ failure–related death, requiring specific treatments and/or intensive management," he added.

To that end, Dr. Moreau looked at 1,343 adult patients hospitalized for at least 1 day who had an acute decompensation of cirrhosis as defined by the acute development of large ascites, hepatic encephalopathy, gastrointestinal hemorrhage, bacterial infection, or any combination of the above.

Patients who were admitted for a scheduled procedure or treatment were excluded from the analysis, as were patients with severe chronic extrahepatic disease and patients with HIV infection.

The study subjects were then divided into four groups. The first group, which was judged not to have ACLF, had no organ failure, a serum creatinine less than 1.5 mg/dL, and no hepatic encephalopathy. This group made up 1,040 of the 1,343 enrolled patients (77.4%), and had 28-day and 90-day mortality rates of 4.7% and 14%, respectively.

The next cohort, called ACLF grade 1, comprised patients with a single coagulation, circulatory or respiratory failure; a serum creatinine between 1.5 and 1.9 mg/dL; and/or mild to moderate hepatic encephalopathy. The 148 patients in this class (11.0%) had 28- and 90-day mortality rates of 22.1% and 40.7%, respectively.

ACLF grade 2 was more severe, with two organ failures; 108 patients (8%) had this at enrollment, and exhibited 28- and 90-day mortality rates of 32.0% and 40.7%, respectively.

The most severely ill patients were classed as having ACLF grade 3, with three organ failures or more. A total of 47 patients (3.5%) fell into this category, and they had 28- and 90-day mortality rates of 76.7% and 79.1%, respectively.

Overall, according to the investigators, patients with ACLF were younger (mean age 56 years versus 58 years in patients without ACLF; P = .02), had a lower mean arterial blood pressure on admittance to the hospital (79 mm Hg versus 85 mm Hg in non-ACLF patients; P less than .001) and more frequently were actively alcoholic.

They also found that patients with ACLF had a significantly higher white cell count (9.7 x 109 compared with 6.6 x 109/L; P less than .001) and plasma C-reactive protein level (40.3 versus 24.9 mg/L; P less than .001) than the group without ACLF.

And finally, in what they called an "outstanding observation," the authors determined that up to 43.6% of patients with ACLF had no precipitating event leading to their acute decompensation, including gastrointestinal hemorrhage, bacterial infection, or active alcoholism.

The authors concluded that their novel diagnostic criteria show that ACLF is "distinct from ‘mere’ AD."

They conceded that their study was not designed to assess ideal management for these patients. "Whether patients with ACLF should be admitted or not to the intensive care unit is controversial," they wrote. "Nevertheless, our results can serve as a resource for designing studies aimed to investigate the appropriate site of hospitalization for patients with ACLF."

The authors disclosed that pharmaceutical companies provided funding for a chronic liver failure consortium, which provided the initiative for this study; several other investigators also disclosed ties with pharmaceutical companies.

The crude incidence of drug-induced liver injury is roughly 19.1 cases per 100,000 inhabitants, with amoxicillin-clavulanate the most commonly implicated agent.

That’s according to the second published population-based cohort study of drug-induced liver injury (DILI), wrote Dr. Einar S. Björnsson. The study was published in the June issue of Gastroenterology.

Dr. Björnsson, of the University of Iceland, and colleagues looked at all patients aged older than 15 years hospitalized for liver disease with suspected DILI, plus outpatients at the National University Hospital of Iceland, and all those seen in private practice between March 1, 2010, and Feb. 29, 2012.

^{Source: American Gastroenterological Association}

According to the authors, "In Iceland, every citizen is issued a specific personal identification number that is, among other things, connected to a nationwide pharmaceutical database on outpatient prescriptions."

Therefore, "The study examined the Icelandic Medicines Registry records of prescriptions for all drugs associated with DILI that had at least a possible causal relationship" according to the Roussel Uclaf Causality Assessment Method.

DILI was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than three times the upper limit of normal, and/or alkaline phosphatase (ALP) levels greater than two times the upper limit of normal.

Acetaminophen toxicity cases were excluded, though patients with preexisting chronic liver injury were not, if they were considered to have developed superimposed DILI on top of their baseline liver enzyme values.

The authors found that over the study period there were 96 cases eligible for inclusion, including 49 cases in the first year and 47 in the second. That translated into a crude annual incidence during the study period of 19.1 cases per 100,000 inhabitants.

Roughly half were female (56%), and the median age was 55 years (range, 16-91 years).

Looking at the clinical characteristics of the cohort, the authors calculated that only 27% of patients developed jaundice, while 10% of patients complained of rash and 6% of fever. Four of the patients had preexisting liver disease.

Overall, liver injury was judged to be due to a single prescription medication in 75% of cases, most commonly amoxicillin-clavulanate (22%), followed by diclofenac (6%), azathioprine (4%) infliximab (4%), and nitrofurantoin (4%).

By tying the injury to Iceland’s prescription drug database, that meant an incidence of DILI among outpatients of 1 per 133 filled azathioprine prescriptions and 1 in 2,350 amoxicillin-clavulanate users; among inpatients, the incidence of injury attributed to amoxicillin-clavulanate was 1 per 729 patients.

By drug classes, after antibiotics, immunosuppressants were found to be commonly associated with DILI (10%), followed by psychotropic drugs, which accounted for 7% of cases, and then nonsteroidal anti-inflammatory drugs, at 6%, "with diclofenac as the only agent."

Single-drug antineoplastic agents were the causes of DILI in 5% of the cohort, and lipid-lowering agents were the cause in just 3.1% of patients (atorvastatin, n = 2; simvastatin, n = 1).

After injuries due to a single agent, dietary supplements were assumed to be the culprit in 16% of cases, and the use of multiple agents was implicated in 9% of cases.

Looking at outcomes, the researchers reported that DILI was mild in 35 patients (36%), moderate in 55 patients (58%), and severe in 5 patients (5%); there was 1 death, in an 82-year-old patient.

Finally, the median duration from diagnosis of DILI to the normalization of liver enzymes was 64 days, and 7% still had abnormal liver tests 6 months after DILI diagnosis.

According to the authors, the only previously published population-based study, done in France, found an annual crude incidence rate of 13.9 cases per 100,000 inhabitants per year (Hepatology 2002;36:451-5).

They conceded that their rate is somewhat higher; however, "the French study provided no information about the patients at risk for DILI because information about drug consumption was not available," they wrote.

The authors stated that the study was funded by a grant from the National University Hospital of Iceland Research Fund; they disclosed no individual financial conflicts of interest.

The crude incidence of drug-induced liver injury is roughly 19.1 cases per 100,000 inhabitants, with amoxicillin-clavulanate the most commonly implicated agent.

That’s according to the second published population-based cohort study of drug-induced liver injury (DILI), wrote Dr. Einar S. Björnsson. The study was published in the June issue of Gastroenterology.

Dr. Björnsson, of the University of Iceland, and colleagues looked at all patients aged older than 15 years hospitalized for liver disease with suspected DILI, plus outpatients at the National University Hospital of Iceland, and all those seen in private practice between March 1, 2010, and Feb. 29, 2012.

^{Source: American Gastroenterological Association}

According to the authors, "In Iceland, every citizen is issued a specific personal identification number that is, among other things, connected to a nationwide pharmaceutical database on outpatient prescriptions."

Therefore, "The study examined the Icelandic Medicines Registry records of prescriptions for all drugs associated with DILI that had at least a possible causal relationship" according to the Roussel Uclaf Causality Assessment Method.

DILI was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than three times the upper limit of normal, and/or alkaline phosphatase (ALP) levels greater than two times the upper limit of normal.

Acetaminophen toxicity cases were excluded, though patients with preexisting chronic liver injury were not, if they were considered to have developed superimposed DILI on top of their baseline liver enzyme values.

The authors found that over the study period there were 96 cases eligible for inclusion, including 49 cases in the first year and 47 in the second. That translated into a crude annual incidence during the study period of 19.1 cases per 100,000 inhabitants.

Roughly half were female (56%), and the median age was 55 years (range, 16-91 years).

Looking at the clinical characteristics of the cohort, the authors calculated that only 27% of patients developed jaundice, while 10% of patients complained of rash and 6% of fever. Four of the patients had preexisting liver disease.

Overall, liver injury was judged to be due to a single prescription medication in 75% of cases, most commonly amoxicillin-clavulanate (22%), followed by diclofenac (6%), azathioprine (4%) infliximab (4%), and nitrofurantoin (4%).

By tying the injury to Iceland’s prescription drug database, that meant an incidence of DILI among outpatients of 1 per 133 filled azathioprine prescriptions and 1 in 2,350 amoxicillin-clavulanate users; among inpatients, the incidence of injury attributed to amoxicillin-clavulanate was 1 per 729 patients.

By drug classes, after antibiotics, immunosuppressants were found to be commonly associated with DILI (10%), followed by psychotropic drugs, which accounted for 7% of cases, and then nonsteroidal anti-inflammatory drugs, at 6%, "with diclofenac as the only agent."

Single-drug antineoplastic agents were the causes of DILI in 5% of the cohort, and lipid-lowering agents were the cause in just 3.1% of patients (atorvastatin, n = 2; simvastatin, n = 1).

After injuries due to a single agent, dietary supplements were assumed to be the culprit in 16% of cases, and the use of multiple agents was implicated in 9% of cases.

Looking at outcomes, the researchers reported that DILI was mild in 35 patients (36%), moderate in 55 patients (58%), and severe in 5 patients (5%); there was 1 death, in an 82-year-old patient.

Finally, the median duration from diagnosis of DILI to the normalization of liver enzymes was 64 days, and 7% still had abnormal liver tests 6 months after DILI diagnosis.

According to the authors, the only previously published population-based study, done in France, found an annual crude incidence rate of 13.9 cases per 100,000 inhabitants per year (Hepatology 2002;36:451-5).

They conceded that their rate is somewhat higher; however, "the French study provided no information about the patients at risk for DILI because information about drug consumption was not available," they wrote.

The authors stated that the study was funded by a grant from the National University Hospital of Iceland Research Fund; they disclosed no individual financial conflicts of interest.

The crude incidence of drug-induced liver injury is roughly 19.1 cases per 100,000 inhabitants, with amoxicillin-clavulanate the most commonly implicated agent.

That’s according to the second published population-based cohort study of drug-induced liver injury (DILI), wrote Dr. Einar S. Björnsson. The study was published in the June issue of Gastroenterology.

Dr. Björnsson, of the University of Iceland, and colleagues looked at all patients aged older than 15 years hospitalized for liver disease with suspected DILI, plus outpatients at the National University Hospital of Iceland, and all those seen in private practice between March 1, 2010, and Feb. 29, 2012.

^{Source: American Gastroenterological Association}

According to the authors, "In Iceland, every citizen is issued a specific personal identification number that is, among other things, connected to a nationwide pharmaceutical database on outpatient prescriptions."

Therefore, "The study examined the Icelandic Medicines Registry records of prescriptions for all drugs associated with DILI that had at least a possible causal relationship" according to the Roussel Uclaf Causality Assessment Method.

DILI was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than three times the upper limit of normal, and/or alkaline phosphatase (ALP) levels greater than two times the upper limit of normal.

Acetaminophen toxicity cases were excluded, though patients with preexisting chronic liver injury were not, if they were considered to have developed superimposed DILI on top of their baseline liver enzyme values.

The authors found that over the study period there were 96 cases eligible for inclusion, including 49 cases in the first year and 47 in the second. That translated into a crude annual incidence during the study period of 19.1 cases per 100,000 inhabitants.

Roughly half were female (56%), and the median age was 55 years (range, 16-91 years).

Looking at the clinical characteristics of the cohort, the authors calculated that only 27% of patients developed jaundice, while 10% of patients complained of rash and 6% of fever. Four of the patients had preexisting liver disease.

Overall, liver injury was judged to be due to a single prescription medication in 75% of cases, most commonly amoxicillin-clavulanate (22%), followed by diclofenac (6%), azathioprine (4%) infliximab (4%), and nitrofurantoin (4%).

By tying the injury to Iceland’s prescription drug database, that meant an incidence of DILI among outpatients of 1 per 133 filled azathioprine prescriptions and 1 in 2,350 amoxicillin-clavulanate users; among inpatients, the incidence of injury attributed to amoxicillin-clavulanate was 1 per 729 patients.

By drug classes, after antibiotics, immunosuppressants were found to be commonly associated with DILI (10%), followed by psychotropic drugs, which accounted for 7% of cases, and then nonsteroidal anti-inflammatory drugs, at 6%, "with diclofenac as the only agent."

Single-drug antineoplastic agents were the causes of DILI in 5% of the cohort, and lipid-lowering agents were the cause in just 3.1% of patients (atorvastatin, n = 2; simvastatin, n = 1).

After injuries due to a single agent, dietary supplements were assumed to be the culprit in 16% of cases, and the use of multiple agents was implicated in 9% of cases.

Looking at outcomes, the researchers reported that DILI was mild in 35 patients (36%), moderate in 55 patients (58%), and severe in 5 patients (5%); there was 1 death, in an 82-year-old patient.

Finally, the median duration from diagnosis of DILI to the normalization of liver enzymes was 64 days, and 7% still had abnormal liver tests 6 months after DILI diagnosis.

According to the authors, the only previously published population-based study, done in France, found an annual crude incidence rate of 13.9 cases per 100,000 inhabitants per year (Hepatology 2002;36:451-5).

They conceded that their rate is somewhat higher; however, "the French study provided no information about the patients at risk for DILI because information about drug consumption was not available," they wrote.

The authors stated that the study was funded by a grant from the National University Hospital of Iceland Research Fund; they disclosed no individual financial conflicts of interest.

ORLANDO – Both 12- and 24-week regimens of an investigational interferon-free therapy for hepatitis C were associated with high sustained virological response rates at 12 weeks post treatment in a phase II study of patients with hepatitis C virus genotype 1 who had baseline characteristics associated with poor response to interferon-based therapies.

The findings of this subgroup analysis of the randomized, open-label, multicenter Aviator trial demonstrate that the high response rates recently reported for the entire cohort also apply to patients with older age, black race, Hispanic/Latino ethnicity, interleukin (IL)-28B non-cc genotype, and higher body mass index (BMI), Dr. Frederick Nunes reported at the annual Digestive Disease Week.

The Aviator trial assessed the safety and efficacy of various dosing regimens and combinations of three AbbVie investigational direct-acting antivirals (DAAs) with or without ribavirin, including the potent hepatitis C virus (HCV) protease inhibitor ABT-450 dosed with 100 mg of ritonavir (ABT-450/r, dosed at 100 or 150 mg daily), the NS5A inhibitor ABT-267 (25 mg daily), and the non-nucleoside NS5B inhibitor ABT-333 (400 mg twice daily). A total of 247 patients were included in the subanalysis, Dr. Nunes reported at the meeting.

The regimen that included all three investigational drugs and ribavirin, known as 3 DAA/RBV, was associated with sustained virological response rates of 99% and 93% at 12 weeks in treatment-naive patients and previous peg-interferon/ribavirin (peg-IFN/RBV) null responders, respectively, said Dr. Nunes, who is clinical associate professor of medicine in the University of Pennsylvania Health System, and section chief of gastroenterology at Pennsylvania Hospital, Philadelphia.

In the current analysis, high sustained virological response rates at 12 weeks (SVR12) were also achieved in the 247 patients with chronic HCV genotype 1, including 159 treatment-naive and 88 previous peg-IFN/RBV null responders, who were assigned to 12 or 24 weeks of 3 DAA/RBV. The virological response rates were 99% and 93% for the treatment-naive 12- and 24-week groups, respectively, and 93% and 98% for the null responder 12- and 24-week groups.

The high responses occurred regardless of treatment duration, age, race, ethnicity, BMI, Homeostatic Model of Assessment–Insulin Resistance (HOMA-IR), IL-28B host genotype, or baseline viral load. The rates did not differ significantly on any comparison made in treatment-naive patients or previous null responders, he said.

In the treatment-naive patients, no breakthroughs occurred, although 1% of those in the 12-week treatment arm relapsed, and 3% of the 24-week treatment group relapsed.

In the null responder group, no relapses occurred, but breakthroughs occurred in 7% of those in the 12-week treatment arm, and in 2% of the 24-week treatment arm, he said.

Treatment was safe and generally well tolerated. Four patients discontinued treatment due to drug-related adverse events, most commonly fatigue (in 32.7% and 23.9% of treatment-naive and null responders, respectively) and headache (31.4% and 30.7%, respectively).

One patient had a serious adverse event (arthralgia) considered to be possibly related to the study drug regimen.

Because ribavirin was included in the treatment regimens, it is impossible to tease out whether the adverse events were associated with that drug or with the investigational DAAs, Dr. Nunes noted.

Patients included in the study were noncirrhotic adults aged 18-70 years with a BMI between 18 and 38 kg/m², and HCV genotype 1.

"The overall efficacy was excellent irrespective of the baseline grouping. So black race, Hispanic/Latino ethnicity, age greater than 50, BMI over 30, male gender, HOMA-IR greater than 3, IL-28B non-cc genotype, and viral load greater than 7 logs all had very high SVR12 response rates," Dr. Nunes said.

The safety and efficacy of this interferon-free 3 DAA/RBV therapy will be further explored in phase III studies, he said.

Dr. Nunes has received grant or research support from Merck, Abbott Laboratories, and Roche Pharma AG.

ORLANDO – Both 12- and 24-week regimens of an investigational interferon-free therapy for hepatitis C were associated with high sustained virological response rates at 12 weeks post treatment in a phase II study of patients with hepatitis C virus genotype 1 who had baseline characteristics associated with poor response to interferon-based therapies.

The findings of this subgroup analysis of the randomized, open-label, multicenter Aviator trial demonstrate that the high response rates recently reported for the entire cohort also apply to patients with older age, black race, Hispanic/Latino ethnicity, interleukin (IL)-28B non-cc genotype, and higher body mass index (BMI), Dr. Frederick Nunes reported at the annual Digestive Disease Week.

The Aviator trial assessed the safety and efficacy of various dosing regimens and combinations of three AbbVie investigational direct-acting antivirals (DAAs) with or without ribavirin, including the potent hepatitis C virus (HCV) protease inhibitor ABT-450 dosed with 100 mg of ritonavir (ABT-450/r, dosed at 100 or 150 mg daily), the NS5A inhibitor ABT-267 (25 mg daily), and the non-nucleoside NS5B inhibitor ABT-333 (400 mg twice daily). A total of 247 patients were included in the subanalysis, Dr. Nunes reported at the meeting.

The regimen that included all three investigational drugs and ribavirin, known as 3 DAA/RBV, was associated with sustained virological response rates of 99% and 93% at 12 weeks in treatment-naive patients and previous peg-interferon/ribavirin (peg-IFN/RBV) null responders, respectively, said Dr. Nunes, who is clinical associate professor of medicine in the University of Pennsylvania Health System, and section chief of gastroenterology at Pennsylvania Hospital, Philadelphia.

In the current analysis, high sustained virological response rates at 12 weeks (SVR12) were also achieved in the 247 patients with chronic HCV genotype 1, including 159 treatment-naive and 88 previous peg-IFN/RBV null responders, who were assigned to 12 or 24 weeks of 3 DAA/RBV. The virological response rates were 99% and 93% for the treatment-naive 12- and 24-week groups, respectively, and 93% and 98% for the null responder 12- and 24-week groups.

The high responses occurred regardless of treatment duration, age, race, ethnicity, BMI, Homeostatic Model of Assessment–Insulin Resistance (HOMA-IR), IL-28B host genotype, or baseline viral load. The rates did not differ significantly on any comparison made in treatment-naive patients or previous null responders, he said.

In the treatment-naive patients, no breakthroughs occurred, although 1% of those in the 12-week treatment arm relapsed, and 3% of the 24-week treatment group relapsed.

In the null responder group, no relapses occurred, but breakthroughs occurred in 7% of those in the 12-week treatment arm, and in 2% of the 24-week treatment arm, he said.

Treatment was safe and generally well tolerated. Four patients discontinued treatment due to drug-related adverse events, most commonly fatigue (in 32.7% and 23.9% of treatment-naive and null responders, respectively) and headache (31.4% and 30.7%, respectively).

One patient had a serious adverse event (arthralgia) considered to be possibly related to the study drug regimen.

Because ribavirin was included in the treatment regimens, it is impossible to tease out whether the adverse events were associated with that drug or with the investigational DAAs, Dr. Nunes noted.

Patients included in the study were noncirrhotic adults aged 18-70 years with a BMI between 18 and 38 kg/m², and HCV genotype 1.

"The overall efficacy was excellent irrespective of the baseline grouping. So black race, Hispanic/Latino ethnicity, age greater than 50, BMI over 30, male gender, HOMA-IR greater than 3, IL-28B non-cc genotype, and viral load greater than 7 logs all had very high SVR12 response rates," Dr. Nunes said.

The safety and efficacy of this interferon-free 3 DAA/RBV therapy will be further explored in phase III studies, he said.

Dr. Nunes has received grant or research support from Merck, Abbott Laboratories, and Roche Pharma AG.

ORLANDO – Both 12- and 24-week regimens of an investigational interferon-free therapy for hepatitis C were associated with high sustained virological response rates at 12 weeks post treatment in a phase II study of patients with hepatitis C virus genotype 1 who had baseline characteristics associated with poor response to interferon-based therapies.

The findings of this subgroup analysis of the randomized, open-label, multicenter Aviator trial demonstrate that the high response rates recently reported for the entire cohort also apply to patients with older age, black race, Hispanic/Latino ethnicity, interleukin (IL)-28B non-cc genotype, and higher body mass index (BMI), Dr. Frederick Nunes reported at the annual Digestive Disease Week.

The Aviator trial assessed the safety and efficacy of various dosing regimens and combinations of three AbbVie investigational direct-acting antivirals (DAAs) with or without ribavirin, including the potent hepatitis C virus (HCV) protease inhibitor ABT-450 dosed with 100 mg of ritonavir (ABT-450/r, dosed at 100 or 150 mg daily), the NS5A inhibitor ABT-267 (25 mg daily), and the non-nucleoside NS5B inhibitor ABT-333 (400 mg twice daily). A total of 247 patients were included in the subanalysis, Dr. Nunes reported at the meeting.

The regimen that included all three investigational drugs and ribavirin, known as 3 DAA/RBV, was associated with sustained virological response rates of 99% and 93% at 12 weeks in treatment-naive patients and previous peg-interferon/ribavirin (peg-IFN/RBV) null responders, respectively, said Dr. Nunes, who is clinical associate professor of medicine in the University of Pennsylvania Health System, and section chief of gastroenterology at Pennsylvania Hospital, Philadelphia.

In the current analysis, high sustained virological response rates at 12 weeks (SVR12) were also achieved in the 247 patients with chronic HCV genotype 1, including 159 treatment-naive and 88 previous peg-IFN/RBV null responders, who were assigned to 12 or 24 weeks of 3 DAA/RBV. The virological response rates were 99% and 93% for the treatment-naive 12- and 24-week groups, respectively, and 93% and 98% for the null responder 12- and 24-week groups.

The high responses occurred regardless of treatment duration, age, race, ethnicity, BMI, Homeostatic Model of Assessment–Insulin Resistance (HOMA-IR), IL-28B host genotype, or baseline viral load. The rates did not differ significantly on any comparison made in treatment-naive patients or previous null responders, he said.

In the treatment-naive patients, no breakthroughs occurred, although 1% of those in the 12-week treatment arm relapsed, and 3% of the 24-week treatment group relapsed.

In the null responder group, no relapses occurred, but breakthroughs occurred in 7% of those in the 12-week treatment arm, and in 2% of the 24-week treatment arm, he said.

Treatment was safe and generally well tolerated. Four patients discontinued treatment due to drug-related adverse events, most commonly fatigue (in 32.7% and 23.9% of treatment-naive and null responders, respectively) and headache (31.4% and 30.7%, respectively).

One patient had a serious adverse event (arthralgia) considered to be possibly related to the study drug regimen.

Because ribavirin was included in the treatment regimens, it is impossible to tease out whether the adverse events were associated with that drug or with the investigational DAAs, Dr. Nunes noted.

Patients included in the study were noncirrhotic adults aged 18-70 years with a BMI between 18 and 38 kg/m², and HCV genotype 1.

"The overall efficacy was excellent irrespective of the baseline grouping. So black race, Hispanic/Latino ethnicity, age greater than 50, BMI over 30, male gender, HOMA-IR greater than 3, IL-28B non-cc genotype, and viral load greater than 7 logs all had very high SVR12 response rates," Dr. Nunes said.

The safety and efficacy of this interferon-free 3 DAA/RBV therapy will be further explored in phase III studies, he said.

Dr. Nunes has received grant or research support from Merck, Abbott Laboratories, and Roche Pharma AG.

ORLANDO – The risk factors for death in patients with nonalcoholic fatty liver disease include older age, male sex, truncal obesity, and a low HDL cholesterol level – in other words, the same factors that increase risk for death from cardiovascular disease and other causes, according to Dr. Naga P. Chalasani.

On the other hand, elevations in alanine aminotransferase (ALT) levels in patients with NAFLD are not associated with an increased risk for death or other poor outcomes, meaning that researchers may have to burrow more deeply through the available data to find risk predictors unique to NAFLD, said Dr Chalasani of Indiana University, Indianapolis.

"How do we identify someone with NAFLD who is at risk for poor outcomes? I think this is the first shot at risk mapping patients," Dr. Chalasani said at the annual Digestive Disease Week.

Dr. Keith D. Lindor, who moderated the session at which the data were presented, agreed.

"What we’re having trouble with, I think, is defining nonalcoholic fatty liver disease easily, particularly amongst the population," he said. "We saw data that ALT, which we commonly used to use, may not be telling, and there are questions about how well ultrasound detects [NAFLD], particularly given that the amount of steatosis in order to be detected by ultrasound has to be relatively dramatic."

It is still not known whether people with steatosis discovered during biopsy but not visible on ultrasound will have risk factors similar to those of people with more grossly evident steatosis, he said in an interview.

Although Dr. Chalasani and colleagues failed to find unique risk markers in this population, it was not for want of trying. The investigators pored over data from the third National Health and Nutrition Examination Survey (NHANES III) for baseline and follow-up information about patients with NAFLD.

The data were collected from 1988 through 1994, and included gallbladder ultrasound with liver images in 14,797 adults aged 20-74. The authors linked the data to the National Death Index in an attempt to determine which factors might be harbingers of early mortality in patients with NAFLD vs. controls.

They defined NAFLD by the presence of moderate to severe hepatic steatosis on ultrasonography, and by the absence of iron overload, hepatitis B or C infections, and excessive alcohol consumption. Controls were participants in the same data set who did not have underlying liver disease and had normal ultrasound and liver function tests.

There were a total of 2,441 people with NAFLD and 8,423 controls. During a median follow-up of 14.3 years, 14% of controls (1,193), and 21% of those with NAFLD (501) died, a difference that was significant in a univariate analysis (P = .0328).

But when they looked at overall mortality, cancer-related mortality, and cardiovascular mortality, they found that all three categories shared male sex, older age, and a low HDL level as independent predictors for death, with cardiovascular mortality having the added bonus of the metabolic syndrome as an additional risk factor.

The authors did not disclose a funding source. Dr. Chalasani and Dr. Lindor reported having no relevant financial disclosures.

ORLANDO – The risk factors for death in patients with nonalcoholic fatty liver disease include older age, male sex, truncal obesity, and a low HDL cholesterol level – in other words, the same factors that increase risk for death from cardiovascular disease and other causes, according to Dr. Naga P. Chalasani.

On the other hand, elevations in alanine aminotransferase (ALT) levels in patients with NAFLD are not associated with an increased risk for death or other poor outcomes, meaning that researchers may have to burrow more deeply through the available data to find risk predictors unique to NAFLD, said Dr Chalasani of Indiana University, Indianapolis.

"How do we identify someone with NAFLD who is at risk for poor outcomes? I think this is the first shot at risk mapping patients," Dr. Chalasani said at the annual Digestive Disease Week.

Dr. Keith D. Lindor, who moderated the session at which the data were presented, agreed.

"What we’re having trouble with, I think, is defining nonalcoholic fatty liver disease easily, particularly amongst the population," he said. "We saw data that ALT, which we commonly used to use, may not be telling, and there are questions about how well ultrasound detects [NAFLD], particularly given that the amount of steatosis in order to be detected by ultrasound has to be relatively dramatic."

It is still not known whether people with steatosis discovered during biopsy but not visible on ultrasound will have risk factors similar to those of people with more grossly evident steatosis, he said in an interview.

Although Dr. Chalasani and colleagues failed to find unique risk markers in this population, it was not for want of trying. The investigators pored over data from the third National Health and Nutrition Examination Survey (NHANES III) for baseline and follow-up information about patients with NAFLD.

The data were collected from 1988 through 1994, and included gallbladder ultrasound with liver images in 14,797 adults aged 20-74. The authors linked the data to the National Death Index in an attempt to determine which factors might be harbingers of early mortality in patients with NAFLD vs. controls.

They defined NAFLD by the presence of moderate to severe hepatic steatosis on ultrasonography, and by the absence of iron overload, hepatitis B or C infections, and excessive alcohol consumption. Controls were participants in the same data set who did not have underlying liver disease and had normal ultrasound and liver function tests.

There were a total of 2,441 people with NAFLD and 8,423 controls. During a median follow-up of 14.3 years, 14% of controls (1,193), and 21% of those with NAFLD (501) died, a difference that was significant in a univariate analysis (P = .0328).

But when they looked at overall mortality, cancer-related mortality, and cardiovascular mortality, they found that all three categories shared male sex, older age, and a low HDL level as independent predictors for death, with cardiovascular mortality having the added bonus of the metabolic syndrome as an additional risk factor.

The authors did not disclose a funding source. Dr. Chalasani and Dr. Lindor reported having no relevant financial disclosures.

ORLANDO – The risk factors for death in patients with nonalcoholic fatty liver disease include older age, male sex, truncal obesity, and a low HDL cholesterol level – in other words, the same factors that increase risk for death from cardiovascular disease and other causes, according to Dr. Naga P. Chalasani.

On the other hand, elevations in alanine aminotransferase (ALT) levels in patients with NAFLD are not associated with an increased risk for death or other poor outcomes, meaning that researchers may have to burrow more deeply through the available data to find risk predictors unique to NAFLD, said Dr Chalasani of Indiana University, Indianapolis.

"How do we identify someone with NAFLD who is at risk for poor outcomes? I think this is the first shot at risk mapping patients," Dr. Chalasani said at the annual Digestive Disease Week.

Dr. Keith D. Lindor, who moderated the session at which the data were presented, agreed.

"What we’re having trouble with, I think, is defining nonalcoholic fatty liver disease easily, particularly amongst the population," he said. "We saw data that ALT, which we commonly used to use, may not be telling, and there are questions about how well ultrasound detects [NAFLD], particularly given that the amount of steatosis in order to be detected by ultrasound has to be relatively dramatic."

It is still not known whether people with steatosis discovered during biopsy but not visible on ultrasound will have risk factors similar to those of people with more grossly evident steatosis, he said in an interview.

Although Dr. Chalasani and colleagues failed to find unique risk markers in this population, it was not for want of trying. The investigators pored over data from the third National Health and Nutrition Examination Survey (NHANES III) for baseline and follow-up information about patients with NAFLD.

The data were collected from 1988 through 1994, and included gallbladder ultrasound with liver images in 14,797 adults aged 20-74. The authors linked the data to the National Death Index in an attempt to determine which factors might be harbingers of early mortality in patients with NAFLD vs. controls.

They defined NAFLD by the presence of moderate to severe hepatic steatosis on ultrasonography, and by the absence of iron overload, hepatitis B or C infections, and excessive alcohol consumption. Controls were participants in the same data set who did not have underlying liver disease and had normal ultrasound and liver function tests.

There were a total of 2,441 people with NAFLD and 8,423 controls. During a median follow-up of 14.3 years, 14% of controls (1,193), and 21% of those with NAFLD (501) died, a difference that was significant in a univariate analysis (P = .0328).

But when they looked at overall mortality, cancer-related mortality, and cardiovascular mortality, they found that all three categories shared male sex, older age, and a low HDL level as independent predictors for death, with cardiovascular mortality having the added bonus of the metabolic syndrome as an additional risk factor.

The authors did not disclose a funding source. Dr. Chalasani and Dr. Lindor reported having no relevant financial disclosures.

ORLANDO – Changes in serum levels of cytokeratin fragments appear to reflect changes in liver histology in patients with nonalcoholic steatohepatitis, Dr. Raj Vuppalanchi reported at the annual Digestive Disease Week.

Among 231 participants in the PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis) trial, every 100-U/L decline in serum cytokeratin fragment (CK-18) level was significantly associated with overall histological improvement (P less than .001); resolution of NASH (P = .002); and improvement of at least 1 point in steatosis grade, hepatocellular ballooning, and nonalcoholic fatty liver disease (NAFLD) score (P less than .001 for all).

"We feel that serum CK-18 is a potentially useful surrogate marker for detection of improvement in clinical trials for NASH," said Dr. Vuppalanchi from Indiana University in Indianapolis.

Dr. Keith D. Lindor, executive vice provost for health at Arizona State University in Phoenix, said in an interview that CK-18 shows promise as a marker for disease activity in NASH but offers only limited information.

"It doesn’t hold the possibility of giving as much detailed information as a biopsy. We look at the amount of fat, amount of inflammation, amount of scarring – the biopsy lets us do that, but I don’t think a single serum assay will allow that," he said.

Dr. Lindor, who was not involved in the study, moderated the session at which the data were presented.

In previous cross-sectional studies, circulating CK-18 levels were shown to be associated with steatohepatitis in people with NAFLD, but it was unclear whether longitudinal changes in CK-18 would reflect changes in liver histology, Dr. Vuppalanchi said.

The investigators looked at CK-18 levels measured at baseline and at 16, 48, and 96 months among 231 of the 247 patients enrolled in the PIVENS trial, which compared vitamin E and/or pioglitazone against placebo in nondiabetic patients with NASH. The participants had liver biopsies at baseline and after 96 weeks of treatment.

The main trial results showed that vitamin E, but not pioglitazone, was significantly better than placebo at improvement of steatohepatitis.

In this substudy, the authors found that, compared with placebo, serum CK-18 levels were significantly lower in vitamin E–treated patients (P = .02 at 16 weeks, and P = .009 at 48 and 96 weeks). Among pioglitazone-treated patients, there was a similar pattern of lower CK-18 levels vs. placebo at all three time intervals (P = .001 for all).

Reductions in CK-18 correlated strongly with disease measures. For each 100-U/L decrease in CK-18 over 96 weeks, the odds ratios (ORs) were as follows: overall histological improvement (OR, 1.41; P less than .001); resolution of NASH (OR, 1.31; P = .002); and 1 point or more improvement in steatosis grade (OR, 1.45; P less than .001), hepatocellular ballooning (OR, 1.36; P less than .001), and NAFLD (OR, 1.41; P less than .001).

The study was supported by the National Institutes of Health with additional funding from Takeda Pharmaceuticals. Dr. Vuppalanchi and Dr. Lindor reported having no financial disclosures.

ORLANDO – Changes in serum levels of cytokeratin fragments appear to reflect changes in liver histology in patients with nonalcoholic steatohepatitis, Dr. Raj Vuppalanchi reported at the annual Digestive Disease Week.

Among 231 participants in the PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis) trial, every 100-U/L decline in serum cytokeratin fragment (CK-18) level was significantly associated with overall histological improvement (P less than .001); resolution of NASH (P = .002); and improvement of at least 1 point in steatosis grade, hepatocellular ballooning, and nonalcoholic fatty liver disease (NAFLD) score (P less than .001 for all).

"We feel that serum CK-18 is a potentially useful surrogate marker for detection of improvement in clinical trials for NASH," said Dr. Vuppalanchi from Indiana University in Indianapolis.

Dr. Keith D. Lindor, executive vice provost for health at Arizona State University in Phoenix, said in an interview that CK-18 shows promise as a marker for disease activity in NASH but offers only limited information.

"It doesn’t hold the possibility of giving as much detailed information as a biopsy. We look at the amount of fat, amount of inflammation, amount of scarring – the biopsy lets us do that, but I don’t think a single serum assay will allow that," he said.

Dr. Lindor, who was not involved in the study, moderated the session at which the data were presented.

In previous cross-sectional studies, circulating CK-18 levels were shown to be associated with steatohepatitis in people with NAFLD, but it was unclear whether longitudinal changes in CK-18 would reflect changes in liver histology, Dr. Vuppalanchi said.

The investigators looked at CK-18 levels measured at baseline and at 16, 48, and 96 months among 231 of the 247 patients enrolled in the PIVENS trial, which compared vitamin E and/or pioglitazone against placebo in nondiabetic patients with NASH. The participants had liver biopsies at baseline and after 96 weeks of treatment.

The main trial results showed that vitamin E, but not pioglitazone, was significantly better than placebo at improvement of steatohepatitis.

In this substudy, the authors found that, compared with placebo, serum CK-18 levels were significantly lower in vitamin E–treated patients (P = .02 at 16 weeks, and P = .009 at 48 and 96 weeks). Among pioglitazone-treated patients, there was a similar pattern of lower CK-18 levels vs. placebo at all three time intervals (P = .001 for all).

Reductions in CK-18 correlated strongly with disease measures. For each 100-U/L decrease in CK-18 over 96 weeks, the odds ratios (ORs) were as follows: overall histological improvement (OR, 1.41; P less than .001); resolution of NASH (OR, 1.31; P = .002); and 1 point or more improvement in steatosis grade (OR, 1.45; P less than .001), hepatocellular ballooning (OR, 1.36; P less than .001), and NAFLD (OR, 1.41; P less than .001).

The study was supported by the National Institutes of Health with additional funding from Takeda Pharmaceuticals. Dr. Vuppalanchi and Dr. Lindor reported having no financial disclosures.

ORLANDO – Changes in serum levels of cytokeratin fragments appear to reflect changes in liver histology in patients with nonalcoholic steatohepatitis, Dr. Raj Vuppalanchi reported at the annual Digestive Disease Week.

Among 231 participants in the PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis) trial, every 100-U/L decline in serum cytokeratin fragment (CK-18) level was significantly associated with overall histological improvement (P less than .001); resolution of NASH (P = .002); and improvement of at least 1 point in steatosis grade, hepatocellular ballooning, and nonalcoholic fatty liver disease (NAFLD) score (P less than .001 for all).

"We feel that serum CK-18 is a potentially useful surrogate marker for detection of improvement in clinical trials for NASH," said Dr. Vuppalanchi from Indiana University in Indianapolis.

Dr. Keith D. Lindor, executive vice provost for health at Arizona State University in Phoenix, said in an interview that CK-18 shows promise as a marker for disease activity in NASH but offers only limited information.

"It doesn’t hold the possibility of giving as much detailed information as a biopsy. We look at the amount of fat, amount of inflammation, amount of scarring – the biopsy lets us do that, but I don’t think a single serum assay will allow that," he said.

Dr. Lindor, who was not involved in the study, moderated the session at which the data were presented.

In previous cross-sectional studies, circulating CK-18 levels were shown to be associated with steatohepatitis in people with NAFLD, but it was unclear whether longitudinal changes in CK-18 would reflect changes in liver histology, Dr. Vuppalanchi said.

The investigators looked at CK-18 levels measured at baseline and at 16, 48, and 96 months among 231 of the 247 patients enrolled in the PIVENS trial, which compared vitamin E and/or pioglitazone against placebo in nondiabetic patients with NASH. The participants had liver biopsies at baseline and after 96 weeks of treatment.

The main trial results showed that vitamin E, but not pioglitazone, was significantly better than placebo at improvement of steatohepatitis.

In this substudy, the authors found that, compared with placebo, serum CK-18 levels were significantly lower in vitamin E–treated patients (P = .02 at 16 weeks, and P = .009 at 48 and 96 weeks). Among pioglitazone-treated patients, there was a similar pattern of lower CK-18 levels vs. placebo at all three time intervals (P = .001 for all).

Reductions in CK-18 correlated strongly with disease measures. For each 100-U/L decrease in CK-18 over 96 weeks, the odds ratios (ORs) were as follows: overall histological improvement (OR, 1.41; P less than .001); resolution of NASH (OR, 1.31; P = .002); and 1 point or more improvement in steatosis grade (OR, 1.45; P less than .001), hepatocellular ballooning (OR, 1.36; P less than .001), and NAFLD (OR, 1.41; P less than .001).

The study was supported by the National Institutes of Health with additional funding from Takeda Pharmaceuticals. Dr. Vuppalanchi and Dr. Lindor reported having no financial disclosures.

The Centers for Disease Control and Prevention is urging hepatitis C testing for all Americans born between 1945 and 1965, as new data indicate that the baby boomers account for the largest proportion of cases yet are largely ignorant of their status.

"The take-home message from today’s report is that you may not remember everything that happened in the ’60s and ’70s, but your liver does," said CDC Director Thomas Frieden in a briefing with reporters.

"The bottom line here is, if you were born between those years, get tested," he said. "And if you’re positive, get follow-up testing."

Besides targeting consumers, the CDC also issued updated testing recommendations for physicians.

The guidelines, published May 7 in Morbidity and Mortality Weekly Report (MMWR), update the CDC’s 2003 testing recommendations.

The agency issued the update "because of changes in the availability of certain commercial HCV [hepatitis C virus] antibody tests, evidence that many persons who are identified as reactive by an HCV antibody test might not subsequently be evaluated to determine if they have current HCV infection, and significant advances in the development of antiviral agents with improved efficacy against HCV," according to the report.

The CDC first proposed such broad testing a year ago. New surveillance data published in MMWR give credence to the idea that baby boomers seem to be at particular risk.

Researchers from the CDC and the New York City Department of Health and Mental Hygiene analyzed hepatitis C testing data from 2005 to 2011 from eight U.S. sites: Colorado, Connecticut, Minnesota, New Mexico, New York City, New York State, Oregon, and San Francisco. Health officials at all of the sites received CDC funding for conducting enhanced surveillance.

The analysis found that 63% of the 217,755 people with newly reported positive HCV were born in the years 1945-1965. Of the total who tested positive, 107,209 (49%) had a positive antibody test, and 110,546 (51%) had a positive follow-up RNA test. That means about half of those who have an initial positive test are not following up with a confirmatory RNA test.

That is discouraging, said Dr. Frieden. "Right now, there are better hepatitis C treatments available than ever, and there are more treatments coming in the coming year," he said. "So, confirming that someone is infected is more important than ever."

The CDC estimates 100,000-120,000 deaths could be prevented with proper testing and follow-up care.

About 3 million people are currently infected; half will end up with cirrhosis, and at least a third will die from complications. Eighty percent of people with hepatitis C are chronically infected.

The CDC is updating its 2003 guidance for physicians on hepatitis C testing by urging that a positive HCV antibody test be followed up with RNA testing.

The findings in the MMWR study "give us an idea of the gap between those who are and are not receiving the test, and show us that we have a substantial challenge in front of us," said Dr. John Ward, director of the division of viral hepatitis in the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention.

Baby boomers are likely to have been infected in their teens or 20s through transfusions or risky behaviors such as injection drug use. The CDC says risk factors for hepatitis C infection also include:

• Receiving clotting factor concentrates made before 1987, when more advanced methods for manufacturing those products were developed.

• Having a solid organ transplant before July 1992, when better testing became available.

• Chronic hemodialysis.

• Known exposure to HCV, such as needlesticks involving HCV-positive blood.

• HIV infection.

• Being born to an HCV-positive mother.

The CDC is exploring ways to make testing more available and to reach out to patients, Dr. Ward said. The agency has funded 25-30 demonstration projects, he added. Among the projects being tested: routine screening in the emergency department, and built-in reminders for physicians to test patients born in the target years.

Dr. Frieden urged immediate adoption of those reminders. "For health care providers, it’s very important to put in automatic systems to make sure that if someone has a positive antibody test, they go on to have follow-up testing and then get into care," he said.

The CDC issued its testing recommendations to coincide with Hepatitis Awareness Month and Hepatitis Testing Day, which is May 19.

[email protected]

On Twitter @aliciaault

The Centers for Disease Control and Prevention is urging hepatitis C testing for all Americans born between 1945 and 1965, as new data indicate that the baby boomers account for the largest proportion of cases yet are largely ignorant of their status.

"The take-home message from today’s report is that you may not remember everything that happened in the ’60s and ’70s, but your liver does," said CDC Director Thomas Frieden in a briefing with reporters.

"The bottom line here is, if you were born between those years, get tested," he said. "And if you’re positive, get follow-up testing."

Besides targeting consumers, the CDC also issued updated testing recommendations for physicians.

The guidelines, published May 7 in Morbidity and Mortality Weekly Report (MMWR), update the CDC’s 2003 testing recommendations.

The agency issued the update "because of changes in the availability of certain commercial HCV [hepatitis C virus] antibody tests, evidence that many persons who are identified as reactive by an HCV antibody test might not subsequently be evaluated to determine if they have current HCV infection, and significant advances in the development of antiviral agents with improved efficacy against HCV," according to the report.

The CDC first proposed such broad testing a year ago. New surveillance data published in MMWR give credence to the idea that baby boomers seem to be at particular risk.

Researchers from the CDC and the New York City Department of Health and Mental Hygiene analyzed hepatitis C testing data from 2005 to 2011 from eight U.S. sites: Colorado, Connecticut, Minnesota, New Mexico, New York City, New York State, Oregon, and San Francisco. Health officials at all of the sites received CDC funding for conducting enhanced surveillance.

The analysis found that 63% of the 217,755 people with newly reported positive HCV were born in the years 1945-1965. Of the total who tested positive, 107,209 (49%) had a positive antibody test, and 110,546 (51%) had a positive follow-up RNA test. That means about half of those who have an initial positive test are not following up with a confirmatory RNA test.

That is discouraging, said Dr. Frieden. "Right now, there are better hepatitis C treatments available than ever, and there are more treatments coming in the coming year," he said. "So, confirming that someone is infected is more important than ever."

The CDC estimates 100,000-120,000 deaths could be prevented with proper testing and follow-up care.

About 3 million people are currently infected; half will end up with cirrhosis, and at least a third will die from complications. Eighty percent of people with hepatitis C are chronically infected.

The CDC is updating its 2003 guidance for physicians on hepatitis C testing by urging that a positive HCV antibody test be followed up with RNA testing.

The findings in the MMWR study "give us an idea of the gap between those who are and are not receiving the test, and show us that we have a substantial challenge in front of us," said Dr. John Ward, director of the division of viral hepatitis in the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention.

Baby boomers are likely to have been infected in their teens or 20s through transfusions or risky behaviors such as injection drug use. The CDC says risk factors for hepatitis C infection also include:

• Receiving clotting factor concentrates made before 1987, when more advanced methods for manufacturing those products were developed.

• Having a solid organ transplant before July 1992, when better testing became available.

• Chronic hemodialysis.

• Known exposure to HCV, such as needlesticks involving HCV-positive blood.

• HIV infection.

• Being born to an HCV-positive mother.

The CDC is exploring ways to make testing more available and to reach out to patients, Dr. Ward said. The agency has funded 25-30 demonstration projects, he added. Among the projects being tested: routine screening in the emergency department, and built-in reminders for physicians to test patients born in the target years.

Dr. Frieden urged immediate adoption of those reminders. "For health care providers, it’s very important to put in automatic systems to make sure that if someone has a positive antibody test, they go on to have follow-up testing and then get into care," he said.

The CDC issued its testing recommendations to coincide with Hepatitis Awareness Month and Hepatitis Testing Day, which is May 19.

[email protected]

On Twitter @aliciaault

The Centers for Disease Control and Prevention is urging hepatitis C testing for all Americans born between 1945 and 1965, as new data indicate that the baby boomers account for the largest proportion of cases yet are largely ignorant of their status.

"The take-home message from today’s report is that you may not remember everything that happened in the ’60s and ’70s, but your liver does," said CDC Director Thomas Frieden in a briefing with reporters.

"The bottom line here is, if you were born between those years, get tested," he said. "And if you’re positive, get follow-up testing."

Besides targeting consumers, the CDC also issued updated testing recommendations for physicians.

The guidelines, published May 7 in Morbidity and Mortality Weekly Report (MMWR), update the CDC’s 2003 testing recommendations.

The agency issued the update "because of changes in the availability of certain commercial HCV [hepatitis C virus] antibody tests, evidence that many persons who are identified as reactive by an HCV antibody test might not subsequently be evaluated to determine if they have current HCV infection, and significant advances in the development of antiviral agents with improved efficacy against HCV," according to the report.

The CDC first proposed such broad testing a year ago. New surveillance data published in MMWR give credence to the idea that baby boomers seem to be at particular risk.

Researchers from the CDC and the New York City Department of Health and Mental Hygiene analyzed hepatitis C testing data from 2005 to 2011 from eight U.S. sites: Colorado, Connecticut, Minnesota, New Mexico, New York City, New York State, Oregon, and San Francisco. Health officials at all of the sites received CDC funding for conducting enhanced surveillance.

The analysis found that 63% of the 217,755 people with newly reported positive HCV were born in the years 1945-1965. Of the total who tested positive, 107,209 (49%) had a positive antibody test, and 110,546 (51%) had a positive follow-up RNA test. That means about half of those who have an initial positive test are not following up with a confirmatory RNA test.

That is discouraging, said Dr. Frieden. "Right now, there are better hepatitis C treatments available than ever, and there are more treatments coming in the coming year," he said. "So, confirming that someone is infected is more important than ever."

The CDC estimates 100,000-120,000 deaths could be prevented with proper testing and follow-up care.

About 3 million people are currently infected; half will end up with cirrhosis, and at least a third will die from complications. Eighty percent of people with hepatitis C are chronically infected.

The CDC is updating its 2003 guidance for physicians on hepatitis C testing by urging that a positive HCV antibody test be followed up with RNA testing.

The findings in the MMWR study "give us an idea of the gap between those who are and are not receiving the test, and show us that we have a substantial challenge in front of us," said Dr. John Ward, director of the division of viral hepatitis in the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention.

Baby boomers are likely to have been infected in their teens or 20s through transfusions or risky behaviors such as injection drug use. The CDC says risk factors for hepatitis C infection also include:

• Receiving clotting factor concentrates made before 1987, when more advanced methods for manufacturing those products were developed.

• Having a solid organ transplant before July 1992, when better testing became available.

• Chronic hemodialysis.

• Known exposure to HCV, such as needlesticks involving HCV-positive blood.

• HIV infection.

• Being born to an HCV-positive mother.

The CDC is exploring ways to make testing more available and to reach out to patients, Dr. Ward said. The agency has funded 25-30 demonstration projects, he added. Among the projects being tested: routine screening in the emergency department, and built-in reminders for physicians to test patients born in the target years.

Dr. Frieden urged immediate adoption of those reminders. "For health care providers, it’s very important to put in automatic systems to make sure that if someone has a positive antibody test, they go on to have follow-up testing and then get into care," he said.

The CDC issued its testing recommendations to coincide with Hepatitis Awareness Month and Hepatitis Testing Day, which is May 19.

[email protected]

On Twitter @aliciaault