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About one in five patients with chronic hepatitis B virus (HBV) infection had persistently elevated alanine aminotransferase (ALT) levels despite long-term treatment with tenofovir disoproxil fumarate, according to data from two phase III trials reported in the July issue of Clinical Gastroenterology and Hepatology (2017. doi: 10.1016/j.cgh.2017.01.032).
“Both host and viral factors, particularly hepatic steatosis and hepatitis B e antigen [HBeAg] seropositivity, are important contributors to this phenomenon,” Ira M. Jacobson, MD, of Mount Sinai Beth Israel Medical Center, New York, wrote with his associates. “Although serum ALT may indicate significant liver injury, this association is inconsistent, suggesting that relying on serum ALT alone is not sufficient to gauge either the extent of liver injury or the impact of antiviral therapy.”
Long-term treatment with newer antivirals such as tenofovir disoproxil fumarate (TDF) achieves complete viral suppression and improves liver histology in most cases of HBV infection. Transaminase levels are used to track long-term clinical response but sometimes remain elevated in the face of complete virologic response and regression of fibrosis. To explore predictors of this outcome, the researchers analyzed data from 471 chronic HBV patients receiving TDF 300 mg once daily for 5 years as part of two ongoing phase III trials (NCT00117676 and NCT00116805). At baseline, about 25% of patients were cirrhotic (Ishak fibrosis score greater than or equal to 5) and none had decompensated cirrhosis. A central laboratory analyzed ALT levels, which were up to 10 times the upper limit of normal in both HBeAg-positive and -negative patients and were at least twice the upper limit of normal in all HBeAg-positive patients.
After 5 years of TDF, ALT levels remained elevated in 87 (18%) of patients. Patients with at least 5% (grade 1) steatosis at baseline were significantly more likely to have persistent ALT elevation than were those with less or no steatosis (odds ratio, 2.2; 95% confidence interval, 1.03-4.9; P = .04). At least grade 1 steatosis at year 5 also was associated with persistent ALT elevation (OR, 3.4; 95% CI, 1.6-7.4; P =.002). Other significant correlates included HBeAg seropositivity (OR, 3.3; 95% CI, 1.7-6.6; P less than .001) and age 40 years or younger (OR, 2.1; 95% CI, 1.01-4.3; P = .046). Strikingly, half of HBeAg-positive patients with steatosis at baseline had elevated ALT at year 5, said the investigators.
Because many patients whose ALT values fall within commercial laboratory reference ranges have chronic active necroinflammation or fibrogenesis, the researchers performed a sensitivity analysis of patients who achieved a stricter definition of ALT normalization of no more than 30 U/L for men and 19 U/L for women that has been previously recommended (Ann Intern Med. 2002;137:1-10). In this analysis, 47% of patients had persistently elevated ALT despite effective virologic suppression, and the only significant predictor of persistent ALT elevation was grade 1 or more steatosis at year 5 (OR, 6.2; 95% CI, 2.3-16.4; P less than .001). Younger age and HBeAg positivity plus age were no longer significant.
Hepatic steatosis is common overall and in chronic HBV infection and often leads to increased serum transaminases, the researchers noted. Although past work has linked a PNPLA3 single nucleotide polymorphism to obesity, metabolic syndrome, and hepatic steatosis, the presence of this single nucleotide polymorphism was not significant in their study, possibly because many patients lacked genotype data, they added. “Larger longitudinal studies are warranted to further explore this factor and its potential effect on the biochemical response to antiviral treatment in [chronic HBV] patients,” they concluded.
Gilead Sciences sponsored the study. Dr. Jacobson disclosed consultancy, honoraria, and research ties to Gilead and several other pharmaceutical companies.
Antiviral therapy for chronic hepatitis B virus in most treated patients suppresses rather than eradicates infection. Despite this, long-term treatment results in substantial histologic improvement – including regression of fibrosis and reduction in complications.
However, as Jacobson et al. report in a histologic follow-up of 471 HBV patients treated long-term, aminotransferase elevation persisted in 18%. Factors implicated on multivariate analysis in unresolved biochemical dysfunction included HBeAg seropositivity, age less than 40 years, and steatosis at entry, in addition to steatosis at 5-year follow-up. The only association with hepatic dysfunction that persisted was steatosis when modified normal ranges for aminotransferases proposed by Prati were applied, namely 30 U for men and 19 U for women. This suggests that metabolic rather than viral factors are implicated in persistent biochemical dysfunction in patients with chronic HBV infection. Steatosis is also a frequent finding on liver biopsy in patients with chronic HCV infection.
Importantly, HCV-specific mechanisms have been implicated in the accumulation of steatosis in infected patients, as the virus may interfere with host lipid metabolism. HCV genotype 3 has a marked propensity to cause fat accumulation in hepatocytes, which appears to regress with successful antiviral therapy. In the interferon era, hepatic steatosis had been identified as a predictor of nonresponse to therapy for HCV. In patients with chronic viral hepatitis, attention needs to be paid to cofactors in liver disease – notably the metabolic syndrome – particularly because successfully treated patients are now discharged from the care of specialists.
Paul S. Martin, MD, is chief, division of hepatology, professor of medicine, University of Miami Health System, Fla. He has been a consultant and investigator for Gilead, BMS, and Merck.
Antiviral therapy for chronic hepatitis B virus in most treated patients suppresses rather than eradicates infection. Despite this, long-term treatment results in substantial histologic improvement – including regression of fibrosis and reduction in complications.
However, as Jacobson et al. report in a histologic follow-up of 471 HBV patients treated long-term, aminotransferase elevation persisted in 18%. Factors implicated on multivariate analysis in unresolved biochemical dysfunction included HBeAg seropositivity, age less than 40 years, and steatosis at entry, in addition to steatosis at 5-year follow-up. The only association with hepatic dysfunction that persisted was steatosis when modified normal ranges for aminotransferases proposed by Prati were applied, namely 30 U for men and 19 U for women. This suggests that metabolic rather than viral factors are implicated in persistent biochemical dysfunction in patients with chronic HBV infection. Steatosis is also a frequent finding on liver biopsy in patients with chronic HCV infection.
Importantly, HCV-specific mechanisms have been implicated in the accumulation of steatosis in infected patients, as the virus may interfere with host lipid metabolism. HCV genotype 3 has a marked propensity to cause fat accumulation in hepatocytes, which appears to regress with successful antiviral therapy. In the interferon era, hepatic steatosis had been identified as a predictor of nonresponse to therapy for HCV. In patients with chronic viral hepatitis, attention needs to be paid to cofactors in liver disease – notably the metabolic syndrome – particularly because successfully treated patients are now discharged from the care of specialists.
Paul S. Martin, MD, is chief, division of hepatology, professor of medicine, University of Miami Health System, Fla. He has been a consultant and investigator for Gilead, BMS, and Merck.
Antiviral therapy for chronic hepatitis B virus in most treated patients suppresses rather than eradicates infection. Despite this, long-term treatment results in substantial histologic improvement – including regression of fibrosis and reduction in complications.
However, as Jacobson et al. report in a histologic follow-up of 471 HBV patients treated long-term, aminotransferase elevation persisted in 18%. Factors implicated on multivariate analysis in unresolved biochemical dysfunction included HBeAg seropositivity, age less than 40 years, and steatosis at entry, in addition to steatosis at 5-year follow-up. The only association with hepatic dysfunction that persisted was steatosis when modified normal ranges for aminotransferases proposed by Prati were applied, namely 30 U for men and 19 U for women. This suggests that metabolic rather than viral factors are implicated in persistent biochemical dysfunction in patients with chronic HBV infection. Steatosis is also a frequent finding on liver biopsy in patients with chronic HCV infection.
Importantly, HCV-specific mechanisms have been implicated in the accumulation of steatosis in infected patients, as the virus may interfere with host lipid metabolism. HCV genotype 3 has a marked propensity to cause fat accumulation in hepatocytes, which appears to regress with successful antiviral therapy. In the interferon era, hepatic steatosis had been identified as a predictor of nonresponse to therapy for HCV. In patients with chronic viral hepatitis, attention needs to be paid to cofactors in liver disease – notably the metabolic syndrome – particularly because successfully treated patients are now discharged from the care of specialists.
Paul S. Martin, MD, is chief, division of hepatology, professor of medicine, University of Miami Health System, Fla. He has been a consultant and investigator for Gilead, BMS, and Merck.
About one in five patients with chronic hepatitis B virus (HBV) infection had persistently elevated alanine aminotransferase (ALT) levels despite long-term treatment with tenofovir disoproxil fumarate, according to data from two phase III trials reported in the July issue of Clinical Gastroenterology and Hepatology (2017. doi: 10.1016/j.cgh.2017.01.032).
“Both host and viral factors, particularly hepatic steatosis and hepatitis B e antigen [HBeAg] seropositivity, are important contributors to this phenomenon,” Ira M. Jacobson, MD, of Mount Sinai Beth Israel Medical Center, New York, wrote with his associates. “Although serum ALT may indicate significant liver injury, this association is inconsistent, suggesting that relying on serum ALT alone is not sufficient to gauge either the extent of liver injury or the impact of antiviral therapy.”
Long-term treatment with newer antivirals such as tenofovir disoproxil fumarate (TDF) achieves complete viral suppression and improves liver histology in most cases of HBV infection. Transaminase levels are used to track long-term clinical response but sometimes remain elevated in the face of complete virologic response and regression of fibrosis. To explore predictors of this outcome, the researchers analyzed data from 471 chronic HBV patients receiving TDF 300 mg once daily for 5 years as part of two ongoing phase III trials (NCT00117676 and NCT00116805). At baseline, about 25% of patients were cirrhotic (Ishak fibrosis score greater than or equal to 5) and none had decompensated cirrhosis. A central laboratory analyzed ALT levels, which were up to 10 times the upper limit of normal in both HBeAg-positive and -negative patients and were at least twice the upper limit of normal in all HBeAg-positive patients.
After 5 years of TDF, ALT levels remained elevated in 87 (18%) of patients. Patients with at least 5% (grade 1) steatosis at baseline were significantly more likely to have persistent ALT elevation than were those with less or no steatosis (odds ratio, 2.2; 95% confidence interval, 1.03-4.9; P = .04). At least grade 1 steatosis at year 5 also was associated with persistent ALT elevation (OR, 3.4; 95% CI, 1.6-7.4; P =.002). Other significant correlates included HBeAg seropositivity (OR, 3.3; 95% CI, 1.7-6.6; P less than .001) and age 40 years or younger (OR, 2.1; 95% CI, 1.01-4.3; P = .046). Strikingly, half of HBeAg-positive patients with steatosis at baseline had elevated ALT at year 5, said the investigators.
Because many patients whose ALT values fall within commercial laboratory reference ranges have chronic active necroinflammation or fibrogenesis, the researchers performed a sensitivity analysis of patients who achieved a stricter definition of ALT normalization of no more than 30 U/L for men and 19 U/L for women that has been previously recommended (Ann Intern Med. 2002;137:1-10). In this analysis, 47% of patients had persistently elevated ALT despite effective virologic suppression, and the only significant predictor of persistent ALT elevation was grade 1 or more steatosis at year 5 (OR, 6.2; 95% CI, 2.3-16.4; P less than .001). Younger age and HBeAg positivity plus age were no longer significant.
Hepatic steatosis is common overall and in chronic HBV infection and often leads to increased serum transaminases, the researchers noted. Although past work has linked a PNPLA3 single nucleotide polymorphism to obesity, metabolic syndrome, and hepatic steatosis, the presence of this single nucleotide polymorphism was not significant in their study, possibly because many patients lacked genotype data, they added. “Larger longitudinal studies are warranted to further explore this factor and its potential effect on the biochemical response to antiviral treatment in [chronic HBV] patients,” they concluded.
Gilead Sciences sponsored the study. Dr. Jacobson disclosed consultancy, honoraria, and research ties to Gilead and several other pharmaceutical companies.
About one in five patients with chronic hepatitis B virus (HBV) infection had persistently elevated alanine aminotransferase (ALT) levels despite long-term treatment with tenofovir disoproxil fumarate, according to data from two phase III trials reported in the July issue of Clinical Gastroenterology and Hepatology (2017. doi: 10.1016/j.cgh.2017.01.032).
“Both host and viral factors, particularly hepatic steatosis and hepatitis B e antigen [HBeAg] seropositivity, are important contributors to this phenomenon,” Ira M. Jacobson, MD, of Mount Sinai Beth Israel Medical Center, New York, wrote with his associates. “Although serum ALT may indicate significant liver injury, this association is inconsistent, suggesting that relying on serum ALT alone is not sufficient to gauge either the extent of liver injury or the impact of antiviral therapy.”
Long-term treatment with newer antivirals such as tenofovir disoproxil fumarate (TDF) achieves complete viral suppression and improves liver histology in most cases of HBV infection. Transaminase levels are used to track long-term clinical response but sometimes remain elevated in the face of complete virologic response and regression of fibrosis. To explore predictors of this outcome, the researchers analyzed data from 471 chronic HBV patients receiving TDF 300 mg once daily for 5 years as part of two ongoing phase III trials (NCT00117676 and NCT00116805). At baseline, about 25% of patients were cirrhotic (Ishak fibrosis score greater than or equal to 5) and none had decompensated cirrhosis. A central laboratory analyzed ALT levels, which were up to 10 times the upper limit of normal in both HBeAg-positive and -negative patients and were at least twice the upper limit of normal in all HBeAg-positive patients.
After 5 years of TDF, ALT levels remained elevated in 87 (18%) of patients. Patients with at least 5% (grade 1) steatosis at baseline were significantly more likely to have persistent ALT elevation than were those with less or no steatosis (odds ratio, 2.2; 95% confidence interval, 1.03-4.9; P = .04). At least grade 1 steatosis at year 5 also was associated with persistent ALT elevation (OR, 3.4; 95% CI, 1.6-7.4; P =.002). Other significant correlates included HBeAg seropositivity (OR, 3.3; 95% CI, 1.7-6.6; P less than .001) and age 40 years or younger (OR, 2.1; 95% CI, 1.01-4.3; P = .046). Strikingly, half of HBeAg-positive patients with steatosis at baseline had elevated ALT at year 5, said the investigators.
Because many patients whose ALT values fall within commercial laboratory reference ranges have chronic active necroinflammation or fibrogenesis, the researchers performed a sensitivity analysis of patients who achieved a stricter definition of ALT normalization of no more than 30 U/L for men and 19 U/L for women that has been previously recommended (Ann Intern Med. 2002;137:1-10). In this analysis, 47% of patients had persistently elevated ALT despite effective virologic suppression, and the only significant predictor of persistent ALT elevation was grade 1 or more steatosis at year 5 (OR, 6.2; 95% CI, 2.3-16.4; P less than .001). Younger age and HBeAg positivity plus age were no longer significant.
Hepatic steatosis is common overall and in chronic HBV infection and often leads to increased serum transaminases, the researchers noted. Although past work has linked a PNPLA3 single nucleotide polymorphism to obesity, metabolic syndrome, and hepatic steatosis, the presence of this single nucleotide polymorphism was not significant in their study, possibly because many patients lacked genotype data, they added. “Larger longitudinal studies are warranted to further explore this factor and its potential effect on the biochemical response to antiviral treatment in [chronic HBV] patients,” they concluded.
Gilead Sciences sponsored the study. Dr. Jacobson disclosed consultancy, honoraria, and research ties to Gilead and several other pharmaceutical companies.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: In patients with chronic hepatitis B virus infection, steatosis was significantly associated with persistently elevated alanine aminotransferase (ALT) levels despite successful treatment with tenofovir disoproxil fumarate.
Major finding: At baseline and after 5 years of treatment, steatosis of grade 1 (5%) or more predicted persistent ALT elevation with odds ratios of 2.2 (P = .04) and 3.4 (P = .002), respectively.
Data source: Two phase III trials of tenofovir disoproxil fumarate in 471 patients with chronic hepatitis B virus infection.
Disclosures: Gilead Sciences sponsored the study. Dr. Jacobson disclosed consultancy, honoraria, and research ties to Gilead and several other pharmaceutical companies.