Old Antivirals Rival New for Cancer Prevention in Hepatitis B

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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