Nucleoside analogues’ benefits in HBV vary

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New studies reveal nuances in chronic hepatitis B treatment

Current guidelines recommend the high-genetic barrier entecavir (nucleoside) or tenofovir (nucleotide) as first-line options for the treatment of chronic hepatitis B (CHB). However, data on their effect on major long-term outcomes and mostly on hepatocellular carcinoma (HCC) have been limited. Moreover, lamivudine, a nucleoside with a low-genetic barrier to resistance, may be still used as first-line therapy in some countries because of its lower direct cost. These two interesting studies using carefully matched large patient cohorts provide important information for these issues.

The first study from Taiwan showed that therapy with nucleoside analogues (lamivudine, entecavir, and telbivudine) decreases the HCC risk in CHB patients, compared with untreated controls (7-year cumulative HCC incidence: 7.3% vs. 22.7%). The second study from Korea showed that entecavir is superior to lamivudine in reducing mortality and liver transplant by approximately 50%, but offers no additional benefit for HCC prevention. The benefit from entecavir was obvious in patients with baseline cirrhosis and not in noncirrhotics who are at low short- or medium-term risk for major outcomes anyway. Since these and other similar studies in CHB come from Asian cohorts, additional long-term outcome data in white patients will be useful.

These results further support previous reports that antiviral therapy reduces but do not eliminate the HCC risk in CHB patients, in whom HCC surveillance should continue if they are at increased baseline HCC risk regardless of viral suppression under treatment. In addition, such findings reinforce the current recommendations for use of high-genetic barrier agents as first-line treatment in CHB.

Dr. George Papatheodoridis is associate professor in medicine and gastroenterology, Athens University, director of the academic department of gastroenterology, Laiko General Hospital of Athens. He is an adviser/lecturer for Bristol-Meyers Squibb, Gilead, Merck, Novartis, Roche; and he has received research grants from Bristol-Meyers Squibb, Gilead, and Roche.



Nucleoside analogues are effective at preventing hepatocellular carcinoma in hepatitis B, but all are not equal when it comes to overall mortality and liver transplant, according to two new studies in the July issue of Gastroenterology.

In the first study, Dr. Chun-Ying Wu of the National Yang-Ming University, in Taipei, Taiwan, and his colleagues examined the long-term protective effects of nucleoside analogue therapy among chronic hepatitis B patients (

They conducted a retrospective nationwide cohort study using data from Taiwan’s National Health Insurance Research Database, collecting records from 1997 through 2010 on patients with chronic hepatitis B.

In total, Dr. Wu looked at 21,595 patients who had been treated for at least 90 days with nucleoside analogues and the same number of propensity-matched patients who had not; patients with hepatitis C, HIV, or cancer developed before the index date were excluded from the analysis.

Among the treated patients, 19,063 received only one nucleoside analogue, including lamivudine (n = 12,938), entecavir (5,748), and telbivudine (377). The remaining 2,532 patients received more than one.

Over a mean follow-up period of 3.46 years and 5.24 years for the treated and untreated cohorts, respectively, the authors found that patients treated with nucleoside analogues had a significantly lower incidence of hepatocellular carcinoma (HCC) (n = 992, or 4.6%), compared with their untreated counterparts (n = 4,454, or 20.6%).

Patients treated with nucleoside analogues also demonstrated a much-lower 7-year cumulative incidence of HCC, compared with untreated patients (7.32% vs. 22.70%; P less than .001).

That translated to an average annual incidence of HCC of 1.05% and 3.24% for treated and untreated patients, respectively.

Dr. Wu and his colleagues disclosed no personal conflicts of interest; they wrote that their work received support from Taiwan’s National Health Research Institutes, the Taipei Veterans General Hospital and Department of Health, and the National Yang-Ming University.

The second study, led by Dr. Young-Suk Lim of the Asan Medical Center, in Seoul, sought to determine which nucleoside analogue offered better protection against not only HCC, but also liver transplant and mortality: entecavir, or the "less potent" lamivudine.

In that report, the researchers conducted a retrospective analysis of 5,374 consecutive adult patients with chronic hepatitis B, treated with entecavir (n = 2,000) or lamivudine (n = 3,374) at a single center in Seoul between 1999 and 2011 (

The researchers found that, when looking at propensity-matched pairs, after 3 years of follow-up the risk of death or transplantation diverged significantly: Compared with the lamivudine cohort, entecavir patients had a hazard ratio for these outcomes of 0.49 (95% confidence interval, 0.37-0.64; P less than .001).

On the other hand, looking at the risk for HCC development, there was no significant difference between groups (HR, 1.01; 95% CI, 0.80-1.27; P = .95).

When an adjusted analysis of matched pairs with cirrhosis at study baseline was undertaken, the results were similar: entecavir was associated with a significantly lower risk of death or transplantation, compared with lamivudine (HR, 0.42; 95% CI, 0.31-0.57; P less than .001), but not HCC (HR, 1.00; 95% CI, 0.78-1.28; P = .999).

An analysis of patients without baseline cirrhosis, however, showed no difference between any of the outcomes: transplant, death, or HCC.

"These results advocate current practice guidelines that recommend the use of two potent antiviral agents (that is, entecavir and tenofovir) as first-line drugs for the treatment of chronic hepatitis B," wrote the authors.

"Further longer-term studies on patients of other races or ethnicity, and studies using other potent antiviral agents such as tenofovir, are warranted."

Dr. Lim disclosed financial relationships with Bayer Healthcare, Bristol-Myers Squibb (maker of entecavir), Gilead Science and Novartis; the investigators stated that their study received funding from the Asan Medical Center and the Korean Association for the Study of Liver.

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