Tenofovir Beats Entecavir for Preventing Liver Cancer?

Alexander M. Castellino, PhD

October 02, 2018

The two antiviral drugs tenofovir disoproxil fumarate (multiple brands) and entecavir (Baraclude, Bristol-Myers Squibb) are both used for the first-line treatment of hepatitis B virus (HBV) infection, and over time, the rates of viral DNA suppression and liver enzyme normalization are similar for the two drugs. However, their efficacy in reducing the risk for hepatocellular carcinoma (HCC) has not received much attention.

Now, a nationwide cohort study from Korea suggests that tenofovir may be more effective than entecavir in decreasing the risk for HCC, as well as reducing the risk of needing a liver transplant and of dying (all-cause mortality). The divergence in rates of HCC was evident 2 years after initiation of treatment.

The study was published online September 28 in JAMA Oncology.

The findings "may have considerable clinical implications" in the prevention of liver cancer in patients with chronic HBV infection, say the study authors, Young-Suk Lim, MD, PhD, of the University College of Medicine, and Min Jung Ko, PhD, of the National Evidence-Based Healthcare Collaborating Agency, both in Seoul, Republic of Korea.

"Based on our data, 185 HCC cases were estimated to have been preventable at 4 years' follow-up if the 11,464 patients in the entecavir group had used tenofovir," they note.

Not yet. Currently, there are not enough data to make such a swap, suggest Jennifer A, Flemming MD, MAS, of Queen's University, Kingston, Ontario, Canada, and Norah A. Terrault, MD, MPH, of the University of California, San Francisco, in an accompanying editorial.

This study should not lead to a widespread paradigm shift in selecting tenofovir over entecavir. Dr NAME

"[This study] is the first to our knowledge to suggest that tenofovir offers advantage over entecavir in terms of HCC prevention," they note, but caution that, "given the inherent limitations of observational data, this study should not lead to a widespread paradigm shift in selecting tenofovir over entecavir."

Insteed, they suggest, this study "should spur more investigators to address the issue of whether any of these HBV drugs is not like the other."

The Korean Study

For their study, Lim and colleagues extracted data from Korea's National Health Insurance Service (NHIS) for the period January 2010 to December 2016 — a period when costs for both of the antiviral drugs were reimbursed. A historic cohort of 24,156 patients with chronic HBV infection was included in this analysis (12,692 patients were receiving tenofovir, and 11,464 were receiving entecavir).

The two groups were well matched: in the tenofovir group, the mean age of patients was 48.6 years, and 27.5% had cirrhosis; in the entecavir group, the mean age of patients was 49.3 years, and 26.1% had cirrhosis.

To compare outcomes with the two drugs, the researchers used propensity score-matching to generate 10,923 pairs. The characteristics were well balanced and showed less than 10% standardized difference for all baseline variables.

The annual incidence of HCC was significantly lower in patients treated with tenofovir (0.64 vs 1.06 per 100 person-years for entecavir). In a multivariate analysis, a reduced risk for HCC favored tenofovir (hazard ratio [HR], 0.61 compared with entecavir; P < .001). The propensity score-matched analysis also provided similar results (HR, 0.62; P < .001).

The annual rate of all-cause mortality or liver transplant was also significantly lower in patients treated with tenofovir (0.36 vs 0.50 per 100 person-years for entecavir). A multivariate analysis favored tenofovir for a reduced risk for all-cause mortality or liver transplant (HR, 0.77 compared with entecavir; P < .001).

Validation Hospital Cohort

The results obtained using the NHIS database were then validated using an independent cohort of patients. For their validation cohort, the researchers used a hospital cohort that consisted of 2701 consecutive treatment-naive adult patients with chronic HBV infection who initiated treatment with either of the two drugs between January 2010 and December 2016 at the Asan Medical Center, a 2700-bed academic tertiary care center in Seoul, Republic of Korea.

The two groups were also well matched in this cohort of patients: in the tenofovir group, the mean age of patients was 48.1 years, and 57.2% had cirrhosis; in the entecavir group, the mean age of patients was 49.2 years, and 59.9% had cirrhosis.

In this cohort, the researchers generated 869 propensity score-matched pairs for an independent analysis.

This cohort provided individual-level laboratory data such as virologic response (VR) and liver function test results. A significantly lower proportion of patients experienced a VR with entecavir: 78.7% vs 85.2% for tenofovir (P < .001). Treatment modification was also significantly higher for patients who received entecavir (11.7% vs 0.2%; P < .001). Virologic response after 1 year of treatment was not predictive of development of HCC (HR, 1.13; P = NS) but was associated with reduced risk for death or transplant (HR, 0.55; P = .02 in favor of tenofovir).

During the 8267 patient-years of follow-up, 154 patients developed HCC, and 91 (3.4%) died or received a liver transplant. Here again, in a multivariate analysis, tenofovir was independently associated with a significantly lower risk for HCC compared with entecavir (HR, 0.66; P = .03). The researchers analyzed data using other models, and in each model, risk for HCC was significantly reduced with tenofovir.

What's Next for Deciding Treatment for Chronic HBV?

The South Korean researchers note that current guidelines across the world do "not state any preference" between tonofovir or entecavir for the treatment of chronic HBV infection.

However, in view of the fact that these drugs are taken long term, "the importance of comparative data on the effectiveness and safety of entecavir and tenofovir is immense," they write.

"Based on our data, 185 HCC cases were estimated to have been preventable at 4 years' follow-up if the 11,464 patients in the entecavir group had used tenofovir," they note.

The editorialists note several limitations to the study, including the fact that the researchers did not capture adherence to antiviral therapy and surveillance programs and that previous studies have shown that an adherence rate of <90% has been associated with a higher risk for HCC.

Another fly in the ointment regards prior exposure to lamivudine (multiple brands) in countries where its use may be prevalent. Patients with prior exposure to lamivudine who undergo treatment with entecavir may be at increased risk for virologic breakthrough over time, and this, in turn, would affect risk for HCC, the editorialists comment.

Hence, adherence to antiviral treatment and resistance to entecavir are likely to be unmeasured confounders in the study. Ideally, a randomized trial would overcome these challenges, they write, but they add that it is unlikely that such a trial will be conducted.

To evaluate this important question of whether to use one drug instead of the other, "we would advocate for additional observational cohorts with data on liver disease severity, virologic response, and adherence to surveillance," they write.

Until more studies become available, physicians should consider treatment history, comorbidities, and cost and accessibility in deciding the best option for a given patient with chronic HBV infection, the editorialists conclude.

One of the study authors (Dr Kim) is an advisory board member and receives investigator-initiated research funding from Bayer AG, Bristol-Myers Squibb, and Gilead Sciences, Inc. The editorialists have disclosed no relevant financial relationships.

JAMA Oncol. Published online September 27, 2018. Full text, Editorial


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