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DDW 2013: Tenofovir and Entecavir Effectively Suppress Hepatitis B Virus

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The newer antivirals tenofovir (Viread) and entecavir (Baraclude) inhibit hepatitis B virus (HBV) replication more effectively than older agents, but good adherence is needed to maintain long-term viral suppression, according to a set of studies presented at the Digestive Disease Week meeting (DDW 2013) last month in Orlando.

A range of nucleoside/nucleotide analogs are active against HBV, but the virus can develop drug resistance that compromises long-term efficacy. Tenofovir disoproxil fumarate and entecavir have a higher barrier to resistance than the older lamivudine (Epivir-HBV) and adefovir (Hepsera).

Clinical Practice

Mindie Nguyen from Stanford University and colleagues evaluated the effectiveness of tenofovir and entecavir in routine clinical use, comparing this to efficacy seen in pivotal trials that supported the drugs' approval. Participants in clinical trials often do better because they are highly motivated, may be selected for favorable response characteristic, and are closely monitored and supported around adherence and side effect management.

This analysis included 845 treatment-naive patients undergoing treatment at 3 U.S. liver clinics between January 2001 and January 2011. Two-thirds were men, almost all were Asian, the mean age was 47, and 63% were hepatitis B "e" antigen (HBeAg) negative. A total of 93 received lamivudine, 198 took adefovir, 447 took entecavir, and 107 received tenofovir.

After 12 months of treatment, rates of complete viral suppression were significantly higher for people taking entecavir (75%) or tenofovir (81%) compared with lamivudine (39%) or adefovir (54%); response to entecavir and tenofovir was statistically similar. Patients in the entecavir and lamivudine groups had similar median ALT and mean HBV DNA levels. Virologic breakthrough was less common with entecavir (2.5%) than with tenofovir (8.6%), and in all cases was attributed to poor adherence.

"Treatment outcomes were clearly favorable with newer agents ([entecavir] and [tenofovir]) compared to old agents ([lamivudine] and [adefovir])," the researchers concluded.

"Antiviral therapy with either [entecavir] or [tenofovir] is highly effective in suppressing HBV viral replication, and non-adherence is the primary cause of treatment failure," they added. "Further patient education and close clinical monitoring by care providers are needed to improve patient adherence to anti-HBV therapy, which is long-term or even life-long in the majority of cases."

Long-term Entecavir

Watcharasak Chotiyaputta from Mahidol University in Bangkokevaluatedthe safety, effectiveness, and antiviral resistance among nucleoside/nucleotide-naive patients receiving entecavir monotherapy in clinical practice in Thailand.

This chart review included records from 535 chronic hepatitis B patients treated with entecavir for at least 1 year. About 60% were men, the mean age was 52 years, 65% were HBeAg negative, and 37% had liver cirrhosis.

Over an average 40 months of follow-up, more than 90% of both HBeAg positive and negative patients reached undetectable HBV viral load by year 5. No cases of viral breakthrough occurred and no drug resistance mutations were detected. HBeAg seroconversion and hepatitis B surface antigen (HBsAg) loss were uncommon, however, at 11% and 2%, respectively. There were no serious adverse events and serum creatinine levels (a potential indicator of kidney toxicity) remained unchanged.

Among 337 patients without cirrhosis at baseline, 20 (6%) developed cirrhosis according to imaging tests during follow-up, but none experienced clinical decompensation. Among 198 patients with cirrhosis at study entry, 5 (3%) developed clinical decompensation. Further, 12 patients (2%) developed hepatocellular carcinoma over 5 years.

"[Entecavir] was safe and effectively suppressed hepatitis B virus without virological breakthrough throughout 5 years of treatment," the investigators concluded.

Entecavir vs Tenofovir

Linyi Gao, also with the Stanford group, and colleagues compared the efficacy of entecavir and tenofovir in chronic hepatitis B patients with high HBV viral load at baseline, a group at risk for liver disease progression.

This retrospective case-control study included 62 consecutive treatment-naive participants at 3 U.S. medical centers with baseline HBV DNA >1,000,000 IU/mL who started treatment with tenofovir. They were matched with 199 control subjects treated with entecavir. About 60% were men, the average age was about 42 years, about one-third were HBeAg negative, and 8% had cirrhosis.

Among HBeAg negative participants, there was no significant difference in rates of viral suppression between tenofovir and entecavir recipients. Among HBeAg positive patients, however, those taking tenofovir achieved viral suppression significantly faster than those taking entecavir. Viral suppression rates in the tenofovir arm were 16% at 6 months, 50% at 12 months, and 71% at 18 months, compared with 11%, 31%, and 39%, respectively, in the entecavir arm.

"[Tenofovir] is significantly more effective than [entecavir] for achieving complete viral suppression in HBeAg positive, treatment-naive hepatitis B patients with HBV DNA >1,000,000 IU/mL," the researchers concluded. "Moreover, the difference between [tenofovir] and [entecavir] becomes more and more pronounced with increasing treatment time."

Tenofovir Kidney Function

While tenofovir is highly effective against HBV,it has the potential to cause kidney toxicity in susceptible individuals; to date this has mostly been studied in people with HIV (tenofovir is effective against both viruses).

Nghi Ha form the University of California at San Francisco and colleagues looked at changes in renal function among treatment-naive chronic hepatitis B patients who at baseline had either normal kidney function, defined as estimated glomerular filtration rate (eGFR) > 80 mL/minute, or mildly impaired function, defined as 50-80 mL/minute. 

This case-control study included 72 participants who received 300 mg once-daily tenofovir disoproxil fumarate and 72 patients matched for age, sex, and baseline eGFR who instead used 1 mg once-daily entecavir. Two-thirds were men, the mean age was 45 years, and 86% had unimpaired kidney function.

The researchers saw no significant difference in kidney function changes between patients exposed to tenofovir and those taking entecavir. The likelihood of worsening function was similar in both groups, and rates of reclassification to a category of worse function were 12.9 and 12.5 cases per 100 person-years, respectively. In a multivariate analysis that included demographic characteristics, baseline eGFR, diabetes, and hypertension, tenofovir use was not significantly associated with renal dysfunction. Older age and impaired function at baseline were significant predictors for worsening function over time. 

"Renal function of HBV patients on antiviral therapy with either [tenofovir] or [entecavir] should be monitored, especially in those who are older and/or with known impaired renal function," they recommended.

6/6/13

References

L Gao, HN Trinh, J Li, et al. Tenofovir Is More Effective Than Entecavir for Achieving Rapid Viral Suppression in HBeAg-Positive Chronic Hepatitis B Patients With High HBV DNA Levels. Digestive Disease Week (DDW 2013). Orlando, May 18-21, 2013. Abstract Sa1009.

W Chotiyaputta, P Charatcharoenwitthaya, SP Chainuvati, et al. Entecavir Is Safe and Highly Effective for Long-Term Treatment of Chronic Hepatitis B Patients: a Single Center Experience. Digestive Disease Week (DDW 2013). Orlando, May 18-21, 2013. Abstract Sa1011.

MH Nguyen, HN Trinh, KT Chaung, et al. Effectiveness of Oral Antiviral Therapy for Treatment-Naive Chronic Hepatitis B (CHB) in Routine Clinical Practice. Digestive Disease Week (DDW 2013). Orlando, May 18-21, 2013. Abstract Sa1006.

NB Ha, KC Ku, NB Ha, et al. Renal Function in Chronic Hepatitis B (CHB) Patients Treated With Tenofovir Dipivoxil Fumarate (TDF) Monotherapy -- a Matched Case Cohort Study. Digestive Disease Week (DDW 2013). Orlando, May 18-21, 2013. Abstract Sa1010.