HBV Antivirals, Viral Breakthrough, and Drug Resistance

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Virological breakthrough is common among people taking nucleoside/nucleotide analogs for HBV, but nearly 40% are unrelated to drug resistance.

As described in the June 2011 issue of Hepatology by Chanunta Hongthanakornand colleagues from the University of Michigan Health System, medication adherence is likely to be lower in real-world clinical practice than in clinical trials. Differentiating between virological breakthroughs caused by drug resistance and those due to poor adherence can help clinicians provide better care and treatment for people with hepatitis.

Most people with chronic hepatitis B virus (HBV) infection require long-term treatment in order to receive clinical benefit. Currently 5 nucleoside/nucleotide analogs are approved for treatment of hepatitis B virus -- adefovir (Hepsera), entecavir (Baraclude), lamivudine (Epivir-HBV), telbivudine (Tyzeka), and tenofovir (Viread).

Long-term use of each of these medications is associated with an increasing risk of drug resistance, at which point they become less effective or ineffective. In clinical settings, virological breakthrough is the first sign of drug resistance. In Phase 3 trials, 0%-88% of participants who experienced virological breakthrough had confirmed genotypic resistance. The data from these trials indicate that not all viral breakthrough is necessarily due to drug resistance.

The researchers in this study set out to determine the incidence of virological breakthrough caused by drug resistance in clinical practice. They reviewed medical charts of 148 patients with chronic hepatitis B seen at the liver clinic of the University of Michigan between January 2000 and July 2010. All of the patients had taken antiviral treatment for at least 1 year and had serum HBV DNA < 10,000 IU/mL after 1 year of treatment.

About 75% of patients were men and the mean age was 45 years. Asians made up just under half of the study population, 41% were Caucasian, and the remaining 10% were of other races/ethnicities. Exclusions from the analysis included people taking nucleoside/nucleotide drugs in combination with interferon therapy, those being treated to prevent HBV recurrence after liver transplantation, patients with HIV, hepatitis C virus or hepatitis D virus coinfection, and those with other potentially confounding factors.

The researchers reviewed and recorded patient demographics, HBV treatment history, and response over the course of treatment. HBV DNA and liver enzyme panels were recorded every 3 months and HBV markers -- hepatitis B "e" antigen (HBeAg) and "e" antibodies (anti-HBe) -- were recorded every 6-12 months. The mean follow-up period was 38 months.

Virological breakthrough was defined as having HBV DNA increase by >1 log from nadir (lowest-ever) level or a re-detection of HBV DNA at levels at least 10-fold higher than the lower limit of detection of the assay after having an undetectable result. Serum samples from patients who experienced viral breakthrough were tested for drug resistance mutations.

Results

Perhaps the most useful finding of this study was that 38% of patients who experienced at least 1 virological breakthrough did not have any known antiviral resistance mutations. The researchers suggested that many virological breakthroughs -- perhaps almost half -- are not the result of drug resistance but, rather, of patient non-adherence.

“[T]his study revealed that virological breakthrough was common in clinical practice,” the researchers wrote. “However, virological breakthrough was not always related to antiviral drug resistance.”

They suggested that people with hepatitis B who are taking antiviral medication should receive counseling about the importance of medication adherence. “The confirmation of virological breakthrough and/or determination of genotypic resistance is prudent before the initiation of rescue therapy to avoid unnecessary changes in antiviral medications.”

They acknowledged that the small number of patients and the lack of data on medication adherence limit the study.

Hongthanakorn and colleagues concluded, “The results of this study highlight the importance of HBV DNA monitoring and counseling on medication adherence throughout the course of [nucleoside/nucleotide] treatment and the fine balance between prompt initiation of rescue therapy versus avoidance of unnecessary changes to the treatment regimen.”

Investigator affiliations: Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan.

7/8/11

Reference

C Hongthanakorn, W Chotiyaputta, K Oberhelman, et al. Virological Breakthrough and Resistance in Patients with Chronic Hepatitis B Receiving Nucleos(t)ide Analogues in Clinical Practice. Hepatology 53(6):1854-1863 (abstract). June 2011.