HBV Antivirals, Viral Breakthrough, and Drug Resistance

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HBV Antivirals, Viral Breakthrough, and Drug Resistance

Details Category: Approved HBV Drugs Published on Tuesday, 12 July 2011 00:00

Written by Learned . .

HBV © Kightley

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

38% of the patients who experienced at least 1 virological breakthrough did not

have antiviral resistance mutations.

39 of 148 patients (26%) had at least 1 virological breakthrough;

24 patients (16%) had at least 1 confirmed virological breakthrough;

Of these 24 patients, 16 had evidence of genotypic resistance;

81 patients (55%) were nucleoside/nucleotide naive.

Among these patients, entecavir and lamivudine monotherapy were the most common

regimens.

Of the 67 (45%) nucleoside/nucleotide experienced patients, 19 received

combination therapy followed in order by monotherapy with adefovir, tenofovir,

entecavir, and lamivudine.

After 1 year on treatment, 71% of the patients had undetectable HBV DNA.

As treatment continued, 87% achieved undetectable HBV DNA.

Of 36 patients who had repeat HBV DNA tests after virological breakthrough, the

mean interval between breakthrough and confirmed breakthrough was 2.4 months.

Baseline characteristics were similar for patients who experienced virological

breakthrough and those who did not.

At 3 and 5 years the cumulative outcome probabilities were: Virological

breakthrough: 21.5% and 46.1%, respectively;

Confirmed virological breakthrough: 13.7% and 29.7%, respectively;

Genotypic resistance: 10.7% and 33.9%, respectively.

Using the traditional definition of virological breakthrough -- an increase in

HBV DNA of >1 log from nadir or re-detection at any level after undetectable HBV

DNA:

45 of 148 patents (30%) would be considered to have experienced at least 1

viral breakthrough;

26 of 45 (58%) 45 would have had confirmed virological breakthrough.

Failure to achieve undetectable HBV DNA at the nadir response (lowest level

during therapy) was the only factor significantly associated with virological

breakthrough in this study population.

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.

[Guest guest]

http://www.hivandhepatitis.com/hbv-treatment/approved-hbv-drugs/3067-hbv-antivir\

als-viral-breakthrough-and-drug-resistance

HBV Antivirals, Viral Breakthrough, and Drug Resistance

Details Category: Approved HBV Drugs Published on Tuesday, 12 July 2011 00:00

Written by Learned . .

HBV © Kightley

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

38% of the patients who experienced at least 1 virological breakthrough did not

have antiviral resistance mutations.

39 of 148 patients (26%) had at least 1 virological breakthrough;

24 patients (16%) had at least 1 confirmed virological breakthrough;

Of these 24 patients, 16 had evidence of genotypic resistance;

81 patients (55%) were nucleoside/nucleotide naive.

Among these patients, entecavir and lamivudine monotherapy were the most common

regimens.

Of the 67 (45%) nucleoside/nucleotide experienced patients, 19 received

combination therapy followed in order by monotherapy with adefovir, tenofovir,

entecavir, and lamivudine.

After 1 year on treatment, 71% of the patients had undetectable HBV DNA.

As treatment continued, 87% achieved undetectable HBV DNA.

Of 36 patients who had repeat HBV DNA tests after virological breakthrough, the

mean interval between breakthrough and confirmed breakthrough was 2.4 months.

Baseline characteristics were similar for patients who experienced virological

breakthrough and those who did not.

At 3 and 5 years the cumulative outcome probabilities were: Virological

breakthrough: 21.5% and 46.1%, respectively;

Confirmed virological breakthrough: 13.7% and 29.7%, respectively;

Genotypic resistance: 10.7% and 33.9%, respectively.

Using the traditional definition of virological breakthrough -- an increase in

HBV DNA of >1 log from nadir or re-detection at any level after undetectable HBV

DNA:

45 of 148 patents (30%) would be considered to have experienced at least 1

viral breakthrough;

26 of 45 (58%) 45 would have had confirmed virological breakthrough.

Failure to achieve undetectable HBV DNA at the nadir response (lowest level

during therapy) was the only factor significantly associated with virological

breakthrough in this study population.

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.