Response to peginterferon alfa-2a (40KD) in HBeAg-negative CHB: On-treatment kinetics of HBsAg serum levels vary by HBV genotype
Maurizia R. Brunettoemail address
,
Patrick Marcellin
,
Beatrice Cherubini
,
Cihan Yurdaydin
,
Patrizia Farci
,
Stephanos J. Hadziyannis
,
Vivien Rothe
,
Loredana Regep
,
Ferruccio Bonino
Received 15 April 2013; received in revised form 4 July 2013; accepted 6 July 2013. published online 22 July 2013.
Accepted Manuscript
Abstract
Background & aims
We investigated whether HBV genotype influences on-treatment HBsAg kinetics and/or the end-of-treatment HBsAg levels associated with long-term virological response in HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a ± lamivudine in the Phase III trial.
Methods
All patients (n = 230) who participated in long-term follow-up were included according to the availability of HBsAg levels measurements. Long-term virological response was defined as HBV DNA ⩽10,000 cp/mL (1786 IU/mL) at 5 years post-treatment. Genotype-specific end-of-treatment HBsAg levels associated with long-term virological response (identified by ROC analysis) were assessed in 199 patients with HBsAg measurements available at baseline and end-of-treatment. HBsAg kinetics according to genotype and long-term virological response were investigated in the 117 patients with additional samples available at weeks 12, 24 and 72.
Results
Baseline HBsAg levels were significantly higher for A than B, C and D genotypes (p<0.05). On-treatment HBsAg kinetics varied according to HBV genotype. The difference between responders and non-responders was greatest for genotype A from weeks 12 to 24; for genotypes B and D from baseline to week 12; there was no significant difference over any timeframe for genotype C. High positive predictive values for long-term virological response could be obtained by applying end-of-treatment genotype-specific cut-offs: 75%, 47%, 71% and 75% for genotypes A (<400 IU/mL), B (<50 IU/mL), C (<75 IU/mL) and D (<1000 IU/mL), respectively.
Conclusions
On-treatment HBsAg kinetics vary between HBV genotypes. Genotype-specific monitoring timeframes and end-of-treatment thresholds could ameliorate response-guided treatment of HBeAg-negative chronic hepatitis B. 作者: StephenW 时间: 2013-8-14 21:05
基线HBsAg水平显着高于A比B,C和D基因型(P <0.05)。治疗乙肝表面抗原动力学变化,根据HBV基因型。反应者和无应答者之间的差异是最大的基因型A从12到24周;基因型B和D,从基线到12周,C基因型的高阳性预测值长期也没有显着的差异,在任何时间段内病毒学应答可以得到应用治疗结束基因型特异性切割取舍:75%,47%,71%和75%,基因型A(<400 IU /毫升),B(<50 IU /毫升), C(<75 IU /毫升)和D(<1000 IU / mL)的分别。
结论
Reuters Health Information
Knowledge of HBV Genotype "Mandatory"
By Megan Brooks
NEW YORK (Reuters Health) Aug 02 - The hepatitis B virus (HBV) genotype is linked with response to interferon therapy, new data show.
"The key message for clinicians is that ... it is mandatory to know the HBV genotype" in patients undergoing pegIFN treatment," Dr. Maurizia Brunetto of Azienda Ospedaliero Universitaria Pisana in Pisa, Italy, told Reuters Health by email.
Dr. Brunetto's group found that genotype significantly influences hepatitis B surface antigen (HBsAg) levels before and during peginterferon treatment, and it also influences end-of-treatment HBsAg levels that are associated with long term virological response.
"Overall our findings suggest that a cost-effective response-guided therapy may be possible by using combined on-treatment and end-of-treatment genotype-specific HBsAg thresholds," Dr. Brunetto said.
The investigators performed a retrospective analysis of serum HBsAg levels in a group of HBeAg-negative chronic hepatitis B patients who entered a long-term observational study after treatment with pegIFN with or without lamivudine in a phase III trial.
They assessed genotype-specific end-of-treatment HBsAg levels associated with long-term virological response five years after treatment in 199 patients with HBsAg measurements available at baseline and end-of-treatment.
They also assessed HBsAg kinetics according to genotype and long-term virological response in 117 patients with additional samples available at weeks 12, 24 and 72.
HBV genotype was a significant factor in HBsAg serum level both before and during pegIFN treatment, the researchers said online July 22 in the Journal of Hepatology.
Although the number of patients with genotype A was low, these patients had baseline HBsAg serum levels significantly higher than patients infected with other genotypes, with the major difference observed when comparing genotype A with genotype C (14,816 vs 3155 IU/mL, p=0.006).
In terms of on-treatment profiles, HBsAg kinetics were genotype-specific and "quite intriguing," the investigators say.
"The mean HBsAg decline from baseline to end of treatment in responders was the highest for genotype A- and lowest for genotype C-infected patients, in whom it was not possible to differentiate responders from non-responders based on HBsAg levels only, because of the minimal reduction observed in responders," Dr. Brunetto and colleagues report.
They also found that the time frame during which HBsAg decline was most likely to be informative differed considerably by genotype. "The greatest difference in HBsAg decline between responders and non-responders was observed between weeks 12 and 24 for genotype A-infected patients and between baseline and week 12 for genotypes B and D.
They say a decline in HBsAg levels from the start of treatment occurred in all patients with HBV genotype A or B, with a more pronounced decline in responders. In contrast, a reduction of HBsAg levels from the start of treatment occurred only in genotype D-infected patients who were responders; HBsAg levels remained steady or increased slightly in non-responders, the investigators say.
The researchers identified genotype-specific cutoffs that substantially improved the positive predictive value of HBsAg quantification at end of treatment for long-term virological response. Positive predictive values, and cutoffs, are: 75% (<400 IU/mL) for genotype A, 47% (<50 IU/mL) for genotype B, 71% (<75 IU/mL) for genotype C and 75% (<1000 IU/mL) for genotype D.
"Of course our data need to be confirmed in larger studies," Dr. Brunetto said, "but the findings indicate the way for a further personalization of antiviral treatment according to on-treatment genotype-specific HBsAg kinetics and shed the light on the controversies raised previously by the simple quantification of HBsAg without stratification by HBV genotype."
Dr. Brunetto added that patient management "can be improved" not only by an early change in treatment in non-responders, "but also by motivating long-term responders to complete the 48 weeks of therapy and optimizing treatment in the remaining patients with new/innovative approaches such as treatment extension, combination or sequential therapies."
The study was funded by Roche, which makes the Amplicor HBV test used in the study. Several of the authors have disclosed relationships with Roche, as well as Abbott, Bristol Myers Squibb and others, all listed with the original paper. 作者: StephenW 时间: 2013-8-14 21:11