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Right First Time – Therapeutic Strategy for Chronic Hepatitis B
Entecavir in Clinical Practice
The effectiveness of entecavir in Italy was studied in 272 ALT levels and no cases of virological breakthrough were reported.
consecutive nucleos(t)ide analogue (NUC)-naïve patients, 84% of The pre-treatment population already had NUC-associated
whom were heaptitis B ‘e’ antigen (HBeAg)-negative. Patients mutations: 23% had either one (17%) or two (6%) mutations, always
received 0.5mg entecavir daily for 16 months. Alanine as a minor population that did not affect virological response rates.
aminotransferase (ALT) and hepatitis B virus (HBV) DNA were Two patients lost HBsAg and 64% of patients had at least a two-point
measured every three months and resistance pattern every six decrease in liver stiffness. The authors concluded that entecavir is
months. By week 48, 89% of all patients achieved undetectable HBV an effective treatment option for NUC-naïve patients in clinical
DNA (92% of HBeAg-negative patients), 85% had normalisation of practice, with a similar virological response to registration trials.
82
n
adverse events reported with tenofovir after treatment for two years, DNA levels. Buti commented that the use of potent NUCs with very low
although renal failure has been reported in HIV-co-infected patients and risk of resistance, such as entecavir or tenofovir, is particularly
therefore Janssen advised monitoring of creatinine clearance.
14,15,85
important for this high-risk group. Cirrhotic patients should be treated if
Adefovir is also associated with nephrotoxicity, and again monitoring of any level of HBV DNA can be detected, independent of the level of viral
creatinine clearance is advised.
69
There are no specific adverse events load. The criteria must be maintained for at least six months to ensure
related to entecavir monotherapy in naïve patients.
86
However, frequent stable disease. The same assays and use of the same laboratory is
monitoring and appropriate resistance testing should be performed in recommended to achieve consistency. Lampertico added that these
lamivudine-refractory patients treated with 1mg entecavir. Telbivudine guidelines are only the minimum criteria when considering initial
may be associated with myopathy and myalgia.
70
treatment. Many other variables must be considered that determine a
physician’s decision-making process, e.g. family history, concomitant
In summary, NUCs for treatment of chronic HBV have resulted in diseases, concomitant medication, pattern of HBV DNA levels, peak
improved virological response and are generally well tolerated with low values of HBV DNA, peaks of ALT, pattern of ALT and follow-up.
rates of discontinuation, although tolerability profiles of individual agents
differ. Five-year clinical trial data for entecavir and adefovir reveal a long- HBeAg-positive patients who achieve HBeAg seroconversion without
term therapeutic effect and clinical practice data for entecavir reveal a complications should maintain treatment for a consolidation period of at
therapeutic effect after 48 weeks of treatment. In addition to high least a further six months. For HBeAg-negative patients, treatment
efficacy, there is evidence that entecavir has a very low incidence of cessation can lead to relapse, even after a prolonged period of complete
resistance and a proven tolerability profile in long-term treatment of viral suppression. For both groups, sustained HBsAg loss with or without
NUC-naïve patients. seroconversion is the ideal end-point. Otherwise, the aim is to maintain
HBV DNA levels at undetectable levels. Patients with decompensated
Impact of the New EASL Guidelines cirrhosis should be treated in specialised liver units. Potent NUCs with
The practical implications of the EASL clinical practice guidelines were low resistance profiles should be administered as quickly and
discussed in an early morning workshop. Chaired by Maria Buti (Spain) effectively as possible. The antiviral regimen should consist of a
and Pietro Lampertico (Italy), the workshop aimed to put the clinical combination of two drugs (e.g.  lamivudine and adefovir), but trials are
practice guidelines into a real-world context outside of clinical trials, under way with entecavir and tenofovir as monotherapy.
where physicians combine clinical knowledge with practical decision-
making. Patients included in registration studies tend to be younger As treatment in most patients will take place over decades, Lampertico
than average, Buti pointed out; older patients or those with poor emphasised the importance of monitoring serum creatinine as the main
creatinine clearance are often excluded.* However, in clinical practice marker for renal function. However, misleading results can occur,
there are many older patients with impaired creatinine clearance who particularly in the elderly. Creatinine clearance should be used prior to
need to be considered. starting therapy to determine the optimum dose of NUCs.
A new aspect of the 2009  clinical practice guidelines  is that Responses to Nucleos(t)ide Analogue Therapy
indications for treatment are not dependent on whether patients are Lampertico outlined three types of response defined in the new clinical
HBeAg-positive or -negative. To begin treatment, at least two out of practice guidelines, including the newer ‘partial virological response’.
three criteria are required: Most registration trials use a lower limit of 300 or 400 copies/ml as a cut-
off point for response, while the clinical practice guidelines use a cut-off
• HBV DNA levels >2,000IU/ml (~10,000copies/ml); and/or point of 10–15IU/ml, which are not strictly equivalent. There are no
• ALT levels above upper limit of normal; and studies that specifically determine the number of patients who are non-
• liver biopsy/non-invasive marker shows at least moderately active responders. Nevertheless, data from the registration trials show that for
necro-inflammation and/or fibrosis (A2F2 by Metavir). both HBeAg-positive and -negative patients, lamivudine, telbivudine and
adefovir are associated with higher rates of partial response compared
This ensures that patients with cirrhosis or advanced fibrosis who may with entecavir or tenofovir (see Figure 3).
2
Partial response is important
have normal ALT levels receive appropriate treatment based on HBV because higher rates of resistance occur with older NUCs during the
*Clinical studies of entecavir included patients with impaired creatinine clearance.
EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW 35
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