Once a decision is made that a patient with HBV infection needs therapy, two major groups of antiviral therapies are currently utilised.
These are interferon therapy (interferon alpha or ‘pegylated’ interferon alpha) or an oral nucleoside or nucleotide agent such as tenofovir, entecavir, lamivudine, adefovir or telbivudine.
The patterns of response observed with nucleotides are broadly similar although these agents have different structures, inhibit different phases of hepatitis B replication and have variable mechanisms of action. Their pharmacokinetics, inhibitory capacity, onset of action, resistance patterns and rates of HBeAg seroconversion vary during the first year of treatment.
There are also a number of therapeutic vaccines in the early stages of clinical development designed to produce a specific cellular immune response against HBV.
Interferon alpha
Interferon alpha is a naturally occurring protein which supports the host’s immune system. The main advantages of interferon alpha (or ‘alfa’) over nucleoside analogues are the theoretical absence of resistance and the possibility of a finite treatment course (48 weeks). Also, pretreatment factors predictive of response to interferon alpha therapy have been partially defined. Treatment requires self-injection three times a week over an extended period – usually six months.
Pegylated forms of interferon alpha (peginterferon alfa-2a) with improved pharmacokinetic profiles (pegylation increases the persistence of the interferon in the blood) and more convenient once-weekly administration are now licenced and may be preferable to interferon alpha. Treatment is given for a year. Peginterferon alfa-2a (PEG IFN alfa-2a) is recommended as a possible first treatment for adults with chronic hepatitis B, as long as it is suitable for the person and the stage of hepatitis B.
Studies in HBeAg-positive and anti-HBe positive patients indicate that the addition of lamivudine to PEG IFN alfa-2a does not improve seroconversion rates when compared to PEG IFN alfa-2a alone. The use of peginterferon alfa-2a and interferon alpha is limited by a response rate of 30–40%. Although rules for stopping treatment have not been absolutely defined, treatment should be discontinued if little change in HBV DNA concentrations has occured after four to six months.
In anti-HBe positive patients, relapse rates remain high after stopping 48 weeks of peginterferon treatment.
Interferon is contraindicated in decompensated cirrhosis. This drug, which has to be injected, causes more side effects than nucleoside analogues and requires a high level of monitoring. Treatment stopping points at present have been only tentatively defined.
Nucleoside analogues
Overall, nucleoside analogues are the most frequently used primary therapeutic agents for all stages of HBV infection, including wild-type and precore/core mutation variants. The goal of therapy is achieved with the currently approved agents in this category. Current guidelines suggest the use of potent agents with high barriers to resistance as first line therapy.
Tenofovir – Tenofovir is a potent agent and has a high barrier to resistance. It can be used alone as a first line de novo treatment for chronic hepatitis B in accordance with NICE recommendations (treatment of chronic HBeAgpositive or HBeAg-negative hepatitis B where antiviral treatment is indicated).
Some experts consider that lamivudine and tenofovir or possibly tenofovir with emtricitabine (Truvada) should be prescribed to patients with cirrhosis and/or high rates of HBV replication. However this policy will require substantiation.
The combination of tenofovir and emtricitabine is licenced for HIV. If patients infected with both HIV and chronic hepatitis B require only treatment for chronic hepatitis B, they should receive antivirals that are not active against HIV, such as peginterferon alfa-2a or adefovir, but this situation is becoming rare. Management of these patients should be co-ordinated between HIV and hepatology specialists. The drug is cleared by the kidneys. Renal tubular disease may occur and requires appropriate monitoring. Osteopaenia has been reported in HIV positive patients.
Entecavir – NICE has recommended entecavir as an option for the treatment of people with chronic HBeAg-positive or HBeAg-negative hepatitis B in whom antiviral treatment is indicated.
Studies suggest that entecavir, which inhibits all three activities of the HBV polymerase/reverse-transcriptase, is a potent inhibitor of hepatitis B virus replication. However, although the mean change from baseline was almost 7 log in HBeAg-positive patients, HBeAg seroconversion occurred in just 21% of entecavir-treated patients after one year of treatment. Genotypic resistance has been reported in 1.2% of naïve patients after five years. Dose adjustments are required in cases of renal impairment.
Entecavir is effective in patients not previously treated with nucleoside analogues. Entecavir should not generallly be used to treat patients with lamivudine resistance, as high rates of both lamivudine and entecavir resistance results. Post marketing surveillance for the risk of malignancy (reported in preclinical studies) is in place.
Lamivudine – Lamivudine is effective in those who have failed interferon alpha therapy (HBeAg-negative patients, for example) and in improving decompensated disease.
Although a relatively inexpensive drug with few side effects, even in patients with advanced disease, the major disadvantage of lamivudine is the high rate of resistance seen in both HBeAg-positive and anti-HBe positive patients. The virus becomes resistant in about 20% of cases after one year of lamivudine treatment and 70% after five years. Resistance has typically been managed by sequential treatment with adefovir or entecavir but the advantage of the strategy compared to more recent combination therapy is questionable. Elimination of the drug occurs mainly by renal clearance and dosages need to be adapted to creatinine clearance. The other clinical concerns during lamivudine therapy are withdrawal or initiating hepatitis flares.
Adefovir – The efficacy of adefovir has been assessed in patients with HBeAg-positive and negative disease and other settings. In HBeAg-positive patients seroconversion rates at one year are low but can increment with time. Recent data have shown that adefovir is a less potent agent than tenofovir and has a relatively low barrier to resistance. Patients with a slower decrement in HBV DNA have been observed to have relatively high rates of resistance.
Adefovir pharmacokinetics are substantially altered in patients with marked and severe renal impairment.
Combination therapy of adefovir with lamivudine may be used first line or second line in the case of lamivudine resistance. Adefovir is likely to be replaced by the more potent tenofovir.
Telbivudine – Telbivudine is licenced for treatment of chronic hepatitis B infection but not recommended by NICE as it was not found to be cost effective.
Clevudine – Phase 3 studies of clevudine were stopped in April 2009 because of reports of myopathy and neuropathy.
Please refer to NICE.org.uk for the latest guidance releases.