Hepatitis B

Treatment of chronic hepatitis B

Therapy with antiviral drugs

In the past few years, numerous substances have been tested which can inhibit virus reproduction directly. The treatment of chronic hepatitis B does not usually lead to the complete elimination of the virus from the body. In some people, a highly replicative progressive form (high virus count) can be transformed permanently into a low replicative form (low virus count). A majority of patients, however, need long-term in some cases, permanent treatment, in order to prevent progression of the illness. Therefore, it is particularly important for the doctor and the patient discuss treatment carefully after the diagnosis is made and to agree upon the treatment necessity and the therapeutic goals. Usually, treatment is always necessary with severe hepatitis and high liver values, with distinct connective tissue reactions in the liver, and with a high HBV-DNA concentration (virus load) in the blood.

With the drugs lamivudine, telbivudine, entecavir, adefovir and/or tenofovir, virus replication and the activity of the chronic hepatitis B can be inhibited. These substances are classed as nucleoside and/or nucleotide analogues.

When is treatment with nucleoside/nucleotide analogues carried out?

In principle, all patients with chronic hepatitis B can be treated with one of the following antiviral agents (brand names are in italics):

  • lamivudine (Zeffix)
  • telbivudine (Sebivo)
  • entecavir (Baraclude)
  • adefovir (Hepsera)
  • tenofovir (Viread)

Hepatitis B patients who are unlikely to respond to interferon therapy will frequently respond to these antiviral agents. In addition, people for whom a therapy with interferon alfa was not successful, and people who cannot be treated with interferon alfa because of another underlying illness (e.g. immune deficiency, following transplantation, HIV infection, amongst other things) can be treated with nucleoside/nucleotide analogues. Lamivudine, telbivudine, entecavir, adefovir and tenofovir are taken in tablet form. The recommended dose for each drug is:

  • lamivudine: 100mg per day (note that this dose differs from the dose used in drug combinations to treat HIV infection)
  • adefovir: 10mg per day
  • entecavir: 0.5 or 1.0mg per day, depending on previous treatment history
  • telbivudine: 600mg per day
  • tenofovir:  245mg per day.

Side-effects of nucleoside/nucleotide analogues

Compared to interferon therapy, side-effects with lamivudine, telbivudine, entecavir, adefovir or tenofovir therapy occur very rarely.

Headache, fever, skin rash, general malaise, gastrointestinal complaints, sleeplessness, cough and, in some cases, inflammation of the pancreas have been described.

When treatment is carried out with adefovir and tenofovir, kidney function should be monitored regularly. Compared to other antivirals, the development of resistance to lamivudine can occur more frequently and sooner. The rate of the development of resistance with lamivudine is 30%, with telbivudine 15%, with entecavir, adefovir and tenofovir less than 2% after two years when used as a single drug (monotherapy). After five years of treatment, the rates of resistance are about 70% (lamivudine), 28% (adefovir) and less than 1% (entecavir).

The rate of development of resistance to entecavir, however, is higher in people who have already developed resistance to lamivudine, so that the use of entecavir is not generally recommended with existing lamivudine resistance. Fortunately, lamivudine and telbivudine-resistant hepatitis B viruses respond to adefovir or tenofovir and, vice versa, adefovir-resistant viruses to lamivudine, telbivudine and entecavir.

Tenofovir-resistant viruses have not been clinically observed so far.

When resistance arises, two suitable (not 'cross-resistant') medications should be taken together (combination therapy). If patients have an insufficient virological response to one antiviral drug, many doctors add a suitable second antiviral drug early on, so that the development of resistance is avoided right from the start.

Treatment with (pegylated) interferon-alfa

Interferon alfa is a human protein which is produced, amongst other things, by the white blood cells. This happens in particular when the body has to defend itself against infective pathogens. Interferon alfa used to treat chronic hepatitis is produced biotechnologically. Interferon alfa has to be injected under the skin in a similar way to insulin used in the treatment of diabetic patients. Newer interferons have a longer duration of action and only have to be injected once a week (these are the so-called pegylated interferons).

What does treatment involve?

Previously, 5 to 6 million international units (IU) of standard interferon alfa were given three times weekly for six months to treat chronic hepatitis B. In more recent studies, long-acting pegylated interferons were used in a dosage of 180µg (micrograms)/week (peginterferon alfa-2a) or 50 to 100µg/week (peginterferon alfa-2b). In the European Union, peginterferon alfa-2a is approved for the treatment of chronic hepatitis B. Treatment with peginterferon is carried out over 48 weeks. Around 30 to 35% of patients with chronic hepatitis B respond to peginterferon therapy. These numbers apply to people who were HB ‘e’-antigen positive before starting treatment. With other patients for example, those who are infected with a variant of the hepatitis B virus (the so-called HBeAg-minus mutant) the permanent response rate on peginterferon therapy is about 20%.1

One aim of therapy is to slow down the rate of virus replication, i.e. to convert a high-replicative chronic hepatitis B into a low- replicative chronic hepatitis B. In the ideal case (rarely), the HB surface antigen can no longer be detected after therapy with peginterferon, which in effect equals a complete cure.

Side-effects of pegylated interferon-alfa

Side-effects are common at the start of interferon-alfa treatment and usually become much less severe as treatment progresses. The most common side-effects are flu-like symptoms such as fever, headaches, pains in the joints and muscles, fatigue, lack of appetite and weight loss. Thyroid dysfunction occasionally occurs. Some people temporarily lose their hair during treatment. Mood changes to the point of depression may also occur. Other major side-effects are changes in the composition of the blood, especially with regard to the white blood cell count. Pegylated interferons have the same spectrum of side-effects as standard interferons.

Combination treatments

The results of the first studies on treatment regimens combining pegylated interferons and nucleoside/nucleotide analogues (e.g. lamivudine) were disappointing, as these regimens did not improve the sustained virological response rate.

Combining two antivirals (e.g. lamivudine plus adefovir) is not more effective than using one on its own. However, it may be useful in preventing resistance from developing in at-risk patients (e.g. before and after a liver transplant). In people who have developed resistance to one or more agent, combination treatment is essential.

Treatment of hepatitis B and HIV co-infection

Treatment recommendations for people living with hepatitis B and HIV differ from those for people with hepatitis B alone. Some drugs have an effect against both HIV and hepatitis B. On one hand, this can be helpful because treatment may control both viruses. If drugs are not chosen carefully, however, treatment for one virus may cause the other virus to become resistant.

According to recent HIV and hepatitis B guidelines,1, 2 most people with this co-infection should receive early treatment that is effective against both viruses.

The European AIDS Clinical Society recommends that all people co-infected with HIV and hepatitis B and with CD4 cell counts below 500 should receive antiretroviral treatment, which should contain two drugs active against hepatitis B.

In people who have received no previous treatment for HIV or hepatitis B, the recommended drugs are tenofovir and either lamivudine or emtricitabine. In people who have received prior treatment with lamivudine, and who may therefore have hepatitis B virus that is resistant to the drug, HIV therapy should contain tenofovir, and another nucleoside analogue should be used instead of lamivudine.  

In people with CD4 counts above 500, antiretroviral treatment containing tenofovir and either lamivudine or emtricitabine is recommended for anyone who is in need of treatment for hepatitis B. These drugs should never be used as HBV monotherapy, because they can cause the emergence of drug-resistant HIV. If a co-infected person with a CD4 count above 500 does not wish to take combination HIV therapy, adefovir, telbivudine or pegylated interferon alfa should be used instead to treat hepatitis B.

This information is adapted from Hepatitis B: Risks, prevention and treatment by Prof. Stefan Zeuzem, published by the European Liver Patients Association, 2007.

References

  1. EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. Journal of Hepatology vol. 57 j167-185, 2012
  2. Rockstroh JK et al. European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults. HIV Med 9:82-88, 2008