Treatment

The aim of treatment for hepatitis B is to reduce liver inflammation, lower hepatitis B viral load and, ideally, to eradicate the virus and produce antibodies. There are currently five approved treatments for chronic hepatitis B in the European Union, which are effective in about one third of recipients: pegylated interferon alfa 2a (Pegasys), conventional interferon alfa (IntronA / Roferon-A / Viraferon), 3TC (lamivudine, Zeffix), adefovir (Hepsera) and entecavir (Baraclude).

Conventional interferon alfa is usually given as an injection of 5,000,000 units daily or 10,000,000 units three times per week for four months. It leads to viral clearance in 20 to 40% of recipients, but seems to have little efficacy among Asian people infected during infancy. Other factors that have been associated with a poor response to interferon alfa are male sex, long duration of hepatitis B infection, HIV co-infection, high levels of hepatitis B virus DNA, HBeAg-negative hepatitis B virus, and other viral and host factors. Key side-effects include influenza-like symptoms, aches and pains, depression, bone marrow suppression (causing low white blood cell counts, or neutropenia), and auto-immune responses.

Pegylated interferon alfa, a longer-acting version that is injected less often, was granted European approval for the treatment of chronic hepatitis B in February 2005. The recommended dose is 180µg once weekly for 48 weeks. Studies indicate that pegylated interferon more effectively clears HBV than either conventional interferon alfa or 3TC, or a combination of peginterferon alfa and 3TC.1 2 3 4 In addition, studies have shown that patients can maintain anti-hepatitis B virus responses for over two years after the end of a course of peginterferon alfa.5 6

3TC inhibits replication of both hepatitis B virus and HIV and is an approved treatment for both infections. It is usually referred to as lamivudine in the context of hepatitis B treatment, but is marketed as Zeffix rather than Epivir. The dose of 3TC for the treatment of hepatitis B virus infection is 100mg taken orally once daily. As a treatment for hepatitis B, 3TC induces viral clearance in about 20 to 30% of people after one year of treatment. The optimal duration of treatment for hepatitis B virus has not been established. Studies have generally treated people for one to two years, but lifelong therapy may be required. Studies show 3TC can reduce the risk of liver failure and liver cancer.7

People with HIV / hepatitis B virus co-infection who are taking or considering 3TC or the similar drug FTC (emtricitabine, Emtriva) should be aware of the potential for hepatitis flares when they cease taking either drug. One clinical trial found that around 20% of co-infected people who stopped 3TC experienced a rebound in hepatitis B viral load, and 2 to 4% had increased ALT and bilirubin levels, a sign of impaired liver function.

The hepatitis B virus does develop resistance to 3TC, but there is evidence that 3TC-resistant HBV remains sensitive to adefovir and tenofovir (Viread), and to newer antiviral drugs such as lobucavir, entecavir (Baraclude), clevudine, and telbivudine.8 9 10 Prolonged use of 3TC leads to resistance in 50% or more of individuals with HBV. See 3TC for further details of research on 3TC and hepatitis B.

Adefovir received European approval as a treatment for hepatitis B in March 2003, following United States endorsement in late 2002. Although it was not approved as an anti-HIV drug due to kidney side-effects at a much higher dose, 10mg adefovir daily is well tolerated and effective against HBV.11 12 13 14 15 A key benefit of adefovir is that it is active against HBV that is resistant to 3TC.16 However, treating HIV co-infected people with adefovir may not be the best strategy because 10mg of adefovir daily is not active against HIV. Some experts have suggested that tenofovir may be a more attractive option for HIV co-infected people whose HIV has already developed resistance to 3TC, as tenofovir has activity against both HIV and HBV. FTC is also active against both viruses, but may not work against 3TC-resistant HBV. Tenofovir and FTC are not yet approved treatments for hepatitis B.

Entecavir (Baraclude), a polymerase inhibitor, has been shown effective in phase III clinical trials in patients with hepatitis B virus, but not HIV and in HIV / hepatitis B co-infected individuals with 3TC-resistant hepatitis B virus.17 10 18 In March 2005, the FDA approved entecavir for the treatment of chronic hepatitis B in both hepatitis B virus monoinfected patients and in HIV co-infected individuals who have previously been treated with 3TC. In July 2006 entecavir was approved in Europe for treatment of hepatitis B infection. Entecavir should not be used as as a treatment for hepatitis B in people with HIV who are not taking antiretroviral therapy, since the drug has been shown to have an anti-HIV effect and may give rise to 3TC-associated resistance mutations.19

Telbivudine (Tyzeka, Sebivo) is approved in the US and Europe for hepatitis B treatment. A one-year study showed that it produced a superior viral load reduction when compared with adefovir in lamivudine-experienced patients, and substantial viral load response in patients with suboptimal responses to adefovir.20

As in the case of anti-HIV therapy, combining two or more drugs to treat hepatitis B is generally regarded as more effective than the use of a single drug (monotherapy), especially in terms of delaying the development of drug resistance.21 However, several studies of the combination of pegylated or conventional interferon alfa plus 3TC failed to show the benefit of either combination over 3TC monotherapy.2 3 One study suggested that combining 3TC and HBV vaccination improves response in patients with chronic hepatitis B.22 Combination therapy studies are currently ongoing with the approved treatments and a wide range of investigational agents. 

United Kingdom guidelines recommend that anti-HIV drugs which have an effect against HBV (3TC, FTC and tenofovir) should only be given as part of a combination anti-HIV treatment regimen or in a clinical trial, and should never be used as HBV monotherapy, because they can cause the emergence of drug-resistant HIV. If a co-infected person is not taking combination anti-HIV therapy, adefovir or pegylated or conventional interferon alfa should be used instead to treat hepatitis B.

Experts recommend that HIV/HBV co-infected individuals with elevated ALT and AST should be considered for hepatitis B treatment. For patients requiring antiretroviral therapy, the suggested first-line regimen is tenofovir plus 3TC or FTC, plus another anti-HIV drug.23 At the First European Consensus Conference on the Treatment of Chronic Hepatitis B and C in HIV Co-infected Patients, held in March 2005, a panel of specialists recommended that individuals whose immune systems have been significantly depressed should receive anti-HIV therapy to increase CD4 cell counts before beginning treatment for HBV, and that the choice of which anti-HIV and anti-HBV regimens to use should be individually tailored.24 Current United States guidelines also recommend using a combination of two NRTIs with anti-HBV activity in HIV co-infected patients to treat HIV to avoid putting patients at risk of the development of resistance in HBV. However, where treatment of HIV, but not HBV is needed, the guidelines recommend using peginterferon alfa or low-dose adefovir, as these do not cause resistance in HIV. Use of 3TC, FTC, or tenofovir without other anti-HIV drugs is not recommended, as this may cause the development of resistance in HIV.

References

  1. Chan HL et al. Long-term follow-up of peginterferon and lamivudine combination treatment in HBeAg-positive chronic hepatitis B. Hepatology 41: 1357-1364, 2005
  2. Berg T New perspectives in the treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B. Hepatology 41: 1402-1406, 2005
  3. Janssen H et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 365: 123-129, 2005
  4. Lau GKK et al. Peginterferon alfa-2a, lamivudine, and the combination for HbeAg-positive chronic hepatitis B. N Engl J Med 352: 2682-2695, 2005
  5. Lau GK et al. Durability of response and occurrence of later response to peginterferon alfa 2a (40KD) [PEGASYS] one year post-treatment in patients with HBeAG-positive chronic hepatitis B. Forty-First Annual Meeting of the European Assoc for the Study of the Liver, Vienna, 2006
  6. Marcellin P et al. The majority of patients with HVeAg-negative chronic hepatitis B treated with peginterferon alfa-2a (40KD) [PEGASYS] sustain response 2 years post-treatment. Forty-first Annual Meeting of the European Association for the Study of the Liver, Vienna, 2006
  7. Liaw YF et al. Lamivudine for patients with chronic hepatits B and advanced liver disease. N Engl J Med 351: 1521-1531, 2004
  8. Delaney W et al. In vitro cross-resistance testing of adefovir, lamivudine, telbivudine (L-DT), entecavir and other anti-HBV compounds against four major mutational patterns of lamivudine-resistant HBV. 55th American Association for the Study of Liver Diseases Meeting, Boston, abstract 181, 2004
  9. Kioko Ono-Nital S et al. Susceptibility of lamivudine-resistant hepatitis B virus to other reverse transcriptase inhibitors. Clin Infect Dis 103: 1635-1640, 1999
  10. Pessoa W et al. Entecavir in HIV / HBV-co-infected patients: safety and efficacy in a phase II study (ETV-038). Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 123, 2005
  11. Benhamou Y et al. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study. Lancet 358: 718-723, 2001
  12. Benhamou Y et al. Adefovir dipivoxil 10 mg suppresses HBV viral replication in HIV/HBV co-infected patients with lamivudine resistant HBV. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 123, 2002
  13. Benhamou Y et al. Long-term treatment with adefovir dipivoxil 10 mg in patients with lamivudine-resistant HBV and HIV co-infection results in significant and sustained clinical improvement. 15th International AIDS Conference, Bangkok, abstract WeOrA1329, 2004
  14. Marcellin P et al. GS-98-437 A double-blind, randomized, placebo-controlled study of adefovir dipivoxil for the treatment of patients with HBeAg+ chronic hepatitis B infection: 48-week results. Hepatology 34: A340, 2001
  15. Marcellin P et al. Increasing serologic, virologic and biochemical response over time to adefovir dipivoxil (ADV) 10 mg in HBeAg+ chronic hepatitis (CHB) patients. Digestive Disease Week, Chicago, abstract M931, 2005
  16. Westland CE et al. Activity of adefovir dipivoxil against all patterns of lamivudine-resistant hepatitis B viruses in patients. J Viral Hepat 12: 67-73, 2005
  17. Chang TT et al. Entecavir is superior to lamivudine for the treatment of HbeAg+ chronic hepatitis B: results of Phase III study ETC-022 in nucleoside naïve patients. 55th American Association for the Study of Liver Diseases Meeting, Boston, abstract 70, 2004
  18. Sherman M et al. Entecavir is superior to continued lamivudine for the treatment of lamivudine-refractory, HBeAg(+) chronic hepatitis B: results of the phase III study ETV-026. 55h American Association for the Study of Liver Diseases Meeting, Boston, abstract 1152, 2004
  19. McMahon M et al. The anti-hepatitis B drug entecavir inhibits HIV-1 replication and selects HIV-1 variants resistant to antiretroviral drugs. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 136LB, 2007
  20. Marcellin P 76 week follow up of HBeAg positive chronic hepatitis B patients treated with telbivudine, adefovir or switched from adefovir to telbivudine. 42nd Annual Meeting of the European Association for the Study of the Liver, Barcelona, 2007
  21. Lau G et al. Randomized, double-blind study comparing adefovir dipivoxil (ADV) plus emtricitabine (FTC) combination therapy versus ADV alone in HBeAg(+) chronic hepatitis B: efficacy and mechanisms of treatment response. 55th American Association for the Study of Liver Diseases Meeting, Boston, abstract 245/1155, 2004
  22. Horiike N et al. In vivo immunization by vaccine therapy following virus suppression by lamivudine: a novel approach for treating patients with chronic hepatitis B. J Clin Virol 32: 156-161, 2005
  23. Soriano V et al. Care of patients with chronic hepatitis B and HIV co-infection: recommendations from an HIV-HBV International Panel. AIDS 19: 221-240, 2005
  24. Alberti A et al. Short statement of the first European consensus conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. J Hepatol 42: 615-624, 2005
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