Curative Options for Hepatitis B and D - European Medical Journal


Curative Options for Hepatitis B and D

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*Frank Tacke

Frank Tacke has served as a consultant and/or speaker for Boehringer-Ingelheim, Tobira, Noxxon, Gilead, BMS, AbbVie, MSD, Falk, and Janssen.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

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The hepatitis B virus (HBV) is a small, partially double-stranded DNA virus that causes acute and chronic hepatitis in humans. About 240 million people are persistently infected with HBV, making it one of the most hazardous viral pathogens for humans and a global public health concern.1 For many years, universal vaccination programmes, highly effective antiviral therapies, and guidelines for liver cancer screening in HBV-infected individuals have been implemented.2 Nonetheless, the number of HBV-related deaths due to cirrhosis or hepatocellular carcinoma (HCC) increased by 33% from 1990–2013 to >686,000 cases in 2013 worldwide.3


European and American guidelines exist that define strategies for the treatment of HBV. In general, two patient groups always require treatment: i) patients with detectable HBV DNA and concomitant liver cirrhosis, and ii) patients with active chronic hepatitis (by histological or biochemical assessment) and high viral load (>2,000 IU/mL).4,5 Antiviral treatment prevents HBV-related complications such as cirrhosis or HCC and even leads to regression of cirrhosis.5 Pegylated interferon (PEG-IFN)-α can be used in selected patients.4 The majority of patients will be treated with orally available, highly effective nucleotide/nucleoside analogues such as entecavir (ETV) or tenofovir (TDF).6


Despite the introduction of immediate active and passive immunisation after the birth of newborns from HBV-infected mothers, perinatal transmission remains a risk in high endemic areas.3 A recent randomised prospective trial tested if TDF therapy during the third trimester would reduce mother-to-child transmission. Two hundred hepatitis B e antigen (HBeAg)-positive pregnant women with HBV DNA levels >200,000 IU/mL were randomised 1:1 to either no treatment or TDF treatment (starting at 30–32 weeks of pregnancy until 4 weeks after delivery) in addition to the simultaneous active and passive immunisation of the newborns.7 It was found that TDF treatment reduced maternal HBV DNA levels with the result that 66 out of 97 TDF-treated women had viral loads <200,000 IU/mL at delivery. This was associated with a significantly reduced risk of HBV mother-to-child transmission. None of the TDF-treated mothers transmitted HBV (per-protocol analysis: 0/92), while 6 out of 88 non-TDF-treated newborns developed HBV; the frequency of birth defects did not differ between both groups.7

At the Annual Meeting of the European Association for the Study of the Liver (EASL), two large Phase III clinical trials were presented that tested the efficacy of a new tenofovir formulation termed tenofovir alafenamide (TAF). TAF is a different prodrug to TDF, resulting in approximately 90% lower plasma levels compared with TDF.8 The two Phase III trials in HBeAg-positive and negative patients revealed a similar antiviral efficacy of 25 mg TAF compared with 300 mg TDF. Interestingly, TAF resulted in a lower reduction in bone mineral density and glomerular filtration rate compared with standard TDF therapy, suggesting an improved safety profile, especially for long-term therapy. At present, the role of TAF in HBV monotherapy is not yet clear.


HBV persists in hepatocytes in the form of a ‘mini-chromosome’ (covalently closed circular DNA) preventing the full elimination of HBV from the body. However, a functional cure is achieved if patients lose hepatitis B surface antigen (HBsAg) (and ideally also develop anti-hepatitis B surface antibodies), as the risk of cirrhosis or HCC is very low in those patients.9 Unfortunately, only a small fraction of patients with ETV or TDF therapy will lose HBsAg, while this rate is higher in patients after IFN-based therapies.6 Different strategies have been proposed to induce HBsAg loss, including sequential or simultaneous treatment with PEG-IFN and nucleoside/nucleotide analogues (‘add-on’ or ‘switch’). In a recent trial with 740 treatment-naïve patients, simultaneous combination therapy (PEG-IFN+TDF) for 48 weeks was most effective in inducing HBsAg loss but the rate of patients achieving this endpoint was only 9.1% 24 weeks after the end of treatment.10 An alternative strategy represents the discontinuation of nucleoside/nucleotide analogue therapy after several years of full viral suppression. In fact, the termination of ETV/TDF therapy induces a viral flare that is often followed by the sufficient control of viral replication through the patient’s immune system. In a recent meta-analysis, the success rate of this strategy was estimated at 38.2%.11 Importantly, the discontinuation of therapy is contraindicated in patients with liver cirrhosis.4

At present, several new therapeutic approaches to cure HBV are being tested. These include HBV entry inhibitors, small interfering RNA against viral transcripts, inhibitors of the HBV capsid formation, and drugs targeting the covalently closed circular DNA.12 Potentially, these antiviral approaches can be combined by new drugs that strengthen immune responses (e.g. toll-like receptor agonists or therapeutic vaccines).13


The co or superinfection of HBV-infected patients with the hepatitis delta virus (HDV) is the most aggressive form of viral hepatitis, often leading to cirrhosis and HCC.14 The only effective therapy to date is PEG-IFN-, but only 30% of patients stably suppress HDV replication, and late relapses occur.15 New potentially curative approaches include the inhibition of HDV entry into hepatocytes (by an inhibitor termed Myrcludex B) or the interference with cellular post-translational modification pathways required for viral particle formation (by the prenylation inhibitor lonafarnib).12

Tacke F, Kroy DC. Treatment for hepatitis B in patients with drug resistance. Ann Transl Med. 2016;4(18):334. Locarnini S et al. Strategies to control hepatitis B: Public policy, epidemiology, vaccine and drugs. J Hepatol. 2015;62(1 Suppl):S76-86. Stanaway JD et al. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013. Lancet. 2016;388(10049):1081-8. European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167-85. Erratum in: J Hepatol. 2013;58(1):201. Terrault NA et al.; American Association for the Study of Liver Diseases. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63:261-83. Aghemo A et al. Assessing long-term treatment efficacy in chronic hepatitis B and C: between evidence and common sense. J Hepatol. 2012;57(6):1326-35. Pan CQ et al.; China Study Group for the Mother-to-Child Transmission of Hepatitis B. Tenofovir to Prevent Hepatitis B Transmission in Mothers with High Viral Load. N Engl J Med. 2016;374(24):2324-34. De Clercq E. Tenofovir alafenamide (TAF) as the successor of tenofovir disoproxil fumarate (TDF). Biochem Pharmacol. 2016;119:1-7. Kim GA et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut. 2014;63(8):1325-32. Marcellin P et al.; Study 149 Investigators Combination of Tenofovir Disoproxil Fumarate and Peginterferon α-2a Increases Loss of Hepatitis B Surface Antigen in Patients With Chronic Hepatitis B. Gastroenterology. 2016;150:134-144 e10. Papatheodoridis G et al. Discontinuation of oral antivirals in chronic hepatitis B: A systematic review. Hepatology. 2016;63(5):1481-92. Durantel D, Zoulim F. New antiviral targets for innovative treatment concepts for hepatitis B virus and hepatitis delta virus. J Hepatol. 2016;64(1 Suppl):S117-31. Fung J et al. Emerging drugs for the treatment of hepatitis B. Expert Opin Emerg Drugs. 2016;21(2):183-93. Hughes SA et al. Hepatitis delta virus. Lancet. 2011;378(9785):73-85. Dastgerdi ES et al. Molecular and clinical aspects of hepatitis D virus infections. World J Virol. 2012;1(3):71-8.