Volume 10, Issue 4, Supplement, Pages S7-S9 (April 2010)

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New developments in the treatment of chronic hepatitis B

published online 14 January 2010.

Article Outline

• Introduction

• HBeAg-positive chronic hepatitis B

• Principles and end-points of treatment in HBeAg-positive CHB

• Efficacy of short-term treatment courses

• With standard and pegylated α-interferons

• With nucleos(t)ide analogues

• Long-term treatment of HBeAg-positive CHB

• HBeAg-negative chronic hepatitis B

• Principles and end-points of treatment in HBeAg-negative CHB

• Finite treatment courses with α-interferon and NUCs

• Long-term/indefinite treatment of HBeAg-negative patients

• Long-term combination therapies with two NUCs

• References

• Copyright

Introduction

Effective treatment of chronic hepatitis B (CHB) is a rapidly evolving subject in medicine. It opened in the early 1990s when recombinant α-interferons, 2a (IFN-α2a) and α2b (IFN-α2b), became available. The treatment was revolutionised in the late 1990s with the introduction and approval of the first oral nucleoside analogue, lamivudine. During the last 5years, it has further expanded with the addition of newer compounds. The current defence against HBV includes two IFN-α preparations and four oral nucleos(t)ide analogues (NUCs), while many more drugs are expected to be licensed in the near future [6], [7], [8], [11], [13], [17], [18].

Although anti-HBV therapy has greatly advanced in recent years, it has hitherto failed to achieve the goal of HBV eradication. However, it has been quite successful towards the goal of potent and durable suppression of HBV replication, resulting in halt/delay of the progression of HBV-induced chronic liver damage to cirrhosis, its life-threatening complications and, hopefully, of the development of hepatocellular carcinoma as well [13], [14], [15], [16], [17].

It is well recognised that the treatment of CHB involves multiple and complex issues and that the various subsets of CHB patients who need to be treated differ greatly in virological, immunological and biochemical profiles as well as in severity and stages of the underlying liver disease. In this context, the topic of recent developments in the treatment of CHB will be critically reviewed separately for HBeAg-positive and HBeAg-negative patients while progress achieved in the treatment of patients with overt cirrhosis and in CHB patients harbouring drug-resistant HBV mutants will be only touched briefly within the discussion of combination therapies with NUCs.

HBeAg-positive chronic hepatitis B

Principles and end-points of treatment in HBeAg-positive CHB

Therapy in HBeAg-positive CHB aims at loss of HBeAg followed by its seroconversion to anti-HBe. If this goal is achieved (and consolidated) under a short-term therapy, usually of up to 12months duration, then the treatment is discontinued. Usually more than 80% of such patients who achieve HBeAg loss remain in sustained virological and biochemical remission after stopping therapy; and a number of them may also lose HBsAg and develop anti-HBs [11], [12], [13], [17].

In the case of short-term treatment with oral NUCs, if HBeAg loss is not achieved, then antiviral therapy can be extended in time, provided that HBV DNA remains greatly reduced, preferably to levels undetectable by sensitive PCR assays, and no HBV resistance develops. If the end-point of HBeAg seroconversion is achieved by treatment extension, then again, following a consolidation period, therapy should be discontinued. This strategy of long-term NUC therapy has become plausible particularly in HBeAg-negative patients and has been greatly advanced with newer oral antivirals exhibiting high antiviral potency and high genetic barrier to HBV resistance [2], [6], [8], [9].

Efficacy of short-term treatment courses

With standard and pegylated α-interferons

In the early days of standard IFN-α2a and -α2b the duration of therapy in HBeAg-positive patients was limited to 3–6months with 10MU tiw or 5MU daily. With the pegylated compounds of IFN-α2a and -α2b, the duration of therapy has been extended to 1year. There are no controlled studies on the efficacy of finite pegylated-IFN-α courses of 18 or 24months duration in CHB.

Twelve months of Peg-IFN-α2a treatment with 180μg per week compared to finite courses of nucleoside analogues of the same duration have been found to achieve the goal of sustained response after stopping treatment in 32% of patients, a rate significantly higher than the rates reported with NUCs, including the latest ones. Moreover, in a number of patients, IFN-induced sustained virological responses (SVRs) are followed by HBsAg loss [6], [12], [16].

With nucleos(t)ide analogues

Treatment courses of 1year duration with all approved nucleos(t)ide analogues achieve the goal of HBeAg loss and seroconversion to anti-HBe, at lower rates compared to interferon-α courses of the same duration. With the extension of NUC treatment to 2years, the sustained response rates usually approach those achieved with interferon courses of 1year duration [3], [12], [17], [21].

Long-term treatment of HBeAg-positive CHB

Data with extension of NUC monotherapy in HBeAg-positive patients to four and more years are available with lamivudine, adefovir and entecavir and to 2years with LdT [2], [3], [4], [5], [7], [9], [14], [15], [22], [23], [24], [27]. They clearly show increasing SVR rates but also progressively increasing rates of development of HBV resistance, except perhaps in the case of entecavir treatment of lamivudine-naïve patients. Moreover, SVR rates have been found to be even higher and resistance rates to become greatly reduced when HBV DNA levels become undetectable by sensitive PCR assays at week 24 in LdT and lamivudine, and at week 48 in adefovir treatment. Currently, highly potent anti-HBV compounds with the high genetic barrier to HBV resistance, such as tenofovir and entecavir [7], [10], [22], represent the best candidates when considering long-term NUC monotherapy in HBeAg-positive CHB patients.

HBeAg-negative chronic hepatitis B

Principles and end-points of treatment in HBeAg-negative CHB

HBeAg loss and seroconversion to anti-HBe is not an end-point applicable in HBeAg-negative CHB. Therapy in this type of chronic hepatitis B aims at suppression of HBV replication to non-detectability of HBV DNA by sensitive PCR assays, which can be maintained under therapy without development of HBV resistance. It is combined with return of alanine transaminase (ALT) to normal and culminates in improvement of liver histology. It is possible that after discontinuation of effective therapy of sufficient duration, a number of patients may remain in sustained virological and biochemical remission.

Finite treatment courses with α-interferon and NUCs

Because of very high relapse rates in HBeAg-negative CHB after stopping effective treatment with conventional interferons of 6–9month duration, treatment courses of IFN have been extended in time. Currently, the experience with α-interferon α therapy is limited to courses of up to 1.5years.

Treatment with conventional and pegylated IFN-α compounds given to HBeAg-negative CHB patients in courses of 1–1.5year duration, represents the best short-term treatment approach that can achieve the goal of SVR in a sizeable number of patients close to 30%. SVR rates have been found to last for years after stopping therapy and to be followed by HBsAg loss of 3% at 6months post-treatment to 8% after 3years ([19]; and reviewed in Refs. [6], [7]).

This goal of SVR is achieved rarely in HBeAg-negative CHB patients treated with short-term NUC courses of 1year duration but has recently been reported to be feasible with longer courses of therapy depending on the potency and the genetic barrier to HBV resistance of the applied compounds [7], [20].

Long-term/indefinite treatment of HBeAg-negative patients

Long-term/indefinite nucleos(t)ide analogue monotherapy has been widely tried in recent years in treating HBeAg-negative patients. Its aim is to maintain on-therapy effective HBV suppression with biochemical remission and without HBV resistance [7], [25], [26], [27].

With newer nucleos(t)ide analogues of high anti-HBV potency and/or high genetic barrier to HBV resistance [1], [20], [25], [26], long-term NUC monotherapy has been found to be able to maintain its efficacy for lengthy periods of time with delayed and infrequent development of HBV resistance [7], [11]. The concept of effective long-term nucleos(t)ide analogue monotherapy without HBV resistance has found additional support from several old and new observations, indicating that an early decrease of HBV DNA levels to non-detectability by sensitive PCR assays has a high positive predictive value for long-term maintenance of the response to ucleos(t)ide analogue mononotherapy; this is true both for HBeAg-positive and HBeAg-negative patients with CHB [3], [5], [13], [27]. Thus, the concept that, in the long run, nucleos(t)ide analogue monotherapy is always expected to fail and end in HBV resistance has started to be questioned for its universality. Moreover, a good percentage of HBeAg-negative patients under effective long-term adefovir therapy for 4–5years has been reported to achieve SVR after stopping of such treatment (Hadziyannis S et al., unpublished data).

Long-term combination therapies with two NUCs

This treatment approach is currently justifiable and should be recommended both to HBeAg-positive and HBeAg-negative patients in advanced stages of chronic liver disease and for those CHB patients who have experienced virological breakthroughs under NUC monotherapy [8], [17], [18]. The preferable treatment approach is to combine two potent NUCs lacking cross-resistant profiles, with high genetic barriers to HBV resistance.

In conclusion: The primary goal of treatment in CHB is potent and durable suppression of HBV replication. It results in biochemical and histological remission of CHB and is the prerequisite for prevention of cirrhosis, its life-threatening complications and hepatocellular carcinoma. Virological responses should be either sustained after stopping the treatment (referred as SVR), or maintained by continuous long-term drug therapy (referred as treatment-maintained responses or MVR). SVR in HBeAg-negative CΗΒ are practically restricted to conventional α-interferons and pegylated interferons and are limited only to patients with compensated liver disease. Long-lasting MVRs without HBV resistance in CHB can be achieved by all approved nucleos(t)ide analogues in highly variable rates, depending on their potency, rapidity of virological response and genetic barrier to HBV resistance. Maintenance of response under 5years of adefovir treatment represents the best treatment paradigm thus far on HBeAg-negative CHB, while entecavir and tenofovir monotherapies may prove even superior in future. In patients with lamivudine-resistant HBV mutants, the preferable treatment strategy is adding adefovir while continuing lamivudine, and the same combination treatment approach is the safest one in treatment-naïve patients with decompensated cirrhosis.

References

[1]. [1]Chang TT, Gish R, De Man R, et al. A comparison of entecavir and mivudine for HBeAg-positive chronic hepatitis B. New Engl J Med. 2006;354:1001–1010. CrossRef

[2]. [2]Colonno RJ, Rose RE, Pokornowski K, et al. Four year assessment of ETV resistance in nucleoside-naive and lamivudine refractory patients. In: Program and abstracts of the 42nd annual meeting of the European association for the study of the liver. Barcelona, Spain: April 11–15, 2007 [Abstract 781].

[3]. [3]DiBisgelie AM, Lai CL, Gane E, Chen Y-C, Thongsawar S, Wang Y, et al. Telbivudine GLOBE trial: Maximal early HBV suppression is predictive of optimal 2-year efficacy. Hepatology. 2006;44(4 Suppl. 1):230A.

[4]. [4]Gane E, Lai CL, Min A, et al. Adefovir salvage therapy for virologic breakthrough in telbivudine-treated patients from the GLOBE study. In: Program and abstracts of the 42nd annual meeting of the European association for the study of the liver. Barcelona, Spain: April 11–15, 2007 [Abstract 493].

[5]. [5]Hadziyannis AS, Mitsoula P, Hadziyannis E. Monitoring serum HBV DNA levels with the TaqMan technique during treatment of HBeAg(−) chronic hepatitis B with lamivudine. Hepatology. 2005;42(4 Suppl 1):726A.

[6]. [6]Hadziyannis SJ. New developments in the treatment of chronic hepatitis B. Expert Opin Biol Ther. 2006;6(9):913–921. CrossRef

[7]. [7]Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5years. Gastroenterology. 2006;131(6):1743–1751. Abstract | Full Text | Full-Text PDF (289 KB) | CrossRef

[8]. [8]Hadziyannis SJ. Treatment paradigms on hepatitis B e antigen-negative chronic hepatitis B patients. Expert Opin Investig Drugs. 2007;16(6):777–786. CrossRef

[9]. [9]Han SH, Lai CL, Gane E, Liaw YF, Thongsawat S, Wang Y et al.Telbivudine GLOBE trial year two: efficacy, safety and predictors of outcome in patients with chronic hepatitis B. Presented at DDW Washington DC, USA: May 19–24, 2007.

[10]. [10]Heathcote E, Gane E, DeMan R, et al. A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg positive chronic hepatitis B (CHB): study GS-US-174-0103. In: Program and abstracts of the 58th annual meeting of the American association for the study of liver diseases. Boston, Massachusetts: November 2–6, 2007 [Abstract LB6].

[11]. [11]Hoofnagle JH. Hepatitis B – preventable and now treatable. New Engl J Med. 2006;354:1074–1076. CrossRef

[12]. [12]Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365:123–129. Abstract | Full Text | Full-Text PDF (94 KB) | CrossRef

[13]. [13]Keeffe EB, Zeuzem S, Koff RS, et al. Report of an international workshop: roadmap for management of patients receiving oral therapy for chronic hepatitis B. Clin Gastroenterol Hepatol. 2007;5:890–897. Abstract | Full Text | Full-Text PDF (346 KB) | CrossRef

[14]. [14]Lai CL, Leung N, Teo EK, et al. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology. 2005;129:528–536. Abstract | Full Text | Full-Text PDF (203 KB) | CrossRef

[15]. [15]Lai C, Gane E, Hsu C, et al. Two-year results from GLOBE trial in patients with hepatitis B: greater clinical and antiviral efficacy for telbivudine (LdT) vs lamivudine. In: Program and abstracts of the 57th annual meeting of the American association for the study of liver diseases. Boston, Massachusetts: October 27–31, 2006 [Abstract 91].

[16]. [16]Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. New Engl J Med. 2005;352:2682–2695. CrossRef

[17]. [17]Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507–539. MEDLINE | CrossRef

[18]. [18]Lok AS, Zoulim F, Locarnini S, et al. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology. 2007;46:254–265. MEDLINE | CrossRef

[19]. [19]Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. New Engl J Med. 2004;351:1206–1217. CrossRef

[20]. [20]Marcellin P, Buti M, Krastev Z, et al. A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg-negative chronic hepatitis B (CHB): study GS-US-174-0102. In: Program and abstracts of the 58th annual meeting of the American association for the study of liver diseases. Boston, Massachusetts: November 2–6, 2007 [Abstract LB2].

[21]. [21]Marcellin P, Chan HLY, Lai CL, Cho M, Moon YM, Chao Y, et al. 76 week follow up of HBeAg-positive chronic hepatitis B patients treated with telbivudine, adefovir or switched from adefovir to telbivudine. J Hepatol. 2007;46(Suppl. 1):S55. Full-Text PDF (126 KB) | CrossRef

[22]. [22]Entecavir Rivkin A. A new nucleoside analogue for the treatment of chronic hepatitis B. Drugs Today (Barc.). 2007;43(4):201–220. MEDLINE

[23]. [23]Ruiz-Sancho A, Sheldon J, Soriano V. Telbivudine: a new option for the treatment of chronic hepatitis B. Expert Opin Biol Ther. 2007;7(5):751–761. CrossRef

[24]. [24]Standring DN, Patty A, Chapron C, et al. Resistance determination in patients experiencing virologic breakthrough following telbivudine or lamivudine therapy in the international GLOBE trial. In: Program and abstracts of digestive disease week. Washington, DC: May 19–24, 2007 [Abstract S1781].

[25]. [25]Tan F, Wong SN, Hussain MT, Oberhelman K, Lok A. Tenofovir (TDF) monotherapy is effective in suppressing serum HBV DNA in chronic hepatitis B (CHB) patients with primary nonresponse to adefovir (ADV) but not those with ADV-resistant HBV. In: Program and abstracts of digestive disease week. Washington, DC: May 19–24, 2007 [Abstract 95].

[26]. [26]Van Bommel F, Brodzinski A, Mihm U, Jung MC, Sarrazin C, Bergk A, et al. Multifactorial analysis of host and virus related risk factors for the development of viral resistance during long-term lamivudine treatment of HBV infection over up to nine years. J Hepatol. 2007;46(Suppl.1):S198. Full-Text PDF (146 KB) | CrossRef

[27]. [27]Yuen MF, Sablon E, Hui CK, et al. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology. 2001;34(4 Pt. 1):785–791. MEDLINE | CrossRef

Department of Medicine and Hepatology, Henry Dunant Hospital, Athens University, Athens, Greece

PII: S1687-1979(09)00318-9

doi:10.1016/j.ajg.2009.12.011

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