Considerations for the long-term treatment of chronic hepatitis B with nucleos(t)ide analogs

Abstract

Treatment of chronic hepatitis B (CHB) with nucleos(t)ide analogs is often required over a prolonged period to achieve durable virologic suppression. One barrier to the success of long-term therapy is the emergence of drug-resistant mutants. Current guidelines therefore recommend the most potent drugs with optimal resistance profiles, that is, entecavir and tenofovir are used as first-line monotherapies in CHB. Characteristics of the hepatitis B virus, the disease, the patient and the drug can influence the response to antiviral treatment and risk of relapse. This review discusses factors to consider maximizing the chances of successful long-term treatment of CHB, and provides an overview of the long-term efficacy and safety data that have become available over the 4–5 years since entecavir and tenofovir were first approved for the treatment of CHB. Recent findings on whether and under what circumstances long-term therapy of CHB might be stopped are also discussed.

Keywords::

• chronic hepatitis B
• entecavir
• long-term treatment
• nucleos(t)ide analogs
• real-life data
• tenofovir

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Release date: 13 December 2012; Expiration date: 13 December 2013

Learning objectives

Upon completion of this activity, participants will be able to:

• • Evaluate prognostic factors for patients with chronic HBV infection

• • Assess treatment criteria for chronic HBV infection

• • Distinguish first-line NA therapy for chronic HBV infection

• • Analyze long-term follow-up issues among patients who receive NA for chronic HBV infection

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD

Health Sciences Clinical Professor, Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Jörg Petersen, MD

IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, Hamburg, Germany

Disclosure: Jörg Petersen, MD, has disclosed the following relevant financial relationships. Writing assistance was provided by ArticulateScience and was funded by Bristol-Myers Squibb.

Maria Buti, MD

Liver Unit, Hospital General Universitario Vall d’Hebron and Ciberehd del Instituto Carlos III Barcelona, Spain

Disclosure: Maria Buti, MD, has disclosed the following relevant financial relationships. Received consulting fees or honorarium from Bristol-Myers Squibb, Gilead, Merck and Novartis for participation in Advisory Boards. Writing assistance was provided by ArticulateScience and was funded by Bristol-Myers Squibb.

Figure 1. Cumulative annual incidence of resistance of nucleos(t)ide analogs.

Data for telbivudine are through year 2, and for adefovir and tenofovir through year 5.

Data taken from [15,16,56–60].

Worldwide, approximately 350–400 million people are affected by chronic hepatitis B (CHB) [1–3]. Approximately a third of those chronically infected with hepatitis B virus (HBV) do not spontaneously control the infection, and require treatment to reduce the risk of development of cirrhosis, fibrosis and hepatocellular carcinoma (HCC) [1–5]. The goal of CHB therapy is to achieve sustained suppression of HBV replication and remission of liver disease, with the aim of preventing the development of long-term complications [1,3]. As the life cycle of HBV involves the formation of a stable intrahepatic reservoir of cccDNA, complete eradication of the virus is not possible with currently available medications. Therefore, treatment is often required over a prolonged period to suppress HBV replication and minimize liver damage. As the course of CHB depends strongly on the interplay of virus and host, the infection can lead to a wide spectrum of disease with distinct risks of morbidity and mortality, and different treatment needs. For instance, the duration of the immune clearance phase correlates with the risk of cirrhosis and HCC. Therefore, in individuals who acquire the infection perinatally or early in life, and thus have long immune tolerance and immune clearance phases, as is often the case for Asian patients and patients in sub-Saharan Africa, the risk of disease progression is higher than in individuals who acquire the infection at a later point in life [5]. Even patients who achieve control of the infection, whether spontaneous or treatment-induced, remain at risk of long-term complications and should be continuously monitored.

Current treatment options for patients with CHB are interferons or antiviral therapy with nucleos(t)ide analogs (NAs) that target the viral polymerase. Interferons have the potential for immune-mediated containment of the virus after a finite duration of treatment in patients who are able to tolerate the subcutaneous administration and frequent side effects [1]. However, interferons are contraindicated in patients with decompensated HBV-related cirrhosis or autoimmune disease [1–5]. NAs are generally better tolerated than interferons, allowing for prolonged use. Early Phase III clinical studies assessing the efficacy of NAs were based on experience with interferon therapy and stipulated that patients stop treatment after a finite time or after achieving a specified end point [6,7]. Subsequent follow-up studies have shown that the majority of hepatitis B e antigen (HBeAg)(-) patients who stop antiviral therapy after 1–2 years experience a virologic relapse [8,9]. Current CHB practice guidelines recommend that NA treatment is continued for an additional 6–12 months after undetectable levels of serum HBV DNA are achieved, and HBeAg seroconversion has occurred in HBeAg(+) patients or hepatitis B surface antigen (HBsAg) clearance has occurred in HBeAg(-) patients [1–5]. However, these end points are not always achieved, or are not sustained after treatment withdrawal even after consolidation treatment in patients who achieve HBeAg seroconversion during NA therapy [10]. A considerable number of CHB patients are likely to need long-term NA therapy, including HBeAg(+) patients who do not achieve HBeAg seroconversion on-treatment or cannot sustain a virologic response off-treatment, HBeAg(-) patients, and patients with advanced liver disease [1–5].

Considerations for the long-term treatment of patients with CHB

Planning for successful long-term treatment of CHB with NAs requires the consideration of a number of factors relating to the virus, the stage of the disease and the patient.

The virus

Serum HBV DNA is a marker of active viral replication in the liver. A high level of serum HBV DNA has been unambiguously established as an important risk factor for disease progression and mortality in adult CHB patients [11]. A high viral load at the start of treatment can reduce the probability of achieving a virologic response and can increase the time taken to achieve undetectable HBV DNA levels in those who do respond [11,12]. Furthermore, high HBV DNA levels at baseline and/or after 6 months of treatment have been shown to predispose to resistance development during lamvuidine treatment [13,14], which is probably also the case for other agents with a low barrier to resistance, such as telbivudine or adefovir. The risk of drug resistance can be minimized by treating with an agent that achieves rapid and profound virologic suppression, and has a high genetic barrier to antiviral resistance [15,16]. Current guidelines therefore recommend the most potent drugs with optimal resistance profiles, that is, entecavir and ­tenofovir, as first-line monotherapies in CHB [1–5].

The HBV genotype is known to influence response to interferon therapy (genotypes C and D are less responsive to interferon therapy compared with genotypes A and B), but appears to have no consistent effect on virologic responses to NA therapy [17,18]; however, HBsAg loss during lamivudine or entecavir treatment has been shown to be less frequent in patients infected with HBV genotypes B and C than in those infected with genotypes A and D [19]. Nevertheless, different HBV genotypes are associated with differences in disease progression and could have an impact on the long-term clinical outcome of treatment in different geographic regions or patient populations. HBV genotypes A and D lead to higher rates of chronicity than genotypes B and C, while genotypes C and D are associated with rarer and delayed spontaneous HBeAg seroconversion, longer duration of high-level HBV replication, and a higher risk of reactivation compared with genotypes A and B. These differences may contribute to more severe liver diseases and an increased risk of cirrhosis and HCC observed in Asian patients with these genotypes [20,21]. Similarly, it has been suggested that distinct sequence characteristics of HBV genotype A1, prevalent in sub-Saharan Africa, may contribute to the increased risk of HCC in individuals infected with HBV genotype A in this region [22].

The stage of liver disease

The course of CHB infection is dynamic and highly variable, necessitating a variety of different management requirements for different patients [1–3]. The stage of liver disease, the level of HBV replication, and the future risk of cirrhosis and HCC inform the decision to start or defer treatment. Treatment is indicated in patients with persistent high levels of viral replication and elevated alanine aminotransferase (ALT) for more than 6 months, as they are at a high risk of disease progression [1–3]. Patients with compensated cirrhosis and detectable HBV DNA should be considered for treatment even if ALT levels are normal. In these patients, the use of potent antivirals and close monitoring for virologic nonresponse or breakthrough is important to prevent the selection of resistant variants and subsequent disease exacerbation. Clinical studies in patients with compensated cirrhosis indicate that prolonged suppression of HBV DNA with NAs can stabilize disease and even lead to significant regression of fibrosis [23,24]. Hepatic decompensation is a serious clinical complication of CHB, associated with high mortality and warranting immediate antiviral treatment to achieve some clinical improvement and/or decrease the risk of HBV recurrence if a liver transplant is needed [1–3]. Interferons are contraindicated in decompensated CHB and guidelines recommend treatment of these patients with potent oral antivirals [1–3]. Both entecavir and tenofovir have demonstrated efficacy and tolerability in CHB patients with decompensated cirrhosis. In a study comparing adefovir and entecavir in CHB patients with a mean baseline Child–Pugh score of 8.59, entecavir demonstrated superior antiviral and biochemical activity compared with adefovir over 48 weeks of treatment, and both agents were well tolerated [25]. In another study comparing tenofovir (±emtricitabine) with entecavir over 48 weeks in CHB patients with a median baseline Child–Turcotte–Pugh score of 7, all the treatments were well tolerated, and resulted in improvements in standard virologic and biochemical efficacy parameters [26]. In a recent retrospective study of 372 CHB patients, including 89 with compensated cirrhosis and nine with decompensated cirrhosis, virologic response to entecavir was not influenced by the severity of liver disease at baseline, indicating that even patients with advanced stages of liver disease can benefit from initiating treatment [27].

The patient

Age, comorbidities & lifestyle factors

Patient characteristics can have a substantial impact on disease severity, complexity of disease management, and treatment tolerability and adherence. An ageing population means that chronic liver disease is increasingly seen in older individuals. In patients with CHB, increasing age has been shown to correlate with progression of fibrosis and incidence of cirrhosis, HCC, and both liver-related and nonliver-related mortality [11]. Treatment of older patients presents a number of challenges related to physiological changes and accumulating comorbidities that may influence the progression of the disease and its treatment. For example, diabetes mellitus, a condition often described as a comorbidity in patients with CHB, is well known to increase in incidence with age [28]. Asian individuals have a higher prevalence of both diabetes ­mellitus and chronic HBV infection compared with Caucasians; a retrospective study in 407 Asian–Americans (median age: 58 years) and Pacific Islanders (median age: 61 years) found a significantly higher prevalence of diabetes mellitus in patients with HBV than in those without (58.9 vs 33.3%; p < 0.001) [29]. The association remained highly significant after adjustment for age, sex, ethnicity, BMI, smoking, alcohol use, corticosteroid use and a family history of diabetes (odds ratio: 3.17; 95% CI: 1.58–6.35). Furthermore, renal impairment is more frequent in patients with diabetes, and this also becomes more prevalent as patients get older [28,30]. The proportion of patients with renal impairment among those with CHB has not been prospectively evaluated. An abstract reporting the results of an analysis of 381 CHB patients from the European VIRGIL database suggested that between 10 and 20% of patients showed signs of impaired renal function. This can affect disease management as dosage adjustments are required for NAs, which are excreted through the kidneys [31]. Renal impairment increases the risk of anemia and reduced bone mineral density, which also increases in incidence with increasing age. In patients with chronic liver disease, bone mineral density is significantly lower in patients with cirrhosis and renal dysfunction, to the extent that it also results in an increased fracture rate in these patients [32].

Obesity, alcohol and smoking all exacerbate liver disease in CHB patients [30,33,34]. Obesity is a predictor for HBV-related HCC and a well-documented risk for diabetes and renal impairment [35]. Chronic alcohol intake can be an additional factor for the development of HCC in patients with liver cirrhosis caused by HBV [33]. Smoking increases the prevalence of cirrhosis in alcoholic, CHB-infected individuals and in patients with primary biliary cirrhosis [34]. A high intake of tobacco also predisposes individuals to insulin resistance, potentially through the inhibition of hepatic adenosine monophosphate kinase [34]. In summary, a myriad of patient factors can impact disease progression and the prognosis and treatment of CHB. As they are interlinked, consideration of appropriate antiviral therapy must be made.

Reactivation during cytotoxic or immunosuppressive therapy

HBV reactivation is a frequent complication in CHB patients undergoing cytotoxic or immunosuppressive therapy, and is associated with high mortality rates and reduced graft survival in transplant patients [36,37]. In HBV carriers receiving chemo­therapy, HBV reactivation is most common in patients with hematologic malignancies and usually occurs a few weeks after the end of chemotherapy. HBV DNA increases, but is not accompanied by clinical or biochemical symptoms. Restoration of the immune system after cessation of chemotherapy results in rapid cytolysis of infected hepatocytes, leading to hepatitis and liver damage. Studies have shown that prophylactic treatment with lamivudine during chemotherapy can reduce the rate of HBV reactivation, the severity of associated hepatitis flares and mortality [36]. In renal transplant patients, pre-emptive lamivudine therapy improves both graft and patient survival rates [37]. Guidelines recommend prophylactic NA therapy during immunosuppressive-/chemo-therapy for all patients who are HBsAg(+) [1–3]. There are limited data on the use of entecavir or tenofovir in this setting [38–41]; however, these agents are preferable to lamivudine because of the reduced risk of resistance development [1,3].

Coinfection

Patients with HBV and hepatitis C virus (HCV) coinfection, or with HBV and hepatitis D virus coinfection, have a two- to threefold higher risk of developing cirrhosis compared with patients infected with HBV alone [42]. Treatment of CHB in coinfected patients is complicated by the need to balance decisions with the treatment of the coinfection. For example, lamivudine, entecavir and tenofovir all have activity against both HBV and HIV, and should, therefore, not be used as single agents for treatment of HBV in HBV-/HIV-infected patients, as this may result in the selection of resistant variants of HIV [1,43]. A number of cohort studies suggest that tenofovir is effective for the treatment of CHB in HBV/HIV-coinfected patients; however, there have been no controlled studies to compare efficacy and safety in co- versus mono-infected patients [44]. HCV is currently usually treated with pegylated interferons and there may be a risk of HBV reactivation if HCV is cleared. Similarly, HIV treatment may lead to hepatitis flares as a result of immune reconstitution.

Antiviral treatment

Efficacy

Current practice guidelines stress the importance of a profound and durable suppression of HBV replication in CHB therapy [1–3]. Among currently available NAs for CHB treatment, entecavir and tenofovir have proved to be the most potent, and are recommended for first-line monotherapy in most current guidelines [1,3,45]. In clinical studies, 1 year of entecavir treatment was associated with a more profound and more rapid reduction in serum HBV DNA than lamivudine or adefovir in HBeAg(+) and HBeAg(-) patients [7,46,47]. In HBeAg(+) patients, longer-term treatment for up to 5 years resulted in undetectable serum HBV DNA in 94% of patients (noncompleter was missing) (Table 1) [24,48]. Similar results have been obtained in real-life studies (Table 1). Two cohorts of HBeAg(+) and HBeAg(-) patients, followed through up to 4 years of continuous treatment with entecavir, reported undetectable HBV DNA in 96–97% of patients [49,50]. Long-term studies of entecavir have also demonstrated a beneficial effect of entecavir on liver disease, including regression of fibrosis and cirrhosis, and improved liver status in patients with hepatic decompensation [24,25,51]. Tenofovir demonstrated superior antiviral efficacy compared with adefovir over 48 weeks of treatment in HBeAg(+) and HBeAg(-) patients [52]. Continued treatment for up to 5 years resulted in 98% of patients achieving undetectable serum HBV DNA (on-treatment analysis including some patients who added emtricitabine after week 72) (Table 2) [53]. In clinical practice, 2 years of treatment with tenofovir in a population of treatment-naive HBeAg(+) and HBeAg(-) patients with or without cirrhosis resulted in a virologic response rate of 91% [54].

Resistance barrier

For long-term CHB treatment to be successful, first-line antiviral agents need to achieve rapid, complete and durable viral suppression and have a high barrier to resistance [55].

Lamivudine, adefovir and telbivudine have low-to-medium barriers to resistance in that the virus requires only one or two mutations in the viral polymerase in order to replicate in the presence of these agents (Figure 1). With lamivudine, drug resistance emerges early during treatment and increases in frequency with prolonged therapy, reaching approximately 80% after 5 years [56]. Likewise, resistance to telbivudine frequently develops during the first 2 years of therapy, in particular in HBeAg(+) patients [57,58]. Adefovir resistance is slightly less frequent than lamivudine and telbivudine resistance; however, after 5 years of treatment, the risk of resistance development is still 29% [59,60]. For this reason, these drugs are not recommended as a first-line therapy for patients with CHB [1]. By contrast, entecavir and tenofovir are both associated with very low rates of resistance, even during long-term therapy (Figure 1). Resistance to entecavir requires the accumulation of at least three mutations in the viral polymerase [16]. Through 6 years of entecavir treatment, only 1.2% of nucleoside-naive patients showed evidence of drug resistance [16]. With tenofovir, no resistance has been observed through 5 years of therapy and no clear pattern of resistance-associated mutations has been identified in clinical trials or real-life studies [15]. Entecavir and tenofovir have both demonstrated activity in patients with failure to previous therapy with NAs [61,62]. However, sequential monotherapy can promote the emergence of viral mutants with resistance to multiple drugs. In the case of entecavir, pre-existing lamivudine resistance-associated mutations provide a foundation for the selection of entecavir resistance-associated mutations; in patients with lamivudine-resistant HBV, the 6-year resistance rate for entecavir increases to 57% [16,63]. By contrast, the resistance profile for adefovir does not overlap with either lamivudine or entecavir. Although the resistance profile for tenofovir has yet to be defined, there is some evidence to suggest that there may be some overlap with adefovir resistance, as the adefovir resistance mutations A181T/V and N236T result in some reduced susceptibility to tenofovir in vitro, and patients failing adefovir have a reduced response to tenofovir treatment compared with treatment-naive patients [55,61,64]. In addition, the use of tenofovir in lamivudine-refractory patients does not always result in suppression of HBV DNA to undetectable levels [61,64]. In patients with drug-resistant HBV, combination therapy with several NAs may provide better long-term control of viral replication [65]. Rescue therapy with entecavir plus tenofovir has been shown to be effective in patients carrying multidrug-resistant HBV or showing only partial antiviral responses to previous therapies [66]. Although patients with resistance to prior antiviral therapy can achieve effective HBV suppression with another regimen, HCC is frequently observed; therefore, these patients are in need of regular HCC surveillance, including ultrasound and α-fetoprotein screening at 6-monthly intervals [67].

Safety profile

Antiviral drugs need to be well tolerated for long-term therapy to be feasible. During registrational Phase III trials, all five NAs demonstrated good tolerability and generally favorable safety profiles. However, some potential barriers to long-term treatment have been identified during postmarketing surveillance. NAs in general are known to be associated with mitochondrial toxicity, the clinical manifestations of which include various hematologic disorders, peripheral neuropathy, skeletal and cardiac myopathy, pancreatitis, hepatic failure, and lactic acidosis [68]. These adverse events have been infrequent in registrational studies of NAs used to treat CHB, which are weaker in vitro inhibitors of mitochondrial DNA polymerase-g than some antiretroviral NAs such as zidovudine [69]. Nevertheless, longer-term surveillance is needed to rule out the possibility of delayed onset. For example, in postmarketing reports, telbivudine has been associated with myopathy and neuropathy in CHB patients, especially in combination with IFN-α [57,58,70]. Rare cases of lactic acidosis have been reported in one study of patients with impaired liver function receiving entecavir [71]. However, the association with the treatment was only seen in patients with decompensated cirrhosis with a model for end-stage liver disease score of more than 20, and in a follow-up study from the same group in patients with decompensated cirrhosis, lactic acidosis was observed in two tenofovir-treated patients and two untreated patients but not in any entecavir-treated patients [72]. No cases of lactic acidosis have been reported in long-term clinical studies of entecavir through up to 5 years of treatment [73].

Renal impairment may be particularly problematic in CHB therapy, as a considerable number of HBV-infected patients have pre-existing renal dysfunction, which may further exacerbate adverse events associated with antiviral therapy [31]. Nephrotoxicity, characterized by increases in serum creatinine and decreases in serum phosphate, has been described as a potential concern with the use of adefovir and tenofovir in HIV-infected patients [44]; however, the effect of NAs on renal function during CHB treatment has so far proved to be mild [68,74–76]. In clinical trials of tenofovir in HBV-infected patients, creatinine and creatinine clearance remained stable over 5 years, and <1% of patients had a confirmed 0.5 mg/dl increase in creatinine [53]. Cohort studies have generally confirmed these observations [61,74,77]. Nevertheless, close observation and characterization of coexisting risk factors for renal injury (e.g., older age, diabetes mellitus, atherosclerotic disease and chemotherapy) are warranted when treating CHB with tenofovir [44,78]. In CHB patients with decompensated liver disease, which often have coexisting renal dysfunction, higher rates of renal impairment have been reported with both agents. In a randomized trial assessing these NAs in decompensated CHB patients, four out of 45 (8.9%) of the tenofovir-treated and one out of 22 (4.5%) of the entecavir-treated patients experienced a confirmed creatinine increase ≥0.5 mg/dl, and one out of 45 (2.2%) of the tenofovir-treated patients had decreased serum phosphoate <2.0 mg/dl [26]. As all NAs used for the treatment of HBV are excreted via the kidney, dose adjustments in case of renal impairment are required and regular monitoring of creatinine clearance in all patients, as well as monitoring of phosphate in patients with renal insufficiency, are recommended.

Can NA therapy be stopped?

Although long-term antiviral therapy of CHB results in ongoing clinical benefit, it should not be continued for any longer than necessary in order to minimize side effects, drug resistance, nonadherence and costs. For CHB patients with cirrhosis, long-term treatment with NAs is recommended [1,3]. In patients without cirrhosis, the ideal end point for stopping treatment is HBsAg loss, preferably with HBsAg seroconversion (hepatitis B s antibody >100 IU/l) [1,3]. However, the likelihood of this occurring after 4–5 years of treatment has been shown to be at most 10% [79]. Therefore, some alternative stopping rules have been proposed. A finite duration of NA treatment is possible in HBeAg(+) patients who achieve sustained HBeAg seroconversion and undetectable HBV DNA [2,3], as well as normal ALT [1]. In these patients, consolidation therapy after HBeAg seroconversion of 6–12 months or even longer is recommended [1–3]. For HBeAg(-) patients, some guidelines recommend long-term treatment because relapse is frequent, even with on-treatment HBV DNA suppression for more than 1 year [1,3]. According to other guidelines, treatment discontinuation can be considered in HBeAg(-) patients if they have been treated for at least 2 years and have undetectable HBV DNA on three separate occasions 6 months apart [2]. A recent study, assessing this stopping rule in HBeAg(-) patients who had been treated with entecavir demonstrated that the rate of relapse (defined as ALT >2 × ULN and HBV DNA >200 IU/ml) with <64 weeks consolidation therapy was 67%, but only 25% with ≥64 weeks [80]. Other stopping rules for HBeAg(-) and HBeAg(+) patients propose quantification of HBsAg levels together with HBV DNA levels for monitoring the response to treatment and estimating the likelihood of a sustained response [81]. Alternatively, mathematical models, based on the kinetics of HBV clearance during antiviral therapy, have been suggested as a way to predict, in individual patients, the outcome after treatment ­discontinuation and, thus, the duration of therapy [82].

Recent reports suggest that, although relapse is common after stopping long-term treatment, the clinical benefits of long-term antiviral treatment continue in some patients. A study of 33 HBeAg(-) patients treated with adefovir for 5 years demonstrated that, although levels of serum HBV DNA and ALT rose in all patients 4 months after treatment cessation, these increases were short-lived and resolved spontaneously, with approximately 50% of patients remaining in remission over a 5-year follow-up [83]. Likewise, among six HBeAg(-) patients who had maintained HBV suppression without HBsAg loss over 3–7 years of NA therapy, and who then experienced virologic and biochemical relapse after treatment discontinuation, two went on to lose HBsAg off-treatment and one developed hepatitis B s antibodies. All six demonstrated normal or close-to-normal ALT levels, with HBV DNA ranging from undetectable to 4.5 × 10⁶ copies/ml, and showed no signs of disease progression [84]. These findings suggest that in some patients, therapy cessation may be a valid option. The immunologic characterization of these patients and further prospective studies are needed to identify clear prognostic markers to define when long-term treatment can be stopped.

HCC surveillance

Although the risk of HCC is significantly reduced by antiviral treatment, it is not completely eliminated, even if viral suppression is maintained [84]. The risk of HCC remains high in treated patients who, at the start of treatment had cirrhosis, were HBeAg(-), had been infected for a long time or were infected with HBV genotype B or C. Development of drug resistance during treatment can also predispose patients to HCC, even if HBV replication is subsequently suppressed by rescue therapy [85]. Therefore, HCC surveillance is an important aspect of long-term CHB management, particularly in patients with cirrhosis. HCC surveillance is also particularly recommended in Asian CHB patients, who are at risk of HCC even in the absence of cirrhosis and after achieving HBsAg clearance [5], and black African patients in whom HCC often presents at a young age [22]. Risk factors such as older age and coinfection with HCV or HIV also warrant regular HCC surveillance [86].

Expert commentary

Considerable progress in understanding the natural history of CHB and in developing new therapeutic approaches has improved disease management. The available evidence suggests that many patients will require long-term treatment with NAs in order to achieve complete and sustained viral suppression. Antiviral agents considered for long-term therapy should be potent inhibitors of HBV replication, associated with minimal resistance and well tolerated. Patients with CHB are a heterogeneous population and require different management strategies. Careful consideration of viral, disease and patient factors before commencing treatment is important to individually optimize therapy. Treatment responses should be assessed regularly to allow early detection of treatment failures such as the emergence of drug resistance. If treatment is stopped, close monitoring for viral relapse is necessary. In addition, regular HCC surveillance is indicated in ­high-risk patients.

Five-year view

Further clinical studies and continued monitoring of patients on-treatment are needed to confirm the long-term safety and efficacy of available antiviral agents. Despite the availability of agents highly potent in suppressing serum HBV DNA, complete eradication of cccDNA has proven difficult; the development of clear, evidence-based guidance on when therapy can be stopped is an important goal of future research.

Table 1. Virologic, biochemical and serologic effectiveness of long-term entecavir therapy in nucleos(t)ide-naive patients with chronic hepatitis B.

Study design	Patients	ETV arm (n)	Treatment duration, mean (years)	Outcomes					Ref.
				Undetectable HBV DNA (%)	ALT ≤1.0 × ULN (%)	HBeAG loss	HBeAG SC (%)	HBeAG loss (n)
Randomized, comparative Phase III trial, followed by open-label rollover (NC = M)	HBeAg(+)	146	5	94^†	80	NR^‡	23^‡	2^‡	[48]
European cohort study	HBeAg(+) or HBeAg(-)	418	Median: 3.5	97^§	88	NR	56^¶	12^¶	[49]
Hong Kong cohort study (prospective, open-label)	HBeAg(+) or HBeAg(-)	222	4	96^§	91	NR	52	1	[50]
Randomized, noncomparative Phase II trial, followed by open-label rollover (NC = M)	Japanese HBeAg(+) or HBeAg(-)	167	3	88^#	90	39^††	26^††	1	[51]

^†<300 copies/ml.

^‡Patients who had lost HBeAg or HBsAg during years 1 or 2 of the Phase III trial discontinued study therapy and did not enrol in the long-term analysis.

^§<12 IU/ml.

^¶Kaplan–Meier estimate.

^#<400 copies/ml.

^††Among those HBeAg(+) at baseline.

ALT: Alanine aminotransferase; ETV: Entecavir; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; M: Missing; NC: Noncompleter; NR: Not reported; SC: Seroconversion; ULN: Upper limit of normal.

Table 2. Virologic, biochemical and serologic effectiveness of long-term tenofovir therapy in nucleos(t)ide-naive patients with chronic hepatitis B.

Study design	Patients	N (TDF arm)	Treatment duration	Outcomes					Ref.
				Undetectable HBV DNA (%)	ALT ≤1.0 × ULN (%)	HBeAG loss (%)	HBeAG SC (%)	HBeAG loss (number of patients)
Comparative, randomized Phase III trial, followed by open-label rollover (on-treatment analysis; missing = excluded)	HBeAg(+) or HBeAg(-)	218^† (327 total)	Up to 5 years	98^‡,§	79	51	40	11^¶	[53]
Retrospective/prospective cohort	HBeAg(+) or HBeAg(-) ± cirrhosis or HCC	302	Median: 28 months	91^#	NR	NR	33	7	[54]

^†Number of patients entering final year.

^‡<400 copies/ml.

^§Includes 19 patients who added emtricitabine.

^¶Kaplan−Meier estimate.

^#<12 IU/ml.

ALT: Alanine aminotransferase; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; NR: Not reported; SC: Seroconversion; TDF: Tenofovir; ULN: Upper limit of normal.

Key issues

• • In patients with chronic hepatitis B (CHB), complete eradication of the virus has proven problematic and treatment is often required over a prolonged period.

• • Clinical studies have shown that prolonged suppression of hepatitis B virus (HBV) DNA with nucleos(t)ide analogs (NAs) can stabilize disease and lead to significant regression of fibrosis; however, success of NA therapy can be compromised when using agents with a low barrier to resistance.

• • Planning for successful long-term treatment of CHB requires the consideration of a number of factors relating to the virus, the stage of the disease and the patient.

• • High baseline HBV can reduce the probability of achieving a virologic response, increase the time taken to achieve undetectable HBV DNA levels and increase the risk of developing drug-resistant strains when treating with agents that have a low barrier to resistance, such as lamivudine.

• • Hepatic decompensation is a serious complication of CHB, associated with high mortality and requiring immediate antiviral treatment in order to decrease the risk associated with a potential liver transplantation.

• • Patient comorbidities (e.g., diabetes and renal impairment) and lifestyle factors (e.g., obesity, alcohol and smoking) can substantially impact CHB disease severity, and influence decisions related to the treatment and management of CHB disease.

• • Among currently available NAs for CHB treatment, entecavir and tenofovir are the most potent and are recommended for first-line monotherapy; both agents have high barriers to resistance, and have demonstrated long-term efficacy and safety over up to 5 years of treatment in clinical studies.

• • Entecavir and tenofovir have both demonstrated efficacy and tolerability in CHB patients with decompensated cirrhosis.

• • Further prospective studies are needed to identify clear prognostic markers to define when long-term treatment can be stopped.

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Considerations for the long-term treatment of chronic hepatitis B with nucleos(t)ide analogs

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. You are seeing a 25-year-old man from China with chronic hepatitis B (CHB) infection and compensated cirrhosis. What can you tell him about the prognosis of his infection?

• □ A Viral load at the start of treatment generally has no effect on the outcome of therapy with nucleoside analogs (NA)

• □ B Genotypes A and D do not respond to NA treatment

• □ C Genotypes A and D are associated with higher risk of chronic disease

• □ D Smoking might be protective against liver damage among patients with CHB infection

2. You consider whether to treat this patient’s CHB infection. Which of the following statements regarding patient selection for treatment is most accurate?

• □ A He should not receive NA therapy due to his cirrhosis

• □ B He should be treated if he has detectable HBV DNA levels

• □ C He should not be treated if his alanine aminotransferase (ALT) levels are normal

• □ D He does not qualify for any treatment due to his cirrhosis

3. Which of the following NAs is regarded as first-line therapy for CHB infection?

• □ A Tenofovir

• □ B Adefovir

• □ C Telbivudine

• □ D Lamivudine

4. You initiate treatment with NA for this patient. What should you consider during his follow-up on treatment?

• □ A Sequential monotherapy with different NA may increase the risk for HBV resistance

• □ B Regular examinations for renal function during treatment with NA are not recommended

• □ C The preferred treatment duration for this patient is one year

• □ D His Chinese ethnicity is associated with a lower risk for incident hepatocellular carcinoma (HCC)