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Current treatment guidelines from the AASLD, EASL, and APASL recognize up to 6 nucleos(t)ide analogues for chronic hepatitis B therapy—lamivudine, adefovir, telbivudine, entecavir, tenofovir DF, and tenofovir AF—as well as 2 formulations of peginterferon—peginterferon alfa-2a and peginterferon alfa-2b. Given the considerable risk of antiviral resistance in patients treated with lamivudine, adefovir, and telbivudine, entecavir, tenofovir AF, or tenofovir DF are recommended as first-line nucleos(t)ide analogues by US and European guidelines.[3,4] Guidelines from the APASL were last updated at the end of 2015 and continue to recommend entecavir or tenofovir DF as preferred first-line nucleos(t)ide analogues.
Entecavir. Entecavir was approved in the United States in March 2005 for the treatment of chronic HBV infection in patients with evidence of viral replication and either evidence of persistent elevations in aminotransferases or histologically active disease (Table 3).[30,31]
Table 3. Currently Approved Anti-HBV Agents and Their Characteristics
Entecavir has been studied in treatment-naive patients, patients with lamivudine-refractory disease, and patients with decompensated cirrhosis. In lamivudine-naive HBeAg-positive patients treated with entecavir, HBV DNA was suppressed to undetectable levels in 67% of patients and HBeAg seroconversion occurred in 21% of patients after 1 year (Figures 1A and 1B). Cumulative rates of HBV DNA undetectability increased to up to 80% and 94% at 2 and 5 years of entecavir therapy, respectively.[33,34] In patients with HBeAg-negative chronic HBV infection, HBV DNA was undetectable in 90% of patients after 1 year of therapy (Figure 1C). Long-term entecavir therapy is associated with improvements in liver histology. Among 57 patients who received at least 3 years (and up to 7 years) of entecavir therapy and had baseline and follow-up biopsies, 96% of patients experienced histologic improvement, as measured by an improvement of ≥ 2 points in Knodell necroinflammatory score and no worsening of the Knodell fibrosis score, and 88% of patients experienced a ≥ 1-point improvement in the Ishak fibrosis score. In addition, of the 10 patients who had advanced fibrosis or cirrhosis at baseline, all experienced improvement in liver histology and Ishak fibrosis score.
The efficacy of entecavir in nucleos(t)ide analogue–naive patients was confirmed in several large investigator-initiated clinical studies. Indeed, a European cohort study of both HBeAg-positive and HBeAg-negative patients showed that 79% of nucleos(t)ide analogue–naive patients achieved a virologic response during the first year of entecavir treatment, and this response rate increased through prolonged therapy.[20,37] The results of an Italian study enrolling predominantly HBeAg-negative patients demonstrated that entecavir therapy resulted in undetectable HBV DNA levels in more than 90% of patients through 5 years of therapy. Very low rates of entecavir resistance (1.2%) have been reported in nucleos(t)ide analogue–naive patients through up to 6 years (Figure 2).[4,39,40] Long-term use of entecavir is associated with excellent survival comparable to the general population.
The combination of entecavir with tenofovir DF yielded comparable virologic response rates to entecavir alone in the general HBV patient population, but combination therapy resulted in higher response rates at Week 96 (79% vs 62%) among patients with high HBV DNA at baseline (> 108 IU/mL). The clinical relevance of this observation for patients without an absolute requirement for swift viral suppression to undetectable levels is currently unclear.
For discussion of the role of entecavir in nucleos(t)ide-experienced HBV patients, please click here.
Figure 1. Treatment outcomes at 1 year: HBV DNA undetectability (1A) and HBeAg seroconversion (1B) in HBeAg-positive patients and HBV DNA undetectability (1C) in HBeAg-negative patients. Studies were not head-to-head comparisons.
Figure 2. Rates of confirmed antiviral resistance.
Tenofovir DF. The nucleotide analogue tenofovir disoproxil fumarate (DF) was approved for the treatment of chronic HBV infection in the United States in 2008, although it was approved for the treatment of HIV in 2001 (Table 3). Tenofovir DF is indicated for the treatment of compensated and decompensated chronic HBV infection in adults.[43,44] Tenofovir DF has demonstrated superior antiviral efficacy compared with adefovir in both HBeAg-positive and HBeAg-negative patients. HBeAg seroconversion and HBV DNA undetectability were achieved in 21% and 76% of HBeAg-positive patients at 1 year of therapy, respectively (Figures 1A and 1B). At 3 years of therapy, the rate of HBeAg seroconversion increased to 26%, and 93% of patients on-treatment had undetectable HBV DNA. In HBeAg-negative patients, HBV DNA undetectability was achieved in 93% of patients after 1 year of tenofovir DF therapy (Figure 1C) and in 90% of patients still on-treatment after 3 years. Prolongation of therapy resulted in continued viral suppression through 5 years of continuous therapy in both HBeAg-positive and HBeAg-negative patients (97% to 99% of patients still receiving treatment had undetectable HBV DNA). Of importance, regression of fibrosis was observed in a large subset of treated patients, even among patients with cirrhosis. Among 348 patients who had paired biopsies at both baseline and Week 240, 87% experienced an improvement in overall liver histology, as measured by an improvement of ≥ 2 points in Knodell necroinflammatory score and no worsening of the Knodell fibrosis score. In addition, of the 96 patients with cirrhosis at baseline, 74% no longer had cirrhosis at Year 5 and only 1% of patients without baseline cirrhosis had progressed to cirrhosis at Year 5 (P < .0001). In those without decompensated cirrhosis, long-term treatment with tenofovir DF is associated with excellent long-term survival comparable to the general population.
A large investigator-initiated study showed that 79% of patients who failed previous nucleos(t)ide analogue treatment achieved HBV DNA levels < 400 copies/mL after a median follow-up of almost 2 years of tenofovir DF therapy. This study also suggests a reduced antiviral effect of tenofovir DF in the adefovir-resistant population. To date, tenofovir DF resistance has not been detected in treatment-naive patients treated for up to 8 years (Figure 2), although viremic patients were allowed to switch to a combination of tenofovir DF and emtricitabine at Week 72.
Another study has investigated the use of tenofovir DF alone or in combination with emtricitabine for HBeAg-positive patients with high HBV DNA and low ALT (commonly referred to as “immune tolerant”). In this study, viral suppression at Week 192 was achieved in 55% of patients treated with tenofovir DF alone compared with 76% of patients treated with combination therapy (P = .016). Rates of HBeAg seroconversion and HBsAg loss were very low (5% and 0%, respectively). Note that US treatment guidelines do not recommend antiviral therapy in this population, except in rare circumstances where there is evidence of significant inflammation or fibrosis on liver biopsy.[3,49]
For discussion of the role of tenofovir DF in nucleos(t)ide-experienced HBV-infected patients, please click here.
Tenofovir AF. Tenofovir AF is a novel alanine ester prodrug of tenofovir first approved for treatment of HIV infection in combination with other antiretroviral agents.[50-54] Despite the excellent antiviral efficacy of tenofovir DF, its long-term use has been associated with renal toxicity (including rare cases of Fanconi’s syndrome) and increased bone turnover.[55-61] In contrast to tenofovir DF, which is converted to tenofovir in the blood and then taken up by cells, tenofovir AF has increased stability in plasma and is largely metabolized intracellularly, allowing for lower dosing than tenofovir DF and reduced toxicity.[62,63]
The antiviral efficacy and safety of tenofovir AF in the treatment of HBV has now been demonstrated in 2 large randomized, placebo-controlled phase III noninferiority studies conducted in HBeAg-positive and HBeAg-negative patients.[64-66] In the HBeAg-positive study, 873 patients were randomly assigned to treatment with tenofovir AF 25 mg/day (n = 581) or tenofovir DF 300 mg/day (n = 292).[64,66] At Week 48, HBV DNA levels < 29 IU/mL were achieved in 64% of patients treated with tenofovir AF compared with 67% of patients treated with tenofovir DF (noninferiority established). By Week 96, these rates had risen to 73% and 75%, respectively. Other endpoints, including HBeAg and HBsAg clearance rates, were similar between the 2 treatment arms. Similarly, in the HBeAg-negative trial, 425 patients were randomly treated with either tenofovir AF (n = 285) or tenofovir DF (n = 140), with 94% and 93% of patients, respectively, achieving HBV DNA < 29 IU/mL at Week 48 (noninferiority established) vs 90% and 91%, respectively, at Week 96.[65,66] Furthermore, no resistance was detected to either tenofovir AF or tenofovir DF in patients qualified for resistance testing in either study through Week 96.
In both studies, patients treated with tenofovir AF had significantly smaller declines in bone mineral density at the hip and the spine, significantly smaller reductions in renal function (ie, median change in estimated glomerular filtration rate), and significantly greater proportions with normalization of ALT concentrations compared with patients receiving tenofovir DF. Thus, the overall antiviral efficacy of tenofovir AF remained similar to tenofovir DF through the second year of therapy, with maintained superiority of bone and renal safety outcomes. However, the absolute differences in the effect of tenofovir AF and tenofovir]DF were small, and the clinical relevance and sustainability of these findings remain to be established through long-term follow-up. Nevertheless, tenofovir AF is expected to be a valuable treatment option, especially for patients in whom the renal toxicity or bone effects of tenofovir DF are a concern. Indeed, tenofovir AF is approved for the treatment of chronic HBV infection in the United States and in Europe, and has been recommended for first-line treatment of chronic hepatitis B by AASLD and EASL HBV management guidelines.[3,4]
Adefovir. Adefovir, a nucleotide analogue, was the second agent approved for the treatment of chronic HBV infection (Table 3). In the United States, adefovir is indicated for the treatment of compensated chronic HBV infection in patients aged 12 years or older; the European prescribing information also includes an indication for patients with decompensated liver disease. Treatment with adefovir for 1 year resulted in HBeAg seroconversion in 12% of HBeAg-positive patients, and 21% achieved HBV DNA negativity (Figures 1A and 1B). At Year 5 of receiving adefovir therapy, 48% of patients experienced HBeAg seroconversion, and 39% had an HBV DNA level < 1000 copies/mL. In HBeAg-negative patients, 1 year of adefovir therapy resulted in HBV DNA negativity in 51% to 63% of patients (Figure 1C).[45,73] The percentage of HBeAg-negative patients receiving prolonged adefovir therapy who had HBV DNA < 1000 copies/mL increased to 67% at 5 years.
The risk of antiviral resistance with adefovir is somewhat lower than with lamivudine, and no resistance was detected through the first year. However, after prolonged therapy through 5 years, adefovir resistance occurred in 29% of patients (Figure 2), which precludes its use as a first-line agent.[4,39]
Lamivudine. Lamivudine was the first nucleoside analogue approved for the treatment of chronic HBV infection, approved in the United States in December 1998. In the United States, lamivudine is indicated for the treatment of compensated chronic HBV infection associated with hepatitis B viral replication if other agents with a higher barrier of resistance cannot be used (Table 3); the European prescribing information also includes an indication for patients with decompensated liver disease.
After 1 year of treatment, 18% of HBeAg-positive chronically HBV–infected patients treated with lamivudine experienced HBeAg seroconversion (Figure 1B) and 36% had undetectable HBV DNA (< 57 IU/mL) (Figure 1A). Prolongation of lamivudine therapy resulted in increasing cumulative rates of HBeAg seroconversion.[77-79] In HBeAg-negative chronic HBV infection, as many as 72% of patients had undetectable HBV DNA levels (< 57 IU/mL) after 1 year of lamivudine therapy (Figure 1C). However, the number of patients with undetectable levels of HBV DNA progressively decreased during prolonged therapy due to an increased frequency of antiviral resistance (Figure 2). This rate of resistance precludes the use of lamivudine as a first-line HBV agent.
Telbivudine. Telbivudine was approved for chronic HBV infection in the United States in October 2006 and is indicated for patients with compensated chronic HBV infection and with evidence of viral replication and either evidence of persistent elevations in aminotransferases or histologically active disease (Table 3).[81,82] Note, however, that telbivudine has been discontinued in the United States. Telbivudine has greater antiviral efficacy compared with lamivudine in both HBeAg-positive and HBeAg-negative chronic HBV infection. In HBeAg-positive patients, HBeAg seroconversion was observed in 23% and 30% of patients after 1 and 2 years of telbivudine therapy, respectively (Figure 1B).[83,84] HBV DNA was undetectable (< 57 IU/mL) in 56% of patients at Year 2. In HBeAg-negative patients, HBV DNA was undetectable in 88% of patients after 1 year of telbivudine (Figure 1C). The corresponding rate at 2 years decreased to 82%.
Despite the high potency of telbivudine, virologic response rates deteriorated over time due to the emergence of telbivudine resistance; indeed, telbivudine resistance mutations were found in up to 17% of patients after 2 years of therapy (Figure 2).[4,39] Notably, telbivudine resistance mutations confer cross-resistance to lamivudine. Telbivudine, therefore, has limited application in the treatment of patients with chronic HBV infection.
Adverse Events. Nucleos(t)ide analogues generally have favorable adverse event profiles. However, all nucleos(t)ide analogues theoretically pose a risk of adverse events because most agents inhibit not only viral but also human DNA polymerases. In addition, some agents inhibit human mitochondrial DNA polymerases that may result in a clinical syndrome including lactic acidosis, neuropathy, and myopathy. Fortunately, most nucleos(t)ide analogues used for chronic HBV infection have shown few adverse events during the first years of therapy, although it should be noted that most studies were performed in relatively healthy patients with compensated liver disease. One population-based study confirmed the relative safety of nucleo(s)tide analogues regarding renal and bone events, although there was an increase of hip fractures with nucleotides when compared with nucleosides (HR: 5.69; P = .001). The absolute risk, however, remains very low.
Lamivudine treatment had similar rates of adverse events compared with placebo in a randomized study, and the adverse event profile of entecavir was indistinguishable from that of lamivudine. By contrast, adefovir is known to be nephrotoxic in up to one third of patients. Renal toxicity has also been described in HIV-infected patients treated with tenofovir DF, necessitating creatinine monitoring, especially during prolonged treatment. Bone density loss has been reported as well in patients receiving tenofovir DF. Nevertheless, tenofovir DF was well tolerated and safe during the first 5 years of therapy in patients with chronic HBV infection.[27,90] Tenofovir AF, a newer formulation of tenofovir approved for the treatment of chronic HBV infection in the setting of compensated liver disease, was shown to have reduced bone and kidney toxicity as compared with tenofovir DF in 2 phase III studies.[64-66] Tenofovir AF may be a valuable alternative to tenofovir DF in patients with renal dysfunction who cannot tolerate tenofovir DF.
A study of patients with advanced liver disease showed that entecavir therapy in patients with a Model for End-Stage Liver Disease score of > 20 may be associated with the occurrence of severe lactic acidosis, although lactic acidosis is a risk with all nucleoside analogues. Lactic acidosis was self-limiting or resolved after entecavir discontinuation in the majority of cases, although 1 fatality was reported. Increases in creatine kinase, as well as myopathy, may be observed in a limited number of patients receiving telbivudine, although notably, telbivudine appears to improve creatinine clearance. The combination of telbivudine with peginterferon is contraindicated because of an increased risk of peripheral neuropathy.
Interferon. Interferon alfa-2b was approved in the United States for the treatment of chronic HBV infection in 1992 and is indicated for chronically HBV–infected patients 1 year of age or older with compensated cirrhosis (Table 3). In Europe, the indication for interferon alfa-2b in chronic HBV treatment is restricted to adults. In a meta-analysis of 15 clinical trials, interferon alfa-2b was associated with HBV DNA suppression in 37% of patients, loss of HBeAg in 33%, and an 18% greater HBeAg seroconversion rate vs patients receiving placebo. Response has been reported to be durable in 80% to 90% of cases over 4-8 years of follow-up. Loss of HBsAg with interferon has been observed in 5% to 10% of treated patients within the first year of therapy and up to 25% of patients after 5 years.[98,99] However, due to the improved response rates and an easier dosing schedule of peginterferon, interferon alfa-2b is now rarely used for the treatment of chronic HBV infection.
Peginterferon. Peginterferon alfa-2a was approved in the United States for the treatment of chronic HBV infection in 2002. Peginterferon alfa-2a is indicated for adult patients with HBeAg-positive and HBeAg-negative chronic HBV infection with compensated liver disease and evidence of viral replication and liver inflammation.[100,101] Although peginterferon alfa-2b is not approved for the treatment of chronic HBV infection, it is often used interchangeably with peginterferon alfa-2a in the management of chronic HBV infection. After 1 year of treatment with peginterferon alfa-2a or peginterferon alfa-2b, 22% to 27% of patients achieved HBeAg seroconversion (Figure 1B).[102,103] Six months after discontinuing treatment, this proportion increased to 29% to 32%. These results were confirmed in 2 other studies, which also established the superiority of 48 weeks vs 24 weeks of treatment.[104,105] Loss of HBsAg with appearance of anti-HBs occurred in 3% to 5% of patients after 1 year of treatment and 6 months of posttreatment follow-up.[102,103] The addition of lamivudine to peginterferon monotherapy did not increase the serologic response rates, although higher rates of undetectable HBV DNA were observed during and at the end of treatment in patients who received the combination regimen (vs peginterferon alone), but this effect was not sustained off-treatment.[102,103] In HBeAg-negative patients, treatment with peginterferon alfa-2a monotherapy for 1 year resulted in a response (defined as HBV DNA < 20,000 copies/mL and normal ALT level at 6 months after treatment discontinuation) in 36% of patients. Serum HBV DNA was undetectable in 19% of patients, and 4% achieved HBsAg clearance at 6 months posttreatment. Similar to HBeAg-positive disease, the addition of lamivudine to peginterferon alfa-2a was beneficial in terms of on-treatment viral suppression but did not result in higher sustained off-treatment response rates.
In another large, randomized trial, 48 weeks of treatment with the de novo combination of peginterferon alfa-2a with tenofovir DF resulted in a cumulatively higher rate of HBsAg clearance than did peginterferon monotherapy (cumulative rate of HBsAg loss: 9.1% vs 2.8% at Week 72, respectively; P = .003). However, HBsAg seroreversion after discontinuation of all therapy attenuated these differences (absolute rates at Week 72: 6.8% vs 2.8%, respectively; P = not significant). Because other endpoints such as off-treatment sustained low or undetectable HBV DNA levels or HBeAg clearance rates were not more frequently achieved with combination therapy, the clinical implications of these findings is not yet clear.
Long-term follow-up after treatment with peginterferon alfa-2b with or without lamivudine increases HBeAg loss in most patients; up to 30% in patients who had cleared HBeAg within 6 months posttreatment (Figure 3A). The loss was sustainable over 5 years of posttreatment in an Asian study; however, HBsAg clearance rates were considerably lower in these Asian patients.
Prolongation of peginterferon therapy may increase sustained response rates. Lampertico and colleagues reported that 29% of genotype D–infected HBeAg-negative patients treated with peginterferon alfa-2a 180 µg for 48 weeks followed by 48 weeks of peginterferon alfa-2a 135 µg achieved a sustained off-treatment response (defined as HBV DNA ≤ 2000 IU/mL at 1 year after treatment discontinuation) compared with only 12% of those treated for 1 year. Prolongation of peginterferon alfa-2a therapy was generally well tolerated.
Results of long-term follow-up studies have shown that the off-treatment sustainability of response to peginterferon-based therapy is lower in patients with HBeAg-negative disease vs HBeAg-positive disease.[112,113] A virologic response, defined as HBV DNA < 10,000 copies/mL at 6 months after peginterferon alfa-2a treatment, was durable in 42% of the patients with an initial response after 3 years of follow-up. Long-term follow-up results 3 years after therapy discontinuation are shown in Figure 3B. Of note, HBsAg loss was 9% in those receiving peginterferon alfa-2a vs 0% with lamivudine.
Figure 3. Long-term follow-up results of peginterferon-based therapy (mean: 3 years posttreatment) in HBeAg-positive (A) and HBeAg-negative (B) chronic HBV infection.
Adverse Events. One year of peginterferon-based therapy is associated with considerable adverse events; most often reported are influenza-like symptoms, myalgia, fatigue, and local reactions at the site of injection (Table 4).[102,103,106] Two years of peginterferon treatment is associated with a similar safety and tolerability profile as 1 year. The combination of peginterferon with telbivudine has been associated with an increased risk of peripheral neuropathy. Therefore, this combination regimen should not be used in clinical practice.
Table 4. Selected Adverse Events in Patients Treated With Peginterferon
Table 5 shows potential interventions that can aid with peginterferon adverse events.
Table 5. Suggested Management of Peginterferon Adverse Events