Mr. A is a 37-year-old Canadian man of Chinese ethnic origin. He referred himself after he was transferred to the United States in his job as a banker. Diagnosed with chronic hepatitis B 5 years ago, he requested that a new physician take over its management.
During his initial appointment with you, he reported that he has been on antiviral therapy with adefovir 10 mg/day for approximately 3 years. Notes from his physician back in Canada indicate that prior to starting therapy his laboratory values were as follows: alanine aminotransferase (ALT) 54 U/L; aspartate aminotransferase (AST) 37 U/L; and hepatitis B virus (HBV) DNA 1,200,000 IU/mL. A liver biopsy done at diagnosis showed grade 2 stage 3 fibrosis (ie, bridging fibrosis). No further or interim results were available for review. He has no family history of hepatocellular carcinoma.
He was asymptomatic and had a normal physical examination. New laboratory tests were ordered, with the following results: ALT 32 U/L; AST 23 U/L; and HBV DNA 118,000 IU/mL. Hepatitis B e antigen (HBeAg) was negative, while antibody to hepatitis B e antigen (anti-HBe) was positive. A serum sample sent for HBV resistance testing detected no adefovir-resistant variants and the patient reported being fully compliant with his prescribed medication.
Clinical Decision Point 1: Next Treatment Step
Question 1: Based on this patientâs history and laboratory values, should he be continued on adefovir?
- No; discontinue adefovir and start the patient on either entecavir or tenofovir
- Yes; continue adefovir at the present dose
- Yes; continue adefovir but increase the dose to 20 mg/day
- Yes; continue adefovir but also add on lamivudine
Answer: (a). The patient has had an inadequate viral response after a full 3 years of therapy. By this time, he should be seronegative for HBV DNA. In the phase III trial of adefovir in HBeAg-negative patients, 51% were seronegative at 2 years,1 and by weeks 96 and 144 in the extension trial, 71% and 79%, respectively, achieved undetectable status.2 It is possible that he became HBV DNA negative at some point on therapy and that HBV DNA then reappeared, implying that viral resistance developed. The absence of adefovir-resistant variants in recent resistance testing suggests this scenario is unlikely, however. The correct course, therefore, is not to continue with the same regimen but to change strategies.
Options for this patient with a suboptimal response to adefovir include switching to a different antiviral or adding a second antiviral.3 Tenofovir and entecavir are potent antivirals with low rates of resistance and represent the current standard of care.3 Either tenofovir or entecavir monotherapy would be a good choice for this patient who has no evidence of adefovir resistance.4-7 It might also be acceptable to add lamivudine to adefovir so the patient is receiving combination therapy, but this would add to the cost of the treatment regimen. (Written communication with A. Di Bisceglie, MD. October 2012.) Also, adherence is likely to be better with a once-daily pill rather than having to take two medications. Telbivudine monotherapy could be used but is not recommended due to its high rate of resistance over time.8
Phase III registration trials of entecavir used lamivudine, not adefovir, as the active comparator. Ninety percent of treatment-naive HBeAg-negative patients who received entecavir monotherapy had undetectable HBV DNA by week 48 compared with 72% of those who received lamivudine.9 A recent meta-analysis evaluated the efficacy of entecavir compared with adefovir in 13 randomized controlled trials enrolling a total of 1230 patients.10 Study authors concluded that âpatients with hepatitis B have a greater likelihood of achieving a viral response and a biomedical response when treated with entecavir than when treated with adefovir.â In HBeAg-positive and -negative patients combined, HBV DNA clearance rates were significantly higher at weeks 24 and 48 with entecavir compared with adefovir. ALT normalization rates were also higher, as were the HBeAg clearance and the HBeAg seroconversion rates in HBeAg-positive patients, at week 48.
A multicenter cohort study prospectively evaluated all consecutive chronic HBV patients who were treated with entecavir monotherapy to determine whether prior therapy with adefovir therapy has any effect on response to entecavir.11 Of the 161 patients enrolled, 36 had been directly switched from adefovir or adefovir-lamivudine to entecavir monotherapy. The duration of adefovir therapy ranged from 3 to 55 months, with a mean of 19 months. Researchers found that antiviral response to entecavir was not influenced by prior adefovir therapy regardless of the presence of adefovir-resistant mutations, after adjusting for prior lamivudine therapy, baseline viral load, HBeAg status, and ALT level.
Nguyen and colleagues reported 2-year data from a multicenter switch study in which patients with suboptimal response to adefovir were switched to entecavir.7 Data at 1 year had previously shown that 68% of the 60 patients included in the analysis achieved undetectable HBV RNA after the switch.6 At 2 years on entecavir, 77.5% of patients with suboptimal response to adefovir (N = 72 at this analysis) achieved undetectable status.7
If resistance testing had confirmed the development of resistance to adefovir in this patient, entecavir would be the treatment of choice for this patient due to its efficacy against adefovir-resistant variants,8 but tenofovir is also partially effective in this setting.12
Tenofovir's phase III trials compared tenofovir monotherapy to adefovir monotherapy. In HBeAg-negative patients, 93% of patients in the tenofovir group were HBV DNA negative at week 48 compared with 63% of patients in the adefovir group.13 HBV DNA declines were noted by week 4, with a mean HBV DNA level of 3 log10 copies/mL at week 12 compared with 7 log10 copies/mL at baseline.
Tenofovir has also proven potent in treatment-experienced patients, including those with prior adefovir therapy. A retrospective multicenter study evaluated the response to tenofovir in patients with failure or resistance to prior therapy.14 Of the 131 enrolled patients (35% HBeAg-negative), 110 had received prior adefovir, either as monotherapy or as sequential or combination therapy with lamivudine. Response to tenofovir was significantly affected by the presence of adefovir-resistant mutants. Over the observation period (mean, 23 months), 100% of those without adefovir resistance achieved HBV DNA undetectable status compared with 52% of those with adefovir resistance.
Marcellin et al conducted a switch study in which HBeAg-negative patients who had been randomized to receive either adefovir (n = 125) or tenofovir (n = 250) for 48 weeks were switched to open-label tenofovir for up to 7 years.15 Among the patients who received adefovir in the original 48-week study and switched to tenofovir, 89% had undetectable HBV DNA at week 96 (intent-to-treat analysis). Among patients who received tenofovir during the original 48 weeks and the open-label period, 90% had undetectable HBV DNA at week 96.
Although tenofovir would not be the optimal choice for rescue therapy, resistance testing showed an adefovir-resistant variant in this patient, due to cross-resistance between adefovir and tenofovir,8 it has demonstrated partial efficacy in the setting of adefovir resistance.12
Consequence of making the wrong choice: Choosing to continue with the same adefovir therapy would allow viremia to persist and would also encourage the development of viral resistance. HBeAg-negative patients treated with adefovir for up 240 weeks showed a 29% probability of developing adefovir polymerase mutations and a 20% probability of developing mutations that resulted in virologic resistance.16 In addition, it has become apparent that prolonged therapy with adefovir is associated with an increased risk of renal injury.17 Five-year data from the extension phase of the adefovir HBeAg-negative registration trial showed that 3% of patients had increases in serum creatinine of at least 0.5 mg/dL compared with baseline.16 In the âreal-lifeâ setting, however, Ha and colleagues suggest that adefovir-related renal toxicity may be underreported when determined by serum creatinine levels rather than by calculating the estimated glomerular filtration rate (eGFR) using the Cockcroft-Gault formula.17 Evaluating renal function in chronic hepatitis B patients with (n = 145) and without (n = 145) adefovir exposure from two community clinics, Ha et al found that 11.7% of adefovir-exposed patients had eGFR decline to 50 mg/mL or less during the observation period, representing a reclassification to moderate renal impairment, compared with 2.1% of unexposed patients.17 Mean duration of therapy for the adefovir-exposed group was 30 months; mean duration of therapy for the unexposed group was 18 months. The study authors calculated that patients exposed to adefovir at a dose of 10 mg had a 3.68-fold higher risk of developing moderate renal impairment or treatment discontinuation due to renal toxicity compared with unexposed patients.17 While higher doses of adefovir might be more potent, these higher doses are also more likely to be associated with renal injury.18 Among patients with chronic hepatitis B monoinfection, prolonged use of tenofovir is associated with lower rate of renal toxicity. After 5 years on tenofovir for chronic hepatitis B, 1.8% of 641 patients had a serum creatinine increase of at least 0.5 mg/dL or a decrease in creatinine clearance to less than 50 mL/min.19
Either entecavir or tenofovir selection would be appropriate. The patient is started on tenofovir 300 mg per day. The importance of close monitoring while he is on therapy is discussed.
In your experience, how receptive are patients to switching therapy due to suboptimal response when they are currently feeling fine? How do you make the case to them that a switch is needed? What are some of the patient-specific factors that can be a barrier to switching?
Audio Commentary by Adrian M. Di Bisceglie, MD, FACP
Clinical Decision Point 2: Monitoring Treatment Response
Question 2: How should the patient be monitored while on tenofovir therapy to ensure that the new treatment regimen is working?
- Check serum HBV DNA every 3â6 months initially
- Check serum aminotransferases every 3â6 months
- Check serum HBV DNA monthly
Answer: (a). A decline in serum HBV DNA should be seen within the first few months of starting the more potent antiviral therapy. AASLD guidelines suggest that the primary response should be at least a 2-log decrease in HCV RNA by 6 months.8 HBV DNA should be checked every 3 to 6 months8 to make sure levels are decreasing at an appropriate rate, reach undetectable status, and show no subsequent evidence of breakthrough disease. Because it may take several months for HBV DNA to decrease on the new therapy and become undetectable, it is not necessary to monitor the patientâs HBV DNA levels more frequently than every 3 months.
Although serum aminotransferases should also be monitoredâAASLD guidelines recommend every 3 months8âthey are not reliable indicators of antiviral response. In addition, this patientâs ALT and AST levels are already near normal.
The patientâs HBV DNA level becomes undetectable 3 months after starting treatment. In addition, his ALT declines to 22 U/L and AST to 15 U/L.
Clinical Decision Point 3: Treatment Duration
Question 3: What should the patient be told about the duration of antiviral therapy?
- Continue until HBV DNA has been undetectable for at least 12 months
- Continue until HBsAg becomes undetectable
- Continue lifelong regardless of HBV DNA or HBsAg status
Answer: (b). According to the FDA-approved product labels for entecavir and tenofovir, the optimal duration of therapy is unknown.20,21 AASLD treatment guidelines offer more guidance regarding the duration of nucleoside analog antiviral therapy. For HBeAg-negative disease, therapy should be continued until HBsAg clearance.8 Patients with HBeAg-negative chronic hepatitis B are likely to have a relapse of hepatitis B if therapy is discontinued prematurely, even if HBV DNA is undetectable.8 Unfortunately, HBsAg clearance is rare. Among patients in the tenofovir HBeAg-negative registration trial, none lost HBsAg after 48 weeks of therapy.13 In the entecavir HBeAg-negative registration trial, one patient in each treatment arm lost HBsAg after 48 weeks.9 For HBeAg-positive disease, AASLD guidelines recommend continuing therapy for at least 6 months after anti-HBe seroconversion with HBV DNA undetectable.8
How long have patients been followed in entecavir and tenofovir clinical extension and rollover trials? What have been the findings for durability of response and development of resistance? What is known about long-term risks?
Audio Commentary by Adrian M. Di Bisceglie, MD, FACP
Twelve months into therapy with tenofovir, the patientâs HCV DNA level remained undetectable and his ALT and AST levels remained within the normal range. While discussing his progress at this 12-month visit, the patient brought up that his first liver biopsy showed significant fibrosis. He asked whether he should have another liver biopsy to check for improvement in his fibrosis due to his current treatment response.
Clinical Decision Point 4: Treatment Effect on Fibrosis
Question 4: Which of the following is the best response to the patientâs question about liver biopsy and fibrosis?
- Follow-up liver biopsy is not indicated; although his fibrosis is not expected to progress due to his current treatment response, his baseline fibrosis is irreversible
- AASLD guidelines recommend an annual liver biopsy for patients undergoing antiviral therapy, although there are no data to suggest that antiviral treatment affects fibrosis
- Follow-up liver biopsy is optional but premature at 12 months; fibrosis has been shown to regress over a period of 3 to 5 years with entecavir and tenofovir antiviral therapy
Answer: (c). The role of liver biopsy is primarily to assess the initial liver histology and to rule out other explanations for liver disease when making the diagnosis of hepatitis B and the decision to treat.8 Liver biopsy is not recommended as a routine component of monitoring therapy. Nevertheless, this patient is correct in linking viral suppression with potential improvement in fibrosis. Assuming that HBV replication is controlled, multiple studies have demonstrated that fibrosis not only does not progress but also actually regresses in the majority of individuals. The time frame for regression is approximately 3 to 6 years.
Entecavir Fibrosis Data
Chang et al evaluated histologic improvement in HBeAg-positive and -negative patients from the two phase III entecavir registration trials who received entecavir for at least 3 years and participated in a rollover study.22 Of the 293 patients enrolled in the rollover study, 57 met eligibility criteria for the histologic analysis, including having had long-term liver biopsies (at baseline and 48 weeks in the original study, and again after an additional 48 weeks in the rollover study, or sooner for those who received at least 3 years of cumulative entecavir). Entecavir was dosed at 0.5 mg/day in the phase III trials and 1.0 mg/day in the rollover study. The two primary endpoints were histologic improvement (defined as â¥2-point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) and improvement in the Ishak fibrosis score (defined as â¥1-point decrease). The mean duration of entecavir therapy was 6 years, after which 96% of patients showed histologic improvement compared with 73% of patients who continued therapy for only 48 weeks. At 6 years, the mean change from baseline in the Knodell necroinflammatory score was a 6.37 reduction compared with a 3.39-point reduction at 48 weeks. Similarly, 88% of patients had at least a 1-point improvement in Ishak fibrosis score at 6 years (Figure 1) compared with 32% after 48 weeks.22 The mean change in the Ishak fibrosis score was a reduction of 1.53 points in the long-term group compared with a reduction of 0.20 points in the 48-week group. No virologic rebound or resistance was observed.
Of the 57 patients studied, 10 had advanced fibrosis or cirrhosis and all had at least a 1-point reduction in Ishak score (Figure 1).22 The 4 patients who had cirrhosis all had a median Ishak score reduction of 3 points. This cohort was evaluated more closely in a paper by Schiff et al.23 The mean change from baseline in Knodell necroinflammatory score was a 7.6-point reduction and the mean change from baseline in Ishak fibrosis score was a 2.2-point reduction. Ishak fibrosis scores decreased to 4 or less for all patients with cirrhosis, indicating a return to noncirrhotic levels.
Figure 1. Long-Term Entecavir: Proportion of Patients Demonstrating a â¥1-Point Improvement in Ishak Fibrosis Score Compared with Baseline22
*Advanced cohort includes patients with advanced fibrosis or cirrhosis.
Tenofovir Fibrosis Data
The effect of tenofovir on histologic status has been studied by Marcellin et al.19 A total of 585 HBeAg-positive and HBeAg-negative patients from the two phase III tenofovir registration trials were enrolled in an open-label extension phase for 5 years. Criteria for inclusion in the efficacy analyses were met by 299 patients and included liver biopsy at baseline and at 5 years. Histologic improvement was observed in 87.5% and 87.2% of HBeAg-positive and -negative patients, respectively. An improvement in Ishak fibrosis score of at least 1 point and 2 points was observed in 75.6% and 74.4% of the 86 patients with cirrhosis, respectively, as shown in Figure 2. No tenofovir resistance was observed through year 5. In a subset of 72 Asian patients enrolled in the two trials, 90.3% had histologic improvement, defined as a 2-point decrease in Knodell necroinflammatory score and no worsening of fibrosis, at year 5.24
Figure 2. Long-Term Tenofovir: Proportion of Patients Demonstrating a â¥1-Point Improvement in Ishak Fibrosis Score Compared with Baseline19
A plan was made for the patient to continue on long-term tenofovir with routine HBV DNA and ALT testing, as well as periodic HBsAg testing to evaluate the potential for stopping therapy if HBV DNA remains undetectable.
Adefovir is not a particularly potent antiviral agent against hepatitis B at the tolerated dose of 10 mg/day. In patients with suboptimal response to adefovir, switching to entecavir or tenofovir, more potent nucleos(t)ide analogs with lower rates of resistance, is a good strategy. A switch to one of these antiviral drugs will not only provide a more potent therapy but will also minimize the risk of renal toxicity associated with long-term use of adefovir. Resistance testing should be performed prior to the switch, however, due to cross-resistance between tenofovir and adefovir. The ability to stay on long-term therapy offers patients with baseline fibrosis or cirrhosis the opportunity for histologic improvement and fibrosis regression over time. Both entecavir and tenofovir have exciting long-term data demonstrating fibrosis reversal.
- Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003;348:800-807.
- Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med. 2005;352:2673-2681.
- Gish RG. Hepatitis B treatment: current best practices, avoiding resistance. Cleve Clin J Med. 2009;76(suppl3):S14-S19.
- Lok AS. Drug therapy: tenofovir. Hepatology. 2010;52:743-747.
- Tan J, Degertekin B, Wong SN, Husain M, Oberhelman K, Lok AS. Tenofovir monotherapy is effective in hepatitis B patients with antiviral treatment failure to adefovir in the absence of adefovir-resistant mutations. J Hepatol. 2008;48:391-398.
- Sheen E, Trinh HN, Nguyen TT, et al. The efficacy of entecavir therapy in chronic hepatitis B patients with suboptimal response to adevofir. Aliment Pharmacol Ther. 2011;34:767-774.
- Nguyen MH, Trinh HN, Do ST, et al. Complete viral suppression (CVS) rates at year 2 in adefovir-experienced chronic hepatitis B (CHB) patients who were switched to entecavir monotherapy: a multicenter study. Hepatology. 2011;54:Abstract 1418.
- Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-662.
- Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011-1020.
- Zhao SH, Liu EQ, Cheng DX, et al. Comparison of entecavir and adefovir for the treatment of chronic hepatitis B. Braz J Infect Dis. 2012;16:366-372.
- Reijnders JG, Deterding K, Petersen J, et al. Antiviral effect of entecavir in chronic hepatitis B: influence of prior exposure to nucleos(t)ide analogues. J Hepatol. 2010;52:493-500.
- Patterson SJ, George J, Strasser SI, et al. Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B. Gut. 2011;60:247-254.
- Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442-2455.
- van BÃ¶mmel F, de Man RA, Wedemeyer H, et al. Long-term efficacy of tenofovir monotherapy for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide analogues. Hepatology. 2010;51:73-80.
- Marcellin P, Buti M, Krastev Z, et al. Two year tenofovir disoproxil fumarate (TDF) treatment and adefovir dipivoxil (ADV) switch data in HBeAg-negative patients with chronic hepatitis B (study 102), preliminary analysis. Hepatology. 2008;48:Abstract 146.
- Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006;131:1743-1751.
- Ha NB, Ha NB, Garcia RT, et al. Renal dysfunction in chronic hepatitis B patients treated with adefovir dipivoxil. Hepatology. 2009;50:727-734.
- Izzedine H, Hulot JS, Launay-Vacher V, et al. Renal safety of adefovir dipivoxil in patients with chronic hepatitis B: two double-blind, randomized, placebo-controlled studies. Kidney Int. 2004;66:1153-1158.
- Marcellin P, Buti M, Gane EJ, et al. Five years of treatment with tenofovir DF (TDF) for chronic hepatitis B (CHB) infection is associated with sustained viral suppression and significant regression of histological fibrosis and cirrhosis. Hepatology. 2011;54:Abstract 1375.
- Baraclude [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2010.
- Viread [package insert]. Foster City, CA: Gilead Sciences, Inc; 2012.
- Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010;52:886-893.
- Schiff ER, Lee SS, Chao YC, et al. Long-term treatment with entecavir induces reversal of advanced fibrosis or cirrhosis in patients with chronic hepatitis B. Clin Gastroenterol Hepatol. 2011;9:274-276.
- Gane EJ, Marcellin P, Sievert W, et al. Five years of treatment with tenofovir DF (TDF) for chronic hepatitis B (CHB) infection in Asian patients is associated with sustained viral suppression and significant regression of histological fibrosis and cirrhosis. Hepatology. 2011;54:Abstract 1429.