Patient Description
Mr. C is a 59-year-old man who was born in Vietnam and emigrated to the United States in 1976. He was referred for consultation based on abnormal liver enzymes found during a routine physical. He reported no symptoms. His medical history included hypertension treated with an angiotensin-converting enzyme inhibitor, and diabetes mellitus treated with oral medications. The patient denied knowledge of any history of hepatitis diagnosis or treatment, but admitted to taking some "herbal medicines for his liver" from a Chinese herbalist and what he thinks was lamivudine prescribed by a physician several years ago. His family history included one brother with a history of hepatocellular carcinoma (HCC) diagnosed at age 60 following liver transplant.
Physical examination showed a slightly enlarged spleen and occasional vascular spiders. Appropriate laboratory tests were ordered with the results as shown in Table 1. Ultrasound imaging confirmed a slightly nodular liver, splenomegaly, and no ascites. Mr. C refused a liver biopsy.
Table 1. Laboratory Test Results
| Test | Patient Results | Reference Range |
| Alanine aminotransferase (ALT) | 98 U/L | 17–45 U/L |
| Aspartate aminotransferase (AST) | 88 U/L | 17–45 U/L |
| Albumin | 4.0 g/dL | 3.5–5.5 g/dL |
| Bilirubin, total | 1.0 | <1.0 mg/dL |
| Alpha-fetoprotein (AFP) | 3.5 ng/mL | 1.6–4.5 ng/mL |
| Hemoglobin | 12 g/dL | 14–18 g/dL |
| White blood cell count | 4600/mm3 | 5000–10,000/mm3 |
| Platelets | 158,000/mm3 | 150,000–400,000/mm3 |
| International Normalized Ratio (INR) | 1.0 | 1.0–1.2 |
| Hepatitis B surface antigen (HBsAg) | Positive | __ |
| Hepatitis B e antigen (HBeAg) | Negative | __ |
| Hepatitis B e antibody (anti-HBe) | Positive | __ |
| HBV DNA | 2.09 x 106 IU/mL | __ |
| Hepatitis A antibody (anti-HAV) | Negative | __ |
| Hepatitis C antibody (anti-HCV) | Negative | __ |
| Hepatitis D antibody (anti-HDV) | Negative | __ |
| Human immunodeficiency virus (HIV) | Negative | __ |
Since it is likely this patient has been infected with hepatitis B since childhood or birth, at which points in his medical history should he have been tested for HBV? In other words, where were the missed opportunities? Audio Commentary by Tram T. Tran, MD.
Clinical Decision Point 1: Identifying Need for Treatment
Question 1: Based on this patient's clinical profile and laboratory results, should he be started on anti-HBV therapy at this time?
Discussion
(c) Treatment should be initiated in this patient, given that his liver enzymes are elevated to greater than twice the upper limit of normal (ULN)1, and his HBV DNA level is greater than the treatment threshold for HBeAg-negative disease identified in both the U.S. Algorithm2 and the American Association for the Study of Liver Disease (AASLD)1 treatment guideline (2000 IU/mL and 20,000 IU/mL, respectively). His low platelet count and abnormal ultrasound—highly suggestive of cirrhosis—further underscore the appropriateness of treatment.1 His absence of symptoms should not be a factor in the decision to treat. Patients with chronic hepatitis B are typically asymptomatic and, therefore, may not be aware of the infection until they have advanced liver disease.3 The presence of cirrhosis also should not preclude a patient from treatment, since reversal of fibrosis with long-term antiviral therapy, even in patients with advanced fibrosis and cirrhosis, is an important benefit of therapy.4,5
The goals of anti-HBV therapy are to improve liver histology and to prevent cirrhosis, liver failure, and HCC by achieving sustained suppression of HBV replication.1,2 The risks associated with high HBV DNA levels were elucidated in the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-HBV (REVEAL-HBV) study, a large prospective natural history study that followed more than 4100 HBsAg-positive Asian subjects for up to 13 years.6 This study demonstrated that high HBV DNA levels at study entry were associated with an increased risk of progression to cirrhosis and HCC.6 A total of 3653 subjects were included in the HCC analysis; 3582 subjects were included in the cirrhosis analysis.6
The hazard ratio for cirrhosis increased incrementally across the range of HBV DNA levels, after being corrected for cigarette smoking, alcohol use, age, and gender (Table 2).6 The risk of progression to cirrhosis was greatest for subjects with HBV DNA levels at or exceeding 106 copies/mL, who had more than a 6-fold higher risk of progressing to cirrhosis compared with subjects with HBV DNA levels less than 300 copies/mL.6 In a subgroup analysis, the stepwise association persisted for HBeAg-negative subjects. Similarly, the risk of HCC increased across the range of HBV DNA levels, independent of ALT level, presence of cirrhosis, or HBeAg status (Table 2).6 HBV DNA levels at or exceeding 104 copies/mL strongly predicted HCC, with a risk more than twice that associated with a level of less than 300 copies/mL.6 The risk gradient was steeper in HBeAg-negative subjects: HBV DNA levels of 106 copies/mL conferred more than a 10-fold greater risk compared with the reference level.6
Table 2. Multivariate Hazard Ratios of Developing Cirrhosis or HCC Based on HBV DNA at Study Entry6
HBV DNA | Cirrhosis Analysis | HCC Analysis | ||
All | HBeAg-Negative | All | HBeAg-Negative | |
<300 | 1.0 | 1.0 | 1.0 | 1.0 |
300–<104 | 1.4 | 1.4 | 1.1 | 1.0 |
104–<105 | 2.5* | 2.4* | 2.3† | 2.6† |
105–<106 | 5.6* | 5.4* | 6.6* | 6.1* |
≥106 | 6.5* | 6.7* | 6.1* | 10.6* |
*P <.001
†P <.05
In a rollover study of participants from two phase III entecavir trials, Chang and colleagues demonstrated that a majority of treatment-naive patients who received long-term entecavir (0.5 mg daily in the phase III trials, followed by 1.0 mg daily in the rollover study) had significant histologic improvement and reversal of fibrosis or cirrhosis.4 Of the 293 patients who enrolled in the rollover study, 57 met inclusion criteria and underwent long-term biopsy.4 The mean baseline HBV DNA level in these patients was 9.4 log10 copies/mL, and the mean Knodell necroinflammatory and Ishak fibrosis scores were 8.0 and 2.4, respectively.4 After a median of 6 years of therapy, 96% of patients showed histologic improvement compared with 73% of patients after 48 weeks of therapy.4 The mean change from baseline in the Knodell necroinflammatory score was a 6.37-point reduction at 6 years compared with a 3.39-point reduction after 48 weeks.4 Similarly, the mean change in the Ishak fibrosis score was a 1.53-point reduction after 6 years compared with a 0.20-point reduction after 48 weeks.4
Improvement in liver histology and reversal of fibrosis or cirrhosis was observed even in patients from this cohort with advanced fibrosis or cirrhosis.5 Of the 57 patients in the rollover study,4 10 had advanced fibrosis or cirrhosis, as indicated by an Ishak fibrosis score ≥4, with a mean Knodell necroinflammatory score of 10.3 and a mean Ishak fibrosis score of 4.6.5 All 10 patients showed histologic improvement and fibrosis regression after a median of 6 years on entecavir therapy.5 The mean changes from baseline in Knodell necroinflammatory score and Ishak fibrosis score were -7.6 and -2.2, respectively.5 Importantly, all patients with cirrhosis at baseline achieved a reduction in fibrosis score to noncirrhotic levels.5 Lamivudine and adefovir also have demonstrated a regressive effect on fibrosis and cirrhosis, but the resistance associated with long-term use of these antivirals limits this effect.5 The effect of tenofovir on histologic status has also been studied with data soon to be available.
What role does this patient's family history play in his need for anti-HBV treatment? Audio Commentary by Tram T. Tran, MD.
Case Continues
Mr. C returned to the clinic to discuss his treatment options.
Clinical Decision Point 2: Selecting Initial Therapy
Question 2: Which of the following current first-line treatment options would be the best choice for this patient?
Discussion
(a or d) Oral nucleoside analogs are preferred over interferon in patients with compensated cirrhosis due to the risk of hepatic decompensation associated with interferon-related flares in this population.1 Among the nucleoside analogs, entecavir or tenofovir are recommended as initial therapy for these patients.1 Although lamivudine, adefovir, and telbivudine also are approved anti-HBV therapies, they are not recommended in patients with compensated cirrhosis due to their high rate of resistance and adefovir's comparatively weaker antiviral effect.1 Furthermore, tenofovir and entecavir are both indicated for patients with lamivudine-resistant disease. Current treatment guidelines, however, suggest that entecavir is not an "optimal treatment" in these patients due to the potential cross-resistance between lamivudine and entecavir and data indicating an increased risk of entecavir resistance over time in patients with lamivudine-refractory HBV.1,7 Without resistance testing, it cannot be known whether this patient has resistant mutation(s).
Interferon is associated with flares in 25% to 40% of treated patients, typically during the second and third months of treatment.8 Flares are most likely to be observed in patients with low baseline ALT levels or cirrhosis.8 A flare—defined as an intermittent increase in ALT to more than 10 times ULN and more than twice the baseline level1,2—is a marker of increased necroinflammatory activity resulting from interferon's stimulatory effect.8 The increased T-cell cytolytic activity and natural killer cell function are important mechanisms of antiviral action, but they can also cause liver damage.8 Due to the already compromised liver reserve in patients with cirrhosis, flares carry a particular risk of liver failure.8
Entecavir resistance requires a pre-existing lamivudine resistance mutation at codon M204I/V, with or without a mutation at L180M, plus at least one additional mutation at codon T184, S202, or M250.9 Entecavir resistance with long-term therapy is rare in treatment-naive patients: 1.2% for genotypic resistance and 0.8% for virologic breakthrough associated with resistance after 5 years of treatment.9 In contrast, the barrier to resistance is reduced in patients with lamivudine-refractory disease, with resistance observed in up to 51% of patients after 5 years of entecavir therapy.9 Combined data from phase II and III entecavir trials found that the cumulative probability of genotypic entecavir resistance in patients with lamivudine-refractory disease was 6%, 15%, 36%, 47%, and 51% in years 1 through 5, respectively.9 Similarly, virologic breakthrough associated with resistance emerged with a cumulative probability of 1%, 11%, 27%, 41%, and 43%, respectively.9 Given this patient's previous exposure to medication that was likely lamivudine for an unknown period of time, the possibility of lamivudine resistance plays a role in treatment choice.
Tenofovir is known to be active against lamivudine-resistant hepatitis B.10,11 It has demonstrated a potency similar to adefovir, but can be given at a dose 30-fold higher due to its improved safety profile.1 Consequently, phase III clinical trials have demonstrated significantly higher in vivo antiviral potency with tenofovir compared with adefovir for 48 weeks in the setting of both HBeAg-positive and -negative disease.12 Importantly, there was no difference in response based on prior lamivudine use. Ninety percent of patients who had received lamivudine for at least 12 weeks achieved HBV DNA suppression to less than 400 copies/mL compared with 88% of those who had no prior lamivudine.12
The efficacy and safety of long-term tenofovir administration in patients with HBeAg-positive and -negative disease is currently being evaluated in an extension phase of the phase III trials.13 Patients who had liver biopsy had the option to continue on open-label tenofovir for 7 more years.13 Heathcote and colleagues recently published data through year 3.13 In patients with HBeAg-positive disease, 72% had HBV DNA levels less than 400 copies/mL, and 74% maintained normal ALT levels. In patients with HBeAg-negative disease, HBV DNA and ALT endpoints were met in 87% and 81% of patients, respectively.13 Tenofovir's safety profile through year 3 was favorable.13
Case Continues
Resistance testing was done and confirmed the presence of a resistance mutation at M204I/V. The patient was started on tenofovir disoproxil fumarate 300 mg daily with a monitoring schedule that included HBV DNA and ALT tests every 3 months. In addition, he was advised to undergo surveillance for HCC—ultrasound and alpha-fetoprotein (AFP) every 6 to 12 months—due to his family history, ethnicity, gender, age (>40 years), elevated ALT level, and elevated HBV DNA level (>2000 IU/mL).1
Sixteen months later, his HBV DNA level became undetectable and his ALT level was 42 U/L. His HBeAg remained negative, and HBsAg remained positive.
At his next clinic visit, Mr. C was noted to be slightly anxious. He said he did not understand why he must continue medication when he "felt fine before" and felt no differently now. He explained that the medication co-pays are expensive. He asked, "Can we discuss coming off the medication?"
Clinical Decision Point 3: Duration of Therapy
Question 3: What would be the likely outcome if the patient stopped anti-HBV medication at this point?
Discussion
(b) Despite the patient's undetectable HBV DNA level after 16 months of treatment, most likely his viral level would rebound to that seen at baseline if he were to discontinue treatment now. The rebound would be due to removal of viral suppression rather than emergence of drug-resistant viral variants.
The treatment endpoint for patients with HBeAg-positive disease is HBeAg seroconversion.1 The majority of these patients will maintain viral suppression if treatment is stopped at this point.1 In patients with HBeAg-negative disease, treatment usually continues indefinitely, however. Relapse after treatment discontinuation is common, even when HBV DNA has been undetectable for a year or more.1 Treatment should be continued long-term in these patients until HBsAg clearance has been achieved.1 HBsAg clearance, however, is rare.14
In a randomized placebo-controlled trial of long-term adefovir in HBeAg-negative patients, Hadziyannis and colleagues evaluated the outcome of stopping therapy after 48 weeks compared with continuing it for an additional 48 weeks.14 Of the 123 patients who received adefovir in the study's first 48-week phase, 79 continued on adefovir and 40 switched to placebo for the second 48-week phase.14 Of the 61 patients who had initially received placebo in the first phase, 60 switched to adefovir for the second phase.14 HBV DNA levels returned to baseline rapidly in the adefovir-to-placebo group—within 4 weeks after adefovir discontinuation in the majority of patients.14 After 96 weeks of therapy, 71% and 76% of patients in the continued-adefovir group and the placebo-to-adefovir group, respectively, had undetectable HBV DNA levels compared with 8% in the adefovir-to-placebo group.14 ALT levels returned to baseline levels or higher in the majority of patients 8 weeks after discontinuing adefovir.14 HBsAg seroconversion was observed in only 2 patients, both from groups receiving adefovir.14
A similar pattern of relapse was observed in patients with HBeAg-negative disease who discontinued successful entecavir or lamivudine therapy after 48 weeks.15 Among the 275 entecavir-treated and 201 lamivudine-treated patients who had achieved suppression of HBV DNA to less than 300 copies/mL, only 3% and 5%, respectively, maintained that suppression 24 weeks after discontinuation.15
Emergence of resistance mutations would be unlikely in this patient, because no reports of confirmed clinical resistance to tenofovir have been observed to date. Throughout the 48 weeks of therapy in the two phase III pivotal tenofovir trials, no resistance mutations were found that conferred clinical resistance.12 In an open-label extension with combined trial cohorts, no resistance mutation has yet been found through week 144.16 Therefore, the likelihood of developing resistance to medication 16 months into therapy is low. In addition, stopping medication would not lead to resistance.
What assistance can a clinician offer to a patient who is having financial difficulty in staying on therapy (ie, expensive co-pays, no insurance)? Audio Commentary by Tram T. Tran, MD.
Case Continues
The rationale for staying on anti-HBV therapy was explained to Mr. C, with particular attention to reviewing his risk factors for progression to HCC, which include family history, high HBV DNA level, and likely cirrhosis. He agreed to remain on medication, as well as continue HCC surveillance.
Why are cirrhosis and HCC more common in patients with HBeAg-negative disease? Audio Commentary by Tram T. Tran, MD.
Conclusion
Treatment decisions must take into account ALT and HBV DNA levels, as well as clinical risk factors, such as family history, and indicators of liver function, such as platelet count and imaging findings. Previous exposure to unidentified liver-related medications may affect treatment response due to pre-existing resistance and should be considered when making the initial treatment choice. For patients with cirrhosis or likely cirrhosis, the possibility that interferon therapy may be associated with a clinically significant hepatitis flare narrows treatment options to nucleoside analogs. For patients with HBeAg-negative disease, the lack of clear treatment endpoints and the likelihood of an indefinite treatment duration must also be considered, with attention to the probabilities of resistance with long-term therapy.
Viral eradication within the liver is difficult to achieve or demonstrate in clinical practice. Therefore, the success of anti-HBV treatment is judged by other markers, including viral suppression, aminotransferase normalization, and histologic improvement or stability. For patients at high risk of HCC, routine surveillance is an important part of achieving therapeutic goals.
References
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