Mr. P, a 45-year-old Vietnamese civil engineer, was found to be positive for hepatitis B surface antigen (HBsAg) during a screening test after his 59-year-old brother was diagnosed with hepatocellular carcinoma (HCC) due to chronic hepatitis B (CHB). His family physician wanted to immediately initiate lamivudine 100 mg PO daily. However, the patient was reluctant to start on treatment due to concerns about the safety of long-term therapy. Instead, he sought a second opinion.
Born in Vietnam, Mr. P's family had immigrated to the United States in 1975 after the fall of Saigon. In addition to the older brother with hepatitis B virus (HBV)-related HCC, his two sisters also are HBsAg positive. No further details concerning their health are available. The patient's mother is alive at 85 years, but her hepatitis B status is unknown. His father, also with an unknown hepatitis B status, died at the age of 70 years due to a stroke. HBV screening has been initiated for the patient's wife, also a Southeast Asian immigrant, and their two children.
The patient appeared to be in good health. He was asymptomatic and reported no previous medical or surgical history. He does not consume alcohol or tobacco and takes no prescribed medications. The patient consumes a daily multivitamin. Physical examination showed a weight of 135 lb. and body mass index of 21. All vital signs were normal, as was the examination.
Laboratory values were as follows: white blood cell count 5100 cells/mm3; hemoglobin 15 g/dL, hematocrit 42%; platelet 128,000/mm3; albumin 4.0 mg/mL, alanine aminotransferase (ALT) 37 IU/mL; and aspartate aminotransferase (AST) 40 IU/mL. According to the testing laboratory, the normal range for ALT is <=38 mg/mL and the normal range for AST is <=40 mg/mL.
What cultural characteristics unique to Vietnamese immigrants should clinicians be aware of when discussing a diagnosis of chronic hepatitis B?
Audio Commentary by Dr. Naoky C.S. Tsai
Clinical Decision Point 1: Assessing Treatment Candidacy
Question 1: Which of the following best describes the most appropriate next step?
- Due to the "normal" ALT level, recommend routine monitoring but no treatment
- Tell the patient he is a healthy carrier and no further action is needed
- Order liver ultrasound and HBV DNA and hepatitis B e antigen (HBeAg) tests
- Start anti-HBV treatment now
(c) Despite apparent good health now, this patient is at risk of serious liver disease, including HCC, and requires careful evaluation and monitoring. Establishing this patient's current HBV DNA level and HBeAg status are important next steps to placing his disease course within the natural history of CHB.1-4 After this assessment of important HBV markers, an advised treatment decision can be made. A baseline liver imaging study and long-term surveillance are also indicated due to his familial risk of HCC.5
The natural history of hepatitis B includes four phases: immune tolerance, HBeAg-positive CHB, HBeAg-negative CHB, and inactive carrier.1-3 Some patients exhibit each of these phases, and in a sequential manner, although others do not. As Table 1 illustrates, these phases are differentiated primarily by HBeAg status, ALT and HBV DNA levels, and liver histology.1-3
The immune tolerance phase can last from 1 to 4 decades in patients with perinatally acquired infection, whereas this phase may be very short or absent when the infection is acquired in adolescence or adulthood.1 This phase is characterized by normal ALT, minimal or no inflammation despite the presence of HBeAg, and high levels of HBV replication. Spontaneous and treatment-induced seroconversion of HBeAg to anti-HBe are infrequent during this phase.1-3
In the second phase, HBeAg-positive CHB, the serologic profile remains the same as in the immune tolerant phase, but active inflammation is evident on biopsy and ALT levels become persistently or intermittently elevated.1-3 A proportion of patients seroconvert, due to treatment or spontaneously, resulting in the development of anti-HBe and the loss of HBeAg. These patients may become inactive carriers, characterized by low or undetectable levels of replicating virus and persistently normal ALT levels. Inflammation and fibrosis, if present on biopsy, are usually mild or minimal and nonprogressive, although residual cirrhosis from the CHB phase may persist in a few patients.
A subset of patients who develop anti-HBe does not move into the inactive carrier phase.1 These patients instead progress directly to the HBeAg-negative CHB phase, also called the HBV reactivation phase. In this phase, one or two viral mutations (precore or basal core promoter) decreases or switches off HBeAg expression, thereby allowing the virus to escape anti-HBV immune activity.6 This phase is characterized by active replication and liver inflammation, and rare spontaneous HBV DNA clearance.1,2
Table 1. Phases of Chronic Hepatitis B Infection1-3
||Normal or minimal elevation
|Minimal or no inflammation
||Persistent or intermittent elevation
||High or fluctuating; >20,000 IU/mL
||Low or undetectable;
|Usually mild inflammation, minimal fibrosis; inactive cirrhosis may have accrued in previous phases
||Elevated or fluctuating
||Moderate or fluctuating; >2000 IU/mL
Abbreviations: ALT, alanine aminotransferase; anti-HBe, antibody to hepatitis B e antigen; CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.
The term "healthy carrier" is a misnomer or oxymoron. In fact, there is no such thing as a healthy carrier of HBV when patients are at substantial risk of cirrhosis or cancer. CHB is characterized by a dynamic viral and host interaction.1 In many individuals, the host immune response keeps the virus under control, as evidenced by undetectable HBV DNA. These individuals are more correctly termed "inactive carriers." Despite effective immune control, HBV DNA persists in liver tissue. Flares of disease represented by replicative activity (ie, elevated or measurable serum HBV DNA) can result in disease progression that would go undetected without routine monitoring.
It is fortunate that this patient was screened before more time had passed. Hepatitis B is endemic in Vietnam, with a prevalence of approximately 11% to 20%.7,8 Up to 90% of infections are believed to be acquired perinatally or shortly after birth in early childhood, a transmission period that confers a high risk of chronicity.8 Among ethnic groups in the United States, Vietnamese have the highest rate of HCC, with 80% of cases related to HBV.9 New CDC guidelines released in late 2008 recommend screening for all individuals who were born in geographic areas with HBsAg prevalence of 2% or greater.10 If this patient had not been screened on the basis of his brother's HCC diagnosis, his country of origin alone would be sufficient cause to prompt screening.
Compared with adult acquisition of HBV, what impact does childhood and perinatal acquisition have on the progression of liver disease?
Audio Commentary by Dr. Naoky C.S. Tsai
A liver ultrasound and additional laboratory tests were ordered to better characterize this patient's infection and liver disease status. HBV-specific tests showed HBeAg positive, HBV DNA 5.2 x 108 IU/mL, and genotype C, with no precore or basal core promoter mutations. Prothrombin time International Normalized Ratio (INR), an indicator of liver function, was 1.1 times control value (normal). Ultrasound imaging showed diffusely coarse hepatic texture, but no hepatosplenomegaly, and was otherwise normal. The patient declined to undergo a liver biopsy.
Clinical Decision Point 2: Initiating First-Line Antiviral Treatment
Question 2: Considering all laboratory and imaging findings, which of the following best reflects the next step according to current treatment guidelines?
- Defer treatment until patient consents to liver biopsy
- Start treatment now with an oral anti-HBV agent
- Start treatment now with subcutaneous interferon alfa-2b or peginterferon alfa-2a
- ALT level indicates treatment is not needed at this time; monitor patient for signs of progression
(b) In general, current treatment guidelinesâincluding the US Treatment Algorithm and guidelines from the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL)ârecommend antiviral therapy for patients who are at risk of liver disease progression, primarily those with HBeAg-positive
or -negative CHB who have evidence of ongoing HBV replication.2-4 Patients in the immune tolerance phase have a minimal degree of liver disease, and therefore, are not usually candidates for antiviral therapy. Inactive carriers are adequately suppressing the virus, and also, therefore, are not candidates. Specific clinical characteristics, such as the need to start chemotherapy or risk factors for HCC, override these generalities, however.2,3,10,11 This patient's cumulative laboratory and imaging findings indicate that he is in the HBeAg-positive CHB phase of infection. The patient has clinical evidence of advanced fibrosis or even early cirrhosis given his age, including a low platelet count and coarse liver texture on ultrasound, with risk factors for disease progression (see Figure).2,3,12 The patient's INR, although normal, does not rule out cirrhosis. Furthermore, given his family history of HCC, he is also at higher risk for HCC development. Successful treatment has been shown to significantly delay clinical progression and reduce the risk of HCC.13
Although liver biopsy is the gold standard method of establishing baseline liver disease and ruling out other causes of injury, it is not absolutely needed to make a decision to treat, particularly when clinical and imaging evidence suggest significant liver disease.2-4 Many patients decide against biopsy due to its invasive nature and cost, deferring instead to the clinician's assessment of these other disease indicators. Liver biopsy is most useful for making treatment decisions in patients that do not otherwise meet criteria for treatment.
At first glance, this patient's ALT level of 37 IU/mL, located at the high end of the testing laboratory's normal range of 0 to 38 IU/mL, appears to challenge the categorization of this patient's infection as HBeAg-positive CHB, which is characterized by ALT elevations of 1 to 2 times the upper limit of normal.2,3 In reality, however, his "normal" ALT level does not preclude him from having serious liver disease.14 Three factors must be considered when interpreting ALT levels. First, current guidelines now suggest that ALT normal (ie, healthy) ranges should be lower than those traditionally used by testing laboratories; specifically, <=30 IU/mL for men and <=19 IU/mL for women.2,3 This move was based on data from two large retrospective cohort studies of first-time blood donors and healthy volunteers that showed ALT levels among "healthy" individuals are significantly lower than previously believed, particularly in the absence of obesity, alcohol use, and hepatotoxic medication, as is the case with this patient.14,15 Second, ALT levels do not always reflect the presence of liver injury and may be persistently normal despite moderate to severe hepatitis.14,16 Third, although ALT elevations associated with this phase of infection are usually persistent, they may also be intermittent.2,3
Of greater significance than ALT level is this patient's HBV DNA level. The strong correlation between HBV DNA levels and progression to cirrhosis was demonstrated in the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (REVEAL-HBV) study, a large, prospective, natural history study that followed more than 3500 HBsAg-positive Taiwanese patients for a mean of 11 years.17 The risk of progression to cirrhosis was greatest for patients with HBV DNA levels of 106 copies/mL or greater (>200,000 IU/mL): adjusted relative risk 6.5 (95% confidence interval [CI], 4.1â10.2; P = .001).17 However, even patients with HBV DNA levels between 103 and 104 copies/mL (200â2000 IU/mL) were at significantly greater risk for cirrhosis compared with those patients whose levels were undetectable (P <.001). In this same REVEAL study cohort, the risk of HCC was also strongly associated with HBV DNA levels.18 Levels at or greater than 104 copies/mL (>=2000 IU/mL) strongly predicted HCC independent of HBeAg status, ALT level, and presence of cirrhosis.
The role of genotype in disease progression is still being assessed. Although genotypes A and C are the most common genotypes in the United States overall, genotypes B and C are the most common among Asians.19 Generally, studies have shown that genotype C is associated with later HBeAg seroconversion, more active disease, faster progression to cirrhosis, and a greater incidence of HCC compared with genotype B.12 These and other factors related to disease progression, including progression to cirrhosis and HCC, are summarized in the Figure.
Figure. Viral and Host Factors Associated with Progression of HBV-Related Cirrhosis and HCC13
Abbreviations: HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus; HIV, human immunodeficiency virus.
With the need for treatment established in this patient, the anti-HBV agent should be selected based on likelihood of suppressing viral replication and the low potential for resistance, as well as patient preferences related to mode of administration, adverse events, duration of therapy, and cost. Currently, seven agents are approved for the treatment of HBV (see Table 2). Of these, two are interferon products and five are nucleos[t]ides. Interferon therapy has shown poor response in patients with high viral load and low ALT level at baseline.3 Furthermore, compared with genotype B, genotype C has shown a poorer response to interferon therapy.20,21 In contrast, genotypes B and C have shown no difference in response to nucleos[t]ides.22,23
Table 2. Anti-HBV Agents
||FDA Approved for CHB
||Experimental Status for CHB in the United States
Abbreviation: CHB, chronic hepatitis B.
What is the goal of therapy in this patient?
Audio Commentary by Dr. Naoky C.S. Tsai
Mr. P was started on entecavir 0.5 mg daily due to its high potency and low rate of drug resistance.2 He was instructed to return for a follow-up appointment in 3 months to monitor his response to treatment. He cancelled the 3-month appointment, but made another appointment 6 months later, which he kept. At this visit, his HBV DNA level was 8.2 x 107 and ALT level was 75 IU/mL. He reported feeling fine except for some fatigue.
Clinical Decision Point 3: Evaluating Nonresponse
Question 3: Which of the following best describes the most appropriate next step?
- Switch to tenofovir since the patient is a primary nonresponder to entecavir
- Continue entecavir and reassess after 12 months of therapy
- Assess patient's adherence to prescribed therapy and then decide whether to continue entecavir or switch agents
- Assess patient's adherence to prescribed therapy and test for drug resistance mutations prior to making treatment decision
(d) With the patient's HBV DNA level remaining high and the ALT level more than doubling, he appears to have had no response to treatment. Whether this reflects primary nonresponse or viral breakthrough (ie, >1-log increase in HBV DNA after initial response), however, cannot be assessed since the patient has not been monitored throughout the first 9 months of therapy.3 Furthermore, the patient's cancellation of the first follow-up appointment and the length of time that passed until he made the next appointment suggests nonadherence may be a reason for the lack of response. The reason behind the lack of response must be determined before continuing treatment.
Closer questioning on adherence should be the first step before taking other action. Nonadherence remains an important barrier to treatment response. In the clinical trial setting, in which patients are closely monitored, up to 30% of virologic breakthrough is attributed to suboptimal adherence to the prescribed regimen with its corresponding inadequate and inconsistent drug exposure.3 Adherence is even more likely to be compromised in the community setting when oversight is often limited to self-reporting at office visits. Long-term adherence is a culturally sensitive issue requiring upfront education in the patient's native language, respect for a patient's desire for non-Western medical approaches, and engagement of the family and other support individuals.
Virologic breakthrough can also be an indicator of drug resistance.3 While resistance can develop during even the most carefully followed courses of therapy, the risk is greater in cases of poor adherence. By not giving the agent sufficient opportunity to suppress the virus, a patient who does not adhere to the prescribed treatment regimen instead gives resistant viral mutants the opportunity to gain a foothold and become the dominant viral variant. Therefore, after assessing this patient's level of adherence since starting therapy, resistant mutation testing should be done to determine current sensitivity to entecavir. Only then can it be determined whether to continue entecavir or switch to another agent.
What strategies can a clinician use to monitor adherence in the community practice setting?
Audio Commentary by Dr. Naoky C.S. Tsai
Upon further questioning, the patient admitted that he stopped taking entecavir when his first month's prescription ran out. Worried now about the doubling of his ALT level, he said he is committed to full adherence going forward. Fortunately, a drug resistance profile showed no resistant mutations, and so the patient was restarted on entecavir. After 3 months on therapy, his ALT level was 20 IU/mL and HBV DNA level was 1.4 x 103 IU/mL. At his 6-month follow-up appointment, his ALT level was 18 IU/mL and HBV DNA level was undetectable.
The patient's wife was found to be HBsAg negative, hepatitis B core antibody (anti-HBc) positive, and anti-HBsAg positive, indicating exposure and immunity. Both children were negative for all HBV markers and were advised to receive HBV vaccination with follow-up testing to confirm immunity.
What is the long-term treatment plan for this patient, including duration of entecavir therapy and monitoring schedule?
Audio Commentary by Dr. Naoky C.S. Tsai
This patient from Vietnam, a geographic region of high endemicity for HBV, represents a typical clinical presentation at risk for advanced liver diseaseâmale gender, persistent HBeAg positivity, older age (>40 years), genotype C, high viral loadâeven though ALT levels at presentation were "normal" as reported by the testing laboratory. He declined a liver biopsy, but advanced fibrosis was suspected on the basis of thrombocytopenia and course texture on ultrasound. With treatment indicated, oral anti-HBV therapy was selected over interferon due to the patient's high viral load, near normal ALT level, and genotype C.
As this case demonstrates, even a thorough pretreatment assessment and treatment plan can be derailed when a patient does not adhere to the prescribed therapy. Nonresponse or virologic breakthrough can accompany poor adherence as does drug resistance, furthering the risk of nonresponse and limiting future treatment options. The clinician can bring therapy back on track in such a case by soliciting from the patient a renewed commitment to adherence and by testing for drug resistance mutations before choosing to restart treatment with the same or a different agent.
- Yim HJ, Lok AS. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2006. Hepatology. 2006;43:S173-S181.
- Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
- Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-539.
- European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol. 2009;50:227-242.
- Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-1236.
- Chu CJ, Keeffe EB, Han SH, et al. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology. 2003;125:444-451.
- Nguyen VT, McLaws ML, Dore GJ. Highly endemic hepatitis B infection in rural Vietnam. Gastroenterol Hepatol. 2007;22:2093-2100.
- Hipgrave DB, Nguyen TV, Vu MH, et al. Hepatitis B infection in rural Vietnam and the implications for a national program of infant immunization. Am J Trop Med Hyg. 2003;69:288-294.
- Taylor VM, Jackson JC, Pineda M, Pham P, Fischer M, Yasui Y. Hepatitis B knowledge among Vietnamese immigrants: implications for prevention of hepatocellular carcinoma. J Cancer Educ. 2000;15:51-55.
- Centers for Disease Control and Prevention. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Morb Mortal Wkly Rep. 2008;57(RR-8):1-20.
- Loomba R, Rowley A, Wesley R, et al. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med. 2008;148:519-528.
- Liaw Y-F, Sollano JD. Factors influencing liver disease progression in chronic hepatitis B. Liver Int. 2006;26:23-29.
- Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521-1531.
- Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137:1-10.
- Kariv R, Leshno M, Beth-Or A, et al. Re-evaluation of serum alanine aminotransferase upper normal limit and its modulating factors in a large-scale population study. Liver Int. 2006;26:445-450.
- Puoti C, Magrini A, Stati T, et al. Clinical, histological, and virological features of hepatitis C virus carriers with persistently normal or abnormal alanine transaminase levels. Hepatology. 1997;26:1393-1398.
- Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678-686.
- Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65-73.
- Chu CJ, Keeffe EB, Han SH, et al. Prevalence of HBV precore/core promoter variants in the United States. Hepatology. 2003;38:619-628.
- Kao JH, Wu NH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes and the response to interferon therapy. J Hepatol. 2000;33:998-1002.
- Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365:123-129.
- Westland C, Delaney W, Yang H, et al. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil. Gastroenterology. 2003;125:107-116.
- Yuen MF, Wong DK, Sablon E, et al. Hepatitis B virus genotypes B and C do not affect the antiviral response to lamivudine. Antivir Ther. 2003;8:531-534.