Halting the Natural History of Hepatitis B Viral Infection: A Paradigm Shift

• ABSTRACT
• CLINICAL SCENARIO
• REEXAMINING THE PROGNOSIS FOR HBV-INFECTED PATIENTS
• ALT Activity and Hepatic Complications
• Serum HBV DNA Concentration and Hepatic Complications
• Serologic Markers and Hepatic Complications
• DISCUSSION OF SCENARIO 1
• SERUM HBV DNA CONCENTRATION AND MEDICATION RESISTANCE
• Serum HBV DNA Concentration and Virologic Response
• POTENTIAL FUTURE TREATMENT PARADIGMS
• CONCLUSION
• ABBREVIATIONS
• REFERENCES

ABSTRACT

The 2007 American Association for the Study of Liver Diseases (AASLD) practice guidelines for managing chronic hepatitis B virus (HBV) infection recommend pharmacologic therapy for patients with alanine aminotransferase (ALT) activity higher than 2 times the upper limit of normal and serum HBV DNA concentration higher than 20,000 IU/mL. Findings reported over the past several years, however, indicate that HBV infection associated with ALT activity and serum HBV DNA concentrations below these treatment thresholds can progress to serious liver disease, such as cirrhosis or hepatocellular carcinoma. These findings suggest that these treatment thresholds may be too conservative. Moreover, emerging data suggest that, in some patient populations, the appropriate goal of therapy may be sustained suppression of HBV DNA with maintenance antiviral therapy. A satellite symposium conducted during the 57th Annual Meeting of the AASLD in Boston, Massachusetts, presented new findings relative to the course of HBV infection.

Chronic hepatitis B virus (HBV) infection affects more than 350 million people worldwide and is responsible for 500,000 to 1 million deaths per year.[1] Although HBV infection is pandemic, it is most endemic to the Asia-Pacific region and sub-Saharan Africa. In the United States, chronic HBV infection affects at least 1.25 million people,[2] most of whom are immigrants from regions where the disease is endemic. Chronic HBV infection is associated with cirrhosis and hepatocellular carcinoma (HCC)[3] and is the underlying cause of 3% of all liver transplantation procedures performed in the United States.[4] Prophylactic vaccines have been available since 1982 and are extremely effective in preventing chronic HBV infection[1]; however, global immunization has been prohibited by cost and a lack of awareness about HBV infection.

In 2001, the American Association for the Study of Liver Diseases (AASLD) issued practice guidelines for the management of HBV infection.[5] Since the original publication of the practice guidelines, several medications have received U.S. Food and Drug Administration (FDA) approval for the treatment of HBV infection. The availability of new therapies along with recently published data from clinical trials prompted the AASLD to publish updated practice guidelines in February 2007.[6] Currently, the threshold for initiating therapy for chronic HBV infection is alanine aminotransferase (ALT) activity higher than 2 times the upper limit of normal (ULN) (range of normal ALT activity is variable between laboratories) and serum HBV DNA concentration higher than 20,000 IU/mL. For patients with HBeAg-negative infection and moderate to severe inflammation or significant fibrosis as documented by liver biopsy, the AASLD guidelines recommend treatment when serum HBV DNA concentration is higher than 2000 IU/mL and ALT activity is one times the ULN or higher.[6] Because available therapies lack proven long-term effectiveness for patients with mild liver disease, the practice guidelines recommend careful consideration of a patient's age, severity of liver disease, likelihood of response, and potential adverse events and complications before treatment is initiated.

As of October 2006, 6 drugs are approved in the United States for the treatment of chronic HBV infection: 2 formulations of interferon and 4 oral nucleos(t)ide analogues. Therapy with pegylated interferon alfa-2a and conventional interferon alfa-2b is of a finite duration, results in a durable treatment response,[7] [8] and is not associated with the development of drug resistance. However, interferons are given by injection and are frequently associated with unpleasant adverse effects.[9] The FDA-approved oral nucleos(t)ide analogues lamivudine, adefovir, entecavir, and telbivudine exert potent antiviral effects with less toxicity than interferon, but these drugs may be associated with viral resistance.[10] [11]

Recent reports suggest that the serum HBV DNA concentration may be more predictive of cirrhosis and HCC than is ALT activity.[12] [13] In addition, current findings indicate that patients with ALT activity or serum HBV DNA concentrations below the 2007 AASLD-recommended treatment thresholds can experience cirrhosis or HCC.[14] [15] Hence, the cutoff values recommended in the AASLD practice guidelines for both ALT activity and serum HBV DNA concentration have been subjected to scrutiny; some experts assert that they may be too high to protect certain patients from cirrhotic complications and HCC. A satellite symposium conducted during the 57th Annual Meeting of the AASLD in Boston, Massachusetts, presented new findings relative to the natural history of chronic HBV infection. The discussion was framed as a clinical scenario for treating HBV infection in a hypothetical patient.

CLINICAL SCENARIO

Win is a 45-year-old, nonobese Asian who was rejected as a blood donor at a local blood donation center 9 months ago. Win reports that he feels well and exercises regularly. He has never been overweight and drinks only an occasional beer. His laboratory results are as follows: ALT activity, 32 and 36 U/L (reference for normal range: roughly 15-45 U/L, though variable between laboratories) on two separate occasions; hepatitis B surface antigen (HBsAg), positive; hepatitis B e antigen (HBeAg), negative; anti-HBe, positive; and serum HBV DNA concentration, 12,000 IU/mL (~67,000 copies/mL; 1 IU equals ~5.6 genomes per mL, depending on the quantification assay). Win's family history is negative for HBV infection. One of his uncles died of liver cancer, but he knows few details about his uncle's condition.

Because Win's ALT activity is within the normal range, his serum HBV DNA concentration is relatively low, and his serum is negative for HBeAg, the 2007 AASLD guidelines would recommend continued monitoring of liver function and HBV markers without pharmacologic intervention.

REEXAMINING THE PROGNOSIS FOR HBV-INFECTED PATIENTS

ALT Activity and Hepatic Complications

Because an increase in serum ALT activity is an indicator of necroinflammatory activity, normal ALT activity (roughly 15-45 U/L, though variable between laboratories) is often considered predictive of histologic quiescence. Compared with patients whose ALT activity is higher than normal, HBV-infected patients with persistently normal ALT activity generally have milder liver inflammation (as demonstrated by review of biopsy specimens) and tend to exhibit a less efficient response to antiviral therapy. For these reasons, HBV infection in patients with normal ALT activity is often not treated.

However, in patients with liver disease, normal ALT activity may misrepresent the degree of underlying disease. In fact, ALT or aspartate aminotransferase (AST) activity between 20 and 40 U/L is positively associated with increases in liver-related mortality rates. Analyses of insurance data collected from a cohort of 142,055 Korean patients demonstrated a significant association between slight elevations in serum aminotransferase activity and death due to liver disease.[14] Although the study did not consider the cause of liver disease, the liver-related mortality risks of patients with ALT and AST activity between 20 and 29 U/L (in men) or between 30 and 39 U/L (in both men and women) were significantly higher than those of patients with serum aminotransferase activity lower than 20 U/L. Similar results have been demonstrated among patients in whom liver disease developed as a result of untreated chronic HBV infection. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-in HBV (REVEAL) Study Group-a prospective study of more than 3000 Taiwanese persons with untreated HBV infection-demonstrated that although the rate of liver disease progression was associated with higher rates of elevated ALT activity (45 U/L or greater), more than 80% of the cases of cirrhosis and HCC occurred in patients with ALT activity lower than 45 U/L.[12] [13] Analyses from this study showed that the risk of liver disease progression increases significantly with serum HBV DNA concentration and is independent of ALT activity and HBeAg status.[12] [13] In a study of Chinese patients with chronic HBV infection who underwent liver biopsy, Yang and colleagues found that 30% to 40% of patients who exhibited normal serum aminotransferase activity for more than 6 months had histologic findings indicating at least grade 2 or stage 2 disease.[14] A total of 327 patients in this study had normal serum aminotransferase activity. Of the 183 patients with normal serum aminotransferase activity and HBeAg-positive infection, 74 had grade 2 or 3 disease and 63 had stage 2, 3, or 4 disease. Of the 144 patients with normal serum aminotransferase activity and HBeAg-negative/anti-HBe-positive infection, 60 had grade 2 or 3 disease and 67 had stage 2, 3, or 4 disease.[14] Taken together, these findings suggest that serum ALT or AST activity within the normal laboratory range is not a reliable predictor of progression of or death due to liver disease.

Patients with mild elevations in ALT activity appear to be at higher risk of cirrhotic complications and HCC than those with normal ALT activity. In a study of 3233 Chinese patients with chronic HBV infection who were grouped on the basis of ALT activity at presentation and followed up for an average of 4 years, Yuen and colleagues found that the group with ALT activity 1 to 2 times the ULN (range of comparison: 0.5 to 6 U/L times the ULN) was at highest risk of cirrhotic complications and HCC.[16] However, the risk of cirrhosis and HCC was greater for the group of patients with ALT activity higher than 0.5 to 1 U/L times the ULN than that of the group with ALT activity lower than 0.5 U/L times the ULN. More than two thirds of the patients who experienced complications were already HBeAg-seronegative when the complications occurred.

Serum HBV DNA Concentration and Hepatic Complications

The serum concentration of HBV DNA is a measure of the level of viral replication. Previously, serum HBV DNA testing was performed with nonamplified hybridization assays (lower limit of quantification, 10⁵ to 10⁶ copies/mL). The AASLD-recommended treatment threshold of serum HBV DNA concentration higher than 10⁵ copies/mL is based on the limits of the previously used assays and on limited studies in which patients with seroconversion from HBeAg-positive to anti-HBe-positive status exhibited corresponding serum HBV DNA clearance and improvement in histologic findings.[17] [18] The threshold serum HBV DNA concentration associated with progressive liver disease is unknown; however, fibrosis and cirrhosis have been reported in patients with serum HBV DNA concentrations lower than 10⁵ copies/mL.[19] In a study that involved 110 patients with cirrhotic complications and HCC, 43.6% had serum HBV DNA concentrations lower than 1.42 × 10⁵ copies/mL either before, when, or after the complications were reported.[16] Similarly, among a cohort of 3754 Asian-American HBV-infected patients, a viral load lower than 10⁵ copies/mL compared with an undetectable serum HBV DNA concentration conferred a relative risk of HCC of 4.1 (95% confidence interval [CI], 1.1-15.5), and a viral load higher than 10⁵ copies/mL conferred a relative risk of HCC of 8.4 (95% CI, 2.8-25.7).[20]

Findings from the REVEAL Study Group suggest that higher baseline serum HBV DNA concentrations are associated with increased risks of cirrhosis and HCC.[12] [13] In an analysis that included more than 3000 patients for a mean follow-up period of 11 years, the cumulative risks of cirrhosis and HCC increased significantly with increased baseline serum HBV DNA concentration. The incidence of cirrhosis increased from 4.5% (relative risk, 1.4; reference: undetectable serum HBV DNA) for patients with baseline serum HBV DNA concentrations lower than 300 copies/mL to 36.2% (relative risk, 9.8) for patients with serum concentrations of 10⁶ copies/mL or higher.[13] This relationship between serum HBV DNA concentration and cirrhosis was independent of HBeAg status and ALT activity. Although the relative risk of cirrhosis was only 2.5 for serum HBV DNA concentrations of at least 10⁴ but lower than 10⁵ copies/mL, serum HBV DNA concentrations of 10⁴ copies/mL or lower were found in 40% of the patients with cirrhosis. Likewise, a high baseline and persistently elevated serum HBV DNA concentration increases the risk of HCC. Of the 164 patients in whom HCC developed, the incidence rates of HCC increased in a dose-response relationship beginning with a baseline serum HBV DNA concentration of 10⁴ copies/mL.[12] Compared with patients whose enrollment serum HBV DNA concentrations were lower than 300 copies/mL, patients whose serum HBV DNA concentrations were 10,000 to 99,999 copies/mL had an adjusted hazard ratio for HCC of 2.3 (95% CI, 1.1-4.9; p = 0.02). This relationship remained statistically significant after the analysis was adjusted for age, sex, cigarette smoking, alcohol consumption, ALT activity, and HBeAg status. Spontaneous reduction in serum HBV DNA concentration over time was protective against the development of HCC. After a median follow-up of ~10 years, participants with persistently elevated serum HBV DNA concentrations (higher than 10⁵ copies/mL) were at greater risk of HCC than those whose serum HBV DNA concentrations had decreased from higher than 10⁵ copies/mL at study entry to lower than 10⁴ copies/mL.

Serologic Markers and Hepatic Complications

HBeAg is generally regarded as a marker of HBV replication; in the past, patients with HBeAg-negative infection were considered to have low level HBV replication. However, specific mutations in the HBV genome can either prevent HBeAg formation or downregulate HBeAg production despite active HBV replication. Although some patients with HBeAg-negative infection are inactive carriers with low levels of virus, others have active disease, and some patients experience fluctuations in ALT activity and serum HBV DNA concentration.

The presence of HBeAg in the serum has also been associated with an increased risk of HCC. Compared with men whose serum tested negative for HBsAg, those whose serum tested positive for both HBsAg and HBeAg had a calculated relative risk of progression to HCC of 60.2 (9.6 for HBsAg-seropositivity alone).[21] The serum HBV DNA concentration decreases substantially in patients with HBeAg loss, but no threshold concentration has been associated with HBeAg clearance.[22] [23] Given the fluctuating course of HBeAg-negative chronic hepatitis, it is impossible to define a single cutoff serum HBV DNA concentration that differentiates inactive carriers from patients with HBeAg-negative chronic hepatitis. In the Yuen and colleagues study[16] of prognostic determinants of chronic HBV infection in Chinese patients, 73% of patients in whom cirrhosis and HCC developed tested positive for serum anti-HBe. Thus, antiviral therapy aimed at maximal suppression of serum HBV may be required even after HBeAg seroconversion.

DISCUSSION OF SCENARIO 1

Given current findings regarding the association of ALT activity and serum HBV DNA concentration with disease progression, Win's prognosis is uncertain. A serum HBV DNA concentration of 10⁴ IU/mL may be associated with late disease complications of cirrhosis or HCC, and his uncle's death from liver cancer suggests that Win's risk of HCC may be increased. One strategy supported by the 2007 AASLD guidelines would be to monitor Win's serum HBV DNA concentration and to perform hepatobiliary ultrasonography and α-fetoprotein screening every 6 months.

Performing a liver biopsy is another option, although many patients prefer to avoid invasive procedures. The 2007 AASLD guidelines recommend biopsy for patients who meet the criteria for chronic HBV infection: serum HBV DNA concentration higher than 10⁵ copies/mL and persistent or intermittent elevation in aminotransferase levels.[6] Win does not meet these criteria, but a biopsy can be useful for assessing fibrotic progression, providing a baseline for future comparisons, detecting mixed liver disorders, and determining which patients should be screened for HCC. Biopsy can be particularly useful for patients who have had long-term infection and those for whom there are concerns about the extent of fibrosis.

If Win continues to exhibit a serum HBV DNA concentration of 10⁴ IU/mL, a more proactive therapeutic strategy might include long-term suppressive therapy for preventing future disease complications.

SERUM HBV DNA CONCENTRATION AND MEDICATION RESISTANCE

A high serum HBV DNA concentration at baseline and persistent viremia during treatment have been shown to be predictive of medication resistance.[23] [24] [25] [26] [27] The resistance rates associated with the nucleos(t)ide analogues used in treatment-naïve chronic HBV infection are highest for lamivudine with genotypic resistance rates of 20% at 1 year and 70% after 4 years of therapy.[28] [29] Lamivudine clinical trial data have shown an association between early virologic response and rates of resistance. In a retrospective cohort study conducted in Korea, data collected from 183 HBV-infected patients were analyzed to determine the risk for resistance for several known predictive factors. Detectable serum HBV DNA at week 24 of lamivudine was shown to be an independent predictor of viral breakthrough at 12 to 36 months of therapy (relative risk 1.43 [CI 95% 1.09-1.89, p = 0.010]).[30] While these data are representative of a small number of patients, they provide evidence to support treatment alteration at 24 weeks of lamivudine therapy for persistent viremia.

Data from telbivudine clinical trials have highlighted the importance of early and sustained suppression of serum HBV DNA concentration. In the GLOBE trial, an international phase III trial comparing telbivudine to lamivudine for the treatment of chronic HBV infection in 1367 patients, the rate of virologic breakthrough after 48 weeks of telbivudine therapy was 4.5%, and genotypic resistance at week 92 was found in ~8% of patients with HBeAg-negative infection and in 21% of patients with HBeAg-seropositive infection. However, among patients who achieved rapid viral suppression at week 24 of therapy, telbivudine resistance rates were found to be much lower (2% for the HBeAg-negative cohort; 4% for the HBeAg-positive cohort at week 92). M2041 substitution in HBV polymerase or wild-type sequence was found in all patients with telbivudine resistance; in some patients, secondary mutations of uncertain significance were also found.[32] The rates of resistance to adefovir in HBeAg-negative infection at weeks 48, 96, 144, 192, and 240 are 0%, 3%, 11%, 18%, and 29%, respectively. These data were extracted from a double-blind, placebo-controlled clinical trial that enrolled 185 patients with HBeAg-negative infection. At study week 49, patients in the placebo grow were switched over to receive adefovir. In this trial, resistance rates remained low until week 144 of treatment. Upon further analysis, it was shown that serum HBV DNA concentration at week 48 was associated with the emergence of resistance at week 144. Resistance rates at treatment year 3 were 4% (3 out of 80 patients), 26% (8 out of 31 patients), and 76% (2 out of 3 patients) for those whose serum HBV DNA concentrations at week 48 were lower than 3 log₁₀ copies/mL, 3 to 6 log₁₀ copies/mL, and higher than 6 log₁₀ copies/mL, respectively.[31]

Data from the GLOBE trial showed that virologic response to telbivudine at treatment week 24 decreased the risk for emergence of resistance. Moreover, persistent viremia after 6 months of telbivudine is associated with a significant risk for resistance at one year of treatment, making it the largest affirmation of week 24 predictability as previously demonstrated with lamivudine.[27] Thus, for patients receiving telbivudine, clinicians should use serum HBV DNA concentration at week 24 of therapy to guide ongoing treatment decisions.

Clinical trial data demonstrate very low resistance rates to entecavir. This finding was demonstrated by Colonno and colleagues in a report of entecavir resistance rates among 679 patients with HBeAg-negative infection who were enrolled in clinical trials. After 4 years of therapy in treatment-naïve infection, the rate of entecavir resistance is 1.2%. Entecavir resistance requires M204V and L180M plus additional residues at S202, T184, or M250, all of which can be selected in patients who have not received lamivudine.[33] [34] While the relationship between week 24 serum HBV DNA concentration and risk for resistance has not been explored in all anti-HBV nucleos(t)ide analogues, many clinicians adapt pharmacotherapy at this time point (or at up to 48 weeks for drugs with a higher barrier to resistance) when viremia persists.

Serum HBV DNA Concentration and Virologic Response

In clinical trials, maximal early reduction of serum HBV DNA concentration with anti-HBV nucleos(t)ide analogue therapy is associated with lower resistance rates. In addition, undetectable serum HBV DNA at week 24 is also associated with significantly higher rates of sustained serum HBV DNA suppression (p < 0.05)[27] and trends toward higher rates of HBeAg seroconversion (in HBeAg-positive infection), HBsAg seroconversion, and ALT normalization.[27] [33] [34] Quantitative results for different antiviral agents may vary, but the observed relationship between early viral response and subsequent effectiveness may apply to all direct-acting anti-HBV agents and may be useful in optimizing patient management. The goals of treatment, selection of appropriate therapy, and indicators of treatment response will be discussed in greater detail in the next article in this supplement.

POTENTIAL FUTURE TREATMENT PARADIGMS

Because current findings indicate that hepatitis B viral load is a stronger predictor of progression to cirrhosis and HCC than ALT activity or HBeAg status, the end point of future treatment paradigms for chronic HBV infection among patients who were exposed early in life will probably be maintaining low or undetectable serum concentrations of HBV DNA. However, even if serum HBV DNA concentration becomes the end point of therapy, several questions remain. What is the serum HBV DNA concentration threshold for treatment? At what age should treatment begin? Some patients-such as women of childbearing potential-may want to delay starting therapy. How will clinicians manage HBV infection in patients with limited access to therapy, particularly those without health insurance or those who live in regions where HBV is endemic? Finally, how will clinicians prevent or manage resistance to nucleos(t)ide therapies?

CONCLUSION

Recent findings indicate that the treatment thresholds for ALT activity and serum HBV DNA concentration suggested by the 2007 AASLD guidelines may need to be expanded if clinicians are to prevent a greater proportion of patients chronically infected with HBV from experiencing the complications of cirrhosis and HCC. Because of the natural history of HBV infection and resulting liver disease, future treatment paradigms will probably attempt to achieve early and sustained suppression of serum HBV DNA concentration.

ABBREVIATIONS

• AASLD American Association for the Study of Liver Diseases

• ALT alanine aminotransferase

• AST aspartate aminotransferase

• CI confidence interval

• HBeAg hepatitis B e antigen

• HBsAg hepatitis B surface antigen

• HBV hepatitis B virus

• HCC hepatocellular carcinoma

• ULN upper limit of normal

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Robert P PerrilloM.D. 

Baylor University Medical Center

3500 Gaston Avenue, 4 Roberts, Dallas, TX 75246

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Robert P PerrilloM.D. 

Baylor University Medical Center

3500 Gaston Avenue, 4 Roberts, Dallas, TX 75246