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A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States: 2008 Update
  A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States: 2008 Update in PDF
Clinical Gastroenterology and Hepatology Dec 2008
Emmet B. Keeffe, Douglas T. Dieterich, Steven-Huy B. Han, Ira M. Jacobson*, Paul Martin, Eugene R. Schiff, Hillel Tobias#
Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California
Department of Medicine, Mount Sinai Medical Center, New York, New York Division of Digestive Diseases, University of California, Los Angeles, Los Angeles, California
* Division of Gastroenterology and Hepatology, Weill Medical College of Cornell University, New York, New York
Center for Liver Diseases, University of Miami School of Medicine, Miami, Florida
# Liver Transplant Service, New York University Medical Center, New York, New York
Chronic hepatitis B (CHB) remains an important public health problem and a leading cause of liver-related morbidity and mortality worldwide.1 In the United States, an estimated 1.25 million individuals, or 0.4% of the population, are infected with hepatitis B virus (HBV).2 During the last 2 decades, the influx of foreign-born persons immigrating to the United States from areas of high endemicity, including Asia, the Middle East, and Africa, has contributed to an increased presence of CHB, particularly in urban areas and communities with a high immigrant population.3, 4 Thus, it is likely that the incidence of CHB is considerably higher than the estimated 1.25 million. When left untreated, individuals with CHB are at increased risk for developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). It is estimated that up to 5000 people die each year in the United States of these complications of HBV infection.1 The cumulative rate of morbidity and mortality from cirrhosis and liver cancer related to CHB is highest among individuals who acquire HBV infection as neonates or in early childhood.1
To help guide clinicians in treating patients with CHB, a panel of U.S. hepatologists published a treatment algorithm in 2004,5 which was subsequently revised in 2006 on the basis of new developments in the field.6 These advances have included a better understanding of the natural history of CHB and the availability of more sensitive molecular diagnostic tests. The number of antiviral agents for the treatment of patients with CHB has expanded from 5 to 7 with the approval of telbivudine in 2006 and tenofovir in 2008 by the U.S. Food and Drug Administration (FDA). In addition, there are now better defined strategies for optimizing patients' responses to oral antiviral therapy.7 Emerging data on promising antiviral therapies in late stages of clinical development, along with the potential likely demonstration of the safety and efficacy of combination therapy, suggest that there will be future management options in addition to the agents that are currently used as monotherapy for the treatment of CHB. Finally, data are accumulating on special patient populations who pose unique challenges and special requirements for antiviral therapy.
In light of these advances, the panel met again to reassess and revise its recommendations. The aim was to build on the existing algorithm, preserving its practical approach and comprehensiveness, and update the guidelines for the diagnosis, treatment, and monitoring of patients with chronic HBV infection in the United States. The panel used the same methods of evaluation as for the previous algorithm by reviewing the literature and current international guidelines.6, 8, 9, 10 A comprehensive, structured literature review was conducted by using the PubMed computerized bibliographic database for English-language articles published between August 1, 2005 and March 28, 2008 that addressed the treatment of CHB. The panel also reviewed abstracts from the following conferences and included them in the evidence table: Digestive Disease Week 2006 and 2007, the American Association for the Study of Liver Diseases Annual Meeting 2006 and 2007, the European Association for the Study of the Liver Annual Meeting 2007 and 2008, and the Asian Pacific Association for the Study of Liver Disease 2007 and 2008. Where possible, the panel based their recommendations solidly on evidence, but where data were lacking, panel members relied on their own clinical experience and expert opinion.
The goal of the revised algorithm presented here is to provide physicians with the most current information on the screening, diagnosis, and treatment of CHB. Specifically, the algorithm provides answers to several practical questions: (1) which patients are candidates for antiviral therapy?, (2) what are the advantages and disadvantages of available treatment options?, (3) when should therapy be initiated?, (4) when can therapy be stopped?, (5) what is the role of on-treatment monitoring?, and (6) which strategies should be used to modify therapy to decrease the risk for antiviral resistance? As a background to an application of the recommendations, this article reviews the current understanding of the clinical aspects of chronic HBV infection and presents updated algorithm recommendations for the management of CHB.
Natural History of Chronic Hepatitis B Virus Infection
The accurate and early diagnosis of chronic HBV infection is an important step in patient management. An understanding of the natural history of CHB is fundamental to the evaluation and management of CHB, playing a critical role in the assessment of patient status and in guiding decisions regarding candidacy for treatment and treatment end points. The natural course of HBV infection is a dynamic interplay of complex interactions involving the virus, the hepatocyte, and the host immune response, which, together with the influence of various external factors, determine disease severity and progression.11, 12, 13, 14, 15 The natural history of HBV infection can be divided into distinct phases: immune tolerance, immune clearance, inactive carrier of HBsAg, and reactivation.16, 17 Each phase is characterized by distinct patterns of serologic markers, HBV DNA levels, and changes in serum levels of ALT and AST that indicate the immunologic and necroinflammatory status of the patient. The clinical terms and definitions used to characterize the stages of CHB adopted at the National Institutes of Health conference on the Management of Hepatitis B are summarized in Table 1.18 Other clinical terms relating to HBV infection are summarized in Table 2.
The clinical course of CHB is variable, and not all patients will experience every phase of infection. Acquisition of HBV at birth or in early childhood is associated with a long latency period of immune tolerance, which might last for 2-3 decades before immune clearance characterized by HBeAg seroconversion to antibody to HBeAg (anti-HBe), whereas infection later in life is associated with a very short immune tolerance phase or none at all.16, 19 The onset of chronic HBV infection is marked by the continued presence of HBsAg, high levels of serum HBV DNA, and the presence of HBeAg in serum. A 5-year follow-up study involving HBsAg-positive individuals in the immune tolerance phase found that these patients exhibit minimal histologic changes, and those remaining in the immune tolerance phase experience no or minimal disease progression.17, 20 Transition to the immune clearance phase is characterized by fluctuating or generally high HBV DNA levels, with frequent hepatitis flares or ongoing hepatic necroinflammatory damage that might lead to variable degrees of fibrosis or cirrhosis. The immune clearance phase ends when the patient undergoes HBeAg seroconversion, with loss of HBeAg and development of anti-HBe. Loss of HBeAg and seroconversion to anti-HBe usually are preceded by a marked decrease in serum HBV DNA levels to <20,000 IU/mL, although often still detectable, and are typically followed by the normalization of ALT levels.21 Thus, HBeAg seroconversion usually represents a transition from the immune clearance phase to an inactive carrier state, although some patients directly transition to the reactivation phase clinically called HBeAg-negative CHB and associated with the presence of the precore and/or double basal core promoter mutant virus.
During the inactive carrier state, there is little evidence of hepatitis by clinical and laboratory evaluation, and serum HBV DNA levels are markedly reduced or undetectable.17, 22, 23, 24 A minority of patients (annual incidence, 0.1%-0.8% for Asians and 0.4%-2% for whites) will lose HBsAg, which is referred to as resolution of the carrier state. It is not uncommon for a small proportion of patients in the inactive carrier state to experience reversion back to HBeAg positivity or reactivation of disease, either spontaneously or through immune suppression after years of inactivity.25, 26 This is most likely caused by the presence of detectable HBV DNA levels in the liver in the form of covalently closed circular DNA (cccDNA).27 These findings underscore the fact that even HBsAg clearance is not tantamount to the complete resolution of HBV infection.
In addition, one third or more of inactive carriers experience a return of high levels of HBV DNA and persistent or intermittent increases in ALT levels, despite the absence of HBeAg.22, 28, 29 This form of chronic HBV infection, referred to as the reactivation phase or HBeAg-negative CHB, is associated with the selection of viral mutants that fail to produce HBeAg or have reduced HBeAg production.30 The most common mutation is a guanine to adenine substitution at nucleotide 1896 in the precore region. This mutation results in a TAG stop codon at codon 28 of the precore protein, thereby preventing HBeAg production, and is termed the precore mutant. A second dual mutation, the double basal core promoter mutant involving 2 nucleotide substitutions (A1762T and G1764A), leads to the down-regulation of HBeAg production.31 Alone or in combination, these mutations account for the majority of HBeAg-negative CHB. The HBeAg-negative form of CHB has been reported to occur more frequently in patients with HBV genotypes B, C, and D compared with genotype A, with genotype D having a particularly strong association with the precore mutation.32
Sustained spontaneous remission is uncommon in patients with HBeAg-negative CHB (incidence, 6%-15%), and the long-term prognosis is reportedly poorer compared with that for HBeAg-positive patients, although this might in part reflect a later stage of HBV infection.29 A recent long-term follow-up study involving 1965 asymptomatic inactive HBsAg carriers who were followed for 20,298 person-years showed that HBeAg-negative hepatitis recurred at an annual incidence of 1.5%, with a cumulative probability of 10% at 5 years, 17% at 10 years, and approximately 20% after 15 years.33 In this study, spontaneous HBsAg seroclearance occurred at an annual incidence of up to 1.15%, with a cumulative probability of 8% at 10 years, 25% at 20 years, and 45% at 25 years of follow-up. It is unclear whether these results can be universally applied to all inactive carriers, because this was a special group of patients with normal ALT levels and serum HBV DNA was not routinely tested. Patients who lose HBsAg have a much better prognosis than do their HBsAg-persistent counterparts.34 Long-term follow-up of HBsAg-positive, HBeAg-negative individuals, involving the serial testing of HBV DNA and ALT levels, is recommended to confirm that the inactive carrier state is maintained.8
Hepatitis B Virus DNA and Disease Progression
Large, long-term population-based studies of HBsAg-positive individuals have demonstrated a strong relationship between the risk of progression to cirrhosis, HCC, or both and ongoing HBV replication.12, 35, 36, 37 In both natural history and therapeutic studies, patients with cirrhosis who are seropositive for HBeAg, HBV DNA, or both have an approximately 4-fold higher risk of further disease progression to decompensation, HCC, and death than do patients who are HBeAg seronegative.15, 38, 39, 40
The relationship between serum HBV DNA levels and risk of disease progression has been most convincingly demonstrated in the Risk Evaluation Viral Load Elevation and Associated Liver Disease (REVEAL) study, a large, prospective cohort study that assessed the natural history of CHB in 3653 untreated HBsAg-positive Asian individuals.12 Patients were followed for an average of 11.4 years, during which 164 study participants developed HCC. The cumulative incidence of HCC increased progressively in a direct relationship to HBV DNA levels at study entry. The multivariable-adjusted relative risk (RR) of HCC increased from 1.1 at HBV DNA levels of 300 to <104 copies/mL to 6.1 at HBV DNA levels of >106 copies/mL.12 However, patients with HBV DNA levels of ≥104 to <105 copies/mL also were at a significant risk of HCC (RR, 2.3), and patients with increasing levels of HBV DNA over time or with persistently increased levels during follow-up were at the highest risk for HCC. In contrast, a lowering of HBV DNA levels from the highest levels was linked with a reduction in risk of HCC, but only when the HBV DNA level decreased to <104 copies/mL. Reanalysis of the REVEAL study data with more sensitive real-time polymerase chain reaction (PCR) methods for quantifying serum HBV levels showed an increasing risk of HCC up to >106 copies/mL.41
In a recent subanalysis of the REVEAL cohort, Ileoje et al35 found that individuals with low levels of HBV DNA (<104 copies/mL), who are often classified as having "inactive" disease, are also at an increased risk for HCC development, compared with uninfected (HBsAg-negative) individuals. This analysis involved 3584 HBsAg-positive and 18,541 HBsAg-negative patients as controls who were followed for 12 years. Moreover, during follow-up, individuals with persistently low levels of HBV DNA (≥300 to <104 copies/mL) had an increased risk of developing HCC, compared with patients whose HBV DNA levels were persistently undetectable (<300 copies/mL). Another analysis of the REVEAL cohort, involving 3582 participants, found a positive direct relationship between the risk of cirrhosis and serum HBV DNA levels.36 More than 90% of the cohort had serum ALT levels <45 U/L; 85% were HBeAg-negative, and 98% had no sonographic evidence of cirrhosis. The cumulative incidence of cirrhosis increased from 5% for patients with a viral load of <300 copies/mL to 36% for patients with a viral load of ≥106 copies/mL (P < .001).36 Furthermore, the risk for cirrhosis was independent of HBeAg status and serum ALT level. These studies provide evidence that viral replication plays a critical role in the progression of chronic HBV infection, thus establishing a rationale for antiviral therapy to arrest the progression of liver disease.
Risk Factors for Disease Progression
Viral and host factors have been shown to influence disease progression to cirrhosis or HCC.15 In large, long-term, natural history studies of HBsAg-positive individuals, viral and disease factors that were predictive of HCC included the presence of HBeAg (hazard ratio [HR], 4.2), HBV DNA levels >104 copies/mL (HR, 2.7), and HBV DNA levels >105 copies/mL (HR, 8.9-10.7).12 Host factors included male gender (HR, 3.0), advanced age (HR, 3.6-8.3), alcohol consumption (HR, 2.6), and cigarette smoking (HR, 1.7). Other factors that have been reported to negatively influence the course of HBV-related liver disease include coinfection with HCV or HDV (usually as the result of injection drug use or multiple sex partners), human immunodeficiency virus (HIV) coinfection, conditions associated with acute or chronic immunosuppression, HBV genotype (particularly genotype C), the presence of HBV precore and especially core promoter mutations, and the severity and frequency of ALT elevations.15
The goal of therapy for CHB is to eliminate or significantly suppress the replication of HBV and prevent the progression of liver disease to cirrhosis, with culmination in liver failure, or HCC, eventually leading to death or transplantation. Hence, the primary aim of treatment should be to reduce and maintain serum HBV DNA at the lowest possible levels (ie, achieve durable HBV DNA suppression). This, in turn, will promote the other aims of therapy, including histologic improvement and ALT normalization. In patients who are HBeAg-positive before therapy, an additional goal of treatment is loss of HBeAg with seroconversion to anti-HBe. The latter is preferable, because attainment of complete HBeAg seroconversion indicates a high likelihood that the benefit will persist once the patient is off therapy, enabling the clinician to discontinue treatment at some point after the seroconversion. Loss of HBsAg, although highly desirable, is rarely achieved with short-term antiviral therapy and, hence, is not a realistic goal for antiviral trials.
Hepatitis B Therapies
Currently, 7 drugs are available for the management of chronic HBV infection in the United States: interferon alfa-2b, lamivudine, adefovir, entecavir, peginterferon alfa-2a, telbivudine, and tenofovir. At present, the preferred first-line treatment choices are entecavir, peginterferon alfa-2a, and tenofovir because of their superior efficacy, tolerability, and favorable resistance profiles in HBeAg-positive (Table 5) and HBeAg-negative (Table 6) CHB over comparable drugs in pivotal clinical trials. Standard interferon alfa-2b has largely been replaced by peginterferon alfa-2a in routine practice.6, 8, 88 Lamivudine has been removed from the list of preferred first-line drugs because of its known high rate of resistance and because of evidence from pivotal trials showing the superiority of entecavir and telbivudine to lamivudine.6, 89, 90, 91, 92 Tenofovir should replace adefovir as a first-line drug in previously untreated patients with HBeAg-positive and HBeAg-negative disease, on the basis of pivotal phase III studies showing the superiority of tenofovir over adefovir.93, 94 In addition, tenofovir has demonstrated potent antiviral activity against HBV in patients coinfected with HBV and HIV.95, 96, 97, 98, 99 Although telbivudine demonstrates superior efficacy over lamivudine and adefovir in clinical trials, it is associated with an intermediate rate of resistance compared with these agents.89, 100 Telbivudine might be a potential treatment option for patients if treatment results in undetectable serum HBV DNA levels at week 24; this is predictive of a very low rate of resistance and continued efficacy, indicated by undetectable virus at week 52.89 Other new antiviral agents and immunomodulatory therapies are under investigation but are not yet available commercially. A brief summary of current data for the preferred first-line agents and treatment recommendations follows. It is important to comment that many patients have been successfully treated with lamivudine and adefovir long-term, with persistently undetectable serum HBV DNA over many years. The risk of subsequent antiviral resistance is very low in these patients, and there is general agreement that they do not require a change in their therapy. However, treatment-naïve patients who are beginning therapy for the first time should be treated with entecavir, peginterferon alfa-2a, or tenofovir on the basis of their superior potency and low rate of antiviral drug resistance.
Treatment and Management of Chronic Hepatitis B
Hepatitis B e Antigen-Positive Patients
Peginterferon alfa-2a

The efficacy of peginterferon alfa-2a has been demonstrated in a large phase III randomized study that compared peginterferon alfa-2a 180 _g/wk, lamivudine 100 mg/day, and both drugs in combination for 48 weeks in patients with HBeAg-positive CHB.63 At the end of treatment, therapy with peginterferon alfa-2a, with or without lamivudine, resulted in significantly greater rates of HBeAg seroconversion, HBV DNA undetectability, and ALT normalization, compared with treatment with lamivudine alone (Table 5). At 24 weeks after the end of treatment, the HBeAg seroconversion rate was 32% in the peginterferon alfa-2a arm, compared with 27% in the peginterferon alfa-2a plus lamivudine arm and 19% in the lamivudine monotherapy arm. Although the combination of peginterferon alfa-2a and lamivudine resulted in a greater degree of viral load reduction, the rate of HBeAg seroconversion was not different from treatment with peginterferon alfa-2a monotherapy. Higher rates of HBeAg seroconversion were observed in patients who were HBV genotype A, had low baseline HBV DNA concentrations, or had increased baseline serum ALT levels. These findings suggest that peginterferon alfa-2a might be a reasonable choice as first-line therapy in patients with genotype A or B who are young, lack significant comorbidities, and have HBV DNA levels <109 copies/mL and ALT levels ≥2-3 - ULN.101
Similar findings have been reported in clinical trials evaluating the efficacy of peginterferon alfa-2b in patients with CHB.50, 102, 103 On the basis of findings from these clinical trials, peginterferon alfa-2b might be an option for the treatment of CHB in countries where it is available. Although the efficacy of peginterferon alfa-2b and peginterferon alfa-2a has not been compared in prospective randomized clinical studies of CHB, data from a small retrospective study comparing the efficacy of agents in 53 HBeAg-positive Chinese patients found a higher rate of sustained virologic response in patients treated with peginterferon alfa-2a for 48 weeks (34.5%), compared with patients treated with peginterferon alfa-2b for 24 weeks.104 This study is limited by small numbers and different treatment durations with the 2 peginterferons. The side effect profile of peginterferon alfa is similar to that of standard interferon, with the most common side effect being influenza-like illness characterized by fever, chills, headache, malaise, and myalgia as well as psychological side effects. Patients require careful monitoring for the potential development of all of these side effects.
Entecavir is a cyclopentyl guanosine analog that inhibits both the priming and elongation steps of viral replication. It is a highly potent inhibitor of HBV polymerase. In vitro, entecavir demonstrates greater antiviral potency than lamivudine or adefovir and is active against lamivudine-resistant HBV mutants. In a phase III randomized study involving 715 patients with compensated liver disease, entecavir 0.5 mg/day demonstrated superior benefit to lamivudine 100 mg/day at 48 weeks in nucleoside-naïve patients with HBeAg-positive CHB.90 At 48 weeks, the entecavir-treated patients had higher rates of histologic improvement (72% vs 62%), HBV DNA reduction (-6.9 vs -5.4 log10), HBV DNA undetectability (<300 copies/mL) (67% vs 36%), and ALT normalization (≦1 _ ULN) (68% vs 60%) (Table 5).90 Although entecavir is the most potent licensed oral agent in terms of its effect on serum HBV DNA, in this study there was no difference in the rate of HBeAg loss or seroconversion between entecavir and lamivudine after 1 year of therapy. The safety profile of entecavir during a period of 48 weeks was similar to that observed with lamivudine.
A recent report showed continued efficacy of entecavir after 96 weeks of therapy that was superior to that observed with lamivudine.105 In the follow-up to the study described above, 709 HBeAg-positive CHB patients were randomized to entecavir 0.5 mg or lamivudine 100 mg once daily.105 At week 52, protocol-defined virologic responders (HBV DNA <0.7 mEq/mL, but positive for HBeAg) could continue blinded treatment for up to 96 weeks. At year 2, a greater proportion of entecavir-treated than lamivudine-treated patients achieved HBV DNA <300 copies/mL (74% vs 37%) and ALT normalization (79% vs 68%). Similar proportions of entecavir-treated and lamivudine-treated patients achieved HBeAg seroconversion (11% vs 12%). Significantly higher proportions of entecavir-treated than lamivudine-treated patients achieved cumulative, confirmed HBV DNA levels <300 copies/mL (80% vs 39%) and ALT normalization (87% vs 79%) through 96 weeks.105 Cumulative, confirmed HBeAg seroconversion occurred in 31% of entecavir-treated and 25% of lamivudine-treated patients.The safety profile was comparable in both groups. Long-term resistance data for entecavir indicate a low resistance rate (1.2%) in nucleoside-naïve patients (HBsAg-positive or -negative) treated for up to 5 years.106, 107, 108 Higher rates of resistance (51% at 5 years) have been reported in patients with lamivudine-resistant CHB.107, 108
The antiviral activity of entecavir is greater than that of adefovir in patients with HBeAg-positive CHB who are treatment-naïve.109 Results from the E.A.R.L.Y. study, a randomized, open-label study that compared entecavir (0.5 mg) with adefovir (10 mg) in such patients, showed a significantly greater mean reduction in viral load from baseline levels among the entecavir-treated patients than among the adefovir-treated patients after 12 weeks of therapy (-6.23 vs -4.42 log10 copies/mL).109 The difference in mean HBV DNA change from baseline was significantly higher for entecavir as early as day 10, and this difference was maintained through week 96. At week 48, a higher proportion of entecavir-treated than adefovir-treated patients achieved HBV DNA levels <300 copies/mL (58% vs 19%). Suppression of HBV DNA levels remained greater for entecavir through the extended dosing phase of the study. At week 96, 79% of entecavir-treated patients and 50% of adefovir-treated patients achieved HBV DNA levels <300 copies/mL.110 Rates of ALT normalization (97% vs 85%) and HBeAg seroconversion (24% vs 25%) were similar for both treatment groups.110
Telbivudine, an L-nucleoside analog of thymidine, is a potent and specific inhibitor of HBV DNA polymerase that preferentially inhibits HBV second-strand (DNA-dependent) DNA synthesis.111 In phase I/II studies, telbivudine demonstrated potent antiviral activity in patients with CHB when compared with lamivudine monotherapy.112 In a phase III trial involving 921 HBeAg-positive patients, virologic and biochemical responses associated with telbivudine were superior to those with lamivudine after 1 and 2 years of treatment.89, 113 A higher proportion of patients treated with telbivudine than treated with lamivudine had undetectable HBV DNA by PCR assay (60% vs 40% at 1 year and 56% vs 39% at 2 years) and ALT normalization (77% vs 75% at 1 year and 70% vs 62% at 2 years) (Table 5). The rate of HBeAg loss and HBeAg seroconversion at the end of 1 year was similar between the treatment groups but was higher among patients treated with telbivudine at the end of 2 years (Table 5). Telbivudine was associated with a lower rate of resistance than was lamivudine. At 1 and 2 years, resistance rates were 5% and 25% for telbivudine, respectively, in HBeAg-positive patients.89, 114 Patients who achieved undetectable HBV DNA levels (<300 copies/mL) at 24 weeks had a lower rate of resistance at 1 year than did patients who had HBV DNA levels of ≥4 log10 copies/mL (1% vs 11%).89 The frequency of adverse events was similar for patients receiving telbivudine and lamivudine, and serious adverse events were reported in 2.6% of patients receiving telbivudine and 4.8% receiving lamivudine.89 Of note, elevations in creatine kinase levels more than 7 times the ULN were more common in patients receiving telbivudine than lamivudine (7.5% vs 3.1%) but decreased spontaneously during continued drug therapy. Muscle-related symptoms correlated poorly with elevations in creatine kinase levels.89
Analyses of the 1-year and 2-year data from the phase III study showed that early virologic response at week 24 is predictive of clinical outcomes.89, 113, 115 Early maximal reduction in HBV DNA levels at 24 weeks correlated with improved clinical outcomes at 1 and 2 years, as measured by rates of HBeAg seroconversion, ALT normalization, HBV DNA undetectability, and resistance.89, 113
Telbivudine also has shown superiority over adefovir in HBeAg-positive CHB patients. Several randomized studies reported rapid and marked reductions in serum HBV DNA levels at 24 weeks of therapy in patients who had initially been treated with telbivudine or who had been switched from adefovir to telbivudine.100 This early viral response was associated with the highest rates of achieving efficacy outcomes at 1 year (HBeAg seroconversion, ALT normalization, and undetectable HBV DNA levels on PCR assay).
Tenofovir, an acyclic nucleotide analog with a molecular structure related to that of adefovir, is approved for the treatment of HIV infection and for HBV infection and was known before licensure for the treatment of CHB to have potent activity against HBV.96, 97 Data from several small studies suggest that tenofovir might be more potent than adefovir in inducing the early and rapid suppression of HBV DNA in both HBeAg-positive and -negative patients.96, 97, 116 Limited clinical data suggest its efficacy in treating lamivudine-resistant patients.96, 97, 116 In a small study that compared the antiviral activity of tenofovir with that of adefovir in lamivudine-resistant patients, the tenofovir group achieved potent and rapid suppression of HBV DNA within weeks of treatment initiation as compared with a less consistent pattern of suppression in patients treated with adefovir.97 At 48 weeks, significantly more patients treated with tenofovir had a reduction of HBV DNA levels to <105 copies/mL than did patients treated with adefovir (100% vs 44%). A follow-up study confirmed the superiority of tenofovir over adefovir in this setting.96
Preliminary results from a multicenter, randomized, phase III trial comparing the safety and efficacy of tenofovir and adefovir in patients with HBeAg-positive CHB have been reported (Table 5).98 A total of 266 patients were randomized in a 2:1 ratio to receive tenofovir 300 mg or adefovir 10 mg for 48 weeks. The primary end point of this study was complete response at week 48, defined as HBV DNA levels of <400 copies/mL and histologic improvement, defined as a ≥2-point reduction in Knodell inflammatory score without worsening of fibrosis. At 48 weeks, 67% of patients in the tenofovir arm achieved a complete response, compared with 12% of patients in the adefovir arm (P < .001). A higher proportion of patients in the tenofovir arm than in the adefovir arm achieved undetectable HBV DNA levels at week 48 (<400 copies/mL: 76% vs 13%). The respective rates for ALT normalization were 69% vs 54% and for HBeAg seroconversion were 21% vs 18%. A higher proportion of patients treated with tenofovir had HBsAg loss (3.2% vs 0%) and HBsAg seroconversion (1.3% vs 0%). The incidence of grade 2-4 adverse events was similar in the tenofovir and adefovir arms. No patients taking tenofovir experienced a 0.5-mg increase in serum creatinine levels or creatinine clearance of <50 mL/min (possible indicators of renal toxicity, which has been associated with tenofovir in some studies of patients with HIV infection), compared with 1% of patients taking adefovir. As with adefovir therapy, new onset or worsening renal impairment might occur, and it is recommended that baseline calculated creatinine clearance be obtained and creatinine clearance and serum phosphorus be monitored in patients at risk during therapy. The incidence of grade 3 or 4 ALT flares 2_ the baseline values were greater in the tenofovir arm than in the adefovir arm (11% vs 4%). All patients taking tenofovir who did not achieve HBV DNA levels of <400 copies/mL by week 48 or who experienced viral breakthrough while receiving treatment underwent genotypic resistance testing. The clinical benefits of tenofovir with respect to suppression of serum HBV DNA levels below the level of detection (79%) and ALT normalization (77%) were maintained through 72 weeks of treatment.117 The rate of HBsAg loss and seroconversion increased from 3% to 5% and from 1% to 2%, respectively, at weeks 48 and 64 in patients in the tenofovir arm, whereas no increase in HBsAg loss was observed among patients in the adefovir arm. No mutations associated with tenofovir resistance were identified at weeks 48 or 72.
Hepatitis B e Antigen-Negative Patients
Peginterferon alfa-2a

Forty-eight weeks of therapy with peginterferon alfa-2a, with or without lamivudine, resulted in a significantly greater percentage of patients with ALT normalization and HBV DNA undetectability (<400 copies/mL) 24 weeks after the end of treatment (Table 6).118 The combination of peginterferon alfa-2a plus lamivudine appeared to offer no advantages over treatment with peginterferon alfa-2a alone. HBsAg seroconversion was reported in 3% of patients treated with peginterferon alfa-2a, 2% of patients treated with peginterferon alfa-2a plus lamivudine, and no patients treated with lamivudine alone. The rate of emergence of lamivudine-resistant mutations was reduced markedly in the combination therapy arm. The safety profile of peginterferon alfa-2a was judged to compare favorably with previous experience with conventional interferon. A recent follow-up study of patients with HBeAg-negative CHB treated with peginterferon alfa-2a or lamivudine monotherapy reported significantly higher rates of ALT normalization, HBV DNA suppression, HBsAg loss, and HBsAg seroconversion in the peginterferon alfa-2a-treated patients.119 At 4 years after treatment, virologic response rates in the peginterferon alfa-2a arms were 24% for both HBV DNA <4000 IU/mL (20,000 copies/mL) and HBV DNA <2000 IU/mL (10,000 copies/mL) levels. Among patients who received peginterferon alfa-2a, 17% had HBV DNA levels <400 copies/mL, compared with 7% of patients who received lamivudine alone. ALT normalization, defined as ALT levels of ≦30 U/L, was reported in 27% of patients who had received peginterferon alfa-2a, compared with 16% of patients who had received lamivudine alone. The rate of HBsAg clearance increased during follow-up for peginterferon alfa-2a-treated patients, reaching 11% at 4 years.119 In contrast, only 2% of lamivudine-treated patients (2/85) experienced HBsAg loss.119
A phase III clinical trial compared the safety and efficacy of entecavir and lamivudine in patients with HBeAg-negative compensated liver disease.92 A total of 648 patients were randomized to receive either entecavir 0.5 mg/day or lamivudine 100 mg/day for 48 weeks. Treatment with entecavir, compared with lamivudine, resulted in a significantly higher rate of histologic improvement, HBV DNA reduction, and HBV DNA undetectability (<300 copies/mL) (Table 6). This high rate of undetectable HBV DNA (90%) shows the remarkable potency of this agent. ALT normalization was also observed more frequently with entecavir than with lamivudine (78% vs 71%), but there was no difference in improvement in fibrosis compared with lamivudine. The safety profile of entecavir during a period of 48 weeks was similar to that observed with lamivudine. A low resistance rate (1.2%) has been observed in nucleoside-naïve HBeAg-negative patients treated with entecavir for up to 5 years.107, 108
A phase III trial involving 466 HBeAg-negative patients showed that virologic response for telbivudine was superior to that for lamivudine after 1 and 2 years of treatment.89, 113 A higher proportion of patients treated with telbivudine than lamivudine achieved undetectable HBV DNA levels (88% vs 71% at 1 year and 82% vs 57% at 2 years) (Table 6). No difference was observed in the proportion of patients with ALT normalization at 1 year (74% vs 79%), although a higher proportion of telbivudine-treated patients achieved ALT normalization after 2 years of treatment (78% vs 70%). Telbivudine was associated with a lower rate of resistance than was lamivudine. Resistance data at 1 and 2 years for telbivudine showed resistance rates of 2.3% and 11.0%, respectively, in HBeAg-negative patients.89, 114 As observed in HBeAg-positive patients, lower rates of resistance at 1 year were observed in HBeAg-negative patients who had undetectable HBV DNA levels at week 24, compared with patients whose HBV DNA levels were ≥4 log10copies/mL (0% vs 30%).89
Preliminary data are available from a randomized phase III study comparing tenofovir and adefovir in patients with HBeAg-negative CHB.99 The primary end point of this study was complete response at week 48, defined as HBV DNA levels <400 copies/mL and histologic improvement (defined as a ≥2-point reduction in Knodell inflammatory score without worsening of fibrosis). In this study, 375 patients were randomized in a 2:1 ratio to receive tenofovir 300 mg (n = 250) or adefovir 10 mg (n = 125) for 48 weeks. At week 48, a significantly higher proportion of patients treated with tenofovir achieved the primary end point, compared with patients treated with adefovir (71% vs 49%) (Table 6). At the end of treatment, 93% of the patients in the tenofovir group had HBV DNA levels of <400 copies/mL, compared with 63% of patients in the adefovir group. The rates of ALT normalization were similar in both treatment groups (Table 6). No patients treated with tenofovir had a confirmed 0.5 mg increase in serum creatinine level or creatinine clearance of <50 mL/min. The incidence of ALT flare (>10 _ ULN and 2 _ baseline) was low and similar in the 2 treatment groups (1.2% vs 0.8%). The clinical benefit of tenofovir with respect to the achievement of HBV DNA levels of <400 copies/mL (98%) and ALT normalization (79%) was maintained through week 72 with continuous tenofovir therapy.120 The resistance rate was 0% for tenofovir at weeks 48 and 72.
Combination Therapy
De novo combination

Current limitations of monotherapy with respect to the achievement of sustained response and clinical end points (ie, HBeAg seroconversion, HBsAg loss) have sparked interest in the development of combination regimens for CHB to optimize responses and minimize problems with resistance. Preclinical studies suggest a benefit from the combination of nucleosides and nucleotides. Enhanced anti-HBV activity has been observed with the addition of tenofovir to lamivudine, emtricitabine, telbivudine, or entecavir.121 In vitro data indicate that adding tenofovir to nucleoside agents produces additive to slightly synergistic anti-HBV activity, without any observed cytotoxic effects. Data on the efficacy of de novo combination therapy is limited, and the results from these studies vary on the basis of the agents used and the study design. Initial clinical studies comparing combination antiviral therapy and monotherapy failed to demonstrate clinical benefit with regard to traditional clinical end points with combination therapy.63, 112, 118, 122
In large randomized phase III studies comparing lamivudine and peginterferon monotherapy and the combination of peginterferon and lamivudine in HBeAg-positive and -negative patients, combination therapy was associated with a more profound decrease in viral load, compared with either monotherapy.63, 118 However, no significant difference was observed in treatment end points such as viral suppression, HBeAg seroconversion, and HBsAg clearance between peginterferon monotherapy and combination therapy. The study design of these trials required the discontinuation of lamivudine, like peginterferon, after 1 year, which is not performed routinely in practice. More recently, preliminary data from several studies have illuminated the potential advantages of combination therapy in patients with CHB.123, 124, 125, 126 Preliminary results of a multicenter, randomized, controlled trial in which HBeAg-negative CHB patients were treated with peginterferon alfa-2a alone or in combination with adefovir showed that significantly more patients in the combination treatment group achieved undetectable HBV DNA levels at 24 weeks than in the group treated with peginterferon alone (71% vs 41%); in addition, there was a significant difference in the reduction in mean viral load (-4.3 vs -3.0 log10).123 Another study evaluated changes in intrahepatic cccDNA levels in patients with HBeAg-positive CHB who were treated with the combination of peginterferon alfa-2a and adefovir.124 This study found that after 48 weeks of therapy, the combination regimen was associated with marked decreases from baseline in levels of serum HBV DNA and intrahepatic cccDNA levels, which, in turn, were significantly correlated with reduced HBsAg.
Preliminary data from studies evaluating oral combination therapy have also been reported.125, 126 Sung et al125 compared the efficacy of lamivudine monotherapy (n = 57) and lamivudine plus adefovir (n = 54) in patients with HBsAg-positive CHB. Reductions in HBV DNA levels were comparable between the 2 treatment arms at week 16 (the primary study end point) and during the first 52 weeks, but after 104 weeks median HBV DNA reductions were _3.41 and _5.22 log, respectively. Similarly, HBV DNA levels were <200 copies/mL in 41% and 40%, respectively, of patients in the 2 arms at 52 weeks but 14% and 26% at 104 weeks. The difference in virologic outcome was associated with a higher rate of viral breakthrough in the monotherapy group than in the combination therapy group (44% vs 19%). In the lamivudine monotherapy group, the M204V/I mutation was detected in 20% and 43% of patients at weeks 52 and 104, respectively, compared with 9% and 15% of patients at the same time points in the combination therapy group. The N236T mutation was noted in only 1 adefovir recipient. Notably, the rate of HBeAg seroconversion was identical, 35%, in each group.
A second study by Hui et al126 compared adefovir alone (n = 16) with a combination of adefovir plus emtricitabine (n = 14), a nucleoside analog with activity and a resistance profile similar to that of lamivudine, in HBeAg-positive patients for 96 weeks. Despite the small number of patients in the study, a significant advantage for combination therapy was noted, with median HBV DNA declines of -3.98 and -5.30 log10 copies/mL for monotherapy and combination therapy, respectively, at 96 weeks and HBV DNA levels of <300 copies/mL in 37.5% and 78.5% of patients, respectively,. No difference was observed in the incidence of HBeAg seroconversion. The design of this small trial makes it difficult to assess the degree to which the greater suppression of HBV DNA with the combination regimen was attributable to a contributory effect of adefovir, or whether it simply represented the efficacy of the more potent drug, emtricitabine.
Although these studies demonstrate potent antiviral effects of de novo combination therapy, they nonetheless fall short of establishing a definitive role for routine combination therapy in all patients, particularly when potent monotherapies with robust long-term resistance profiles are available. In addition, several issues need to be addressed before considering combination treatment with nucleosides and nucleotides for CHB. These include the resistance profiles of the agents, the previous therapies that the patient has received, the potential for negative drug-drug interactions among the agents, especially with long-term use, and cost considerations.18 Larger clinical trials of combination therapy with appropriate end points are needed before the adoption of de novo combination therapy with currently available anti-HBV agents.
Combination versus switching
Evidence from several recent clinical studies suggests that combining lamivudine with adefovir, compared with sequential monotherapy, is associated with an improvement in virologic response and a lower rate of resistance, particularly in the setting of lamivudine resistance.127, 128, 129, 130, 131 In one study among patients who had received more than 6 months of adefovir therapy, 50% failed to achieve an initial virologic response to adefovir.130 The patients who developed adefovir resistance were more likely to have been switched from lamivudine to adefovir monotherapy. In a second study involving 95 HBeAg-positive patients treated with adefovir for 48 weeks, the emergence of adefovir resistance was more common in patients with lamivudine resistance than in the patients who were treatment-naïve.127 These findings suggest that switching from lamivudine to adefovir is associated with an increased risk of adefovir resistance, compared with the addition of adefovir to existing lamivudine therapy.
The addition of adefovir to lamivudine has been shown to be superior to switching to adefovir monotherapy in HBeAg-negative patients who have lamivudine resistance.127, 128, 131, 132 In one study evaluating these strategies, both were comparable in terms of the proportion of patients achieving suppression of serum HBV DNA to undetectable levels and normalization of ALT at 12 months.128 However, significantly more patients who had been switched to adefovir experienced virologic and biochemical breakthroughs as a result of adefovir resistance mutations at 15-18 months from treatment initiation (21% for switched therapy vs 0% for combination; P = .01). In another study that compared the efficacy of combining adefovir with lamivudine and switching from lamivudine to adefovir monotherapy in 82 patients with HBeAg-negative CHB, the rate of virologic breakthrough as a result of the emergence of adefovir resistance mutations was higher among patients who were switched from lamivudine to adefovir than among patients who received combination therapy (22% vs 0%).132
These findings have been confirmed by recent data demonstrating excellent suppression with virtually no long-term resistance to adefovir when that drug is added to lamivudine in patients with lamivudine resistance.133 In a study involving 145 lamivudine-resistant patients with CHB treated with adefovir 10 mg in addition to lamivudine 100 mg for 42 months (range, 12-74 months), 116 patients (80%) cleared serum HBV DNA, 67 patients (84%) had normalized ALT levels, and 145 patients (100%) remained free of virologic and clinical breakthroughs, independent of the degree of HBV suppression. The 1-, 2-, 3-, and 4-year cumulative rates of de novo rtA181T were 1%, 2%, 4%, and 4%, respectively. None of the cirrhotic patients clinically decompensated, but 11 (12%) developed HCC.133
The above findings are in accordance with results of a large retrospective/prospective cohort study of patients with lamivudine-resistant HBeAg-negative CHB who received either adefovir monotherapy or combination adefovir plus lamivudine.131 This study analyzed 588 patients with lamivudine-resistant CHB at 31 centers in Italy who received add-on therapy with adefovir 10 mg or were switched from lamivudine 100 mg/day to adefovir monotherapy. Virologic and biochemical response rates at 33 months of follow-up were similar between the 2 treatment groups. However, patients who were switched from lamivudine to adefovir monotherapy had a higher incidence of virologic breakthrough than did patients who had adefovir added to lamivudine (24% vs 5%), as well as higher rates of adefovir resistance (11% vs 0%). The overall 3-year cumulative probability of virologic breakthrough (30% vs 6%) and adefovir resistance (16% vs 0%) was higher among patients who were switched from lamivudine than among patients who received add-on adefovir therapy. A significantly greater proportion of patients in the combination therapy group experienced 3-year overall rates of maintained virologic response (74% vs 59%). The switch to combination therapy optimally should be made as soon as possible after lamivudine resistance has been detected. Adding adefovir to maintenance lamivudine therapy has been associated with poorer control of viral replication when lamivudine resistance is well-established (HBV DNA >6 log10 copies and elevated ALT levels).134
The efficacy of switching to entecavir therapy in patients with CHB and persistently high levels of viral replication after 1 year of adefovir therapy has also been evaluated.135 In this study, 12 patients with HBV DNA levels >5 log10 copies/mL after 48 weeks of adefovir were switched to entecavir 1 mg/day for 24 weeks. Of the 12 patients, 3 had adefovir-resistance substitutions at baseline, and 6 had a history of lamivudine resistance. At 24 weeks, the median decrease of HBV DNA (3.8 log10 copies/mL) was suboptimal for the entecavir-switched patients, none of whom achieved undetectable HBV DNA levels. The majority of these patients had HBV DNA levels >3 log10 copies/mL at the end of the 24-week period.
A retrospective study involving 121 patients with CHB evaluated the efficacy of switching to tenofovir monotherapy in nucleoside- and nucleotide-experienced patients with CHB.136 Eligible patients included those with HBV DNA >105 copies/mL and prior treatment with lamivudine or lamivudine with consecutive adefovir therapy as a result of lamivudine resistance. Patients with genotypic resistance to adefovir (n = 14) were excluded. At week 48, 91% and 78% of the patients had undetectable HBV DNA levels and ALT normalization, respectively. HBeAg seroconversion occurred in 23% of patients after an average of 9 months. HBsAg loss was observed in 4% of patients after an average of 13 months.
However, another study of a small cohort of patients with lamivudine-resistant CHB who were switched to adefovir monotherapy showed limited efficacy with subsequent tenofovir monotherapy.137 These patients had all developed genotypic resistance to adefovir after receiving an average of 24 months of adefovir monotherapy. The patients treated with tenofovir still had detectable HBV DNA and elevated ALT levels at week 24, week 48, and the end of observation. In a retrospective analysis of antiviral response to tenofovir therapy in 127 patients with prior nucleoside analog experience with lamivudine, adefovir, or both, patients with genotypic adefovir resistance had a significantly slower decrease of HBV DNA levels at month 12 than did patients without adefovir resistance.138 Similar findings were reported in a study investigating virologic response to tenofovir alone and in combination with emtricitabine in patients with adefovir-resistant CHB therapy. Combination therapy resulted in a greater reduction in HBV DNA levels than did tenofovir monotherapy in patients with virologic breakthrough or a suboptimal response to adefovir.139 All patients who received combination therapy had undetectable HBV DNA levels within 3-12 months, including 2 patients who had adefovir resistance at baseline. Despite findings indicating that tenofovir has antiviral efficacy in patients with genotypic adefovir resistance, the suppression of HBV DNA replication with tenofovir occurs at a much slower rate, and the complete suppression of HBV DNA replication occurs in only a minority of patients. Moreover, the selection of adefovir resistance mutations is not prevented. Thus, as observed with entecavir, tenofovir might have less activity in patients with genotypic resistance to adefovir than in treatment-naïve patients.
No evidence to date supports combining lamivudine with telbivudine, as might be expected, because these drugs are cross-resistant. One multicenter randomized study showed similar efficacy (reduction in HBV DNA levels, normalization of ALT levels) between telbivudine alone and telbivudine in combination with lamivudine.112 A long-term concern with this approach is that cross-resistance for lamivudine and telbivudine has been demonstrated at codon 204 (rtM204I).140 Moreover, HBV harboring M204V and L180M mutations is resistant to telbivudine, even if M204V mutations in isolation do not confer telbivudine resistance.
Treatment Recommendations
Hepatitis B e Antigen-Positive Patients

The recommendations for the treatment of HBeAg-positive patients are summarized in Table 7. The panel recommends an HBV DNA level of ≥20,000 IU/mL as a reasonable threshold for determining candidates for treatment, in combination with elevated ALT levels. HBeAg-positive patients who have HBV DNA levels of <20,000 IU/mL are atypical and are not recommended routinely for treatment because the majority of these individuals have inactive disease. However, because these individuals might be at risk for biochemical, histologic, and clinical progression of disease, they should be monitored actively by a sensitive HBV DNA assay. On a case-by-case basis, liver biopsy examination might be performed and therapy considered when there is histologic evidence of significant liver disease. Patients who are not treated should initially be monitored every 3 months for 1 year to ensure stability of HBV DNA and ALT levels. Then, if the levels remain stable, the patient should be monitored every 6-12 months.
HBeAg-positive patients with a serum HBV DNA level of ≥20,000 IU/mL should be considered for treatment, depending on their ALT levels. However, patients with normal ALT levels might have significant liver disease, and because viral suppression is associated with histologic response, biopsy examination should be considered, particularly in individuals older than 35-40 years of age. Such patients should be treated if disease is found. Further studies are required to investigate the efficacy of antiviral therapy in patients with HBV DNA levels of ≥20,000 IU/mL and normal ALT levels, especially in the younger individuals, who are typically in the immune tolerance phase of infection.
For patients with serum HBV DNA levels of ≥20,000 IU/mL and elevated ALT levels, entecavir, tenofovir, or peginterferon alfa-2a might be considered as first-line options; however, entecavir or tenofovir would be preferred for patients with high levels of serum HBV DNA and/or normal levels of ALT, given that response to interferon-based therapy is low in this population. Lamivudine is not recommended as a first-line therapy in HBeAg-positive patients because entecavir and telbivudine have been shown to be superior to lamivudine in randomized clinical trials, and lamivudine is associated with high rates of resistance. Telbivudine is associated with a moderate rate of resistance, although low rates of resistance and sustained suppression can be achieved with telbivudine if HBV DNA levels are undetectable by week 24. However, the panel did not include telbivudine as a preferred agent because of the high rate of resistance compared with entecavir and tenofovir and lack of long-term resistance surveillance in telbivudine-treated patients. A therapeutic change is advisable if there is detectable HBV DNA at week 24 of telbivudine therapy. In addition, both telbivudine and tenofovir have been shown to be superior to adefovir in clinical trials; therefore, adefovir is not recommended as a first-line therapy in HBeAg-positive patients.
Duration of therapy
The panel recommends that HBeAg-positive patients continue to be treated after HBeAg seroconversion as long as HBV DNA levels are decreasing and until the HBV DNA levels are undetectable by PCR. Treatment then should be continued for an additional 12 months. In patients who undergo HBeAg seroconversion but who still have detectable but stable HBV DNA levels, treatment should be continued for 6 months; seroconversion should be documented again, and then consideration should be given to stopping treatment in patients without cirrhosis. Patients who relapse can be re-treated. HBeAg-positive patients who fail to lose HBeAg should be treated long-term because the chance of HBeAg seroconversion increases with time, and there is a high risk of recurring viremia if therapy is stopped in the absence of HBeAg seroconversion.
Hepatitis B e Antigen-Negative Patients
The end point of therapy for HBeAg-negative patients with chronic HBV infection is more difficult to assess than that for HBeAg-positive patients because HBeAg-negative disease does not allow for HBeAg seroconversion. Thus, HBV DNA suppression and ALT normalization are the only practical measures of response to therapy, and long-term therapy is most often required to maintain these responses.
Recommendations for the treatment of HBeAg-negative patients are shown in Table 8. Because HBeAg-negative patients tend to have lower levels of serum HBV DNA than do HBeAg-positive patients but still might have active disease, the panel recommends treating patients who have serum HBV DNA levels of ≥2000 IU/mL. Otherwise, the recommendations are similar to those for HBeAg-positive patients. Entecavir, tenofovir, and peginterferon alfa-2a can be considered first-line options. Because long-term treatment is required in most cases (unless HBsAg seroconversion occurs, which is unlikely), lamivudine is not recommended because of the high risk for the development of resistance,141 and tenofovir is preferred over adefovir because of evidence of its superiority.98, 99 As in patients with HBeAg-positive CHB, telbivudine was not recommended as a first-line option on the basis of the intermediate rate of resistance with use of this drug.
Duration of therapy
HBeAg-negative patients who are receiving therapy should be monitored every 6 months. The duration of therapy with peginterferon remains unclear, although longer treatment (12 months) appears to be more beneficial in terms of sustained virologic response off treatment than do shorter periods of treatment (4-6 months). Tolerability is clearly an issue for patients undergoing interferon-based therapy, as compared with therapy involving oral agents. Entecavir, tenofovir, and telbivudine need to be given for the long-term; however, there are currently no long-term data on sustained virologic response available beyond 1 year (tenofovir), 2 years (telbivudine), and 5 years (entecavir). Special monitoring guidelines might be needed for HBeAg-negative patients to determine when treatment might safely be stopped. Despite the prolonged negativity of serum HBV DNA levels, relapse is common in patients with HBeAg-negative CHB.142 Serum HBsAg concentrations appear to decline rapidly during therapy with peginterferon but not lamivudine.143 The slope of decline for HBsAg concentration during extended peginterferon therapy might provide a clue that sustained virologic response is likely to occur.144 Prolonged therapy with nucleoside and nucleotide analogs after HBV undetectability is associated with lower rates of relapse in patients with HBeAg-negative CHB. Increasing relapse rates as a result of rebound in virema have been reported after stopping prolonged therapy with either lamivudine142or adefovir145. The probability of clinical and virologic relapse 6, 12, and 18 months after treatment withdrawal were 12% and 30%, 18% and 50%, and 30% and 50%, respectively.142 In a 5-year follow-up study of adefovir therapy in patients with HBeAg-negative CHB, approximately 25% of patients had long-term HBV DNA negativity after stopping therapy.145 Future trials are needed to better understand the optimal duration of therapy in HBeAg-negative patients.
Monitoring Virologic Response and Management of Resistance to Oral Antiviral Therapy
Prolonged antiviral therapy with the oral nucleosides and nucleotides is associated with the development of antiviral resistance.146 The rate of resistance depends on a number of factors, including pretreatment HBV DNA levels, potency of the antiviral agent, prior exposure to oral nucleoside or nucleotide antiviral therapy, duration of treatment, and the degree of genetic barriers to resistance to the individual drug. The long-term rates of resistance are highest for lamivudine (65%-70% at 4-5 years),147 intermediate for telbivudine (25% in HBeAg-positive patients and 11% in HBeAg-negative patients at 2 years),114 lower for adefovir (29% at 5 years),145 and lowest for entecavir in the absence of prior lamivudine resistance (1.2% at 5 years)107 and for tenofovir in treatment-naïve patients (0% at 1 year).98, 99 Patients with lamivudine resistance have a 51% rate of novel mutations after 5 years of entecavir therapy.107 The development of resistance is associated with loss of initial response and HBV DNA rebound, which is followed by biochemical breakthrough and eventual reversion of histologic improvement; in some cases, resistance leads to progressive liver disease associated with severe exacerbations.39 Thus, when possible, it is most beneficial to use the most potent nucleosides and nucleotides that possess the lowest risk of genotypic resistance as initial therapy for patients with nucleoside-naïve disease.
Antiviral Resistance Testing
The detection of antiviral resistance before virologic and biochemical breakthrough can prevent more serious liver-related complications and the development of cross-resistance to other nucleoside or nucleotide analog therapies, which might limit future treatment options.146 Standardized nomenclature and definitions of terms used to define resistance are indicated in Table 9.148 Clinically, antiviral resistance manifests as virologic breakthrough, which is defined as a ≥1 log10 IU/mL increase in serum HBV DNA levels from nadir in 2 consecutive samples taken 1 month apart in patients who have responded and been adherent to therapy with antiviral medications.148
When virologic breakthrough occurs in a patient who has adhered to antiviral therapy, the presence of mutations directly associated with drug resistance should be confirmed by using an in vitro assay. There are 2 types of HBV resistance analyses, genotypic and phenotypic. Genotypic resistance testing can be used to monitor treatment responses and diagnose primary and secondary treatment failures. Genotypic resistance assays identify the mutations in HBV polymerase that confer resistance by the direct sequencing of PCR products. Information from genotypic resistance testing can aid in the selection of appropriate add-on or alternative antiviral therapy. In clinical practice, genotypic resistance testing is recommended when virologic breakthrough occurs to confirm the presence of mutations directly associated with drug resistance to a particular nucleoside or nucleotide analog.148 In contrast, in vitro phenotypic resistance analyses can be used to confirm, by cell culture-based or enzymatic assays, that a mutation confers resistance and the level of susceptibility or resistance conferred by a specific mutation. Phenotypic assays are typically reserved for research studies.
Baseline genotypic testing for resistance is not recommended for routine use at this time because of the low sensitivity of the tests and the low incidence of drug resistance mutations at baseline as reported in clinical studies, although such testing might provide useful information regarding the potential for resistance to specific agents. For instance, in large clinical trials of entecavir involving nucleoside-naïve patients with CHB, the incidence of drug resistance mutations at baseline was 0.6%.149, 150 A 3-year follow-up study of patients with lamivudine resistance, who were being treated with lamivudine plus adefovir or lamivudine monotherapy, reported a 4% incidence of adefovir-resistant strains (rtA181V/T) at baseline, which was not found to influence the antiviral response rates.129
Methods for resistance testing are shown in Table 10. Direct sequencing-based assays are the gold standard for genotypic HBV resistance testing because all mutations that confer resistance can be detected. Other methods available that identify resistance mutations by sequence include real-time PCR analysis with specific probes, hybridization methods (line probe assay), restriction fragment length polymorphism analysis, and allele-specific PCR analysis.151, 152 The most commonly used methods in clinical practice include direct sequencing and line probe assays. Direct PCR sequencing allows the identification of mutations that comprise ≥20% of the total viral population. More sensitive assays involving hybridization and real-time PCR methods can detect emerging viral resistance when the HBV DNA encoding the resistance mutations comprises 5% of the total viral population.148, 153 Although more sensitive tests enable the early identification of patients who harbor HBV encoding resistance mutations at baseline, before the definition of clinical resistance is met, their use is currently restricted to clinical research and high-risk populations because of the expense involved and the complicated nature of performing the tests.
oinfection with HIV is a common result of shared routes of transmission. In the United States and the European Union, approximately 10% of all patients who are HIV-positive are coinfected with HBV.159 Coinfected individuals are more likely to develop chronic infection than are individuals with HBV monoinfection (23% vs 4%). HIV-HBV coinfection is associated with higher HBeAg positivity rates and HBV DNA levels, longer duration of viremia, lower aminotransferase values, milder necroinflammation, and more rapid progression to cirrhosis compared with HBV monoinfection. Data from large cohort studies showed that liver-related mortality in HIV-HBV coinfected patients is 14-fold higher than that in patients with either virus alone.160, 161
The general principles of diagnosis are not different for HBV-infected persons with or without HIV infection. However, HIV-HBV coinfection is often associated with atypical patterns of serologic markers of HBV infection, which hinder an appropriate diagnosis. The presence of occult hepatitis B, defined as the presence of HBV DNA without circulating HBsAg, might also complicate the diagnosis and management of HIV-HBV-coinfected individuals.162, 163, 164 Patients should be monitored for liver disease, particularly when HIV infection is not going to be treated immediately, because of the increased risk for cirrhosis and liver-related mortality.160, 165 The impact of HIV on the risk of HCC is unknown, and thus the current recommendations for HCC surveillance in patients with CHB should be followed.
The criteria for HBV therapy in persons with concomitant HIV infection are the same as for patients with HBV monoinfection.166, 167, 168 Individuals who have fluctuating, mildly elevated (1-2 X ULN) ALT levels or normal ALT values, and elevated HBV DNA levels (>20,000 IU/mL in HBeAg-positive individuals and >2000 IU/mL in HBeAg-negative individuals) should undergo liver biopsy and be considered for treatment if liver biopsy shows necroinflammation or significant fibrosis. Treatment generally is not recommended for HIV-infected patients (either HBeAg-positive or HBeAg-negative) if they have persistently normal ALT levels, low HBV DNA levels (a precise cutoff for "low" is not well-defined, but <2000 IU/mL is reasonable), and no fibrosis on a liver biopsy specimen.
Management of HBV infection in HIV coinfection is complicated by several factors. Current treatment options for treating the HBV infection in HIV-coinfected patients include interferon and nucleoside or nucleotide analogs.166 However, many of the nucleoside or nucleotide analogs, including lamivudine, tenofovir, emtricitabine, and entecavir, possess dual activity against HBV and HIV.169 Of greatest concern is the potential for the development of resistance, which could compromise the future management of either virus. The rate of lamivudine resistance is higher in HIV-HBV coinfected patients, reaching 90% at 4 years.170 Moreover, prolonged treatment with lamivudine has been shown to be associated with the development of vaccine mutations to HBV, which might have important public health implications for transmission of the virus.171 Thus, the primary consideration in initiating treatment under conditions of HIV-HBV coinfection is to determine which virus requires treatment. The chosen therapy must be designed to avoid the development of drug-resistant HBV or HIV.
Recommendations for the treatment of HIV-HBV coinfection have recently been published by the U.S. Department of Health and Human Services.172 In HIV-infected patients, if therapy for either HIV or HBV infection is indicated, initiation of a fully suppressive antiretroviral regimen that includes tenofovir and either lamivudine or emtricitabine is recommended to prevent the development of antiretroviral drug resistance. The use of lamivudine, emtricitabine, or tenofovir as the only active anti-HBV agent should be avoided because of the risk for resistance. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine for the management of HBV infection. Management of HIV should be continued with a combination regimen to provide maximal suppression. If antiretroviral therapy is not initiated, HBV therapy should include only agents that have the least potential of selecting HIV resistance mutations.
In instances when HIV treatment is not an option or is not desirable, peginterferon alfa-2a or alfa-2b, adefovir, and telbivudine are potential options. Telbivudine is not known to be active against HIV, and one drawback to its use is that resistance might develop rapidly when it is used as monotherapy.114 Adefovir at a low dose (10 mg) is not active against HIV, although higher doses of adefovir do demonstrate activity. Adefovir is also the least potent of these choices. Although clinical data supporting the use of interferons in the HIV setting are limited, the advantage of peginterferons is that they do not select for drug-resistant HIV. Patients who are more likely to respond to this treatment are those who are young and immunocompetent and have low HBV DNA levels and high ALT levels; they must also not be harboring any known drug-resistant HBV. Individuals with HBeAg-negative CHB do not typically respond well to peginterferons, so in the setting of HIV infection these agents are not a first-line choice.
Antiviral agents that inhibit both HIV reverse transcriptase and HBV DNA polymerase include tenofovir, adefovir at doses of >10 mg, lamivudine, emtricitabine, and entecavir. Exposure to these antiviral agents without a fully active HIV regimen could potentially compromise future HIV care. Accordingly, these agents should not be used without concomitant HIV therapy for the treatment of HBV in coinfected patients. Lamivudine and emtricitabine should also be avoided as the only anti-HBV active agent in the initial treatment of HBV infection in HIV-coinfected patients because of the high incidence of resistance in this population.171, 173
For patients who require treatment for HIV alone or both HIV and HBV, tenofovir plus emtricitabine (Truvada; Gilead Sciences, Foster City, CA) is recommended, along with other classes of antiretroviral agents, to form a potent anti-HIV regimen. The combination of efavirenz 600 mg, emtricitabine 200 mg, and tenofovir 300 mg (coformulated as Atripla; Bristol-Myers Squibb Company, Princeton, NJ, and Gilead Sciences; Foster City, CA) is available for the management of HIV infection and is a reasonable choice in a patient naïve to therapy. If tenofovir cannot be used, an alternative HIV regimen along with entecavir might be considered. If both viruses need to be treated but the patient has lamivudine-resistant HBV, the best option is still to include both tenofovir and emtricitabine or lamivudine as part of the anti-HIV regimen. The combination is advocated, because it might reduce the rate of development of tenofovir-resistant HBV.174
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