Effectiveness of Hepatitis B Treatment in Clinical Practice

GASTROENTEROLOGY 2012;142:1360 –1368

Effectiveness of Hepatitis B Treatment in Clinical Practice

Steven J. Scaglione

Anna S. F. Lok

CLINICAL LIVER

Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan

It is important to examine the effectiveness of current therapies for chronic hepatitis B in clinical practice, given the therapeutic advances over the past 15 years. A 2010 Institute of Medicine report on hepatitis and liver cancer stated that the public and health care providers have a lack of knowledge and awareness about viral hepatitis, and that there is a gap between medical innovation and community care. We review the efficacy of hepatitis B treatment, based on results from clinical trials, and discuss the effectiveness of these treatments in clinical practice. We also discuss why having efficacious treatments alone would have a small impact on the global health burden of hepatitis B, and highlight the importance of educating the public and the medical community and coordination of care. Keywords: Antiviral Therapy; Efficacy; Interferon; Nucleos(t)ide Analogues; Screening.

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even drugs have been approved for the treatment of chronic hepatitis B (CHB). These drugs can suppress hepatitis B virus (HBV) replication and prevent disease progression, but their efficacy in clinical trials does not always correspond to their effectiveness in practice; approval of efficacious treatments alone will not necessarily reduce the global burden of this disease. Clinical trials involve highly selected, motivated patients with few comorbidities, and treatment is supervised by experienced physicians and research staff who follow strict protocols. Furthermore, costs of medications and monitoring usually are covered by the trial sponsor. On the other hand, in clinical practice, physicians have to care for all patients, could be less experienced, and have less support in monitoring their patients (Table 1). In addition, although the cost of HBV treatment is covered by national health systems in some countries, patients in many countries, including the United States, often have to bear part or all of the costs of treatment. Of even greater importance, realization of treatment benefits requires proper diagnosis, referral to care, initiation of treatment, tolerance and

adherence to treatment, and ability to pay for the medications and monitoring. A chasm between efficacy in clinical trials and effectiveness in the community was described in the 2010 Institute of Medicine (IOM) report Hepatitis and Liver Cancer,1 and a Hepatitis Summit Report, The State of Hepatitis B and C in Europe.2 We review the efficacy of hepatitis B treatment, as evaluated in clinical trials, and discuss the effectiveness of these treatments in practice, the barriers between efficacy and effectiveness, and strategies to remove these barriers.

Burden of Hepatitis B Despite advances in prevention and treatment, HBV infection remains a global public health concern. Worldwide, approximately 2 billion people have been exposed and 350 million people are chronically infected with HBV, which is estimated to be responsible for 620,000 deaths per year.3 HBV infection is a major burden in resource-limited countries, accounting for 30% of cases of cirrhosis and 53% of cases of hepatocellular carcinoma (HCC).4 Even in developed countries with universal vaccination programs and availability of efficacious treatment, the burden of HBV-related disease remains high. The prevalence of chronic HBV infection in the US population is estimated to be 0.27%,5 but many screening programs conducted in Asian American communities have shown prevalence rates of 10%–15%.6 Furthermore, the IOM committee estimated that of the 0.8 –1.4 million persons in the United States with chronic HBV infection, 65% are not aware of their infection.1 The prevalence of HBV infection in Europe varies from 0.2% in Ireland to 7% in Turkey. It has been estimated that 14 million EuropeAbbreviations used in this paper: ALT, alanine aminotransferase; CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HIV, human immunodeficiency virus; IFN, interferon; IOM, Institute of Medicine; PCR, polymerase chain reaction; PEG-IFN, pegylated interferon; ULN, upper limit of normal. © 2012 by the AGA Institute 0016-5085/$36.00 doi:10.1053/j.gastro.2012.01.044

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Table 1. Efficacy of CHB Treatment in Clinical Trials vs Effectiveness in Clinical Practice Efficacy Utility of a medical treatment evaluated under optimal conditions Highly selected, motivated patients Experienced physicians and support staff Standardized algorithm for monitoring of response and management of suboptimal response/breakthrough Frequent visits and laboratory tests Free medications, evaluations, and tests

Effectiveness Utility of medical treatment in routine clinical settings (ie, real life) All patients All physicians with varying knowledge and experience, limited or no support staff Monitoring of response and management of suboptimal response/breakthrough at discretion of physician Less frequent office visits and laboratory tests Costs borne by health insurance and/or patient

ans are chronically infected with HBV, resulting in 36,000 deaths each year, but accurate data are lacking in most European countries; as many as 90% of HBV-infected Europeans are not aware of their infection.2

Efficacy of Treatments for CHB Goals and End Points The ultimate goal of CHB treatment is to prevent the development of cirrhosis, liver failure, and HCC. Clinical trials have relied on surrogate end points that correlate with clinical end points. Surrogate end points are biochemical (a normalized level of alanine aminotransferase [ALT]), virologic (suppression of HBV DNA to undetectable levels by polymerase chain reaction [PCR] assays), serologic (loss of hepatitis B e antigen [HBeAg], with or without seroconversion to hepatitis B e antibody, in HBeAg-positive patients and loss of hepatitis B surface antigen [HBsAg], with or without seroconversion to hepatitis B surface antibody), as well as histologic (decrease in necrosis and inflammation score by ⱖ2 points with no worsening of fibrosis). PCR assays with lower limits of detection of 300 –1000 copies/ mL, or roughly 60 –200 IU/mL, were used in phase 3 trials, but real-time PCR assays with improved sensitivity (a lower limit of detection of 10 –20 IU/mL) are available and should be used to monitor virologic response.

Eligibility Criteria Phase 3 trials of therapies for CHB have focused on enrolling patients with high levels of HBV DNA, abnormal levels of ALT, and compensated liver disease. Phase 3 trials of pegylated-interferon (PEG-IFN), with or without lamivudine, compared with lamivudine monotherapy, enrolled adult HBeAg-positive patients with serum levels of HBV DNA greater than 500,000 copies/mL (⬃100,000 IU/mL) and HBeAg-negative patients with levels of HBV DNA greater than 100,000 copies/mL (⬃20,000 IU/mL), along with abnormal levels of ALT (1–10 times the upper limit of normal [⫻ULN]) and evidence of chronic hepa-

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titis from liver biopsy specimens.7–10 Phase 3 trials of nucleos(t)ide analogues generally have enrolled HBeAgpositive patients with levels of HBV DNA greater than 1,000,000 copies/mL (⬃200,000 IU/mL) and HBeAg-negative patients with levels of HBV DNA greater than 100,000 copies/mL (⬃20,000 IU/mL), along with levels of ALT 1.3–10 ⫻ULN and evidence of chronic hepatitis from liver biopsy specimens.11–17 These trials excluded patients with decompensated liver disease; other causes of liver disease; co-infection with human immunodeficiency virus (HIV), hepatitis C virus, or hepatitis D virus; severe or unstable medical comorbidities; or medical conditions that require chronic immunosuppressive therapies, along with women who were pregnant or of child-bearing potential but were unwilling to practice contraception.

Responses Published reports from phase 3 trials have focused on responses at the end of 1 year of treatment. Although responses up to year 5 had been reported from some trials, these follow-up studies did not include all patients in the original trial, and some studies had modifications to the original treatment after the first year. Tables 2 and 3 summarize responses to the approved drugs in HBeAgpositive and in HBeAg-negative patients with CHB. PEG-IFN. A large, phase 3 trial of PEG-IFN with or without lamivudine, compared with lamivudine monotherapy, in HBeAg-positive patients showed that PEGIFN, with or without lamivudine, was superior to lamivudine monotherapy—the addition of lamivudine to PEGIFN did not provide any benefit.7 Similar responses were observed in other trials of PEG-IFN (Table 2).9,10 Follow-up evaluation of patients from one trial in Europe and Asia (of mixed HBV genotypes) showed that 19% had undetectable levels of HBV DNA, 37% had lost HBeAg, and 11% had lost HBsAg after a mean of 3.5 years from completion of PEG-IFN treatment. Patients with genotype A infection had a significantly higher rate of HBsAg loss than those with non-A genotype infection (28% vs 3%). Among the initial responders, 81% had durable loss of HBeAg and 30% lost HBsAg.18 By contrast, follow-up evaluation of patients in a trial in Hong Kong (only genotypes B and C) found that only 2.4% of patients lost HBsAg at 5 years, despite similarly high rates (82%) of durable seroconversion of HBeAg.19 A large, phase 3 trial of a 48-week course of PEG-IFN, with or without lamivudine, compared with lamivudine monotherapy, in patients with HBeAg-negative CHB showed that patients who received PEG-IFN had a significantly higher rate of sustained, off-treatment response (Table 3).8 This difference was maintained when patients were re-evaluated 3 years after treatment was discontinued.20 Nucleos(t)ide analogues. Phase 3 clinical trials of nucleos(t)ide analogues in patients with HBeAgpositive CHB showed that after 1 year of treatment, 21%–76% had an undetectable level of HBV DNA and 41%–77% had a normalized level of ALT, but only 12%– 22% achieved HBeAg seroconversion and 0%–3% lost

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Table 2. Response Rates to Approved Therapies for HBeAg-Positive CHB

Treatment response parameters

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Telbivudine

Tenofovir disoproxil fumarate

PEG-IFNa

PEG-IFN plus lamivudinea

6.9 67 68 22 21 2 72 0

6.5 60 77 26 22 ⬍1 65 4.4

6.2 76 77 21 21 3 74 0

2–4.5 25 34–39 ⬃30 27 3 38 0

5–7.2 69 46–51 27–44 24 3–7 41 4–11

94 (5) 41 (5) 5 (5) 1.2 (6)

79 (4) 42 (4) 1.3 (2) 21 (2)

65 (5) 31 (4) 10 (5) 0 (5)

19 (3.5)d 37 (3.5)d 11 (3.5)d 0

26 (3)d 25 (3)d 15 (3)d N/A

Lamivudine

Adefovir dipivoxil

Entecavir

5.5 36–44 41–75 17–32 16–21 ⬍1 49–56 27

3.5 13–21 48–61 24 12–18 0 53 0 39 (5) 48 (5) 2 (5) 42 (5)

Responses at weeks 48–52 Log reduction in HBV DNA, copies/mL Undetectable HBV DNA, % ALT normalization, % Loss of HBeAg, % HBeAg seroconversion, % Loss of HBsAg, % Histologic improvement, %b Genotypic resistance Responses during extended treatmentc Undetectable HBV DNA, % HBeAg seroconversion, % Loss of HBsAg, % Genotypic resistance

39 (2) 47 (3) 0–3 (2–3) 65 (5)

NOTE. The percentage of patients in the original cohort included in extended response reports was as follows: lamivudine, 17%–72%; adefovir, 38%; entecavir, 49% (entecavir 1.0 mg was used beginning in year 3 instead of approved 0.5 mg); tenofovir, 76% (34 of 39 patients with detectable HBV-DNA levels at week 72 opted to add emtricitabine); PEG-IFN, 65%. Data are from references 10 –13, 14 –20, 21, 24, 25–29. N/A, not available. aLiver biopsy performed at weeks 72 or 78, 24 weeks after stopping treatment. bHistologic improvement defined as a ⱖ2-point decrease in necroinflammatory score and no worsening of fibrosis score. cThe time point at which response was assessed in years from start of treatment is shown in parentheses. dAssessment performed off treatment.

HBsAg (Table 2).11,12,14,16,17,21 Extension of the duration of nucleos(t)ide analogue treatment to 4 –5 years was associated with a progressive increase in the rate of HBeAg seroconversion, to 31%– 48%, but the rate of HBsAg loss remained low (0%–10%) (Table 2). In some studies, treatment in later years differed from that of standard clinical practice; the dose was increased (1 mg/d instead of the approved dose, 0.5 mg/d) from year 3 onward in the entecavir study, and 34 of 39 patients who had detectable levels of HBV DNA at week 72 opted to receive additional emtricitabine treatment in the tenofovir study.22–25

The durability of HBeAg seroconversion after treatment with nucleos(t)ide analogues has been reported to be less than 50% in some studies and more than 80% in others. Nucleos(t)ide analogues were found to induce only temporary HBeAg seroconversion in one study of 9 patients.26 However, a study of 178 patients reported the durability of HBeAg seroconversion to be 78% in the overall cohort and 91% among 117 patients who completed at least 12 months of consolidation therapy (the duration of continued treatment after HBeAg seroconversion).27 A 1-year course of treatment with nucleos(t)ide analogues produced high rates of undetectable levels of

Table 3. Response Rates to Approved Therapies for HBeAg-Negative CHB

Treatment response parameters Responses: weeks 48–52 Histologic improvement, %b Undetectable HBV DNA, % HBsAg loss, % Genotypic resistance, % Responses: extended treatmentc Undetectable HBV DNA, % HBsAg loss, % Genotypic resistance, %

Telbivudine

Tenofovir disoproxil fumarate

PEG-IFNa

PEG-IFN plus lamivudinea

70 90 ⬍1 0.2

67 88 ⬍1 2.7

72 93 0 0

48 63 4 0

38 87 3 1

NA NA NA

84 (4) ⬍1 (2) 8.6 (2)

83 (5) 0.3 (5) 0 (5)

18 (3)d 8 (3)d 0

13 (3)d 8 (3)d N/A

Lamivudine

Adefovir dipivoxil

Entecavir

60–66 60–73 ⬍1 23

64–69 51 0 0

6 (4) ⬍1 (4) 70–80 (5)

67 (5) 5 (5) 29 (5)

NOTE. The percentage of patients in the original cohort included in the extended response reports was as follows: lamivudine, 17%–72%; adefovir, 47%; entecavir, 50%; telbivudine, 100%; tenofovir, 76% (34 of 39 patients with detectable HBV-DNA levels at week 72 opted to receive additional emtricitabine); PEG-IFN, 58%. Data are from references 11, 17, 18, 20, 23, 26, 32, 33. N/A, not available. aLiver biopsy performed at week 72, 24 weeks after stopping treatment. bHistologic improvement defined as a ⱖ2-point decrease in necroinflammatory score and no worsening of fibrosis score. cThe time point at which response was assessed in years from the start of treatment is shown in parentheses. dAssessment performed off treatment.

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Clinical Outcomes Because of the slow course of chronic HBV infection, it is a challenge to implement randomized, controlled trials of antiviral agents with liver failure or HCC (clinical outcomes) as end points. Evidence to support the ability of antiviral therapy to prevent clinical outcomes has been obtained mainly from retrospective or prospective cohort studies and meta-analyses. However, fewer patients have been listed for liver transplantation for HBV-related end-stage liver disease since 1999 (after the approval of the first nucleos[t]ide analogue), indicating that these drugs reduce clinical outcomes.31 Interferon. Most of the studies that reported that interferon (IFN) treatment prevented clinical outcomes used conventional IFN. Several studies found that IFNtreated patients had a reduced incidence of cirrhosis, decompensation, liver-related death, and HCC, compared with untreated patients, and that there was a greater benefit among the responders.32,33 Meta-analyses confirmed that IFN therapy prevented complications of cirrhosis and HCC, although the studies analyzed had a high degree of heterogeneity.34,35 Nucleos(t)ide analogues. A randomized, controlled trial of lamivudine therapy in 651 patients with advanced fibrosis or cirrhosis, who were HBeAg-positive or had serum levels of HBV DNA greater than 0.7 MEq/mL (⬃⬎140,000 IU/mL), reported that nucleos(t)ide analogues prevented clinical outcomes. After a median of 32 months, 7.8% of lamivudine-treated and 17.7% of patients who received placebo (controls) reached the combined end point (an increase in Child–Turcotte–Pugh score by ⱖ2 points or development of clinical complications of cirrhosis, HCC, or liver-related death); HCC developed in 3.9% of the patients who received lamivudine and 7.4% of controls.36 Fewer patients who maintained viral suppression reached the combined end point than those who developed resistance to lamivudine. Nucleos(t)ide analogues that have a higher genetic barrier to resistance, such as entecavir or tenofovir, are therefore more likely to reduce clinical outcomes. A systematic review and a meta-analysis found a reduction in the incidence of HCC among patients who received nucleos(t)ide analogue therapy.35,37 Long-term treatment with nucleos(t)ide analogues also was associ-

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ated with a decrease in liver fibrosis and reversal of cirrhosis.29,38,39 These data indicate that long-term viral suppression not only prevents further liver damage but also might reverse previous damage.

Predictors of Response PEG-IFN. Pretreatment factors that have been shown to predict the response of HBeAg-positive patients to IFN therapy include a high level of ALT, a low level of HBV DNA, and infection with HBV genotype A.7,9 Younger age, female sex, a high level of ALT, a low level of HBV DNA, and infection with HBV genotypes B or C were associated with a higher rate of sustained response in a phase 3 trial in HBeAg-negative patients.40 Recently, it was suggested that a decreased titer of HBsAg at weeks 12 or 24 of PEG-IFN treatment predicted a sustained response in HBeAg-positive and in HBeAg-negative patients, and that this factor could be used to decide whether treatment should be continued.41 However, these algorithms have not been validated in prospective studies. Nucleos(t)ide analogues. A high pretreatment level of ALT is the best predictor of the response of HBeAg-positive patients to nucleos(t)ide analogues,16,42 but there is no consistent predictor of response for HBeAg-negative patients. All major genotypes of HBV have similar levels of response to nucleos(t)ide analogues.

Adverse Events Interferon. IFN therapy produces a wide range of side effects, including fatigue, flu-like symptoms, mood changes, bone marrow suppression, and development or exacerbation of autoimmune illnesses. As many as 40% of patients have an increase in ALT level during IFN therapy, which generally is associated with response, but also could precipitate liver failure in patients with cirrhosis. Nucleos(t)ide analogues. All 5 nucleos(t)ide analogues that have been approved for treatment of CHB are well tolerated, but produce several adverse reactions. Telbivudine has been associated with myopathy and peripheral neuropathy.14,43 Tenofovir and adefovir have been associated with nephrotoxicity and renal tubular dysfunction; tenofovir also has been associated with decreased bone mineral density. Entecavir was associated with lactic acidosis in a case series of patients with decompensated liver disease,44 but this finding was not reported in larger studies.45,46

Effectiveness of CHB Treatment Efficacy is the ability of a drug or intervention to produce an effect under optimal conditions, whereas effectiveness is its usefulness in routine practice. Clinical trials differ in many ways from clinical practice (Table 1), so efficacy does not always result in effectiveness. For example, clinical trials have stringent eligibility criteria. Many physicians in clinical practice treat patients that fall outside these criteria, assuming that efficacy and safety observed in clinical trials can be extrapolated to their patients.

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HBV DNA (51%–93%) and normalization of ALT levels (62%–78%), but low rates of HBsAg loss (⬍1%) in nucleoside-naive patients with HBeAg-negative CHB (Table 3).14,15,17,28 Viral relapse occurred in almost all patients when treatment was discontinued. Extending treatment with adefovir or tenofovir to 4 –5 years maintained viral suppression in 67%– 83% of patients, but the rate of HBsAg loss remained low (0%–5%).24,29 Virus resistance to nucleos(t)ide analogues limits their long-term success. The reported incidence of viral resistance to the 5 approved drugs ranged from 0% to 27% after 1 year of therapy to 0%– 80% after 5 years of therapy (Tables 2 and 3).12,14 –17,23,28,30

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Patients With Normal Levels of ALT

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Traditionally, treatment for CHB is recommended only for patients with increased levels of ALT. A threshold level of ALT that is 2⫻ ULN has been recommended in guidelines from the American Association for the Study of Liver Diseases and the Asian Pacific Association for the Study of the Liver, based on the assumption that ALT level is a reliable marker of liver injury.47,48 Furthermore, increased levels of ALT predict HBeAg seroconversion during treatment with IFN or nucleos(t)ide analogues. Guidelines from the European Association for the Study of the Liver do not require increased levels of ALT for patients to receive therapy, but rather histologic evidence of moderate to severe necroinflammation and/or fibrosis.49 Several large, population-based studies have associated high levels of HBV DNA with increased risk for cirrhosis, HCC, and liver-related mortality,50–52 so many experts advocate treatment of patients with CHB based only on level of HBV DNA. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease study found that participants with a high baseline level of HBV DNA that decreased during follow-up evaluation had a lower risk of HCC than those with persistently high levels of HBV DNA. Participants with persistently abnormal levels of ALT had an 8-fold higher risk of HCC than those with persistently low to normal levels of ALT.53 These findings indicate that an HBsAg-positive patient with persistently normal levels of ALT and a single measurement of a high level of HBV DNA might not need treatment. Clinicians also might initiate antiviral treatment for patients with normal levels of ALT based on reports that they can develop histologically significant liver disease. However, most of these studies included small numbers of patients, and the normal level of ALT was determined based on only 1 or 2 values. Studies that focused on HBeAg-positive patients in the immune-tolerant phase have shown that hepatic inflammation and fibrosis were negligible to mild in most patients with normal levels of ALT,54,55 and studies of HBeAg-negative patients who had persistently normal levels of ALT (based on ⱖ3 values over a period of ⱖ12 months) found that less than 10% had significant amounts of inflammation or fibrosis.56,57 Patients with normal levels of ALT (particularly those with persistently normal levels), therefore have a lower risk of clinical outcomes and histologically advanced liver disease, so the benefits of antiviral treatment might be less than for those with abnormal levels of ALT. Furthermore, the effects of antiviral agents in clinical trials, which only include patients with abnormal levels of ALT, cannot be extrapolated to patients with normal levels of ALT. Data from 2 large, global trials of PEG-IFN showed that HBeAg-positive patients (infected with genotypes A–D) with pretreatment levels of ALT ⱕ2⫻ ULN had lower rates of sustained response, defined as loss of HBeAg and level of HBV DNA less than 2000 IU/mL, 6 months after stopping treatment than those with pretreatment levels of ALT ⱖ2⫻ ULN.58 There was a more than 7-fold difference

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in the percentage of patients with sustained response between the least responsive group (HBV genotype D, HBV DNA ⱖ9 log copies/mL and ALT level ⬍2⫻ ULN; 7% response) and the most responsive group (HBV genotype A, HBV DNA ⬍9 log copies/mL and ALT ⱖ2⫻ ULN; 54% response). A phase 3 trial of entecavir in HBeAgpositive nucleoside-naive patients showed that patients with pretreatment levels of ALT 1.3–2⫻ ULN had lower rates of response than patients with pretreatment levels of ALT ⬎2⫻ ULN; the responses in these groups at 1 year were 62% and 75% for histologic improvement, 48% and 73% for level of HBV DNA ⬍300 copies/mL, 55% and 73% for normal levels of ALT, and 8% and 26% for HBeAg seroconversion.59 Therefore, there is a wide range in responses, even among patients who meet the stringent criteria for inclusion in phase 3 trials (which do not include normal levels of ALT). Responses to IFN and nucleos(t)ide analogue therapy are lower in patients with pretreatment level of ALT 1–2⫻ ULN in clinical trials, so responses of patients with normal pretreatment levels of ALT, seen in clinical practice, are likely to be even lower.

Patients With Low Levels of HBV DNA Phase 3 clinical trials of PEG-IFN and nucleos(t)ide analogues enrolled HBeAg-positive patients with serum levels of HBV DNA greater than 100,000 IU/mL and HBeAgnegative patients with levels greater than 20,000 IU/mL. Based on data from the Risk Evaluation of Viral Load Elevation and Associated Liver Disease study, it was proposed that the threshold for initiation of treatment should be reduced to 2000 IU/mL.49 Virologic response rates (suppression of HBV DNA to undetectable levels) are likely to be higher in patients with lower pretreatment levels of HBV DNA; but the benefits of preventing clinical outcomes and the cost effectiveness of many years of nucleos(t)ide analogue therapy are likely to be lower for patients with levels of HBV DNA between 2000 and 20,000 IU/mL.

Extending Duration of Treatment Practice guidelines recommend that treatment for HBeAg-positive patients should be continued for at least 6 months after HBeAg seroconversion.47,49 However, a longer duration of consolidation treatment, 12 months, is preferred.27 Long-term follow-up data from phase 3 trials showed that approximately 50% of HBeAg-positive patients achieved HBeAg seroconversion after 4 –5 years of continuous treatment, so half of the patients will require more than 5– 6 years of nucleos(t)ide analogue treatment. There are no published data on the safety and efficacy of nucleos(t)ide analogues beyond 5 years, yet in clinical practice most physicians recommend continuing treatment beyond 5 years for patients who have not achieved HBeAg seroconversion. This recommendation is based on the assumption that the treatment is safe and that incremental responses will be observed with time. In fact, many experts have argued that treatment should be continued indefinitely, even for patients who have achieved HBeAg seroconversion, be-

cause of the low durability of nucleos(t)ide-related HBeAg seroconversion and because HBV replication can persist even in patients with durable HBeAg seroconversion.26,60 For HBeAg-negative patients, none of the guidelines provide clear-cut recommendations on when nucleos(t)ide analogues can be stopped, although it has been suggested that treatment could be discontinued for patients who have cleared HBsAg. HBsAg loss, however, is a rare event, occurring in 0%–5% of patients after 4 –5 years of continuous treatment. Therefore, most HBeAg-negative patients in clinical practice are treated indefinitely. In clinical practice, rates of response and of drug resistance during extended treatment with approved doses of entecavir or tenofovir monotherapy might be lower than those reported from clinical trials. Studies of treatment of CHB in the community showed a wide range of responses because of variations in inclusion and exclusion criteria, and definitions of response. Reports from larger studies found similar rates of response as those reported in phase 3 clinical trials, indicating that efficacy in clinical trials can be replicated in the community, if the criteria for treatment are similar and treatment is monitored by experienced physicians. A study of 63 HBeAg-positive patients treated with PEG-IFN for 48 weeks found that 32% achieved HBeAg seroconversion at the end of treatment and only 6.5% discontinued therapy owing to adverse reactions.61 Another study compared the effects of telbivudine and entecavir in 195 HBeAg-positive patients and found that after 1 year of treatment, serum levels of HBV DNA were undetectable in 82% and 94.9% of patients, respectively, and drug resistance developed in 6.7% and none, respectively.62 Although nucleos(t)ide analogues are well tolerated and generally very safe, adverse events have been reported, albeit rarely in clinical trials, which include highly selected patients who are treated only for up to 5 years. Patients who receive adefovir or tenofovir and have other medical conditions, such as diabetes or hypertension, which increase the risk of renal failure, and those who receive concomitant medications that are potentially nephrotoxic, have increased risks of renal impairment. These situations are more likely to arise in clinical practice. In long-term carcinogenicity studies, doses of entecavir that are 35– 42 times higher than those used in clinical practice were associated with tumor development in rodents. There is no evidence for an association between entecavir and cancer risk in human beings. Although data from an ongoing long-term safety study are not yet available, many patients worldwide have been receiving entecavir continuously for more than 5 years.

Adherence Treatment can be effective only if patients take their medications as prescribed. In phase 3 trials of PEGIFN, approximately half of the patients required dose reduction and 2%–7% had early discontinuation.7,8 Similar to PEG-IFN and ribavirin treatment of chronic hepatitis C, the rate of sustained response could be lower in patients with CHB who receive lower doses or have a shorter duration of therapy.

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Adherence to nucleos(t)ide analogues is a bigger concern because of the need for long durations of treatment and the increased risk of drug resistance among patients with poor adherence. In phase 3 clinical trials of entecavir and tenofovir, 2% of patients experienced virologic breakthrough during the first year, but none were found to have drug-resistance variants, indicating that the breakthrough resulted from poor adherence. Adherence to nucleos(t)ide analogues in clinical practice could be lower than in clinical trials because patients are less motivated, less frequently monitored, and often have to pay for part of the costs of the medications. In a study of a pharmacy claims database with more than 11,000 adult patients who received nucleos(t)ide analogues for CHB in the United States between 2007 and 2009, the mean persistence rate (defined as continued refill of medication over a 12-month period) was 81% and the mean adherence rate (defined as the percentage of days during which a patient had medications in his/her possession during the period in which the medication was prescribed) was 88%.63 Another study found that 26% of patients who received nucleos(t)ide analogue treatment at an academic liver center in the United States reported having missed 1 or more doses during the past 30 days,24 and patients with lower adherence had a trend toward a higher rate of virologic breakthrough. A third study found that the 5-year cumulative probability of virologic breakthrough was 46% among patients who received nucleos(t)ide analogue therapy in clinical practice, but 40% of the breakthroughs were not related to viral resistance.64 These findings confirm the effects of adherence on the effectiveness of CHB treatment.

Reducing the Burden of Hepatitis B Despite the proven efficacy of CHB treatments, numerous barriers keep these advances from reducing the global burden of HBV infection. Identifying and removing these barriers require coordinated efforts from policy makers and health care providers (Table 4).

Diagnosis and Access to Care Most people with CHB are asymptomatic until they reach advanced stages of liver disease. Early diagnosis requires recognition of persons with risk factors (by themselves or by a health care provider) and screening. The IOM committee estimated that 65% of individuals chronically infected with HBV in the United States are not aware of their infection. Self-awareness of risks of HBV infection among high risk populations in the United States is low, varying from 26% to 70%.65,66 Among AsianPacific Islanders, only 30%– 40% are aware of their HBV status, and as few as 8%– 65% of foreign-born Asian-Pacific Islanders have been screened for HBV.66,67 Even among those who are diagnosed, only 40%– 66% had been referred to appropriate care.68,69 Many factors contribute to the low rate of referral, including lack of health care insurance, language and cultural barriers, and failure (by individuals or health care providers) to recognize that absence

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Table 4. Barriers Between Efficacy of CHB Treatment in Clinical Trials and Effectiveness in Clinical Practice and Solutions to Bridge the Gap Between Efficacy and Effectiveness Barriers Diagnosis

Lack of awareness of risk Fear of stigmatization Lack of infrastructure in primary care clinics to flag at-risk patients and to implement screening Lack of access to care

Access to care

Language and cultural barrier Lack of health care insurance

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Evaluation of disease and indications for treatment

Lack of referral to appropriate physicians Failure to perform appropriate evaluation and to recommend treatment when indicated

Initiation of treatment with appropriate drugs

Lack of knowledge Costs and availability of drugs

Adherence to treatment

Lack of knowledge about importance of medication adherence Lack of tools to remind patients High costs or co-pay

Solutions to bridge the gap between efficacy and effectiveness Education of public (particularly high-risk groups) and providers Education of public (particularly high-risk groups) Re-engineered care processes such as use of electronic medical records to prompt screening of at-risk patients Incorporate HBV screening in clinics with a high percentage of at-risk patients (eg, HIV and sexually transmitted disease clinics) Financial incentives for providers to perform HBV screening and vaccination Free HBV screening for persons with risk factors through public health clinics and community screening programs Community health centers with staff who understand the language and culture serving as navigators, strategic location of these centers Social workers to help eligible persons apply for health care insurance through private or government programs Affordable Care Act in the United States Education of patients about outcomes of chronic HBV infection and available treatments Navigators to assist with access to appropriate providers Education of providers on diagnostic evaluation, natural history, and treatment options Remote learning, consultation, and shared management via video conference Quality measures of care Adaptation of guidelines for resource-limited countries Education of providers Coordinated efforts of policymakers, providers, and pharmaceutical companies to ensure availability of approved drugs worldwide and to provide generic or discounted drugs to resource-limited countries and patients with limited resources Education of patients and providers Counseling and reminders at follow-up visits Pill box, reminders from pharmacy Alerts from pharmacy to providers Patient assistance program Affordable Care Act in the United States

of symptoms or normal levels of liver enzymes does not preclude the presence of liver disease or risk of cirrhosis or HCC. Studies have shown that primary care physicians in the United States have significant deficits in their knowledge of risk factors for HBV infection, use of HBV serology tests, interpretation of test results, and available treatment options and their efficacy.1,70,71 One study estimated that 20%–30% of Americans with CHB have been diagnosed, fewer than 50% have been referred to care, and only 3% are receiving treatment (Figure 1).72 Similar gaps in diagnosis and referral to care also were identified by a European panel.2 It is likely that these gaps are wider in resource-limited countries where HBV infection is more prevalent.

Implementation of Treatment and Choice of First-Line Medication Implementation of treatment requires an understanding of the indications and options for treatment, the logistics of patient evaluation, the availability and affordability of treatment, and the infrastructure for monitoring response, adverse events, and drug resistance. In resource-limited countries, HBV-DNA assays and the capacity to perform liver biopsy are not readily available,

so treatment decisions are made based on clinical assessment, age, level of ALT, and HBeAg status.73 In many countries, noninvasive methods, such as blood tests for panels of fibrosis markers and tools to measure liver stiffness, are increasingly used in place of liver biopsies to assess liver disease and need for antiviral therapy. These methods are expensive and not available in resource-limited countries, but indices derived from routinely available laboratory tests, such as aspartate aminotransferase–platelet ratio index, are available and can provide additional information on the likelihood of advanced liver disease.74 Ideally, patients should be treated with the medication that is most likely to produce the desired response and be tolerated by the patient. Professional organization guidelines recommend PEG-IFN, entecavir, and tenofovir as first-line medications, based on their efficacy and low risk for resistance in clinical trials. The decision whether to give PEG-IFN or a nucleos(t)ide analogue usually is based on patient preference, although it also is based on physician bias, medical or psychiatric comorbidities, the severity of liver disease, and level of commitment to long durations of treatment. In general, patients who are more likely to respond to PEG-IFN

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but are not sufficient to reduce the global burden of HBV; barriers to diagnosis, care, and treatment must be overcome. Advances in diagnostic tests and approval of new drugs must be coupled with education programs for the public and health care providers, and innovative strategies are needed to improve access to care and affordability. Only then can the efficacy of HBV treatment in clinical trials be translated into effectiveness in the real world. Given the need for long durations of anti-HBV therapy, the most effective method to decrease the global burden of HBV infection would be to implement universal vaccination of newborns worldwide.

Figure 1. HBV treatment, from efficacy to effectiveness. Of the estimated 1.4 –2 million persons in the United States with chronic HBV infection, only approximately 33% are aware of the infection. Among the estimated 350,000 –500,000 persons eligible for HBV treatment, approximately 50% are in care and 12.5% are receiving treatment. Rx, treatment.

(high pretreatment levels of ALT and low pretreatment levels of HBV DNA) are also more likely to respond to nucleos(t)ide analogues. The only exception is HBeAg-positive patients with genotype A infections who are predicted to have a high rate of HBeAg and HBsAg loss with PEG-IFN treatment, but not with nucleos(t)ide analogue treatment. In clinical practice, costs of medications (to the patients or the health care system) are also important determinants. Therefore, despite a high rate of viral resistance, lamivudine is the preferred first-line medication in some countries because of its low cost. The availability of the medications is another important determinant of care. Although tenofovir was approved for treatment of CHB in the United States and Europe in 2008, it is still not available in many Asian countries where hepatitis B is endemic and a large proportion of treated patients have received lamivudine. In some resource-limited countries, various organizations have developed comprehensive programs to screen at-risk persons for HIV and provide care to those who are infected; these organizations have succeeded in collaborating with pharmaceutical companies in securing antiretroviral drugs at low cost. An expert panel convened by the World Health Organization proposed that the infrastructure established for HIV care in these countries could be used for HBV screening and treatment.73 However, this proposal might not be applicable in many Asian countries, where similar programs are not available and where the stigmatization of HIV infection could discourage persons with HBV from seeking care.

Conclusions Approved therapies for CHB suppress HBV replication and prevent disease progression in clinical trials,

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