The detection of hepatitis B surface antigen

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1 Clinical Utility of Hepatitis B Surface Antigen Quantitation in Patients With Chronic Hepatitis B: A Review Yun-Fan Liaw This clinically relevant review focuses on recent findings concerning hepatitis B surface antigen (HBsAg) quantitation in untreated patients and treated patients with chronic hepatitis B. Recent studies and emerging data have shown that both HBsAg and hepatitis B virus (HBV) DNA levels decline during the natural course of a chronic HBV infection; they are lowest in the inactive phase, which is also characterized by the highest HBsAg/HBV DNA ratio. It has been demonstrated that the combined use of HBsAg and HBV DNA levels might help in the identification of true inactive carriers with high accuracy. Retrospective analyses of HBsAg levels in patients undergoing therapy have suggested a role for HBsAg quantitation in monitoring the response to therapy. In comparison with nucleos(t)ide analogues (NAs), interferon-based therapy results in greater overall declines in serum HBsAg levels. A rapid on-treatment decline in HBsAg levels appears to be predictive of a sustained response. With the aid of HBsAg quantitation, it appears that we can anticipate an individualized approach to tailoring the treatment duration. The proposal of early stopping rules for patients not responding to pegylated interferon (according to a lack of any HBsAg decline) represents a step toward a response-guided approach. The development of stopping rules for patients treated with NAs is desirable for reducing the need for lifelong therapy. However, before stopping rules for antiviral therapy can be applied, we need to learn more about the kinetics of HBsAg declines during the natural history of the infection and as a response to therapy so that we can better define the best timing, the relevant HBsAg cutoff levels, and the best ways to apply these rules in clinical practice. (HEPATOLOGY 2011;53: ) Abbreviations: ALT, alanine aminotransferase; anti-hbe, antibody to hepatitis B e antigen; cccdna, covalently closed circular DNA; CHB, chronic hepatitis B; ETV, entecavir; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; IFN, interferon; LAM, lamivudine; LdT, telbivudine; NA, nucleos(t)ide analogue; NPV, negative predictive value; PEG-IFN, pegylated interferon; PPV, positive predictive value; TDF, tenofovir. From the Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan. Received November 26, 2010; accepted April 7, The author thanks the Chang Gung Medical Research Fund for its longterm grant support (SMRPG1005 and BMRPG380061) and Roche Diagnostics (Rotkreuz, Switzerland) for its financial support. Address reprint requests to: Yun-Fan Liaw, M.D., Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 199 Tung Hwa North Road, Taipei, Taiwan liveryfl@gmail.com; fax: Copyright VC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: The author has been involved in clinical trials and has served as a global advisory board member for Roche, Bristol-Myers Squibb, Novartis, and Gilead Sciences. The detection of hepatitis B surface antigen (HBsAg) in serum was pivotal to the discovery of hepatitis B virus (HBV) more than 4 decades ago and remains the cornerstone of diagnosis today. 1-3 HBsAg seroclearance is considered to be the closest thing to a cure for chronic hepatitis B (CHB): it reflects immunological control of the infection and confers an excellent prognosis in the absence of preexisting cirrhosis or concurrent infections with other viruses. 2-6 Not surprisingly, HBsAg seroclearance has attracted considerable attention in both natural history studies and therapeutic trials. The incidence of spontaneous HBsAg seroclearance is low, especially in younger patients. Interferon (IFN) therapy appears to be able to enhance the rate of HBsAg seroclearance from 0.72% (controls) to 2.25% per year in European patients and from 0.07% to 0.43% per year in Asian patients. 6 A greater understanding of the factors influencing HBsAg levels might enable us to improve this still further. Recently, a wealth of new data on HBsAg quantitation has emerged, and it is becoming apparent that information on HBsAg levels can add to our understanding of both the natural history of the disease and its response 2121

2 2122 LIAW HEPATOLOGY, June 2011 Fig. 1. Pathways of HBsAg production during HBV infection. Adapted from J Hepatol 2010;52: and HEPATOLOGY 2010;51: to therapy. This is a good time to review and discuss issues concerning the clinical utility of HBsAg quantitation and the ways in which this may help us with patient management in the future. HBsAg and HBV DNA Levels Our understanding of the pathogenesis and natural history of CHB has been facilitated by technological advances that have improved the sensitivity of both serological assays for quantifying antigens (including HBsAg) and polymerase chain reaction assays for measuring HBV DNA. Several independent groups have compared HBsAg and HBV DNA levels during different phases of the disease, and their findings have been rather consistent. To put these findings into context, we must consider the HBsAg production pathway and the ways in which this is related to serum HBV DNA levels and intrahepatic covalently closed circular DNA (cccdna). HBsAg is produced by more than one pathway (Fig. 1): the translation of transcriptionally active cccdna molecules, which serve as a template for replication, and the translation of viral genes transcribed from integrated HBV DNA sequences in the host genome. 7,8 In addition to being the envelope of infectious HBV particles, HBsAg is also found in the form of noninfectious spheres or filaments, which exceed infectious virions in number by 10 2 to Serum HBsAg appears to correlate with transcriptionally active cccdna and is considered a surrogate marker of infected cells Although cccdna is the most accurate reflection of the number of infected hepatocytes, it can be assessed in tissue only with complex techniques that are restricted to specialized research centers. This excludes the analysis of cccdna levels from general clinical applications. The quantitation of HBV DNA by polymerase chain reaction is now a standard part of the diagnostic workup for CHB. A serum HBV DNA decline reflects a reduction in viral replication. In contrast, a serum HBsAg decline represents a reduction in the translation of messenger RNAs produced from transcriptionally active cccdna or integrated sequences. 14 Thus, HBsAg quantitation provides different but complementary information that may aid us in the characterization of an individual s infection status.

3 HEPATOLOGY, Vol. 53, No. 6, 2011 LIAW 2123 Table 1. Levels of HBsAg and HBV DNA During the Natural Course of CHB and Their Relationship Immune Tolerance Phase Immune Clearance Phase Immune Control/ Inactive Carrier Reactivated HBeAg-Negative Disease HBeAg status HBeAg-positive/ anti-hbe negative HBeAg-positive/ anti-hbe negative HBeAg-negative/ anti-hbe positive HBeAg-negative/ anti-hbe positive Reference HBsAg level (log 10 IU/mL) HBV DNA level (log 10 IU/mL) < HBsAg/HBV DNA ratio (log IU/mL) Abbreviation: anti-hbe, antibody to hepatitis B e antigen. HBsAg and HBV DNA Levels During Different Phases of CHB Several cross-sectional studies have compared HBsAg and HBV DNA levels during different phases of CHB (Table 1). The results are encouragingly similar, even though the studies were conducted in different patient populations and, therefore, with different genotypes. Both HBsAg and HBV DNA levels vary during the natural course of the infection, and they are highest in the initial immune tolerance phase when the serum alanine aminotransferase (ALT) level is normal with no or minimal hepatitis activity. HBsAg levels become lower during the immune clearance phase and decrease slowly and progressively in those who maintain persistently normal ALT levels after hepatitis B e antigen (HBeAg) seroconversion. 10 All groups have observed the lowest levels of HBsAg and HBV DNA during this inactive phase, which is also characterized by the highest HBsAg/HBV DNA ratio. 7,10,15 A Hong Kong follow-up study of 68 HBeAg-negative patients over a median period of 8 years showed a slow overall decrease in HBsAg levels, and a >1 log 10 IU/mL HBsAg decline between the initial and last visits reflected improved immune control, which was associated with a higher HBsAg seroclearance rate and stronger viral suppression. 10 Two European studies of inactive HBsAg carriers showed that those with subsequent HBsAg seroclearance had a significantly greater HBsAg decline than those who remained HBsAg-seropositive ( versus log 10 IU/mL/year). 16,17 A longitudinal study of 47 Taiwanese HBeAg-negative carriers of HBsAg with subsequent HBsAg seroclearance showed that the median HBsAg level decreased to <2 log 10 IU/mL; 82% of the patients reached a level < 200 IU/mL, and 67% reached a level < 100 IU/mL 3 years before HBsAg seroclearance (Chen and Liaw, unpublished data). There is still debate about the HBV DNA cutoff level used to define the inactive HBsAg carrier state. According to information from natural history studies, it may be possible to better differentiate between true inactive carriers and those with active disease. In comparison with inactive carriers, HBeAg-negative patients who experience reactivation have higher HBsAg and HBV DNA levels. 7,10,15,16 Several groups have proposed cutoff levels of HBsAg and HBV DNA that, when used together, reliably identify patients with inactive disease Although the exact values differ slightly, they are approximately 1 to IU/mL for HBsAg and IU/mL for HBV DNA. With these values, inactive carriers can be identified with 94% to 100% accuracy. The cutoff values derived from large studies by Brunetto et al. 16 and Martinot-Peignoux et al. 17 seem to be most applicable (Table 2). However, the results of retrospective analyses require further validation by prospective studies of patients infected with all the major genotypes. Although we can anticipate some differences according to the genotype, further studies will likely confirm that HBsAg levels have potential value in managing CHB patients because they can be used to define more clearly who requires treatment and who does not. Their use could even reduce the need for liver biopsy in those who concurrently have mildly elevated ALT levels and low levels of both HBsAg and HBV DNA. 20 For patients with values above these cutoff levels, more frequent monitoring would be advised for the detection of reactivation. HBsAg Levels During Therapy Decline of HBsAg During Therapy With Various Agents The suggestion that the measurement of HBsAg levels might be valuable for monitoring responses to IFN

4 2124 LIAW HEPATOLOGY, June 2011 Table 2. HBsAg and HBV DNA Cutoffs Proposed for Differentiating True Inactive Carriers From Patients With Reactivated HBeAg-Negative Disease Parameter Performance Patients (n) Reference HBsAg < 1000 IU/mL and HBV DNA < 2000 IU/mL Diagnostic accuracy for identifying inactive carriers (genotype D) ¼ 94%, sensitivity ¼ 91.1%, specificity ¼ 95.4%, PPV ¼ 87.9%, NPV ¼ 96.7% 209 HBsAg < 3500 IU/mL NPV for reactivation ¼ 95% 30 HBsAg < 2000 IU/mL and PPV for inactive carriers ¼ 93%, PPV ¼ 100% 122 HBV DNA < 2000 IU/mL HBsAg < 1000 IU/mL Sensitivity ¼ 74.3%, specificity ¼ 87.5%, predictive value ¼ 89.7% therapy in HBeAg-positive patients was first proposed in 1994 when a significant HBsAg decline was observed in patients who responded to IFN with HBeAg seroconversion but not in patients without HBeAg seroconversion (P < 0.001); thus, HBsAg quantitation was proposed as a simple means of monitoring patients with CHB. 21 However, the lack of commercially available assays precluded its widespread application until recently. Reports of HBsAg quantitation in HBeAg-negative patients with HBV infections or HBV/hepatitis delta virus dual infections who were undergoing therapy again suggested the potential of this marker for monitoring the response to therapy. 22,23 It was also proposed that HBsAg monitoring could predict eventual HBsAg clearance 23,24 after approximately 5.4 years of a sustained response to IFN or after 10.6 years of viral suppression with lamivudine (LAM) maintenance therapy. 23 Subsequent studies have clearly demonstrated that IFN-based therapy results in a greater overall HBsAg decline than treatments with a nucleos(t)ide analogue (NA), as summarized in Table 3. 22,25-34 This suggests that the HBsAg decline is affected more by immune modulation than an antiviral effect. Predicting Responses to IFN-Based Therapy With HBsAg Levels Because a sustained response to pegylated interferon (PEG-IFN) is achieved in only approximately 30% of HBeAg-positive patients and 20% of HBeAg-negative patients, identifying a potential treatment success is valuable for both the patient and the physician. A number of groups have retrospectively analyzed response rates in PEG-IFN cohorts with respect to ontreatment HBsAg declines. Predicting a Sustained Response. In HBeAg-positive patients, one study showed that a baseline HBsAg level < 10,000 IU/mL was associated with a higher rate of response to PEG-IFN therapy. 35 Other studies have not confirmed this observation but have reported a significant association between on-treatment levels of HBsAg and responses to PEG-IFN. A large European Table 3. Decline of HBsAg Levels During Therapy Reference IFN/PEG-IFN PEG-IFN and NA NA Comment HBeAg-positive 25 PEG-IFN: 0.8 log 10 IU/mL þlam 1.1 log 10 IU/mL LAM: 0.4 log 10 IU/mL From the baseline to week 48 ( 0.9 log 10 IU/mL) ( 1.3 log 10 IU/mL) 26 PEG-IFN: 0.87 log 10 IU/mL* þlam: 1.46 log 10 IU/mL* From the baseline to week 48 (P ¼ 0.04)* 27 PEG-IFN: 0.4 log 10 IU/mL þldt: 1.3 log 10 IU/mL LdT: 0.4 log 10 IU/mL From the baseline to week ETV: 0.4 log 10 IU/mL From the baseline to month 12 (P < 0.001) 29 PEG-IFN: 0.9 log 10 IU/mL ETV: 0.4 log 10 IU/mL From the baseline to week 48 (P > 0.05) 30 LdT: 0.5 log 10 IU/mL From the baseline to week 48 LdT: 0.8 log 10 IU/mL From the baseline to year 3 31 TDF: 0.3 log 10 IU/mL From the baseline to week 48 HBeAg-negative 22 IFN: 129 IU/mL/month LAM: 13.2 IU/mL/month P ¼ for IFN versus LAM 32 PEG-IFN: 0.71 log 10 IU/mL þlam: 0.67 log 10 IU/mL LAM: 0.02 log 10 IU/mL From the baseline to week PEG-IFN: 0.75 log 10 IU/mL þlam: 0.6 log 10 IU/mL LAM: 0.1 log 10 IU/mL From the baseline to week PEG-IFN: 0.6 log 10 IU/mL ETV: þ0.1 log 10 IU/mL From the baseline to week 48. (P < 0.001) 34 6RBV: 0.47 log 10 IU/mL From the baseline to week 48 (P < 0.001) For comparison only (this was not a randomized controlled trial).

5 HEPATOLOGY, Vol. 53, No. 6, 2011 LIAW 2125 study of 202 patients treated with PEG-IFNa 2b with or without LAM for 52 weeks showed that responders (response was defined as an HBeAg loss with HBV DNA levels < copies/ml 26 weeks after treatment) experienced a more profound HBsAg decline at week 52 (3.3 versus 0.7 log 10 IU/mL) and week 78 (3.4 versus 0.35 log 10 IU/mL, P < 0.001). Moreover, any HBsAg decline at week 12 had a positive predictive value (PPV) of 25% for a response and a PPV of 15% for HBsAg loss up to 3 years after treatment. 26 A Hong Kong study of 92 patients who were treated with PEG-IFNa 2b with or without LAM for 32 to 48 weeks found that HBsAg levels < 1500 IU/mL at month 3 and HBsAg levels < 300 IU/mL at month 6 (21% of the patients) could predict a sustained response 12 months after treatment (the PPVs were 46% and 62%, respectively). In addition, the combination of an HBsAg level 300 IU/mL and a >1 log reduction at month 6 had a PPV of 75%. 35 A small study from China showed that an HBsAg level < 1500 IU/mL at week 12 of IFNa/PEG-IFNa therapy had a PPV of 33% for HBeAg seroconversion after 24 weeks of treatment. 36 Piratvisuth et al. 37 reported that HBsAg levels < 1500 IU/mL at week 12 of PEG- IFNa 2a treatment (23% of the patients) were associated with an HBeAg seroconversion rate of 57% 6 months after treatment; 18% of these patients experienced HBsAg clearance. In HBeAg-negative patients, the baseline HBsAg level could not predict the response to PEG-IFN therapy, 32,38,39 but sustained responders had marked decreases in their serum HBsAg levels at the end of treatment ( log 10 IU/mL) and at week Brunetto et al. 32 further indicated that both an HBsAg level 10 IU/mL at week 48 (12% of the patients) and an on-treatment HBsAg decline > 1.1 log 10 IU/mL (22% of the patients) were significantly associated with HBsAg clearance 3 years after treatment (relative risks of 22.8 and 10.8, respectively, P < ). Moucari et al. 38 also found a significant association between an HBsAg decline and a sustained response; they reported that decreases of 0.5 and 1.0 log 10 IU/ ml at week 12 (19% of patients) and week 24 (25% of patients) of PEG-IFNa 2a therapy had high PPVs (89% at week 12 and 92% at week 24). A study of 120 patients showed that a decline 10% at week 12 of PEG-IFNa 2a therapy was associated with a 1-year off-therapy sustained response of 47% and an HBsAg seroclearance rate of 23% 5 years after treatment. 33 In contrast, the HBV DNA declines throughout treatment were nearly identical for sustained responders and relapsers; this suggests that measurements of the HBsAg concentration may more reliably distinguish those destined to have a sustained response. 38 Furthermore, the association of HBsAg reductions with sustained responses was observed across the major genotypes (A-D). 40 Although these low on-treatment levels were reached by less than 25% of the treated patients, these encouraging data suggest a potential role for HBsAg levels in predicting the response to PEG-IFN. This could encourage or motivate patients to complete their course of therapy. Predicting Nonresponse. The ability to determine who is most unlikely to achieve a sustained response to PEG-IFN might be of more practical value for patient management. The early identification of nonresponders would allow the discontinuation of therapy and/or changes in the treatment strategy for these patients. High negative predictive values (NPVs) for response have been reported for both HBeAg-positive and HBeAg-negative patients. Sonneveld et al. 26 reported an NPV of 97% for 202 PEG-IFNa 2b treated, HBeAg-positive patients (74% with genotype A or D HBV), which was based on any decline in HBsAg levels at week 12. An HBsAg decline at week 12 had an NPV of 82% in another large study of PEG-IFNa 2a therapy (88% with genotype B or C HBV). 41 The Hong Kong study reported an NPV of 86% for HBsAg levels < 1500 IU/mL at month 3 and an NPV of 89% for levels < 300 IU/mL at month The Chinese study also showed that an HBsAg level < 1500 IU/mL at week 12 had an NPV of 91%, whereas the NPV was 95% when the cutoff level was 2890 IU/mL at week For HBeAg-negative patients, Moucari et al. 38 reported an NPV of 90% for an HBsAg decline > 0.5 log 10 IU/mL at week 12 and an NPV of 97% for a decline of 1 log 10 IU/mL at week 24 in a mixedgenotype population. In a population that mainly had genotype D, Rijckborst et al. 39 reported an NPV of 100%, which was based on a combination of an HBsAg decline and a 2 log 10 IU/mL decline in HBV DNA levels from the baseline to week 12. This proposed stopping rule was recently validated in another cohort of patients treated with PEG-IFN. 42 These apparently robust early stopping rules with high NPVs could help with the management of patients and may even encourage patients to consider PEG-IFN as first-line therapy. This may be particularly applicable when the alternative is most likely lifelong therapy with NAs, especially for patients with HBeAgnegative disease. On the basis of these studies in different populations with different genotypes, week 12 of

6 2126 LIAW HEPATOLOGY, June 2011 Table 4. On-Treatment Prediction of Responses to PEG-IFN Therapy Sustained Response HBsAg Seroclearance Week 12 HBsAg Decline Patients (n) PPV (%) NPV (%) PPV (%) NPV (%) Reference HBeAg-positive Any decline <1500 IU/mL Not available Not available <1500 IU/mL Not available Not available <1500 IU/mL Not available Not available HBeAg-negative 10% decline >0.5 log 10 IU/mL Not available Not available Any decline* 107 Not available 100 Not available Not available *A positive 2 log 10 decline in the HBV DNA level. Three years after therapy. Five years after therapy. IFN-based therapy seems to be the right time for assessing an HBsAg decline (Table 4). However, the most appropriate degree of this decline still needs to be established before it can be adopted by the community as a guide for clinical practice. Prediction in Patients With Dual Infections. HBsAg profiles were also analyzed retrospectively in hepatitis C virus (HCV)/HBV-coinfected individuals treated with PEG-IFN and ribavirin for their predominant HCV infection. The HBsAg levels tended to be lower in this patient cohort (median ¼ 120 IU/mL) versus HBV-monoinfected patients and decreased gradually during treatment. Low baseline HBsAg levels were associated with HBsAg clearance (40% for baseline HBsAg levels 20 IU/mL and 2% for levels > 120 IU/mL, P < 0.05). Interestingly, a 50% decrease in the HBsAg level from the baseline to week 12 was associated with a reduced likelihood of HBV DNA reactivation in patients with serum HBV DNA levels that were undetectable at the baseline (PPV ¼ 89.5%). 43 This raises the possibility that we might be able to identify those HCV/HBV-coinfected patients who are likely to experience HBV reactivation and may need additional therapy with NAs. Predicting Responses to NAs With HBsAg Levels HBsAg declines during NA therapy appear more apparent in HBeAg-positive patients than HBeAg-negative patients, at least in the short term (Table 3). Although differences in the inclusion criteria preclude a comparison of HBsAg reduction across studies, one study involving both HBeAg-positive patients and HBeAg-negative patients showed that a substantial HBsAg decline during entecavir (ETV) therapy was restricted to HBeAg-positive patients. 29 A small study from Korea showed that a decrease > 1 log 10 IU/mL in serum HBsAg levels during therapy (5 of 28 patients) was associated with a much higher cumulative incidence of HBeAg loss (80% versus 30%, P ¼ 0.034) after 1 year of ETV therapy. 28 Notably, one study showed that the HBsAg decline during ETV therapy was restricted to patients with baseline ALT levels greater than or equal to 2 times the upper limit of normal (P ¼ 0.007), and it was most profound in those who lost HBeAg. 29 This suggests that the HBsAg decline might be linked to increased immunological activity. HBsAg seroclearance is sometimes reported during NA therapy in HBeAg-positive patients. With tenofovir (TDF), HBsAg seroclearance rates of 3%, 6%, and 8% were reported after 1, 2, and 3 years of therapy in HBeAg-positive patients, but seroclearance was not observed in HBeAg-negative patients. 44 HBsAg seroclearance rates for HBeAg-positive patients treated with ETV or LAM after 96 weeks on treatment and 24 weeks off therapy were 5% and 3%, respectively. 45 Recent studies have shown that a rapid decline in HBsAg levels during the first year of NA therapy in HBeAg-positive patients is associated with a higher probability of HBsAg seroclearance: 8 of 32 patients with a rapid HBsAg decline > 1log 10 IU/mL during telbivudine (LdT) therapy achieved HBsAg clearance in year 3, whereas 0 of 56 patients with steady HBsAg levels achieved this (P ¼ ). 30 Similarly, patients with HBsAg loss during TDF therapy, who were most frequently infected with genotype A or D, exhibited a rapid HBsAg decline, and the HBV DNA decline pattern in patients with or without HBsAg loss was similar. 31 There would be a considerable advantage in being able to determine whether a patient could stop NA therapy after a successful response. The current recommendation is to consider stopping after 12 months of consolidation therapy following HBeAg seroconversion, whereas NAs should be stopped only after

7 HEPATOLOGY, Vol. 53, No. 6, 2011 LIAW 2127 Table 5. Potential Applications of HBsAg Level Monitoring Potential Application Benefit During natural history Identification of true inactive carriers Reassurance that treatment is not required Identification of patients who need therapy now or whose disease is likely to be reactivated in the near future Identification of patients who need closer monitoring and possible identification of patients who need treatment During therapy Early identification of patients who are unlikely Early stopping rule for avoiding unnecessary and ineffective therapy to respond to PEG-IFN Early identification of patients who are responding to PEG-IFN Motivation for patients to continue therapy Early identification of patients who experience a rapid decline in HBsAg levels during NA therapy (LdT or TDF) Identification of patients who have a high chance of HBsAg clearance and development of a stopping rule that enables patients with a low chance of relapse to stop NA therapy HBsAg clearance is achieved in HBeAg-negative patients. 3 However, the durability of NA-induced HBeAg seroconversion is at best 80% in LdT-treated patients during 2 years of off-therapy follow-up. 46 A small study of 17 patients who showed a sustained response to LdT (defined as HBV DNA levels < 300 copies/ml, HBeAg seroconversion, and ALT normalization 2 years off treatment) found that the HBsAg decline rates at weeks 24 and 52 were better predictors of the off-treatment response than the HBV DNA decline rates. Moreover, an HBsAg level < 2 log 10 IU/ ml at treatment week 104 was highly predictive of a sustained off-treatment response (PPV ¼ 93%, NPV ¼ 100%). 47 If this is confirmed by other appropriate studies, HBsAg quantitation may help us to identify patients who are able to stop NAs with only a very low chance of relapse. Currently, data on HBsAg levels during NA therapy are insufficient. Although a rapid HBsAg decline (>1 log 10 IU/mL) during NA therapy appears predictive of an off-treatment response, the reports to date are based on only small numbers of patients, and predictors have not been clearly defined. Although a stopping rule for NA-treated patients is highly desirable from a clinical perspective, further studies are clearly required to explore the potential of HBsAg in this context. Conclusions and Perspectives In summary, recent studies and emerging data have shown that HBsAg levels change during the natural course of a chronic HBV infection, and a rapid decline in HBsAg levels indicates a strong response to therapy, regardless of which treatment approach is being used. It appears that the information provided by the monitoring of HBsAg levels (in addition to HBV DNA levels) may help us to determine the best management strategy for a considerable proportion of patients. An overview of the potential clinical applications of HBsAg quantitation is provided in Table 5. Proposed early stopping rules for PEG-IFN that are based on HBsAg declines can increase the appeal of trying this approach first and represent a step toward a responseguided approach. The development of a stopping rule for highly potent NAs would be a desirable step for reducing the burden of lifelong therapy. The accessibility of an assay contributes considerably to its value and its likelihood for implementation in routine clinical practice. If HBsAg levels are to be used as a potential guide to patient management, there is a clear need for standardized commercial assays providing accurate results that are traceable to a standard reference serum. The Architect HBsAg assay (Abbott Diagnostics) was used in most of the studies reviewed here. This assay requires a 1:100 to 1:1000 dilution of patient sera in most instances. An excellent correlation between the Architect assay and the Elecsys HBsAg II assay (Roche Diagnostics) has been demonstrated. 48 Using an automated onboard dilution step, the latter has a broad linear range that covers the HBsAg levels most frequently encountered and thus reduces the need for manual dilutions, which are potential sources of error. 49 Currently, the cost of these assays is not reimbursed in many countries, and they are not commercially available in the United States, so researchonly tests are the only option at present. However, this can be expected to change in the future. 50 Undoubtedly, there is still more to learn about the kinetics of the HBsAg decline and the ways to best use this in practice to optimize therapy. It remains to be confirmed whether HBsAg levels can reliably predict HBeAg seroconversion or HBsAg seroclearance. Studies in regions other than Europe and Asia are needed because the HBsAg kinetics for different HBV genotypes may differ during the natural course of the disease or in response to anti-hbv therapy. The ontreatment predictive value of HBsAg quantitation also needs to be studied in a sufficiently large number of patient with consistent time points (e.g., weeks 12 and 24 of therapy) and with the same definition of

8 2128 LIAW HEPATOLOGY, June 2011 response. The optimal HBsAg cutoff with the ideal PPV and NPV also awaits clarification. Prediction models combining the quantitation of HBsAg with HBV DNA and ALT levels should also be explored. Until these issues are resolved, HBsAg quantitation will not be ready for clinical practice. Nevertheless, with the assistance of HBsAg quantitation, we may be on our way to establishing an individualized approach that might enable us to tailor anti-hbv treatments. Acknowledgments: The author thanks Karen Searle (Elements Communications, Ltd.) for her editorial assistance and Su-Chiung Chu for her secretarial assistance. References 1. Blumberg BS, Alter HJ, Visnich S. A new antigen in leukemia sera. JAMA 1965;191: Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009;373: Lok AS, McMahon BJ. Chronic hepatitis B: update HEPATOLOGY 2009;50: Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, et al. 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