Liver International ISSN 1478-3223
REVIEW ARTICLE
New therapeutic perspectives in HBV: when to stop NAs rez-Cameo, Mo nica Pons and Rafael Esteban Cristina Pe Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Barcelona, Spain
Keywords chronic hepatitis B – nucleos(t)ide analogues – treatment Abbreviations ADV, adefovir; CHB, chronic hepatitis B; ETV, entecavir; HCC, hepatocellular carcinoma; IFN, interferon; LAM, lamivudine; NAs, nucleos(t)ide analogues; NPV, negative predictive value; SVR, sustained virological response; TBV, telbivudine; TFV, tenofovir. Correspondence Cristina P erez-Cameo, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Barcelona, Spain Tel: +34932746140 Fax: +34932746068 e-mail: [email protected]
Abstract The goal of chronic hepatitis B (CHB) treatment is to achieve seroclearance of HBsAg. Nucleos(t)ide analogues (NAs) are one of the first-line treatments for CHB. NAs produce a potent suppression of viral replication but are associated with a low rate of HBsAg seroclearance and a high risk of virological relapse after discontinuation. Because of these reasons, long-term treatment is needed. They are well-tolerated oral drugs, and it seems they do not produce important side-effects in long-term administration. The duration of NA treatment remains unclear, nevertheless, in some patients NAs can be stopped with a low rate of relapse. HBeAg-positive patients could discontinue NA therapy if they achieved HBeAg seroclearance and maintain undetectable HBV DNA. For HBeAg-negative patients, to stop NA treatment is not recommended. In addition to other factors, serum HBsAg titres during treatment have recently been proposed to guide NA-based therapy duration in selected patients. All patients could be stopped from taking treatment if they achieve HBsAg loss.
DOI:10.1111/liv.12398
Hepatitis B virus (HBV) infection is an important public health problem. Approximately one-third of the world’s population has serological evidence of past or present HBV infection, and 350–400 million people are chronic HBsAg carriers. The spectrum of disease and natural history of chronic HBV infection are diverse and variable, ranging from an inactive carrier state to progressive chronic hepatitis B (CHB), which may lead to the development of cirrhosis or hepatocellular carcinoma (HCC) (1–5). Patients with CHB can be HBeAgpositive or HBeAg-negative (1). Serum HBsAg appears to correlate with the presence of covalently closed circular DNA (cccDNA) and is considered a surrogate marker of infected cells (4, 6). Seroclearance of HBsAg is the closest event to a cure of HBV infection and it is the main goal of CHB therapy (6). However, the time to HBsAg loss is important. A loss of HBsAg before the onset of cirrhosis is associated with a more favourable outcome of the infection; that is, a lower risk of cirrhosis, decompensation, and HCC (1). The currently available therapies for CHB are interferon (IFN) [standard or pegylated (PEG)] and nucleos (t)ide analogues (NAs) (1, 2, 4), including lamivudine (LAM), adefovir (ADV), telbivudine (TBV), tenofovir (TFV), and entecavir (ETV). TFV and ETV are considered first-line treatments because of their potent antiviral activity and high barrier to resistance (1, 2, 4).
146
However, most of the studies investigating long-term treatment have been performed with LAM and ADV, as they were the first approved drugs. IFN-based therapy has been found to induce HBsAg seroclearance in HBeAg-positive and HBeAg-negative patients (7) and it is a finite therapy (1). However, NA treatment must be long term, as the annual rate of HBsAg loss is very low and virological relapse is common after discontinuation of treatment (5, 8, 9). This article reviews the factors that can predict HBsAg loss, and discusses the importance of HBsAg loss and other variables that can help identify patients who are candidates for discontinuing antiviral therapy with NAs. Importance of HBsAg loss
HBsAg seroclearance is considered to be the closest event to a cure of CHB. Patients who achieve HBsAg loss have a more favourable prognosis: survival is greater, there is a lower risk of liver disease-related decompensation and in some cases, HCC, and liver fibrosis may regress (10). Closed circular DNA is the transcriptional template of HBV. It exists in the cell nucleus as a viral minichromosome and serves as the intrahepatic reservoir for HBV (11). HBsAg is one of the subviral replication Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
P erez-Cameo et al.
products of cccDNA, so HBsAg level reflects the transcriptional activity of cccDNA (6). Clearance of intrahepatic cccDNA is the main challenge of antiviral therapy for CHB (11). However, in clinical practice, it is difficult to obtain liver tissue from patients to study cccDNA levels, and serum HBsAg level is used as a partial surrogate marker of this molecule (6). Spontaneous HBsAg seroclearance, defined as serum HBsAg loss on two analyses at least 6 months apart and persisting to the last visit, is a rare event in the natural history of CHB infection, occurring in 0.12–2.38% of patients per year in cohorts from Asian countries and in 0.54–1.98% of patients in cohorts from western countries (7, 10). The cumulative HBsAg seroclearance rate is 8.1% at 10 years, 24.9% at 20 years and 44.7% at 25 years of follow-up (7, 10). Several viral and host factors have a significant association with HBsAg seroclearance. Older age, normal ALT levels, the presence of cirrhosis or fatty liver, negative status for HBeAg or HBV DNA, genotypes A and B, adr HBsAg serotype, and having an acute viral superinfection are the factors associated with higher rates of HBsAg loss (7). Up to 80% of patients achieve detectable anti-HBs (antibody against HBsAg) after HBsAg seroclearance, but the percentage varies during follow-up: only 17% of patients have detectable anti-HBs within 1 year after HBsAg seroclearance, 56% are positive carriers for antiHBs after the fifth year, and 76% are positive after the tenth year (7). At the time of HBsAg seroclearance, most patients test negative for HBV DNA. Despite the extremely low viremic state, 5–18% of carriers have abnormal ALT levels after HBsAg seroclearance. However, in these cases, non-HBV-related etiologies of abnormal ALT levels can be identified in 75–100% of patients (7, 10). Liver function can improve or remain stable at the time of seroclearance in carriers with cirrhosis who have no evidence of viral superinfection, and hepatic decompensation rarely occurs. However, HCC can still develop, although at a very low rate, especially when cirrhosis is established before HBsAg seroclearance or when HBsAg seroclearance occurs at an older age (4, 7, 10). Recent studies have shown that serum HBsAg titres strongly correlate with intrahepatic cccDNA levels (4, 6, 10, 11), and several authors have proposed that HBsAg quantification may be a useful marker to monitor IFN treatment (10). Serum HBsAg levels tend to be higher in HBeAg-positive than in HBeAg-negative patients and also differ according to HBV genotype. Genotype A is associated with the highest HBsAg levels, followed by genotype B and then further behind genotype C, whereas levels are lowest in genotype D (11). Furthermore, HBsAg levels vary during the natural course of HBV infection and can reflect the stage of the disease. HBsAg is highest in the immune-tolerLiver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
When to stop NAs in HBV
ant phase (4.5–5.0 log10 IU/ml), begins to decline during the immune-clearance phase (3.0–4.5 log10 IU/ml), and decreases slowly and progressively after HBeAg seroconversion, with no differences compared with HBeAg-positive patients who have persistently active disease (4, 11). Spontaneous HBeAg seroconversion occurs in 2–15% of patients per year, and depends on factors such as age, ALT levels and HBV genotype (1). Seroconversion from HBeAg to anti-HBe (antibody against HBeAg) leads to an ‘inactive HBV carrier state’ characterized by very low or undetectable serum HBV DNA levels (20 000 IU/ml at weeks 12 or 24 of PEG-IFN-a-2a were considered not to have achieved a post-treatment response, and this would be used as a stopping rule. Patients with HBsAg levels 1 log10
DNA decline ≤ 1 log10
Continue PEG-IFN
Extended duration of PEG-IFN treatment?
Switch to NAs
Fig. 1. Suggested algorithm for HBeAg-positive patients treated with PEG-IFN. HBeAg-positive patients treated with PEG-IFN should be tested for HBsAg titres at 12 weeks. If titres are higher than 20 000 IU/ml, they could stop PEG-IFN and switch to NAs. If titres are lower than 20 000 IU/ml and the titres at week 24 are higher than 300 IU/ml they could stop PEG-IFN and switch to NAs.
HBeAg-negative
In HBeAg-negative virological responders treated with PEG-IFN, HBsAg loss occurs at a rate of approximately 10% per year (20). In a long-term follow-up study, HBsAg loss was achieved in 44% patients who maintained sustained HBV DNA suppression to undetectable levels 3 years after treatment (21). On-treatment quantification of HBsAg in HBeAgnegative patients treated with PEG-IFN identifies those likely to achieve HBsAg loss. An HBsAg level 1 log10 IU/ml are significantly associated with sustained HBsAg clearance 3 years after treatment (12). The likelihood of HBsAg loss in patients who achieve HBsAg levels 2 log10 IU/ml (1, 11, 22).
149
Perez-Cameo et al.
When to stop NAs in HBV
mal or null associated drug resistance (1, 2, 4). Because of the high antiviral potency of these drugs, most patients achieve undetectable HBV DNA in long-term treatment, even those with a high viral load. In addition, several studies have shown that NAs can improve liver fibrosis, and lead to the regression of cirrhosis and carcinogenesis (24). NAs are orally administered drugs with minimal side effects and can be used in all stages of the disease, including advanced and decompensated cirrhosis (1, 8). Nucleos(t)ide analogues produce a rapid reduction in HBV DNA and normalization of serum ALT levels (25). However they have little effect on HBV cccDNA, that maintains viral replication and is responsible for relapses (7, 25). Thus, HBsAg seroclearance is uncommon, usually
REVIEW ARTICLE
New therapeutic perspectives in HBV: when to stop NAs rez-Cameo, Mo nica Pons and Rafael Esteban Cristina Pe Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Barcelona, Spain
Keywords chronic hepatitis B – nucleos(t)ide analogues – treatment Abbreviations ADV, adefovir; CHB, chronic hepatitis B; ETV, entecavir; HCC, hepatocellular carcinoma; IFN, interferon; LAM, lamivudine; NAs, nucleos(t)ide analogues; NPV, negative predictive value; SVR, sustained virological response; TBV, telbivudine; TFV, tenofovir. Correspondence Cristina P erez-Cameo, Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Barcelona, Spain Tel: +34932746140 Fax: +34932746068 e-mail: [email protected]
Abstract The goal of chronic hepatitis B (CHB) treatment is to achieve seroclearance of HBsAg. Nucleos(t)ide analogues (NAs) are one of the first-line treatments for CHB. NAs produce a potent suppression of viral replication but are associated with a low rate of HBsAg seroclearance and a high risk of virological relapse after discontinuation. Because of these reasons, long-term treatment is needed. They are well-tolerated oral drugs, and it seems they do not produce important side-effects in long-term administration. The duration of NA treatment remains unclear, nevertheless, in some patients NAs can be stopped with a low rate of relapse. HBeAg-positive patients could discontinue NA therapy if they achieved HBeAg seroclearance and maintain undetectable HBV DNA. For HBeAg-negative patients, to stop NA treatment is not recommended. In addition to other factors, serum HBsAg titres during treatment have recently been proposed to guide NA-based therapy duration in selected patients. All patients could be stopped from taking treatment if they achieve HBsAg loss.
DOI:10.1111/liv.12398
Hepatitis B virus (HBV) infection is an important public health problem. Approximately one-third of the world’s population has serological evidence of past or present HBV infection, and 350–400 million people are chronic HBsAg carriers. The spectrum of disease and natural history of chronic HBV infection are diverse and variable, ranging from an inactive carrier state to progressive chronic hepatitis B (CHB), which may lead to the development of cirrhosis or hepatocellular carcinoma (HCC) (1–5). Patients with CHB can be HBeAgpositive or HBeAg-negative (1). Serum HBsAg appears to correlate with the presence of covalently closed circular DNA (cccDNA) and is considered a surrogate marker of infected cells (4, 6). Seroclearance of HBsAg is the closest event to a cure of HBV infection and it is the main goal of CHB therapy (6). However, the time to HBsAg loss is important. A loss of HBsAg before the onset of cirrhosis is associated with a more favourable outcome of the infection; that is, a lower risk of cirrhosis, decompensation, and HCC (1). The currently available therapies for CHB are interferon (IFN) [standard or pegylated (PEG)] and nucleos (t)ide analogues (NAs) (1, 2, 4), including lamivudine (LAM), adefovir (ADV), telbivudine (TBV), tenofovir (TFV), and entecavir (ETV). TFV and ETV are considered first-line treatments because of their potent antiviral activity and high barrier to resistance (1, 2, 4).
146
However, most of the studies investigating long-term treatment have been performed with LAM and ADV, as they were the first approved drugs. IFN-based therapy has been found to induce HBsAg seroclearance in HBeAg-positive and HBeAg-negative patients (7) and it is a finite therapy (1). However, NA treatment must be long term, as the annual rate of HBsAg loss is very low and virological relapse is common after discontinuation of treatment (5, 8, 9). This article reviews the factors that can predict HBsAg loss, and discusses the importance of HBsAg loss and other variables that can help identify patients who are candidates for discontinuing antiviral therapy with NAs. Importance of HBsAg loss
HBsAg seroclearance is considered to be the closest event to a cure of CHB. Patients who achieve HBsAg loss have a more favourable prognosis: survival is greater, there is a lower risk of liver disease-related decompensation and in some cases, HCC, and liver fibrosis may regress (10). Closed circular DNA is the transcriptional template of HBV. It exists in the cell nucleus as a viral minichromosome and serves as the intrahepatic reservoir for HBV (11). HBsAg is one of the subviral replication Liver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
P erez-Cameo et al.
products of cccDNA, so HBsAg level reflects the transcriptional activity of cccDNA (6). Clearance of intrahepatic cccDNA is the main challenge of antiviral therapy for CHB (11). However, in clinical practice, it is difficult to obtain liver tissue from patients to study cccDNA levels, and serum HBsAg level is used as a partial surrogate marker of this molecule (6). Spontaneous HBsAg seroclearance, defined as serum HBsAg loss on two analyses at least 6 months apart and persisting to the last visit, is a rare event in the natural history of CHB infection, occurring in 0.12–2.38% of patients per year in cohorts from Asian countries and in 0.54–1.98% of patients in cohorts from western countries (7, 10). The cumulative HBsAg seroclearance rate is 8.1% at 10 years, 24.9% at 20 years and 44.7% at 25 years of follow-up (7, 10). Several viral and host factors have a significant association with HBsAg seroclearance. Older age, normal ALT levels, the presence of cirrhosis or fatty liver, negative status for HBeAg or HBV DNA, genotypes A and B, adr HBsAg serotype, and having an acute viral superinfection are the factors associated with higher rates of HBsAg loss (7). Up to 80% of patients achieve detectable anti-HBs (antibody against HBsAg) after HBsAg seroclearance, but the percentage varies during follow-up: only 17% of patients have detectable anti-HBs within 1 year after HBsAg seroclearance, 56% are positive carriers for antiHBs after the fifth year, and 76% are positive after the tenth year (7). At the time of HBsAg seroclearance, most patients test negative for HBV DNA. Despite the extremely low viremic state, 5–18% of carriers have abnormal ALT levels after HBsAg seroclearance. However, in these cases, non-HBV-related etiologies of abnormal ALT levels can be identified in 75–100% of patients (7, 10). Liver function can improve or remain stable at the time of seroclearance in carriers with cirrhosis who have no evidence of viral superinfection, and hepatic decompensation rarely occurs. However, HCC can still develop, although at a very low rate, especially when cirrhosis is established before HBsAg seroclearance or when HBsAg seroclearance occurs at an older age (4, 7, 10). Recent studies have shown that serum HBsAg titres strongly correlate with intrahepatic cccDNA levels (4, 6, 10, 11), and several authors have proposed that HBsAg quantification may be a useful marker to monitor IFN treatment (10). Serum HBsAg levels tend to be higher in HBeAg-positive than in HBeAg-negative patients and also differ according to HBV genotype. Genotype A is associated with the highest HBsAg levels, followed by genotype B and then further behind genotype C, whereas levels are lowest in genotype D (11). Furthermore, HBsAg levels vary during the natural course of HBV infection and can reflect the stage of the disease. HBsAg is highest in the immune-tolerLiver International (2014) © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
When to stop NAs in HBV
ant phase (4.5–5.0 log10 IU/ml), begins to decline during the immune-clearance phase (3.0–4.5 log10 IU/ml), and decreases slowly and progressively after HBeAg seroconversion, with no differences compared with HBeAg-positive patients who have persistently active disease (4, 11). Spontaneous HBeAg seroconversion occurs in 2–15% of patients per year, and depends on factors such as age, ALT levels and HBV genotype (1). Seroconversion from HBeAg to anti-HBe (antibody against HBeAg) leads to an ‘inactive HBV carrier state’ characterized by very low or undetectable serum HBV DNA levels (20 000 IU/ml at weeks 12 or 24 of PEG-IFN-a-2a were considered not to have achieved a post-treatment response, and this would be used as a stopping rule. Patients with HBsAg levels 1 log10
DNA decline ≤ 1 log10
Continue PEG-IFN
Extended duration of PEG-IFN treatment?
Switch to NAs
Fig. 1. Suggested algorithm for HBeAg-positive patients treated with PEG-IFN. HBeAg-positive patients treated with PEG-IFN should be tested for HBsAg titres at 12 weeks. If titres are higher than 20 000 IU/ml, they could stop PEG-IFN and switch to NAs. If titres are lower than 20 000 IU/ml and the titres at week 24 are higher than 300 IU/ml they could stop PEG-IFN and switch to NAs.
HBeAg-negative
In HBeAg-negative virological responders treated with PEG-IFN, HBsAg loss occurs at a rate of approximately 10% per year (20). In a long-term follow-up study, HBsAg loss was achieved in 44% patients who maintained sustained HBV DNA suppression to undetectable levels 3 years after treatment (21). On-treatment quantification of HBsAg in HBeAgnegative patients treated with PEG-IFN identifies those likely to achieve HBsAg loss. An HBsAg level 1 log10 IU/ml are significantly associated with sustained HBsAg clearance 3 years after treatment (12). The likelihood of HBsAg loss in patients who achieve HBsAg levels 2 log10 IU/ml (1, 11, 22).
149
Perez-Cameo et al.
When to stop NAs in HBV
mal or null associated drug resistance (1, 2, 4). Because of the high antiviral potency of these drugs, most patients achieve undetectable HBV DNA in long-term treatment, even those with a high viral load. In addition, several studies have shown that NAs can improve liver fibrosis, and lead to the regression of cirrhosis and carcinogenesis (24). NAs are orally administered drugs with minimal side effects and can be used in all stages of the disease, including advanced and decompensated cirrhosis (1, 8). Nucleos(t)ide analogues produce a rapid reduction in HBV DNA and normalization of serum ALT levels (25). However they have little effect on HBV cccDNA, that maintains viral replication and is responsible for relapses (7, 25). Thus, HBsAg seroclearance is uncommon, usually
