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HepB Forum : Unofficial Research Thread (URT) Tx info
I am reposting articles / summaries on the treatment management of chronic HepB. "cajim" located these articles which are quite informative. I thought about putting them on a seaprate Health Page but didn't think it was appropriate since we didn't write them.
Let's make this a sort of "Unofficial Research Thread" or "URT" for this type of information. Let's keep this URT free of comments. For comments, start a new thread indicating that it's in reference to URT.
We'll see how it goes.
Let's make this a sort of "Unofficial Research Thread" or "URT" for this type of information. Let's keep this URT free of comments. For comments, start a new thread indicating that it's in reference to URT.
We'll see how it goes.
Notes on “A Practical Approach to Management of Chronic Hepatitis B,” Ke-Qin Hu, 2005.
Indications of HBV Treatment
Historically, levels of HBV DNA and ALT, and histological activity of liver biopsy have been used as the three main factors to determine if a patient needs HBV treatment or not [1-3].
HBV DNA Levels
It is known that HBV is not directly pathogenic to hepatocytes and host immune response to HBV antigens expressed on the infected hepatocytes is the principle determinants of the liver injury. Thus, a high HBV load has been the primary indication for HBV infection. However, the threshold HBV level that is associated with progressive liver disease remains to be determined. In addition, patients with CHB may have fluctuating HBV DNA levels. A study revealed that only one third of patients with HBeAg-negative CHB and elevated ALT had HBV DNA levels persistently > 105 copies/ml [19]. This suggested that an even lower HBV DNA threshold might be reasonable to indicate HBV treatment in patients HBeAg-negative CHB. Thus, it has recently been recommended that different HBV DNA levels should be used to determine HBV treatment depending on HBeAg status and clinical presentation of CHB [3]. As summarized in Figure 1, HBV treatment should be considered in patients with HBeAg-positive CHB and HBV DNA ? 105 copies/ml in combination with elevated ALT level and histological activity. While in patients with HBeAg negative-CHB and patients with compensated HBV cirrhosis regardless HBeAg status, HBV treatment should be considered when HBV DNA ? 104 copies/ml [3]. It should be noted that above cutoff HBV DNA levels are arbitrarily made based on limited research results, and not endorsed by all guidelines [1-3]. Additional studies will be needed to verify these criteria.
Histological Activity and Stage
Liver biopsy provides us with valuable information of histological activity and stage of HBV disease in patients with HBV infection. It is known that patients with chronic HBV infection and active hepatic inflammation carry a significantly higher risk of disease progression. Histological staging of HBV disease is clinically very valuable in assessing degree of fibrosis and predicting disease progression. Good response to HBV treatment has been well associated with improved histology. Therefore, a pre-HBV treatment liver biopsy is usually preferred by most hepatologists. However, for those with clear-cut indications for HBV treatment, a liver biopsy may not be necessary. As it will be discussed below, histological assessment is very valuable in determining HBV treatment in patients with persistently normal transaminases.
ALT Levels
For many years, ALT has been used as a standard surrogate for the activity of CHB. Thus, ALT level in combination with HBV DNA level and histological activity has been used as a determinant for HBV treatment [1-3]. It is well accepted that elevated ALT should be used as one of the determinants for HBV treatment in patients with CHB. However, it remains controversial on at what level of ALT elevation a patient with CHB should be considered for HBV treatment [3].
On the other hand, patients with detectable HBV load (i.e. by HBV hybridization or HBV ? 105 copies/ml), but persistently normal transaminases have historically not been considered as candidates for HBV treatment based on the assumption that these patients usually have a slow progression and evidence that these patients usually have a low response rate to HBV treatments. However, the extent of liver injury and fibrosis is not always correlated with ALT levels [20]. Furthermore, a sustained suppression of HBV replication is now more achievable than before. In addition, an active HBV replication has been associated with increased risk for HCC [21]. Thus, it has become more accepted that a normal ALT level alone should not be used to determine HBV treatment in these patients. Instead, in patients with HBV DNA ? 105 copies/ml and persistently normal ALT levels, a liver biopsy might be considered (Figure 1). If active liver inflammation or advanced fibrosis is histologically confirmed, the patient should be considered for HBV treatment. Additional studies will be needed to further assess the efficacy and benefit of HBV treatment in this group of patients.
Indications of HBV Treatment
Historically, levels of HBV DNA and ALT, and histological activity of liver biopsy have been used as the three main factors to determine if a patient needs HBV treatment or not [1-3].
HBV DNA Levels
It is known that HBV is not directly pathogenic to hepatocytes and host immune response to HBV antigens expressed on the infected hepatocytes is the principle determinants of the liver injury. Thus, a high HBV load has been the primary indication for HBV infection. However, the threshold HBV level that is associated with progressive liver disease remains to be determined. In addition, patients with CHB may have fluctuating HBV DNA levels. A study revealed that only one third of patients with HBeAg-negative CHB and elevated ALT had HBV DNA levels persistently > 105 copies/ml [19]. This suggested that an even lower HBV DNA threshold might be reasonable to indicate HBV treatment in patients HBeAg-negative CHB. Thus, it has recently been recommended that different HBV DNA levels should be used to determine HBV treatment depending on HBeAg status and clinical presentation of CHB [3]. As summarized in Figure 1, HBV treatment should be considered in patients with HBeAg-positive CHB and HBV DNA ? 105 copies/ml in combination with elevated ALT level and histological activity. While in patients with HBeAg negative-CHB and patients with compensated HBV cirrhosis regardless HBeAg status, HBV treatment should be considered when HBV DNA ? 104 copies/ml [3]. It should be noted that above cutoff HBV DNA levels are arbitrarily made based on limited research results, and not endorsed by all guidelines [1-3]. Additional studies will be needed to verify these criteria.
Histological Activity and Stage
Liver biopsy provides us with valuable information of histological activity and stage of HBV disease in patients with HBV infection. It is known that patients with chronic HBV infection and active hepatic inflammation carry a significantly higher risk of disease progression. Histological staging of HBV disease is clinically very valuable in assessing degree of fibrosis and predicting disease progression. Good response to HBV treatment has been well associated with improved histology. Therefore, a pre-HBV treatment liver biopsy is usually preferred by most hepatologists. However, for those with clear-cut indications for HBV treatment, a liver biopsy may not be necessary. As it will be discussed below, histological assessment is very valuable in determining HBV treatment in patients with persistently normal transaminases.
ALT Levels
For many years, ALT has been used as a standard surrogate for the activity of CHB. Thus, ALT level in combination with HBV DNA level and histological activity has been used as a determinant for HBV treatment [1-3]. It is well accepted that elevated ALT should be used as one of the determinants for HBV treatment in patients with CHB. However, it remains controversial on at what level of ALT elevation a patient with CHB should be considered for HBV treatment [3].
On the other hand, patients with detectable HBV load (i.e. by HBV hybridization or HBV ? 105 copies/ml), but persistently normal transaminases have historically not been considered as candidates for HBV treatment based on the assumption that these patients usually have a slow progression and evidence that these patients usually have a low response rate to HBV treatments. However, the extent of liver injury and fibrosis is not always correlated with ALT levels [20]. Furthermore, a sustained suppression of HBV replication is now more achievable than before. In addition, an active HBV replication has been associated with increased risk for HCC [21]. Thus, it has become more accepted that a normal ALT level alone should not be used to determine HBV treatment in these patients. Instead, in patients with HBV DNA ? 105 copies/ml and persistently normal ALT levels, a liver biopsy might be considered (Figure 1). If active liver inflammation or advanced fibrosis is histologically confirmed, the patient should be considered for HBV treatment. Additional studies will be needed to further assess the efficacy and benefit of HBV treatment in this group of patients.
Summary: Implications for Clinical Practice: . Hepatitis B virus is a partially double-stranded DNA virus that replicates through an RNA intermediate. Replication occurs within the viral nucleocapsid in the cytoplasm of the hepatocyte. . A robust polyclonal and multispecific cytotoxic and helper T-cell response is necessary for control of HBV replication. . The cccDNA represents a stable, episomal form of HBV DNA that resides in the hepatocyte nucleus. It is the template for transcription of all viral mRNAs. . Levels of cccDNA are maintained by an intracellular recycling pathway from nascent viral nucleocapsids. Elimination of cccDNA primarily occurs through cytolytic and noncytolytic mechanisms induced by the immune system. . Levels of cccDNA may decline during antiviral therapy but usually persist following serologic recovery from HBV infection. This accounts for the viral rebound observed when antiviral agents are stopped. Therefore, patients who achieve spontaneous or treatment-induced recovery need to be monitored lifelong for HBsAg seroreversion. The frequency of monitoring should be every 6-12 months. . Loss of HBsAg is the most robust endpoint of nucleos(t)ide therapy but is achieved in < 3% of treated patients. Rates of HBsAg loss are higher with interferon/peginterferon therapy (3% to 8%) but are still poor overall. . Long-term therapy with nucleos(t)ide analogues has been associated with decreased progression of liver disease, improved survival, and decreased rates of hepatocellular carcinoma. The development of drug resistance is associated with loss of clinical benefit. . Seroreversion of HBsAg has been described following immunosuppression with high-dose steroids, cancer chemotherapy, and bone and stem cell transplantation for hematologic and solid organ malignancies as well as following orthotopic liver transplantation in HBsAg-negative individuals receiving livers from anti-HBcCpositive donors. . Patients receiving chemotherapy consisting of potent immunosuppressive agents should be screened for HBsAg. Positive individuals should receive anti-HBV prophylaxis against HBsAg seroreversion. . There is insufficient evidence to recommend anti-HBV prophylaxis in HBsAg-negative patients. Patients at high risk for HBsAg seroreversion (ie, those receiving a steroid-containing regimen or a monoclonal antibody against B or T cells, those with detectable HBV DNA, or those with underlying cirrhosis) should be considered for prophylaxis. . Patients who do not receive anti-HBV prophylaxis should be monitored indefinitely.
The rate of seroreversion and viral reactivation in HBsAg-negative patients receiving chemotherapy or undergoing bone marrow transplantation is lower (3.3%)[56] than that in HBsAg-positive patients (26.0%),[59] but there is insufficient data to recommend routine prophylaxis. However, if prophylaxis is not used, it is important to monitor patients closely with serial HBV DNA level and HBsAg determinations to detect reactivation and seroreversion. The issue that needs to be resolved is whether routine prophylaxis is more or less cost-effective than intensive monitoring. Until such data are available, an individualized approach is recommended. By contrast, because of the high rate of HBsAg seroreversion following liver transplantation using anti-HBc positive donor livers in seronegative recipients, prophylaxis is advised. Strategies that have been used with varying success include hepatitis B immune globulin alone, lamivudine alone, or a combination of the 2.[60-64] No firm recommendations can be made because of the absence of controlled trials.
A suggested approach for managing HBsAg-positive and HBsAg-negative individuals undergoing chemotherapy or bone marrow or stem cell transplantation is given in Figure 3. Lamivudine or telbivudine can be used as prophylaxis in HBeAg-positive individuals if the anticipated duration of treatment is short (< 12 months).[1] Adefovir or entecavir are preferred if longer treatment durations are anticipated.[1] Patients should be monitored closely while receiving antiviral therapy and after discontinuation to ensure that reactivation does not occur. It is equally important to closely monitor untreated patients by collecting serial HBV DNA measurements for the first 12 months after the completion of chemotherapy.[56] The frequency of monitoring can be decreased after this period but should continue indefinitely, since HBsAg seroreversion has been reported beyond 3 years after bone marrow transplantation. Antiviral therapy should be started immediately if HBV DNA levels increase.
Figure 3. Suggested Approach for Managing Immunosuppressed HBV-Infected
Individuals to Prevent HBV Reactivation
A suggested approach for managing HBsAg-positive and HBsAg-negative individuals undergoing chemotherapy or bone marrow or stem cell transplantation is given in Figure 3. Lamivudine or telbivudine can be used as prophylaxis in HBeAg-positive individuals if the anticipated duration of treatment is short (< 12 months).[1] Adefovir or entecavir are preferred if longer treatment durations are anticipated.[1] Patients should be monitored closely while receiving antiviral therapy and after discontinuation to ensure that reactivation does not occur. It is equally important to closely monitor untreated patients by collecting serial HBV DNA measurements for the first 12 months after the completion of chemotherapy.[56] The frequency of monitoring can be decreased after this period but should continue indefinitely, since HBsAg seroreversion has been reported beyond 3 years after bone marrow transplantation. Antiviral therapy should be started immediately if HBV DNA levels increase.
Figure 3. Suggested Approach for Managing Immunosuppressed HBV-Infected
Individuals to Prevent HBV Reactivation
Reactivation of HBV is poorly defined in clinical studies. The term reactivation is used interchangeably in the literature to refer to an increase in serum HBV DNA and/or an increase in serum alanine aminotransferase (ALT) levels and/or reappearance of HBsAg in serum (Table 3). This latter scenario is better termed HBsAg seroreversion, which can occur with or without hepatitis, although HBsAg seroreversion is almost always accompanied by an increase in HBV DNA levels and hepatitis. During cytotoxic therapy, a proposed definition of HBV reactivation used in several studies is a rise in HBV DNA level of > 1 log10 when compared with baseline or an absolute increase that exceeds 1000 x 106 genome equivalents/mL together with hepatitis defined as a 3-fold increase in serum ALT that exceeds the reference range or an absolute increase of serum ALT > 100 IU/L.[40-42]
Table 3. Definition of HBV Reactivation During Cytotoxic Therapy
Seroreversion of HBsAg has been described following chemotherapy,[40] high-dose steroid use,[43] and bone marrow or hematopoietic stem cell transplantation.[44,45] In addition, de novo HBV infection following liver transplantation has been reported in HBsAg-negative individuals who received anti-HBcCpositive donor livers.[46] These multiple clinical observations provide the most convincing evidence that HBV may persist following serologic recovery and that long-term control of HBV replication is dependent on an intact immune response that is probably maintained by continuous priming from residual virus. Rates of reactivation during chemotherapy are lower in HBsAg-negative (serologically recovered) compared with HBsAg-positive (inactive carriers) patients.[40] It has been difficult to accurately determine the prevalence of seroreversion because of several factors: small sample sizes, the sensitivity of the assays used, the different periods of follow-up, the different chemotherapeutic regimens administered, and the different populations studied. Based on case-series, the seroreversion rate ranges from 14% to 30% in patients receiving chemotherapy,[40,47] 11% to 50% in patients undergoing bone marrow or stem cell transplantation,[44,48-50] and 50% to 78% in HBsAg-negative individuals receiving anti-HBcpositive liver grafts.[46,51,52]
Seroreversion and reactivation of HBsAg most likely results from the low-level persistence of cccDNA within hepatocytes with immunosuppression-induced augmentation of HBV replication.[53] Seroreversion with reactivation usually occurs later (6-52 months; median: 19 months) compared with reactivation in HBsAg-positive patients.[54] In the setting of allogeneic bone marrow or stem cell transplantation, the absence of donor immunity may also play a role in HBsAg seroreversion.[50] Recurrence of clinical hepatitis may be mediated by cytotoxicity resulting from very high intracellular levels of HBV DNA or by loss of immune-mediated control of HBV replication with rapid clearance of virally infected hepatocytes upon immune reconstitution.
Which Patients Are at Risk for HBsAg Seroreversion?: Seroreversion of HBsAg may occur either during or after the period of immunosuppression. Identifying risk factors for seroreversion has been difficult because of the small numbers of patients included in published reports. Some risk factors that have been identified are the use of high-dose corticosteroids, the administration of regimens containing rituximab and corticosteroids, the lack of anti-HBs in liver donors, and the development of graft-vs-host disease. In general, the risk of HBsAg seroreversion is related to the degree and duration of immunosuppression and the level of detectable HBV DNA before immunosuppression. Therefore, the risk of HBsAg seroreversion is higher in patients undergoing hematopoietic bone marrow or stem cell transplantation or in those receiving specific monoclonal antibodies directed against B and T cells, such as rituximab and alemtuzumab. The severity of hepatitis following HBsAg seroreversion is influenced by the stage of liver disease. Patients with cirrhosis are at higher risk for decompensation and hepatic failure following HBsAg seroreversion with clinical reactivation. A high baseline level of cccDNA in HBsAg-positive patients has been shown to be predictive of HBsAg seroreversion during chemotherapy.[55] However, quantifying cccDNA is not a practical strategy for risk assessment in the general clinical care setting. Predictors of HBsAg seroreversion that have been identified in uncontrolled studies include declining anti-HBs levels and a 100-fold increase in serum HBV DNA.[50,56]
Clinical Presentation and Management of HBV HBsAg Seroreversion With Clinical Reactivation: The presentation of HBsAg seroreversion with clinical reactivation may range from an asymptomatic, mild increase in serum ALT levels to frank hepatic decompensation and fulminant hepatitis.[41] Mortality of patients with fulminant hepatitis are high and range from 5% to 40%, even with the institution of antiviral therapy.[56,57] Seroreversion-related hepatitis usually leads to severe liver dysfunction and is also independently associated with a higher risk of developing fulminant hepatic failure.[56] The management of established hepatitis involves aggressive supportive therapy and the discontinuation of chemotherapy with prompt, early institution of antiviral therapy with the most potent agent available. The goal should be to suppress HBV DNA levels as rapidly as possible. Once clinical hepatitis develops, there is high mortality despite initiation of antiviral therapy. This highlights the need to monitor patients closely by following HBV DNA levels using a sensitive assay and to intervene before the development of clinical hepatitis. A suggested approach would be to monitor serum HBV DNA levels every 2-4 weeks for the first 3 months after chemotherapy is discontinued and every 3 months thereafter. In one study, a 100-fold increase in serum HBV DNA level preceded seroreversion and clinical hepatitis in all patients.[56] This approach needs to be evaluated in other prospective trials.
Can HBsAg Seroreversion and Reactivation Be Prevented?: Because serum HBV DNA rises before serum ALT levels increase, antiviral therapy initiated before the start of chemotherapy or transplantation should reduce or prevent clinical hepatitis. Indeed, this has been demonstrated in HBsAg-positive inactive carriers. In a randomized controlled trial, 30 lymphoma patients undergoing chemotherapy with or without hematopoietic stem cell transplantation were randomized to receive immediate lamivudine as prophylactic therapy or deferred lamivudine initiated upon clinical evidence of HBV reactivation (as previously defined).[42] Compared with deferred lamivudine, prophylactic lamivudine significantly reduced the rate of HBV reactivation (0% vs 53%, respectively) and improved hepatitis-free survival compared with deferred lamivudine. Based on this, another randomized study, and several case reports,[58] clinicians are advised to initiate antiviral therapy 1 month before the institution of chemotherapy and to continue antiviral therapy for 6 months after immune-system recovery in patients with HBV DNA levels 2000 IU/mL.[1]
Table 3. Definition of HBV Reactivation During Cytotoxic Therapy
Seroreversion of HBsAg has been described following chemotherapy,[40] high-dose steroid use,[43] and bone marrow or hematopoietic stem cell transplantation.[44,45] In addition, de novo HBV infection following liver transplantation has been reported in HBsAg-negative individuals who received anti-HBcCpositive donor livers.[46] These multiple clinical observations provide the most convincing evidence that HBV may persist following serologic recovery and that long-term control of HBV replication is dependent on an intact immune response that is probably maintained by continuous priming from residual virus. Rates of reactivation during chemotherapy are lower in HBsAg-negative (serologically recovered) compared with HBsAg-positive (inactive carriers) patients.[40] It has been difficult to accurately determine the prevalence of seroreversion because of several factors: small sample sizes, the sensitivity of the assays used, the different periods of follow-up, the different chemotherapeutic regimens administered, and the different populations studied. Based on case-series, the seroreversion rate ranges from 14% to 30% in patients receiving chemotherapy,[40,47] 11% to 50% in patients undergoing bone marrow or stem cell transplantation,[44,48-50] and 50% to 78% in HBsAg-negative individuals receiving anti-HBcpositive liver grafts.[46,51,52]
Seroreversion and reactivation of HBsAg most likely results from the low-level persistence of cccDNA within hepatocytes with immunosuppression-induced augmentation of HBV replication.[53] Seroreversion with reactivation usually occurs later (6-52 months; median: 19 months) compared with reactivation in HBsAg-positive patients.[54] In the setting of allogeneic bone marrow or stem cell transplantation, the absence of donor immunity may also play a role in HBsAg seroreversion.[50] Recurrence of clinical hepatitis may be mediated by cytotoxicity resulting from very high intracellular levels of HBV DNA or by loss of immune-mediated control of HBV replication with rapid clearance of virally infected hepatocytes upon immune reconstitution.
Which Patients Are at Risk for HBsAg Seroreversion?: Seroreversion of HBsAg may occur either during or after the period of immunosuppression. Identifying risk factors for seroreversion has been difficult because of the small numbers of patients included in published reports. Some risk factors that have been identified are the use of high-dose corticosteroids, the administration of regimens containing rituximab and corticosteroids, the lack of anti-HBs in liver donors, and the development of graft-vs-host disease. In general, the risk of HBsAg seroreversion is related to the degree and duration of immunosuppression and the level of detectable HBV DNA before immunosuppression. Therefore, the risk of HBsAg seroreversion is higher in patients undergoing hematopoietic bone marrow or stem cell transplantation or in those receiving specific monoclonal antibodies directed against B and T cells, such as rituximab and alemtuzumab. The severity of hepatitis following HBsAg seroreversion is influenced by the stage of liver disease. Patients with cirrhosis are at higher risk for decompensation and hepatic failure following HBsAg seroreversion with clinical reactivation. A high baseline level of cccDNA in HBsAg-positive patients has been shown to be predictive of HBsAg seroreversion during chemotherapy.[55] However, quantifying cccDNA is not a practical strategy for risk assessment in the general clinical care setting. Predictors of HBsAg seroreversion that have been identified in uncontrolled studies include declining anti-HBs levels and a 100-fold increase in serum HBV DNA.[50,56]
Clinical Presentation and Management of HBV HBsAg Seroreversion With Clinical Reactivation: The presentation of HBsAg seroreversion with clinical reactivation may range from an asymptomatic, mild increase in serum ALT levels to frank hepatic decompensation and fulminant hepatitis.[41] Mortality of patients with fulminant hepatitis are high and range from 5% to 40%, even with the institution of antiviral therapy.[56,57] Seroreversion-related hepatitis usually leads to severe liver dysfunction and is also independently associated with a higher risk of developing fulminant hepatic failure.[56] The management of established hepatitis involves aggressive supportive therapy and the discontinuation of chemotherapy with prompt, early institution of antiviral therapy with the most potent agent available. The goal should be to suppress HBV DNA levels as rapidly as possible. Once clinical hepatitis develops, there is high mortality despite initiation of antiviral therapy. This highlights the need to monitor patients closely by following HBV DNA levels using a sensitive assay and to intervene before the development of clinical hepatitis. A suggested approach would be to monitor serum HBV DNA levels every 2-4 weeks for the first 3 months after chemotherapy is discontinued and every 3 months thereafter. In one study, a 100-fold increase in serum HBV DNA level preceded seroreversion and clinical hepatitis in all patients.[56] This approach needs to be evaluated in other prospective trials.
Can HBsAg Seroreversion and Reactivation Be Prevented?: Because serum HBV DNA rises before serum ALT levels increase, antiviral therapy initiated before the start of chemotherapy or transplantation should reduce or prevent clinical hepatitis. Indeed, this has been demonstrated in HBsAg-positive inactive carriers. In a randomized controlled trial, 30 lymphoma patients undergoing chemotherapy with or without hematopoietic stem cell transplantation were randomized to receive immediate lamivudine as prophylactic therapy or deferred lamivudine initiated upon clinical evidence of HBV reactivation (as previously defined).[42] Compared with deferred lamivudine, prophylactic lamivudine significantly reduced the rate of HBV reactivation (0% vs 53%, respectively) and improved hepatitis-free survival compared with deferred lamivudine. Based on this, another randomized study, and several case reports,[58] clinicians are advised to initiate antiviral therapy 1 month before the institution of chemotherapy and to continue antiviral therapy for 6 months after immune-system recovery in patients with HBV DNA levels 2000 IU/mL.[1]
cccDNA as a Therapeutic Target: The HBV cccDNA is an attractive target for therapy because of the critical role it plays in viral replication and persistence. Nucleos(t)ide analogues inhibit the viral polymerase but do not inhibit the intracellular recycling pathway that replenishes cccDNA. As a consequence, viral replication often returns to pretreatment levels after withdrawal of these agents. Using a variety of molecular techniques, studies examining changes in patients cccDNA during nucleos(t)ide analogue therapy, either alone or in combination with peginterferon, have demonstrated a 1.0-2.4 log10 copies/cell decline in cccDNA levels, but not eradication, compared with the other HBV replicative DNA forms in the liver.[8-10] Based on these data, mathematical models predict that it would take longer than 14 years to completely clear a chronically HBV-infected human liver of intracellular cccDNA.[11] The clinical implications of this finding are that nucleos(t)ide analogues have to be administered for extremely long periods of time, if not indefinitely. The goal of a cure of chronic hepatitis B with currently available oral agents is not possible because these agents cannot be effectively administered for this length of time, and they are inefficient at eradicating cccDNA from the liver. Recently, other novel approaches have been explored to target cccDNA. In one study, a genetically modified cytotoxic T cell carrying a chimeric T-cell receptor directed against HBV surface proteins present on HBV-infected cells was developed and used to provide primary human T cells with antibody-like specificity.[12] When coincubated with HBV-infected primary human hepatocytes, these engineered, antigen-specific T cells selectively eliminated HBV-infected and, therefore, cccDNA-positive target cells. However, finding a delivery system for this therapeutic modality and the potential risk of liver damage may limit this approach. Another in vitro study used a small interfering RNA targeted against the nuclear localization signal within the HBV core protein and observed that this agent markedly inhibit cccDNA amplification.[13] Based on this result, further studies in animal models of this class of agents is clearly warranted.
Is There a Role for cccDNA in Predicting the Response to Antiviral Therapy?: Given the role of cccDNA in the persistence of viral replication, quantification of cccDNA may have clinical utility. Studies have shown a correlation between cccDNA and intrahepatic HBV DNA levels; however, it is not practical to measure cccDNA in liver biopsies during routine clinical practice.[14] Therefore, a surrogate marker for cccDNA levels would be a useful tool for monitoring the activity of HBV-related liver disease. Given that cccDNA is the major template for the transcription and translation of viral antigens, including HBsAg, changes in serum HBsAg levels might be used as a surrogate marker for changes in cccDNA levels. One study that examined this potential relationship between pretreatment serum HBsAg levels and total intrahepatic HBV DNA and cccDNA levels in patients undergoing therapy with peginterferon and lamivudine found a correlation between serum HBsAg levels and intrahepatic HBV DNA levels.[15] Patients with lower baseline cccDNA, intrahepatic HBV DNA, and HBsAg levels, but not serum HBV DNA levels, were more likely to develop sustained virologic suppression. Similar results have been observed in patients treated with peginterferon alfa and adefovir.[8,9] These studies provide preliminary evidence that might explain why spontaneous or treatment-induced HBsAg loss is the most robust serologic indicator of sustained virologic suppression, although the findings need to be confirmed by other studies that include larger numbers of subjects.
What Is the Rate of HBsAg Loss With Current Therapies?: As mentioned previously, HBsAg loss is the most robust surrogate marker of a long-term response to antiviral therapy. The rates of HBsAg loss during treatment with approved monotherapies and experimental anti-HBV agents and regimens are shown in the Table 1. Loss of HBsAg is rarely achieved during treatment with nucleos(t)ide analogues[16-25] [22] ( 1.0% to 3.2%).[23] Marginally better results (3.0% to 7.8%)[16,17,25] are obtained with interferon alfa regimens.[17] Combining peginterferon alfa with lamivudine provides no additional benefit in HBsAg clearance over peginterferon alfa alone.[16] The effects of antiviral therapy on cccDNA levels are shown in Table 2.
Table 1. Rates of HBsAg Loss at 1 Year With Monotherapies and Combination
Regimens
Table 2. Median Change in Intrahepatic cccDNA, Intrahepatic HBV DNA, and Serum
HBV DNA Levels During Antiviral Therapy for 48-52 Weeks[8,10,15,28,29]
The Impact of Antiviral Therapy on Liver Disease Outcomes and the Development of Hepatocellular Carcinoma Improvements in HBV-related liver disease and mortality have been observed in patients who are able to maintain long-term HBV DNA suppression either on or off treatment. Long-term data (> 5 years) on clinical outcomes following antiviral therapy are available for interferon alfa and lamivudine, whereas shorter-term follow-up data (4-5 years) are available for adefovir and entecavir. Long-term follow-up of Western studies of HBeAg-positive patients treated with interferon alfa demonstrated improved patient survival and a decreased incidence of hepatic decompensation in patients who achieved persistent clearance of HBeAg.[30-32] By contrast, the long-term clinical benefits of interferon alfa therapy in Asian HBeAg-positive patients are unclear, and no long-term benefit in the prevention of hepatocellular carcinoma or other cirrhosis-related complications has been observed in Asian patients who underwent HBeAg seroconversion compared with controls over a median follow-up of 9 years.[33] Although the rate of sustained HBV DNA clearance with interferon alfa therapy is lower in HBeAg-negative patients compared with HBeAg-positive patients, decreased rates of progression to cirrhosis and liver-related death have also been observed.[34] Finally, the role of interferon alfa in preventing hepatocellular carcinoma is uncertain. The administration of nucleos(t)ide analogue therapy for 1 year or more has been associated with improvements in biochemical, virologic, and histologic parameters in the absence of antiviral resistance. Reductions in hepatic necroinflammation and fibrosis, and even regression of cirrhosis, have been observed in patients who maintained viral suppression on lamivudine for more than 3 years.[35,36] By contrast, histologic benefits were lost among patients with drug resistance.[36] A randomized, placebo-controlled trial reported that patients with advanced liver disease who were treated with lamivudine had lower rates of hepatic decompensation, reduced need for liver transplantation, reduced development of hepatocellular carcinoma, and lower liver-related mortality compared with controls.[37]
In one study, long-term treatment with adefovir for 5 years was associated with decreased fibrosis in patients who maintained a virologic response.[38] Nonetheless, 2% of patients developed hepatocellular carcinoma, indicating that long-term antiviral treatment does not completely prevent this complication. Short-term studies of entecavir, telbivudine and tenofovir therapy report higher rates of viral suppression compared with lamivudine and adefovir.[24,39] Given the superior potency and durability of entecavir and telbivudine, one would predict similar or even superior outcomes with long-term use. However, long-term data on the impact of these agents on the development of hepatocellular carcinoma remains to be demonstrated. Evidence for Lack of Cure: Reactivation With Seroreversion From Anti-HBs and Anti-HBc Positivity to HBsAg Positivity
Is There a Role for cccDNA in Predicting the Response to Antiviral Therapy?: Given the role of cccDNA in the persistence of viral replication, quantification of cccDNA may have clinical utility. Studies have shown a correlation between cccDNA and intrahepatic HBV DNA levels; however, it is not practical to measure cccDNA in liver biopsies during routine clinical practice.[14] Therefore, a surrogate marker for cccDNA levels would be a useful tool for monitoring the activity of HBV-related liver disease. Given that cccDNA is the major template for the transcription and translation of viral antigens, including HBsAg, changes in serum HBsAg levels might be used as a surrogate marker for changes in cccDNA levels. One study that examined this potential relationship between pretreatment serum HBsAg levels and total intrahepatic HBV DNA and cccDNA levels in patients undergoing therapy with peginterferon and lamivudine found a correlation between serum HBsAg levels and intrahepatic HBV DNA levels.[15] Patients with lower baseline cccDNA, intrahepatic HBV DNA, and HBsAg levels, but not serum HBV DNA levels, were more likely to develop sustained virologic suppression. Similar results have been observed in patients treated with peginterferon alfa and adefovir.[8,9] These studies provide preliminary evidence that might explain why spontaneous or treatment-induced HBsAg loss is the most robust serologic indicator of sustained virologic suppression, although the findings need to be confirmed by other studies that include larger numbers of subjects.
What Is the Rate of HBsAg Loss With Current Therapies?: As mentioned previously, HBsAg loss is the most robust surrogate marker of a long-term response to antiviral therapy. The rates of HBsAg loss during treatment with approved monotherapies and experimental anti-HBV agents and regimens are shown in the Table 1. Loss of HBsAg is rarely achieved during treatment with nucleos(t)ide analogues[16-25] [22] ( 1.0% to 3.2%).[23] Marginally better results (3.0% to 7.8%)[16,17,25] are obtained with interferon alfa regimens.[17] Combining peginterferon alfa with lamivudine provides no additional benefit in HBsAg clearance over peginterferon alfa alone.[16] The effects of antiviral therapy on cccDNA levels are shown in Table 2.
Table 1. Rates of HBsAg Loss at 1 Year With Monotherapies and Combination
Regimens
Table 2. Median Change in Intrahepatic cccDNA, Intrahepatic HBV DNA, and Serum
HBV DNA Levels During Antiviral Therapy for 48-52 Weeks[8,10,15,28,29]
The Impact of Antiviral Therapy on Liver Disease Outcomes and the Development of Hepatocellular Carcinoma Improvements in HBV-related liver disease and mortality have been observed in patients who are able to maintain long-term HBV DNA suppression either on or off treatment. Long-term data (> 5 years) on clinical outcomes following antiviral therapy are available for interferon alfa and lamivudine, whereas shorter-term follow-up data (4-5 years) are available for adefovir and entecavir. Long-term follow-up of Western studies of HBeAg-positive patients treated with interferon alfa demonstrated improved patient survival and a decreased incidence of hepatic decompensation in patients who achieved persistent clearance of HBeAg.[30-32] By contrast, the long-term clinical benefits of interferon alfa therapy in Asian HBeAg-positive patients are unclear, and no long-term benefit in the prevention of hepatocellular carcinoma or other cirrhosis-related complications has been observed in Asian patients who underwent HBeAg seroconversion compared with controls over a median follow-up of 9 years.[33] Although the rate of sustained HBV DNA clearance with interferon alfa therapy is lower in HBeAg-negative patients compared with HBeAg-positive patients, decreased rates of progression to cirrhosis and liver-related death have also been observed.[34] Finally, the role of interferon alfa in preventing hepatocellular carcinoma is uncertain. The administration of nucleos(t)ide analogue therapy for 1 year or more has been associated with improvements in biochemical, virologic, and histologic parameters in the absence of antiviral resistance. Reductions in hepatic necroinflammation and fibrosis, and even regression of cirrhosis, have been observed in patients who maintained viral suppression on lamivudine for more than 3 years.[35,36] By contrast, histologic benefits were lost among patients with drug resistance.[36] A randomized, placebo-controlled trial reported that patients with advanced liver disease who were treated with lamivudine had lower rates of hepatic decompensation, reduced need for liver transplantation, reduced development of hepatocellular carcinoma, and lower liver-related mortality compared with controls.[37]
In one study, long-term treatment with adefovir for 5 years was associated with decreased fibrosis in patients who maintained a virologic response.[38] Nonetheless, 2% of patients developed hepatocellular carcinoma, indicating that long-term antiviral treatment does not completely prevent this complication. Short-term studies of entecavir, telbivudine and tenofovir therapy report higher rates of viral suppression compared with lamivudine and adefovir.[24,39] Given the superior potency and durability of entecavir and telbivudine, one would predict similar or even superior outcomes with long-term use. However, long-term data on the impact of these agents on the development of hepatocellular carcinoma remains to be demonstrated. Evidence for Lack of Cure: Reactivation With Seroreversion From Anti-HBs and Anti-HBc Positivity to HBsAg Positivity
Notes on “Can Hepatitis B Be Cured?” Norah Terrault, 2008.
Introduction: Chronic hepatitis B remains a major health problem worldwide.[1] Progression to cirrhosis, decompensated liver disease, and hepatocellular carcinoma are the major adverse consequences of untreated disease. Therefore, the goals of therapy are to prevent these complications to ultimately prevent premature death from chronic hepatitis B. Six drugs are now approved for the treatment of chronic hepatitis B in the United States: interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir, and telbivudine.[1] The nucleos(t)ide analogues control viral replication very well with variable levels of long-term durability. However, viral replication typically returns to detectable levels after nucleos(t)ide therapy is stopped, even in patients who are initially hepatitis B e antigen (HBeAg) positive but who undergo HBeAg loss and develop antibody to HBeAg (anti-HBe)HBeAg seroconversionor who lose hepatitis B surface antigen (HBsAg) during their treatment. Therefore, although chronic hepatitis B virus infection can be controlled with these agents, it is rarely, if ever, cured by them. The probable explanation lies with a viral form termed covalently closed circular DNA (cccDNA), which plays a key role in viral persistence and viral reactivation after treatment withdrawal. This module highlights the critical role of cccDNA in the course of natural and treated hepatitis B virus (HBV) infection.
What Is cccDNA?: Hepatitis B virus cccDNA constitutes a stable form of the viral DNA genome. The cccDNA resides in an infected hepatocyte nucleus as a nonintegrated minichromosome or episome, where it acts as a template for the transcription of viral genes.[2] The number of copies of cccDNA present in any given hepatocyte is highly variable but generally ranges from 10-50 copies per hepatocyte.[2]
How Is cccDNA Produced and Maintained?: The cccDNA is produced during viral replication. Although HBV is a partially double-stranded DNA virus, it replicates through an RNA intermediate by employing a viral polymerase with reverse transcriptase activity. Replication of HBV predominantly occurs in hepatocytes.[2] Upon entry into the cell, the virus sheds its protein coat, and the relaxed, partially double-stranded genome is transported into the nucleus.[2] In the nucleus, host and viral polymerases repair the relaxed, partially circular genome to a fully double-stranded, covalently closed circular genome or cccDNA (Figure 1). The cccDNA serves as the template for transcription of all viral messenger RNAs (mRNAs). The viral mRNAs include 1) the pregenomic RNA, which serves as the template for both reverse transcription and the synthesis of the core protein and polymerase enzyme; 2) 3 subgenomic mRNAs necessary for the translation of the envelope proteins; and 3) the X protein, the function of which is poorly understood.[2,3] Once synthesized, the viral mRNAs are transported to the cytoplasm where translation of viral proteins, nucleocapsid assembly, and viral replication occur.
Figure 1. The HBV life cycle.
Replication occurs within the viral nucleocapsid that consists of the core protein, pregenomic RNA, and polymerase.[2,3] Nucleocapsid formation requires coordinated binding of the polymerase to an RNA stem-loop structure called epsilon that is located at the 5 end of the pregenomic RNA䡪a process that triggers encapsidation by core particles. The epsilon-bound polymerase serves as a protein primer for DNA synthesis, with epsilon serving as the template for this reaction. After the negative strand of DNA has been completely synthesized, the RNA is degraded by the viral RNase H that is part of the polymerase. Positive-strand synthesis and circularization of the viral genome then follows. Once replication is complete, the viral nucleocapsid interacts with envelope proteins in the endoplasmic reticulum to form mature virions that are secreted from the cell. Viral nucleocapsids can also be transported back to the nucleus, which represents a critically important pathway for maintenance of cccDNA within the hepatocyte. This pathway is thought to be regulated by the large surface protein.[4]
How Is cccDNA Eliminated?: The immune response plays a fundamental role in viral clearance as well as in mediating disease. Therefore, it is beneficial to review the immune response to HBV infection to understand how viral replication is controlled. Successful control of HBV is dependent on the complex interplay between the innate, cellular, and humoral responses to the infecting virus (Figure 2). However, the exact role of the innate response in acute HBV infection is unclear. The nonspecific innate immune response involves
production of interferon, activation of natural killer cells, and activation of Kupffer cells, all of which may help to control viral replication and limit the spread of the virus during the early stages of infection.[5,6] The roles of the cellular and humoral responses are better defined. The T-cell response during acute, self-limited HBV infection is characterized by a strong, polyclonal, multispecific cytotoxic and helper T-cell response. By contrast, the immune response in chronic carriers is feeble or undetectable. The CD4+ helper T lymphocytes recognize processed viral antigen presented by major histocompatibility complex class II molecules.[5,6] There are 2 subsets of these CD4+ helper T cells. The first is type 1 helper T cells which secrete interferon gamma, interleukin (IL)-2, and tumor necrosis factor-alpha and clear HBV-infected hepatocytes through cytolytic and noncytolytic mechanisms. The second are the type 2 helper T cells that secrete IL-4, IL-5, IL-6, and IL-10 and lead to B-cell antibody production, which is necessary for neutralizing free viral particles and preventing reinfection of hepatocytes.
Figure 2. Control of HBV by the immune system.
The immune system is thought to eliminate cccDNA by 2 possible mechanisms: 1) a cytolytic mechanism in which infected hepatocytes are killed and replaced by noninfected cells and 2) a noncytolytic mechanism in which antiviral cytokines downregulate HBV gene expression and eliminate HBV from hepatocytes without cell death.[7] Hepatocytes have a long half-life; therefore, elimination of cccDNA by hepatocyte turnover is not a major means of clearance, except perhaps during periods of rapid cell turnover, such as during acute hepatitis infection. The observation that cccDNA may persist even in patients with serologic evidence of viral clearance highlights the important role of the immune response in controlling viral replication and offers insight into potential nonvirologic approaches to the treatment of chronic hepatitis B (Capsule Summary).[8] [Coder link to: Hep JO Werle-Gastro-2004-06]
Introduction: Chronic hepatitis B remains a major health problem worldwide.[1] Progression to cirrhosis, decompensated liver disease, and hepatocellular carcinoma are the major adverse consequences of untreated disease. Therefore, the goals of therapy are to prevent these complications to ultimately prevent premature death from chronic hepatitis B. Six drugs are now approved for the treatment of chronic hepatitis B in the United States: interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir, and telbivudine.[1] The nucleos(t)ide analogues control viral replication very well with variable levels of long-term durability. However, viral replication typically returns to detectable levels after nucleos(t)ide therapy is stopped, even in patients who are initially hepatitis B e antigen (HBeAg) positive but who undergo HBeAg loss and develop antibody to HBeAg (anti-HBe)HBeAg seroconversionor who lose hepatitis B surface antigen (HBsAg) during their treatment. Therefore, although chronic hepatitis B virus infection can be controlled with these agents, it is rarely, if ever, cured by them. The probable explanation lies with a viral form termed covalently closed circular DNA (cccDNA), which plays a key role in viral persistence and viral reactivation after treatment withdrawal. This module highlights the critical role of cccDNA in the course of natural and treated hepatitis B virus (HBV) infection.
What Is cccDNA?: Hepatitis B virus cccDNA constitutes a stable form of the viral DNA genome. The cccDNA resides in an infected hepatocyte nucleus as a nonintegrated minichromosome or episome, where it acts as a template for the transcription of viral genes.[2] The number of copies of cccDNA present in any given hepatocyte is highly variable but generally ranges from 10-50 copies per hepatocyte.[2]
How Is cccDNA Produced and Maintained?: The cccDNA is produced during viral replication. Although HBV is a partially double-stranded DNA virus, it replicates through an RNA intermediate by employing a viral polymerase with reverse transcriptase activity. Replication of HBV predominantly occurs in hepatocytes.[2] Upon entry into the cell, the virus sheds its protein coat, and the relaxed, partially double-stranded genome is transported into the nucleus.[2] In the nucleus, host and viral polymerases repair the relaxed, partially circular genome to a fully double-stranded, covalently closed circular genome or cccDNA (Figure 1). The cccDNA serves as the template for transcription of all viral messenger RNAs (mRNAs). The viral mRNAs include 1) the pregenomic RNA, which serves as the template for both reverse transcription and the synthesis of the core protein and polymerase enzyme; 2) 3 subgenomic mRNAs necessary for the translation of the envelope proteins; and 3) the X protein, the function of which is poorly understood.[2,3] Once synthesized, the viral mRNAs are transported to the cytoplasm where translation of viral proteins, nucleocapsid assembly, and viral replication occur.
Figure 1. The HBV life cycle.
Replication occurs within the viral nucleocapsid that consists of the core protein, pregenomic RNA, and polymerase.[2,3] Nucleocapsid formation requires coordinated binding of the polymerase to an RNA stem-loop structure called epsilon that is located at the 5 end of the pregenomic RNA䡪a process that triggers encapsidation by core particles. The epsilon-bound polymerase serves as a protein primer for DNA synthesis, with epsilon serving as the template for this reaction. After the negative strand of DNA has been completely synthesized, the RNA is degraded by the viral RNase H that is part of the polymerase. Positive-strand synthesis and circularization of the viral genome then follows. Once replication is complete, the viral nucleocapsid interacts with envelope proteins in the endoplasmic reticulum to form mature virions that are secreted from the cell. Viral nucleocapsids can also be transported back to the nucleus, which represents a critically important pathway for maintenance of cccDNA within the hepatocyte. This pathway is thought to be regulated by the large surface protein.[4]
How Is cccDNA Eliminated?: The immune response plays a fundamental role in viral clearance as well as in mediating disease. Therefore, it is beneficial to review the immune response to HBV infection to understand how viral replication is controlled. Successful control of HBV is dependent on the complex interplay between the innate, cellular, and humoral responses to the infecting virus (Figure 2). However, the exact role of the innate response in acute HBV infection is unclear. The nonspecific innate immune response involves
production of interferon, activation of natural killer cells, and activation of Kupffer cells, all of which may help to control viral replication and limit the spread of the virus during the early stages of infection.[5,6] The roles of the cellular and humoral responses are better defined. The T-cell response during acute, self-limited HBV infection is characterized by a strong, polyclonal, multispecific cytotoxic and helper T-cell response. By contrast, the immune response in chronic carriers is feeble or undetectable. The CD4+ helper T lymphocytes recognize processed viral antigen presented by major histocompatibility complex class II molecules.[5,6] There are 2 subsets of these CD4+ helper T cells. The first is type 1 helper T cells which secrete interferon gamma, interleukin (IL)-2, and tumor necrosis factor-alpha and clear HBV-infected hepatocytes through cytolytic and noncytolytic mechanisms. The second are the type 2 helper T cells that secrete IL-4, IL-5, IL-6, and IL-10 and lead to B-cell antibody production, which is necessary for neutralizing free viral particles and preventing reinfection of hepatocytes.
Figure 2. Control of HBV by the immune system.
The immune system is thought to eliminate cccDNA by 2 possible mechanisms: 1) a cytolytic mechanism in which infected hepatocytes are killed and replaced by noninfected cells and 2) a noncytolytic mechanism in which antiviral cytokines downregulate HBV gene expression and eliminate HBV from hepatocytes without cell death.[7] Hepatocytes have a long half-life; therefore, elimination of cccDNA by hepatocyte turnover is not a major means of clearance, except perhaps during periods of rapid cell turnover, such as during acute hepatitis infection. The observation that cccDNA may persist even in patients with serologic evidence of viral clearance highlights the important role of the immune response in controlling viral replication and offers insight into potential nonvirologic approaches to the treatment of chronic hepatitis B (Capsule Summary).[8] [Coder link to: Hep JO Werle-Gastro-2004-06]
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