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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.
Therapy of Chronic Hepatitis B: Who to Treat and When to Treat? A Case-Based Discussion , 2008
Introduction
Substantial advances have been made in the treatment of chronic hepatitis B in the past decade. Currently, there are 6 approved therapies, including 2 formulations of interferon alfa (standard interferon alfa and peginterferon alfa) and 4 nucleos(t)ide analogues (lamivudine, adefovir, entecavir, and telbivudine). It is anticipated that another nucleotide analogue, tenofovir, may be approved in the near future. Therefore, many treatment options are available that are effective in suppressing hepatitis B virus (HBV) replication, can be administered orally, and have excellent safety profiles. This has prompted some experts to recommend that all HBV carriers should receive treatment because chronic HBV infection can progress to cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). However, current treatments do not eradicate HBV (see “Can Hepatitis B Be Cured?” by Marc G. Ghany, MD). Therefore, most patients require long durations of treatment, and in many instances, life-long treatment is required to maintain viral suppression. Sustained viral suppression, in turn, is required to achieve continued clinical benefit and to prevent hepatitis flares resulting from virologic relapse associated with the withdrawal of treatment. Not all HBV carriers will experience adverse consequences of chronic HBV infection, and for those individuals who do experience such complications, they may not occur until years or decades later. Furthermore, host immune response can result in spontaneous remission in some patients, which can at times be long lasting. Therefore, until a safe and affordable “cure” for hepatitis B is available, it is prudent to assess the long-term benefits vs long-term risks before recommending treatment (Figure 1).
When evaluating the benefits associated with treatment, one must take into consideration not only on-treatment viral suppression but also the durability of viral suppression after treatment is discontinued, the ability to maintain viral suppression during continued treatment, and most importantly, the impact on liver disease progression and HCC development. Risks associated with treatment include adverse effects, potential development of drug resistance, and costs. Interferon alfa is associated with a wide spectrum of adverse events.[1] Nucleos(t)ide analogues are generally well tolerated. However, adefovir has been associated with a low rate of nephrotoxicity,[2,3] and telbivudine has been reported to be associated with rare cases of myopathy and peripheral neuropathy.[4] Copyright © 2008 Clinical Care Options, LLC. All rights reserved. 7 Recognition that the natural course of chronic HBV infection involves different phases with marked variations in HBV replication and activity of liver disease over time has shifted the paradigm in hepatitis B treatment from “who to treat” to “when to treat” (Figure 2). Therefore, all persons with chronic hepatitis B are potential treatment candidates. A patient who is not a treatment candidate at the time of presentation may become a treatment candidate during the course of follow-up if serum HBV DNA or alanine aminotransferase (ALT) levels increase or if there is clinical evidence of hepatic decompensation. For this reason, all patients who are not considered treatment candidates at presentation should be monitored and treatment initiated later if indications arise.
The decision of whether to treat now or to defer treatment hinges on 3 key questions: 1) How active or advanced is the liver disease now? 2) What is the risk of progression to cirrhosis, hepatic decompensation, or HCC in the next 10-20 years? 3) What is the likelihood that clinical benefit can be maintained after a finite course of treatment, for example, 3-5 years? In this review, examples are presented of clear-cut scenarios in which treatment should be initiated, clear-cut scenarios in which treatment can be deferred, and debatable scenarios in which the decision to treat should be individualized. Moreover, the rationale for recommending immediate treatment vs deferral of treatment is discussed for each case. The choice of treatment and the endpoints of therapy are covered in “Therapy of Chronic Hepatitis B: What to Choose, When to Stop, and When to Change” by Ira M. Jacobson, MD.
Clear-cut Cases in Which Treatment Should Be Initiated
Patients With Detectable Serum HBV DNA and Hepatic Decompensation
Case 1
A 58-year-old white man presented with jaundice and ascites for 2 weeks. Blood test results showed HBV DNA 7000 IU/mL, ALT 38 IU/L (normal < 40 IU/L), total bilirubin 3.1 mg/dL, and international normalized ratio (INR) of prothrombin time of 1.6.
Discussion
Although the serum HBV DNA level is not very high in this patient, nucleos(t)ide therapy should be initiated in this case. Interferon alfa–based treatment is contraindicated in patients with decompensated cirrhosis because of high rates of treatment-associated adverse events.[5,6] However, several studies have shown that lamivudine is effective in stabilizing the liver disease in these patients.[7-9] This may allow patients to undergo liver transplantation,[10,11] or in some cases reversal of liver failure may allow patients to be removed from the transplant waiting list.[12,13] It should be emphasized that although viral suppression can be evident within 4 weeks of antiviral therapy, clinical benefit takes 3-6 months to be apparent. Therefore, all patients who present with hepatic decompensation should be evaluated for liver transplantation.[11] Furthermore, HCC surveillance should be continued as HCC has been reported even in patients in whom HBV DNA had been suppressed.[8,14] For patients who proceed to transplantation, viral suppression before transplantation can decrease the risk of HBV reinfection after transplantation. In addition, antiviral therapy should be continued posttransplantation, and the combination of hepatitis B immune globulin and nucleos(t)ide analogues such as lamivudine and adefovir have significantly improved patient outcomes.[15] Although most of these data are based on studies of lamivudine therapy, it is reasonable to assume that other nucleos(t)ide analogues will provide the same benefits.
Patients With Severe Hepatitis Flare
Case 2
A 41-year-old Chinese man presented with a 3-week history of fatigue. Blood test results showed ALT 725 IU/L, total bilirubin 1.7 mg/dL, INR 1.2, platelet count 145,000/mm3, HBeAgpositive, and HBV DNA 64,000 IU/mL. Repeat blood tests 1 week later showed ALT 650 IU/L, total bilirubin 2.1 mg/dL, INR 1.3, and IgM antibodies to hepatitis B core antigen (anti-HBc) positive.
Introduction
Substantial advances have been made in the treatment of chronic hepatitis B in the past decade. Currently, there are 6 approved therapies, including 2 formulations of interferon alfa (standard interferon alfa and peginterferon alfa) and 4 nucleos(t)ide analogues (lamivudine, adefovir, entecavir, and telbivudine). It is anticipated that another nucleotide analogue, tenofovir, may be approved in the near future. Therefore, many treatment options are available that are effective in suppressing hepatitis B virus (HBV) replication, can be administered orally, and have excellent safety profiles. This has prompted some experts to recommend that all HBV carriers should receive treatment because chronic HBV infection can progress to cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). However, current treatments do not eradicate HBV (see “Can Hepatitis B Be Cured?” by Marc G. Ghany, MD). Therefore, most patients require long durations of treatment, and in many instances, life-long treatment is required to maintain viral suppression. Sustained viral suppression, in turn, is required to achieve continued clinical benefit and to prevent hepatitis flares resulting from virologic relapse associated with the withdrawal of treatment. Not all HBV carriers will experience adverse consequences of chronic HBV infection, and for those individuals who do experience such complications, they may not occur until years or decades later. Furthermore, host immune response can result in spontaneous remission in some patients, which can at times be long lasting. Therefore, until a safe and affordable “cure” for hepatitis B is available, it is prudent to assess the long-term benefits vs long-term risks before recommending treatment (Figure 1).
When evaluating the benefits associated with treatment, one must take into consideration not only on-treatment viral suppression but also the durability of viral suppression after treatment is discontinued, the ability to maintain viral suppression during continued treatment, and most importantly, the impact on liver disease progression and HCC development. Risks associated with treatment include adverse effects, potential development of drug resistance, and costs. Interferon alfa is associated with a wide spectrum of adverse events.[1] Nucleos(t)ide analogues are generally well tolerated. However, adefovir has been associated with a low rate of nephrotoxicity,[2,3] and telbivudine has been reported to be associated with rare cases of myopathy and peripheral neuropathy.[4] Copyright © 2008 Clinical Care Options, LLC. All rights reserved. 7 Recognition that the natural course of chronic HBV infection involves different phases with marked variations in HBV replication and activity of liver disease over time has shifted the paradigm in hepatitis B treatment from “who to treat” to “when to treat” (Figure 2). Therefore, all persons with chronic hepatitis B are potential treatment candidates. A patient who is not a treatment candidate at the time of presentation may become a treatment candidate during the course of follow-up if serum HBV DNA or alanine aminotransferase (ALT) levels increase or if there is clinical evidence of hepatic decompensation. For this reason, all patients who are not considered treatment candidates at presentation should be monitored and treatment initiated later if indications arise.
The decision of whether to treat now or to defer treatment hinges on 3 key questions: 1) How active or advanced is the liver disease now? 2) What is the risk of progression to cirrhosis, hepatic decompensation, or HCC in the next 10-20 years? 3) What is the likelihood that clinical benefit can be maintained after a finite course of treatment, for example, 3-5 years? In this review, examples are presented of clear-cut scenarios in which treatment should be initiated, clear-cut scenarios in which treatment can be deferred, and debatable scenarios in which the decision to treat should be individualized. Moreover, the rationale for recommending immediate treatment vs deferral of treatment is discussed for each case. The choice of treatment and the endpoints of therapy are covered in “Therapy of Chronic Hepatitis B: What to Choose, When to Stop, and When to Change” by Ira M. Jacobson, MD.
Clear-cut Cases in Which Treatment Should Be Initiated
Patients With Detectable Serum HBV DNA and Hepatic Decompensation
Case 1
A 58-year-old white man presented with jaundice and ascites for 2 weeks. Blood test results showed HBV DNA 7000 IU/mL, ALT 38 IU/L (normal < 40 IU/L), total bilirubin 3.1 mg/dL, and international normalized ratio (INR) of prothrombin time of 1.6.
Discussion
Although the serum HBV DNA level is not very high in this patient, nucleos(t)ide therapy should be initiated in this case. Interferon alfa–based treatment is contraindicated in patients with decompensated cirrhosis because of high rates of treatment-associated adverse events.[5,6] However, several studies have shown that lamivudine is effective in stabilizing the liver disease in these patients.[7-9] This may allow patients to undergo liver transplantation,[10,11] or in some cases reversal of liver failure may allow patients to be removed from the transplant waiting list.[12,13] It should be emphasized that although viral suppression can be evident within 4 weeks of antiviral therapy, clinical benefit takes 3-6 months to be apparent. Therefore, all patients who present with hepatic decompensation should be evaluated for liver transplantation.[11] Furthermore, HCC surveillance should be continued as HCC has been reported even in patients in whom HBV DNA had been suppressed.[8,14] For patients who proceed to transplantation, viral suppression before transplantation can decrease the risk of HBV reinfection after transplantation. In addition, antiviral therapy should be continued posttransplantation, and the combination of hepatitis B immune globulin and nucleos(t)ide analogues such as lamivudine and adefovir have significantly improved patient outcomes.[15] Although most of these data are based on studies of lamivudine therapy, it is reasonable to assume that other nucleos(t)ide analogues will provide the same benefits.
Patients With Severe Hepatitis Flare
Case 2
A 41-year-old Chinese man presented with a 3-week history of fatigue. Blood test results showed ALT 725 IU/L, total bilirubin 1.7 mg/dL, INR 1.2, platelet count 145,000/mm3, HBeAgpositive, and HBV DNA 64,000 IU/mL. Repeat blood tests 1 week later showed ALT 650 IU/L, total bilirubin 2.1 mg/dL, INR 1.3, and IgM antibodies to hepatitis B core antigen (anti-HBc) positive.
Norah Terrault, MD, MPH: Treatment of cirrhotics is associated with clinical benefits such as preventing progression to decompensation, but the benefit in terms of cancer reduction is uncertain. These patients clearly should continue to be monitored for hepatocellular carcinoma.
Patrick Marcellin, MD: We do not know well the mechanisms responsible for the occurrence of hepatocellular carcinoma in cirrhotic patients. Even if antiviral therapy inhibits HBV replication and decreases liver necroinflammation, the “precancer” cirrhotic lesions and persistent HBVinfection in the liver might explain the continuing risk for hepatocellular carcinoma. Largecohort studies with long follow-up are needed to determine the magnitude of the risk and for how long it persists.
Long-term Entecavir in Chinese Patients With Lamivudine-Refractory HBV
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Yao and colleagues[29] evaluated the long-term efficacy of entecavir monotherapy in 138Chinese patients with lamivudine-refractory chronic hepatitis B who enrolled in the ETV-056and ETV-050 studies (Increasing Rates of Virologic Suppression Through Year 3 of Entecavir Treatment in Chinese Cohort With Lamivudine Resistance). In ETV-056, patients received 12weeks of entecavir 1 mg daily or placebo followed by 36 weeks of open-label entecavir 1 mgdaily. A total of 141 patients from ETV-056 rolled over into ETV-050 and continued entecavir1 mg daily. These patients were relatively young (mean age: 35 years), 76% were male with a moderately high HBV DNA (8.78 log10 copies/mL), and 90% were HBeAg positive. In this study, the proportion of patients achieving undetectable HBV DNA increased over time, from 30% at Year 1 to 47% at Year 2 and 55% at Year 3. This contrasts with findings from thepivotal entecavir studies that showed an increasing rate of HBV DNA negativity for the first 2years in lamivudine-refractory patients, followed by a decrease in rates of undetectable HBVDNA by the third year along with the emergence of entecavir resistance (Assessment at threeyears shows high barrier to resistance is maintained in entecavir-treated nucleoside naïve patients while resistance emergence increases over time in lamivudine refractory patients).[30]In addition, there was a fairly acceptable rate of cumulative HBeAg loss (11%, 13%, and 17%at Years 1, 2, and 3, respectively) and cumulative HBeAg seroconversion (7%, 11%, and12% at Years 1, 2, and 3). By contrast, however, the proportion of patients with ALT ≤ 1 xupper limit of normal (ULN) decreased from 85% at Year 1 to 65% at Year 3.Although entecavir monotherapy is approved for use in lamivudine-experienced patients, many experts feel that there are more effective treatment options for this patient population.
Patrick Marcellin, MD: This study confirms that patients with lamivudine-resistant HBV respond less well to entecavir than do treatment-naive patients. In addition, we know that they are at increased risk of developing entecavir resistance. Therefore, there is some consensus that it is more appropriate to use drugs without cross-resistance with lamivudine, such as adefovir ortenofovir. In addition, the use of interferon may be another option in these patients, especially in countries where adefovir or tenofovir is not available.
Preexisting Resistance Mutations in Treatment-Naive Patients
Norah Terrault, MD, MPH: It has been postulated that a proportion of treatment-naive HBV-infected patients may have resistance mutations present at baseline. Indeed, a previous study using direct sequencing reported that 10% of treatment-naive patients had preexisting lamivudine resistance mutations.[31] However, in general, only viral variants present at a prevalence of ≥ 20% among the total HBV quasispecies pool are detectable using this technique.[32.] Fung and colleagues[33] presented data using a very sensitive line probe assay, which is more sensitive than direct sequencing (lower level of detection for antiviral-resistant variants at ≥ 5% of the total HBV quasispecies pool[34]) to screen for the presence of lamivudine mutations at codons180 and 204 in 146 nucleos(t)ide-naive patients. They found that preexisting mutations in thert180/204 pathway were relatively common, with M204V/I present in 13% of patients and L180M present in 7%. This was a cross-sectional analysis, so no data were available to demonstrate whether the presence of these mutations affected subsequent response to therapy. Nevertheless, it is plausible that baseline resistance testing might influence the choice of antiviral therapy in the future. For example, if a patient had the M204V/I mutation, one might avoid nucleoside analogues such as lamivudine or entecavir as first-line therapy and instead consider nucleotides such as adefovir or tenofovir. Because this concept is still emerging, it is not yet clear how to best use this type of information. Regardless, it is important to note that even patients with no previous drug exposure can have resistance mutations present in their viral quasispecies due to the error-prone replication of HBV.
Patrick Marcellin, MD: Longitudinal studies are necessary to determine the clinical relevance of these findings by assessing the influence of these minority HBV populations on the antiviral response and the incidence of resistance.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: These data are very interesting and warrant confirmation in subsequent studies. We currently have only 1 class of drugs for treatment of chronic HBV infection—nucleos(t)ide analogues—and there is a high frequency of cross-resistance with some of the available antiviral agents. Therefore, routine baseline testing for presence of treatment-associated mutations may become clinically useful and cost-effective in the future if such mutations are found at similar rates in other studies.
Patrick Marcellin, MD: We do not know well the mechanisms responsible for the occurrence of hepatocellular carcinoma in cirrhotic patients. Even if antiviral therapy inhibits HBV replication and decreases liver necroinflammation, the “precancer” cirrhotic lesions and persistent HBVinfection in the liver might explain the continuing risk for hepatocellular carcinoma. Largecohort studies with long follow-up are needed to determine the magnitude of the risk and for how long it persists.
Long-term Entecavir in Chinese Patients With Lamivudine-Refractory HBV
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Yao and colleagues[29] evaluated the long-term efficacy of entecavir monotherapy in 138Chinese patients with lamivudine-refractory chronic hepatitis B who enrolled in the ETV-056and ETV-050 studies (Increasing Rates of Virologic Suppression Through Year 3 of Entecavir Treatment in Chinese Cohort With Lamivudine Resistance). In ETV-056, patients received 12weeks of entecavir 1 mg daily or placebo followed by 36 weeks of open-label entecavir 1 mgdaily. A total of 141 patients from ETV-056 rolled over into ETV-050 and continued entecavir1 mg daily. These patients were relatively young (mean age: 35 years), 76% were male with a moderately high HBV DNA (8.78 log10 copies/mL), and 90% were HBeAg positive. In this study, the proportion of patients achieving undetectable HBV DNA increased over time, from 30% at Year 1 to 47% at Year 2 and 55% at Year 3. This contrasts with findings from thepivotal entecavir studies that showed an increasing rate of HBV DNA negativity for the first 2years in lamivudine-refractory patients, followed by a decrease in rates of undetectable HBVDNA by the third year along with the emergence of entecavir resistance (Assessment at threeyears shows high barrier to resistance is maintained in entecavir-treated nucleoside naïve patients while resistance emergence increases over time in lamivudine refractory patients).[30]In addition, there was a fairly acceptable rate of cumulative HBeAg loss (11%, 13%, and 17%at Years 1, 2, and 3, respectively) and cumulative HBeAg seroconversion (7%, 11%, and12% at Years 1, 2, and 3). By contrast, however, the proportion of patients with ALT ≤ 1 xupper limit of normal (ULN) decreased from 85% at Year 1 to 65% at Year 3.Although entecavir monotherapy is approved for use in lamivudine-experienced patients, many experts feel that there are more effective treatment options for this patient population.
Patrick Marcellin, MD: This study confirms that patients with lamivudine-resistant HBV respond less well to entecavir than do treatment-naive patients. In addition, we know that they are at increased risk of developing entecavir resistance. Therefore, there is some consensus that it is more appropriate to use drugs without cross-resistance with lamivudine, such as adefovir ortenofovir. In addition, the use of interferon may be another option in these patients, especially in countries where adefovir or tenofovir is not available.
Preexisting Resistance Mutations in Treatment-Naive Patients
Norah Terrault, MD, MPH: It has been postulated that a proportion of treatment-naive HBV-infected patients may have resistance mutations present at baseline. Indeed, a previous study using direct sequencing reported that 10% of treatment-naive patients had preexisting lamivudine resistance mutations.[31] However, in general, only viral variants present at a prevalence of ≥ 20% among the total HBV quasispecies pool are detectable using this technique.[32.] Fung and colleagues[33] presented data using a very sensitive line probe assay, which is more sensitive than direct sequencing (lower level of detection for antiviral-resistant variants at ≥ 5% of the total HBV quasispecies pool[34]) to screen for the presence of lamivudine mutations at codons180 and 204 in 146 nucleos(t)ide-naive patients. They found that preexisting mutations in thert180/204 pathway were relatively common, with M204V/I present in 13% of patients and L180M present in 7%. This was a cross-sectional analysis, so no data were available to demonstrate whether the presence of these mutations affected subsequent response to therapy. Nevertheless, it is plausible that baseline resistance testing might influence the choice of antiviral therapy in the future. For example, if a patient had the M204V/I mutation, one might avoid nucleoside analogues such as lamivudine or entecavir as first-line therapy and instead consider nucleotides such as adefovir or tenofovir. Because this concept is still emerging, it is not yet clear how to best use this type of information. Regardless, it is important to note that even patients with no previous drug exposure can have resistance mutations present in their viral quasispecies due to the error-prone replication of HBV.
Patrick Marcellin, MD: Longitudinal studies are necessary to determine the clinical relevance of these findings by assessing the influence of these minority HBV populations on the antiviral response and the incidence of resistance.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: These data are very interesting and warrant confirmation in subsequent studies. We currently have only 1 class of drugs for treatment of chronic HBV infection—nucleos(t)ide analogues—and there is a high frequency of cross-resistance with some of the available antiviral agents. Therefore, routine baseline testing for presence of treatment-associated mutations may become clinically useful and cost-effective in the future if such mutations are found at similar rates in other studies.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: I think another key issue is how tenofovir resistance is defined. At present, it is being reported that no signature mutation(s) for tenofovir resistance have been found. The investigators noted that polymorphisms are being selected for in some patients during therapy, but HBVDNA still decreases during tenofovir treatment. Therefore, the impact of those mutations on tenofovir resistance is unclear. Nevertheless, it is clear that the presence of signature mutations for adefovir was associated with a reduced rate of response to tenofovir, and so those mutations clearly confer reduced susceptibility to tenofovir.
Norah Terrault, MD, MPH: Although all the adefovir-resistant patients had documented adefovir resistance mutations, the investigators could not identify a specific mutation or pattern of mutations that was associated with a poor response and that could be, therefore, considered a tenofovir signature mutation or mutations. Even in the patients with adefovir resistance, there were no cases of virologic breakthrough observed.
Patrick Marcellin, MD: Despite the caveats of this study previously discussed, the results raise the possibility that a different potent analogue such as entecavir might be preferred in patients who developed resistance to adefovir. In vitro data support this strategy since viral strains resistant to adefovir show no cross-resistance to entecavir and less susceptibility to tenofovir.[24]
Norah Terrault, MD, MPH: Continuing our review of tenofovir use in nucleos(t)ide-experienced patients, Berg and colleagues[25] compared the safety and efficacy of tenofovir monotherapy vs coformulated tenofovir/emtricitabine in patients with persistent viremia following treatment with adefovir(Similar Efficacy of Tenofovir vs Coformulated Tenofovir/Emtricitabine in HBV-Infected Patients With Persistent Viremia on Adefovir). Coformulated tenofovir/emtricitabine iscurrently approved for the treatment of HIV and because emtricitabine has also been shown to also have efficacy against HBV, there is the potential to use a single tablet containing 2drugs with activity against HBV. Interestingly, however, there was no incremental benefit observed with the addition of emtricitabine to tenofovir, and there were no significant differences between tenofovir monotherapy and tenofovir/emtricitabine at Week 48 regarding the percentage of patients achieving HBV DNA < 400 copies/mL, normalization of ALT, or HBeAg seroconversion, and no difference in the mean reduction in HBV DNA levels.
One important aspect of the study was that the investigators analyzed the impact of adherence on treatment response. In an analysis in which both study arms were combined, there was a nonsignificant trend toward higher response rates in patients with high adherence vs low adherence (87% vs 71%, respectively; P = .15). This is what would be expected, but itwas good to see the numbers. To me, that was the most significant finding of this study.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Of note, the slope of the viral suppression curve was clearly blunted in patients with preexisting adefovir resistance mutations (A181T or N236T), consistent with the previous study demonstrating reduced efficacy of tenofovir in adefovir-resistant patients. However, theoverall rates of suppression were similar.[23]
Patrick Marcellin, MD: All of these studies confirm data from in vitro studies regarding susceptibility of adefovirresistant viruses to other nucleos(t)ide analogues. These clinical observations are notsurprising since adefovir and tenofovir are structurally closely related drugs
Adefovir Plus Lamivudine in Lamivudine-Resistant HBV
Norah Terrault, MD, MPH: Lampertico and colleagues[26] evaluated the long-term safety and efficacy of adefovir/lamivudine combination therapy in 63 patients with lamivudine-resistant chronic hepatitis B (Similar Efficacy of Tenofovir vs Coformulated Tenofovir/Emtricitabine in HBVInfected Patients With Persistent Viremia on Adefovir). By a median follow-up of 57 months, more than 80% of patients achieved undetectable HBV DNA levels (< 35 copies/mL) and nearly all patients (90%) experienced ALT normalization. This study was not controlled but nevertheless touched on the important question of whether nucleos(t)ide analogue therapycan effectively reduce the risk of hepatocellular carcinoma. Data previously published by Liawand colleagues[27] suggest that treatment of cirrhosis does reduced the risk of hepatocellular carcinoma, but this study enrolled a more mixed population of whom 73% were cirrhotic. After a median follow-up of 24 months, 17 patients developed hepatocellular carcinoma, a higher number than would be predicted from Lau and colleagues[28] data in patients with similar rates of viral suppression. The investigators concluded that treating lamivudine-resistant patients by the addition of adefovir to ongoing lamivudine does provide clinical benefits and viral suppression, but the risk for hepatocellular carcinoma remains relatively high. The study population was relatively small—63 patients. Moreover, with a treatment duration of approximately 4 years, the lead time for liver cancer means that some of those patients may have developed cancer in the first or second year that then subsequently became detectable. It is therefore hard to interpret these data on hepatocellular carcinoma, although they do underscore the important message that providing antiviral treatment to a cirrhotic patient does not eliminate the risk of cancer.
Norah Terrault, MD, MPH: Although all the adefovir-resistant patients had documented adefovir resistance mutations, the investigators could not identify a specific mutation or pattern of mutations that was associated with a poor response and that could be, therefore, considered a tenofovir signature mutation or mutations. Even in the patients with adefovir resistance, there were no cases of virologic breakthrough observed.
Patrick Marcellin, MD: Despite the caveats of this study previously discussed, the results raise the possibility that a different potent analogue such as entecavir might be preferred in patients who developed resistance to adefovir. In vitro data support this strategy since viral strains resistant to adefovir show no cross-resistance to entecavir and less susceptibility to tenofovir.[24]
Norah Terrault, MD, MPH: Continuing our review of tenofovir use in nucleos(t)ide-experienced patients, Berg and colleagues[25] compared the safety and efficacy of tenofovir monotherapy vs coformulated tenofovir/emtricitabine in patients with persistent viremia following treatment with adefovir(Similar Efficacy of Tenofovir vs Coformulated Tenofovir/Emtricitabine in HBV-Infected Patients With Persistent Viremia on Adefovir). Coformulated tenofovir/emtricitabine iscurrently approved for the treatment of HIV and because emtricitabine has also been shown to also have efficacy against HBV, there is the potential to use a single tablet containing 2drugs with activity against HBV. Interestingly, however, there was no incremental benefit observed with the addition of emtricitabine to tenofovir, and there were no significant differences between tenofovir monotherapy and tenofovir/emtricitabine at Week 48 regarding the percentage of patients achieving HBV DNA < 400 copies/mL, normalization of ALT, or HBeAg seroconversion, and no difference in the mean reduction in HBV DNA levels.
One important aspect of the study was that the investigators analyzed the impact of adherence on treatment response. In an analysis in which both study arms were combined, there was a nonsignificant trend toward higher response rates in patients with high adherence vs low adherence (87% vs 71%, respectively; P = .15). This is what would be expected, but itwas good to see the numbers. To me, that was the most significant finding of this study.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Of note, the slope of the viral suppression curve was clearly blunted in patients with preexisting adefovir resistance mutations (A181T or N236T), consistent with the previous study demonstrating reduced efficacy of tenofovir in adefovir-resistant patients. However, theoverall rates of suppression were similar.[23]
Patrick Marcellin, MD: All of these studies confirm data from in vitro studies regarding susceptibility of adefovirresistant viruses to other nucleos(t)ide analogues. These clinical observations are notsurprising since adefovir and tenofovir are structurally closely related drugs
Adefovir Plus Lamivudine in Lamivudine-Resistant HBV
Norah Terrault, MD, MPH: Lampertico and colleagues[26] evaluated the long-term safety and efficacy of adefovir/lamivudine combination therapy in 63 patients with lamivudine-resistant chronic hepatitis B (Similar Efficacy of Tenofovir vs Coformulated Tenofovir/Emtricitabine in HBVInfected Patients With Persistent Viremia on Adefovir). By a median follow-up of 57 months, more than 80% of patients achieved undetectable HBV DNA levels (< 35 copies/mL) and nearly all patients (90%) experienced ALT normalization. This study was not controlled but nevertheless touched on the important question of whether nucleos(t)ide analogue therapycan effectively reduce the risk of hepatocellular carcinoma. Data previously published by Liawand colleagues[27] suggest that treatment of cirrhosis does reduced the risk of hepatocellular carcinoma, but this study enrolled a more mixed population of whom 73% were cirrhotic. After a median follow-up of 24 months, 17 patients developed hepatocellular carcinoma, a higher number than would be predicted from Lau and colleagues[28] data in patients with similar rates of viral suppression. The investigators concluded that treating lamivudine-resistant patients by the addition of adefovir to ongoing lamivudine does provide clinical benefits and viral suppression, but the risk for hepatocellular carcinoma remains relatively high. The study population was relatively small—63 patients. Moreover, with a treatment duration of approximately 4 years, the lead time for liver cancer means that some of those patients may have developed cancer in the first or second year that then subsequently became detectable. It is therefore hard to interpret these data on hepatocellular carcinoma, although they do underscore the important message that providing antiviral treatment to a cirrhotic patient does not eliminate the risk of cancer.
Durability of HBeAg Seroconversion With Telbivudine or Lamivudine
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Two large pivotal phase III trials compared telbivudine 600 mg/day or lamivudine 100 mg/day over a 2-year period in a predominantly HBeAg-positive population. The GLOBE study enrolled 1367 patients from 20 countries,[19] whereas Study 015[20] was conducted in China and enrolled 332 patients. Poynard and colleagues[21] conducted a retrospective combined analysis of these 2 studies evaluating the durability of HBeAg loss and HBeAg seroconversion, which occurred during therapy in 1211 HBeAg-positive patients (HBeAg Seroconversion Sustained for 52 Weeks in Chronic Hepatitis B Patients Treated With Telbivudine or Lamivudine Following Consolidation Therapy). These patients were subsequently treated for ≥ 6 months with consolidation therapy followed by treatment discontinuation because of efficacy at the discretion of the investigator. The inclusion criteria for this analysis required patients to have received at least 1 year of therapy and to have had HBV DNA 104 copies/mL at the start of tenofovir therapy, of whom 93%were lamivudine experienced and 85% were adefovir experienced. Of 113 available genotypic analyses from serum samples, YMDD mutations were present in 61 patients (54%)at baseline and adefovir resistance was detected in 19 patients (17%). Overall, 85% of patients achieved HBV DNA undetectability. The percentage of patients achieving undetectable HBV DNA (< 400 copies/mL) with tenofovir was not significantly affected by the presence of genotypic lamivudine resistance at baseline, but was significantly decreased by either pretreatment with adefovir (P < .0001) or the presence of adefovir genotypic resistanceat baseline (P < .0001). The probability of achieving undetectable HBV DNA was 90% inpatients without adefovir resistance vs 30% in adefovir-resistant patients (P = .001),suggesting that tenofovir may have a limited role in adefovir-resistant patients.
Norah Terrault, MD, MPH: This study involved only 19 adefovir-resistant patients, so caution is warranted before drawing conclusions about the efficacy of tenofovir in this setting. In addition, the median duration of tenofovir therapy in patients who did not achieve undetectable HBV DNA was 11 months vs18 months for patients who did achieve undetectable HBV DNA, which was a significant difference (P = .002). Therefore, it is possible that more patients may achieve undetectability if treated for a longer duration. Another baseline factor associated with response in patients with genotypic adefovir resistance was the mean HBV DNA level at baseline, which was 3.3 x108 copies/mL in nonresponders vs 1.4 x 108 copies/mL in responders (P = .047).
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: I do not think the small numbers involved necessarily invalidate these conclusions because the viral kinetic response curves from this study show the 2 groups separating out quickly over time, and therefore, there is no reason to think this would be different with larger numbers.
Norah Terrault, MD, MPH: I agree that separation in the viral response curves did occur early. However, it is difficult topredict how those curves might evolve with longer durations of therapy.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Two large pivotal phase III trials compared telbivudine 600 mg/day or lamivudine 100 mg/day over a 2-year period in a predominantly HBeAg-positive population. The GLOBE study enrolled 1367 patients from 20 countries,[19] whereas Study 015[20] was conducted in China and enrolled 332 patients. Poynard and colleagues[21] conducted a retrospective combined analysis of these 2 studies evaluating the durability of HBeAg loss and HBeAg seroconversion, which occurred during therapy in 1211 HBeAg-positive patients (HBeAg Seroconversion Sustained for 52 Weeks in Chronic Hepatitis B Patients Treated With Telbivudine or Lamivudine Following Consolidation Therapy). These patients were subsequently treated for ≥ 6 months with consolidation therapy followed by treatment discontinuation because of efficacy at the discretion of the investigator. The inclusion criteria for this analysis required patients to have received at least 1 year of therapy and to have had HBV DNA 104 copies/mL at the start of tenofovir therapy, of whom 93%were lamivudine experienced and 85% were adefovir experienced. Of 113 available genotypic analyses from serum samples, YMDD mutations were present in 61 patients (54%)at baseline and adefovir resistance was detected in 19 patients (17%). Overall, 85% of patients achieved HBV DNA undetectability. The percentage of patients achieving undetectable HBV DNA (< 400 copies/mL) with tenofovir was not significantly affected by the presence of genotypic lamivudine resistance at baseline, but was significantly decreased by either pretreatment with adefovir (P < .0001) or the presence of adefovir genotypic resistanceat baseline (P < .0001). The probability of achieving undetectable HBV DNA was 90% inpatients without adefovir resistance vs 30% in adefovir-resistant patients (P = .001),suggesting that tenofovir may have a limited role in adefovir-resistant patients.
Norah Terrault, MD, MPH: This study involved only 19 adefovir-resistant patients, so caution is warranted before drawing conclusions about the efficacy of tenofovir in this setting. In addition, the median duration of tenofovir therapy in patients who did not achieve undetectable HBV DNA was 11 months vs18 months for patients who did achieve undetectable HBV DNA, which was a significant difference (P = .002). Therefore, it is possible that more patients may achieve undetectability if treated for a longer duration. Another baseline factor associated with response in patients with genotypic adefovir resistance was the mean HBV DNA level at baseline, which was 3.3 x108 copies/mL in nonresponders vs 1.4 x 108 copies/mL in responders (P = .047).
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: I do not think the small numbers involved necessarily invalidate these conclusions because the viral kinetic response curves from this study show the 2 groups separating out quickly over time, and therefore, there is no reason to think this would be different with larger numbers.
Norah Terrault, MD, MPH: I agree that separation in the viral response curves did occur early. However, it is difficult topredict how those curves might evolve with longer durations of therapy.
Patrick Marcellin, MD: I agree that longer-term follow-up is necessary to see if this phenomenon is confirmed. I was surprised that HBsAg loss was observed only in HBeAg-positive patients. One might expect itto occur in HBeAg-negative patients too, as has been observed with interferon alfa–based treatments.[7] I agree, however, that a 5% HBsAg loss rate is impressive and has not been demonstrated with any other nucleos(t)ide analogue. If these rates are confirmed in subsequent studies, that could provide an advantage for using tenofovir compared with other nucleos(t)ide analogues. Moreover, if it transpires that tenofovir induces HBsAg loss and seroconversion through a different mechanism of action from interferon-based therapy, that may provide a rationale for studying the combination of both drugs, with the goal of inducing HBsAg loss in as many patients as possible, rather than keeping patients on therapy all their lives.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: It seems unlikely that simple differences in potency are sufficient to explain the phenomenon of HBsAg loss and seroconversion because although tenofovir was more potent than adefovirin these studies, comparable rates of HBV DNA suppression have been observed in separate studies with telbivudine or entecavir. Regardless of whether this observation is simply random chance or reflects some unique mechanism of action of tenofovir, this novel finding definitely bears watching closely.
Long-term Efficacy of Entecavir
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Several studies on the long-term efficacy of entecavir were presented at EASL. Leung and colleagues[14] presented 96-week data from the EARLY study of entecavir 0.5 mg/day vs adefovir 10 mg/day in 69 treatment-naive HBeAg-positive patients with high baseline HBVDNA of ≥ 108 copies/mL. The number of patients with data available at Year 2 was relatively small—29 for entecavir and 20 for adefovir—but the results were consistent with those from previous comparisons of these agents. At Week 12, the mean viral reduction from baseline was -6.23 log10 copies/mL with entecavir vs -4.42 log10 copies/mL with adefovir (P < .0001).The mean decrease in HBV DNA at Week 96 from baseline was -7.82 log10 copies/mL with entecavir vs -5.96 log10 copies/mL vs adefovir. Rates of undetectable HBV DNA for entecavir vs adefovir at Year 2 were 79% and 50%, respectively. Seroconversion rates of HBeAg were comparable (24% and 25%), and no virologic breakthroughs were reported in either arm. There were similar rates of any-grade adverse events in the entecavir and adefovir arms(83% vs 82%), but more grade 3/4 adverse events and treatment discontinuations occurred in the adefovir arm.
Patrick Marcellin, MD: Even though the number of patients was small, this head-to-head comparison of entecavir with adefovir confirms that adefovir has a less potent antiviral effect than entecavir, as was previously suggested by cross-study comparison of the pivotal studies of adefovir and entecavir.[3,4,15,16]In another small study, Mochida and colleagues[17] evaluated the safety and efficacy of entecavir 0.5 mg/day in 68 treatment-naive Japanese patients enrolled in 3 studies (ETV-047,ETV-053, and ETV-060) (Long-term Entecavir Treatment Safe and Effective in Japanese Treatment-Naive Chronic Hepatitis B Patients Through Year 3). The proportion of patients with HBV DNA < 400 copies/mL increased over time, reaching 87% after 3 years. Entecavir continued to show a high barrier to resistance, with a 1.7% cumulative rate of resistance or resistance with subsequent virologic breakthrough at Year 3. This study confirmed the findings from the pivotal studies. However, a general limitation of the pivotal studies was the difficulty in interpreting the exact incidence of entecavir resistance as the long-term follow-up of those studies (ETV-022) restricted the calculation to a subgroup of patients receiving therapy. It is, therefore, reassuring to have another independent long-term follow-up of patients on entecavir confirming the low rate of cumulative resistance. However, the number of patients in this analysis is small and the follow-up duration is currently only 3 years, whereas data from the pivotal studies through 5 years of follow-up have recently been presented.[18]
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: I agree with Dr. Marcellin. Some have been critical of the resistance data from the long-term entecavir rollover treatment study because of the higher dose of entecavir used (1.0 vs 0.5mg) and the fact that not all treated patients in the pivotal trials entered the rollover long-term treatment study. However, the fact that the incidence of resistance in this study, albeit with smaller sample size, is very similar to that previously reported in the rollover study confirms the very low resistance risk with extended treatment with entecavir in nucleos(t)ide-naïve patients.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: It seems unlikely that simple differences in potency are sufficient to explain the phenomenon of HBsAg loss and seroconversion because although tenofovir was more potent than adefovirin these studies, comparable rates of HBV DNA suppression have been observed in separate studies with telbivudine or entecavir. Regardless of whether this observation is simply random chance or reflects some unique mechanism of action of tenofovir, this novel finding definitely bears watching closely.
Long-term Efficacy of Entecavir
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Several studies on the long-term efficacy of entecavir were presented at EASL. Leung and colleagues[14] presented 96-week data from the EARLY study of entecavir 0.5 mg/day vs adefovir 10 mg/day in 69 treatment-naive HBeAg-positive patients with high baseline HBVDNA of ≥ 108 copies/mL. The number of patients with data available at Year 2 was relatively small—29 for entecavir and 20 for adefovir—but the results were consistent with those from previous comparisons of these agents. At Week 12, the mean viral reduction from baseline was -6.23 log10 copies/mL with entecavir vs -4.42 log10 copies/mL with adefovir (P < .0001).The mean decrease in HBV DNA at Week 96 from baseline was -7.82 log10 copies/mL with entecavir vs -5.96 log10 copies/mL vs adefovir. Rates of undetectable HBV DNA for entecavir vs adefovir at Year 2 were 79% and 50%, respectively. Seroconversion rates of HBeAg were comparable (24% and 25%), and no virologic breakthroughs were reported in either arm. There were similar rates of any-grade adverse events in the entecavir and adefovir arms(83% vs 82%), but more grade 3/4 adverse events and treatment discontinuations occurred in the adefovir arm.
Patrick Marcellin, MD: Even though the number of patients was small, this head-to-head comparison of entecavir with adefovir confirms that adefovir has a less potent antiviral effect than entecavir, as was previously suggested by cross-study comparison of the pivotal studies of adefovir and entecavir.[3,4,15,16]In another small study, Mochida and colleagues[17] evaluated the safety and efficacy of entecavir 0.5 mg/day in 68 treatment-naive Japanese patients enrolled in 3 studies (ETV-047,ETV-053, and ETV-060) (Long-term Entecavir Treatment Safe and Effective in Japanese Treatment-Naive Chronic Hepatitis B Patients Through Year 3). The proportion of patients with HBV DNA < 400 copies/mL increased over time, reaching 87% after 3 years. Entecavir continued to show a high barrier to resistance, with a 1.7% cumulative rate of resistance or resistance with subsequent virologic breakthrough at Year 3. This study confirmed the findings from the pivotal studies. However, a general limitation of the pivotal studies was the difficulty in interpreting the exact incidence of entecavir resistance as the long-term follow-up of those studies (ETV-022) restricted the calculation to a subgroup of patients receiving therapy. It is, therefore, reassuring to have another independent long-term follow-up of patients on entecavir confirming the low rate of cumulative resistance. However, the number of patients in this analysis is small and the follow-up duration is currently only 3 years, whereas data from the pivotal studies through 5 years of follow-up have recently been presented.[18]
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: I agree with Dr. Marcellin. Some have been critical of the resistance data from the long-term entecavir rollover treatment study because of the higher dose of entecavir used (1.0 vs 0.5mg) and the fact that not all treated patients in the pivotal trials entered the rollover long-term treatment study. However, the fact that the incidence of resistance in this study, albeit with smaller sample size, is very similar to that previously reported in the rollover study confirms the very low resistance risk with extended treatment with entecavir in nucleos(t)ide-naïve patients.
Norah Terrault, MD, MPH: HBsAg titer tests are not currently commercially available in the United States. However, that would presumably change if this association is confirmed and becomes important in predicting response to peginterferon. It would be of particular interest if the investigators had been able to identify baseline predictors of HBsAg decline, which might allow us to identify a target group who would respond well to peginterferon alfa treatment and avoid the unnecessary 24-48 week treatment in patients who are unlikely to achieve a response to this treatment. It would also be particularly helpful if the ideal duration of peginterferon alfa treatment in HBeAg-negative patients could be better defined as this issue is not currently clear.
Patrick Marcellin, MD: In a related abstract, Brunetto and colleagues[11] also evaluated the association between HBsAg level reduction and HBV DNA level at end of treatment. Among patients receiving peginterferon, the mean decline in HBsAg level from baseline to Week 48 was significantly greater in patients with HBV DNA ≤ 400 copies/mL at Week 72 vs those with HBV DNA > 400copies/mL at Week 72 (1.077 vs 0.263 log10 IU/mL, respectively; P < .001). This relationship only held true for peginterferon because HBsAg levels did not decline with lamivudine, regardless of the degree of HBV DNA suppression.
Tenofovir vs Adefovir in Chronic Hepatitis B
Patrick Marcellin, MD: Updates on 2 pivotal large, randomized, controlled trials comparing tenofovir vs adefovir in treatment-naive patients with chronic hepatitis B were presented at EASL. Study 102 enrolled375 patients with HBeAg-negative chronic hepatitis B (Rapid, Persistent HBV DNA Suppression With Tenofovir Treatment in HBeAg-Negative Chronic Hepatitis B)[12] whereas Study 103 enrolled 266 patients with HBeAg-positive chronic hepatitis B (Continued Efficacy With Tenofovir Through Week 72 of Therapy in HBeAg-Positive Patients).[13] In both studies, patients were randomized to 48 weeks of tenofovir or adefovir; after 48 weeks, all patients on adefovir were switched to tenofovir regardless of response to adefovir. Forty-eight–week data from these studies were previously presented at the 2007 Annual Meeting of the American Association for the Study of Liver Diseases, in which superior potency with tenofovir was demonstrated at Week 48 in both HBeAg-positive patients (A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HbeAgpositive chronic hepatitis B (CHB)[1] and HBeAg-negative patients (A randomized, doubleblind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg-negative chronic hepatitis B (CHB)).[2] Tenofovir was associated with HBV DNA levels< 400 copies/mL at Week 48 in 93% of HBeAg-negative patients and 76% of HBeAg-positive patients (compared with 63% of HBeAg-negative and 13% of HBeAg-positive patients treated with adefovir). This high rate of undetectable HBV DNA at 48 weeks is comparable with that seen with entecavir.[3,4] Both tenofovir and adefovir were associated with biochemical responses and histologic improvement. Based on these results, tenofovir was recently approved for the treatment of chronic hepatitis B virus (HBV) infection in Europe.
The updated analyses present at EASL provide an additional 6 months of follow-up since the previous reports and also encompass 24 weeks of tenofovir therapy in patients who initially received 48 weeks of adefovir. Among the patients initially randomized to tenofovir, the investigators showed that the proportions with HBV DNA < 400 copies/mL were maintained in91% of HBeAg-negative patients and 79% of HBeAg-positive patients between Week 48 and Week 72. No cases of resistance were noted in HBeAg-positive or HBeAg-negative patients, and no new safety findings were reported. Although there had been some concern about the potential for nephrotoxicity, this was not observed at a significant rate. Importantly, rates of viral suppression increased among patients who initially received adefovir for 48 weeks and then switched to tenofovir. By Week 72, 88% of HBeAg-negative patients and 76% of HBeAg-positive switch patients had HBV DNA < 400 copies/mL, which was not significantly different from the rates of suppression observed in patients who were treated with tenofovir from the study outset.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: The high rate of response to tenofovir in patients initially treated with adefovir is an important finding from these extended studies, especially for those patients who are suboptimal responders to adefovir after 48 weeks of treatment. In HBeAg-negative patients, there were no significant differences in rates of alanine aminotransferase (ALT) normalization or adverse events between those assigned to continuous tenofovir vs those who switched from adefovirto tenofovir. In HBeAg-positive patients, there were no significant differences in HBeAg loss and seroconversion rates between these groups, but higher percentages of patients who received continuous tenofovir vs those who switched therapy achieved normal serum ALT levels at Week 72 (77% vs 61%, respectively; P = .014) and HBsAg loss at Week 64 (5% vs0%, respectively; P = .004). Otherwise, it appears that exposure to 48 weeks of adefovir therapy before the switch to tenofovir did not place these patients at any particular disadvantage in follow-up to date. The rate of HBsAg loss was notable in the HBeAg-positive study. Among these patients randomized to tenofovir from the outset, rates of HBsAg loss were 3% at Week 48[1] and, as mentioned, 5% at Week 64. With the exception of interferon alfa–based treatments, no other treatment has achieved comparable rates of HBsAg loss. Rates of HBsAg seroconversion among patients receiving tenofovir were 1% at Week 48[1] and 2% at Week 64, which are quite remarkable. By contrast, none of the HBeAg-positive patients initially treated with adefovir had HBsAg loss or seroconversion. It will be important to confirm these results to demonstrate whether this is a true treatment effect of tenofovir or simply a chance occurrence.
Patrick Marcellin, MD: In a related abstract, Brunetto and colleagues[11] also evaluated the association between HBsAg level reduction and HBV DNA level at end of treatment. Among patients receiving peginterferon, the mean decline in HBsAg level from baseline to Week 48 was significantly greater in patients with HBV DNA ≤ 400 copies/mL at Week 72 vs those with HBV DNA > 400copies/mL at Week 72 (1.077 vs 0.263 log10 IU/mL, respectively; P < .001). This relationship only held true for peginterferon because HBsAg levels did not decline with lamivudine, regardless of the degree of HBV DNA suppression.
Tenofovir vs Adefovir in Chronic Hepatitis B
Patrick Marcellin, MD: Updates on 2 pivotal large, randomized, controlled trials comparing tenofovir vs adefovir in treatment-naive patients with chronic hepatitis B were presented at EASL. Study 102 enrolled375 patients with HBeAg-negative chronic hepatitis B (Rapid, Persistent HBV DNA Suppression With Tenofovir Treatment in HBeAg-Negative Chronic Hepatitis B)[12] whereas Study 103 enrolled 266 patients with HBeAg-positive chronic hepatitis B (Continued Efficacy With Tenofovir Through Week 72 of Therapy in HBeAg-Positive Patients).[13] In both studies, patients were randomized to 48 weeks of tenofovir or adefovir; after 48 weeks, all patients on adefovir were switched to tenofovir regardless of response to adefovir. Forty-eight–week data from these studies were previously presented at the 2007 Annual Meeting of the American Association for the Study of Liver Diseases, in which superior potency with tenofovir was demonstrated at Week 48 in both HBeAg-positive patients (A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HbeAgpositive chronic hepatitis B (CHB)[1] and HBeAg-negative patients (A randomized, doubleblind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg-negative chronic hepatitis B (CHB)).[2] Tenofovir was associated with HBV DNA levels< 400 copies/mL at Week 48 in 93% of HBeAg-negative patients and 76% of HBeAg-positive patients (compared with 63% of HBeAg-negative and 13% of HBeAg-positive patients treated with adefovir). This high rate of undetectable HBV DNA at 48 weeks is comparable with that seen with entecavir.[3,4] Both tenofovir and adefovir were associated with biochemical responses and histologic improvement. Based on these results, tenofovir was recently approved for the treatment of chronic hepatitis B virus (HBV) infection in Europe.
The updated analyses present at EASL provide an additional 6 months of follow-up since the previous reports and also encompass 24 weeks of tenofovir therapy in patients who initially received 48 weeks of adefovir. Among the patients initially randomized to tenofovir, the investigators showed that the proportions with HBV DNA < 400 copies/mL were maintained in91% of HBeAg-negative patients and 79% of HBeAg-positive patients between Week 48 and Week 72. No cases of resistance were noted in HBeAg-positive or HBeAg-negative patients, and no new safety findings were reported. Although there had been some concern about the potential for nephrotoxicity, this was not observed at a significant rate. Importantly, rates of viral suppression increased among patients who initially received adefovir for 48 weeks and then switched to tenofovir. By Week 72, 88% of HBeAg-negative patients and 76% of HBeAg-positive switch patients had HBV DNA < 400 copies/mL, which was not significantly different from the rates of suppression observed in patients who were treated with tenofovir from the study outset.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: The high rate of response to tenofovir in patients initially treated with adefovir is an important finding from these extended studies, especially for those patients who are suboptimal responders to adefovir after 48 weeks of treatment. In HBeAg-negative patients, there were no significant differences in rates of alanine aminotransferase (ALT) normalization or adverse events between those assigned to continuous tenofovir vs those who switched from adefovirto tenofovir. In HBeAg-positive patients, there were no significant differences in HBeAg loss and seroconversion rates between these groups, but higher percentages of patients who received continuous tenofovir vs those who switched therapy achieved normal serum ALT levels at Week 72 (77% vs 61%, respectively; P = .014) and HBsAg loss at Week 64 (5% vs0%, respectively; P = .004). Otherwise, it appears that exposure to 48 weeks of adefovir therapy before the switch to tenofovir did not place these patients at any particular disadvantage in follow-up to date. The rate of HBsAg loss was notable in the HBeAg-positive study. Among these patients randomized to tenofovir from the outset, rates of HBsAg loss were 3% at Week 48[1] and, as mentioned, 5% at Week 64. With the exception of interferon alfa–based treatments, no other treatment has achieved comparable rates of HBsAg loss. Rates of HBsAg seroconversion among patients receiving tenofovir were 1% at Week 48[1] and 2% at Week 64, which are quite remarkable. By contrast, none of the HBeAg-positive patients initially treated with adefovir had HBsAg loss or seroconversion. It will be important to confirm these results to demonstrate whether this is a true treatment effect of tenofovir or simply a chance occurrence.
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