Hepatitis B Management in Clinical Practice
Guidelines recommend all patients should be monitored closely during treatment to evaluate response, tolerability, and adherence. Patients receiving IFN require frequent clinical and laboratory monitoring. Guidelines recommend monitoring patients receiving IFN/PEG-IFN therapy with blood counts and a liver panel every 4 weeks initially and then every 4 to 12 weeks. The AASLD and EASL also recommend thyroid-stimulating hormone testing every 12 weeks. The AASLD and APASL recommend monitoring HBV DNA levels every 12 weeks, and the EASL recommends HBV DNA testing at weeks 24 and 48. The EASL guideline also recommends monitoring HBsAg levels at week 12. For patients who initially were HBeAg positive, the AASLD and EASL recommend HBeAg and hepatitis B e antibody (anti-HBe) testing every 24 weeks during treatment, and the APASL recommends testing every 12 weeks. After completion of IFN/PEG-IFN therapy, blood counts, liver panel, HBeAg, and anti-HBe if initially HBeAg-positive should be tested every 12 weeks during the first 24 weeks. In the post-treatment period, the APASL recommends monitoring ALT and HBV DNA levels monthly for the first 3 months and then every 3 months in the first year. The AASLD and EASL recommend HBsAg testing every 6 to 12 months in patients with HBeAg seroconversion and undetectable HBV DNA levels. Patients receiving NUC should have their renal function checked initially to ensure appropriate dosing. Patients who are at risk of impaired renal function should have their renal function monitored regularly, particularly if they are receiving adefovir or tenofovir because of the risk of nephrotoxicity. A phase 3 trial of tenofovir showed that only 1% of patients had an increase in serum creatinine level after 5 years treatment.
All guidelines recommend administration of PEG-IFN for 48 to 52 weeks in both HBeAg-positive and HBeAg-negative patients. There is some variation in recommendations regarding when NUC can be stopped. All guidelines recommend that in HBeAg-positive patients, NUC can be stopped when the patient has achieved HBeAg seroconversion and undetectable HBV DNA levels and completed 6 to 12 months of consolidation treatment. Because of the high rate of relapse after withdrawal of NUC and the persistence of HBV replication in some patients despite HBeAg seroconversion, the EASL recommends continuing NUC until HBsAg loss in patients with severe fibrosis and cirrhosis. Given the low rate of NUC-induced HBsAg loss, most of these patients will remain on treatment indefinitely.
In HBeAg-negative patients, the EASL and AASLD agree that NUC should be continued until the patient has achieved HBsAg clearance; however, the APASL recommends considering withdrawal of treatment in HBeAg-negative patients who have been treated for 2 years with undetectable HBV DNA levels documented on 3 separate measurements 6 months apart. The basis for the APASL recommendation is related mainly to cost.
All guidelines recommend lifelong NUC in patients with cirrhosis before treatment; however, discontinuation of treatment may be considered in patients who had compensated cirrhosis if they achieved HBsAg loss. After withdrawal of treatment, patients need to be monitored closely for relapse so that treatment can be re-instituted promptly if needed.
We follow the guidelines regarding monitoring of patients on treatment. In patients receiving IFN, we continue treatment if there is an ALT flare unless the patient is symptomatic or bilirubin level is increased. In patients receiving NUC, we monitor serum HBV DNA levels less often now than in the past when we were using drugs with a lower barrier to resistance. We test serum HBV DNA levels every 3 months until it becomes undetectable and every 6 months thereafter. We check HBeAg and anti-HBe levels every 6 to 12 months in patients who are HBeAg positive, and we check HBsAg every year in patients who are HBeAg negative with undetectable serum HBV DNA levels.
For patients receiving NUC, we continue treatment indefinitely in those who had cirrhosis before treatment and in many older patients (>60 y) unless they lose HBsAg. For noncirrhotic HBeAg-positive patients, we discontinue treatment after 12 months of consolidation therapy because of reports of low durability of NUC-induced HBeAg seroconversion and the encouraging results of 12 months of consolidation therapy in one study. For noncirrhotic HBeAg-negative patients, we discontinue treatment after confirmed HBsAg loss, but this has happened to only 1 patient in the past 5 years. We have, however, discontinued treatment in several patients who can no longer afford or are no longer willing to commit to long-term treatment if they have completed at least 5 years of treatment with undetectable HBV DNA levels in the past 3 years. Although all patients experienced virologic relapse after treatment was stopped, most patients continue to have low HBV DNA levels and normal ALT levels and have not required resumption of treatment, confirming the observations of Hadziyannis et al.
Monitoring During Treatment and Deciding When to Stop Treatment
Guidelines recommend all patients should be monitored closely during treatment to evaluate response, tolerability, and adherence. Patients receiving IFN require frequent clinical and laboratory monitoring. Guidelines recommend monitoring patients receiving IFN/PEG-IFN therapy with blood counts and a liver panel every 4 weeks initially and then every 4 to 12 weeks. The AASLD and EASL also recommend thyroid-stimulating hormone testing every 12 weeks. The AASLD and APASL recommend monitoring HBV DNA levels every 12 weeks, and the EASL recommends HBV DNA testing at weeks 24 and 48. The EASL guideline also recommends monitoring HBsAg levels at week 12. For patients who initially were HBeAg positive, the AASLD and EASL recommend HBeAg and hepatitis B e antibody (anti-HBe) testing every 24 weeks during treatment, and the APASL recommends testing every 12 weeks. After completion of IFN/PEG-IFN therapy, blood counts, liver panel, HBeAg, and anti-HBe if initially HBeAg-positive should be tested every 12 weeks during the first 24 weeks. In the post-treatment period, the APASL recommends monitoring ALT and HBV DNA levels monthly for the first 3 months and then every 3 months in the first year. The AASLD and EASL recommend HBsAg testing every 6 to 12 months in patients with HBeAg seroconversion and undetectable HBV DNA levels. Patients receiving NUC should have their renal function checked initially to ensure appropriate dosing. Patients who are at risk of impaired renal function should have their renal function monitored regularly, particularly if they are receiving adefovir or tenofovir because of the risk of nephrotoxicity. A phase 3 trial of tenofovir showed that only 1% of patients had an increase in serum creatinine level after 5 years treatment.
All guidelines recommend administration of PEG-IFN for 48 to 52 weeks in both HBeAg-positive and HBeAg-negative patients. There is some variation in recommendations regarding when NUC can be stopped. All guidelines recommend that in HBeAg-positive patients, NUC can be stopped when the patient has achieved HBeAg seroconversion and undetectable HBV DNA levels and completed 6 to 12 months of consolidation treatment. Because of the high rate of relapse after withdrawal of NUC and the persistence of HBV replication in some patients despite HBeAg seroconversion, the EASL recommends continuing NUC until HBsAg loss in patients with severe fibrosis and cirrhosis. Given the low rate of NUC-induced HBsAg loss, most of these patients will remain on treatment indefinitely.
In HBeAg-negative patients, the EASL and AASLD agree that NUC should be continued until the patient has achieved HBsAg clearance; however, the APASL recommends considering withdrawal of treatment in HBeAg-negative patients who have been treated for 2 years with undetectable HBV DNA levels documented on 3 separate measurements 6 months apart. The basis for the APASL recommendation is related mainly to cost.
All guidelines recommend lifelong NUC in patients with cirrhosis before treatment; however, discontinuation of treatment may be considered in patients who had compensated cirrhosis if they achieved HBsAg loss. After withdrawal of treatment, patients need to be monitored closely for relapse so that treatment can be re-instituted promptly if needed.
Our Practice
We follow the guidelines regarding monitoring of patients on treatment. In patients receiving IFN, we continue treatment if there is an ALT flare unless the patient is symptomatic or bilirubin level is increased. In patients receiving NUC, we monitor serum HBV DNA levels less often now than in the past when we were using drugs with a lower barrier to resistance. We test serum HBV DNA levels every 3 months until it becomes undetectable and every 6 months thereafter. We check HBeAg and anti-HBe levels every 6 to 12 months in patients who are HBeAg positive, and we check HBsAg every year in patients who are HBeAg negative with undetectable serum HBV DNA levels.
For patients receiving NUC, we continue treatment indefinitely in those who had cirrhosis before treatment and in many older patients (>60 y) unless they lose HBsAg. For noncirrhotic HBeAg-positive patients, we discontinue treatment after 12 months of consolidation therapy because of reports of low durability of NUC-induced HBeAg seroconversion and the encouraging results of 12 months of consolidation therapy in one study. For noncirrhotic HBeAg-negative patients, we discontinue treatment after confirmed HBsAg loss, but this has happened to only 1 patient in the past 5 years. We have, however, discontinued treatment in several patients who can no longer afford or are no longer willing to commit to long-term treatment if they have completed at least 5 years of treatment with undetectable HBV DNA levels in the past 3 years. Although all patients experienced virologic relapse after treatment was stopped, most patients continue to have low HBV DNA levels and normal ALT levels and have not required resumption of treatment, confirming the observations of Hadziyannis et al.
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