Editorial

Boxed Warning, HCV Guidelines Give Impetus for HBV Testing, Monitoring

Just when HCV therapy seemed as if it has never been more straightforward, we have witnessed the emergence of an unexpected caveat regarding HCV-infected patients with concomitant hepatitis B virus infection or, seemingly, even markers of what most people would have regarded as prior infection that has resolved.

A recent update to the AASLD/IDSA HCV Guidelines on September 16, 2016, (found at HCVGuidelines.com) recommended assessment for hepatitis B infection in all patients with hepatitis C infection, followed by a highly publicized Safety Communication from the FDA on October 4, 2016, with a concomitant black box warning about direct-acting antiviral HCV therapy implicated in HBV reactivation.

Ira M. Jacobson

Many of us did not know what to make of the warning. I, for example, have never seen a reactivation of HBV during DAA therapy and neither have the majority of my colleagues with whom I’ve discussed the issue. But, while the concern may seem exaggerated to those of us who’ve treated hundreds or even thousands of patients without experiencing problems, it’s not negligible. The dilemma for us as clinicians is what to do with this information.

To be sure, HBV testing prior to HCV therapy has been a standard measure to eliminate other causes of liver disease and to ensure immunization of patients with HCV against HBV and, for that matter, hepatitis A. There’s nothing new about the recommendation to test HCV-infected patients for HBV. What’s new is the added rationale put forth by the boxed warning in approved HCV regimens. If reactivations are at risk of occurring, we need to know about it so we can either offer preventive therapy or monitor appropriately for early detection. If for any reason a clinician has not implemented this testing, the warning is a wake-up call.

The boxed warning is based on 24 cases of HBV reactivation reported to FDA and from the published literature in HCV/HBV co-infected patients treated with HCV DAAs during the 31 months from November 2013 to July 2016, including two deaths and a third patient who required a liver transplantation. Most of the cases occurred within 4 to 8 weeks of initiating therapy.

So far, we don’t have strong evidence to believe this is an issue pertaining to patients who have completed therapy or who have achieved sustained virologic response at the 12 week timepoint after the end of treatment. If cases of reactivation were to appear at that late date, it would add to the concern.

Although a reading of the FDA Safety Communication leaves one wanting more details about these cases, it does provide us with enough information to underscore considerable heterogeneity in the patients with hepatitis B reactivation. Of the 24 patients, seven had detectable HBV DNA and were presumably HBsAg-positive; four had positive hepatitis B surface antigen (HBsAg) and undetectable HBV DNA; and three had both undetectable HBsAg and undetectable HBV DNA. The status of the remaining 10 was unknown.

The patients with undetectable HBsAg and undetectable viral load — even though there were “only” three — is perhaps of greatest concern because such patients are by far more common than those who are HBsAg-positive. Our experience with reactivation in patients with hepatitis B core antibody without HBsAg has thus far mostly been limited to patients who take certain types of immunosuppressive drugs like rituximab or those who are profoundly immune suppressed in settings such as bone marrow transplantation.

If hepatitis B can reactivate with similarly serious consequences with HCV DAA therapy even in patients with anti-HBc alone, whether with or without anti-HBs, we’re going to have to be cautious with a large number of patients. So the question is: Right now, how should one interpret these revised guidelines and new warning?

The revised AASLD/IDSA Guidelines offer what seems a very reasonable group of recommendations. The Guidelines reiterate the need to test all patients initiating HCV DAA therapy for HBsAg, anti-HBs, and anti-HBc, with HBV vaccination of all susceptible individuals. Patients who are HBsAg positive should have a quantitative test for HBV DNA and receive HBV antiviral therapy before or simultaneous with initiation of HCV DAAs if they meet the criteria for treatment of active HBV infection set forth in the AASLD Guidelines for Treatment of Chronic Hepatitis B.

The HCV Guidelines state that patients with low or undetectable HBV DNA levels should be monitored for HBV reactivation and treated if the aforementioned criteria are then met. In my practice, I might consider giving a top-line HBV antiviral regardless of viral level if HBV DNA is detectable, especially in patients with advanced fibrosis.

Finally, the AASLD Guidelines state “there are insufficient data to provide clear recommendations for the monitoring of patients testing positive either for anti-HBc alone (isolated anti-HBc) or for anti-HBs and anti-HBc (immune recovery).” At present, my perspective is that while we must acknowledge the apparent reality of the potential for HBV reactivation in such patients, the incidence must be so low that assays for viral levels could be limited to patients whose ALT levels fail to normalize or rise as HCV replication is suppressed.

This FDA boxed warning underscores the importance of doing something that we’re supposed to be doing already, but with newly understood ramifications.

– Ira M. Jacobson

HCV Next

Co-Chief Medical Editor

Just when HCV therapy seemed as if it has never been more straightforward, we have witnessed the emergence of an unexpected caveat regarding HCV-infected patients with concomitant hepatitis B virus infection or, seemingly, even markers of what most people would have regarded as prior infection that has resolved.

A recent update to the AASLD/IDSA HCV Guidelines on September 16, 2016, (found at HCVGuidelines.com) recommended assessment for hepatitis B infection in all patients with hepatitis C infection, followed by a highly publicized Safety Communication from the FDA on October 4, 2016, with a concomitant black box warning about direct-acting antiviral HCV therapy implicated in HBV reactivation.

Ira M. Jacobson

Many of us did not know what to make of the warning. I, for example, have never seen a reactivation of HBV during DAA therapy and neither have the majority of my colleagues with whom I’ve discussed the issue. But, while the concern may seem exaggerated to those of us who’ve treated hundreds or even thousands of patients without experiencing problems, it’s not negligible. The dilemma for us as clinicians is what to do with this information.

To be sure, HBV testing prior to HCV therapy has been a standard measure to eliminate other causes of liver disease and to ensure immunization of patients with HCV against HBV and, for that matter, hepatitis A. There’s nothing new about the recommendation to test HCV-infected patients for HBV. What’s new is the added rationale put forth by the boxed warning in approved HCV regimens. If reactivations are at risk of occurring, we need to know about it so we can either offer preventive therapy or monitor appropriately for early detection. If for any reason a clinician has not implemented this testing, the warning is a wake-up call.

The boxed warning is based on 24 cases of HBV reactivation reported to FDA and from the published literature in HCV/HBV co-infected patients treated with HCV DAAs during the 31 months from November 2013 to July 2016, including two deaths and a third patient who required a liver transplantation. Most of the cases occurred within 4 to 8 weeks of initiating therapy.

So far, we don’t have strong evidence to believe this is an issue pertaining to patients who have completed therapy or who have achieved sustained virologic response at the 12 week timepoint after the end of treatment. If cases of reactivation were to appear at that late date, it would add to the concern.

Although a reading of the FDA Safety Communication leaves one wanting more details about these cases, it does provide us with enough information to underscore considerable heterogeneity in the patients with hepatitis B reactivation. Of the 24 patients, seven had detectable HBV DNA and were presumably HBsAg-positive; four had positive hepatitis B surface antigen (HBsAg) and undetectable HBV DNA; and three had both undetectable HBsAg and undetectable HBV DNA. The status of the remaining 10 was unknown.

The patients with undetectable HBsAg and undetectable viral load — even though there were “only” three — is perhaps of greatest concern because such patients are by far more common than those who are HBsAg-positive. Our experience with reactivation in patients with hepatitis B core antibody without HBsAg has thus far mostly been limited to patients who take certain types of immunosuppressive drugs like rituximab or those who are profoundly immune suppressed in settings such as bone marrow transplantation.

If hepatitis B can reactivate with similarly serious consequences with HCV DAA therapy even in patients with anti-HBc alone, whether with or without anti-HBs, we’re going to have to be cautious with a large number of patients. So the question is: Right now, how should one interpret these revised guidelines and new warning?

The revised AASLD/IDSA Guidelines offer what seems a very reasonable group of recommendations. The Guidelines reiterate the need to test all patients initiating HCV DAA therapy for HBsAg, anti-HBs, and anti-HBc, with HBV vaccination of all susceptible individuals. Patients who are HBsAg positive should have a quantitative test for HBV DNA and receive HBV antiviral therapy before or simultaneous with initiation of HCV DAAs if they meet the criteria for treatment of active HBV infection set forth in the AASLD Guidelines for Treatment of Chronic Hepatitis B.

The HCV Guidelines state that patients with low or undetectable HBV DNA levels should be monitored for HBV reactivation and treated if the aforementioned criteria are then met. In my practice, I might consider giving a top-line HBV antiviral regardless of viral level if HBV DNA is detectable, especially in patients with advanced fibrosis.

Finally, the AASLD Guidelines state “there are insufficient data to provide clear recommendations for the monitoring of patients testing positive either for anti-HBc alone (isolated anti-HBc) or for anti-HBs and anti-HBc (immune recovery).” At present, my perspective is that while we must acknowledge the apparent reality of the potential for HBV reactivation in such patients, the incidence must be so low that assays for viral levels could be limited to patients whose ALT levels fail to normalize or rise as HCV replication is suppressed.

This FDA boxed warning underscores the importance of doing something that we’re supposed to be doing already, but with newly understood ramifications.

– Ira M. Jacobson

HCV Next

Co-Chief Medical Editor