HBV: React Before the Virus Does

The Key to Preventing HBV Reactivation

William F. Balistreri, MD


April 01, 2015

In This Article

Prevention of HBV Reactivation: What Can Be Done?

The recently released official recommendations were prepared in an effort to help investigators and practicing medical providers in addressing key areas with respect to reactivation of HBV.[2,3,4] There is good evidence to support routine screening and careful monitoring of all patients for hepatitis B prior to undergoing chemotherapy or immunosuppressive treatment because the prompt administration of antiviral treatment will reduce the risk for severe or fatal reactivation of hepatitis B. However, the recent AASLD/AGA reports indicated that several aspects of HBV reactivation prevention remain unclear, including:

  • The optimal population to screen;

  • In whom to use prophylaxis with HBV therapeutic agents;

  • The best specific therapeutic agent to use;

  • The duration of prophylaxis; and

  • The type and duration of monitoring if prophylaxis is not used in those at risk.[3,4]

Experts emphasize that further advances will benefit from close interactions between various medical specialties, regulatory agencies, and researchers.[2,3,4]

Universal or Risk-Based Screening?

The AASLD/AGA reports clearly summarize the data supporting the recommendation that all patients undergoing chemotherapy, immunosuppressive therapy, or stem cell or solid-organ transplantation be screened for active or previous HBV infection by testing for HBsAg and anti-HBc in serum.[2,3,4] The reports also recognize factors that are impediments to screening in this patient population and include the cost of testing, the remote possibility of false-positive screening results, and the potential emotional and financial impact of a new diagnosis of HBV infection. Both documents provide clinical decision support tools and algorithm(s) for guidance.[2,3,4]

The reports recommend that patients who are found to be HBsAg positive should start appropriate antiviral therapy to prevent reactivation. Those who have recovered from hepatitis B will benefit from antiviral therapy in certain circumstances because of the risks associated with "reverse seroconversion." If patients develop reactivation of HBV while on therapy with ofatumumab or rituximab, that treatment should be immediately discontinued and appropriate treatment for hepatitis B initiated.

The Role of Antiviral Agents

Given the high rates of HBV reactivation, the role of antiviral prophylaxis has been explored. Well-tolerated, orally administered antiviral agents active against HBV have proven to be effective in the treatment and prevention of reactivation. Several prospective, randomized controlled trials of antiviral therapy designed to prevent HBV reactivation document reduced rates of HBV reactivation and hepatitis in patients who are appropriately recognized and treated.[17,28,29,38,39,40,41,42,43,44,45,46]

Lamivudine. Lamivudine (Epivir®), a nucleoside analogue with potent antiviral activity against HBV, is considered safe, well-tolerated, and inexpensive. In a review of 14 clinical trials of lamivudine in the prevention of HBV reactivation during chemotherapy of 636 HBsAg-positive patients with lymphoma, the rate of HBV reactivation, the incidence of hepatitis, and the incidence of hepatitis owing to HBV reactivation in patients with lamivudine prophylaxis was significantly lower than in those who received no prophylaxis.[2,28,47] Moreover, patients given prophylactic lamivudine had significant reductions in overall mortality and mortality attributable to HBV reactivation compared with control groups, along with a trend toward a reduced incidence of chemotherapy disruption. The key concern demonstrated in clinical trials of lamivudine is the frequent emergence of resistant viral variants after prolonged use.[2,48]

Other Antiviral Agents

The AGA strongly recommends the use of antivirals that have a high barrier to resistance, in preference to lamivudine, in most patients. However, the evidence comparing various antivirals is weak, and the drugs vary considerably in price.[2,3,4] Agents associated with a lower risk for antiviral drug resistance (telbivudine [Tyzeka®] and entecavir [Baraclude®]) may replace lamivudine as first-line agents to treat chronic hepatitis B.[2,41,48] Tenofovir (Viread®) and adefovir (Hepsera®) would likely also be effective prophylaxis agents; however, there are no published clinical trials.[49]

Telbivudine. Telbivudine administered concurrently with the initiation of chemotherapy effectively reduced HBV reactivation in HBsAg-positive patients with lymphoma; the efficacy was independent of the baseline HBV viral loads.[50] The rate of HBV reactivation in telbivudine recipients was 12%, compared with 18% and 75% in patients treated with rituximab-based chemotherapy and rituximab maintenance therapy, respectively. The rate of fulminant hepatitis was 7%.

Entecavir. Hsu and colleagues[51] prospectively searched for HBV reactivation in 150 newly diagnosed patients with lymphoma who had resolved HBV infection and were to receive R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone)-based chemotherapy. Patients with documented HBV reactivation (11%) were treated with entecavir for 48 weeks. The time between evidence of reactivation and hepatitis flare was 49 days; despite the prompt administration of entecavir, severe hepatitis occurred in more than 40% of patients with a flare. This indicates that initiation of entecavir after viral replication has begun, even with early recognition, may not prevent development of hepatitis.

Entecavir vs lamivudine. Huang and colleagues[52] compared the efficacy of entecavir and lamivudine in preventing HBV reactivation in untreated patients with B-cell lymphoma. Patients who were seropositive for HBsAg and had normal liver enzymes, low serum HBV DNA levels, and no previous antiviral therapy were randomly assigned to receive daily entecavir or lamivudine beginning 1 week before the initiation of R-CHOP treatment, continuing to 6 months after completion of chemotherapy. The incidence of HBV-associated hepatitis was significantly lower in the entecavir recipients, as was the incidence of clinically meaningful endpoints, including HBV reactivation, hepatitis of any cause, and disruption of the chemotherapy regimen. The median time from chemotherapy initiation to HBV reactivation was 3 months in entecavir recipients and 6 months in lamivudine recipients. This study presents a strong argument that entecavir should be considered standard prophylactic therapy for patients seropositive for HBsAg undergoing rituximab-based chemotherapy for lymphoma and leukemia.[2,49,53] Entecavir should ideally be administered before the initiation of chemotherapy; however, chemotherapy should not be delayed pending the results of HBV serologic testing. Reactivations are not immediate, and antiviral prophylaxis can be safely initiated during the first cycle of chemotherapy.[17]


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