HBV reactivation in immunosuppressed patients: Prevention or containment?
Authors: Emmy Ludwig
Journal: Hepatology (2014)

Patients with chronic (hepatitis B surface antigen [HBsAg]-positive) or "resolved" (HBsAg-negative, hepatitis B core antibody [HBcAb]-positive) hepatitis B virus (HBV) infection who are exposed to immunosuppressive agents can develop reactivation of HBV (HBVr), which initially manifests with an acute rise in HBV DNA levels, which in turn can lead to severe acute hepatitis, hepatic synthetic dysfunction, fulminant liver failure, and death. The question of how to prevent and/or manage this condition has been a matter of debate for many years, especially in the larger subset of patients with resolved HBV. Hsu et al. describe their experience and discuss their recommendations in this issue of Hepatology.1 By now well-recognized, HBVr was characterized in 1991 when Lok et al.2 demonstrated that 48% of patients with chronic HBV infection and 4% of patients with resolved HBV infection developed reactivation hepatitis while undergoing chemotherapy for non-Hodgkin's lymphoma (NHL). Three patients (11%) in this series developed subsequent hepatic failure, one (4%) of whom died from reactivation hepatitis. Multiple subsequent studies3-5 have documented the high incidence of HBVr with chemotherapy administration, with most of the literature predominantly in Asian populations and in patients with hematologic malignancies. Patients with resolved HBV infection have been reported to reactivate with profound iatrogenic immunosuppression, especially in the context of treatment with rituximab. Estimates of incidence rates vary widely, likely due to differences among the patient populations studied, definition of HBVr, screening practices, and duration of follow-up. Historical data show rates of HBVr of 24-88% in chronic HBV patients, and 3-25% in resolved HBV.6-8 Information on the incidence, risk factors, and cost of HBVr and its management in Western populations receiving immunosuppression is still relatively sparse. Increased awareness of this issue led to a recent Food and Drug Administration (FDA) statement revising the prescribing information on rituximab (and ofatumumab) by including a black box warning about the risk and potential serious outcomes of HBVr.9 Screening for HBV prior to institution of immunosuppression is recommended by multiple gastroenterology, hepatology, and infectious disease societies (national and international).10, 11 Dermatology, oncology, and rheumatology societies have tended to be more equivocal about the need for screening and subsequent prophylaxis,12 which has likely impacted screening rates in the U.S. This lack of consensus is unfortunate; the institution of antiviral prophylaxis has been shown to be markedly effective at reducing the rate of HBVr by 80-100% in meta-analysis.13 The nucleoside analog reverse transcriptase inhibitor lamivudine has been studied most extensively but its utility is limited by the development of drug resistance over a relatively short period of time. For this reason, more recent studies have used entecavir, another nucleoside inhibitor with far less potential for drug resistance; this has proven very effective.14 Because of the increased risk of entecavir resistance in patients already exposed to lamivudine, the choice of prophylactic drug should be based on several factors, including history of prior treatment, access to and cost of medication, and anticipated duration of administration. It is likely that the other antiviral medications which include tenofovir, telbivudine, and adefovir would be beneficial for prophylaxis as well, although studies are lacking. Effective prophylaxis against HBVr exists but who should receive it? This question is most contentious for the group of patients with resolved HBV. Hsu et al. present data on one management strategy for the above patient population. This labor-intensive, well-planned, and executed prospective study was conducted in lymphoma patients with serologies consistent with resolved HBV infection and reports on various outcomes, including the incidence, severity, and clinical course of HBVr during and after rituximab-CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone, or the equivalent) chemotherapy. HBV DNA levels were checked before the start of every cycle of chemotherapy, and then every 4 weeks for the 12 months following completion of the r-CHOP therapy. Antiviral therapy was initiated if HBV DNA increased >10-fold over baseline, or, for patients who had a baseline viral load below the level of detection (<1,000 copies/mL) a DNA level which rose to an absolute level of >10,000 copies/mL during or following treatment. An associated elevation in alanine aminotransferase (ALT) was not required to meet criteria for initiation of entecavir. The more sensitive assay used for the serial measurements of HBV DNA appeared to allow for detection of HBV viremia at an earlier point in time, which may have improved outcomes. Severe HBV-related hepatitis (ALT >10-fold of upper normal limit) occurred in seven patients despite prompt initiation of entecavir treatment, and, in turn, these HBV-related hepatitis flares resulted in delays of weeks in r-CHOP chemotherapy in two of these patients. The absence of HBsAb appeared to be a risk factor for reactivation, a finding which has been seen in prior literature. Although no statistically significant difference was seen in objective response rates to r-CHOP therapy between patients with or without HBVr, patients with HBVr trended toward a poorer overall and progression-free survival. In this study no deaths occurred in patients with HBVr. From diagnosis of HBVr as defined above to the occurrence of a hepatitis flare was a mean duration of 49 days (range, 16-350 days). This important finding implies that initiation of entecavir after viral replication has begun—no matter how early it is detected—does not prevent hepatitis. If treatment is not fail-safe in this carefully guarded, scrutinized, and compliant study population, it is far less likely to be successful in a more typical treatment group. Although no deaths occurred in this carefully guarded population, this has not been the case in other similar studies, in which death rates were 5-40%.15 For a potentially lethal condition which has a safe, well-studied, widely accessible preventative strategy, even one death can be seen as one too many. It is also imperative to consider the characteristics of the population in which an HBVr management strategy will be implemented. In an underserved community with a high prevalence of HBV exposure, the decision may be very different from that made in a well-insured and lower prevalence population. It is unclear whether such close observation with frequent HBV DNA testing and medical provider visits could be more cost-effective than universal prophylaxis. Different subspecialty physicians may look at the data differently, and be convinced—or not—of the clear rationale for prevention. If indeed it can be shown that there is a worse disease-specific clinical outcome secondary to HBVr, this discrepancy is likely to disappear. Absent that data, there will continue to be debate as to the importance of preventing HBVr rather than treating it after it has occurred. In conclusion, Hsu et al. contribute to the body of the literature on HBVr in lymphoma patients treated with r-CHOP, and propose one strategy for management. The potential difference between this very closely monitored group of patients and resolved patients in general cannot be stressed enough. Furthermore, despite the lack of statistical significance, this study suggests a trend toward worse outcomes in the patients who reactivated, perhaps further supporting the benefit of appropriate prophylaxis. There can be no doubt, given the vast and ever-growing body of rigorous literature that HBVr occurs, and can be highly morbid and indeed lethal. The key to consensus and subsequent universal protection of this vulnerable patient population is to prove that oncologic outcomes worsen with HBVr, to define the timing and appropriate administration of antiviral prophylaxis, and to study the group of patients with resolved HBV to see who requires prophylaxis and who can be monitored. Above all, the problem of HBVr can only be solved through a multidisciplinary approach which respects the differing expertise of each specialty, and strives for consensus rather than antagonism. Emmy Ludwig, M.D. Memorial Sloan Kettering Cancer Center, New York, NY