Hepatitis B surface antigen seroconversion after HBV reactivation in non-Hodgkin’s lymphoma

Abstract

Reactivation of hepatitis B virus (HBV) can occur in lymphoma patients infected with HBV when they receive chemotherapy or immunotherapy. Prophylactic administration of lamivudine (LAM) reduces the morbidity and mortality associated with HBV reactivation. However, what defines HBV reactivation and the optimal duration of treatment with LAM have not yet been clearly established. HBV reactivation may occur due to the cessation of prophylactic LAM, although re-treatment with nucleoside analogs may sometimes result in hepatitis B surface antigen (HBsAg) seroconversion, which is a satisfactory endpoint for the management of HBV infection. We report a case of HBV reactivation in a 68-year-old HBsAg-positive patient who received rituximab-based immunochemotherapy for follicular lymphoma. HBV reactivation developed following cessation of prophylactic LAM therapy. The patient subsequently received treatment with entecavir (ETV), which led to a rapid and sustained suppression of HBV replication and HBsAg seroconversion. We also appraised the literature concerning HBV reactivation and the role of ETV in the management of HBV reactivation in lymphoma patients. A total of 28 cases of HBV reactivation have been reported as having been treated with ETV during or after immunosuppressive chemotherapy in lymphoma patients. We conclude that ETV is an efficacious and safe treatment for HBV reactivation following LAM cessation in lymphoma patients treated with rituximab-based immunochemotherapy.

Key Words: Hepatitis B surface antigen, Seroconversion, Non-Hodgkin’s lymphoma, Rituximab, Entecavir

Core tip: We describe the case of a 68-year-old hepatitis B surface antigen (HBsAg)-positive male patient who received rituximab-based immunochemotherapy for follicular lymphoma, and experienced hepatitis B virus (HBV) reactivation following cessation of lamivudine prophylaxis. Subsequent entecavir treatment produced rapid, sustained viral suppression and HBsAg seroconversion. Lamivudine prevents HBV reactivation but resistance rates may be as high as 17% in lymphoma patients. Available data suggest that entecavir is effective and safe for the treatment of HBV reactivation in lymphoma patients. Prophylactic antiviral therapy is recommended for patients with active or occult HBV infection following chemotherapy or immunochemotherapy. Potent antiviral drugs with a high genetic barrier to resistance should be considered in these cases.

INTRODUCTION

Hepatitis B virus (HBV) is highly prevalent in many malignancies, such as hepatocellular carcinoma and non-Hodgkin’s lymphoma (NHL)[1,2]. In recent years, rituximab, a chimeric monoclonal antibody directed against the CD20 antigen on B cells, has greatly improved the prognosis and outcome of patients with NHL[3,4]. However, rituximab induced profound and persistent depletion of the circulating population of B cells, leading to dysregulation of host immunity to HBV and increased risk of HBV reactivation[5,6]. Consequently, viral reactivation is an area of concern whenever an HBV-positive patient receives chemotherapy or immunochemotherapy[7]. Prophylactic administration of antiviral agents may reduce the incidence of HBV reactivation but flares do occur in 60% of patients following discontinuation of antiviral treatment[8]. We report a case of HBV reactivation following cessation of prophylactic lamivudine (LAM) in a patient with NHL who received rituximab-based treatment. Early administration of entecavir (ETV) successfully prevented further progression of HBV infection, leading to hepatitis B surface antigen (HBsAg) seroconversion.

CASE REPORT

A 68-year-old male was admitted to our hospital for follicular lymphoma in March 2009. He had chronic HBV infection for more than two decades. On admission, his alanine aminotransferase (ALT) levels were within the upper limit of normal (< 40 U/L). The patient’s serology was found to be positive for HBsAg, hepatitis B surface antibody (anti-HBs), hepatitis B envelope antibody (anti-HBe), and hepatitis B core antibody (anti-HBc). However, he was HBeAg-negative. His HBsAg and anti-HBs titers were > 250 IU/mL and 45.81 mIU/mL, respectively, as measured by chemiluminescence microparticle immunoassays. His serum HBV DNA concentration was undetectable (limit of detection by polymerase chain reaction: 1000 copies/mL). The time course of the levels of liver enzymes and HBV DNA is shown in Figure 1.

Figure 1 Time course of serum hepatitis B virus DNA and alanine aminotransferase levels during and after immunochemotherapy. HBsAg: Hepatitis B surface antigen; ALT: Alanine aminotransferase.

From March 2009 to July 2009, administration of 5 cycles of immunochemotherapy (rituximab, fludarabine, cyclophosphamide) led to partial remission of the patient’s lymphoma. No additional treatment with anticancer drugs or corticosteroids followed. Prophylactic LAM (100 mg daily) was administered on the first day of immunochemotherapy and continued for 4 mo after completion of immunochemotherapy (total: 8 mo). In February 2010, 3 mo following cessation of LAM therapy, the patient’s HBV DNA level rose to 8.15 × 10⁴ copies/mL. His ALT, HBsAg, and anti-HBs levels were 24 U/L, 121 IU/mL and 0.18 mIU/mL, respectively. Reactivation of HBV infection was considered and antiviral treatment with ETV 0.5 mg daily was administered immediately. In March 2010, 1 mo after ETV initiation and while still receiving ETV therapy, the patient’s HBV DNA concentration fell below detectable levels, while his ALT level increased to 62 U/L. In April 2010, 2 mo after ETV initiation, the patient achieved clearance of HBsAg and normalization of ALT levels. In July 2010, 4 mo after ETV initiation, the patient became anti-HBs-positive (titer: 13.5 mIU/mL), indicating HBsAg seroconversion. In December 2010, 7 mo after HBsAg seroconversion, ETV treatment was stopped (total: 10 mo). In March 2011 (4 mo after discontinuing ETV treatment), his HBsAg level was still negative and the patient’s anti-HBs titer had increased to 93.6 mIU/mL. The patient’s ALT levels remained normal and his HBV DNA level was undetectable. Until September 2012, 21 mo after ETV discontinuation, his HBsAg level remained negative and the patient’s anti-HBs titer had increased to 112.3 mIU/mL (Figure 2). His ALT levels also remained normal, while the HBV DNA concentration was undetectable at the patient’s last two visits (Figure 1). Administration of ETV was well tolerated throughout the treatment period.

Figure 2 Time course of quantitative titers of hepatitis B surface antigen and hepatitis B surface antibody antibodies after entecavir treatment. Anti-HBs: Hepatitis B surface antibody; HBsAg: Hepatitis B surface antigen.

Other reported cases

The nucleoside analog ETV provides the advantage of a higher genetic barrier to resistance than LAM for the treatment of chronic hepatitis B[9]. ETV has also been used to prevent HBV reactivation during chemotherapy or immunosuppressive therapy, although this experience is limited[10]. Several studies have examined the use of ETV in the treatment of HBV reactivation in lymphoma patients and suggest its effectiveness and safety[11-13]. A total of 28 cases of HBV reactivation reported in the literature involved ETV administration during or after immunosuppressive chemotherapy in patients with lymphoma (Table 1). Nine cases of HBV reactivation developed during chemotherapy or immunochemotherapy[11-17], while the remaining cases occurred after chemotherapy or immunochemotherapy[11,14,18-22]. Twenty-four patients received rituximab-based immunochemotherapy regimens[12-22]. Five patients died of hepatic failure following HBV reactivation[11,15,17,20,22], 4 of whom received rituximab-based regimens[15,17,20,22]. Clearance of HBsAg was observed in only 5 patients[11,19,21]. LAM was administered with the intention of preventing HBV reactivation in 4 patients from 2 different studies[11,18]. Of these, 3[18] developed HBV reactivation-related hepatitis 2-4 mo after discontinuation of LAM while the remaining case of HBV reactivation occurred 8 mo after cessation of LAM treatment[11].

Table 1 Hepatitis B virus reactivation in patients with lymphoma and treated with entecavir.

Author	Patients (n)	Hematologic malignancy	Pre-treatment HBV markers	Prophylaxis with anti-viral drugs	Rituximab-based regimen	Time of HBV reactivation (during/after anti-tumor therapy)	Outcome (alive/died)	HBsAg clearance (yes/no)
Ferreira et al[22]	1	DLBCL	HBsAg-, anti-HBs+, anti-HBc-	No	Yes	0/1	0/1	NR
Niitsu et al[14]	6	DLBCL	HBsAg-	No	Yes	2/4	5/11	NR
Chung et al[15]	1	DLBCL	HBsAg-, anti-HBs+, anti-HBc+	No	Yes	1/0	0/1	0/1
Lee et al[16]	1	FL	HBsAg-, anti-HBs+	No	Yes	1/0	1/0	NR
Stange et al[17]	2	B cell lymphoma	unknown	No	Yes	2/0	1/1	NR
Brost et al[11]	4	AML and lymphoma	Unknown for all	1 Yes, 3 No	No	2/2	3/1	3/1
Sanchez et al[12]	1	CLL	HBsAg-	No	Yes	0/1	1/0	NR
Colson et al[13]	1	B cell lymphoma	HBsAg-, anti-HBs-, anti-HBc+	No	Yes	1/0	1/0	NR
Mimura et al[18]	3	B cell lymphoma	HBsAg+	Yes	Yes	0/3	3/0	NR
Matsue et al[19]	5	B cell lymphoma	HBsAg-	No	Yes	0/5	5/0	1/4
Wu et al[20]	1	DLBCL	HBsAg-, anti-HBc+	No	Yes	0/1	0/1	0/1
Fukushima et al[21]	2	NHL, DLBCL	HBsAg-	No	Yes	0/2	2/0	1/1

DLBCL: Diffuse large B cell lymphoma; FL: Follicular lymphoma; AML: Acute myeloid leukemia; CLL: Chronic lymphocytic leukemia; NHL: Non-Hodgkin’s lymphoma; NR: Not reported.

¹Patient died of lymphoma-related causes.

DISCUSSION

Malignant lymphoma is a leading cause of cancer-related mortality, despite the fact that the long-term prognosis of patients with diffuse large B cell lymphoma has improved following the introduction of immunochemotherapeutic agents, such as rituximab[23]. The occurrence of HBV infection has been associated with lymphoma and hepatocellular carcinoma[24]. In addition, reactivation of HBV may be a fatal complication in patients with HBV infection who receive immunochemotherapy for lymphoma, especially rituximab-based regimens. While the exact definition of HBV reactivation differs among investigators[25], reactivation of HBV is deemed to occur in both HBsAg-positive or -negative patients. Among patients who only present with anti-HBc antibody-positive serology, the risk factors for HBV reactivation include male gender and low anti-HBs titer[14].

Given the substantial morbidity and mortality associated with HBV reactivation and hepatitis flares, prophylactic antiviral therapy should be administered to HBsAg-positive cancer patients if they receive immunochemotherapy. LAM has been shown to be clinically effective in reducing the incidence and severity of HBV reactivation, but treatment guidelines differ in their recommendations for prophylactic antiviral therapy[26-28]. In addition, the optimal duration of prophylactic LAM therapy has not yet been clearly established. For instance, the incidence of YMDD mutation and HBV reactivation following withdrawal of LAM in patients with NHL were similar to that for patients with chronic hepatitis B. In a long-term study, 17% of HBsAg-positive NHL patients developed YMDD mutation during LAM therapy (median duration: 11.5 mo), and 4% developed HBV reactivation following LAM withdrawal[29]. In one prospective study, 23.9% of 46 patients with hematological malignancies developed HBV reactivation after withdrawal of LAM prophylaxis[30]. HBV reactivation was more likely to develop in patients with elevated HBV DNA levels prior to chemotherapy. A prolonged administration of antiviral therapy may be necessary in these patients; however, drug resistance must be considered. ETV may be the preferred drug because of its high antiviral potency and high barrier to resistance. In a retrospective study, ETV showed a very low rate of prophylaxis failure. HBV reactivation was not detected in 31 HBsAg-positive patients treated with ETV prophylaxis (median duration: 17 mo)[31]. A randomized controlled trial confirmed that ETV prophylaxis until 3 mo after completion of chemotherapy was insufficient even in patients with undetectable hepatitis B. One of the 41 patients in the ETV prophylaxis group had delayed HBV reactivation, almost 7 mo after discontinuing ETV prophylaxis. Therefore, it is important to routinely monitor HBV DNA levels after discontinuation of ETV[32].

In a community-based follow-up study, spontaneous clearance of HBsAg from serum occurred in 562 chronic hepatitis B patients during 24829 person-years of follow-up evaluation, resulting in an overall annual seroclearance rate of 2.26%[33]. The levels of HBV DNA at baseline and follow-up evaluation were the most significant predictor of HBsAg seroclearance[34]. To our knowledge, there has been no report to date of spontaneous HBsAg seroclearance following HBV reactivation. It is therefore unclear whether the HBsAg seroconversion observed in our patient could be attributed to the ETV treatment or considered spontaneous.

In conclusion, prophylactic antiviral therapy is highly recommended in patients with active or occult HBV infection who receive chemotherapy or immunochemotherapy. In the event of HBV reactivation at the time HBV prophylaxis is stopped, administration of a potent antiviral agent with a high genetic barrier to resistance should be considered.

ACKNOWLEDGMENTS

The authors thank Timothy Stentiford from MediTech Media Asia Pacific for providing editorial assistance on this manuscript. Editorial assistance was supported by the Bristol Myers Squibb Company.

COMMENTS

Case characteristics

A 68-year-old patient was admitted to hospital for follicular lymphoma, with a 2-decade history of chronic hepatitis B virus (HBV) infection. He received rituximab-based immunochemotherapy for follicular lymphoma and experienced HBV reactivation following cessation of lamivudine prophylaxis.

Clinical diagnosis

The patient had no symptoms or signs when HBV reactivation occurred.

Differential diagnosis

Hepatitis due to drugs, alcoholic hepatitis, and other factors were excluded.

Laboratory diagnosis

After cessation of lamivudine (LAM) prophylaxis, the patient’s HBV DNA (by polymerase chain reaction) rose to 8.15 × 10⁴ copies/mL from an undetectable baseline level, followed by elevated alanine aminotransferase.

Treatment

The patient received entecavir (ETV) 0.5 mg/d for 10 mo and experienced sustained viral suppression with HBsAg seroconversion.

Related reports

ETV provides the advantage of a higher genetic barrier to resistance than LAM for the treatment of chronic hepatitis B. Several studies examining the use of ETV for treating HBV reactivation in lymphoma patients suggest that it is a safe and effective therapy.

Term explanation

HBV reactivation was defined as a tenfold increase in HBV DNA level or the reappearance of detectable HBV DNA.

Experience and lessons

Prophylactic antiviral therapy is highly recommended in patients with active or occult HBV infection who receive chemotherapy or immunochemotherapy; a potent antiviral agent with a high genetic barrier to resistance should be considered.

Peer review

This case reports the relatively uncommon finding of hepatitis B surface antigen seroconversion following ETV therapy in a lymphoma patient with chronic HBV who experienced HBV reactivation following rituximab-based immunochemotherapy. It is well written.