Management strategies for hepatitis B–infected patients undergoing immunomodulatory therapy: Is lamivudine enough?

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Abbreviations

ALT

alanine aminotransferase

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

IMT

immunomodulatory therapies.

Current guidelines recommend antiviral prophylaxis for patients at risk for HBV reactivation in the context of immunomodulatory therapies (IMT)1 (Table 1). HBsAg‐positive patients should receive antiviral prophylaxis routinely. For patients with markers of resolved HBV infection, that is, positive for anti‐HBc with or without anti‐HBs, routine antiviral prophylaxis is not recommended except in select circumstances. The choice of antiviral agent and duration of antiviral drug treatment can be individualized to the patient and type of IMT received. For patients with active HBV disease (elevated ALT and HBV DNA levels) for whom antiviral therapy is indicated independent of IMT, treatment with preferred HBV antivirals — entecavir or tenofovir — is recommended. For those patients who need antiviral therapy because of receipt of IMT, several antiviral options can be considered, including lamivudine.

Table 1.

Prophylaxis in Patients Undergoing Immunomodulatory Therapy

	Risk Groups*	Antiviral Prophylaxis Recommended
HBsAg+	Low risk (<1%	Optional, monitoring for HBV DNA acceptable
	Moderate (1%‐10%)	YES
	High (≥10%)	YES
Anti‐HBc+ (HBsAg negative)	Low risk (<1%)	Optional
	Moderate (1%‐10%)	Optional. Preferred, if corticosteroids for ≥4 weeks
	High (≥10%)	Preferred. YES, if rituximab given

(1)

Antiviral Options for HBV Prophylaxis in Setting of IMT

There are five antiviral drugs approved for the treatment of chronic HBV infection (Table 2). All drugs have an excellent safety profile. Side effects are infrequent to rare, but worthy of mention to ensure that they are not missed. In addition, all HBV agents are nucleoside analogues with a class effect of lactic acidosis, and evaluation for this rare complication needs to be undertaken in the appropriate clinical setting. Dose adjustments for renal dysfunction are required for all drugs.

Table 2.

Antiviral Options

Antiviral Drug	Usual Daily Dose (If Normal Renal Function)	Risk for Resistance After 1‐Year treatment	Potential Toxicities	Monitoring Recommended
Lamivudine	100 mg	20%	Pancreatitis	Serum amylase if symptoms
Adefovir	10 mg	5%	Renal	Creatinine, phosphate levels every 6 months
Telbivudine	600 mg	20%	Myositis/myopathy	Creatinine kinase if symptoms
Entecavir	0.5 mg	0%	None
Tenofovir	300 mg	0%	Renal	Creatinine, phosphate levels every 6 months

For treatment of chronic HBV outside the setting of IMT prophylaxis, tenofovir and entecavir are the preferred antivirals, as these drugs have potent antiviral activity and a high genetic barrier to resistance. These characteristics are important, as patients with active HBV disease require years of therapy to achieve the treatment end points of HBeAg and/or HBsAg seroconversion, and prevention of resistance is essential in achieving treatment success. Treatment with lamivudine, adefovir, or telbivudine is not recommended in patients with active HBV disease, as these drugs have a risk for resistance with long‐term use that is unacceptably high (Table 2).

For treatment of patients undergoing IMT who otherwise do not have an indication for HBV treatment, the choice of antiviral therapy should be guided by the baseline HBV DNA level, prior history of antiviral drug exposure, and the anticipated duration of therapy (Table 3).

Table 3.

Choosing Antiviral Prophylaxis Drug: Lamivudine Versus Entecavir/Tenofovir

Ideal Candidates for Lamivudine Prophylaxis	Reasonable Candidates for Lamivudine Prophylaxis	Candidates Best Treated With Entecavir or Tenofovir
• HBV DNA undetectablea • No prior history of lamivudine or telbivudine therapy • Duration of prophylaxis short (<12 months)	• Low‐level HBV DNA < 2000 IU/mL • No prior history of lamivudine or telbivudine therapy • Duration of prophylaxis short (<12 months)	• High HBV DNA levels • Need for RTX • If prior history of lamivudine or telbivudine treatment tenofovir • If no prior history of lamivudine or telbivudine treatment entecavir • Extended period of prophylaxis expected

^aIncludes HBsAg and HBsAg‐negative (anti‐HBc‐positive) patients.

Lamivudine as Prophylaxis for Patients Receiving IMT

Lamivudine was the first approved oral antiviral drug and has been used widely as prophylaxis in patients undergoing IMT. Several meta‐analyses have established its benefits compared with untreated controls.2, 3, 4, 5, 6 Lamivudine reduces by ∼80% the rate of HBV reactivation and the incidence of hepatitis due to HBV reactivation compared with no prophylaxis. Some but not all studies also report reduced frequency of chemotherapy interruptions and overall mortality. The risk of lamivudine resistance with IMT prophylaxis varies from 10% to 20% with treatment up to 1 year, and higher rates of resistance are seen with longer duration of lamivudine therapy6 and with high baseline HBV DNA levels.3 These latter results argue against the use of lamivudine in patients with higher baseline HBV DNA levels (>2000 IU/mL) or IMT extending beyond a year. In addition, given that drug‐resistant variants are archived and reemerge quickly on reexposure to the antiviral drug, patients with a history of prior lamivudine or telbivudine treatment would be best treated with tenofovir, as this is the most effective drug for patients with prior resistance.

Entecavir and Tenofovir as Prophylaxis in Patients Receiving IMT

Entecavir and tenofovir are predicted to be effective IMT prophylaxis based on the well‐established antiviral efficacy of these drugs in treating chronic HBV patients outside the IMT setting. However, studies using these drugs as IMT prophylaxis are more limited. There are no studies of tenofovir use but several cohort studies and a randomized trial using entecavir. In preliminary results of 121 patients with lymphoma treated with RCHOP and randomized to lamivudine and entecavir prophylaxis, HBV reactivation and HBV reaction with hepatitis were seen in 8% and 13%, respectively, of lamivudine‐treated patients and none of the entecavir‐treated patients. Chemotherapy interruptions were also lower in entecavir‐treated patients (1.6% versus 18.3%).7 In cohort studies with various antivirals used as IMT (based on provider preference), reported rates of HBV reactivation with entecavir varied from 0% to 12%.8, 9, 10 In a retrospective study of 40 patients (38% HBsAg positive, remainder anti‐HBc positive) with hematological malignancies treated with lamivudine and entecavir prophylaxis by provider preference, the efficacy was high with both therapies, with only one treatment failure overall, in a patient with pretreatment HBV DNA > 10⁷ IU/mL who experienced reactivation with a hepatitis flare in association with resistance to lamivudine in the second year of treatment.10 Overall, these results support the use of entecavir over lamivudine as prophylaxis in patients undergoing IMT, especially in patients with high HBV DNA levels or prolonged duration of therapy. Recommendations for tenofovir use must be based on anticipated parallel benefits to entecavir, as both drugs are of high antiviral potency and have low risk of resistance with prolonged therapy. There are no studies comparing the risks/benefits of tenofovir and entecavir, and the decision to use one or the other is likely to be determined by provider preference, patient access, and cost.

Duration of Antiviral Prophylaxis in the IMT Setting

Current American Association for the Study of Liver Diseases and Asian Pacific Association for the Study of the Liver guidelines recommend that antiviral prophylaxis be initiated at least 1 week prior to starting IMT and continue for at least 6 months after the end of the IMT,11, 12 whereas European Association for the Study of the Liver guidelines recommends prophylaxis for 12 months following cessation of IMT.13 Reports of late reactivation in a few patients, especially those treated with rituximab or who had elevated HBV DNA levels at baseline, support a longer duration of prophylaxis. If antiviral prophylaxis is stopped sooner than 12 months after IMT is completed, monitoring for reactivation with the use of serial HBV DNA testing is an appropriate strategy. Whether a longer duration of monitoring is indicated is unknown.

Prophylaxis for HBsAg‐Negative Liver Transplant Patients Receiving an Anti‐HBc Positive Donor

Use of livers from donors that are HBsAg negative but anti‐HBc positive is an important means of expanding the donor pool, especially in countries with a high prevalence of HBV. Natural history studies have shown that the risk of de novo infection in the recipient is related to the antibody status of the recipient (presence of anti‐HBc and/or anti‐HBs) and use of prophylaxis. The incidence of de novo hepatitis B infection in the absence of prophylaxis is 60% among recipients lacking anti‐HBc or anti‐HBs and 6% among those with anti‐HBs. Prophylactic antiviral therapy is recommended to prevent de novo infection in the recipient, and lamivudine has been shown to be highly effective, reducing incident infection to <3%.14 Because donors positive for anti‐HBc (and HBsAg negative) typically have undetectable or very low level HBV viremia, it is not surprising that lamivudine is sufficient for prophylaxis, and risk for resistance in this setting is low. Moreover, lamivudine is highly cost‐effective compared with use of entecavir or tenofovir prophylaxis in this setting.15 The addition of hepatitis B immune globulin to lamivudine does not yield higher efficacy rates and thus is not recommended.14 Most programs utilize prophylaxis therapy indefinitely,16 and the high prevalence of intrahepatic cccDNA in those on prophylaxis supports long‐term antiviral therapy.17 There is likely a subgroup of patients in whom prophylaxis can be safely stopped once immunosuppression levels are low and stable, but studies to define such a group of patients are lacking.

Choice of Antiviral Therapy for Patients Who Experience HBV Reactivation

There are no studies comparing the efficacy and safety of specific antivirals in the management of HBV reactivation. If antiviral prophylaxis is given, this will likely be an infrequent event. In a meta‐analysis of studies evaluating the efficacy of specific antivirals in the management of acute‐on‐chronic HBV (not in IMT setting), lamivudine and entecavir showed similar short‐term outcomes (3 months).18 In a study of anti‐HBc‐positive patients who experienced HBV reactivation in the absence of prophylaxis, entecavir was used, but a significant proportion of patients (4 of 17) experienced severe hepatitis flares (ALT > 10 times ULN) despite treatment.19 These data suggest that providing timely treatment is most important when reactivation occurs.

In the absence of additional data specific to this setting, reliance on principles used in treating any patients with active HBV disease is the best strategy.11 Since the duration of therapy in a patient with reactivation is likely to be prolonged and there is a need to minimize risk of resistance with prolonged therapy, entecavir or tenofovir would be the preferred antiviral agents.

Summary

For patients undergoing antiviral prophylaxis in the context of IMT, entecavir and tenofovir are drugs of choice if baseline HBV DNA is greater than 2000 IU/mL and ALT levels are elevated, similar to management for chronic HBV outside the setting of IMT. Lamivudine may be considered for patients with inactive chronic HBV (HBsAg positive, HBV DNA <2000 IU/mL) and patients who are HBsAg negative and anti‐HBc positive. Use of lamivudine rather than more expensive prophylaxis drugs, such as entecavir and tenofovir, is also a rationale choice in resource‐limiting clinical settings. For other groups, entecavir and tenofovir are better options to minimize reactivation risk during IMT. Regardless of the drug used for prophylaxis, monitoring for reactivation after drug discontinuation is recommended for up to 1 year after IMT.