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B. Wang et al.
Treatment
Treatment of HBV reactivation can either be prophylac- tic or pre-emptive; the former approach offers antiviral treatment to all patients considered at moderate or high risk prior to commencing immunosuppression, whereas the latter involves regular monitoring of ALT, HBsAg, and HBV DNA during treatment, with antiviral therapy start- ed when HBV DNA and/or ALT levels rise.9 Studies have compared the two strategies and found prophylactic treat- ment to be more effective in preventing reactivation.67-69 One study comparing prophylactic versus pre-emptive antiviral therapy in HBsAg-positive patients undergoing chemotherapy for NHL found significantly lower rates of reactivation and hepatitis in the prophylactic group (11.5% vs. 56%; P=0.001).69 Similarly, a study of 80 anti- HBc positive patients treated with rituximab for lym- phoma also demonstrated that prophylactic antiviral ther- apy resulted in lower rates of reactivation (4.3% vs. 23.9% at 18 months after chemotherapy; P=0.019).68 In consider- ing who requires prophylactic antiviral treatment, one needs to assess the risk of reactivation, as discussed earlier, both in terms of the individual patient and the immuno- suppressive therapy being considered (Table 2).
HBsAg-positive patients
Following referral to a specialist service, these patients should receive nucleoside / nucleotide analog antiviral therapy prior to commencement of immunosuppression.4 This will either be active treatment in those with chronic HBV hepatitis who would require antiviral therapy in any event, or prophylaxis in those with chronic infection with- out hepatitis. HBV DNA and ALT should be monitored every three months throughout immunosuppression. For patients with chronic HBV infection without hepatitis, if the underlying infection remains stable following comple- tion of immunosuppression then it may be appropriate to stop prophylactic antiviral therapy (see below: Duration of therapy). HBsAg-positive patients may also require sur- veillance for hepatocellular carcinoma, which would be undertaken as part of a specialist review.
Anti-HBc positive patients
The risk of reactivation in this group of patients varies and management depends mostly on the immunosuppres- sion regimen proposed. Antiviral prophylaxis is strongly recommended in all patients receiving high-risk (>10%) regimens such as rituximab or HSCT. Those receiving low-risk (<1%) regimens, such as short course low-dose corticosteroids, do not require prophylaxis and can be monitored with regular ALT, HBsAg, and HBV DNA test- ing. There is some debate regarding those in the interme- diate category of moderate risk (1-10%), with some rec- ommending prophylaxis25 and others recommending monitoring and a pre-emptive approach.4 Patients in this group may require an individualized evaluation and con- sideration of other factors, such as co-morbidities and the likely duration of immunosuppression required.
For HBsAg-positive patients requiring active or prophy- lactic antiviral treatment, third-generation nucleoside / nucleotide analogs such as tenofovir disoproxil fumarate (TDF) and entecavir are generally recommended.4 Until recently, the recommendation for anti-HBc positive patients has been to use lamivudine for prophylaxis. Large meta-analyses have demonstrated the efficacy of lamivu- dine in significantly reducing the rate of reactivation and
related mortality in the setting of systemic chemothera- py.70,71 However, lamivudine is associated with drug-resis- tant HBV mutants due to its relatively inferior antiviral potency, and rates of lamivudine resistance have been shown to be as high as 56% after two years of treatment.72 Given that some of the immunosuppressive treatments discussed above may continue for more than one year or be given in repeated courses, prolonged antiviral prophy- laxis and resistance may be a significant issue. Therefore, there has been a shift in recommendation towards use of TDF or entecavir for prophylaxis in anti-HBc positive patients if immunosuppression is likely to be prolonged or with very high-risk regimens. The efficacy of entecavir in prophylaxis against HBV reactivation has been demon- strated in large comparator studies with lamivudine, whereas the data for TDF are more limited.73,74 One study of HBsAg-positive patients receiving rituximab-based therapy for diffuse large B-cell lymphoma showed signifi- cantly lower rates of HBV reactivation in those treated with entecavir (6.6% vs. 30%), as well as lower rates of chemotherapy disruption. Therefore, current recommen- dations suggest lamivudine should only be considered for anti-HBc positive patients requiring short duration (< 12 months) prophylaxis in the setting of moderate- or low- risk immunosuppression.
Safety
Extensive data regarding long-term TDF and entecavir use in terms of efficacy and safety have been reported in the setting of management of chronic HBV infection. The main concerns surrounding long-term TDF use are renal toxicity with reduction in glomerular filtration rate, and bone toxicity with a decline in bone mineral density.75 These are potentially of additional concern in patients with hematologic disorders, and long-term safety data specifically in such patients are lacking. As for any patient on TDF, close monitoring of renal function with measure- ment of estimated glomerular filtration rate and serum phosphate is recommended. Recently, tenofovir alafe- namide (TAF), a prodrug that results in lower circulating plasma levels of tenofovir, has been licensed for use in chronic HBV infection in patients with TDF-related toxic- ity and/or renal co-morbidities. Results at 96 weeks of a randomized, double blind study have demonstrated non- inferiority compared with TDF in terms of antiviral poten- cy with an improved safety profile.76-78 In patients with existing renal/bone disease, or in whom the potential tox- icity associated with TDF is unacceptable, entecavir or TAF are good alternatives.4
Duration of therapy
For patients with chronic HBV-related hepatitis, antiviral therapy with nucleoside / nucleotide analogs is long-term. In patients for whom antiviral therapy was started for pro- phylaxis alone, the evidence to support recommendations on the total duration required is not robust and such recom- mendations are based on cases of when reactivation has occurred.25 Antiviral prophylaxis for a minimum of six months after completion of chemotherapy or immunosup- pression is recommended; in the case of rituximab and B- cell depleting therapies, as reactivation has been reported later, the recommendation is for prophylaxis to continue for a minimum of 12 months. The situation following HSCT is more complex and depends on occurrence of complications such as GvHD, and the viral status of the recipient and
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haematologica | 2019; 104(3)