To the best of our knowledge, the present study is the first randomized controlled trial evaluating the efficacy of 24-week versus 48-week extended TDF treatment in preventing HBV reactivation in patients receiving cancer chemotherapy in the medical literature. The major findings of this study are as follows: 1) 24-week and 48-week extended TDF had no significant difference in the cumulative incidence of virological relapse; 2) 24-week and 48-week extended TDF had no significant difference in a clinical relapse in patients with high baseline HBV DNA; 3) high baseline HBsAg QT and high HBV DNA are associated with the risk of HBV relapse; 4) kidney function did not appear to be affected by the extended TDF treatment.
HBV reactivation, a well-known complication in HBV-infected cancer patients receiving systemic chemotherapy or immunosuppressive therapy, is a severe condition that can lead to potentially fatal hepatic decompensation.17 Reactivation can be avoided if at-risk patients are identified through screening and assigned to an appropriate treatment strategy.18 Where HBV is endemic, reported HBV reactivation rates with immunosuppression are as high as 41.5–70%.19 Importantly, prophylactic nucleos(t)ide analogs (NUCs) with high genetic barriers, such as entecavir (ETV), tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF), are recommended for HBV-infected cancer patients undergoing chemotherapy.9,20,21 However, using ETV or TDF is also challenging in some ways. While ETV is associated with a high risk of resistance in lamivudine-experienced patients, TDF is associated with significant renal and bone safety concerns.22
A recent randomized controlled trial compared TDF with ETV in the prophylaxis of HBV reactivation in patients receiving immunosuppressive treatments (IST). 23 According to the local practice guidelines, the TDF or ETV was continued for 6 to 12 months after completion of IST. The authors concluded that ETV and TDF had similar efficacy in preventing HBV reactivation in patients undergoing IST, with none experiencing reactivation.23 Another randomized controlled trial evaluated TDF prophylaxis against HBV reactivation in anti-HBc-positive patients with rituximab (RTX)-based regimens to treat hematologic malignancies. The authors concluded that HBV reactivation did not occur when given TDF prophylaxis in patients with hematological cancers and resolved HBV receiving RTX-based regimens. Although the efficacy of TDF prophylaxis in preventing HBV reactivation in patients undergoing IST is evident, these studies did not focus on the duration of TDF prophylaxis, leaving the optimal course of the prophylactic treatment unclear.
The present study found that a 24-week and 48-week extended TDF treatment have similar results on either virological or clinical relapse. According to National Health Insurance Administration rules and the American Association for the Study of Liver Diseases (AASLD) treatment recommendations, NUC antiviral prophylaxis was prescribed from one week before chemotherapy began until six months after chemotherapy ended; the HBV DNA level was monitored every six months while on NUC therapy.9 On the contrary, several associations advise receiving antiviral treatment for an extra 12 months following chemotherapy.21,24 However, determining evidence is still lacking on whether 6 months or 12 months TDF prophylaxis is optimal, especially from prospective trials. Our study thus contributes to the current medical literature and guidelines in providing evidence for TDF treatment duration. Based on the present study's results, a 24-week extended TDF may be sufficient in preventing HBV relapse for patients receiving cancer chemotherapy.
Renal dysfunction is a critical issue in the treatment of HBV infection. Depending on the type and stage of cancer, the chemotherapy regimen, and comorbidities, cancer patients undergoing chemotherapy are especially vulnerable to renal dysfunction.25 Expressly, current evidence indicated that, as compared to ETV, TDF might lead to a higher risk of renal dysfunction.26 However, following up to 18 months, the present study did not observe a deterioration of patients’ eGFR. The unaffected kidney function in this trial may be explained by adequate hydration (e.g., by normal saline) during chemotherapies. In addition, although Vitamin D deficiency is considered highly prevalent in the general population in Taiwan,27 the extended TDF prophylactic treatment did not significantly affect blood vitamin D levels among the patients.
Important virological and serological indicators are closely connected with HBV reactivation, including detectable HBV DNA, HBsAg, HBeAg, and anti-HBc.28,29 The strongest of these risk factors is high HBV DNA, and HBsAg-positive patients had an 8-fold increased chance of developing HBVr than HBsAg-negative or anti-HBc-positive individuals.28,29 According to the present study's findings, high HBV DNA and HBsAg levels independently predicted the HBV virological relapse, and the cumulative incidence of clinical relapse was significantly greater in patients with high baseline HBV DNA as compared to those with low HBV DNA levels. Taking together, although a 24-week prophylactic TDF treatment duration would be recommended, as mentioned above, patients who had a high baseline HBV viral load still need to be closely monitored to avoid unfavorable treatment outcomes.
Strengths and limitations
The most significant strength is that this study is a prospective randomized trial. The criteria for inclusion and exclusion were strictly set, and the virological and clinical relapse, HBV DNA, HBsAg, ALT, and renal function throughout the study period were closely followed and recorded at multiple time points. The patients were followed at least one year after the prophylactic TDF treatment completion, in which the long-term efficacy of the two TDF treatment duration can be determined. Nevertheless, this study has certain limitations. First, the patients are from a single medical center. Second, seropositive HBeAg may have some roles in the HBV reactivation; however, these cases were too few and thus could not be further analyzed.