Jurnal Internasional Terapi HBV dan anti-CD20 teratasi
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It has long been recognized that patients with chronic HBV (HBsAg positive) experience a high risk of HBV reactivation when exposed to rituximab. 2 Recently, it has been recognized that patients with resolved infections also have a risk of HBV reactivation with rituximab. 3 The Kusumoto et al report is the first to show that obinutuzumab is associated with an important risk of HBV reactivation in this population as good.
Kusomoto et al reported that nucleos prophylaxis (t) idea analog therapy (NAT) is strongly related by reducing the risk of HBV reactivation; However, even so, they argue that NAT prophylaxis may not be needed in all patients with completed HBV. 1 On GOYA and GALLIUM, patients are prospectively screened for HBsAg and anti-HBcAb. Researchers have the choice to treat patients with HBV who are resolved with their chosen prophylactic NAT or monitor HBV DNA levels every month for 1 year after completing anti-CD20 treatment with preemptive NAT (triggered) given if HBV DNA levels rise above 29 IU / mL , a very low definition of HBV reactivation. Patients with measurable HBV DNA (> 29 IU / mL) at baseline did not qualify for this study. Importantly, Kusumoto et al. Reported that while more HBV reactivation occurred with a preemptive / triggered strategy, there were no HBV-hepatitis episodes in both groups, indicating that both strategies were safe.
The authors argue that avoiding NAT prophylaxis may be desirable because prolonged maintenance costs, potential side effects from NAT, risk of HBV resistance, and risk of HBV rebound when antiviral drugs are stopped. NAT is generally well tolerated with rare side effects. Virus resistance, however, is a known and potentially dangerous phenomenon when NAT inhibitors with low resistance such as lamivudine are used. 4 Fortunately, HBV resistance is not common with high NAT barrier resistance such as entecavir and tenofovir 5 6 and has not been reported in the context of prevention of HBV reactivation in cancer patients. Reactivation of HBV rebound has been reported after cessation of prophylactic NAT, 7 but the risk is unknown and, in many cases, can be reduced by testing HBV DNA levels after stopping NAT. Thus, the risks and relative benefits of HBV prophylaxis vs. preemptive strategies are unclear.
Kertas Kusomoto et al. Suggest that in the context of clinical trials, monitoring for HBV reactivation with preemptive NAT is a safe strategy, especially for patients with HBV DNA who do not detected at the start and HBsAb measured. 1 Whether this approach can or should be generalized to the real world is still unclear and is likely to depend on a combination of feasibility and economy.
HBV monitoring strategy used by Kusomoto et al (monthly HBV DNA test for 1 year beyond the last anti-CD20 dose) is conservative and therefore also resource intensive. Many regions do not have ready access to HBV DNA testing 8 or have access to less sensitive HBV DNA testing then used in reference studies. Kusomoto et al's results should not be extended to these centers. Even in areas with access to sensitive HBV DNA testing, it is important for doctors to be realistic about the ability of patients and their clinics to adhere to a monthly HBV DNA test for long periods of time. A large amount of evidence documents the ongoing challenges of achieving high levels of HBV screening before cancer treatment. 9 In this environment, one wonders whether a monthly HBV DNA test is feasible, especially considering that after completing treatment for lymphoma, most patients transition to less frequent contact with their oncology provider. Indeed, even in the context of clinical trials, Kusomoto et al reported 2 patients experienced high HBV DNA levels after a delay in the scheduled monthly HBV DNA test. 1
Economics will also have an impact on real-world management strategies that are ideal for patients with resolved HBV who receive anti-CD20 antibodies. In many areas, patients bear the costs of not only drugs but also monitoring tests, which require difficult sacrifices for patients and their providers. Common high barrier NATs are now available in most regions; however, the cost of generic drugs can vary dramatically between jurisdictions. Likewise, both accessibility and the cost of monitoring HBV DNA vary. In some areas, it may be cheaper to provide a high profile NAT barrier with HBV DNA monitoring which is less frequent than monitoring HBV DNA every month for years.
Like all important studies, Kusomoto et al's paper answers several questions but raises others. Monthly HBV monitoring seems safe for the majority of resolved HBV patients who receive anti-CD20 therapy (provided the test is adhered to), but it is not known whether it is less frequent, and thus cheaper, HBV DNA monitoring may be adequate. Likewise, it is not known whether monitoring to reverse seroconversion (changing from negative HBsA to positive) may be sufficient. New HBsAg immunoassay with sensitivity close to the polymerase chain reaction is under development; because these are becoming more available, they can be the choice test tool. Other new tools such as HBV RNA and antigen related HBV nuclei correlate with transcription of intrahepatic HBV DNA and allow better predictions of the risk of reactivation. Finally, as mentioned above, many decisions in this field are influenced by economics and clinical trials. Formal cost-effectiveness analysis is needed that compares various HBV management strategies; However, the results will almost certainly vary by region.
Meanwhile, what should the doctor do with patients with HBV and lymphoma to do? We describe one approach (see figure) which is based in part on the results of the paper Kusomoto et al, previous literature, 10 and our belief that for each monitoring strategy to be safe, anticipating compliance with monitoring needs becomes high.
Disclosure of conflict of interest: LKH has received research funding from Gilead. J.J.F. has received research funding from Abbvie, Gilead, Janssen, and Merck and has completed consulting work for Abbvie, Contravir, Enanta, Gilead and Merck.
- © 2019 by The American Society of Hematology