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See the micro-knowledge, prevent buds and stop germination! Several studies have explored the role of TAF in preventing HBV reactivation

 Last Update: 2023-01-05
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To reduce the risk of HBV reactivation, preventive antiviral therapy is key!

To this day, hepatitis B virus (HBV) infection remains a serious global public health problem, with approximately 887 000 deaths each year from HBV-related liver failure, cirrhosis, and hepatocellular carcinoma (HCC) ^[1].

During HBV infection, host immune response, viral replication status, and antiviral therapy are important factors in achieving clinical outcomes in patients with chronic hepatitis B (CHB) ^[2].
。 HBV reactivation manifested by liver inflammation and elevated HBV DNA levels may occur when the host uses chemotherapy drugs, immune checkpoint inhibitors, and biologics for other diseases that result in inhibition of the associated immune response ^[3].
HBV reactivation not only increases the risk of abnormal liver function and liver failure, but also delays tumor treatment and affects prognosis ^[4].

Because immunosuppressive therapy is widely used in clinical practice, including antitumor therapy, rheumatic diseases, blood diseases, kidney diseases and other treatments, the risk of HBV reactivation is high
.
Data suggest that the risk of HBV reactivation can reach 45 to 100 percent and 6 to 29 percent in patients who are HBsAg-positive or negative and undergo hematopoietic stem cell transplantation, respectively [5-9], and 9.
1 to 17 percent in patients with HBsAg-positive tumors treated with immune checkpoint inhibitors ^[^10,11].
The risk can be up to 10 percent in patients with HBsAg-negative lymphoma treated with rituximab ^[12].
The management of HBV reactivation is a matter
of great concern in clinical diagnosis and treatment by many disciplines.

In order to deeply explore the clinical hot issue of HBV reactivation management, the following review will be made on the new research progress of HBV reactivation
.

The importance of prophylactic antiviral therapy

As early as 1975, Dr.
Jack R.
Wands and his team first observed the phenomenon of HBsAg turning from negative to positive in patients with hematologic tumors undergoing chemotherapy, and pioneered the concept of HBV reactivation ^[13].
Over the next 40 years, with advances in detection technology, scholars continued to improve the definition of HBV reactivation ^[14,15].
At present, the definitions of HBV reactivation in domestic and foreign guidelines are as follows:
Table The definition
of HBV reactivation in each guideline is due to the persistence of covalent, closed, circular DNA molecules (cccDNA) that form supercoils, Any person with chronic HBV infection and previous HBV infection is at risk
of HBV reactivation.
The ideal strategy for HBV reactivation prevention and management is to screen high-risk patients for appropriate prophylactic antiviral therapy ^[21].

In terms of screening, the consensus among the guidelines is that all patients who are going to receive chemotherapy and immunosuppressive therapy should be screened for HBV serological markers and monitored for HBV DNA levels
.

In terms of treatment, interventions for HBV reactivation include preventive treatment and preemptive treatment
.
Prophylactic therapy refers to the administration of antiviral therapy to all patients at intermediate and high risk before initiating immunosuppressive therapy, preemptive treatment is close monitoring of alanine aminotransferase (ALT), HBsAg, and HBV DNA levels during immunotherapy, and antiviral therapy is started only when HBV DNA and/or ALT levels are elevated ^[21].
。 In a study of 80 patients with HBcAb-positive lymphoma receiving rituximab, prophylactic antiviral therapy was more effective than preemptive therapy at reducing the risk of HBV reactivation (HBV reactivation rate 4.
3 versus 23.
9 percent 18 months after chemotherapy, P = 0.
019) ^[22].
。 The 2021 clinical practice guidelines for HBV reactivation associated with immunosuppressive therapy developed by the Asia-Pacific Liver Association also clearly pointed out the value of prophylactic antiviral therapy in reducing the risk of HBV reactivation ^[19]
.

Efficacy and safety of TAF in preventing HBV reactivation

Among the first-line antiviral therapies recommended by domestic and foreign guidelines, entecavir (ETV), tenofovir fumarate (TDF) and tenofovir propofovir fumarate (TAF), although TAF was approved at the latest, more and more data
have been accumulated in the past two years on the prevention of HBV reactivation.

At this year's APASL 2022 Annual Meeting, a team of researchers at Hokkaido University Hospital in Japan evaluated the efficacy of TAF in preventing HBV reactivation associated with antitumor therapy or immunosuppressive therapy and HBV reactivation associated with hepatitis ^[23].

In this multicenter prospective study, a total of 132 patients with HBV infection (HBsAg-positive and/or HBV DNA-positive) receiving antineoplastic therapy (n=72) or immunosuppressive therapy (n=60) were enrolled, of whom 108 were treated with TAF for HBV reactivation and 24 were previously HBV infected with HBV after HBV reactivation during immunosuppressive therapy.
Use TAF to prevent HBV reactivation-related hepatitis
.

The primary endpoint of the study was the proportion
of patients who developed HBV reactivation and HBV reactivation associated with HBV reactivation after 6 months and 12 months of TAF.
HBV reactivation is defined as a 100-fold increase in HBV DNA from baseline, and HBV reactivation-related hepatitis is defined as ALT greater than 3 times the upper limit of normal (ULN).

In the end, a total of 119 patients completed 6 months follow-up and 84 patients completed 12 months follow-up
.
None of the patients had HBV reactivation or HBV reactivation-related hepatitis during the entire follow-up period, and there were no events of discontinuation of TAF therapy
.
This suggests that prophylactic antiviral therapy with TAF is effective and safe
.

Table Efficacy and safety data on TAF in preventing HBV reactivation At
this year's European Association of Liver Diseases Annual Meeting (EASL 2022), a study by the Faculty of Medicine of Marmara University in Turkey also explored the role of TAF in preventing HBV reactivation associated with chemotherapy or immunosuppressive therapy ^[24]
。
This multicenter observational study included 326 patients with HBV infection with benign and malignant conditions requiring chemotherapy or immunosuppressive therapy who enrolled in patients receiving TAF (25 mg/day) as a prophylactic antiviral regimen
.
HBV reactivation is defined as HBsAg positive and/or HBV DNA positive or elevated
.

Finally, 158 patients (male/female: 83/75) with 6-month follow-up records were included in the analysis, with a mean age of 59.
55±12.
2 years, of which 30 were HBV DNA-positive patients, 5% HBeAg-positive, and solid tumors were the most common primary disease
.

During the entire follow-up period, none of the patients receiving TAF prophylactic antiviral therapy experienced HBV reactivation, no HBV-related deaths were observed, and there were no significant changes
in renal function and lipid levels during treatment.
In 77% of patients with detectable HBV DNA at baseline
, HBV DNA is negative.
None of the patients had discontinued chemotherapy or immunosuppressive therapy
.

The above two foreign studies have verified that TAF has good efficacy and safety as a treatment plan to prevent HBV reactivation in patients receiving immunosuppressive therapy
.

Efficacy and safety of TAF in the treatment of HBV reactivation

Clinically, what should be done if a patient has HBV reactivation, especially in a patient already receiving antiviral therapy?
In order to explore whether TAF can be used as a salvage treatment after HBV reactivation in treated patients with HBV-associated HCC, the research team of the Fifth Medical Center of the Chinese People's Liberation Army published a study in APASL 2022 ^[25].

This randomized, open-label, single-center study enrolled 665 patients with HBV-associated HCC treated with ETV, and a total of 48 patients were screened for HBV reactivation
.
Upon enrollment, these patients were randomized to either switch to TAF (Group A) or add TAF (Group B).

The results of the patient enrollment criteria
showed that 17 patients (mean age 57.
4±7.
7 years) were eventually included in the analysis
.
Overall, after 3 months of follow-up, 41.
2% of patients achieved HBV DNA unpredictability after treatment with TAF, and there was no significant difference between groups A and B (55.
6% vs.
37.
5%, P=0.
637).

It can be seen that for HCC patients with HBV reactivation treated with ETV, whether TAF alone or in combination with ETV, it can effectively inhibit viral replication, which is safe and well tolerated
.

Efficacy of TAF in preventing HBV reactivation in patients undergoing solid organ transplantation

As mentioned above, TAF can reduce the risk of HBV reactivation in patients receiving immunosuppressive therapy, so can TAF also play a role in preventing HBV reactivation for patients who need surgery such as liver transplantation?
At APASL 2022, a study by Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine in China evaluated the efficacy and safety of TAF in HBsAg-positive liver transplant patients ^[26].

This retrospective study included 10 HBsAg-positive adult patients who underwent liver transplantation and were divided into treatment-naïve (n=2) and treated (n=8, NAs other than TAF 48 weeks prior to transplantation)
according to whether they received antiviral therapy before enrollment.
When these patients are on the liver transplant list, TAF therapy
is initiated or switched.
The primary endpoint of the study was the proportion of
patients who received a virological response (HBV DNA< 20 IU/mL) 24 weeks postoperatively.

The results showed that 8 out of 10 patients had undetectable HBV DNA at baseline, and the remaining 2 patients had HBV DNA of 800 IU/mL and 90,000 IU/mL
, respectively 。 After 24 weeks postoperatively, five patients with unpredictable baseline HBV DNA remained unpredictable after surgery, and patients with a baseline HBV DNA of 90,000 IU/mL had HBV DNA levels decreased to 2,180 IU/mL after 4 weeks of preoperative TAF treatment and achieved a virologic response
8 weeks after liver transplantation.
Another patient with baseline HBV DNA positive also achieved a virologic response
24 weeks after transplantation.

The remaining 2 patients had transient elevation of HBV DNA after liver transplantation, followed by rapid decline, and no drug-related adverse events were reported
.
ALT returned to normal
in 90% of patients 4 weeks after surgery.
Throughout the study, the patient's kidney function remained stable
.
This suggests that TAF is safe and effective
in preventing HBV reactivation after liver transplantation.

In conclusion, domestic and foreign studies have verified the efficacy and safety
of TAF in preventing HBV reactivation.
With the emergence of more and more new anti-tumor drugs, the clinic is also facing more and more immunosuppressive therapy-related HBV reactivation problems, for patients with HBV infection with neoplastic diseases and those who need to receive immunosuppressive therapy, how to evaluate the risk of HBV reactivation brought by each treatment regimen and formulate a better preventive antiviral treatment plan will be the key issue that clinicians need to face in the future
。

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Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013.
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Natural history of chronic hepatitis B virus infection and long-term outcome under treatment.
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Hepatitis B Virus Reactivation Increased the Risk of Developing Hepatic Failure and Mortality in Cirrhosis With Acute Exacerbation.
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Role of hepatitis B antibody in predicting reactivation of resolved hepatitis B virus infection in leukemia patients[J].
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[10]Pu D, Yin L, Zhou Y, et al.
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Hepatitis B virus reactivation in cancer patients with positive Hepatitis B surface antigen undergoing PD-1 inhibition.
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, Yu, ML.
, Wong, G.
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APASL clinical practice guideline on hepatitis B reactivation related to the use of immunosuppressive therapy.
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1.
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2.
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3.
From the latest real-world research, look at the current status of first-line treatment of CHB | cutting-edge insights

4.
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