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Chronic hepatitis D (CHD) is the most serious form of viral hepatitis. Patients co-infected with hepatitis D (HDV) are at higher risk of related complications such as cirrhosis and hepatic decompensation. Progression from compensated (cACLD) to decompensated advanced chronic liver disease (dACLD) is a critical event because the risk of death increases substantially once decompensation occurs. With reference to the current Baveno VII consensus criteria, decompensation is defined as the presence of significant ascites, hepatic encephalopathy (HE), or variceal hemorrhage. In addition to treating complications of cirrhosis, treatment of the underlying condition is critical to ultimately improving liver function and resolving complications of cirrhosis, and clinically specific treatment regimens for patients who progress to dACLD are also required.
In the field of congenital heart disease (CHD), the European Medicines Agency gave conditional approval for the first time to brevirotide (BLV), which is now fully approved. BLV is a hepatitis D virus entry inhibitor that blocks sodium taurocholate co-transport polypeptide (the main transporter for bile acid absorption), which is required for hepatitis D virus and hepatitis B virus entry. Clinical trials have shown that BLV can cause viral and biochemical responses, but according to the study inclusion criteria, approval of BLV is limited to patients with cACLD, leaving the most vulnerable dACLD patient population without an option for antiviral therapy.
近期，德国汉诺威医学院的Katja Deterding教授团队Hepatology发表了《Safety and efficacy of off-label bulevirtide monotherapy in patients with HDV with decompensated Child-B cirrhosis—A real-world case series》，显示在特定病例中，尽管存在肝功能失代偿，BLV治疗可能安全有效。 研究旨在提供更多关于dACLD 患者使用BLV的现实世界经验。
01
Research Methods:
In collaboration with centres in Germany, Austria and Italy, we collected anonymized retrospective data from patients with decompensated liver disease due to CHD. Given the anonymized and retrospective data collection, written informed consent is not required. We included patients who received monotherapy for BLV at a dose of 2 mg subcutaneously per day. According to the Baveno VII consensus, decompensation is defined as severe ascites, HE, or variceal bleeding.
02
Findings:
The retrospective analysis included 19 patients with cirrhosis of Child-Pugh class B and clinical symptoms of hepatic decompensation. Twelve (63%) patients developed ascites (n=5 grade 1, n= 6 grade 2, n= 1 grade 3). Fifteen (79 percent) patients had albumin levels below 35 g/L, five (26 percent) had an INR higher than 1.5, and nine (47 percent) had bilirubin levels above 34 micromol/L. All patients had a decreased platelet count (a surrogate for portal hypertension). The median observation period was 41 weeks (16–104, IQR: 26–75). All but one patient who required an early liver transplant at week 16 completed at least 24 weeks of treatment.
Throughout the observation period (Figure 1), 14 patients (74%) achieved a virologic response after a median treatment time of 17 weeks (IQR: 16–32). Three patients (16 percent) had a partial response and two patients (11 percent) had no virologic response. Among the patients with virologic response, 4 patients had HDV-RNA recurrence. It was accompanied by a slight increase in ALT in 2 patients and a significant increase in ALT in 1 patient (ALT>3 ULN). After the increase, HDV-RNA levels decreased in two patients, while those in the other remained elevated. Fourteen patients (74%) developed a biochemical response after a median of 13 weeks of treatment (IQR: 9–16) and ALT returned to normal.
Figure 1. Virologic and ALT indicators of virologic response (A, B) and partial/no response (C, D) in 19 patients
When the median Child-Pugh and MELD scores at baseline were compared to each patient's most recent treatment week, the scores were found to be stable. When analyzing individual changes in liver function, in some cases, liver function decreases, followed by an increase in MELD (Figure 2A) and bilirubin (Figure 2B), which ultimately leads to liver transplantation. The improvement in albumin levels was particularly pronounced (n = 6), with a significant decrease of more than 1 g/L in 3 patients (Figure 2C). An increase in platelet count was measured in 10 patients and a significant increase in platelet count > 10,000/microL in 4 patients, which was confirmed by at least 2 consecutive measurements and can be used as a surrogate indicator of improvement in portal hypertension (figure 2D).
Figure 2. LONGITUDINAL DEVELOPMENT OF (A) MELD, (B) BILIRUBIN, (C) ALBUMIN, AND (D) PLATELET COUNTS
Adverse events included ascites in 3 patients, 2 of whom had virologic reactions. Normalization of ALT did not occur in any of these cases. The development of ascites is associated with an elevated MELD score, leading to the need for liver transplantation (n = 1). Another patient had HCC, which is another risk factor for decompensation. A total of 3 patients required liver transplantation, with decreased liver function and worsening ascites despite reduced HDV-RNA levels (n = 3) and improved ALT (n = 2). BLV treatment is terminated at the time of liver transplantation. During BLV treatment, 2 patients had elevated ALT with an elevated ALT of >3 ULN. These elevations are self-limiting. One patient had an elevated ALT with elevated HDV-RNA>1 log and ascites, while the other showed a stable virologic response. During treatment, 1 patient developed an acute abdomen that required surgical treatment and was subsequently decompensated due to hernia incarceration; One patient died from other causes.
03
Conclusions of the study
This report on off-label treatment of BLV in patients with decompensated HDV cirrhosis showed that virological and biochemical response rates were similar to those of compensated liver disease. There was significant improvement in liver function and portal hypertension. However, not all patients experienced this improvement. Controlled trials are needed to confirm the safety and efficacy of BLV in decompensated HDV cirrhosis.
Ponder
This study reports the real-world experience of 19 patients with decompensated HDV cirrhosis treated with BLV. Based on our results, the use of BLV in this vulnerable population appears to be similar to the virological and biochemical response rates of compensated patients. However, not all patients experienced clinical improvement, and some experienced further decompensation, including the need for liver transplantation in three patients. BLV may have a beneficial effect on the transplant waiting list by reducing the risk of further decompensation and/or HBV/HDV reinfection in liver transplantation. Importantly, close monitoring is required due to differences in clinical response in patients with decompensated HDV cirrhosis after treatment with BLV. The use of BLV in decompensated liver disease is not currently recommended. Therefore, there is an urgent need for controlled trials.
文献索引：Hepatology. 2024 Sep 1; 80(3):664-673. doi: 10.1097/HEP.0000000000000847. Epub 2024 Mar 13.
Source: Hepatobiliary Photography Platform