Liver health in hemophilia in the era of gene therapy

Abstract

Gene therapy for hemophilia is a groundbreaking treatment approach with promising results and potential to reduce the burden of the disease. However, uncertainties remain, particularly regarding the liver side effects of AAV gene therapy, which are more common in hemophilia A.

Unlike some other diseases, such as spinal muscular atrophy, where the target cell for gene therapy is different from the one affected by side effects, hemophilia gene therapy operates within the same cellular domain-the hepatocyte. This overlap is challenging and requires a targeted strategy to mitigate the risks associated with liver injury, which often requires temporary immunosuppressive therapy. A comprehensive approach is essential to increase the efficacy of gene therapy and reduce the likelihood of hepatocyte damage. Key components of this strategy include a thorough pre-gene therapy assessment of liver health, careful post-gene therapy liver monitoring, and prompt therapeutic intervention for loss of transgene expression and liver injury. Collaboration between hematologists and hepatologists is essential to ensure a well-coordinated management plan for patients undergoing hemophilia gene therapy.

This review addresses the critical aspect of hepatic comorbidities in patients with hemophilia, emphasizing the need to identify and address these issues prior to initiating gene therapy. It examines the known mechanisms of liver damage and emphasizes the importance of liver monitoring after gene therapy. In addition, the review draws insights from experiences with other AAV-based gene therapies, providing valuable lessons that can guide hemophilia centers in effectively managing liver damage associated with hemophilia gene therapy.

Introduction

Hemophilia is a rare X-linked inherited disorder caused by a deficiency of either factor VIII (hemophilia A) or factor IX (hemophilia B). The liver, specifically hepatocytes, is crucial for synthesizing these coagulation factors, while hepatic sinusoidal endothelial cells produce factor VIII. Many patients with hemophilia (PWH) born before 1985 faced liver health challenges and were exposed to hepatitis B and C viruses through plasma-derived replacement therapies and blood transfusions [1]. Today, these patients over the age of 40 may be candidates for hemophilia gene therapy (GT). However, those born after 1985 have been spared such exposure due to advances in treatment safety. PWH generally have lower physical activity and more sedentary lifestyles than non-hemophilic peers [2], a trend exacerbated in developing countries without early prophylaxis [3]. Sedentary lifestyles can lead to obesity and hepatic steatosis [2,4]. Chronic pain from hemophilic arthropathy often requires analgesics [5], posing hepatotoxic risks. GT using AAV technology targets hepatocytes and may induce liver toxicity, requiring careful assessment of liver function and monitoring of PWH before and after GT. Healthcare professionals at hemophilia treatment centers, as well as hepatologists, must have a thorough understanding of the essential role of liver health in patients considered for GT. Liver disease is the second leading cause of years of working life lost in Europe, after ischemic heart disease [6]. Excessive alcohol consumption, ultra-processed foods and obesity are key factors in liver-related health problems. Early detection and management of liver disease in hemophiliacs is critical to minimizing its impact.

As innovative hemophilia therapies that target hepatocytes become more widely available, collaboration between hematologists and hepatologists is expected to increase. This collaboration is particularly important not only in the management of hepatitis B and C infections in PWH, but also in the selection of patients for GT, the follow-up after GT with regard to the risk of liver toxicity during the first year and the theoretical long-term risk of developing a hepatocellular carcinoma (HCC).

This article reviews common liver diseases in PWH, highlighting the need for their thorough screening and management before GT. It also discusses multidisciplinary post-GT monitoring to minimize liver toxicity and maximize therapeutic efficacy. The overarching goal is to optimize hemophilia care, improve GT outcomes, and protect the liver from potential toxicities associated with this innovative treatment.

Section snippets
Viral hepatitis and hemophilia
Despite a decline in HIV-related deaths since the 1990s [7], viral infections remained a significant mortality risk for PWH until the early 2000s [8]. Hepatitis C complications, including severe cirrhosis, liver failure and HCC, were the leading causes of death in this population. Proactive screening for HCV infection, such as testing for serum anti-HCV antibodies, remains critical for this population in countries where blood products are still widely used [9]. Acute HCV infection is often

Metabolic dysfunction-associated steatotic liver disease (MASLD)
Metabolic dysfunction-associated steatotic liver disease (MASLD) [26] is the most frequent liver disease worldwide. It results from the accumulation of triglycerides containing lipid droplets in hepatocytes in the absence of an excessive consumption of alcohol. MASLD prevalence is of about 30 % in the general population [27]. It is estimated that this figure will double by 2030, and that MASLD-related cirrhosis and HCC will triple by that time [28,29]. Sustained weight loss over 10 %, through

Hepatocellular carcinoma
The increasing life expectancy of people with hemophilia (PWH) presents new challenges in the management of associated cardiovascular diseases and cancers, particularly HCC due to hepatitis C and liver diseases [35]. HCC is the most common solid tumor in PWH [36]. Prevention, diagnosis and treatment of HCC in PWH do not differ from the general population [37,38]. Although antiviral treatments of HCV and HBV infections can reduce the risk of HCC, surveillance remains critical for early detection

Liver disease staging in hemophilia
Liver biopsy, the “gold standard” for the assessment of liver histology, can be safely performed in PWH by experienced operators under substitution therapy. Trans-jugular liver biopsy (TJLB) has been recommended for these patients at high risk of bleeding [42,43]. One of the major limitations of TJLB is the small size of the liver sample, which may also be fragmented during the procedure thus rendering a correct histological interpretation difficult. In addition, the area of biopsy is not

Gene therapy of hemophilia and liver health
Market authorization has been granted in Europe and North America for valoctocogene roxaparvovec for hemophilia A (HA) and etranacogene dezaparvovec for hemophilia B (HB). These two gene therapies are based on viral transduction of hepatocytes. They use recombinant vectors derived from the adeno-associated virus serotype 5 (AAV5), unable to replicate. In both cases, AAV5 vectors contain a codon optimized single strand of DNA (factor [F]VIII or FIX transgene) to improve expression of the

Insights gained from investigating liver toxicity in other AAV-based gene therapies
Onasemnogene abeparvovec GT for spinal muscular atrophy, using an AAV9 vector, is associated with hepatotoxicity [88]. Intravenous administration of AAV9, though effective for gene transfer, requires remarkably high doses to target the central nervous system (CNS), often exceeding 1 × 1014 vg/kg. This high dose requirement is due to the predominant distribution of AAV genomes in organs outside the CNS, particularly the liver. Consequently, in a minority of patients, this significant

Conclusion
Hematologists in hemophilia centers and hepatologists have a long history of collaboration, particularly in managing hepatitis B and C. This partnership is expected to deepen with the introduction of GT. Their collaboration is essential for several aspects: interpreting pre-GT liver tests during eligibility assessment, diagnosing and managing post-GT liver toxicity, screening for silent hepatitis B before prescribing corticosteroids, considering liver biopsy in complex cases, and preventing