Adults with hemophilia have one of the highest prevalence rates of hepatitis C virus (HCV) among all populations at risk for this disease. Similarly, patients with hemolytic disorders requiring chronic transfusions (e.g., sickle cell disease and thalassemia) were at high risk for HCV acquisition before adequate blood donor screening practices were instituted. HCV management in these patient populations may be complicated by the underlying disease processes. Liver biopsy, which is often performed before the treatment of HCV genotype 1, is controversial in the setting of hemophilia because of the perceived risk of bleeding. Ribavirin, an essential component of HCV therapy, typically induces hemolysis, which is problematic in a patient with an underlying hemolytic disorder.
Epidemiology of HCV, Hemophilia, and Hemolytic Disorders
Almost all patients treated with plasma products for hemophilia before 1987 were exposed to HCV, and more than 80% developed chronic infections. Nearly 20% have progressed to end-stage liver disease after more than 3 decades of follow-up.1 The incidence of infection peaked in the late 1960s and the early 1970s, perhaps as a result of the use of cryoprecipitate and factor concentrates, which were pooled from large numbers of donors.2 After the discovery of human immunodeficiency virus (HIV), improved donor screening practices and the introduction of heat inactivation likely contributed to the sharp decline in the incidence of HCV after 1984, well before HCV-specific screening was instituted (Fig. 1).
A high proportion of the deaths in the population of patients with hemophilia between 1990 and 2007 have been attributed to complications of HCV.3 An HIV coinfection is present in 25% of HCV-positive patients with hemophilia, and it represents a substantial burden for these patients.1 HIV is a strong independent risk factor for the development of end-stage liver disease in these patients, and liver disease is increasingly being recognized as an important complication in HIV-positive patients. Furthermore, the predominant causes of mortality have shifted with the advent of effective therapies for HIV. Between 2000 and 2007, more patients with hemophilia died from HCV-related complications than from acquired immune deficiency syndrome.3 The mean age at infection is lower in this group (9-10 years) versus other groups at risk for HCV (e.g., injection drug users).2 Because a longer duration of infection is also associated with an increased risk of end-stage liver disease, these patients may be more likely to develop liver-related complications.
In comparison with hemophilia, less is known about the relationship between HCV and hemolytic disorders. Reports of the prevalence of HCV among people with sickle cell disease (∼10%-20%) and thalassemia (∼35%) vary widely.4 Many of these cases are presumed to result from blood transfusions before sensitive screening tests for HCV were instituted in 1992. The risk of cirrhosis in this group is confounded by secondary iron overload.
HCV Treatment Issues and Management Strategies
Liver biopsy is often performed before the treatment of HCV genotype 1 to assess the degree of necroinflammatory activity and fibrosis. Hemophilia and other inherited disorders of coagulation have been considered relative contraindications to percutaneous liver biopsy, primarily because of the risk of bleeding. However, in the absence of factor VIII or IX inhibitors, the use of clotting factor replacement before biopsy and for another 48 hours at home through self-administration, although costly, minimizes the bleeding risk. It appears that the risk of bleeding with appropriate factor replacement is no greater than the risk for the general population5,6 (Table 1). Transjugular biopsy is another approach that has been used to minimize bleeding complications in patients with hemophilia.7 Thus, liver biopsy may be cautiously performed in patients with hemophilia when it contributes to therapeutic decision making. Noninvasive markers of fibrosis such as serum biomarker panels and transient elastography may be promising alternatives to liver biopsy in this population.8,9
|Study||Year||Patients (n)||Procedures (n)||Liver Biopsy Method||Outcome|
|Lesesne et al.||1977||6||6||Percutaneous||Not available|
|Preston et al.||1978||8||8||Percutaneous||Not available|
|White et al.||1982||15||15||Not available||Not available|
|Aledort et al.||1985||115||126||Not available||Death (n = 2)|
|Hay et al.||1987||34||43||Not available||No bleeding|
|Makris et al.||1991||77||99||Not available||No bleeding|
|Ahmed et al.||1996||50||50||Percutaneous||No bleeding (pain: n = 2)|
|Hanley et al.||1996||22||22||Laparoscopy||No bleeding|
|Wong et al.||1997||35||35||Percutaneous||No bleeding|
|Gupta et al.||1997||6||6||Transjugular||No bleeding|
|Fukuda et al.||1998||36||36||Percutaneous||No bleeding|
|Adamowicz et al.||1999||13||13||Not available||No bleeding|
|Farell et al.||1999||5||5||Percutaneous||No bleeding|
|McMahon et al.||2000||17||21||Percutaneous||No bleeding|
|Venkataramani et al.||2000||12||12||Percutaneous||Bleeding (n = 1)|
|Shields et al.||2000||21||Not available||No bleeding|
|Lethagen et al.||2001||27||39||Percutaneous||No bleeding|
|Delladetsima et al.||2002||24||25||Percutaneous||No bleeding|
|Denzer et al.||2003||1||Mini-laparoscopy||Not available|
|Dimichele et al.||2003||10||10||Transjugular||No bleeding (pain: n = 3)|
|Stieltjes et al.||2004||69||88||Transjugular||Bleeding (n = 4)|
|Saab et al.||2004||11||11||Transjugular||No bleeding|
|Shin et al.||2005||56||65||Transjugular (n = 64) or femoral (n = 1)||Bleeding (n = 7)|
|Dawson et al.||2005||5||5||Transjugular||No bleeding|
|Detrait et al.||2007||9||9||Transjugular||No bleeding|
|Sterling et al.||2007||29||29||Percutaneous||No bleeding|
|Total||713||778||Bleeding (n = 12)|
The current standard of care for the treatment of HCV is peginterferon α and ribavirin with or without a protease inhibitor (specific for genotype 1). The response to treatment is variable and depends on many different patient- and virus-level factors. Persons with hemophilia are exclusively male and have a longer duration of infection than others; these factors have been associated with reduced responsiveness to interferon-based therapy.10 However, despite the higher prevalence of these negative predictors, studies of pegylated and nonpegylated interferon with ribavirin have demonstrated response rates comparable to those for the general population with HCV10-13 (Table 2). Unfortunately, most patients with hemophilia are not treated because of unrelated comorbidities or concerns about adverse treatment events, which are no different than the concerns about (or incidence of) adverse events seen in the general population.8 The development of factor VIII and IX inhibitors has been reported in association with the use of interferon but only rarely in case reports of patients with or without underlying congenital hemophilia.14
|Study||Year||Treatment||Treatment Duration (Weeks)||Patients (n)||Genotype 1 Patients (n)||HIV-Positive Patients (n)||Patients With Sustained Virological Response (%)|
|Fried et al.10||2002||Interferon and ribavirin||48||56||39||0||29||Not reported||—|
|Meijer et al.11||2004||Interferon and ribavirin||52||66||51||0||50||39||—|
|Mancuso et al.12||2006||Peginterferon and ribavirin||24 or 48*||64||41||0||63||50||—|
|Posthouwer et al.13||2007||Peginterferon and ribavirin||Variable||85||Not reported||23||59||33||48|
In contrast to hemophilia, side effects are a prime concern in the treatment of patients with sickle cell disease, thalassemia, or other hemolytic disorders. Ribavirin itself causes a hemolytic anemia that often requires a dose reduction or discontinuation. When this is combined with an underlying hemolytic disorder, increased transfusion requirements are commonplace.4 To prevent worsening iron overload, chelation therapy may need to be intensified. In addition, patients with secondary iron overload from chronic hemolysis are prone to the development of heart failure and may not tolerate a reduction in hemoglobin.15
The direct-acting antiviral medications telaprevir and boceprevir, in combination with peginterferon and ribavirin, have not been studied specifically in persons with hemophilia or hemoglobinopathies. Their rates of sustained response and adverse event profiles are expected to be similar to those seen in the general population from phase 3 clinical trials. Thus, patients with hemophilia are appropriate candidates for treatment with triple therapy combinations. In contrast, hemoglobinopathies remain a strong relative contraindication to treatment with triple therapy because of the exacerbation of anemia by multiple factors.
HCV represents a significant burden for patients with hemophilia and hemolytic disorders, and those at high risk should be screened. Studies have demonstrated response rates in hemophilia patients comparable to those in the general population without a higher risk of adverse events. In contrast, treatment-induced anemia is problematic for those with preexisting hemolytic anemia. Clinical trials are needed to assess the efficacy and tolerability of direct-acting antiviral agents in these patient groups.