Abstract
Hereditary bleeding disorders include a group of diseases with abnormalities of coagulation. Prior 1990, infection with hepatitis C virus (HCV) was mainly transmitted due to pooled plasma products as a treatment for hereditary bleeding disorders. Anti-HCV positivity in these patients may be as high as >70% in some areas while some of them have been also coinfected with human immunodeficiency virus (HIV). Since about 20% of HCV infected patients naturally clear the infection, chronic HCV infection represent a significant health problem in this group of patients. Mortality because of chronic HCV infection is estimated >10 times higher in patients with hemophilia than in general population, mainly due to liver cirrhosis and hepatocellular carcinoma (HCC). The antiviral treatment of HCV in patients with hereditary bleeding disorders is not different from that of any other infected patients. Even though, many patients with hereditary bleeding disorders had declined (Peg)Interferon-based (IFN) treatment due to side effects. In recent years multiple orally administrated direct-acting antivirals (DAAs) have been approved for HCV treatment. Unfortunately, there is not much experience in treating these patients with these regimens as major studies and real life data did not include adequate number of patients with inherited hemorrhagic disorders. However, available data indicates an excellent safety profile with a sustained virological response (SVR) rate >90%.
Keywords Hepatitis C virus, hereditary bleeding disorders, interferon, ribavirin, direct-acting antivirals
Introduction
Chronic hepatitis C (CHC) is a common global public health problem [1]. In 2015, 71 million individuals were infected with hepatitis C virus (HCV) worldwide [2]. Although the prevalence of HCV infections has decreased in developed countries as a result of effective prevention plans, it remains high in developing countries [3,4]. HCV is the main cause of liver diseases in both developed and developing countries leading to an increased risk of liver failure and hepatocellular carcinoma (HCC) worldwide [3,5]. In Europe, HCV is nowadays responsible for the vast majority (70%) of all chronic hepatitis cases and HCC’s (60%), while is, also, responsible for 40% of all liver cirrhosis cases and 30% of infections in liver transplants [6]. Today the major cause of HCV infections is parenteral drug use. However, in the 1970s and 1980s, before effective and universal screening of blood and blood-derived clotting factors was implemented, most patients with hereditary bleeding disorders who received transfusions have been infected.
Hereditary bleeding disorders include a group of diseases with abnormalities of coagulation. The most frequently encountered hereditary bleeding disorders include von Willebrand's disease and haemophilia A and B. Hemophilia is the most well-known hereditary bleeding disorder and it is estimated to affect between 1 to 5 individuals per 50,000 male population [7]. Prior 1990 almost all patients acquired HCV infection; moreover some of them have been also coinfected with human immunodeficiency virus (HIV).
Rates of disease progression among patients with congenital bleeding disorders and chronic HCV infection vary; however, time of infection and coinfection with HIV appear to be correlated with more rapid progression [8].
Antiviral treatment is no different from that of other infected individuals and aims to eradicate HCV and improve liver fibrosis [9].
In this article, we aimed to review comprehensively the data regarding the epidemiology, natural history and especially management and treatment of HCV infection in patients with hereditary bleeding disorders.
Epidemiology
Prior to the widespread development of viral inactivation of coagulation factor concentrates in the mid-1980s followed by universal screening, infection with HCV was virtually inevitable in patients who received pooled plasma products as a treatment for hereditary bleeding disorders, such as hemophilia [10,11]. In 1993 the observed prevalence of hemophilia in Greece was 14 per 100.000 males. However, the prevalence at birth was 23.1 per 100,000 male births which was 65% higher than the observed prevalence mainly due to the presence of not registered or misdiagnosed patients and deaths due to HIV [12]. CHC has been reported not only in patients who were treated with plasma-derived factor concentrate but also in patients who received cryoprecipitate and fresh-frozen plasma [13]. Since only 20% of patients infected with HCV naturally clear the infection, CHC represent a significant health problem in this group of patients [14].
Several studies have recorded data about the epidemiology of HCV infection worldwide. In general, depending on the laboratory methods used (anti-HCV positivity or viraemia status) and the time data was presented, the prevalence of HCV infection has a marked geographical variation [15]. In Scotland, according to the NHS the total number of patients with bleeding disorders who were infected with HCV as a result of receiving pooled plasma products administered between 1970 and 1989 is estimated to 455. Of these, 255 had a documented positive anti-HCV test while 200 were assessed as likely infected [16]. In a study from Bosnia, HCV infection was positive in 38.7% of cases of hemophilia, while it was found 68% in Netherlands and 44.3% in Greece [17,18, 19]. By 1993, 89% of hemophiliacs in the United States were infected with HCV from exposure to contaminated clotting factor concentrates [20]. In a meta-analysis about the prevalence of hepatitis C in countries under the Eastern Mediterranean Region Office of WHO (EMRO) the researchers concluded that most of the EMRO countries fail to report the precise number of hemophilic patients which varies from 1 per 100,000 male population in Saudi Arabia and Pakistan to 15.8 per 100,000 male population in Qatar [21]. The seroprevalence of anti-HCV positivity among hemophilic patients in Iran varies from 15.6% to 76.7% and was estimated to be 40.8% in a meta-analysis [22]. In another study conducted in Korea, anti-HCV positivity in 1999 was reported to be 49.1% and 47.9% for hemophilia A and B, respectively, while it has decreased to 40.1% and 34.1% in 2005 and 33% and 23.8% in 2012 respectively [23] (figure 1).
Figure 1 Geographical variation of HCV infection, among patients with hereditary blood disorders
In general, genotype distribution in HCV population has a wide ethnic and geographical variation. Therefore, in patients with hemophilia the genotype distribution usually reflects the genotypes of the respective blood donor population. One important characteristic of this group of patients is the significant proportion is of mixed genotypes infection due to multiple exposures over years with contaminated blood products [24].
Overall, HCV genotype 1 seems to be the dominant one (Iran with 72.7%, in Australia with 65%, USA with 46.2%) followed by genotype 3, (27.3%, 30% and 42% respectively) [25,26,27].
In this context, interesting early data upon genotype distribution have been provided from the Multicenter Hemophilia Cohort Study in1998. Genotyping was performed in 109 blood samples collected during follow up (about 10 years) from 32 hemophilic patients (17 HIV positive and 15 HIV negative). In 58% of the patients multiple changes of the genotype have been observed during follow up, significantly more frequent in the HIV positive (76%) patients compared to the HIV negative (33%) [26].
Natural history
Hepatitis C progresses slowly but after about two decades of chronic infection end-stage liver disease may occur in 10-20% of patients [28’30]. It seems that progression to end-stage liver disease (ESLD) in patients with inherited bleeding disorders is similar to HCV positive individuals in the general population. Despite this fact, the overall mortality rate of patients with hemophilia was found to be from two to five times higher than the general population [31]. Moreover, other researchers reported an extreme high mortality rate due to HCV namely 16 times higher in patients with hemophilia compared with the general population, mainly due to the development of liver cirrhosis and hepatocellular carcinoma [32]. After 12’25 years of infection, reported incidences of end-stage liver disease vary mainly depending to the definition criteria of cirrhosis (liver biopsy or non-invasive techniques like liver elastography) [33,34]. In some series, up to 30% of patients with bleeding disorders have developed long-term complications of chronic HCV infection and death from liver failure was documented as being the commonest causes of death in these patients. [35]. Co-infection with human immunodeficiency virus (HIV), duration of HCV infection and barriers to HCV treatment seem to represent the most important factors that have been associated with ESLD in these patients [36]. In general, coinfection with HIV in these patients revealed a negative influence on the natural course of the hepatic disease. Early studies have shown that HCV RNA levels were significantly higher in HIV+ than in HIV- patients with hemophilia [37].
Moreover, co-infection with HIV was found to be associated with an increased rate of progression of chronic HCV to cirrhosis [38]. In a study, ten years ago, the cumulative incidence of ESLD ranged from 12% in HIV negative patients to 35% in patients co-infected with HIV [39].
Similarly, an early Greek study followed 138 hemophiliacs with HCV infection for 28 years in order to determine factors which influence the natural history of the liver disease in these patients. 19% of the patients developed cirrhosis and 9% liver failure, with HIV positivity being one of the major risk factors independently associated with worse outcome [40].
However, as highly active antiretroviral therapy (HAART) has dramatically improved the course of HIV infection, HCV-related liver disease has emerged as the leading cause of mortality in HCV/HIV co-infected patients and is one of the most common causes of death in such patients with haemophilia A and B [41]. Duration of HCV infection has, also, been strongly associated with an increased risk of ESLD. As most of these patients acquired HCV infection in early years of life, hazard rates for ESLD increased from 0.10 in the ‘rst decade of infection to 0.90 after more than 20 years of infection [39].
Another risk factor for more rapid progression of the liver disease was found to be represented by the genotype 1 HCV infection. In one study from Italy in a cohort of 88 HCV positive HIV negative hemophilia patients followed for 25 years , 6 patients (4 with genotype 1) developed cirrhosis and 4 patients (all genotype 1) developed liver failure [28]. Furthermore, presence of genotype 1 HCV infection (hazard ratio 2.2 [95% C.I. 1.1-4.2]), and alcohol abuse (hazard ratio 4.9, 95% C.I. 2.5-9.6) were also associated with a higher risk of ESLD [39].
Management
Treatment results with interferon based therapies in HIV negative and treatment na”ve patients appear to be similar to those in the general population with an overall sustained virological response (SVR) rate of 50-60% [42]. However, data for treatment response rate in the subgroup of HIV positive and treatment experienced patients is very limited [43,44]. Although, treatment has been offered in patients with bleeding disorders, many of them have declined interferon-based therapy mainly due to expected side effects [18]. Side-effects were common and the frequency of dose reduction or discontinuation of antiviral therapy was a common problem among studies with interferon based therapies [45]. Nowadays, direct-acting antivirals (DAAs) have changed the landscape of HCV treatment. Although clinical data is still limited in patients with hereditary blood disorders, it seems high-efficient, safe and well tolerated [46-51]. The antiviral treatment of CHC in patients with hereditary bleeding disorders is not different from that of any other infected patients and should follow recently published guidelines such as those proposed by the European Association for the Study of the Liver (EASL) [9, 52].
Interferon based therapies
(Peg)Interferon-based (IFN) treatment had been the standard of care for many years in HCV treatment [53-55]. Several studies have examined the effect of combination therapy with pegylated interferon (PegIFN) plus ribavirin (RBV) in patients infected with HCV. A review of 35 studies with 1151 patients with haemophilia revealed that combination therapy with RBV is superior to interferon monotherapy with reported responses in the haemophilia population being similar to those seen in the general population: 10-20% for IFN monotherapy, 30-40% for IFN plus RBV and 50-60% for PegIFN plus RBV [53,56]. However, the majority of patients included in these studies were treatment na”ve and HIV-negative. This selective population could explain the contrast with previous reports which suggested that patients with haemophilia might have a worse response to antiviral therapy [57]. The first meta-analysis performed in HCV-infected haemophilic patients confirmed that the combination of PegIFN plus RBV was superior compared with the combination of IFN plus RBV (SVR rate 61% versus 43%), though this difference was not statistically significant by meta-regression. Moreover, the relationship between SVR and type of IFN used, at least for non-1 genotypes, was not clear [58].
On the other hand, many patients with inherited bleeding disorders were resistant to start treatment with PegIFN plus RBV, mainly because of side-effects and relatively low SVR rates, especially in HCV genotype 1, which is the most prevalent in this population. Most frequently reported side-effects of IFN-based treatment are fatigue, headache, influenza-like symptoms, hematological abnormalities and neuropsychiatric symptoms [53,59].
In a recent study, investigators assessed the occurrence of side-effects and the changes in quality of life during antiviral treatment with PegIFN and RBV in patients with inherited bleeding disorders and CHC [60]. Irritability was reported in more than 10% of patients, while during treatment, all patients reported fatigue. Other frequently reported side-effects were headache (94%), pruritus and skin rash (94%), cerebral dysfunction such as concentration problems (89%), decreased appetite (89%), fever (85%), hair loss (85%), and sleeping problems (83%). Most of these side-effects have been started during the first week of IFN-based treatment, while within four weeks after cessation of treatment most of the side-effects have been ameliorated. However, fatigue, pruritus and skin rash, concentration and sleeping problems were still present in a large number of patients (59%, 42%, 39% and 34% respectively). Other reported side-effects were dyspnea (43%), cough (21%), dry mouth and thirst (19%), dry and painful eyes (13%), changes in sensation of taste (11%), and memory loss (9%). Two patients stopped treatment prematurely due to side-effects.
The most usual neuropsychiatric symptom during treatment with PegIFN plus RBV is depression. The pathogenesis through which IFN-” induces depression is largely unknown. However, IFN seems to have a direct effect on different cerebral processes. Down-regulation of the glucocorticoid receptor, which is an important component of the negative feedback system of the hypothalamic-pituitary-adrenal axis and of the serotonin receptor 1A (5-HTR1A), is suggested to play an important role [61]. In addition, an increase in transcription and uptake activity of serotonin transporters may also induce depression [62]. Changes in the levels of certain cytokines, such as increased levels of interleukin-6 and IL-8, may be associated with depression during IFN-based treatment [63]. The opioid and the noradrenaline system may also be involved in depression symptoms during IFN-based treatment, while RBV is reported to enhance this phenomenon [64-65]. Drug induced depression might enhance the psycho-social problems in this group of patients. A prospective study assessed the occurrence, course, treatment and risk factors of depression during antiviral treatment for CHC in patients with inherited bleeding disorders [66]. Forty-seven patients were included in the study. At baseline, forty-two patients had no depression. Finally, 23 (55%) developed depression during antiviral treatment and in the majority (78%), during the first 12 weeks.
Treatment with DAA’s
In recent years HCV treatment is undergoing a major revolution. Multiple orally administrated DAAs have been approved for HCV treatment. According to the action mechanism and the therapeutic target, four classes of DAAs have been defined: nonstructural proteins 3/4A (NS3/4A) protease inhibitors (PIs) including simeprevir (SMV), paritaprevir (PRV) and grazoprevir (GZR), NS5B nucleoside polymerase inhibitors (NPIs) including sofosbuvir (SOF), NS5B non-nucleoside polymerase inhibitors (NNPIs) including dasabuvir (DSV), and NS5A inhibitors including ombitasvir (OBV), ledipasvir (LDV), daclatasvir (DCV), elbasvir (EBR) and velpatasvir (VEL) [67]. The major studies with DAA’s did not include patients with special comorbidities, while real life studies are also lacking significant data in patients with inherited hemorrhagic disorders and HCV or HCV/HIV infections. Therefore until recently, there is not much experience in treating these patients with DAA’s [68].
One of the most popular combinations used in the treatment of HCV infection is the fixed-dose combination of SOF/LDV. In phase III studies including patients from the general population with genotype 1 HCV infection, LDV/SOF combination for 8’12 weeks achieved SVR 12 weeks post therapy (SVR12) rates >90% with only few adverse effects [46]. A study was conducted to explore the efficacy and safety of fixed dose combination SOF/LDV plus RBV in patients with CHC and inherited bleeding disorders: fourteen patients with inherited bleeding disorders infected by genotype 1 were enrolled. All of them experienced rapid viral suppression after initiating treatment and all of them (100%, 95% CI: 77′ 100%) achieved both SVR4 and SVR12. No patient experienced virological failure during treatment and no patient experienced virological relapse. Overall 13 patients (93%) experienced at least one adverse event during treatment. The most common adverse events were fatigue, headache, nausea and insomnia [47]. The fixed SOF/LDV combination for 12 weeks was further evaluated in 69 HCV genotype 1 patients and in one genotype 4 patient with inherited bleeding disorders (HIV positive 19%, cirrhosis 28%) with an overall SVR 12 of 99% [48]. Five difficult to treat HCV genotype 1a patients (treatment experienced with cirrhosis) were, also, included and have been treated with the same combination for 24 weeks with an overall SVR 12 of 100%. A small number of HCV genotype 2 and 3 patients were, also, enrolled in this well designed study. Ten HCV genotype 2 (HIV positive 40%, cirrhosis 20%, treatment experienced 30%) patients have been treated with SOF plus RBV for 12 weeks with an overall SVR 12 of 100% and six HCV genotype 3 (HIV positive 50%, cirrhosis 33%, treatment experienced 17%) patients have been treated with SOF/RBV for 24 weeks with an overall SVR of 83%. The high efficacy of SOF/LDV therapy was further documented in a study by Nagao A and Hanabusa H: 43 patients with hemophilia and HCV genotype 1/4 infection (HIV positive 75%) have been treated with SOF/LDV for 12 weeks with an overall SVR 12 of 95% [49]. Further-more the efficacy was not signi’cantly different between the HIV-negative and HIV-positive patients (SVR12: 100% in HIV-negative and 95% in HIV-positive, p=0.12).
The efficacy of SOF/DCV combination has, only, been evaluated in two HCV genotype 1a patients with haemophilia and non-compensated cirrhosis who achieved SVR 12 after a course of 24 weeks duration [50].
And in finally, a randomized placebo-controlled phase III study (C-EDGE IBLD) was conducted to reveal the safety and efficacy of EBR 50mg/d plus the protease inhibitor GZR 100mg/d as fixed combination for 12 weeks in patients with inherited bleeding disorders and HCV genotype 1 or 4 infection [51]. Overall, 107 patients were enrolled (including patients with sickle cell disease and thalassemia) to EBR/GZR arm: SVR 12 was 93.5%, while virological relapse was 5.6%. SVR rate was as high as 100% even in difficult to treat subgroups like treatment-experienced and/or cirrhotic patients. However, presence of baseline NS5A resistance-associated substitutions (RASs) among patients with GT1a infection had a dramatic impact on SVR rate, as it was recorded as low as 25%. Moreover, in this study, lower response rates have been recorded in patients with hemophilia A/B or von Willebrand disease (89.4%) versus patients with sickle cell disease (94.7%) or ”-thalassemia (97.6%). This finding is more likely to be attributed to the presence of baseline NS5A RASs in most of these patients (4/6 patients who experienced virological relapse suffered from hemophilia A/B or von Willebrand disease, while 3/4 of them had baseline RASs). The safety profile was similar in patients receiving EBR/GZR versus those receiving placebo. The most frequent side-effects were headache, fatigue, nausea, and asthenia but there were no discontinuations. All available studies with DAA’s in inherited bleeding disorders including patients’ characteristics and SVR rates are shown in table 1.
Table 1 Treatment of chronic hepatitis C with DAA’s in patients with inherited bleeding disorders
Patients (N) HIV, (%) Genotypes, (%) Cirrhosis, (%) Treatment experience, (%) Regimens SVR rate, (%) Reference
14 – 1a: 71
1b: 29 7 – SOF/LDV/RBV 12 weeks SVR12: 100 Stedman 2015 [43]
99 19 1: 1
1a: 67
1b: 31
4: 1 (1) 28% 39 SOF/LDV 12 weeks SVR12: 99 Walsh 2017 [44]
5 0 1a: 100 100 100 SOF/LDV 24 weeks SVR12: 100
10 40 2: 100 20 30 SOF/RBV 12 weeks SVR12: 100
6 50 3: 100 33 17 SOF/RBV 24 weeks SVR12: 83
43 75 1a: 58
1b: 28
4: 11.5
1a/2b: 2.5 21 42 SOF/LDV 12 weeks SVR12: 95 Nagao 2017 [45]
2 100 1a: 100 100 100 SOF/DCV 24 weeks SVR24: 100 Ackens 2016 [46]
107 5.6 1a: 44
1b: 43
4: 11
1-other: 2
24.5 50.5 EBR/GZR 12 weeks SVR12: 94.5 Hezode 2017 [47]
Concluding remarks
Improvements in blood banking procedures have led to almost no new cases of transfusion-associated HCV infections among patients with hereditary bleeding disorders. However, still a high proportion of these patients suffer from chronic hepatitis C which may lead to liver cirrhosis. Patients with HIV/HCV coinfection represented in the past a difficult group of patients with a more rapid progression of their liver disease. The ‘classic’ IFN-based treatment has been the standard of care for many years and seemed to be efficient as in general population. Nowadays, DAA’s are the standard of care in HCV treatment. Although, these agents are very effective and well tolerated, clinical data in these patients are limited. However, it seems that treatment is similar to the general population and DAA’s are applicable to patients with hereditary bleeding disorders and chronic hepatitis C according to recently published EASL guidelines [9]. Moreover the HIV/HCV coinfected patients are no longer a ‘difficult to treat’ group in the era of DAA’s
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