Hepatitis C and bleeding disorders in Europe

Between December 2016 and March 2017, the EHC developed and sent out a questionnaire to its 45 national member organisations (NMOs). The questionnaire (reproduced in full in the appendix to this article, Figure A1) consisted of 17 questions and was developed by members of the EHC Steering Committee, members of the EHC Data and Economics Committee, other EHC staff and a hepatologist. EHC NMOs were asked to respond to the questionnaire together with the support of local clinicians. The questionnaire was available in both English and Russian, and focused on three main areas: identifying the patient population with bleeding disorders infected with HCV within each country; the viral status of those currently living with HCV; and the care and treatment available to PWBD with HCV. HCV infection was defined as any person with a bleeding disorder who was exposed to the virus and seroconverted to become HCV antibody (anti-HCV) positive, irrespective of whether they later cleared the virus spontaneously or achieved an SVR through treatment (thus becoming anti-HCV positive and PCR negative).

In terms of PWBD who were infected with HCV, ten countries (Austria, Denmark, France, Hungary, Ireland, Montenegro, the Netherlands, Slovakia, Slovenia and Sweden) stated they were able to provide exact figures, seven of which reported their data came from a national registry (Austria, Ireland, France, Montenegro, Slovakia, Slovenia and Sweden). Data reported from the Netherlands came from national surveys or clinical research [11]. For Denmark and Hungary, the data source was not specified.

Eighteen countries gave estimates in numbers or a percentage of a given population (e.g. adult). Data for these countries came from a variety of sources, including national registries, patient organisation records, treatment centres, patient records, scientific publications, and anecdotal information collected by the patient organisation [12]. Respondents in Latvia and Poland reported that they had no data on this topic.

Taken together, a total of 4,751 PWBD were infected with HCV in the ten countries that provided exact numbers. Using reports from the EHC and the World Federation of Hemophilia (WFH) on current numbers of PWBD, and estimates provided in other responses to the questionnaire, a further 11,000 patients could have been infected in the remaining 18 countries that were unable to provide exact numbers [3, 4].

Survey participants were asked to identify which hepatitis C treatments are available in their countries as well as the level of reimbursement (see Table 3). The oldest and hence most available treatment is PEG-interferon with ribavirin, which is available in 26 countries and fully reimbursed in 24 countries. In Belarus and Ukraine, the treatment is available but co-payment from the patient is required.

PEG-interferon with ribavirin with first-generation DAAs (telaprevir or boceprevir) is available in 18 countries. It is fully reimbursed in seven countries (Austria, Greece, France, Italy, Lithuania, Poland and Slovakia). It is available but not reimbursed in 11 countries. This treatment is not available in two countries (Finland and Macedonia).

PEG-interferon with ribavirin combined with sofosbuvir is available in 20 countries. It is fully reimbursed in 17 countries. It is available but not reimbursed in three countries (Albania, Austria and Ukraine). It is not available in Macedonia.

Combinations of second generation DAAs are available in 21 countries. In 19 countries the treatment is fully reimbursed by the national healthcare system. In Montenegro, the treatment is available, however the patient must contribute to the cost of the treatment. In Austria patients can access treatment, however the full cost has to be paid by the individual. The treatment is not available in Albania, Macedonia, and Ukraine.

Additionally, as shown in Table 4, the Czech Republic, Cyprus, Denmark, Finland, Germany, Greece, Hungary and Ireland reported on patients with bleeding disorders and HCV achieving SVR with second-generation DAAs to date (either provided by the government programmes or clinical trials).

Survey participants were also asked whether patient access to these treatments is prioritised based on disease progression and/or having a bleeding disorder. Patients are prioritised based on the progression of liver disease in 21 countries. This is not the case in six countries (Albania, France, Germany, Lithuania, Montenegro and the Netherlands). PWBD are prioritised in eight countries (Austria, Bosnia and Herzegovina, Cyprus, Finland, Hungary, Ireland, Italy and Lithuania).

Finally, 15 countries reported that they had a national hepatitis C treatment programme (Cyprus, Finland, France, Hungary, Ireland, Italy, Latvia, Lithuania, Montenegro, Poland, Portugal, Slovakia, Slovenia, Sweden and Ukraine). Ten countries noted that they did not have such a programme, and seven countries reported no information on this.

Participants were asked where hepatitis C treatment is administered in the country. Twenty-seven countries reported on this (Azerbaijan, Romania and Switzerland did not respond). In 11 countries (Bulgaria, Finland, Greece, Hungary, Lithuania, the Netherlands, Poland, Portugal, Slovenia, Sweden and Ukraine) administration of treatment may be provided by more than one service. Hepatitis C treatment is most commonly administered in specialised hepatology, gastroenterology and infectious disease services in hospitals (26 countries). In Lithuania and Poland, treatment can be prescribed by a general practitioner. Seven countries reported that treatment can be administered through the haemophilia treatment centre (Bulgaria, Greece, Hungary, Lithuania, Portugal, Sweden and Ukraine).

Survey participants were asked about the current cost of a 12-week treatment course for sofosbuvir or sofosbuvir/ledipasvir as an indicator of current payment levels for second-generation DAAs. 19 countries responded, of which 16 reported prices. For a 12-week treatment course with sofosbuvir, the median price was €37,000 (range €15,000-€54,000), and the median price for a 12-week treatment course with sofosbuvir/ ledipasvir was €40,000 (range €14,000- €54,000). Twelve countries reported that bulk price negotiations for the purchase of second-generation DAAs have been carried out in their country, and that prices may be significantly different to actual prices paid (which were not available due to commercial sensitivity).

Survey participants were asked to specify whether PWBD who had been infected with HCV had received financial compensation (see Table 5). All those infected in Cyprus, France, Hungary, Ireland and Sweden received some form of compensation. No compensation was provided in ten countries (Austria, Czech Republic, Denmark, Greece, Macedonia, Montenegro, the Netherlands, Portugal, Slovakia, and Slovenia). Variable forms of compensation were offered in other countries. In the UK, for example, financial support was given to most of those infected, except those who spontaneously cleared the virus; while in Germany only those co-infected by HIV were compensated. An estimated 10% of the infected population in Albania received some compensation. In Italy 37% of those infected received some compensation in 2004, and there is an ongoing lawsuit for an estimated 17% of the infected population. Respondents did not provide details as to why only a certain percentage of the infected population received compensation.

As highlighted by other authors, the infection of tens of thousands of PWBD with HCV through their treatment is one of the largest medical treatment disasters in history [1]. A new paradigm in treatment regimens may create the opportunity for the eradication of HCV from the bleeding disorders community. Data reported to European Haemophilia Safety Surveillance (EUHASS) show that hepatocellular cancer is the most common cancer in patients with haemophilia, and liver disease is the most common cause of death in these individuals. In Ireland and Portugal we have seen the dramatic eradication of HCV either through the prioritisation of PWBD or a dedicated national commitment to the eradication of the virus, respectively [13, 14, 15]. It is in support of the objective of eradication of HCV in PWBD in Europe that this survey aims to identify the gaps in care, access and monitoring of hepatitis C in this population. The importance of this objective was recognised by the European Directorate for the Quality of Medicines and Healthcare (EDQM) of the Council of Europe in their 2016 recommendation, which states: “Treatment for hepatitis C with direct-acting antiviral agents should be provided to all people with haemophilia on a high priority basis.” [16]

Data on the initial prevalence of HCV infections in PWBD, co-infection of HIV, survival rates and SVR varies significantly across Europe. Also, the data provided in relation to the number of PWBD infected with HCV needs to be interpreted with a degree of caution. For example, in the case of Ireland, because of the existence of a specific database for patients [9], it is probable that numbers reported include those who were co-infected with HIV and may have died prior to being diagnosed with hepatitis C.

Only five of the 30 countries that responded to the survey were able to provide an accurate breakdown of initial infections, co-infection with HIV, historic deaths due to hepatitis C, treatment success and ability to identify patients who still require treatment.

Four countries were unable to provide any data on hepatitis C prevalence in the PWBD population. In the remaining 18 countries, information is estimated based on best available information. It is also important to note that the variations in infected population are related to the size of the bleeding disorders population as well as the type, quality and quantity of access to clotting factor concentrates. For example, Montenegro reported that only two PWBD were infected with HCV, while the UK reported an estimated 3,000 patients infected. Interestingly, with data collected in a 2012 survey, 14 of the 22 countries who were unable to provide accurate data, were countries with a national haemophilia registry [3]. This identifies a clear gap in comprehensive care, especially considering the rates of hepatocellular carcinoma and deaths related to HCV that could be used to accurately identify patients with HCV. Countries with national registries may be comforted by their ability to track annual bleeding rates (ABR), but it is just as important for them to have an accurate picture of hepatitis C in PWBD, not least because it is the leading cause of mortality in this population in Western Europe [1].

The rate of HIV co-infection ranges from 1% in the Czech Republic, Hungary and Ukraine to 51% in Denmark. The most probable explanation for such variations is access to different treatment products at the height of the treatment-related infections. While clotting factor concentrates were the predominant treatment in Western Europe, fresh frozen plasma or cryoprecipitate predominated in Central and Eastern Europe due to restrictions on the purchase of US plasma sourced concentrates prior to 1989. This changed with the concurrent fall of the Berlin Wall and the discovery of HCV and its identification as the culprit of what was then known as non-A/non-B (NANB) hepatitis.

In four countries (Austria, Belarus, Poland and Ukraine) testing for HCV is not part of the routine review for PWBD. Of more interest is that it is a routine component of care in 22 countries, yet despite this a limited number of countries were able to provide accurate data on infection status in PWBD. There is a significant disconnect between the data available in patient records and how this should be used to monitor what is clearly a significant cause of patient mortality.

In terms of testing, the movement away from liver biopsy as the “gold standard” towards FibroScan^® makes identifying current levels of liver damage in patients significantly easier. Twenty countries use this as a routine way of monitoring PWBD who are infected with HCV. Due to the potential complications with haemophilia, liver biopsy is now rarely used as a testing standard. Of the countries that responded to the survey, there is some disparity in monitoring timings, with 44%, 39% and 17% of countries monitoring every six months, annually, and biennially, respectively. However, it was not reported whether there was a stratification for those with more advanced fibrosis or cirrhosis.

The development of DAAs, resulting in greatly increased probability of SVR, reduction in treatment duration with specific stop and extension rules and significantly reduced side effects, allows for a paradigm shift in the availability of treatment. In 81% of the countries that responded to the survey, treatment is provided through the traditional specialties of hepatology, gastroenterology and infectious disease clinics. In Lithuania and Poland (6% of the responding countries) treatment is available through general practitioners. Interestingly, in 23% of the countries that responded to the survey, patients may avail of therapy through haemophilia treatment centres. This has significant benefits, as they are often the key point of contact for patients with bleeding disorders and their respective healthcare systems. The task shifting of HCV treatment to non-specialist providers, which may or may not be overseen by hepatologists, may improve access to treatment and help bridge the remaining gaps [17]. This has become more practical given the much lower side-effect profile of second-generation DAAs compared to previous therapies. [18]

As highlighted internationally, cost implications are the greatest impediment to the treatment of those with HCV, with costs differing up to five-fold between countries for some products. This level of disparity puts patients at risk in two ways. Firstly, it limits access to treatment in the patient’s own country. In this scenario, access to treatment is often based on progression, which ultimately defeats the purpose of treating early. Secondly, it drives vulnerable patients to seek cheaper options in other countries or via the internet, who then potentially appear with a prescription asking to be monitored and tested, creating significant clinical dilemmas. [19]

In the case of infected PWBD, the cost should be considered in terms of lives already lost and providing immediate recompense for those who are still infected to live a life free of the virus. Market forces have lowered the costs of treatment with newer regimens. All individuals with bleeding disorders should be considered candidates for treatment irrespective of the stage of fibrosis within the liver. The eradication of HCV in PWBD in Europe is an idea whose time has come. [1]