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This article summarises the evolution of management of hepatitis C over the last two decades and its implications for public health
Chaitra C Shekar MBBS MRCP(UK)
John F Dillon MBBS MD MRCP(UK) FRCP(Edin)
Gut Group, Medical Research Institute,
NHS Tayside Ninewells Hospital,
University of Dundee, Dundee, UK
In the 25 years since its discovery, hepatitis C virus (HCV) infection has gone from an esoteric cause of transfusion related hepatitis to a major threat to the health of more than 180 million people worldwide and more than 1% of the European population by causing cirrhosis, liver failure and hepatocellular cancer. With the rapid development and availability of drugs specifically designed and directed at inhibiting key points of the HCV virus life cycle, we have now entered an era where we can cure all patients with HCV infection. Today we can prevent it causing any liver disease and potentially eliminate the virus from Europe. The staff and infrastructure to achieve this is in place across Europe and the only question is if there is a wiliness to pay the costs of these new drugs to achieve this level of disease control or if there is no willingness to pay to treat everyone then how will the drugs be rationed.
Natural history of HCV
Hepatitis C virus was identified in 1989 while looking for the causative agent of non-A, non-B hepatitis particularly associated with blood transfusion. HCV was shown to be the major cause of transfusion hepatitis. It was only following the availability of diagnostic tests in 1991 that the true massive scale and consequences of hepatitis C became apparent. In Europe 10% of acute hepatitis cases are due to acute hepatitis C.1,3 The majority of patients with acute hepatitis C infection are asymptomatic, with symptoms occurring in only 10–25% of patients. The initial infection is characterised by detection of virus in the blood (2–14 days), elevation of liver enzymes and eventually antibodies to HCV (20–150 days).2,4–6
The diagnosis of hepatitis C infection is based upon detection of anti-HCV antibodies. However these indicate only current or previous infection and active infection must be confirmed by detecting HCV viral RNA in the blood. As the majority of patients are asymptomatic or minimally symptomatic, the diagnosis is usually not made in the acute phase and is missed with resultant underestimation of the incidence. The natural history of acute infection is for a minority to clear the virus. A variety of host and viral factors aid spontaneous clearance of the virus in acutely infected patients. If the virus persists for more than six months it indicates chronic infection. 75% of patients go on to develop chronic infection, which progresses to fibrosis slowly in the first 15 years.
Longer duration of infection and increasing age of the patient correlates with higher morbidity and mortality. The probability of progression to cirrhosis is greater than 16% at 20 years after infection and increases exponentially after that.2,7 Once cirrhotic or possibly even with only fibrosis, there is progression to hepatocellular cancer. In HCV-related cirrhosis this is thought to occur at an annual rate of 2–4%.8,9 The risk of hepatocellular cancer increases as fibrosis advances. Host cofactors such excessive alcohol consumption, smoking etc. can accelerate disease progression. The overall standardised mortality ratio for HCV positive individuals ranges from 1.6–4.5 compared to the general population.1,10 In patients who acquire HCV infection through injecting drug use, the estimated mortality from liver disease is 20–25%.1,11
It is important to emphasise that the majority of the patients infected with the virus remain asymptomatic and hence results in under reporting of the cases. According to the European centre for disease prevention and control data on the surveillance of hepatitis B and C published in July 2014, 30,607 incident cases of hepatitis C were reported in 27 EU/EEA Member States in 2012, representing an overall notification rate of 7.8 cases per 100,000 population. The male-to-female ratio in 2012 was 2:1. Just over a half (54.0%) of all the hepatitis C cases reported were aged between 25 and 44 and 9.5% of cases were younger than 25 years. The most commonly reported route of transmission in 2012 was injecting drug use, accounting for 76.5% of all cases. The next most commonly reported transmission routes were through blood and blood products (4.3%), sexual transmission (not specified) (4.3%) and nosocomial transmission (4.0%).12
Although the main route of transmission continues to be injecting drug use there has been a steadily increasing proportion of cases amongst men who have sex with men (MSM). In older populations, especially in Southern European countries, there is a large excess of apparent nosocomial infection. What led to this method of transmission is unclear but it does not appear to be ongoing and across Europe the main driver for new infections are people who inject drugs (PWID).
HCV prevalence across Europe ranges between 0.4% and 3.5%, with wide geographical variation and higher rates in the South and the East.1,13–15 There are seven HCV genotypes (1–7) with large number of subtypes. Genotype 1 is predominant worldwide. In Europe, there are significant populations of genotype 2 and 3 which together equal genotype 1. The remaining genotypes are much less common and strongly associated with emigration from endemic areas. Genotype 4 is especially common in emigrants from Africa. The PWID groups are assimilating immigrants as demonstrated by an increase in the incidence and prevalence of genotype 4 acquired by this route.
Association of HCV infection with the PWID population means it is a predominant healthcare problem in a group that is multiply disadvantaged and relatively excluded from healthcare. This stigma extends across all those infected. Hepatitis C impacts not only the physical health of the individual but also their mental health, social relationships and quality of life. As the major route of HCV acquisition in Europe is by drug use, those individuals affected with hepatitis C are often reluctant to be tested for HCV or disclose it if they have it for fear of the stigma associated with the diagnosis.
It can lead to social isolation due to this stigma combined with a fear of transmitting the infection in intimate contact. Lack of knowledge in society and amongst healthcare workers to some extent tends to amplify these misconceptions. Changing the attitudes of healthcare workers and their approach to dealing with these patients is key to the wider treatment of this infection. Patients should be made aware of the nature of the disease and that it can be cured. This will encourage patients to seek medical care. Managing hepatitis C in a holistic way by involving the patient, family members and healthcare providers is likely to impact the course of the disease and will help reduce the disease burden.
Treatment revolution and brief pharmacology
The aim of treating hepatitis C is to achieve a cure with resolution of liver disease. The success of therapy is cure, which is defined as the absence of HCV RNA from serum, originally 24 weeks after cessation of therapy (SVR24) and now (as defined by the FDA) 12 weeks after cessation (SVR12). Therapy has evolved significantly from interferon monotherapy, which achieved SVR rates of 5–20%, to the addition of ribavirin in the late 1990s with SVR rates of 40%. Until 2011, dual therapy with pegylated interferon-α (pegIFN-α) and ribavirin (RBV) was the approved treatment for chronic hepatitis C. HCV genotype 1 had SVR rates of 50% in Western Europe with similar response seen in patients with genotype 4.
The introduction of telaprevir and boceprevir in 2011, the first generation of direct acting antivirals (DAAs) that target the NS3/4A serine protease and hence are called protease inhibitors (PIs), led to a step change in HCV treatment. These PIs were specific for the genotype protease and were used along with pegIFN/RBV as triple therapy. This regimen proved clinically effective in treatment-naïve patients and treatment-experienced patients including previous null responders to dual therapy.1 Duration of treatment was 24–48 weeks and PIs needed to be administered orally every 7–9 hours.
These regimens were specific to genotype 1, were complex to administer and came with a high and serious side effect burden. Despite an increase in the SVR rate to 70% for triple therapy, a large proportion of patients continued to be intolerant to the side effects of pegIFN-α and PIs. Also the high replication rate of HCV and the numerous variants produced during replication result in drug resistant strains, especially given the low genetic barrier to resistance associated with first generation DAAs. Although triple therapy has been effective, the SVR rates in cirrhotics and previous null responders to dual therapy, those who are most at risk of progressive disease, are much lower than in treatment-naïve patients.
Expanding knowledge on the life cycle of HCV and its structural proteins has triggered the development of second generation DAAs. These DAAs can be divided into 3 classes based on the viral protein they are directed against (and can be identified by their suffix): protease inhibitors (–previr), NS5A inhibitors (–asvir) and NS5B inhibitors (–buvir). The drugs have variable activity against different genotypes and sub types. Pan-genotypic coverage would be the ideal. New DAAs approved for use in 2014 include; simeprevir (SMV) and faldaprevir (FDV), the first once daily PIs, sofosbuvir (SOF) the first available NS5B polymerase inhibitor and daclatasvir (DCV), the first NS5A inhibitor.
There are several other agents in this classes that will be licenced imminently. These latest agents in various combinations (combined with pegIFN/RBV or pegIFN-free or both pegIFN/RBV-free regimens) have been shown to increase cure rates in genotype 1 to in excess of 95% and reduce treatment duration from 48 weeks to 8–12 weeks.
Competitor agents in each of the three classes will join these drugs in the next few months. In addition, more than 30 anti-HCV agents are or have been in Phase II or III trials. Many of these drugs are directed mainly at genotype 1 in trials, most have activity against other genotypes and some of the drugs coming to market are pan-genotypic, having activity against all genotypes. So while cures for genotype 2 and 3 are currently only around 90% these will rise further with the new agents coming online. These drugs also have a higher barrier to drug resistance and significantly less side effects. The efficacy of these new drugs have not been extensively studied in genotype 4 yet but triple therapy with SOF + pegIFN/RBV for 12 weeks has resulted in 96 –100% SVR in small numbers of patients.
It is expected that they will be highly efficacious in the wider population. These new agents with high treatment efficacy and an excellent safety profile remove the need for most of the monitoring and support work that was required for interferon based regimens.
We are entering an era where virtually all HCV infection is curable. If infection is detected before complications supervene, the mortality, morbidity and healthcare cost of HCV infection can be avoided entirely. The cost of newer agents differs across the globe and sofosbuvir in particular as the first of the second generation drugs to reach market comes at a premium price in developed countries. This poses dilemmas for healthcare providers; we have a curative treatment for a common disease that causes substantial morbidity and mortality, but it is so common that we will struggle to find funds to treat all patients. Additionally to get the maximum cost efficiency from these pharmaceutical developments we need to invest in a testing programme to detect patients before they develop complications of liver disease and liver cancer.
The stunning breakthroughs in the treatment of HCV create a great challenge to the healthcare community to deliver the benefits of these new therapies to our patients.