FICHAS DE PROYECTOS PRIORITARIOS

Currently there is no vaccine available for either the prevention (prophylactic vaccination) or the treatment (therapeutic vaccine) of HCV. Until recently, the treatment of HCV with the best available therapy was costly, lengthy, and frequently ineffective and the development of an effective vaccine is felt to be an urgent priority towards eradication if HCV.

Among the estimated 170 million people estimated to be infected with HCV worldwide, at least 8 million live in Europe, with prevalence rates of over 5% in some European countries [107]. It is estimated between 20,000 and 50,000 individuals are affected by Hepatitis C in Ireland [108]. Primary (acute) infection is usually asymptomatic, though sometimes patients may present with jaundice. Unlike hepatitis B virus infection, fulminant liver failure during primary infection is extremely rare. Given its asymptomatic nature, it is possible that the true prevalence of infection is greater than reported.

Persistent HCV is a significant cause of morbidity and mortality, due to progressive liver fibrosis, with 20-50% of patients developing cirrhosis and hepatocellular cancer [27]. Chronic HCV is now a leading cause of liver failure, hepatocellular cancer and liver transplantation, and is among the most common causes of death in patients co-infected with HIV-1 on combination ART [109]. Additionally data shows that individuals infected with HCV are large users of

emergency departments, outpatient and inpatient services, reflecting the public health burden of HCV [110].

As mentioned above, HCV therapies were frequently associated with significant toxicity. Until recently, the mainstay of therapy for over a decade was Pegylated- Interferon-a (PEG-IFN) in combination with ribavirin. Sustained virological responses (SVR; defined as undetectable HCV RNA 24 weeks after treatment termination) were achieved in less than 50% of mono-infected patients with genotype 1 disease, the most common genotype in Western Europe. SVR rates for HIV/HCV co-infected individuals varied from 15-70% according to genotype, HCV RNA level and IL-28B genotype, and were as low as 22% for genotype 1 in a recent international trial [111]. In addition, multiple studies have demonstrated that SVR rates were markedly lower in patients with HIV/HCV co-infection, compared to those with HCV alone [112-114].

Eradication of HCV after therapy with interferon and ribavirin in HIV/HCV co- infected patients has not only been associated with a reduction in liver-related events but also with a reduction in HIV progression and mortality not related to liver disease [115].

The field of HCV therapeutics has evolved rapidly in recent years. Basic science enhancements in HCV cell culture systems and replication assays have led to a broadening of our understanding of many of the mechanisms of HCV replication and, therefore, potential novel antiviral targets. These steps broadly encompass viral attachment, entry, and fusion; viral RNA translation; posttranslational processing; HCV replication; and viral assembly and release [116].

Two direct-acting anti-viral (DAA) agents (Telaprevir and Boceprevir) for HCV received regulatory approval in 2011. Telaprevir and Boceprevir are first generation DAA agents and are classed as NS3/4A protease inhibitors. These compounds target the serine protease NS3/4A, which cleaves the HCV polyprotein at four sites during its replication cycle [117]. However, the additional cost for these medications was more than €25,000 per patient. This

DAA therapy significantly improved response rates in both HCV-mono-infected and HCV/HIV-co-infected patients with genotype 1 disease. However, in the latter, up to 40% still failed to clear HCV infection.

Because mono-therapy with either agent resulted in viral resistance, these agents needed to be used in combination with PEG-IFN and ribavirin. As a result, Telaprevir and Boceprevir-based therapy were associated with more frequent and severe adverse effects, coupled with drug-drug interactions, including with antiretroviral drugs [118]. Despite suboptimal SVR rates with these therapies, favourable treatment outcomes have been associated with short courses of therapy [119], highlighting the fact that our knowledge of positive predictors of response to HCV therapy needs to be expanded.

Universal hope for future and emerging DAA therapy is for an all-oral combination regimen that is highly potent, well tolerated, pan-genotypic, of short duration and with little possibility of the emergence of drug resistance. Ideally drug-drug interactions associated with concomitant HIV antiretroviral therapy and other medication should be minimal. Recent trials assessing these newer DAA agents have shown great promise [120, 121], with SVR rates typically greater than 90% with few side effects.

Current approved DAAs inhibit 3 specific steps in the HCV lifecycle including NS3/4A protease enzyme (as described above), NS5A protein and the NS5B polymerase. The NS5B enzyme is crucial for HCV replication as it catalyses the synthesis of the complementary minus-strand RNA and subsequent genomic plus-strand RNA. There are two types of NS5B polymerase inhibitors: nucleotide inhibitors (active site inhibitors) and nonnucleoside inhibitors (allosteric inhibitors). NS5A inhibitors target a protein that appears to be essential to the replication machinery of HCV and essential in the assembly of new infectious virus particles. The specific functions of this protein have yet to be elucidated. Table 1.1 lists the approved DAAs in Europe in 2016. Other treatment regimens are at the clinical development stage and will likely reach the market within the next two years.

Table 1.1 Approved HCV DAAS in Europe in 2016

Sofosbuvir Dasabuvir

Sofosbuvir/ledipasvir Grazoprevir/elbasvir Sofosbuvir/velpatasvir Daclatasvir

Paritaprevir/ombitasvir/ritonavir Simeprevir

Following on from the clinical trials of DAA medications, experience is emerging from prospective cohorts showing all-oral DAA regimens are well tolerated and associated with a high virologic efficacy in cirrhotic HIV/HCV co-infected patients, long considered a population that are difficult to treat [122]. Multiple studies have demonstrated similar SVR rates to those observed in trials of HCV- mono-infected individuals [123].

However the cost of these newer agents will continue to be a deterrent for population-wide applications of these highly effective regimens [124]. A major consideration in treating HCV in individuals with HIV co-infection is the identification and management of drug interactions between DAAs and antiretroviral agents [125]. Additionally, HCV viral resistance may represent a challenge in the future. We have reported a previously undescribed case of treatment-emergent non-structural protein 5A (NS5A) resistance mutations, Q30H and Y93C, leading to a failure of 24-week course of sofosbuvir/ledipasvir and ribavirin therapy for the treatment of HCV genotype 1a in an interferon- experienced, HIV-1 co-infected patient with cirrhosis [126]. Onward transmission of treatment-resistant virus may also pose challenges towards eradication of HCV in the future [127].

Anticipated advances in HCV therapy will have a limited impact on the burden of HCV-related disease on a population level unless barriers to HCV education, screening, evaluation and treatment are addressed and treatment uptake improves [128].

The development of a T cell-based vaccine that prevents HCV infection, or induces effective T cell responses during treatment and impacts on HCV viral load could therefore be of major benefit to patients and would have a substantial impact on morbidity, quality of life and treatment costs.