HCV HISTORY & EPIDEMIOLOGY

An overview of Hepatitis C Virus (HCV)

The Hepatitus C Virus (HCV) was first discovered in 1989. Even if seemingly new, this chronic disease is increasingly spreading all over the world. For example, it constitutes the most ordinary chronic liver disease in the United States. Indeed, it infects the liver and, if ignored, it can produce liver cancer, liver damage and eventually liver failure.

Hepatitis C is the most frequent among blood related infections. The WHO estimates that 170 million persons suffer from Hepatitis C Virus infection and 350.000 die from liver diseases related to HCV. The spread of the infection reaches 3-4 million persons, yearly.

The still growing number of HCV patients’ population is surprising. When confronted with HIV – which is commonly considered the greatest viral disease in the World – the numbers are astonishing: 170 million HCV cases versus 37 million HIV patients.

HCV Characteristics

HCV makes part of the Flaviviridae family and is positive-stranded RNA virus. In order to succeed in producing an effective pharmaceutical answer to such a widespread virus, we should evaluate HCV’s main features

In order to exist, HCV needs to replicate continuously, as it replicates its genome directly into RNA without extending across any DNA intermediate. It differs from HIV and HBV because it does not present any nuclear form.

The Hepatitis C genotype has six different subtypes. In order to understand the difficulty of producing an effective treatment for chronic HCV, it must be clear that although usually only one genotype infects a patient, every genotype includes several other closely related strains, called quasi species. These last have the skill to mutate quickly, thus far frustrating any therapeutic approach.

In the United States, genotype 1 is both the most diffused and the hardest to cure. In order to offer a targeted therapeutic solution, identification of the patient’s genotype is of most importance for physicians. Genotype 2 and 3-patients react three times better than genotype 1 to a therapy with alpha interferon or to the combination of alpha interferon and ribavirin. Besides this, in a combined therapy, identification of the right genotype influences the duration of the treatment. That is also why testing the genotype can be of enormous clinical importance.

Afflicting almost half of worlds HCV cases, genotype 1 is the most diffused in the world: its population is estimated as over 80 million cases, one third of which in East- Asia. The second in grade of importance is HCV genotype 3 with close to 55 million infections. Genotype 2, 4 and 6 account for 23 % of all cases. Genotype 5 covers the remaining <1 %. If genotype 1 and 3 are common in whatever social context, genotype 4 and 5 typically afflict lower-income countries. Even if genotype 1 is the most diffused, non-genotype 1 HCV cases still cover more than the half of the total HCV cases.

HCV Vaccine Development

Although vaccines exist for Hepatitis A and Hepatitis B, the development of a Hepatitis C vaccine has presented challenges. No vaccine is currently available, and although several vaccines are currently under development, the Hepatitis C virus is highly variable among strains and fast mutating, making development of an effective vaccine very difficult.

Sofosbuvir (brand name Sovaldi) is an antiviral drug, developed by Gilead Sciences and used to treat Hepatitis C infection. In combination with other therapies, Sofosbuvir can effectively cure Hepatitis in 90 per cent of patients. It inhibits the RNA polymerase, that the Hepatitis C virus (HCV) uses, to replicate its RNA. It was discovered at Pharmasset and developed by Gilead Sciences. Sofosbuvir is a component of the first all-oral, interferon-free regimen, approved for treating chronic Hepatitis C. Interferon-free therapy for treatment of Hepatitis C reduces the side effects associated with the use of interferon. Sofosbuvir treatment regimens last 12 weeks for genotypes 1, 2 and 4, and 24 weeks for the treatment of genotype 3. This is surprisingly half of the time that was required in previous treatments. The price of Sofosbuvir has created considerable controversy, particularly with respect to accessibility in developing countries.

As Sofosbuvir is always combined with other drugs such as Ribavirin and Interferon, only the adverse effects of these combinations have been evaluated. Common side effects are fatigue, headache, nausea, rash, and irritability. Most side effects are significantly more common in interferon containing regimens, compared to Interferon-free ones.

It is clear that although Sofosbuvir provides significant advantages over previous Hepatitis C medications, it can hardly be called an ideal drug. Taking in consideration the extremely high treatment costs, the 12 to 24-weeks treatment period and the significant side effects, they may argue that there is ample space for improvement. Nevertheless, Sofosbuvir sales reached an astonishing $10 billion in 2014! Can our DDX3 Helicase Inhibitors outperform Sofosbuvir? Why not? Our current available HCV Inhibition assays showed exceptionally good efficacy and very low cytotoxicity. Our compounds might very well provide a much more patient friendly and cost effective alternative for a Hepatitis C viral infection therapy.

Hepatitis C Virus (HCV) is successfully inhibited by our Translation Inhibitor compounds, with excellent sub-micro molar concentrations. combined with very high CC50 values. As such, our DDX3 Helicase Inhibiting compounds are considered  as highly promising drug candidates against HCV.

HCV Microbiology

HCV replicates mainly in the hepatocytes of the liver, where it is estimated that daily each infected cell produces approximately fifty virions with a calculated total of one trillion virions generated.

NS5 Inhibitors

A development of resistance to HCV is to be expected with such a heavy viral load, speed of replication and mutation rate. It is quite hard to develop inhibitors of viral proteins able to avoid the development of new resistant strains.