Hepatitis C is an infectious disease caused by a virus of the flavoviridae family that can infect and damage the liver.
Course Of the Disease
People become infected with hepatitis because of blood-to-blood contact associated with intravenous drug use, poorly sterilized medical equipment and transfusions. In most cases, hepatitis C causes no noticeable symptoms until the liver has been significantly damaged. When symptoms do occur, they are often vague and can be easily mistaken for another condition. Only around 15% of cases shows symptoms during the first six months of a hepatitis C infection: this stage is known as acute hepatitis C. The symptoms may include high temperature, tiredness, loss of appetite and they occur a few weeks after infection.
In an estimated one in five cases of hepatitis C, the immune system will successfully eliminate the virus and the person will have no further symptoms (unless they become infected again).
In the remaining cases, the virus persists inside the body for many years. This is known as chronic hepatitis C.
The symptoms of hepatitis C can vary widely from case to case. In some people, symptoms may be barely noticeable. In others, they can have a significant impact on quality of life. The symptoms can also go away for long periods of time ( remission ) and then return. Some of the most commonly reported symptoms of hepatitis C include: tiredness, headaches, depression, problems with short-term memory, concentration and completing relatively complex mental tasks, joint and muscle aches and pain, itchy skin, flu-like symptoms, like those that occur in the acute phase of the infection, abdominal pain, pain in the liver area (which is located in the right upper side of abdomen).
Depending on other risk factors, such as alcohol use, between 10% and 40% of people with untreated chronic hepatitis C will go on to develop scarring of the liver ( cirrhosis ), often more than twenty years after first catching the virus. Around one in five people with cirrhosis will then develop liver failure, and one in 20 will develop liver cancer, both of which can be fatal.
There are seven major genotypes of hepatitis C, but most cases are 1, 2 or 3. Genotype 1 is the most common subtype in the U.S. Genotypes 2 and 3 are more common in Europe than in the U.S. and genotype 3 is very prevalent on the Indian subcontinent.
In general, treatment is recommended for those with proven HCV infection liver abnormalities; treatments consisted of a combination of pegylated interferon alpha (polyethylene glycol is added to make the interferon last longer in the body) and the antiviral drug ribavirin for a period of 24 or 48 weeks, depending on HCV genotype. This treatment was shown to cure rates of between 70 and 80% for genotype 2 and 3, and 45 to 70% for other genotypes.
Although the results has been encouraging, this treatment can cause cause severe nausea and depression, and other debilitating symptoms such as itchy skin, rash, tiredness, nausea, anemia, neutropenia.
Emergence of new drug-resistant virus strains are rare also because the virus does not have an animal reservoir, meaning that it is not harboured by other animals, and it is not easily spread between people, except through blood. Improved screening of blood supplies used for transfusions and better patient-screening techniques have already greatly cut transmission rates over the last 15 years. But researchers has been studying new treatments to increase cure rates, to avoid collateral effects and to eliminate latent form of the virus.
New Treatments: Sofosbuvir
In December 2013, US Food and Drug Administration (FDA) approved a new drug , Sofosbuvir (brand name, SOVALDI™) from Gilead Sciences in Foster City, California for Hepatitis C treatment. The major point of this decision was a study in which it was shown that if taken in combination with ribavirin, the treatment eliminates hepatitis C in around 80% of people. Also in another study, a combination of Sofosbuvir and Simeprevir in 197 people with HCV who had either not responded to interferon or who had advanced liver fibrosis caused by the virus cleared the virus in more than 90% of participants.
United States to approve potent oral drugs for hepatitis C
Sofosbuvir (Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate) is a prodrug that is metabolized to the active antiviral agent 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate. The triphosphate acts like a substrate for the viral RNA polymerase, and inhibites of viral RNA synthesis. Prior to the discovery of Sofosbuvir, a variety of nucleoside analogs had been examined as anti-hepatitis C treatments, but these exhibited relatively low potency. This low potency originates in part because the enzymatic addition of the first of the three phosphate groups of the triphosphate is slow. The design of Sofosbuvir avoids this slow step by building the first phosphate group into the structure of the drug during synthesis. Additional groups are attached to the phosphorus to temporarily mask the two negative charges of the phosphate group, thereby facilitating entry of the drug into the infected cell.
Sofosbuvir and other nucleotide inhibitors of the HCV RNA polymerase exhibit a very high barrier to resistance development. This is an important advantage relative to HCV drugs that target other viral enzymes such as the protease, for which rapid resistance development has proved to be an important cause of therapeutic failure.
From December 2013, Sofosbuvir is a component of the first all-oral, interferon-free regimen approved for treating chronic hepatitis; interferon-free therapy for treatment of hepatitis C reduces the side effects associated with use of interferon.
The FDA approved Sofosbuvir in combination with ribavirin (RBV) for oral dual therapy of HCV genotypes 2 and 3, and for triple therapy with injected pegylated interferon (pegIFN) and RBV for treatment-naive patients with HCV genotypes 1 and 4. Sofosbuvir treatment regimens last 12 weeks for genotypes 1, 2 and 4, and 24 weeks for treatment of genotype 3. This is typically half the time as with prior treatments.
Adverse effects and Interactions
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 as compared to interferon-free ones. For example, fatigue and headache are nearly cut in half, influenza-like symptoms are reduced to 3–6% as compared to 16–18%, and neutropenia is almost absent in interferon-free treatment.
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP). Drugs that are potent P-gp inducers in the intestine (e.g., rifampin or St. John's wort) may decrease Sofosbuvir plasma concentration leading to reduced therapeutic effect of it and thus should not be used with. Sofosbuvir should not be taken in association with anticonvulsants, antimycobacterials, HIV protease inhibitors.
The intracellular metabolic activation pathway of Sofosbuvir is mediated by generally low affinity and high capacity hydrolase and nucleotide phosphorylation pathways that are unlikely to be affected by concomitant drugs.
Sofosbuvir will cost $84,000 for 12 weeks of treatment used for genotype 1 and 2, and $168,000 for the 24 weeks used for genotype 3. The price has moved controversy, with critics contending the drug is unaffordable and supporters suggesting that the drug brings price savings relative to older treatments associated with severe side effects, lengthy treatment, and low cure rates. There is also concern that patients in developing countries may not have sufficient access due to high prices; a key issue is that there are no international agencies or groups that purchase hepatitis C drugs for distribution to poor countries. Doctors of the world and other association wrote an essay to stress the inability of most of common people and country to cope with such high prices.
Letter of Doctors of the World
What is the minimum cost per person to cure HCV?, 2013
Authorization in Europe
Sofosbuvir was approved by the European Medicines Agency (EMA) in January 2014; marketing of Sofosbuvir, authorized in all the 28 country of European Union, will be in 400 mg tablets for once-a-day oral administration, in association with other antiviral agents, while mono therapy is not recommended.
The authorization was supported by five “Phase 3” studies data, NEUTRINO , FISSION , POSITRON , FUSION and VALENCE . In those studies, 12 or 16 week therapy, was found to be superior or not inferior to the current option of treatment with RBV/peg-IFN or to historical controls, thanks to rates of patient that got SVR (sustained viral responds, which is HCV not detected) 12 weeks after finishing the therapy. Rates were includes between 70-90%.
Nowadays, Sofosbuvir has been approved in USA, Canada, Europe; authorization is on examination in Australia, New Zealand, Switzerland and Turkey.
Sofosbuvir for previously untreated chronic hepatitis C infection, 2013