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Hepatitis C is an infectious disease caused by a virus of the flavoviridae family that can infect and damage the liver.
People become infected with hepatitis because of blood-to-blood contact associated with intravenous drug use, poorly sterilized medical equipment and transfusions. 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). 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. 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. 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. 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.
Sofosbuvir and other nucleotide inhibitors of the HCV RNA polymerase exhibit a very high barrier to resistance development. 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. As Sofosbuvir is always combined with other drugs such as ribavirin and interferon, only the adverse effects of these combinations have been evaluated.
Sofosbuvir is a substrate of drug transporter P-gp and breast cancer resistance protein (BCRP).
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.
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 .
Nowadays, Sofosbuvir has been approved in USA, Canada, Europe; authorization is on examination in Australia, New Zealand, Switzerland and Turkey. Hepatitis C virus is a single-stranded RNA virus, and its open-reading frame encodes ten structural proteins (viral capsid and envelope) and non-structural proteins (required for viral replication). The effect of sofosbuvir 400 and 1200 mg on QTc interval was evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover thorough QT trial in 59 healthy subjects.
The pharmacokinetic properties of sofosbuvir and the predominant circulating metabolite GS-331007 have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Relative to fasting conditions, the administration of a single dose of SOVALDI with a standardized high fat meal did not substantially affect the sofosbuvir Cmax or AUC0-inf. Sofosbuvir is extensively metabolized in the liver to form the pharmacologically active nucleoside analog triphosphate GS-461203. Following a single 400 mg oral dose of [14C]-sofosbuvir, mean total recovery of the dose was greater than 92%, consisting of approximately 80%, 14%, and 2.5% recovered in urine, feces, and expired air, respectively. Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polyme-rase, which is essential for viral replication. HCV replicons with reduced susceptibility to sofosbuvir have been selected in cell culture for multiple genotypes including 1b, 2a, 2b, 3a, 4a, 5a and 6a. In a pooled analysis of 982 subjects who received SOVALDI in Phase 3 trials, 224 subjects had post-baseline NS5B genotypic data from next generation nucleotide sequencing (assay cutoff of 1%).
Treatment-emergent substitutions L159F (n= 6) and V321A (n= 5) were de-tected in post-baseline samples from GT3a-infected subjects across the Phase 3 trials.
In the trial done in subjects with hepatocellular carcinoma awaiting liver transplantation where subjects received up to 48 weeks of sofosbuvir and ribavirin, the L159F substitution emerged in multiple subjects with GT1a or GT2b HCV who experienced virologic failure (breakthrough and relapse).
HCV replicons expressing the sofosbuvir-associated resistance substitution S282T were susceptible to NS5A inhibitors and ribavirin. In the FISSION study, 499 treatment-naive patients with genotype 2 or 3 HCV were randomized to sofosbuvir 400 mg plus ribavirin for 12 weeks or peginterferon plus ribavirin for 24 weeks in a noninferiority trial.
The NEUTRINO study was a 12-week open label study of sofosbuvir plus ribavirin in treatment naive patients with HCV genotype 1, 4, 5 or 6 (of whom 98% had genotype 1 or 4). POSITRON evaluated sofosbuvir plus ribavirin compared with placebo in patients with genotype 2 and 3 HCV in whom interferon was not an option (previously intolerant of interferon, unwilling or unable to take interferon). The FUSION study was a blinded, active-control study involving patients with genotype 2 or 3 HCV who had not had a response to prior treatment with an interferon-containing regimen. One obvious clinical need is for data regarding safety and efficacy of sofos-buvir in patients who have decompensated chronic liver disease, are peri-transplant or post-liver-transplant. The US FDA has recently (6 December, 2013) approved sofosbuvir under the brand name Sovaldi for the treatment chronic HCV infection under a breakthrough therapy designation, because it has shown a substantial improvement over the other available therapies.
Although sofosbuvir is by no means one of the first DAA drugs to reach phase III clinical trials, the collective trial data for sofosbuvir do represent a significant paradigm shift in the management of HCV infection. During its October 2013 meeting, the CHMP gave an opinion on the conditions under which early access to sofosbuvir, in combination with other medicines, could be given in compassionate-use programmes, for patients with chronic hepatitis C infection before or after liver transplantation.
Such programmes, set up at the national level (in italy as well), are intended to give patients with a life-threatening, long-lasting or seriously disabling disease who have no available treatment options access to treatments that are still under development and that have not yet been authorised.
During its November meeting, the CHMP also provided an opinion on the use of a combination of sofosbuvir with the antiviral daclatasvir in certain patients with chronic hepatitis C virus (HCV) infection, in a compassionate-use programme.
From the above discussion, it seems that sofosbuvir is a promising therapy for chronic HCV infection, as it offers several advantages over the existing therapies, particularly in dealing with patients with decompensated liver disease and patients who cannot tolerate interferon-containing therapies. Read What Your Physician is Reading on Medscape Hepatitis A »One of the more common causes of acute hepatitis is hepatitis A virus (HAV). Cirrhosis is a chronic liver disease that is the result of damage to liver tissue with scarring of the liver (fibrosis - nodular regeneration) causing progressive decrease in liver function, excessive fluid in the abdomen (ascites), bleeding disorders (coagulopathy), increased pressure in the blood vessels (portal hypertension), and brain function disorders (hepatic encephalopathy). The main damage in cirrhosis is triggered by scarring (fibrosis) that occurs from injuries due to alcohol, viruses, or other assaults. The spleen overproduces nitric oxide, a chemical that causes blood vessels in the spleen to widen (dilate). Bilirubin also builds up in the bloodstream, resulting in jaundice, a yellowish cast in the skin and eyes, as well as dark-colored urine. The liver processes all of the nutrients the body requires, including proteins, glucose, vitamins, and fats.
One of the liver's major functions is to render harmless potentially toxic substances, including alcohol, ammonia, drugs, and harmful by-products of digestion. The portal vein carries to the liver blood that has been circulating through the stomach, spleen, and intestine. Chronic alcoholism particularly endangers the liver by causing alcoholic liver disease (also called alcohol-induced liver disease). Chronic hepatitis, both hepatitis B and hepatitis C, is another primary cause of cirrhosis. The hepatitis virus can produce inflammation in liver cells, causing injury or destruction. Hepatitis C is a virus-caused liver inflammation which may lead to jaundice, fever, and cirrhosis.
Autoimmune hepatitis, like other autoimmune disorders, develops when a misdirected immune system attacks the body's own cells and organs.
Disorders that block or damage the bile ducts can cause bile to back up in the liver, leading to inflammation and cirrhosis.
Nonalcoholic fatty liver disease (NAFLD) resembles alcoholic liver disease, but it occurs in people who do not drink a lot of alcohol. Schistosomiasis, a disease caused by a parasite found in the Asia, Africa, and South America. Long-term or high-level exposure to certain chemicals and drugs, including arsenic, methotrexate, toxic doses of vitamin A, and certain types of prescription medication. Jaundice is a condition produced when excess amounts of bilirubin circulating in the bloodstream dissolve in the subcutaneous fat (the layer of fat just beneath the skin), causing a yellowish appearance of the skin and the whites of the eyes. Spontaneous bacterial peritonitis is a form of peritonitis (inflammation of the membrane that lines the abdomen), which is associated with ascites. Hepatorenal syndrome occurs if the kidneys drastically reduce their own blood flow in response to the altered blood flow in the liver. One of the most serious consequences of portal hypertension is the development of varices, veins that enlarge to provide an alternative pathway for blood diverted from the liver.
Spontaneous bacterial peritonitis is a life-threatening bacterial infection of the ascitic fluid.
Early symptoms of hepatic encephalopathy include forgetfulness, unresponsiveness, and trouble concentrating. People with cirrhosis have an increased risk for hepatocellular carcinoma, a type of liver cancer. Osteoporosis is a condition characterized by progressive loss of bone density, thinning of bone tissue, and increased vulnerability to fractures.
If the abdomen is swollen, the doctor will check for ascites by tapping the flanks and listening for a dull thud and feeling the abdomen for a shifting wave of fluid. The doctor will also check for signs of jaundice, muscle wasting, and (in male patients) breast enlargement. A patient’s medical history can reveal risk factors (such as alcoholism) that warrant screening for conditions such as hepatitis.
Magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound are all imaging techniques that are useful in detecting and defining the complications of cirrhosis, such as ascites and hepatocellular carcinoma.
A biopsy involves a doctor inserting a biopsy fine needle, guided by ultrasound, to remove a small sample of liver tissue. This approach uses a needle inserted through the skin over the liver area to obtain a tissue sample from the liver.
This approach uses a catheter (a thin tube) that is inserted in the jugular vein in the neck and threaded through the hepatic vein (which leads to the liver). This procedure requires a small abdominal incision through which the doctor inserts a thin tube that contains small surgical instruments and a tiny camera to view the surface of the liver. Some doctors recommend endoscopy for patients newly diagnosed with mild-to-moderate cirrhosis in order to screen for esophageal varices. Patients with cirrhosis are susceptible to infections and bleeding, both of which can be life threatening. Weight reduction through diet and exercise, and diabetes and cholesterol management are the primary approaches to treating these diseases. Large-volume paracentesis, (which involves using a thin needle to withdraw fluid from the abdomen), may be used for ascites refractory to medical treatment or when complications are present.
Transjugular intrahepatic portosystemic shunt (TIPS) uses a stent placed in veins in the middle of the liver to keep open a passage connecting the hepatic and portal veins.
Patients with ascites who have high white blood cell counts should receive intravenous antibiotic therapy (usually cefotaxime) or oral antibiotic therapy with ofloxacin. Patients with medium-to-large varices that have not bled may also be treated with a surgical procedure called endoscopic variceal ligation (EVL). Other types of therapies, (such as nitrate drugs, shunts, or sclerotherapy), are generally not recommended for primary prevention of variceal bleeding.
The primary treatment for variceal hemorrhage is drug therapy with ocreotide (Sandostatin). If these treatments do not control the bleeding, or bleeding recurs, a transjugular intrahepatic portosystemic shunt (TIPS) procedure is performed. Another procedure, called balloon tamponade, may be used to temporarily control bleeding prior to the TIPS procedure. A scoring system called Model for End-Stage Liver Disease (MELD) is used to determine which patients are most in need of a donor liver.
Unfortunately, there are many more patients waiting for liver transplants than there are available organs.
Transplantation surgery generally takes 4 - 12 hours to perform, and patients stay in the hospital for up to 3 weeks after the surgery. Patients who require transplantation for primary biliary cirrhosis are those who develop major complications of portal hypertension and liver failure or who have poor quality of life and short survival without the procedure.
Berg CL, Gillespie BW, Merion RM, Brown RS Jr, Abecassis MM, Trotter JF, et al Improvement in survival associated with adult-to-adult living donor liver transplantation.
The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. In most cases, hepatitis C causes no noticeable symptoms until the liver has been significantly damaged. 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. This treatment was shown to cure rates of between 70 and 80% for genotype 2 and 3, and 45 to 70% for other genotypes. Improved screening of blood supplies used for transfusions and better patient-screening techniques have already greatly cut transmission rates over the last 15 years. 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. The triphosphate acts like a substrate for the viral RNA polymerase, and inhibites of viral RNA synthesis.


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. Sofosbuvir treatment regimens last 12 weeks for genotypes 1, 2 and 4, and 24 weeks for treatment of 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. The uridine nucleotide analog sofosbuvir is a phosphoramidate prodrug that has to be triphosphorylated within the cells to produce its action. At a dose three times the maximum recommended dose, SOVALDI does not prolong QTc to any clinically relevant extent. Following oral administration of SOVALDI, sofosbuvir was absorbed with a peak plasma concentration observed at ~0.5-2 hour post-dose, regardless of dose level.
The metabolic activation pathway involves sequential hydrolysis of the carboxyl ester moiety catalyzed by human cathepsin A (CatA) or carboxylesterase 1 (CES1) and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 (HINT1) followed by phosphorylation by the pyrimidine nucleotide biosynthesis pathway.
The majority of the sofosbuvir dose recovered in urine was GS-331007 (78%) while 3.5% was recovered as sofosbuvir. Sofosbuvir is a nucleotide pro-drug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator.
Reduced susceptibility to sofosbuvir was associated with the primary NS5B substitution S282T in all replicon genotypes examined. No detectable shift in the phenotypic susceptibility to sofosbuvir of subject isolates with L159F or V321A substitutions was seen. HCV replicons expressing the ribavirin-associated substitutions T390I and F415Y were susceptible to sofosbuvir.
It has the key function of replicating the HCV's viral RNA by using the viral positive RNA strand as its template and catalyzes the polymerization of ribonucleoside triphosphates (rNTP) during RNA replication. In this trial, despite a marked difference in the RVR rates (99% versus 67%, respectively), the SVR12 rates were identical at 67% [Lawitz et al.
SVR12 rates of 90% were observed overall, with 81% response rates in genotype 1 with cirrhosis. Patients were randomly assigned to either 12 weeks of sofosbuvir and ribavirin followed by 4 weeks of matching placebo, or 16 weeksof sofosbuvir and ribavirin.
The excellent safety data to date and the lack of significant drug interactions makes sofosbuvir an appealing choice to be studied in these groups. The most interesting feature of this approval lies in the fact that this drug can be administered without the need of interferon therapy.
With sofosbuvir-based regimens, successful interferon-free treatment of HCV is now achievable across multiple genotypes, but different patterns of genotypic response to treatment have emerged compared with those seen in traditional interferon-based therapy. On account of its excellent performance in clinical trials, this drug has got FDA approval on 6 December, 2013, under the breakthrough therapy designation. BackgroundCirrhosis is an irreversible result of various disorders that damage liver cells over time. The scar tissue and other changes in liver cells gradually replace healthy liver tissue and act like small dams to alter the flow of blood and bile in and out of the liver.
Bile contains bilirubin, a yellow-green pigment produced from the breakdown of hemoglobin, the oxygen-carrying component in red blood cells. The liver is divided into two major lobes, a right and a smaller left, which are separated by tough, fibrous connective tissue.
The bile ducts in the column corners collect bile draining from tiny canals around the liver cells. Alcoholic liver disease includes fatty liver (build-up of fat cells in the liver), alcoholic hepatitis (inflammation of the liver caused by chronic drinking), and alcoholic cirrhosis.
Chronic hepatitis C is a more common cause of cirrhosis in developed countries, while hepatitis B is a more common cause of cirrhosis worldwide, especially in sub-Saharan Africa and parts of Asia.
If the condition is severe enough, the cell damage becomes progressive, building a layer of scar tissue over the liver. The people most at risk for contracting and spreading hepatitis C are those who share needles for injecting drugs and health care workers or emergency workers who may be exposed to contaminated blood.
People who have autoimmune hepatitis also often have other autoimmune conditions, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, scleroderma, inflammatory bowel disease, glomerulonephritis, and hemolytic anemia. In people with PBC, the immune system attacks and destroys cells in the liver’s bile ducts.
Primary sclerosing cholangitis (PSC) is a chronic disease that mostly affects men, usually around age 40. Other inherited diseases that can cause cirrhosis include Wilson’s disease (which causes an accumulation of copper in the body), alpha-1 antitrypsin deficiency (a genetic disorder caused by defective production of a particular enzyme), and glycogen storage diseases (a group of disorders that cause abnormal amounts of glycogen to be stored in the liver). Patients with decompensated cirrhosis develop many serious and life-threatening symptoms and complications.
This yellowish cast to the skin and eyes occurs because the liver cannot process bilirubin for elimination from the body. With the exception of normal newborn jaundice in the first week of life, all other jaundice indicates overload or damage to the liver, or inability to move bilirubin from the liver through the biliary tract to the gut. Possible ComplicationsA damaged liver affects almost every bodily process, including the functions of the digestive, hormonal, and circulatory systems. Impaired brain function occurs when the liver cannot detoxify harmful substances, and can lead to coma. It is a life-threatening complication of late-stage liver disease that occurs in patients with ascites.
The main symptoms include confusion and altered mental status, fever, chills, and abdominal pain. Hepatic encephalopathy is caused by a buildup in the blood of harmful intestinal toxins, particularly ammonia, which then accumulate in the brain.
Sudden changes in the patient's mental state, including agitation or confusion, may indicate an emergency condition. Hepatitis B and C, alcoholism, hemochromatosis, and primary biliary cirrhosis -- all causes of cirrhosis -- are some of the major risk factors for liver cancer.
Patients with a history of alcoholism, hepatitis B or C, or certain other medical conditions are at high risk. The results of these tests along with the presence of specific complications (ascites and encephalopathy) are used for calculating the Child-Pugh Classification. The PT test measures in seconds the time it takes for blood clots to form (the longer it takes the greater the risk for bleeding). One of the most important factors indicative of liver damage is bilirubin, a red-yellow pigment that is normally metabolized in the liver and then excreted in the bile. It also helps determine its cause, treatment possibilities, the extent of damage, and the long-term outlook. Various forms of needles are used, including those that use suction or those that cut out the tissue.
Low levels of protein in the fluid plus a low white blood cell count suggest that cirrhosis is the cause of the ascites. People with cirrhosis are typically malnourished and require increased calories and nutrients. Patients with cirrhosis should ask their doctors which vaccinations (such as hepatitis A, hepatitis B, influenza, pneumococcal pneumonia) they need. Before you take any medications, (including nonprescription pain relievers such as acetaminophen, aspirin, naproxen, and ibuprofen), ask your doctor if they are safe for you. Certain types of herbal remedies (kava, chaparral, kombucha mushroom, mistletoe, pennyroyal, and some traditional Chinese herbs) can increase the risk for liver damage. Autoimmune hepatitis is treated with the corticosteroid prednisone and also sometimes immunosuppressants, such as azathioprine (Imuran).
Ursodeoxycholic acid (Actigall), also known as ursodiol or UDCA, is used for treating primary biliary cirrhosis but does not slow the progression.
Investigators are also studying whether various drugs used to treat type 2 diabetes may help treat NAFLD and NASH. Hemachromatosis is treated with phlebotomy, a procedure that involves removing about a pint of blood once or twice a week until iron levels are normal. This is a life-threatening condition in which kidney failure develops because of altered blood flow in the liver. The laxative lactulose, given as a syrup or enema, is used to empty the bowels and to help improve mental status.
Primary prevention means treating the varices (swollen or distended veins) before they have bled.
When varices located in the digestive tract begin to bleed (variceal hemorrhage), it is considered an emergency situation. This drug is given for 3 - 5 days after the bleeding began to reduce the risk for rebleeding. Balloon tamponade is now performed only for bleeding that cannot be controlled by drugs or endoscopy. Patients who survive an episode of variceal bleeding need to be treated with drugs to prevent bleeding recurrence.
Liver TransplantationWhen cirrhosis progresses to end-stage liver disease, patients may be candidates for liver transplantation. Patients report improved quality of life and mental functioning after liver transplantation. A MELD score predicts 3-month survival based on laboratory tests of creatinine, bilirubin, and blood-clotting time.
Most patients return to normal or near-normal activities 6 - 12 months following the transplant.
One of the primary problems with many hepatitis patients is recurrence of the virus after transplantation. The outlook is also good for patients who have autoimmune hepatitis who require a transplant. Liver transplantation is generally not recommended for patients with active alcohol or drug abuse addictions. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program.
Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Meta-analysis: Combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis.
Lactulose improves cognitive functions and health-related quality of life inpatients with cirrhosis who have minimal hepatic encephalopathy. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data.
A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions.
When symptoms do occur, they are often vague and can be easily mistaken for another condition. But researchers has been studying new treatments to increase cure rates, to avoid collateral effects and to eliminate latent form of the virus. 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. 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. Most side effects are significantly more common in interferon containing regimens as compared to interferon-free ones.
John's wort) may decrease Sofosbuvir plasma concentration leading to reduced therapeutic effect of it and thus should not be used with. 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. The required enzymes for its activation are present in the human hepatic cells, therefore, it is converted to its active metabolite during the first-pass metabolism, directly at the desired site of action: The liver. After a single 400 mg dose of [14C]-sofosbuvir in healthy subjects, the blood to plasma ratio of 14C-radioactivity was approximately 0.7. Dephosphorylation results in the formation of nucleoside metabolite GS-331007 that cannot be efficiently rephosphorylated and lacks anti-HCV activity in vitro. An M289L substitution developed along with the S282T substitution in genotype 2a, 5 and 6 replicons. The sofosbuvir-associated resistance substitution S282T was not detected at baseline or in the failure isolates from Phase 3 trials. In addition, S282R and L320F substitutions were detected on-treatment by next generation sequencing in a subject infected with GT1a HCV with a partial treatment response. Several crystal structures of NS5B polymerase in several crystalline forms have been determined based on the same consensus sequence BK (HCV-BK, genotype 1). These cirrhotic patients also had extremely low rates of treatment discontinuation of only 2%, suggesting that this combination is safe and extremely well tolerated even in cirrhotic patients [Lawitz et al. Degree of liver fibrosis did not appear to significantly influence outcomes in genotype 2 patients (94% SVR12 even in those with cirrhosis), but in genotype 3 patients, SVR12 rates were low at 21% in patients with cirrhosis [Jacobson et al.
To date there is one case report published of a patient with severe recurrent cholestatic hepatitis C, 6 months post-transplant, who was effectively rescued and achieved SVR with treatment with sofosbuvir and daclatasvir in combination [Fontana et al. It is now clear that in the current DAA era, genotypes 2 and 3 should be evaluated quite separately, as SVR rates in genotype 3 patients are significantly lower than those seen in genotype 2 [Jacobson et al. This drug is effective against all HCV genotypes, has a better safety profile, and low risk of development of resistance; however, careful clinical use and monitoring is still essential, to gather more data on this drug.


Eventually, damage becomes so extensive that the normal structure of the liver is distorted and its function is impaired.
These ducts eventually join to form the large common bile duct that leads from the liver to the gallbladder. The veins supply the liver cells with blood containing the nutrients and toxins that the liver cells process. People with chronic hepatitis B who are co-infected with hepatitis D are especially at risk for cirrhosis. In advanced cases, as with alcoholic cirrhosis, the liver shrivels in size, a condition called postnecrotic or posthepatic cirrhosis. Some evidence suggests that insulin resistance (the primary problem in type 2 diabetes) is a major factor in development of a fatty liver. Decompensated cirrhosis increases the risk of serious and potentially life-threatening complications. Ascites is caused by a combination of portal hypertension (high pressure in the blood vessels of the liver) and low albumin levels. Symptoms include dark colored urine and a reduction in volume, yellowish skin, abdominal swelling, mental changes (such as delirium and confusion), jerking or coarse muscle movement, nausea, and vomiting.
Encephalopathy can be triggered by many different conditions including internal bleeding, infection, constipation, and dehydration. Cirrhosis due to hepatitis C is the leading cause of hepatocellular carcinoma, while cirrhosis due to hepatitis B is the leading cause of deaths related to liver cancer. Regular exercise and vitamin and mineral supplements may reduce and even reverse loss of bone density.
This is a staging system (A to C) that helps doctors determine the severity of cirrhosis and predict the development of future complications. In patients with hepatitis, the liver cannot process bilirubin, and blood levels of this substance rise, sometimes causing jaundice. The National Cancer Institute recommends against it.) These imaging tests can also provide information on the extent of liver damage.
For example, hepatitis C patients who show no significant liver scarring when biopsied may have a low risk for cirrhosis. This approach should not be used in patients with bleeding problems, and it must be used with caution in patients with ascites or severe obesity. Treatment goals are to slow the progression of liver damage and reduce the risk of further complications. Although some herbs, such as milk thistle (silymarin) have been studied for possible beneficial effects on liver disease, there is no scientific evidence to show that they can help. Itching is usually controlled with cholesterol drugs such as cholestyramine (Questran) and colestipol (Colestid). In the procedure, a long needle is inserted into the jugular vein in the neck and passed down to the hepatic and portal veins.
Varices that are present in the esophagus, stomach, or intestines are always at risk of bleeding.
The first step is to immediately achieve normal blood clotting (hemostasis) in order to stop the current bleeding episode. It involves inserting a tube through the nose and down through the esophagus until it reaches the upper part of the stomach. Patients are prescribed either a combination of a nitrate drug [such as isosorbide (Ismo), which is used to treat angina] and a nonselective beta-blocker (propanolol or nadolol) or a beta-blocker alone.
Patients with liver cancer that has not spread beyond the liver are also candidates for transplant. Patients should seek medical centers that perform more than 50 transplants per year and produce better-than-average results.
In living-donor transplantation, surgeons replace the patient’s diseased liver with a part of the liver taken from a donor.
For the rest of their lives, patients need to take immunosuppressive medication to prevent rejection. 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. This low potency originates in part because the enzymatic addition of the first of the three phosphate groups of the triphosphate is slow. 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 should not be taken in association with anticonvulsants, antimycobacterials, HIV protease inhibitors. 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. The median terminal half-lives of sofosbuvir and GS-331007 were 0.4 and 27 hours, respectively. Site-directed mutagenesis of the S282T substitution in replicons of 8 genotypes conferred 2- to 18-fold reduced susceptibility to sofosbuvir and reduced the replication viral capacity by 89% to 99% compared to the corresponding wild-type. However, an S282T substitution was detected in one genotype 2b subject who relapsed at Week 4 post-treatment after 12 weeks of sofosbuvir monotherapy in the Phase 2 trial P7977-0523 [ELECTRON]. Notably, in this study there was a marked difference in response rates between patients with genotype 2 (97% SVR 12) and genotype 3 (56% SVR12) HCV, and between cirrhotic (47% SVR12) and noncirrhotic (72% SVR12) patients. Overall rates of SVR were significantly higher in the 16-week arm (73%) than in the 12-week arm (50%), and again the genotype 2 patients had higher SVR rates (86% and 94% for 12 and 16 weeks, respectively) than genotype 3 patients (30% and 62% respectively for 12 and 16 weeks) [Jacobson et al. Earlier it was under the FDA's priority review program (an expedited review of drugs useful for serious conditions, which, after their approval, would provide significant improvement in safety or effectiveness). Data on the effectiveness of this combination in cirrhotic genotype 1 null responders is awaited.
Large post-marketing studies, including pharmacoepidemiological and pharmacovigilance studies, can solve many unanswered questions for the future of this novel drug.
Dehydration may become serious and life-threatening in some affected individuals, so symptoms of dehydration need to be quickly addressed, often by a medical caregiver.
It is located immediately below the diaphragm and occupies the entire upper right quadrant of the abdomen. Bracing the corners of each lobule column are an artery and a vein that carry blood and a bile duct that drains bile.
A central vein runs through each column and collects the processed blood from both sources. It develops in 10 - 20% of heavy drinkers, usually after 10 - 15 years of heavy alcohol consumption. The longer a patient has had chronic hepatitis, the greater the risk for eventually developing cirrhosis.
A diet high in fatty foods may also be a risk factor, as dietary fat accumulates in the liver. Varices pose a high risk for rupture and bleeding because they are thin-walled, twisted, and subject to high pressure.
The tube contains tiny cameras to view the inside of the esophagus, where varices are most likely to develop. There are currently no drugs available to treat liver scarring, although researchers are investigating various antifibrotic drugs.
It is best to eat fresh vegetables and fruits whenever possible and to avoid eating processed foods. Antibiotics for infections in the bile ducts and drugs that quiet the immune system (prednisone, azathioprine, cyclosporine, methotrexate) may also be used.
TIPS is used for patients with ascites unresponsive to treatment and those who may require a liver transplant. Nonselective beta-blockers drugs, which are commonly used to treat high blood pressure, may be given to prevent bleeding.
A balloon at the tube's end is inflated and positioned tightly against the esophageal wall.
Patients are also given several sessions of endoscopic variceal ligation over the course of several months.
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The symptoms may include high temperature, tiredness, loss of appetite and they occur a few weeks after infection. 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).
The design of Sofosbuvir avoids this slow step by building the first phosphate group into the structure of the drug during synthesis. This analog then mimics the physiological nucleotide and competitively blocks the NS5B polymerase, thus inhibiting the HCV-RNA synthesis by RNA chain termination.
Relative to healthy subjects administered sofosbuvir alone (N = 272), the sofosbuvir AUC0-24 was 39% higher and GS-331007 AUC0-24 was 39% lower, respectively, in HCV-infected subjects. Evaluation of sofosbuvir in combination with interferon alpha or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells. The isolate from this subject displayed a mean 13.5-fold reduced susceptibility to sofosbuvir.
The encircled active site, unique to NS5B, is contained within the palm structure of the protein.
This is promising, and results of future trials of sofosbuvir in these types of patient groups are awaited with interest.
Positive results from major clinical trials, plus a demonstration of efficacy in patients who cannot tolerate interferon-based regimens and in patients with liver cancer undergoing liver transplantation, make this drug a valuable and very useful therapy for these patient populations.
A new era of successful interferon-free DAA therapy for HCV is emerging, with potential to broaden treatment of HCV to include patient groups who have either avoided or not been suitable for previous interferon- based therapy, and it is likely that sofosbuvir will form the backbone of this treatment approach.
As of now, sofosbuvir is among the most promising agents available for the treatment of chronic HCV infection.
People who drink heavily and who also have hepatitis C are at particular risk of developing cirrhosis. In general, TIPS should be a second-line option for ascites that does not respond to diuretics. Studies suggest that the vasoconstrictor drug terlipressin, given in combination with albumin, may be helpful for treating hepatorenal syndrome. Propanolol (Inderal) or nadolol (Corgard) are the standard beta-blockers used for variceal prevention. In endoscopic sclerotherapy, the endoscopic tube is inserted through the mouth and a sclerosant (a solution that toughens the tissue around the variceal blood vessels) is injected to stop the bleeding. The TIPS procedure may be recommended for patients who experience recurrent bleeding despite drug and endoscopic therapy. This procedure produces excellent results for patients, but there are some risks for the donor. In 2007, the Food and Drug Administration (FDA) approved HepaGram B, an immune globulin, to prevent recurrence of hepatitis B after transplantation.
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. The catalytic site of the enzyme is also highly conserved across all the HCV genotypes, accounting for pan-genotypic efficacy of sofosbuvir. Sofosbuvir and GS-331007 AUCs are near dose proportional over the dose range of 200 mg to 1200 mg. For this subject,the S282T substitution was no longer detectable at Week 12 post-treatment by next generation sequencing with an assay cut off of 1%. Recent studies on NS5B protein genotype 1b strain J4’s (HC-J4) structure indicate a presence of an active site where possible control of nucleotide binding occurs and initiation of de-novo RNA synthesis. Cirrhosis was associated with a decreased rate of SVR, particularly in genotype 3 receiving 12 weeks of therapy rather than 16 weeks (SVR 19% versus 61%).
Because bile can also travel directly from the liver to the intestines, patients who have had their gallbladders removed can still absorb fat normally. In the liver, alcohol converts to toxic chemicals that trigger inflammation and tissue injury, which lead to cirrhosis. Balloon tamponade poses a risk for serious complications, the most dangerous being rupture of the esophagus. Any duplication or distribution of the information contained herein is strictly prohibited.
In genotype 2 patients SVR rates ranged from 60% to 78% in cirrhotic patients, and up to 100% in noncirrhotic patients without cirrhosis who were treated for 16 weeks.
In contrast, the presence of advanced liver fibrosis has a significant detrimental effect on SVR rates in genotype 3 patients when a 12-week regimen is used. Current research attempts to bind structures to this active site to alter its functionality in order to prevent further viral RNA replication. The other strategy that could be considered is addition of another DAA to the regimen, but until these data are available to clarify the optimal interferon-free treatment of genotype 3 HCV patients with advanced fibrosis or previous treatment failure, there may be an initial role for continuing to use peginterferon together with sofosbuvir in this group of patients.



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  • Simpaty_Alien, 20.12.2015 at 23:11:40
    Suppressive treatment of HSV-2 with valacyclovir stress, menstruation, a weakened immune system and operating amok.
  • yjuy, 20.12.2015 at 15:42:37
    Travels via the nerves and.