Hepatitis C Medications

There are at least six different types of HCV, known as viral genotypes. In the United States, HCV genotype 1 is the most common.

Hepatitis is a general term that means inflammation of the liver that may be caused by viral infections, alcohol, medications, chemicals, poisons, etc. Hepatitis C is inflammation of the liver caused by infection with hepatitis C virus (HCV), which is commonly referred to as "Hep C."

• There are at least six different types of HCV, known as viral genotypes.
• In the United States, HCV genotype 1 is the most common.
• Once infected with HCV, the immune system begins to fight the virus.
• In about 15 to 25% of people, the immune system is able to fight the virus and clear the virus for good.
• Most people infected with HCV, however, become chronically infected with the virus.
• Over many years, chronic inflammation from hepatitis C damages the liver. This may lead to liver scarring, liver failure, or liver cancer.

The hepatitis C is part of a family of viruses called flaviviruses.

There are no vaccinations that prevent the hepatitis C virus. Vaccinations for hepatitis A and B, however, are given to patients with HCV to prevent the possibility of acquiring another hepatitis virus. Getting hepatitis A or hepatitis B on top of hepatitis C can add liver damage or even cause severe hepatitis. People with hepatitis C should be screened for past infection with hepatitis A and B. If they have no evidence of antibodies, they should receive vaccines for hepatitis A and/or B.

Hepatitis A vaccine may be given alone or in combination with hepatitis B vaccine, depending on whether the patient needs one or both. Hepatitis A vaccine (Havrix, Vaqta) is inactivated (killed) hepatitis A virus that stimulates the immune system to develop antibodies against hepatitis A. These antibodies kill the virus before it can cause infection. It is given in 2 doses intramuscularly 6 months apart.

Hepatitis B vaccine (Engerix-B, Recombivax HB) is made with hepatitis B antigens (pieces of the virus) that stimulate antibodies against the hepatitis B virus. There is no live virus in the vaccine. It is given in 3 doses intramuscularly; the second dose is given 1-2 months after the first, and the last is given 6 months after the first dose. The A and B vaccine is a combination of the above and is dosed in the same way as the Hepatitis B vaccine. It is available under the brand name Twinrix.

Symptoms of Acute Hepatitis C Infection

The majority of newly-infected patients identified with HCV do not have symptoms. The minority of patients who have symptoms typically have complaints of

• fatigue,
• loss of appetite,
• muscular aches, and
• fever.

Symptoms of Chronic Hepatitis C Infection

Chronic hepatitis C usually causes no symptoms until very late in the disease. Over the years or decades, chronic inflammation may cause scarring ("fibrosis"). Extensive scarring in the liver is called cirrhosis.

Becoming infected with another viral hepatitis or other exposures that damage the liver in addition to hepatitis C can increase liver damage or even cause severe hepatitis. Having HIV infection along with HCV accelerates the progression of chronic hepatitis C to end-stage liver disease, sometimes shortening the course to a few years instead of decades.

Hepatitis C treatments once involved months of injected interferons with up to 50% cure rates, and serious side effects. With newer medications, hepatitis C can be treated with oral combinations of medicines for several weeks. These are generally well-tolerated and yield sustained cure of virus from the blood in over 90% of cases.

The goal of treating HCV-infected persons is to reduce the risk of death, end-stage liver disease, and other liver-related adverse events by the achievement of a virologic cure which is determined by the sustained virologic response (SVR). Sustained virology response means complete disappearance of the HCV for at least 12 weeks after stopping treatment.

These drugs are called direct-acting agents (DAA) because unlike interferons and ribavirin, they directly block the growth of the hepatitis C virus. They are most often used in combinations.

Examples of HCV treatment combinations containing protease inhibitors and nucleotide polymerase inhibitors:

• telaprevir (Incivek), (voluntarily withdrawn from the market in August 2014)
• boceprevir (Victrelis)
• simeprevir (Olysio)
• Technivie (ombitasvir/paritaprevir/ritonavir)
• Viekira Pak (ombitasvir/paritaprevir/ritonavir and dasabuvir)
• Zepatier (grazoprevir and elbasvir)
• Sovaldi (sofosbuvir)
• Harvoni (sofosbuvir and ledipasvir)
• Daklinza (daclatasvir)
• Epclusa (Sofosbuvir and velpatasavir)
• Mavyret (Glecaprevir and pirbrentasavir)

How do protease inhibitors work?

Protease Inhibitors are termed direct-acting antiviral agents (DAA). They directly act on the virus by inhibiting certain enzymes and proteins necessary for replication of the HCV virus.

How do nucleotide polymerase inhibitors work?

Nucleotide analog polymerase inhibitors are another type of direct-acting antiviral agent (DAA). They block the action of proteins that HCV uses for making new viruses.

How do NS5A inhibitors work?

These are direct-acting antivirals that block the action of the HCV NS5A protein and interfere with making new viruses.

Who should not use these medications?

The contraindications, warnings, and precautions for ribavirin apply when ribavirin is combined with these agents.

• Zepatier, Viekira Pak, and Technivie should not be used by people with moderate to severe liver disease.
• Harvoni is indicated for people with moderate to severe cirrhosis, including those who have received liver transplants.

The most common side effects of DAAs include:

• Fatigue
• Headache
• Some diarrhea

Less frequent side effects may include:

• Dysgeusia (distortion of the sense of taste)
• Insomnia
• Hair loss
• Muscle pain
• Joint pain
• Nausea

Other side effects of DAAs include:

• Rash
• Itching (pruritus)
• Photosensitive drugs
• Anemia
• Vomiting
• Reduced number of white blood cells
• Shortness of breath
• Increased bilirubin

The addition of protease inhibitors to PegIFN/RBV is associated with an additional decrease in red blood cells (anemia) and white blood cells (neutropenia) compared with PegIFN/RBV alone.

Daklinza commonly causes

• fatigue,
• flu-like symptoms,
• loss of weight,
• fever,
• headache
• insomnia,
• diarrhea, and
• elevated liver enzymes.

Certain heart rhythm medications, especially amiodarone (Cordarone, Pacerone), can cause slow heartbeat or heart block and should be avoided with daclatasvir.

Victrelis (oceprevir)

• 800 mg is taken three times a day, and simeprevir 150 mg is taken once daily with food, combined with ribavirin.

Technivie (ombitasvir/paritaprevir/ritonavir)

• Technivie is given with ribavirin for 12 weeks for genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis.
• Each tablet contains 12.5 mg ombitasvir, 75 mg paritaprevir and 50 mg ritonavir.
• Two tablets are taken every morning, with ribavirin dosed by weight: 1000 mg per day for patients weighing less than 75 kg, and 1200 mg per day for those 75 kgs and over; this is divided into a twice-daily dose with food.

Viekira Pak (ombitasvir/paritaprevir/ritonavir and dasabuvir)

• Viekira is used for genotype 1a or 1b chronic hepatitis C, including people with or without cirrhosis and no liver failure symptoms.
• Viekira Pak is ombitasvir 12.5 mg, paritaprevir 75mg, ritonavir 50 mg in each tablet, packaged with dasabuvir 250mg tablets.
• It is dosed as two ombitasvir, paritaprevir, ritonavir tablets once daily (in the morning) and one dasabuvir tablet twice daily (morning and evening), along with a meal.
• It is given with or without ribavirin (dosed as above).
• Genotype 1a is most resistant to treatment, so Viekira is given with ribavirin for 12 weeks if there is no cirrhosis, or 24 weeks if there is cirrhosis.
• Genotype 1b is usually treated with Viekira alone for 12 weeks if no cirrhosis; with cirrhosis (or in some cases of prior treatment) it must be given with ribavirin for 12 weeks.
• Viekira may also be used in liver transplant recipients.

Zepatier (grazoprevir and elbasvir)

• Zepatier is elbasvir 50 mg and grazoprevir 100 mg in one tablet, and it is given for chronic hepatitis C genotype 1 or 4 with or without cirrhosis, and with or without certain resistance mutations.
• While Zepatier can be given to patients who have never been treated, it offers a special treatment option to patients who have failed treatment with PegIFN/RBV, as well as protease inhibitors.
• One tablet is taken orally once daily with or without food, and maybe given with or without RBV as above, depending on the individual patient.
• Patients who have been treated before or have certain resistance mutations ("NS5A") are dosed differently and for longer than other patients.
• Genotypes 1a with NS5A mutations and genotype 4 that has failed PegIFN/RBV are treated with Zepatier and RBV for 16 weeks.
• All others are treated for 12 weeks, with the addition of RBV in those with genotype 1 who have failed PegIFN/RBV and protease inhibitors.

Sovaldi (sofosbuvir)

• Sovaldi is used to treat chronic hepatitis C genotype 1 or 4 with PegIFN/RBV, or genotype 2 or 3 with RBV alone.
• One 400mg tablet is taken once orally with or without food.
• All genotypes except for three are treated for 12 weeks; genotype 3 is treated for 24 weeks.
• Advantages of Sovaldi include the option to treat genotype 1 patients who are not candidates for using interferons; these patients may take Sovaldi alone for 24 weeks.
• Sovaldi can also be given with RBV for up to 48 weeks to patients awaiting a liver transplant, as an attempt to prevent HCV infection of the new liver.

Harvoni (sofosbuvir and ledipasvir)

• Harvoni is a nucleotide analog inhibitor combination of ledipasvir 90 mg/sofosbuvir 400 mg in one tablet.
• It is taken orally once daily with or without food.
• Harvoni is used to treat chronic hepatitis C genotypes 1, 4, 5, or 6.
• All genotypes may be treated with Harvoni alone regardless of prior treatment and with or without cirrhosis. With the addition of RBV, however, Harvoni extends the option of treatment to patients with genotype 1 who have cirrhosis and liver failure (decompensated cirrhosis).
• All treatment durations are 12 weeks except for genotype 1 with cirrhosis.

Daklinza (daclatasvir)

• Daklinza is an NS5A inhibitor used to treat genotype 3 chronic hepatitis C. It is given combined with Sovaldi (sofosbuvir).
• Either 30mg or 60mg tablets are given orally once a day with sofosbuvir for 12 weeks for patients without cirrhosis, with the exact dose depending on drug interactions with other medications the patient may be taking.
• There is no specific duration offered for patients with cirrhosis, but there is no specification against using this drug in people with even severely impaired liver function.

Mavyret

• is a fixed-dose combination of Glecaprevir NS34A protease inhibitor and Pibrentasavir an HCV NS5A inhibitor
• Indicated for Genotype 1-6 Hep C without Cirrhosis and compensated Cirrhosis
• Indicated for previously treated Genotype 1 with  either NS5A inhibitor or NS3/4A protease inhibitor, but not both
• Take 3 tabs daily taken orally with food for 8-12 weeks

Epclusa

• a fixed-dose combination of sofosbuvir, a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor, and velpatasvir, an HCV NS5A inhibitor,
• indicated for the treatment of adult patients with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infections without cirrhosis or with compensated cirrhosis AND with decompensated cirrhosis fur use in combination with ribavirin
• One tablet (400 mg of sofosbuvir and 100 mg of velpatasvir) is taken orally once daily with or without food.

• Many drugs are metabolized (eliminated) from the body by enzymes in the liver. DAA are metabolized by one of the more important of these enzymes in the liver (CYP3A). As a result, drugs that enhance or reduce the activity of this liver enzyme will affect blood levels.
• Some drugs increase the activity of CYP3A and result in reduced levels of DAA and thereby reduce their effectiveness, for example, corticosteroids (for example, prednisone).
• Other drugs decrease the activity of CYP3A and result in elevated levels of the and possibly can lead to toxicity, for example, some of the anti-fungal drugs (for example, itraconozole [Sporanox]). 
• Some HIV medications may need to be changed while taking some of the hepatitis C DAA.
• The list of drugs that interact with DAA is large and includes many commonly-used drugs. It is important to review all of the drugs that patients are taking to identify drugs that interact with these drugs before treatment is begun.

• Previously, interferons were used in conjunction with ribavirin (RibaPak and others) to treat hepatitis C infection; however, currently they are infrequently used due to the availability of newer drugs on the market that can cure hepatitis C.
• Interferons include drugs such as peginterferon alfa-2a (Pegasys), peginterferon alfa-2b (Pegintron), recombinant interferon alfa-2a (Roferon), and recombinant interferon alfa-2b (Intron A).
• Pegylation slows the elimination of interferon from the body so that its effects last longer.
• Pegylated interferons are given by injection once weekly.

How do interferons work?

Interferons are virus-fighting proteins the body makes naturally in response to viral infections. Interferons also have other actions in the body and have been used to treat a variety of diseases, for example, leukemias, other types of cancers, and multiple sclerosis. They indirectly act to help the immune system fight hepatitis C.

Who should not use interferons?

Individuals with autoimmune hepatitis, decompensated liver disease, or allergy to interferons should not use these medications. Peginterferon cannot be used in newborns.

Dosage Forms and Administration:

• Peginterferon (PegIFN) is given as an injection under the skin once per week.
• Recombinant interferon alfa-2a or alfa-2b is injected 3 times per week.

Drug or food interactions:

Peginterferon may increase theophylline levels in the blood.

Side effects:

Common side effects resemble flu symptoms and include

• fatigue,
• low blood cell counts (anemia),
• muscle aches,
• nausea and vomiting,
• mild fever,
• headache, and/or
• weight loss.

Depression is a common side effect. Interferon should be discontinued if a person's depression becomes severe and he or she does not respond to antidepressant therapy or dose decreases.

Periodic eye examinations are recommended.

Ribavirin (RBV) drugs include medications such as Rebetol, Copegus, Ribasphere, RibaPak, and Moderiba. Interferons require ribavirin to increase effectiveness against hepatitis C. Some patients with certain hepatitis C genotypes must take ribavirin along with oral drug combinations.

How do ribavirin drugs work?

Ribavirin is a nucleoside analogue. Nucleoside analogues are man-made chemicals that closely resemble the building blocks of genetic material (RNA and DNA). Ribavirin works by tricking the HCV virus into using it instead of the normal building blocks of RNA, thereby slowing viral replication. By itself, ribavirin has little effect on HCV, but it does help interferon work better.

Who should not use ribavirin?

Individuals with allergy to ribavirin and those with severe kidney disease should not take these drugs. Because of the risk of birth defects, pregnant women, and men whose partners are pregnant, should not take ribavirin. Once treatment is started, both men and women must practice effective birth control measures during treatment and for 6 months after stopping ribavirin.

Dosage and Administration:

Ribavirin tablets or capsules are taken each day.

Drug or food interactions:

• Bexaropine, azathioprine (Azasan, Imuran), didanosine (Videx, Videx EC), and mercaptopurine (Purinethol) have major drug interactions with ribavirin. When taken with bexarotene (Targretin) or didanosine (Videx), life-threatening inflammation of the pancreas has occurred. Azathioprine and mercaptopurine can reduce bone marrow function if given with ribavirin.
• Didanosine is no longer marketed for treatment of HIV. The other medications are not commonly prescribed except in people with cancer or transplants.

• Ribavirin may cause severe
  • anemia,
  • worsening of heart disease or heart attack,
  • rash, and
  • inflammation of the pancreas.
• Ribavirin can produce pregnancy loss and severe birth defects.
• It is considered a Pregnancy Category X medication, meaning that it should be avoided in pregnancy.
• Ribavirin stays in the body for up to 6 months, so patients who take it must use highly effective birth control methods during treatment and for 6 months after stopping ribavirin.

Various pharmaceutical companies are conducting clinical research to determine the efficacy and safety use of their novel compounds in treating hepatitis C in the near future per FDA approval:

BI 201335 and BI 207127 (Boehringer Ingelheim Pharmaceuticals) are being developed for the treatment of chronic HCV infection. BI 201335 and BI 207127 work by preventing the virus from replicating.

Thymosin alpha-1 (Zadaxin, by SciClone) is a protein that enhances the body's immune system to counteract viruses. Research is being done to determine the efficacy and safety of thymosin alpha-1 in combination with peginterferon alfa- 2a and ribavirin for the therapy of chronic hepatitis C nonresponsive to the combination of IFN and ribavirin

ISIS 14803 (Isis Pharmaceuticals and Elan) is a nucleoside analog that disrupts the production of viral proteins during viral cell division, thereby decreasing the ability of HCV to multiplyABT450/r and ABT 267 (Abbott Pharmaceuticals) are being studied in combination with peginterferon alpha-2a and ribavirin in patients with HCV who did not respond to treatment in a previous study of standard combination therapy

Other interferons are being investigated, including recombinant interferon beta-1a (Serono Lab), omega interferon (BioMedicines), and VX-497 (Vertex Pharmaceuticals).

When a diagnosis of hepatitis C is made, patients are encouraged to adhere to the following recommendations to guard against further damage to the liver and prevent transmitting HCV to others:

• Do not drink alcohol of any kind, including beer, wine, and hard liquor.
• Avoid medicines and substances that can harm the liver, for example, large doses of acetaminophen (Tylenol) and other acetaminophen-containing preparations.
• Eat a healthy diet balanced with fruits and vegetables.
• Use condoms during sexual intercourse to avoid transmitting HCV, and to avoid getting infected with HIV, hepatitis B, and other sexually transmitted diseases.
• Avoid sharing razors or toothbrushes with others.

For end stage liver disease, liver transplantation may be the only viable option. It is, however, not a cure. Post-transplant surgery, antiviral medical treatment usually is continued as hepatitis C viral infection often re-occurs in the new liver.

• Prevention programs aimed at avoiding needle sharing among drug addicts.
• Safe needle-usage techniques have been developed to reduce accidental needle-sticks in healthcare workers.
• There is no clear way to prevent transmission of hepatitis C from mother to fetus at this time.
• People with multiple sexual partners should use barrier precautions such as condoms to limit the risk of hepatitis C and other sexually transmitted diseases (STDs) including HIV.
• Screening tests of the blood products have almost eliminated the risk of transmission of hepatitis C infection through transfusion.
• People who want to get a body piercing(s) or tattoo(s) are encouraged to do so only at licensed piercing and tattoo shops (facilities), and verify that the body piercing or tattoo shop uses infection-control practices.
• Health-care professionals and clinics must follow manufacturers and regulatory agency directions for sterilizing/cleaning instruments and that disposable instruments be discarded properly.
• Casual contact like shaking hands, kissing, and hugging is not behaviors that increase the risk of transmission. There is no need to use special isolation procedures when dealing with people infected with hepatitis C.