Oral Hepatitis C Treatments: The Evolving Landscape
Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on June 15, 2021.
What is Chronic Hepatitis C Virus (HCV)?
Hepatitis C Virus (HCV) - a blood-borne infectious disease and a leading cause of chronic liver disease - has been at the center of a rapidly evolving treatment regimen.
HCV can damage the liver over time, leading to scarring, cirrhosis, liver cancer and even death. To complicate matters, symptoms of HCV may not appear for 20 to 30 years after infection, so the disease may develop quietly for decades.
Roughly 30% of those infected with HCV will eventually develop cirrhosis. Older treatment options for HCV were plagued by:
- lack of an all-oral regimen
- unpleasant side effects with interferon agents
- long treatment times often over 1 year.
HCV: Symptoms and Diagnosis
People with HCV may have acute symptoms for up to 3 months that can include:
- yellow-colored skin or eye sclera (jaundice)
- poor appetite
- nausea and stomach pain.
Longer-term (chronic) symptoms may include weight loss, poor appetite, feeling tired, and painful joints. Fifteen to twenty percent of people may eliminate the HCV virus completely from their body, but most people remain infected and develop chronic hepatitis C.
Diagnosis involves a blood test and to determine the subtypes (genotypes) of HCV. It is important to know the genotypes to select the correct treatment.
In some patients, a liver biopsy is required. In those who eventually develop cirrhosis (scarring disease of the liver), symptoms may include stomach swelling, easy bruising, difficulty breathing, jaundice, and confusion. About 5% to 20% of HCV patients will develop cirrhosis over a period of 20 to 30 years.
About 1 to 5 out of every 100 people with HCV in the U.S. will die each year due to cirrhosis and liver cancer.
Hepatitis C Virus Infection: How Do You Get It?
HCV is transmitted through contact with infected blood -- mainly by:
- sharing needles or devices during drug abuse
- from an accidental needle stick
- renal dialysis
- from mother to child during childbirth
- less commonly from contaminated tattoo or body piercing equipment
- less commonly from haring personal care items comtaminated with HCV+ blood, such as razors or toothbrushes
- less commonly from from unprotected sexual intercourse or blood transfusions.
Hepatitis C is not spread through food or water. You also don't get it from sharing food utensils, breastfeeding your baby, kissing, holding hands, coughing or sneezing.
If you were born from 1945 through 1965, or otherwise are at increased risk for HCV infection, speak to your doctor about being tested for HCV.
The Different Genotypes for Hepatitis C Virus
There are six different genotypes for HCV 1 through 6 (with multiple subtypes). A genotype classification is based on the genetic material in the RNA viral strands. Generally, patients are only infected with one genotype, but genotypes may mutate and become drug resistant. Superinfections can be common among injectable drug users.
- Sovaldi (sofosbuvir), approved as the first all-oral regimen in 2013. It is used in adults for genotype 1 or 4 infection without cirrhosis or with compensated cirrhosis in combination with pegylated interferon and ribavirin. It also treat genotype 2 or 3 infection without cirrhosis or with compensated cirrhosis for use in combination with ribavirin. In children 3 years and older, it is approved for chronic HCV genotype 2 or 3 infection in those without cirrhosis or with compensated cirrhosis for use in combination with ribavirin.
- Harvoni (ledipasvir and sofosbuvir) was approved in 2014 as the first all-oral, ribavirin and interferon-free treatment. It can be used for Genotype 1, the most common subgroup, occurring in roughly 70% of infected patients, as well and types 4, 5 and 6. Ribavirin may need to be added in certain patients with liver dysfunction or if a liver transplant. It is now approved in pediatric patients 3 years of age and older.
- Epclusa (sofosbuvir and velpatasvir) was approved for all 6 major genotypes in June 2016. With advanced liver disease, it is combined with ribavirin. It is approved for use in adults and children 3 years of age and older.
- Zepatier (elbasvir and grazoprevir) from Merck was approved in Jan. 2016 for the treatment of chronic hepatitis C virus (HCV) genotypes 1 and 4 infections in adult patients, with or without ribavirin. Elbasvir is classified a an NS5A inhibitor and grazoprevir is a NS3/4A protease inhibitor.
- Gilead's Vosevi (sofosbuvir, velpatasvir and voxilaprevir) was given the FDA clearance in July 2017 as a re-treatment option in all 6 genotypes (for patients who previously received a NS5A inhibitor) or for genotypes 1a or 3 (previously received sofosbuvir without an NS5A inhibitor). An added benefit of Vosevi over sofosbuvir/velpatasvir (Epclusa) was not shown in adults with genotype 1b, 2, 4, 5, or 6 infection previously treated with sofosbuvir without an NS5A inhibitor.
- In August of 2017, Mavyret (glecaprevir and pibrentasvir) from AbbVie was also approved for all 6 genotypes, in patients without cirrhosis or with compensated cirrhosis (Child-Pugh A). It is also used for genotype 1 in patients who have previously been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor (PI), but not both. Mavyret is a NS3/4A protease inhibitor and NS5A inhibitor combination. It is used in adults and children 12 years of age and older or weighing at least 45 kg.
What's Involved With An HCV Diagnosis?
Discuss your risk factors for hepatitis C infection with your healthcare provider. Drug abuse and having a blood transfusion prior to 1992 may have put you at risk, but there are other risks factors, too.
Hepatitis C screening starts with a blood test to look for viral antibodies. HCV antibodies can be detected in the blood within 2 to 3 months after infection. If this test is positive, a confirmatory blood test would be ordered.
An HCV viral load may be ordered to determine your chances for responding to treatment. In addition, HCV genotyping can help to guide the best treatment option and duration.
Your doctor may also order liver function tests - known as AST, ALT and GGT tests - to monitor the health of your liver.
A liver biopsy, usually performed as an outpatient surgical procedure, may be needed to determine the level of liver damage.
Former Standard HCV Treatments: Side Effects an Issue
The standard treatments for HCV in the past have included injectable interferon, oral ribavirin and one of the protease inhibitors, such as Vertex's Incivek (telaprevir) or Merck's Victrelis (boceprevir) -- both now discontinued off of the U.S. market. Incivek and Victrelis have been replaced by more effective and safe HCV antivirals.
Adherence with interferon and ribavirin regimens due to side effects can be an issue. Interferon and ribavirin are given for 6 to 12 months and can be difficult to tolerate due to side effects such as:
- flu-like symptoms
In addition, this regimen is not always effective for the hard-to-treat and most common genotype 1 infections.
Research and recommendations are rapidly changing in the area of chronic HCV. For many patients, these older treatments are no longer required. You should always seek the most recent treatment advice from your doctor.
What Do Experts Suggest About Diagnosis and Treatment of HCV?
Both the United States Preventive Services Task Force (USPSTF) and the Centers for Disease Control and Prevention (CDC) recommend that all "baby boomers" -- those born from 1945 to 1965 -- be tested for HCV.
This group of adults represents about 75% of all cases, but most are not currently diagnosed. People at high risk for the hepatitis C virus includes those with a history of IV drug use and those who received blood transfusions before 1992, but many other risk factors exist.
Increased rates of screening and diagnosis will likely result in accelerated demand for treatments.
New oral combination treatments for HCV have been shown to result in HCV cures for most newly diagnosed patients.
All-Oral HCV Treatments
The new HCV oral treatments now on the market are capable of causing a sustained virologic response (SVR).
- In SVR, the virus is no longer detectable and 80% to 100% of patients can be cured, sometimes after only 8-12 weeks of treatment.
- However, resistance can develop; therefore, two or more oral HCV drugs are used together to help prevent resistance.
Drug combinations tablets are increasingly being approved to ease treatment regimens, too.
Side effect profiles are more tolerable than interferon, with fatigue and headache as the most common side effects with many of the direct-acting oral antivirals, like Sovaldi, Harvoni, Epclusa, and Vosevi. Epclusa can commonly lead to nausea and vomiting in children.
How Does Sovaldi Work in Hepatitis C Virus?
Sovaldi (sofosbuvir), a nucleotide analogue inhibitor, acts as an imposter to trick the hepatitis C virus (HCV).
- Sovaldi blocks a polymerase enzyme that plays an essential role in HCV replication. The polymerase enzyme builds new RNA genomes (the complete viral hereditary information) so that the virus can replicate.
- Sovaldi slips into the RNA, which prevents the virus from growing because it does not recognize Sovaldi in the RNA.
- Many of the newer oral agents are known as direct-acting agents (DAA), meaning that they interfere directly with the HCV life cycle by suppressing viral replication.
What Evidence Supports the Sovaldi FDA-Approval?
Sovaldi’s effectiveness for initial FDA approval was evaluated in six clinical trials with 1,947 subjects. Patients had not previously received treatment for their disease or had not responded to previous treatment, including participants co-infected with HCV or HIV.
The trials were designed to measure whether HCV was no longer detected in the blood at least 12 weeks after treatment end (sustained virologic response), denoting HCV cure. The treatment regimen containing Sovaldi was effective in treating multiple genotypes of HCV.
Additionally, Sovaldi was effective in those who could not tolerate or take an interferon-based treatment regimen and in participants with liver cancer awaiting transplantation, addressing unmet medical needs.
History Made: Sovaldi and Harvoni
In October 25, 2013 the FDA Advisory Committee unanimously recommended approval of Gilead's sofosbuvir (Sovaldi) for chronic HCV genotypes 1-4. The FDA announced final approval of Sovaldi on December 6, 2013. Historically, Gilead's Sovaldi sales surpassed $10 billion in 2014, a record for any previous brand name launch at that time.
Harvoni contains sofosbuvir and the antiviral NS5A inhibitor ledipasvir. Harvoni -- also a Gilead drug -- hit mega-blockbuster status, too.
However, newer approvals have put pressure on sales of these original oral Hep C agents. Since the approval of Sovaldi and Harvoni, 6 additional oral HCV treatments have been approved.
Safety and Effectiveness for Sovaldi, Harvoni
In clinical trials evaluating interferon-free treatment regimens designed for genotype 3 HCV patients with and without cirrhosis, the most common Sovaldi side effects occurring in 10% or more of patients were:
- asthenia (lack of energy)
Some of these adverse events were consistent with the safety profile of ribavirin, such as fatigue, nausea, and headache.
However, study results with ribavirin-free treatment regimens using the all-oral sofosbuvir plus ledipasvir (Harvoni) have shown cure rates in 94% to 99% of patients within 12 to 24 weeks. Harvoni for 8 weeks can be considered in genotype 1 patients who have never been treated for HCV, without cirrhosis who have pretreatment HCV RNA levels less than 6 million IU/mL.
Once-daily dosing, no ribavirin or interferon side effects, and potentially fewer doctor visits are major advantages to ribavirin-free HCV regimens.
Costs of New HCV Treatments: How Will They Be Sustained?
HCV healthcare costs in the U.S. may surpass $9 billion annually by 2024. Insurance companies have reported that the cost figures double for an HCV patient compared to a non-HCV patient. Added costs with ongoing HCV infection involve treatment of liver disease, liver cancer, and/or needs for a liver transplant.
- Prices can vary from pharmacy to pharmacy and over time, but many agents can cost tens of thousands of dollars per 8-to-12-week regimen, if paying cash.
- The good news? Prices of Hep C meds have come down since the oral DAA agents were first approved, and generics for Harvoni and Epclusa are now available. But prices are still unrealistic for most people.
- Cost can be much higher if longer treatment regimens are required or if there is a need to combine with other antivirals. You may need to interact with a specialty pharmacy to help you acquire the medication and use it safely.
- Many insurance plans have an HCV treatment covered under their formularies. Always check and ask for specifics on copay and co-insurance. Manufacturers may have patient assistant programs to help with finances, if you qualify.
Latest Approvals in HCV
- In January 2016 the FDA approved Zepatier from Merck. Zepatier is a once-daily oral NS5A inhibitor (elbasvir) and NS3/4A protease inhibitor (grazoprevir) fixed-dose combination, used with or without ribavirin, for the treatment of HCV genotypes 1 and 4.
- In studies, sustained virologic response at 12 weeks ranged from 94 to 97 percent in genotype 1 and from 97 to 100 percent in genotype 4-infected subjects.
- Common side effects may included headache, stomach upset, and tiredness.
- Daklinza was fully discontinued from the US market in 2019.
Other Oral Combo Approvals
- Viekira Pak from AbbVie was approved in December 2014. It's used for treatment of genotype 1a and 1b HCV in patients with or without cirrhosis. Viekira Pak is ombitasvir, paritaprevir, ritonavir fixed dose combination tablets copackaged with dasabuvir tablets.
- Viekira Pak is used in combination with ribavirin (RBV) in certain patient populations.
- Viekira Pak contains an oral NS5A inhibitor (ombitasvir), NS3/4A protease inhibitor (paritaprevir), and CYP3A inhibitor (ritonavir) combination co-packaged with a non-nucleoside NS5B palm polymerase inhibitor (dasabuvir).
- Viekira Pak is NOT used in patients with moderate to severe hepatic impairment (Child-Pugh B and C).
- Single tablet Viekira XR, containing all 4 ingredients, was approved in July 2016, but was removed from the US market in 2019.
- Technivie was FDA-approved in July 2015, but discontinued from the US market in 2019.
HCV Treatments: Epclusa
In June 2016 the FDA gave the go-ahead to Gilead's Epclusa (sofosbuvir and velpatasvir), a nucleotide analog polymerase inhibitor and pan-genotypic NS5A inhibitor fixed-dose combination for the treatment of chronic hepatitis C virus (HCV) infection in adults. It is approved for use in adults and children 3 years of age and older.
- Epclusa was the first direct-acting antiviral to target all the major HCV genotypes 1 through 6, with or without cirrhosis. Epclusa is given once-daily in an oral, fixed-dose combination.
- In studies, 95% to 99% of Epclusa-treated patients without cirrhosis or with mild cirrhosis had no virus detected in the blood 12 weeks after finishing the 12-week regimen.
- In patients with moderate to severe cirrhosis, some of whom required ribavirin, 94% were cleared of the virus 12 weeks after finishing treatment.
- The most common side effects of Epclusa in adults and children over 6 years include headache and tiredness. In children, vomiting and spitting up the drug are common side effects.
- In August 2017, the FDA also approved Epclusa to be used for the treatment of chronic HCV in patients co-infected with HIV.
- It is now also available as a generic option.
Vosevi: Another Pan-Genotypic Direct-Acting Antiviral
- Genotype 1, 2, 3, 4, 5, or 6 previously treated with an NS5A inhibitor regimen.
- Genotype 1a or 3 previously treated with a sofosbuvir regimen without an NS5A inhibitor.
Vosevi is used in patients without liver disease (cirrhosis) or with compensated cirrhosis who were not previously successfully treated with other HCV drugs. Vosevi contains all 3 classes of DAA agents used in Hep C treatment.
In studies, 96% to 97% of patients who received Vosevi had no virus detected 12 weeks after treatment ended, suggesting that infections were cured (a sustained virologic response, or SVR12).
Common side effects include headache, fatigue, diarrhea, and nausea.
Mavyret Approved: A Pan-Genotypic 8 Week Regimen
In August of 2017, the FDA approved AbbVie's Mavyret (glecaprevir and pibrentasvir), the first 8 week treatment approved for all hepatitis C virus (HCV) genotypes (1-6) in adult patients without cirrhosis (liver disease) who have not been previously treated. Glecaprevir inhibits NS3/4A protease and pibrentasvir inhibits HCV NS5A.
In April 2019, the FDA also approved Mavyret tablets to treat all six genotypes (1-6) of hepatitis C virus (HCV) in children ages 12 to 17 or weighing at least 45 kg, without cirrhosis or with compensated cirrhosis (Child-Pugh A).
In Sept. 2019, FDA also granted approval to shorten the once-daily treatment duration from 12 to 8 weeks in treatment-naïve, compensated cirrhotic, chronic hepatitis C (HCV) patients across all genotypes (GT1-6).
Specifically, Mavyret is approved for:
- HCV genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis and with compensated cirrhosis (Child-Pugh A).
- Patients with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor, but not both.
Mavyret is a fixed-dose combination given as 3 tablets taken once daily with food (total dose per day is glecaprevir 300 mg and pibrentasvir 120 mg). Treatment durations range from 8 to 16 weeks based on HCV genotype, treatment history, and liver status. It is contraindicated (not to be used) in patients taking the drugs atazanavir and rifampin.
Studies demonstrated that 92% to 100% of patients had no virus detected in the blood after finishing treatment, denoting a cure.
Use of Oral DAAs in Children with HCV
The development of the oral direct-acting antivirals (DAAs) has transformed the treatment of adults and children with HCV. It is estimated that there are 23,000 to 46,000 children in the U.S. with HCV infection. The occurrence of HCV in children is much less frequent than in adults and is usually acquired at birth.
Treatments are available for children as young as 3 years of age. For children under 3 years of age, treatment should be deferred until at least the 3rd birthday, as many cases will resolve on their own.
- Approved for genotypes 1, 2, 3, 4, 5, and 6 in children 12 years and older or weighing at least 45 kg (99 lbs). Mavyret is available as oral tablets.
- Approved for genotypes 1, 4, 5 or 6 chronic HCV infection in children 3 years and older. Harvoni is available as oral tablets or as an oral pellet formulation for children who cannot swallow tablets. Dosing in children is based on weight.
- Approved for treatment of chronic HCV genotype 2 or 3 in children at least 3 years old, in those without cirrhosis or with compensated cirrhosis, in combination with ribavirin. Sovaldi is available as oral tablets or as an oral pellet formulation for children who cannot swallow tablets. Dosing in children is based on weight.
- Approved for the treatment of chronic HCV in patients as young as 3 years of age, regardless of HCV genotype or liver disease severity. A new oral pellet formulation was approved in 2021 as well, for children who cannot swallow tablets. Dosing in children is based on weight, and in those less than 6 years old, give the pellets with food to improve palatability.
HBV Concerns with Direct-Acting Antivirals
In October 2016, FDA warned of 24 cases of hepatitis B virus (HBV) reactivation in HCV/HBV co-infected patients treated with direct-acting antivirals (DAAs) -- such as Harvoni, Epclusa and Viekira -- from November 2013 to July 2016. Because of this concern, Boxed Warnings and consumer documents were update to include the risk of HBV reactivation on all DAA labels.
View Epclusa Boxed Warning here.
- Providers should screen and monitor for evidence of current or prior HBV in all patients receiving DAA treatment, and monitor patients using blood tests for HBV flare-ups or reactivation during treatment and post-treatment follow-up.
- Patients should tell their doctor of any history of hepatitis B infection or other liver problems before being treated for hepatitis C.
- Patients should not stop taking their hepatitis medicine without first talking to their doctor.
Plus, the ACIP guidelines now recommend a hepatitis B vaccine for patients with HCV and chronic liver disease.
HCV: Now and Later
It was only in 2012 that standard treatment involved a combination of injectable interferon and ribavirin. This regimen that was curative in only about 50% of patients, took one-half year to complete, and often failed due to intolerable side effects. Since then, HCV regimens have evolved immensely.
Treatment options have grown. The length of treatment varies from 8 to 24 weeks depending upon factors such as:
- patient liver function
- genotypes and infection subtypes
- resistance testing
- whether the patient is treatment-naïve or treatment-experienced.
For many regimens and patients, interferon and ribavirin-free, once-daily single pills are the norm. Cure rates for these new regimens range between 80% and 100%, and shorter pan-genotypic treatment regimens, even for 8 weeks, are now approved.
However, cost and insurance coverage can be a barrier in the U.S. Patients should always contact their insurance company to see which HCV agents are covered under their plan, and speak to their doctor about changing treatment guidelines, pricing and coverage, too.
Finished: Oral Hepatitis C Treatments: The Evolving Landscape
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Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.