Oral Hepatitis C Treatments: The Evolving Landscape

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.

Newer oral treatment regimens - Sovaldi (sofosbuvir), Harvoni (ledipasvir), Zepatier, Epclusa (velpatasvir), Vosevi, and Mavyret - aim to be more tolerable with shorter treatment times - some as short as 8 or 12 weeks.

Some people with HCV may have acute symptoms for up to 3 months that might include:

• yellow-colored skin or eye sclera (jaundice)
• weakness
• fatigue
• 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.

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.

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.

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.

There are six different genotypes for HCV. A genotype classification is based on the genetic material in the RNA viral strands. Generally, patients are only infected with one genotype, but genotypes can mutate quickly and become drug resistant.

Effectiveness of drugs vary based on which HCV strain a patient may be infected with -- for example, a few of the top approvals include:

• Sovaldi (sofosbuvir), approved as the first all-oral regimen in 2013, can be combined with ribavirin to treat genotypes 2 and 3; add peginterferon alfa and genotypes 1 and 4 can be treated.
• 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.
• Epclusa (sofosbuvir and velpatasvir) was approved for all 6 major genotypes in June 2016. With advanced liver disease, it is combined with ribavirin.
• Gilead's Vosevi (sofosbuvir, velpatasvir and voxilaprevir) was given the FDA clearance in July 2017 as a re-treatment option in all 6 genotypes (previously received prior NS5A inhibitor) or for types 1a or 3 (previously received sofosbuvir without an NS5A inhibitor).
• In August of 2017, Mavyret (glecaprevir and pibrentasvir) from AbbVie was also approved for all 6 genotypes.

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.

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
• anemia
• depression.

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.

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 are expected to result in HCV cures for most newly diagnosed patients.

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 12 weeks of treatment. However, resistance can develop; therefore, two or more oral HCV drugs will be 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.

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 a direct-acting agents (DAA), meaning that they interfere directly with the HCV life cycle by suppressing viral replication.

Sovaldi and Harvoni, which is a combo drug that contains ledipasvir and sofosbuvir, are both given once-a-day, with or without food.

Sovaldi’s effectiveness 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.

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.

New indications for the older drugs may be helpful for sales: in April 2017 the FDA approved both Sovaldi and Harvoni for treatment of certain HCV genotypes in pediatric patients 12 years and older.

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:

• headache
• fatigue
• itching
• asthenia (lack of energy)
• nausea.

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. Once-daily dosing, no ribavirin or interferon side effects, and potentially fewer doctor visits are major advantages to ribavirin-free HCV regimens.

Olysio was originally FDA-approved in 2013 for adults with chronic hepatitis C virus (HCV) infection. A once-a-day, 150 milligram oral capsule, it was used:

• in combination with sofosbuvir in patients with HCV genotype 1 without cirrhosis or with compensated cirrhosis.
• in combination with peginterferon alfa (Peg-IFN-alfa) and ribavirin (RBV) in patients with HCV genotype 1 or 4 without cirrhosis or with compensated cirrhosis.

Olysio was discontinued by the manufactuer Janssen in May of 2018. According to the Janssen, the decision was not driven by any safety, efficacy or quality issues, but by market factors and newer treatments to the market that treat all possible genotypes (pangenotypic combination agents).

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 range from $70,000 to $98,000 per 12-week regimen.
• Cost can be much higher if longer treatment regimens are required or if there is a need to combine with other antivirals.
• Many insurance plans have HCV treatments covered under their formulaires; however, you should always check and ask for specifics on copay and co-insurance.
• You will most likely be involved with a specialty pharmacy to help you acquire the medication and use it safely.

Nonetheless, treatment availability for patients is also a major concern with newer HCV treatments. Some insurance companies are pushing back to treat only patients with advanced liver disease with the newer agents; lawsuits have been filed disputing the ethics of these policies. Plus, lower-cost oral biosimilars for HCV won't appear for many years in the U.S. However, continued growth and competition in the HCV marketplace may help to lower drug prices and push more affordable drugs to the top of the formulary.

Zepatier (elbasvir and grazoprevir)

• 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 (daclatasvir) discontinued

• Daklinza was fully discontinued from the US market in 2019.
• Daklinza, from Bristol-Myers Squibb, received FDA approval in July 2015. Daklinza, an oral NS5A inhibitor used with sofosbuvir for the treatment of HCV genotype 1 or 3, was the first drug approved to treat genotype 3 HCV without need for interferon or ribavirin.
• In studies, 98 percent of the treatment-naive participants with no liver cirrhosis achieved sustained virologic response (a cure) with Daklinza + sofosbuvir for 12 weeks.
• In Feb. 2016, the FDA approved Daklinza for treatment of genotype 1, in addition to genotype 3 HCV patients with: HIV-1 coinfection, advanced cirrhosis, or post-liver transplant recurrence of HCV.

Viekira Pak

• 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 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.

Viekira XR discontinued

• Single tablet Viekira XR, containing all 4 ingredients, was approved in July 2016, but was removed from the US market in 2019.

Technivie discontinued

• Technivie was FDA-approved in July 2015, but discontinued from the US market in 2019. It was not discontinued due to any safety issues.
• Technivie was an NS5A inhibitor (ombitasvir), NS3/4A protease inhibitor (paritaprevir), and CYP3A inhibitor (ritonavir) fixed-dose combination used with ribavirin.
• The Technivie plus ribavirin regimen was a 12-week regimen approved for genotype 4 HCV infections without the need for interferon.

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.

• Epclusa was the first direct-acting antiviral to target all the major HCV genotypes 1 through 6, with or without cirrhosis.
• 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 include headache and tiredness. Epclusa is given once-daily in an oral, fixed-dose combination.
• In August 2017, the FDA also approved Epclusa to be used for the treatment of chronic HCV in patients co-infected with HIV.

In July 2017, the U.S. Food and Drug Administration (FDA) gave the go-ahead to Gilead’s Vosevi (sofosbuvir, velpatasvir and voxilaprevir) for the re-treatment of adults with chronic HCV of two types:

• 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.

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.

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, weighing at least 45 kg.

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.

The development of the oral direct-acting antivirals (DAAs) has transformed the treatment of adults with HCV. Uses for children 12 and older are now approved, and expanded use for children younger than 12 are anticipated in the near future.

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 via perinatal transmission (from mother to baby during the period immediately before and after birth).

For treatment of children 12 years of age and older, at least one approved oral DAA treatment is available for every genotype 1 through 6:

Mavyret (glecaprevir-pibrentasvir)

• Approved in April 2019 for genotypes 1, 2, 3, 4, 5, and 6 in children 12 years and older and weighing at least 45 kg (99 lbs), with treatment duration ranging from 12 to 16 weeks based on prior treatment and liver disease status.
• The most common side effects with Mavyret in children are headache and fatigue, similar to adult side effects.

Harvoni (ledipasvir and sofosbuvir):

• Approved in April 2017 for genotypes 1, 4, 5 or 6 chronic HCV infection in children 12 years and older and weighing at least 35 kg (77 lbs), with treatment duration ranging from 12 to 24 weeks based on prior treatment and liver disease status.
• The most common side effects with Harvoni in children are fatigue, headache and asthenia (lack of energy, weakness).

For children 12 years of age and under, deferring treatment until they are eligible or enrolling in a clinical trial is often an option. Most, but not all children with HCV have mild liver disease that does not advance quickly.

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.

• 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.

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.