Oral Hepatitis C Treatments: The Evolving Landscape
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 percent 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 and long treatment times often over 1 year. Newer oral treatment regimens - Sovaldi, Olysio, Harvoni, Daklinza, Zepatier, and Epclusa - aim to be more tolerable with shorter treatment times - some as short as 8 or 12 weeks.
HCV: Symptoms and Diagnosis
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. 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.
Longer-term (chronic) symptoms may include weight loss, poor appetite, feeling tired, and painful joints. 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.
Hepatitis C Virus Infection: How Do You Get It?
Roughly 2.7 to 3.9 million people in the U.S. are infected with hepatitis C, but a good majority remain undiagnosed. About 1 to 5 out of every 100 people in the U.S. die from HCV every year due to cirrhosis and liver cancer, according to the CDC.
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, from contaminated tattoo or body piercing equipment, and rarely from unprotected sexual intercourse or blood transfusions.
If you were born from 1945 through 1965 speak to your doctor about being tested for HCV.
The Different Genotypes for Hepatitis C Virus
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, Sovaldi (sofosbuvir), approved as the first all-oral regimen in 2013, can be combined with only ribavirin to treat genotypes 2 and 3; add peginterferon alfa and genotypes 1 and 4 can be treated. Harvoni (ledipasvir/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. Epclusa (sofosbuvir and velpatasvir) was approved for all 6 major genotypes in June 2016.
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 - AST, ALT and GGT tests - to monitor your liver's health.
A liver biopsy, usually performed as an outpatient surgical procedure, may be needed to determine the level of liver damage.
What Were the Standard HCV Treatments?
The standard treatments for HCV have included injectable interferon, oral ribavirin and one of the protease inhibitors, such as Vertex's Incivek (telaprevir) - now off of the market - or Merck's Victrelis (boceprevir). However, interferon and ribavirin are given for 6 to 12 months and are difficult to tolerate for some patients due to side effects such as flu-like symptoms, anemia and depression. In addition, this regimen is not always effective for the hard-to-treat and most common genotype 1 infections.
These treatments can cure roughly 70 percent of newly diagnosed cases, but patients must remain adherent with treatment and complete the full course of medications.
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) recommended that all "baby boomers" - those born from 1946-1964 - be tested for HCV. This group of adults represents about 75 percent of all cases, but most are not currently diagnosed. People at high risk for the hepatitis C virus, which includes those with a history of IV drug use and those who received blood transfusions before 1992 should also be tested.
Increased rates of screening and diagnosis will likely result in accelerated demand for treatments. New oral treatments for HCV are expected to result in HCV cures for most newly diagnosed patients.
What's All the Buzz About New All-Oral HCV Treatments?
The new HCV oral treatments now on the market are capable of causing a sustained virologic response (SVR), which means the virus is no longer detectable and the 80 to 100 percent 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, like Viekira Pak and once-daily Viekira XR, are increasingly being approved. Side effect profiles are more tolerable than interferon - fatigue and headache are the most common side effects with many of the direct-acting oral antivirals, like Sovaldi, Harvoni, and Epclusa.
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 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.
What Evidence Supports the Sovaldi FDA-Approval?
Sovaldi’s effectiveness was evaluated in six clinical trials (n=1,947). 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.
Blockbuster Status: Solvadi 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. 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. Sales of Harvoni and Sovaldi in 2015 were tallied at $19.1 billion, over a 50% boost from the $12.4 billion in sales for 2014. New approvals, like Zepatier and Epclusa, may put pressure on sales of the originally-approved oral Hep C agents.
Safety and Effectiveness for All-Oral Treatments
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 percent of patients were headache, fatigue, itching, asthenia (lack of energy) and 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 12-24 weeks. Once-daily dosing, no ribavirin or interferon side effects, and less doctor visits are major advantages to ribavirin-free HCV regimens.
How Does Olysio Work in HCV?
Olysio (simeprevir) works by blocking the protease enzyme that enables the hepatitis C virus to replicate in host cells. The NS3 protease and its associated cofactor NS4A process proteins that are essential for viral replication.
Janssen’s Olysio is a second generation NS3/4A protease inhibitor and is intended to target genotype 1 HCV, the most common genotype of HCV. Other HCV protease inhibitors like boceprevir (Victrelis) are typically dosed three times a day - while Olysio is given once a day - which may improve compliance.
What Evidence Supports the FDA-Approval of Olysio?
In HCV-1 trials for simeprevir (QUEST-1, QUEST-2) treatment-naive patients were able to achieve sustained virologic response (SVR) 12 weeks after treatment - (a cure) - in 80% of patients compared to 50% who received placebo. In PROMISE, 79% of prior-relapsed patients in the simeprevir group achieved SVR12 compared to 37 percent in the placebo group.
Results from ASPIRE demonstrated that use of Olysio led to SVR24 in 65 percent of prior partial-responders and 53 percent of prior-null responders compared to 9% and 19% in the placebo groups, respectively.
The Olysio plus Sovaldi once-daily combo - for use in interferon- and ribavirin-free regimens for genotype 1 - was FDA-approved in 2014.
More Info: Olysio
Olysio, a protease inhibitor, is a once-a-day, 150 milligram oral capsule. Olysio was originally FDA-approved in 2013 for HCV genotype 1 infected adults with compensated liver disease, including cirrhosis.
Olysio is now approved to treat genotypes 1 or 4 AND patients with genotype 1 and co-infected with HIV. Treatments regimens vary based on patient characteristics. The all-oral Olysio plus Sovaldi regimen for HCV genotype 1 is given for either 12 weeks (without cirrhosis) or 24 weeks (with cirrhosis). In studies, common side effects for the two-drug regimen included fatigue, headache, nausea, trouble sleeping, and itching.
Other Safety Concerns for Olysio
Severe rashes and skin reactions to sunlight may occur in patients treated with Olysio plus peginterferon and ribavirin. These skin reactions occur most frequently in the first 4 weeks of treatment. There is also the possibility for multiple drug interactions and patients should have a doctor or pharmacist review their medication profiles.
Due to the possibility of birth defects, females and males must use two effective forms of birth control during treatment and for 6 months after treatment with Olysio, peginterferon alfa, and ribavirin combination therapy. Itching and nausea are other common side effects that may occur with Olysio.
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 (daclatasvir), 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.
Other Oral Combo Approvals
Viekira Pak, Viekira XR
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 an 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. Single tablet Viekira XR, containing all 4 ingredients, was approved in July 2016.
Technivie was FDA-approved in July 2015. It's an NS5A inhibitor (ombitasvir), NS3/4A protease inhibitor (paritaprevir), and CYP3A inhibitor (ritonavir) fixed-dose combination used with ribavirin. The Technivie plus ribavirin regimen is a 12-week regimen approved for genotype 4 HCV infections without the need for interferon. Technivie should not be used in patients with moderate to severe hepatic impairment.
Novel HCV Treatment: 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. Epclusa is the first direct-acting antiviral to target all the major HCV genotypes 1 through 6, with or without cirrhosis.
In studies, 95 to 99 percent 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 percent 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.
Costs of New HCV Treatments: How Will They Be Sustained?
HCV healthcare costs were $6.5 billion in 2012; by 2024 this figure may surpass $9 billion. Insurance companies have reported that the cost burden for an HCV patient doubles. Added costs with ongoing HCV infection involve treatment of liver disease, liver cancer, and/or needs for a liver transplant.
Victrelis added $50,000 to costs with interferon and ribavirin. Sovaldi costs roughly $85,000 for a 12-week course, while Olysio is roughly $66,000 for 12 weeks. Harvoni, Gilead's all-oral combo drug that combines sofosbuvir and ledipasvir, has a price tag exceeding $94,000 per 12-week regimen. Insurance companies are obviously pushing back to treat only patients with advanced liver disease. Plus, lower-cost oral biosimilars for HCV won't appear for many years. But continued growth and competition in the HCV marketplace may help to lower drug prices.
HCV: Now and Later
In the future, more oral agents, combination regimens, and faster treatment time, coupled with a cure rate approaching 100 percent are expected. 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.
Top-line treatments may include Harvoni, Viekira Pak/ribavirin, Daklinza plus Solvadi, Olysio plus Sovaldi for 12 weeks. Plus, there's Epclusa, the first agent to treat all six major forms of HCV. Cure rates for these new regimens range between 80 and 100 percent, and shorter treatment regimens are being developed. However, cost and insurance coverage can be a barrier. Patients should always contact their insurance company to see which HCV agents are covered under their plan..
Finished: Oral Hepatitis C Treatments: The Evolving Landscape
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