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?
According to the Centers for Disease Control and Prevention (CDC), roughly 3.5 million people in the United States have chronic hepatitis C. About 1 to 5 out of every 100 people in the U.S. die from HCV every year due to cirrhosis and liver cancer.
The CDC estimated there were actually about 34,000 new hepatitis C infections nationwide in 2015. In 2017 it was also reported that rates of HCV are on the rise due to the growing use of injected drugs linked to the current opioid epidemic.
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, 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. 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. 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.
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 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.
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 and depression. In addition, this regimen is not always effective for the hard-to-treat and most common genotype 1 infections. Adherence with interferon and ribavirin regimens due to side effects can be an issue. Research and recommendations are rapidly changing in the area of chronic HCV, and 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) recommended that all "baby boomers" - those born from 1945 to 1965 - 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 includes those with a history of IV drug use and those who received blood transfusions before 1992, but 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.
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.
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. 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.
However, newer approvals have put pressure on sales of these original oral Hep C agents. According to FiercePharma, Harvoni revenues dove 34% in 2016 compared to 2015, and Sovaldi sank 24%, shaving off $6 billion in Gilead sales in 2016 versus 2015.
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 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 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.
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 Sovaldi costs roughly $87,000 for a 12-week course, while Olysio costs roughly $69,000 for 12 weeks, if paying full cash price with discount coupons. Harvoni, Gilead's all-oral combo drug that combines sofosbuvir and ledipasvir, has a price tag exceeding $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.
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.
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 (a diseased liver that is still functioning), including cirrhosis, who are treatment naïve (not received prior HCV therapy) or who are treatment experienced (previous treatment has not been effective).
Olysio is also approved to also 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.
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. Olysio is not used as a single drug (monotherapy). It is given in combination with peginterferon alfa and ribavirin or with sofosbuvir (Sovaldi) for the treatment of chronic HCV infection genotype 1 or 4 in adults and is taken once daily with food.
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.
Safety Concerns: 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. Costs for 12 weeks of Zepatier run roughly $57,000.
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. Price of 12 weeks of Daklinza is about $66,000. 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
- post-liver transplant recurrence of HCV.
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, and costs approximately $87,000 for 12 weeks.
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. Technivie costs about $80,000 for 12 weeks of treatment.
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, and costs roughly $78,000 per 12 weeks of treatment.
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.
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. They should not stop taking their hepatitis medicine without first talking to their doctor.
Plus, the latest 2017 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. Today, in 2017, regimens have evolved immensely.
Top-line treatment options include Harvoni, Epclusa, Zepatier, Viekira XR, Daklina plus Sovaldi, or Olysio plus Sovaldi. Length of treatment varies from 8 to 24 weeks depending upon factors such as patient liver function, genotypes and infection subtypes, resistance testing, and whether they are treatment-naïve or treatment-experienced. For many regimens, once-daily single pills and interferon and ribavirin-free are the norm. Cure rates for these new regimens range between 80 and 100 percent, and shorter treatment regimens, even less than 8 weeks, are being investigated.
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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