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Harvoni, Sovaldi, Olysio and the Evolving Treatment of HCV

What is Chonic Hepatitis C Virus (HCV)?

Hepatitis C virus (HCV) - a blood-borne infectious disease and a leading cause of chronic liver disease - is at the center of a rapidly evolving treatment regimen. As a chronic disease, it can damage the liver over time, leading to scarring, cirrhosis, possible liver cancer and 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. Treatment options for HCV have been plagued by lack of an all-oral regimen, unpleasant side effects and extended treatment times. Newer oral treatment regimens aim to be more tolerable with a shorter treatment period.

What Are the Common Symptoms of HCV and How is it Diagnosed?

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, fatigue, and painful joints. Diagnosis involves a blood test to determine exposure to HCV and the subtypes (genotypes) of HCV. It is important to know the genotypes to select the best treatment. In some patients, a liver biopsy is required.

How Common is Hepatitis C Virus Infection and How Do You Get It?

Roughly 3.2 million people in the U.S. are infected with hepatitis C, but a good majority remain undiagnosed. About 15,000 people in the U.S. die from HCV every year, primarily due to cirrhosis and liver cancer. The death rates from HCV are expected to rise as fatalities are occurring due to infections from decades ago. 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.

Explain 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 on December 6, 2013, can be combined with ribavirin for the first all-oral treatment for genotypes 2 and 3. Harvoni (ledipasvir/sofosbuvir) was approved in October 2014 the first all-oral, ribavirin and interferon-free treatment, for Genotype 1, the most common subgroup, occurring in roughly 70% of infected patients.

What's Involved With an HCV Diagnosis?

Discuss your risk factors for hepatitis C infection with your healthcare provider. Hepatitis C screening starts with a blood test to look for viral antibodies. HCV antibodies can be detected in the blood within 2-3 months after infection. If this test is positive, a confirmatory PCR 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 in the best treatment 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 Have Been 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) 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 like 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?

In 2012-2013, 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 patients.

What's All the Buzz About New All-Oral HCV Treatments?

The new HCV oral treatments moving into the market now are capable of causing a sustained virologic response (SVR), which means the virus is no longer detectable and the patient is cured in 80 to 100 percent of patients, often after only 12 to 24 weeks. However, resistance can develop; therefore, two or more oral HCV drugs will be used together to help prevent resistance. Side effect profiles are more tolerable than interferon - fatigue and headache are the most common side effects with either Sovaldi (sofosbuvir) plus ribavirin or Harvoni (ledipasvir/sofosbuvir). Ledipasvir is new antiviral approved for the oral combo Harvoni.

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. Sovaldi is known as a direct-acting agent (DAA), meaning that it interferes 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 demonstrated efficacy 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.

What is the Approval History of Solvadi and Harvoni?

Gilead submitted the sofosbuvir NDA to the FDA on April 8, 2013 and was granted a Priority Review and a Breakthrough Therapy designation. The FDA assigns these designations to drug candidates that may offer major advances over existing treatment options. On October 25, 2013 the FDA Advisory Committee unanimously recommended approval of sofosbuvir for chronic HCV genotypes 1-4. The FDA announced final approval of Sovaldi on December 6, 2013. Harvoni contains sofosbuvir and the new antiviral NS5A inhibitor ledipasvir. Analysts predict Gilead's Sovaldi sales could reach $8 billion in 2014. Harvoni is also expected to reach mega-blockbuster status, surpassing $10 billion per year.

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, recent study results with ribavirin-free treatment regimens using the all-oral sofosbuvir plus ledipasvir (Harvoni) have shown cure rates in 94-99% 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 simeprevir is a second generation NS3/4A protease inhibitor and is intended to target genotype 1 HCV, the most common genotype of HCV. Simeprevir is one of at least eleven NS3/4A protease inhibitors currently in clinical trials. Other HCV protease inhibitors like telaprevir (Incivek) and 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 is under FDA review for use in interferon- and ribavirin-free regimens.

What is the Approval Status of Olysio?

Olysio was FDA-approved on November 22, 2013 for HCV genotype 1 infected adults with compensated liver disease, including cirrhosis. Olysio is a once-a-day, 150 milligram oral dose, given for 12 weeks, used in combination with peginterferon and ribavirin (PR). Peginterferon and ribavirin are dosed for 24 or 48 weeks based on prior treatment and history. Olysio may be of benefit to patients who have never received HCV treatment or who have failed prior interferon-based therapy. Olysio plus PR effectiveness is reduced in patients with genotype 1a Q80K - testing is available for this genotype and patients should discuss alternate therapies with their provider if needed.

What About 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.

What's On the Horizon for Oral HCV Therapy?

There are over 40 investigational compounds in the HCV pipeline. Compounds come from different classes, including NS3/4A protease inhibitors, nucleoside/nucleotide NS5B polymerase inhibitors, non-nucleoside NS5B polymerase inhibitors, and NS5A inhibitors. Sofosbuvir combined with either simeprevir or other NS5A inhibitors, in all-oral, ribavirin-free regimens are under research. New, non-invasive methods for determining extent of liver damage are being studied. Researchers anticipate an all-oral regimen to encompass treatment for all genotypes (pangenotypic regimens) by 2016-2017. Several manufacturers are working to develop treatment regimens that last only 4 weeks.

Overview: HCV Late-Stage Drug and Class Pipeline

Selected investigational HCV Agents in Phase II-III studies:
  • NS3/4A protease inhibitors: Asunaprevir (BMS) ABT-450 (AbbVie), Faldaprevir (Boehringer Ingelheim) Danoprevir (Roche) Vedroprevir (Gilead)
  • Non-nucleoside NS5B polymerase inhibitors: ABT-333 (AbbVie), BI-207127 (Boehringer Ingelheim) Tegobuvir (Gilead) ABT-072 (AbbVie)
  • NS5A inhibitors: ABT-267 (AbbVie), Daclatasvir (BMS), GSK2336805 GlaxoSmithKline

What About Costs of New HCV Treatments?

HCV healthcare costs were $6.5 billion in 2012; by 2024 this figure may surpass $9 billion. Insurance companies have suggested the cost burden for an HCV patient doubles. Added costs with HCV involve treatment of liver disease, liver cancer, and/or needs for a liver transplant; these costs are only expected to rise. Incivek and Victrelis added $50,000 to costs with interferon and ribavirin - new oral agents will replace these therapies. Sovaldi costs roughly $85,000 for a 12-week course, while Olysio is roughly $66,000 for 12 weeks. Harvoni, the new Gilead all-oral combo drug that combines sofosbuvir and ledipasvir, has a price tag exceeding $94,000 per 12-week regimen.

HCV Research: What Questions Still Remain?

Clinical trials for new treatments often exclude high risk groups. Experts suggest more studies will be needed to assess HCV patients coinfected with HIV, in certain racial and ethnic groups, drug abusers, and other high-risk populations. Gilead recently reported that an interferon-free regimen of sofosbuvir plus ribavirin achieved SVR12 in 76 percent (87 of 114 patients) of patients with HIV-HCV. In addition, more trial data is forthcoming on all-oral regimens. The combination of sofosbuvir and simeprevir has been effective - but with both approved individually, will providers be willing to use the combo off-label? With Harvoni and upcoming all-oral approvals, revised HCV guidelines will be needed.

Finished: Harvoni, Sovaldi, Olysio and the Evolving Treatment of HCV

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