Hepatitis C virus treatment is a rapid and ever-changing field. Since the discovery of HCV in 1989, diagnosis, disease management and treatments have changed dramatically. WHO estimates that more than 185 million people around the world have been infected with HCV, of whom 350,000 die each year. Approximately one-third of patients with HCV go on to develop complications of the disease, such as liver cirrhosis or hepatocellular carcinoma.
Chronic HCV also is the most common cause of liver-related death and reasons for liver transplantation. Research and development have been in full throttle designing new HCV treatment modalities. The field of HCV has evolved rapidly, and numerous new products have come to market in the past 5 years. It is estimated that these new treatments can cure more than 90% of individuals with HCV infection and are effective against genotypes that were previously difficult to treat. The research and development of new products are not slowing down.
Standard treatments for HCV
The gold standard of treatment strategies has included ribavirin and interferon alfa (IFN-alfa). But the addition of the protease inhibitor as the backbone led to increased rates of viral cure. The treatment adherence has been relatively low due to the associated adverse effects, drug interactions and contraindications. With these findings, research and development have led to other protease inhibitors, nucleoside inhibitors, non-nucleoside inhibitors and NS5A inhibitors. Currently licensed treatments for HCV infection include pegylated and standard IFN-alfa; ribavirin; protease inhibitors, including boceprevir (Victrelis, Merck), telaprevir (Incivek, Vertex Pharmaceuticals) and simeprevir (Olysio, Janssen); and the newest NS5B nucleotide polymerase inhibitor, sofosbuvir (Sovaldi, Gilead Sciences).
The protease inhibitors and the NS5B nucleotide polymerase inhibitor are new to market since 2011.
Regulation and advancements
A key regulatory move by the FDA enabled rapid clinical development of direct-acting antiviral (DAA) agents by allowing phase 2 studies of all oral regimens without standard-of-care comparators. Advances in biomedical technologies have led to better diagnosis and molecular characterization of the viral genome, as well as specific drug design and development. Additionally, studies are underway to investigate the ability to eliminate IFN from the treatment regimen and allow an all-oral regimen. The rapidity of drug development mimics the late ’80s and early ’90s during the time of the HIV epidemic. We know from that experience that combination therapy of potent agents from two or more classes may provide rapid suppression of viral replications. These combination approaches for treating HCV are estimated to exceed 90% SVR.
Trials of note
One notable trial is the randomized, open-label, phase 2a COSMOS clinical trial evaluating a once-daily combination of the HCV protease inhibitor simeprevir and the nucleotide analog protease inhibitor sofosbuvir with and without ribavirin for 12 and 24 weeks. This combination treatment is for genotype 1 HCV in adult treatment-naive patients with advanced liver fibrosis and non-responders. Janssen announced on May 7 that it submitted a supplemental new drug application (sNDA) to the FDA for the above noted combination.
Janssen also has announced two phase 3 trials initiated in April: OPTIMIST-1 AND OPTIMIST-2. These trials will evaluate the safety and efficacy of simeprevir and sofosbuvir without INF or ribavirin for the treatment of chronic genotype 1 HCV infection. The OPTIMIST-1 trial will evaluate once-daily combination therapy in treatment-naive or treatment-experienced patients without cirrhosis for 8 to 12 weeks. OPTIMIST-2 will evaluate patients with cirrhosis who are treatment-naive or treatment-experienced after receiving the combination for 12 weeks.
The drugs currently in phase 2 and phase 3 studies in combination with IFN or ribavirin, or combination with other DAAs, are impressive.
DAA inhibitors currently in trials
There are currently five individual DAA agents under investigation, including three protease inhibitors, one NS5A inhibitor and one polymerase inhibitor. The protease inhibitors include ACH-2684 and sovaprevir (formerly known as ACH-1625, Achillion Pharmaceuticals), and danoprevir (formerly RG7227, Genentech). Also in development is ACH-3102 (Achillion), a NS5A inhibitor, and VX-135 (formerly ALS-2200, Vertex/Alios), a polymerase inhibitor.
Simeprevir is being studied in combination with other DAA agents without INF in four phase 2 trials. These combinations include simeprevir with two NS5A inhibitors and two polymerase inhibitors. Daclatasvir (BMS-790052, Bristol-Myers Squibb) is in two phase 2 combination trials; one with simeprevir and one with VX-135. Bristol-Myers Squibb also has a phase 3 trial ongoing that is evaluating daclatasvir with INF and ribavirin and a phase 3 trial with sofosbuvir. Sofosbuvir is in a phase 2 trial evaluating a combination that also includes GS-5816 (Gilead), an NS5A inhibitor, and a recently completed phase 3 trial with ledipasvir (GS-5885, Gilead), an NS5A inhibitors.
Another phase 3 trial that includes a two-drug combination without INF is being conducted by Merck: MK-5172, a protease inhibitor, with MK-8742, a NS5A inhibitor. Two phase 3 clinical trials that include three drug combinations also are underway. The first, conducted by Abbott/Enanta is a combination of ABT-450/r, a protease inhibitor, ombitasvir (ABT-267), a NS5A inhibitor, and dasabuvir (ABT-333), a polymerase inhibitor. The next is a similar combination of Bristol-Myers Squibb drugs that includes daclatasvir, a NS5A inhibitor; asunaprevir (BMS-650032), a protease inhibitor; and BMS-791325, a polymerase inhibitor.
The drug development and treatment of HCV is promising. It may be that we are on the forefront of HCV disease eradication. Screening for HCV is still a crucial part of managing the disease. Now with more available treatment options with less adverse effects, administration limitations due to side effects, drug-drug interactions or IV therapy, compliance may increase.
A huge hurdle still exists with these new agents. They all are extremely expensive, with some of the newer agents coming to market costing more than $20,000 for a 4-week supply. To add to that cost, if these combination trials prove to have the predicted cure rates, regimens will be upward of $80,000 to $120,000 for a treatment course. One could argue if these treatments exceed more than 90% cure rates that the price might be worth it. It is undeniable that DAA treatment for HCV is rapidly growing and the management for HCV infection will forever be changed.
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HCV Advocate. Hepatitis C treatments in current clinical development. April 2014. Available at: www.hcvadvocate.org/hepatitis/hepC/HCVDrugs.html. Accessed on May 9, 2014.
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Inc.; 2013.
Olysio [package insert]. Titusville, NJ: Janssen Products; 2013.
Sovaldi [package insert]. Foster City, CA: Gilead Sciences Inc.; 2013.
Victrelis [package insert]. Whitehouse Station, NJ: Merck & Co. Inc.; 2013.
WHO. Guidelines for the screening, care and treatment of persons with hepatitis C infections. Available at: www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/. Accessed on May 9, 2014.
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Kimberly D. Boeser, PharmD, is an infectious disease clinical pharmacist and antimicrobial stewardship coordinator at the University of Minnesota Medical Center-Fairview and the University of Minnesota Amplatz Children’s Hospital.
Disclosure: Boeser reports no relevant financial disclosures.