Advances in HCV Therapy: Beginning of the End?

The advances in treatment of chronic hepatitis C virus (HCV) infection over the past five years have been nothing short of historic in scope and impact. Since 2011, a total of 12 oral direct acting antiviral agents (DAAs) have been approved by the U.S. Food and Drug Administration across four classes of drugs, including NS3/4A protease inhibitors, NS5A inhibitors and both nucleoside and non-nucleoside NS5B polymerase inhibitors. On the backbone of pegyated interferon and ribavirin, the addition of first-generation protease inhibitors boceprevir and telaprevir in 2011 significantly improved sustained virologic response (SVR) rates to over 70 percent for patients with genotype 1 HCV, but were associated with many limitations, including weekly injections, substantial pill burden (up to 18 pills per day), long treatment courses (up to 48 weeks), inconvenient dosing (q8 hours), high resistance, a lengthy list of drug-drug interactions, and substantial adverse effects beyond those of interferon (e.g., rash, anemia, dysgeusia, anal itching/burning and Stevens Johnson Syndrome).

Wouldn’t it be wonderful if we could design a regimen that could simplify dosing to one pill a day for 2 or 3 months, eliminate interferon injections, cause few adverse effects, have efficacy across all six HCV genotypes, and achieve cure rates over 90 percent across all key subgroups? Check.

As of July 2016, we have now for the first time achieved all of these elements of an ideal HCV regimen. A total of six all-oral regimens combining two or three DAA classes have been approved, including sofosbuvir (Sovaldi)/simeprevir (Olysio) for GT1 and 4, sofosbuvir/ledipasvir (Harvoni) for GT1/4/5/6, paritaprevir/r/ombitasvir ± dasabuvir (Viekira Pak and Technivie) for GT1 and 4, sofosbuvir (Sovaldi)/daclatasvir (Daklinza) for GT1 and 3, grazoprevir/elbasvir (Zepatier) for GT1 and 4, and most recently sofosbuvir/velpatasvir (Epclusa) for GT1 through 6, which represents the first all-oral, single pill, pangenotypic regimen for HCV.

Phase 3 clinical trials across each program have confirmed SVR rates of 93 to 99 percent, and remarkably, multiple U.S.-based and international observational cohorts such as HCV-TARGET, TRIO, VA, Kaiser and GECCO have demonstrated similarly high SVR rates over 90 percent in real-world populations. Even traditional “special populations” who were previously “difficult to treat” are now deemed “less special” as SVR rates for patients with HIV co-infection, end-stage renal disease, decompensated cirrhosis and prior recipients of liver or kidney transplantation now approach those of “easy-to-treat” populations, and the impact of pre-existing and/or treatmentemergent resistance associated variants (RAVs) is diminished by improving susceptibility to next generation all-oral combination regimens.

Furthermore, SVR is associated with an improvement in key clinical outcomes, including a decreased risk of cirrhosis, hepatic decompensation, need for liver transplantation, hepatocellular carcinoma, post-transplant recurrence, both liver-related and all-cause mortality, and other important patient-reported outcomes including health-related quality of life. Even at the inflated sticker prices of these all-oral regimens, which range from $54,600 to $94,500 for a 12-week course, HCV treatment of all patients across all stages is more costeffective than treating only patients with stages three and four using a lifetime horizon, and can avert cases of liver transplant, decompensated cirrhosis, hepatocellular carcinoma and liverrelated death by 17 to 26 percent. Most cost analyses are limited by the use of wholesale acquisition cost (WAC) prices which in reality are never utilized due to discounts negotiated with public or private payors, and therefore the true cost-effectiveness of HCV treatment may be underestimated.

In light of these accomplishments, it is easy to understand the sentiment that we’ve solved the hepatitis C puzzle, and that eradication of HCV is near. For baby boomers, the population known to represent over 80 percent of all HCV-infected individuals in the U.S. per NHANES, the memory of the historic eradication of polio in 1979 remains a fresh reminder of what is possible to accomplish with HCV in the U.S. But make no mistake, we have much work to do before we can declare HCV a rare disease in this country, much less across the globe. The reality is that there remains a striking lack of awareness by the public and health professionals regarding HCV. In addition, there is a lack of support and funding by the U.S. government and global non-governmental organizations, a lack of knowledge by clinicians, underscreening of at-risk populations, poor linkage to care, a shortage of specialists who treat HCV, limited attention to quality of care provided for patients with HCV and treatment is not covered for all patients due to payor restrictions. There is also a subset of treated patients who continue to fail to achieve SVR.

Multiple studies have documented the “waterfall” effect of key deficits along each step of the care cascade for HCV, in which only half of all infected individuals in the U.S. have been diagnosed, and even fewer have been confirmed with HCV viral load and genotype, linked to care, offered, started and completed antiviral therapy, and achieved viral eradication. A sobering Centers for Disease Control and Prevention study published in the New England Journal of Medicine in 2013 revealed that only an estimated 18 percent of HCV RNA+ individuals had ever received treatment, and only 5 to 6 percent of the infected cohort had achieved SVR.

Urgent action is needed to address key deficits in the care cascade to ensure that our goal of HCV eradication in the U.S. can be achieved.

Urgent action is needed to address key deficits in the care cascade to ensure that our goal of HCV eradication in the U.S. can be achieved. The key rate-limiting step is screening and diagnosis, for which innovative strategies are sorely needed. Recommendations of the CDC and U.S. Preventive Services Task Force to screen baby boomers born between 1945 and 1965 are an important first step, but will be insufficient alone to identify all infected patients, and therefore strategies to screen both baby boomers (e.g. using electronic medical record-based prompts and clinical reminders) and other at-risk individuals (e.g. young injection drug users) require formal examination and validation so we can provide clinicians and health systems evidence-based guidance.

Once patients are diagnosed and confirmed with HCV RNA, we then need to improve linkage to care by a provider who can offer antiviral therapy. Investment in the training of both GI, infectious disease and liver specialists and non-specialists (e.g., primary care, methadone clinics, community health centers, prison clinics) in antiviral therapy can significantly reduce the linkage to care barrier, and expand treater capacity.

With the increasing simplicity of all-oral DAA regimens, it is conceivable that we may soon have one-size-fit-all strategies with one-pill-a-day for 3 months or shorter that may be comparable to our current paradigm of Helicobacter pylori treatment in primary care: only patients who fail a primary regimen or have other medical factors (e.g., cirrhosis, ESRD, transplant, HIV) may require specialty care. Finally, important work remains to increase access to HCV medications for all patients with HCV who desire treatment, which will require broad advocacy efforts to decrease the cost of HCV treatment and remove barriers to drug access by payors. Just a quarter century removed from its original discovery in 1989, it is thrilling that HCV now represents a curable infection in over 90 percent of patients with all-oral regimens, and we face a historic opportunity to bring an end to the HCV epidemic.

Dr. Lim has consulted for and received research support from Bristol-Myers Squibb and Gilead.


1. AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology 2015; 62:932-54.

2. Van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virologic response and all cause mortality among patients with chronic hepatitis C and advanced hepatic
fibrosis. JAMA 2012; 308:2584-93.

3. Chahal HS, Marseille EA, Tice JA, et al. Cost effectiveness of early treatment of hepatitis C virus genotype 1 by stage of liver fibrosis in a US treatment-naïve population. JAMA Intern Med 2016; 176:65-73.

4. Holmberg SD, Spradling PR, Moorman AC, et al. Hepatitis C in the United States. N Engl J Med 2013; 368:1859-61.

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