The revolution in treatment for hepatitis C virus (HCV) infection continues at an unprecedented pace, especially for genotype 1, which affects approximately 75 percent of patients with HCV in the United States.
By the end of 2015, four Food and Drug Administration-approved, all-oral regimens of direct-acting antiviral agents were available, most with a sustained virologic response (SVR) above 95 percent, even in patients who failed prior interferon-based triple therapy. SVR is equivalent to a cure because the durability of response is nearly universal; unfortunately, however, response to treatment does not protect patients from reinfection.
The new antiviral agents include Harvoni — sofosbuvir combined with the NS5A inhibitor ledipasvir; Viekira Pak, a combination of ombitasvir, paritaprevir and ritonavir plus dasabuvir; and Olysio (simeprevir) combined with Sovaldi (sofosbuvir). These regimens are effective against genotypes 1a and 1b.
The NS5A inhibitor Daklinza (daclatasvir) is approved for use with sofosbuvir for chronic genotype 3 HCV infection. A fourth drug regimen, Technivie — combined ombitasvir, paritaprevir and ritonavir — is approved for treatment of genotype 4 HCV without cirrhosis in combination with ribavirin.
Of the interferon-free treatment options for genotype 1 HCV, the fixed-dose combination drug Harvoni provides the simplest regimen and has demonstrated efficacy in patients with advanced liver disease, including decompensated cirrhosis.
Harvoni is taken as a single pill, once daily for 12 weeks or for 24 weeks in patients with cirrhosis, with a sustained viral response rate of 95 percent. It has a relatively clean side effect profile and few drug-drug interactions.
It is also expensive, with a price tag close to $1,000 a pill. In the first half of 2015, Medicare's prescription drug program spent nearly $4.6 billion on new HCV medications, including 119,000 prescriptions for Harvoni.
Viekira Pak, which was approved later than Harvoni and has since been linked to serious liver problems in patients with underlying cirrhosis, requires a more nuanced approach, according to Hugo E. Vargas, M.D., vice chair of Gastroenterology and Hepatology at Mayo Clinic's campus in Scottsdale, Arizona.
"Viekira Pak has a greater pill burden than Harvoni, and the spectrum of patients it can treat is more limited — it is contraindicated for those with moderate to severe hepatic impairment. Although it is still effective for a significant portion of patients, that effectiveness is shadowed by those factors. On the plus side, it's about 12 percent less expensive than Harvoni, and its presence in the market has decreased the cost of treatment for all patients," he says.
Daclatasvir plus sofosbuvir
Daclatasvir plus sofosbuvir is an all-oral, once-daily regimen for difficult-to-treat genotype 3. In phase III trials, it achieved SVR12 in 96 percent of patients without cirrhosis who had not been treated before. Patients with genotype 3 who have prior treatment exposure and cirrhosis have lower response rates with interferon-free regimens. Still, of the few options for patients with decompensated cirrhosis, daclatasvir is the only agent recommended across genotypes.
Two new, all-oral regimens will likely be approved in 2016 that may further close the gaps that currently exist in the management of HCV.
The price of a cure
Virological efficacy, ease of use and tolerability make interferon-free, direct-acting antiviral regimens the best treatment option for all patients, even those with relatively mild fibrosis, Dr. Vargas says.
"Studies, including a Centers for Disease Control and Prevention study published in Clinical Infectious Diseases in 2015, have shown that deferring treatment leads to detrimental outcomes, such as progression to cirrhosis, hepatic decompensation and hepatocellular carcinoma. There is also an immediate benefit to treating people with early disease — quality of life and survival both improve, and patients are much more likely to have a reversal of damage. Treating sooner instead of warehousing patients until they become sicker makes much more sense from both an individual and a public health standpoint," he explains.
Insurers, however, are often reluctant to cover people who don't have advanced cirrhosis or fibrosis even though such an approach only addresses the final and most dramatic manifestations of HCV infection. Thus, assessment of the extent of liver disease is more critical than ever in patients with HCV, says Andrew P. Keaveny, M.D., chair of Transplant Medicine at Mayo Clinic's campus in Jacksonville, Florida.
"We are able to offer state-of-the-art noninvasive testing for liver fibrosis at all three Mayo sites, including point-of-care transient elastography as well as magnetic resonance elastography, which was developed at Mayo Clinic," he explains.
But debate still rages as to how much high-priced HCV medications will save the broader health system by preventing liver transplants and other costs associated with hepatic disease.
"It's an extremely difficult decision to tell patients they have to wait on therapy because the price is too high," Dr. Vargas observes. "All the interested parties have to come together and voice their concerns in order to arrive at a commonsense solution. Doctors, patients, pharmaceutical interests and the third-party payers have to engage in a dialogue to arrive at a national strategy that will lead to broad coverage of these effective new agents. The entry of more new HCV agents into the marketplace over the next 12 months will likely exert price pressure, too."
For now, Dr. Vargas says the daunting prices shouldn't keep patients with HCV from seeking care. "All patients deserve to be considered. At all three Mayo sites, we can easily and noninvasively assess each patient's needs, make recommendations and serve as advocates," he says.
For more information
Xu F, et al. All-cause mortality and progression risks to hepatic decompensation and hepatocellular carcinoma in patients infected with hepatitis C virus. Clinical Infectious Diseases. 2016;62:289.