To mark our 30th anniversary, Infectious Disease News will be examining some of the infectious diseases that have defined and changed the field over the past 3 decades.
At the American Association for the Study of Liver Diseases annual meeting in 2011, Ed Gane, MBChB, MD, FRACP, MNZM, presented data on PS7977, an antiviral agent for the treatment of hepatitis C virus infection. The treatment approach changed slightly across patient groups — some participants were treated for longer than others, and some received PS7977 in combination with ribavirin and pegylated interferon — but the results were always the same.
In all, Gane, deputy director of the New Zealand Liver Transplant Unit at Auckland City Hospital and clinical professor of medicine at the University of Auckland School of Medicine, presented data on 40 patients; all 40 were cured of HCV.
“As soon as he presented the data on the last group of patients, it was so quiet you could hear a pin drop,” Mitchell L. Shiffman, MD, of the Liver Institute of Virginia, told Infectious Disease News. “It was only quiet for about 5 seconds, probably, but it seemed like 5 minutes.”
The data on PS7977 — later known as Sovaldi (sofosbuvir, Gilead Sciences) — led to the direct-acting antiviral (DAA) revolution in HCV. This revolution, however, has taken place in the last several years. When HCV was first discovered in 1989, it was known only as non-A, non-B hepatitis.
This trajectory is “nothing short of a miracle,” according to Zobair M. Younossi, MD, MPH, chairman of the department of medicine at Inova Fairfax Hospital and vice president for research at Inova Health System in Falls Church, VA.
“In the span of 30 years or so, we’ve gone from discovering the most common cause of liver disease, liver cancer and liver transplantation in the United States to providing a cure for it,” Younossi said.
The DAA revolution
Michael Houghton, PhD, of the University of Alberta, and colleagues discovered HCV in 1989. Shortly after that, researchers began investigating whether interferon was an effective treatment.
“Interferon was exciting, on one hand, because you could cure some people, but the side effects were so awful that a lot of patients didn’t complete the full course or had a lot of trouble tolerating therapy,” Michael S. Saag, MD, the Jim Straley Chair in AIDS Research and Director of the Center for AIDS Research at the University of Alabama at Birmingham, said in an interview. “Then they switched from interferon to pegylated interferon, but you still had to use ribavirin. Cure rates were around 40% for genotype 1.”
Early use of interferon required a lot of coaching, according to both Saag and Shiffman.
“Back then, a physician had to be the cheerleader to get people through therapy,” Shiffman said. “We could tell that people were responding to interferon, and we knew that, if the virus became undetectable, there was a good chance of cure. But if you didn’t want to deal with the side effects, and if the physician wasn’t an advocate, the patient didn’t have a chance. The cure rate was 40%. That’s not nearly good enough, but it’s not insignificant.”
The barriers associated with interferon — and the lack of a wide-reaching cure — made interferon-free treatment the “holy grail” in HCV. The first-generation DAAs, Victrelis (boceprevir, Merck) and Incivek (telaprevir, Vertex), were approved by the FDA in May 2011. However, side effects remained a problem.
“The first-generation DAAs were pretty good — and much better than the therapies we had in the past — but were associated with significant side effects that prevented a lot of people from taking the medication,” Younossi said.
As a result, the approval of sofosbuvir in December 2013 for genotypes 1 through 4 — and the second- and third-generation DAAs that followed — was “a game-changer,” according to Saag.
The approval of sofosbuvir was preceded by Olysio (simeprevir, Janssen) in November 2013. In all, nine DAAs have been approved since late 2013.
“The second- and third-generation DAAs are associated with very few side effects,” Younossi told Infectious Disease News. “Cure rates are approaching 100%, and the duration of treatment is short, at only 3 months for most patients.”
In addition to improving cure rates, the DAA revolution has changed the use of interferon and ribavirin. There is no longer a role for interferon in this setting, according to Saag and Younossi, and the circumstances in which ribavirin is still used are limited and will continue to fade, according to Shiffman.
“There are still some situations where adding ribavirin is effective,” Shiffman said. “But the next generation of therapies will not use ribavirin at all, in any patients.”
The barrier of cost
Despite the progress of the last several years, there are still barriers that prevent the use of DAAs in all patients. Cost is the “fundamental hurdle” that prevents every patient from receiving treatment, according to Saag.
An analysis from November 2015 shows that Harvoni (ledipasvir/sofosbuvir, Gilead Sciences) can range from $63,000 for an 8-week course of therapy to $189,000 for 24 weeks. A 12-week course of sofosbuvir costs $84,000, or $1,000 per pill.