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Left to right: David L. Wyles, MD; Nancy S. Reau, MD; Norah Terrault, MD, MPH; and Paul Pockros, MD.

Hepatitis C (HCV) therapy has never been better. The latest data show sustained viral response rates (SVR) of 96 percent across the general population, while tweaks to existing regimens and new agents promise to bring SVRs closer to 100 percent.

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Nancy S. Reau, MD

“There have always been problem populations in [HCV],” said Nancy S. Reau, MD, chief of hepatology at Rush University Medical Center, Chicago, IL. “Our biggest problem improving SVRs today is getting access to all the patients who could benefit from treatment.”

Dr. Reau was the first of four presenters to discuss the prospects for new HCV treatments during an AASLD symposium at Digestive Disease Week® (DDW) 2016.

Elevated body mass index and genotype 1a (GT1a) disease have emerged as the most important factors limiting treatment success in the general population, she said. Both can be overcome using familiar solutions, such as increasing duration of treatment, switching agents or adding ribavirin. The same strategies are usually sufficient to achieve success in other difficult populations, including patients with drug interactions, decompensated cirrhosis and initial treatment failure. Access barriers are more difficult, Dr. Reau said.

Barriers vary by state for Medicaid patients and by payor for private coverage. The most frequent denials of coverage involve substance use, or abuse and disease stage. A growing body of evidence suggests that achieving SVR does more than cure HCV.

“If you eradicate the virus, there is significant improvement over at least 15 years,” Dr. Reau said. “There is this false notion that you can ignore early-stage fibrosis for decades without impacting outcomes. The data clearly show otherwise. The earlier you eradicate HCV, the greater the long-term benefit and the greater the long-term savings.”

Many payors have not caught up with the changing demographics of HCV, Dr. Reau noted. While the familiar baby boomer cohort accounts for the majority of disease, HCV is emerging in populations that are excluded from treatment, particularly those who use illicit substances and abuse alcohol.

Treatment is most often denied because the disease has not progressed beyond the earliest stages of fibrosis, or the assumption that concomitant use of alcohol or illicit substances interferes with treatment. The data show otherwise.

Alcohol dependence in HCV infection increases the risk of death four-fold, Dr. Reau said, making early treatment even more important. And the evidence shows that illicit substance abuse during treatment does not reduce SVR as long as patients remain adherent to their regimen, she said.

“Denying access to treatment has the effect of selecting for populations with the highest risk of progression,” she said. “Denying treatment to these people is creating the next wave of patients who will progress and die of HCV.”

Liver disease
Not long ago, cirrhosis was a risk factor for HCV treatment failure. Today, there are few patients with liver disease who should not be treated for HCV, according to Norah Terrault, MD, MPH, professor of medicine and transplant surgery and director of the Viral Hepatitis Center at the University of California, San Francisco.

“The vast majority of patients with advanced liver disease can achieve SVR,” Dr. Terrault said. “We have clear evidence of the benefits of treatment in reducing the risks of liver-related complications and improving liver-related survival.”

There may be a point of no return beyond which HCV treatment is not beneficial, Dr. Terrault noted, but that evaluation must be made on a case-by-case basis. Treating patients with liver disease improves survival, reduces the need for transplantation and improves quality of life, she explained. But advanced liver disease reduces the number of potential agents, and SRV rates decline as the severity of liver disease increases.

Among patients wait-listed for liver transplantation who are treated for HCV, 36 percent achieve complete response and no longer need a transplant, Dr. Terrault said. Even among patients with Child-Pugh (CP) C disease, 25 percent are able to move off the transplantation waiting list.

The cut point for remaining on the waiting list appears to be a CP score of about 7.5, Dr. Terrault said. Patients with CP A and early CP B disease are more likely to have good outcomes from HCV treatment, she added.

Resistance-associated variants
One not-so-surprising side effect of successful treatment is the emergence of resistance-associated variants (RAV), said David L. Wyles, MD, associate professor of infectious diseases at the University of California, San Diego. But if new generations of direct-acting antiviral agents perform in the real world as they do in clinical trials, RAVs could remain a relatively minor problem, he added.

All RAVs are specific to particular viral proteins — NS3, NS5A or NS5B — and can appear following incomplete viral response. A few patients, primarily those with GT1a and genotype 3 disease, have RAVs prior to treatment, Dr. Wyles said.

“Resistance is not universal in HCV and having a RAV is not a contra-indication to treatment,” he said. “In most cases you will be extending duration of treatment or using alternative agents.”

NS5B nucleotides have high barriers to the emergence of RAVs, Dr. Wyles explained, while NS3 protease inhibitors, NS5B non-nucleosides and NS5A inhibitors have lower barriers to resistance.

“NS5A is the class we worry about the most for resistance,” he said. “All of the agents in this class have some degree of cross-reactivity. When you have resistance to one NS5A, you are likely to see it in them all.”

All patients with GT1a disease should be tested for NS5A RAVs, Dr. Wyles advised. Treatment can generally proceed with the addition of ribavirin, or by moving to another category.

GT1a patients who have failed treatment and GT3 patients who take any of the NS5A agents should also be tested for resistance. Extending the duration of treatment or adding ribavirin usually improves SVR, Dr. Wyles said.

It may be helpful to test GT1a patients who are treatment-experienced and GT3 patients who are non-cirrhotic and will be taking an NS5A. Switching to another category and adding ribavirin may improve treatment results.

“Resistance probably has a role, at least until we get a new generation of agents,” Dr. Wyles said. “If you don’t need to retreat a resistant patient right away, I would consider waiting for new agents.”

New agents
It could be a short wait, according to Paul Pockros, MD, director of the Liver Disease Center at Scripps Clinic and clinical director of research at the Scripps Translational Science Institute, La Jolla, CA. The Food and Drug Administration is expected to approve a new antiviral in June, with other agents poised for approval through 2017 and into 2018.

“What we need is standardization of therapy, without ribavirin, with no variation between subtypes or genotypes, at a reasonable cost,” Dr. Pockros said. “We would also like a shorter duration. We want to see HCV become like treating Helicobacter pylori — one prescription and you’re done.”

The first new agent approved, possibly as early as June, will likely be a combination of sofosbuvir and velpatasvir. Trials showed 100 percent SVR at 12 weeks in all genotypes, Dr. Pockros said.

A triple combination of sofosbuvir/velpatasvir plus GS-9857 showed very high efficacy in GT1 patients who had prior direct-acting antiviral treatment.

AbbVie is testing a pangenotypic NS3/4A protease inhibitor, ABT-493, plus a pangenotypic NS5A inhibitor, ABT0530. The combination is potent against common NS3 and NS5A variants, and offers once-daily oral dosing with minimal renal excretion, Dr. Pockros said. The agent is currently in phase 3 trials with results expected later this year.

Merck is developing a combination of elbasvir/grazoprevir plus sofosbuvir and ribavirin in patients who failed prior short-term treatment. The drug was 100 percent effective in all genotypes, Dr. Pockros said. The company is also testing an eight-week combination of grazoprevir plus MK-3682 plus M-8408 for GT1, GT2 and GT3 patients.

One of the most exciting findings is a six-week regimen of sofosbuvir/ledipasvir showing efficacy against GT1 mono-infection, Dr. Pockros said.

“The goal for all is shorter duration of treatment,” he said. “Until that happens, infectious disease specialists, internists and gastroenterologists will continue to defer therapy.”