DDW - HCV patients may be able to delay therapy...

Posted 5/23/12 on Med Page Today.com, Coverage on DDW conference ending earlier this week, specifically regarding the possibility of delaying treatment until new, easier-to-tolerate HCV therapy is available. The point is made that patients should delay therapy only if they do not have significant fibrosis or co-morbidities. 

HCV Patients May Be Able to Delay Therapy

By Kristina Fiore, Staff Writer, MedPage Today
Published: May 22, 2012

SAN DIEGO -- Hepatitis C patients without significant fibrosis may be able to delay triple therapy and wait for simpler, shorter, and potentially all-oral regimens that are currently under investigation, researchers said here.

The addition of new protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) to previous standard therapy of interferon and ribavirin have significantly boosted sustained viral response for many patients, especially for blacks and Latinos, according to Maribel Rodriguez-Torres, MD, of the Fundacion de Investigation in Rio Piedras, Puerto Rico.

But patients with less severe disease may be able to hold off until a handful of newer agents -- offering less complex regimens that potentially cut the symptomatic interferon from the mix -- come to market, possibly within the next two years, Rodriguez-Torres said during a symposium at Digestive Disease Week (DDW) here.

"This is a slowly progressing disease and most of the time we have the time and opportunity to determine what's the best [treatment strategy] for our patients," she said. "Patients without significant fibrosis should wait. Those with more advanced disease should consider therapy today."

Triple Therapy Presents Challenges

Clinicians have cited a number of challenges with triple therapy. Both new agents are only indicated for patients with genotype 1 disease -- though this comprises the majority of patients -- and they add a significant cost to treatment, Rodriguez-Torres said.

The regimen is also complex and long-lasting, with both new agents adding multiple daily pills to ribavirin's four to six pills per day and weekly interferon injections, extending for 24 to 48 weeks.

There's also an increased risk of drug-drug interactions, as both new agents inhibit the common CYP34A metabolic pathway, potentially increasing levels of other drugs metabolized that way. That list includes some statins and ACE inhibitors, which "aren't unusual drugs," Rodriguez-Torres said.

Side effects include anemia, a concern because ribavirin already lowers blood hemoglobin levels, she said. Also, telaprevir appears to cause rash in more than 50% of patients.

Instead, a "dream regimen" is a simple one with fewer pills, contains only oral agents, spans all genotypes, and is highly effective with an excellent safety and tolerability profile -- though that possibility is not that far from reality, Rodriguez-Torres said.

Improvements Are on the Horizon

"We've never had such an explosion of drug development in the last 75 years compared to what we see now in chronic hepatitis C," she said. That robust pipeline includes not only a number of protease inhibitors and NS5A inhibitors -- which are typically genotype-specific -- but also nucleoside and cyclophilin inhibitors that are pan-genotypic.

Such robustness may help keep prices down as a result of increased competition, Rodriguez-Torres said. Also, the majority of drugs in development are dosed once or twice daily and some have a much shorter duration of therapy than the current standard of 24 to 48 weeks.

Early data also have shown that it's possible to drop interferon from the regimen. Last month at the European Association for the Study of the Liver meeting Barcelona, researchers reported that high proportions of patients has sustained virologic response rates with an all-oral regimen of ribavirin plus two investigational agents, ABT-450/r, a protease inhibitor, and ABT-072, a non-nucleoside NS5B polymerase inhibitor.

Also at that meeting, an early trial showed that a combination of daclatasvir, an NS5B inhibitor, plus GS-7977, a nucleotide NS5B inhibitor, led to rapid and sustained viral response in patients with genotypes 1-3, with or without ribavirin.

Treatment Issues Remain Complex

The pressing question facing clinicians, then, has been determining who to treat and when. Rodriguez-Torres said the simple answer is to treat those with severe fibrosis now, but hold off on treating those without significant fibrosis.

But Andrew Muir, MD, clinical director of hepatology at Duke University, told MedPage Today the decision should rest largely with the patient.

"I get concerned about us being too heavy handed deciding which patients should or should not get hepatitis C treatment," he said. "Our role should be to guide patients about potential options, and those discussions can take quite a bit of time."

He noted, however, that the side effects "will be much better for these patients with future therapies. But I have had patients elect to proceed with treatment even with early-stage disease. Some have felt it was the right time for them to proceed with treatment for a number of personal reasons. Some worried if they would have stable health insurance in the future."

On the other hand, Zobair Younossi, MD, of Inova Health System in Great Falls, Va., said some of his patients actually "warehouse themselves for regimens that do not include interferon."

Muir also noted that even some advanced fibrosis patients may be eligible for watchful waiting, since not all of them will progress quickly.

"If the patient has great risks to treatment, or if the patient does not think the chance of response is good enough to take on the side effects, then delaying therapy is the right thing for that individual [advanced fibrosis] patient as well," he told MedPage Today. "If they do not take treatment, they must get aggressive about liver wellness. That means no alcohol, get in shape and lose weight if needed, and get tight control of your blood sugars if you have diabetes."

Rodriguez-Torres reported relationships with Abbott Laboratories, Anadys, Bristol-Myers Squibb, Glaxo-SKB, Idera, Intarcia, Merck, Novartis, Pfizer, Pharmasset, Roche, Sanofi-Aventis, Valeant, Vertex Pharmaceuticals, ViroChem Pharma Inc, and Wyeth.

The other researchers reported no conflicts of interest.