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.

The emerging role of the Infectious Disease physician in treating HCV...

An article published in POZ magazine on 4/13/12 on an opinion piece e-published ahead of print in   'Clinical Infectious Diseases' authored by Barbara McGovern, MD of Tufts University School of Medicine.  She makes a plea for Infectious Disease doctors to start treating Hepatitis C and relieve some of the burden on the thin and overworked ranks of Hepatologists.  She suggests 'establishing "centers of excellence" and instituting joint fellowships wherein HCV experts can pass their knowledge along to ID physicians; presenting conferences and workshops devoted to HCV evaluation and management; collecting data from the membership of the Infectious Diseases Society of America (IDSA) on obstacles to hepatitis C patient care; and offering real-time updates to HCV treatment guidelines.'  It's my opinion that IDs offer the perfect discipline for treating HCV and HCV/HIV co-infection as newer, all-oral, interferon-free regimens greatly expand the the pool of patients elgible (and willing) to be treated.  IDs have treated HIV for years - a disease state whose early treatment years display some uncanny parallels to the genesis of Direct Acting Antiviral therapy for Hepatitis C. The IDs know virology, they understand the implications for viral resistance, the concept of 'drug cocktails' which attack the virus at different points along it's life cycle, they know about side effect management, and most of all, their economic model is strikingly similar to that of the in-the-trenches Hepatologist.  It seems like a good fit from out here looking in. 

April 13, 2012

More Infectious Disease Docs Treat Hep C

We may soon see an end to obstacles in the care of people living with chronic hepatitis C virus (HCV)—but only if infectious disease (ID) doctors work with and learn from hepatologists, according to an opinion piece authored by Barbara McGovern, MD, of Tufts University School of Medicine and published online ahead of print by Clinical Infectious Diseases.

ID specialists have historically been reluctant to treat hepatitis C, even among their own patients living with HIV, because of the complexities of prognostic testing and combination treatment, low cure rates among people with genotype 1 HCV and the need for expert management of side effects.

HCV coinfection is more amenable to treatment now than in the past—including for those coinfected with both HIV and HCV—with the current generation of direct antiviral agents providing a 75 to 85 percent cure rate.

Further improvements—such as all-oral regimens that don't involve interferon—are expected within the next few years and will likely benefit both HCV-monoinfected and HIV/HCV-coinfected patients. This would be a great boon for all people living with HCV, for whom treatment can lead to remission of liver disease and reduced risk of liver cancer and cirrhosis.

With an estimated 170 million HCV cases worldwide—including 5 million in the United States, where hepatitis C death rates now exceed those from HIV—hepatologists, the usual go-to medical experts for hepatitis C care and management, are overwhelmed by the number of patients seeking their services. Their efforts will be stretched even thinner if the Centers for Disease Control and Prevention (CDC) implements planned screening guidelines that recommend testing everyone born between 1945 and 1965—an age range with an especially high HCV prevalence.

Bringing more people into care for hepatitis C, McGovern argues, will require expanding the ranks of ID specialists capable of dealing with the virus and its complications.

One reason HCV care has required highly specialized attention from hepatologists was the need for a liver biopsy to measure the progress of the disease. This may no longer be necessary, thanks to noninvasive testing via such methods as blood tests and elastography (measurement of tissue stiffness via ultrasound or magnetic resonance), which can be performed by ID specialists.

Another main reason why hepatologists have been needed for HCV therapy is the risk of decompensated cirrhosis—when a cirrhotic liver begins to lose its ability to function—for patients who don't receive antiviral therapy or whose therapy fails. Managing the complications of decompensated cirrhosis requires a hepatologist's specialized training. However, early HCV treatment greatly decreases the risks of cirrhosis.

Lastly, modern combo therapies for HCV require extensive knowledge of the relevant antiviral drugs and their interactions.

McGovern recommends sidestepping this dearth of hepatologists by cross-training ID specialists in the intricacies of HCV infection. Her recommendations include establishing "centers of excellence" and instituting joint fellowships wherein HCV experts can pass their knowledge along to ID physicians; presenting conferences and workshops devoted to HCV evaluation and management; collecting data from the membership of the Infectious Diseases Society of America (IDSA) on obstacles to hepatitis C patient care; and offering real-time updates to HCV treatment guidelines.

"Although HCV does not command the same media attention as for some emerging infectious diseases," McGovern wrote, "advancing liver disease will be exacting a tremendous toll in morbidity and mortality in the decades to come if wider access to treatment is not realized in the near future. In fact, in 2007, deaths from HCV infection exceeded deaths from HIV in the United States. Millions of HCV-infected patients will be depending on an expeditious response from the ID community, as we have done for many other infections in the past."

Post-Scripps Conference Download "New Treatments in Chronic Liver Disease"

I attended the Scripps Clinic 'New Treatments in Chronic Liver Disease' conference this past weekend in La Jolla, CA.  There were three sessions focusing just on HCV - 'Management of Chronic Hepatitis C in the DAA Era'; 'Controversy - Should We Treat IL28B CC Patients Without DAAs?' and the 'New Directions for HCV Therapy (2012 - 2014)'.  Adrian Di Bisceglie MD, Paul Pockros MD and Anna Lok, MD - all three superstars of Hepatology - did the honors. Below are some of the highlights (for me, anyway) in terms of the future of HCV treatment. Reductionism at its most subjective.

·        The future of Interferon & Ribavirin:

o   Interferon will likely be with us for at least the next 5 years, but may be regulated to patients that are tough to treat (i.e. cirrhotics, G1a)

o   Ribavirin will be a mainstay of therapy for the majority of patients.

o   A nuc may be able to replace RBV in a small subset of patients in combination therapy (PI +nuc + nonnuc, for example) The subset of patients were characterized as G2 & G3, non-cirrhotic, low BMI, non-smoking and/or post-transplant / dialysis patients and perhaps G1b with CC allele). 

o   The  economic ramifications of this strategy where examined. if a generic like RBV worked just as well as a nuc, then why use two or more DAAs where the cost of treatment will likely be much higher?

·        Ribavirin dose reduction with current therapy:

o   Docs doing CDCs every two weeks. When patient drops below 10 g/Dl, theydrop RBV down to 600.  If that doesn’t provide enough EPO is added.

o   Approval of EPO an issue – may take three weeks, what do we do then?

o   One doctor on the panel said “we don’t know how how we can go with RBV. Can we stop RBV for a couple of days until the patient normalizes? We don’t know.”

o   Another doctor on the panel replied that the current data on stopping RBV is “inadequate” (very vociferous on this).  Referenced the HCV Target registry Mike Fried was involved in to take a closer look at this issue.  Cautioned against this until the data is more clear.

·         New treatment notables: 

o   GS-7977 + RBV (no INF)  much less likely to cause anemia than current DAA therapy. Referenced a slide from the ELECTRON study that showed only an average of a 2 g drop in hemoglobin, no reduction in absolute neutrophil count. Also much less propensity for DDIs than current DAA therapy.

o   All agreed that the data they are most anxiously awaiting is the G1 treatment naïve data from the ELECTRON trial with GS-7997 + RBV (to be presented at EASL)

o   Doctor on the panel referenced ELECTRON demographics – G1a, no cirrhosis. “We need to see VERY high SVR rates in this INF-free trial in this population. I’m looking for 100% SVR”.

o   Resistance will always be a concern given the error-prone, highly replicative capacity of the virus. Less of a concern with the polymerase inhibitors because of the higher barrier to resistance.

o   Future much more certain for polymerase inhibitors and protease inhibitors than cyclophilin inhibitors at this point.

o   Less danger of drug-drug interactions with upcoming therapies – good news for post-transplant, dialysis and HIV/HCV co-infected patients.

·         Timeline predictions on evolution of HCV therapy:

o   Q4 2013/ Q1 2014 – Quad therapy vs new triple therapy options (PI + nuc/nonnuc + PEG/RBV)

o   Q4 2013/Q1 2014 IFN-free regimens for G2/3 and perhaps G1b (w/ CC allele)        and for those intolerant to IFN. (PI +nuc/nonnuc/NS5A w/+ RBV)…. Maybe w/out RBV for small segment of patients.

Clinical Care Options: "Importance of Pharmacokinetics and Adherence to Avoid Emergence of Resistant HCV Variants"

A new CCO module is available here, focusing on the importance of PK and compliance to regimens in an effort to stem HCV resistance. The parallels between HCV antivirals and the evolution of HIV antiretrovirals are becoming numerous. Pharmacokinetics, pharmacogenetics and pharmacodynamics will all increase in importance as HCV drug development marketplace continues to move forward and potentially become as competitive as the HIV marketplace was back in the mid-90's and 2000's.

Cell Permeable Peptide Identified that Inhibits Hepititis C Replication...

Posted today on Health News Digest.com and published in the Jan 30 issue of 'Hepatology'. UCLA researchers identify heat shock proteins (HSPs) that are important for viral infection and that the natural compound Quercetin inhibits synthesis of these proteins In Vitro.

Cell Permeable Peptide Identified that Inhibits Hepititis C Replication...

By Staff Editor
Jan 30, 2012 - 3:23:54 PM

Discovery Could Lead to a New Treatment for a Disease that Impacts up to 160 Million People Worldwide

(HealthNewsDigest.com) - Researchers from UCLA’s Jonsson Comprehensive Cancer Center have identified a cell-permeable peptide that inhibits a hepatitis C virus protein and blocks viral replication, which can lead to liver cancer and cirrhosis.

This finding by Dr. Samuel French, an assistant professor of pathology and senior author of the study, builds on previous work by the French laboratory that identified two cellular proteins that are important factors in hepatitis C virus infection.

French and his team initially set out to identify the cellular factors involved in hepatitis C replication and, using mass spectrometry, found that heat shock proteins (HSPs) 40 and 70 were important for viral infection. HSP70 was previously known to be involved, but HSP40 was linked for the first time to hepatitis C infection, French said. They further showed that the natural compound Quercetin, which inhibits the synthesis of these proteins, significantly inhibits viral infection in tissue culture.
In this study, published Jan. 30, 2012 in the peer-reviewed journal Hepatology, French and his team demonstrated that the viral non-structural protein 5A (NS5A) directly binds to HSP70 and mapped the site of the NS5A/HSP70 complex on NS5A. While HSP70 was previously shown to bind NS5A in cells, a direct NS5A/HSP70 interaction and complex formation was established in this study. In an effort to stop this interaction, they tested peptides that might inhibit HSP70.

“This is important because we’ve developed a small peptide that binds to that site and blocks the interaction between the proteins that is important for viral replication,” French said. “This is another, potentially highly efficacious way to block replication of hepatitis C.”

An estimated 160 million people worldwide are infected with hepatitis C and the conventional treatments – interferon and ribavirin – can have significant side effects. A new drug targeting cellular proteins rather than viral proteins would be a valuable addition to the treatment arsenal, French said.
“We were surprised that this peptide works this well,” French said. “While its mechanism is different, the activity of this peptide is comparable to other newly developed anti-virals.”

The study, done in tissue culture, shows that the peptide gains entry into the cell easily and blocks the cascade of cellular events that allows the virus to replicate, French said. Blocking the HSP70 protein rather than a viral protein also reduces the chance of patients with the hepatitis C virus developing resistance to the peptide.

“There’s no direct pressure on the virus, so it is less likely to mutate and develop resistance,” French said. “The goal is to achieve a sustained response, essentially a cure, meaning there is no more virus replication. There are a lot of drugs coming out now that are designed to stop hepatitis C replication, but resistance is still an issue. About 10 to 20 percent of patients on the new drugs become resistant. This new peptide may help combat resistance.”

Going forward, French and his team are testing variants of the newly discovered peptide to see if they can develop one with an even higher affinity and can decrease the size of the peptide to improve cellular penetration and liver targeting. The new and improved peptides will be tested in animal models.

This peptide “may be a candidate for hepatitis C therapy,” the study states. “Considering the potency of the peptide in suppressing viral translation levels, treatment with this peptide may significantly improve the efficacy of conventional treatments in patients who become resistant to conventional therapies.”

The study was supported in part by the National Institutes of Health and by the California Center for Antiviral Drug Discovery at the University of California.

UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2011, the Jonsson Cancer Center was named among the top 10 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 11 of the last 12 years. For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu.

Medscape article: Adverse CNS Effects of HCV Treatment Discourage Adherence

Medscape interviews clinical psychologist Jeffrey J. Weiss, PhD, MS, from Mount Sinai School of Medicine in New York City and Raymond Chung, MD,vice chief of the gastrointestinal unit and medical director of the liver transplant program at Massachusetts General Hospital in Boston regarding a large prospective study looking at CNS effects of Peg + riba and the resulting effect on adherence because of depression and/or 'brain fog'.

Adverse CNS Effects of HCV Treatment Discourage Adherence

Neil Canavan

November 18, 2011 (San Francisco, California) — Patients infected with hepatitis C virus (HCV) can experience a marked decline in neuropsychological cognitive function in the first 14 weeks of combination pegylated interferon and ribavirin therapy. This poses a potential treat to treatment adherence, said clinical psychologist Jeffrey J. Weiss, PhD, MS, from Mount Sinai School of Medicine in New York City, here at The Liver Meeting 2011: American Association for the Study of Liver Diseases 62nd Annual Meeting.

These data are from a large prospective study looking at early treatment discontinuation and the onset of neuropsychiatric symptomatology in HCV monoinfected and HCV/HIV coinfected treatment-naïve patients receiving combination pegylated interferon/ribavirin therapy, Dr. Weiss explained.

"A lot of work has focused on depression, and not to the decrements in cognitive function," said Dr. Weiss. A host of neuropsychiatric symptoms should be considered when initiating a new treatment.

"In this era of direct-acting antivirals, when we're asking patients to take medications 3 times a day (every 6 to 9 hours)..., we need to be aware that, just at baseline, 40% to 50% of patients...[have] substantial deficits in cognitive functioning."

This investigation established the degree of neurocognitive decline during the first 12 and 48 weeks of treatment. Both HCV-infected and HCV/HIV-coinfected patients were evaluated. Neuropsychological instruments were used to explore which domains of cognitive functioning are most affected by combination pegylated interferon/ribavirin treatment, and whether being coinfected with HIV adds to the decrements in cognitive functioning.

There were no significant differences at baseline between the HCV-infected and HCV/HIV-coinfected cohorts for age, sex distribution, ethnicity, HCV RNA viral load, HCV genotype, or stage of liver disease. There were also no differences between the 2 groups at baseline for neuropsychological scores. However, although the same percentage of patients in the HCV and HCV/HIV cohorts reported depression, HCV patients had significantly worse depression scores.

After treatment, global neuropsychological function declined significantly in HCV patients during the first 24 weeks of HCV treatment. Domains with the greatest declines were memory, executive function, and motor function. "The HCV monoinfected group also had a greater decline in neuropsychological function than the coinfected group in the first 12 weeks," said Dr. Weiss. "This is probably due to more depression among HCV patients at baseline."

How a patient's declining neuropsychological function affects their behavior is key, and can depend on clinical history, Dr. Weiss explained. "Patients who have a history of cognitive dysfunction might respond less to the onset of new symptoms. Patients with a significant pathology who are already well engaged in psychiatric treatment tend to do quite well on [antiretroviral] treatment because they are familiar with the symptoms and are being well managed." Those who are high functioning at baseline will have more trouble; to be successfully managed, the healthcare provider must be aware of the potential for central nervous system (CNS)-related treatment nonadherence.

CNS and the Hepatologist

Raymond T. Chung, MD, vice chief of the gastrointestinal unit and medical director of the liver transplant program at Massachusetts General Hospital in Boston, agrees that the hepatologist must be part psychiatrist. "We field these patients rather then pass them off since there can often be overlap with true advanced hepatic disease and hepatic encephalopathy."

He is mindful of the potential impact of HCV medications. "It has been a modest issue with both HCV/HIV and HCV alone." Symptoms are often called "brain fog," Dr. Chung explained. "This fog does get in the way, in high-functioning individuals, of their ability to carry out intricate calculative functions and memory at work, for instance." It would not be surprising for such a patient to become frustrated and consider forgoing medication, he observed.

Dr. Chung considers the issue manageable if it is proactively addressed. However, like many clinicians at the meeting, he's looking more toward preventing than managing adverse effects by eliminating pegylated interferon from standard HCV treatment.

Dr. Weiss reports being a consultant for Vertex Pharmaceuticals and Kadmon Pharmaceuticals. Dr. Chung has disclosed no relevant financial relationships.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Abstract 972. November 6, 2011.

Medscape Medical News © 2011 WebMD, LLC
Send comments and news tips to news@medscape.net.

HCV Resistance: Similarities and Differences With HIV CME on Clinical Care Options

A great new CME with Stuart Ray, MD from Johns Hopkins University reviewing the similarities and differences in HCV resistance compared to HIV. Highly recommended. Free, but registration to Clinical Care Options required. Link here

Zobair M. Younossi, MD discusses "A New Era of Hepatitis C Therapy"

Zobair M. Younossi, MD, the Executive Director of the Center for Liver Diseases and Vice President of Research at the Inova Health System in Falls Church, Virginia discusses the STAT-C drugs and other novel therapies for Hepatitis C from AASLD 2010. Features a video and transcript. Watch and read here.