Genotype 3 HCV: The Next Hurdle in Hepatitis C Therapy

[pooh55811]

From Clinical Care Options:

Genotype 3 HCV: The Next Hurdle in Hepatitis C Therapy
Graham R. Foster, FRCP, PhD - 6/14/2013  

The emerging wave of new direct-acting antivirals almost seems an embarrassment of riches as we learn of improving efficacies, reduced adverse event profiles, and simpler treatment regimens seemingly by the day. Much as was seen in HIV during the mid- to late-1990s, the excitement grows with treatment efficacies reaching 90% or better at hand. Indeed, clinical studies have crossed that threshold for patients infected with genotype 2 HCV treated with daclatasvir plus peginterferon and ribavirin or sofosbuvir plus ribavirin alone. Our patients infected with genotypes 1, 4, 5, and 6 also have a very real expectation of reaching that goal very soon.

Stumbling Over a Divergent Step
However, genotype 3 remains stubbornly different, challenging the high expectations for a pangenotypic HCV cure. A substantial departure from the other HCV genotypes, genotype 3 presents a unique diagnostic and treatment challenge with treatment success rates substantially lower than those of other HCV genotypes. The FUSION trial of sofosbuvir plus ribavirin for 12 or 16 weeks in treatment-experienced patients reported that 94% of HCV genotype 2–infected patients treated for 16 weeks achieved SVR12 vs only 62% of those infected with genotype 3. Similarly, treatment-naive patients in the FISSION trial of sofosbuvir plus ribavirin for 12 weeks experienced SVR12 rates of 97% if they were infected with HCV genotype 2, but only 56% if infected with HCV genotype 3. Currently, EASL treatment guidelines report SVR rates of 69% for genotype 3-infected, treatment naive patients treated for 24 weeks with peginterferon plus ribavirin (Management Guidelines).[EASL 2011]

Steatosis is commonly associated with genotype 3 infection, and may challenge the latest noninvasive hepatic imaging devices rendering their results less reliable for this viral strain making it more difficult to accurately assess fibrosis severity. Intrahepatic fat may be, at least in part, responsible for the persistently low rates of SVR associated with genotype 3. It is unclear whether intrahepatic fat sequestration by the replicating virus reduces access to direct acting anti-viral agents thereby reducing the efficacy of these drugs and further work to examine the mechanisms underlying treatment failure with this genotype is urgently required.

Where to From Here?
So what do we do for our genotype 3–infected patients who do not respond to treatment with peginterferon and [ribavirin]? Fundamental questions of management strategy, such as retreatment duration, remain unanswered. In general, the data are equivocal. For example, the recent N-CORE study showed little or no difference in treating genotype 2/3 patients with peginterferon and [ribavirin] for 24 vs 48 weeks if they failed to achieve RVR.

For Genotype 3 and investigational agents, we’ve seen instances where promising initial data provided hope that an effective agent was on the way, but these data often are derived from studies in small numbers of patients and given the enormous diversity of genotype 3 small studies may not provide an accurate reflection of response rates. Pangenotypic efficacy is a claim that many agents would like to make. However, because of the unique characteristics of genotype 3, I remain highly skeptical that we will see an anti-HCV agent with truly pangenotypic potent activity any time soon.

As my colleague Norah Terrault, MD, MPH, pointed out recently, genotype 3 is the “stress test” for new drugs entering the HCV arena. It’s likely to remain a stressor both for patients infected with it and the clinicians charged with treating it for the foreseeable future.


I copied and pasted the entire article. To read this article on-line you need to go to the Clinical Care Options website and register.

http://www.clinicaloptions.com/login.aspx?item=%2fhepatitis%2fconference+coverage%2fberlin+2011%2ffrom+podium+to+practice%2fcapsules%2f12&user=extranet%5cAnonymous&site=website&qs=lg%3dprint

[Shyrlgame]

"Steatosis is commonly associated with genotype 3 infection, and may challenge the latest noninvasive hepatic imaging devices rendering their results less reliable for this viral strain making it more difficult to accurately assess fibrosis severity."

Finding this interesting too ABN, and questioned my own Fibroscan. . . .

Thanks for the article.

[desrt]

Since the IL28B test is also a predictor for non-RVR type 2s, one place to start might be, "What do these two types have in common?" Both have more nucleotide pairs than geno1. In this case, complexity might equal fragility. Dr. Richard Sallie's paper on replicative homeostasis - the mechanism that allows a wildly mutating RNA virus to remain genetically identical to itself year after year - speaks of "error catastrophe" in Section 6.0 of his paper.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1847443/?tool=pubmed

But also of "overly faithful replication (rendering the virus susceptible to immune-mediated clearance or destruction through attenuation and loss of replicative plasticity)" in Section 7.0.

Personally, I haven't got the math or the molecular biology to understand this (and I don't want the doc to have to come back on here and kick my bvtt for misexplaining  his work), but it seems like a more considered approach might work better than just throwing stuff at the wall to see what sticks.

[ActingBrandNew]

"This is the reason I still bring up the IL28B test, especially for G3s who do not RVR. "

Exactly my thoughts.

[desrt]

It may be that in the mad dash for newer cocktails they have overlooked a couple facets of G3s. One is patient genetics. This is the reason I still bring up the IL28B test, especially for G3s who do not RVR. The other is viral subtype. I cleared with fewer than 24 weeks SOC and know of another 3e who had to stop tx at 16 weeks and cleared. They can keep throwing PIs - protease and polymerase - at the virus if that's what's profitable, but there's going to continue to be wide ranging tx response until they understand the underlyng mechanisms, the why.

[Dee1956]

Hey there lady!  Thanks for the information, I am passing this along to help others
Have a great weekend
D

[ActingBrandNew]

"Steatosis is commonly associated with genotype 3 infection, and may challenge the latest noninvasive hepatic imaging devices rendering their results less reliable for this viral strain making it more difficult to accurately assess fibrosis severity."

Very interesting