Good synopsis Pablo,

The main article is a head full of information and very easy to  misread and misinterpret.

Thank you for sharing that!

SF

Pablo, Good defining with concise explanation.

The reason the article is so boggling is because it is fairly recent, all-inclusive, long. Lots of data and concepts, drugs and studies to include and get through.

I picked out one area that perplexes me ... only because it still lacks some of the thinking i recently found in gossip/writings elsewhere about sof/vel/vox (the benefits of Gilead's sof/vel/vox triple) and how it can be best utilized. (I posted this over in ... GT 3's and SOF/VEL trials ).

The section I picked out (of the article HP brought forward) highlights the still-in-effect recommendations and ways to get around RAV testing costs, still the reliance on riba, it had little to say about the newest (NS3/4a) triple drug VOX in conjunction with sof/vel (still refering to VOX as GS-9857), and does not delve into Gileads idea that their sof/vel/vox triple is pan enough for all GT's period, without necessarily even burdening countries with genotyping costs, nor RAV identification, and covers difficult people such as GT3's, cirrhotics, and is a relapsers rescue regime!

... Resistance Testing Before First-Line Therapy There are many conditions for broad use of HCV resistance tests in clinical practice. First, a standardized assay should be available as a purchasable kit, externally validated for its performance, and easy to use routinely in any virology laboratory with experience in molecular biology. Whatever the technology used, the assay should reliably report the presence of RASs with a validated and repeatable sensitivity of 15%, equivalent to population sequencing. Second, interpretation and reporting of HCV resistance data should be homogenized and standardized through recommendations by an international organization. Thirdly, clinically relevant RASs should be clearly identified, and only these should be reported and used for treatment decisions. Finally, guidelines should be provided by international societies for treatment decisions based on results of drug resistance tests. The guidelines should be based on data from clinical trials and real-life studies that reported strong predictive values of the different RAS profiles. Because none of these conditions have yet been met, systematic testing for HCV resistance before treatment should not be recommended. Systematic testing would seriously limit access to care and lead to erroneous decisions for a number of cases. Instead, treatment can be optimized for groups of patients known to have specific RASs in NS5A that reduce response to therapy. In patients with cirrhosis, guidelines already recommend adding ribavirin to 12 weeks of treatment with sofosbuvir/ledipasvir, sofosbuvir plus daclatasvir, or sofosbuvir plus simeprevir or to prolong therapy to 24 weeks to reduce the rate of failure.53,54 Resistance data from the integrated analysis of phase 2 and 3 studies with sofosbuvir/ledipasvir12 indicate that the same measures would reduce treatment failure in patients without cirrhosis who are prior nonresponders to pegylated IFNbased regimens. On the other hand, the guideline-recommended use of ribavirin with 12 weeks of treatment with ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, in patients with genotype 1a or 4 infection, as well as prolongation of treatment to 24 weeks in patients with genotype 1a infection and cirrhosis (especially those who did not respond to pegylated IFNbased treatment), reduces the rate of failure of this regimen. With grazoprevir/elbasvir, patients who do not respond to treatment with pegylated IFN and ribavirin (partial and null responders) can be treated for 16 weeks with ribavirin without a pretreatment resistance test, making this regimen more widely accessible.28 Finally, patients with HCV genotype 3 infection (particularly those with advanced liver disease) need reinforcement of therapy with sofosbuvir/velpatasvir.30,31 These simple strategies can be used to optimize conditions for achievement of an SVR, without the need for resistance testing. This will be made easier by the rapid diminution of these treatment ... 

When I first started cruising hepc websites looking for info on the best drugs for me, I looked at all the good big, well used North American websites and in other countries as well. I stuck with this site. Discovering trials, I soon settled on wanting sof/vel as my treatment, and the only way i ever got it was via a trial, and, the trial was the only reason i ever got the triple with VOX as well. I considered sof/dac of course early on, and explored how i would be able to get it, it was my back-up plan, but as a Canadian, in my locale and position, I would have had to flunk sofa/riba, before sof/dac would be offered to me here, it took me back to Australian hepc sites - so of course i did quite a bit of exploration of Aus hepc sites.

More than a year ago, I found almost no talk whatsoever about sof/vel happening on the Aus website, it was all about sof/dac out of India, subsequently the floodgates opened in Aus and everyone in Aus could access sof/dac (good and nice). All the Aus site talk after that was still not of sof/vel. Fast forward to today, I happened to inadvertently get back to the Aus website again (it just came up during one of my searches for VOX info), and I was horrified to stumble into a semi-desperate conversation between a member and moderator of that website - they were writing from a web area called the "relapse corner"! They were just then starting a thread to talk about VOX as in sof/vel/vox triple for relapsers!! OMG! I wish Gilead would hurry up and get VOX rolled out for use as a sof/vel/vox triple regime and as their triple "rescue" regime for heavens sake!! C. 

Nice job Pablo! That is an excellent, easier to understand description of RAV/RAS mutation. There are also some of the new and old NS3/4A Protuease Inhibitors that are playing a role as well.  Grazoprevir, Paritaprevir and Simeprevir. Merck has Zepatier (Elbasvir NS5A and Grazoprevir NS3/4A) which has provided some very good results as well. 

The good news is they have been getting these treatment plans down to a science and have developed several effective options that are less affected by these resistant variants. Proper pre-treatment workups and evaluation are vitally important.

Good paper.  Complicated, I agree, but we only need to understand the gist of things.

My understanding of RAVs is....

The 4 classes of DAAs act by blocking the enzymes involved in HCV viral replication, each acting on a different enzyme.  Of the classes the 2 mains ones are NS5A inhibitors (lepidasvir, velpatasvir etc) and NS5Bs (sofusbuvir).  

The HCV replicates millions of times a day.  But a small percentage of these copies are inaccurate, genetically different and are, thus, resistant to the enzyme blockage of DAAs.  These RAVs vary in quantity and strength from person to person.

Nearly everyone goes UND with treatment.  The DAAs zap the regular copies of HCV and our VLs drop quickly.  However, if RAVs are present and they are sufficiently strong enough they multiply after we stop treatment and in a small quantity of people they lead to a relapse.

Of the 2 main categories of DAAs the NS5Bs have a high barrier to resistance and, hence, they are the backbone of all treatments.  However, they are not sufficiently potent enough to use as a monotherapry and, hence, we add in an NS5A.  These are highly potent but have a low barrier to resistance.  

If RAVs are not present we have no problems and SVR is achieved.  But if RAVs are present, particularly to these NS5As, then there can be a problem.

This is one of the reasons why longer treatments have higher SVR rates.  If NS5A RAVs are present then the extra 12 weeks of a NS5B (i.e. sofosbuvir) in a 24 week treatment is more likely to be enough to get us over the finish line.

RAVs are also the reason why the very new treatments include a third drug from a different DAA class to the NS5As or NS5Bs.  With three different class of drugs hitting HCV there is a higher chance of overcoming any RAVs present.  Finally, we have the option of adding in ribavirin, which acts in a very different way than the DAAs by artificially boosting our immune systems to defeat the virus.

Other factors, like cirrhosis, genotype and genetics (IL28) play a role too in terms of how we respond to DAAs but from my reading it's RAVs that are the main enemy.

Hope that helps.

Pablo

Thank you HP! You're not alone, it made my brain start to overheat, so I'll tackle it in sessions! The article is very informative. 

Welcome to the forum. Feel free to introduce yourself in our New Members section. 

Thanks, this is a good read.  RC