Hep C Discussion Forum

Hi all,

RAV= Resistance Associated Variant. Also called mutations, treatment-induced variants or viral polymorphisms. When infected by HCV, we know there is a dominant viral structure called the 'Wild-Type', and it has a family of very similar viruses, with substitutions of an amino acid or two in vital spots. These substitutions are due to an error in replication. Many are poor copies and cannot replicate or enter cells, so these quickly disappear. It's survival of the fittest. We are probably left with a few dozen mutations ( forming 5-10% of the VL), and some of these may have changes at replication sites. Significant RAV's have been named, using the protein number where the changes have occurred. The type of protein change is identified by two letters, so we have names like 'RAV S282T'.

With the loss of Interferon, and hopefully Ribavirin, these RAV's are now the subject of countless papers. RAV's are drug and Genotype specific, and probably account for most treatment failures or relapses.

Pre-Treatment Screening: With Olysio, we have seen the advice to check for the Q80K RAV. This only occurs in Geno 1a, and is present naturally in up to 50% of US patients. As Olysio is unlikely to get much use, except with another DAA until better drugs are approved, this is probably of no significance. Naturally occurring RAV's to virtually every DAA have been found. There is debate as to whether this matters, as no DAA will be used as monotherapy. It is of interest to researchers, but in practice this is expensive and unjustified.

Anti-proteases: From the replicon studies, this NS-3 site was found to be easy to block. The first generation antiproteases, Incivek and Victrelis, lifted the SVR rates significantly for Geno1. Incivek has some nasty side-effects, and Victrelis was less potent and needed thrice daily dosing, and only worked after the VL was reduced by a leadin with Peg and Riba. RAV's quickly developed to both and the Geno 1a's were most at risk. The specific RAV's are well-documented, and I have discussed these in previous posts. Patients on these early drugs had the safeguard of Peg and Riba to destroy the RAV's, providing the patient was Interferon-sensitive, and Ribavirin was at adequate blood levels. The antiproteases RAV's were said to have reduced 'fitness', but Geno 1b RAV's persisted for up to 6 months, and 1a RAV's persisted for up to 2 years.

Enter the second generation antiproteases. These were meant to have a more complex structure, reducing the likelihood of RAV production. They were also intended to be pan-genotype, and free of nasty side-effects. The only one that comes close is Merck's MK-5172. This is active against all known RAV's from other antiproteases, but not much has been said about any RAV's it may produce.

NS-5A inhibitors: Again, this is a complex, unstable site. Potent blockers have been developed, and Ledipasvir and Daclatasvir are well known. Pretreatment screening has shown naturally occurring RAV's at protein sites 28, 30, 31 and 93. Significant RAV's are M28V and Y93H. As these drugs will be always used with another DAA, the significance of these RAV's is uncertain. A number of treatment-induced RAV's have been identified, but these should be destroyed by the other DAA, e.g. Sovaldi.

NS-5B inhibitors: Here we have the non-nucleosides( e.g ABT-333) and the nucleosides (e.g. Sovaldi). The non-nucs have a low barrier to resistance, and RAV's rapidly appear, particularly at sites 452, 316 and 159. Again, we hope the additional DAA's will take care of these. The nucs, like Sovaldi, have an inherently high barrier to RAV's but they do occur.

So what does all this mean. Basically, I think pre-treatment screening for RAV's is a waste of time and money. Assuming Peg and Riba are not used, the choice of drugs is important. Until drugs like Ledispavir and MK-5172 are approved, we have to go what we've got. Forgetting cost, we want the drugs with the least chance of treatment failure, and with the fewest side-effects. My choice would be Sovaldi and Olysio, and as a cirrhotic, I'd want Riba as well- Rx duration of 24 weeks! Down the road, I'd want Sovaldi and Ledipasvir +/- MK-5172. Maybe 12 weeks of that would suffice.

For treatment failures, Sovaldi can be re-used. You would need a different second, and possibly third DAA ( to protect against surviving RAV's). Antiprotease failures should switch to another site. Treatment duration has not been established, and cirrhotics may need 24 weeks.

All this stuff is complex and still far from clear. I understand patients can't walk into a Hepatologist's office and demand a certain drug regime. It's just information. Cheers.