TOPIC: Daclatasvir relapse options

If you relapse G3 on Daclatasvir/Sofosbuvir, what are the options? Not including Riba and Int.

My thought is to wait for Velpatasvir to become available from Mesochem.

Any other options? Can you retreat the same two drugs?(I don't think so)

(It is not me.... I just tested negative G1, SVR6 weeks after Sofdac.)

I don't know what the drug you're talking about is made up of( To lazy to check right now)
I know Sob used in conjunction with other drugs has worked with those who fail.

I think we'll have a better idea over the next year or so.........I think over all
everyone will have a great chance of being cured.

Velpatasvir is the new pangenotypic addition Gliead's arsenal. It is due for approval under FDA priority review. Mesochem have it under R&D. I'm hoping it will be available from China this year. It will be added to Sofosbuvir in a single pill.

Hi Johnboy,

It will depend on why you relapsed. So length of original treatment, fibrosis, any resistance to Dac developed, etc.

So original Tx of 12 weeks with no resistance developed would likely indicate retreating with 24 weeks if no peg and/or riba was acceptable. Or as you say, wait to see Velpatasvir availability and results.

If NS5a resistance to Dac was developed then wait and look at Velpatasvir when available assuming that your HCV resistance path is suited to its use. Or another new DAA as available, maybe something other than NS5a inhibition?

So based on individual case I suspect but as Sir says the future looks bright.

The person probably relapsed because he only did twelve weeks but his liver was worse than thought. He is a very big fellow as well. Of course, that is conjecture. He was F3/4.

So, are you saying he can be tested for resistance to Dac and if he hasn't developed it then he can re-treat with the same drug over the longer course?

Thanks for answering.

Addendum: I believe the date for US approval of Velpatasvir is June 28th 2016.

I'm not sure of general availability of testing outside of research/trial situations ATM but certainly possible depending on where and when. And even if some resistance has developed it will depend on the resistance sites as to how strong the effect is, so as far as I understand longer treatment may still produce good results.

scholar.google.com.au/scholar?q=testing+...xqYKHawcAwMQgQMIGDAA

Thank you for the information.

He is going to be re-treated soon on the PBS through JF.

Read an article yesterday on the website Clinical Care Options
How I manage Pts with HCV after DAA tx failure
By Jordan J Feld, MD, MPH

Sorry don't really know how to post it here, but was an interesting read. Maybe someone here better pc savy could find it and post.

CC2B wrote: Here ya go -
www.clinicaloptions.com/Hepatitis.aspx
Unfortunately you need to register to read it.
The precis on the front page says:

No options for G3 for a different DAA. Dac resistance seems very low. Re-treat over longer period is OK.

The remarkable success of the new direct-acting antiviral (DAA) therapies for chronic HCV infection has led many patients and physicians to expect a cure whenever these agents are used. Although this is indeed the outcome for most, what can we offer the few patients in whom these treatments fail?

The data on retreatment are just starting to emerge. Whereas these studies cannot address every situation, a few general approaches are supported both by good logic and at least some empirical evidence: 1) switching to a different DAA class or classes, 2) treating for longer, and 3) adding ribavirin.

Treating With a Different DAA Class
The simple approach of switching DAA classes is an obvious option for retreatment. It is certainly effective as there is no cross-resistance across DAA classes. This was established by the outstanding results of clinical trials in which patients who experienced protease inhibitor (telaprevir or boceprevir) failure were retreated with combinations of a nucleotide polymerase inhibitor (sofosbuvir) and an NS5A inhibitor (daclatasvir or ledipasvir).

However, switching to a different DAA class is not always possible, owing to contraindications, comorbidities, or potential drug–drug interactions, and may not be absolutely necessary if the other approaches are followed.

The biggest challenge in treating with a different class is NS5A resistance. NS5A resistance associated variants (RAVs) are very fit; they often emerge even before treatment and almost always persist in patients for whom an NS5A-containing regimen fails. Since NS5A inhibitors are part of most approved and investigational regimens, it can be difficult to avoid NS5A inhibitors when retreating.

Extending Treatment Duration
Retreating patients with a longer duration of the same treatment that failed can help many patients, but it may not be enough to overcome RAVs. This was demonstrated in the initial retreatment trial presented at EASL 2015 by Lawitz and colleagues. Patients for whom 8 or 12 weeks of ledipasvir/sofosbuvir failed were retreated with ledipasvir/sofosbuvir again—this time for 24 weeks. Among patients without NS5A RAVs, this approach worked very well, resulting in an SVR12 rate of 100%. However, among those with NS5A RAVs, this strategy was suboptimal, with an SVR12 rate of only 60%. Even more concerning, 4 of the patients who failed the second course of therapy also developed RAVs to sofosbuvir. Fortunately, lessons were learned and the retreatment trials presented at AASLD this year proved much more successful.

Adding Ribavirin
Data from the 2015 AASLD annual meeting highlight that retreatment with a previously unsuccessful regimen is possible with the help of ribavirin. In the C-SWIFT trial, patients who had relapsed after 4-8 weeks of treatment with grazoprevir (a protease inhibitor), elbasvir (an NS5A inhibitor), and sofosbuvir (an NS5B inhibitor) were retreated with the same combination of DAAs but for longer (12 weeks) and with the addition of ribavirin. With this approach, all 23 patients achieved SVR12.

The benefit of adding ribavirin to retreatment is not exclusive to NS5A inhibitors. In a small study of patients for whom a protease inhibitor regimen had failed, most patients were retreated with a protease inhibitor–containing regimen (ombitasvir/paritaprevir/ritonavir plus dasabuvir) plus sofosbuvir and ribavirin. Fourteen of these 15 patients achieved SVR12.

Although the mechanism(s) of action of ribavirin remain elusive, almost all studies using ribavirin with DAAs have shown that it delays or prevents the emergence of resistance, particularly in difficult-to-cure populations. Because ribavirin seems to raise the barrier to resistance, particularly for low-barrier DAAs including NS5A and protease inhibitors, it makes sense to add ribavirin to DAAs when retreating patients with presumed or known resistance.

Combining Strategies
All of the small retreatment studies I’ve mentioned successfully combined at least 2 of 3 approaches: switching to a different DAA class, treating for longer, or adding ribavirin. However, most of these retreatment studies were in patients without cirrhosis, a relatively easy-to-cure population. In clinical practice, many of the patients whose first treatment fails are those with advanced cirrhosis. For these tougher-to-treat patients, a combination of all 3 approaches would likely be worthwhile.

Consider Waiting to Retreat
Although retreatment strategies are becoming more clearly defined, it is also important to consider that, for most patients, retreatment is not an emergency. For all patients except those with life-threatening cryoglobulinemic vasculitis, retreatment can almost certainly wait. Even for patients with advanced cirrhosis, waiting is not always a bad decision; SVR does not reverse liver failure in many patients, so those who cannot wait may actually be better served by being listed for a transplant.

There are at least 2 advantages to exercising a bit of patience. First, unfit RAVs, such as those to sofosbuvir, often disappear with time. Of more importance, research in HCV management continues to move at breakneck speed. The next meeting in this field may well offer the data we need to guide our decisions so we avoid failing a second time.

Your Thoughts?
Which approaches or combinations of approaches have you found effective for retreating patients whose DAAs have failed? When do you begin retreatment? I encourage readers to share their experiences below.

PS Here is a copy and paste of the entire article. I was able to copy and paste it on my mac, I was on my ipad before and not sure how to do that on the ipad

CC2B quoted:
It seems the presence or absence of NS5A RAVs is critical to predicting retreatment success. Is it possible to test for NS5A RAVs before starting any retreatment? If so where, and how?


Ouch! Is it also possible to test for sofosbuvir RAVs?

Is it known whether ribavirin was used in the retreatment trials by Lawitz and colleagues cited as the source of the above figures?

Maybe Dr Freeman can give an answer to your questions Thurl.
This is all new information and I am sure more will be coming out as more results come in for all the new DAA's being used.

Thank you very much for that.
Seems a wait and a test for RAVs is a good option for G3. Even perhaps adding Ribavirin. It's proving unnecessary for the six month regime but for a re-treat?. This person may have stopped too early. I wonder if that makes any difference. There may not be resistant virus there?? Would the safest and best option be Velpatasvir? If you are going to wait for the Sof resistant to wane that would be say six months.... Velpat may be coming from China by then. Better than 6months of Sofdac and Riba any day.

AFAIK RAV testing is performed by genetic sequencing and only relevant for a small percentage of patients.
This study from Glasgow University is interesting:
www.bhiva.org/documents/Conferences/EHHC...210/Emma-Thomson.pdf