In his interview broadcast on NZ Radio Prof Gane referred to a possible risk of some generic ledipasvir emanating from China and Bangladesh not being effective against the hep c virus. There is another thread specifically devoted to the potential application of this to Twinvir – a Bangladeshi generic used by many members of this forum, including me.

(Link to radio broadcast: http://www.radionz.co.nz/national/programmes/ni…tis-c-buyers%27-club )

In elaborating this point Prof Gane makes another observation which may have potential implications for relapse and so be worthy of a separate thread. Prof Gane points out that the common combination to treat hep c comprises what he calls a “nuke” and what he calls an “NS5A”. The “NS5A” he is most concerned about is ledipasvir, basically because it is so difficult to make – requiring, he says, very sophisticated factories.

Two implications for responding to relapse may arise from Prof Gane’s comments. The first implication applies generally to all DAA (direct-acting antiviral) treatment relapses. The second is specific to those relapses which may arise if Prof Gane’s concerns about defective ledipasvir turn out to be well-founded and some people relapse as a result.

Taking first the implication of general application: Prof Gane argues that even if a generic does contain defective or substandard ledipasvir this will not be come apparent until after the course of treatment is ended. It will not be revealed by viral load tests during treatment because, he says, even where the NS5A is not working the “nuke” alone will be sufficient to suppress the virus to below the detectable limit as long as treatment continues, but not after. Only when treatment is finished will the defectiveness of the NS5A drug be revealed by allowing the virus to spring back.

What is the “nuke”? Well, by a process of exclusion, as it is not ledipasvir, and although Prof Gane does not expressly say so, he must mean sofosbuvir. If so, am I right in interpreting Prof Gane as saying that sofosbuvir taken alone, although not sufficient to achieve a cure, is capable, while treatment continues, but not beyond, of suppressing the virus to below detectable limits?

If this is true, could this be of potential help to those who are unlucky enough to relapse after DAA treatment? At the moment, I believe I am right in saying, there’s some uncertainty as to how to treat DAA relapsers, mainly because it is assumed that relapsers will have developed at least some resistance to an NS5A inhibitor, whether that be ledipasvir or daclatasvir. As a consequence simply repeating the same course of treatment won’t be an option.

So would an option for a relapser be to go on permanent, lifelong sofosbuvir in the same way that, for example, Type 1 diabetics take lifelong insulin, or HIV patients take lifelong viral suppression medication? It wouldn’t provide a cure; but it would suppress the virus and thereby prevent any further damage to the liver, reducing the risk of going on to develop liver failure or HCC, as well as relieving the symptoms of hep c. There would be a continuing financial cost of buying the sofosbuvir but uncombined sofosbuvir is now one of the cheaper generic DAAs – a bottle of 28 can be obtained for US$275 and, if the Indian licensed generic manufacturers actually start to compete against one another, this price may fall further in the future. Many might regard that as a price worth paying to avoid liver failure or HCC.

What is more, in practice, it may not even have to be lifelong. A new generation of DAAs may eventually become available – perhaps as soon as in 3 to 4 years time. It may then only be necessary for a relapser to take sofobuvir as viral suppression until such time as a new treatment – or more precisely a generic version of the new treatment – becomes available

The second implication of Prof Gane’s remarks is specific to those people who have taken generics with defective ledipasvir, and who relapse as a result. If the ledipasvir in their generic medicine was not in the right form to be effective against the virus would this mean that it also would not be effective to give rise to resistance? If so, there would be no NS5A inhibitor resistance and hence no obstacle to simply doing another course of genuine sofosbuvir/ledipasvir obtained from a more reliable source. But if the defective ledipasvir, while not effective enough to cure, is effective enough to give rise to resistance then the unfortunate patients will truly have had the worst of both worlds – no chance of a cure but developing NS5A resistance and so closing the option of re-treatment with authentic versions of the same drugs.

I would most welcome any comments on either of the above questions. I am genuinely worried.