Hi, Gaj!

I dont know about studies which show persistence of virus after SVR due to modern “DAA-only” therapy. But this does not mean that such persistence is impossible. In this article (http://www.hindawi.com/journals/grp/2015/579147/) there are some concerns:

With the shorter duration of therapy with the new DAA and in the absence of interferon that has the potential to induce an immunologic attack directed at the putative “protected reservoirs” of HCV, concern for an increased prevalence of OCI in the future as a result of treatment with DAA represents a worrisome possibility.

The currently widely held assumption of a HCV-cure in individuals having had “SVR” after 8–12 weeks of a course of DAA therapy as recently defined may not be entirely valid. Careful longitudinal followup utilizing highly sensitive assays and unique approaches to viral isolation are needed.

If i correctly understand, this is relatively old discussion in “medical world”, which was started before approving of modern DAAs, from times of interferon-based treatment (see, for example, http://www.journal-of-hepatology.eu/article/S0168-8278(13)00598-9/fulltext – “Therefore, definite evidence for the clinical efficacy of interferon therapy was never established and SVR was never formally validated. The use of SVR as surrogate outcome measure thus remains with some uncertainty.” The problem lies in “slow progressing” nature of HCV-infection. According to priciples of evidence-based medicine, randomized controlled trials on “hard points” (such as death, liver transplantation etc.) must be performed to validate SVR as surrogate outcome. In other words, roughly speaking, we need to randomize many (for example, several thousands) patients to 2 groups, one group will receive treatment and other group will not receive treatment. If patients in first group (treated) will demonstrate statistically better survival, than in second (untreated) group, then we can say that treatment is effective in term of improving survival. But, due to “slow” nature of HCV infection, such trials are costly and will require many years of observation (or even decades for people with mild fibrosis). FDA, EMA etc. approved HCV medications without such trials, probably due to ethical reasons (otherwise, appearance of medication on market was delayed for many years). But, as a result, we have no complete evidence base from point of view of evidence-based medicine. Roy M.Poses points to this fact in his article. If i correctly understand, many world-known hepatologists (for example, authors of http://www.journal-of-hepatology.eu/article/S0168-8278(13)00598-9/fulltext) agreed with this fact (so, this is not only “my” point of view). Yes, Roy M.Poses may seems as “outlier in the medical community”… But, anyway, this not affects the fact of absence of required (from point of view of evidence based medicine) trials. Also, is it possible that Big Pharma may “pressure” medical community, guideline makers etc. – to “suppress” such voices like Dr.Poses, for promoting treatment and for maximizing profit from selling drugs?

Hi, Gaj!

Yes, I agree. There are situations, in which it will be very hard to obtain complete evidence. Speaking “formally”, from point of view of EBM, we should start “prescription” treatment only after having of “complete evidence” from trials. Obviously, it may be unethical – for example, if required trials may require decades. But, i believe that patients should be informed about such situations, in which treatment is initiated without having of full evidence base, because this fact may affect treatment decision.

In terms of having adverse events, not all evidence must be positive, according to EBM. For example, many drugs have serious adverse events, they are not safe, and, at the same time, they have good medical evidence. Key point is that drug must demonastrate their effectiveness in randomized trials on relevant “solid clinical endpoint”. For example, for treatment of pneumonia with penicillin, randomized controlled trial will show significantly improved survival in group of treated compared to group of untreated. But penicillin have adverse events (as almost every medication) – and some people may die from allergic reaction caused by penicillin, for example. But, when it is decided to take penicillin, patient will be sure that, based on trials, there are good evidence that overall probability to improve survival is much more than probability “to worse” survival. In other word, on the average, “benefits outweigh harm” or “drug do more good than harm”. Other possible example – many serious anticancer drugs have good medical evidence (based on randomized trials, these drugs, on the average, improve survival) but they have serious adverse events also.

Generally, I dont think like this. Usually, it is possible to perform clinical trials according to EBM principles. Such situation as with HCV treatment – seems as “exception rather than the rule”.

Probably, his point was – to percieve this argument together with available “evidence base” about treatment. For example, in situation when every infected with some disease will definitely die within 5 years without treatment, applying of some experimental treatment is justified (in situation of absence of other alternatives). But, if only 10-20% will die from disease without treatment during lifetime – applying of experimental treatment may seems questionable. Antihypertensive drugs usually have good evidence in preventing strokes etc., hence, they are not experimental treatment.

This statement is a consequence of fact of absence of required trials, according to EBM. He seems as enthusiast of EBM, and, i think, he tries to inform people in “simple words” about such things. But, these things, by their nature, may seems quite scary and, hence, psychologically, it may be difficult to accept them… Personally, i am not very easy accepted these things several years ago.

Best wishes,
Serg.

Hi, GT2!

Firstly, I am sorry for my posting about such “cold facts” – definitely, it may be psychologically difficult to accept these things for many people. Also, I believe that, mainly, these are not “my” arguments, or “my” “strict interpretation of EBM” – these are arguments/interpretetion of several famous medical experts (Roy M Poses etc.). And, probably, you may argue with Dr.Poses, if you feel that he is wrong in his interpretation of EBM, for example. Also, I never wrote that “modern DAA treatment must be stopped as ethically unapproved ” – please do not attribute to me such thoughts.

You are better advised to take up your arguments with the patent holders.

My voice has not weight at all. But, possibly, we have cheap generics available, also, due to such articles from medical experts about lacking of good medical evidence. This is one of arguments for pressuring of patents holders for reducing price of HCV medications.