[Peak Dialogue]Revolution in DAA era: Genotyping and RAV testing and management

 

In the era of direct-acting antiviral agents (DAAs), the side effects, intolerance, long treatment duration and unsatisfying cure rate of interferon may become a historical footnote, while certain DAA related issues came up, including the necessity of identifying genotype before initiating treatment, as well as the resistance-related variants (RAV). However, new DAAs being researched may be able to address these issues in the future. Professor Peng Hu from the Second Affiliated Hospital of Chongqing Medical University, and Professor Marc Bourliere from Saint Joseph Hospital, Marseille, shared their analysis with us on this matter. All DAAs mentioned by Professors Hu and Bourliere have not been approved in China.

 

Genotyping

 

The majority of the DAAs are only applicable to genotype 1/4 HCV infected patients, and some regimens showed different effects on sub-genotype 2, 3 and 6 patients. So, the accurate genotyping is a prerequisite for successful DAAs treatments. However, the situation might be changed with the new pan-genotype drugs under investigation or available in the US and Europe.

 

Pan-genotype drugs lower the dependence of DAAs on genotyping

 

"These new drugs such as sofosbuvir and/velpatasvir and grazoprevir/elbasvirre present a new era of the hepatitis C treatments." Prof. Bourliere told us. When the pan-genotype compounds become available worldwide, we can think about treatments without genotyping, which is mandatory now. Also, the efficacy of these new treatments will be the same to all genotypes, “things will be easier since there will be no need for mandatory genotyping". However, Prof. Bourliere also pointed out that although the response rate of the pan-genotype drugs is very high, they are not always the same across patients with different genotypes.

 

How about the situation of genotyping in China? Professor Hu told that there still are considerabledeficiencies in HCV genotyping, not only in some basic level hospital, but also in some medium scale hospital. Identification of HCV genotype is necessary before we start the therapy with DAAs, which makes genotyping a routine like liver function testing. It's true that there will be pan-genotype drugs less dependent on genotyping. However, during the EASL conference and AASLD meeting, we can see that genotyping is included into the criteria for diagnosing difficult-to-treat hepatitis C in regions in America and Europe, and it is completely accordance with the current recommendation in China. So Chinese physicians should make the therapy decision based on our current conditions." 

 

When should genotyping be done in the future

 

Professor Bourliere thought that genotyping may have an interest in term of epidemiology or a higher risk of re-infections or new infections suspected, for example in the patients who are intravenous drug users or at risk of getting new hepatitis C virus infection.

 

Resistance-associated variations（RAVs）

 

Impact of RAV

 

Some RAVs pre-exist to treatments while some come up during the treatment and is associated with the treatment. Professor Bourliere said:" there is an impact of this initial RAS on SVR even if this impact is small, because the numbers of patients who are detectable of this resistance initially is quite low. For example, for the NS5A RAS, about 15% or 16% of the populations in clinical trials had this RAS prior to any treatment with NS5A. In some sub-genotype such as genotype 1A, they could have an impact on the SVR rate with the current regimens, but these consequences may vary depending on the specific regimen, for example the effect may only observed into treatment experienced patients for certain regimens. So taking that in considerations, the real impact of pre-existing RAS to any treatment is very limited".

 

On the contrary, the situation is completely different for patients fail the first DAA treatment. Professor Hu pointed out "clearly the efficacy of certain kinds of DAAs is impacted by RAV significantly. The existence of RAV will interfere with the treatment strategies.

 

For example, when patients relapsed after or failed DAA treatment, lots of them are going to have a RAS against NS5A inhibitors, re-treating them with the same treatment won’t deliver an optimal result. So the regimens have to be changed.

 

Different resistance profiles between DAAs

 

Since DAAs are against different targets in HCV life cycle, like NS3/4A, NS5A, NS5B, their resistance profiles are different. Professor Hu and Professor Bourliere explained their drug resistance characteristics for us. 

 

The second type is NS3/4A protease inhibitor. The drug resistance to the first generation of NS3/4A protease inhibitor arises very rapidly, but after a brief time, like one year, most of the resistances disappear.

 

Then we have NS5A inhibitor, it is very important because that’s also a pan genotype treatment. Its resistance can persist for very long term and impact the treatment result if it appears, and that raises concerns.

 

Management of NS5A resistance

 

With NS5B inhibitors, protease inhibitors and NS5A inhibitors available, and by combining 3 or 2 of them, this problem of resistance could be overcome.

 

As demonstrated in the POLARIS-1 study for example, including patients who previously failed an NS5A inhibitors-containing regimen, 96% efficacy rate was achieved in clinical trials with the new investigational combinations of sof/vel/vox. Similar results were shown in the case of GP (glecaprevir/pibrentasvir) from Abbvie and the MK3 combinations in experienced patients. So in the near future, we would have at least three different combinations that can overcome this problem of resistance mutations.

 

And before the launch of new products, we could overcome this resistance problem by combining currently existed regimens. For example, sofosbuvir plus grazoprevir/elbasvir or sofosbuvir plus 3D are proposed to retreat NS5A inhibitors-containing therapy experienced genotype 1/4 patients.

 

For genotype 3, there were a very few options and the only option that has been proposed in current guidelines was to retreat the patient for a long period of time.

 

"It was a problem, the resistance issue, but now we have some solutions to overcome this problem. The recommendation from the updated EASL guidelines on how to treat these patients is that you can combine certain DAAs to overcome this problem and achieve high rate of SVR. Clearly with the new compound that will be available within the next one or two years, I think this problem would be largely solved", concluded by Professor Bourliere. 

 

Should RAV be tested prior to treatment?

 

"Resistance-associated gene mutation might need to be tested before treatment." Said Professor Hu," RAV testing before the initiation of DAAs is required in some Asian countries and regions, including Japan, Korea and Taiwan. However, testing for resistance on a universal scale is relatively a much more difficult. What clinic really needed is something truly commercialized and can be widely applied. Now some specialized laboratory companies or research institutions in China are able to carry out a series of testing of resistance gene mutation. I believe large-scale testing of resistance would come true in the future in China."

 

As saying by Professor Bourliere, because of the high expense and the poor practicability of the current RAV testing, "I think nobody is able to do a routine RAS determination at baseline", and at the same time, "the implications of these baseline RAS on SVR are very limited, so there is no real interest to do so except if you want to make science".

 

The above posting is sponsored by Gilead Sciences to support scientific and medical education, and with non-promotional intent.