Aa
Resistance in 2-DAA combos
Following on from the discussion on resistance in another thread, I found this study.
http://www.pharmasset.com/assets/1/Page/ALam_combo_studies_invitro_7977_938_June10.pdf
"Selection study in replicon cells treated with the nucleotide analogs PSI-7977 and PSI-352938 did not select for resistance over a 120-day time period. Combining VX-950 plus HCV-796 selected for dually resistant HCV replicons within 46 days. Results suggest that combination therapies using complementary NS5B nucleotide analogs could provide a significant barrier to resistance selection that might not be seen with a combination of a protease inhibitor and a non-nucleoside inhibitor."
I think it is an important study because it is showing that if you don't get the 2-DAA combo right you could be looking at dually resistant mutations within 46 days of tx. The viral superbugs already! From experience with HIV we know that multiple drug resistance does emerge eventually, but it is the 46 days that I find such a shocker, such a short time.
The good news is that the 2 NS5B nucleotide analogs used in the study did not produce any resistant mutations within 120 days of tx.
Anyhow, this wrecks my previous complacency about 2-DAA combos being the magic bullet. We are going to have to be very cautious about resistance with these combos - I presume even when there is SOC in the mix but poor ifn response.
dointime
PS - and thanks to willbb for waking me up.
http://www.pharmasset.com/assets/1/Page/ALam_combo_studies_invitro_7977_938_June10.pdf
"Selection study in replicon cells treated with the nucleotide analogs PSI-7977 and PSI-352938 did not select for resistance over a 120-day time period. Combining VX-950 plus HCV-796 selected for dually resistant HCV replicons within 46 days. Results suggest that combination therapies using complementary NS5B nucleotide analogs could provide a significant barrier to resistance selection that might not be seen with a combination of a protease inhibitor and a non-nucleoside inhibitor."
I think it is an important study because it is showing that if you don't get the 2-DAA combo right you could be looking at dually resistant mutations within 46 days of tx. The viral superbugs already! From experience with HIV we know that multiple drug resistance does emerge eventually, but it is the 46 days that I find such a shocker, such a short time.
The good news is that the 2 NS5B nucleotide analogs used in the study did not produce any resistant mutations within 120 days of tx.
Anyhow, this wrecks my previous complacency about 2-DAA combos being the magic bullet. We are going to have to be very cautious about resistance with these combos - I presume even when there is SOC in the mix but poor ifn response.
dointime
PS - and thanks to willbb for waking me up.
I see, haven't really kept up with the most recent polymerase trials. There is no doubt in my mind future treatment will not include interferon and it may be so refined that ribavirin is no longer required either. In this phase of the polymerase trials that exclude interferon it's a matter of risk vs reward and that's a tough call.
There is no interferon on Pharmasset and the Riba is for 24 weeks if that is the arm you get randomized to. It is the Polymerase agents that are emphasized.
12 weeks only of daily Incivek - RVR = 6 mo. total treatment time.
You will have side effects with the PI's recently released or the Pharmasset trial drugs but with Incivek it is stopped after 12 weeks regardless. An option might be a 4 week lead in with SOC and add either Victrelis or Incivek according to SOC response. In my opinion a bird in the hand (Victrelis or Incivek) is worth two in the bush.
You will be effected by the drugs regardless of what drugs you choose and there is no way to gauge the degree it will effect you until you take the plunge. You might be able to schedule throw up time but you can't schedule fatigue or anemia or the myriad of other side effects that can happen. If you commit to treatment you take what comes a day at a time and the primary focus is beating the virus. Lifestyle changes may be necessary when trying to achieve that and if you absolutely cannot be flexible maybe it isn't a good time to treat now.
You will have side effects with the PI's recently released or the Pharmasset trial drugs but with Incivek it is stopped after 12 weeks regardless. An option might be a 4 week lead in with SOC and add either Victrelis or Incivek according to SOC response. In my opinion a bird in the hand (Victrelis or Incivek) is worth two in the bush.
You will be effected by the drugs regardless of what drugs you choose and there is no way to gauge the degree it will effect you until you take the plunge. You might be able to schedule throw up time but you can't schedule fatigue or anemia or the myriad of other side effects that can happen. If you commit to treatment you take what comes a day at a time and the primary focus is beating the virus. Lifestyle changes may be necessary when trying to achieve that and if you absolutely cannot be flexible maybe it isn't a good time to treat now.
Thanks Spectda, very sobering.
To all on this thread: Here is my dilemna. I am treatment naive and have the choice of going into a trial (Pharmasset - PSI 7977 +BMS 79002 and Riba) or getting SOC with triple therapy right off the bat.
I must continue to work at a job which requires maximum alertness but is home based. Little or no family support. I cannot be taking time off but my morns are free for vomiting. Research is being conducted at a major University hospital. I am genotype 1a, blood tests normal with FLD. I am over 60. Signs look good for no cirrohsis but biopsy will tell the story.
The trial is randomly assigned but open. The relevant arms are PSI 7977 add BMS after 7 days and both for 6 months; PSI 7977 and BMS for 6 months; PSI+BMS+Riba 1000mg for 6 months. Once assigned you cannot switch.
The director of hepatology says they like that study. There is no control arm so everyone gets meds. But if I don't clear in one arm or if I have severe sides, I cannot then be reassigned to another.
They will give me SOC if I fail (he is unconcerned about resistence).
Which would you pick if you were in my shoes all things considered?
To all on this thread: Here is my dilemna. I am treatment naive and have the choice of going into a trial (Pharmasset - PSI 7977 +BMS 79002 and Riba) or getting SOC with triple therapy right off the bat.
I must continue to work at a job which requires maximum alertness but is home based. Little or no family support. I cannot be taking time off but my morns are free for vomiting. Research is being conducted at a major University hospital. I am genotype 1a, blood tests normal with FLD. I am over 60. Signs look good for no cirrohsis but biopsy will tell the story.
The trial is randomly assigned but open. The relevant arms are PSI 7977 add BMS after 7 days and both for 6 months; PSI 7977 and BMS for 6 months; PSI+BMS+Riba 1000mg for 6 months. Once assigned you cannot switch.
The director of hepatology says they like that study. There is no control arm so everyone gets meds. But if I don't clear in one arm or if I have severe sides, I cannot then be reassigned to another.
They will give me SOC if I fail (he is unconcerned about resistence).
Which would you pick if you were in my shoes all things considered?
My last three biopsies
diagnosed 1998 and stopped drinking (didn't drink heavily prior)
1rst tx 2010
1999-stage 0 (about 20 years after infection)
2004-stage 0 (about 25 years after infection)
2010-stage 2/3 (very close to bridging) (about 31 years after infection)
diagnosed 1998 and stopped drinking (didn't drink heavily prior)
1rst tx 2010
1999-stage 0 (about 20 years after infection)
2004-stage 0 (about 25 years after infection)
2010-stage 2/3 (very close to bridging) (about 31 years after infection)
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