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On Harvoni, what exactly kills existing HCV?
Hello everyone,
On day 3 of my Harvoni treatment. What a nice feeling that after so many years the tables are turned and I have this ******* on the run.
I was wondering if anyone knew how the existing viral load is killed off? I'm guessing 3 mechanisms come into play:
1) Immune system (but I'm under impression it doesn't do much against HCV)
2) Over time viruses break down due to mechanisms like reduction in the cytoplasm (?)
3) As each virus enters a cell, attempts replication and is blocked by Harvoni, it is destroyed.
Any thoughts?
On day 3 of my Harvoni treatment. What a nice feeling that after so many years the tables are turned and I have this ******* on the run.
I was wondering if anyone knew how the existing viral load is killed off? I'm guessing 3 mechanisms come into play:
1) Immune system (but I'm under impression it doesn't do much against HCV)
2) Over time viruses break down due to mechanisms like reduction in the cytoplasm (?)
3) As each virus enters a cell, attempts replication and is blocked by Harvoni, it is destroyed.
Any thoughts?
Thank you for the thoughts.
I guess I'm thinking about the specifics of how the existing HCV dies of old age.
My best speculation is that the remaining HCV continues to enter cells where they uncoat, translate, and then get interrupted by the Harvoini during replication. In the process that virus is "consume" because it didn't replicate.
But I really haven't been able to find a description anywhere on the web. I'll ask my doctor next time I see him and post the answer here.
I guess I'm thinking about the specifics of how the existing HCV dies of old age.
My best speculation is that the remaining HCV continues to enter cells where they uncoat, translate, and then get interrupted by the Harvoini during replication. In the process that virus is "consume" because it didn't replicate.
But I really haven't been able to find a description anywhere on the web. I'll ask my doctor next time I see him and post the answer here.
Harvoni interfears with viral replication if you neuter a population it dies off. Harvoni does not kill the virus ir prevents it from making copies or simply put stops it from making babies.
No virus babies no more virus.
Or for a more technical explanation from the Harvoni prescribing information sheet that comes with every bottle:
http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf
Starting on Page 17
12.4 Microbiology
Mechanism of Action
Ledipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action.
Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotypes 1b, 2a, 3a and 4a with IC50 values ranging from 0.7 to 2.6 M. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.
Antiviral Activity
In HCV replicon assays, the EC50 values of ledipasvir against full-length replicons from genotypes 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC50 values of ledipasvir against chimeric replicons encoding NS5A sequences from clinical isolates were 0.018 nM for genotype 1a (range 0.009–0.085 nM; N=30) and 0.006 nM for genotype 1b (range 0.004–0.007 nM; N=3). Ledipasvir has less antiviral activity compared to genotype 1 against genotypes 4a, 5a, and 6a, with EC50 values of 0.39 nM, 0.15 nM, and 1.1 nM, respectively. Ledipasvir has substantially lower activity against genotypes 2a, 2b, 3a, and 6e with EC50 values of 21–249 nM, 16–530 nM, 168 nM, and 264 nM, respectively.
In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotypes 1a, 1b, 2a, 3a, and 4a, and chimeric 1b replicons encoding NS5B from genotypes 2b, 5a, or 6a ranged from 14–110 nM. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 62 nM for genotype 1a (range 29–128 nM; N=67), 102 nM for genotype 1b (range 45–170 nM; N=29), 29 nM for genotype 2 (range 14–81 nM; N=15), and 81 nM for genotype 3a (range 24–181 nM; N=106). In replication competent virus assays, the EC50 values of sofosbuvir against genotypes 1a and 2a were 30 nM and 20 nM, respectively. Evaluation of sofosbuvir in combination with ledipasvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells.
No virus babies no more virus.
Or for a more technical explanation from the Harvoni prescribing information sheet that comes with every bottle:
http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf
Starting on Page 17
12.4 Microbiology
Mechanism of Action
Ledipasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate ledipasvir targets NS5A as its mode of action.
Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotypes 1b, 2a, 3a and 4a with IC50 values ranging from 0.7 to 2.6 M. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.
Antiviral Activity
In HCV replicon assays, the EC50 values of ledipasvir against full-length replicons from genotypes 1a and 1b were 0.031 nM and 0.004 nM, respectively. The median EC50 values of ledipasvir against chimeric replicons encoding NS5A sequences from clinical isolates were 0.018 nM for genotype 1a (range 0.009–0.085 nM; N=30) and 0.006 nM for genotype 1b (range 0.004–0.007 nM; N=3). Ledipasvir has less antiviral activity compared to genotype 1 against genotypes 4a, 5a, and 6a, with EC50 values of 0.39 nM, 0.15 nM, and 1.1 nM, respectively. Ledipasvir has substantially lower activity against genotypes 2a, 2b, 3a, and 6e with EC50 values of 21–249 nM, 16–530 nM, 168 nM, and 264 nM, respectively.
In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotypes 1a, 1b, 2a, 3a, and 4a, and chimeric 1b replicons encoding NS5B from genotypes 2b, 5a, or 6a ranged from 14–110 nM. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 62 nM for genotype 1a (range 29–128 nM; N=67), 102 nM for genotype 1b (range 45–170 nM; N=29), 29 nM for genotype 2 (range 14–81 nM; N=15), and 81 nM for genotype 3a (range 24–181 nM; N=106). In replication competent virus assays, the EC50 values of sofosbuvir against genotypes 1a and 2a were 30 nM and 20 nM, respectively. Evaluation of sofosbuvir in combination with ledipasvir showed no antagonistic effect in reducing HCV RNA levels in replicon cells.
My oversimplified answer to this question is that the new treatments interrupt replication of the virus. The various drugs interrupt that cycle at various places in the virus. This is unlike interferon which is an immune modulator and depends on the person's immune system to destroy the virus.
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