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Future Therapies of HCV

Future Therapies of HCV. Miranda Surjadi, NP San Francisco General Hospital Department of Gastroenterology/Hepatology. Virology of Hepatitis C . HCV is a small, enveloped single stranded RNA virus in the Flaviviridae family There are six major genotypes and more than 100 subtypes.

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Future Therapies of HCV

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  1. Future Therapies of HCV Miranda Surjadi, NP San Francisco General Hospital Department of Gastroenterology/Hepatology

  2. Virology of Hepatitis C • HCV is a small, enveloped single stranded RNA virus in the Flaviviridae family • There are six major genotypes and more than 100 subtypes

  3. Hepatitis C • Blood bank screening for HCV in 1987 • 4 million in the US with chronic HCV • Leading cause of cirrhosis in the US • Most common reason for liver transplantation • 8000-10,000 deaths/ year

  4. Natural history of HCV

  5. Factors that increase the evolution to cirrhosis • Infection at an older age (>40yo) • Male sex • Drinking more than 50grams of alcohol per day (5 drinks) • Obese or with hepatic steatosis on biopsy • HIV/HBV co-infection

  6. History of HCV therapy • Interferon was approved for use in HCV in 1992. It was shown to decrease HCV RNA levels and lead to SVR in some patients. • Ribavirin is a nucleoside analog known to have activity against several flaviviruses. Ribavirin does not have much effect on HCV RNA levels alone. However, in combination with interferon, SVR rates were increased. • Ribavirin was approved for use as an adjunct to interferon in 1998. • Pegylated interferon allowed for once weekly injections instead of 3x/week and also yielded higher rates of SVR. This was approved for use in 2001.

  7. Goal of HCV therapy • Goal of HCV therapy is SVR (sustained viral response). • SVR is defined as an undetectable HCV RNA 24 weeks after finishing HCV therapy • SVR and duration of treatment is determined by HCV genotype

  8. Current therapy of HCV • Genotype 1: • Duration of treatment: 48 weeks • SVR: 42-50% • 70% of US population • Genotypes 2 and 3: • Duration of treatment: 24 weeks • SVR: 80% • 25% of US population

  9. IL 28B: strong predictor of SVR • IDEAL study: PegIntron vs. Pegasys in genotype 1 • Analysis of on treatment response by IL 28B polymorphism found it to be strong predictor of SVR. • This pattern of SVR is similar across Caucasians, Latinos, and African Americans • CC allele : 69% SVR • CT allele: 33% SVR • TT allele: 27% SVR

  10. SVR rates of past and current HCV therapies 76 61 46 45 37 21

  11. More common : Flu-like symptoms Fatigue, muscle aches, joint aches, fever, headaches Injection site reaction Psychiatric symptoms: depression, anxiety, mood lability Lab alterations: neutropenia, anemia, thrombocytopenia Anorexia, nausea Alopecia Less common : Autoimmune disorders, like thyroid disorders Numbness/tingling in feet Eye disorders, especially in diabetics (very rare) Side effects to pegylated interferon

  12. Side effects to ribavirin • Hemolytic anemia • Teratogenicity, category X • Pruritus, rash • Insomnia

  13. Contraindications to HCV treatment * • Major, uncontrolled depression/anxiety • Current alcohol or drug use • Autoimmune hepatitis or autoimmune conditions known to be exacerbated by pegIFN and RBV (IBD, SLE, RA, etc.) • Recent neoplasm (BCC and SCC ok) • Untreated hyperthyroidism • Pregnant or unwilling to comply with double contraception • Severe, poorly controlled concurrent medical conditions: CHF, COPD, DM, CAD *For SFGH Liver Clinic only

  14. Monitoring HCV RNA during treatment • Rapid viral response: undetectable HCV RNA at wk 4 • Early virological response: undetectable HCV RNA at wk 12 • Complete responder: HCV RNA undetectable at the end of therapy • Patient needs at least a 2-log drop in HCV RNA at wk 12 and an undetectable HCV RNA at wk 24 to continue with treatment.

  15. Monitoring HCV RNA during treatment Non responder if HCV RNA present at week 24 Relapser if HCV RNA present

  16. Future therapies of HCV HCV RNA genome encodes for a single polyprotein. The polyprotein is cleaved during and after translation into mature viral proteins by host and viral encoded proteases. The NS3/4A viral protein contains a serine protease activity that is required for cleavage of the viral polyprotein. NS3/4A Protease inhibitors • Phase 3: Telaprevir and Boceprevir

  17. Telaprevir • Phase 1 studies show marked reduction in HCV RNA by a mean of 4.4 log IU/ml • Phase 1 studies also show a rapid emergence of viral resistant mutants with telaprevir monotherapy • These resistant mutants are still sensitive to pegylated interferon • Subsequent trials combine pegylated interferon, ribavirin, and telaprevir

  18. Telaprevir: PROVE 1 and 2 • TPV/pIFN/RBV 12 wks + pIFN/RBV 36 wks= 69%SVR • TPV/pIFN/RBV 12 wks + pIFN/RBV 12wks = 60%SVR • Control group: pegIFN/RBVx48wks= 46% SVR • 12% of patients had to stop treatment due to TPV related rash All patients in PROVE 1 and 2 are treatment naïve

  19. Boceprevir: SPRINT 1 and 2 • pIFN/RBV 4wks + BOC/pIFN/RBV x 28 or 48wks = 56%/75% SVR • BOC/pIFN/RBV x 28 or 48wks = 54%/67% SVR • Control group: pIFN/RBV x 48wks = 38% SVR • 10-26% of patients had to stop due to anemia from BOC All patients in SPRINT 1 and 2 were HCV treatment naïve

  20. Boceprevir • Anemia was more common in the boceprevir arm • 10-26% of patients in the boceprevir group had treatment discontinuations secondary to anemia compared to 9% in the control group • The addition of Epogen reduced the discontinuation rate to 2-8% in the boceprevir arms.

  21. Relapsers and non responders • Relapsers: defined as patients who initially responded to pegylated interferon/ribavirin (HCV RNA undetectable at week 12/24 and end of therapy), but their HCV RNA relapsed 24 weeks after finishing HCV treatment. • Non responders: defined as patients who did not have a 2-log drop in 12 weeks OR did not have an undetectable HCV RNA at week 24.

  22. PROVE 3: Telaprevir in relapsers • TPV/pIFN/RBV 12 wks + pIFN/RBV 12wks = 69% SVR • TPV/pIFN/RBV 24 wks + pIFN/RBV 24 wks = 76% SVR • TPV 24 wks + pegIFN 24 wks (no RBV)= 42 %SVR • Control group: pegIFN/RBV 48 wks = 20% SVR

  23. PROVE 3: Telaprevir in non responders • TPV/pIFN/RBV 12 wks + pIFN/RBV 12wks = 39% SVR • TPV/pIFN/RBV 24 wks + pIFN/RBV 24 wks = 38% SVR • TPV 24 wks + pegIFN 24 wks (no RBV)= 10 %SVR • Control group: pegIFN/RBV 48 wks = 9% SVR

  24. RESPOND 2: BOC in relapsers and non-responders • Control: pIFN/RBV 48wks = 21% SVR • pIFN/RBV 4wks + BOC/pIFN/RBV 44wks = 66% SVR • Response guided therapy arm: • HCV RNA undetectable at wk 8: pIFN/RBV 4wks + BOC/pIFN/RBV 36wks = 86% SVR • HCV RNA detectable at wk 8, but undetectable at wk 12: pIFN/RBV 4wks + BOC/pIFN/RBV 48wks = 40%

  25. Boceprevir and anemia • Anemia (hgb <10) in up to 43% of patients in the BOC arm (vs. 24% in control group) • Anemia (hgb <8.5) in up to 14% of patients in the BOC arm (vs. 1% in control group) • Erythropoietin use: 41-46% in BOC arm (vs. 21% in control group) • Mean days of EPO use was 130-135 days in BOC arm • Mean days of EPO use was 65 days in control group

  26. HIV/HCV: Telaprevir phase II • TPV/pIFN/RBV 12wks + pIFN/RBV 36wks • Group 1: not on ART, CD4 >500, HIV VL < 100,000 copies/ml • Group 2: on ART, CD4 > 300, HIV VL < 50 copies/ml • Control: pIFN/RBV x 48wks All patients naïve to HCV therapy

  27. HIV/HCV: TPV week 12 data • Group 1: no ART • 71% had eVR vs. 17% of control • Group 2: on ART • Efavirenz based ART: 75 % had eVR vs. 12% of control • Reyataz based ART: 57% had eVR vs. 12% of control

  28. HCV protease inhibitors and ART • ART groups: chosen b/c they were most suitable to be used with telaprevir • Atripla • Reyataz/tenofovir + emtricitabine or lamivudine Telaprevir has moderate drug/drug interactions with several antiretroviral agents: Lopinavir/ritonavir (Kaletra) Darunavir (Prezista) Fosamprenavir (Lexiva)

  29. HIV/HCV: TPV side effects • No cases of HIV breakthrough in ART group • CD4 counts did not change significantly • Main side effects: • Nausea 35% • Pruritus 35% • Dizziness 22% • Anorexia 19% • Vomiting 19%

  30. Direct acting antivirals in Clinical testing NS3/4A protease inhibitors (11) Nucleoside NS5B polymerase inhibitors (3) Non-nucleoside NS5B polymerase inhibitors (8) NS5A inhibitors (2) NS4B inhibitors (1) Entry inhibitors (1)

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