future therapies of hcv miranda surjadi, np san francisco general hospital department of...
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Future Therapies Future Therapies of HCVof HCV
Miranda Surjadi, NPMiranda Surjadi, NPSan Francisco General HospitalSan Francisco General Hospital
Department of Department of Gastroenterology/HepatologyGastroenterology/Hepatology
Virology of Hepatitis Virology of Hepatitis CC
HCV is a small, enveloped single HCV is a small, enveloped single stranded RNA virus in the stranded RNA virus in the Flaviviridae familyFlaviviridae family
There are six major genotypes There are six major genotypes
and more than 100 subtypesand more than 100 subtypes
Hepatitis CHepatitis C
• Blood bank screening for HCV in Blood bank screening for HCV in 19871987
• 4 million in the US with chronic HCV4 million in the US with chronic HCV
• Leading cause of cirrhosis in the USLeading cause of cirrhosis in the US
• Most common reason for liver Most common reason for liver transplantation transplantation
• 8000-10,000 deaths/ year8000-10,000 deaths/ year
Natural history of HCVNatural history of HCV
ACUTE HCV INFECTION
15-25% clear HCV75-85% chronic HCV
20% cirrhosisin 20 yrs
1-5% risk of HCC per year
Factors that increase the Factors that increase the evolution to cirrhosisevolution to cirrhosis
Infection at an older age (>40yo)Infection at an older age (>40yo) Male sexMale sex Drinking more than 50grams of Drinking more than 50grams of
alcohol per day (5 drinks)alcohol per day (5 drinks) Obese or with hepatic steatosis on Obese or with hepatic steatosis on
biopsybiopsy HIV/HBV co-infectionHIV/HBV co-infection
Positive HCV Ab
HCV RNA positive HCV RNA negative
Recheck in 6 monthsto verify
Evaluate: LFTs, ANA, HBV,HIV, Iron studies, lipids, HCV genotype, imaging
Refer to Liver Clinic for treatment
If HCV RNA negative x 2, then no need for further f/u.
History of HCV therapyHistory of HCV therapy Interferon was approved for use in HCV in 1992. It Interferon was approved for use in HCV in 1992. It
was shown to decrease HCV RNA levels and lead to was shown to decrease HCV RNA levels and lead to SVR in some patients.SVR in some patients.
Ribavirin is a nucleoside analog known to have Ribavirin is a nucleoside analog known to have activity against several flaviviruses. Ribavirin does activity against several flaviviruses. Ribavirin does not have much effect on HCV RNA levels alone. not have much effect on HCV RNA levels alone. However, in combination with interferon, SVR rates However, in combination with interferon, SVR rates were increased.were increased.
Ribavirin was approved for use as an adjunct to Ribavirin was approved for use as an adjunct to interferon in 1998.interferon in 1998.
Pegylated interferon allowed for once weekly Pegylated interferon allowed for once weekly injections instead of 3x/week and also yielded higher injections instead of 3x/week and also yielded higher rates of SVR. This was approved for use in 2001.rates of SVR. This was approved for use in 2001.
Goal of HCV therapyGoal of HCV therapy
Goal of HCV therapy is SVR Goal of HCV therapy is SVR (sustained viral response).(sustained viral response). SVR is defined as an undetectable HCV SVR is defined as an undetectable HCV
RNA 24 weeks after finishing HCV RNA 24 weeks after finishing HCV therapytherapy
SVR and duration of treatment is SVR and duration of treatment is determined by HCV genotypedetermined by HCV genotype
Current therapy of HCVCurrent therapy of HCV
Genotype 1: Genotype 1: Duration of treatment: 48 weeksDuration of treatment: 48 weeks SVR: 42-50%SVR: 42-50% 70% of US population70% of US population
Genotypes 2 and 3:Genotypes 2 and 3: Duration of treatment: 24 weeksDuration of treatment: 24 weeks SVR: 80%SVR: 80% 25% of US population25% of US population
IL 28B: strong predictor IL 28B: strong predictor of SVRof SVR
IDEAL study: PegIntron vs. Pegasys in IDEAL study: PegIntron vs. Pegasys in genotype 1genotype 1 Analysis of on treatment response by IL Analysis of on treatment response by IL
28B polymorphism found it to be strong 28B polymorphism found it to be strong predictor of SVR. predictor of SVR.
This pattern of SVR is similar across This pattern of SVR is similar across Caucasians, Latinos, and African Caucasians, Latinos, and African AmericansAmericans
CC allele : 69% SVRCC allele : 69% SVR CT allele: 33% SVRCT allele: 33% SVR TT allele: 27% SVRTT allele: 27% SVR
SVR rates of past and SVR rates of past and current HCV therapiescurrent HCV therapies
0
10
20
30
40
50
60
70
80
Genotype 1 Genotypes 2,3
PegIFN
IFN/ RBV
PegIFN/ RBV
21
37
46 45
61
76
Side effects to pegylated Side effects to pegylated interferoninterferon
More common :More common : Flu-like symptomsFlu-like symptoms
Fatigue, muscle Fatigue, muscle aches, joint aches, aches, joint aches, fever, headaches fever, headaches
Injection site reactionInjection site reaction Psychiatric symptoms: Psychiatric symptoms:
depression, anxiety, depression, anxiety, mood labilitymood lability
Lab alterations: Lab alterations: neutropenia, anemia, neutropenia, anemia, thrombocytopeniathrombocytopenia
Anorexia, nauseaAnorexia, nausea AlopeciaAlopecia
Less common Less common ::
Autoimmune Autoimmune disorders, like thyroid disorders, like thyroid disordersdisorders
Numbness/tingling in Numbness/tingling in feetfeet
Eye disorders, Eye disorders, especially in diabetics especially in diabetics (very rare)(very rare)
Side effects to ribavirinSide effects to ribavirin
Hemolytic anemiaHemolytic anemia
Teratogenicity, category XTeratogenicity, category X
Pruritus, rashPruritus, rash
InsomniaInsomnia
Contraindications to HCV Contraindications to HCV treatment treatment **
Major, uncontrolled depression/anxietyMajor, uncontrolled depression/anxiety Current alcohol or drug useCurrent alcohol or drug use Autoimmune hepatitis or autoimmune Autoimmune hepatitis or autoimmune
conditions known to be exacerbated by conditions known to be exacerbated by pegIFN and RBV (IBD, SLE, RA, etc.)pegIFN and RBV (IBD, SLE, RA, etc.)
Recent neoplasm (BCC and SCC ok)Recent neoplasm (BCC and SCC ok) Untreated hyperthyroidismUntreated hyperthyroidism Pregnant or unwilling to comply with Pregnant or unwilling to comply with
double contraceptiondouble contraception Severe, poorly controlled concurrent Severe, poorly controlled concurrent
medical conditions: CHF, COPD, DM, CADmedical conditions: CHF, COPD, DM, CAD
*For SFGH Liver Clinic only*For SFGH Liver Clinic only
Monitoring HCV RNA Monitoring HCV RNA during treatmentduring treatment
Rapid viral response: undetectable Rapid viral response: undetectable HCV RNA at wk 4HCV RNA at wk 4
Early virological response: Early virological response: undetectable HCV RNA at wk 12undetectable HCV RNA at wk 12
Complete responder: HCV RNA Complete responder: HCV RNA undetectable at the end of therapyundetectable at the end of therapy
Patient needs at least a 2-log drop in Patient needs at least a 2-log drop in HCV RNA at wk 12 and an HCV RNA at wk 12 and an undetectable HCV RNA at wk 24 to undetectable HCV RNA at wk 24 to continue with treatment.continue with treatment.
Monitoring HCV RNA Monitoring HCV RNA during treatmentduring treatment
Relapser if HCV RNA present
Non responder if HCV RNA present at week 24
Future therapies of HCVFuture therapies of HCV
HCV RNA genome encodes for a single HCV RNA genome encodes for a single polyprotein. The polyprotein is cleaved polyprotein. The polyprotein is cleaved during and after translation into mature during and after translation into mature viral proteins by host and viral encoded viral proteins by host and viral encoded proteases.proteases.
The NS3/4A viral protein contains a serine The NS3/4A viral protein contains a serine protease activity that is required for protease activity that is required for cleavage of the viral polyprotein.cleavage of the viral polyprotein.
NS3/4A Protease inhibitorsNS3/4A Protease inhibitors
Phase 3: Telaprevir and BoceprevirPhase 3: Telaprevir and Boceprevir
TelaprevirTelaprevir
Phase 1 studies show marked Phase 1 studies show marked reduction in HCV RNA by a mean of reduction in HCV RNA by a mean of 4.4 log IU/ml4.4 log IU/ml Phase 1 studies also show a rapid Phase 1 studies also show a rapid
emergence of viral resistant mutants emergence of viral resistant mutants with telaprevir monotherapywith telaprevir monotherapy
These resistant mutants are still sensitive These resistant mutants are still sensitive to pegylated interferonto pegylated interferon
Subsequent trials combine pegylated Subsequent trials combine pegylated interferon, ribavirin, and telaprevirinterferon, ribavirin, and telaprevir
Telaprevir: PROVE 1 and Telaprevir: PROVE 1 and 22
TPV/pIFN/RBV 12 wks + pIFN/RBV 36 wks= TPV/pIFN/RBV 12 wks + pIFN/RBV 36 wks= 69%SVR69%SVR
TPV/pIFN/RBV 12 wks + pIFN/RBV 12wks = TPV/pIFN/RBV 12 wks + pIFN/RBV 12wks = 60%SVR60%SVR
Control group: pegIFN/RBVx48wks= 46% SVRControl group: pegIFN/RBVx48wks= 46% SVR
12% of patients had to stop treatment due to 12% of patients had to stop treatment due to TPV related rashTPV related rash
All patients in PROVE 1 and 2 are treatment naïveAll patients in PROVE 1 and 2 are treatment naïve
Boceprevir: SPRINT 1 Boceprevir: SPRINT 1 and 2and 2
pIFN/RBV 4wks + BOC/pIFN/RBV x 28 or 48wks pIFN/RBV 4wks + BOC/pIFN/RBV x 28 or 48wks = 56%/75% SVR= 56%/75% SVR
BOC/pIFN/RBV x 28 or 48wks = 54%/67% SVRBOC/pIFN/RBV x 28 or 48wks = 54%/67% SVR
Control group: pIFN/RBV x 48wks = 38% SVRControl group: pIFN/RBV x 48wks = 38% SVR
10-26% of patients had to stop due to anemia 10-26% of patients had to stop due to anemia from BOCfrom BOC
All patients in SPRINT 1 and 2 were HCV treatment All patients in SPRINT 1 and 2 were HCV treatment naïvenaïve
BoceprevirBoceprevir
Anemia was more common in the Anemia was more common in the boceprevir armboceprevir arm 10-26% of patients in the boceprevir 10-26% of patients in the boceprevir
group had treatment discontinuations group had treatment discontinuations secondary to anemia compared to 9% in secondary to anemia compared to 9% in the control groupthe control group
The addition of Epogen reduced the The addition of Epogen reduced the discontinuation rate to 2-8% in the discontinuation rate to 2-8% in the boceprevir arms.boceprevir arms.
Relapsers and non Relapsers and non respondersresponders
Relapsers:Relapsers: defined as patients who defined as patients who initially responded to pegylated initially responded to pegylated interferon/ribavirin (HCV RNA interferon/ribavirin (HCV RNA undetectable at week 12/24 and end of undetectable at week 12/24 and end of therapy), but their HCV RNA relapsed therapy), but their HCV RNA relapsed 24 weeks after finishing HCV treatment.24 weeks after finishing HCV treatment.
Non responders:Non responders: defined as patients defined as patients who did not have a 2-log drop in 12 who did not have a 2-log drop in 12 weeks OR did not have an undetectable weeks OR did not have an undetectable HCV RNA at week 24.HCV RNA at week 24.
PROVE 3: Telaprevir in PROVE 3: Telaprevir in relapsersrelapsers
TPV/pIFN/RBV 12 wks + pIFN/RBV 12wks = TPV/pIFN/RBV 12 wks + pIFN/RBV 12wks = 69% SVR69% SVR
TPV/pIFN/RBV 24 wks + pIFN/RBV 24 wks = TPV/pIFN/RBV 24 wks + pIFN/RBV 24 wks = 76% SVR76% SVR
TPV 24 wks + pegIFN 24 wks (no RBV)= 42 TPV 24 wks + pegIFN 24 wks (no RBV)= 42 %SVR%SVR
Control group: pegIFN/RBV 48 wks = 20% SVRControl group: pegIFN/RBV 48 wks = 20% SVR
PROVE 3: Telaprevir in non PROVE 3: Telaprevir in non respondersresponders
TPV/pIFN/RBV 12 wks + pIFN/RBV 12wks = TPV/pIFN/RBV 12 wks + pIFN/RBV 12wks = 39% SVR39% SVR
TPV/pIFN/RBV 24 wks + pIFN/RBV 24 wks = TPV/pIFN/RBV 24 wks + pIFN/RBV 24 wks = 38% SVR38% SVR
TPV 24 wks + pegIFN 24 wks (no RBV)= 10 TPV 24 wks + pegIFN 24 wks (no RBV)= 10 %SVR%SVR
Control group: pegIFN/RBV 48 wks = 9% SVRControl group: pegIFN/RBV 48 wks = 9% SVR
RESPOND 2: BOC in RESPOND 2: BOC in relapsers and non-relapsers and non-
respondersresponders Control: pIFN/RBV 48wks = 21% SVRControl: pIFN/RBV 48wks = 21% SVR
pIFN/RBV 4wks + BOC/pIFN/RBV 44wks = 66% pIFN/RBV 4wks + BOC/pIFN/RBV 44wks = 66% SVRSVR
Response guided therapy arm:Response guided therapy arm: HCV RNA undetectable at wk 8: pIFN/RBV HCV RNA undetectable at wk 8: pIFN/RBV
4wks + BOC/pIFN/RBV 36wks = 86% SVR4wks + BOC/pIFN/RBV 36wks = 86% SVR
HCV RNA detectable at wk 8, but HCV RNA detectable at wk 8, but undetectable at wk 12: pIFN/RBV 4wks + undetectable at wk 12: pIFN/RBV 4wks + BOC/pIFN/RBV 48wks = 40%BOC/pIFN/RBV 48wks = 40%
Boceprevir and anemiaBoceprevir and anemia Anemia (hgb <10) in up to 43% of patients in Anemia (hgb <10) in up to 43% of patients in
the BOC arm (vs. 24% in control group)the BOC arm (vs. 24% in control group)
Anemia (hgb <8.5) in up to 14% of patients Anemia (hgb <8.5) in up to 14% of patients in the BOC arm (vs. 1% in control group)in the BOC arm (vs. 1% in control group)
Erythropoietin use: 41-46% in BOC arm (vs. Erythropoietin use: 41-46% in BOC arm (vs. 21% in control group)21% in control group) Mean days of EPO use was 130-135 days in BOC Mean days of EPO use was 130-135 days in BOC
armarm Mean days of EPO use was 65 days in control Mean days of EPO use was 65 days in control
groupgroup
HIV/HCV: Telaprevir HIV/HCV: Telaprevir phase IIphase II
TPV/pIFN/RBV 12wks + pIFN/RBV TPV/pIFN/RBV 12wks + pIFN/RBV 36wks36wks
Group 1: not on ART, CD4 Group 1: not on ART, CD4 >>500, HIV VL 500, HIV VL < < 100,000 copies/ml100,000 copies/ml
Group 2: on ART, CD4 Group 2: on ART, CD4 >> 300, HIV VL 300, HIV VL << 50 50 copies/mlcopies/ml
Control: pIFN/RBV x 48wksControl: pIFN/RBV x 48wks
All patients naïve to HCV therapyAll patients naïve to HCV therapy
HIV/HCV: TPV week 12 HIV/HCV: TPV week 12 datadata
Group 1: no ARTGroup 1: no ART 71% had eVR vs. 17% of control71% had eVR vs. 17% of control
Group 2: on ARTGroup 2: on ART Efavirenz based ART: 75 % had eVR vs. Efavirenz based ART: 75 % had eVR vs.
12% of control12% of control Reyataz based ART: 57% had eVR vs. Reyataz based ART: 57% had eVR vs.
12% of control12% of control
HCV protease inhibitors HCV protease inhibitors and ARTand ART
ART groups: chosen b/c they were most ART groups: chosen b/c they were most suitable to be used with telaprevir suitable to be used with telaprevir AtriplaAtripla Reyataz/tenofovir + emtricitabine or Reyataz/tenofovir + emtricitabine or
lamivudinelamivudine
Telaprevir has moderate drug/drug interactions Telaprevir has moderate drug/drug interactions with several antiretroviral agents: with several antiretroviral agents:
Lopinavir/ritonavir (Kaletra)Lopinavir/ritonavir (Kaletra)
Darunavir (Prezista)Darunavir (Prezista)
Fosamprenavir (Lexiva)Fosamprenavir (Lexiva)
HIV/HCV: TPV side HIV/HCV: TPV side effectseffects
No cases of HIV breakthrough in ART No cases of HIV breakthrough in ART groupgroup
CD4 counts did not change significantlyCD4 counts did not change significantly Main side effects:Main side effects:
Nausea 35%Nausea 35% Pruritus 35%Pruritus 35% Dizziness 22%Dizziness 22% Anorexia 19%Anorexia 19% Vomiting 19%Vomiting 19%
Direct acting antivirals in Direct acting antivirals in Clinical testingClinical testing
NS3/4A protease inhibitors (11)NS3/4A protease inhibitors (11) Nucleoside NS5B polymerase Nucleoside NS5B polymerase
inhibitors (3)inhibitors (3) Non-nucleoside NS5B polymerase Non-nucleoside NS5B polymerase
inhibitors (8)inhibitors (8) NS5A inhibitors (2)NS5A inhibitors (2) NS4B inhibitors (1)NS4B inhibitors (1) Entry inhibitors (1)Entry inhibitors (1)