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)