# Presentation: 465115

## Clinical Experience:

**Difficulties in Clinical Trial Design for**
**Therapeutic Products to Treat **
**Chronic HCV Infection**
- John M. Vierling, M.D., F.A.C.P.
- Professor of Medicine and Surgery
- Director of Baylor Liver Health
- Chief of Hepatology
- Baylor College of Medicine
- Houston, TX

## Chronic HCV Infection Ultimate Therapeutic Goals

- HCV as vaccine-preventable disease
- Safe and effective pharmacological cure for acute and chronic HCV infections resulting in:
- Termination of hepatic and extrahepatic disease(s)
- Dissolution of existing hepatic fibrosis
- Reduction in incidence of associated diseases:
- Diabetes mellitus
- Non-Hodgkin B cell lymphoma

## Topic Outline

- Clearance of HCV: Lessons from HCV pathogenesis
- Interferon and ribavirin mechanisms of action in SVR
- Relevance of prior clinical trials in the study of new therapeutic agents
- Selection of patient populations for clinical trials of new agents
- New clinical trials
- Design
- Endpoints

## HCV PathogenesisInfection versus Disease

**HCV**** **

**Hepatocytes**
**Lymphocytes**
**Other Tissues:**
**Pancreas, Adrenal gland, Bone Marrow**

**HCV**

**Not cytopathic **
**for hepatocytes**

**B cells**

**T cells**

**Immune    Response**

**Infects different cells **

**Minimal **
**Fibrosis**

**Advanced**
**Fibrosis**

## Natural History of HCV Infection

**Acute**
**Hepatitis C**

**Spontaneous **
**Resolution**
** ****Anti-HCV+**
** ****RIBA+**
** ****HCV RNA-**

**Cirrhosis**

**Cirrhosis**

******ALT**

******ALT**

**Chronic Infection**
**Anti-HCV+**
**HCV RNA+**

**Biochemical**
**Outcome**
**Histological**
**Outcome**

**85%****	****	****	****	****   ****	****15%**

**75%**

**25%**

**20%**

**2%**

**Key Role for **
**liver biopsy**
**to detect **
**progressive**
**fibrosis**

**Viremia**

**Notes:**
Dr. Rustgi: Could not locate on Medline. Please supply full reference cite.

## Natural History of Hepatitis C CirrhosisAnnual Rates of HCC, Decompensation and Death

**%**

**Natural History of Hepatitis C Cirrhosis****Annual Rates of HCC, Decompensation and Death**

**Notes:**
Dr. Regenstein: Please spell out VH.

## Immunopathogenesis of HCV Infection

**Class II**
**HLA**

**Immunopathogenesis of HCV Infection**
**T Cell Activation to HCV Antigens**

**Immune Response**
**Vigorous**
**Polyclonal**
**Multispecific **

**Class I**
**HLA**

**CD8**

**CD4**

**HCV**
**Core 21-40**
**NS3 1253-1272**
**NS3 1767-1286**
**NS4 1909-1229**

**Antigen****Presenting****Cell**

## Immunopathogenesis o f HCV Infection Dynamic Balance of CD4 T-Helper Cells 

**Immunopathogenesis o f HCV Infection**** ****Dynamic Balance of CD4 T-Helper Cells **

**IL-12**

**TGF ********, IL-10**

**?**

**Greater**
**Immunopathology**

**Lesser**
**Immunopathology**

**Treg**

**Th1**

**Th2**

**IL-2, TNF ********/********, IFN ******

**IL-4, IL-5,********IL-6, IL-10**

**IFN ******

**IL-4**

**APC**

**MHC Class II**

**HCV Peptide Antigen**

**CD4**

**Th0**

**TCR/CD3**

## Immune-Mediated Clearance of HCV

**Immune-Mediated Clearance of HCV**

**CD8**

**TCR**

**Class I MHC**

**HCV-Infected**
**Hepatocyte**

**TNF ******
**IFN ******

**Clearance**
**of Infected**
**Hepatocytes**

**Apoptosis**

**CTL**

**CD8**

## Immune-Mediated Clearance of HCV

**Immune-Mediated Clearance of HCV**

**CD8**

**TCR**

**Class I MHC**

**HCV-Infected**
**Hepatocyte**

**TNF ******
**IFN ******

**Ineffective**
**Clearance**
**of Infected**
**Hepatocytes**

**Apoptosis**

**CTL**

**CD8**

**HCV antagonism**
**promoting viral**
**persistence **

## HCV Therapy with Interferon Dual Mechanisms of Biphasic HCV Kinetics

## HCV InfectionAntiviral Mechanism of Action of Interferon-α

**HCV Infection****Antiviral Mechanism of Action of Interferon-****α**

**Infected**
**Hepatocyte**

**HCV**

**IFN****α**

**IFN****α****-Treated**
**Hepatocyte**

**IFN****α**

**IFN****α**

**IFN****α**

**IFN****α**

**IFN****α**

**IFN****α**

**α****/******

**HCV **
**Replication**

**IFN****α**

**Jak**
**STAT**
**IRF9**

**IFN Regulated **
**Proteins**

**ISGF-3**

**Exogenous IFN****α**

**α****/******

## HCV InfectionAntiviral Mechanisms of Action of Interferon-α

**Protein Kinase **
**PKR**

**eIF-2****α**

**P-eIF-2****α**

**Inhibit mRNA**
**Translation**

**2’,5’OASi**

**2’,5’OASa**

**2’,5’OAA**

**RNase L**

**RNase L**

**Adenosine**
**Deaminase **
**ADAR1**

**RNA**
**Editing**

**RNA Degradation**

**Protein **
**GTPase Mx**

**Target**
**Nucleocapsids**
**+**
**Inhibit RNA**
**Synthesis**

## HCV Infection

**HCV Infection**
**Interferon-******** Effects on NK and Th1 Cells **

**IL-12**

****** ****Immunopathology**
**Fibrogenesis**

****** ****Immunopathology**

**Th1**

**Th2**

**IL-2, TNF ********/********, IFN ******

**IL-4, IL-5,********IL-6, IL-10**

**IFN******

**IL-4**

**Dendritic**
**Cell**

**MHC Class II**

**HCV **
**Antigen**

**CD4**

**Th0**

**TCR/CD3**

**HCV**
**Infected**
**Cells**

**NK**

**IFN******

**HCV Infection?**

## HCV InfectionAntagonism of INFα Effects

**HCV Infection****Antagonism of INF****α**** Effects**

**E1  E2**

**	****NS2****	****NS3****	****NS4****	****NS5**

**5’**

**C**

**3’**

****** ****HCV-Specific**
**CTL**

**Inhibit**
**NK Functions**
**(CD81)**

**Antagonize PKR Functions**
** ****Antiproliferation**
** ****Phosphorylation-eIF-2****α**
** ****Maintenance of cellular proteins**
** ****Apoptosis**

**Notes:**
DESIGN: WHEN DESIGNING THIS, NOTE THAT THE ALIGNMENT OF THE “X”s BELOW SPECIFIC PARS OF THE COLORED SECTIONS OF THE GENOME ABOVE IS IMPORTANT TO MAINTAIN

## HCV InfectionInterferon- Inhibition of Hepatic Fibrosis

**Antifibrotic Mechanisms**
****** ****mRNA Expression:**
** ****TGF-******
** ****Procollagen type I**
** ****Procollagen III**
** ****Procollagen IV**
** ****Serum Levels:**
** ****Procollagen type III peptide**
** ****Hyaluronate**
** ****TIMP-1**
** ****mRNA Expression:**
** ****Collagenase**
** ****MMP **

**Collagen**

**Cytokine-Activated**
**Stellate Cell**

**Fenestratred**
**Endothelial Cells**

**HCV-Infected**
**Hepatocytes**

## ?

**Immune**
**Modulation**

**Anti-Fibrotic**

## HCV Infection Ribavirin Antiviral Mechanisms

**HCV-Infected**
**Hepatocyte**

**HCV **
**Replication**

**IFN Regulated **
**Proteins**

**ISGF-3**

**RBV**

**RTP**

**RDP**

**RMP**

**RBV**

**RTP Inhibition:**
** ****NS5B RNAdRNAp BVDV**
** ****NS5B RNAdRNAp HCV**
**RBV Mutagenic for:**
** ****Poliovirus **
** ****HGV**
**RMP Inhibits IMPDH**
**No Effect of RBV on:**
** ****NS3 protease **
** ****RNA helicase/NTPase**
** ****5’-IRES**

**Purine**
**Synthesis**

**RMP**

**IMPDH**

**purine**
**salvage**

## HCV Infection

**HCV Infection**
**Interaction of Interferon-******** and Ribavirin**

**IL-12**

****** ****Immunopathology**
**Fibrogenesis**

****** ****Immunopathology**
**Fibrogenesis**

**Th1**

**Th2**

**IL-2, TNF ********/********, IFN ******

**IL-4, IL-5,********IL-6, IL-10**

**IFN******

**IL-4**

**MHC Class II**

**HCV **
**Antigen**

**CD4**

**Th0**

**TCR/CD3**

**HCV**
**Infected**
**Cells**

**NK**

**IFN******

**RBV**

**RBV Inhibition**

**TNF********, IL-1******

**Dendritic**
**Cell**

**HCV Infection?**

## HCV Therapy with Interferon RegimensSustained Virological Response (SVR)

**R****esponse **
**to Continued**
**Treatment**

**Adapted from Pawlotsky JM, Hepatology vol. 32, #5, 2000 **

**HCV RNA**

**Initial**
**IFN-Based**
**Treatment**

**	****SVR**
** ****Durable (“cure”)**
** ****212/217 (98%) HCV RNA (-)**
**  ****5/217 (  2%) HCV RNA (+)**
** ****4/5 liver**
** ****1/5 PBMC**

**LLD**

**Notes:**
Patterns in resistance to therapy has led researchers to classify patients according to a least 3 distinct patterns:
Nonresponders-This is a group of patients defined as having no decrease in viral load from baseline levels through the maintenance phase of therapy
Breakthrough-This is a group of patients who achieve HCV RNA negativity but lose response while on therapy.  This is most likely due to sub-optimal suppression on the virus
Relapsers-This is a group of patients who achieve HCV RNA negativity during therapy but lose response once the virus is no longer suppressed by therapy
The two drugs currently used in the treatment of HCV, interferon alfa and ribavirin, have complex and indirect actions, making the mechanisms of HCV resistance generally different from those of viral resistance to specific antiviral agents.  Treatment of chronic HCV is aimed at cure.  IFNs are natural cellular proteins with various actions, including induction of an antiviral state in their target cells and cytokine secretion, recruitment of immune cells, and induction of cell differentiation.  After subcutaneous administration, IFN- is specifically fixed onto high-affinity receptors at the surface of target cells. IFN-receptor fixation triggers a cascade of intracellular reactions leading to activation of numerous IFN-inducible genes.  The products of these genes are the mediators of the various cellular actions of IFN .  They are responsible for the antiviral effects of IFN- through two distinct but complementary mechanisms: the induction of an antiviral state not specific to the virus in infected cells, which results in a direct inhibition of HCV replication; also, induction of immunomodulatory effects that enhance specific anti-HCV immune responses of the host.   Ribavirin is a synthetic guanosine analogue used principally in the past for the treatment of severe respiratory syncitial virus infections in infants. Given alone, ribavirin has not proved to be efficient in chronic HCV infection.  When added to IFN , ribavirin increases the initial response, i.e., the ratio of patients who clear HCV RNA during therapy, and markedly reduces relapse rates in these patients.  The mechanisms underlying these effects are not yet fully understood.  Ribavirin selectively inhibits viral RNA polymerases in vitro. It has been reported to inhibit in vitro the replication of bovine viral diarrhea virus, a pestivirus close to HCV, and to synergize the antiviral effect of IFN  in this model.  Ribavirin also appears to potentiate the immunomodulatory properties of IFN . The underlying mechanisms are poorly known. It has been suggested that ribavirin could alter the Th1/Th2 balance by causing a shift towards Th1 responses.   The greater efficacy of combination therapy with IFN  plus ribavirin might also be related to ribavirin ability to suppress HCV-specific IL-10 production.

## HCV Therapy with Interferon RegimensFour Patterns of Non-Response

**“****Breakthrough”**

**Relapse**

**“****Non-response”**

**R****esponse **
**to Continued**
**Treatment**

**Adapted from Pawlotsky JM, Hepatology vol. 32, #5, 2000 **

**HCV RNA**

**Initial**
**IFN-Based**
**Treatment**

**“****Nonresponse”**
**Based on EVR**

**LLD**

**Notes:**
Patterns in resistance to therapy has led researchers to classify patients according to a least 3 distinct patterns:
Nonresponders-This is a group of patients defined as having no decrease in viral load from baseline levels through the maintenance phase of therapy
Breakthrough-This is a group of patients who achieve HCV RNA negativity but lose response while on therapy.  This is most likely due to sub-optimal suppression on the virus
Relapsers-This is a group of patients who achieve HCV RNA negativity during therapy but lose response once the virus is no longer suppressed by therapy
The two drugs currently used in the treatment of HCV, interferon alfa and ribavirin, have complex and indirect actions, making the mechanisms of HCV resistance generally different from those of viral resistance to specific antiviral agents.  Treatment of chronic HCV is aimed at cure.  IFNs are natural cellular proteins with various actions, including induction of an antiviral state in their target cells and cytokine secretion, recruitment of immune cells, and induction of cell differentiation.  After subcutaneous administration, IFN- is specifically fixed onto high-affinity receptors at the surface of target cells. IFN-receptor fixation triggers a cascade of intracellular reactions leading to activation of numerous IFN-inducible genes.  The products of these genes are the mediators of the various cellular actions of IFN .  They are responsible for the antiviral effects of IFN- through two distinct but complementary mechanisms: the induction of an antiviral state not specific to the virus in infected cells, which results in a direct inhibition of HCV replication; also, induction of immunomodulatory effects that enhance specific anti-HCV immune responses of the host.   Ribavirin is a synthetic guanosine analogue used principally in the past for the treatment of severe respiratory syncitial virus infections in infants. Given alone, ribavirin has not proved to be efficient in chronic HCV infection.  When added to IFN , ribavirin increases the initial response, i.e., the ratio of patients who clear HCV RNA during therapy, and markedly reduces relapse rates in these patients.  The mechanisms underlying these effects are not yet fully understood.  Ribavirin selectively inhibits viral RNA polymerases in vitro. It has been reported to inhibit in vitro the replication of bovine viral diarrhea virus, a pestivirus close to HCV, and to synergize the antiviral effect of IFN  in this model.  Ribavirin also appears to potentiate the immunomodulatory properties of IFN . The underlying mechanisms are poorly known. It has been suggested that ribavirin could alter the Th1/Th2 balance by causing a shift towards Th1 responses.   The greater efficacy of combination therapy with IFN  plus ribavirin might also be related to ribavirin ability to suppress HCV-specific IL-10 production.

## Chronic HCV InfectionGenotype Distribution in the U.S.A.  (N = 6807) 

- Blatt LM, et al, J. Viral Hepatitis*.* 2000;(3):196-202.

**Notes:**
DR. BLATT: SUGGEST DELETING

DR. BLATT: SUGGEST DELETING THIS SLIDE.
IF KEEPING, NOTE: COULD NOT LOCATE REFERENCE ON MEDLINE. IF POSSIBLE, PLEASE ADD FULL CITE.

## HCV Therapeutic TrialsLiver Biopsy Stratification and as Endpoint 

- Assessment:
-  Grade: Inflammation
-  Stage:  Fibrosis (1-4)
-  Significant change >1 or 2?
- Caveats:
-  Adequate specimens required:
-  8-10 portal tracts
-  16 gauge needle
-  Aspiration biopsy better than “gun”
-  Optimal timing of before and after
-    comparison (6-18 months):
-  T1/2 inflammatory infiltrates
-  Conversion from fibrogenesis to
-          collagenase activity

## Non-Response to HCV TherapyRelated to Combination of Viral and Host Factors

- 0

- 20

- 40

- 60

- 80

- 100

**Genotype**

**Viral Load**

**Weight (kg)**

**Fibrosis**

**SVR (%)**

**Data from:****Manns MP et al. Lancet. 2001;358:958.**
**Fried MW et al. N Engl J Med. 2002;347:975.**
**FDA Antiviral Drug Products Advisory Committee, 2002.**

**79**

**45**

**70**

**47**

**62**

**41**

**57**

**44**

**2/3**

**1**

**Lo**

**Hi**

**<75**

**>75**

**F0/1**

**F3/4**

**11**

**55**

**30**

**53**

**48**

**59**

**43**

**56**

## Interferon-Ribavirin for Chronic HCV InfectionEVR Predicts Probability of SVR

**Interferon-Ribavirin for Chronic HCV Infection****EVR Predicts Probability of SVR**

## Therapy for Chronic HCV InfectionResponse Predicted by Adherence

## Interferon-Ribavirin for Chronic HCV InfectionDifferences in SVR for African Americans and Caucasians

**Conjeevaram HS, et al. Gastroenterology 2006; 131: 470-7**

## HCV-HIV Co-InfectionAdverse Effect on Survival

## HCV-HIV Co-Infection

- Reviewed in: Stribling R, et al. Gastro Clin NA 2006; 35: 463-86.

**HCV-HIV Co-Infection**
**Decreased Response to Interferon-Ribavirin Therapy**

## Recurrent HCV Infection Post-OLTAccelerated Progression and Increased Mortality

**Forman LM et al. Gastroenterology 2002; 122: 889-96**

**Braun M and Vierling JM. Liver Transpl 2003; 9: S79-S89**

## Candidates for Clinical Therapeutic Trials

**Treatment-naïve patients at risk for progression***
- Chronic HCV infection with detectable HCV RNA
- Elevated ALT
- Active inflammation by liver biopsy
- Absence of contraindications
**Treatment-experienced patients not achieving SVR:**
- Relapsers from ETR
- Non-responders discontinued due to absence of EVR
- Non-responders with absence of any virological response
- Non-responders with breakthrough after EVR
**Special populations:**
- Children
- Co-infection with HIV or HBV
- Decompensated cirrhosis
- OLT Patients
- Pre-OLT
- Recurrent hepatitis C post-OLT
- Extrahepatic diseases

***2002 NIH HCV Consensus Conference, Hepatology 2002**

## Candidates for Clinical Therapeutic TrialsPriority Ranking

**Treatment-naïve patients at risk for progression**
- Chronic HCV infection with detectable HCV RNA
- White, Black, Latino
- Elevated ALT
- Stratified on basis of
- Genotype: 1, 2, 3 highest priority due to frequency in U.S.A.
- Histopathology
- Grades 1-4
- Stage 0-4
**Treatment-experienced patients not achieving SVR**
- Non-responders documented at 12, 24 or 48 wks of therapy
- Relapsers with documented ETR
- White, Black, Latino
**Special populations**
- Co-infection with HIV > HBV: Treatment-naïve or -experienced
- Decompensated cirrhotics
- Orthotopic liver transplantation
- Pre-OLT
- Recurrent hepatitis C post-OLT
- Chronic renal failure

## Candidates for Clinical Therapeutic TrialsStudy Design

**Treatment-naïve patients at risk for progression**
- Proof of short-term monotherapy effect:  Log10 HCV RNA)
- Assessment of resistance to short-term monotherapy
- Randomized, placebo controlled trial for superiority, non-inferiority
- PEG-IFN + RBV + Active Drug
- PEG-IFN + RBV + Placebo
- Genotypes:
- 1: 48 wk
- 2: 24 wk
- 3: 24 wk
- Assess HCV RNA at wks 4, 12, 24, 48, 60, 72
- Compare AEs-SAEs in Placebo vs Active Drug Groups
**Endpoints**
- Primary: SVR at post-treatment wk 12 and 24
- Secondary:
- Normalization of ALT
- Improvement of histological Grade and/or Stage wk 72

## Candidates for Clinical Therapeutic TrialsStudy Design

**Treatment-Experienced patients not achieving SVR**
- Proof of short-term monotherapy effect:  Log10 HCV RNA
- Assessment of resistance to short-term monotherapy
- Randomized, placebo controlled trial for superiority
- PEG-IFN + RBV + Active Drug
- PEG-IFN + RBV + Placebo
- Genotypes: 1, 2, 3  treatment for 48 wk
- Assess HCV RNA at wks 4, 12, 24, 48, 60, 72
- Compare AEs-SAEs in Placebo vs Active Drug Groups
**Endpoints**
- Primary: SVR at post-treatment wk 12 and 24
- Secondary:
- Normalization of ALT
- Improvement of histological Grade and/or Stage wk 72

## Candidates for Clinical Therapeutic TrialsSpecial Populations Study Design

**Co-infected HIV: Treatment-naïve**
- Proof of short-term monotherapy effect in HCV-HIV:  Log10 HCV RNA
- Proof of short-term safety, absence drug interactions with HAART
- Stable HAART without hepatotoxicity
- CD4 T cells count stable: 200 mm3
- Elevated ALT
- Stratified on basis of
- Genotype: 1, 2, 3
- Histopathology
- Grades 1-4
- Stage 0-4
- Randomized, Placebo Controlled Trial of superiority
- PEG-IFN + RBV + Active Drug
- PEG-IFN + RBV + Placebo
- Treatment for 48 wks
- Assess HCV RNA at wks 4, 12, 24, 48, 60, 72
- Compare AEs-SAEs in Placebo vs Active Drug Groups

**Endpoints**
-   Primary: SVR at post-treatment wk 12 and 24
-   Secondary:
-   Normalization of ALT
-   Improvement of histological Grade and/or Stage wk 72

## Candidates for Clinical Therapeutic TrialsSpecial Populations Study Design

**Decompensated Cirrhotics (Listed for OLT)**
- Proof of short-term monotherapy effect:  Log10 HCV RNA
- Proof of short-term safety in cirrhosis
- Stable therapy for complications of portal hypertension
- No hypervascular hepatic lesions on imaging with contrast
- CBC: Hgb  12 g/dL; WBC  3,000 mm3, ANC  1,500 mm3, Plt  70,000
- Elevated ALT
- Stratified on basis of genotype: 1, 2, 3
- Randomized, Placebo Controlled Trial of superiority
- PEG-IFN **+** RBV + Active Drug (half dose PEG-IFN?)
- PEG-IFN + Active Drug (RBV substitution)
- PEG-IFN **+** RBV + Placebo
- PEG-IFN + Placebo
- Treatment for 48 wks
- Assess HCV RNA at wks 4, 12, 24, 48, 60, 72
- Compare AEs-SAEs in Placebo vs Active Drug Groups

**Endpoints**
-   Primary: SVR at post-treatment wk 12 and 24
-   Secondary:
-   Normalization of ALT
-   Improvement in MELD (15)-CTP (7) scores, synthetic function, manifestations
-     of decompensation, transplant-free survival
-  Absence of HCC on long-term follow-up

## Candidates for Clinical Therapeutic TrialsSpecial Populations Study Design

**Recurrent HCV Infection Post-OLT**
- Proof of short-term monotherapy effect:  Log10 HCV RNA
- Proof of short-term safety in immunosuppressed OLT recipients
- Assessment of drug interactions with immunosuppressive and prophylactic drugs
- CBC: Hgb  12 g/dL; WBC  3,000 mm3, ANC  1,500 mm3, Plt  70,000
- Elevated ALT
- Biopsy:
- Grade and Stage assessment
- Exclusion of ACR or CR
- Genotype 1
- Randomized, Placebo Controlled Trial of superiority
- PEG-IFN **+** RBV + Active Drug (Low dose PEG-IFN?)
- PEG-IFN + Active Drug (RBV substitution)
- PEG-IFN **+** RBV + Placebo
- PEG-IFN + Placebo
- Treatment for 48 wks
- Assess HCV RNA at wks 4, 12, 24, 48, 60, 72
- Compare AEs-SAEs in Placebo vs Active Drug Groups

**Endpoints**
-   Primary: SVR at post-treatment wk 12 and 24
-   Secondary:
-   Normalization of ALT
-   Improvement in histological grade and/or stage

## Candidates for Clinical Therapeutic TrialsSpecial Populations Study Design

**Chronic Renal Failure on Dialysis:**
- Proof of short-term monotherapy effect:  Log10 HCV RNA
- Proof of short-term safety in dialysis patients
- Assessment of effect of dialysis on drug levels
- CBC: Hgb  12 g/dL; WBC  3,000 mm3, ANC  1,500 mm3, Plt  70,000
- Elevated ALT
- Biopsy: Grade and Stage assessment
- Genotype 1, 2, or 3
- Randomized, Placebo Controlled Trial of superiority
- PEG-IFN **+** Active Drug (RBV substitution)
- PEG-IFN **+** Placebo
- Treatment for 48 wks
- Assess HCV RNA at wks 4, 12, 24, 48, 60, 72
- Compare AEs-SAEs in Placebo vs Active Drug Groups

**Endpoints**
-   Primary: SVR at post-treatment wk 12 and 24
-   Secondary:
-   Normalization of ALT
-   Improvement in histological grade and/or stage at wk 72

## Chronic HCV InfectionClinical Therapeutic Trials of Two or More Agents  

**Rationale:**
- Potentially eliminate need for IFN and/or RBV
- Retard or prevent HCV resistance (Model of HAART for HIV)
- Possible AE and SAE profile favorable for chronic treatment
**Primary endpoints)**
- Sustained virological response (post-therapy)
- Sustained virological suppression (chronic therapy)
**Secondary endpoints**
- Improved histopathology
- Prevention of disease progression
- Reduced incidence of hepatocellular carcinoma
- Improved health-related quality of life

## Chronic HCV InfectionOld versus New Paradigms of Treatment  

- Concerns regarding selection of patients for HCV therapy reminiscent of those regarding the use of arsenicals for the treatment of syphilis due to the variable efficacy and frequency of AEs and SAEs.
- Once penicillin proved to be safe and efficacious, therapy offered to all, regardless of prior selection criteria.
- When will similar success be achieved in HCV infection?