The Frontier of Research The Frontier of Research Advocacy: Advocacy:

Hepatitis C Drug Hepatitis C Drug DevelopmentDevelopment

HIV Research Catalyst ForumHIV Research Catalyst Forum

Michael Carden, SUNY Michael Carden, SUNY Downstate/CornellDownstate/Cornell

Tracy Swan, Treatment Action GroupTracy Swan, Treatment Action Group

OverviewOverview• HCV & HIV/HCV: US Epi--who has it? HCV & HIV/HCV: US Epi--who has it?

• Natural history of HCV and HIV/HCV-what Natural history of HCV and HIV/HCV-what happens to people with HCV and HIV/HCV?happens to people with HCV and HIV/HCV?

• Current standard of care for hepatitis C: how Current standard of care for hepatitis C: how well well

does it work, what are the side effects?does it work, what are the side effects?

• The future of HCV treatment--what’s next? The future of HCV treatment--what’s next?

• Activist checklist--what do you think?Activist checklist--what do you think?

True or False?True or False?• One phase II HCV treatment trial excluded One phase II HCV treatment trial excluded African AmericansAfrican Americans

• People who are using drugs are usually People who are using drugs are usually eligible to participate in HCV clinical eligible to participate in HCV clinical trials of new drugs, as long as they show up trials of new drugs, as long as they show up for study visitsfor study visits

• People with cirrhosis (serious liver People with cirrhosis (serious liver scarring) are excluded from HCV clinical scarring) are excluded from HCV clinical trials until the drugs are approvedtrials until the drugs are approved

• All pre-approval HCV treatment trials have All pre-approval HCV treatment trials have excluded HIV/HCV coinfected peopleexcluded HIV/HCV coinfected people

HCV in the USHCV in the US 1.8% of the US population (4 to 5 million people) 1.8% of the US population (4 to 5 million people) has been infected has been infected with HCV, and ~3.3 million people are with HCV, and ~3.3 million people are chronically infectedchronically infected

Armstrong et al; Ann Intern Med 2006; Edlin; AASLD 2005; Sulkowski et a; JAMA 2002

~300,000 people ~300,000 people In the USIn the US

are HIV/HCV are HIV/HCV coinfectedcoinfected

HCV Prevalence HCV Prevalence (US)(US)

General General populationpopulation

1.6%1.6%White: 1.5%White: 1.5%

African American: 3%African American: 3%African American Males, African American Males, 50-59 years of age: 13.6%50-59 years of age: 13.6%

Veterans(esp. Vietnam) : ~20%Veterans(esp. Vietnam) : ~20%HIV + people: 25-30%HIV + people: 25-30%Homeless people: ~40%Homeless people: ~40%

Current & former IDU: up to 90%Current & former IDU: up to 90% People who received pre-1987 clotting factor: up to 95%People who received pre-1987 clotting factor: up to 95%

Why is HCV a Problem?Why is HCV a Problem?HCV enters the bloodstream, & HCV enters the bloodstream, & infects liver cellsinfects liver cells

HCV becomes chronic (lifelong) HCV becomes chronic (lifelong) in 55-85% of people who get itin 55-85% of people who get it

The hepatitis C virus does not The hepatitis C virus does not not damage the liver; scarring is not damage the liver; scarring is caused when the immune system caused when the immune system responds to the virus by walling responds to the virus by walling

off off infected liver cells infected liver cells

15 to 50 years later, serious 15 to 50 years later, serious liverliver

scarring (scarring (cirrhosis), cirrhosis), develops in develops in 20-20-

30% of people with chronic HCV30% of people with chronic HCV

Range of HCV Outcomes,Range of HCV Outcomes,Over DecadesOver Decades

• No symptoms, no liver damage No symptoms, no liver damage

• Symptoms (fatigue & depression) & some liver damageSymptoms (fatigue & depression) & some liver damage

• Fat in the liver (steatosis)Fat in the liver (steatosis)

• Liver scarring (fibrosis)Liver scarring (fibrosis)

• Serious liver scarring, making it difficult for the Serious liver scarring, making it difficult for the liver to function, calledliver to function, called cirrhosis cirrhosis (20-30%) (20-30%)

• Liver cancer (1% to 5% of people with cirrhosis per Liver cancer (1% to 5% of people with cirrhosis per year)year)

Liver failure (3% to 4% of people with cirrhosis per Liver failure (3% to 4% of people with cirrhosis per year)year)

HCV Progression: HCV Progression: CofactorsCofactors

• HIV coinfectionHIV coinfection

• Age >40 at time of infectionAge >40 at time of infection

• Insulin resistance, obesity, Insulin resistance, obesity, steatosissteatosis

• Aging/duration of HCV infectionAging/duration of HCV infection

• Chronic HBV infectionChronic HBV infection

• MaleMale

HCV & HCV & AlcoholAlcoholAlcohol accelerates HCVAlcohol accelerates HCV

progression, especially progression, especially >50>50

grams/daygrams/day

Safe amount? Safe amount?

Cutting down or quittingCutting down or quittingmay be more important may be more important

than than HCV treatment for HCV treatment for some peoplesome people

Many physicians won’t Many physicians won’t treat drinkers, biased by treat drinkers, biased by

data data from old studiesfrom old studies

Goal of HCV Treatment Goal of HCV Treatment

Is……to get rid of the virus, Is……to get rid of the virus, permanently, permanently, an outcomean outcome

called SVRcalled SVR

SVRSVR (sustained virological response), meaning that (sustained virological response), meaning that

no HCV is detected in the blood 6 months after HCVno HCV is detected in the blood 6 months after HCV

treatment completion)treatment completion)

SVRSVR is durable (>10 years), and reduces liver-related is durable (>10 years), and reduces liver-related

Illness and death, regardless of HIV statusIllness and death, regardless of HIV status

Barreiro et al; Antiviral Ther 2006; Lau et al; Hepatology 1998; Maylin et al; Gastroenterology

2008; Vedt et al; Ann Intern Med 2007; Yu et al; Antivir The 2006

How Does HCV How Does HCV Treatment Work?Treatment Work?

HCV treatment works in 2 ways:HCV treatment works in 2 ways:

By killing infected cells By killing infected cells ((immunologic effectimmunologic effect))

By blocking viral By blocking viral replication, to protect replication, to protect uninfected cells from HCV uninfected cells from HCV ((anti-viral effectanti-viral effect))

Successful HCV Successful HCV treatment rapidly—& treatment rapidly—& completely —suppresses completely —suppresses the virus, & keeps it the virus, & keeps it suppressed throughout suppressed throughout the course of treatment the course of treatment (12-72 weeks)(12-72 weeks)

Get Get Down, Down, & Stay & Stay Down!Down!

HCV: Current HCV: Current SOCSOC

Peg Intron Peg Intron pegylated interferon alfa 2bpegylated interferon alfa 2b

dosed by weightdosed by weightSchering PloughSchering Plough / / MerckMerck

Pegasyspegylated interferon alfa 2a

flat dosingHoffman La Roche

Ribavirin dosed by weightgeneric

Drugs: Drugs: Pegylated interferon & ribavirinPegylated interferon & ribavirinDuration: Duration: 12 to 72 weeks12 to 72 weeksEfficacy: Efficacy: ~50%, depends on several ~50%, depends on several factorsfactorsSide effects: Side effects: NASTY!NASTY!

Interferon Interferon (IFN)(IFN)Interferon Interferon is a synthetic version of a chemical is a synthetic version of a chemical

messenger messenger made by the human body; it stimulates the immune system made by the human body; it stimulates the immune system & fights viruses& fights viruses

Pegylated Interferon (PEG-IFN) Pegylated Interferon (PEG-IFN) is the standard of care is the standard of care

Pegylation Pegylation means thatmeans that a small molecule has beena small molecule has beenattached to interferon to keep it in the body longer & attached to interferon to keep it in the body longer & make it more effectivemake it more effective

PegylatedPegylated interferoninterferon is injected 1 X per week; old- is injected 1 X per week; old-school school

interferon was injected 3 X per week (sometimes even 1 interferon was injected 3 X per week (sometimes even 1 X X

per day) per day)

Side Effects of Side Effects of IFNIFNFlu-likeFlu-like

(fever, aches, nausea, appetite loss, (fever, aches, nausea, appetite loss, weakness, & weakness, &

fatigue)fatigue)Lab AbnormalitiesLab Abnormalities (anemia, neutropenia, thrombocytopenia)(anemia, neutropenia, thrombocytopenia)NeuropsychiatricNeuropsychiatric(s(suicidal ideation/suicide (rare), uicidal ideation/suicide (rare), depression,depression,

insomnia, anxiety, irritability, mood insomnia, anxiety, irritability, mood swings, mania,swings, mania,

psychosis)psychosis)OtherOther(hair loss, optic nerve damage)(hair loss, optic nerve damage)

Ribavirin (RBV)Ribavirin (RBV)• Pill or capsule, taken 2 X a dayPill or capsule, taken 2 X a day

• Same family (NRTI) as some HIV Same family (NRTI) as some HIV drugs but it does not work drugs but it does not work against HIVagainst HIV

• RBV dosing is based on weightRBV dosing is based on weight

• There are interactions between There are interactions between RBV and some HIV drugsRBV and some HIV drugs

RBV Side RBV Side EffectsEffects

Anemia: major, sometimes treatment-limiting side effect

Cardiac events

Shortness of breath, coughing

Itchy skin/rash

May also cause depression, irritability

HCV Treatment EfficacyHCV Treatment Efficacy(how well does it work?)(how well does it work?)Data from clinical trials; 24- 48 weeks of PEG-Data from clinical trials; 24- 48 weeks of PEG-

IFN + RBV IFN + RBV (all treatment naïve; by genotype and HIV status)(all treatment naïve; by genotype and HIV status)

SVR,overall

SVR, genotype 1

SVR, genotype 2 & 3

HIV/HCV coinfected

27% to 44% 14% to 38% 53% to 73%

HCV alone

56% to 61% 42% to 44% 70% to 82%

(Carrat et al; JAMA 2004; Chung et al: NEJM 2004; Fried et al; NEJM 2002; Manns et al; Lancet 2001; Laguno et al; AIDS 2004; Torriani et al; NEJM 2004)

HCV Treatment in African HCV Treatment in African Americans & Latino/asAmericans & Latino/as SVR, SVR, SVR, SVR, SVR, SVR,

Study Study African American African American Latino/a WhiteLatino/a WhiteMuir, et al; NEJM 2004 Muir, et al; NEJM 2004 19%19% 52%52%

Rodriguez-Torres et al; Rodriguez-Torres et al; NEJM 2009 NEJM 2009

34%34% 49%49%

Conjeevaram et al; Conjeevaram et al; Gastroenterology 2006Gastroenterology 2006

28%28% 52%52%

Jeffers et al; Jeffers et al; HepatologyHepatology20042004

26%26% 39%39%

Muir et al; AASLD Muir et al; AASLD 2008* 2008*

44% 44% 65%65% 62% 62%

* plus an HCV protease inhibitor* plus an HCV protease inhibitor

HCV TX Response: HCV TX Response: Prognostic FactorsPrognostic Factors

PretreatmentPretreatment Genetics (IL-28b CC vs. TT) Genetics (IL-28b CC vs. TT) Hepatitis C genotype Hepatitis C genotype (2,3,4,1) (2,3,4,1) & subtype (1b vs 1a)& subtype (1b vs 1a) Race Race (Asian> White > Latino/a> AA)(Asian> White > Latino/a> AA) HCV RNA<400,000HCV RNA<400,000 HIV status (not CD4 count HIV status (not CD4 count or HIV RNA)or HIV RNA) Liver damage/steatosisLiver damage/steatosis BMIBMI Insulin resistance, diabetes Insulin resistance, diabetes

On TreatmentOn TreatmentSupportEnduranceAggressive side effects managementWBD of ribavirinEarly response to TXAdequate TX duration

Adherence (80/80/80)

Population-Population-Specific IssuesSpecific Issues

Treatment Naïve VS. Treatment Treatment Naïve VS. Treatment ExperiencedExperienced

• More than one type of experience: null response, More than one type of experience: null response, non-response, viral breakthrough, relapsenon-response, viral breakthrough, relapse

• Response to retreatment better for some treatment Response to retreatment better for some treatment experienced groups (relapsers>breakthrough experienced groups (relapsers>breakthrough >non-responder>null responder)>non-responder>null responder)

What was original treatment regimen, duration, What was original treatment regimen, duration, dose, & how were side effects managed?dose, & how were side effects managed? (Shiffman; Hepatology 2002)(Shiffman; Hepatology 2002)

The CandidatesThe Candidates HCV protease inhibitors HCV protease inhibitors HCV polymerase inhibitorsHCV polymerase inhibitors NS5a inhibitorsNS5a inhibitors Cyclophilin inhibitors Entry inhibitorsEntry inhibitors MicroRNAMicroRNA NitazoxanideNitazoxanide ImmunomodulatorsImmunomodulators Novel InterferonsNovel Interferons Monoclonal AntibodiesMonoclonal Antibodies Therapeutic VaccinesTherapeutic Vaccines Milk ThistleMilk Thistle Anti-fibrotic AgentsAnti-fibrotic Agents

The Big Question(s)The Big Question(s)Will antiviral therapy cure HCV Will antiviral therapy cure HCV without an immune-based therapy? without an immune-based therapy?

Will it work for everyone? Will it work for everyone?

If so, how long will it take? If so, how long will it take? -may differ by population & -may differ by population & individual individual factorsfactors

What are the least risky, most What are the least risky, most efficient ways to answer these efficient ways to answer these questions?questions?

2010 Landscape2010 LandscapeHCV clinical trialsHCV clinical trials

(phase 1, 2 and 3) in(phase 1, 2 and 3) in monoinfected monoinfected

(TX naïve & TX experienced)(TX naïve & TX experienced)peoplepeople

people add a single people add a single antiviral to SOCantiviral to SOC

HCV clinical trials in HCV clinical trials in HIV/HCVHIV/HCV

coinfectedcoinfected (TX naïve) (TX naïve) peoplepeople

a single a single HCV antiviral +HCV antiviral + SOCSOC

HCV clinical trials in HCV monoinfected (TX naïve & TX experienced)people with 2 oral antivirals, with or without SOC

HCV Trial Design HCV Trial Design IssuesIssues

Drug-drug interactions (especially for HIV+ people)Drug-drug interactions (especially for HIV+ people)

Overlapping safety issues (ANEMIA, RASH)Overlapping safety issues (ANEMIA, RASH)

Confusing dosing (tid + bid)Confusing dosing (tid + bid) Design of trials and control arms as SOC continues to Design of trials and control arms as SOC continues to evolve, especially for treatment experienced peopleevolve, especially for treatment experienced people

Will/should stopping rules change?Will/should stopping rules change?

What role will genetics have? What role will genetics have?

HCV Replication & HCV Replication & MutationMutation • Hepatitis C makes Hepatitis C makes billions billions of of

copies each day, called virionscopies each day, called virions

• These virions are not identical; These virions are not identical; some have changes in the genetic some have changes in the genetic structure of the virus, called structure of the virus, called mutationsmutations

• Mutations in viral enzymes occur Mutations in viral enzymes occur randomlyrandomly

• Some mutations make it harder for Some mutations make it harder for the virus to reproduce; others can the virus to reproduce; others can stop drugs from workingstop drugs from working

• HCV mutations that cause resistance HCV mutations that cause resistance to the new antiviral drugs are to the new antiviral drugs are present in many people who have present in many people who have never taken themnever taken them

HCV ReplicationHCV Replication

Drug ResistanceDrug Resistance the ability the ability of an organism to of an organism to

grow in the grow in the presence of apresence of a

drug that drug that would normally would normally

kill it or limit kill it or limit its growth; drug its growth; drug resistance can resistance can

developdevelopor emerge within or emerge within

daysdays

With HCV, no one knows With HCV, no one knows how long resistance how long resistance

mutations will last, and mutations will last, and if they will compromise if they will compromise

future TX optionsfuture TX options

Drug Levels & Drug Levels & ResistanceResistance

HCV Protease HCV Protease InhibitorsInhibitors

Resistance: cross-resistance is a problem, Resistance: cross-resistance is a problem, resistance emerges / develops within days & resistance emerges / develops within days & can still be can still be

found years later; long-term consequences found years later; long-term consequences unclearunclear

Activity may be genotype-specificActivity may be genotype-specific

More side effects (rash, GI) and cost!More side effects (rash, GI) and cost!All of the HCV protease inhibitors may All of the HCV protease inhibitors may cause anemiacause anemia

Different treatment strategies/ durations Different treatment strategies/ durations for each drug, makes comparison difficultfor each drug, makes comparison difficult

In the ClinicIn the Clinic Phase IIIPhase III

• Boceprevir (Merck/Schering-Plough) 3X Boceprevir (Merck/Schering-Plough) 3X dayday

• Telaprevir (Vertex/Tibotec) 3X day, Telaprevir (Vertex/Tibotec) 3X day, possibly possibly

2X day2X dayPhase IPhase I Phase IIPhase II

ABT 450*ABT 450*ACH 1625ACH 1625IDX 316IDX 316MK 5172MK 5172 PHX 1766PHX 1766VX 813 VX 813

BI 201355BI 201355BMS-650032BMS-650032CTS 1027CTS 1027MK 7009MK 7009RG7227*RG7227*TMC435350TMC435350

*studied with low-dose ritonavir

HCV Polymerase HCV Polymerase InhibitorsInhibitors

Toxicity has been an issueToxicity has been an issue Nucleoside/nucleotideNucleoside/nucleotide: Active against all HCV : Active against all HCV genotypes, genotypes,

high genetic barrier/ resistance less likelyhigh genetic barrier/ resistance less likely

Non-nucleosides: Non-nucleosides: Genotype-specific, Genotype-specific, resistance-proneresistance-prone

Phase IIPhase II

IDX 184IDX 184 , PSI 7851 , PSI 7851, RG7128, RG7128

Phase IPhase I Phase IIPhase IIAA-837093, ABT 072 AA-837093, ABT 072

BI-207127, BMS-824393 ,BI-207127, BMS-824393 ,

GSK625433, IDX 375,GSK625433, IDX 375,

MK-3281, VCH/VX 759MK-3281, VCH/VX 759

ABT 333, ANA 598, GS9190ABT 333, ANA 598, GS9190

PF-868,554PF-868,554

RO5024048 RO5024048

VCH/VTX 222VCH/VTX 222

NS5a Inhibitors: Potent,

PROMISINGA-832 and BMS 790052 are in Phase IIA-832 and BMS 790052 are in Phase II

Combination TrialsCombination TrialsRoche/Genentech INFORM-3 Roche/Genentech INFORM-3 (HCV (HCV protease + HCV polymerase)protease + HCV polymerase) Delayed, Delayed, dosing issues dosing issues BMSBMS: pairing BMS-650032 (a protease : pairing BMS-650032 (a protease inhibitor)inhibitor) with 790052 ( an NS5a inhibitor) with 790052 ( an NS5a inhibitor) in null responders: Openin null responders: Open

Vertex:Vertex: pairing telaprevir (a pairing telaprevir (a protease inhibitor)protease inhibitor)with VX 222 (a polymerase with VX 222 (a polymerase inhibitor) inhibitor) Open soonOpen soon

HCV TX Trials in HCV TX Trials in HIV/HCV Coinfected HIV/HCV Coinfected

PeoplePeople•Two HCV protease inhibitors Two HCV protease inhibitors trials in HIV/HCV coinfected trials in HIV/HCV coinfected people open in US/Europepeople open in US/Europe (boceprevir and telaprevir) (boceprevir and telaprevir)

•Nitazoxanide in US onlyNitazoxanide in US only

What do You Think?What do You Think?CRAPPYVIR: Big study planned

No women No methadone / buprenorphine use

Drug testingNo HIV+ people

No psych meds or history of depression, etc

Trial in HIV+ NO ARVs

Must have >500 CD4 cellsNo cirrhosis