The Frontier of Research
Advocacy:
Hepatitis C Drug Development
HIV Research Catalyst Forum
Michael Carden, SUNY Downstate/Cornell
Tracy Swan, Treatment Action Group
Overview
• HCV & HIV/HCV: US Epi--who has it?
• Natural history of HCV and HIV/HCV-what
happens to people with HCV and HIV/HCV?
• Current standard of care for hepatitis C: how well
does it work, what are the side effects?
• The future of HCV treatment--what’s next?
• Activist checklist--what do you think?
True or False?
• One phase II HCV treatment trial excluded African
Americans
• People who are using drugs are usually eligible to
participate in HCV clinical trials of new drugs, as
long as they show up for study visits
• People with cirrhosis (serious liver scarring) are
excluded from HCV clinical trials until the drugs are
approved
• All pre-approval HCV treatment trials have
excluded HIV/HCV coinfected people
HCV in the US
1.8% of the US population (4 to 5 million people) has been infected
with HCV, and ~3.3 million people are chronically infected
~300,000 people
In the US
are HIV/HCV coinfected
Armstrong et al; Ann Intern Med 2006; Edlin; AASLD 2005; Sulkowski et a; JAMA 2002
HCV Prevalence (US)
General
population
1.6%
White: 1.5%
African American: 3%
African American Males,
50-59 years of age: 13.6%
Veterans(esp. Vietnam) : ~20%
HIV + people: 25-30%
Homeless people: ~40%
Current & former IDU: up to 90%
Why is HCV a Problem?
HCV enters the bloodstream, &
infects liver cells
HCV becomes chronic (lifelong)
in 55-85% of people who get it
The hepatitis C virus does not
not damage the liver; scarring is
caused when the immune system
responds to the virus by walling off
infected liver cells
15 to 50 years later, serious liver
scarring (cirrhosis), develops in 2030% of people with chronic HCV
Range of HCV Outcomes,
Over Decades
• No symptoms, no liver damage
• Symptoms (fatigue & depression) & some liver damage
• Fat in the liver (steatosis)
• Liver scarring (fibrosis)
• Serious liver scarring, making it difficult for the liver to function,
called cirrhosis (20-30%)
• Liver cancer (1% to 5% of people with cirrhosis per year)
• Liver failure (3% to 4% of people with cirrhosis per year)
HCV Progression: Cofactors
• HIV coinfection
• Age >40 at time of infection
•
Insulin resistance, obesity, steatosis
• Aging/duration of HCV infection
•
Chronic HBV infection
•
Male
HCV & Alcohol
Alcohol accelerates HCV
progression, especially >50
grams/day
Safe amount?
Cutting down or quitting
may be more important than
HCV treatment for
some people
Many physicians won’t
treat drinkers, biased by data
from old studies
Goal of HCV Treatment
Is……to get rid of the virus, permanently, an outcome
called SVR
SVR (sustained virological response), meaning that
no HCV is detected in the blood 6 months after HCV
treatment completion)
SVR is durable (>10 years), and reduces liver-related
Illness 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 Treatment
Work?
HCV treatment works in 2 ways:
By killing infected cells
(immunologic effect)
By blocking viral replication, to protect
uninfected cells from HCV
(anti-viral effect)
Get Down,
& Stay Down!
Successful HCV treatment
rapidly—& completely —
suppresses the virus, & keeps
it suppressed throughout the
course of treatment (12-72
weeks)
HCV: Current SOC
Drugs: Pegylated interferon & ribavirin
Duration: 12 to 72 weeks
Efficacy: ~50%, depends on several factors
Side effects: NASTY!
Peg Intron
pegylated interferon alfa 2b
dosed by weight
Schering Plough / Merck
Ribavirin
dosed by weight
generic
Pegasys
pegylated interferon alfa 2a
flat dosing
Hoffman La Roche
Interferon (IFN)
Interferon is a synthetic version of a chemical messenger
made by the human body; it stimulates the immune system
& fights viruses
Pegylated Interferon (PEG-IFN) is the standard of care
Pegylation means that a small molecule has been
attached to interferon to keep it in the body longer &
make it more effective
Pegylated interferon is injected 1 X per week; old-school
interferon was injected 3 X per week (sometimes even 1 X
per day)
Side Effects of IFN
Flu-like
(fever, aches, nausea, appetite loss, weakness, &
fatigue)
Lab Abnormalities
(anemia, neutropenia, thrombocytopenia)
Neuropsychiatric
(suicidal ideation/suicide (rare), depression,
insomnia, anxiety, irritability, mood swings, mania,
psychosis)
Other
(hair loss, optic nerve damage)
Ribavirin (RBV)
• Pill or capsule, taken 2 X a day
• Same family (NRTI) as some HIV drugs
but it does not work against HIV
• RBV dosing is based on weight
• There are interactions between RBV and
some HIV drugs
RBV Side Effects
Anemia: major, sometimes treatment-limiting side effect
Cardiac events
Shortness of breath, coughing
Itchy skin/rash
May also cause depression, irritability
HCV Treatment Efficacy
(how well does it work?)
Data from clinical trials; 24- 48 weeks of PEG-IFN + RBV
(all treatment naïve; by genotype and HIV status)
SVR,
overall
SVR,
genotype 1
27% to 44%
14% to 38%
SVR,
genotype
2&3
53% to 73%
HCV alone 56% to 61%
42% to 44%
70% to 82%
HIV/HCV
coinfected
(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
Americans & Latino/as
SVR,
African American
Study
SVR,
Latino/a
Muir, et al; NEJM 2004 19%
Rodriguez-Torres et al;
NEJM 2009
34%
SVR,
White
52%
49%
Conjeevaram et al;
28%
Gastroenterology 2006
52%
Jeffers et al;
Hepatology
2004
26%
39%
Muir et al; AASLD
2008*
44%
65%
* plus an HCV protease inhibitor
62%
HCV TX Response:
Prognostic Factors
Pretreatment
Genetics (IL-28b CC vs. TT)
Hepatitis C genotype
(2,3,4,1)
& subtype (1b vs 1a)
Race
(Asian> White > Latino/a> AA)
HCV RNA<400,000
HIV status (not CD4 count
or HIV RNA)
Liver damage/steatosis
BMI
Insulin resistance, diabetes
On Treatment
Support
Endurance
Aggressive side
effects management
WBD of ribavirin
Early response to TX
Adequate TX duration
Adherence (80/80/80)
Population-Specific
Issues
Treatment Naïve VS. Treatment Experienced
• More than one type of experience: null response, non-
response, viral breakthrough, relapse
• Response to retreatment better for some treatment
experienced groups (relapsers>breakthrough >nonresponder>null responder)
What was original treatment regimen, duration,
dose, & how were side effects managed?
(Shiffman; Hepatology 2002)
The Candidates
HCV protease inhibitors
HCV polymerase inhibitors
NS5a inhibitors
Cyclophilin inhibitors
Entry inhibitors
MicroRNA
Nitazoxanide
Immunomodulators
Novel Interferons
Monoclonal Antibodies
Therapeutic Vaccines
Milk Thistle
Anti-fibrotic Agents
The Big Question(s)
Will antiviral therapy cure HCV without an
immune-based therapy?
Will it work for everyone?
If so, how long will it take?
-may differ by population & individual
factors
What are the least risky, most efficient ways
to answer these questions?
2010 Landscape
HCV clinical trials
(phase 1, 2 and 3) in
monoinfected
(TX naïve & TX experienced)
people
people add a single
antiviral to SOC
HCV clinical trials in HIV/HCV
coinfected (TX naïve) people
a single HCV antiviral +
SOC
HCV clinical trials in HCV monoinfected
(TX naïve & TX experienced)
people with 2 oral antivirals, with or
without SOC
HCV Trial Design Issues
Drug-drug interactions (especially for HIV+ people)
Overlapping safety issues (ANEMIA, RASH)
Confusing dosing (tid + bid)
Design of trials and control arms as SOC continues to
evolve, especially for treatment experienced people
Will/should stopping rules change?
What role will genetics have?
HCV Replication & Mutation
•
Hepatitis C makes billions of copies each
day, called virions
•
These virions are not identical; some
have changes in the genetic structure of
the virus, called mutations
•
Mutations in viral enzymes occur
randomly
•
Some mutations make it harder for the
virus to reproduce; others can stop drugs
from working
•
HCV mutations that cause resistance to
the new antiviral drugs are present in
many people who have never taken them
HCV Replication
Drug Resistance
the ability of an
organism to grow in the
presence of a
drug that would
normally kill it or limit
its growth; drug
resistance can develop
or emerge within days
With HCV, no one knows how
long resistance mutations will last,
and if they will compromise future
TX options
Drug Levels & Resistance
HCV Protease Inhibitors
Resistance: cross-resistance is a problem,
resistance emerges / develops within days & can still be
found years later; long-term consequences unclear
Activity may be genotype-specific
More side effects (rash, GI) and cost!
All of the HCV protease inhibitors may cause anemia
Different treatment strategies/ durations for each drug,
makes comparison difficult
In the Clinic
Phase III
•
•
Boceprevir (Merck/Schering-Plough) 3X day
Telaprevir (Vertex/Tibotec) 3X day, possibly
2X day
Phase I
Phase II
ABT 450*
ACH 1625
IDX 316
MK 5172
PHX 1766
VX 813
BI 201355
BMS-650032
CTS 1027
MK 7009
RG7227*
TMC435350
*studied with low-dose ritonavir
HCV Polymerase Inhibitors
Toxicity has been an issue
Nucleoside/nucleotide: Active against all HCV genotypes,
high genetic barrier/ resistance less likely
Phase II
IDX 184 , PSI 7851, RG7128
Non-nucleosides: Genotype-specific, resistance-prone
Phase I
Phase II
AA-837093, ABT 072
BI-207127, BMS-824393 ,
GSK625433, IDX 375,
MK-3281, VCH/VX 759
ABT 333, ANA 598, GS9190
PF-868,554
RO5024048
VCH/VTX 222
NS5a Inhibitors: Potent,
PROMISING
A-832 and BMS 790052 are in Phase II
Combination Trials
Roche/Genentech INFORM-3 (HCV protease +
HCV polymerase) Delayed, dosing issues
BMS: pairing BMS-650032 (a protease inhibitor)
with 790052 ( an NS5a inhibitor) in null
responders: Open
Vertex: pairing telaprevir (a protease inhibitor)
with VX 222 (a polymerase inhibitor)
Open soon
HCV TX Trials in
HIV/HCV Coinfected
People
•Two HCV protease inhibitors trials in HIV/HCV
coinfected people open in US/Europe
(boceprevir and telaprevir)
•Nitazoxanide in US only
What do You Think?
CRAPPYVIR: Big study planned
No women
No methadone / buprenorphine use
Drug testing
No HIV+ people
No psych meds or history of depression, etc
Trial in HIV+
NO ARVs
Must have >500 CD4 cells
No cirrhosis