Transcript Hepatitis C Scaling Up Current and Future Standard of Care

Hepatitis C:
Scaling up to Current &
Future Standard of Care
OSI HCV TX Scale-Up
Meeting
March 2009
Tracy Swan
Essential Elements
• Diagnostics & pre-treatment
assessments
• Treatment
–
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Monitoring during treatment
Side effects management
HCV treatment issues for HIV+ people
New HCV TX in development
• Successful models for delivering care
and treatment
HCV Diagnostics: What Tests
Are Necessary?
“My doctor says I have hepatitis but not to
worry about it…”
Signal:
Liver Enzymes
Diagnose:
Antibody testing
Hepatitis C viral load (HCV RNA)
Before treatment:
HCV genotype
Liver biopsy (&/or alternatives)
HCV Antibody & Viral Load Testing
Antibody testing
•
A positive HCV antibody test result does not always
indicate chronic hepatitis C infection; it means
someone
has been infected with HCV
(15-45% will spontaneously clear HCV but remain antibody
positive for years afterwards)
• Will not pick up recent infection; antibodies develop in
6--24 weeks after infection
(Less reliable in people who are immunosuppressed-especially HIV+ people with <200 CD4 cells--can be
“false” negative)
Viral load testing (HCV RNA)
• Will confirm or rule out chronic hepatitis C infection;
usually detectable 2 weeks after infection
fluctuates; if HCV RNA is undetectable repeat in 6 months
HCV antibody testing for: all HIV+ people, also people with past or
current risks and/or elevated liver enzyme levels or other signs and
symptoms of hepatitis
Non-reactive
No recent risk/
exposure
No signs or
symptoms
HIV+ & CD4 >200
Non-reactive
Recent risk/exposure and/ or
signs & symptoms, HIV+ & CD4
<200
Reactive
HCV RNA testing
Undetectable
repeat HCV RNA in 6 months to
rule out chronic HCV
Detectable:
Chronic HCV
All: offer risk reduction information & vaccination against
HAV and HBV
HCV RNA Testing
• Qualitative tests: is it there?
– More sensitive: Range of >10 to >50
IU/mL
• Used as confirmatory diagnostic
• Used to monitor response to treatment:
essential!
• Quantitative tests: how much is
there?
– Pre-treatment assessment (important
prognostic factor for response to HCV TX)
Future Tests
Oct 2008: Orasure submits application to
FDA for OraQuick® (first rapid HCV
antibody test, can be used for oral fluid,
fingerstick, venipuncture, plasma and serum)
Sometime in the future:
HCV resistance testing?
Crucial: HCV Genotype
>6 different HCV genotypes, numbered as discovered;
each genotype has subtypes, lettered as discovered
HCV genotype can be determined by a blood test
Key determinant of HCV treatment duration & strongest
prognostic factor for response to treatment (2,3,6,5,4,1)
• Most people with genotypes 2 and 3 only require 12-24 weeks of
treatment
• a subset of people with genotype 1 may only need 24 weeks of
treatment
• Some new HCV antiviral drugs have genotype-specific activity and
efficacy
Predominant HCV
Genotypes in EE & NE
Estonia: HCV-1 most common, followed by HCV-3a (shifted
from 1b to 3a [1999-2000] and back again [2000 on]; not
related to mode of acquisition
Poland : HCV -1 most common, but most IDU have HCV- 3a
St Petersburg: HCV-1b more common among dialysis
recipients; HCV-3a most common among IDU
Western Siberia: HCV-1b followed by HCV-3a
(Chlabicz et al; J Clin Virol 2008;Kalinina et al; J Med Virol 2001; Tallo et al;
J Med Virol 2007)
Predominant HCV
Genotypes in SE & SC Asia
India: HCV-3a/3b; HCV-1a & 1b; also HCV-4?
Iran: HCV-1a & HCV-3a
Nepal: HCV-3 (many subtypes)
Pakistan: HCV-3a & 3b; HCV-1a
Thailand: HCV-3a, HCV-1b and HCV-6
Uzbekistan: HCV -1 most common, but most IDU have
HCV-3a
(Idrees et al;BMC Infect Dis 2008;Kanistanon et al; J Clin Microbiol 1997;
Kurbanov et al; J Med Virol 2003; Raghuraman et al;J Clin Virol 2004;
Singh et al; Indian J Medical Res 2004;Tokita et al; J Gen Virol 1994)
Pre-TX: Liver Biopsy?
PROs:
Only test that can grade (how much inflammation) & stage
(how much scarring) liver tissue
Can identify other causes of liver disease
Can identify steatosis (fatty liver)
CONs
Expensive, requires 1/2 day observation—access is limited
Invasive and painful—unpopular
Risky—complications and very small risk of death
Not always accurate—depends on sample size &
location, pathologist expertise
Not as necessary for people with genotypes 2 & 3, due to
high treatment success rates
Normal Liver Tissue
Steatosis (fatty liver)
Fibrosis (mild/moderate scarring)
Cirrhosis (serious scarring)
Biopsy Alternatives
Serum marker panels (Fibrotest, APRI, etc)
can detect cirrhosis/advanced fibrosis, not
mild-to-moderate liver damage—not ready for
prime time (especially for HIV+ people)
FIBROSCAN uses sound waves to assess
liver stiffness; not as good for inflammation,
not as accurate for overweight people
(machine very costly)
Who To Treat?
“ All patients with chronic hepatitis C are
potential candidates….Treatment is
recommended for patients with an increased
risk of developing cirrhosis…… characterized by
detectable HCV RNA …a liver biopsy with portal
or bridging fibrosis, and at least moderate
inflammation and necrosis.”
NIH Consensus Statement 2002
“Consider HCV treatment in all HIV/HCV
coinfected patients…”
Veterans Administration 2005
Current SOC
Peg Intron
pegylated interferon alfa
2b
dosed by weight
Schering Plough
Ribavirin
dosed by weight
generic
Duration: 12 to 72 weeks, depending on:
•early response to treatment
•HCV genotype and baseline RNA
•HIV status
•condition of the liver
•treatment status: experienced vs.naive
Pegasys
pegylated interferon alfa 2a
flat dosing
Hoffman La Roche
Response to HCV TX
SVR: sustained virological response (6 months
after finishing HCV treatment) No detectable HCV
RNA in the blood; many experts consider SVR a
“cure”;durable ( >10 years) lowers liver-reated
morbidity and mortality
RVR: rapid virological response (4 weeks)
High likelihood of SVR if HCV RNA is undetectable;
used more in research than clinical practice-but not
accurate for early stopping rule
EVR: early virological response (12 weeks) If
there is less than a 2 log (99%) drop, SVR is VERY
unlikely--HCV TX usually discontinued
RVR
no RVR
Continue HCV TX for
8 weeks
No EVR
EVR
HCV Treatment Efficacy
(Data from clinical trials of PEG-IFN + RBV)
SVR overall SVR,
HCV-1
SVR,
HCV2&3
27% to 44% 14% to 38% 53% to 73%
HIV/HCV
(48 weeks)
HCV (24-48 56% to 61% 42% to 44% 70% to 82%
weeks)
(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)
Response to HCV TX:
Prognostic Factors
Pretreatment
On Treatment
Hepatitis C genotype (2,3,6,5,4,1)
Race (White>African American)
Hepatitis C viral load <400,000)
HIV status (but not CD4 cell
count or HIV RNA)
Amount of liver damage
Treatment history (naïve vs.
experienced) & prior TX
outcome
Steatosis
BMI
Insulin resistance/diabetes
Education on HCV
Support
Endurance
Aggressive side effects
management
WBD of ribavirin
Early response to TX
Adequate TX duration
Adherence (80/80/80)
Alcohol intake???
Are You Experienced?
Population Specific Issues
Treatment Naïve VS. “Treatment Failures”
Treatment-experienced:
• fastest growing population; in the US, ~650,000
• more than one type of experience: null response, nonresponse, partial response, viral breakthrough, relapse
Response to retreatment >for some
• relapsers>partial responders/ breakthrough>
non-responder>null responder
What was original treatment regimen, duration, dose, &
how were side effects managed?
(Shiffman; Hepatology 2002)
IFN: Side Effects
Flu-like/Constitutional
– fever, aches, nausea, appetite and weight 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, etc……
RBV: Side Effects
Anemia: major, sometimes treatment-limiting
side effect
Cardiac events
Shortness of breath, coughing
Itchy skin/rash
May also cause depression, irritability
Managing Side Effects
Flu-like symptoms: evening/Friday night IFN shot, low-dose
paracetamol, anti-nausea medication, drinking lots of water
Appetite/weight loss: many small, light meals, marinol
Fatigue: exercise/napping
Anemia: growth factor ($$$), dose reduction, transfusion if severe
Neutropenia: growth factor ($$$), dose reduction
Thrombocytopenia: if severe dose reduction or stop TX
Neuropsychiatric: baseline psychiatric assessment, ongoing access
to mental health care, peer support, and pre-emptive or as-needed
medication
HIV Treatment Issues For
Coinfected People
Serious liver damage more likely in people with <200
CD4 cells; HIV treatment can delay HCV progression:
recent HIV guidelines recommend early TX initiation but….
HCV coinfection triples the risk for liver toxicity from
ART--some drugs less liver friendly than others
Coinfected people more likely to d/c HIV TX for
toxicity
HCV treatment reduces liver toxicity risk from HIV TX
SVR reduces risk of liver-related morbidity & mortality
HCV Treatment Issues For
HIV/HCV Coinfected People
Side effects are more severe; drop out rates from HCV treatment
trials up to 40%
Drug-drug interactions/toxicity problematic: No AZT, ddI, d4T;
abacavir ???
This may be an increasingly important issue w/new HCV drugs
CD4 count--but not percentage--can drop dramatically during
HCV treatment even with use of stable ART, although not
associated with increased risk of OIs, may warrant more vigilant
monitoring ; returns to baseline after
HCV TX less effective, more necessary
2009 HCV TX Landscape
Stuck with SOC as the backbone
--SVR lower, relapse rates higher w/o ribavirin
Development of several candidates halted
--due to concerns about toxicity, efficacy, & financial issues:
NM283, HCV-796 ACH-806, AVI-4065, CPG 10101,
MAXY-alpha, R1626, VGX 410, XTL 2125 and XTL 6865
Two HCV protease inhibitors in phase III trials
--studies in HIV/HCV coinfected people slated to open in
mid-to-late 2009
Many more candidates in preclinical development
HCV TX in 2019?
Pipeline full of oral antiviral agents
These new drugs target different steps of
the HCV lifecycle
Must be used with SOC for now--but new
drugs may abbreviate treatment duration &
improve outcomes
Drug resistance may be present at baseline
and can develop rapidly during TX
HCV antivirals will have to stop HCV
replication & clear infected liver cells: will
this be possible without interferon?
+ or -
HCV Replication
• 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 Replication
Drug Resistance
the ability to grow in the
presence of a
drug that would
normally kill it or limit its
growth
Candidates……
HCV protease inhibitors
HCV polymerase inhibitors
Other antivirals
Entry inhibitor
Shhhhh…..
Nitazoxanide
Others…
Immunomodulators
Novel Interferons
Monoclonal Antibodies
Therapeutic Vaccines
Milk Thistle
Anti-fibrotic Agents
HCV Protease Inhibitors
• Resistance develops quickly--within days
– Phase I studies shortened to ≤3 days
• Cross-resistance a concern
• Activity may be genotype-specific
• Anemia may be a class-wide side effect
• Additional toxicities (rash, GI)
• Duration of treatment with an HCV PI varies
• Different treatment strategies used; makes comparison difficult
– Lead in versus triple therapy
What’s in the Clinic?
2 candidates in Phase III
Boceprevir (Schering-Plough) 3X day
Telaprevir (Vertex/Tibotec) 3 X day, possibly 2X
day
Other candidates in hot pursuit
— May be once or twice daily, may have a different
resistance profile
Phase I
Phase II
ABT 450
ITMN 191
MK 7009
PHX 1766,
VX 500
VX 813
BI 201335
SCH 900518
TMC435350
HCV Polymerase Inhibitors
Nucleoside/nucleotide: Active against all HCV genotypes,
high genetic barrier/ resistance less likely, toxicity issues
Phase I
Phase II
IDX 184
R7128 1st Q 2009
IDX 184
Non-nucleosides: Genotype-specific, resistance-prone,
toxicity issues
Phase I
Phase II
AA-837093
ANA 598
GSK625433
GS9190
PF-868,554
VCH/VX 759
VCH/VX 916
Groundbreaker!
November 2008: Roche,
InterMune & Pharmasset
open INFORM-1 in
New Zealand & Australia
INFORM-1 is the first study of two oral anti-virals
without SOC: ITMN 191, a protease inhibitor and
R7128, a polymerase inhibitor): results expected
in the second quarter of 2009
Current & Future Acce$$ Issues
Currently, SOC costs ~$32,000/year*
This does not include:
• Clinician/ nursing staff time
• HCV RNA testing (at multiple time points)
• Lab work, monitoring
• Side effects management: white and red blood cell growth
factors cost ~$8000 per month
• Psychiatric assessment, periodic screening for depression,
mental health care, medication
• Drug treatment, OST
• Longer treatment duration (may extend beyond 48 weeks)
• Disability/lost income to individual, family, society
In the future, we may need to factor in additional costs for
resistance testing (and possibly other lab work), adherence
support programs/staff, new drugs *According to DrugStore.com, accessed 9/08
We Need…..
Medical, mental health, narcology,
prison and community infrastructure
to deliver HCV care and treatment to highprevalence populations; quality of care and
treatment is as important as access
HCV treatment may improve, but people will still need
supportive services--treatment is only as effective as
the people and system that deliver it!
Capacity to deliver HCV treatment to multiply-diagnosed
people must be scaled-up to meet increased demand with
improvements in treatment access and efficacy
SVR: Drug Users vs. Non-Users
treatment with standard interferon and ribavirin
IDU, methadone, buprenorphine vs.
non-users
(Cournot; Gastroenterol Clin Bio 2004)
Recent ( <6 months) & current drug
use, methadone vs.
non-using, matched control group
21% vs.
28%
33% vs.
37%
(Van Thiel et al; Am J Gastroenterol 2003)
Registration trials (HIV-negative; bestcase scenario participants)
44-47%
(Fried et al; NEJM 2002; Manns et al; Lancet 2001)
HIV/HCV coinfected people
(Chung 2004; Torriani 2004)
12-19%
HCV TX & Operational Research:
What Works in the Real Word
Multidisciplinary care
• Provide co-located medical & mental health care
• Peer support & education: explain HCV natural HX, assessment
process for TX, risks/benefits of TX
• Offer options for drug/alcohol treatment as requested: OST,
pharmacotherapy, counseling, in/out patient treatment
Flexible eligibility criteria
• Patient willingness/interest in HCV TX & reasonable adherence
to clinic visits, engagement in psychiatric care, when indicated
--No abstinence requirements
Offer DOT PEG-IFN
• Gives clinicians a chance to closely monitor & immediately treat
side effects
• Useful for people in recovery who want to avoid self-injection,
due to concerns about relapse
• Has been outrageously successful at a clinic serving HIV-positive
people with concurrent issues
(Taylor; CID 2005)
Address Provider Concerns
Discomfort with caring for drug/ alcohol users
Due to inadequate training
•
Only 19% of 769 med school faculty teaching about drugs
& alcohol actually certified in addiction medicine
Comfort, satisfaction & competence improve with training
Concerns about relapse (drug use)
• Continue HCV treatment:intermittent drug/alcohol use not
always associated with poorer HCV treatment outcomes
• Prescribe methadone or buprenorphine when possible,
increase methadone dose if necessary
Concerns about HCV reinfection
Educate providers on low reinfection rates, risk reduction
• Inform IDUs about the risk of reinfection; offer risk reduction
options: demonstrate safer injection techniques, refer to SEP
when available, prescribe or provide syringes and other
injection equipment when feasible; offer OST when possible
(Backmund et al; Hepatology 2001; Fleming, et al; J Family Practice 1999;
Karam-Hage; Addiction 2001; Litwin et al; CID 2005; Matthews et al; Acad Med
2002; Miller et al; Acad Med 2001; Saitz et al; J Gen Intern Med 2002; Schaefer et
al; Hepatology 2003; Sylvestre; CID 2005; Van Theil et al; Am Journal Gastro 2003)
Overlap of Mental Illness &
Drug Use/Abuse
US Adult Population: ~ 218 million
22% will have a diagnosable mental disorder at
some point in their lives
• People with mental disorders are almost 3 X more likely to
have an addictive disorder
• 53% of people with (drug) addictive disorders have
a co-occurring mental disorder
• 47% among people with schizophrenia
• 56% among people with bipolar disorder
• 27% in people with major depression
Regier et al; Comorbidity of mental disorders with alcohol and other drug abuse.
Results from the Epidemiologic Catchment Area (ECA) Study. JAMA 1990; US
Census Bureau News; 2004
Mental Health & HCV
5-Site Health & Risk Study:
Blood- Borne Infections in People with
Serious Mental Illness
969 people with SMI: >42% of them had a
concurrent substance use disorder
HCV prevalence was more than 11X greater
than that of the general population (in the US)
(19.6% versus 1.6%)
(Armstrong et al; Ann Intern Med 2006 ;Rosenberg et al; Psychiatr Serv 2003)
People with psychiatric disorders
can be safely & effectively treated
for HCV; they just need to be
stabilized
• A baseline psychiatric assessment and on-going
mental health care are essential
• Strategies for managing IFN-induced
depression : pre-emptive vs. as-needed
(Schaefer, et al; Hepatology 2003; Sylvestre CID 2003; Taylor, et al; AIDS Reader 2005)
Adherence
• Complicated issue for with many
diseases, and across different
populations
• Resistance is not a significant issue
w/ current standard of care, but we
need to plan for the future
• Look to what’s worked w/ HIV
treatment-where >95% adherence
is necessary vs. 80/80/80
Last Words…….
Current standard of care for HCV is not always effective,
difficult to tolerate but likely to remain the therapeutic
backbone
HCV treatment somewhat of a moving target; likely to
improve in the future
HIV/HCV coinfected people face additional treatment
issues for each virus
Broader access to HCV TX is not sufficient; must prepare
infrastructure to deliver high-quality care & treatment
High-prevalence, “hard-to-treat” populations can be
safely and effectively treated