Transcript Biomarkers of Inflammation in Acute/Early HIV

When to Treat HCV
in our HIV coinfected patients
2013 Perspective
Brad Hare, MD
Annie Luetkemeyer, MD
Associate Professor of Medicine, UCSF
Assistant Professor of Medicine, UCSF
Disclosures
• Brad has received grant support to UCSF
from Vertex Pharmaceuticals, Genentech, and
serves in an advisory capacity to Bristol-Myers
Squibb
• Annie has received research grant support to
UCSF from Bristol-Myers Squibb, Gilead, &
Vertex
Goals of this activity
• Changing paradigms in HCV treatment with
availability of new HCV drugs: FDA approved
and in clinical trials
• What to do NOW for HCV-coinfected
patients?
• Who should be treated, who can wait?
Glossary
• DAA: Direct Acting Agent. Anti-HCV medications
that target specific aspects of HCV viral replication
• PEG: Pegylated interferon
• RBV: Ribavirin
• PR: PEG + ribavirin
• Genotype: Strains of HCV that affect treatment
response (1-6)
– Genotypes 1&4 harder to cure than 2&3
• IL28b – human gene that contributes to response to
IFN-based treatment
– Response from best to worst: CC>CT>TT
Glossary (2)
• SVR: Sustained virologic response (HCV viral
load undetectable off of treatment) SVR12 and
SVR24 considered cures
• Null response: Failure to attain at least 2
log10 drop in HCV after 12 weeks of
treatment
• Response Guided Therapy: Shortening
therapy based on good early virologic
response (1st 12 weeks)
Case #1
• 35 year old African American man, CD4+ 450,
HIV RNA <40 copies/ml, on Atripla
• HCV treatment naïve, HCV RNA 500,000 IU/ml
• Genotype 1a, IL28b genotype T/T (least
favorable)
• Biopsy: Fibrosis Stage 2 (scale 0-4), Inflammation
Grade 1 (scale 0-4)
• No other comorbidities, including psychiatric
• In terms of HCV treatment readiness: “I’ll do
whatever you say, Doc”
Case #1 Audience vote, pre-debate
1) Treat now?
2) Wait to treat?
Case: 35 y.o. man, HCV Treatment Naïve,
Genotype 1a, IL28B genotype T/T (least favorable),
Fibrosis Stage 2. HIV well controlled on Atripla
Argument to Treat Now
Telaprevir
Boceprevir
in coinfection
80
in coinfection
80
74%
70
70
60
60
50
60.5%
50
45%
40
TVR
40
30
PEG/RBV
30
BOC
26.5%
20
20
10
10
0
0
SVR12
SVR12
Dieterich D, et al. CROI 2012, Abstract 46. Sulkowski M, et al CROI 2012. Abstract 47
PEG/RBV
Telaprevir works with Atripla
(Remember to dose adjust)
Dieterich D, et al. CROI 2012, Abstract 46.
Telaprevir and IL28b
In ADVANCE Study (HIV-negative), TPV improved response across all IL28b
genotypes, including T/T
SVR Rates in Patients
Genotyped for IL28B
100
90
T8PR
64
60
73
71
88
59
57
40
SVR Rates in Patients
With RVR
100
100
94
88
77
72
PR
93
84
80
SVR (%)
T12PR
25
23
20
0
n/N = 45/50 38/45 35/55
CC
48/68 43/76 20/80 16/22 19/32 6/26
CT
Jacobson I, et al. EASL 2011. Abstract 1369.
TT
n/N = 39/42 30/32 9/9
CC
36/41 34/47 2/2
CT
10/13 14/16
TT
0/0
Even Fibrosis F2 is Bad
Risk of End-Stage Liver Disease, Hepatocellular Carcinoma and
Liver Related Death by Fibrosis Score in Co-Infected Patients
Fraction not meeting an endpoint
1.00
0.75
N = 638 adults
0.50
0.25
F0
F1
F2
F3
F4
0.00
0
5
10
Time Since Biopsy (years)
11
Sulkowski MS et al. CROI 2010. Abstract 166.
Argument to Wait
48 weeks of PEG/RBV + Telaprevir
80
12 weeks of 3-4 oral drugs
70
60
50
TVR (n=38)
PEG/RBV (n=22)
40
30
74%
45%
20
10
N=76
0
SVR12
N=44
Dieterich D, et al. CROI
2012, Abstract 46.
Kowdley AASLD 2012
Argument to Wait
• IL28b T/T: up to 25% worse SVR compared to
C/C1 (HIV negative)
• African American response with HCV PI’s <
White patients (SVR AA 50-62% vs. non-AA 68-75%2)
• No data yet to support response guided
therapy in HIV+
– Therefore 48 weeks of therapy
• Relatively young patient with intermediate
fibrosis - can afford to wait and will spare
himself a year of toxicity by doing so
1 Kwo Liver Int 2011; 32(S1):39
2
Burton SMJ 2012;105(8):431
Rebuttal: Treat Now
Rebuttal: Wait to treat
Case #1 Audience vote, post-debate
1) Treat now?
2) Wait to treat?
Case: 35 y.o. man, HCV Treatment Naïve,
Genotype 1a, IL28B genotype T/T (least favorable),
Fibrosis Stage 2. HIV well controlled on Atripla
Case #2
• 60 year old Caucasian man, CD4+ 815, HIV
RNA < 40 copies/ml on Raltegravir/Epzicom
• Treatment naïve, HCV Genotype 3a, HCV RNA
1.2 million IU/ml, HCV infection “since the 70’s”
• Normal platelets and coagulation
• Ultrasound: no evidence of cirrhosis
• Mild depression, well controlled on SSRI, no
other comorbidities.
• “I’ll do whatever you recommend, except stick
a needle in my liver!”
Case #2, Audience vote, pre-debate
1) Treat now?
2) Wait to treat?
Case: 60 y.o. man, HCV treatment naïve,
Genotype 3a, no cirrhosis by imaging, HIV well
controlled on raltegravir+ Epzicom
Argument to Treat now
Study Cohort
RIBAVIC1
2004
ACTG 50712
2004
APRICOT3
2004
PRESCO4
2007
1
Carrat F JAMA 2004
2 Chung R NEJM 2004
3 Torriani FJ NEJM 2004
Sustained Virologic
Response Rate
Rx
Peg IFN α-2b
RBV 800mg QD
Overall
Genotype 1
Genotype non-1
27%
15%
43%
Peg IFN α-2a
RBV 600mg → 800mg QD
Overall
Genotype 1
Genotype non-1
27%
14%
73%
Peg IFN α-2a
RBV 800mg QD
Overall
Genotype 1
Genotype non-1
40%
29%
62%
Peg INF α-2a
RBV 1000mg (<75kg) or RBV
1200mg (>75kg) QD
Overall
Genotype 1
Genotype non-1
50%
35%
72%
4 Nunez
M AIDS Research and Human
Retroviruses 2007
5 Rodriguez-Torres AASLD 2009 #1561
Argument to Treat now
Treating at a younger age associated with better
cure rates
Our patient is
60 years old
Mauss CROI 2012 #763
More Fibrosis in HIV+
Liver fibrosis and age among persons coinfected with HIV and HCV and those with only HCV.
For each age, predicted liver fibrosis scores were calculated using a regression equation that included the race, sex, alcohol use,
body mass index, hepatitis B virus surface antigen level status, and HCV RNA level values for a representative participant (black
overweight male who has no regular alcohol use, is hepatitis B virus surface antigen–negative, and has high HCV viral load) for
persons coinfected with HIV and HCV (dashed line) and for persons with only HCV (solid line). For example, a 40-year-old HIV and
HCV coinfected person with these characteristics was calculated to have a predicted FibroScan score of 9.04 kPa. For this same
degree of fibrosis, the predicted age in a similar person but with only HCV was 49.2 years. Over the entire age range, the average
difference in estimated age between persons coinfected with HIV and HCV and those with only HCV was 9.2 years (90% coverage
limit, 5.2 to 14.3 years). HCV = hepatitis C virus.
Kirk GD HIV, Age, and the Severity of Hepatitis C Virus–Related Liver Disease: A Cohort StudyAnn Intern Med. 2013
Argument to Wait
Treatment related side effects in Apricot study of HIV/HCV coinfection
IFN
+ RBV
(n = 285)
PEG
+ placebo
(n = 286)
PEG
+ RBV
(n = 288)
Fatigue
36%
36%
40%
Pyrexia
32%
35%
41%
Headache
34%
29%
35%
Myalgia
27%
29%
32%
Nausea
19%
19%
22%
Insomnia
23%
16%
19%
Asthenia
23%
20%
26%
Depression
20%
16%
20%
Torriani et al. 11th CROI, 2004; Abstract 112
What’s coming for Geno 2/3
100[1]
100[1]
96[2]
100
SVR12 or 24 (%)
80
60
40
20
0
Geno 2/3 Naive
Sofosbuvir (nuc) + RBV x 12 wks + pegIFN x 4-12 wks
Sofosbuvir (nuc) + RBV x 12 wks
Sofosbuvir (nuc) + daclatasvir (NS5A) ± RBV x 24 wks
1. Gane EJ, et al. AASLD 2012. Abstract 229. 2. Sulkowski M, et al. AASLD 2012. Abstract LB-2.
Rebuttal: Treat Now
Rebuttal: Wait to treat
Case #2, Audience vote, post-debate
1) Treat now?
2) Wait to treat?
Case: 60 y.o. man, HCV treatment naïve,
Genotype 3a, no cirrhosis by imaging, HIV well
controlled on raltegravir+ Epzicom
Case #3
• 48 y.o. Latina woman, CD4+ 388, HIV RNA < 40
copies/ml on Atazanavir/ritonavir + Truvada
• Genotype 1b, HCV RNA 750,000 IU/ml, IL28b
genotype C/T (intermediate)
• PEG/RBV 4 years ago, stopped after 12 weeks
due to < 2 log10 HCV RNA drop (null response),
tolerated reasonably well
• Imaging now suggestive of early cirrhosis, biopsy
Fibrosis stage 3-4, no history of decompensation
• No other signficant comorbidities
Case #3, Audience vote, pre-debate
1) Treat now?
2) Wait to treat?
Case: 48 y.o. woman, prior null responder, HCV
Genotype 1b, Fibrosis stage 3-4, IL28b C/T
(intermediate). HIV well controlled on
Atazanavir/ritonavir + Truvada
Argument to Treat Now
She has early cirrhosis – don’t wait
Survival among HIV/HCV Coinfected patients with cirrhosis
Lopez-Dieguez, M; AIDS. 25(7):899-904, April 24, 2011.
Telaprevir is the best option
REALIZE study of retreatment in individuals with prior treatment failures
HIV negative
Butt A, and Kanwal F Clin Infect Dis. 2012;54:96-104
Argument to Wait
Bourliere Liver
International 2012
Feb;32 Suppl 1:113-9
Cross-resistance of NS3 Protease Inhibitors
Linear
Telaprevir
*
*
*
Boceprevir
Narlaprevir
Macrocyclic
Danoprevir
*
*
MK-7009
TMC 435
BI 201335
*Mutations associated with in vitro resistance but not described in patients.
Susser S et al. Hepatology. 2009;50:1709-18; Sarrazin C, Zeuzem S. Gastroenterology. 2010;138:447-62.
DAA regimens in Nulls & Cirrhosis
12 weeks of HCV PI + NS5A in Null
Responders, Genotype 1b (BMS)
SOUND-C (HCV Protease inhibitor +
polymerase+ RBV) cirrhosis
subanalysis
GT1a
86
80
80
68
57
60
50
43
43
0
n/ 3/
N= 7
8/
14
2/
4
4/
5
0/
0
1/
3
Cirrhosis
TID
16, 28, 40
+
90% SVR rate
Chayama Hepatology 2012 Mar;55(3):742-8
60
42
33
40
20
GT1b
BID
28
+
11
40/ 84/
93 124
11/ 37/
26 43
2/
18
15/
25
No Cirrhosis
TID
28
-
TID
16, 28, 40
+
BID
28
+
80% SVR rate
Zeuzem S, et al. AASLD 2012. Abstract 232.
TID
28
-
Rebuttal: Treat Now
Rebuttal: Wait to treat
Case #3, Audience vote, post-debate
1) Treat now?
2) Wait to treat?
Case: 48 y.o. woman, prior null responder, HCV
Geno 1b, Fibrosis stage 3-4, IL28b C/T
(intermediate). HIV well controlled on
Atazanavir/ritonavir + Truvada
Summary
• HCV treatment is in a very dynamic period with the
promise of improved SVR rates, shorter treatment
and improved tolerability
– Certain patients are likely to remain more challenging to
treat: HIV coinfection, cirrhotics, prior non-responders
• Less data are available for HIV co-infected patients
and there may be more wrinkles
– Drug-drug interactions
– Possibly lower SVR rates than mono-infection
• Patients and clinicians are left to apply limited data
and weigh available options against hopeful, but
uncertain, future options