![Page 1: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/1.jpg)
When to Treat HCV in our HIV coinfected
patients2013 Perspective
Brad Hare, MD Annie Luetkemeyer, MD Associate Professor of Medicine, UCSF Assistant Professor of Medicine, UCSF
![Page 2: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/2.jpg)
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
![Page 3: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/3.jpg)
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?
![Page 4: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/4.jpg)
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
![Page 5: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/5.jpg)
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)
![Page 6: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/6.jpg)
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”
![Page 7: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/7.jpg)
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
![Page 8: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/8.jpg)
Argument to Treat Now
Telaprevir Boceprevir in coinfection in coinfection
0
10
20
30
40
50
60
70
80
SVR12
TVR
PEG/RBV
Dieterich D, et al. CROI 2012, Abstract 46. Sulkowski M, et al CROI 2012. Abstract 47
74%
45%
0
10
20
30
40
50
60
70
80
SVR12
BOC
PEG/RBV
60.5%
26.5%
![Page 9: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/9.jpg)
Telaprevir works with Atripla(Remember to dose adjust)
Dieterich D, et al. CROI 2012, Abstract 46.
![Page 10: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/10.jpg)
Telaprevir and IL28b
In ADVANCE Study (HIV-negative), TPV improved response across all IL28b genotypes, including T/T
Jacobson I, et al. EASL 2011. Abstract 1369.
SVR Rates in Patients Genotyped for IL28B
SV
R (
%)
T12PR T8PR PR
60
100
80
40
20
0n/N = 45/50 38/45 35/55
CC
48/68 43/76 20/80
CT
16/22 19/32 6/26
TT
90 84
6471
57
25
7359
23
SVR Rates in Patients With RVR
n/N = 39/42 30/32 9/9
CC
36/41 34/47 2/2
CT
10/13 14/16 0/0
TT
93 94100
8872
100
7788
![Page 11: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/11.jpg)
0.00
0.25
0.50
0.75
1.00
0 5 10Time Since Biopsy (years)
Even Fibrosis F2 is Bad
Sulkowski MS et al. CROI 2010. Abstract 166.
11
N = 638 adults
F0 F1 F2 F3 F4
Risk of End-Stage Liver Disease, Hepatocellular Carcinoma and Liver Related Death by Fibrosis Score in Co-Infected Patients
Fra
ctio
n no
t mee
ting
an e
ndpo
int
![Page 12: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/12.jpg)
Argument to Wait
74%
45%
N=76 N=44
48 weeks of PEG/RBV + Telaprevir12 weeks of 3-4 oral drugs
Dieterich D, et al. CROI 2012, Abstract 46. Kowdley AASLD 2012
![Page 13: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/13.jpg)
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
![Page 14: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/14.jpg)
Rebuttal: Treat Now
![Page 15: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/15.jpg)
Rebuttal: Wait to treat
![Page 16: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/16.jpg)
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
![Page 17: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/17.jpg)
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!”
![Page 18: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/18.jpg)
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
![Page 19: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/19.jpg)
Study Cohort RxSustained Virologic
Response Rate
RIBAVIC1
2004
Peg IFN α-2bRBV 800mg QD
OverallGenotype 1Genotype non-1
27%15%43%
ACTG 50712
2004
Peg IFN α-2aRBV 600mg → 800mg QD
OverallGenotype 1Genotype non-1
27%14%73%
APRICOT3
2004
Peg IFN α-2aRBV 800mg QD
OverallGenotype 1Genotype non-1
40%29%62%
PRESCO4
2007
Peg INF α-2aRBV 1000mg (<75kg) or RBV 1200mg (>75kg) QD
OverallGenotype 1Genotype non-1
50%35%72%
1 Carrat F JAMA 20042 Chung R NEJM 20043 Torriani FJ NEJM 2004
4 Nunez M AIDS Research and Human Retroviruses 20075 Rodriguez-Torres AASLD 2009 #1561
Argument to Treat now
![Page 20: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/20.jpg)
Argument to Treat now Treating at a younger age associated with better cure rates
Mauss CROI 2012 #763
Our patient is 60 years old
![Page 21: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/21.jpg)
Kirk GD HIV, Age, and the Severity of Hepatitis C Virus–Related Liver Disease: A Cohort StudyAnn Intern Med. 2013
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.
More Fibrosis in HIV+
![Page 22: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/22.jpg)
Argument to Wait
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%
IFN PEG PEG+ RBV + placebo + RBV
(n = 285) (n = 286) (n = 288)
Torriani et al. 11th CROI, 2004; Abstract 112
Treatment related side effects in Apricot study of HIV/HCV coinfection
![Page 23: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/23.jpg)
What’s coming for Geno 2/3
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
100
80
60
40
20
0
SV
R12
or
24 (
%)
100[1] 100[1]
Geno 2/3 Naive
96[2]
1. Gane EJ, et al. AASLD 2012. Abstract 229. 2. Sulkowski M, et al. AASLD 2012. Abstract LB-2.
![Page 24: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/24.jpg)
Rebuttal: Treat Now
![Page 25: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/25.jpg)
Rebuttal: Wait to treat
![Page 26: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/26.jpg)
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
![Page 27: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/27.jpg)
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
![Page 28: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/28.jpg)
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
![Page 29: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/29.jpg)
Argument to Treat NowShe 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.
![Page 30: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/30.jpg)
Telaprevir is the best option
Butt A, and Kanwal F Clin Infect Dis. 2012;54:96-104
REALIZE study of retreatment in individuals with prior treatment failuresHIV negative
![Page 31: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/31.jpg)
Argument to Wait
![Page 32: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/32.jpg)
Bourliere Liver International 2012 Feb;32 Suppl 1:113-9
![Page 33: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/33.jpg)
Cross-resistance of NS3 Protease Inhibitors
V36A/MR155K/T/Q/P
V55AA156/V/T
V170A/T/L
D168A/V/T/H
T54S/A
*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.
A156SQ80R/K
* *
*
* * Telaprevir
Narlaprevir
Danoprevir
TMC 435
BI 201335
MK-7009
BoceprevirLine
arM
acro
cycl
ic
![Page 34: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/34.jpg)
DAA regimens in Nulls & Cirrhosis
90% SVR rate
GT1a GT1b
43
0
20
40
60
80
3/ 7
57
8/ 14
TID16, 28, 40
+
BID28+
TID28-
50
2/ 4
80
4/ 5
11 2/ 18
60
15/25
Cirrhosis No Cirrhosis
TID16, 28, 40
+
BID28+
TID28-
0/ 0
33
1/ 3
42
11/26
86
37/43
43
40/93
68
84/124
n/ N =
12 weeks of HCV PI + NS5A in Null Responders, Genotype 1b (BMS)
SOUND-C (HCV Protease inhibitor + polymerase+ RBV) cirrhosis subanalysis
80% SVR rate
Zeuzem S, et al. AASLD 2012. Abstract 232. Chayama Hepatology 2012 Mar;55(3):742-8
![Page 35: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/35.jpg)
Rebuttal: Treat Now
![Page 36: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/36.jpg)
Rebuttal: Wait to treat
![Page 37: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/37.jpg)
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
![Page 38: When to Treat HCV in our HIV coinfected patients 2013 Perspective](https://reader035.vdocument.in/reader035/viewer/2022081511/56815853550346895dc5ad32/html5/thumbnails/38.jpg)
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