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Eliot Godofsky, MD, Director
University Hepatitis Center
Sarasota, Florida
Treatment of HCV in Patients
with HIV Coinfection
Recorded on 6/17/2014
Slide 2 of XX
Disclosure
Dr. Godofsky has received research support from
Janssen, AbbVie, Achillion Pharmaceuticals, Inc,
Bristol-Myers Squibb, Gilead Sciences, Inc,
Boehringer Ingelheim, GSK and Vertex
Pharmaceuticals, Inc.
Dr. Godofsky has served as a scientific advisor or as a
consultant to AbbVie, Genetech and Janssen
Pharmaceuticals (Past 2 years, updated 6/14)
Slide 3 of XX
Lecture Outline
Evolution of HCV Treatment in Patients with HIV
Coinfection
Timing of Treatment
Patient Evaluation and Selection
Important Drug-Drug Interactions
Therapy Considerations for Patients on HIV ART
Summary of Current AASLD/IDSA/IAS-USA Treatment
Recommendations
Slide 5 of XX
HCV/HIV Treatment Outcomes:
PegIFN plus RBV
0
25
50
75
100
G1 G2/3
Monoinfection
APRICOT
ACTGRIBAVICLaguno et al.
PRESCO
Genotype 1
SVR 14–38%
Genotype 2/3
SVR 44–73%
Genotype
SV
R (
%)
Fried et al, NEJM 2002, 347: 975-982, Torriani et al, NEJM 2004; 351: 438-50, Chung R, et al, NEJM 2004: 351; 451-9,
Carrat F, et al, JAMA 2004: 292: 2839-42, Laguno et al, AIDS 2004; 18: F27-F36, Nunez et al, JAIDS 2007: 45: 439-44
Slide 6 of XX
No ARTEFV/TDF/FTCATV/ritonavir + TDF/FTC
Total
SV
R (
%)
n/N = 5/7
11/16
12/15
28/38
Telaprevir + PegIFN/RBV
PegIFN/RBV
2/6
4/8
4/8
10/22
Sulkowski MS, et al. Ann Intern Med. 2013;159:86-96. Sulkowski M, et al. Lancet Infect Dis. 2013;13:597-605. Poordad F, et
al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
100
80
60
40
20
0
71 69
8074
33
50 5045
First Generation HCV Protease Inhibitors
plus PegIFN/RBV in GT 1 Coinfection
0
20
40
60
80
100
SV
R (
%)
PegIFN/RBV
n/N =
29
63
Boceprevir + PegIFN/RBV
SVRs comparable to GT1 HCV-monoinfected patients:
Boceprevir 68% Telaprevir 75%
Slide 7 of XX
Recently Released DAAs
Multi-genotypic
NS3/4A PI
QD dosing
Second Wave PI
Low barrier to
resistance
+ DDI with ARVs
Rash, photosensitivity
HIV not a special pop
Simeprevir Sofosbuvir
Pan-genotypic NS5B
QD dosing
Nucleotide analogue
Exceptional barrier to
resistance
No significant DDI
No AE
Approved for HIV/HCV
as special population
Slide 8 of XX
Sofosbuvir + PR for 12 weeks in HCV/HIV
Coinfection:Treatment Outcomes
No change in ART regimens
SVR12 rates by ART regimen
PI: 93%
NNRTI: 91%
Raltegravir: 100%
No on-treatment breakthroughs
Relapse (n=1)
HIV breakthroughs (n=2)
Discontinuations due to adverse events:
9%
Most common adverse events
Anemia (52%), fatigue (35%), neutropenia
(17%), thrombocytopenia (17%),
myalgia (13%)
Hyperbilirubinemia (17%)
Pa
tie
nts
(%
)
SVR12 Rates
91%87%
Overall(n=23)
100%
Genotype
Rodriguez-Torres M, et al. IDWeek 2013. Abstract 714.
1a(n=19)
1b(n=4)
2(n=1)
3(n=2)
4(n=1)
100% 100% 100%
Slide 9 of XX
PHOTON-1 Study:
Treatment Outcomes SVR12 rates in genotype 1
Similar regardless of baseline HCV RNA, IL28b
genotype, presence of cirrhosis, age, gender,
race
Lower in genotype 1b versus 1a
No resistance (deep sequencing)
detected in virologic failures
HIV breakthroughs (n=2)
Discontinuations due to AEs: 3%
Most common adverse events Fatigue, insomnia, headache, nausea
Grade >3 hyperbilirubinemia in patients
receiving atazanavir versus no atazanavir (13%
versus 1%)
SVR in treatment experienced pts
receiving 24 weeks of therapy: 92%
GT2 and 88% GT3
Sulkowski MS, et al. Hepatology. 2013;58(suppl 1):313A-314. Abstract 212.
Pa
tie
nts
(%
)
SVR12 Rates
76%
88%
Genotype 1(n=114)
Genotype 2(n=26)
Genotype 3(n=42)
67%
24 WeeksTherapy*
12 WeeksTherapy*
*Sofosbuvir 400 mg qd + RBV.
Slide 10 of XX
Study C212: Simeprevir + PR
in HCV/HIV Infection: GT 1
Phase III open label. Naïve/Relapse
(RGT arm) and PR null/partials (48
week tx)
SVR12 rates in HCV/HIV coinfected
were similar to HCV monoinfected
trials
SVR12 rates were high,
regardless of baseline METAVIR
fibrosis score
SVR12 67% GT1a + Q80k vs.
89% GT1b
Safety profile similar to
monoinfected patients
Pruritus and photosensitivity in
20% and 2%, respectively
Grade 3/4 hemoglobin: 1.9%
Naïve(n=53)
Relapser(n=15)
Partial(n=10)
Overall(n=106)
Pati
en
ts (
%)
87%
70%
57%
74%79%
SVR12 Rate
Dieterich D, et al. 14th EACS. Brussels, 2013. Abstract LBPS9/5.
Null(n=28)
Slide 11 of XX
COSMOS Study: Interim Results With Simeprevir +
Sofosbuvir + RBV in HCV Monoinfection
Jacobson IM, et al. Hepatology. 2013;58(suppl 1):73A. Abstract LB-3.
Pati
en
ts (
%)
SVR12: No Cirrhosis (F0-F2)(Prior PR Null Responders)
92.9%
24 Weeks(n=24/15)
12 Weeks(n=27/14)
Simeprevir + sofosbuvir
No RBV With RBV
96.3%93.3%
79.2%
Pa
tie
nts
(%
)
SVR4: Cirrhosis (F3-F4)*(Naives and Prior PR Null Responders)
100%
Naives(n=7/12)
Overall(n=14/14)
96.3%100%
93.3%
*Interim analysis: SVR4 rates in patients receiving the 12-week regimens.
Nulls(n=7/15)
100%
Simeprevir + sofosbuvir
No RBV With RBV
Slide 13 of XX
HIV/HCV Coinfection:
Who to Treat
All HCV/HIV coinfected patients are candidates for HCV therapy
Consider comorbid conditions that limit life expectancy or increase the risks associated with HCV therapy
HCV cure may decrease risk of ART-associated liver injury
HIV disease should be stable with or without ART
IFN-based regimens
Defer HCV treatment if CD4 <200 cells/mm3
Interferon can exacerbate pre-existing mental illness
Evaluate patients with underlying psychiatric disease before initiating HCV treatment
Decompensated cirrhosis
Refer to medical practitioner with expertise
Substance abuse
Active substance abuse is not a contraindication
Associated with high rates of treatment nonadherence and may compromise treatment outcomes
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version January 29, 2014.
Sulkowski MS, et al. J Viral Hepatitis. 2007;14:371-386.
Slide 14 of XX
Specific Risks of Deferring Therapy in HIV/HCV-
Coinfected Patients
Accelerated rate of HCV-related hepatic fibrosis progression in coinfected patients with increasing immune deficiency Progression to cirrhosis risk 3-fold higher in coinfected vs
HCV-monoinfected patients
Relative risk of decompensated liver disease 6-fold higher in coinfected vs HCV-monoinfected patients
HCC occurs earlier and more aggressive
Coinfected patients have reduced access to liver transplantation and reduced survival
ART may delay liver disease progression
Taylor LE, et al. Clin Infect Dis. 2012;55(suppl 1:S33-42). DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013. Naggie S, et al. Gastroenterology. 2012;142:1324-1334. Macías J, et al. Clin Infect Dis. 2013;57:1401-1408.
Slide 15 of XX
0.2
0.4
0.6
0.8
1
Bonn Cohort: Benefits of ART on
Mortality in HCV/HIV-Coinfection
HCV/HIV-coinfected patients
(n=285)
Liver-related mortality rates (per
100 person-years)
With ART: 0.45
No ART: 1.70
Predictors for increased liver-
related mortality
No ART
Low CD4 cell count
Increasing age
ART therapy can slow fibrosis
progression and decrease
mortality in coinfection
Qurishi N, et al. Lancet. 2003:362:1708-1713.
Overall Mortality
Cu
mu
lati
ve
Su
rviv
al
Days0 1000 2000 3000 4000 5000 6000
ART*
No therapy*P<0.001
0.2
0.4
0.6
0.8
1
Liver-Related Mortality
Cu
mu
lati
ve
Su
rviv
al
Days0 1000 2000 3000 4000 5000 6000
HAART*
No therapy
*P=0.018
Slide 16 of XX
ALIVE Study: HIV, Age, and Severity
of HCV-Related Liver Diseases
Prospective cohort of HCV-infected IDUs
(2006-2011) (n=1176)
HIV co-infected (n=394)
Baseline and semi-annual elastography
Fibrosis was significantly greater in
HCV/HIV co-infected versus HCV
monoinfection (P<0.001)
No cirrhosis (12.9% versus 9.5%)
With cirrhosis (19.5% versus 11.0%)
Independently associated with increasing
age and HIV infection
HCV/HIV patients have liver fibrosis
similar to HCV mono-infected patients
who are nearly 10 years older
Kirk GD, et al. Ann Intern Med. 2013;158:658-666.
Pre
dic
ted
Fib
roS
ca
n S
co
re (
kP
a)
30 35 40 45 50 55 60
Liver Fibrosis and Age:HCV/HIV Versus HCV Infection
Age (years)
HCV/HIV
HCV
9.2 years
ALIVE: AIDS Linked to the IntraVenous Experience.
Slide 17 of XX
HCV Coinfection vs Monoinfection:
Cumulative Incidence of Decompensation
10-year hepatic decompensation risk 83% higher in coinfected patients
Adjusted HR 1.83 (95% CI: 1.54-2.18)
P < .001
HIV/HCV coinfectedHCV monoinfected
0.074
0.048
. Lo Re V, et al. IAC 2012. Abstract WEAB0102.
0
0.1
0.2
0 1 2 3 4 5 6 7 8 9 10
Yrs to Hepatic Decompensation
Slide 18 of XX
HCV Treatment and Incidence
of ESLD, HCC, and Death
Prospective US cohort (1993-2011)
(n=638)
Liver biopsy at baseline
35% underwent HCV treatment with PR
Baseline >F2 versus <F2 fibrosis
Higher treatment rates: 54% versus
28% (P<0.001)
Similar SVR rates: 17% versus 16%
No clinical events (ESLD, HCC, and
death) among patients achieving SVR
Cu
mu
lati
ve
Su
rviv
al
0 2 4 6 8 10
Survival Free ofESLD, HCC, or Death
Time Since Biopsy (years)
Log-rank P=0.005
No HCV treatment
SVR
Relapse
Nonresponse
Limketkai BN, et al. JAMA. 2012;308:370-378.
Slide 19 of XX
Assessing HIV+ Patients for Immediate or
Deferred HCV Therapy
Antiretroviral therapy for HIV treatment-naive
HIV/HCV-coinfected patients
CD4+ cell count < 500 cells/mm3: initiate antiretroviral therapy
for HCV treatment optimization
CD4+ cell count > 500 cells/mm3: may defer antiretroviral
therapy until HCV therapy completed
EACS Guidelines, Version 7.0. October 2013. . DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013.
Macías J, et al. Clin Infect Dis. 2013;2013;57:1401-1408.
HCV Therapy in HIV/HCV-Coinfected, HCV Treatment-Naive Patients
Liver FibrosisConsider
HCV Therapy
Eligible to
Defer HCV Therapy
No/minimal fibrosis (F0-F2) ●
Advanced fibrosis (F3-F4); cirrhosis[ ●
Slide 20 of XX
Staging of Liver Disease
Staging is disease assessment with meaningful
information for patients and providers
Liver stage is the CD4 count of HCV
Who and When to treat (i.e. now or later?)
Screening for HCC and varices
Modalities:
Liver biopsy
Blood markers,
Elastography,
Combination
Slide 21 of XX
Noninvasive Serum-Based Tests for Detection
of Fibrosis
FibroTest
Combines 5 markers: α2-macroglobulin, haptoglobin, GGT, total bilirubin, and
apolipoprotein A1
FibroSpect II
Combines 3 markers: α2-macroglobulin, hyaluronic acid, and tissue inhibitor of
metalloproteinase-1
APRI
AST-to-platelets ratio index
Forns fibrosis index
Age, platelet count, GGT, cholesterol
FIB-4
Combines 4 markers: platelets, ALT, AST, and age
Slide 22 of XX
Validity of Noninvasive Methods of
Detecting Cirrhosis
Test % Sens % Spec AUROC Pos LR Neg LR
Fibrotest1 >.56 85 74 .86 3.3 0.2
Fibrotest > .73 56 81 - 2.9 0.54
FIB42, >1.45 90 58 .87 2.1 0.17
APRI3, >1.0 77 75 0.73 3.1 0.31
Forns4, >4.2 98 27 87 1.3 0.07
Chou Ann Intern Med 2013
Slide 23 of XX
FibroScan (Elastography)
• The probe induces an elastic wave through the liver
• The velocity of the wave is evaluated in a region located from 2.5 to 6.5 cm below the skin surface
• Diagnostic accuracy:• Significant fibrosis: 0.79• Advanced fibrosis: 0.91• Cirrhosis: 0.97
8.8 9.6 14.6
FibroScan (kPa)
Liver Fibrosis(METAVIR)
F0-F1 F2 F3 F4
Ziol M, et al. Hepatology. 2005;41:48-54.
Slide 24 of XX
Which staging test should be done?
297 HIV/HCV coinfected patients with Liver Stiffness Model and biopsy within 12 months Dec 2005-Dec 2011.
LSM-based models performed 8.4% better than liver biopsy prediction survival and liver-decompensation
Macias AIDS 2013
Slide 25 of XX
Which staging test should be done?
Elastography provides the most, currently useful
information when valid
Elastography and noninvasive can confidently rule
out cirrhosis when concordant
Serum alone may confidently rule out cirrhosis
Biopsy done by specialists and when discordance or
other questions
Do something
Slide 27 of XX
DAA Drug Interactions
Phase III Study: Rilpivirine (15%), Raltegravir (87%), Maraviroc, Enfuvirtide, NRTIs
ARV BOC TPV SMV SOF* DCV FDV
ATV/r CAUTION STAND CONTRA STAND DCV FDV
DRV/r CONTRA CONTRA CONTRA STAND N/A FDV
EFV CONTRA TPV CONTRA STAND DCV FDV
RPV STAND CAUTION STAND STAND STAND N/A
ETV CAUTION CAUTION CONTRA STAND N/A N/A
RGV STAND STAND STAND STAND STAND STAND
DGV N/A N/A CAUTION STAND N/A N/A
MVC MVC MVC STAND STAND STAND STAND
*Tipranavir CONTRA with SOFOuwerkerk-Mahadevan et al. IDSA 2012 Abstract #49; Hulskotte et al. Clin Infect Dis 2013; de Kanter et al. CROI 2012; Bifano et al. CROI 2012; Kirby et al. AASLD 2012
Slide 28 of XX
AASLD and IDSA Guidelines:
Preferred HCV Regimens in HCV/HIV Coinfection
HCV treatment-naïve and prior PR relapsers
IFN eligible
IFN ineligible
Sofosbuvir + PR 12 weeks
Sofosbuvir + RBV 24 weeks
Sofosbuvir + simeprevir† + RBV 12 weeks
HCV treatment experienced* Sofosbuvir + simeprevir† + RBV 12 weeks
*Prior PR non-responders regardless of IFN eligibility. †For genotype .
Allowable ART: Sofosbuvir: all except the NRTIs didanosine and zidovudine.
Simeprevir: INSTI (raltegravir); NNRTI (rilpivirine); Entry/Fusion Inhibitor (maraviroc, enfuvirtide);
NRTIs (tenofovir, emtricitabine, lamivudine, abacavir).
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version January 29, 2014.
Genotype 1
Regardless of HCV treatment history Sofosbuvir + RBV 12 weeks
Genotype 2
Genotype 3
Regardless of HCV treatment history Sofosbuvir + RBV 24 weeks
Regardless of HCV treatment history
IFN eligible
IFN ineligible
Sofosbuvir + PR 12 weeks
Sofosbuvir + RBV 24 weeks
Genotype 4
Genotypes 5 or 6Regardless of HCV treatment history Sofosbuvir + PR 12 weeks
Slide 29 of XX
AASLD and IDSA Guidelines:
Alternative HCV Regimens in HCV/HIV Coinfection
HCV treatment-naïve and prior PR relapsers
IFN eligible
IFN ineligible
Simeprevir† 12 weeks + PR 24 weeks
None
HCV treatment experienced*
IFN eligible
IFN ineligible
Sofosbuvir + PR 12 weeks
Sofosbuvir + RBV 24 weeks
*Prior PR non-responders.†For genotype 1a, baseline resistance testing for Q80K should be performed and alternative treatments considered if present.
Allowable ART: Sofosbuvir: all except the NRTIs didanosine and zidovudine.
Simeprevir: INSTI (raltegravir); NNRTI (rilpivirine); Entry/Fusion Inhibitor (maraviroc, enfuvirtide);
NRTIs (tenofovir, emtricitabine, lamivudine, abacavir).
Genotype 1
None
HCV treatment-naïve and prior PR relapsers None
HCV treatment experienced*
IFN eligible
IFN ineligible
Sofosbuvir + PR 12 weeks
None
Genotypes 2 or 3
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version January 29, 2014.
Genotypes 4, 5, or 6
Slide 30 of XX
AASLD and IDSA Guidelines: HCV Regimens
Not Recommended in HCV/HIV Coinfection
Telaprevir + PR 24 or 48 weeks (RGT)
Boceprevir + PR 28 or 48 weeks (RGT)
PR 48 weeks
Simeprevir 12 weeks + PR 48 weeks
Genotype 1
Any regimen with telaprevir, boceprevir, or simeprevir
PR 24 to 48 weeks
Genotypes 2 or 3
Any regimen with telaprevir, boceprevir, or simeprevir
PR 48 weeks
Genotypes 4, 5, or 6
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version January 29, 2014.
Slide 31 of XX
NIAID ERADICATE Study: Sofosbuvir/Ledipasvir in HCV
Genotype 1 With HIV Coinfection (Interim Analysis)
No change within groups
CD4 counts or CD4 T-cell percentages
Serum creatinine or estimated GFR
HIV RNA status during HCV treatment
ART-naïve: no clinically significant change
On ART: transient HIV RNA breakthrough
(missed ART for 4 days), re-suppressed
No change within groups
Sofosbuvir/ledipasvir was well tolerated
No deaths, grade 4 adverse events or
discontinuations due to adverse events
Laboratory abnormalities
Grade 3: neutropenia (n=1), AST (n=1)
Grade 4: creatinine phosphatase (n=1)
Osinusi A, et al. J Hepatol. 2014;60(suppl 1):S7. Abstract O14.
SV
R (
%)
100% 100% 100%
Not Yet
Available
SVR Rates(Interim, Observed)
ART-Naïve(n=12/10)
SVR4
SVR12
On ART(n=22/0)
Slide 32 of XX
HCV/HIV Coinfection:
Summary
Liver disease is a leading cause of morbidity and mortality
Controlling HIV with ART may slow progression of HCV-
related liver disease
All HIV patients should be screened for HCV
First-generation PIs + PR regimens present significant
challenges and limitations
Newer, once-daily DAAs
Simplify and shorten duration of regimens
Improve SVR rates with fewer adverse events
Minimize drug-drug interactions
Recommended