Transcript Document

HIV and Hepatitis C Co-infection:
Current Standards and New
Paradigms
Todd S. Wills, MD
Associate Professor of Internal Medicine
Division of Infectious Disease
and International Medicine
USF Health
Faculty, Florida/Caribbean
AIDS Education and Training Center
Disclosure of Financial Relationships
This speaker has significant financial
relationships with the following commercial
entities to disclose:
• Grants/Research Support: Gilead Sciences
This speaker will not discuss any off-label use or
investigational product during the program.
This slide set has been peer-reviewed to ensure that there are no conflicts
of interest represented in the presentation.
Objectives
• Review current HCV standard of care
• Discuss the current use of HCV protease
inhibitors in dually infected patients
• Identify agents in the HCV therapeutic
pipeline and implications for HIV care
Hepatitis C Treatment Guideline Resource Card
Available online at www.fcaetc.org/treatment
HCV/HIV Co-infection
• Higher rates of progressive liver
disease in HIV/HCV co-infection
• Unclear whether HCV increases HIV
progression
• Poor prognosis; unclear whether HIV
treatment improves morbidity and
mortality for untreated HCV
• Higher rates of ARV-associated
hepatotoxicity
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed
February 20, 2012
To Treat or Not to Treat:
A Constellation of Considerations
Genotype:
virus,
patient (IL28B)
Histologic stage
20%+ lifetime risk
of cirrhosis
Duration of
infection
Personal plans
(marriage,
pregnancy)
Age
Family and
other support
Patient mindset
ALT
Occupation
HIV co-infection
Contraindications
& comorbidities;
insulin resistance
Extrahepatic
features
(fatigue, EMC, PCT)
from Clinical Care Options
In which clinical situation is treatment of
HCV absolutely contraindicated?
A. Renal Failure
B. Cyroglobulinemic
vasculitis
C. Uncontrolled Major
Depression
D. Current alcohol or
drug use
54%
28%
16%
2%
A.
B.
C.
D.
HCV/HIV Co-infection
• Higher rates of progressive liver
disease in HIV/HCV co-infection
• Unclear whether HCV increases HIV
progression
• Poor prognosis; unclear whether HIV
treatment improves morbidity and
mortality for untreated HCV
• Higher rates of ARV-associated
hepatotoxicity
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed
February 20, 2012
HCV/HIV Co-infection: When to Treat
• Strongly recommended for detectable
plasma HCV RNA and bridging or portal
fibrosis on liver biopsy
• Consider other factors:
–
–
–
–
–
Stage and stability of HIV disease
Other comorbidities
Probability of adherence
Possible contraindications to HCV medications
Prognosis for favorable response
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed
February 20, 2012
Assessment of Alcohol and Substance Abuse
• Ongoing Alcohol use? Amount?
• Ongoing Substance Abuse? Amount?
• How much use is acceptable?
Indicators of Decompensated Cirrhosis
•
•
•
•
•
Development of ascites
Variceal hemorrhage
Hepatic encephalopathy*
Jaundice
Hepatocellular carcinoma*
– Screen via ultrasound every 6 months for patients with
cirrhosis or bridging fibrosis
* can occur even in incomplete cirrhosis
Morgan T, Hepatitis Annual Update 2009. clinicaloptions.com – accessed March 12, 2011
Evaluation of Liver Status and Transplantation
Referral
• Prognosis via MELD (Model for end stage liver
disease) score should be assessed
periodically
• Calculator available at:
http://www.mayoclinic.org/mel/mayomodel6.html
• Score greater than 10 indicates need for
possible liver transplantation referral
Mental Health Assessment
• Mental Health Referral
• CES-D or PHQ-9 questionnaires
Factor Predicting Favorable Response
•
•
•
•
•
•
•
•
HCV Genotype 2, 3
HCV RNA level <400,000
May be less predictive of
IL-28B genotype CC
response with use of
direct acting antivirals
Non-African American race
Absence of bridging fibrosis or cirrhosis
Body weight <75 kg
Age <40
Baseline ALT > 3x ULN
Sulkowski, M, et al. A Guide for Evaluation and Treatment of Hepatitis C in Adults Coinfected
with HIV http://hab.hrsa.gov/deliverhivaidscare/files/hepccoinfectguide2011.pdf. Accessed
February 21,2012
Factors Favoring Initiation of Therapy
• Patient motivation
• Biopsy with chronic hepatitis and greater
than portal fibrosis
• Cryoglobulinemic vasculitis or
Cryoglobulinemic kidney disease
• Stable HIV disease
• Compensated liver disease
• Acceptable hematologic parameters
• Serum creatinine <1.5
Overcoming Barriers to Treatment Initiation
•
•
•
•
•
•
Substance Abuse Counselors
Opioid Dependence Treatment
Patient Education
Peer-Based Counseling
Group Counseling
Clinic-Based Injections
Selecting Patients for Treatment
• Need to differentiate between nonsignificant fibrosis and
significant fibrosis
• International Association for the Study of the Liver scoring system
for staging liver fibrosis
•
Stage
0
1
2
3
4
Score
None
Significance
Mild
Moderate
Nonsignificant
Severe
Significant
• Assess liver fibrosis; options include
– Liver biopsy
– Noninvasive markers of hepatic fibrosis
– Transient elastography
Ghany M, et al. Hepatol. 2009;49:1335-1374. Soriano V, et al. AIDS. 2007;21:1073-1089.
Cirrhosis
Absolute Contraindications to Therapy
• Uncontrolled active major psychiatric illness
• Hepatic decompensation (hepatic
encephalopathy, coagulopathy, or ascites)
• Uncontrolled HIV with advanced
immunosuppression (CD4 < 100 cells/mm3)
• Known allergy or severe adverse reaction to
interferon and/or ribavirin
Sulkowski, M, et al. A Guide for Evaluation and Treatment of Hepatitis C in Adults Coinfected
with HIV http://hab.hrsa.gov/deliverhivaidscare/files/hepccoinfectguide2011.pdf. Accessed
February 21,2012
Absolute Contraindications to Therapy
• Women who are pregnant, nursing, or are of
childbearing potential and not able to practice
contraception
• Men who have pregnant partners or partners of
childbearing potential and unwilling to practice
contraception during treatment and for 6 months after
treatment ends
• Active, untreated autoimmune disease (e.g., systemic
lupus erythematosus) known to be exacerbated by
peginterferon and ribavirin
• Uncontrolled thyroid disease
Sulkowski, M, et al. A Guide for Evaluation and Treatment of Hepatitis C in Adults Coinfected
with HIV http://hab.hrsa.gov/deliverhivaidscare/files/hepccoinfectguide2011.pdf. Accessed
February 21,2012
Relative Contraindications to Treatment
• Significant hematologic abnormality:
hemoglobin < 10.0 g/dl, absolute neutrophil
count < 1,000/μl, or platelet count < 50,000/μl
• CD4 <200 cells/mm3
• Patients concurrently receiving zidovudine
• Renal dysfunction – (consider specialist
referral)
Sulkowski, M, et al. A Guide for Evaluation and Treatment of Hepatitis C in Adults Coinfected
with HIV http://hab.hrsa.gov/deliverhivaidscare/files/hepccoinfectguide2011.pdf. Accessed
February 21,2012
Relative Contraindications to Treatment
• Autoimmune disorders (systemic lupus
erythematosus, rheumatoid arthritis)
• Active substance use or ongoing alcohol use if
interference with adherence is anticipated
• Untreated mental health disorder
• Hemoglobinopathies (e.g., thalassemia major and
sickle cell anemia)
• Sarcoidosis
• Solid organ transplantation patients
Sulkowski, M, et al. A Guide for Evaluation and Treatment of Hepatitis C in Adults Coinfected
with HIV http://hab.hrsa.gov/deliverhivaidscare/files/hepccoinfectguide2011.pdf. Accessed
February 21,2012
PegIFN/RBV: Current Standard-of-Care Treatment for HCV/HIV
Co-infected Patients
Regimens for Genotype 1 and 4 x 48 weeks
180 mcg sc weekly
pegylated interferon alfa-2a AND
ribavirin*
≤ 75 kg: 1000 mg/day in 2 divided doses
>75 kg: 1200 mg/day in 2 divided doses
pegylated interferon alfa-2b AND
ribavirin
1.5 mcg/kg sc weekly
< 65 kg: 800 mg/day in 2 divided doses
66-80 kg: 1,000 mg/day in 2 divided
doses
81-105 kg: 1,200 mg/day in 2 divided
doses
>105 kg: 1,400 mg/day in 2 divided doses
Regimens for Genotype 2 and 3 x 48 weeks
pegylated interferon alfa-2a* OR
180 mcg sc weekly
pegylated interferon alfa-2b
1.5 mcg/kg sc weekly
AND ribavirin*
800 mg daily
*ribavirin and pegylated interferon alfa-2a doses should be reduced in patients with a creatinine
clearance <50 ml/min. No data is available for the use of pegylated interferon alfa-2b/ribavirin in
patients with a CrCl <50 mL.min.
Ribavirin Dose Adjustments in Renal
Impairment
Creatinine Clearance
pegylated interferon alfa-2a
dose
Ribavirin dose
30-50 mL/min
180 mcg/week
200 mg alternating with
400 mg every other day
< 30 mL/min
135 mcg/week
200 mg daily
Hemodialysis
135 mcg/week
200 mg daily
Specialty referral recommended for HCV treatment in the setting of renal impairment
Labeling change for Pegasys and Copegus re: dosing patients with renal impairment.
http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm267594.htm
Accessed March 6, 2012
Areas of Advancement in HIV/HCV Therapy
• Specific HCV antiviral therapy trials
• Limitations of Predictive Biomarkers
• Implications of HCV drug resistance
HCV Response Rates in HIV+ and HIV- Patients
Treated with PegIFN/RBV
APRICOT
HIV-Positive
PRESCO
HIV-Positive
FRIED
HIV-Negative
Overall SVR: 40%
Overall SVR: 50%
Overall SVR: 56%
Patients With SVR (%)
100
80
76
72
62
60
40
46
36
29
20
0
n = 176
95
191
152
298
140
GT1/4 GT2/3
GT1/4 GT2/3
GT1/4 GT2/3
48 Wks of Therapy,
600 mg RBV
24, 48, or 72 Wks
of Therapy,
Weight-Based RBV
48 Wks of Therapy,
Weight-Based RBV
Soriano V, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated
recommendations from the HCV–HIV International Panel AIDS. 2007;21:1073-1089.
Potential HCV Antiviral Targets
5’
Internal
ribosomal
entry site
C
RNA
binding
site
E1
E2/NS1
Envelope
glycoproteins
NS2
Signal
peptide
NS3
NS4A
NS4B
Serine protease/
helicase
telaprevir, boceprevir
NS5A
NS5B
RNA dependent
RNA polymerase
3’
An HCV viral load below the quantitative limit of
detection 4 weeks after initiating HCV treatment is
called:
A. Early virologic
response (EVR)
B. End-of-treatment
response (EOT)
C. Rapid virologic
response (RVR)
D. Sustained virologic
response (SVR)
52%
42%
5%
2%
A.
B.
C.
D.
Response Terminology
Term
Time Point
HCV RNA Level
Rapid virologic
response (RVR)
Wk 4 of therapy
Undetectable
Early virologic response
(EVR)
Wk 12 of therapy
≥ 2 log10 IU decrease from
baseline
Complete early virologic
response (cEVR)
Wk 12 of therapy
Undetectable
Slow to respond
Wk 24 of therapy
Undetectable (but with
detectable HCV RNA at Wk 12)
End of therapy
Undetectable
6 mos post-therapy
Undetectable
End of treatment
response (EOT or ETR)
Sustained virologic
response (SVR)
Adherence
• Triple therapy presents
challenges with already
busy schedules[143]
– TID dosing
– Food requirements
• Data show pegIFN/RBV
adherence decreases
over time[5]
– Addition of PIs may
exacerbate this trend
Busy Sales Professional
Monday
Monday
6:00 AM TVR/BOC (with food) + RBV
TVR/BOC (with food) + RBV
7:00 AM
8:00 AM
9:00 AM
Daily Team Conference Call
11:00 AM
English Composition
Travel to and Meet With
Client
Lunch
Lunch
1:00 PM
Lunch
Biology
TVR/BOC
(with food)
Dentist Appt
4:00 PM
Work
Travel to and
Meet With
Clients
5:00 PM
Dinner
RBV
Patient
Appointments
TVR/BOC (with
food)
Pick up kids, commute home
RBV
7:00 PM
Running Club
Dinner
Study Group
Researching Trade Articles
9:00 PM
10:00 PM
TVR/BOC
(with food)
Calls to Clients
3:00 PM
8:00 PM
TVR/BOC (with food) + RBV
Wake, feed, and dress children
for school
School and daycare drop-off,
commute to work
Patient Appointments
12:00 PM
2:00 PM
Mother With Small Children
and Full-time Nurse
Monday
Chemistry Lab
10:00 AM
6:00 PM
1. Telaprevir [package insert]. May 2011.
2. Boceprevir [package insert]. May 2011.
3. EMA. Boceprevir [package insert] 2011.
4. EMA. Telaprevir [package insert] 2011.
5. Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.
Typical Student
TVR/BOC (with food)
TVR/BOC (with food)
from Clinical Care Options
Dinner
RBV
Get children ready for and in to
bed
Dinner cleanup, make lunches
for next day
TVR/BOC (with food)
Study 110: High Rates of Early Response With
TVR + PR in Co-infected Patients
•
•
•
Similar efficacy results observed with or without concurrent ART
Nausea, pruritus, dizziness, fever more common with TVR vs placebo
Pharmacokinetic interactions with ATV or EFV not clinically significant
Undetectable HCV RNA, Week 4 (ITT)
No ART
EFV-based ART
Undetectable HCV RNA, Week 12 (ITT)
ATV/RTV-based ART
Total
80
100
71 75
64 70
60
40
12
20
0
n/N = 5/7 12/16 9/14 26/37
Telaprevir + PR
0
0
5
0/6 1/8
0/8
1/22
Undetectable
HCV RNA (%)
Undetectable
HCV RNA (%)
100
80
60
71 75
68
57
40
17 12 12 14
20
0
PR
Sulkowski M, et al. CROI 2011. Abstract 146LB.
n/N = 5/7 12/16 8/14 25/37
Telaprevir + PR
1/6
1/8
1/8
PR
3/22
Study 110 – SVR 12 Data
Telaprevir Group N=38 Placebo Group
SVR12
28/38 (74)
10/22 (45)
On Treatment Virologic
Failure
3/38 (8)
8/22 (36)
Not Suppressed at End
of Treatment
5/37 (14)
9/22 (41)
Relapse
1/32 (3)
2/13 (15)
Dieterich D, et al. CROI 2012 Abstract 46
Telaprevir plus PegINF and Ribavirin in HIV/HCV
Infected Patients – Side Effects
Adverse Effect
TVR+PR
PR
Pruritis or Itching
39%
9%
Headache
37%
27%
Nausea
34%
23%
Skin Rash*
34%
23%
Fever
21%
9%
Anemia
13%
18%
Depression
21%
9%
Insomnia
13%
23%
*no cases of severe rash
Sherman, KE et al.. AASLD Conference November 2011 – Late Breaker Abstract 8
Boceprevir in Addition to Pegylated INF alfa 2a in
HIV/HCV Patients on ARVs
Sulkowski, M. CROI 2012 Abstract 47
Boceprevir Interactions with HIV Medications
• No clinically relevant changes in boceprevir exposure
when co-administered with ethinyl estradiol or tenofovir.
• Boceprevir AUC and Cmax decreased, minimum
concentration (Cmin) fell by about 40% when
administered with efavirenz.
• Boceprevir co-administered with ritonavir-booster HIV
protease inhibitors may reduce the levels of both drugs.
CROI 2011 Abstract 118: Merck & Co, Inc, Kenilworth, NJ.
Merck & Co. Inc. Results of pharmacokinetic study in healthy volunteers given VICTRELIS™
(boceprevir) and ritonavir-boosted HIV protease inhibitors may indicate clinically significant
drug interactions for patients coinfected with chronic hepatitis C and HIV. Feb 6 , 2012.
(http://www.merck.com/newsroom/pdf/FINAL_DHCP_2_6_2012.pdf)
Telaprevir Interactions with HIV PIs
• Telaprevir AUC and Cmin decreased by only about 15%
when administered 750 mg 3-times-daily with boosted
atazanavir.
• Telaprevir levels fell by about 50% when administered at
the same dose with lopinavir/ritonavir.
• Telaprevir levels decreased by about 30% when taken with
darunavir/ritonavir or fosamprenavir/ritonavir.
• Conversely, darunavir and fosamprenavir levels fell by
more than half when co-administered with telaprevir.
• Atazanavir Cmin nearly doubled when taken with 750 mg
telaprevir.
CROI 2011 Abstract 119: Tibotec BVBA, Beerse, Belgium; Vertex Pharmaceuticals Inc,
Cambridge, MA
Telaprevir Dosing Recommendations
• Based on these findings, researchers
chose 750 mg 3-times-daily telaprevir
plus atazanavir/ritonavir, or telaprevir
1125 mg 3-times-daily with efavirenz as
regimens to evaluate in clinical trials of
HIV/HCV coinfected patients.
CROI 2011 Abstract 119: Tibotec BVBA, Beerse, Belgium; Vertex Pharmaceuticals Inc,
Cambridge, MA
Telaprevir Interactions with Raltegravir
• Co-administration of raltegravir did not influence
telaprevir exposure or pharmacokinetics.
• Co-administration of telaprevir increased exposure
to raltegravir by 31%.
• The least square means ratios for raltegravir
Cmin, Cmax, and AUC12h were 1.78, 1.26, and
1.31, respectively.
• The 2 drugs were generally well-tolerated.
• All adverse events were mild-to-moderate (grade
1-2) and no participants discontinued early due to
adverse events.
R van Heeswijk et al. The Pharmacokinetic Interaction Between Telaprevir & Raltegravir in
Healthy Volunteers ICAAC Chicago Sept 17-20 2011
Investigational Agents
PSI-7977 – Phase II Trial Data
HCV uridine nucleotide analogue
12 WEEK Treatment
PSI-7977/P/R
n=47
PSI 7977/P/R PSI 7977/R
n=54
n=10
PSI-7977
n=10
EOT
43
54
10
10
Week 1-4 Relapse
1
0
0
4
SVR 4
42
54
10
6
> Week 4 Relapse
0
0
0
0
SVR 12
42
54
10
pending
SVR 24
42
41 (11 pend)
4 (6 pend)
pending
Genotype 1
Genotype 2/3
Lawritz, E. et al. J of Hepatology 54 (s1) 2012
TMC-435 – Phase IIb Trial Data
•
HCV NS3/4A Protease Inhibitor (Once-Daily)
• Prior Treatment Failures
TMC12/P
R48
n=66
TMC24/
PR48
N=65
TMC48/P
R48
N=66
TMC12/P
R48
n-=66
TMC24/P
R48
N=68
TMC48/PR Pbo48/P
48
R48
N=65
N=66
RVR Total
44/66
(67)
38/65
(59)
35/66
(53)
41/66
(62)
46/68
(68)
43/65
(66)
1/66
(2)
SVR Total
46/66
(70)
43/65
(66)
40/66
(61)
44/66
(67)
49/68
(72)
52/65
(80)
15/66
(23)
SVR Null
6/16
(38)
9/16
(56)
8/18
(44)
9/17
(53)
7/17 (41)
10/17
(59)
3/16
(19)
SVR Partial
16/23
(70)
11/23
(48)
12/22
(55)
15/23
(65)
18/24
(75)
19/22
(86)
2/23
(9)
SVR
Relapse
24/27 (
89)
23/26
(89)
20/26
(77)
20/26
(77)
24/37
(89)
23/26
(89)
10/27
(37)
100 mg
150 mg
P<0.001 vs placebo
Zeuzem S., et al. J of Hepatology 54 (s1) 2012
Interferon Sparing Strategies
• ABT 450/r – ritonovir boosted HCV PI +
• ABT 072 – HCV polymerase inhibitor +
• Weight-based ribavirin
• Open label 12 week treatment trial 11 patients
• Interferon sparing
• 91% SVR24
• One patient relapsed 8 weeks post Rx
• All patients were IL28B CC
Lawritz, E. et al. J of Hepatology 56 (s1) 2012
Interferon AND Ribavirin Sparing Strategies
• Daclatasvir (NS5A replication complex inhibitor) +
• Asunaprevir (HCV NS3 PI)
• Open label trial of both drugs in 43 prior null
responders or with IFN/R intolerance
Null Responders
N=21
IFN/R Ineligible or
Intolerant N=22
IL28B CC
3/21 (14.3)
16/22 (72.7)
RVR
11/21 (52.4)
19/22 (86.4)
cEVR
19/21 (90.5)
20/22 (90.9)
EOT
18/21 (85.7)
16/22 (72.7)
SVR 12
19/21 (90.5)
14/22 (63.6)
Suzuki, F. et al. J of Hepatology 56 (s1) 2012
Predictive Biomarkers
Which of the following is more likely if a
patient is IL28B genotype CC?
A. Spontaneous
clearance of HCV
B. HCV treatment
failure with interferon
based therapy
C. Slower progression
to cirrhosis if
HIV/HCV co-infected
47%
29%
24%
A.
B.
C.
Percentage of SVR by Genotypes for IL-28B Region
DL Ge et al. Nature 461, 399-401 (2009)
Rate of SVR and IL-28 Region C-allele
Frequency in Diverse Ethnic Groups
DL Ge et al. Nature 461, 399-401 (2009)
SVR to Telaprevir by Response Category and IL28B Genotype
Pol S, et al. EASL 2011. Abstract O-13.
Effect of Unfavorable IL28b Genotype is Less
in Caucasian Genotype 2/3 HCV Infection
P=0.45
P=0.34
Genotype 2, N=213; Genotype 3, N=55
Mangia A, et al. Gastroenterology 139 (3) 821-827 (2010)
P=0.0002
Proportion of HIV/HCV Co-infected Patients with
Liver Cirrhosis, According to IL28B Variants and HCV
Genotypes
Barreiro P et al. J Infect Dis. 2011;203:1629-1636
Risk for Developing HCV–related Liver Cirrhosis Over
Time in HIV/HCV Co-infected Patients, According
IL28B Variant
Barreiro P et al. J Infect Dis. 2011;203:1629-1636
Predictors of Liver Cirrhosis in Human Immunodeficiency
Virus (HIV)–Hepatitis C Virus (HCV) Co-infected Patients, by
Logistic Regression Analysis
Variable
OR (95% CI)
P-value
Age (per year)
1.05 (0.99-1.12)
0.08
Male Sex
1.20 (0.42-3.44)
0.72
Prior ETOH >60g/d
1.97 (0.95-4.06)
0.07
ALT (per IU/L)
0.99 (0.94-1.06)
0.93
Nadir CD4
0.98 (0.99-1.01)
0.63
Receipt of ARVs
2.04 (0.42-9.93)
0.38
IL28B CC vs CT/TT
2.32 (1.22-4.41)
0.01
Barreiro P et al. J Infect Dis. 2011;203:1629-1636
Stable Viral Reservoirs Prevent Eradication
of HIV Infection
Courtesy of RF Siliciano from Clinical Care Options
HCV Life Cycle
From Clinical Care Options 2011HIV/HCV Annual Symposium; Stuart Ray, MD
Reversion of Drug Resistance Mutations
Following Telaprevir Failure
US DHHS. Advisory committee briefing document for NDA 201-917 telaprevir 375 mg tablets.
Primary Mutations Conferring Resistance
to NS3/4A Protease Inhibitors
Soriano V et al. Clin Infect Dis. 2009;48:313-320
Conclusions
• HCV treatment in HIV-infected patients is of
increasing importance as proportion of liverrelated morbidity and mortality in HIV
increases
• A comprehensive clinical approach is helpful in
managing the multiple co-morbidities and
treatment related complications in HIV/HCV
infected patients
• Novel HCV antivirals are significantly
improving disease outcome in HCV