Transcript Best Practices in the Management of HCV/HIV Coinfection

Best Practices in the Management
of HCV/HIV Coinfection:
Optimizing Treatment Success
Jürgen K. Rockstroh, MD
Professor of Medicine
University of Bonn
Bonn, Germany
This program is supported by an educational grant from
Background and Epidemiology
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Background and Epidemiology
 HIV accelerates the natural course of hepatitis C[1]
 Successful antiretroviral therapy can slow fibrosis progression but not
back to the rate in HCV monoinfection[2]
 Liver disease associated with HCV infection has become a leading
cause of morbidity and mortality among HCV/HIV-coinfected patients[3]
 HIV/HCV epidemiology[4]
– Approximately 25% of HIV+ patients are coinfected with HCV
– Approximately 80% of HIV+ patients who inject drugs are coinfected with
HCV
– All patients with HIV infection should be tested for HCV
 HIV+ patients are at 4.1 times the risk of HCV as HIV- patients[5]
1. Rockstroh JK, et al. Am J Gastroenterol. 1996;91:2563-2568. 2. Graham CS, et al. Clin Infect Dis.
2001;33:562-569. 3. Weber R, et al. Arch Intern Med. 2006;166:1632-1641. 4. CDC. HIV and viral
hepatitis. May 2013. 5. Yaphe S, et al. Sex Transm Infect. 2012;88:558-564.
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Sexual Transmission of HCV Among
HIV+ MSM: An Emerging Population
 Reports of epidemic of sexually transmitted HCV among HIV+ MSM
– United States: 6-fold higher incidence rate in HIV+ vs HIV- MSM[6]
– Swiss HIV Cohort Study: HCV incidence increased 18-fold from
1998 to 2011[7]
– Sydney, Australia: 9% of HIV+ MSM coinfected with HCV vs 1.9%
HIV- MSM[8]
– Amsterdam, Netherlands: HIV/HCV coinfection prevalence
increased from 14.6% to 20.9% from 2000-2007[9]
 Phylogenic analysis indicates HCV transmission clusters in some
areas[9,10]
6. Witt MD, et al. Clin Infect Dis. 2013;57:77-84. 7. Wandeler G, et al. Clin Infect Dis. 2012;55:1408-1416.
8. Lea T, et al. Sexual Health. 2013;10:448-451. 9. Urbanus AT, et al. AIDS. 2009;23:F1-F7.
10. MMWR. 2011;60:945-950.
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Risk Factors for Sexual HCV Transmission
Among HIV+ MSM
 Multiple factors associated with HCV transmission[11,12]
– Unprotected receptive anal intercourse
– Online casual sexual partners
– Sex at sex venues
– Older age
– Syphilis
– Recreational drug use
– Drinking > 13 alcoholic drinks per week
11. Witt MD, et al. Clin Infect Dis. 2013;57:77-84. 12. Larsen C, et al. PLoS ONE. 2011;6:e29322.
Screening Guidelines
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Screening, Surveillance, Treatment
Initiation for HCV in HIV+ Patients
 US and international treatment guidelines recommend[1316]:
– HCV screening at HIV diagnosis, then annually and as
indicated
– More frequent surveillance if ongoing risk (eg, MSM, IDU)
– HCV RNA if HCV Ab+ or suspected acute infection
13. EACS Guidelines, Version 7.0. October 2013. 14. DHHS Antiretroviral Guidelines for Adults and
Adolescents. February 2013. 15. Brook G, et al. HIV Med. 2010;11:1-30. 16. Ghany MG, et al. Hepatology.
2009;49:1335-1374.
Treat or Wait?
Treatment Decisions in 2013
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Why Is HCV Therapy Deferred in Many
HIV/HCV-Coinfected Patients?
 Challenges with interferon- and/or ribavirin-based regimen
 Anticipated approval of new agents
– Greater efficacy
– All-oral regimens
– Shorter duration
– Improved tolerability
– Fewer drug-drug interactions
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Challenges With Telaprevir- or BoceprevirBased HCV Therapy in Coinfected Patients
 Regimen complexity[17,18]
– High pill burden
– Long duration, complex RGT rules
– Multiple drug-drug interactions
– Overlapping toxicities
– With/without food dosing requirements
 Tolerability
– Additional AEs beyond peginterferon/ribavirin
17. Taylor LE, et al. Clin Infect Dis. 2012;55(suppl 1):S33-S42. 18. DHHS Antiretroviral Guidelines for
Adults and Adolescents. February 2013.
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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[19-22]
– Progression to cirrhosis risk 3-fold higher in coinfected vs
HCV-monoinfected patients[20]
– Relative risk of decompensated liver disease 6-fold higher in
coinfected vs HCV-monoinfected patients[21]
 Coinfected patients have reduced access to liver
transplantation and reduced survival
19. Taylor LE, et al. Clin Infect Dis. 2012;55(suppl 1:S33-42). 20. DHHS Antiretroviral Guidelines for
Adults and Adolescents. February 2013. 21. Naggie S, et al. Gastroenterology. 2012;142:1324-1334.
22. Macías J, et al. Clin Infect Dis. 2013;57:1401-1408.
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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)
0.2
HIV/HCV coinfected
HCV monoinfected
0.1
0.074
0.048
P < .001
0
0
1
2
3
4
5
6
7
8
Yrs to Hepatic Decompensation
23. Lo Re V, et al. IAC 2012. Abstract WEAB0102.
9
10
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Importance of Informed Deferral:
Know What You Are Waiting for
 Need for individualized decision-making and informed
consent
 Stepwise progress in HCV therapy anticipated
– New interferon-based regimens
– All-oral regimens retaining ribavirin
– All-oral regimens of just DAAs
 Uncertain timeline
 Initial DAA studies excluded coinfected patients
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Assessing HIV+ Patients for Immediate or
Deferred HCV Therapy
HCV Therapy in HIV/HCV-Coinfected, HCV Treatment-Naive Patients
Liver Fibrosis
Consider
HCV Therapy
●
No/minimal fibrosis (F0-F2)[24,25]
Advanced fibrosis (F3-F4); cirrhosis[26]
Eligible to
Defer HCV Therapy
●
 Antiretroviral therapy for HIV treatment-naive HIV/HCVcoinfected patients
– CD4+ cell count < 500 cells/mm3: initiate antiretroviral
therapy for HCV treatment optimization[24,25]
– CD4+ cell count > 500 cells/mm3: may defer antiretroviral
therapy until HCV therapy completed[25]
24. EACS Guidelines, Version 7.0. October 2013. 25. DHHS Antiretroviral Guidelines for Adults and
Adolescents. February 2013. 26. Macías J, et al. Clin Infect Dis. 2013;2013;57:1401-1408.
HCV Therapy in 2013
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SVR With PegIFN/RBV by Genotype:
Coinfection vs Monoinfection
HIV/HCV Coinfection
SVR Range, %
PegIFN/RBV
(600-1200 mg)
HCV Monoinfection
GT1 or
GT4[27-31]
GT2 or
GT3[27-31]
GT1 or
GT4[32]
GT2 or
GT3[32]
14-35
44-73
0-82*
76-82
*SVR rates for GT1 or GT4 unaffected by baseline viral titer. PegIFN/RBV for 48 weeks
using 1000 mg or 1200 mg dose of pegIFN resulted in higher rates of SVR compared
with 24 weeks of therapy and/or 800 mg dose of pegIFN.
27. Carrat F, et al. JAMA. 2004;292:2839-2848. 28. Laguno M, et al. Hepatology. 2009;49:22-31. 29.
Chung RT, et al. N Engl J Med. 2004;351:451-459. 30. Torriani FJ, et al. N Engl J Med. 2004;351:438-450.
31. Núñez M, et al. AIDS Res Hum Retroviruses. 2007;23:972-982. 32. Peginterferon alfa 2a [package
insert].
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Proposed Optimal Duration of PegIFN/RBV
Therapy in Coinfected Patients
Wk 4
HCV RNA
negative
Wk 12
Wk 24
GT2/3
24-wk
therapy*
Wk 48
GT1/4**
HCV RNA
negative
> 2 log drop
in HCV RNA
HCV RNA
positive
HCV RNA
positive
< 2 log drop
in HCV RNA
Stop
33. EACS Guidelines, Version 7.0. October 2013.
GT2/3
GT1/4
Wk 72
48-wk
therapy
72-wk
therapy
Stop
*In patients with baseline low viral load and
minimal liver fibrosis.
**Where no access to DAA available or high
chances of cure even with dual therapy
(favorable IL28B genotype, low HCV viral
load, and no advanced fibrosis).
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Study 110: Telaprevir + PegIFN/RBV in
GT1 HCV/HIV Coinfection

Phase II randomized controlled
trial[34]
100
– Telaprevir TID + pegIFN/RBV vs
pegIFN/RBV alone for 48 weeks


HCV treatment-naive HIV+ patients
(N = 60)
No HIV breakthrough
Safety and tolerability
– Increased pruritus, headache,
nausea, rash, and dizziness with
telaprevir-based therapy
80
SVR (%)

SVR comparable to GT1 HCVmonoinfected patients (75%)[35]
74
71 69
60
50 50
40
45
33
20
– Anemia: 18% in both groups

80
No ART
EFV/TDF/FTC
ATV/ritonavir
+ TDF/FTC
Total
n/N =
34. Sulkowski MS, et al. Ann Intern Med. 2013;159:86-96.
35. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
0
5/
7
11/
16
12/
15
28/
38
Telaprevir +
PegIFN/RBV
2/
6
4/
8
4/
8
10/
22
PegIFN/RBV
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Study P05411: Boceprevir + PegIFN/RBV
in GT1 HCV/HIV Coinfection

Phase II randomized controlled
trial[36]
– PegIFN/RBV lead-in 4 weeks then
boceprevir + pegIFN/RBV for 44
weeks vs pegIFN/RBV alone for 48
weeks
80
HCV treatment-naive HIV+ patients
(N = 98)
60
– All with HIV-1 RNA < 50 cells/mL
on antiretroviral therapy


No difference in HIV breakthrough
Safety and tolerability
– Increased anemia, pyrexia, and
decreased appetite with boceprevirbased therapy

100
SVR comparable to GT1 HCVmonoinfected patients (68%)[37]
63
SVR (%)

40
29
20
n/N =
0
36. Sulkowski M, et al. Lancet Infect Dis. 2013;13:597-605.
37. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
40/64
10/34
Boceprevir +
PegIFN/RBV
PegIFN/RBV
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Recommendations for Coadministration of
TVR and BOC With Select Antiretroviral Agents
Antiretroviral Agent
Telaprevir
Boceprevir
Europe[38-40]
US[41]
Europe[38-40]
US[41]
Monitor for
hyperbilirubinemia
Standard dose
Case-by-case
consideration
Do not use
Not
recommended
Not
recommended
Not
recommended
Not
recommended
No dose
adjustment
No dose
adjustment
No dose
adjustment
No dose
adjustment
Efavirenz
Increase dose
(1125 mg q8h)
Increase dose
(1125 mg q8h)
Not
recommended
Do not use
Rilpivirine
No dose
adjustment
No guidance
No dose
adjustment
No dose
adjustment[44]
Atazanavir/ritonavir
Darunavir/ritonavir;
fosamprenavir/ritonavir
; lopinavir/ritonavir
Raltegravir
Note: Telaprevir and boceprevir interact with CYP3A4/5 and p-glycoprotein. Simeprevir should not be
coadministered with any boosted or unboosted PI or any NNRTI except rilpivirine.[42] Sofosbuvir has no
reported DDIs with HIV drugs except tipranavir/ritonavir.[43]
38. Telaprevir [EU package insert]. 39. Boceprevir [EU package insert]. 40. Kakuda TN, et al. IWCPHT 2012. Abstract O-18. 41.
DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013. 42. Simeprevir [package insert]. 43. Sofosbuvir
[package insert]. 44. Boceprevir [package insert].
The Treatment Pipeline
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Advantages of Future HCV Therapies
 Once-daily dosing
 Shorter duration
 Simpler regimens—no response-guided therapy
 Fewer adverse events
 Interferon-free
 High efficacy
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Caveats to Future HCV Therapies
 Clinical trial data in HIV/HCV coinfection still emerging
– DDI data incomplete
– Performance outside select trial populations yet to be seen
 Timeline
– Late 2013: FDA approval of simeprevir (GT1) and sofosbuvir
(GT1-4)
– 2014: anticipated FDA approval of faldaprevir (GT1);
first all-oral regimens for GT1 expected to be approved
 Costs uncertain, but likely an issue in many regions
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C212 Study: Simeprevir + PegIFN/RBV in
GT1 HCV/HIV Coinfection

Phase III randomized controlled
trial[45]
– 24- or 48-week regimens: SPV +
pegIFN/RBV for 12 weeks, then 100
pegIFN/RBV alone
80
HCV treatment-naive or -
experienced HIV+ patients
(N = 106)
– 88% on ART (VL < 50 cells/mL)
– Excluded: boosted PIs,
NNRTIs other than RPV

Safety profile similar to
monoinfected pts
– Pruritus and photosensitivity in
20% and 2%, respectively

SVR12 (%)

87
74
79
70
57
60
40
20
n/N =
0
78/
106
42/
53
Overall
Naive
13/
15
7/
10
Relapsers Partial
SVR comparable to GT1 HCVmonoinfected pts (80%)[46]
45. Dieterich D, et al. EACS 2013. Abstract LBPS9/5. 46. Jacobson I, et al. EASL 2013. Abstract 1425.
16/
28
Null
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PHOTON-1: Sofosbuvir + RBV in GT1/2/3
HIV/HCV Coinfection



Phase III open-label study
– 12- (GT2/3 treatment-naive) or 24week regimens (GT1 treatmentnaive, GT2/3 treatment
experienced): sofosbuvir + RBV
100
HCV treatment-naive or experienced HIV+ patients
(N = 223)
– Approx 76% on ART (VL < 50
cells/mL), various standard
regimens
Safety profile similar to
monoinfected patients; consistent
with RBV
– Most frequent AEs: fatigue,
insomnia, headache, nausea,
diarrhea
2 patients had transient HIV
rebound due to nonadherence
47. Sulkowski MS, et al. AASLD 2013. Abstract 212.
Virologic Outcomes for
Treatment-Naive Patients
by GT
88
80
76
67
SVR12 (%)

60
40
20
n/N
87/
114
23/
26
28/
42
GT1
GT2
GT3
0
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STARTVerso4: Faldaprevir + PegIFN/RBV
in GT1 HCV/HIV Coinfection

Phase III open-label study
100
– 24- or 48-week regimens:
faldaprevir + pegIFN/RBV for 12 or
24 weeks, then pegIFN/RBV alone
HCV treatment-naive or previous
relapser HIV+ patients (N = 308)
– 96% on ART (VL < 50 cells/mL)

Safety profile similar to
monoinfected pts
–
–

Most frequent AEs: nausea, fatigue,
diarrhea, headache
Decrease in hemoglobin consistent with
pegIFN/RBV historical data
1 patient had HIV rebound requiring
new ART regimen
49. Rockstroh JK, et al. AASLD 2013. Abstract 1099.
SVR4 (%)

80
79
84
72
60
40
20
n/N =
0
89/
123
66
84
72/
86
Faldaprevir Faldaprevir Faldaprevir
240 mg†
120 mg*
240 mg*
*24 wks of therapy; †12 wks of therapy
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Selected Ongoing or Upcoming Clinical
Trials in HIV/HCV Coinfection
 Boceprevir + pegIFN/RBV: HIVCOBOC-RGT study, RVR-guided
therapy
 Telaprevir + pegINF/RBV : INSIGHT, RVR-guided therapy;
additional study in coinfected cirrhotic patients
 Daclatasvir + pegIFN lambda + RBV: DIMENSION study, GT1-4
naive patients, 24-48 weeks
 Daclatasvir + asunaprevir + pegINF/RBV: QUADRIH study, GT1/4
nulls, 28 weeks
 Sofosbuvir + RBV: GT1/4 naive and GT2/3 naive/experienced
patients, 12-24 weeks
 ABT450/r/ABT-267 + ABT-333 + RBV: TURQUOISE-1 study, GT1
naive/experienced patients, 12-24 weeks
 MK-5172 + MK-8742 + RBV: 047 study, GT2,4,5,6 naive patients
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Summary
 Liver disease leading cause of morbidity and mortality in
HIV/HCV coinfection
– Antiretroviral therapy may slow progression
 HCV screening at HIV diagnosis and at least annually
 HCV treatment considerations
– Treat now or wait for future options?
– First-generation DAAs complex, long duration, AEs, DDIs
– New agents may improve outcomes with shorter therapy,
fewer AEs
– Consider HCV disease stage and risk of progression