1. Jointly provided by Postgraduate Institute for Medicine and Clinical Care Options, LLC
Clinical Focus: The Role of New HCV Agents in Managing HIV/HCV Coinfection
Mark S. Sulkowski, MD
Professor of Medicine
Medical Director, Viral Hepatitis Center
Divisions of Infectious Diseases and Gastroenterology/Hepatology
Johns Hopkins University School of Medicine
Baltimore, Maryland
This activity is supported by an independent educational grant from Gilead Sciences.
Image: BioMedical/Copyright©2014 Shutterstock Images LLC. All Rights Reserved

2. Background

3. Total Treatment Duration
FDA-Approved Regimens for Simeprevir and Sofosbuvir in Pts With HCV Infection
Population
Regimen
Total Treatment Duration
Simeprevir
GT1, treatment naive and previous relapsers
Simeprevir + pegIFN/RBV for 12 wks, followed by pegIFN/RBV for 12 wks
24 wks
GT1, previous partial or nonresponders
Simeprevir + pegIFN/RBV for 12 wks, followed by pegIFN/RBV for 36 wks
48 wks
Sofosbuvir
GT1 or GT4*
Sofosbuvir + pegIFN alfa/RBV
12 wks
GT2
Sofosbuvir + RBV
GT3
HCC awaiting transplantation
Up to 48 wks or until transplantation, whichever first
FDA, US Food and Drug Administration; GT, genotype; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IFN, interferon; pegIFN, peginterferon; RBV, ribavirin.
*A 24-wk course of sofosbuvir + RBV can be considered in IFN-ineligible GT1 pts.
1. Simeprevir [package insert]. 2. Sofosbuvir [package insert].

4. Simeprevir: Dosing and Administration
Characteristic
Simeprevir
Dose
150 mg/day PO*
Formulation
150-mg capsule
Dose reductions
Never
Pills per day 1
With food
Take with food
PegIFN
Either pegIFN acceptable; use according to package instructions
RBV
Weight-based dosing according to peginterferon used
Most common AEs
With pegIFN/RBV: rash, pruritus, nausea
Drug class PI
Additional considerations
Strongly consider Q80K testing in patients with genotype 1a infection; if present, consider alternative therapies
AE, adverse event; pegIFN, peginterferon; PI, protease inhibitor; PO, orally; RBV, ribavirin.
*Used in combination with both pegIFN and RBV in registrational trials.
3. Simeprevir [package insert].

5. Sofosbuvir: Dosing and Administration
Characteristic
Sofosbuvir
Dose
400 mg/day PO*
Formulation
400-mg tablet
Dose reductions
Never
Pills per day 1
With food
No food restrictions
PegIFN
Either pegIFN acceptable, use according to package instructions
RBV
Weight-based dosing according to package instructions; dose reduction required in patients with renal impairment
Most common AEs
With pegIFN/RBV: fatigue, headache, nausea, insomnia, anemia
With RBV: fatigue, headache
Drug class
NS5B nucleotide inhibitor
AE, adverse event; HCV, hepatitis C virus; pegIFN, peginterferon; PO, orally; RBV, ribavirin.
*Used in combination with RBV ± pegIFN, depending on HCV genotype and other patient characteristics, in registrational trials.
7. Sofosbuvir [package insert].

6. Therapeutic Options Are Evolving
Protease Inhibitors
NS5A Replication Complex Inhibitors
NS5B
Nucleoside Inhibitors
NS5B Nonnucleoside Inhibitors
Other
FDA Approved Agents
Telaprevir
Sofosbuvir
Peginterferon
Boceprevir
Ribavirin
Simeprevir
Phase III Agents (as of September 2014)
Asunaprevir
Daclatasvir
Dasabuvir
Paritaprevir (previously ABT-450)
Ledipasvir
Beclabuvir (previously BMS )
MK-5172
Ombitasvir
MK-8742
FDA, US Food and Drug Administration.

7. Treatment Guidelines

8. AASLD/IDSA Guidance: When to Start Treatment in HCV/HIV-Coinfected Patients
Treatment is recommended for patients with chronic HCV infection
Treatment should be prioritized in patients at high risk for liver-related complications
Includes patients with HCV/HIV coinfection, regardless of fibrosis stage
Treating patients at high risk for transmitting HCV to others may decrease transmission and HCV disease prevalence
Includes MSM with high-risk sexual practices and active injection drug users
AASLD, American Association for the Study of Liver Diseases; HCV, hepatitis C virus; IDSA, Infectious Diseases Society of America; MSM, men who have sex with men.
9. AASLD and IDSA. HCV Management Guidance. September 2014. 8

9. AASLD/IDSA Guidance: Recommended Regimens for HCV/HIV-Coinfected Pts
Genotype
Recommended Regimens
Genotype 1
HCV treatment naive and prior PR relapsers
IFN eligible
Sofosbuvir + pegIFN/RBV for 12 wks
IFN ineligible
Sofosbuvir + RBV for 24 wks
Sofosbuvir + simeprevir ± RBV for 12 wks
HCV treatment experienced*
Genotype 2
Regardless of HCV treatment history
Sofosbuvir + RBV for 12 wks
Genotype 3
Genotype 4
Genotype 5 or 6
AASLD, American Association for the Study of Liver Diseases; HCV, hepatitis C virus; IDSA, Infectious Diseases Society of America; IFN, interferon; pegIFN, peginterferon; PR, peginterferon/ribavirin; RBV, ribavirin.
*Previous PR nonresponders regardless of IFN eligibility.
12. AASLD and IDSA. HCV Management Guidance. September 2014.

10. AASLD/IDSA Guidance: Allowable ARVs in HCV/HIV-Coinfected Pts Receiving DAAs
Sofosbuvir: ALL except didanosine, zidovudine, and tipranavir[1]
Simeprevir: raltegravir, rilpivirine, maraviroc, enfuvirtide, tenofovir, emtricitabine, lamivudine, and abacavir[15]
Clinically significant drug interactions were observed when simeprevir coadministered with ritonavir or with efavirenz in healthy volunteers[17]
AASLD, American Association for the Study of Liver Diseases; ARV, antiretroviral; DAA, direct-acting antiviral; HCV, hepatitis C virus; IDSA, Infectious Diseases Society of America.
15. AASLD and IDSA. HCV Management Guidance. September Simeprevir [package insert].

11. AASLD/IDSA Guidance: HCV Regimens NOT Recommended in HIV-Coinfected Pts
The following are NOT recommended for treatment-naive or treatment-experienced HCV/HIV-coinfected patients:
Telaprevir- or boceprevir-containing therapy
Monotherapy with pegIFN, RBV, or a DAA
AASLD, American Association for the Study of Liver Diseases; DAA, direct-acting antiviral; HCV, hepatitis C virus; IDSA, Infectious Diseases Society of America; pegIFN, peginterferon; RBV, ribavirin.
19. AASLD and IDSA. HCV Management Guidance. September 2014.

12. Clinical Trial Data on New HCV Agents in HCV/HIV-Coinfected Patients
HCV, hepatitis C virus.

13. Sofosbuvir + PegIFN/RBV for 12 Wks in Treatment-Naive GT1 HCV Patients
NEUTRINO Single-Arm Study in HCV Monoinfection: SVR12[20]
P Single-Arm Study in HCV/HIV Coinfection: SVR12[21]
100
100
100 90 89
SVR12 (%) 89 87 80 80 60 60
SVR12 (%) 40 40
HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. 20 20
n/N =
295/327
261/292
17/19
13/15
4/4
Overall
GT1
GT1
GT1a
GT1b
20. Lawitz E, et al. N Engl J Med. 2013;368: Rodriguez-Torres M, et al. ID Week Abstract 714.

14. PHOTON-1: Sofosbuvir + RBV in GT1-3 HCV Patients Coinfected With HIV
Nonrandomized, open-label phase III study; primary endpoint: SVR12
Stable ART (HIV-1 RNA < 50 copies/mL for > 8 wks before enrollment)
95% on ART: TDF/FTC, 100%; EFV, 35%; ATV/RTV, 17%; DRV/RTV, 15%; RAL, 16%; RPV, 6%
Cirrhosis at baseline: GT1, 4%; GT2/3 tx naive, 10%; GT2/3 tx-exp’d: 24%
Wk 12
Wk 24
SVR12, % (n/N)
GT1: 76 (87/114)
GT2: 88 (23/26)
GT3: 67 (28/42)
GT2: 92 (22/24)
GT3: 94 (16/17)
Sofosbuvir + RBV (n = 114)
Tx-naive GT1
ART, antiretroviral therapy; ATV, atazanavir; DRV, darunavir; EFV, efavirenz; FTC, emtricitabine; GT, genotype; HCV, hepatitis C virus; QD, once daily; RAL, raltegravir; RBV, ribavirin; RPV, rilpivirine; RTV, ritonavir; SVR, sustained virologic response; TDF, tenofovir; Tx, treatment.
Sofosbuvir + RBV (n = 68)
Tx-naive GT2/3
Sofosbuvir + RBV (n = 41)
Tx-exp’d GT2/3
Sofosbuvir 400 mg QD; weight-based RBV 1000 or 1200 mg/day
22. Sulkowski MS, et al. JAMA. 2014;312:

15. PHOTON-2: Sofosbuvir + RBV in GT1-4 HCV Patients Coinfected With HIV
Nonrandomized, open-label phase III study; primary endpoint: SVR12
Stable ART (HIV-1 RNA < 50 copies/mL for ≥ 8 wks before enrollment)
97% on ART: TDF/FTC, 100%; EFV, 25%; ATV/RTV, 17%; DRV/RTV, 21%; RAL; 23%; RPV, 5%
Cirrhosis at baseline: All pts, 20%; tx-naive patients, 13%; tx-exp’d patients, 45%
Wk 12
Wk 24
Sofosbuvir + RBV (n = 200)
Tx-naive GT1,3,4
ART, antiretroviral therapy; ATV, atazanavir; DRV, darunavir; EFV, efavirenz; FTC, emtricitabine; GT, genotype; HCV, hepatitis C virus; QD, once daily; RAL, raltegravir; RBV, ribavirin; RPV, rilpivirine; RTV, ritonavir; SVR, sustained virologic response; TDF, tenofovir; Tx, treatment.
Sofosbuvir + RBV (n = 19)
Tx-naive GT2
Sofosbuvir + RBV (n = 55)
Tx-exp’d GT2,3
Sofosbuvir 400 mg QD; weight-based RBV 1000 or 1200 mg/day
29. Molina JM, et al. AIDS Abstract MOAB0105LB.

16. PHOTON-2: SVR12 by Genotype and Cirrhosis89
100 78 92 91 75 83 88 65 87 62
24-wk noncirrhotic
100
24-wk cirrhotic
12-wk noncirrhotic 80
12-wk cirrhotic 60
Patients With SVR (%) 40 20
GT, genotype; RBV, ribavirin; SVR, sustained virologic response.
84/ 95
11/ 17
76/ 87 8/ 13 7/ 7 3/ 4
16/ 18 1/ 1 3/ 4 2/ 2
49/ 54 3/ 3
24/ 26
18/ 23
19/ 23 7/ 8
Total
GT1a
GT1b
Naive
Exp’d
Naive
Exp’d
Naive
GT1 Naive
GT2
GT3
GT4
Absolute CD4+ count—but not CD4%—decreased, consistent with effect of RBV on lymphocytes
31. Molina JM, et al. AIDS Abstract MOAB0105LB.

17. C212 Study: Simeprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection
Open-label phase III study in treatment-naive and treatment-experienced pts (N = 106)
Response-guided therapy if HCV RNA < LLOQ Wk 4 and < LLOD Wk 12: 89% of treatment-naive pts and previous PR relapsers without cirrhosis met RGT criteria and were eligible for shortened therapy to 24 wks, with 87% achieving SVR12
Wk 12
Wk 24
Wk 48
Wk 72
SVR12, % (n/N)
Naive: 79 (42/53)
Relapse: 87 (13/15)
Partial: 70 (7/10)
Null: 57 (16/28)
SMV/PR PR
Follow-up
HCV treatment naive or relapse
GT, genotype; HCV, hepatitis C virus; LLOD, lower limit of detection; LLOQ, lower limit of quantification; pegIFN, peginterferon; PR, peginterferon/ribavirin; RBV, ribavirin; RGT, response-guided therapy; SMV, simeprevir; SVR, sustained virologic response.
RGT
SMV/ PR PR
Follow-up
Partial or null response or cirrhotic
SMV/PR PR
Follow-up
Simeprevir dosed 150 mg/day.
35. Dieterich D, et al. CROI Abstract 24.

18. COSMOS: Sofosbuvir + Simeprevir ± RBV in GT1 HCV Monoinfection
Cohort 1 (F0-F2 Nulls): SVR12[43] (N = 80, all arms)
Cohort 2 (F3-F4 Naives/Nulls): SVR12[43] (N = 87, all arms)
SMV + SOF + RBV
SMV + SOF
100
100 96
100 93 93 93 93 93 79 80 80 60 60
SVR12 (%)
SVR12 (%) 40 40 20
GT, genotype; HCV, hepatitis C virus; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response. 20
19/24
14/15
26/27
13/14
28/30
16/16
25/27
13/14
24-Wk Arms
12-Wk Arms
24-Wk Arms
12-Wk Arms
SVR in pts with Q80K mutation = 83% to 100%
Study investigating SOF + SMV in HCV/HIV-coinfected patients planned[2]
43. Lawitz E, et al. Lancet. 2014;[Epub ahead of print]. 49. ClinicalTrials.gov. NCT

19. Approach to Treatment of HCV/HIV-Coinfected Patients
HCV, hepatitis C virus.

20. SVR With Single-DAA Regimens by Genotype: Coinfection vs Monoinfection
SVR Range*, %
HIV/HCV Coinfection
HCV Monoinfection
GT1
GT2
GT3
Simeprevir + PR
74[1] NA
80-81[2,3]
Sofosbuvir + PR
89[4]
89[5]
97[6]
Sofosbuvir + RBV
76-88[7,8]
88-89[7,8]
67-91[7,8]
68-90[9]
93[10]
85[10]
*Treatment-naive patients.
DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; NA, not available; PR, peginterferon/ribavirin; RBV, ribavirin; SVR, sustained virologic response.
52. Dieterich D, et al. CROI Abstract Jacobson IM, et al. Lancet. 2014;[Epub ahead of print] Manns M, et al. Lancet. 2014;[Epub ahead of print]. 55. Rodriguez-Torres M, et al. ID Week Abstract Lawitz E, et al. N Engl J Med. 2013;368: Gane EJ, et al. EASL Abstract Sulkowski MS, et al. JAMA. 2014;312: Molina JM, et al. AIDS Abstract MOAB0105LB. 60. Osinusi A, et al. JAMA. 2013;310: Zeuzem S, et al. N Engl J Med. 2014;370: 20

21. Considerations When Managing HCV/HIV-Coinfected Patients
Drug–drug interactions among HCV antivirals and antiretrovirals are expected and may be difficult to predict
CYP3A4 inhibition (ritonavir); induction (efavirenz)
Must study the DAA regimen + ART regimen in healthy volunteers
However, long-term adherence to ART/clinic visits also demonstrate ability to adhere to HCV therapy
ART, antiretroviral therapy; DAA, direct-acting antiviral; HCV, hepatitis C virus.

22. Drug–Drug Interactions With ARVs
Simeprevir
Sofosbuvir
DTG
No interaction expected
RAL
Use standard doses
EFV
Do not coadminister
DLV, ETR, NVP
RPV
Any PI
DRV/RTV
RTV
TPV/RTV
TDF
COBI
ARV, antiretroviral; COBI, cobicistat; DLV, delavirdine; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; ETR, etravirine; NVP, nevirapine; RTV, ritonavir; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir; TPV, tipranavir.
63. Sofosbuvir [package insert]. 64. Simeprevir [package insert]. 65. Kirby B, et al. AASLD Abstract Ouwerkerk-Mahadevan S, et al. IDSA Abstract 49.

23. Considerations Regarding Treatment Initiation in HCV/HIV-Coinfected Pts
Is the pt ready and able to start therapy?
Pts not receiving ART
Treat HCV now and defer ART?
Pts receiving ART
Is there an HCV regimen available that can be coadministered with current ART or is ART switch needed?
Should ART interruption ever be considered?
Associated with increased risk of OI/death in HIV infected pts[1]
Associated with increased risk of fibrosis progression in HCV/HIV- coinfected pts[2]
ART, antiretroviral therapy; HCV, hepatitis C virus; OI, opportunistic infection.
69. El-Sadr WM, et al. N Engl J Med. 2006;355: Thorpe J, et al. AIDS. 2011;25:

24. Forthcoming DAAs Sofosbuvir/ledipasvir
Paritaprevir/RTV/ombitasvir + dasabuvir
Daclatasvir
Use of daclatasvir + sofosbuvir ± RBV resulted in SVR12 in 98% of GT1 monoinfected pts, 92% of GT2 monoinfected pts, 89% of GT3 monoinfected pts[1]
Phase III ALLY 2 study evaluating daclatasvir + sofosbuvir in HCV/HIV-coinfected patients ongoing (NCT )[2]
DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; RBV, ribavirin; RV, ritonavir; SVR, sustained virologic response
71. Sulkowski MS, et al. N Engl J Med. 2014;370: ClinicalTrials.gov. NCT

25. Patients with GT1 HCV and HIV coinfection (N = 50)
ERADICATE: SOF/LDV in ARV-Treated and Untreated HCV/HIV-Coinfected Patients
Single-arm phase II trial in GT1, HCV treatment-naive, coinfected pts
ARV-untreated pts: stable CD4+ and HIV-1 RNA < 500 c/mL, or CD4+ > cells/mm3;
ARV-treated patients: CD4+ > 100 cells/mm3, HIV-1 RNA < 40 c/mL, stable ARV regimen for ≥ 8 wks (TDF, FTC, EFV, RPV, RAL only)
Primary endpoint: SVR12
ARV use in 37 ARV-treated patients: EFV (41%), RAL (27%), RPV (21%), RPV and RAL (8%), EFV and RAL (3%)
AE, adverse event; ARV, antiretroviral; EFV, efavirenz; FDC, fixed-dose combination; FTC, emtricitabine; GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; NA, not yet available; RAL, raltegravir; RPV, rilpivirine; SOF, sofosbuvir; SVR, sustained virologic response; TDF, tenofovir
Wk 12
SVR12, %
Patients with GT1 HCV and HIV coinfection (N = 50)
100 in ARV-untreated pts;
NA in ARV-treated pts
SOF/LDV FDC
Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily.
73. Osinusi A, et al. EASL Abstract O14.

26. TURQUOISE I: Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV in GT1 HCV/HCV Pts
Open-label phase II/III trial in GT1, DAA-naive, coinfected pts
HIV-1 RNA < 40 c/mL on ATV or RAL regimen; CD4+ count ≥ 200 or CD4+% ≥ 14%
Primary endpoint: SVR12
19% of patients per arm had cirrhosis
Wk 12
Wk 24
SVR12, %
Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV
(n = 31)
93.5 NA
DAA-naive
HIV-coinfected pts with HCV GT1
(N = 63)
ATV, atazanavir; BID, twice daily; DAA, direct-acting antiviral; FDC, fixed dose combination; GT, genotype; HCV, hepatitis C virus; NA, not yet available; RAL, raltegravir; RBV, ribavirin; RTV, ritonavir; QD, once daily; SVR, sustained virologic response.
For more information about this study, go online to
Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV
(n = 32)
Paritaprevir/RTV/ombitasvir 150/100/25 mg QD FDC; dasabuvir 250 mg BID; RBV mg/day.
75. Sulkowski M, et al. AIDS Abstract MOAB0104LB.

27. Summary
Sofosbuvir and simeprevir are currently recommended as part of preferred or alternative regimens for HCV/HIV- coinfected patients
Boceprevir and telaprevir are not recommended
SVR rates in HCV/HIV-coinfected patients treated with sofosbuvir or simeprevir are comparable to those in HCV- monoinfected patients
Management of drug–drug interactions between HCV DAAs and ART remains important
Additional all-oral regimens expected to be approved in late 2014
ART, antiretroviral therapy; DAA, direct-acting antiviral; HCV, hepatitis C virus; SVR, sustained virologic response.