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Challenges in the Management and
Treatment of HIV/Hepatitis C Virus
Coinfection
Ricardo A. Franco, MD
Assistant Professor of Medicine
University of Alabama at Birmingham
Birmingham, Alabama
FORMATTED: 04-05-16
Atlanta, Georgia: April 8, 2016
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Learning Objectives
After attending this presentation, participants will
be able to:
 Apply best HCV treatment strategies to clinical care
 Merge evolving concepts of HIV and HCV co-management
 Address unmet needs of HIV/HCV co-infected patients
Slide 2 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
HCV Mono-infection and HIV/HCV Co-infection Burden
 An estimated 2%–3% of the world's population is living with HCV
– >350 000 die each year of HCV-related cirrhosis and liver cancer1
 Among HIV-infected individuals, HCV co-infection
– Ranges from 10–30% in MSM
– Up to 80–90% in IVDU2
 Two types of HIV/HCV co-infected patients can be distinguished
– Those infected for decades (often have severe fibrosis and several comorbidities)
– Those recently infected with HCV
1) G.M. Lauer, B.D. Walker. Hepatitis C virus infection. N Engl J Med, 345 (2001), pp. 41–52
2) K.E. Sherman, S.D. Rouster, R.T. Chung, N. Rajicic. Hepatitis C Virus prevalence among patients infected with Human Immunodeficiency Virus: a
cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis, 34 (2002), pp. 831–837
Slide 3 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
HIV Co-infection Shortens Survival in HCV-related
Decompensated Cirrhosis
Pineda JA, Romero-Gómez M, Díaz-García F, et al. HIV coinfection shortens the survival of patients with
hepatitis C virus-related decompensated cirrhosis. Hepatology. 2005;41:779-789.
Slide 4 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
HIV Control does not Completely Overturn Risk of ESLD
ART decreases hepatic decompensation events: 0.72 (0.54-0.94)
Lo Re V. Ann Intern Med 2014. Anderson JP. CID 2014.
Slide 5 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Prior Experience in HIV/HCV – INF Era
1. Chung RT, Andersen J, Volberding P, et al. N Engl J Med. 2004;351:451-9. 2.Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. N Engl J Med. 2004;351:438-50.
3. Laguno M, Murillas J, Blanco JL, et al. AIDS. 2004;18:F27-36. 4. Carrat F, Bani-Sadr F, Pol S, et al. JAMA. 2004;292:2839-48. 5.Núñez M, Miralles C, Berdún MA, et
al. AIDS Res Hum Retroviruses. 2007;23:972-82. 6.Núñez M, Miralles C, Berdún MA, et al.. AIDS Res Hum Retroviruses. 2007;23:972-82.
Slide 6 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Poor Rates of HCV Treatment Uptake and Cure
Mehta; Sulkowski et al. Limited effectiveness of antiviral treatment for hepatitis C in an urban HIV clinic. AIDS. 20(18):2361-2369, November 28, 2006.
Slide 7 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
HCV Therapeutics Timeline
Consensus IFN
1989
HCV
identified
Peg-IFNa-2b
1995
In vitro
HCV
replication
HCV
replicons
IFN a-2b + RBV
TPV
2005
2000
IFN a-2b
IFN a-2a
BOC
2010
Peg-IFNa-2a
in HCV/HIV
IFN-free
GT1 DAA
regimens
2016
Sofosbuvir
Simeprevir (US)
Daclatasvir (EU)
Peg-IFNa-2a
IFN-free Treatment Options in 2016 (FDA Approved)
SOF/
LDV
SOF
SOF
Slide 8 of 26
SOF
RBV
SMV
OBV/
PTV/r
RBV
DCV
GZR
EBR
DSV
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
SVR12 Rates in DAA Trials (HIV/HCV vs HCV Mono)
Mostly HCV GT1
Arends JE et al. Natural history and treatment of HCV/HIV coinfection: Is it time to change paradigms?
Journal of Hepatology, Volume 63, Issue 5, 2015, 1254–1262
Slide 9 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Treatment Naïve GT1
Recommended and Alternative Options
GZR/EBR
SOF/LDV
OBV/PTV/r
+DSV
SOF/SMV
SOF/DCV
Noncirrhotic
12w*
12w
12w + RBV
12w
12w
Cirrhosis
12w*
12w
24w + RBV
24w +/RBV**
24w +/RBV
Noncirrhotic
12w
12w
12w
12w
12w
Cirrhosis
12w
12w
12w
24w +/RBV
24w +/RBV
GT1a
GT1b
* If no baseline NS5A RAVs for elbasvir are detected; if detected, 16w + RIBA is an alternative option
** If no Q80K polymorphism is detected
hcvguidelines.org
Slide 10 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Treatment Experienced GT1
Recommended and Alternative Options
Failed
PR
PR + PI
PR + SOF
or SOF/RBV
Cirrhosis
Status
GZR/EBR
SOF/LDV
PrOD
SOF+SMV
SOF+DCV
NC
12w*
12w
12w
12w
12w
C
12w*
12w + RBV
or 24w
1a: 24w+R
1b: 12w
1a: 24w+/-R**
1b: 24w+/-R
24w +/RBV
NC
12w+R*
NR
12w
C
12w+R*
NR
24w +/RBV
NC
12w#
12w + RBV
1a: 12w+R#
1b: 12w#
12w#
12w#
C
12w#
24w + RBV
1a: 24+R#
1b: 12w#
1a: 24w+/-R**#
1b: 24w+/-R#
24w +/RBV#
12w
NR
hcvguidelines.org
12w + RBV
NR
or 24w
* If no baseline NS5A RAVs for elbasvir are detected; if detected, 16w + RIBA is an alternative option;
** If no Q80K polymorphism is detected;
#There are no published data on retreatment of sofosbuvir-containing treatment failures with non-sofosbuvir based DAA regimens
hcvguidelines.org
Slide 11 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
GT2/3
Recommended and Alternative Options
Status
SOF/RBV
SOF/DCV
PR + SOF
NC
12w
12w*
SR-TE: 24w+/-R
NR
SR-TE: 12w**
C
16-24w
16-24w*
SR-TE: 24w+/-R
TN: NR
PR-TE: 12w**
SR-TE: 12w**
NC
24w#
12w
12w**
24w#
TN: 24w +/- RBV##
PR-TE: 24w+RBV##
SR-TE: 24w+RBV##
12w**
GT2
GT3
C
*If not eligible to receive RBV ; ** If INF-eligible; #If DCV-ineligible; ## If INF-ineligible
hcvguidelines.org
Slide 12 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
New Paradigms Bring New Challenges
 Treat a few patients
–
Prefer highly motivated patients
–
Restrict treatment to the ones at
risk of liver disease progression
–
Select optimal INF/RBV
candidates
 Treat most patients
–
Engage the unmotivated
–
Treat regardless of liver disease
stage
–
Many rx options to choose from

–
–
W/wo ART switches
DDI, resistance, reinfection
Warehousing; harm reduction
HIV co-infected patient is treated like mono-infected ones in most cases
Slide 13 of 39
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
ART in HIV/Hepatitis C Virus Coinfection
 When to Start
–
–
ART should be initiated regardless of CD4
count
 Can defer ART in TN pts w CD4 >500
and treat HCV first
Pts with CD4 <200 had lower SVR and
toxicity rates in PegIFN/RBV era
 Data is lacking on DAA response in pts
with advanced immunosuppression
 Prompt ART and delay HCV rx until
immune recovery
 What to Start
–
Same initial ARV combinations are
recommended for HIV mono-infection
and HIV/HCV co-infection
Check for DDIs
 Avoid overlapping toxicities
 Hepatically metabolized ART and DAAs
may be contraindicated or require dose
modification (Child-Pugh class B and C)

–
Hepatotoxicity (DILI)
The risk among newer ART options is
low [monitor LFTs (>5x ULN)]
 Hypersensitivity reactions can occur

aidsinfo.nih.gov
Slide 14 of 39
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
2014 Recommendations of the International Antiviral
Society–USA Panel
EVG/c/TAF/FTC
TAF/FTC/RPV
TAF/FTC
JAMA. 2014;312(4):410-425. doi:10.1001/jama.2014.8722
Slide 15 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
ART Switches
 Previous ART history
– Demonstrated or possible ARV resistance

–
–
–
–
Resistance remain archived in latent cells even if not detected in resistance assays
Likelihood of adherence to new regimen
Patient acceptance of potential new side effects
Other medications of DDIs
Affordability
 Use available evidence to guide switch decisions
Slide 16 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
DDIs (ART vs DAA)
SOF + SIM
SOF/LDV
SOF + DCV
PTV/RTV/OBV +
DSV
GZR/EBV
Atazanavir + RTV





Darunavir + RTV





Raltegravir





Dolutegravir





Elvitegravir + COBI





Elvitegravir/COBI/
TAF/emtricitabine



*

Efavirenz





Rilpivirine





Abacavir/lamivudine





Tenofovir DF/
emtricitabine

 nephrotoxicity



Adapted from AASLD/IDSA Guidelines. February 2016.
Slide 17 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
DDIs (DAA vs Other Selected Drugs)
Concomitant Medication
SOF
SIM
Acid-reducing agents
LDV
PTV/RTV/OBV
+ DSV
X
X
DCV
GZR/EBV
Amiodarone
X
X
X
X
X
X
Anticonvulsants
X
X
X
X
X
X
X
X
X
X
X
X
Digoxin
Ethinyl estradiol–containing products
X
Glucocorticoids
X
X
PDE5 inhibitors
X
X
Rifamycin antimicrobials
X
Sedatives
St John’s wort
Statins
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adapted from AASLD/IDSA Guidelines. February 2016.
Slide 18 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Virologic Barriers to Resistance
Genetic barrier
 Number and type of nucleotide changes required for a virus to acquire resistance to an
antiviral regimen[1]
Viral fitness
 Relative capacity of a viral
1
% Fitness
variant to replicate in a
given environment
Fitness of Polymerase Inhibitor Mutants[2,3]
.75
.5
.25
0
1.
2.
3.
Rong L, et al. Sci Transl Med. 2010;2:30ra32.
Le Pogam S et al. J Virol. 2006;80:6146-6154.
Le Pogam S, et al. J Infect Dis. 2010;202:1510-1519
Slide 19 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
AASLD/IDSA Guidance for Resistance Testing When
Considering SMV + SOF
 In pts with both genotype 1a HCV infection and compensated cirrhosis,
if considering SMV + SOF, test for Q80K polymorphism
–
If Q80K variant is present, consider a regimen other than SMV + SOF
 Applies to treatment-naive and treatment-experienced pts
 Q80K testing not required for:
– Pts with genotype 1b HCV infection
– Pts without cirrhosis
– Pts in whom you are considering other DAAs
AASLD/IDSA. HCV Guidance.
Slide 20 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Resistance Analysis of Select
NS5A Inhibitors in Genotype 1 HCV
Fold-Change in
EC50
Position
Genotype 1a
Genotype 1b
M28T
Q30R
L31M/V
Y93H/N
L31V
Y93H/N
Daclatasvir[1,3]
> 100 x
> 1000 x
> 100 x
> 1000 x
< 10 x
< 100 x
Ledipasvir[1]
20 x
> 100 x
> 100 x
> 1000 x
Ombitasvir[2]
> 1000 x
> 100 x
FDA approved
> 100 x
<3x
> 100 x
3 to 100 x
> 10,000 x
> 1000 x/?
< 10 x
< 100 x
<3x
1. Cheng G, et al. EASL 2012. Abstract 1172. 2. Krishnan P, et al. Antimicrob Agents Chemother.
2015;59:979-987. 3. Yang G, et al. EASL 2013. Abstract 1199. 4. Ng T, et al. CROI 2014. Abstract 639.
Slide 21 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
GT1 Pts: Who Needs Resistance Testing?
 GT1a patients needs testing at baseline when considering GZR/EBR
 If previous failure of any NS5A inhibitors (DCV + SOF, LDV/SOF, OMV/PTV/RTV +
DSV) and minimal liver disease, deferral preferred pending further data
–
If cirrhosis or other need for urgent treatment, test for NS3 and NS5A RAVs
–
Applies to genotype 1a and 1b HCV infection
 NS3 and NS5A testing not required for:
–
–
–
Previous failure of NS3/4A PIs (including simeprevir, boceprevir, telaprevir)
Previous failure of NS5B inhibitors (sofosbuvir)
Tx-naive pts (unless considering SMV + SOF in cirrhotic GT1a)
AASLD/IDSA. HCV Guidance.
Slide 22 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Selecting Treatment Based on Resistance Testing Results
 If genotype 1a or 1b HCV infection and previous failure
with any NS5A inhibitors and cirrhotic or other need for
urgent treatment:
RAV Testing Result
No NS5A RAVs
NS5A but no NS3 RAVs
NS5A and NS3 RAVs
Retreatment Regimen
Duration
Ledipasvir/sofosbuvir + ribavirin
24 wks
Simeprevir + sofosbuvir + ribavirin
24 wks
Retreatment in a clinical trial setting
AASLD/IDSA. HCV Guidance.
Slide 23 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
4.5
16
4.0
14
3.5
12
3.0
10
2.5
8
2.0
6
1.5
1.0
4
0.5
2
0
0
Healthcare Cost ($ Billion)
Prevalence (Millions)
Despite Declining HCV Infections, Healthcare
Costs Will Increase due to ESLD
Razavi H, et al. Hepatology. 2013;57:2164-2170.
Slide 24 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Cost of FDA Approved Regimens
Regimen
Duration
$$$ (in US)
SOF + P/R
12 weeks
$94,500
SOF + RIBA
12 weeks
$91,500
SOF + RIBA
24 weeks
$183,000
SOF + SMV
12 weeks
$150,000
SOF + SMV
24 weeks
$300,000
SOF + LDV
12 weeks
$94,500
SOF + LDV
24 weeks
$189,000
PAR/r/OMB + DAS
12 weeks
$90,900
PAR/r/OMB + DAS
24 weeks
$90,900
GZR/EBR
12 weeks
$54,000
HIV ART*
35 years
$20,000/year
*~30% of PLWH in US are on therapy and virally suppressed ($7.2 billion/year)
- This same budget could accommodate ~75,000 HCV patients / year
- Federal Budget for domestic and global HIV efforts – 2016: $31.7 billion
Slide 25 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Increasing Use of High SVR Therapy (~ 90%) Will
Eliminate HCV in the US by 2029
Treated
No more
pts
available
to treat
200,000
150,000
100,000
50,000
0
160,000
120,000
80,000
40,000
0
Cured
Razavi H, et al. Hepatology. 2013;57:2164-2170.
Slide 26 of 26
From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.