Transcript HIV-Hepatitis C Treatment in 2015

HIV-Hepatitis C Treatment in
2016
Shobha Swaminathan, MD
Associate Professor of Medicine
Rutgers New Jersey Medical School
Disclosure
• Grant funding and advisory board from Gilead Sciences
Overview
• Background
• Benefits and data to support all oral treatment for HCV
• Case discussion
Epidemiology
• 3.6 million cases in the United States1
• 1.3 % of the United States population1
• 13,000 deaths annually in the United States
• HCV is the leading cause of liver transplant in the US2
1 Denniston
NM et al, Ann Intern Med 2014; 160(5):293
2 Verna EC, Brown RS, Clin Liver Dis 2006; 10(4) 919
Reported number of acute hepatitis C cases —
United States, 2000–2014
3,500
Number of cases
3,000
2,500
2,000
1,500
1,000
500
0
Year
Source: CDC, National Notifiable Diseases Surveillance System (NNDSS)
Incidence of acute hepatitis C,
by age group — United States, 2000–2014
3
Reported cases/100,000 population
0-19 yrs
20-29 yrs
2.5
30-39 yrs
2
40-49 yrs
50-59 yrs
1.5
> 60 yrs
1
0.5
0
Year
Source: CDC, National Notifiable Diseases Surveillance System (NNDSS)
702
328
Injection-drug
use
Yes
No
1,164
Missing§
27
203
Men who have
sex with men¶
937
3
32
Sexual
contact
2,159
150
344
Multiple
sex partners
1,700
0
200
400
600
800
Source: CDC, National Notifiable Diseases Surveillance System (NNDSS)
*A total of 2,194 case reports of acute hepatitis C were received in 2014.
† More than one risk exposure/behavior may be indicated on each case-report.
§Risk data not reported.
¶A total of 1,174 acute hepatitis C cases were reported among males in 2014.
1,000 1,200 1,400 1,600 1,800 2,000 2,200
Epidemiology of HIV-HCV Infection
 Liver disease associated with HCV infection has become a leading cause of
morbidity and mortality among HCV/HIV-coinfected patients1
 HIV/HCV epidemiology2
– 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- patients3
1. Weber R, et al. Arch Intern Med. 2006;166:1632-1641. 2. CDC. HIV and viral hepatitis. May 2013. 3. Yaphe S, et al. Sex Transm Infect. 2012;88:558-564.
Distribution of HCV Worldwide
Fang J. Clin. Liver Dis 1997
Natural History of HCV Infection
Acute HCV
Resolved
15% to 45%
Chronic HCV
55% to 85%
Cirrhosis
5% to 25%
Stable
75% to 95%
Stable
97% to 99%/yr
HCC or
Decompensation
1% to 3%/yr
Infection with HCV can also cause extrahepatic diseases: mixed cryoglobulinemia, types II and III
1.
2.
3.
Thomas DL, et al. Clin Liver Dis. 2005;9:383-398,
Strader DB, et al. Eur J Gastroenterol Hepatol 1996;8:324-328
Seeff LB, et al. Hepatology. 2002;36(suppl):S1-S2,
4. Seeff LB, et al. Hepatology. 2002;36(suppl):S35-S46,
5. Liang TJ, et al. Ann Intern Med. 2000;132:296-305,
6. Fattovich G, et al. Gastroenterology. 1997;112:463-472.
Impact of HIV on HCV-related Disease
• Coinfected pts have a faster (almost twice as fast) rate of progression to
fibrosis
• Accelerated rate of liver failure
• Cirrhotic patients with HIV do worse
• Hepatocellular carcinoma occurs at a younger age
• Increasing mortality from liver disease related to HCV in HIV-infected
patients
• Serum HCV-RNA titers are 1.5-2 fold higher
• People with lower CD4 count have faster progression of HCV
Hepatitis C Screening
• Birth Cohort (1945-1965)
• Injection drug users (current or past)
• received clotting factor concentrates produced before 1987
• long-term hemodialysis
• persistently abnormal alanine aminotransferase levels (ALT)
• HIV infection
• Received blood products or transplant before 1992
USPSTF, CDC
HCV Antibody
Positive
Negative
HCV RNA
Stop
Not
Detected
No current HCV
infection
Additional Testing
as needed
Detected
Link to
care
Treatment Objectives and Outcomes
• Goal of HCV therapy
• To prevent complications and death from HCV infection
• Treatment responses currently defined by short-term surrogate parameters
rather than clinical endpoints
• Biochemical (normalization of serum ALT levels)
• Virologic (undetectable serum HCV RNA by PCR)
• Histologic (> 2 point improvement in necroinflammatory score with no worsening in
fibrosis score)
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
HCV Treatment Landscape in 2016: All-Oral
Therapy for Genotype 1 HCV Infection
• NS5B Polymerase Inhibitors (“buvir”)
• Sofosbuvir
• Dasabuvir
• NS5A Inhibitors (“asvir”)
• Ledipasvir
• Ombitasvir
• Daclatasvir
• Elbasvir
• Velpatasvir (Non-approved: Investigational Use)
• Protease Inhibitors (“previr”)
• Simeprevir
• Paritaprevir
• Grazoprevir
AASLD Guidance on HCV/HIV DDIs
Atazanavir + RTV
Darunavir + RTV
Lopinavir/RTV
Tipranavir + RTV
Efavirenz
Rilpivirine
Etravirine
Raltegravir
Elvitegravir + COBI
Dolutegravir
Maraviroc
Tenofovir DF
SMV + SOF
SOF
LDV/SOF
DCV + SOF



































 nephrotoxicity












No clinically significant interaction expected
AASLD/IDSA. HCV guidelines. December 2015.
Potential interaction may require adjustment to dosage, timing of
administration, or monitoring
OMV/PTV/RTV
+ DSV












Do not coadminister
AASLD/IDSA Guidance for HCV/HIV Coinfection
• Use same regimens as in HCV-monoinfected pts, but consider drug–drug
interactions
– Avoid combination of LDV and tenofovir DF if CrCl < 60 mL/min or if
receiving tenofovir DF with RTV-boosted PIs
– When LDV/SOF and tenofovir DF are coadministered with antiretrovirals,
monitor for nephrotoxicity
– Tenofovir levels increased with efavirenz, rilpivirine, or dolutegravir, when
administered with LDV/SOF and tenofovir DF
– Adjust/withhold RTV if receiving a boosted PI with OMV/PTV/RTV + DSV
– Adjust DCV with atazanavir/RTV, efavirenz, or etravirine
• DCV + SOF ± RBV recommended when ART regimen changes cannot be made
to accommodate other DAAs
AASLD/IDSA. HCV guidelines. April 2016
Sofosbuvir
• NS5B Nucleotide Polymerase Inhibitor
• 400 mg daily
• A/E: fatigue, headache, nausea, rash, and irritability.
• Active against genotype 1,2,3,4
• ARV: ALL except tipranavir; didanosine, zidovudine, (if given with
ribavirin)
• No response guided therapy
Simeprevir
• NS3/4A protease inhibitor
• 150 mg daily
• Genotype 1 and 4
• A/E: rash, pruritus, nausea
• ARV: LIMITED to raltegravir, rilpivirine, maraviroc, enfuvirtide, tenofovir,
emtricitabine, lamivudine, abacavir
• *For genotype 1a, baseline resistance testing for Q80K should be performed
and alternative treatments should be considered if this mutation is present.
Ledipasvir
• NS5A inhibitor
• Available co-formulated with
sofosbuvir
• Generally well tolerated
• Risk of Serious Symptomatic
Bradycardia When Coadministered
with Amiodarone
• Risk of Reduced Therapeutic Effect
of HARVONI Due to P-gp Inducers
• Genotype 1, 4,5,6
• Can increase levels of tenofovir
when co-administered with
ritonavir
Genotype 1
Genotype 4, 5, or 6
Patient Population
Duration
Treatment-naïve
with or without
cirrhosis
12 weeks
Treatmentexperienced
without cirrhosis
12 weeks
Treatmentexperienced with
cirrhosis
24 weeks
Treatment-naïve
12 weeks
and treatment
experienced, with
or without cirrhosis
ION-4: LDV/SOF for 12 Wks in GT1/4 HCV/
HIV–Coinfected Pts
100
95
97
321/
335
142/
150
179/
185
Overall
Naive
Exp’d
96
96
94
258/
268
63/
67
98
90
99
SVR12 (%)
80
60
40
20
n/N =
0
103/
115
No
Cirrhosis Exp’d + Black
Cirrhosis
Cirrhosis
• Permitted ARTs: TDF/FTC plus efavirenz, raltegravir, or rilpivirine
• Effective across subgroups, but with lowered SVR in black pts
Cooper C, et al. EASL 2015. Abstract P1353.
46/
47
215/
217
Nonblack
•
•
•
•
•
•
Daclatasvir
NS5A inhibitor
FDA approval for GT 1, 3
Genotype 1
Recommended in the guidelines for GT1, 2,3
CYP3A4 substrate
60 mg PO daily with sofosbuvir for 12 weeks
Dose modification: Reduce dosage to 30 mg once
daily with strong CYP3A inhibitors and increase
dosage to 90 mg once daily with moderate
CYP3A inducers
• Daclatasvir requires dose adjustment with
Genotype 3
ritonavir-boosted atazanavir (a decrease to 30
mg daily) and efavirenz or etravirine (an increase
to 90 mg daily).
• CONTRAINDICATIONS
• Strong inducers of CYP3A, including
phenytoin, carbamazepine, rifampin, and St.
John’s wort
Patient
Population
Duration
Without cirrhosis
DCV + SOF for
12 weeks
Compensated
(Child-Pugh A)
cirrhosis
Decompensated
(Child-Pugh B or
C) cirrhosis
DCV + SOF+ RBV
for 12 weeks
Post-transplant
Without cirrhosis
With cirrhosis
(including
decompensated)
Post-transplant
DCV + SOF for
12 weeks
DCV + SOF+ RBV
for 12 weeks
ALLY-2: DCV + SOF for 12 Wks in GT1-4
HCV/HIV–Coinfected Pts
SVR12 (%)
100
96
98
97
98
80/
83
43/
44
98/
101
51/
52
Naive, 12 wks of DCV + SOF
Exp’d 12 wks of DCV + SOF
80
60
40
20
n/N =
0
GT1
All Treated
• Permitted ARTs: atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, efavirenz,
nevirapine, rilpivirine, dolutegravir, raltegravir, enfuvirtide, maraviroc, zidovudine, lamivudine,
abacavir, tenofovir DF, emtricitabine
• Cirrhosis: 8.9% of naive pts, 28.8% of experienced pts
• No significant difference in SVR12 rates among black vs nonblack pts (92% vs 97%, respectively)
Wyles DL, et al. EASL 2015. Abstract LP01.
Paritaprevir/Ritonavir/Ombitasvir/Dasabuvir (PrOD)
• PI/NS5A/NS5B combination
• Activity against GT1, 4
• atazanavir, dolutegravir,
emtricitabine, enfuvirtide,
lamivudine, raltegravir, and
tenofovir
• Adjust dose of ritonavir if
part of HIV combo
• HIV PI should be given at the
same time
• 2 tab P/r/O daily plus 1 tab
Dasabuvir BID with ribavirin
PATIENT POPULATION
TREATMENT*
DURATION
Genotype 1a, without cirrhosis
PrOD + ribavirin
12 weeks
Genotype 1a, with cirrhosis
PrOD + ribavirin
24 weeks**
PrOD
12 weeks
PrOD + ribavirin
12 weeks
Genotype 1b, without cirrhosis
Genotype 1b, with cirrhosis
TURQUOISE-I: Paritaprevir/RTV/Ombitasvir + Dasabuvir +
RBV in HIV/GT1 HCV Pts
• Open-label phase II/III trial; compensated cirrhosis
(Child-Pugh A) allowed; DAA naive but pegIFN/RBV naive
or experienced
Paritaprevir/RTV/Ombitasvir +
Dasabuvir + RBV
(n = 31)
DAA-naive
HIV-infected pts with
GT1 HCV infection
(N = 63)
100
Wk 12
Wk 24
Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV
(n = 32)
93.5 90.6
93.8 100
93.3
29/ 29/
31 32
15/ 12/
16 12
14/ 17/
15 20
Overall
Atazanavir
Raltegravir
85.0
SVR12 (%)
80
60
40
20
n/N =
0
Sulkowski MS, et al. JAMA. 2015;313:1223-1231.
Eron JJ, et al. Glasgow HIV. Abstract O222.
Slide credit: clinicaloptions.com
Elbasvir/Grazoprevir
• NS5A/protease inhibitor
• GT1, 4
• 1a test for polymorphism
• 1 tab daily +/- food
• Approved for renal
impairment including HD
• Fatigue, headache, nausea
• Monitor for DDI
Patient Population
Duration
Genotype 1a: Treatment-naïve or
PegIFN/RBVexperienced* without baseline NS5A
polymorphisms†
12 weeks
Genotype 1a: Treatment-naïve or
PegIFN/RBVexperienced* with baseline NS5A
polymorphisms†
16 weeks
Genotype 1b: Treatment-naïve or
PegIFN/RBVexperienced*
12 weeks
Genotype 1a or 1b: PegIFN/RBV/PI-experienced‡
12 weeks
Genotype 4: Treatment-naïve
12 weeks
Genotype 4: PegIFN/RBV-experienced*
16 weeks
C-EDGE Coinfection: Grazoprevir/Elbasvir for
12 Wks in GT1-4 HCV/HIV–Coinfection
100
93
93
93
93
203/
218
134/
144
41/
44
26/
28
All Pts
GT1a
GT1b
GT4
SVR24 (%)
80
60
40
20
n/N =
0
• SVR rates similar across pt subgroups, including in black pts and pts with cirrhosis
• Tx failure in 2 pts attributable to posttreatment reinfection with GT3 HCV
Rockstroh JK, et al. AASLD 2015. Abstract 210.
C-EDGE TN: Impact of Baseline NS5A RAVs
SVR12 With 12 Wks of Grazoprevir/Elbasvir
92
99
99
SVR12 (%)
100
58
80
60
40
20
n/N =
0
144/
157
129/
131
133/
135
11/
19
GT1a
GT1b
GT1a,
No BL
NS5A
RAVs
GT1a,
BL
NS5A
RAVs
Zeuzem Z, et al. Ann Intern Med. 2015;163:1-13.
Slide credit: clinicaloptions.com
HCV Treatment Terms
• RVR- HCV negative at week 4 of treatment
• EOT_ HCV negative at the end of treatment course
• SVR 4- HCV negative at week 4 after completion of therapy
• SVR12- HCV negative at week 12 after completion of therapy-”Cured”
Monitoring of Patients
• Within 12 weeks before
treatment
• CBC, INR, CMP
• Any time prior
• HCV GT
• HCV Viral load
• NS3 resistance
• PI therapy
• RAV testing
• Per guidelines
• During therapy
• Monitor adherence
• CBC, GFR, LFT at week 4
• HCV PCR at week 4, EOT, 12 weeks
after t/t
• Closer monitoring for cirrhotics
• Discontinuation of treatment
• HCV RNA at wk 4 if detectable,
repeat at wk 6, if higher,
discontinue
Case Presentation-1
• A 54 year old male with HIV HCV
• HIV VL < 20, CD4- 554
• HCV, GT 1a, VL- 6 million
• Fibrosure: F2
• ARV: TDF/FTC, ATV/r
• What are your treatment considerations
• ARV
• Pill burden
• Drug interaction
GT 1 a
Preferred
Alternative
Cirrhosis EBV/GZV 12 WKS (no RAVs)
DCV SOF 12 WKS
LDV/SOF 12 WKS
PrOD RBV 12 WKS
SOF/SMV 12 WKS
EBV/GZV 16 WKS (high NS5A
RAVs)
Cirrhosis +
EBV/GZV 12 WKS
LDV/SOF 12 WKS
PrOD RBV 24 WKS
SOF/SMV 24 WKS
DCV SOF 24 +/- RBV
EBV/GZV 16 WKS (high
NS5A RAVs)
Genotype 1b
GT 1 b
Preferred
Cirrhosis EBV/GZV 12 WKS
Cirrhosis +
EBV/GZV 12 WKS
DCV SOF 12 WKS
LDV/SOF 12 WKS
LDV/SOF 12 WKS
PrOD RBV 12 WKS
SOF/SMV 12 WKS
Alternative
PrOD RBV 12 WKS
SOF/SMV 24 WKS
DCV SOF 24 +/- RBV
Case Presentation -2
• A 45 year old injection drug user with HIV-HCV, (GT2) was previously
successfully treated with pegylated interferon and RBV. He comes back for a
routine visit and is found to have elevated LFTs and found to have HCV
infection again with GT2.
• Further questioning reveals that he has been sharing needles with his
girlfriend who also has HCV. She does not have HIV
• His HIV is well controlled, VL < 50, CD4- 450, on Atripla
Case Presentation -2 Contd
• What are the issues that come up:
• HIV PrEP
• Risk reduction messaging
• Would you treat him again
• What different would you do
Genotype 2
GT
Cirrhosis -
Cirrhosis +
2
DCV SOF 12 WKS
Consider 16-24
weeks
SOF RBV 12 WKS
Genotype 3
GT3
Recommended
Alternative
Cirrhosis DCV SOF 12 WKS
SOF RBV IFN 12
WKS
SOF/RBV 24 WKS
Cirrhosis +
DCV SOF 24 +/RBV
SOF RBV IFN 12
WKS
Genotype 4
GT 4
Recommended
Alternative
Cirrhosis LDV/SOF 12 WKS
Cirrhosis +
LDV/SOF 12 WKS
PrOD RBV 12 WKS
EBV/GZV 12 WKS
PrOD RBV 12 WKs
EBV/GZV 12 WKS
SOF RBV IFN 12 WKS
SOF RBV IFN 12 WKS
Genotype 5,6, Naïve
• Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400
mg) for 12 weeks
• Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG-IFN
for 12 weeks
Case Presentation-3
• A 55 year old woman with compensated cirrhosis, HIV
• HIV VL <20, CD4: 356
• HCV, GT 1a, HCV VL- 4 million
• Treatment experienced with Peg IFN
• TDF/FTC, RAL
• ARV
• HCV treatment option
• Duration of therapy
GT 1 a
Preferred
Alternative
Cirrhosis EBV/GZV 12 WKS (no RAVs)
DCV SOF 12 WKS
LDV/SOF 12 WKS
PrOD RBV 12 WKS
SOF/SMV 12 WKS
EBV/GZV 16 WKS (high NS5A RAVs)
Cirrhosis +
EBV/GZV 12 WKS
LDV/SOF 12 WKS
PrOD RBV 24 WKS
SOF/SMV 24 WKS
DCV SOF 24 +/- RBV
EBV/GZV 16 WKS (high NS5A
RAVs)
What if the patient has ESRD
Case Presentation-4
• A 55 year old woman with HIV and HCV and compensated cirrhosis
was successfully treated with LDV/SOF for 12 weeks.
• Does she require any future monitoring for her liver disease?
1. None required she is cured
2. Repeat HCV PCR every 6 months to ensure that she remains negative
3. She will require ongoing surveillance for hepatocellular carcinoma
Case Presentation-5
• A 56 year old male with HIV/HCV treated with LDV/SOF for 12 weeks.
However, his HCV PCR was positive 4 weeks after treatment
completion.
• What should you do now:
• Defer treatment
• Retreat with same regimen but now for 24 weeks
• Retreat with another combo
Case Presentation- 6
• A 60 year old AA male with HIV (VL <20, CD4 of 564)
• Has HCV GT1a, compensated cirrhosis
• Treated with LDV/SOF for 24 weeks
• Now relapsed
• What will you do next
• Defer
• Retreat with LDV/SOF/RBV for 24 weeks
• Treat with SOF/SMV/RBV for 24 weeks
Prior NS5b Failure
• Deferral of treatment is recommended, for those who do not have
cirrhosis, and do not have reasons for urgent retreatment.
• Testing for resistance-associated variants that confer decreased
susceptibility to NS3 protease inhibitors and to NS5A inhibitors is
recommended
• When using nucleotide-based (eg, sofosbuvir) dual DAA therapy a
treatment duration of 24 weeks is recommended, and weight-based RBV,
unless contraindicated, should be added.
• If available, quadruple DAA regimens may be considered. In these settings
treatment duration ranges from 12 weeks to 24 and weight-based ribavirin,
unless contraindicated, are recommended.
Case Presentation-7
• A 56 year old male with HIV, HCV (GT1a), ESRD on HD
• ARV: Dolutegravir, Lamivudine, Darunavir/r (h/o NNRTI resistance)
• No cirrhosis
• What can you treat him with
•
•
•
•
•
LDV/SOF
PrOD
DCV/SOF
SOF/RBV
Elbasvir/grazoprevir
Dosing Considerations for Pts With Renal
Impairment
eGFR/CrCl
SOF/LDV[2]
SOF + SIM[3,4]
SOF + DCV[3,5]
RBV[6]
GZR/EBV[7]
No adjustment
needed
No adjustment
needed
No adjustment
needed
No adjustment needed
Alternating
200 mg and
400 mg every
other day
15-30 mL/min
No adjustment
needed
Safety and
efficacy not
established
SMV/DCV: no
adjustment needed;
SOF: safety and efficacy
not established
200 mg/day
No adjustment
needed
< 15 mL/min or
hemodialysis
Safety and efficacy
not established
Safety and
efficacy not
established
Safety and efficacy not
established
200 mg/day
No adjustment
needed
30-50 mL/min

PTV/RTV/OBV +
DSV[1]
In pts with CrCl < 30 mL/min for whom treatment is urgent and renal transplant not an immediate option: [3]
–
Recommended: 12 wks GZR/EBV (GT1a or GT1b); 12 wks PTV/RTV/OBV + DSV (GT1b)
–
Alternative: 12 wks PTV/RTV/OBV + DSV + reduced-dose RBV (GT1a)
Slide credit: clinicaloptions.com
SUMMARY
• All patients should be considered for treatment
• Priority for those with more advanced liver disease
• Treatment will likely be expanded for all with additional medications
being approved which will hopefully drive the costs down
• In general HIV/HCV co-infected patients respond similar to HCV
mono-infected patients
• Ongoing risk reduction is necessary to reduce likelihood of reinfection