HIV HCV HBV - What`s New in Medicine

Report
2014: HIV, HCV, and HBV Update
David Spach, MD
Professor of Medicine, Division of Infectious Diseases
University of Washington
Last Updated: June 12, 2013
Chronic Viral Diseases and Mortality in United States
• Which one of the chronic viral diseases was
responsible for the most number of deaths in the
United States in 2007?
A. Hepatitis A virus
B. Hepatitis B virus
C. Hepatitis C virus
D. HIV
Age-Adjusted Mortality Rates from HBV, HCV, & HIV
United States, 1999-2007
7
HIV
Rate per 100,000 PY
6
5
4
Hepatitis C
3
2
1
Hepatitis B
0
1999
2000
2001
2002
2003
Year
Source: Ly KN, et al. Ann Intern Med. 2012:156:271-8.
2004
2005
2006
2007
Forecasted 2010-2060 Annual HCV-Related Deaths in the United States
Persons with Chronic Hepatitis C and no Cirrhosis in 2005
45,000
Peak
40,000
Deaths
35,000
Number
30,000
25,000
20,000
15,000
10,000
5,000
0
2010 2014 2018 2022 2026 2030 2034 2038 2042 2046 2050 2054 2058
Year
Source: Rein DR, et al. Dig Liver Dis. 2011:43:66-72.
Hepatitis C Update
Hepatitis C: Progression of Disease
Time
20-25 years
Normal Liver
25-30 years
Chronic
Hepatitis
Cirrhosis
HCC
ESLD
Death
HCV Infection
Comparative Treatment Goals with Antiviral Therapy
HIV
HBV
HCV
(latent reservoir)
(latent reservoir)
(no latent reservoir)
HCV RNA
ccDNA
Proviral DNA
Host DNA
Host DNA
Host DNA
Host Cell
Host Cell
Host Cell
Lifelong suppression
of viral replication
Long-term reduction
of viral replication
Source: Kieffer TA, et al. J Antimicrob Chemother. 2010:65:2012-12
Definitive
Viral Clearance
Virologic Responses with HCV Therapy
Sustained Virologic Response (SVR12)
10,000,000
Treatment
Post Treatment
HCV RNA IU/ml
1,000,000
SVR12
100,000
10,000
End of Treatment
1,000
12 Weeks
100
10
1
Undetectable
-8
-4
0
4
8
12
16
20
24
28
32
36
40
44
Treatment Week
Sustained Virologic Response (SVR12) = Undetectable HCV RNA 12 Weeks Post Treatment
48
Evolution of Hepatitis C Treatment
• In 2015, what is the realistic expectation for achieving
SVR (cure) of hepatitis C with state-of-the-art
treatment?
A. 60%
B. 75%
C. 85%
D. 95%
Therapy for Hepatitis C: Historical Milestones
Sustained Virologic Response (%)
100
Timeline
1986
1998
2001
2002
2011
80
70
60
55
42
40
34
39
16
20
6
0
IFN
6m
IFN
12m
IFN + RBV
6m
IFN + RBV
12m
PegIFN
12m
PegIFN +
RBV
12m
PegIFN +
RBV + PI 612m
Therapy for Hepatitis C
SVR Rates with DAA-Based Therapy
Timeline
1986
1998
2001
2002
2011
Sustained Virologic Response (%)
100
2014
90
80
70
55
60
42
40
34
39
16
20
6
0
IFN
6m
IFN
12m
IFN + RBV IFN + RBV
6m
12m
PEG
12m
PEG +
RBV
12m
PEG +
RBV + PI
6-12m
Multiple
DAAs
3m
Therapy for Hepatitis C
SVR Rates with Multiple DAAs
Timeline
1986
1998
2001
2002
2011
2014
2015
Sustained Virologic Response (%)
100
97
90
80
70
60
55
40
42
34
39
20
0
6
IFN
6m
16
IFN
12m
IFN + RBV
6m
IFN + RBV
12m
PEG
12m
PEG + RBV PEG + RBV PEG + RBV
12m
+ PI
+ SOF
6-12m
3m
Multiple
DAAs
2-3m
Hepatitis C Virus
Structural and Nonstructural Proteins
Hepatitis C Proteins
Structural Proteins
C
E1
E2
Nonstructural (NS) Proteins
p7
NS2
Cysteine
Protease
Vioporin
NS4
A
NS3
NS4B
Serine Protease
Cofactors
Serine
RNA
Protease Helicase
NS5A
NS5B
RNA binding and assembly
recognition complex
Membranous
Web Induction
RNA-Dependent
RNA
Polymerase
Categories of Direct Acting Antiviral Agents
Hepatitis C Direct Acting Antiviral Agent (DAA) Categories
NS3/4A
Protease Inhibitor
NS5A
Inhibitor
NS5B
Polymerase Inhibitor
NS3
NS4A
NS5A
NS5B
Serine
Protease
Cofactors
RNA binding and
assembly recognition
complex
RNA-Dependent
RNA Polymerase
Serine
Protease
Future HCV Direct Acting Agents (DAAs)
NS3
NS5A
NS5B
Protease Inhibitors
NS5A Inhibitors
Polymerase Inhibitors
Asunaprevir
Daclatasvir
Mericitabine
Danoprevir
Ledipasvir
Sofosbuvir
Faldaprevir
Ombitasvir
Dasabuvir
Simeprevir
IDX-719
BMS-791325
NS4A
Vaniprevir
ABT-450/r
BI-207127
Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6
NEUTRINO Trial: Design
Week
N =327
0
12
Sofosbuvir + PEG + RBV
24
SVR12
Drug Dosing
Sofosbuvir: 400 mg once daily
Peginterferon alfa-2a: 180 µg once weekly
Ribavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6
NEUTRINO Trial: Results
NUTRINO: SVR 12 by Genotype
Patients with SVR 12 (%)
100
80
89
97
92
82
60
40
20
261/292
206/225
54/66
34/35
GT 1
(all subtypes)
GT 1a
GT 1b
GT 4,5,6
0
GT = genotype
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
Hepatitis C Treatment
• According to 2014 AASLD/IDSA/IAS-USA guidance,
which on of the following regimens is recommended for
initial treatment of patients with genotype 1 chronic
HCV? Assume the patient is eligible to receive
interferon.
A. Peginterferon + Ribavirin + Telaprevir x 12 weeks
B. Peginterferon + Ribavirin + Sofosbuvir x 12 weeks
C. Peginterferon + Ribavirin + Sofosbuvir x 12 weeks
D. Sofosbuvir + Simeprevir x 24 weeks
AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations
Initial Recommended Therapy for Patients with Chronic HCV
HCV: Recommended Initial Treatment & Retreatment of Relapsers*
Interferon Eligible
GT1
Sofosbuvir + Peginterferon + Ribavirin x 12 weeks
Not Interferon Eligible
Sofosbuvir + Simeprevir +/- Ribavirin x 12 weeks
GT2
Sofosbuvir + Ribavirin x 12 weeks
GT3
Sofosbuvir + Ribavirin x 24 weeks
Interferon Eligible
GT4
Sofosbuvir + Peginterferon + Ribavirin x 12 weeks
Not Interferon Eligible
Sofosbuvir + Ribavirin x 24 weeks
*Patients who experienced relapse after Peginterferon plus Ribavirin therapy
Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org).
Hepatitis C Genotype 1
Costs of Different Regimens for Treatment of Genotype 1
Estimated Medication Cost for Treatment of Genotype 1 Chronic HCV
Regimen and Duration
Regimen Cost
Sofosbuvir + Ribavirin + Peginterferon x 12 weeks
$97,000
Sofosbuvir x 12 weeks + [Ribavirin + Peginterferon] x 24 weeks
$109,000
Sofosbuvir + Ribavirin x 24 weeks
$169,000
Sofosbuvir + Simeprevir +/- Ribavirin x 12 weeks
$150,000
Simeprevir x 12 weeks + [Ribavirin + Peginterferon] x 24
weeks
$79,000
Simeprevir x 12 weeks + [Ribavirin + Peginterferon] x 48
weeks
$104,000
Note: sofosbuvir cost = $1000 per day of treatment
INVESTIGATIONAL
Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1
ION-1 Study: Study Design
Week
0
12
24
36
n = 214
LDV-SOF
SVR12
n = 217
LDV-SOF + RBV
SVR12
n = 217
LDV-SOF
SVR12
n = 217
LDV-SOF + RBV
SVR12
GT-1
Naive
GT-1
Naive
Drug Dosing
Ledipasvir-sofosbuvir
(90/400 mg): fixed dose combination; one pill once daily
N =14
Ribavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg
Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin
Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.
INVESTIGATIONAL
Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1
ION-1 Study: Results
ION-1: SVR 12 by Treatment Duration and Regimen
Patients with SVR 12 (%)
100
99
97
98
99
211/214
211/217
212/217
215/217
LDV-SOF
LDV-SOF +RBV
LDV-SOF
LDV-SOF + RBV
80
60
40
20
0
12-Week Regimen
LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin
Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.
24-Week Regimen
INVESTIGATIONAL
Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1
ION-1 Study: Results
ION-1: SVR12 by Treatment Regimen and Liver Disease
Without Cirrhosis
Patients (%) with SVR 12
100
100
97
100
100
99
97
178/178
33/33
181/182
31/32
With Cirrhosis
100
100
179/179
36/36
80
60
40
20
179/179
32/33
0
LDV-SOF
LDV-SOF + RBV
12-Week Treatment
LDV-SOF
24-Week Treatment
Note: subgroup results do not include patients who withdrew consent or were lost to follow-up
Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.
LDV-SOF + RBV
INVESTIGATIONAL
3D (ABT-450/r-Ombitasvir + Dasabuvir) + Ribavirin
GT 1 and Compensated Cirrhosis: TURQUOISE-II Study
TURQUOISE II: SVR12
12-Week Group
24-Week Group
Patients (%) with SVR 12
100
92
96
80
94
99
100
89
60
40
20
0
Overall
GT1a
Source: Poordad F, et al. N Engl J Med. 2014;370:1973-82.
GT1b
HCV Treatment: Key Concepts
• Very high SVR rates with new therapies
• Excellent SVR rates regardless of cirrhosis, race
• Excellent SVR rates in treatment experienced
• Genotype 3 is most difficult to treat
• All oral therapies wave of future
• Cost of new therapies is huge barrier
University of Washington: Hepatitis C Online
Hepatitis C Online: www.hepatitisc.uw.edu
HIV Update
New HIV Testing Recommendations
HIV Testing
• Which one of the following best describes the initial
recommended HIV screening test in the 2014 CDC
recommendations?
A. 4th generation p24 antigen-antibody assay
B. Western blot
C. HIV RNA
Traditional Approach to HIV Diagnostic Testing
Initial
Supplemental
EIA
Western blot
or
IFA
Optimized for Sensitivity
Optimized for Specificity
Drawbacks with Conventional HIV Diagnostic Algorithm
• Does not detect acute HIV
• Does not differentiate HIV-1 and HIV-2
• Problems with indeterminate Western blot
Laboratory Diagnosis of Early HIV Infection
30
1,000,000
25
HIV Antibody
100,000
10,000
20
HIV RNA
1,000
100
15
10
1
HIV p24 antigen
0
5
10
15
20
25
30
35
40
Days following HIV Acquisition
Timing of HIV RNA, HIV p24 antigen, and HIV Antibody
45
50
10
Antibody Titer
HIV RNA (copies/ml)
10,000,000
4th Generation HIV Ag/Ab Combination Assays
HIV p24 Antigen
HIV Antibodies
Detects HIV-1 p24 antigen and antibodies to HIV-1 and HIV-2
2014 CDC Recommendations
Recommended Laboraatory HIV Testing Algorithm
HIV-1/2 Antigen/Antibody Combination Immunoassay
(-)
(+)
Negative for HIV-1 and HIV-2
antibodies and p24 Ag
HIV-1/HIV-2 Ab Differentiation Immunoassay
HIV-1 (+)
HIV-2 (-)
HIV-1 antibodies
detected
HIV-1 (-)
HIV-2 (+)
HIV-1 (+)
HIV-2 (+)
HIV-2 antibodies
detected
HIV antibodies
detected
HIV-1 (-) or Indeterminate
HIV-2 (-)
HIV-1 NAT
HIV-1 NAT (+)
HIV-1 NAT (-)
Acute HIV-1 infection
Negative for HIV-1
Source: Centers for Disease Control and Prevention. 2014.
Antiretroviral Therapy
US Health and Human Services (HHS)
May 1, 2014 Antiretroviral Therapy Guidelines
Source: 2014 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)
HHS Antiretroviral Therapy Guidelines: 2013
Initiating Therapy in Treatment-Naïve Patients
CD4 Cell Count
1000
Antiretroviral therapy (ART) is recommended for all HIV-infected
individuals to reduce the risk of disease progression.
800
Recommend (BIII)
600
500
Strongly Recommend (AII)
400
350
200
Strongly Recommend (AI)
0
Source: 2013 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)
HIV Prevention Trials Network (HPTN) Study 052
1,763 HIV Serodiscordant Couples (97% heterosexual)
-
+
n = 873
Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.
+
n = 890
-
HIV Prevention Trials Network (HPTN) Study 052
CD4 Cell Count
1000
800
+
+
600
550
Early Therapy
400
200
CD4 350-550 cells/mm3
350
Deferred Therapy
CD4 < 250 cells/mm3 or AIDS Related Event
0
Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.
250
HIV Prevention Trials Network (HPTN) Study 052
96% Reduction
P < 0.001
1
Early Therapy
27
Deferred Therapy
0
5
10
15
20
Linked Transmissions
Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.
25
30
HHS Antiretroviral Therapy Guidelines: May 1, 2014
Recommended Regimens Regardless of Baseline HIV RNA or CD4 Count
Class
Therapy
NNRTI-Based
Efavirenz-Tenofovir-Emtricitabine
Pill Burden
Atazanavir + Ritonavir + Tenofovir-Emtricitabine
PI-Based
Darunavir + Ritonavir + Tenofovir-Emtricitabine
Raltegravir + Tenofovir-Emtricitabine
^Elvitegravir-Cobicistat-Tenofovir-Emtricitabine
INSTI-Based
Dolutegravir + *Abacavir-Lamivudine
Dolutegravir + Tenofovir-Emtricitabine
^Elvitegravir-Cobicistat-Tenofovir-Emtricitabine: only for patients with pre-ART CrCl ≥ 70 ml/min
*Abacavir recommended only if HLA-B5701 negative
Source: 2014 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)
Single Tablet Antiretroviral Regimens
Efavirenz-Tenofovir-Emtricitabine
Atripla
Rilpivirine-Tenofovir-Emtricitabine
Complera
Elvitegravir-Cobicistat-Tenofovir-Emtricitabine
Stribild
Dolutegravir Phase 3 Studies in Treatment-Naïve Subjects
Study
1 SPRING-2
2 SINGLE
3 FLAMINGO
•
ARV History
Comparison
Results
ARV-Naïve
Dolutegravir QD
versus
Raltegravir
• Non-inferior
ARV-Naïve
Dolutegravir QD
versus
Efavirenz
• Dolutegravir superior
ARV-Naïve
Dolutegravir QD
versus
Darunavir-RTV
• Dolutegravir superior
1 Raffi
F, et al. Lancet 2013;381:735-43.
2 Walmsley S. N Engl J Med. 2013:369:1807-18.
3 Clotet B, et al. Lancet. 2014 March 31 [Epub ahead of print]
.
(88% versus 85%)
(88% versus 81%)
(90% versus 83%)
Future Single Tablet Regimen
Dolutegravir-Abacavir-Lamivudine
“Tri Pill”
Occupational PEP
2013
Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.
Case History
HIV Exposure in a Health Care Worker
• A 41-year-old male nurse has a needlestick injury on his left
thumb. The site bled for about 2 minutes after the injury. The
source patient has documented HIV infection, has never taken
antiretroviral medications, and most lab studies showed HIV RNA
level of 2,350 copies/ml and CD4 count of 658 cells/mm3.
• Based on USPHS 2013 Guidelines, what is recommended?
A. 2 drugs: Zidovudine-lamivudine
B. 2 drugs: Tenofovir-emtricitabine
C. 3 drugs: Tenofovir-emtricitabine + Raltegravir
D. 3 drugs: Tenofovir-emtricitabine + Darunavir + ritonavir
2013 USPHS Occupational PEP Guidelines
Number of Antiretroviral Medications to Use
“…the PHS working group recommends prescribing 3
(or more) tolerable drugs as PEP for all occupational
exposures to HIV.”
Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.
2013 USPHS Occupational PEP Guidelines
Recommendations for Antiretroviral Regimens
Recommended Antiretroviral Regimens for Occupational PEP (28-Day Duration)
Preferred Regimen
INSTI
NNRTI
Raltegravir (Isentress) Tenofovir-Emtricitabine (Truvada)
400 mg twice daily
1 pill daily
Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.
Pill Burden
Post-Exposure Prophylaxis Line (PEPline)
888-448-4911
HBV Update
HBV Treatment and Entecavir Resistancne
• What percentage of patients with chronic HBV and long
term entecavir treatment will develop resistance?
Resistance with Entecavir
• 222 nucleoside-naïve patients treated for 3 years
- Cumulative -resistance to entecavir of 1.3% at 3 years
Yuen MF, et al. Am J Gastroenterol. 2011;106:1264-71.
• 474 nucleoside-naïve treated for 4 years
- Cumulative resistance to entecavir of 0.4%
Ono A, et al. J Hepatol. 2012;57:508.
• Overall Estimates of Resistance Rates
- Treatment naïve: < 1% at 5 years
- Prior lamivudine failure: approximately 50% at 5 years
Duration of HBV Therapy with Entecavir
• Can you stop entecavir after long-term treatment (> 2
years) for patients with HBeAg- chronic HBV and HBeAgand sustained virologic suppression?
Duration of HBV Therapy with Entecavir
• Background
- 184 patients with HBeAg- chronic HBV
- On entecavir for ≥ 2 years
- Undetectable HBV DNA on ≥3 occasions 6 months apart
• Following Entecavir Cessation
- Virologic relapse at 24 weeks: 74%
- Virologic relapse at 48 weeks: 91%
“…therapy should be continued indefinitely until the
recognised treatment endpoint of HBsAg seroclearance.”
Source: Seto WK, et al. Gut. 2014; May 15 [E pub Ahead of Print]

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