2014: hiv, hcv, and hbv update
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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2014: HIV, HCV, and HBV Update
David Spach, MDProfessor of Medicine, Division of Infectious DiseasesUniversity of Washington
Last Updated: June 12, 2013
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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 virusB. Hepatitis B virusC. Hepatitis C virusD. HIV
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Age-Adjusted Mortality Rates from HBV, HCV, & HIV United States, 1999-2007
Source: Ly KN, et al. Ann Intern Med. 2012:156:271-8.
Rate
per
100,0
00 P
Y
Year
HIV
1999 2000 2001 2002 2003 2004 2006 20072005
5
4
3
2
1
0
7
6
Hepatitis C
Hepatitis B
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Source: Rein DR, et al. Dig Liver Dis. 2011:43:66-72.
Forecasted 2010-2060 Annual HCV-Related Deaths in the United States
Persons with Chronic Hepatitis C and no Cirrhosis in 2005N
um
ber
Year
2010
Deaths
2014 2018 2022 2026 2030 2034 2038 2042 2046 2050 2054 2058
40,000
35,000
30,000
25,000
20,000
15,000
10,000
5,000
0
45,000Peak
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Hepatitis C Update
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Hepatitis C: Progression of Disease
25-30 yearsNormal Liver
Chronic Hepatitis
HCCESLDDeath
HCV Infection
20-25 years
Cirrhosis
Time
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Source: Kieffer TA, et al. J Antimicrob Chemother. 2010:65:2012-12
Comparative Treatment Goals with Antiviral Therapy
HBV(latent reservoir)
HIV(latent reservoir)
HCV(no latent reservoir)
Host CellHost Cell Host Cell
Host DNAHost DNA Host DNA
ccDNA
Proviral DNA
HCV RNA
Definitive Viral Clearance
Lifelong suppression of viral replication
Long-term reductionof viral replication
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Virologic Responses with HCV TherapySustained Virologic Response (SVR12)
Sustained Virologic Response (SVR12) = Undetectable HCV RNA 12 Weeks Post Treatment
-8 -4 0 4 8 12 16 20 24 28 32 36 40 44 481
10
100
1,000
10,000
100,000
1,000,000
10,000,000
Treatment Week
HC
V R
NA
IU
/ml
End of Treatment
12 Weeks
Undetectable
SVR12
Treatment Post Treatment
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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%
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Therapy for Hepatitis C: Historical Milestones
0
20
40
60
80
100
6
16
34
42 39
55
70
Su
sta
ine
d V
iro
log
ic R
es
po
ns
e (
%)
1986 1998 2001 2002
Timeline
2011
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Therapy for Hepatitis CSVR Rates with DAA-Based Therapy
0
20
40
60
80
100
6
16
3442 39
55
70
90
Su
sta
ine
d V
iro
log
ic R
es
po
ns
e (
%)
1986 1998 2001 2002
Timeline
2011 2014
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Therapy for Hepatitis CSVR Rates with Multiple DAAs
0
20
40
60
80
100
6
16
3442 39
55
70
9097
Su
sta
ine
d V
iro
log
ic R
es
po
ns
e (
%)
1986 1998 2001 2002
Timeline
2011 2014 2015
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Hepatitis C VirusStructural and Nonstructural Proteins
Hepatitis C Proteins
Vioporin
CysteineProtease
Serine Protease
RNAHelicase
Serine Protease Cofactors
Membranous Web Induction
RNA-Dependent RNA Polymerase
C NS4B NS5ANS2 NS3E1 NS4Ap7E2 NS5B
Structural Proteins Nonstructural (NS) Proteins
RNA binding and assembly recognition complex
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Categories of Direct Acting Antiviral Agents
Hepatitis C Direct Acting Antiviral Agent (DAA) Categories
Serine Protease
Serine Protease Cofactors
RNA-Dependent RNA Polymerase
NS5ANS3 NS4A NS5B
RNA binding and assembly recognition
complex
NS3/4A Protease Inhibitor
NS5A Inhibitor
NS5B Polymerase Inhibitor
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Future HCV Direct Acting Agents (DAAs)
Faldaprevir
Daclatasvir
Danoprevir
Asunaprevir Mericitabine
Vaniprevir
Ledipasvir
Simeprevir
Sofosbuvir
Ombitasvir Dasabuvir
ABT-450/r
NS5ANS3 NS5B
IDX-719 BMS-791325
Protease Inhibitors Polymerase InhibitorsNS5A Inhibitors
BI-207127
NS4A
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Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Design
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
24Week 0 12
Sofosbuvir + PEG + RBVN =327 SVR12
Drug DosingSofosbuvir: 400 mg once dailyPeginterferon alfa-2a: 180 µg once weeklyRibavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg
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Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Results
NUTRINO: SVR 12 by Genotype
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
GT 1_x000d_(all
subtypes)
GT 1a GT 1b GT 4,5,6 0
20
40
60
80
100
89 92
82
97
Pat
ien
ts w
ith
SV
R 1
2 (%
)
GT = genotype
261/292 206/225 54/66 34/35
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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 weeksB. Peginterferon + Ribavirin + Sofosbuvir x 12 weeksC. Peginterferon + Ribavirin + Sofosbuvir x 12 weeksD. Sofosbuvir + Simeprevir x 24 weeks
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AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsInitial Recommended Therapy for Patients with Chronic HCV
Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org).
HCV: Recommended Initial Treatment & Retreatment of Relapsers*
GT1
Interferon Eligible
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
GT4
Interferon Eligible
Sofosbuvir + Peginterferon + Ribavirin x 12 weeks
Not Interferon Eligible
Sofosbuvir + Ribavirin x 24 weeks
*Patients who experienced relapse after Peginterferon plus Ribavirin therapy
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Hepatitis C Genotype 1Costs 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
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Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.
Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Study Design
LDV-SOF SVR12
Week 0
N =14Drug DosingLedipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg
36
GT-1Naive
n = 214
24
LDV-SOF SVR12
LDV-SOF + RBV SVR12
Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin
LDV-SOF + RBV SVR12
GT-1Naive
12
n = 217
n = 217
n = 217
INVESTIGATIONAL
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Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Results
ION-1: SVR 12 by Treatment Duration and Regimen
Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.
LDV-SOF LDV-SOF +RBV LDV-SOF LDV-SOF + RBV0
20
40
60
80
10099 97 98 99
Pat
ien
ts w
ith
SV
R 1
2 (%
)
211/214
12-Week Regimen
211/217 212/217 215/217
LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin
24-Week Regimen
INVESTIGATIONAL
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Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1
ION-1 Study: Results
ION-1: SVR12 by Treatment Regimen and Liver Disease
Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.
LDV-SOF LDV-SOF + RBV LDV-SOF LDV-SOF + RBV0
20
40
60
80
100100 100 99 10097 100 97 100
Without Cirrhosis With Cirrhosis
Pa
tie
nts
(%
) w
ith
SV
R 1
2
32/33
12-Week Treatment 24-Week Treatment
179/179 33/33178/178 31/32181/182 36/36179/179
Note: subgroup results do not include patients who withdrew consent or were lost to follow-up
INVESTIGATIONAL
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3D (ABT-450/r-Ombitasvir + Dasabuvir) + RibavirinGT 1 and Compensated Cirrhosis: TURQUOISE-II Study
TURQUOISE II: SVR12
Source: Poordad F, et al. N Engl J Med. 2014;370:1973-82.
Overall GT1a GT1b0
20
40
60
80
100
9289
9996 94100
12-Week Group 24-Week Group
Pa
tie
nts
(%
) w
ith
SV
R 1
2
INVESTIGATIONAL
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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
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Hepatitis C Online: www.hepatitisc.uw.edu
University of Washington: Hepatitis C Online
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HIV Update
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New HIV Testing Recommendations
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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 assayB. Western blotC. HIV RNA
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Traditional Approach to HIV Diagnostic Testing
Initial Supplemental
EIAWestern blot
orIFA
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
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Laboratory Diagnosis of Early HIV Infection
Timing of HIV RNA, HIV p24 antigen, and HIV Antibody
0 5 10 15 20 25 30 35 40 45 501
10
100
1,000
10,000
100,000
1,000,000
10,000,000
10
15
20
25
30
Days following HIV Acquisition
HIV
RN
A (
cop
ies/
ml)
An
tib
od
y T
iter
HIV p24 antigen
HIV Antibody
HIV RNA
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4th Generation HIV Ag/Ab Combination Assays
HIV Antibodies HIV p24 Antigen
Detects HIV-1 p24 antigen and antibodies to HIV-1 and HIV-2
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HIV-1 NAT (+)
2014 CDC RecommendationsRecommended Laboraatory HIV Testing Algorithm
Source: Centers for Disease Control and Prevention. 2014.
(-)(+)
HIV-1 (+)HIV-2 (-)
HIV-1 (-)HIV-2 (+)
HIV-1 (-) or Indeterminate HIV-2 (-)
HIV-1 NAT (-)
Negative for HIV-1 and HIV-2antibodies and p24 Ag
HIV-1 antibodiesdetected
Acute HIV-1 infection Negative for HIV-1
HIV-1/2 Antigen/Antibody Combination Immunoassay
HIV-1 NATHIV-2 antibodies
detected
HIV-1 (+)HIV-2 (+)
HIV antibodiesdetected
HIV-1/HIV-2 Ab Differentiation Immunoassay
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Antiretroviral Therapy
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Source: 2014 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)
US Health and Human Services (HHS)
May 1, 2014 Antiretroviral Therapy Guidelines
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HHS Antiretroviral Therapy Guidelines: 2013Initiating Therapy in Treatment-Naïve Patients
Source: 2013 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)
0
100
200
300
400
500
600
700
800
900
1000Chart Title
CD
4 C
ell
Co
un
t
500
350
Strongly Recommend (AI)
Recommend (BIII)
Strongly Recommend (AII)
Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression.
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HIV Prevention Trials Network (HPTN) Study 052
1,763 HIV Serodiscordant Couples (97% heterosexual)
Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.
n = 873 n = 890
+ -- +
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Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.
HIV Prevention Trials Network (HPTN) Study 052
0
100
200
300
400
500
600
700
800
900
1000Chart Title
CD
4 C
ell
Co
un
t
550Early Therapy
CD4 350-550 cells/mm3 350
250
Deferred TherapyCD4 < 250 cells/mm3 or AIDS Related Event
++
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Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.
HIV Prevention Trials Network (HPTN) Study 052
Deferred Therapy
Early Therapy
0 5 10 15 20 25 30
27
1
Linked Transmissions
P < 0.001
96% Reduction
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HHS Antiretroviral Therapy Guidelines: May 1, 2014 Recommended Regimens Regardless of Baseline HIV RNA or CD4
Count
Source: 2014 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)
Class Therapy Pill Burden
NNRTI-Based Efavirenz-Tenofovir-Emtricitabine
PI-BasedAtazanavir + Ritonavir + Tenofovir-Emtricitabine
Darunavir + Ritonavir + Tenofovir-Emtricitabine
INSTI-Based
Raltegravir + Tenofovir-Emtricitabine
^Elvitegravir-Cobicistat-Tenofovir-Emtricitabine
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
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Single Tablet Antiretroviral Regimens
Efavirenz-Tenofovir-Emtricitabine
Rilpivirine-Tenofovir-Emtricitabine
Elvitegravir-Cobicistat-Tenofovir-Emtricitabine
Atripla
Complera
Stribild
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.
Dolutegravir Phase 3 Studies in Treatment-Naïve Subjects
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]
Study ARV History Comparison Results
1 SPRING-2 ARV-Naïve
Dolutegravir QD versusRaltegravir
• Non-inferior
(88% versus 85%)
2 SINGLE ARV-Naïve
Dolutegravir QD versusEfavirenz
• Dolutegravir superior
(88% versus 81%)
3 FLAMINGO ARV-Naïve
Dolutegravir QD versusDarunavir-RTV
• Dolutegravir superior
(90% versus 83%)
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Future Single Tablet Regimen
Dolutegravir-Abacavir-Lamivudine“Tri Pill”
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Occupational PEP
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Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.
2013
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Case HistoryHIV 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-lamivudineB. 2 drugs: Tenofovir-emtricitabineC. 3 drugs: Tenofovir-emtricitabine + RaltegravirD. 3 drugs: Tenofovir-emtricitabine + Darunavir + ritonavir
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2013 USPHS Occupational PEP GuidelinesNumber of Antiretroviral Medications to Use
Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.
“…the PHS working group recommends prescribing 3 (or more) tolerable drugs as PEP for all occupational exposures to HIV.”
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Recommended Antiretroviral Regimens for Occupational PEP (28-Day Duration)
Preferred Regimen
INSTI NNRTI Pill Burden
Raltegravir (Isentress)400 mg twice daily
Tenofovir-Emtricitabine (Truvada)1 pill daily
2013 USPHS Occupational PEP Guidelines
Recommendations for Antiretroviral Regimens
Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.
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Post-Exposure Prophylaxis Line (PEPline)888-448-4911
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HBV Update
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HBV Treatment and Entecavir Resistancne
• What percentage of patients with chronic HBV and long term entecavir treatment will develop resistance?
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Resistance with Entecavir
• 222 nucleoside-naïve patients treated for 3 years- Cumulative -resistance to entecavir of 1.3% at 3 yearsYuen 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
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Duration of HBV Therapy with Entecavir
• Can you stop entecavir after long-term treatment (> 2 years) for patients with HBeAg- chronic HBV and HBeAg- and sustained virologic suppression?
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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]