Understanding Optimal Use and Interpretation of Assays in HCV This program is supported by educational grants from
Dec 03, 2014
Understanding Optimal Use and Interpretation of Assays in HCV
This program is supported by educational grants from
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
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clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Faculty Affiliation and Disclosure
Paul Y. Kwo, MDProfessor of MedicineMedical Director of TransplantationDivision of Medicine/Gastroenterology/HepatologyIndiana University School of MedicineIndianapolis, Indiana
Paul Y. Kwo, MD, has disclosed that he has received consulting fees from Abbott, Anadys, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Johnson & Johnson, Merck, Novartis, and Vertex; has received fees for non-CME services from Bristol-Myers Squibb, Gilead Sciences, Merck, and Roche; and has contracted research with Abbott, Anadys, Bayer, Bristol-Myers Squibb, Conatus, GlaxoSmithKline, Merck, Novartis, Roche, and Vertex.
New Standard of Care for Patients With HCV
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Patterns of Virologic Response
7
6
5
4
3
2
1
00-2-4-8 4 8 12 16 20 24 32 40 48 52 60 72
Wks After Start of Therapy
HC
V R
NA
(lo
g10
IU/m
L)[1
]
Undetectable
RVR EVR EOT SVR
Relapse
Partial response
Null response
1. Ghany MG, et al. Hepatology. 2009;49:1335-1374. 2. McHutchison JG, et al. N Engl J Med. 2009;361:580-593.
40% chance of SVR with
pegIFN/RBV[2]
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Addition of TVR or BOC to PegIFN/RBV Improves SVR in Genotype 1 Patients HCV NS3/4A protease inhibitors BOC and TVR approved by FDA, May 2011[1,2]
– Indicated in combination with pegIFN/RBV for treatment of genotype 1 HCV–infected patients who are previously untreated or who have failed previous therapy
1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011. 3. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 4. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 5. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 6. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 7. Vierling J, et al. AASLD 2011. Abstract 931.
0
20
40
60
80
100
SV
R (
%)
Relapsers[5,6] Partial Responders[5,6]
PegIFN + RBV
NullResponders[6,7]
BOC/TVR + pegIFN + RBV
24-29
7-15
29-38
5
69-83
40-59
63-75
38-44
Treatment Naive[3,4]
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Proper Use of HCV Assays Essential For Successful Management With HCV PIs HCV RNA level important throughout treatment to
determine
– Eligibility for shortened therapy (response-guided therapy)
– Discontinuation of therapy due to futility
– Minimizes risk of resistance and unnecessary adverse events
– Assessment of EOT response
– Assessment of SVR
Additional genetic testing may help predict response to treatment
HCV RNA Assays in the Protease Inhibitor Era
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Key Challenges Regarding Use of HCV RNA Assays in Protease Inhibitor Era Package inserts for BOC and TVR specify different
time points for monitoring HCV RNA
Available HCV RNA assays in practice have different quantifiable ranges
Different HCV RNA thresholds used for RGT determination vs SVR
Different HCV RNA thresholds used for defining treatment futility with BOC vs TVR
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
HCV RNA Assays: LLOD Is Distinct From LLOQ LLOQ
– Lowest HCV RNA concentration within linear range of assay
– ie, smallest amount of HCV RNA that can be not only detected but also accurately quantified
LLOD
– Lowest amount of HCV RNA concentration that can be detected with 95% probability to determine presence or absence
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
0
1
2
4
6
8
0 Time
Lo
g10
Vir
al T
iter
Detectable/quantifiable
SVR
Not quantifiable/not detectable
LLOQLLOD
Detectable/not quantifiable
Adapted from Naeger LK, et al. Intl Workshop on Clinical Pharmacology of Hepatitis Therapy 2011. Abstract R-8.
HCV RNA Levels and Relationship to LLOD and LLOQ
HCV Treatment
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Assay (Manufacturer ) Method LLOD, IU/mL Setting
Amplicor HCV v2.0 (Roche Molecular Systems)
Manual RT-PCR 50Diagnosis and
monitoring
Cobas Amplicor HCV v2.0 (Roche Molecular Systems)
Semiautomated RT-PCR 50Diagnosis and
monitoring
Ampliscreen (Roche Molecular Systems)
Semiautomated RT-PCR < 50 Blood
screening
Versant HCV RNA Qualitative Assay (Siemens Healthcare Diagnostics)
Semiautomated TMA 10Diagnosis and
monitoring
Procleix HIV-1/HCV Assay (Chiron Corporation)
Manual TMA < 50 Blood
screening
Ghany MG, et al. Hepatology. 2009;49:1355-1374.
All assays report HCV RNA as detected/not detected
FDA-Approved Qualitative HCV RNA Assays
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Quantitative HCV RNA Assays
Assay (Manufacturer)[1] Method Dynamic Range, IU/mL(LLOQ-ULOQ)
LLOD, IU/mL FDA Approved
Amplicor HCV Monitor (Roche Molecular Systems) Manual RT-PCR 600-500,000 N/A Yes
Cobas Amplicor HCV Monitor V2.0 (Roche Molecular Systems) Semiautomated RT-PCR 600-500,000 600 Yes
Versant HCV RNA 3.0 Assay (bDNA) (Siemens Health Care Diagnostics)
Semiautomated bDNA signal amplification 615-7,700,000 615 Yes
LCx HCV RNA-Quantitative Assay (Abbott Diagnostics) Semiautomated RT-PCR 25-2,630,000 23 No
SuperQuant (National Genetics Institute) Semiautomated RT-PCR 30-1,470,000 30 No
Cobas TaqMan HCV Test (Roche Molecular Systems)
Semiautomated RT-PCR 43-69,000,000 18 Yes
COBAS TaqMan HCV Test v2.0 for use with High Pure System (Roche Molecular Systems)
Semiautomated RT-PCR 25-300,000,000 15 Yes
Abbott RealTime HCV Assay (Abbott Diagnostics) Semiautomated RT-PCR 12-100,000,000 12 Yes
Phase III registration trials for both BOC and TVR used COBAS TaqMan HCV Test v2.0 for use with High Pure System
– 1.3% false-positive rate[2]
1. Ghany MG, et al. Hepatology. 2009;49:1355-1374. 2. Naeger LK, et al. Intl Workshop on Clinical Pharmacology of Hepatitis Therapy 2011. Abstract R-8.
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
SVR Rate by HCV RNA Status (LLOQ vs LLOD) for BOC and TVR
BOC/PR RGT T12/PR
SVR rate lower when HCV RNA not undetectable at key time points during therapy
100
0
40
SV
R (
%)
60
20
80
100
0
40S
VR
(%
)
60
20
4
80
8 10 12 16 20
Undetectable (Below LLOD)Detectable/Below LLOQAbove LLOQ (> 25 IU/mL)
Treatment Wk
4 6 10 12 16 208
Naeger LK, et al. Intl Workshop on Clinical Pharmacology of Hepatitis Therapy 2011. Abstract R-8.
Treatment Wk
Using HCV RNA Assays in Clinical Practice
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
61
192/314
Predictive Value of Baseline HCV RNA for Achieving SVR
100
0
50
7874
SV
R (
%)
75
25
207/281
64/82
> 800,000 IU/mL≤ 800,000 IU/mL
ADVANCE (TVR)[1]
1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
100
0
50
SV
R (
%)
75
25
SPRINT-2 (BOC)[2]
8576
41/54
45/53
63
197/313
BOC/PR48 BOC/PR RGTT12PR arm
n/N = n/N =
≥ 800,000 IU/mL< 800,000 IU/mL
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Patients Responding Early Can Achieve High SVR Rates With Shortened Therapy Response-guided therapy: patients who achieve optimal virologic
response at early time points can receive abbreviated therapy without reducing their chance of SVR
Patients eligible for RGT
– Boceprevir: noncirrhotic treatment-naive patients, previous relapsers, and previous partial responders[1,2]
– RGT criterion: Must achieve undetectable HCV RNA at Wk 8 (ie, Wk 4 of triple therapy) and maintain it at Wk 24
– Telaprevir: noncirrhotic treatment-naive patients and previous relapsers*[2,3]
– RGT criterion: Must achieve undetectable HCV RNA at Wk 4 of triple therapy and maintain it at Wk 12
1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. May 2011.
*AASLD guidelines state that RGT may be considered with TVR in previous partial responders.
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Response-Guided Therapy Paradigm With BOC + PegIFN/RBV in Tx-Naive Patients
BOC + PegIFN +RBV
480 28124
PegIFN + RBV
8 3624
Early response stop at Wk 28; f/u 24 wks
HCV RNA Undetectable Undetectable
480 28124
PegIFN + RBVPegIFN + RBV
8 36
BOC + PegIFN +RBV
24
HCV RNA Detectable Undetectable Slow response extend triple therapy
to Wk 36; PR to Wk 48; f/u 24 wks
< 100 IU/mL
< 100 IU/mL
Indicated for all noncirrhotic treatment-naive patients
Boceprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Response-Guided Therapy Paradigm With BOC + PegIFN/RBV in Tx-Exp Patients
BOC + PegIFN +RBV
480 28124
PegIFN + RBV
8 3624
HCV RNA Undetectable Undetectable
480 28124
PegIFN + RBVPegIFN + RBV
8 36
BOC + PegIFN +RBV
24
HCV RNA Detectable Undetectable
< 100 IU/mL
< 100 IU/mL
Indicated for noncirrhotic previous relapsers or partial responders
Boceprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
Early response stop at Wk 36; f/u 24 wks
Slow responsePR to Wk 48; f/u 24 wks
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Response-Guided Therapy Paradigm With TVR + PegIFN/RBV in Tx-Naive Patients
TVR + PegIFN + RBV
480 24124
eRVR stop at Wk 24, f/u 24 wksPegIFN + RBV
TVR + PegIFN + RBV
480 24124
PegIFN + RBV
HCV RNAUndetectable
Undetectable
Detectable (≤ 1000 IU/mL)
Undetectable or detectable (≤ 1000 IU/mL) No eRVR extend pegIFN +
RBV to Wk 48; f/u 24 wks
HCV RNA
Indicated for all noncirrhotic treatment-naive patients
Telaprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
Undetectable
Undetectable
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Response-Guided Therapy Paradigm With TVR + PegIFN/RBV in Tx-Exp Patients
TVR + PegIFN + RBV
480 24124
PegIFN + RBV
Detectable (≤ 1000 IU/mL)
Undetectable/detectable (≤ 1000 IU/mL)
No eRVR extend pegIFN + RBV to Week 48; f/u 24 wks
HCV RNA
1. Telaprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
*AASLD guidelines say RGT “may be considered” for prior partial responders [2] but package insert recommends 48 weeks of therapy[1]
Same as naives; indicated for noncirrhotic previous relapsers[1]*
TVR + PegIFN + RBV
480 24124
eRVR stop at Wk 24, f/u 24 wksPegIFN + RBV
HCV RNAUndetectable
Undetectable
Undetectable
Undetectable
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
HCV RNA Assay Characteristics for RGT With BOC or TVR A quantitative assay with an LLOQ of ≤ 25 IU/mL and an
LLOD of approximately 10-15 IU/mL must be used
“Confirmed detectable but below limit of quantification HCV RNA result should not be considered equivalent to an undetectable HCV RNA result”
Boceprevir [package insert]. May 2011. Telaprevir [package insert]. May 2011.
0
1
2
4
6
8
0 Time
Lo
g10
Vir
al T
iter
Detectable/quantifiable
Undetectable/not quantifiable
LLOQ
LLODDetectable/not quantifiable
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Predictive Value of Response to 4-Wk Lead-in Phase ≥ 1 log10 vs < 1 log10 decline in HCV RNA following
4-wk lead-in phase with pegIFN/RBV strongly predicts SVR in patients receiving BOC-based therapy
– Treatment-naive patients[1]
– OR: 9.0; P < .001
– Treatment-experienced patients[2]
– OR: 5.2; P < .001
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Zeuzem S, et al. EASL 2011. Abstract 484.
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Boceprevir [package insert]. May 2011.
BOC + PegIFN +RBV
480 28124
PegIFN + RBV
PegIFN + RBV
8 36
BOC + PegIFN +RBV
24
Early response*; stop at Wk 28 or 36; f/u 24 wks
F/u 24 wks
*Undetectable HCV RNA at Wks 8 and 24 of therapy (Wk 4 of triple therapy).
Wks
Stop all treatment if HCV RNA ≥ 100 IU/mL
Stop all treatment if HCV RNA detectable
(> LLOD)
Use quantitative assay to determine if HCV RNA
< or ≥ 100 IU/mL at Wk 12
Use assay with LLOD of 10-15 IU/mL to determine if
HCV RNA detectable at Wk 24
Boceprevir Futility Rules: Wks 12 and 24 Key Time Points Treatment-naive and treatment-experienced patients
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Telaprevir Futility Rules: Wks 4, 12, and 24 Key Time Points Treatment-naive and treatment-experienced patients
TVR + PegIFN +RBV
Wks480 24124
eRVR*; stop at Wk 24; f/u 24 wksPegIFN + RBV
No eRVR; PegIFN + RBV
Telaprevir [package insert]. May 2011.
F/u 24 wks
*Undetectable HCV RNA at Wks 4 and 12 of triple therapy.
Use quantitative assay to determine if HCV RNA ≤ or > 1000 IU/mL
at Wks 4 and 12
Use assay with LLOD of 10-15 IU/mL to determine if
HCV RNA detectable at Wk 24
Stop all treatment if HCV RNA > 1000 IU/mL
Stop all treatment if HCV RNA > 1000 IU/mL
Stop all treatment if HCV RNA detectable
(> LLOD)
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
EOT response defined as[1,2] – HCV RNA < LLOD at EOT
– Using an assay with a sensitivity of 10-15 IU/mL[1,2]
Detectable but < LLOQ values while on treatment predict lower SVR rates[3]
1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011. 3. Naeger LK, et al. Intl Workshop on Clinical Pharmacology of Hepatitis Therapy 2011. Abstract R-8.
HCV RNA Thresholds for EOT Response With BOC or TVR
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Use of HCV RNA Assays to Assess SVR With BOC or TVR-Based Therapy SVR to pegIFN/RBV previously defined as
– Absence of detectable HCV RNA in serum using assay with sensitivity of at least 50 IU/mL 6 mos after EOT[1]
SVR defined by FDA in BOC and TVR package inserts as
– HCV RNA < 25 IU/mL (LLOQ) 6 mos after EOT[2-3]
1. Lindsay KL, et al. Hepatology. 2002;36:S114-S120. 2. Boceprevir [package insert]. May 2011. 3. Telaprevir [package insert]. May 2011.
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Summary: Use of HCV RNA Assays in Managing Patients Receiving BOC or TVR A quantitative assay with an LLOQ of ≤ 25 IU/mL and an LLOD of
approximately 10-15 IU/mL must be used
HCV RNA < LLOQ not identical to HCV RNA < LLOD
– HCV RNA < LLOD required to qualify for RGT
– HCV RNA < LLOQ appropriate for assessing SVR
Qualification/Endpoint BOC TVR
RGT HCV RNA < LLOD at Wks 8 and 24
HCV RNA < LLOD at Wks 4 and 12
Futility HCV RNA ≥ 100 IU/mL at Wk 12
HCV RNA > LLOD at Wk 24
HCV RNA > 1000 IU/mL at Wk 4 or 12
HCV RNA > LLOD at Wk 24
EOT response HCV RNA < LLOD at EOT
SVR HCV RNA < LLOQ 24 wks after EOT
Other Assays
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
P < .0001
P < .0001
P < .0001
P < .0001
P < .0001
P = .004
Thompson AJ, et al. Gastroenterol. 2010;139:120-129.
IL28B Genotype the Strongest Baseline Predictor of SVR With PegIFN/RBV
Metavir F0-2
White vs Black
Fasting Serum Glucose < 5.6 mmol/L
Hispanic vs Black
HCV RNA ≤ 600,000 IU/mL
CC vs Non-CC
Odds Ratio (95% CI)
0 1 2 3 4 5 6 7 8
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.
SPRINT-2: BOC + PR48[1]
SV
R (
%)
44/55
82/115
26/44
CC CT TT
80
100
80
60
40
20
0
71
59
n/N =
ADVANCE*: T12PR[2]
SV
R (
%)
45/50
48/68
16/22
CC CT TT
90100
80
60
40
20
0
71 73
n/N =
*IL28B testing in ADVANCE was in white pts only.
IL28B Genotype Also Predicts Likelihood of Achieving SVR With BOC or TVR
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
IL28B Genotype Predicts Likelihood of Shortened Therapy With BOC or TVR
1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.
Elig
ibili
ty f
or
Sh
ort
ened
T
her
apy
(%)
118/132
158/304
CC CT/TT
89
52
Elig
ibili
ty f
or
Sh
ort
ened
T
her
apy
(%)
39/50
39/68
10/22
78
57
45
SPRINT-2: BOC + PR[1] ADVANCE*: T12PR[2]
*IL28B testing in ADVANCE was in white pts only.
80
60
40
20
0
n/N =
CC CT TT
100
80
60
40
20
0
n/N =
100
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
When to Consider IL28B Genotype Testing
IL28B genotype testing may be considered prior to therapy if more information about probability of response or treatment duration desired[1]
– Commercially available tests
If patients have favorable CC genotype
– Likelihood of SVR is high with pegIFN/RBV alone, but triple therapy may allow shorter therapy and, in one TVR study, higher SVR rates[2]
If patients have unfavorable CT/TT genotype
– Likelihood of SVR is higher with triple therapy than with pegIFN/RBV [2,3]
Limited value of IL28B genotyping in treatment-experienced patients
– Most have unfavorable TT or CT genotype
1. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 2. Jacobson IM, et al. EASL 2011. Abstract 1369. 3. Poordad F, et al. EASL 2011. Abstract 12.
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
HCV Genotype and Subtype
HCV classified into 6 major genotypes (1-6)[1]
Genotype 1 (subtypes a and b) most common in United States (~ 75%)[2]
– Subtype 1a more common than subtype 1b
Determining major genotype recommended for proper clinical management and predicting likelihood of response[3]
No current recommendations regarding HCV subtype testing
1. Simmonds P, et al. Hepatology. 2005;42:962-973. 2. Zein N. Clin Microbiol Rev. 2000;13:223-235. 3. Ghany MG, et al. Hepatology. 2009;49:1335-1374.
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Higher SVR Rates With TVR in Patients With HCV Genotype 1b vs 1a
Tx Naive[1]
T12/PR48Tx Naive[1]
T12/PR48
7171
4747
SV
R (
%)
SV
R (
%)
0
20
40
60
80
100 Genotype 1aGenotype 1a
Genotype 1bGenotype 1b
Relapsers*[2]Relapsers*[2] Null Responders*[2]
Null Responders*[2]
Partial Responders*[2]
Partial Responders*[2]
1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Zeuzem S, et al. EASL 2011. Abstract 5.
79798484
8888
2727
6868
3737
*Pooled TVR arms.*Pooled TVR arms.
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Higher SVR Rates With BOC in Patients With HCV Genotype 1b vs 1a
BOC RGTBOC RGT
59595050
Genotype 1aGenotype 1a
Genotype 1bGenotype 1b
Treatment Naive[1]Treatment Naive[1]
BOC/PR48BOC/PR48 BOC/PR48BOC/PR48BOC RGTBOC RGT
Treatment Experienced[2]Treatment Experienced[2]
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
6666 6363
7070
61616565
7373
0
20
40
60
80
100
SV
R (
%)
SV
R (
%)
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Genotype assay Manufacturer Method
Trugene 5'NC HCV Genotyping kit
Siemens Direct sequence analysis of the 5' noncoding region
INNO-LiPa HCV II Innogenetics Reverse hybridization analysis using genotype-specific oligonucleotide
probes located in the 5' noncoding region
Versant HCV Genotyping Assay 2.0
Siemens Reverse hybridization analysis using genotype-specific oligonucleotide
probes located in the 5' noncoding region
Abbott RealTime HCV Genotype II
Abbott Genotype-specific real-time PCR of the 5' noncoding region and NS5b
Incorrect typing among major genotypes rare (< 3%)
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
Commercially Available HCV Genotype Assays
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Resistance-associated variants occur naturally[1]
– Present in 5% to 7% of subject samples prior to treatment[2,3]
– No apparent impact on likelihood of SVR
– Selected for/enriched in patients failing PI-based therapy
Following treatment failure, resistance-associated variants decline over time after withdrawal of PI but may remain detectable for up to 2.5 yrs[4,5]
Lower genetic barrier to resistance (number of mutations required to overcome virologic activity of the regimen) with genotype 1a vs 1b with BOC/TVR–based regimens
Strict adherence to futility rules, ensuring patient adherence and tolerability of regimen essential to avoid resistance
1. Pawlotsky JM. Clin Liver Dis. 2003;7:45-66. 2. Telaprevir [package insert]. May 2011. 3. Boceprevir [package insert]. May 2011. 4. Vierling JM, et al. EASL 2010. Abstract 2016. 5. Sullivan JC, et al. EASL 2011. Abstract 8.
HCV Resistance With TVR/BOC
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
HCV Resistance Testing
Commercial resistance test for HCV NS3/4 mutations now available
– Provides genetic sequence for the nonstructural proteins NS3 and NS4A of HCV genotypes 1a and 1b
Role of resistance testing prior to treatment remains to be defined
– No current recommendation to perform resistance testing for patients failing therapy
clinicaloptions.com/hepatitisUnderstanding the Optimal Use and Interpretation of Assays in HCV
Summary: Use of Genotype and Resistance Assays With BOC/TVR IL28B genotype testing
– May be considered prior to therapy if more information about probability of response or treatment duration desired[1]
HCV subtype testing
– No current recommendation to test prior to treatment
– Patients with genotype 1b may be counseled that their chance of SVR is slightly higher than 1a patients
HCV resistance testing
– No current recommendation regarding testing at baseline or upon treatment failure
1. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
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