HCV Viral Load Determination and Therapeutic Consequences? - - PowerPoint PPT Presentation

HCV Viral Load Determination and Therapeutic Consequences?

Christoph Jochum Clinic for Gastroenterology & Hepatology University Hospital Essen

What Can HCV viral load possibly tell a physican?

When do I need to initiate therapy? How do I have to treat a patient?

Natural Course of HCV-Infection

1/3

Resolve after acute Hepatitis C

1/3 chronic asymptomatic HCV-Carrier 1/3 chronic progressive Hepatitis C

(´ Cirrhosis, ´ HCC-development)

Does the HCV Viral Load Tell Something About the Natural Course?

• No! Certainly not a single meassurement.
• Factors which influence the natural course:
• IL28B Genotype
• Inflammation in the liver (Elevated ALT)
• Age at infection
• Race
• Alcohol consumption/ Fatty liver disease
• HIV/HBV coinfection
• High BMI
• Iron/HFE Gene

When to Start Therapy – German Guidelines

+/- DAA

Chronic HCV Infection

untreated pretreated

Chronic hepatitis Patients wish Other reasons Extraheaptic manifestations

• ptimizing

urgency

+ + +

• Contra-

Indications for Peg-IFN + Riba

„watch and wait“ Control every 6-12 Mo Therapy with Peg-IFN + Riba +/. DAA

What can HCV viral load tell a physican?

How do I have to treat a patient?

Therapeutic Options for HCV-Infection 2012

1992 2001 1998 2011 Interferon Interferon Ribavirin Peg-Interferon Alpha 2a Ribavirin 2002 Peg-Interferon Alpha 2b Ribavirin Telaprevir Boceprevir

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)

1 2 3 4 5 6 7 8

Source: CCO

• 1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.

SPRINT-2: BOC + PR48[1] SVR (%) 44/ 55 82/ 115 26/ 44 CC CT TT 80 100 80 60 40 20 71 59 n/ N = ADVANCE*: T12PR[2] SVR (%) 45/ 50 48/ 68 16/ 22 CC CT TT 90 100 80 60 40 20 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

Source: CCO

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.

Eligibility for Shortened Therapy (%) 118/ 132 158/ 304 CC CT/TT 89 52 Eligibility for Shortened Therapy (%) 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 n/ N = CC CT TT 100 80 60 40 20 n/ N = 100

Source: CCO

German Hepatitis C Guidelines Genotype 1 + 4

Stop therapy

Tx start HCV-RNA Week 4 HCV-RNA Week 12 HCV-RNA Week 24 HCV-RNA

HCV-RNA <12-15 IU/ml HCV-RNA <12-15 IU/ml HCV-RNA <12-15 IU/ml At start <8 x105 IU/ml

+ 24 weeks therapy 48 weeks therapy 72 weeks therapy

<2log decline bzw >30000 IU/ml HCV -RNA positive

German Hepatitis C Guidelines Genotype 2 + 3

Stop therapy

Tx start HCV-RNA week 4 HCV-RNA Week 8 HCV-RNA

HCV-RNA <12-15 IU/ml HCV-RNA <12-15 IU/ml HCV-RNA >2 log Abfall start <8 x105 IU/ml

+ 24 weeks therapy 48 weeks therapy

<2 log decline

16 week therapy

Patterns of Virologic Response

7 6 5 4 3 2 1

• 2
• 4
• 8

4 8 12 16 20 24 32 40 48 52 60 72 Wks After Start of Therapy HCV RNA (log10 IU/mL)[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

• f SVR with

pegIFN/RBV[2]

Source: CCO

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.

20 40 60 80 100 SVR (%) Relapsers[5,6] Partial Responders[5,6] PegIFN + RBV Null Responders[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]

Source: CCO

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

Source: CCO

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

Time

Detectable/not quantifiable

0.001 0.01 1 10 100 1000000 Viral RNA Titer

SVR

LLOQ LOD

Detectable/ quantifiable

100000 10000 1000 0.1

Not quantifiable ± detectable Undetectable Goal of anti- HCV therapy

HCV Treatment

Source: CCO

SVR Rate by HCV RNA Status for BOC or TVR

BOC/PR RGT T12/PR

• SVR rate lower when HCV RNA not undetectable at

key time points during therapy

100 40 SVR (%) 60 20 80 100 40 SVR (%) 60 20 4 80 8 10 12 16 20 Undetectable Detectable/Below LLOQ Above LLOQ (> 25 IU/mL)

Treatment Wk

4 6 10 12 16 20 8

Naeger LK, et al. Intl Workshop on Clinical Pharmacology of Hepatitis Therapy 2011. Abstract R-8.

Treatment Wk

Source: CCO

61 192/ 314

Predictive Value of Baseline HCV RNA for Achieving SVR

100 50 78 74 SVR (%) 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 50 SVR (%) 75 25

SPRINT-2 (BOC)[2]

85 76 41/ 54 45/ 53 63 197/ 313

BOC/PR48 BOC/PR RGT T12PR arm

n/N = n/N =

≥ 800,000 IU/mL < 800,000 IU/mL

Source: CCO

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.

Source: CCO

Response-Guided Therapy Paradigm With BOC + PegIFN/RBV in Tx-Naive Patients

BOC + PegIFN + RBV 48 28 12 4 PegIFN + RBV 8 36 24 Early response stop at Wk 28; f/u 24 wks

HCV RNA

Undetectable Undetectable 48 28 12 4 PegIFN + RBV PegIFN + 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.

Source: CCO

Response-Guided Therapy Paradigm With BOC + PegIFN/RBV in Tx-Exp Patients

BOC + PegIFN + RBV 48 28 12 4 PegIFN + RBV 8 36 24

HCV RNA

Undetectable Undetectable 48 28 12 4 PegIFN + RBV PegIFN + 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 response PR to Wk 48; f/u 24 wks

Source: CCO

Response-Guided Therapy Paradigm With TVR + PegIFN/RBV

TVR + PegIFN + RBV 48 24 12 4 eRVR stop at Wk 24, f/u 24 wks PegIFN + RBV TVR + PegIFN + RBV 48 24 12 4 PegIFN + RBV

HCV RNA

Undetectable 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 and noncirrhotic

previous relapsers

Telaprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Undetectable Undetectable

Source: CCO

HCV RNA Assay Characteristics for RGT With BOC or TVR

• A quantitative assay with a LLOQ of ≤ 25 IU/mL and a 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.

Detectable/not quantifiable 0.001 0.01 1 10 100 1000000 Viral RNA Titer SVR LLOQ LOD Detectable/ quantifiable 100000 10000 1000 0.1 Not quantifiable ± detectable Undetectable Goal of anti- HCV therapy

Source: CCO

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.

Source: CCO

Boceprevir [package insert]. May 2011. BOC + PegIFN + RBV 48 28 12 4 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

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 “target not detected” at Wk 24

Boceprevir Futility Rules: Wks 12 and 24 Key Time Points

• Treatment-naive and treatment-experienced patients

Source: CCO

Telaprevir Futility Rules: Wks 4, 12, and 24 Key Time Points

• Treatment-naive and treatment-experienced patients

TVR + PegIFN + RBV Wks 48 24 12 4 eRVR*; stop at Wk 24; f/u 24 wks PegIFN + 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 “target not detected” 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

Source: CCO

• EOT response defined as[1,2]
• HCV RNA undetectable (or “target not detected”) 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

Source: CCO

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 undetectable
• HCV RNA undetectable (HCV RNA target not detected) required to qualify for

RGT

• HCV RNA < LLOQ appropriate for assessing SVR
• Carefully read HCV RNA assay report to ensure HCV RNA was undetected or

“target not detected” prior to committing to truncated therapy

Qualification/Endpoint BOC TVR RGT HCV RNA undetectable at Wks 8 and 24 HCV RNA undetectable at Wks 4 and 12 Futility

• HCV RNA ≥ 100 IU/mL

at Wk 12

• HCV RNA detectable at Wk 24
• HCV RNA > 1000 IU/mL

at Wk 4 or 12

• HCV RNA detectable at Wk 24

EOT response HCV RNA undetectable at EOT SVR HCV RNA < LLOQ 24 wks after EOT

Source: CCO

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.

Source: CCO

Thank you for your attention!