Hepatitis C: 12wk Rule in Standard Therapy SOC

Even with all the excitement of telaprevir and boceprevir the fact remains there are numerous people treating right now with standard therapy; peginterferon alfa plus ribavirin. This blog has not posted information on standard therapy in sometime. With this entry I hope to remind everyone of the 12 week stopping rule.

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This information isn't new, however, until its brought out into the spotlight it could be easily forgotten, or overlooked. During the 2010 AASLD meeting we were slammed with new information, with a lot of attention focused on the new drugs.

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Presented at the AASLD meeting was this abstract on SOC therapy; "High Correlation Between Week 4 and Week 12 as the Definition for Null Response to Peginterferon alfa (PEG) Plus Ribavirin (R) Therapy: Results From the IDEAL Trial"

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Predictive SVR In Viral Load Testing At 4 and 12 weeks

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This was powerful information with results showing a "less" then 1 log drop in viral load at week 4, equates to a "less" then 2 log drop in viral load at week 12. Both are an earlier predictor of "null response".

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Fact; 97% to 100% of genotype 1 patients in the study who failed to attain an early virologic response (less then a 2-log drop at week 12 of treatment) failed to attain a sustained virologic response (SVR)

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What is null response ?

"Null response means that hepatitis C viral load drops by "less" than one log (10%) after four weeks of treatment, and drops by less than two logs (99%) drop after 12 weeks of treatment."

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What is a two log drop ?
Example; 2 log drop = 15,000,000 IU/Ml with a drop to 150,000 IU/mL
Or a viral load that starts at 15,000,000 IU/mL and does not decrease to 150,000 IU/mL or lower.

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12 week stopping rule

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In 2009 the FDA Approved an Expanded Indication for Peginterferon-based Combination Therapy for Patients with Chronic Hepatitis C

Excerpted from the press release see full info here;

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This new expanded indication covered patients with compensated liver disease who did not achieve sustained response to prior treatment. Patients less likely to benefit from retreatment after failing a course of therapy include those with previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, or HCV genotype 1 infection.

Data from the clinical study supporting the approval helped to define those patient groups most likely to respond to retreatment as well as those unlikely to respond.

In the clinical study supporting the approval, achievement of undetectable virus (HCV RNA) at treatment week 12 was a strong predictor of SVR. Patients who still had detectable virus at week 12 of therapy were highly unlikely to achieve SVR.

A quote from Dr. Schiff ;

"Patients with "undetectable" virus at week 12 have a better chance for success and can be motivated to continue treatment," Schiff added, "and those patients who fail to achieve an early response can have their therapy stopped with confidence, thus avoiding unnecessary treatment and potential adverse events."

With this data made readily available to the public it brings to light the importance of understanding your own particular treatment protocol. Knowing the protocol will be especially important in the future when telaprevir and boceprevir make its way into clinical practice.

A quick review of the terminology;

Terms for HCV treatment response

Relapse means that HCV became—and remained—undetectable during treatment, but reappeared within weeks to months after finishing it.

Viral breakthrough means that HCV reemerged after becoming undetectable during treatment.

Non-response means that the hepatitis C viral load drops by "two logs (99%) but does not ever become undetectable during treatment".

Null response means that hepatitis C viral load drops by less than one log (10%) after four weeks of treatment, and drops by less than two logs (99%) drop after 12 weeks of treatment.

Time point

Very rapid virological response (vRVR) is a new term, used to indicate that HCV RNA has become undetectable after 14 days of treatment.

Rapid virological response (RVR) means that HCV cannot be detected in the blood after four weeks of treatment. RVR is a significant milestone in response-guided therapy because it predicts sustained virological response (see below) in ~90% of cases—regardless of HIV status, but a person can still be cured in the absence of RVR.

Sustained virological response (SVR) means that no HCV is detectable in a person’s bloodstream six months after completion of treatment. SVR is durable, and linked to reductions in liver-related morbidity and mortailty; HCV is cured.

Extended rapid virlogic response (eRVR) is a newly coined term indicating that HCV RNA has becomes undetectable after 4 weeks of treatment and remains undetectable at week 12.

Partial early virological response (pEVR) means that HCV RNA has dropped by at least two logs (99%).

Complete early virological response (cEVR) means that HCV RNA is undetectable after 12 weeks of treatment. SVR is more likely for people who have a cEVR than people who have a pEVR.

Although an early virological response cannot predict who will be cured, it does indicate who will not be cured if they remain on treatment.

Since SVR is extremely unlikely in people who don’t have a pEVR or cEVR, HCV treatment is usually discontinued at this point. Sometimes this is called an early stopping rule.

End-of-treatment response (EOT) means that HCV viral load is undetectable at the end of HCV treatment.

SVR-12 means that HCV remains undetectable 12 weeks after completion of treatment. Although it has not been prospectively validated (meaning that researchers have found this to be true by looking back at trial results rather than planning in advance to see if it is true), SVR-12 is a good predictor of SVR because relapse usually occurs within a few weeks after treatment completion.

Source For Terms

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The Data

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High Correlation Between Week 4 and Week 12 as the Definition for Null Response to Peginterferon alfa (PEG) Plus Ribavirin (R) Therapy: Results From the IDEAL Trial

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. Detailed Information can be found here; Recent Advances in Hepatitis C: Entitled "Highlights from the 2010 AASLD Meeting"

In the IDEAL study, 3,070 treatment-naive patients with genotype 1 HCV infection received up to 48 weeks of treatment with 1 of 3 regimens:

Peginterferon a-2b (1.0or 1.5 μg/kg/week) plus ribavirin (800–,400 mg/day) or peginterferon α-2a (180 μg/week) plus ribavirin(1,000–,200 mg/day).

In the current analysis, Poordad and colleagues evaluated data from patients enrolled in the IDEAL study to determine the concordance between virologic response at Weeks 4 and 12.

A null response was defined as a failure to achieve an HCV RNA decline of at least 1 log IU/mL at Week 4 or a decline of at least 2 log IU/mL at Week 12.

The investigators found high positive correlations between the change in HCV RNA levels at Weeks 4 and12 for all peginterferon and ribavirin regimens.

A null response at Week 12 corresponded to an HCV RNA decline of 0.7–1.1 log IU/mL at Week 4 in patients receiving peginterferon α-2b (1.5 μg/kg/week) plus ribavirin. The concordance rate for attaining a null or non-null response at both time points was 89% overall, with similarly high rates across the study’s 3 treatment arms (Table 1).

In a pooled analysis of patients in all 3 treatment arms, concordance rates at Weeks 4 and 12 according to IL-28B genotype were 98% in patients with CC alleles and 83% in patients with CT/TT alleles.

The more unfavorable allele was present in almost all patients with a null response at Week 4 or 12.

The investigators concluded that a viral load decline of less than 1 log IU/mL at Week 4 is roughly similar to a decline of less than 2 log IU/mL at Week 12. Therefore, Week 4 null response may provide an early method of predicting "null response", which could help guide early treatment decisions.

The Bottom Line

Patient is given a PCR/viral load test at four weeks, results are.... "less" then a 1 log drop.

This equates with "less" then two log drop at 12 weeks, which is an earlier predictor of "null reponse".

The Stats...

97% to 100% of genotype 1 patients in the study who failed to attain an early virologic response (less then a 2-log drop at week 12 of treatment) failed to attain a sustained virologic response (SVR)

Patients with an "undetectable" virus at week 12 in the study had an SVR rate of 79% .

This stopping rule can save the patient adverse effects, time, money and emotional/physical pain. Should a patient stop at week 4 if they had less then a 1 log drop? What if the patient had the IL-28B genotype test and had the good allele "CC"? What if the patient had very little liver damage ? What if the patient is under 30 and just contracted HCV? What if the patient has time to wait ? What if ? What if? When should you stop treatment ?

If I were treating today, I would be asking my physician all these questions.

What do we know for sure ? The 12 week stopping rule remains in place.