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HCV Therapy Adherence; New drugs
Reported by Jules Levin
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In this afternoon,s oral session on Novel Hepatitis C Therapies Histamine showed nothing I or other observers in the audience could see. The study of IL-12 was stopped for both lack of antiviral activity against HCV and for adverse events, among them thrombocytopenia (reduced platelets) and hemoglobin reduction. The ISIS 14803 antisense showed antiviral activity in some patients (2/4 „ 1-log reduction in viral load) but was accompanied by high spikes in liver enzymes as viral load reduced. The enzyme spikes resolved when drug was stopped. Also a negative, ISIS drug is administered by subcutaneous injection, I think 3 times per week by 2-hour intravenous infusion (which is I think how the drug is administered in the study beginning shortly), or by bolus subcutaneous injection following, by at least 7 days, a single dose.
Peter Ferenci from Vienna gave an interesting presentation in his talk on Early Prediction of Response to Peginterferon alfa-2a (Pegasys) Plus Ribavirin in patients with HCV. An analysis on early response was presented at DDW 2001 from the Pegasys/RBV study, which reported that a patient,s viral load response by week 12 appears to indicate the capacity to achieve a sustained virologic response. This was explored further by Ferenci in an analysis from the same study, which he presented today at AASLD. This is preliminary data from a sort of pilot study. This is data that was generated after the study. The study was not designed to look at these questions on adherence and early response. The data do appear to make sense but follow-up study is required. Ferenci also showed preliminary data suggesting that a dose reduction may not reduce response rates. The data previously reported at DDW showed that patients who fail to achieve an early viral response (EVR) with Pegasys were highly unlikely (negative predictive value=97%) to achieve a sustained viral response (SVR).
The purpose of this study presented by Ferenci at AASLD was to determine the effect of HCV genotype and adherence to study regimen on positive and negative predictive values for sustained virologic response using the EVR. They used study NV 15801 where patients were treated with Pegasys once weekly and Ribavirin 1000-1200 mg per day (Fried et al, DDW 2001).
Predictive value (PPV) is the probability that patients who achieve an EVR will eventually achieve an SVR. Negative predictive value is the probability that patients who do not achieve an EVR will not achieve an SVR. This data is the first time its reported so it,s preliminary. Further time may be needed to discuss and explore the reliability of the data. Additional data and studies will continue to look at these questions.
A brief summary of key points-
(1) The data presented by Ferenci suggests Adherence Matters:
· 86% (81% genotype 1) achieved undetectable viral load at week 12 in the Fried study of Pegasys+RBV. 65% of them achieved a sustained virologic response. 86% with genotype 2/3 and fully adherent achieved an SVR. This compares with a 76% SVR in the study for genotype 2/3
· Adherence appeared matter more for genotype 1 to achieving a viral response: 81% of patients with genotype 1 had an EVR. 67% (105/151) of genotype 1 patients who were fully adherent achieved an SVR. This compares with the 46% SVR for genotype 1 in the Pegasys/RBV study‹an improvement of 21%, and with 40% who were <80% adherent
(2) you will see from the discussion below that the data suggests that (again, data is preliminary) perhaps atients may be able to dose reduce and still maintain equal or close to equal chance of achieving sustained viral response. Since the data is preliminary, further research needs to be done before trying this. Do not try dose reducing on your own. Read the details below.
Michael Fried reported at DDW that 86% (n=390) of patients at week 12 (total n=453) achieved an EVR. Again, the original study was not designed to explore these questions. 65% (PPV) of those achieving the EVR (n=253) achieved an SVR, and 35% (n=135) did not achieve an SVR. So, if you had undetectable viral load by week 12 you had a 65% chance of achieving an undetectable viral load 24 weeks after stopping 48 weeks of therapy. 14% (n=63) did not achieve an EVR at week 12, and 3% of them (n=2) achieved an SVR. 97% (NPV) (n=61) did not achieve an SVR. So, if you had undetectable viral load at week 12 you had a 65% chance of achieving an SVR, and if you did not have an EVR at week 12 you had a 97% chance of not achieving an SVR. This suggests that, depending on other considerations, you may want to stop therapy at week 12 if undetectable viral load was not reached. However, if you are trying to improve histology you may want to continue therapy for the full 48 weeks. As reported in yesterday,s reports from this conference several new studies report what has been previously reported‹it appears as if interferon therapy improves, slows, or stops liver disease progression. Perhaps nonresponders may not accomplish this but the data indicate transient viral responders and sustained viral responders achieved this. Still, it,s my understanding that even nonresponders may achieve stopping or slowing progression while on interferon therapy. This has not been well established but two large studies are exploring this now.
GENOTYPE
In the Fried study 81% (240/298) of patients with genotype 1 had an EVR at week 12. The PPV was 57%. 137 patients (57%) achieved a SVR, while 43% did not achieve an SVR. Not surprisingly genotype 2 did better. 19% of patients with genotype 1 had no EVR at week 12. 2% (n=1) had an SVR. 98% (n=57) had no SVR (NPV=98%).
The PPV for genotype 2/3 was 77%, as 97% had an EVR and 77% of them had an SVR. 23% had no SVR. 3% (n=4) of genotype 2/3 had no EVR and 25% (n=1) had an SVR, while 3 patients (NPV=75%) had no SVR.
ADHERENCE MATTERS; IS DOSE REDUCTION OK?
For this discussion, full dose or full adherence in this analysis of the Fried study equals taking 80% of drug and completing at least 38 weeks of therapy. Less than 80% adherence is due to early withdrawal or dropout or dose reduction.
86% achieved EVR at week 12. 75% who took their full dose achieved an SVR. 48% who were <80% adherent achieved an SVR. 145 patients were <80% adherent. 94 of them (67%) dose reduced and 63 (67%) achieved an SVR. Of the 145 patients who were not 80% adherent 51 withdrew early or dropped out. 12% (n=6) achieved an SVR. What is the importance of this?? Perhaps a patient could dose reduce and still achieve close to or equal to the response they would achieve with full adherence. If a patient is not tolerating drugs, dose reduction may help them stay on drug and maintain an equal or close to equal chance for achieving an SVR. However, the analysis of this data is new and so we don,t know yet whether patients dose reduced the Peg IFN, RBV, or both. And we don,t know how much dose reduction is ok. This data suggests a patient may be able to dose reduce to 600 mg per day RBV and still hold a good chance of achieving an SVR. Here is the data further broken down by genotype 1 and 2.
81% (n=240) of patients with genotype 1 had an EVR. 67% (105/151) who were fully adherent achieved an SVR. 40% who were <80% adherent achieved an SVR. But, 56% who dose reduced (<80% adherence) were still able to achieve an SVR. Genotype 2/3 did better. 97% achieved an EVR (n=136). 86 were fully adherent and 76/86 (86%) achieved an SVR. 50 patients had <80% adherence. 29 of the 50 dose reduced and 88% of them achieved an SVR.
These are preliminary data from 1 study. It,s premature to presume it,s ok to reduce your dose of either Peg IFN or ribavirin. Further analysis of these data are forthcoming and we should take a wait and see approach.
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