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Early Viral Kinetics Prediction of Sustained Viral Response After 1 or 4 Weeks of Peg-Interferon-a-2a (40KD) and Ribavirin Therapy (DITTO-HCV Project)
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Public policy implications
Reported by Jules Levin
Avidan Neumann is perhaps the leading HCV viral kinetics researcher. He is the Alan Perelson (HIV) of HCV. I have been following his research presented by him at liver conferences for several years. He has been fine tuning his concept of using viral kinetics in HCV on therapy to find an early stopping approach. His talk at this meeting (2003 AASLD) appears to be the culmination of putting his various concepts into a composite criteria for an early stopping rule at week 4 after starting therapy. Neumann used Pegasys plus ribavirin (Copegus) treatment for this study. He studied 134 patients who received 48 weeks treatment with a 24 week follow-up period, and applied several of his methods for stopping therapy by week 4. The results from this preliminary study show his 3 methods had better positive predictive values and specificity than the current 12 week stopping rule. In other words, the results of his study suggest that his method for stopping therapy at week 4 appears better than the 12 week method. He summarizes his talk by saying that larger studies are needed to confirm his findings. The Neumann methods utilize 3-5 viral load measurements in the first 4 weeks after starting therapy to predict the probability of achieving a sustained viral load response, which is an undetectable (<50 IU/ml) viral load after 48 weeks of therapy plus a 24 week follow-up period.
There are clear public policy implications to Neumann's research. If Neumann's method is confirmed as reliable and utilized it might be cost effective and facilitate private and public insurers in providing more accessible testing/counseling, care and treatment, and it can improve patient quality of life regarding treatment. It might also support patients in their often difficult attempts in deciding whether to begin treatment.
Neumann gave this background. Early Hepatitis C viral (HCV) kinetics has been previously shown to predict sustained virological response (SVR). The current consensus stopping rule is defined at 12 weeks of treatment with peginterferon-alfa and ribavirin. Earlier prediction is needed in order to improve the cost/effect ratio. However, the predictive value of earlier viral kinetics for the current standard of care has not yet been established. The DITTO-HCV European funded project is for now the largest study of frequent early viral kinetics during therapy with peginterferon-alfa and ribavirin. We aim to optimize viral kinetics prediction criteria in order to enable stopping or tailoring treatment as early as possible. Our objectives: 1) negative predictive value (NPV) as close as possible to 100% (thus minimalizing stopped patients with missed SVR), 2) high specificity (thus increasing the fraction of patients that can be safely stopped). 3) a high positive predictive value (PPV) using the same criteria.
The current consensus stopping rule is: Early Viral Response (EVR) at week 12—PCR negative (<50 IU/ml or viral decline >2 log—STOP therapy if there is no EVR.
Neumann provided:
Current Standard Results with Pegasys-ribavirin
EVR wk 12 prediction for Peg-IFN a-2a (Pegasys)
(Fried et al, NEJM, 2002)
--Negative Predictive Value (NPV) = 97%
--Specificity = 31%
--Positive Predictive Value (PPV) = 65%
NPV is the probability that a negative prediction gives a no-response. Neumann asked, how sure are you that no SVR patients are lost by stopping early due to negative prediction. He said we should be as close to 100% as possible.
Specificity (Sp) The fraction of non-responding patients that are indeed identified by the prediction criteria. Neumann said goal should be as large as possible specificity with NPV=100%.
Positive Predictive Value The probability that a positive prediction indeed gives an SVR. Neumann said the goal is to obtain a good PPV with same criteria.
Neumann said the EVR w12 has good NPV, but 69% of non-responders are not identified early, and best PPV obtained is not great.
He described his previous work of identifying the 2nd slope of viral decline of faster than 0.3 log/week during weeks 2-4 as the best predictor of SVR (NPV>98%) consistently in all studies of viral kinetics with various treatment regimens.
He said there are some indications that viral decline of 0.5 or 0.6 log on the 1st day of treatment may also predict SVR (Ferenci et al, Lancet 2002; Laydon et al, JVH, 2002).
But the predictive value of early viral kinetics was not studied in large studies. There is no prediction with current standard of care treatment of PegIFN plus ribavirin.
The goal of the DITTO-HCV Project
Neumann said this is the largest study of frequent early viral kinetics in the HCV field. The aim is to optimize SVR prediction with the standard therapy (PegIFN and RBV) using early viral kinetics in the most clinically applicable way possible.
METHODS
134 treatment-naïve patients with chronic hepatitis C were studied. HCV gentype 1 (67%), genotype 2/3 (28%), genotype 4 (5%).
48 weeks of treatment with peginterferon alfa-2a (40KD) (Pegays) 180 mcg once weekly plus ribavirin (Copegus) 1000-1200 mg per day.
HCV RNA (viral load) was quantified on days 0, 1, 4, 7, 8, 15, 22, and 29; and then on weeks 6, 8, 10, and 12. Test used: Cobas Amplicor HCV Monitor v2 Roche (LD=50 IU/ml.
Neumann said we tested a number of prediction criteria (EVR) and thresolds, which were all prospectively defined. However, prediction analysis was done retrospectively.
DITTO RESULTS – Prediction consensus rule
SVR= 64% (48 nonresponders; 86 SVR)
As you can see below the analysis examined 5 ways to evaluate EVR in predictinf SVR: (1) EVR week 12; (2) EVR week 4; (3) Ditto 2nd slope (slope of VL decline >0.6 log/wk on days 8-29 and/or 15-29; (4) DITTO 1st week viral kinetics (VL <4.5 log on day 4 and/or >1.5 log at day 7); (5) DITTO 4 weeks viral kinetics (DITTO 2nd slope plus DITTO 1st week).
Neumann found that by using the composite criteria for DITTO 4 weeks (DITTO 2nd slope plus DITTO 1st week) the best results were obtained: specificity was greater (49%) and the positive predictive value was greater.
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| EVR criteria |
Week |
# VL |
NPV |
Spec |
PPV* |
P Defintion |
| EVR w12 (HCV RNA negative and/or decline >2 log at wk 12) |
12 |
2 |
100% |
21% |
84% |
0.001 |
| (*) PPV for EVRw12 obtained for patients with Neg PCR |
| EVR w4 (HCV RNA negative and/or decline >1.2 log at week 4) |
4 |
2 |
<93% |
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| DITTO-2nd-slope (slope >0.3 log/wk on days 8-29 and/or 15-29) |
4 |
4 |
100% |
34% |
90%* |
0.001 |
| (*) PPV for DITTO-2nd slp obtained for patients with slopes >0.6 log/wk |
| DITTO-1st-week-VK (VL <5.5 log on day 4 and/or >0.5 log at day 7) |
1 |
3 |
100% |
28% |
93%* |
0.001 |
(*) PPV for DITTO-1-week obtained with VL <4.5 log on day 4 and decline >1.5 log on day 7
| DITTO-4 weeks-VK (DITTO-2nd slp + DITTO-1st-wk) |
4 |
5 |
100% |
49% |
93% |
0.001 |
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Neumann’s Conclusions:
Using 3-5 viral load measurements within the first 4 weeks and a composite algorithm, we were able to predict SVR:
--with 100% Negative Predictive Value
--with high specificity (about 50%)
--with good positive predictive value (93%)
in a genotype independent method.
CONSIDERATIONS by Neumann
--even with 5 viral load measurements this prediction is cost effective and can improve quality of life; and prediction and help in tailoring treatment regimen
--the suggested DITTO prediction algorithm must be confirmed prospectively by other large studies
--the feasability of the prediction method should be tested in clinical practice
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