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Model to Predict Outcome of Pegasys plus Ribavirin Therapy
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Reported by Jules Levin
"COMBINATION THERAPY WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS®) PLUS RIBAVIRIN (COPEGUS) IN TREATMENT-NAIVE PATIENTS WITH CHRONIC HEPATITIS C AND GENOTYPE 1 INFECTION: INDIVIDUAL ESTIMATED PROBABILITY OF SUSTAINED VIROLOGICAL RESPONSE (SVR)"
O. Weiland (Karolinska Institutet, Stockholm, Sweden) presented the results of this study at EASL (April 14-18, 2004, Berlin, Germany). Here is his report.
Brief summary: This results from this study can be helpful in contributing to making decisions about treatment for HCV, including when to begin HCV therapy. These study results provide data showing response rates to Pegasys/Copegus for patients with specific characteristics. The information in this study discusses how to consider age, HCV viral load, BMI (body mass index, i.e. body weight), ALT, and stage of liver disease in considering when to begin therapy, the authors report how these factors affected patient outcome and response rates.
Weiland said: Extensive analyses of date from pivotal studies has demonstrated that SVR rates are heterogenous and are influenced by a range of patient- and virus-specific characteristics. For this reason it is possible to accurately predict the outcome of treatment for an individual patient with chronic hepatitis C. The ability to more accurately predict the outcome of treatment in an individual patient would be of practical value. More accurate predictability data would allow physicians to better counsel their patients on treatment decisions, and could be used to motivate patients to start and to adhere to treatment with Pegasys/Copegus by providing an accurate estimate of the probability of a cure. To this end we constructed an "SVR Calculator'' for estimating the probability that an individual patient will achieve an SVR after treatment with PEGASYS/COPEGUS. The probability can be calculated at baseline, or after 12 weeks' treatment, and can include assumptions about adherence.
The study objective was to present data from our logistic regression model that demonstrates the ability to predict SVR in patients with HCV genotype 1 when treated with Pegasys/Copegus.
Data included were from patients treated with PEGASYS 180mcg/week and COPEGUS 800 or 1000/1200mg/day in two phase III trials (Fried NEJM 2002; Hadziyannis 2002).
The influence of pretreatment factors (gender, age, race, BMI/weight, viral load, ALT quotient, histology, adherence) on SVR rates was examined by a logistic regression model. Data falling outside the 5th-95th percentiles were excluded; thus, data from 736 of 1037 genotype 1 patients with these characteristics were used in the model: Caucasian men and women, aged 18-65yrs, BMI 18-32 kg/m, ALT quotient, HCV RNA 0.1-24 million copies/mL, histology.
SVR was defined as a single undetectable HCV RNA measurement (COBAS AMPLICOR HCV Test v 2.0, limit of detection <50 IU/L) on or after week 36 for patients treated for 24 weeks in the study of Hadziyannis et al or after 60 weeks for patients treated for 48 weeks in either study.
Cut-points used to establish the model:
| lower limit | upper limit | | Pre-treatment viral load-(IU/ml) | 8150* | no limit | | Age | 18 | 65 | | Pre-treatment ALT quotient | 1 | 8 | | BMI (Kg/m2) | 18 | 32 |
*HCV RNA was reported in copies/ml in the studies, but is reported throughout this report as IU/ml by using a conversion factor of 0.37 (i.e. 22,000 copies/ml x 0.37=8150 IU/ml).
As the treatment duration and ribavirin dose exert a highly significant influence on the probability of achieving an SVR in patients infected with HCV genotype 1, all calculations for these patients assume a treatment duration of 48 weeks with Pegasys 180 ug/wk plus standard RBV dose (1000 or 1200 mg/day). This is in agreement with current treatment guidelines.
RESULTS
1737 patients treated with Pegasys/Copegus in phase III trials considered.
699 were genotype non-1.
1037 were genotype 1.
301 were excluded (non-caucasian, age >65, no BMI or BMI >32, viral load <8150 IU/ml, ALT quotient >8.
Factors that significantly modified the probability of an SVR in patients infected with genotype 1 included: age, viral load, ALT quotient, histology, and BMI.
Note that these results are based on actual patient data from the two studies and show the effects of two factors while ignoring other factors included in the final model.
SVR RATES ACCORDING TO BASELINE AGE AND HCV RNA LEVEL
(data from 392 HCV genotype 1 patients treated for 48 weeks with Pegasys and RBV 1000 or 1200 mg/day in Fried & Hadziyannis studies)
LOW HCV RNA <800,000 IU/mL
Age 18-34: 75% (27/36)
Age 35-50: 54.8% (40/73)
Age 51-65: 55.9% (19/34)
HIGH HCV RNA >800,000 IU/ml
Age 18-34: 53.5% (24/43)
Age 35-50: 51.9% (81/156)
Age 51-65: 28% (14/50)
SVR RATES ACCORDING TO BASELINE AGE AND HCV RNA LEVEL (ADHERENT PATIENTS ONLY)
(analysis limited to adherent patients—datafrom 392 HCV genotype 1 patients treated for 48 weeks with Pegasys/Copegus 1000 or 1200 mg/day in Fried & Hadziyannis studies)
LOW HCV RNA <800,000 IU/ml
Age 18-34: 83.9% (26/31)
Age 35-50: 65.6% (40/61)
Age 51-65: 58.1% (18/31)
HIGH HCV RNA >800,000 IU/ml
Age 18-34: 59.5% (22/37)
Age 35-50: 65.0% (80/123)
Age 51-65: 36.4% (12/33)
SVR RATES ACCORDING TO BASELINE ALT QUOTIENT AND HCV RNA LEVEL
(data from 392 HCv genotype 1 patients treated for 48 weeks with pegasys/Copegus 1000 or 1200 mg/day in Fried & Hadziyannis studies)
LOW HCV RNA <800,000 IU/ml
ALT Quotient <2.5 x ULN: 62.5% (55/88)
ALT Quotient 2.5-5.0 x ULN: 59.6% (28/47)
ALT Quotient >5.0 x ULN: 37.5% (3/8)
HIGH HCV RNA >800,000 IU/mL
ALT Quotient <2.5 x ULN: 42.4% (59/139)
ALT Quotient 2.5-5.0 x ULN: 50.0% (44/88)
ALT Quotient >5.0 x ULN: 68.2% (15/22)
SVR RATES ACCORDING TO BASELINE BMI AND HCV RNA LEVEL
(data from 392 HCV genotype 1 patients treated for 48 weeks with pegasys and Copegus 1000 or 1200 mg/day in fried & Hadziyannis studies)
LOW HCV RNA <800,000 IU/mL
BMI <= 25: 64.6% (42/65)
BMI >= 25: 56.4% (44/78)
HIGH HCV RNA >800,000 IU/ml
BMI <= 25: 57.1% (64/112)
BMI >= 25: 39.4% (54/137)
SVR RATES ACCORDING TO BASELINE AGE AND CIRRHOSIS STATE
(data from 392 HCV genotype 1 patients treated for 48 wks with pegasys/Copegus 1000 or 1200 mg/day in Fried & Hadziyannis studies)
NO CIRRHOSIS
Age 18-34: 62.7% (47/75)
Age 35-50: 55.9% (105/188)
Age 51-65: 47.3% (26/55)
CIRRHOSIS/BRIDGING CIRRHOSIS
Age 18-34: 75% (3/4)
Age 35-50: 39% (16/41)
Age 51-65: 24.1% (7/29)
SVR RATES ACCORDING TO BASELINE ALT QUOTIENT AND CIRRHOSIS STATE
(data from 392 HCV genotype 1 patients treated for 48 wks with pegasys and Copegus 1000 or 1200 mg/day in Fried & Hadziyannis studies)
NO CIRRHOSIS
ALT Quotient <2.5 x ULN: 53% (106/200)
ALT Quotient 2.5-5.0 x ULN: 58.2% (57/98)
ALT Quotient >5.0 x ULN: 75% (15/20)
CIRRHOSIS/BRIDGING CIRRHOSIS
ALT Quotient <2.5 x ULN: 29.2% (8/27)
ALT Quotient 2.5-5.0 x ULN: 40.5% (15/37)
ALT Quotient >5.0 x ULN: 30.0% (3/10)
SVR RATES ACCORDING TO BASELINE BMI AND CIRRHOSIS STATE
(data from 392 HCV genotype 1 patients treated for 48 wks with Pegasys and Copegus 1000 or 1200 mg/day in Fried & Hadziyannis studies)
NO CIRRHOSIS
BMI <= 25: 62.3% (96/154)
BMI >= 25: 50% (82/164)
CIRRHOSIS/BRIDGING CIRRHOSIS
BMI <= 25: 43.5% (10/23)
BMI >= 25: 31.4% (16/51)
EFFECT OF VARIATION IN A SINGLE BASELINE
The effect of varying a single baseline characteristic on the probability of achieving an SVR in a hypothetical 'standard patient' is presented below, Note that individual estimated probabilities were generated with the SVR calculator based on the final model.
PROBABILITY OF ACHIEVING A SUSTAINED VIROLOGIC RESPONSE
Standard patient: 52%
Viral load=60 x 103 IU/mL: 72%
Viral load=9000 x 103 IU/ml: 36%
Age=20 yrs: 70%
Age=60 yrs: 36%
BMI=20 kg/m2: 59%
BMI=30 kg/m2: 46%
ALT quotient=1.0: 45%
ALT quotient=4.0: 64%
Cirrhosis: 34%
Assuming adherence >80%: 62%
The characteristics of the 'standard patient' are as follows: HCV RNA level 1200 x 103 IU/mL, age 43 yrs, BMI 26 kg/m2, ALT quotient 2.0, no cirrhosis, and with no assumptions about adherence.
INDIVIDUAL ESTIMATED PROBABILITY OF AN SVR IN 8 HYPOTHETICAL PATIENTS WITH GENOTYPE 1 FOR 48 WEEKS WITH PEGASYS PLUS COPEGUS 1000 or 1200 mg/day
The individual estimated probabilities of achieving an SVR is presented for 8 hypothetical patients below. Baseline characteristics used to calculate the probabilities are presented.
PROBABILITY OF ACHIEVING SUSTAINED VIRAL RESPONSE
| 97% | 85% | 74% | 52% | 36% | 19% | 14% | 7% | | Cirrhosis: | No | No | No | No | No | No | No | Yes | | ALT quotient: | 7 | 2 | 2 | 2 | 2 | 2 | 1 | 1 | | Age: | 20 | 20 | 43 | 43 | 43 | 60 | 60 | 60 | | BMI (kg/m2): | 20 | 20 | 26 | 26 | 26 | 30 | 30 | 30 | | HCV RNA: | 40 | 40 | 40 | 1200 | 9000 | 9000 | 9000 | 9000 |
(IU/ml x 103)
The authors CONCLUDED: the results of the SVR Calculator project demonstrate that it is possible to refine the ability to estimate the probability that an individual patient will achieve an SVR when treated with Pegasy/Copegus. By varying the input parameters acci=ording to the characteristics of an individual patient the probability of achieving an SVR can be calculated. Important baseline factors include HCV genotype, HCV RNA level, age, BMI, ALT quotient, presence or absence of cirrhosis, and assumptions about adherence. This tool can be used to make treatment decisions in clinical practice and to motivate patients to stay on therapy.
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