email Dr. Cecil

INDIVIDUALIZED HEPATITIS C THERAPY OF MILITARY VETERANS: INTERFERON DOSE ESCALATION IMPROVES THE SUSTAINED RESPONSE RATE
Bennet Cecil, MD Mary Lavelle ARNP
Louisville VAMC

Poster Presentation AASLD 2001 Dallas Texas.

Background & Aims: Hepatitis C infects 8-10 % of military veterans receiving care at Veterans Administration Medical Centers, causing premature death. We report our results treating our initial 97 patients with chronic hepatitis C using individualized doses of interferon alfa 2b and ribavirin. We tested the ability of the simple exponential decay equation to predict success after 30 days of treatment.
Methods: All 770 patients identified at the Louisville Veterans Administration Medical Center with hepatitis C antibodies were sent clinic appointments. A total of 97 consecutive patients began treatment for chronic hepatitis C with interferon alpha 2b plus ribavirin from May 1st, 1998 through December 31st, 1999. An additional 173 patients have started since Jan 1,2000. The HCV-RNA is measured before and after 30 days of treatment. The percent fall in HCV-RNA after 30 days was calculated for each patient
Results: All 97 hepatitis C patients starting antiviral therapy at the Louisville VAMC in 1998 and 1999 are included in this report. The mean age is 50 years (range 36-69). The mean weight is 200 lb (range 117-434). Thirty-two are African-American and 65 are white. Four are female and 93 are male. HCV genotyping is not available at the Louisville VAMC and was not performed. Our African-American patients had a poor treatment response (4 of 32= 12.5%) compared to our white patients (32 of 65= 49%) Chi Square= 12.395 Fisher’s exact P= .0004. Similarly, the sustained response rate was lower in African-American veterans than in white veterans. In our cohort, 2 of 30 (7%) African-American patients and 18 of 55 (33%) white patients with a known response are sustained responders Chi Square= 6.768 Fisher’s exact P= .0136. Eighty-five of the 97 patients have completed treatment while 12 continue therapy. Twenty of 85 (23%) are sustained responders. Patients with >99% fall in HCV-RNA at 30 days had a 91% chance of a sustained response, and those with <80% fall had only a 3% chance of a sustained response. Patients with 80-99% HCV-RNA fall at 30 days had a 24% chance of a sustained response
Interferon dose escalation: Fifteen of 50 patients (30%) treated with interferon dose escalation were able to obtain a treatment response (HCV-RNA <50 IU/ml on treatment). Five of them became sustained responders and four relapsed after therapy was stopped. Six are treatment responders still on treatment. Four of the five sustained responders who were successfully given interferon dose escalation had low levels (about 220 IU/ml) of detectable HCV-RNA after 6 - 7 months of treatment. These four patients would have been denied their sustained response by the manufacturer’s recommendation to stop treatment if the qualitative HCV-RNA is still detectable after 24 weeks. If we did not use interferon dose escalation, we would have had only 15 of 89 sustained viral responders (16.8%).

Conclusions: Interferon dose escalation plus ribavirin in military veterans with poor response at 30 days improves the treatment and the sustained response rates. The overall sustained response rate was 23%. Patients with >99% fall in HCV-RNA at 30 days had a 91% chance of a sustained response, and those with <80% fall had only a 3% chance of a sustained response. Patients with 80-99% HCV-RNA fall at 30 days had a 24% chance of a sustained responseFig 1. It takes more than 30 viral elimination half-lives for the total body HCV burden to fall to one viral IU. If the HCV-RNA concentration is 1 million IU/ml, and the virus is distributed in 5,000 ml of body space, the total viral burden is 5 billion IU.  Exponential decay equation:
The concentration of HCV-RNA falls exponentially with interferon treatment, and complicated two-phase models have been published.1 We suggest the routine use of the simple exponential decay equation, (HCV-RNA t) = (HCV-RNA pretreatment) exp –at, which is analogous to the radioactive decay equation and Newton’s law of cooling.2 It approximates the HCV-RNA level at any time, t, where “t” is the number of days between the start of therapy and the second HCV-RNA level and “a” is a constant that is different for each patient and each treatment regimen.
(HCV-RNA t)/(HCV-RNA pretreatment)= exp –at
take the inverse of both sides of the equation to get rid of the negative power
[(HCV-RNA pretreatment)/(HCV-RNA t )] / = exp at
Take the natural logarithm of both sides
The ln of a quotient is equal ln of the numerator minus the ln of the denominator
The ln of exp at = at
Divide both sides by t, and solve for a
[(ln HCV-RNA pretreatment) - (ln HCV-RNA t)] /t = a
Once “a” is calculated, the elimination half-life of the virus is easily calculated.
The ratio of (HCV-RNA t)/(HCV-RNA pretreatment) =1/2 the half life by definition(HCV-RNA t)/(HCV-RNA pretreatment) = exp –atln (1/2)=ln (e –at) ln (0.5) = -atln (0.5)/-a = t = T1/2
Once “a” is calculated, the theoretical HCV-RNA concentration can be calculated for any length of treatment “t”. Even if the second
viral level is done at day 20 or 40 for example, the level at 30 days can be calculated.
The time in days for the HCV-RNA concentration to reach 1 IU/ml is:T to reach 1 IU/ml HCV-RNA= [(ln HCV-RNA pretreatment) - (ln HCV-RNA t)] /a
[(ln HCV-RNA pretreatment) - (ln 1)]/a =
ln HCV-RNA pretreatment /a
because the ln of 1 is 0
[(ln HCV-RNA pretreatment)] /a = t
Assuming that the average patient has HCV evenly distributed in 5000 cc of space (plasma, liver, spleen plus other spaces),
there are still 5000 IU in the patient when the HCV-RNA level is down to 1 IU/ml. One can calculate the theoretical time to go from a
total body burden of 5000 viral particles to a body burden of only 1 viral particle using the equation below.
T (in days to go from 1 IU/ml HCV-RNA to 1 IU/ whole patient) =
[(ln 5000) - (ln HCV-RNA t)]/a
[(ln 5000) - (0)]/a
because the ln of 1 is 0
ln 5000/ a
T (in days to go from pretreatment level to HCV-RNA to a total body burden of only 1 viral particle) is the sum of these two intervals.
T total = ln HCV-RNA pretreatment /a + ln 5000/a
This final equation estimates the minimal number of treatment days for a sustained response. One can use the percent HCV-RNA fall at 30 days,
which is easy to calculate, instead of the minimum number of treatment days, to predict success or failure
1. Herrmann E, Neumann AU, Schmidt JM, Zeuzem S Hepatitis C virus kinetics. Antivir Ther 2000 Jun; 5(2): 85-90
2. Silvanus PT, Gardner M. Calculus made easy. New York: St. Martin’s Press; 1998