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HCV Viral Kinetics During Therapy
Reported by Jules Levin
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"HEPATITIS C VIRUS DYNAMICS DURING THERAPY WITH PEGINTERFERON ALFA-2A (40KD)
(PEGASYS) COMPARED TO PEGINTERFERON ALFA-2B (12KD) (PEGINTRON) IN NAIVE
PATIENTS WITH CHRONIC HEPATITIS C" (poster abstract 159)
Italian study investigators (poster abstract 159) randomized 22 previously
untreated patients to receive Pegasys 180 mcg or 1.0 mcg/kg, both once weekly
plus 1000/1200 mg ribavirin. Patients had chronic HCV and had persistently
elevated ALT. Baseline viral load was about the same. 6/12 on PegIntron and
7/10 on Pegasys had genotype 1. 20% (2/10) of patients had
cirrhosis/transition to cirrhosis in the Pegasys group vs 16% (2/12) in the
PegIntron group. Investigators reported that the average reduction in VL
after 1 and 4 weeks was about the same for both drugs: after 1 week Pegasys
patients had 4.88 log viral load, PegIntron patients had 4.95 log viral load;
Pegasys VL at baseline 5.75 log, week 4 was 3.32 log; PegIntron baseline VL
5.64, week 4 was 3.64 log. At week 12 the viral load was significantly lower
in Pegasys group (2.81 log vs 3.87 log). When authors assessed viral load
over time out to 12 weeks in only patients with genotype 1 there was an
observed difference between the two treatment groups but the difference was
not significant. By looking at the graph the difference in genotype 1
patients started to diverge after 1 week increased by 4 weeks and appeared
wider by week 12.
The authors said these results could be due to different exposure of the two
drugs, which may result a different sustained exposure to the two agents
during the dosing interval.
"HCV DYNAMICS IN HIV/HCV COINFECTED PATIENTS TREATED WITH PEGYLATED
INTERFERON AND RIBAVIRIN" (poster abstract 154).
Andrew Talal and colleagues reported on viral kinetics in HCV/HIV coinfected
patients. Talal reported that this is the first study in HCV monoinfected or
HCV/HIV coinfected with a detailed characterization of HCV dynamics of the
first 3 doses of peg-IFN. 20 coinfected patients received PegIntron 1.5 ug/kg
and ribavirin weight based dose at 13 mg/kg. All patientsreceived liver
biopsy to assess grade and stage. All patients were hospitalized for 24 hours
during the first two doses of Peg-IFN administration with outpatient visits
on day 2, 3, 5, 6, 9, 14, 15 and 16. Talal is collecting data on various
types of immune system related cells to assess the immune response. HCV RNA
was measured regularly during day 1, at 48 and 72 hours; and days 5 and 6
after the first dose; at 0.6, 12, 24, and 48 hours after the second dose.;
and on days 0, 1, 2 after the third dose. Baseline HCV viral load was 6.5
log, 14/20 patients were on HAART. Most patients had undetectable HIV.
Average CD4 count among responders was 400 and nonresponders 550, but both
groups had the same stage & grade of disease at baseline. Patients were
excluded if they had <100 CD4 count. If they had 100-200 CD4s they were
required to have undetectable HIV. There were 4 African-Americans among
responders vs 6 among the nonresponders. Average 9 patients had undetectable
HIV viral load, and some patients had viral load that was not low; average
cd4 count was 469. All patients were genotype 1, except 1 who had
indeterminate genotype.
Of 13 patients analyzed and reported early, 4 demonstrated rapid HCV RNA
decline (more than 2 logs in the first week), 5 demonstrated a partial
decline (1 log or less during the first 28 days), and 4 are nonresponders
without a discernable decline. As of Sept 2002 8/20 individuals had a
virologic response. 2 of 10 were late responders: 3-8 months on treatment; in
these patients HCV RNA begins to decline after week 8 and becomes
undetectable after week 24; 10 of 20 patients had no phase 1 decline in viral
load. These data find the coinfected patients responding apparently less well
in the first few weeks of therapy, and Avidan Neumann reports that early
viral load decline (kinetics) correlate with the ability to achieve a
sustained viral response. Talal finds a lower percentage of coinfected
patients achieve substantial viral load reductions. In Neumannıs study of
monoinfected patients the percentage of monoinfected achieving substantial
viral load reductions are higher.
These study data, as well as data from other studies, suggests HIV impairs
the response to therapy. Talal reports it takes longer for cells to die off
for these patient: average infected cell half-life ranged from 18 hours to 5
days. Average free virus half-life is 4.6 hours. This suggests perhaps
conifected patients should be treated for longer. 10/20 patients had no phase
1 decline during therapy, phase I is the first few days.
Immunologic Responses. Talal reports observing significant decreases in
responses to C22.5 (NS3) and NS5 in responders compared to nonresponders.
Decrease in response to HIV gag also observed at week 1.
Some researchers and doctors anecdotally report they see response to therapy
is delayed for some coinfected patients, but this needs confirmation with
further study. Viral load response may appear after the first 28 days or be
slow in starting and gaining momentum.
Talal conclusions. We have developed a new model that includes the decline in
effectiveness, due to the exponential decay in peg-IFN concentrations, and
which explains the data over the first week. With subsequent administrations
of the drug, the high efficacy is reestablished and the viral load once again
drops sharply. Immunomodulatory effect of IFN is different in responders
compared with nonresponders.
Viral Kinetics in HCV Monoinfection During Therapy
Avidan Neumann (a noted viral kineticist) presented data from his viral
kinetics study in which patients received PegIntron plus ribavirin at the
Viral Hepatitis Therapy Workshop just prior to AASLD. So I can report that
information but his more detailed poster at AASLD is not presented yet so
these details will be reported later. At the Workshop Neumann reported viral
load on average declined substantially during the first few days of PegIntron
plus ribavirin. However, after a few days all the patients experienced an
increase in viral load. Of course at the end of the first week on therapy
there was a net decline in viral load. Viral load declines again in each
following week in a similar fashion: down the first few days with increase in
the next few days of the week.
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