An interesting article on Medscape entitled "Viral Kinetics in the treatment
of Chronic Hepatitis C".

http://www.medscape.com/viewarticle/543530?src=mp

If the link doesn't work and for those who don't have a Medscape signon,
I've cut and pasted the latter part of the article. I'm afraid I can't copy
the diagrams. I thought the section on EVR was interesting, showing how
tests at week 4 and even day one can be indicative.

Jack

Viral Kinetics of Pegylated Interferons
Treatment with pegylated IFNs plus ribavirin has yielded improved response
rates compared with unmodified IFNs plus ribavirin.[9,10] During pegylation,
a large, chemically inactive polyethyleneglycol (PEG) molecule is attached
to IFN-?2a or IFN-?2b. Currently, there are two commercially available forms
of pegylated IFNs: PEG-IFN-?2b (12 kD), a covalent conjugate of a linear
12-kD PEG moiety to recombinant IFN-?2b; and PEG-IFN-?2a (40 kD), a covalent
conjugate of a branched 40-kD PEG molecule to recombinant IFN-?2a.[27-30]
The primary benefit of pegylated IFNs over unmodified IFNs is their improved
pharmacokinetics. Pegylation slows the absorption rate of IFN; in healthy
volunteers, the mean time (tmax) to reach maximum serum concentration (Cmax)
was 78 h for PEG-IFN-?2a and 10 h for IFN-?2a.[27] Moreover, the clearance
rate was >100-fold lower (0.08 vs 11.8 L/h), and the terminal elimination
half-life (t1/2) was about ninefold longer (77 vs 9 h), for PEG-IFN-?2a than
for IFN-?2a.

The two different forms of pegylated IFNs have different pharmacokinetics.
PEG-IFN-?2b has a half-life in plasma of about 40 h, whereas PEG-IFN-?2a has
a half-life in plasma of 77 h.[27,31] One small study that compared the
pharmacokinetics of the two drugs showed that PEG-IFN-?2b reached a maximum
serum concentration at 24 h, whereas PEG-IFN-?2a reached a maximum serum
concentration between 48 and 168 h.[32]

Viral kinetic analysis has only recently been used to study pegylated IFNs,
and interesting observations have already been made. One of the first
studies compared the viral kinetics of standard and PEG-IFN-?2a.[33]
Pegylated IFN produced a biphasic viral decline that consisted of a rapid
first-phase decline and a subsequent slower second-phase decline. Similar to
the findings of previous studies with unmodified IFN, the first- and
second-phase viral declines were faster in patients infected with genotype
non-1 virus, and the second-phase viral decline was predictive of an SVR.

Another study evaluated viral kinetics in patients treated with high- or
low-dose PEG-IFN-?2b plus ribavirin.[34] The viral decay was biphasic, and
the first-phase decline was dose dependent, as was illustrated in initial
studies. In some patients, a viral rebound occurred during the end of the
first week of therapy, a finding that was also observed in patients treated
with standard IFN, with or without ribavirin.[19,21]

The different pharmacokinetic profiles of pegylated and unmodified IFNs
generally have not been considered in the viral kinetic studies of pegylated
IFNs performed to date. It will be necessary to include pharmacokinetic
parameters to adequately address these differences in future investigations.
A pilot study showed that incorporating pharmacokinetics into the
traditional model allowed for a good fit of the data.[35]

Viral Kinetics of Ribavirin
While the addition of ribavirin to IFN therapy has substantially improved
treatment response rates, the mechanism of action of ribavirin has remained
an enigma. Ribavirin may act as an immune modulator,[36] and/or it may
reduce the infection rate of uninfected target cells by increasing the
mutational frequency of the virus.[37-39]

The impact of ribavirin on viral kinetic parameters is still being defined.
Ribavirin monotherapy causes either a transient initial decline or no
decrease in viral levels.[40-43] In one study, viral kinetics were evaluated
in patients treated with varying doses of IFN-?, with or without
ribavirin.[43] The addition of ribavirin partially decreased the rebound
noted before the second dose of IFN, but it did not have a significant
impact on the second-phase viral decline. During thrice-weekly dosing with
unmodified IFN, however, the administration of ribavirin was associated with
an increase in the slope of the second-phase viral decline. In another
report, ribavirin did not appear to affect either the first- or second-phase
viral decline.[26]

Kinetic parameters were also studied when ribavirin was used in conjunction
with pegylated IFN.[44] In this study, it was hypothesized that ribavirin
served as an immune modulator. To account for this effect, the basic kinetic
model also included an additional term called an inflation factor that had
an impact on the rate of loss of infected cells after an initial delay. The
study confirmed the observation that ribavirin had little impact on the
first-phase viral decline, but increased the second-phase viral decline,
when IFN effectiveness was low. A third phase was also noted, which may
represent an enhanced loss in the rate of infected cells.

A recent study that modelled the impact of ribavirin on IFN therapy has
provided further insight into the mechanism of action of ribavirin.[45] This
study tested the hypothesis that ribavirin acts by causing lethal
mutagenesis to the virus, and the traditional model was, therefore, extended
to incorporate a term accounting for these effects. The results fit well
into this revised model. Moreover, findings from this study indicated that
ribavirin enhances the second-phase viral decline, but that its enhancement
was substantial only when IFN effectiveness was low. Figure 4 shows
theoretic decay profiles for high and low IFN effectiveness. In patients
with high IFN effectiveness, the second-phase viral decline is not
significantly affected by increasing the effectiveness of ribavirin. In
contrast, when IFN effectiveness is low, increasing ribavirin effectiveness
has a greater impact on the second-phase viral decline. The authors of this
study also theorized on what ETR and SVR rates should be, based on the
addition of ribavirin. In general, predictions from this model were in
agreement with the response rates from previous clinical trials.

Early Virologic Response
In clinical practice, simple viral kinetic measurements made early during
the course of therapy are used to identify patients who are unlikely to
achieve an SVR with a full 48 weeks of treatment. Data from a large registry
trial of unmodified IFN and ribavirin showed that 99% of patients who had
detectable HCV RNA at week 24 of treatment failed to achieve an SVR.[46]

Early virologic response (EVR) is determined at week 12 of treatment for
patients receiving pegylated IFN and ribavirin. Retrospective analyses have
shown that patients who fail to achieve a 2-log10 reduction in virus level
from baseline or undetectable HCV RNA at week 12 have a negligible chance of
an SVR with an additional 36 weeks of treatment.[9,47] These findings
provide the basis for recommending that treatment with pegylated IFN and
ribavirin be discontinued in patients with genotype 1 infection who do not
reach EVR at week 12. In contrast, it is not cost-effective to assess for
EVR in patients with genotypes 2 and 3 infection, because 99% reach this
endpoint.[47] Additional studies have shown that the 12-week EVR predicts
nonresponse in populations underrepresented or not represented in large
registry trials, including African-Americans and patients with HIV
co-infection.[48,49] It is important to recognize that the positive
predictive value of a 12-week EVR is only 65-72%.[9,47] In other words,
while failure to achieve an EVR predicts nonresponse, an EVR does not
guarantee an SVR. In some circumstances, continued therapy might be
considered in patients who fail to reach an EVR, such as when a maintenance
approach is used in a patient with cirrhosis.[48]

There is interest in assessing response at even earlier time points to
further limit the duration and side effects of antiviral therapy in patients
who are unlikely to achieve an SVR. A study of patients treated with
unmodified IFN found that all sustained responders had a greater than 3
log10 decrease in virus level from baseline to week 4 of therapy.[50]
Compiled data from 260 patients treated with a variety of regimens,
including unmodified IFN and pegylated IFN and ribavirin, showed that all
patients with an HCV RNA level greater than 450 000 IU/mL at treatment week
4 were nonresponders.[51] However, this 4-week assessment identified only
15% of nonresponders.

Additional studies have evaluated the association between virologic response
at 24 h and SVR. A detailed kinetic analysis of patients treated with high
doses of unmodified IFN showed failure to achieve a 98% reduction in viral
load, and a virus level <250 000 copies/mL within 24 h of treatment
initiation had a 100% negative predictive value for SVR.[52] In another
report, the reduction in virus level with a single 9-MU test dose of
unmodified IFN was associated with response to pegylated IFN and
ribavirin.[53] All patients who had >1.4 log10 reduction in virus level 24 h
after the test dose of unmodified IFN achieved an SVR, whereas only 2 of 12
patients who had <0.8 log10 change with the test dose achieved an SVR.

Further studies of the use of very early time points to assess EVR are
needed before they are adopted into clinical practice. An ideal measure of
EVR should have a negative predictive value of 100% to avoid discontinuation
of therapy in patients who have a chance of achieving an SVR. At present,
the 12-week EVR determination remains the standard of care.

Conclusion
The field of viral kinetics has provided important insights into the life
cycle of HCV and the mechanisms of antiviral therapy. Further research is
needed to develop models to predict nonresponse at early time points.
Additional studies should focus on special populations, such as liver
transplant recipients and patients co-infected with HIV. Finally, as newer
antiviral therapies are introduced, viral kinetic models will provide a
means to study the mechanisms of action and antiviral efficacies of these
agents.