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San Diego, California; Wednesday, May 21, 2008 -- The
management of hepatitis C is constantly changing. The current
therapeutic standard of care (combination therapy with pegylated
interferon and ribavirin) has been available for years, thus allowing
incredible insight into the population undergoing treatment. Because
the current standard of care results in long-term viral clearance in
only 42% to 82% of patients, the development of new, small-molecule
therapies, the so-called specifically targeted antiviral therapies for
HCV (STAT-C), is highly anticipated [1,2] This report highlights some of the key research in this area as presented during Digestive Disease Week (DDW) 2008.
Insights Into the Natural History of Hepatitis C
It
is difficult to describe an effectively treated hepatitis C virus
(HCV)-infected patient as "cured." However, sustained virologic
response (SVR; defined as HCV RNA undetectable 24 weeks after treatment
discontinuation) does predict long-term clearance of virus. Pooled data
from 2 large clinical trials found that 99% of patients treated with
pegylated interferon with or without ribavirin remained aviremic over 5
years after treatment was stopped. Unfortunately, 4 patients did
relapse late, one at year 5.[3] SVR is traditionally
determined 24 weeks after treatment discontinuation, yet in a cohort of
62 patients treated with the standard of care who achieved
end-of-treatment response (EOTR; defined as undetectable virus by PCR
at the end therapy), undetectable HCV RNA level at 12 weeks after
treatment was found to be well correlated with SVR. No patients
relapsed between week 12 and 24.[4]
Although the
incidence of HCV infection has declined dramatically, the overall
disease burden is projected to peak around the year 2015, as many
patients will have been infected for more than 20 years, placing them
at risk for complications.[5,6] Despite this projection, the
waitlist for liver transplantation reveals that although the number of
patients listed for hepatocellular carcinoma (HCC) has continued to
increase, the number of patients with end-stage liver disease due to
HCV infection listed for liver transplantation has decreased since
2000. Kim and colleagues[7] interrogated the national death
registry and found that after 1994, the HCV-related death rate
increased until leveling off in 2002. In addition, after 2002, death
rates for HCC did not increase among whites, whereas deaths from HCC
continued to rise among nonwhites. In contrast, using a national sample
of veterans with chronic HCV infection, investigators examined changes
in the prevalence and new diagnoses of cirrhosis and decompensated
cirrhosis for each year from 1996 to 2006.[8] They found that the chronic hepatitis C cohort size increased substantially, from 23,303 in 1996 to 122,368 in 2006.[8] From 1996 to 2006, the prevalence of cirrhosis increased by 1.5-fold
and decompensated cirrhosis increased by 2-fold. However, similar to
the findings of Kim and colleagues, mortality among patients with
cirrhosis peaked between 2003 and 2004, and then leveled off.
Optimizing the Standard of Care
As
indicated above, the current standard of care for the treatment of HCV
infection, is combination therapy with pegylated interferon and
ribavirin. Well-established negative baseline patient characteristics
include HCV genotype 1 or 4, viral load > 400,000 IU/mL, age > 40
years, male sex, nonwhite race, cirrhosis, and steatosis. The
recognition of these factors can help predict treatment response and
allow for the implementation of strategies to improve viral outcomes.[9,10] In studies presented during this year's DDW meeting, several other factors were assessed for their value in predicting SVR.
Latino Patients
Race
is known to have an impact on response to treatment with the standard
of care in hepatitis C. Black race is an established poor baseline
predictor of response to therapy, but Latinos have been
underrepresented in most hepatitis C trials. The LATINO study
prospectively compared response to the current standard of care among
treatment-naive Latino and non-Latino white patients with genotype 1
infection.[11] The authors found that SVR rates were
significantly higher in non-Latinos (49% vs 33%). In addition, some
baseline predictors of SVR were different between the 2 groups. For
example, although more Latino patients had a body mass index (BMI) >
27 kg/m2, increased BMI was only a poor predictor of response in the non-Latino population. Yu and colleagues[12] corroborated these findings in a retrospective analysis of
treatment-naive Hispanic and non-Hispanic white patients with HCV
infection. They also found that Hispanic patients were less likely to
achieve SVR, but only those with HCV genotype 2/3 infection. The
difference in genotype 2/3 SVR rates was secondary to relapse, as early
virologic response (EVR; defined as a 2-log decline in virus at
treatment week 12) and EOTR did not significantly differ between the 2
groups.
Previous Nonresponders
Further analysis
from the REPEAT (REtreatment with PEgasys in PATients Not Responding to
Peg-Intron Therapy) study offered insight into identifying which
nonresponders to the current standard of care might respond to a
subsequent therapeutic course. Data presented at DDW 2008 suggested
that for nonresponder patients, the type of prior response to the
standard of care was predictive of achieving a week 12
undetectable/unquantifiable HCV RNA level upon re-treatment.[13] The more potent the viral decline at 12 weeks during the first
treatment course, the higher the likelihood of virologic clearance at
week 12 with repeat therapy. Other data showed that HCV RNA status at
week 12 of treatment with the standard of care was predictive of SVR in
patients with prior nonresponse when retreated with pegylated
interferon and ribavirin.[14] Seventy-five percent of
patients who cleared virus at week 12 with their first course of
antiviral therapy cleared virus by week 12 with the subsequent
therapeutic course. In addition, SVR rates were highest for patients
with complete loss of virus at week 12, especially for those who
received 72 weeks of therapy and had favorable baseline prognostic
factors. [14] Concentrating on the 2 extremes at week 12:
null response (< 1-log drop in viral load) and complete response
(HCV RNA undetectable), the study authors used multiple logistic
regression analysis to identify predictive baseline and on-treatment
factors during the first 12 weeks, both for null response and complete
response.[15] In addition to the previously established
factors, complete response was found to be associated with the use of
360 mcg/week pegylated interferon,* greater on-treatment reduction in
platelets, and decline in serum alanine aminotransferase (ALT).
Conversely, null response was associated with lower dose of pegylated
interferon, higher baseline BMI, and lower declines in hemoglobin,
platelets, and body weight during 12 weeks of treatment, suggesting the
lack of a systemic response to therapy.
On-Treatment Response
Perhaps
even more important than baseline factors for predicting response to
standard of care therapy is the actual viral response while on
treatment. Treatment effect can be demonstrated within the first 24
hours and correlates significantly with response at week 12.[16] In further data presented at DDW 2008, rapid virologic response (RVR;
defined as on-therapy qualitative viral response at week 4 [HCV RNA
undetectable by qualitative PCR] ) was again demonstrated to be an
excellent positive predictor of SVR in all HCV genotypes.[17] Relapse rates were higher for those patients who did not achieve RVR,
but RVR was a poor negative predictor of SVR. Lack of EVR remains the
best negative predictor for SVR. Imperative to understanding response
is obtaining a viral load at the key timepoints (treatment week 4 and
12).
It is important for clinicians to understand the current
process of care for all major chronic diseases, including chronic
hepatitis C, and to measure whether variability exists in the process
of care Unfortunately, when searching the national United Healthcare
claims database for markers of quality assurance, it was found that
quality of care varied substantially.[18] Only 51.7% of
20,233 patients positive for HCV antibody underwent confirmatory HCV
PCR. Imperative to understanding treatment response is obtaining a
viral load at the key timepoints (treatment week 4 and 12)., and thus
it is even more disturbing that among HCV-infected patients receiving
antiviral treatment, only 12.7% of 1556 were tested for EVR or
underwent quantitative HCV RNA testing 11-13 weeks after starting
therapy.[18]
Occasionally, when monitoring therapeutic
response, a highly sensitive assay such as the HCV TMA
(transcription-mediated amplification), with a sensitivity down to 5
IU/ML, will be positive when the quantitative HCV PCR test is negative.
A persistently positive HCV TMA is highly predictive of relapse.
However, DiGiorno and colleagues[19] investigated the
significance of a transiently TMA-positive PCR-negative finding by
analyzing patients who were TMA-positive and PCR-negative with a prior
and subsequent TMA-negative, PCR-negative test result. They found that
this "TMA blip" was also associated with a higher risk for relapse,
especially in HCV genotype 1 patients.
Innate Immunity
Why
some HCV-infected patients respond to therapy and others do not remains
poorly understood, but immune response has been postulated as an
influence on viral clearance. One of the reasons that the mechanisms
underlying treatment failure remain poorly defined is because the
effect of interferon alfa in the liver has not been studied as a result
of the difficulty of obtaining liver biopsies from patients undergoing
therapy. In this context, investigators examined interferon
alfa-induced hepatic signaling in 12 paired human liver biopsies taken
from patients with chronic hepatitis C before (at baseline) and 4 hours
after first injection of pegylated interferon.[20] In
addition, blood for peripheral blood mononuclear cell (PBMC) isolation
was collected before and after injection of drug. It is interesting to
note that in patients with RVR, interferon-stimulated gene expression
(ISG) increased significantly after pegylated interferon
administration. Among patients without RVR, ISG expression was
maximally induced at baseline and did not increase after pegylated
interferon injection. PBMCs were not a good surrogate for interferon
alfa responses in the liver. To help further our understanding of the
pattern and causes of nonresponse to standard-of-care therapy in
patients infected with HCV genotype 1, an analysis was performed of
baseline gene expression in biopsy specimens from the VIRAHEP-C (Viral
Resistance to Antiviral Therapy of Chronic Hepatitis C) study.[21] Patients were classified by viral decline at day 28 from baseline.
Subjects with a more vigorous response (2-log or greater) had a much
lower baseline expression of genes associated with innate immune
response, regulation of RNA metabolism, antigen presentation, and
interferon signaling. Subjects with high baseline gene expression were
not only more likely to have a poor 4-week viral response, but also had
higher baseline HCV viral load. Although the VIRAHEP-C study was
designed to investigate differences in black patients with HCV genotype
1 infection, these findings were independent of race. Both of these
studies suggest that in nonresponders to therapy with the standard of
care, the innate immune response to HCV is activated but ineffective in
clearing the virus and may even impede treatment response.
New Agents
As
more patients are identified as "treatment failures" with the current
standard of care, or are found to have multiple poor baseline
characteristics for response, clinicians anxiously await the
development of new therapies. During this year's DDW, data were
presented on several of these emerging agents in the evolving arsenal
for hepatitis C.
VX-950 (Telaprevir)
Telaprevir*
is a potent inhibitor of the HCV NS3-4A serine protease. The final
results from the US and European phase 2 studies of telaprevir were
presented at DDW 2008. PROVE 1 involved HCV genotype 1 treatment-naive
US patients and included 4 treatment arms: (1) triple therapy
(pegylated interferon/ribavirin + telaprevir) for 12 weeks only; (2)
triple therapy for 12 weeks followed by 12 weeks of standard of care
(pegylated interferon/ribavirin); (3) triple therapy followed by 36
weeks of standard of care; or (4) 48 weeks of standard of care therapy
(control group). The RVR and EVR rates were striking in the
triple-therapy arms (59%-81% vs 11% for standard of care), but SVR was
suboptimal in the 12-week arm, at only 35%, with a 33% relapse rate.
There was no significant difference between the 24-week and 48-week
telaprevir arms (relapse 2%-6% and SVR 61%-67%), establishing treatment
duration as 12 weeks of triple therapy followed by 12 weeks of standard
of care. Severe rash and anemia were the only side effects more common
in the telaprevir arms.[22]
The design of PROVE 2 was
slightly different. PROVE 2 is a phase 2 study of telaprevir in
combination with pegylated interferon with or without ribavirin in
treatment-naive patients with chronic hepatitis C genotype 1; it was
conducted primarily at European centers. Patients were randomized to
triple therapy (pegylated interferon + ribavirin + telaprevir) for 12
weeks only, pegylated interferon + telaprevir (no ribavirin) for 12
weeks, triple therapy for 12 weeks followed by 12 weeks of pegylated
interferon + ribavirin, or pegylated interferon + ribavirin for 48
weeks. Similar to PROVE 1, RVR and EVR were substantially higher
(69%-80%) in the triple-therapy arms, but the relapse rate was
significant for those who only received 12 weeks of triple therapy
(28%). Without ribavirin, only 51% of patients achieved RVR and 29%
EVR, reinforcing the continued importance of ribavirin in the treatment
paradigm for hepatitis C. Rash, nausea, pruritus, and anemia were more
common in the telaprevir arms, with 7% of patients discontinuing
treatment due to rash.[23] Previous studies have
demonstrated that patients who fail to clear virus or experience
breakthrough have higher rates of telaprevir resistance.
Boceprevir
Boceprevir*
is an inhibitor of the HCV-NS3 protease. During this year's DDW
meeting, results were presented for prior HCV genotype 1 nonresponders
to the standard of care who were retreated with a lead-in of 1 week of
pegylated interferon + ribavirin followed by pegylated interferon and
varying doses of boceprevir, boceprevir + ribavirin, or pegylated
interferon + ribavirin alone.[24] In mid-study, an
independent drug safety monitoring board determined that ribavirin was
necessary to avoid resistance and that the optimal dose of boceprevir
was 800 mg thrice daily. At that point, all arms of the study
transitioned to pegylated interferon/ribavirin and 800 mg boceprevir
for an additional 24 weeks. Thus, patients received different doses for
variable duration prior to this transition. The SVR rate ranged between
2% and 14% in this difficult-to-treat population. Response was highest
in patients who achieved RVR and who received more than 36 weeks of
therapy after HCV RNA negativity. In those patients who received only
pegylated interferon/ribavirin before the addition of boceprevir, viral
response also varied with response to pegylated interferon + ribavirin
at 12 weeks, with 100% of those patients with a greater than 2-log
decline in viral load clearing virus after the addition of boceprevir.
Resistance mutations were detected in most patients who did not achieve
SVR. Side effects included anemia and nausea but not rash.
Albinterferon Alfa-2b
Albinterferon
alfa-2b* is a long-acting recombinant protein composed of interferon
alfa-2b genetically fused to human albumin. A study presented during
DDW 2008 assessed the potential of this recombinant protein for use in
combination with the STAT-C therapies.[25] Data including
viral dynamics and pharmacodynamics from a phase 2 dose-ranging study
conducted in interferon-naive genotype 1 patients with chronic
hepatitis C were used to determine whether 2 albinterferon
alfa-2binjectionsdosed 14 days apart could offer continuous antiviral
pressure, thus decreasing the risk of developing drug-resistant
mutations with the STAT-C therapies.[25] Both the 900- and
1200-mcg doses of albinterferon alfa-2b fit this profile, exhibiting
strong pharmacodynamic properties and maintaining high antiviral
effectiveness; they may be used in combination with STAT-C drugs to
prevent development of resistance. The 900-mcg albinterferon
alfa-2bdose administered every other week was also associated with
improved health-related quality of life and fewer missed workdays when
compared with pegylated interferon, while maintaining equal efficacy.[26]
Conclusion
At
the conclusion of DDW 2008, it is evident that the current standard of
care for chronic hepatitis C, combination pegylated interferon +
ribavirin, will continue to be the backbone of anti-HCV therapy,
despite the development of novel agents. Additionally, improved
understanding of innate immune response offers insight into the
mechanisms of nonresponse. Finally, measurement of viral response at
both 4 and 12 weeks is imperative and will remain so, even with the
addition of small-molecule therapies.
*The US Food and Drug Administration has not approved this medication for this use.
http://www.medscape.com/viewarticle/573933
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