Hepatitis C: New Clinical Insights

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From Medscape Gastroenterology

More: Digestive Disease Week (DDW) 2008

Hepatitis C: New Clinical Insights

Posted 05/22/2008

S. Reau, MDAuthor Information

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.

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