COMMENTARY

Hepatitis C: New Clinical Insights

Nancy S. Reau, MD

Disclosures

May 22, 2008

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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