Boston, Massachusetts; Tuesday, November 6, 2007 -- The management of viral hepatitis is constantly changing. Modifications in the approach to treatment are made as we gain insight into the natural history of the disease as well as when new therapies become available. Therapeutic options for viral hepatitis have been available for years, and have thus allowed clinicians to identify individuals likely to benefit from therapy. They have also altered the affected population, as patients have either failed to respond or developed resistance to current therapeutic modalities. This report highlights some of the key research in this area as presented during the 58th Annual meeting of the American Association for the Study of Liver Diseases (AASLD).
Evolving Issues in Treatment
Although clinicians have been managing hepatitis B virus (HBV) infection for nearly 40 years, there remains much confusion regarding who, when, with what, and how long to treat. Treatment decisions are especially important in hepatitis B, where drug exposure may increase the risk of developing antiviral resistance. Not only does the development of resistance influence the effect of the given drug, but it may decrease the efficacy of other agents as well.[1,2] No medication is perfect. Thus, when perfection is unobtainable, the quest metamorphoses into understanding how to best use the agent with its given shortcomings. The current FDA-approved therapies for hepatitis B include interferon alfa-2b, pegylated interferon alfa-2a, lamivudine, adefovir, entecavir, and telbivudine, with tenofovir currently under review and expected to be approved in the near future.
Who Should Be Treated?
Hepatitis B DNA levels were again a dominant focus of studies during this year's meeting. Previously published data from the REVEAL (Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-HBV Study) study demonstrated a strong association between hepatocellular carcinoma (HCC) risk and baseline HBV DNA levels. Additional analysis from that same cohort found that those patients who maintained high levels of HBV DNA, as opposed to those who spontaneously achieved undetectable HBV DNA, had a significantly higher risk of developing HCC. Although the risk may be lower with lower levels of virus, no level of viremia is safe. Even individuals with HBV DNA <104 copies/mL had a 2- to 3-fold increased risk for HCC vs those with undetectable virus. Not every person with high HBV DNA levels will progress, however. Thus, multiple studies also focused on alternatives to identify the highest-risk subsets of HBV-infected patients. In addition to high viral load, increasing age and elevated serum alanine aminotransferase (ALT) were also associated with more advanced histology.[6,7]
What Can Be Used?
Tenofovir. The newest anti-HBV drug of focus at AASLD 2007 is actually an "old" drug, already approved and in wide use for the treatment of HIV infection. Tenofovir is a nucleotide analogue with potent activity against HBV. In a heterogeneous population of HBV-monoinfected patients, tenofovir suppressed HBV DNA <400 copies/mL in 72% and 91% at weeks 24 and 48, respectively. There was no viral rebound to suggest resistance; 23% experienced hepatitis B e antigen (HBeAg) seroconversion after a mean of 9 months and 4% lost hepatitis B surface antigen (HBsAg) within the first 18 months of treatment. Additionally, 48-week results from the pivotal tenofovir trials in HBeAg-negative and HBeAg-positive patients confirm its superiority over adefovir.[9,10] The primary endpoint of both studies was a composite of HBV DNA < 400 copies/mL and histologic improvement at 48 weeks, and was achieved in 71% of HBeAg-negative patients (vs 29% with adefovir) and in 67% of HBeAg-positive patients (vs 12% with adefovir). HBV DNA suppression is rapidly growing to be the primary measure of response; 92% of HBeAg-negative chronic hepatitis B patients suppressed HBV DNA levels to < 400 copies/mL (vs 59% with adefovir), and 74% of HBeAg-positive patients suppressed HBV DNA levels to < 400 copies/mL (vs 12% with adefovir). No resistance mutations developed.
Entecavir. Entecavir continues to demonstrate effective virologic suppression after 4 years of treatment in a nucleoside-naive HBeAg-positive cohort. HBV DNA remained undetectable in 91% of patients, with HBeAg loss in 41% and HBeAg seroconversion in 16%. A minority (30/679) of nucleoside-naive patients were initial entecavir "nonresponders" (defined as failure to decrease viral load below 105 copies/mL) during the first 2 years of therapy. A subset of these patients (21/30) was treated in a rollover study; 71% ultimately became HBV DNA undetectable during follow-up and 33% experienced HBeAg seroconversion.
Telbivudine. Although telbivudine has been associated with higher rates of resistance compared with entecavir and adefovir, patients who effectively suppress virus after 24 weeks of treatment have a very low risk of developing drug resistance mutations. Further analysis of patients enrolled in the GLOBE study identified lower baseline viral load and elevated serum ALT as predictors of subsequent response. However, viral load at week 24 remained the most significant predictor of week 104 outcome. Effective suppression of HBV DNA was found to not only decrease the development of drug resistance, but also to decrease the risk for histologic progression.
Interferon-based Therapy. Conventional interferon alfa-2b and pegylated interferon alfa-2a are approved for the treatment of chronic hepatitis B. The pegylated formulation is typically given for 48 weeks. However, Rezzonico and colleagues found that there was no difference in sustained virologic response (SVR) rates between patients treated for 24 and 48 weeks in a carefully selected population. Patients with low viral load, increased serum ALT, and genotype A infection respond best to interferon-based therapy.[15,16]
How Long Do We Use It? Although therapeutic effectiveness is judged by HBV DNA suppression, HBeAg seroconversion and HBsAg loss are often used as treatment endpoints as well. In a cohort of patients who spontaneously cleared HBsAg, loss of HBsAg did not translate to HBV eradication. Intrahepatic DNA remained and some patients continued to have low levels of viremia. In addition, patients remained at risk for development of HCC. HBeAg seroconversion was also found to be less durable when achieved via therapeutic intervention. After 4 years, viremia reoccurred in 44% of a cohort subset who had been recurrence-free 1 year after discontinuation of lamivudine.
The incidence of hepatitis C virus (HCV) infection has declined dramatically over the past decade. Conversely, the overall disease burden is projected to peak around 2015, as many patients with chronic HCV infection will have been infected for more than 20 years, placing them at risk for complications.[20,21] Thus, the importance of effective treatment is paramount. The development of new, small-molecule therapies, the so-called Specifically Targeted Antiviral Therapies for HCV (STAT-C), may revolutionize hepatitis treatment. However, approval and integration of these medications is still years away.
"Profiling" Hepatitis C
The current standard of care for the treatment of chronic hepatitis C is combination therapy with pegylated interferon and ribavirin; this regimen results in long-term viral clearance in 42% to 82% of treatment-naive patients.[22,23] Baseline patient characteristics such as genotype and viral load help predict treatment response and allow implementation of strategies to improve viral outcomes.[24,25] However, the concept of what constitutes a treatment challenge continues to evolve.
One of the most exciting areas of development is gene "profiling," although cost and availability limit the current application of this technology to research. In pretreatment liver tissue, Chen and colleagues recognized an 18-gene expression signature with a positive predictive value of 92% for identifying treatment responders. When expression by real-time polymerase chain reaction of a smaller gene subset was assessed, the positive predictive value only decreased to 80%. Several of these "signature" genes reflect expression of interferon-stimulated genes. This technology not only helps to identify those patients likely to respond to therapy, but it also offers insight into disease pathogenesis.
Typically, HCV genotypes 2 and 3 have been grouped together as responding favorably to therapy. Growing evidence suggests that although both of these genotypes have a treatment advantage over genotype 1, these viruses are not equal. The Canadian POWeR (Peginterferon alfa-2b Prospective Optimal Weight-based Dosing Response) study included 276 HCV genotype 2 and 389 HCV genotype 3 patients. Patients infected with HCV genotype 3 had lower SVR rates than genotype 2 patients (72% vs 79%), especially those with high viral load (64% v 83%) and stage 4 fibrosis (47% v 76%). Rapid viral response (RVR; defined as undetectable viral load at week 4 of therapy) is a strong positive predictor of SVR in HCV genotype 1, but its role in genotype 2/3 patients is less secure. Traditional thinking is that because this population responds well to therapy, obtaining an RVR is not essential. The ACCELERATE (A Study of PEGASYS [Peginterferon alfa-2a 40KD] in Combination With COPEGUS [Ribavirin] in Interferon-Naive Patients With Chronic Hepatitis C Infection) trial involved 1463 HCV genotype 2/3 patients who received combination pegylated interferon plus ribavirin for either 16 or 24 weeks. In this large study, low rates of SVR were associated with lack of RVR. Among those who did not achieve RVR, longer duration therapy, genotype 2, lack of cirrhosis, and younger age were associated with a higher chance of achieving SVR. Week 2 viral response may be even more sensitive in predicting SVR in HCV genotype 3 patients with a high viral load. Viral clearance at this time point was highly predictive of SVR (positive predictive value of 100%), but did not predict nonresponse.
New Strategies, Old Agents
Alternative strategies for fine-tuning existing therapy have evolved as frustrated clinicians are increasingly faced with subsets of patients with anticipated suboptimal outcomes. A total of 942 nonresponders to pegylated interferon + ribavirin therapy were enrolled in the REPEAT (REtreatment with PEgasys in PATients Not Responding to Peg-Intron Therapy) study to determine whether intensified treatment with higher fixed-dose induction of pegylated interferon and/or longer treatment duration may increase SVR rates; 28% to 33% of patients achieved an end-of-treatment (EOT) response. However, 52% to 78% relapsed. Ultimately, 7% to 16% achieved SVR. Although combined fixed-dose induction and longer duration achieved the highest SVR rate, re-treatment with longer-duration therapy (72 weeks with pegylated interferon alfa-2a) resulted in higher SVR rates compared with 48 weeks of therapy.
The traditional measure of on-treatment success is an early virologic response (EVR), defined as a 2-log or greater decline in viral load at 12 weeks of therapy. Evidence suggests that residual viremia (partial EVR) at 12 weeks predicts relapse. Patients pooled from several trials found that 74% of EVR avirmeic (cEVR) patients obtained SVR in contrast to only 16% of HCV-infected patients who had residual virus. In a separate study of HCV genotype 1 patients receiving 48 weeks of combination pegylated interferon + ribavirin therapy, the occurrence of relapse was significant among those who did not achieve cEVR. Patients who had residual virus had an EOT response rate of only 32%, with relapse rates of 50% to 79% as compared with cEVR patients who had an EOT response rate of 90% with a relapse rate of 10% to 32%. Extending therapy to 72 weeks in suboptimal responders improved SVR rates primarily by decreasing the risk for relapse.
One of the most frustrating hepatitis C patient populations to treat are those with significant fibrosis who fail to achieve an SVR with combination therapy. Although maintenance therapy is an attractive option for this group, the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) trial found no difference in the risk for death, decompensation, HCC, or increasing fibrosis among patients who were treated vs not treated with long-term low-dose (90 mcg per week) pegylated interferon alfa-2a.
Another option offered to patients who fail to respond to combination pegylated interferon + ribavirin is treatment with consensus interferon. Unfortunately, this therapeutic strategy is also less than desirable. The DIRECT (Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy) trial involved 343 previous nonresponders to pegylated interferon + ribavirin therapy. Noncirrhotic patients with previous partial response achieved the highest rate of SVR (26% with 9 mcg consensus interferon/ribavirin and 33% with 15 mcg consensus interferon/ribavirin). Only 2% to 11% of null responders achieved an SVR.
There has been a response to clinical need as evidenced by the number of novel drugs in development for hepatitis C. Current strategies include: polymerase as well as protease inhibitors to "shut down" viral replication; immune augmentation via vaccine; and new and improved interferons or small interfering RNAs (siRNA). Despite its limitations, combination pegylated interferon plus ribavirin therapy does not cause drug resistance. However, a key concern in new drug development is the risk for viral mutations leading to reduced drug sensitivity. Experience gleaned from the treatment of HBV and HIV infection suggests that resistance mutations not only compromise the exposed drug, but may also affect viral response to other medications.
VX-950. VX-950 is a selective, specific, and potent peptidomimetic inhibitor of the HCV NS3-4A serine protease. Several studies presented during AASLD 2007 confirmed the potency of this investigational agent, with most patients clearing virus within 1 month of treatment.[36,37] Results revealed that 74.3% of patients receiving pegylated interferon/ribavirin plus VX-950 were HCV-RNA negative at 4 weeks compared with only 14.3% who received pegylated interferon/ribavirin alone after interim analysis of the PROVE2 phase 2 study. (PROVE 2 is a randomized, placebo-controlled phase 2 study of telaprevir [VX-950], in combination with pegylated interferon alfa-2a and ribavirin, in treatment-naive subjects with genotype 1 chronic hepatitis C infection.) Side effects were relatively common, with discontinuation of treatment in 11% to 17.1% of those on the triple-therapy regimen.[37,38] Viral resistance may also cause concern, especially given that resistance mutations could be detected after relapse or breakthrough in patients treated with VX-950 with and without pegylated interferon± ribavirin.[37,39] However, the clinical implications are not clear, as some subjects with VX-950 resistance do suppress virus with subsequent pegylated interferon/ribavirin treatment. The addition of VX-950 to the treatment armamentarium may also truncate therapy duration in some patients; 9 of 20 patients receiving the triple-therapy regimen (VX-950 + pegylated interferon/ribavirin) for 12 weeks achieved RVR, 6 of whom also achieved an SVR.
R1626. Results of interim analysis with another investigational agent, R1626, a nucleoside analog oral HCV RNA polymerase inhibitor, also appear promising. Treatment with this polymerase inhibitor, which has a high barrier to resistance, in combination with pegylated interferon/ribavirin resulted in undetectable HCV RNA at 4 weeks in 81% of patients.
Boceprevir/NM107. Although the addition of a protease inhibitor to the current standard of care (combination pegylated interferon plus ribavirin) has increased SVR rates in studies, this strategy has led to the development of drug resistance in some patients. In an in-vitro replicon system, boceprevir, another investigational potent oral protease inhibitor, combined with NM107 (the active form of valopicitabine), an investigational HCV polymerase inhibitor, demonstrated more antiviral inhibition than either drug alone. There was no cross-resistance; mutations conferring resistance to boceprevir were sensitive to NM107 and vice versa. Thus, combination therapy could potentially increase viral response as well as decrease the risk for drug resistance.
As this year's AASLD meeting drew to a close, it was evident that our understanding of viral hepatitis continues to rapidly evolve. It seems that combination pegylated interferon plus ribavirin will continue to be the backbone of HCV therapy, despite the development of a number of novel agents. Concerns centered on drug resistance will continue to grow with respect to the management of both HCV and HBV infection. Indeed, the advancements presented at this year's meeting ensure that the field of viral hepatitis will remain dynamic over the coming years.
Supported by an independent educational grant from Bristol-Myers Squibb
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