Anne S. Henkel, MD; Steven L. Flamm, MD
Authors and Disclosures
CME Released: 10/27/2010;
Valid for credit through 10/27/2011
Hepatitis C virus (HCV) infection is a common cause of chronic liver disease worldwide and is currently the leading indication for liver transplantation in the United States.[1] The current standard of care for the initial treatment of chronic HCV infection is combination therapy with pegylated interferon alfa-2a or -2b and ribavirin. Unfortunately, less than half of treatment-naive patients with HCV genotype 1 infection successfully eradicate the virus with this regimen.[2-4]
Patients infected with HCV genotype 2 or 3 have a much greater chance of attaining a sustained virologic response (SVR; defined as undetectable HCV RNA [less then 50 IU/mL] 24 weeks after completion of treatment),[5] but there remains a significant number of patients who do not respond to standard-of-care therapy.
This column addresses factors associated with nonresponse to the current standard-of-care therapy and discusses the efficacy of strategies for the management of these patients. Definitions of Virologic Response and Nonresponse to HCV Therapy The efficacy of treatment with combination pegylated interferon alfa-2a or -2b and ribavirin is most commonly assessed by monitoring the serum hepatitis C viral load (HCV RNA level).
The ultimate goal of therapy is to achieve an SVR. HCV genotype 1 patients who achieve an SVR have a 99% chance of maintaining HCV RNA negativity over the long-term.[6] Additional virologic goals include an early virologic response (EVR) and a rapid virologic response (RVR), which are highly predictive of the likelihood of achieving an SVR. Partial EVR (pEVR) is defined as a 2-log or greater decline in viral load from the pretreatment level at 12 weeks of therapy. If EVR is not achieved, it is highly unlikely that an SVR will be achieved.[7] Complete EVR (cEVR) is defined as undetectable HCV RNA at week 12 of therapy. This is highly associated with achieving an SVR. RVR is defined as undetectable HCV RNA at week 4 of treatment.[5]
Patients with HCV genotype 1 demonstrating an RVR are predicted to have a 90% chance of ultimately achieving an SVR.[8] There are data to indicate that patients with HCV genotype 2 or 3 disease who achieve an RVR may require only 14 weeks of therapy instead of 24 weeks, but this remains controversial.[9] Additionally, there are data to support reducing the length of treatment from 48 weeks to 24 weeks in patients with HCV genotype 1 infection who achieve an RVR.[10] Patients who do not achieve an EVR are considered nonresponders, and therapy should be discontinued.[7,11]
If an EVR is achieved, treatment should be continued and serum HCV RNA should be reassessed at week 24 of therapy. If the serum HCV RNA remains detectable (ie, more then 600 IU/mL) at week 24 of therapy, the likelihood of achieving an SVR is exceedingly low.[7] Such patients are also considered nonresponders, and therefore therapy should be discontinued.[5]
For patients with HCV genotype 1 infection who are HCV RNA undetectable at week 24 of therapy, treatment should be maintained for 48 weeks if the patient is tolerating the treatment well.[7,11] Nonresponders can be subcategorized into partial responders and null responders. Null responders are patients who fail to achieve at least a 2-log decline in HCV RNA after 24 weeks of therapy. Partial responders demonstrate a more then 2-log decline in HCV RNA at treatment week 12 (EVR) but fail to achieve an undetectable level at week 24. The term "slow responder" has been applied to patients who have detectable HCV RNA at week 12 but successfully eradicate the virus by week 24. There are data to indicate that this subgroup of patients may benefit from 72 weeks of therapy rather than 48, although this is controversial.[5,12]
Viral breakthrough and relapse are also types of nonresponse. Viral breakthrough is uncommon and is characterized by detectable HCV RNA in a patient maintained on therapy who previously had undetectable HCV RNA. Relapse is defined as a detectable HCV RNA level in a patient who had undetectable HCV RNA at the completion of a full course of therapy. Unlike breakthrough, relapse is common with standard therapy.[5]
Factors Associated With Nonresponse to Hepatitis C Therapy
Numerous factors influence the likelihood of achieving an SVR with the standard-of-care therapy, combination pegylated interferon and ribavirin. Some factors are innate to the host or the virus and therefore are not modifiable. Other predictors of nonresponse are potentially modifiable, such as patient adherence and appropriate medication dosing by the physician.
Viral Factors
The strongest predictor of response to treatment is HCV genotype. HCV genotype 1 is present in approximately 75% of HCV-infected individuals in the United States, making it the most prevalent genotype in this country.[13] Unfortunately, HCV genotype 1 is also less responsive to standard-of-care treatment than is genotype 2 or 3. Large trials demonstrating the efficacy of combination pegylated interferon and ribavirin therapy found that patients with HCV genotype 1 infection have about a 40% chance of achieving an SVR.[2,3] This is in contrast to a greater than 80% rate of achieving SVR in patients with genotypes 2 and 3.[2,3]
Baseline viral load has been identified as an independent predictor of response to pegylated interferon and ribavirin therapy.[2,3,14] Patients with high pretreatment viral loads, defined as more then 600,000 IU/mL, have lower SVR rates than those with lower pretreatment viral loads (42% vs 78%, respectively).[2,5]
Host Factors
Race has also been shown to have a significant impact on the response to HCV therapy. Less than one third of black patients with HCV genotype 1 will achieve an SVR with pegylated interferon and ribavirin-based therapy, compared with over 50% of white patients.[15] Black patients with HCV genotype 1, in particular, benefit from weight-based dosing of ribavirin; however, even with optimal ribavirin dosing, the disparity in SVR rates is not eliminated.[16] Latino patients are also less responsive to conventional HCV therapy compared with whites.[17]
Metabolic factors such as insulin resistance, obesity, and the presence of hepatic steatosis may also affect response to HCV therapy. A study conducted in HCV genotype 1 patients found that only 32.8% of persons with insulin resistance achieved an SVR, compared with 60.5% of those without insulin resistance.[18] A subsequent study examined whether enhancing insulin sensitivity with metformin* in conjunction with pegylated interferon and ribavirin would translate to improved rates of SVR in HCV genotype 1 patients.[19] The triple-therapy regimen (compared with standard-of-care therapy) resulted in statistically significant improvement in SVR rates in women only (58% vs 29%, respectively).
Obesity may be associated with therapeutic nonresponse in HCV-infected patients as well, but data are conflicting. The suboptimal response of some obese patients to conventional therapy may be related in part to inadequate dosing of ribavirin.[20-22] Hepatic steatosis is often present in patients with HCV infection and is associated with a more aggressive disease course. Furthermore, there are data to indicate that the presence of hepatic steatosis reduces the virologic response to standard-of-care therapy with pegylated interferon and ribavirin.[23]
Therapy should be strongly considered in patients with advanced fibrosis or cirrhosis secondary to HCV infection given the high likelihood for disease progression and hepatic decompensation. Advanced fibrosis is associated with a lower virologic response rate compared with less advanced disease.[2,3,14,24] Data from the HALT-C (Hepatitis C Antiviral Long-term Treatment Against Cirrhosis) study showed that SVR rates in response to pegylated interferon and ribavirin ranged from 23% in HCV genotype 1 patients with bridging fibrosis and platelet counts > 125,000cells/mm3 to only 9% in patients with cirrhosis and platelet counts less then 125,000 cells/mm3.[24]
Active alcohol use is associated with a more aggressive disease course in patients with chronic HCV infection and also diminishes the likelihood of responding to antiviral therapy.[25] Although the mechanism mediating this effect is not well established, it has been suggested that alcohol may potentiate HCV replication.[25] Patients should be counseled to discontinue alcohol use prior to beginning antiviral therapy for HCV infection.
Coinfection with HCV is common among patients with HIV as a result of similar risk factors for transmission. HIV coinfection has been associated with more rapid progression of liver disease in patients with chronic hepatitis C and is associated with poor response to HCV therapy. A meta-analysis of 6 randomized controlled trials found that patients with HCV/HIV coinfection had only a 37% chance of achieving an SVR with standard-of-care therapy.[26]
There has been recent interest in identifying molecular markers that can help identify patients who are unlikely to respond to treatment. Three genome-wide association studies identified single nucleotide polymorphisms in the gene that encodes interleukin 28B (IL28B) on chromosome 19 as strongly predictive of response to HCV therapy in HCV genotype 1 patients.[27-29]
A recent study found that among white HCV genotype 1 patients, the rate of SVR was 69% in those with IL28B genotype CC compared with 33% and 27% in patients with genotypes CT and TT, respectively.[30] It was concluded that the IL28B genotype is the strongest predictor of SVR among HCV genotype 1 patients. The variation in IL28B genotype among racial/ethnic groups may partially explain the discrepancy in response rates to standard HCV therapy. IL28B genotyping is not yet standard practice. Its role is unclear, but this test has recently become commercially available in the United States and may become a routine component of the evaluation of potential treatment candidates in the near future.
Medication Dosing and Adherence
Suboptimal dosing of ribavirin is a significant factor that contributes to therapeutic nonresponse. Initially, the approved combination regimen for the treatment of HCV infection included a flat dose of ribavirin at 800 mg/day. However, numerous subsequent trials have demonstrated better SVR rates with higher doses as well as with weight-based dosing of ribavirin.[14,16] Weight-based ribavirin dosing is now approved for use with both pegylated interferon alfa-2a and -2b.
Dose reductions of pegylated interferon and/or ribavirin are common during the course of treatment, occurring in an estimated 27% and 43% of HCV genotype 1 patients, respectively.[31] Dose reductions may occur because of patient nonadherence or due to physician management of adverse events associated with the standard-of-care therapy, such as influenza-type symptoms, emotional disturbances, or hematologic toxicity.[5] Reductions in the cumulative doses of pegylated interferon and ribavirin have been shown to adversely affect the likelihood of achieving an SVR. It has been shown that patients who receive less than 60% of the cumulative dose of ribavirin over 48 weeks of treatment have reduced SVR rates.[31] In the HALT-C trial, reductions in the dose of pegylated interferon also resulted in reduced rates of SVR.However, contrary to findings from previous studies, reductions in the total dose of ribavirin did not result in decreased SVR rates if the full dose of pegylated interferon was maintained throughout.[32]
Management of Nonresponders**
There is no standardized approach to the management of patients who have failed to respond to interferon-based therapy. However, a number of options exist. Factors to consider include the specific type of previous therapy received (ie, standard vs pegylated interferon, with or without ribavirin) and tolerability to the initial therapeutic regimen. The type of prior nonresponse is another factor to consider. For example, previous relapsers will have a higher chance of achieving an SVR than will pure nonresponders.[5,33] Other factors to consider include the presence of advanced liver disease or an unfavorable HCV genotype, either of which may warrant a more aggressive approach to re-treatment.[5]
It has been clearly established that combination therapy with pegylated interferon and ribavirin is superior to standard interferon (nonpegylated) alone or standard interferon plus ribavirin for the management of treatment-naive patients with chronic HCV infection.[2,3,20] In the HALT-C trial, 604 patients with hepatitis C and advanced fibrosis who had failed to respond to prior treatment with interferon alone or in combination with ribavirin were re-treated with pegylated interferon and ribavirin. The response rate was 28% in patients who had previously been treated with interferon alone and 12% in patients previously treated with interferon plus ribavirin.[21] Other studies have shown similarly disappointing SVR rates in nonresponders. Most experts agree that until more effective treatment options become available, it is reasonable to consider a trial of pegylated interferon plus ribavirin in nonresponders to previous treatment with standard interferon who have HCV genotype 2 or 3 infection or moderate-to-advanced liver disease and who tolerated the initial course of antiviral therapy reasonably well. For patients with HCV genotype 1 infection and minimal liver fibrosis, or poor tolerance to the initial therapeutic regimen, observation or enrollment in a clinical research trial (if eligible) with an investigational agent is preferable.[5]
There is a rapidly growing population of patients who have failed to respond to treatment with pegylated interferon and ribavirin. As noted, there is no standardized approach to the management of these challenging patients. Re-treatment with the same regimen is generally regarded as an ineffective strategy. The EPIC (Evaluation of Pegintron in Control of Hepatitis C Cirrhosis )-3 trial found that among patients who had previously failed to respond to treatment with pegylated interferon and ribavirin-based therapy, re-treating with pegylated interferon alfa-2b and weight-based ribavirin resulted in an SVR rate of only 17%.[34] If, however, there was significant dose reduction or early termination of the initial treatment course, it is reasonable to consider re-treatment with pegylated interferon and ribavirin in select patients. Regarding the possible use of longer-duration or higher-dose pegylated interferon and ribavirin in this patient population, the results of clinical trials have not demonstrated sufficient benefit to support such strategies.[12,35,36]
In addition, there is no evidence to suggest that switching pegylated interferon products is helpful. There has been considerable interest in whether long-term viral suppression with maintenance therapy may be of benefit in nonresponders by slowing the progression of liver disease in the absence of SVR. The most notable study to examine this issue was the HALT-C trial, which concluded that prolonged treatment (average, 3.5 years) with low-dose pegylated interferon alfa-2a (90 µg per week) did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis who had failed to respond to previous treatment with pegylated interferon and ribavirin.[37] The EPIC-3 and CoPilot (Colchicine Versus PEG-Intron Long Term) trials demonstrated similarly disappointing results with maintenance therapy.[34,38] There is also little evidence that high-dose, daily interferon alfacon-1 (consensus interferon) given in combination with ribavirin is helpful in most patients who have failed to respond to previous pegylated interferon and ribavirin-based therapy (the DIRECT [Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy] study).[39]
Patients who have failed to respond to treatment with pegylated interferon and ribavirin may benefit from enrolling in a clinical trial with one of the emerging therapies if they are eligible and if a trial is available. If a trial is not an option, watchful waiting may be the best option while optimizing other conditions that can affect disease progression. In patients with cirrhosis and signs of decompensation, early referral for a liver transplant evaluation is appropriate.
Emerging Therapies for HCV
Given the limitations of the currently available therapy for HCV infection, there has been a strong effort to develop novel therapies to enhance efficacy. Although a number of strategies are currently in development, the most promising class of medications closest to approval are the direct-acting antiviral agents (DAAs). Whereas the currently available treatment for chronic HCV infection works by enhancing the immune system response to the virus, these newer therapies are designed to directly target HCV by inhibiting viral-specific enzymes. These compounds target HCV-specific enzymes such as the NS3/4A serine protease and the NS5B RNA-dependent RNA-polymerase. The DAAs furthest along in development are the protease inhibitors telaprevir (VX-950)* and boceprevir (SCH 503034).* Trials using these DAAs in nonresponders have focused on HCV genotype 1 patients only. Data in nonresponders with genotypes 2 and 3 are eagerly awaited. Numerous data are available on the effectiveness of these DAAs in treatment-naive HCV-infected patients, but this topic is beyond the scope of this column.
Telaprevir is a selective inhibitor of the NS3/4A serine protease. The results of the PROVE (Protease Inhibition for Viral Evaluation) 3 trial (phase 2), which were published recently, investigated the efficacy of telaprevir in patients with HCV genotype 1 infection who had failed to respond to previous treatment with pegylated interferon and ribavirin.[40] Subjects were randomly assigned to 1 of 3 telaprevir-based regimens or to the control group (standard of care). The rate of SVR was an impressive 51% among patients who received triple therapy (pegylated interferon alfa-2a, ribavirin, and telaprevir) for 12 weeks followed by pegylated interferon alfa-2a and ribavirin for an additional 12 weeks. By comparison, the control group, which received pegylated interferon alfa-2a plus ribavirin only for 48 weeks, had an SVR rate of only 14%. SVR was highest among patients whose previous treatment failure was due to relapse rather than nonresponse (69% vs 39%, respectively). Berg and colleagues[41] recently presented data from the Study 107 trial, in which open-label access to telaprevir-based therapy was provided to HCV genotype 1 patients enrolled in the control arms of the PROVE 1, 2, and 3 trials and who did not achieve an SVR after 48 weeks of pegylated interferon and ribavirin. Seventy percent of these patients had previously received at least 2 courses of pegylated interferon and ribavirin. All patients were treated with triple therapy (telaprevir, pegylated interferon alfa-2a, and ribavirin) for the initial 12 weeks of the study. Subsequently, patients were treated with pegylated interferon alfa-2a and ribavirin for either 12 weeks or 36 weeks depending on the type of nonresponse to initial therapy. Overall, the rate of SVR among all cohorts was 59%. When analyzed by type of nonresponse, the SVR rates were 97%, 75%, 55%, and 37% in patients with prior relapse, viral breakthrough, partial response, and null response, respectively.[7] A preliminary unpublished report from REALIZE (REtreAtment of nonresponders to peginterferon/ribavirin with teLaprevir based regimen to optimIZEoutcomes), a phase 3 trial of telaprevir in previous nonresponders to pegylated interferon and ribavirin, was released recently.[42] Treatment with telaprevir in combination with the current standard of care, pegylated interferon and ribavirin, resulted in a 65% overall SVR rate in patients with HCV genotype 1 who did not achieve viral cure after at least 1 prior course of pegylated interferon and ribavirin-based therapy. When analyzed according to the type of previous nonresponse, the rates of SVR were 86%, 57%, and 31% among previous relapsers, partial responders, and null responders, respectively.
Boceprevir is another potent inhibitor of the HCV NS3 serine protease that has demonstrated promising results. A preliminary, unpublished report from RESPOND (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol)-2, a phase 3 trial examining the efficacy of boceprevir in previous HCV genotype 1 nonresponders to pegylated interferon and ribavirin-based therapy, was recently made available.[43] Patients who received boceprevir plus the standard of care, pegylated interferon alfa-2b and ribavirin, for 48 weeks had an SVR rate of 66% compared with only 21% in controls treated with pegylated interferon and ribavirin alone.
Although the use of triple therapy is expected to significantly advance the management of chronic HCV infection, complicating factors such as an increase in side effects and the emergence of viral resistance are anticipated.
Other Strategies on the Horizon
A number of other agents are in development, including new interferons, ribavirin-like molecules, protease and polymerase inhibitors, and cyclophilin inhibitors,[44-47] among others; each holds promise for the therapy of treatment-experienced patients. In addition, data are available on the use of RG7128,* an oral cytidine nucleoside analog that inhibits the HCV RNA-dependent RNA polymerase, in treatment-experienced patients with HCV genotype 2 and 3. In a recent study by Gane and colleagues,[48] 20 previous nonresponders with HCV genotype 2 or 3 were randomly assigned to receive RG7128 plus pegylated interferon alfa-2a and ribavirin for 28 days followed by pegylated interferon alfa-2a and ribavirin alone for 20-44 weeks. In the cohort that received triple therapy followed by 44 weeks of the standard of care, the SVR rate was 90%.
Conclusion
Understanding the factors associated with nonresponse to HCV therapy is critical in the management of patients seeking treatment. The current standard of care for the management of chronic hepatitis C is not effective in nearly half of treatment-naive patients with genotype 1 infection. The side effects, associated cost, and inconvenience of therapy may outweigh the potential benefits in those patients who possess numerous predictors of nonresponse. Among potential treatment candidates, optimizing the modifiable predictors of nonresponse can help increase the chance of achieving an SVR. The management of patients with chronic hepatitis C who do not respond to standard-of-care therapy remains a challenge. The most promising therapies in clinical development appear to be the DAAs. Novel agents will likely assume a key role in the future management of the increasing number of patients who do not respond to the current standard of care.
*The US Food and Drug Administration has not approved this medication for this use.
**This section includes discussion of non-US Food and Drug Administration (FDA)-approved therapies and/or administration options that deviate from FDA recommendations.
Supported by independent educational grants from Vertex Pharmaceuticals, Genentech, and Merck.
Also See : Changing the Game in Hepatitis C: Where Are We and Where Are We Going? MedscapeCME Gastroenterology, October 27, 2010
http://cme.medscape.com/viewarticle/730978
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