From Medscape Education Gastroenterology
Andrew J. Muir, MD
CME Released: 07/31/2013; Valid for credit through 07/31/2014
In May 2011, the US Food and Drug Administration (FDA) approved the use of direct-acting antiviral agents telaprevir and boceprevir for treatment of chronic hepatitis C (HCV) genotype 1 infection in combination with pegylated interferon (PEG-IFN) and ribavirin (RBV). This represented a new paradigm in the management of HCV. On May 29, 2013, Medscape spoke to Andrew J Muir, MD, Associate Professor of Medicine and Director of GI/Hepatology Research at Duke Clinical Research Institute in Durham, North Carolina, to discuss the current HCV treatment approaches and provide a case-based illustration of the decision whether a patient is a candidate for treatment with the current standard of care.
Medscape: To start, please briefly describe the current standard of care for HCV genotype 1 infection in the United States. According to the guidelines, what patients are considered appropriate candidates for treatment with the current standard of care?
Andrew J. Muir, MD: The current standard of care for treatment of chronic HCV genotype 1 infection in the United States is the combination of PEG-IFN-alfa, RBV, and one of the HCV NS3/4A protease inhibitors boceprevir or telaprevir.[1] In clinical studies, the addition of boceprevir or telaprevir to the previous standard of care for these patients (ie, PEG-IFN plus RBV) was associated with a significantly increased rate of sustained virologic response (SVR) in both treatment-naïve and previously treated patients.[2-5]
Medscape: How are patients evaluated with regard to their eligibility for HCV therapy?
Dr Muir: The key to treatment eligibility right now is a patient’s ability to tolerate PEG-IFN. Many of the adverse effects and risks associated with the currently available treatment are driven by PEG-IFN. For example, patients need to have no significant mental illness, including active depression, because it can be exacerbated by PEG-IFN.[6,7] Presence of other comorbidities -- such as advanced heart failure or lung disease -- should also be considered. Liver disease stage is important. In order to be eligible for treatment, patients should not have decompensated cirrhosis, and no complications of cirrhosis such as ascites, variceal bleeding, or hepatic encephalopathy. Finally, as there is a significant risk of anemia, thrombocytopenia, and neutropenia, it is important for patients to have appropriate blood counts prior to the start of treatment.
The guidelines recommend that treatment should be considered in all patients who qualify; we take that approach on a case-by-case basis to determine whether treatment is appropriate for an individual patient at this time. A number of the new HCV agents are expected to become available in the next few years, and we expect that there will be an IFN-free regimen available for HCV genotype 2 and 3 by late 2013, and hopefully for genotype 1 by 2015 or so. The question, then, is this: Should you treat the patient now, or wait until these new therapies are available?
I think that patients should weigh this decision and discuss it carefully with their provider. As we just discussed, the IFN adverse effects are real and significant, and it’s very reasonable for many of these patients to delay treatment for now. However, I do not think that providers should make that decision for their patients. We should tell them about the chances of cure and the risks associated with the current therapies. Patients with advanced fibrosis have the most concern about progression of their liver disease, and therefore might be more motivated to get treatment right away. These are also patients with a lower chance of cure and potentially at increased risk for adverse events, such as prior nonresponders and those with advanced liver disease. We need to work through that with them. Finally, some patients may be highly motivated to begin treatment right away because they want to be cured or for other reasons (eg, fear of losing health insurance coverage while they await newer therapies). Understanding the patients’ concerns and motivations helps guide our clinical decisions. On the other hand, we need to ensure that the patients understand what is involved in HCV treatment right now: length of time on treatment, regimen complexity, likelihood of treatment success, and so on.
Medscape: Please describe a case scenario in which the patient is a candidate for therapy with the current standard of care.
Dr Muir: I saw a patient recently for whom it was quite reasonable to consider moving forward with treatment (Table). This was a 30-year-old woman recently diagnosed with HCV genotype 1a infection, which is the most difficult-to-treat genotype, yet the most common in the United States. She was treatment-naïve, and had mild liver disease. Her laboratory test results were all within normal range, and her aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were mildly elevated. Her HCV RNA was 1,100,000 IU/mL, which is a somewhat high viral load. Finally, her IL28B genotype, which is associated with treatment response, was CC. This is the most favorable IL28B haplotype in terms of likelihood of treatment response.
Table. A Patient With Recently Diagnosed Hepatitis C Infection Considering Therapy
30-year-old woman
HCV diagnosis in 2013
- Genotype 1a
- HCV RNA 1,100,000 IU/mL
- Liver enzymes slightly elevated
- Platelets, albumin, bilirubin, prothrombin within normal range
- IL28B CC haplotype
Medscape: What makes this patient an appropriate candidate for treatment now?
Dr Muir: She was very motivated to initiate treatment right away because she wanted to put HCV infection behind her. Clinically, she has a number of favorable prognostic factors that would suggest she has a great chance to be cured: young age, female gender, and a favorable IL28B haplotype (IL28B CC).[8] Although she would also do well on therapies that are currently in development, she and similar patients also have good response rates to the first-generation protease inhibitors boceprevir and telaprevir. She may also be a candidate for a shortened treatment course, what is called a response-guided therapy approach (Figures 1 and 2).[9]
Figure 1. Response-guided therapy algorithm for boceprevir. Adapted from Shiffman ML, et al. Liver Int. 2012;32:54-60. [9]
Figure 2. Response-guided therapy algorithm for telaprevir. Adapted from Shiffman ML, et al. Liver Int. 2012;32:54-60.[9]
Medscape: What are some of the issues that you would want to discuss with this patient?
Dr Muir: First, I would want her to know the data, particularly as it relates to patients with her disease characteristics. We just talked about response-guided therapy. Could she be a candidate for an even shorter treatment course? In the PROVE-2 study of telaprevir given in combination with PEG-IFN and RBV, the overall SVR rates were only 60% in patients who received a total of 12 weeks of triple therapy.[10] This was a disappointing result and this treatment approach was discontinued moving forward. However, a retrospective subanalysis of 12 patients with IL28B CC genotype revealed that 100% of those patients achieved SVR with just 12 weeks of triple therapy.[11]
Subsequently, a randomized study called CONCISE was initiated to examine two durations of therapy with telaprevir, PEG-IFN, and RBV. In CONCISE, patients who had undetectable HCV RNA at week 4 of triple therapy were randomly assigned at 12 weeks to either stop all treatment (T12PR12 arm) or continue for 12 more weeks with PEG-IFN plus RBV only (T12PR24 arm).[12] At the European Association for the Study of the Liver (EASL) conference in 2013, interim results of CONCISE showed an SVR12 rate of 87% for patients in the T12PR12 arm compared with 97% in the T12PR24 arm,[12] which is encouraging. It should be noted that boceprevir is also administered in a response-guided approach. For treatment-naive patients whose HCV RNA is undetectable at weeks 8 and 24 of treatment, all treatment can be stopped at 28 weeks, whereas if HCV RNA is detectable at week 8 but undetectable at week 24 of treatment, the total duration of triple therapy with boceprevir, PEG-IFN, and RBV is 32 weeks, followed by 12 weeks of PEG-IFN plus RBV only for a 48-week total treatment course (Figure 1).[9]
Although 12 weeks of total therapy is not presently an FDA-approved approach, it does give some indication of these agents’ potency. Also, if a patient is having significant adverse effects after 12 weeks of therapy and is trying to decide whether it is worthwhile to continue, I think I am going to be much more comfortable if this patient stops treatment at week 12 provided he or she had undetectable HCV RNA at week 4. This is something we should discuss with our patients.
Medscape: The currently available therapies are fairly complex. What should providers keep in mind with regard to patients’ treatment readiness and willingness to adhere to a complex regimen?
Dr Muir: Yes, this is a challenging treatment course. We need to provide patients with much education upfront, and to support them as much as possible while on treatment. Administration schedules are different for the 3 regimen components. The IFN injection is given once a week; patients inject themselves at home on a day of the week that they choose. Ribavirin is dosed twice daily and boceprevir and telaprevir are dosed 3 times daily. Boceprevir should be taken with food, and telaprevir should be taken with food that includes 20 g of fat with each dose. Patients have to be very organized, not only to remember which medicine is taken at which time, but also to make sure that they’ve worked out their meals for the day. It takes planning.
A variety of strategies can be used to address treatment adherence. Patients can use pill boxes or set alarms or mobile phone reminders to help them remember, but all of these take some planning. This is why the patient needs to be motivated to receive therapy and to understand what impact treatment is going to have on his or her life. I think that it’s our job as providers to let them know what is involved and how to ensure the highest likelihood of success.
Patients also need to adhere to their scheduled appointments. Their lab values require close monitoring, especially in the first few weeks after treatment initiation, to ensure that they are tolerating the regimen. We sometimes have to make adjustments in the dose of RBV based on their blood counts.[13,14] Additionally, the patient’s HCV viral load has to be obtained at specific times in order to evaluate his or her candidacy for response-guided therapy, so appointments need to be scheduled and attended in the appropriate time frame.
Medscape: Do you evaluate the patient to assess whether he or she is at risk for treatment nonadherence before you recommend treatment?
Dr Muir: We try to address this issue with our patients in a couple of different ways. For instance, we look at the notes from the referring providers to see whether there have been any concerns raised about medication and/or visit adherence in the past. Have they had other medical conditions -- such as diabetes -- for which they didn’t take their medications regularly? We also need to see how the patients interact with us. At our clinic, we would never start treatment the first time we see a patient. We want to see that they keep their appointments and that they follow our advice as far as educating themselves about what they will need to do. We really like to see them have somebody else with them at teaching visits, for example, because there is much information to absorb. Do they comply with those recommendations so that we are doing all that we can to educate them and their support team as they get ready for this therapy? These are just some of the ways to address patient readiness to adhere to the treatment plan.
Medscape: Let’s return to the patient case you described earlier. What is her status at this point in time?
Dr Muir: The patient is currently on treatment and we are waiting to see how her HCV infection will respond.
Medscape: To conclude, what are some key messages that providers should take away with regard to selecting the appropriate patient to start HCV therapy at this time?
Dr Muir: Realistically, most patients are going to want to delay starting HCV therapy until the newer agents come along. However, I think it would be inappropriate to suggest that no one will be treated until IFN-free regimens are available. There will be some patients who will want to move forward with the current treatment options. Some of them will have advanced disease and are concerned about disease progression. Some may consider it the most appropriate time for them to move forward with treatment; they may have favorable prognostic characteristics to suggest a high probability of treatment success. Therefore, the decision to treat now or wait should be made by each patient with the help of his or her provider on an individual basis that takes all of these factors into account.
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