Boceprevir in chronic hepatitis C infection: a perspective review

Abstract

Boceprevir (Victrelis), from the oral α-ketoamide class of slow-binding reversible hepatitis C virus (HCV)-NS3 protease inhibitors, creates a new class of drugs: direct acting antivirals (DDAs). Boceprevir is highly selective against HCV serine protease. Its use is restricted to genotype 1 HCV infection and it must not be used as monotherapy. Boceprevir is given orally, rapidly absorbed, reaching plasma peak concentration within 1–2 h and is metabolized by aldo-ketoreductase and partly by the cytochrome P450 enzyme CYP3A4/5. Administration with drugs that induce or inhibit CYP3A4/5 could decrease or increase its plasma concentration. The optimal dosage is 800 mg three times daily; capsules should be taken with food. Boceprevir was approved by the US Food and Drug Administration and the European Medicines Agency and is indicated in combination with peginterferon plus ribavirin for the treatment of patients with genotype 1 HCV who have not received previous treatment or whose condition has failed to respond to previous therapy. In the Serine Protease Inhibitor Therapy 2 (SPRINT-2) trial (treatment-naïve patients) and RESPOND-2 trial (patients whose condition relapsed or did not respond to previous treatment), the boceprevir-containing regimen was always more effective than standard of care (SOC). Adverse events were similar in the treatment groups, but in the boceprevir treated group, anemia was more frequent, requiring erythropoietin in nearly 40% of cases. Discontinuation of therapy because of adverse events was identical in all treated groups. As for cost effectiveness, two studies showed that boceprevir plus SOC is cost effective with regard to the lifetime incidence of liver complications, quality of life years, and the incremental cost-effectiveness ratio. The management of this therapy is more complex than before for physicians and patients. The educational role of the physician is crucial for successful therapy and counseling should be carefully given, especially for adherence to the assigned treatment.

Introduction

Any new therapy for the treatment of hepatitis C virus (HCV) infection is certainly welcome [Jensen and Ascione, 2008]. There are at least two reasons for saying this: over 180 million people worldwide are affected by HCV chronic liver disease with an ominous outcome in nearly 20% after a very long, asymptomatic period lasting as long as 20–30 years [Craxi et al. 2008]; and the results of therapy in genotype 1 HCV infection in particular are not exciting. According to recently published data, the eradication of viral replication [i.e. HCV-RNA negative 24 weeks after the end of therapy, defined as a sustained virological response (SVR)] in genotype 1 naïve patients ranges from 40.9% to 55% [McHutchison et al. 2009; Rumi et al. 2010; Ascione et al. 2010], which is not very satisfactory. Moreover, if we analyze the group of patients with advanced fibrosis or cirrhosis, the SVR is even worse (30–42%). However, after more than 10 years in which peginterferon (pegINF) α-2a/2b plus ribavirin were the standard of care (SOC), two new antiviral molecules have recently been approved in the USA and Europe: boceprevir and telaprevir. With the approval of these two drugs, a new era of better results in HCV treatment will begin [Jensen, 2011]. Although treatment with these drugs is currently restricted to genotype 1 infection, the SVR in naïve patients and in those whose condition relapsed or did not respond to previous treatment is much higher compared with SOC. There are many other drugs under investigation that showed in vitro and in vivo antiviral activity, creating a new class: direct acting antivirals (DAAs). However, many of these drugs are in phase I or II studies, and a few are in phase III studies, and so there is still a long way to go before they can potentially receive approval from the regulatory authorities.

This review is restricted to boceprevir (Victrelis), from the oral α-ketoamide class of slow-binding reversible HCV-NS3 protease inhibitors, which showed no cross reactivity with other serine proteases and no major interactions with other general enzymes. This compound is highly selective against the HCV serine protease. From the beginning, this drug has shown good performance in stopping viral replication and in inhibiting the HCV life cycle in vitro and in vivo. The drug is given orally and is rapidly absorbed, reaching the plasma peak concentration within 1–2 h, with an elimination half life of between 7 and 15 h [Boceprevir, 2010; Foote et al. 2011]. Boceprevir is metabolized by aldo-ketoreductase and partly by the cytochrome P450 enzyme, CYP3A4/5. Therefore, administration of boceprevir with drugs that induce or inhibit CYP3A4/5 could decrease or increase the plasma concentration of boceprevir and significantly interfere with the metabolism of many drugs currently used in clinical practice. We will return to this point later. The optimal dosage has been fixed at 800 mg three times daily; the optimal interval between doses is 7–9 h and the capsules should be taken with food. A big meal is not necessary, a snack is sufficient. In clinical practice, since the capsules are 200 mg each, four capsules should be administered every 8 h. Therefore, the patient should take 12 capsules of boceprevir plus five or six of ribavirin each day. This could cause problems with compliance, but currently, not only for boceprevir, there is no simpler therapy. Careful monitoring of adherence to therapy is required, and patients should be informed about the importance of taking medication diligently. Boceprevir was approved by the US Food and Drug Administration in May 2011. It is indicated in combination with pegIFN plus ribavirin for the treatment of patients with genotype 1 HCV who have received no previous treatment or whose condition has failed to respond to previous treatment. The European Medicines Agency approved boceprevir in July 2011 for use in the European Union, with the same indications. Boceprevir capsules contain lactose, as excipient. Patients with problems of galactose intolerance, lactase deficiency, or glucose or galactose malabsorption should avoid taking this drug (Victrelis, 2011).

Boceprevir in treatment-naïve patients

The SPRINT-2 trial

In treatment-naïve patients, the final study was published some months ago, called SPRINT-2 (Serine Protease Inhibitor Therapy 2) [Poordad et al. 2011a]. The aim of this phase III study was to verify the safety and efficacy of boceprevir in combination with pegIFN α-2b plus ribavirin. This study was an international, randomized, double-blind, placebo-controlled trial, enrolling two cohorts of adult patients: 938 nonblack and 159 black patients. Those who met the inclusion criteria were randomized into three groups after 4 weeks of SOC (lead-in phase). After this phase, group 1 patients were treated for a further 44 weeks with SOC plus placebo (control group); group 2 received SOC plus boceprevir and the therapy was continued for 28 weeks. After this period, those who were HCV-RNA negative at week 8 (4 weeks of SOC plus 4 weeks of boceprevir) and at week 28 stopped treatment [response-guided therapy (RGT) group], while those who were HCV-RNA positive at any time between week 8 and week 24 continued to receive SOC plus placebo. In the third group, after the lead-in phase, the triple therapy was continued from week 5 to week 48. Treatment was stopped in all three groups if HCV-RNA was still positive at week 24. The therapeutic regimen was pegINF α-2b given subcutaneously weekly at one dose of 1.5 µg/kg body weight; ribavirin was administered orally at a dose of 600–1400 mg daily, according to body weight; and boceprevir was given at a dose of 800 mg three times daily. The SVR was as follows in the nonblack population (938 patients): SOC, 40%; group 2, 67%; while in the third group there was success in 68%. In the group of 159 black patients the SVR was 23%, 42%, and 53%, respectively. It is quite interesting that in the RGT group, those who were eligible for 28-week treatment had an SVR of 97% (nonblack) and 87% (black). Although this subgroup is not very large, even when using the triple therapy, the rapid response is a factor highly predictive of SVR. In the two cohorts considered together, the relapse rate was 22% in group 1 and 9% in each of the remaining two groups. The difference was statistically significant. The results were statistically better when compared black versus nonblack population. In the all-treated population, the boceprevir-containing regimen was always more effective than SOC. Even with triple therapy, as in SOC, there are different responses due to racial differences which must be considered in subsequent studies. However, there are many other predictive factors that may affect the response to the triple therapy. We will come back to this later.

Boceprevir in patients who were previously treated but did not achieve sustained virological response

The RESPOND-2 trial

The purpose of the RESPOND-2 trial (Clinical Trials.gov number NCT00708500) was to evaluate treatment response in patients who did not achieve SVR after a cycle of SOC [Bacon et al. 2011]. A total of 403 patients whose condition had relapsed or not responded to previous treatment were enrolled with a randomization scheme of 1:2:2 (80 in group 1 as control, 162 in group 2, and 161 in group 3). The therapeutic regimen was the same as in SPRINT-2. All groups started with SOC for 4 weeks (lead-in phase). After that, group 1 (control) received SOC plus placebo for a further 44 weeks; group 2 (RGT) received SOC plus boceprevir for a further 32 weeks; and group 3 received SOC plus boceprevir for a further 44 weeks. Group 2 patients stopped treatment at week 36 if they were HCV-RNA negative at weeks 8 and 12; however, if HCV-RNA was positive at week 8 but undetectable at week 12, the treatment continued with SOC and placebo until week 48. In all three groups, treatment was considered to have failed in patients with detectable HCV-RNA at week 12 and the therapy was stopped. The SVR was 21% in the control group, while it was 59% in group 2 and 66% in group 3. Considering the results of previous treatment, patients whose condition relapsed had an SVR of 29% in group 1, 69% in group 2, and 75% in group 3, while those whose condition did not respond to prior treatment obtained an SVR of 7% in the control group, 40% in group 2, and 52% in group 3. Here again, in all the treated population, the boceprevir-containing regimen was always more effective than SOC and the results were statistically significant. It is important to note that a relatively lower SVR was seen in patients whose condition showed a poor response to SOC during the lead-in period (i.e. decrease in HCV-RNA of less than 1 log₁₀): 0% in group 1, 33% in group 2, and 34% in group 3. The rate of SVR was found to be very different in those whose condition showed a better response to SOC during the lead-in period (decrease in HCV-RNA of 1 log₁₀ or more) reaching 25% in group 1, 73% in group 2, and 79% in group 3. The relapse rate was 32% in group 1, 15% in group 2, and 12% in group 3. In this group of patients, viral monitoring is crucial because there is no point in continuing therapy if at week 12 there is no decrease in HCV-RNA. Viral breakthrough (HCV-RNA detectable after a period of undetectability while on therapy) was very uncommon: 1% in group 1, 6% in group 2, and 4% in group 3.

The PROVIDE study

In RESPOND-2, patients with a null response to previous treatment failure were excluded. The aim of the PROVIDE study was to understand if boceprevir could improve SVR in this category of patients [Vierling et al. 2011]. The patients with a null response who were dropped from SPRINT-2 and RESPOND-2 were enrolled in this prospective study. The number of patients was relatively small at 46. The treatment was based on boceprevir plus SOC for 44 weeks, after the lead-in phase. A total of 41% achieved HCV-RNA negativity at the end of therapy, but the study is in progress and we do not know how many patients will achieve a SVR. Despite that, this result is remarkable in null responders who are the patients most difficult to treat.

Practical considerations

HCV-RNA measurement

Measurement of HCV-RNA is a critical issue in the management of this new antiviral therapy. The physician must ask the laboratory to use a test with the highest sensitivity otherwise there is a real risk of making the wrong decision. In fact, using the RGT approach, patients may be classified incorrectly, with the result that they may receive less prolonged therapy with less SVR [Lawitz et al. 2011]. However, the RGT approach is also important because we can significantly reduce the risk of side effects and decrease costs. Another critical factor is the time that the laboratory takes to provide the results of HCV-RNA tests. Many institutions have difficulties because sometimes laboratories take up to 2 weeks to provide the data. It is important, therefore, to ask the laboratory to be very quick in providing the results for these tests.

The studies described above have taught us many things and created a new perspective in the treatment of patients with genotype 1 HCV – those who are treatment naïve and those whose condition has not responded to treatment or whose condition has relapsed. At present, triple therapy has no indication for any other genotype and therapy based on pegINF α plus ribavirin remains the cornerstone for the treatment of all the other genotypes. Moreover, boceprevir must not be used alone due to the high probability of emerging resistance when it is not combined with SOC. In addition, boceprevir must not be used in patients under the age of 18 as it has not been tested in this patient group.

Optimizing treatment

It is very important to follow the recommendations for stopping treatment: all therapy must stop if HCV-RNA is equal to or more than 100 IU/ml at week 12 and if it is still detectable at week 24 [Jacobson et al. 2011]. In this way we can avoid side effects and, above all, the onset of mutation that may induce resistance to future therapies.

It is now well established that, at least for genotype 1, we have a new SOC, however the lead-in phase could give the hepatologist some insight on how to proceed further. It is quite clear that if the patient is young (up to 40 years old, with no advanced fibrosis or cirrhosis, with basal HCV-RNA of less 400.00 IU/ml and no comorbidities) it is likely they will achieve an SVR. The difficulties in managing this therapy are more complex than before for physicians and patients. Physicians should carefully follow the recommendations for stopping treatment, appropriately manage any adverse events, ensure the laboratories use the most sensitive systems to detect HCV-RNA, give patients advice, especially on how to administer medications, and inform them that perfect adherence to the treatment program is essential to avoid mutations and maximize the result.

The educational role of the physician is crucial for successful therapy and counseling should also be carefully given. First, because patients need to take boceprevir every 8 h (range 7–9) with food, in clinical practice it is possible that a dose may be missed. If a patient forgets to take a dose, it is important to establish whether the time until the next dose is less than or more than 2 h. If it is less than 2 h, the missed dose should not be taken. If it is more than 2 h before the next dose, then the missed dose should be taken and the normal schedule resumed. The patient must be advised before starting therapy and during therapy not to take drugs that may interact with boceprevir. Many patients have taken ‘herbs’ for various conditions (constipation, insomnia, nervousness) for years and they do not feel that they are taking ‘drugs’ that could affect treatment. In our experience, during antiviral treatment, 13% of patients took this kind of remedy (personal trial in progress). Patients should be warned not to do so because we do not know how they will interact with the prescribed drugs.

Predictors of response

Some of the findings from the SPRINT-2 and RESPOND-2 trials confirm what we already knew from using SOC for more than 10 years. Some factors continue to be relevant for successful therapy, such as race (although less relevant with triple therapy), age of the patient (young patients respond better, but few patients over 65 have been included in the trials), baseline HCV-RNA (the lower the better; although this aspect is still relevant, triple therapy has reduced the basal viral load weight) [Gordon et al. 2011], and the absence of significant fibrosis. In SPRINT-2, patients with fibrosis grade F0–F2 had a good response rate: SVR was 38% in the control group and 67% in the two boceprevir-treated groups (p < 0.001). In patients with advanced fibrosis or cirrhosis the SVR was 38% in group 1 (control), 41% in group 2 and 52% in group 3 (this difference was not statistically significant).

The RESPOND-2 trial has given encouraging results, which is particularly relevant in practice because the patients enrolled in this trial were taken from our busy clinics. In patients whose condition had not responded to prior therapy, the SVR in those with minimal fibrosis (F0–F2) was 9% in the SOC group, and from 47% to 55% in the two boceprevir-treated groups. In the group of patients with advanced fibrosis or cirrhosis the results were 13% in the control group, 44% in group 2, and 68% in group 3, reaching 90% in patients with undetectable HCV-RNA at week 8. In this analysis, the patients who received boceprevir for 48 weeks did much better than those treated in the RGT group (group 2 in both trials). But it is important to note that, although these results are very encouraging, the number of patients enrolled in this retrospective subanalysis was small and the population was not stratified according to Metavir score at enrollment into the study [Bruno et al. 2011]. A randomized controlled trial should be performed in this group of patients to understand the true benefit of this regimen. For the time being, a trial of triple therapy is indicated and it appears ethically justified and correct to give hope to these patients with no further treatment options at present. The results in terms of SVR in this trial again confirm the great importance of the decline in viral load at week 4 and negativity at week 8, and the role of these measures as favorable and strong predictive factors.

Fibrosis assessment

Because the assessment of fibrosis grade is crucial, it is important to ask how we can assess fibrosis in clinical practice. In registration trials, liver biopsy was mandatory, but ‘at the bedside’ the story is different. Personally speaking, the author has in 40 years of clinical practice met only one patient who enthusiastically agreed to receive a needle in the liver. Nowadays noninvasive methods can be used (clinical examination, biochemistry, ultrasound, liver stiffness measurement and upper gastrointestinal endoscopy) to obtain a good staging of the disease, as suggested by the European Association for the Study of the Liver (EASL) guidelines recently published [EASL, 2011]. In the setting of HCV chronic liver disease, it is very rare in clinical practice that liver biopsy helps in determining the utility or the treatment strategy [Almasio et al. 2005].

Viral response to therapy

Another important finding from the boceprevir trials is that the treatment period could be shortened if the viral response is quick and complete. Cumulative data from SPRINT-2 demonstrate that patients with undetectable HCV-RNA at weeks 8 and 24 could stop treatment at week 28 (considering the lead-in period) with a 97% SVR rate, while those with detectable HCV-RNA at week 8 but undetectable at week 24 had an SVR of 74%. Those who had to stop treatment for any reason (detectable HCV-RNA at week 24, adverse events, personal choice, etc.) and had treatment for less than 28 weeks achieved an SVR of 15%. Unfortunately, patients in the group with rapid response accounted for 44%, while 22% were HCV-RNA negative only at week 24 and 33% had to discontinue therapy.

In the RESPOND-2 trial, the decision to reduce the treatment period in the RGT group was taken at week 8 (SOC for 4 weeks plus triple therapy for a further 4 weeks) for those with undetectable HCV-RNA. This group had the highest SVR rate: 100% in group 1 (only seven patients in this group), 86% in group 2 (74 patients), and 88% in group 3 (84 patients). The difference between groups 2 and 3 was not statistically significant. Even with detectable HCV-RNA at week 8 but a reduction in viral replication of more than 1 log₁₀, the SVR was quite good: 25% in the control group, 73% in group 2, and 79% in group 3. This difference is not statistically significant. The message from both studies seems to be that if the response is rapid, the treatment period can be safely reduced without losing effect in both treatment-naïve patients and those whose condition has previously relapsed or not responded to treatment. In boceprevir-treated patients, negative HCV-RNA at week 8 seems to be the strongest predictive factor of successful therapy.

Other predictors of response

Other predictors of response have been established during SOC therapy over the years, however some of them will be less relevant to triple therapy, especially for patients who received treatment in the past and showed poor response to SOC. Among the predictors of response to triple therapy, we have already analyzed some individual characteristics of patients but baseline viral load and fibrosis or cirrhosis appear to be the most relevant for determining SVR. The decline in HCV-RNA levels while on therapy is one of the most important factors affecting final viral eradication [Bacon et al. 2011]. Among the predictive response factors, the interleukin (IL)-28B genotype also has great importance in boceprevir therapy [Poordad et al. 2011b]. In SPRINT-2 and RESPOND-2, despite the CC genotype showing a good correlation with SVR, when the virological response at week 4 was introduced into a multiple stepwise logistic regression model, IL-28B was no longer a strong predictor of response. However, these data should be analyzed with caution because this is a retrospective analysis, IL-28B genotyping was not available for all patients in the two studies, and the numbers are quite small in some subgroups. However, despite all the caveats described above, in the RESPOND-2 trial, people with a favorable genotype (CC) reported an SVR of nearly 80% in all boceprevir-treated groups, and those with an unfavorable genotype (CT) had an SVR of 61% and 73% in the triple therapy groups, while those treated with SOC reported an SVR of 17%. Therefore, at this stage we cannot tell patients that they have a less favorable outcome on the basis of IL-28B – this applies to patients who are treatment naïve and, especially, those whose condition has failed to respond to previous treatment. Further studies are necessary.

Another interesting and intriguing observation is that ribavirin is still essential in this type of treatment. In the SPRINT-1 study, an arm was included with low-dose ribavirin due to anemia [Kwo et al. 2010]. The SVR was reduced in this arm (less than 14%) in comparison with patients taking the standard ribavirin dose. Although we do not know exactly how ribavirin works, in new therapy protocols it is important to maintain the ribavirin dose and reduce it by only 200 mg, unless the initial dose is 1400 mg. Moreover, anemia appears to be associated with SVR for pegINF plus ribavirin and when boceprevir is added to pegINF plus ribavirin. Thus, maximizing the ribavirin dose allows anemia to be a pharmacodynamic marker of ribavirin exposure. This observation was also observed in in vitro studies of protease inhibitors [Hofmann al. 2011]. So, the mystery of ribavirin continues [Brillanti et al. 2011].

HCV subtypes

Triple therapy has changed our opinion on the response rate of HCV subtype 1a versus 1b. Data from a multicenter Italian study [Alberti et al. 2007] in more than 1000 patients show that SOC gives an SVR of 51% for subtype 1a versus 38% for 1b (p = 0.01). The same situation has been reported in the control arm of the boceprevir trials: 1a achieves an SVR of 23.9% versus 17.6% for 1b. However, when the results obtained in the two groups of boceprevir-treated patients are analyzed, the SVR in group 2 is 53.2% in 1a and 66.7% in 1b; and in group 3 the percentage is 63.5% in 1a and 70.5% in 1b. These results also highlight the fact that old ideas need to be forgotten and there is a need to understand how to manage patients with the new antiviral treatment.

Another important difference between subtypes 1a and 1b is that resistance is more frequent in subtype 1a, and double mutation has nearly always been reported in subtype 1a. Also, the variants in the two subtypes are different. Analyses of data from SPRINT-2 and RESPOND-2 showed that the patterns of boceprevir resistance variants are different in the two genotype 1 subtypes. In 1a the commonest variants were found to be V36M, T54S, and R155K, while in 1b, T54A/S, V55A, A156S, and l/V170A were more frequent [Ogert et al. 2011]. More data are necessary to understand the true meaning of these variations, however the wild-type virus emerges sooner or later when therapy is stopped [Barnard et al. 2011]. We must remember that we are dealing with the first generation of protease inhibitors with quite a low genetic barrier. Also, a certain percentage of patients (approximately 10%) have variants resistant to treatment before the start of therapy, although this does not seem to preclude successful treatment. The tools for monitoring resistance are not commercially available – they are only available to research centers and cannot be used in clinical settings for therapeutic decisions. In addition, there are many systems for detecting variants but they all have some kind of problem in terms of sensitivity, specificity, standardization, possibility of automatization and cost [Halfon and Locarnini, 2011]. In conclusion, we need more data in order to understand these mutations and whether there is any cross reaction among the other DAAs.

Contraindications and drug interactions

Contraindications for boceprevir-based triple therapy are the same as those for SOC: decompensated liver disease, decompensated metabolic diseases, pregnancy, autoimmune disease, and any kind of serious/life-threatening chronic disease of other organs (kidney, heart, and lung). A negative pregnancy test before therapy and monthly during therapy should be mandatory during SOC. Obviously, a system of contraception must be used during therapy by both partners, bearing in mind that there are no data on administration of SOC with oral contraceptives.

There are some specific contraindications related to boceprevir as detailed by the manufacturer, such as administration with medicines that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious or life-threatening events. This warning is due to the observation that boceprevir is a strong inhibitor of CYP3A4/5. Drugs metabolized primarily by CYP3A4/5 may have increased exposure when administered with boceprevir, which could increase or prolong their therapeutic and adverse effects. These drugs are orally administered midazolam, amiodarone, bepridil, ergot derivatives (dihydroergotamine, ergotamine, methylergonovine), flecainide, pimozide, propafenone, and quinidine. In clinical practice, these drugs should not be used during therapy. For other drugs widely used in clinical practice there are no data available, for example, oral contraceptives, opioids (methadone, buprenorphine), immunosuppressants, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, rifampicin, and hypericum. However, medications taken by patients during participation in the SPRINT-1, SPRINT-2, and RESPOND-2 trials were analyzed and the results were encouraging because there were no adverse effects (including no severe adverse effects) [Poordad et al. 2011c]. Therefore, the physician’s level of attention must be high, especially when the drug can be freely used.

Adverse effects

So far, we have examined the results in terms of elimination of viral replication and there is no doubt that regimens that include boceprevir produce much better eradication rates than SOC in different types of patients. But what is the cost?

When considering any kind of adverse event, there are no differences among all treated groups and all studies done so far. Nearly 100% of treated patients have some kind of side effect in SOC and in boceprevir groups. Even when serious adverse events are considered, there are no significant differences between groups (SOC 9%, boceprevir 12%), and only 1%, equally distributed in all groups, had life-threatening adverse events. Erythema at injection site, influenza-like syndrome, pyrexia, asthenia, fatigue, myalgia, arthralgia, nausea, insomnia, irritability, depression, and anxiety were not statistically different in patients treated with SOC compared with boceprevir-treated groups. However, triple therapy showed a good safety profile [Flamm et al. 2011; Manns et al. 2011]. The most important statistically significant differences in patients treated with boceprevir compared with those treated with SOC were reported for anemia (p < 0.001), drop in neutrophil count between 500 and 750/mm³ (p < 0.001) [Reddy et al. 2011], and the use of erythropoietin (EPO) (24% in the SOC group versus 43% in the boceprevir group, p < 0.001). The need for red blood cell transfusion was more frequent in boceprevir-treated patients, but only in the group treated for 44 weeks versus SOC; the difference was statistically significant (p = 0.006). How can we manage anemia? Traditionally, during SOC, we reduced ribavirin in steps of 200 mg and then watched and waited, but this action clearly depends on two aspects: symptoms and decreased hemoglobin levels. We already know that this policy might not be enough in patients treated with triple therapy, especially in those taking the drugs for 44 weeks. Reducing boceprevir dosage would not help because of the pharmacokinetic and pharmacodynamic properties of the drug [Stone et al. 2011]. One emerging finding that may explain the decrease in hemoglobin levels has recently been confirmed and involves inosine triphospatase activity. Patients with a deficiency of this enzyme have reduced anemia and less need for EPO [Sulkowski et al. 2011]. There is no doubt that, in patients with hemoglobin levels less than 10 g/dl, EPO should start at a dose of 40,000 units weekly and then hemoglobin levels should be checked weekly. A recent meta-analysis clearly demonstrated that administration of EPO results in a higher SVR rate than the reduction in dose of ribavirin to correct anemia [Alavian et al. 2012]. When the hemoglobin level increases, EPO must be reduced according to the levels reached. Close monitoring is necessary. Although a drop in hemoglobin to below 6.5 g/dl was found to be rare, it is necessary to give a blood transfusion in these cases.

Two other relevant adverse effects for treated patients were dysgeusia (11% in the SOC group, 37–45% in the boceprevir-treated groups, p < 0.001) and dry skin, but again the difference was statistically significant only when the SOC group was compared with the group of patients treated for the longest period of time. Discontinuation of therapy rates because of adverse events in SPRINT-2 were identical in all treated groups, while in RESPOND-2 discontinuation was necessary in 2% of the control group, 8% in group 2, and 12% in group 3. Here again, as was expected, the group treated for a prolonged period of time had more problems compared with the SOC and RGT groups. As for side effects, the risk–benefit ratio is in favor of boceprevir therapy.

Cost effectiveness

Finally, at a time of global economic crisis, we cannot ignore the cost effectiveness of any drug. Recently, two studies reported on SOC and boceprevir therapy in treatment-naïve patients and those whose condition had relapsed or not responded to previous treatment. Both studies showed that boceprevir plus SOC is cost effective when considering the lifetime incidence of liver complications, quality-adjusted life years and the incremental cost-effectiveness ratio [Ferrante et al. 2011; Chhatwal et al. 2011].

Conclusion

Triple-based therapy with DAA drugs, such as boceprevir, heralds a new approach to HCV genotype 1 treatment. The SPRINT-2 and RESPOND-2 studies in treatment-naïve patients and those whose condition had relapsed or not responded to previous treatment provide new hope for the successful treatment of chronic hepatitis C with boceprevir-based triple therapy in genotype 1 HCV infection.