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Keywords:

  • Triple Therapy;
  • Protease Inhibitors;
  • boceprevir;
  • Hepatitis C;
  • Lead-in;
  • response guided therapy

Abstract

  1. Top of page
  2. Abstract
  3. Risk/benefit ratio: selecting the ideal patient
  4. Optimal treatment design – label and personalized approaches
  5. Challenges during treatment: optimal therapy management
  6. Conclusions
  7. Disclosure
  8. References

There are 160–170 million people with chronic hepatitis C virus (HCV) infection worldwide. The marketing of protease inhibitors (PIs) has been a milestone in the history of HCV therapy. In phase III studies, up to 75% of the patients achieved a sustained virological response (SVR) after triple therapy with pegylated-interferon (PEG-IFN)-α, ribavirin (RBV) and boceprevir (BOC). However, triple regimens are more expensive and associated with drug–drug interactions (DDIs) and more adverse events (AEs). According to results in ‘real-world’ settings, safety seems to be limited, in particular in patients with advanced liver disease. To optimize efficacy while minimizing AEs as well as costs, the optimal treatment strategy must be determined for BOC. Optimizing treatment is based on patient selection, the most efficient treatment design, management of side effects and the challenge of DDIs. Therapy-associated risks, treatment urgency and chances of SVR must all be considered for patient selection. In addition, certain differences between the two approved PIs may help identify the ideal candidates for each HCV PI. Optimal treatment design is based on the results of phase II and III studies, in which different approaches have been tested including ‘lead-in’ and response-guided strategies. Treatment regimens and stopping rules recommended by the FDA and EMA should normally be followed. Still, there are some cases in which more personalized strategies may be more promising. Management of side effects is a major challenge and plays a crucial role in ensuring safety and adherence.

Abbreviations
AEs

adverse events

AUC

area under the concentration time-curve

BOC

boceprevir

DAAs

direct acting antivirals

DDI's

drug–drug interactions

eRVR

extended rapid virological response

HCV

hepatitis C virus

PI

protease inhibitors

RGT

response-guided therapy

SAEs

serious adverse events

SOC

standard of care

SVR

sustained virological response

TLV

telaprevir

TT

triple therapy

Chronic hepatitis C virus (HCV) infection is a global health problem affecting 160–170 million people worldwide [1]. HCV is a major cause of liver cirrhosis and hepatocellular carcinoma. Risk of liver-related morbidity and mortality can be significantly reduced by eradication of the virus ([2][3, 4]). With the previous standard of care (SOC) including a combination therapy of pegylated-interferon-α and ribavirin (PEG-IFN/RBV), less than 50% of HCV genotype 1 (GT1)-infected patients achieved a sustained virological response (SVR) [5]. Things changed dramatically in 2011 with the approval of the protease inhibitors (PI) boceprevir (BOC) and telaprevir (TLV) as the first generation direct acting antivirals (DAAs). In phase III studies, 63–75% of treatment-naïve and 59–66% of treatment-experienced patients achieved an SVR after triple therapy consisting of PEG-IFN/RBV and a PI, two to six times more than those treated with PEG-IFN/RBV alone [12-15]. However, triple regimens were also accompanied by additional as well as more severe adverse events (AEs). First experiences with these new regimens in clinical practice revealed that in the ‘real-world’ setting, even more AEs may be expected [6, 7]. With the introduction of PIs, hepatologists must also manage drug–drug interactions (DDI). Finally, new PIs markedly increase the cost of treatment.

Table 1. Certain characteristics of boceprevir (BOC) and telaprevir in different populations
 TelaprevirBoceprevir
  1. a

    Not recommended in the label information.

  2. eRVR, extended rapid virological response; PI, protease inhibitor; RVR, rapid virological response; RGT, response-guided therapy; SVR, sustained virological response.

Treatment-naïve (non-cirrhotic)
Treatment duration24–48 weeks28–48 weeks
PI costs only (€)36 46323 920–31.894
CommentOngoing trial whether 12 weeks of treatment are sufficient for those with eRVR and IL28B CC (NCT01459913)

‘lead-in’ allows identification of patients eligible for P/R only (RVR)

and

of patients behaving like null-responders (<0.5 log after 4 week ‘lead-in’), that might benefit from 44 weeks BOC

Relapsers (non-cirrhotic)
Treatment duration24–48 weeks(36–48) weeks
PI costs only (€)36 46331 894
 CommentRGT possible

Fixed treatment duration recommended in Europe

aRGT as an individualized approach in certain cases

Partial Responders (non-cirrhotic)
Treatment duration48 weeks(36–48) weeks
 PI costs only (€)36 46331 894
 CommentRGT not recommended

Fixed treatment duration recommended in Europe

aRGT as an individualized approach in certain cases

Null-Responders
Treatment duration48 weeks48 weeks
 PI costs only (€)36 46343 855
 CommentaIn certain cases individualized regimen with ‘lead-in’ (+4 weeks) to predict chances for SVRNot investigated in pivotal phase III trials. PROVIDE study: 40% SVR for well defined null-responders[36]
Cirrhotics
Treatment duration48 weeks48 weeks
 PI costs only (€)36 46343 855
 CommentaIn certain cases, i.e. null-responders individualized regimen with ‘lead-in’ (+4 weeks) to predict chances for SVRAt least 32 weeks of BOC recommended depending on P/R/BOC tolerability

To use limited resources most efficiently, reduce the number of AEs and achieve high SVR rates, an optimal approach to these new therapies is essential. This includes optimal treatment design, appropriate management of side effects and above all a careful patient selection. This article will review available data with a special focus on optimal treatment with BOC.

Risk/benefit ratio: selecting the ideal patient

  1. Top of page
  2. Abstract
  3. Risk/benefit ratio: selecting the ideal patient
  4. Optimal treatment design – label and personalized approaches
  5. Challenges during treatment: optimal therapy management
  6. Conclusions
  7. Disclosure
  8. References

According to international guidelines, in principle, every patient with chronic HCV infection is a candidate for antiviral treatment [8]. Because of the results of phase III trials, patients infected with HCV GT1 should receive a triple regimen including either BOC or TLV [9, 10]. However, not all patients with chronic HCV GT1 infection are eligible for these therapies [7]. The risk/benefit ratio can be poor in certain patient cohorts. Therefore, at least three key factors should be considered when selecting the best patients: Therapy-associated risk, chances of achieving an SVR and treatment urgency.

Therapy-associated risk/adverse events

Current antiviral therapies are still based on interferon (IFN), which is associated with several AEs, i.e. flu-like symptoms or fatigue [5, 11] and with the addition of PIs more side effects will occur [12-15]. In certain cases, AEs can be dangerous or even life threatening, i.e. systemic infections or severe anaemia. Various possible risk factors for serious adverse events (SAEs), i.e. cardiovascular or autoimmune diseases need to be considered. A very important risk factor is liver cirrhosis, in particular in the advanced stages with signs of portal hypertension. At week 16 of triple therapy in the French CUPIC study including only non-responder patients with cirrhosis, a higher frequency of SAEs of 38–49% was found compared with phase III trials (9–14%); 1.3–2% of the patients died, emphasizing that safety must be carefully considered when evaluating the benefits and risks of treatment [12-15, 6].

Chances of a sustained virological response

Pretreatment predictors of response should significantly influence treatment decisions. Chances of SVR range from more than 80% in relapse patients without significant fibrosis to only 15% in cirrhotic null-responders. Still, accurate prediction can be difficult because there is no valid scoring system and experience with new regimens is limited in particular in difficult to treat patients. Some of the baseline markers for SVR that have been identified for PEG-IFN/RBV are still valid for the new triple therapy regimens. However, because of the higher antiviral potency, the impact of several predictive factors is less relevant for triple therapy. Useful markers include the stage of liver fibrosis, platelet count, HCV subtype and certain genetic polymorphisms within the IL28B promoter, which are also associated with spontaneous clearance of HCV infection [12, 13, 16, 17]. At baseline, the previous response to PEG-IFN/RBV has the highest predictive value, while on-treatment ‘lead-in’ response and extended rapid virological response (eRVR)1 are the most important markers of treatment response [13-16]. As there is a separate review focusing on the predictive factors of response to treatment, this will not be discussed in more detail [49].

Treatment urgency

The next generation of direct acting antiviral agents (DAAs) is in various stages of clinical development [18]. Less complicated dosing regimens, a better safety profile and a lower incidence of AEs as well as an IFN-free treatment regimen can be expected in the not too distant future [19, 20]. The development of cirrhosis in chronic HCV infection is usually a long process. Patients with no or only mild liver fibrosis can wait until new drugs are approved. Still, delaying treatment until fibrosis has reached stage F3 (METAVIR) may be a less effective strategy than treating patients as soon as they have reached F2 [21]. However, the ideal strategy for each patient may better be determined depending on the individual disease progression, which is influenced by the prevalence of risk factors such as steatosis or older age [22, 23]. Monitoring should include the regular assessment of the stage of fibrosis to determine disease progression and the best moment to initiate treatment. The introduction and increased use of non-invasive tests such as transient elastography have made this approach more feasible, although unfortunately the accuracy of these tests is limited, in particular for the intermediate stages of liver fibrosis [24, 25]. In addition, there might be non–liver-related issues motivating immediate treatment, i.e. extrahepatic manifestations or at the patient's request.

Based on the above mentioned factors, the ideal candidate for triple therapy should have the following characteristics: F2/F3 fibrosis, previous relapse and no significant co-morbidities, which means the need for treatment is high, the safety profile is reasonable and there is a significant chance of achieving an SVR. Unfortunately, the decision to treat is not necessarily that easy in most patients. Patients who are most urgently in need of treatment often present with cirrhosis and are older, which are both associated with higher risk. In addition, a history of previous treatment failure is associated with a poor chance of SVR except in cases of relapse from previous therapy. On the other hand, young, treatment-naïve patients with F0/F1-fibrosis have a moderate risk and a good chance of SVR, but can easily wait for better therapies.

Defining the ideal candidate for boceprevir

Choosing the optimal PI can also be difficult as there are no studies available directly comparing the two PIs approved for HCV. However, the phase III trials did not seem to show any significant difference in efficacy and only minor differences in the safety profile of these two drugs [12-15]. Nevertheless, because of the special characteristics of BOC and TLV one or the other of these PIs may be preferable in certain cases.

Because the ‘lead-in’ phase is part of the BOC treatment regimen, this drug offers advantages in certain ‘easy-to-treat’ patients who are treatment-naïve, without cirrhosis and with low pretreatment viral load [16]. A certain number of these patients will become HCV RNA negative after the 4-week ‘lead-in’ and will thus achieve rapid virological response (RVR).2 About 90% of these patients achieve an SVR after 24 weeks of therapy if the treatment with PEG-IFN/RBV is continued alone. This rate does not increase by adding a PI as recently confirmed in a randomized trial [12, 14, 47]. Shortening treatment in these patients following response-guided therapy (RGT) is possible with dual therapy according to European guidelines. Thus, treatment with dual therapy should carefully be considered in these cases as it is associated with fewer AEs and is more cost-effective [26]. However, this decision can be difficult in patients with a high baseline viral load (>800 000 IU/ml) as the recommended treatment duration without a PI would be longer (28 vs. 48 weeks respectively) [8]. Nevertheless, it is possible to use TLV after a ‘lead-in’ phase as well, since this was tested in the REALIZE study [15]. However, this makes it difficult to determine stopping rules and RGT criteria in those without a RVR.

During this era of limited resources, the cost of treatment is increasingly important. Costs per month are higher for TLV than for BOC (12 154€ vs. 3987€).3 On the other hand TLV is taken for a shorter time period of only 12 weeks, limiting the total cost to 36 463€3. In treatment-naïve patients without cirrhosis the cost of a full 48 weeks of treatment is similar for both PIs because of the 32 week course of BOC (31 894€ for BOC vs. 36 463€ for TLV). However, in those who meet the criteria for shortened BOC regimens, BOC is less expensive (23 920€ compared to 36 463€ for TLV)3. Boceprevir is also less expensive in case of early treatment failure because of AEs or virological non-response and the associated stopping rules. On the other hand in Europe, shorter treatment in relapse patients based on RGT has only been approved with TLV therapy, which may therefore be preferable in these cases. Treatment of non-responders or those with cirrhosis requires BOC for 44 weeks in addition to the 4 week ‘lead-in’ phase with PEG-IFN/RBV, which is again more expensive (43 855€ compared to 36 463€ for TLV)3 than 12 weeks of treatment with TLV (Table 1).

So far only limited data are available in patients with advanced liver disease. In the CUPIC study, TLV was associated with more SAEs, a higher rate of infections and a higher mortality rate than BOC. It should be noted that this was an interim-analysis after 16 weeks of treatment and unlike TLV, BOC must be continued for the entire treatment duration [6]. Thus, no strict recommendations can be made based on safety issues. Prevalence of Anaemia seems to be the same for both first generation HCV PIs, BOC and TLV [12-15].

Although they have only been approved for HCV GT1 the antiviral potency of BOC and TLV is not strictly limited to HCV GT1. TLV has been shown to have good antiviral potency in HCV GT2, but not in HCV GT3 infection [27]. In contrast, there are some data showing that BOC has limited, but greater efficacy than TLV in HCV GT3 [28, 29]. Thus, in patients co-infected with more than one HCV genotype, the specific HCV genotypes can support the use of one protease inhibitor of another.

As PIs are added to HCV therapy, physicians must be aware of DDIs. When TLV is chosen, this challenge is limited to a maximum of 12 weeks. In patients with certain co-morbidities, in which several DDIs are possible TLV may be the better choice because management is easier during the last 36 weeks with the PEG-IFN/RBV tail of treatment. In post-transplant patients, however, BOC has a less challenging extent of DDIs.

Normally, either PI can be used in patients eligible for triple therapy. The risks and potential benefits of both PIs seem to be balanced. Nevertheless, the patient may have a completely different point of view. Some subjects may find the strict 8-h regimen difficult and prefer a shorter period of PI treatment with TLV, which in addition seems to be as effective if taken twice daily at least in treatment-naive patients [48]. Others may find the fatty meals required for sufficient absorption of TLV to be difficult and may therefore choose BOC. Patients may not tolerate a visible rash because of their social or work environment, while others may not tolerate dysgeusia. As treatment adherence is a key factor for successful therapy, the patient's personal preference based on the side effect profile will certainly strongly influence the choice of PI.

Optimal treatment design – label and personalized approaches

  1. Top of page
  2. Abstract
  3. Risk/benefit ratio: selecting the ideal patient
  4. Optimal treatment design – label and personalized approaches
  5. Challenges during treatment: optimal therapy management
  6. Conclusions
  7. Disclosure
  8. References

The optimal regimen for treatment with BOC according to the FDA and EMA is set out on the European and US label respectively. According to the prescription information (or labelling), all patients are supposed to be treated with a 4-week ‘lead-in’ phase with PEG-IFN/RBV. RGT is possible in treatment-naïve patients without cirrhosis, and treatment can be terminated after 28 weeks (4-week PEG-IFN/RBV ‘lead-in’ followed by 24 weeks PEG-IFN/RBV/BOC) if HCV RNA becomes undetectable at week 8 and until week 24 of therapy, which was defined as an eRVR. In contrast, previous non-responders and patients with cirrhosis need to be treated for a fixed duration of 48 weeks including a 4-week ‘lead-in’ phase followed by a 44-week course of triple therapy. European and US labelling do not agree on the treatment of previous PEG-IFN/RBV partial responders and relapsers. The FDA recommends a RGT approach, while the EMA suggests a fixed duration of treatment of 48 weeks (4-week PEG-IFN/RBV ‘lead-in’ followed by 32 weeks PEG-IFN/RBV/BOC and 12 weeks of dual therapy). Treatment should be stopped in the presence of HCV RNA >100 IU/ml at week 12 or detectable HCV RNA at week 24 of therapy according to the stopping rules defined in the prescribing information. These patients have no realistic chance to achieve an SVR (Fig. 1) [30, 31].

image

Figure 1. Recommended treatment regimen with boceprevir with implications for individualized alterations based on the individual risk/benefit ratio.

Download figure to PowerPoint

Various treatment schedules have been tested in phase II/III trials to define the optimal BOC containing regimen. In particular, two questions were supposed to be answered: (a) Whether the virological outcome with the ‘lead-in’ strategy is better or has any other benefits; and (b) whether therapy can be shortened with the same efficacy with a RGT approach in patients with a RVR. Results of these trials mainly support the treatment design recommended in the prescribing information. However, there is also some room for a personalized approach, which may even be more beneficial in certain individual cases.

‘Lead-in’: a controversial debate

The value of a ‘lead-in’ phase with PEG-IFN/RBV is controversial. The initial rationale for a ‘lead-in’ strategy was to lower the likelihood of resistant variants by reducing the viral load prior to administration of BOC. In the SPRINT-1 trial, a phase II study of treatment-naïve patients, those treated with a 4-week ‘lead-in’ achieved higher SVR rates than those immediately started on triple therapy (66% vs. 60%) [32]. Furthermore, there were fewer relapses and virological breakthroughs in the ‘lead-in’ arms (13% vs. 18% and 4% vs. 9% respectively). Although differences in SVR were not statistically significant, all BOC containing regimens included a ‘lead-in’ phase in the following phase III trials [12, 13, 32].

The REALIZE trial also tested the ‘lead-in’ strategy with TLV-based triple therapy. However, no virological benefit was found with the ‘lead-in’ arm and no difference in SVR rates compared to immediate PEG-IFN/RBV/TLV triple therapy (66% vs. 64%) [15]. Nevertheless, certain other points support a ‘lead-in’ strategy.

‘Lead-in’ can be used as a test period to obtain treatment relevant information. Previous treatment response may sometimes be uncertain because of suboptimal dosing, non-compliance or insufficient documentation. Re-assessment of IFN susceptibility during the ‘lead-in’ helps classify patients, which is essential to determine the optimal therapy regimen. Furthermore, treatment-naïve patients with a less than 0.5 log10 decline after the ‘lead-in’ are considered to be very poor responders to PEG-IFN/RBV. These patients may therefore benefit from longer BOC treatment like previous null-responders [28]. Furthermore, the ‘lead-in’ is of special value in patients with a borderline risk/benefit ratio due to a poor chance of SVR and/or increased treatment-associated risk. [16]. In these cases, the predictive value of the ‘lead-in’ provides a better estimation of the chance of SVR. In patients with a prior null-response and cirrhosis, the ‘lead-in’ response may be used as stopping rule. Previous null-responders with cirrhosis have a chance of clearing the virus after PEG-IFN/RBV/PI therapy of approximately 15% [33]. If these patients have a <1 log10 decline in HCV RNA after the ‘lead-in’ chances of an SVR are <10% and discontinuation should be strongly considered because of a very poor risk/benefit ratio. In addition, IFN-tolerance can be tested in at-risk patients before adding a PI and the possibility of even more AEs. Moreover, the value of the ‘lead-in’ response is not limited to patients whose expected outcome is poor as it also identifies ‘easy-to-treat’ patients who do not require a PI as above described.

Response-guided therapy (RGT) vs. fixed treatment duration

One aim of the SPRINT-1 trial was to determine the ideal treatment duration. Patients were either treated for 28 or 48 weeks. Overall SVR rates were 13–19% higher in those who were treated for 48 weeks. However, the differences were less marked (10–12%) in those with undetectable HCV RNA at 4 weeks of BOC treatment. This indicated that shorter treatment might also be possible in patients with an early response [32]. The possibility of RGT was further investigated in the following phase III trials. In the SPRINT-2 study, patients were either treated for a fixed duration of 48 weeks (4-week ‘lead-in’ followed by 44 weeks triple therapy) or with RGT. Patients randomized into the RGT arm were first treated with a 4-week ‘lead-in’ with PEG-IFN/RBV therapy followed by 24 weeks PEG-IFN/RBV/BOC. Therapy was discontinued after 28 weeks in those with an eRVR. Otherwise patients continued with PEG-IFN/RBV, but without BOC for 20 more weeks. Overall, SVR rates were 63% in the RGT arm and 66% in those treated with a fixed duration of 48 weeks. However, no difference could be found between RGT and fixed duration in patients without advanced liver fibrosis (F0-F2). More importantly, SVR rates were equal between the two arms in patients who achieved an eRVR and were therefore selected for shorter treatment (96% vs. 96%) [12]. Based on these results, labelling of BOC by the EMA and FDA suggested RGT for treatment-naïve patients. However, these agencies declared that the optimal strategy in patients without an eRVR was unclear because this has not been studied directly. Finally, the label relied on the results of the RESPOND-2 trial considering the non-eRVR cohort as a mixture of partial and non-responders to IFN [34, 35].

Both RGT and a fixed treatment duration were analysed in the RESPOND-2 study. In contrast to the fixed duration arm, the RGT design was slightly different from that in the SPRINT-2 study. All patients in the RGT arm were treated for at least 36 weeks (4-week ‘lead-in’ followed by 32 weeks PEG-IFN/RBV/BOC). Patients without eRVR received an additional 12 weeks lasting tail of P/R dual therapy. Overall, there were only minimal differences in the absence of advanced fibrosis, while RGT was markedly inferior for those with F3/F4-fibrosis. Overall, RGT was less effective in those with a previous partial response (40% vs. 52%), while differences were less marked in relapse patients (69% vs. 75%). Most important SVR rates were nearly similar in those with an eRVR in whom treatment could be shortened (86% vs. 88%) [13]. These data support the decision of the FDA to suggest a RGT approach in relapse and partial responder patients. The analysis of the RESPOND-2 data by the EMA was different, but also reasonable. For their comparison of RGT and fixed duration they only included patients with an eRVR that completed at least 36 weeks of treatment. They suggested that patients who stopped treatment before this stage received exactly the same treatment in both arms. Thus, a causal relationship of the outcome was excluded for this population. After removing these patients, results revealed an advantage for the fixed duration, driven by seven relapses (10%) in the RGT arm, while there were no relapses in the longer treatment group [34]. It is difficult to judge which label, FDA or EMA, represents the optimal strategy. Although the EMA approach seems reasonable, the decision is based on just seven patients [34]. In patients with a poor tolerance to treatment who achieve an eRVR a low and thus very limited risk of relapse might be an acceptable price to pay for shorter treatment and can be discussed on an individual basis.

Treatment duration may also be discussed individually in patients with detectable but non-quantifiable HCV RNA (<25 IU/ml) at week 8 of treatment who do not meet eRVR criteria. In phase III trials, the outcome differed between patients with an eRVR and those with an HCV RNA level below the limit of quantification (<25 IU/ml4) [36]. However, classification in this grey area is uncertain and dependent on several factors, i.e. the assay that has been used and with conflicting results if testing is repeated [37].

Null-responders and patients with cirrhosis

Data on BOC in patients with cirrhosis and previous null-responders are limited as they were either underrepresented (cirrhosis) or not investigated at all (null-responders) in the pivotal trials. Because they both represent ‘difficult-to-treat’ patients, maximum treatment is recommended (Fig. 1) [28, 29]. However, because of their poor tolerance to IFN, physicians are encouraged to find individual solutions for patients with cirrhosis [30, 31]. The initial results of the PROVIDE study (a roll-over protocol for treatment naïve patients who were randomized into the PEG-IFN/RBV control arm in phase II/III trials) revealed that about 40% of null-responders achieve an SVR after 48 weeks of triple therapy including 44 weeks of BOC [38].

Optimal stopping rules

Stopping rules on prescription information differ from those applied in the phase III trials, i.e. there were no week 12 stopping criteria in the SPRINT-2 study, while patients should discontinue treatment if they had any detectable HCV RNA at week 12 in the RESPOND-2 trial [12, 13]. However, none of the 65 patients with a HCV RNA level ≥100 IU/ml at week 12 including 22 subjects with a HCV RNA level <1000 IU/ml achieved an SVR in the SPRINT-2 study [39]. In contrast, in 13 patients with an HCV RNA level ≥50 but <100 IU/ml at week 12, 4 and 21/49 patients with <100 IU/ml, but detectable HCV RNA permanently cleared the virus [39]. Thus, some SVR patients would have been missed by stricter stopping criteria. Although based on a small number of patients, this supports the chosen cut-off. In addition, treatment was continued in 7/39 patients in the RESPOND-2 trial with detectable <100 IU/ml HCV RNA at week 12 despite the protocol stipulation. Five of seven patients achieved an SVR [39]. There is no week 8 stopping rule in the prescribing information for BOC, while comparable stopping criteria have been established for TLV (at 4 weeks of triple therapy) [30, 31, 40, 41]. However, phase III data provide some support for a stopping rule at week 8. HCV RNA ≥1000 IU/ml at week 8 is associated with a very poor chance of SVR. Only 5/88 patients who met these criteria were cured in the RESPOND-2 and SPRINT-2 studies. If a <3log10 decline at week 8 had been chosen as a stopping rule 53 patients would have been stopped and only two SVR would have been missed [39]. The question is whether achieving SVR in two more patients, while exposing 51 patients unnecessarily to four more weeks of triple therapy with the associated costs and AEs is reasonable. Treatment discontinuation could be discussed in these patients on an individual basis, as well as in previous null-responders with cirrhosis and a poor ‘lead-in’ response of <1 log10 HCV RNA decrease as discussed above.

Optimal dosing

There have been extensive studies to define the optimal dosing of BOC. In the SPRINT-1 study, a lower dose of RBV was tested, although the cohort and the results were ineffective [32]. In contrast, there are no studies on the optimal dosing of PEG-IFN in triple therapy. The efficacy and safety of low-dose PEG-IFN-α-b (1.0 μg/kg) compared with the standard dose (1.5 μg/kg) in dual therapy with RBV was tested in HCV GT1 infection in the IDEAL study [42]. More patients had to discontinue treatment because of a virological non-response in the low-dose arm, but there was no overall difference in SVR. Furthermore, patients treated with the lower dose experienced significantly fewer haematological side effects including anaemia [42]. Thus, because the optimal PEG-IFN dose in triple therapy is unclear, results of the IDEAL study may encourage using lower dosages if the management of side effects is difficult.

Challenges during treatment: optimal therapy management

  1. Top of page
  2. Abstract
  3. Risk/benefit ratio: selecting the ideal patient
  4. Optimal treatment design – label and personalized approaches
  5. Challenges during treatment: optimal therapy management
  6. Conclusions
  7. Disclosure
  8. References

There are several challenges prior to and during treatment, including the management of DDIs and AEs.

The challenge of DDI's is a completely new field in the treatment of HCV. BOC is an inhibitor and substrate of the p-glycoprotein and cytochrome P450 3A4/5 [30], which metabolizes more than 50% of clinically used drugs and is often involved in adverse DDI's [43]. The area under the concentration time-curve (AUC) of drugs that are metabolized via CYP3A4/5 may therefore be altered resulting in either elevated or decreased serum levels. The AUC of the immunosuppressant tacrolimus for example is 17.1 times higher if it is co-administered with BOC [44]. Other drugs can influence the AUC of BOC as well. Some drugs may be co-administered at a modified dosage while others should be avoided strictly especially if alternatives are available that do not interfere with BOC. Knowledge and awareness of drug-interactions is crucial. All physicians, especially those who are not familiar with the newly approved PIs, should be aware of the potential DDIs. Although in vivo data on DDI are still limited, some help can be obtained at www.hep-druginteractions.org, a regularly updated website with open access to available data. Furthermore, the patient must be told that he must not self-medicate, i.e. with St. Johns wort as interactions are not limited to approved drugs [45].

The various possible AEs during triple therapy have already been discussed. Management of these AEs is essential to optimize safety and adherence. As anaemia is highly prevalent, optimal management has been widely discussed. Two main options, erythropoietin (EPO) and RBV dose reduction have been considered. In many countries including Germany, EPO is not reimbursed for the treatment of HCV infection and it may have side effects. On the other hand, there is concern that RBV dose reduction could impair the virological outcome. A recent randomized trial showed that dose reductions of RBV and EPO did not influence the SVR differently and were equally effective in reducing anaemia. This supports an RBV dose reduction as the primary strategy [46]. Based on the results of the IDEAL study, a dose reduction in IFN could be considered in difficult cases [42]. As there is a separate review article in this issue of Liver International on the management of side-effects, this will not be discussed in detail [50].

Conclusions

  1. Top of page
  2. Abstract
  3. Risk/benefit ratio: selecting the ideal patient
  4. Optimal treatment design – label and personalized approaches
  5. Challenges during treatment: optimal therapy management
  6. Conclusions
  7. Disclosure
  8. References

PIs are a milestone in the history of HCV therapy. However, optimal patient selection is crucial to achieve high SVR rates accompained by a reasonable safety profile. In certain cases, one of the two PIs may be preferable. The treatment schedule chosen for BOC labelling can be considered as the optimal regimen for the average patient and should be followed as it is based on the results of phase III trials. Nevertheless, individual evaluation of the risks and benefits of treatment for a more personalized treatment regimen and stopping rules can be considered in certain patients. In these cases, the ‘lead-in’ strategy offers a valuable tool for more individualized and more personalized treatment regimens and strategies.

Disclosure

  1. Top of page
  2. Abstract
  3. Risk/benefit ratio: selecting the ideal patient
  4. Optimal treatment design – label and personalized approaches
  5. Challenges during treatment: optimal therapy management
  6. Conclusions
  7. Disclosure
  8. References

M. P. Manns, MD. Speaker Bureau: Roche, Bristol Myers Squibb, GlaxoSmithKline, Gilead, Merck, Janssen; Consultant: Roche, Bristol Myers Squibb, Gilead, Boehringer Ingelheim, Novartis, Tibotec, Vertex, Glaxo Smith Kline, Merck, Janssen; Grant/Research Support: Roche, Gilead, Novartis, Boehringer Ingelheim, BMS, Merck, Janssen. B. Maasoumy has no disclosure.

  1. 1

    As described in Sarrazin et al. [9]

  2. 2

    As described by Sarrazin et al. [9]

  3. 3

    PI costs in Germany [9]; total treatment cost higher owing to the additional costs of peginterferon plus ribavirin (PEG-IFN/RBV).

  4. 4

    Assessed with the Roche COBAS Taqman 2.0 assay [31]

References

  1. Top of page
  2. Abstract
  3. Risk/benefit ratio: selecting the ideal patient
  4. Optimal treatment design – label and personalized approaches
  5. Challenges during treatment: optimal therapy management
  6. Conclusions
  7. Disclosure
  8. References
  • 1
    Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011; 17: 10715.
  • 2
    Maasoumy B, Wedemeyer H. Natural history of acute and chronic Hepatitis C. Best Pract Res Clin Gastroenterol 2012; 26: 40112.
  • 3
    Backus LI, Boothroyd DB, Phillips BR, et al. A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol 2011; 9: e1.
  • 4
    Morgan TR, Ghany MG, Kim HY, et al. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology 2010; 52: 83344.
  • 5
    Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C: efficacy, side effects, and complications. Gut 2006; 55: 13509.
  • 6
    Hezode C, Dorival C, Zoulim F, et al. Safety of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in cirrhotic non responders. First results of the french early access program (ANRS CO20-CUPIC). J Hepatol 2012; 56: S4.
  • 7
    Maasoumy B, Port K, Markova AA, et al. Eligibility, safety and efficiency of triple therapy for chronic HCV genotype 1 infection in a real world setting. Hepatology 2012; 56 (Suppl): 1030A1A.
  • 8
    EASL Clinical Practice Guidelines. management of hepatitis C virus infection. J Hepatol 2011; 55: 24564.
  • 9
    Sarrazin C, Berg T, Cornberg M, et al. Expert opinion on boceprevir- and telaprevir-based triple therapies of chronic hepatitis C. Z Gastroenterol 2012; 50: 5772.
  • 10
    Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54: 143344.
  • 11
    Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 95865.
  • 12
    Poordad F, McCone JJ, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1195206.
  • 13
    Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 120717.
  • 14
    Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 240516.
  • 15
    Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364: 241728.
  • 16
    Poordad F, Bronowicki JP, Gordon SC, et al. Factors that predict response of patients with hepatitis C virus infection to boceprevir. Gastroenterology 2012; 143: e5.
  • 17
    Estrabaud E, Vidaud M, Marcellin P, Asselah T. Genomics and HCV infection: progression of fibrosis and treatment response. J Hepatol 2012; 57: 111025.
  • 18
    Asselah T, Marcellin P. Direct acting antivirals for the treatment of chronic hepatitis C: one pill a day for tomorrow. Liver Int 2012; 32(Suppl. 1): 88102.
  • 19
    Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366: 21624.
  • 20
    Dusheiko G, Wedemeyer H. New protease inhibitors and direct-acting antivirals for hepatitis C: interferon's long goodbye. Gut 2012; 61: 164752.
  • 21
    Deuffic-Burban S, Deltenre P, Buti M, et al. Predicted effects of treatment for HCV infection vary among European countries. Gastroenterology 2012; 143: 97485.
  • 22
    Adinolfi LE, Gambardella M, Andreana A, et al. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001; 33: 135864.
  • 23
    Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997; 349: 82532.
  • 24
    Castera L. Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients with viral hepatitis. J Viral Hepat 2009; 16: 30014.
  • 25
    Castera L. Invasive and non-invasive methods for the assessment of fibrosis and disease progression in chronic liver disease. Best Pract Res Clin Gastroenterol 2011; 25: 291303.
  • 26
    Camma C, Petta S, Enea M, et al. Cost-effectiveness of boceprevir or telaprevir for untreated patients with genotype 1 chronic hepatitis C. Hepatology 2012; 56: 85060.
  • 27
    Foster GR, Hezode C, Bronowicki JP, et al. Telaprevir alone or with peginterferon and ribavirin reduces HCV RNA in patients with chronic genotype 2 but not genotype 3 infections. Gastroenterology 2011; 141: 8819 e1.
  • 28
    Gottwein JM, Scheel TK, Jensen TB, Ghanem L, Bukh J. Differential efficacy of protease inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant viruses. Gastroenterology 2011; 141: 106779.
  • 29
    Silva M, Kasserra C, Gupta S, et al. Antiviral Activity of Boceprevir Monotherapy in Treatment-Naive Subjects With Chronic Hepatitis C Genotype 2/3. The 21st Conference of the Asian Pacific Association for the Study of the Liver. 2011
  • 30
    Food and Drug Administration. Victrelis label information. 2011.
  • 31
    European Medicines Agency. Victrelis label information. 2012.
  • 32
    Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010; 376: 70516.
  • 33
    Foster GR, Zeuzem S, Andreone P, et al. Subanalyses of the telaprevir lead-in arm in the realize study: response at week 4 is not a substitute for prior null response categorization. J Hepatol 2011; 54: S34.
  • 34
    European Medicines Agency. CHMP assessment report: Victrelis. 2011.
  • 35
    Jeffry F, Jadhav Pravin R, Shashi A, et al. Boceprevir dosing for late responders and null responders: the role of bridging data between treatment-naive and experienced subjects. Hepatology 2012. doi: 10.1002/hep.25843
  • 36
    Lawitz E, Poordad F, Bronowicki JP, et al. The effect of using lower limit of quantitation (LLQ) vs lower limit of detection (LLD) for the definition of undetectable HCV RNA: data from the RESPOND-2 and SPINT-2 trials. Hepatology 2011; 54(Suppl.): 442A.
  • 37
    Fevery B, Susser S, Lenz O, et al. Comparison of two quantitative HCV RNA assays in samples from patients treated with a protease inhibitor-based therapy: implications for response guided therapy. J Hepatol 2012; 56: S26.
  • 38
    Bronowicki JP, Davis M, Flamm S, et al. Sustained virologic response (SVR) in prior peginterferon/ribavirin (PR) treatment failures after retreatment with boceprevir (BOC)+ PR: PROVIDE Study Interim Results. J Hepatol 2012; 56: S6.
  • 39
    Jacobson IM, Marcellin P, Zeuzem S, et al. Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin. Hepatology 2012; 56: 56775.
  • 40
    Incivo. EMA label information. 2011
  • 41
    Incivec. FDA label information. 2011
  • 42
    McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 58093.
  • 43
    Bieche I, Narjoz C, Asselah T, et al. Reverse transcriptase-PCR quantification of mRNA levels from cytochrome (CYP)1, CYP2 and CYP3 families in 22 different human tissues. Pharmacogenet Genomics 2007; 17: 73142.
  • 44
    Hulskotte E, Gupta S, Xuan F, et al. Pharmacokinetic interaction between the hcv protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers. Hepatology 2012; 56: 162230.
  • 45
    Kiser JJ, Burton JR, Anderson PL, Everson GT. Review and management of drug interactions with boceprevir and telaprevir. Hepatology 2012; 55: 16208.
  • 46
    Poordad FF, Lawitz EJ, Reddy KR, et al. A randomized trial comparing ribavirin dose reduction versus erythropoietin for anemia management in previously untreated patients with chronic hepatitis c receiving boceprevir plus peginterferon/ribavirin. J Hepatol 2012; 56: S559.
  • 47
    Pearlman B, Ehleben C. Hepatitis C virus (HCV) genotype 1 (GT1) infection with low viral load (LVL) and rapid virological response (RVR) to peginterferon and ribavirin (PEG/RBV) can be treated without a protease inhibitor (PI), irrespective of IL-28B status or patient ethnicity. Hepatology 2012; 56(Suppl.): 268A.
  • 48
    Buti M, Agarwal K, Horsmans Y, et al. OPTIMIZE Trial: Non-inferiority of twice-daily telaprevir versus administration of every 8 hours in treatment-naïve, genotype 1 HCV infected patients. American Association for the Study of Liver Diseases (AASLD). Hepatology 2012; abstract final ID: LB-8.
  • 49
    Petta S, Craxi A. How to optimize current HCV therapy in G1 patients: predictors of response. Liver Int 2012; 33(Suppl.). In press.
  • 50
    Chopra A, Klein PL, Drinnan T, Lee SS. Optimizing antiviral treatment of HCV genotype 1 patients: management of side effects. Liver Int 2012(Suppl). In press.