UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients
Alimentary Pharmacology & Therapeutics
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The nonstructural 3 serine protease inhibitors (PIs), boceprevir and telaprevir, represent the first in a new generation of directly acting antivirals against genotype 1 hepatitis C (HCV) infection. When used in combination with pegylated interferon and ribavirin, these drugs greatly improve sustained virological response rates in both treatment-naïve patients and patients who have had previous virological failure on treatment. However, the addition of these new agents will increase the complexity of therapeutic regimens, the rates of side-effects and costs.
To review concisely the current evidence and to suggest current best practice, for the use of telaprevir and boceprevir in the management of chronic genotype 1 HCV infection.
These guidelines for the use of boceprevir and telaprevir have been formulated following extensive review of the current literature, are based on the consensus opinion of a panel of national experts, and have been openly discussed and debated at a national meeting of HCV care providers.
We have made recommendations on a number of the key practical issues facing HCV care providers: (i) Which patients to treat?; (ii) Standards for the provision of care; (iii) Pre-treatment considerations; (iv) Which treatment regimens to use?; (v) Stopping rules; and (vi) Management of adverse effects. Finally, we have produced suggested algorithms for the assessment and treatment of these patients.
These UK Consensus guidelines indicate the current best practice for the use of boceprevir and telaprevir in the management of genotype 1 chronic HCV infection.
Efficacy of Protease Inhibitor-Based Therapy
Patients who have had virological failure with previous treatment
- Virological relapse: Patients who have undetectable HCV RNA at the end of treatment, but do not achieve an SVR (i.e. detectable HCV RNA during follow-up period).
- Virological partial response: Patients who have a ≥2 log10 IU/mL drop in HCV RNA by 12 weeks of treatment, but never achieve undetectable HCV RNA
- Virological null response: Patients who have a <2 log10 IU/mL drop in HCV RNA by 12 weeks of treatment
Cost-Effectiveness of PI Treatment
Factors Predictive of Response to Treatment
Table 3. Factors predisposing genotype 1 patients to a reduced likelihood of achieving an SVR with PI-based triple therapy
|High baseline HCV RNA levels (>800 000 IU/mL in most studies)|
|Presence of advanced fibrosis or cirrhosis|
|Adverse IL-28B genotype (CT/TT)|
|In previous treatment-failure patients: prior null response|
|Post-treatment initiation: reduction of <1 log10 IU/mL of HCV RNA after lead-in 4 weeks of peginterferon-ribavirin alone|
|Age (>40–45)||High BMI (>30)|
|Ethnic origin (Black vs. Nonblack)||Presence of Type 2 DM|
|HCV Genotype 1a|
|In previous treatment-failure patents: prior partial response|
With telaprevir treatment regimens, the adverse effect profile is slightly different from boceprevir (Table 5). Studies have shown an increase in skin rash (see below) and anorectal symptoms (discomfort and pruritus) with telaprevir treatment. The anorectal symptoms are usually tolerable for the duration of telaprevir treatment, and rarely (0.5%) led to discontinuation.
Anaemia in PI treatment
Rash in PI treatment
- Mild localised.
- Severe affecting >50% surface area or mucous membranes or with systemic symptoms
- (including SCARs.2)
HCV RNA Testing
- Due to the improvements in cure rates and potential for shortened therapy, protease inhibitor-based regimens should be considered for all genotype 1 chronic HCV-infected patients. This is applicable for treatment-naïve patients and patients who have had virological failure following prior exposure to SoC therapy
- Where resources determine that there may be a delay in initiation of treatment, priority for PI treatment should be based on clinical need. Specific consideration should be given to patients likely to develop complications in the next 5 years or who have other pressing need for early therapy (e.g. concerns regarding fertility or disabling nonhepatic consequences of infection). Conversely, certain patients with a good liver prognosis may, following discussion, elect to wait for novel therapies.
- Nongenotype 1 chronic HCV-infected patients should be treated without a PI, according to SoC regimens.
- The adoption of PI-based regimens should not reduce the total number of HCV-infected patients being treated and cured.
- Due to the importance of RGT and stopping rules in PI-based regimens and the increased risk of adverse effects, the use of PI treatment should be limited to centres providing the following standards of care:
- Adherence to national standards for HCV.
- Continuous audit of SVR rates to therapy.
- Continuous audit of treatment discontinuation rates.
- A high level of expertise in the use of anti-viral drugs.
- Access to viral load estimation results within five working days of sampling.
- Access to HCV PCR with a lower limit of detection of at most 15 IU/mL.
- Access to non-invasive investigations and/or liver biopsy to assess the degree of hepatic fibrosis.
- Sufficient specialised medical and nursing staff to provide year round support to patients on therapy.
- A series of protocols to minimise the risk of developing and to manage adverse reactions to therapy.
- A comprehensive and skilled consultation service for patients emphasising the risks and benefits of therapy along with the requirement for adherence.
- Where possible, all patients should be invited to participate in ongoing research initiatives (e.g. enrolment to the HCV research UK3 database).
- Ongoing recruitment to clinical trials should continue where feasible.
- Assessment of likelihood of response.
- All patients should have an assessment including baseline viral titres, an assessment of disease stage/cirrhosis (using non-invasive means or biopsy) and other demographic factors (see Table 3).
- IL-28B genotyping and subtyping of HCV virus (1a or 1b) have some predictive value for treatment response, and may be used with other data to assist management discussions with patients about therapy, but are not required for treatment decisions.
- In previously treated patients, if the data are available to determine the degree of prior response, this should be used to aid decision on treatment duration.
- Co-morbid conditions.
- HIV co-infected patients are at risk of rapid liver disease progression. Although no large scale clinical trial data currently exists, relevant drug interactions have been studied and treatment with PIs may be considered by expert physicians on a case-by-case basis, with active recruitment to ongoing clinical trials where available or audit of outcomes.
- Protease inhibitor-based triple therapy can not currently be recommended in patients with decompensated liver disease, hepatitis B co-infection, active cancer or post-transplant due to limited data. The use of protease inhibitor triple therapy regimens in these groups should be the subject of new clinical trials.
- Caution should be exercised in using PI treatment in patients with significant baseline neutropenia (<1200/mm3), thrombocytopenia (<90 000/mm3) or anaemia (Hb <12 g/dL for females or Hb <13 g/dL for males).
- Due to potentially dangerous drug–drug interactions, dual peginterferon and ribavirin therapy might be considered more appropriate for some patients where there are serious concerns regarding these interactions with prescribed or illicit medication.
- Dual therapy should be considered in conditions that impair adherence to therapy and thus reduce the effectiveness of triple therapy and increase the risk of development of resistance mutations.
- Depression does not appear to be increased with PI treatment, but should be considered and monitored as per SoC treatment regimes.
- Drug interactions.
- Prior to prescribing a PI, a careful drug history (prescribed and nonprescribed) should be taken and relevant prescribing information and databases (e.g. www.hep-druginteractions.org) should be consulted for any potential drug–drug interactions. Primary Care providers need these issues specifically highlighted to avoid potentially ‘toxic’ interactions on therapy.
Which peginterferon-ribavirin to use?
The treatment regimens used differ between the two PIs and the different trials. One critical difference between the studies is the use of different peginterferon-ribavirin preparations and doses. In general, in the boceprevir studies, pegylated IFN-2b (PegIntron; Merck, Whitehouse Station, NJ, USA) at a dose of 1.5 μg/kg once weekly and ribavirin (Rebetol; Merck) at weight-based dose of 600–1400 mg daily in two divided doses were used. In the telaprevir studies, pegylated IFN-2a (Pegasys; Roche, Welwyn Garden City, UK) at a dose of 180 μg/week and ribavirin (Copegus; Roche) at a weight dependent dose of 1000 mg (<75 kg) or 1200 mg (≥75 kg) per day were used. Direct comparison studies between Peg IFN-2a and Peg IFN-2b in SoC treatment have not shown any significant difference in overall response rates. Furthermore, in small studies, telaprevir has been used with Peg IFN-2b and boceprevir with IFN-2a with no detrimental effect.
Peg IFN-2a or Peg IFN-2b can be used interchangeably with either telaprevir or boceprevir according to local preferences.
Ribavirin brands can be used interchangeably in treatment regimens.
Which protease inhibitor to use?
The documented evidence clearly shows a benefit for the use of either boceprevir or telaprevir as part of a triple therapy regimen in both treatment-naïve patients and patients with previous virological failure. Largely, the magnitude of beneficial effect is similar for either drug. No direct comparison studies between boceprevir and telaprevir have been conducted, and thus, neither drug can be recommended over the other. However, specific characteristics of each drug may lead to their use in certain circumstances. Boceprevir-based regimens use a 4-week lead-in with peginterferon-ribavirin, which may offer extra information on treatment tolerability and the likelihood of achieving an SVR. In addition, differences in side-effect profiles and the duration of treatment may lead to the choice of either PI for specific patients. Furthermore, the pill burden for patients differs, with boceprevir currently four tablets t.d.s., whereas telaprevir is two tablets t.d.s. It is therefore important that both drugs are available to treating units to enable selection of the most appropriate regimen for individual patients.
Both boceprevir and telaprevir are effective and should be available for use by treating units.
Which regimens to use?
As discussed above, triple therapy regimens with either boceprevir or telaprevir for genotype 1 chronic HCV-infected patients significantly improve SVR rates in both treatment-naïve and experienced patients. Some treatment-naïve patients achieve high SVR rates with SoC treatment alone. Specifically, noncirrhotic genotype 1 patients who have a low baseline viral load (<400 000–800 000 IU/mL) and achieve an RVR (HCV RNA undetectable (≤50 IU/mL) at 4 weeks of treatment) with peginterferon-ribavirin are highly likely (80–90%) to achieve an SVR. Indeed, the achievement of an RVR and low basal viral loads are the most significant predictors of achieving an SVR with SoC treatment, and recent guidelines would suggest that treatment duration with peginterferon-ribavirin in these patients could be shortened to 24 weeks. Thus, such good response group patients may not gain much additional benefit in SVR rates from the addition of a PI, but will be exposed to the increased side-effects and risks of resistance. Furthermore, the use of PIs in this group of patients is unlikely to be cost-effective (see above).
As discussed, some of the protease inhibitor clinical trial arms compared response-guided therapy (RGT) with fixed-duration therapy. In treatment-naïve patients, both the SPRINT-2 and ADVANCE studies showed that response-guided therapy had no detrimental effect on overall SVR rate. Furthermore, using RGT in the ADVANCE study enabled reduced treatment duration to 24 weeks in 58% of patients. In addition, the ILLUMINATE study demonstrated that in patients who achieve an eRVR (undetectable HCV RNA at treatment weeks 4 and 12) on telaprevir-based triple therapy, overall treatment can be reduced to 24 weeks with no detrimental effect on SVR rate. In treatment-experienced patients, in the RESPOND study, no statistically significant differences were seen with boceprevir between the RGT arm and the fixed-duration therapy of 48 weeks. However, nonsignificant trends were observed to better SVR rates in the 48 week treatment duration in both prior relapsers and partial responders. In the REALISE study, no RGT arm was included.
The presence of advanced hepatic fibrosis or cirrhosis is a major risk factor for treatment failure. In the PI studies comparing RGT with fixed-duration treatment, the number of patients with cirrhosis is generally small. Furthermore, in these patients, there are nonsignificant trends towards better SVR rates with fixed-duration therapy.[16, 20, 41] Therefore, there is currently insufficient evidence for the use of RGT in cirrhotic patients.
The most difficult to treat group of patients, cirrhotic prior null responders, were only specifically studied in the REALISE trial, with fairly modest numbers. Whilst there was an improved outcome in these patients with telaprevir-based triple therapy compared with SoC, the SVR rate was still only 22–28%. Furthermore, relapse rates were high (25–27%) with even higher levels of virological failure (47–57%), predominantly due to the emergence of resistant variants. Detailed analysis of the lead-in peginterferon-ribavirin T12PR48 group demonstrated that in prior null responders, poor response to lead-in therapy (<1 log10 reduction in HCV RNA at week 4) was also predictive of a poor SVR rate of under 20%. Similarly, in RESPOND-2, a poor response to lead-in peginterferon-ribavirin was associated with low SVR rates in prior partial responders. Therefore, whilst improved over previous therapies, SVR rates are likely to remain low in cirrhotic prior null responders, particularly in the context of a poor response to lead-in peginterferon-ribavirin. Treating these patients with PIs is also likely to increase development of resistance mutants, potentially jeopardising the use of future DAAs. Therefore, careful consideration should be given to the best management option for this group.
Regimens in treatment-naïve patients (see Figure 1).
Either boceprevir or telaprevir can be used according to the relevant prescribing information.
In noncirrhotic treatment-naïve patients with low baseline viral loads (<800 000 IU/mL) and no additional risk factors for treatment failure, who are treated with regimens incorporating a 4 week lead-in with peginterferon-ribavirin and who achieve an RVR following lead-in, consideration can be given to continuing treatment with SoC therapy alone without addition of a PI. This decision should be made following a balanced discussion with the patient regarding the rates of SVR and the potential side-effects from the addition of a PI.
Response-guided therapy with either boceprevir or telaprevir can be used in noncirrhotic treatment-naïve patients, enabling reduced treatment duration in a proportion of patients with no adverse effects on SVR. This should be done according to the relevant prescribing information.
In cirrhotic treatment-naïve patients, a full 48 week course of treatment, incorporating 12 weeks of telaprevir or 44 weeks of boceprevir, should be instituted according to the relevant prescribing information
Figure 1. Proposed algorithm for the use of protease inhibitors in treatment-naïve HCV genotype 1 infected patients. Pre-treatment assessment should include careful consideration of lifestyle factors, co-morbid conditions, potential drug interactions (prescribed and nonprescribed) and assessment for the presence of cirrhosis (by non-invasive or invasive means). In noncirrhotic patients, the presence of factors predictive of a poor response to therapy should be evaluated (#IL-28B genotype; age; ethnic origin; BMI; Type 2 diabetes; HCV genotype 1a vs. 1b). *In noncirrhotic patients with no risk factors for a poor response to therapy, the decision to use a 4-week lead-in with peginterferon and ribavirin and to continue on SoC in those who achieve an RVR should only be taken following careful and balanced discussion with the patient.
Regimens in patients with previous virological failure (see Figure 2).
Either boceprevir or telaprevir can be used according to the relevant prescribing information.
Where no data are available on the degree of previous response, patients should be treated with a full treatment course as per prior null responders to maximise cure rates.
In patients with factors predicting poor treatment response, who also currently have a low risk of progressive liver disease, before therapy, a discussion should occur to consider watchful waiting as an alternative to PI treatment pending the development of new treatment options.
Figure 2. Proposed algorithm for the use of protease inhibitors in HCV genotype 1 infected patients who have had prior virological failure on treatment. Pre-treatment assessment should include careful consideration of lifestyle factors, co-morbid conditions, potential drug interactions (prescribed and nonprescribed), assessment for the presence of cirrhosis (by non-invasive or invasive means) and the presence of factors predictive of a poor response to therapy. Identification of the degree of previous response should be attempted. If this information is not available, patients should be considered as prior null responders to maximise cure rates. *In cirrhotic prior null responders, the decision to watch and wait for novel therapies or to use a 4-week lead-in with peginterferon and ribavirin to identify patients more likely to achieve an SVR should only be taken following careful and balanced discussion with the patient.
- All treatment should be stopped if HCV RNA is >100 IU/mL at treatment week 12 (week 8 of boceprevir) or HCV RNA is detectable at treatment week 24 (week 20 of triple therapy).
- If there is virological breakthrough4 or incomplete virological response and rebound,5 treatment with boceprevir should be stopped, but peginterferon-ribavirin may be continued up to 48 weeks at the discretion of the treatment team.
- All treatment should be discontinued in patients who have an HCV RNA level >1000 IU/mL after 4 weeks or 12 weeks of triple therapy.
- All treatment should be discontinued if <2 log10 decline from baseline in HCV RNA levels after week 12 of triple therapy
- All treatment should be discontinued if HCV RNA is detectable at any point between treatment week 24 and 44.
- Telaprevir treatment should be stopped if there is virological breakthrough or incomplete virological response and rebound, but peginterferon-ribavirin may be continued at the discretion of the treatment team
- In cirrhotic prior null responders treated with regimens incorporating 4 week lead-in peginterferon-ribavirin, who achieve an HCV RNA reduction of <1 log10 IU/mL following lead-in, consideration should be given to stopping treatment. This should be following a balanced discussion with the patient regarding the consequences of a delay in therapy, low SVR rates, high chance of resistance mutations and potential effects this might have on eligibility for next generation treatments (Figure 2).
Management of anaemia in PI treatment:
- Anaemia (defined as Hb <10 g/dL) in the context of PI treatment should be managed using an escalating combination of:
- Ribavirin dose reduction: it should be started at full treatment dose and dose reduction instituted for anaemia at decrements of 200 mg.
- Reduction in dose of interferon, if bone marrow suppression is evident.
- Erythropoietin administration may be considered and used until Hb > 12 g/dL.
- Supportive treatment with blood transfusion should be considered in extreme circumstances.
- The dose of protease inhibitor should not be reduced for managing anaemia. If required, due to the severity of anaemia, the PI should be stopped completely
- Management of neutropenia.
- Significant neutropenia (absolute neutrophil count <750/mm3) should be managed according to current practice for SoC treatment. Consideration should be given to dose reduction of Pegylated interferon.
- The dose of protease inhibitor should not be reduced for managing neutropenia or bone marrow suppression. If required due to the severity of neutropenia, the PI should be stopped completely.
- Management of rash in telaprevir-treated patients.
- Rash management plan.
- Mild/moderate: Topical steroids, topical anti-histamines, avoidance of sun exposure, wearing loose-fitting clothes. Continue triple therapy.
- Moderate progressive: Stop telaprevir. Monitor for 7 days and consider stopping peginterferon-ribavirin if not improving.
- Severe or SCARs: Stop all treatment. Urgent dermatology review.
The advent of protease inhibitor-based triple therapy for chronic genotype 1 HCV infection heralds a new era of treatment for these patients. Cure rates are significantly enhanced, and there is now a viable therapeutic option for the large group of patients who previously failed SoC therapy. Clearly, the ongoing development of the second generation PIs and other directly acting antiviral drugs will yield further improvements in the future, but the judicious use of boceprevir and telaprevir in clinical practice will be invaluable for the management of chronic HCV infection in 2012.
List prices obtained from National Electronic Library for Medicines (http://www.nelm.nhs.uk/en/).
Severe Cutaneous Adverse Reactions (SCARs) includes DRESS (drug rash with eosinophilia and systemic symptoms) and Stevens-Johnson Syndrome.
HCV research UK is a Medical Research Council (MRC) funded initiative to create a database and biobank of 10 000 HCV-infected patients for research and quality improvement.
Virological breakthrough is defined as an achievement of undetectable HCV RNA with subsequent occurrence of HCV RNA >1000 IU/mL.
Incomplete virological response and rebound is defined as an ‘on treatment’ increase of 1 log10/mL of HCV RNA from the nadir with the HCV RNA level >1000 IU/mL.
- 15 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: 705–16., , , et al.
- 24 Cost-Effectiveness of Boceprevir Based Regimens in Previously Untreated Adult Subjects with Chronic Hepatitis C Genotype 1. San Francisco: AASLD, 2011., , , et al.
- 25 Cost-effectiveness of Boceprevir Use in Patients with Chronic Hepatitis C Genotype-1 Who Failed Prior Treatment with Peginterferon/Ribavirin. San Francisco: AASLD, 2011., , , et al.
- 26 The Cost-Effectiveness of a Telaprevir-Inclusive Regimen as Initial Therapy for Genotype 1 Hepatitis C Infection in Individuals with the CC IL-28B Polymorphism. San Francisco: AASLD, 2011., , , et al.
- 34 Different likelihood of achieving svr on a telaprevir-containing regimen among null responders, partial responders and relapsers irrespective of similar responses after a peginterferon/ribavirin 4-week lead-in phase: realize study subanalysis. Hepatology 2011; 54: 986A–7., , , et al.
- 40 Long-term follow-up of patients with chronic hepatitis c treated with telaprevir in combination with peginterferon alfa-2a and ribavirin: interim analysis of the extend study. Hepatology 2010; 52: S436A., , , et al.
- 42 Impact of anemia and ribavirin dose reduction on SVR to a telaprevir-based regimen in patients with HCV genotype 1 and prior peginterferon/ribavirin treatment failure in the phase III REALIZE study. Hepatology 2011; 54: 1007A–8., , , et al.
- 43 Effect of On-Treatment Undetectable or Detectable/BLOQ HCV RNA MEasurements on SVR Rates in Phase 3 Clinical Trials of Boceprevir and Telaprevir. In: 6th International Workshop on Hepatitis C – Resistance and New Compounds; 2011 24/06/2011; Cambridge, USA; 2011., .
- 44 Hepatitis C action plan for Scotland: phase II (May 2008–March 2011). Euro Surveill 2008; 13: 211–2., , , et al.
- 46 High sustained virologic response (SVR) among genotype i previous Non-responders and relapsers to peginterferon/ribavirin when re-treated with boceprevir (BOC) plus peginterferon alfa-2A/ribavirin. Gastroenterology 2011; 140: S145., , , et al.
- 48 Dual therapy with the NS5A inhibitor BMS-790052 and the NS3 protease inhibitor BMS-650032 in HCV genotype 1b-infected null responders. Hepatology 2011 [Epub ahead of print]., , , et al.