Treatment with telaprevir or boceprevir

7.3 Treatment with telaprevir or boceprevir

Treatment with telaprevir or boceprevir, given in combination with pegylated interferon and ribavirin, is suggested for genotype 1 chronic hepatitis C infection rather than pegylated interferon and ribavirin alone. Conditional recommendation, moderate quality of evidence Treatment regimens • Treatment duration of telaprevirPEG-IFNRBV for treatment-naive patients is 24–48 weeks depending on the response to treatment telaprevir is given for 12 weeks only. • Treatment duration of boceprevirPEG-IFNRBV in treatment-naive patients is 28–48 weeks depending on the response to treatment. • Treatment duration in previously treated patients varies by previous response to treatment. Background The PIs boceprevir and telaprevir, used in combination with PEG-IFN and RBV, have substantially increased SVR rates in persons with genotype 1 HCV infection. 84,85,170 These PIs have limited activity against other genotypes and are therefore licensed for use only in persons infected with HCV genotype 1. The availability of newer DAAs for HCV will expand rapidly over the coming years and the treatment guidelines will be updated accordingly as these are licensed for use; these have a broader spectrum of activity and are likely to be suitable for non-genotype 1 infections. The use of PIs adds substantial costs to treatment regimens and increases the likelihood of adverse events and thus the need for frequent monitoring for side-effects. Current administration schedules are discussed in Chapter 8: Monitoring. Evidence A systematic review of the DAAs telaprevir and boceprevir versus PEG-IFNRBV alone for adults with chronic genotype 1 HCV infection provided high-quality evidence for the outcome of SVR; DAAPEG-IFNRBV would result in 315 per 1 000 fewer virological failures compared with PEG-IFNRBV given alone baseline failure rate 643 per 1 000. Triple therapy was found to be effective in persons with both mild and advanced liver ibrosis. The incidence of side-effects was higher in persons treated with triple therapy and there was moderate-quality evidence that the inclusion of a PI increased the treatment discontinuation rate from a baseline of 95 cases per 1 000 by 17 additional cases per 1 000. In addition, there was high-quality evidence that a PI given with PEG-IFN and RBV was associated with 41 additional cases of grade 3 or 4 anaemia Hb 8.5 gdL per 1 000 persons baseline with IFN and RBV only: 22 cases of anaemia per 1 000 persons. Evidence of an increase in cases of grade 3 or 4 neutropenia was moderate and increased the risk from 174 cases per 1 000 by 106 additional cases per 1 000. Deaths occurred less frequently, however, in persons treated with a PI from 6 deaths per 1000 to 3 deaths per 1 000. The CUPIC Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study 171 revealed a higher risk of side-effects in treatment-experienced persons with compensated cirrhosis. Among 497 persons who completed at least 16 weeks of treatment with PEG-IFNRBV and either telaprevir or boceprevir, 40 of patients developed a serious adverse event and 11.7 had to stop therapy. Those patients with a starting serum albumin level of 35 gL or a platelet count ≤100 x10 9 L were at highest risk. 172 The use of DAAs has been inadequately studied in children as they were excluded from the phase III studies of boceprevir and telaprevir. 84,85 Boceprevir and telaprevir are approved only for adults 18 years of age. Triple therapy with boceprevir or telaprevir and PEG-IFNRBV is currently being tested in HIV-positive patients in phase III clinical trials. A major potential problem is that of drug–drug interactions see Table 8.3. Both boceprevir and telaprevir are inhibitors of CYP3A4, which mediates many drug metabolic pathways and therefore any potential interaction must be carefully evaluated before commencing treatment. c Boceprevir has been been evaluated in HIV-positive individuals who were either not on ART or were treated with two nucleoside reverse transcriptase inhibitors NRTIs plus one of the following agents: efavirenz, raltegravir, lopinavir ritonavir, atazanavirritonavir or darunavirritonavir. Data from these studies has led to the FDA recommendation that efavirenz and PIs should not be used with boceprevir but that raltegravir can be co-prescribed. Telaprevir is currently in phase III trials in patients receiving a dual NRTI backbone plus one of efavirenz telaprevir must be given in a higher dose, raltegravir or atazanavirritonavir. Further studies exploring the potential for drug–drug interactions between ART c. A useful resource for searching for drug–drug interactions can be found at the following website: http:www.hep-druginteractions.org. regimens and newer compounds under development for the treatment of HCV are eagerly awaited and phase III trials of simeprevir, faldaprevir, and the NS5A inhibitor daclatasvir are under way among persons with HIV infection. Rationale for the recommendation Balance of benefits and harms: The consideration of the Guidelines Development Group was that the addition of telaprevir or boceprevir to a PEG-IFN and RBV- based regimen provided the beneit of an increased likelihood of SVR. Persons treated with these DAAs had an estimated SVR almost twice that of persons receiving only PEG-IFN and RBV. However, these two DAAs also considerably increased the likelihood of harms, in particular, anaemia and neutropenia. The use of these medicines among persons with more advanced liver disease resulted in high rates of treatment discontinuation. Despite this, the Guidelines Development Group concluded that the beneit of increased SVR outweighed the increased risk of side-effects, and that triple therapy for genotype 1 HCV infection was preferable to dual therapy. Values and preferences: The inclusion of a DAA to a PEG-IFN and RBV-based regimen was considered to be likely to be acceptable due to the substantially higher chance of SVR. The considerable risk of adverse events would be a deterrent to individuals, particularly as safer medicines are now available. No dificulties were anticipated in relation to unforeseen consequences or cultural contexts. Some dificulty in obtaining high-fat meals for cultural reasons, for example during Ramadan, was considered by the Group but it was thought likely that stakeholders would approve use in the context of medical illness. Resource considerations: The resources required to treat patients with a PI in addition to PEG-IFNRBV include treatment costs and the costs associated with increased frequency of laboratory and clinical monitoring. An important barrier to the use of boceprevir and telaprevir is their high cost US 55 000 and US 37 000, respectively, in the United Kingdom for a single course of treatment, in addition to the cost of PEG-IFNRBV. 95,96 Additional costs are related to the need for greater frequency of monitoring for and treatment of adverse events while using these medicines. In high-income settings, an assessment by the National Institute for Health and Clinical Excellence in the UK evaluated DAAs as being cost–effective. 95,96 For patients with mild disease METAVIR F0–F1, the incremental cost was considered to be small relative to the net beneit. For more advanced disease F4, due to the increased risk of severe adverse events, this was considered to be less certain and would be likely to require increased monitoring, particularly for evidence of anaemia. Feasibility is variable in different infrastructure and health-care service settings. While DAA therapy is associated with a marked increase in SVR rate, it is also associated with an increase in the incidence of adverse reactions. Monitoring for these adverse reactions does not require different laboratory tests from those used to monitor IFN and RBV therapy, but does require more frequent clinic visits primarily to assess rash and laboratory tests primarily to assess anaemia. Thus, policy-makers will need to consider the impact on the health system of these additional tests and visits. Athough persons with more advanced disease have more side-effects and a lower chance of SVR, the potential beneits of achieving SVR are signiicantly higher. The availability of enhanced monitoring is likely to be highly context- speciic in low- and middle-income countries. In countries that can afford triple therapy, it was considered by the Group that it should be feasible to also fund appropriate monitoring. Implementation First-generation triple therapy should be given in centres where appropriate clinical and laboratory monitoring can be carried out and where experienced clinicians are available for advice. The availability and cost of irst-generation DAAs varies in different countries and is likely to affect the feasibility of roll- out, especially in low-income settings. The duration of therapy is dependent on treatment response and previous response to antiviral therapy see Section 8.2. HCVHIV-coinfected persons treated with PEG-IFNRBV and a irst-generation PI who require HIV therapy should be treated with compatible ART Table 8.3. They require regular monitoring of CD4 counts during treatment. 173 Research questions Data on the use of irst-generation DAAs in children is an important area for future research. Improvements in virological response may lead to improvements in liver-related morbidity and mortality. However, there are no direct data available from studies to make deinite conclusions about longer-term outcomes. Data are also missing on the use of these medicines in low- and middle-income countries.

7.4 Introduction to recommendations concerning sofosbuvir and simeprevir