Trends in Hepatitis C Virus Infection Therapy: Protease Inhibitors a Step Forward in the Era of Direct Acting Antivirals

Trends in Hepatitis C Virus Infection Therapy: Protease Inhibitors a Step Forward in the Era of Direct Acting Antivirals CRISTINA POPESCU 1, 2, SMARANDA GLIGA 1, VICTORIA ARAMĂ 1, 2 1 Matei Bals National Institute of Infectious Diseases, Bucharest, Romania 2 Carol Davila University of Medicine and Pharmacy, Bucharest, Romania The standard of care for the treatment of HCV infected patients was until 11 the association peginterferon-ribavirin with a sustained virologic response of 5%. In 11 another class of antivirals was approved by the FDA and EMEA the HCV-NS3 protease inhibitors. Two molecules are now available: boceprevir and telaprevir. The protease inhibitors are used in association with peginterferon and ribavirin, which remain vital therapy components. Protease inhibitor regimens substantially increased the rate in naïve patients and also in previously relapse patients. Because of the high risk of emerging resistance to protease inhibitors, prior null responders are not yet suitable candidates for triple therapy, the rate in these patients is still very low. Keywords: protease inhibitor, HCV, treatment, sustained virologic response. A. INTRODUCTION B. BACKGROUND Chronic HCVinfection is an important public health problem, affecting more than million people globally (approximately 3% of the global population), patients infected being at risk for progression to cirrhosis (3%) and hepatocellular carcinoma (5%) [1]. What is vital to know is that HCV infection can be cured, the cure rate depending also on the accuracy of antiviral treatment administration. Recent years have signalled a real effervescence regarding introduction of new antiviral drugs, especially the ones with direct antiviral action (DAA direct acting antiviral). Because the response rate to the current standard of care is around 5% [2], two important problems need solving in the near future: improving treatment response for naïve patients and finding new therapeutic solutions for previously treated patients, with therapy failure. The introduction of protease inhibitors represents a major step in managing patients infected with HCV genotype 1, widely accepted as the most frequently involved and difficult to treat viral genotype [3]. The major purpose of antiviral therapy in HCV infected patients is obtaining Sustained Virologic Response (), i.e. demonstrating undetectable HCV viral load, 6 months after completion of therapy. Treatment of HCV infection has consistently improved since 1989. The rate has continually increased through permanent changes made to the STANDARD of CARE (SoC). Thus, from the introduction of standard interferon monotherapy with a duration of 6 months and an of 6%, therapy has changed permanently in order to increase the cure rate. Ribaviarin was the first milestone along the road, which caused an additional 3%. A second milestone was pegylated interferon with improved pharmacokinetic and pharmacodynamic qualities, adding 25% of versus standard interferon [4]. Increasing the rate of to 75 % by adding IP to SoC is clearly a step forward in the fight against HCV (Fig. 1). In addition, a better knowledge of the adverse effects of antiviral drugs in adjunction to supportive medication (erythropoietin) determines a lower rate of therapeutic discontinuation and obviously improves the rate. ROM. J. INTERN. MED., 12, 5, 2, 117 127

118 Cristina Popescu et al. 2 PEG-RBV-PI PEG-RBV 12 m 54 PEG 12 m 39 IFN-RBV 12 m IFN-RBV 6 m 34 42 IFN 12 m 16 IFN 6 m 6 6 1 Fig. 1. History of HCV treatment. C. USE OF PROTEASE INHIBITORS IN CHRONICALLY HCV INFECTED PATIENTS Improved knowledge of the HCV life cycle, its complex structure, led to the discovery of new compounds, so-called Directly acting antiviral agents (DAA). Among the many molecules that are currently under evaluation, two molecules belonging to the IP class receive extensive studies including Phase III trials, and were recently introduced in international treatment guidelines, for both naïve and previously treated patients in therapy failure. We are talking about boceprevir (approved for use in May 11 in the and July 11 in the EU) and telaprevir (approved for use in May 11 in the and September 11 in the EU). We cannot predict when the rest of the molecules under study will be used in the treatment of HCV infection. If we were to consider what happens overall to HCV chronically infected patients following the current SoC, we could say that: 5% register 25% are relapsers % are non-responders 5% register breakthrough (Fig. 2). Because only half of HCV chronically infected patients have a favorable response to the current regimen, the need for new molecules that can improve rates is self-evident. RESPONSE RATE 1 patients 5 patients RVS 5 patients non-rvs 99% undetectable at 5 years 25 relapse 5 breakthrough null responders Failure Require re-treatment Fig. 2. The virologic response after PEG-RBV.

3 Trends in Hepatitis C Virus Infection Therapy 119 C.1. USING PI IN NAIVE PATIENTS a. Using boceprevir in naive patients Boceprevir is the first PI introduced in the treatment of HCV infection. The efficacy of boceprevir in treating naïve patients was demonstrated by clinical trials: SPRINT 1 [5] (Phase 2) and SPRINT 2 [6] (Phase III) that led to the approval of its marketing. The SPRINT I study followed the safety, tolerability and antiviral effectiveness of boceprevir in combination with peg interferon and ribavirin and included 5 naïve patients who were randomly assigned in one of the 5 groups: peginterferonribavirin for 48 weeks (PR48w), boceprevirpeginterferon-ribavirin for 24 weeks (BPR24w), boceprevir-peginterferon-ribavirin for 48 weeks (BPR48w), 4 weeks lead-in with peginterferonribavirin then boceprevir-peginterferon-ribavirin for 24 weeks (PR4w/BPR24w) and 4 weeks lead-in with peginterferon-ribavirin then boceprevir-peginterferon-ribavirin for 44weeks (PR4w/BPR44w). Figure 3 shows the rates, according to the treatment regimens that were used. The best rate was achieved with lead-in regimen followed by triple therapy for 44 weeks. The addition of boceprevir to PR is associated with an improved of 37%. 1 6 38 55 67 56 75 PR48 BPR 24 BPR48 PR4/BPR24 PR4/BPR44 Fig. 3. The effectiveness of triple therapy using boceprevir, with different regimens. In the phase III SPRINT 2 study 197 naïve patients were included, subsequently randomised in three arms, after a lead- in period of 4 weeks with PR: the first arm with PR and placebo; the second arm used response guide therapy with BPR for 24 weeks, then PR for another weeks and the third arm with 44 weeks of BPR. rates were 38% for arm 1, 63% for arm 2 and 66% for arm 3. Both SPRINT studies demonstrated an additional rate of at least 25%. b. Using telaprevir in naive patients PROVE 1 [7] and PROVE 2 [8] studies evaluated telaprevir- peg interferon- ribavirin (TPR) triple therapy regimens in patients infected with genotype 1 virus. PROVE 1 included 233 patients randomized in one of the three arms. Patients who had received peg interferon- ribavirin (PR) placebo for 48 weeks were included in the control group. Patients who received telaprevir were divided as follows: 12 wks telaprevir + 12 wks PR 12 wks telaprevir + 24 wks PR 12 wks telaprevir + 48 wks PR The rates are presented in Fig. 4. The highest rate was obtained with the 12 week triple therapy regimen followed by 36 weeks of PR. PROVE 2 study enrolled 334 naïve patients, who received various regimens containing telaprevir. The results were similar to the PROVE 1 study. The regimen with the highest was the 12 week telaprevir- peginterferon-ribavirin, followed by 36 weeks of peg interferon- ribavirin. Both PROVE 1 and PROVE 2 studies have shown that shortening the duration of antiviral treatment with peg interferon-ribavirin lowers the rate. In addition, these studies emphasized the role of ribavirin in reducing the risk of relapse and breakthrough.

1 Cristina Popescu et al. 4 1 9 7 6 5 3 1 67 61 5 41 PEG-RBV-placebo 12T12PR 12T24PR 12T48PR Fig. 4. The effectiveness of different triple therapy regimens with telaprevir. The Phase 3 ADVANCE [9] study enrolled 188 patients who were divided into three arms: arm 1 with PR and placebo for 48 weeks (PR48w), arm 2 8 weeks triple therapy followed by response guided duration of PR (T8PR) and arm 3 12 weeks triple therapy, followed by response guided duration of PR (T12PR). Patients with undetectable viral loads at 4 and 12 weeks, received only 24 weeks of treatment. Those with positive viral loads at 4 weeks received 48 weeks of treatment. The best rate was achieved for patients who received 12 weeks of telaprevir (75% vs. 69% if telaprevir was given for 8 weeks) (Fig. 5). These three studies were the basis for the approval of telaprevir marketing. In 11 the results of the ILLUMINATE [1] study were published. This study included 5 naïve patients who received 12 weeks of TPR followed by response guided therapy with PR. The patients with extended rapid virologic response (E-RVR undetectable viral load at weeks 4 and 12 of TPR) were randomly assigned in one of the two groups: T12PR24 and T12PR48. All the patients without received 48 weeks of PR. The rates for the patients with E-RVR were 92% for T12PR24 arm and 88% for T12 PR48 arm, establishing noninferiority of short treatment for the patients with E-RVR. 1 6 69 75 44 PR48 T8PR T12PR Fig. 5. The effectiveness of triple therapy regimens with telaprevir and response guided therapy PR. C.2. USING PIS IN EXPERIENCED PATIENTS About half the patients treated with PEG- RBV fail to achieve. These patients require re-treatment with new molecules that improve the response rate. Patients who have failed previous therapies can be grouped into: Relapser patient with undetectable viral load (VL) at end of treatment but detectable VL after 6 months of follow-up Partial virologic response reduction of VL with at least 2log1 after 12 weeks of treatment, but not undetectable VL Null- responders reduction of VL with less than 2log1 after 12 weeks of treatment.

5 Trends in Hepatitis C Virus Infection Therapy 121 a. Using boceprevir in previously treated patients The RESPOND-2 (11) study enrolled 3 experienced patients in therapeutic failure, prior relapsers or partial responders. They were divided into three branches: 4 wks PR (lead-in), then PR-placebo 44 wks 4 wks PR (lead-in), then PR-BOC 32 wks 4 wks PR (lead-in), then PR-BOC 44 wks The best rate, of more than 65%, was achieved with 48 weeks of PEG-RBV and 44 weeks of boceprevir. Compared to the control group, treated with PEG-RBV with an rate of 21%, it is estimated that the association of boceprevir increases the rate to 66%. For relapsers there is a 29% to 75% increase in the (Fig. 6) and for partial response patients an increase from 7 to 52% (Fig. 7). It can be appreciated that for relapsers the combination of PIs has become imperative, while for partial response patients further studies are needed in order to decide whether the association of a PI is sufficient. Unfortunately, the risk of developing resistance to a PI is very high, therefore it has been decided that for nonresponders with a low degree of fibrosis (F1-F2) therapy should be postponed until the release of new molecules that could improve the response rate. PI resistance develops in half the patients, compromising future regimens that contain new molecules (nucleoside or non-nucleoside NS5B polymerase inhibitors, NS5A inhibitors) and need the association of a PI. Triple therapy can be used for patients with a high degree of fibrosis (F3, F4), at risk for progression to HCC. 1 9 7 6 5 3 1 66 59 21 PR 48 PR36B32 PR48B44 Fig. 6. The rates using boceprevir for previous relapse or partial responder patients. 46% increase in Fig. 7. Improving rates in relapsers.

122 Cristina Popescu et al. 6 b. Using telaprevir in previously treated patients The PROVE 3 study [12] enrolled 453 previously treated patients (relapsers, non-responders, breakthrough). The rates analysis for various regimens is presented in Fig. 8. If we look separately at rates for triple and bitherapy, for relapsers and non-responders, we can conclude: 1. The rate for relapsers increases from %, in the case of bitherapy to 69% for triple therapy, an addition of 49% (2.7 times higher) 2. The rate for non-responders increases from 9 to 39% by adding telaprevir to the bitherapy. As a follow-up to the ADVANCE study, the REALIZE Phase III study enrolled 663 previously treated patients, divided into 3 arms: T12/PR48, lead-in PR4 + 12T/PR 44 and PR48 (Fig. 9). The rates were: 64%, 66% and 17%, respectively. Therefore, the currently agreed regimen for triple therapy is 12 weeks of telaprevir and PEG-RBV, followed by 36 weeks of PEG-RBV. Analyzing patient categories: relapsers, partial responders and null responders showed: for relapsers rates of 24% for PEG- RBV, compared to 83% and 88% for the two regimens containing telaprevir (Fig. 1) for partial responders rates of 15% with SoC, 59% and 54% with triple therapy (Fig. 11) for null responders rates of 5% and 29% with SoC and 33% with triple therapy (Fig. 12). As with boceprevir- based regimens, using telaprevir in null- responders increases the risk of resistance to PIs, which will compromise future DAA regimens. 45% increase in Fig. 8. Improving rates for partial response patients. 7 69 76 6 5 3 1 39 57 38 5 42 1 36 9 relapser non-responder breakthrough T12PR24 T24PR48 T24P24 PR48 Fig. 9. rates for various telaprevir regimens.

7 Trends in Hepatitis C Virus Infection Therapy 123 1 88 6 24 Increasing with 64% bitherapy triple therapy Fig. 1. Improving rates for relapsers. 1 6 54 15 Increasing with 39 % bitherapy triple therapy Fig. 11. Improving rates for partial responders. 1 6 29 5 bitherapy triple therapy Increasing with 24% Fig. 12. Improving rates for null responders. D. PI BASED REGIMENS APPROVED BY INTERNATIONAL GUIDELINES In late 11, the American Association for the Study of Liver Diseases (AASLD) amended therapeutic guidelines for HCV infected patients, introducing boceprevir and telaprevir in both naive and previously treated patients [14]. The same changes were published in early 12 in the UK [15]. D.1. BOCEPREVIR- BASED REGIMEN Boceprevir therapy is always associated with PEG-RBV, after 4 weeks of lead-in. The total duration of treatment is presented in Table I.

124 Cristina Popescu et al. 8 D.2. TELAPREVIR- BASED REGIMEN Telaprevir based regimens are always associated with PEG-RBV. Telaprevir and PEG-RBV are initiated simultaneously and continued for 12 weeks. The duration of the subsequent PEG-RBV treatment is presented in Table II. E. IMPROVING RATES WITH PROTEASE INHIBITORS Numerous studies using protease inhibitors have been published recently. New molecules are being studied, besides the already approved boceprevir and telaprevir. Table III shows some of the recently conducted studies, that used PIs in naive and previously treated patients. F. ADVERSE EFFECTS OF PROTEASE INHIBITORS The main adverse effects of boceprevir and telaprevir are presented in Table IV. We only listed the adverse events reported for regimens subsequently included in the current guidelines. The main side-effects associated with boceprevir are: dysgeusia (which does not require changes in treatment regimen), anaemia and neutropenia. Telaprevir has slightly different side- effects, with an increase in skin rash and anorectal symptoms. The rash leads to discontinuation of telaprevir in 5 7% of cases. The rash could be eczematous and pruritic, and in about 5% of cases appears in the first month of treatment. The anorectal symptoms are rarely a cause of discontinuation. Because of the risk of resistance, dose reduction for boceprevir and telaprevir should not be used. Table I Therapeutic algorithm for boceprevir- based regimens HCV RNA Duration of therapy S8 S24 Naive patients undetectable undetectable 4 wks lead-in PEG-RBV + 24 wks triple therapy detectable undetectable 4 wks lead-in PEG-RBV + 32 wks triple therapy + 12 wks PEG-RBV Naive patients, without risk factors for poor outcome;viral load after lead-in. If viral load is undetectable, the patient will receive biotherapy. Naive patients, with cirrhosis, 44 wks of triple therapy. Naive patients, with cirrhosis,viral load at 4 wks has not decreased by at least 1 log, discontinuation of therapy to prevent risk of resistance. Therapy failure (nonresponder undetectable undetectable 4 wks lead-in PEG-RBV + and relapser) detectable undetectable 32 wks triple therapy + 12 wks PEG-RBV Patients with cirrhosis and null-responders, treated with 44 wks of triple therapy. Patients with cirrhosis and null-repsponders, viral load after lead-in has not decreased by at least 1 log, discontinuation of therapy to prevent risk of resistance. If viral load> 1 UI/ml at S 12, stop therapy Detectable viral load at S24, stop therapy Boceprevir dose is mg x 3/day Table II Therapeutic algorithm for telaprevir- based regimens HCV-RNA Duration of therapy S4 S12 Naive patients and relapsers undetectable undetectable 12 wks triple therapy + 12 wks PEG-RBV detectable detectable/undetectable 12 wks triple therapy + 36 wks PEG-RBV R Partial and null responders Undetectable or <1 Undetectable or <1 UI/ml 12 wks triple therapy + UI/ml 36 wks PEG-RBV Patients with cirrhosis, partial and null responders will receive 48 wks of therapy, regardless of EVR. For patients with undetectable VL at S12, but under 1 UI/ml, repeat VL at S24. If positive, regardless of value, stop therapy. VL>1UI/ml at S4 or S12 requires stopping all regimens

9 Trends in Hepatitis C Virus Infection Therapy 125 Vierling J (16) NEXT-1 nerlaprevir + PR 12NVR/PR/12PR Table III Studies with Pis based regimens Study Year Sample naïve patients relapsers nonresponders 1 111 85 % Okanoue T, (17) Telaprevir+PR 12T/24PR Nelson D.R (18) ZENITH study telaprevir +PR 12VX-222/T/PR Gordon S.C (19) Boceprevir+PR 4PR/24BPR/PR Larrey DG() Danoprevir+PR 2DNPPR/46PR Ogert R.A (21) (NEXT-2, RESPOND-2) Boceprevir + PR Vierling JM (22) PROVIDE study Boceprevir + PR 4PR/44BPR McCone J (23) Treatmentnaive black patients from SPRINT-2 Boceprevir + PR 4PR/44BPR Mann M (24) Vaniprevir (MK-79) + PR 4MK-79PR44PR 11 Japan 11 15 (197 naïve, 3 trtfailure) 1 France 1 1 1 9 Germany 333 73%.6% (% cumulative RBV) 59 82 93% 83% (from 197 patients) 39 7.8 % 15 (197 naïve) 66% G1b 53% G1a 88.1%, 92.8% (% cumulative RBV) 78% (from 3 patients) 73% G1b 64% G1a 34.4% 45.5% (% cumulative RBV) 46 41% AT EOT.svr not available yet 159 26 53% 94 61 84% Table IV The main adverse effects Boceprevir(6,11) SPRINT 2/RESPOND 2 (response guided therapy) Telaprevir (9, 1, 13) ADVANCE, REALISE, ILLUMINATE (T12PR) Serious adverse events 1 11% 9 12% Discontinuation due to adverse events 8 12% 1 18% Anorectal symptoms NR 8 15% Dysgeusia 37 43% 12% Anaemia 43 49% 3 39% Neutropenia 19 24% 14% Rash 17 25% 37% Fatigue 53 55% 55 68% Pruritus 18 24% 5 52% Nausea 43 48% 35 47% Diarrhoea 22 23% 25 3% Anaemia during PI treatment The use of PIs is associated with a 25% increase in the rate of anaemia. Only 3 7% of the patients who developed anaemia during PI treatment registered severe anaemia (grade 3 or 4 haemoglobin level below 8 g/dl). Only 2 3% of the patients discontinued the treatment. In boceprevir studies, anaemia was treated with erythropoietin but in studies using telaprevir, the use of erythropoietin was forbidden. For telaprevir studies, the management of anaemia meant reducing the ribavirin dose, which did not induce a decrease in the rate.

126 Cristina Popescu et al. 1 CONCLUSIONS 1. For relapse patients, it is highly advisable to use a protease inhibitor (boceprevir or telaprevir) for the next therapeutic regimen. The association of boceprevir and telaprevir doubles the rate. 2. The rate for non-responders is much lower than the rate for relapsers, with an increased risk of PI resistance. It is therefore recommended, if the fibrosis is not very advanced to postpone therapy until new molecules are approved. 3. Determining the IL28b polymorphism is useful in choosing the right regimen for naive patients. Patients with unfavourable IL28b genotypes are candidates for triple therapy. 4. The rates for naive patients are close to % with the use of protease inhibitors associated to peginterferon-ribavirin. Standardul de aur în tratamentul hepatitei cronice cu VHC a fost până în 11 terapia combinată peginterferon-ribavirină, cu o rată a răspunsului virusologic susţinut () de 5%. În 11 FDA şi EMEA au aprobat o nouă clasă de antivirale inhibitorii de protează HCV-NS3. În prezent, sunt disponibile două molecule: boceprevir şi telaprevir. Inhibitorii de protează sunt utilizaţi în asociere cu peginterferon şi ribavirină, acestea din urmă rămânând în continuare componente vitale ale terapiei antivirale în hepatita cronică cu VHC, care actualmente din biterapie tinde să devină triterapie. Inhibitorii de protează cresc semnificativ rata de la pacienţii naivi, dar şi la relapseri. Din cauza riscului crescut de apariţie a rezistenţei la inhibitorii de protează, null-responderii anteriori nu sunt candidaţi la triplă terapie iar rata de este încă foarte scăzută la aceşti pacienţi. Corresponding author: Prof. Victoria Aramă, Matei Balş National Institute of Infectious Diseases, 1, Calistrat Grozovici, 2115, Bucharest, Romania E-mail: ralsan@gmail.com REFERENCES 1. LAVANCHY D., The global burden of hepatitis C, Liver Int 9; 29 (Suppl. 1): 74 81. 2. McHUTCHISON J.G., LAWITZ E.J., SHIFFMAN M.L. et al., Peginterferon alfa-2b or alfa- 2a with ribavirin for treatment of hepatitis C infection, N Engl J Med 9; 361: 5 93. 3. HADZIYANNIS S.J., SETTE H. Jr., MORGAN T.R. et al., for PEGASYS International Study Group, Peginterferonalpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose, Ann Intern Med 4;1: 346 355. 4. BROK J., GLUUD L.L., GLUUD C., Meta-analysis: Ribavirin Plus Interferon vs. Interferon Monotherapy for Chronic Hepatitic C an Updated Cochrane Review, Alimentary Pharmacology & Therapeutics, 1; 32 (7): 8 85. 5. KWO P.Y., LAWITZ E.J., 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 1; 376: 75 16. 6. POORDAD F., MCCONE J. Jr., BACON B.R. et al., Boceprevir for untreated chronic HCV genotype 1 infection, N Engl J Med 11; 364: 1195 6. 7. McHUTCHISON J.G., EVERSON G.T., GORDON S.C. et al., Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection, N Engl J Med 9; 36: 1827 38. 8. HEZODE C., FORESTIER N., DUSHEIKO G. et al., Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 9; 36: 1839 5. 9. JACOBSON I.M., McHUTCHISON J.G.,DUSHEIKO G. et al., Telaprevir for previously untreated chronic hepatitis C virus infection, N Engl J Med 11; 364: 25 16. 1. SHERMAN K., FLAMMS, AFDHAL N. et al., Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus Infection, N Engl J Med 11, 365, 11. 11. BACON B.R., GORDON S.C., LAWITZ E. et al., Boceprevir for previously treated chronic HCV genotype 1 infection, N Engl J Med 11; 364: 17 17. 12. McHUTCHISON J.G., MANNS M., MUIR A. et al., Telaprevir for Previously Treated Chronic HCV Infection, N Engl J Med 1, 362,14. 13. ZEUZEM S., ANDREONE P., POL S. et al., Telaprevir for retreatment of HCV infection, N Engl J Med 11; 364: 2417 28.

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