bs_bs_banner

doi:10.1111/jgh.12632

REVIEW Response-guided therapy in patients with genotype 1 virus: Current status and future prospects Eric J Lawitz and Fernando E Membreno

The Texas Liver Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

Key words Abstract direct-acting antiviral, HCV RNA, protease inhibitors, response-guided therapy. On-treatment responses to antiviral therapy are used to determine duration of therapy in patients being treated for genotype 1 infection. Such use of response- Accepted for publication 9 March 2014. guided therapy has successfully reduced exposure of patients to the side-effects of pegylated and without jeopardizing overall treatment success. Correspondence Response-guided therapy is an integral part of treatment using the current standard treat- Dr Eric J Lawitz, 607 Camden Street, ments involving the direct-acting antiviral (DAA) agents— or — University of Texas Health Science Center, combined with pegylated interferon/ribavirin. Improvements in our understanding of the San Antonio, TX 78215, USA. kinetics of viral load during antiviral therapy have shown us that more potent suppression Email: [email protected] of viral replication increases the rate of viral eradication, providing impetus for the development of more potent DAAs. Emerging results from clinical trials of these agents— including trials of interferon-free DAA combinations—suggest that very high rates of viral eradication are achievable, even in patients who failed to respond to previous courses of interferon-based therapy. Furthermore, because of these high rates of treatment success, on-treatment assessment of viral response may become unnecessary. The field of hepatitis C virus therapy is evolving rapidly and current trends indicate that the era of simple treatment regimens with high rates of success and good tolerability are near.

Disclosures: The authors received no direct compensation related to the development of the manuscript. Eric Lawitz, MD, has disclosed that he has received research or grant support from Abbott, Achillion, Anadys, Biolex, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck, Novartis, Pharmasset, Pfizer, Roche, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec/Janssen Therapeutics, Vertex, ViroChem Pharma, and ZymoGenetics; is on the speaker’s bureaus for Gilead Sciences, Merck, and Vertex; and is on the advisory board for Abbott, Achillion, Anadys, Biolex, GlobeImmune, Inhibitex, Merck, Pharmasset, and Tibotec/Janssen Therapeutics. Fernando Membreno, MD, has disclosed that he has received research or grant support from Abbott, Achillion, Anadys, Biolex, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inhibitex Pharmaceuticals, Medarex, Medtronic, Merck, Novartis, Pharmasset, Pfizer, Roche, Schering-Plough, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Tibotec/Janssen Therapeutics, Vertex, ViroChem Pharma, Exelixis, and ZymoGenetics; is on the speakers’ bureau for Merck, Otsuka, and Bayer; and is on the advisory board for GlaxoSmithKline and Gilead.

Writing Assistance: Editorial support was provided by Ken Scholz, PhD, and Katharine Howe, PhD, of Adelphi Communications, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Authors’ contributions: The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE).

1574 Journal of Gastroenterology and Hepatology 29 (2014) 1574–1581 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd EJ Lawitz and FE Membreno Response-guided therapy for HCV

Introduction and background Table 1 On-treatment response criteria and their definitions Response type Definition The goal of treating chronic hepatitis C is sustained virological response (SVR), historically defined as undetectable hepatitis C RVR (rapid virological Undetectable (< 50 IU/mL) HCV RNA at virus (HCV) RNA 24 weeks after the end of treatment. Among response)† week 4 patients who achieved SVR in nine therapeutic trials, 99.1% still EVR (early virological Greater than 2 log10 decline in HCV RNA had undetectable HCV RNA after several years of follow-up response)† at week 12 after having detectable HCV (mean 3.9 years).1 SVR is associated with improvements in RNA at week 4 markers of hepatic function and strong reductions in the long-term Complete (cEVR) Undetectable HCV RNA at week 12 after risks of hepatocellular carcinoma and other liver-associated mor- having detectable HCV RNA at week 4 ‡ bidity and mortality.2,3 For a number of years, the standard therapy Extended RVR (eRVR) Triple therapy with Undetectable HCV RNA at weeks 8–12 for chronic hepatitis C was pegylated interferon (PegIFN) α2a or boceprevir (week 8 comprises a 4-week lead-in α2b in combination with ribavirin (RBV), given for 48 weeks to period of PegIFN/RBV followed by 4 patients with genotype 1 or 4 HCV infection, or for 24 weeks to weeks of triple therapy) 4 patients with genotype 2 or 3 HCV infection. However, PegIFN/ Triple therapy with Undetectable HCV RNA at weeks 4 and RBV therapy is difficult to tolerate, leading to high rates of treat- telaprevir 12 ment discontinuation.5,6 Furthermore, only 40–50% of genotype 1 patients achieve SVR after a first course of PegIFN/RBV.6–10 The †Undetectable HCV RNA historically defined as < 50 IU/mL. ‡ prolonged course of therapy required for treating patients with Undetectable HCV RNA defined as ≤ 25 IU/mL. genotype 1 HCV, along with the associated relatively low SVR HCV, hepatitis C virus; PegIFN, pegylated interferon; RBV, ribavirin. rates and poor tolerability, have been significant drawbacks to the use of PegIFN/RBV. The desire to minimize exposure to PegIFN/RBV and to opti- mize response rates led to the development of the concept of underpinning, it is predicted that more rapid and effective suppres- response-guided therapy (RGT), which can be defined as deter- sion of virus production will shorten the duration of treatment mining treatment duration on the basis of viral load at a specific necessary to achieve SVR.22,23 It should be noted, however, that time after initiation of therapy.5 The use of RGT began in the era pre-existing factors also influence the second phase—factors such of PegIFN/RBV, where it was demonstrated that certain patient as the host interleukin 28B (IL28B) genotype, baseline viral load, subgroups with favorable baseline characteristics associated with degree of fibrosis or cirrhosis, and HIV co-infection.11,22,24,25 Fur- higher rates of SVR could receive a shorter duration of therapy.4,11 thermore, durable viral suppression requires the use of antiviral In patients with genotype 1 HCV infection receiving PegIFN/RBV, therapy that prevents the development of treatment-resistant strains, for example, those achieving a rapid virological response (RVR; generally necessitating combination therapies. HCV RNA < 50 IU/mL at week 4) were eligible for shortened This paper gives an overview of current clinical practice regard- duration of therapy (24 weeks instead of the usual 48 weeks), ing RGT in patients with genotype 1 HCV infection and sets the without experiencing a reduction in SVR rates.12–17 RVR, or stage for how the introduction of new direct-acting antiviral agents on-therapy response to PegIFN, has been shown to be a better (DAAs) will change RGT. predictor of SVR than various baseline factors, including geno- type, patient age, viral load, alanine aminotransferase ratios, and 18 presence of liver fibrosis. The development and evolution of Interferon-based triple therapy RGT greatly improved the treatment experience for patients with regimens incorporating viral genotype 1 HCV, allowing shorter courses of therapy for strong protease inhibitors responders and cessation of therapy in those unlikely to achieve SVR, decreasing exposure to adverse drug effects and costs in both In 2011, the first DAAs, boceprevir and telaprevir, became avail- types of patients. Unfortunately, only a small proportion of able. These agents inhibit the NS3/4A viral protease. Addition of treatment-naïve, genotype 1 patients achieve an RVR during either agent to a standard PegIFN/RBV regimen dramatically PegIFN/RBV therapy; the remainder must endure a full 48-week improved SVR rates among patients with genotype 1 HCV infec- course of therapy or are discontinued because of virological tion. Just as importantly, DAAs have increased the proportion of failure, defined as not achieving an early virological response patients eligible for shortened duration of therapy using the prin- (Table 1) or by having detectable virus at treatment week 24.19 ciples of RGT. Between 44% and 65% of treatment-naïve, patients Studies of the kinetics of viral load during antiviral therapy20–22 achieved criteria for RGT during phase 3 studies and stopped have provided a mechanistic underpinning for RGT and guideposts therapy after 24 weeks (telaprevir) or 28 weeks (boceprevir) for the development of improved antiviral therapies. According to without significantly increasing their risk of relapse. However, the current models of viral load in patients who respond to PegIFN/ addition of telaprevir/boceprevir to PegIFN/RBV has led to an RBV,22,23 HCV RNA levels decline in two phases. The first phase of increase in adverse events.26–29 decline represents suppression of virus production, and the slower Boceprevir and telaprevir were studied in five phase 3 clinical second phase represents clearance of infected cells or cell cure, in trials in both treatment-naïve and treatment-experienced patients. which intracellular viral RNA is eliminated. A key aspect of this These trials have been extensively reviewed, so we will limit our model and its application to RGT is that the rate of decline during discussion to a brief overview and focus on the implications for the second phase is influenced by antiviral efficacy. With this use of RGT.

Journal of Gastroenterology and Hepatology 29 (2014) 1574–1581 1575 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Response-guided therapy for HCV EJ Lawitz and FE Membreno

Boceprevir. Triple-therapy using boceprevir was studied in the lead-in treatment with PegIFN/RBV (< 1 log10 IU/mL decline in SPRINT-2 trial, which enrolled treatment-naïve patients with HCV RNA level; 33% and 34% in the two boceprevir-containing chronic, genotype 1 HCV infection.26 This trial employed a arms). Furthermore, those patients who had a weak response to the 4-week lead-in period of PegIFN/RBV, after which treatments lead-in phase (who can be considered comparable with prior null diverged into three groups. Group 1 received placebo plus PegIFN/ responders) and who received RGT had a high rate of emergence RBV; group 2 (response-guided arm) received boceprevir triple of boceprevir-resistant variants.29 Based on these results, RGT therapy for 24 weeks, at which time all treatment was discontinued with boceprevir was not recommended for prior null responders. in those who had undetectable HCV RNA at clinic visits between However, the PROVIDE trial retreated patients who did not week 8 and week 24 (not including week 24) and those with achieve SVR during phase 2/3 boceprevir trials with 44 weeks of detectable HCV RNA continued treatment with PegIFN/RBV plus boceprevir-triple therapy. Of 168 patients, SVR was achieved in placebo to complete 48 weeks of therapy; and group 3 that 38% of prior null responders, 67% of prior partial responders, and received boceprevir plus PegIFN for a total of 44 weeks (after a 93% of prior relapsers.30 Cirrhotic patients were underrepresented 4-week lead in) even if virus levels were undetectable between in the RESPOND-2 trial, and those in the boceprevir-containing weeks 8 and 24. Patients in any group who had detectable HCV groups had significantly lower SVR rates after RGT than after the RNA at week 24 were discontinued according to rules of futility.26 full 48 weeks of treatment (35% vs 77%).29 The PROVIDE study Forty-four percent of patients in the boceprevir response-guided showed SVR rates of 74% for patients with advanced fibrosis who arm were eligible to stop therapy at week 28 based on undetectable received 44 weeks of boceprevir-triple therapy.30 HCV RNA levels between weeks 8 and 24. Similarly, 44% of patients in the 48-week triple therapy arm had undetectable HCV Telaprevir. Triple therapy using telaprevir was studied in two RNAbetween weeks 8 and 24 but continued therapy to full 48-week trials of treatment-naïve patients, the ADVANCE trial27 and the duration as per the study protocol; HCV RNAlevels were undetect- ILLUMINATE trial.28 The three-arm ADVANCE trial did not able in only 12% of patients in the control arm between weeks 8 and employ a lead-in phase. Participants were randomized to receive 24. Ninety-six percent of patients in each boceprevir treatment arm 12 weeks of PegIFN/RBV in combination with telaprevir for the who achieved undetectable HCV RNAbetween weeks 8 and 24 also first 8 or 12 weeks. In those two groups, patients who satisfied the achieved SVR (group 2: 156/162; group 3: 155/161).26 criteria for extended RVR (eRVR) (see Table 1) received another The SPRINT-2 trial had a 4-week lead-in of PegIFN/RBV, and 12 weeks of PegIFN/RBV, whereas those not satisfying those 5% of patients achieved RVR (undetectable HCV RNA after 4 criteria received an additional 36 weeks of PegIFN/RBV. A third weeks of PegIFN/RBV) during that time. Previous guidelines rec- group received PegIFN/RBV plus placebo for 12 weeks followed ommended that these patients could be considered for a shortened by 36 weeks of PegIFN/RBV. The eRVR criteria for shortened duration of PegIFN/RBV therapy if baseline factors supported duration of therapy were satisfied by 58% of participants in the such a decision.4 With the addition of a DAA and the application of telaprevir-containing groups but only 8% of participants in the different RGT criteria, more patients are eligible for shortened placebo (PegIFN/RBV) group. Among those who received a short- duration of therapy with triple therapy (44%) than would have ened duration of therapy, 86% achieved SVR.27 been eligible with PegIFN/RBV alone (12%).26 The use of RGT in a telaprevir-containing regimen was studied The RESPOND-2 trial studied boceprevir-containing triple explicitly in the ILLUMINATE trial,28 which enrolled treatment- therapy among chronically infected, genotype 1 HCV-infected naïve (TN) patients with chronic HCV genotype 1 infection. All patients who had prior exposure to PegIFN/RBV and were either patients received telaprevir-based triple therapy for 12 weeks. partial responders or relapsers (prior null responders were not Those who experienced eRVR were then randomized to receive included in the trial).29 The RESPOND-2 trial used a lead-in of PegIFN/RBV for either 12 or 36 more weeks (those not experi- PegIFN/RBV treatment similar to the SPRINT-2 trial. To be eli- encing eRVR received PegIFN/RBV for 36 more weeks.) Sixty- gible for a shortened duration of therapy, however, participants in five percent of participants experienced eRVR. Among those the response-guided arm of the RESPOND-2 trial had to have participants who had eRVR, those randomized to receive an addi- undetectable HCV RNA at weeks 8 and 12. In boceprevir- tional 12 weeks of PegIFN/RBV achieved SVR rates of 92% and containing regimens, 49% of participants had undetectable HCV those randomized to receive an additional 36 weeks of PegIFN/ RNA at weeks 8 and 12 compared with 9% of participants in the RBV achieved SVR rates of 88%. The results satisfied the criteria placebo (PegIFN/RBV) group. Those eligible for a shortened for non-inferiority, allowing the investigators to conclude that the duration of therapy received 36 weeks of treatment (4-week shorter duration of therapy for patients who achieved eRVR was lead-in followed by 32 weeks of triple therapy). There was no non-inferior to the longer duration. Notably, significantly more significant difference in SVR rates between the group that received participants randomized to the longer duration of therapy discon- boceprevir-containing triple therapy for 48 weeks and the group tinued treatment because of adverse events compared with those treated according to response-guided principles (odds ratio, 1.4; randomized to the shorter duration (12% vs 1%; P < 0.001).28 95% confidence interval 0.9–2.2). The trend toward a difference Telaprevir was also studied in previously treated patients in the may be explained by differing responsiveness of patients with REALIZE trial.31 However, the treatment protocol for that trial did cirrhosis in the two groups.29 not employ RGT. Although SVR rates in the boceprevir-containing groups of the RESPOND-2 trial were not significantly different (59% in the Clinical use of RGT in patients treated with response-guided group and 66% in the group that received full 48 boceprevir- or telaprevir-based triple therapy. weeks of therapy), SVR rates were substantially lower among the Current guidelines note that the use of boceprevir- or telaprevir- subgroup of patients who had a weak response to the 4-week containing therapy, in combination with PegIFN/RBV, is optimal

1576 Journal of Gastroenterology and Hepatology 29 (2014) 1574–1581 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd EJ Lawitz and FE Membreno Response-guided therapy for HCV for treatment-naïve patients with genotype 1 HCV.2 Treatment HCV.35–37 Later, we give a brief overview of selected new DAAs regimens employing boceprevir should use a 4-week PegIFN/RBV and DAA-containing regimens in late-stage clinical development lead-in period prior to initiation of triple therapy.32 Triple therapy for patients with genotype 1 HCV. It is not our intention to give a should then be administered for 24 weeks in patients eligible for comprehensive view but to highlight important trends and key RGT (i.e. those without cirrhosis and who have undetectable HCV studies, particularly those with implications for the future of RGT. RNA levels at weeks 8 and 24). Patients with cirrhosis should receive triple therapy for 44 weeks. Triple therapy should be stopped if the HCV RNA level is > 100 IU/mL at treatment week Interferon-containing regimens 12 or detectable at treatment week 24.32 Telaprevir-containing regimens do not require a lead-in period. Triple therapy with . Simeprevir (TMC435) is a recently approved 38 telaprevir should be administered for 12 weeks, followed by 12 inhibitor of the NS3/4A HCV protease. Simeprevir is a macrocy- weeks of PegIFN/RBV in patients eligible for RGT (i.e. those clic, non-covalent protease inhibitor, unlike boceprevir and 5 without cirrhosis and who have undetectable HCV RNA levels at telaprevir, which are covalent, ketoamide inhibitors. US Food and weeks 4 and 12). Patients with cirrhosis should continue PegIFN/ Drug Administration (FDA) approval was based on data from three RBV therapy for a total of 48 weeks. Triple therapy should be randomized, placebo-controlled, phase 3 clinical trials of stopped at week 12 if HCV RNA levels are > 1000 IU/mL at weeks simeprevir-containing triple therapy (with PegIFN/RBV), all of 39–41 4 and 12 of the triple-therapy phase, or at week 24 if HCV RNA is which used RGT. In the QUEST-1 trial, previously untreated detectable at that time.2 patients with genotype 1 chronic HCV infection received For patients previously treated with PegIFN/RBV, the guide- simeprevir-containing triple therapy (or placebo plus PegIFN/ 39 lines recommend retreatment with a boceprevir- or telaprevir- RBV) for 12 weeks, followed by 12 or 36 weeks of PegIFN/RBV. containing regimen for patients who relapsed (undetectable HCV In this trial, 85% of participants who received simeprevir- RNA at the end of treatment but detectable during follow-up) or containing therapy were eligible for the shorter duration of therapy had a partial response (HCV RNA declined by at least based on RGT criteria, 91% of whom achieved SVR12. The primary outcome of the trial was SVR12, which was reported in 2 log10 IU/mL at treatment week 12 with detectable HCV RNA at week 24) during prior treatment; retreatment can be considered for 80% of patients in the simeprevir-containing group (vs 50% in the placebo group). In the simeprevir-containing group, 3% of patients prior null responders (HCV RNA declined less than 2 log10 IU/mL at treatment week 12 with detectable HCV RNA at week 24).2 The discontinued because of adverse events. The most common side- use of RGT can be considered in prior relapsers. In prior partial effects were fatigue, headache, and pruritus; hyperbilirubinemia 39 responders, RGT can be considered for boceprevir-containing but due to inhibition of OATP1B1/MRP2 transporters was also noted. not telaprevir-containing regimens. RGT is not recommended for The QUEST-2 trial, which also enrolled treatment-naïve patients prior null responders, poor IFN responders, or patients with cir- with genotype 1 HCV, yielded similar results; 91% of simeprevir- rhosis.29,32,33 The HCV RNA threshold for discontinuing therapy in treated patients met RGT criteria and were eligible to stop treat- retreated patients is lower for boceprevir (patients with HCV ment at week 24 and among those patients, 86% achieved SVR12. RNA ≥ 100 IU/mL at week 12 should discontinue) than for Overall SVR12 rates were 81% in the simeprevir-based triple telaprevir (patients with HCV RNA ≥ 1000 IU/mL at week 4 or 12 therapy arm versus 50% in the placebo plus PegIFN/RBV arm < 40 should discontinue).2 (P 0.001). In a trial of previous relapsers to PegIFN/RBV (PROMISE), 93% of participants receiving simeprevir-containing therapy were eligible for the shortened duration of therapy, and Future prospects overall, 79% achieved SVR12.41 These large phase 3 trials are In patients with genotype 1 HCV infection, boceprevir and consistent with phase 2 trials of simeprevir-containing triple therapy42–44 and suggest that newer protease inhibitors may be telaprevir suppress HCV RNA levels by 2–4 log10 units. Although this represents 99–99.99% inhibition, mounting evidence indicates associated with substantial increases in the percentage of patients that DAAs offering even more potent suppression of HCV RNA eligible to stop therapy after 24 weeks compared with the first- levels could yield additional improvements in SVR rates and generation agents boceprevir and telaprevir. Simeprevir is also shorter durations of therapy.24 Indeed, a number of new DAAs, or active against a broader set of HCV genotypes, including 2, 4, 5, combinations of DAAs, have been approved or are in late-stage and 6, although phase 3 trials were not designed to investigate 38 clinical development and offer more potent suppression of viral non-genotype 1 patients. Simeprevir has a number of desirable replication. These new agents target the NS3/4A protease or other properties compared with the first-wave protease inhibitors, includ- viral proteins such as the NS5B RNA polymerase or NS5A.5 In ing more tolerable adverse events, fewer drug–drug interactions, addition, many of these new agents are active against other geno- and once-daily dosing, which may favorably impact compliance 32,33 types, unlike boceprevir and telaprevir, which are approved only relative to boceprevir (12 pills/day) and telaprevir (6 pills/day). for genotype 1 HCV.5,34 As these developments unfold, the future role of RGT is becom- Faldaprevir. Faldaprevir is another macrocyclic, non-covalent ing uncertain. With the more potent suppression of viral replica- inhibitor of the NS3/4A protease in late-stage clinical development tion, it may become possible to shorten therapy for all patients, for treatment of chronic HCV.45 Faldaprevir potently suppresses obviating the need to tailor therapy duration to viral response. HCV RNA levels in patients with genotype 1 chronic HCV infec- 46 Emerging therapies with and without IFN have now demonstrated tion by about 4 log10 IU/mL, and has pharmacokinetic properties 90% or better SVR rates with fixed durations of 12 weeks in suitable for once-daily dosing.45 Faldaprevir in combination with previously untreated, non-cirrhotic patients with genotype 1 PegIFN/RBV was studied in a randomized, double-blind, phase 3

Journal of Gastroenterology and Hepatology 29 (2014) 1574–1581 1577 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Response-guided therapy for HCV EJ Lawitz and FE Membreno trial (STARTVerso1) in treatment-naïve patients with chronic, sible for many of the most challenging side-effects of treatment. genotype 1 HCV infection.47 All patients received PegIFN/RBV Furthermore, durations of therapy for highly potent, IFN-free regi- for 24–48 weeks and were also randomized to receive either mens are expected to be less dependent upon on-treatment placebo, faldaprevir 120 mg once daily for 12 or 24 weeks based responses.55 Indeed, recently completed phase 2 trials and ongoing on RGT, or faldaprevir 240 mg once daily for 12 weeks. Patients in phase 3 trials of IFN-free regimens using DAAs have eliminated either faldaprevir group who achieved early treatment success the use of RGT. (defined as HCV RNA < 25 IU/mL at week 4 and undetectable Two studies provided proof-of-concept support for the use of HCV RNA at week 8) stopped all treatment at 24 weeks, whereas IFN-free regimens utilizing a DAA or combinations of DAAs.56,57 other patients continued PegIFN/RBV for a total of 48 weeks. More recently, the combination of and (with Overall, 88% of patients receiving faldaprevir achieved early treat- or without RBV) was studied in a phase 2 trial that included both ment success and discontinued therapy at 24 weeks; among those, treatment-naïve patients and patients who had failed a prior course 88% achieved SVR12. Overall, 80% of patients receiving of IFN-based therapy that included telaprevir or boceprevir.58 In faldaprevir achieved SVR12. Study medications were discontin- both treatment-naïve patients and prior non-responders, the com- ued because of adverse events in 4–5% of patients.47 These results bination of sofosbuvir and daclatasvir (for 12 or 24 weeks) was are consistent with an earlier phase 2 trial in treatment-naïve associated with a 100% SVR24 rate, even without the use of patients (SILEN-C1).48 RBV.58 Similar SVR rates were observed in the phase 2 In the phase 3 STARTVerso3 study of faldaprevir in treatment- LONESTAR study, in which 60 treatment-naïve, non-cirrhotic experienced patients with HCV genotype 1 infection, only patients were given a once-daily, fixed-dose combination of relapsers were eligible for RGT following results from the phase 2 sofosbuvir and (an NS5A inhibitor) with or without SILEN-C2 trial that showed continuing PegIFN/RBV for a total of RBV.59 In this study, 95% of treatment-naïve patients in the no 48 weeks was significantly better than discontinuing at 24 weeks RBV arms achieved SVR12 whether they were treated for 8 or 12 in patients with a prior non-response (SVR 72% vs 43%; weeks. In the 12-week arm with RBV, 100% of patients achieved P = 0.035).49 Among prior relapser patients in STARTVerso3, SVR12. This study also evaluated an additional cohort of 40 86–87% achieved early treatment success and were eligible to stop patients (50% with compensated cirrhosis) who had failed previ- treatment at week 24; 75% of these patients achieved SVR12.50 ous DAA therapy; 100% of patients who received a 12-week Study medications were discontinued because of adverse events in course of fixed-dose sofosbuvir and ledipasvir with RBV achieved 6–7% of patients who received faldaprevir.50 SVR12 compared with 95% in the RBV-free arm.59 The phase 2 ELECTRON study included treatment-naïve Sofosbuvir. Sofosbuvir (GS-7977) is a recently approved patients and prior null responders with genotype 1 HCV who were nucleotide analog inhibitor of the HCV RNA-dependent RNA treated with 12 weeks of sofosbuvir plus RBV and either ledipasvir 60,61 polymerase (NS5B) with activity against all HCV genotypes.35,51 or GS-9669 (a non-nucleoside NS5B inhibitor). Results indicate Sofosbuvir in combination with PegIFN/RBV was associated with that 100% of treatment-naïve (25/25) and 100% of prior non- high rates of SVR (87–92%) in phase 2 trials of treatment-naïve responders (9/9) achieved SVR12 when ledipasvir was added to the 60 patients with genotype 1 chronic HCV.52,53 The NEUTRINO trial sofosbuvir plus RBV regimen. The addition of GS-9669 to was a phase 3, single-arm, open-label study of sofosbuvir plus sofosbuvir and RBV also yielded a 92% SVR12 rate (23/25) in 61 PegIFN/RBV in treatment-naïve patients with genotype 1, 4, 5, or 6 treatment-naïve patients; 100% of treatment-experienced patients chronic HCV (69% had genotype 1a, and 20% had genotype 1b).35 with F3/F4 fibrosis achieved SVR12 when sofosbuvir and 61 Two notable features of this trial were that 17% of patients had ledipasvir were combined with either RBV or GS-9669. cirrhosis at baseline, and total treatment duration was 12 weeks for The phase 2a COSMOS trial evaluated the all-oral combination all study drugs and all patients (RGT criteria were assessed but did of sofosbuvir and simeprevir, with and without RBV, in cirrhotic not dictate course of therapy). At week 2, 91% of patients had HCV and non-cirrhotic treatment-naïve or prior null responder patients RNA < 25 IU/mL, which increased to 99% at week 4. The primary with genotype-1 (GT-1) HCV. Interim analysis of cohort 1 (non- end-point, SVR12, was achieved in 90% of patients, which was cirrhotic prior null responders), showed that 93% and 96% of those significantly higher than adjusted historical controls for PegIFN/ treated with or without RBV for 12 weeks achieved SVR12 and RBV alone (60%; P < 0.001). Pretreatment factors such as IL28B 93% and 79% of those treated for 24 weeks achieved SVR12. Early genotype (SVR12 98% in CC IL28B vs 87% in non-CC IL28B) and results from cohort 2 (prior null responders and treatment-naïve, presence of cirrhosis (SVR12 80% in cirrhotic patients vs 92% in F3-F4) showed that 100% of treatment-naive patients treated with non-cirrhotic patients) were predictive of lower response rates. or without RBV achieved SVR4 after 12 weeks of treatment, as did Only 2% of patients discontinued because of adverse events. This 93% and 100% of prior null responders. For both cohorts, relapse study, which offers the best response rate in patients with cirrhosis occurred only in those GT-1a patients with known Q80K mutations, to date, and future trials like it may herald the onset of a new era of and treatment was generally safe and well tolerated with approxi- 62 fixed short-duration therapy with high SVR.35 mately 3% of patients experiencing serious adverse events. Although not FDA-approved, the recent Infectious Diseases Society of America/American Association for the Study of Liver Interferon-free regimens. The development of DAAs Diseases HCV treatment guidelines recommended the all-oral IFN- with potent antiviral efficacy has led to an evolving paradigm shift free combination for treatment of HCV GT1 patients who are IFN in which IFN may be eliminated from treatment regimens for HCV ineligible.63 infection.54 Elimination of IFN from treatment is highly desirable Two phase 2a trials (PILOT and COPILOT) investigated because its use requires intense patient monitoring and is respon- another potent viral protease inhibitor, ABT-450, boosted with

1578 Journal of Gastroenterology and Hepatology 29 (2014) 1574–1581 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd EJ Lawitz and FE Membreno Response-guided therapy for HCV low-dose in combination with RBV and a non-nucleoside patients with sustained virological response on long-term follow-up. inhibitor of RNA polymerase (ABT-072 or ABT-333).37,64 Both J. Viral Hepat. 2012; 19: e97–104. trials demonstrated SVR rates above 90% in treatment-naïve 4 Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, patients, whereas 47% of treatment-experienced patients achieved management, and treatment of hepatitis C: an update. Hepatology 49 SVR.37,64 A larger phase 2b trial (AVIATOR) added ABT-267 (an 2009; : 1335–74. 5 Fusco DN, Chung RT. Novel therapies for hepatitis C: insights from NS5A inhibitor) and demonstrated SVR12 rates of 99% in the structure of the virus. Annu. Rev. Med. 2012; 63: 373–87. treatment-naïve patients and 93% in previous null responders with 6 Lee SS, Bain VG, Peltekian K et al. Treasting chronic hepatitis C 36 12 weeks of therapy. In the PEARL-1 trial, patients with geno- with pegylated interferon alfa-2a (40 KD) and ribavirin in clinical type 1b infection received ABT-450/r and ABT-267. SVR12 was practice. Aliment. Pharmacol. Ther. 2006; 23: 397–408. achieved by 95% of treatment-naïve patients and 90% of prior null 7 Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa-2b responders.65 plus ribavirin compared with interferon alfa-2b plus ribavirin for A large number of phase 3 trials are now underway testing initial treatment of chronic hepatitis C: a randomised trial. Lancet various DAAs and DAA combinations for treatment of chronic 2001; 358: 958–65. HCV. In general, these trials are designed without RGT. If the 8 Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a N. Engl. J. results of phase 2 trials are confirmed, treatment of HCV could plus ribavirin for chronic hepatitis C virus infection. Med. 2002; 347: 975–82. become much more effective and much simpler in the near future, 9 Hadziyannis SJ, Sette H Jr, Morgan TR et al. Peginterferon-alpha2a > leading to eradication of infection in 90% of patients without the and ribavirin combination therapy in chronic hepatitis C: a use of RGT. randomized study of treatment duration and ribavirin dose. Ann. Intern. Med. 2004; 140: 346–55. Conclusion 10 McHutchison JG, Lawitz EJ, Shiffman ML et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C RGT for the treatment of genotype 1 HCV infection is the current infection. N. Engl. J. Med. 2009; 361: 580–93. standard of care for IFN-based therapy with telaprevir or 11 Davis GL. Monitoring of viral levels during therapy of hepatitis C. boceprevir, and has undoubtedly spared countless patients from Hepatology 2002; 36 (Suppl. 1): S145–51. 12 Jensen DM, Morgan TR, Marcellin P et al. Early identification of unnecessarily long treatment durations, as well as the side-effects HCV genotype 1 patients responding to 24 weeks peginterferon and costs associated with PegIFN/RBV therapy. Despite these alpha-2a (40 kd)/ribavirin therapy. Hepatology 2006; 43: 954–60. benefits, the need to monitor HCV RNA levels during treatment 13 Zeuzem S, Buti M, Ferenci P et al. Efficacy of 24 weeks treatment adds another layer of complexity to already complex treatment with peginterferon alfa-2b plus ribavirin in patients with chronic regimens. The increased potency of DAAs is allowing more rapid hepatitis C infected with genotype 1 and low pretreatment viremia. viral kinetics in both the first and second phases of viral load J. Hepatol. 2006; 44: 97–103. declines, reducing the need for on-treatment measurements of 14 Ferenci P, Laferl H, Scherzer TM et al. Peginterferon alfa-2a and response for determining duration of therapy. These improvements ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid will likely lead to the approval of IFN-free regimens in the near virological response. Gastroenterology 2008; 135: 451–8. future. All-oral direct antiviral therapies are expected to have high 15 Liu CH, Liu CJ, Lin C et al. Pegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus cure rates with short treatment duration and limited adverse events. genotype 1 infection: a multicenter, randomized controlled trial. Furthermore, treatment regimens will likely be simpler, without Clin. Infect. Dis. 2008; 47: 1260–9. requiring on-treatment measurement of response, and likely not 16 Mangia A, Minerav N, Bacca D et al. Individualized treatment requiring pretreatment assessment of factors that have traditionally duration for hepatitis C genotype 1 patients: a randomized controlled influenced response rates—such as HCV genotype, IL28B geno- trial. Hepatology 2008; 47: 43–50. type, baseline viral load, and degree of fibrosis. In the future, 17 Yu ML, Dai CY, Huang JF et al. Rapid virological response and studies will focus on the improvement of SVR rates in special treatment duration for chronic hepatitis c genotype 1 patients: a populations of patients with HCV including those with compen- randomized trial. Hepatology 2008; 47: 1884–93. sated and decompensated cirrhosis, prior null response (particu- 18 Fried MW, Hadziyannis SJ, Shiffman ML, Messinger D, larly those with genotype 3 infection), renal failure, and HCV Zeuzem S. Rapid virological response is the most important predictor of sustained virological response across genotypes in recurrence after a liver transplant. The role of RGT in these groups patients with chronic hepatitis C virus infection. J. Hepatol. 2011; is still to be determined. 55: 69–75. 19 Moreno C, Deltenre P, Pawlotsky JM, Henrion J, Adler M, Mathurin References P. Shortened treatment duration in treatment-naive genotype 1 HCV patients with rapid virological response: a meta-analysis. J. Hepatol. 1 Swain MG, Lai MY, Shiffman ML et al. A sustained virologic 2010; 52: 25–31. response is durable in patients with chronic hepatitis C treated with 20 Lam NP, Neumann AU, Gretch DR et al. Dose-dependent acute peginterferon alfa-2a and ribavirin. Gastroenterology 2010; 139: clearance of hepatitis C genotype 1 virus with interferon alfa. 1593–601. Hepatology 1997; 26: 226–31. 2 Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An 21 Neumann AU, Lam NP, Dahari H et al. Hepatitis C viral dynamics update on treatment of genotype 1 chronic hepatitis C virus in vivo and the antiviral efficacy of interferon-alpha therapy. Science infection: 2011 practice guideline by the American Association for 1998; 282: 103–7. the Study of Liver Diseases. Hepatology 2011; 54: 1433–44. 22 Dahari H, Guedj J, Perelson AS, Layden TJ. Hepatitis C viral 3 Maruoka D, Imazeki F, Arai M, Kanda T, Fujiwara K, Yokosuka O. kinetics in the era of direct acting antiviral agents and IL28B. Curr. Longitudinal changes of the laboratory data of chronic hepatitis C Hepat. Rep. 2011; 10: 214–27.

Journal of Gastroenterology and Hepatology 29 (2014) 1574–1581 1579 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd Response-guided therapy for HCV EJ Lawitz and FE Membreno

23 Pawlotsky JM. Treatment of chronic hepatitis C: current and future. 44 Fried MW, Buti M, Dore GJ et al. Once-daily simeprevir (TMC435) Curr. Top. Microbiol. Immunol. 2013; 369: 321–42. with pegylated interferon and ribavirin in treatment-Naive genotype 24 Pearlman BL. Chronic hepatitis c therapy: changing the rules of 1 hepatitis C: the randomized PILLAR study. Hepatology 2013; 58: duration. Clin. Gastroenterol. Hepatol. 2006; 4: 963–71. 1918–29. 25 Pearlman BL. Protease inhibitors for the treatment of chronic 45 White PW, Llinas-Brunet M, Amad M et al. Preclinical hepatitis C genotype-1 infection: the new standard of care. Lancet characterization of BI 201335, a C-terminal carboxylic acid inhibitor Infect. Dis. 2012; 12: 717–28. of the hepatitis C virus NS3-NS4A protease. Antimicrob. Agents 26 Poordad F, McCone J Jr, Bacon BR et al. Boceprevir for untreated Chemother. 2010; 54: 4611–18. chronic HCV genotype 1 infection. N. Engl. J. Med. 2011; 364: 46 Manns MP, Bourliere M, Benhamou Y et al. Potency, safety, and 1195–206. pharmacokinetics of the NS3/4A protease inhibitor BI201335 in 27 Jacobson IM, McHutchison JG, Dusheiko G et al. Telaprevir for patients with chronic HCV genotype-1 infection. J. Hepatol. 2011; previously untreated chronic hepatitis C virus infection. N. Engl. J. 54: 1114–22. Med. 2011; 364: 2405–16. 47 Ferenci P, Asselah T, Foster GR et al. Faldaprevir plus pegylated 28 Sherman KE, Flamm SL, Afdhal NH et al. Response-guided interferon alfa-2a and ribavirin in chronic HCV genotype-1 telaprevir combination treatment for hepatitis C virus infection. N. treatment-naïve patients: final results from STARTVerso1, a Engl. J. Med. 2011; 365: 1014–24. randomised, double-blind, placebo-controlled phase III trial. J. 29 Bacon BR, Gordon SC, Lawitz E et al. Boceprevir for previously Hepatol. 2013; 58: S567–77. treated chronic HCV genotype 1 infection. N. Engl. J. Med. 2011; 48 Sulkowski MS, Asselah T, Lalezari J et al. Faldaprevir combined 364: 1207–17. with peginterferon alfa-2a and ribavirin in treatment-naive patients 30 Vierling JM, Davis M, Flamm S et al. Boceprevir for chronic HCV with chronic genotype-1 HCV: SILEN-C1 trial. Hepatology 2013; genotype 1 infection in patients with prior treatment failure to 57: 2143–54. peginterferon/ribavirin, including prior null response. J. Hepatol. 49 Sulkowski MS, Bourliere M, Bronowicki JP et al. Faldaprevir 2014; 60: 748–56. combined with peginterferon alfa-2a and ribavirin in chronic HCV 31 Zeuzem S, Andreone P, Pol S et al. Telaprevir for retreatment of genotype-1 patients with prior nonresponse: SILEN-C2 trial. HCV infection. N. Engl. J. Med. 2011; 364: 2417–28. Hepatology 2013; 57: 2155–63. 32 VICTRELIS™ (boceprevir) [prescribing information]. Whitehouse 50 Jacobson IM, Asselah T, Ferenci P et al. STARTVerso 3: a Station, NJ: Merck & Co.; 2013. randomized, double-blind, placebo-controlled phase III trial of 33 INCIVEK™ (telaprevir) [prescribing information]. Cambridge, MA: faldaprevir in combination with pegylated interferon á-2a and Vertex Pharmaceuticals Incorporated. 2013. ribavirin in treatment-experienced patients with chronic HCV 34 Membreno FE, Lawitz EJ. The HCV NS5B nucleoside and genotype-1 infection. Hepatology 2013; 58 (Suppl. 1): 742A. non-nucleoside inhibitors. Clin. Liver Dis. 2011; 15: 611–26. 51 Lam AM, Murakami E, Espiritu C et al. PSI-7851, a pronucleotide 35 Lawitz E, Mangia A, Wyles D et al. Sofosbuvir for previously of beta-D-2′-deoxy-2′-fluoro-2′-C-methyluridine monophosphate, is a untreated chronic hepatitis C infection. N. Engl. J. Med. 2013; 368: potent and pan-genotype inhibitor of hepatitis C virus replication. 1878–87. Antimicrob. Agents Chemother. 2010; 24: 3187–96. 36 Kowdley K, Lawitz E, Poordad F et al. Phase 2b trial of 52 Kowdley KV, Lawitz E, Crespo I et al. Sofosbuvir with pegylated interferon-free therapy for hepatitis c virus genotype 1. N. Engl. J. interferon alfa-2a and ribavirin for treatment-naive patients with Med. 2014; 370: 222–32. hepatitis C genotype-1 infection (ATOMIC): an open-label, 37 Poordad F, Lawitz E, Kowdley KV et al. Exploratory study of oral randomised, multicentre phase 2 trial. Lancet 2013; 381: 2100–7. combination antiviral therapy for hepatitis C. N. Engl. J. Med. 2013; 53 Lawitz E, Lalezari JP, Hassanein T et al. Sofosbuvir in combination 368: 45–53. with peginterferon alfa-2a and ribavirin for non-cirrhotic, 38 Tanwar S, Trembling PM, Dusheiko GM et al. TMC435 for the treatment-naive patients with genotypes 1, 2, and 3 hepatitis C treatment of chronic hepatitis C. Expert Opin. Investig. Drugs 2012; infection: a randomised, double-blind, phase 2 trial. Lancet Infect. 21: 1193–209. Dis. 2013; 13: 401–8. 39 Jacobson I, Dore GJ, Foster GR et al. Simeprevir (TMC435) with 54 Membreno FE, Lawitz EJ. Non-interferon therapies for hepatitis C. peginterferon/ribavirin for chronic HCV genotype-1 infection in Curr. Hepat. Rep. 2012; 13: 401–8. treatment-naïve patients: results from QUEST-1, a phase III trial. J. 55 Pawlotsky JM. Treatment of hepatitis C: how will we use viral Hepatol. 2013; 58: S567–77. kinetics, response-guided therapy? Curr. Gastroenterol. Rep. 2013; 40 Manns M, Marcellin P, Poordad FF et al. Simeprevir (TMC435) 15: 309–14. with peginterferon/ribavirin for treatment of chronic HCV 56 Gane EJ, Roberts SK, Stedman CA et al. Oral combination therapy genotype-1 infection in treatment-naïve patients: results from with a nucleoside polymerase inhibitor (RG7128) and for QUEST-2, a phase III trial. J. Hepatol. 2013; 58: S567–77. chronic hepatitis C genotype 1 infection (INFORM-1): a 41 Lawitz E, Forns X, Zeuzem S et al. Simeprevir (TMC435) with randomised, double-blind, placebo-controlled, dose-escalation trial. peginterferon/ribavirin for treatment of chronic HCV genotype 1 Lancet 2010; 376: 1467–75. infection in patients who relapsed after previous interferon-based 57 Lok AS, Gardiner DF, Lawitz E et al. Preliminary study of two therapy: results from PROMISE, a phase III trial. Gastroenterology antiviral agents for hepatitis C genotype 1. N. Engl. J. Med. 2012; 2013; 77: S151. 366: 216–24. 42 Manns M, Ressink H, Berg T et al. Rapid viral response of 58 Sulkowski MS, Gardiner DF, Rodrigues-Torres M et al. Daclatasvir once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C plus sofosbuvir for previously treated or untreated chronic HCV genotype-1 patients: a randomized trial. Antivir. Ther. 2011; 16: infection. N. Engl. J. Med. 2014; 370: 211–21. 1021–33. 59 Lawitz E, Poordad FF, Pang PS et al. Sofosbuvir and ledipasvir 43 Zeuzem S, Berg T, Gane E et al. Simeprevir increases R=rate of fixed-dose combination with and without ribavirin in treatment-naive sustained virologic response among treatment-experienced patients and previously treated patients with genotype 1 hepatitis C virus with HCV genotype-1 infection: a phase IIb trial. Gastroenterology infection (LONESTAR): an open-label, randomised, phase 2 trial. 2014; 146: 430–41. Lancet 2014; 383: 515–23.

1580 Journal of Gastroenterology and Hepatology 29 (2014) 1574–1581 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd EJ Lawitz and FE Membreno Response-guided therapy for HCV

60 Gane EJ, Stedman CA, Hyland RH et al. Nucleotide polymerase 63 Infectious Diseases Society of America/American Association for the inhibitor sofosbuvir plus ribavirin for hepatitis C. N. Engl. J. Med. Study of Liver Diseases. Recommendations for testing, managing, 2013; 368: 34–44. and treating hepatitis C. Cited 3 Mar 2014. Available from: 61 Gane EJ, Stedman CA, Hyland RH et al. Efficacy of nucleotide http://www.hcvguidelines.org/ polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir 64 Lawitz E, Poordad F, Kowdley KV et al. A phase 2a trial of or the NS5B non-nucleoside inhibitor GS-9669 against HCV 12-week interferon-free therapy with two direct-acting antivirals genotype 1 infection. Gastroenterology 2014; 146: 736–43. (ABT-450/r, ABT-072) and ribavirin in IL28B C/C patients 62 Jacobson IM, Ghalib R, Rodriguez-Torres M et al. SVR results of a with chronic hepatitis C genotype 1. J. Hepatol. 2013; 59: once-daily regimen of simeprevir (SMV, TMC435) plus sofosbuvir 18–23. (SOF, GS-7977) with or without ribavirin in cirrhotic and 65 Lawitz E, Hezode C, Varunok P et al. Interferon- and ribavirin free non-cirrhotic HCV genotype 1 treatment-naïve and prior null regimen of ABT-450/r + ABT-267 in HCV genotype 1b-infected responder patients: The COSMOS study. The American Association treatment-naive patients and prior null responders. Hepatology 2013; for the Study of Liver Diseases 64th Annual Meeting 2013, 58 (Suppl. 4): 244A. [Abstract 75]. Washington, DC, Nov 1–5, 2013.

Journal of Gastroenterology and Hepatology 29 (2014) 1574–1581 1581 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd