January 19, 2014

Boehringer Ingelheim HCV Announcement

Following an assessment of the blinded Phase 3 trial data from HCVerso® 1 and 2 for the combination of deleobuvir, faldaprevir and ribavirin, Boehringer Ingelheim has decided to halt further development of deleobuvir-containing hepatitis C (HCV) regimens.

The combination showed a higher rate of premature discontinuations suggesting a lower efficacy rate compared to other interferon-free therapies in development. Boehringer Ingelheim has therefore concluded that the expected therapeutic value of the deleobuvir-containing regimen would not justify further development.

Faldaprevir, Boehringer Ingelheim's investigational HCV protease inhibitor, has shown promising results in combination with pegylated interferon and ribavirin in the STARTVerso™ trials. Ongoing regulatory reviews of faldaprevir are not affected by the decision on the deleobuvir-containing regimens. In the US, Boehringer Ingelheim will move forward with the submission process for faldaprevir.

Boehringer Ingelheim is committed to developing new treatments that provide high therapeutic value in areas of unresolved medical need. The company is focusing its efforts on numerous promising development projects in areas, such as immunology, cardiovascular, respiratory, metabolic diseases, diseases of the central nervous system and oncology.

Source Boehringer Ingelheim

Source: Project Inform

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It is important to know that the STARTVerso trials are still being conducted and will be completed.  _AF of HCV Advocate

Provided by NATAP

Download the PDF here

Download the PDF here

N Engl J Med January 16, 2014

"We assessed daclatasvir plus sofosbuvir in untreated patients and patients in whom previous treatment with telaprevir or boceprevir had failed. Overall, most patients had a sustained virologic response, including 98% of patients with genotype 1 infection, regardless of viral subtype or failure of prior treatment with protease inhibitors, and 91% of patients infected with genotype 2 or 3. The most common adverse event was fatigue, which was reported in approximately one third of patients. Our study shows that the combination of an NS5A inhibitor and an NS5B inhibitor was associated with high cure rates in a range of HCV-infected patients, including patients who had persistent HCV variants conferring resistance to protease inhibitors after unsuccessful treatment with telaprevir or boceprevir."

"Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea......

................None of the patients with genotype 1 infection had a virologic breakthrough, and all had an HCV RNA level of less than 25 IU per milliliter at the end of the treatment period. After the treatment period, no patient had a virologic relapse. Overall, 164 of 167 patients with genotype 1 infection (98%) had a sustained virologic response at week 12 after treatment, including 84 of 85 patients who received treatment for 24 weeks (all 44 patients who had not received previous treatment and 40 of 41 patients who had received a protease inhibitor) and 80 of 82 patients who received treatment for 12 weeks. Of the 3 patients who were classified as not having a sustained virologic response 12 weeks after treatment, 2 missed the assessment visit at 12 weeks but had a sustained virologic response at week 24 after treatment, and 1 was lost to follow-up.....Of 126 patients with previously untreated genotype 1 infection, 120 (95%) had a sustained virologic response at week 24 after treatment (Table 2). Of the 6 patients who were classified as not having a sustained virologic response at week 24 after treatment, 4 missed the assessment visit at week 24 but were classified as having a sustained virologic response at week 36 after treatment, and 1 was lost to follow-up. The remaining patient, whose history included injection-drug use, had a high level of viremia (HCV RNA level, 670,772 IU per milliliter), and viral sequences at week 24 after treatment that differed from the sequences at baseline suggested a new HCV infection. Furthermore, no daclatasvir-resistant or sofosbuvirresistant variants were detected......All patients infected with genotype 2 or 3 had an undetectable HCV RNA level during the treatment period. One patient with genotype 3 infection who was treated without ribavirin had a detectable HCV RNA level of less than 25 IU per milliliter at weeks 8 and 10, which, per protocol, was defined as a virologic breakthrough (Table 2). However, before the initiation of rescue therapy at week 12, HCV RNA was undetectable; the patient had a sustained virologic response at 24 weeks after rescue therapy. Overall, 91% of the patients infected with genotype 2 or 3 had a sustained virologic response 12 weeks after treatment and 93% had a sustained virologic response 24 weeks after treatment (Table 2). Rates of sustained virologic response 12 weeks after treatment were 92% among patients with genotype 2 infection (24 of 26 patients) and 89% among patients with genotype 3 infection (16 of 18)

Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection

Mark S. Sulkowski, M.D., David F. Gardiner, M.D., Maribel Rodriguez-Torres, M.D., K. Rajender Reddy, M.D., Tarek Hassanein, M.D., Ira Jacobson, M.D., Eric Lawitz, M.D., Anna S. Lok, M.D., Federico Hinestrosa, M.D., Paul J. Thuluvath, M.D., Howard Schwartz, M.D., David R. Nelson, M.D., Gregory T. Everson, M.D., Timothy Eley, Ph.D., Megan Wind-Rotolo, Ph.D., Shu-Pang Huang, Ph.D., Min Gao, Ph.D., Dennis Hernandez, Ph.D., Fiona McPhee, Ph.D., Diane Sherman, M.S., Robert Hindes, M.D., William Symonds, Pharm.D., Claudio Pasquinelli, M.D., Ph.D., and Dennis M. Grasela, Pharm.D., Ph.D. for the AI444040 Study Group

N Engl J Med 2014; 370:211-221January 16, 2014

Presented in part at the 48th annual meeting of the European Association for the Study of the Liver, Amsterdam, April 24-28, 2013; the 63rd annual meeting of the American Association for the Study of Liver Diseases, Boston, November 9-13, 2012; and the 47th annual meeting of the European Association for the Study of the Liver, Barcelona, April 18-22, 2012.

Abstract

Background

All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3.

Methods

In this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa-ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) at week 12 after the end of therapy.

Results

Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea.

Conclusions

Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.)

Chronic infection with hepatitis C virus (HCV) affects approximately 170 million people worldwide and is a major cause of cirrhosis and hepatocellular carcinoma.1,2 HCV-related morbidity and mortality are increasing; since 2007, HCV-related deaths in the United States have exceeded those from human immunodeficiency virus (HIV) infection.3,4 HCV is classified into six major genotypes.5,6 Genotypes 1, 2, and 3 are found worldwide, with subtype 1a predominating in the United States and subtype 1b predominating in Europe, Japan, and China.5,7,8

Peginterferon alfa-ribavirin treatment for chronic HCV infection is associated with a sustained virologic response (undetectable HCV RNA level after treatment) in approximately 40% of patients with genotype 1 infection and 75% of patients infected with genotype 2 or 3.9,10 Adding boceprevir or telaprevir has been shown to improve the response in patients with genotype 1 infection.11,12 However, the addition of boceprevir or telaprevir is limited to HCV genotype 1 and is associated with adverse events, complicated dose regimens, and viral resistance.11-14 Currently, patients who have virologic failure (no sustained virologic response) with telaprevir or boceprevir plus peginterferon alfa-ribavirin have no other treatment options.

Daclatasvir is a first-in-class HCV NS5A replication complex inhibitor, and sofosbuvir is a nucleotide analogue HCV NS5B polymerase inhibitor.15,16 Both have potent antiviral activity and broad genotypic coverage and are administered orally once daily.15,17,18 Each is effective in patients infected with genotype 1, 2, or 3 when this treatment is combined with peginterferon alfa-ribavirin,19-22 and sofosbuvir plus ribavirin is effective in patients infected with genotype 1, 2, or 3 in the absence of treatment with peginterferon alfa-ribavirin.23 We evaluated daclatasvir plus sofosbuvir, with or without ribavirin, in previously untreated patients infected with genotype 1, 2, or 3, and in patients with genotype 1 infection who had not had a response to previous treatment with telaprevir or boceprevir.

Methods

Patients

Eligible patients were 18 to 70 years of age and had chronic HCV genotype 1, 2, or 3 infection with an HCV RNA level of 100,000 IU per milliliter or higher. Patients did not have evidence of cirrhosis as documented by means of either liver biopsy within the previous 24 months or noninvasive assessment of serum markers of fibrosis (a FibroTest score of ≤0.72, on a scale of 0 to 1, with higher scores indicating more severe fibrosis, and an aspartate aminotransferase:platelet ratio index of ≤2, with higher scores indicating a greater likelihood of extensive fibrosis) at screening.24,25 Patients who had received prior treatment had confirmed virologic failure during or after treatment with telaprevir (at a dose of 750 mg three times daily) or boceprevir (at a dose of 800 mg three times daily) plus peginterferon alfa-ribavirin. Virologic failure was defined as a nonresponse (detectable HCV RNA levels at the end of the treatment period), breakthrough (>1 log10 increase from the nadir in the HCV RNA level or a quantifiable HCV RNA level in a patient with an undetectable level during the treatment period), or relapse (a quantifiable HCV RNA level during follow-up in a patient with an undetectable level at the end of the treatment period).

Patients who had discontinued telaprevir or boceprevir because of adverse events were excluded. Other exclusion criteria were chronic liver disease other than HCV infection and coinfection with HIV or hepatitis B virus. All patients provided written informed consent.

Study Oversight

The study was conducted in accordance with Good Clinical Practice guidelines and was approved by the institutional review board or independent ethics committee at each site. Bristol-Myers Squibb (the sponsor) and Pharmasset (now Gilead Sciences), which provided the study drug, designed the study; the sponsor conducted the study in collaboration with the principal investigators, collected the data, monitored the conduct of the study, and performed the statistical analyses. The first draft of the manuscript was prepared by the academic and industry authors, with assistance from a medical writer paid by the sponsor. The academic authors vouch for the completeness and accuracy of the data and data analyses and for the fidelity of the study to the protocol (available with the full text of this article at NEJM.org).

Study Design

In this open-label study, untreated patients were randomly assigned, in a 1:1:1 ratio, to receive sofosbuvir for 1 week, then daclatasvir and sofosbuvir for 23 weeks (groups A and B); daclatasvir and sofosbuvir for 24 weeks (groups C and D); or daclatasvir, sofosbuvir, and ribavirin for 24 weeks (groups E and F). Patients with genotype 1 infection were assigned to group A, C, or E, and patients infected with genotype 2 or 3 were assigned to group B, D, or F (Fig. S1a in the Supplementary Appendix, available at NEJM.org).

The purpose of the lead-in period of therapy with sofosbuvir was to determine whether initial HCV suppression with sofosbuvir would reduce the emergence of daclatasvir-resistant variants. In accordance with a protocol amendment, 123 additional patients with genotype 1 infection were randomly assigned in a 1:1 ratio to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 untreated patients, assigned to group G or H) or 24 weeks (41 patients who did not have a response to prior treatment with HCV protease inhibitors, assigned to group I or J) (Fig. S1b and S1c in the Supplementary Appendix). Daclatasvir and sofosbuvir were administered orally at a dose of 60 mg once daily and 400 mg once daily, respectively. Ribavirin was administered orally twice daily at a dose of 1000 to 1200 mg per day, according to body weight (1000 mg in patients with a body weight of <75 kg, and 1200 mg in patients with a body weight ≥75 kg), in patients with genotype 1 infection, and at a dose of 800 mg per day in patients infected with genotype 2 or 3. A reduction in the dose of ribavirin to 600 mg daily was permitted if the hemoglobin level decreased to below 10 g per deciliter.

Efficacy and Safety Monitoring

Serum HCV RNA levels were assayed centrally with the use of the COBAS TaqMan HCV test, version 2.0 (Roche Molecular Systems), with a lower limit of quantification of 25 IU per milliliter and a lower limit of detection of 10 IU per milliliter. HCV RNA levels were measured at baseline; on treatment days 1 through 7, 9, 11, 14, and 21; every 2 weeks from treatment week 4 through week 24; and at weeks 4, 12, and 24 after the end of the treatment period. Adverse events were recorded throughout the study. Clinical laboratory tests, physical examinations, and electrocardiographic monitoring were performed at screening, at baseline, and at scheduled visits throughout treatment.

Virologic Breakthrough, Relapse, and Resistance Monitoring

Virologic breakthrough during the treatment period was defined as a confirmed increase from the nadir in the HCV RNA level of at least 1 log10 IU per milliliter or a confirmed HCV RNA level of 25 IU per milliliter or higher at or after week 8. In groups A through F, breakthrough also included detectable HCV RNA of less than 25 IU per milliliter at or after week 8; results from the first cohort showed that detectable but unquantifiable HCV RNA was not associated with the clinical outcome, so this definition was later removed. For patients with virologic breakthrough, peginterferon alfa and ribavirin could be added as rescue therapy (unless they were already receiving ribavirin). Virologic relapse was defined as a confirmed HCV RNA level of 25 IU per milliliter or higher in patients with an HCV RNA level that was less than 25 IU per milliliter at the end of treatment.

At baseline, the HCV NS5A and NS5B regions from all samples and the NS3 region from samples in groups I and J were analyzed by means of population sequencing (sensitivity, approximately 20%). Samples from patients with virologic breakthrough or relapse were analyzed by means of population sequencing if the HCV RNA level was at least 1000 IU per milliliter. After viral RNA was isolated from plasma, the HCV NS3, NS5A, and NS5B regions were amplified by means of polymerase chain reaction and sequenced. Consensus sequences in samples obtained from the patients were compared with the appropriate reference sequences (GT1a [H77], GT1b [Con1], GT2 [JFH1], and GT3 [S52]) by means of the Basic Local Alignment Search Tool.

End Points

The primary efficacy end point was the proportion of patients with a sustained virologic response (an HCV RNA level of less than 25 IU per milliliter) at week 12 after the end of treatment. Secondary efficacy end points included a sustained virologic response at 4 weeks after treatment and at 24 weeks after treatment. Safety end points included adverse events, discontinuation of a study drug due to adverse events, and grade 3 or 4 laboratory abnormalities.

Statistical Analysis

With sample sizes of 14, 20, and 40 patients, the probability of observing at least one safety event occurring at an incidence rate of 10% was 0.771, 0.878, and 0.985, respectively. With these three sample sizes, the two-sided 80% exact confidence intervals for a sustained virologic response at week 12 after treatment were, respectively, 58 to 92% if the observed rate was 79% (11 of 14 patients with an event), 59 to 87% if the observed rate was 75% (15 of 20 patients with an event), and 64 to 84% if the observed rate was 75% (30 of 40 patients with an event). For efficacy end points, the analyses included all patients who received at least one dose of study medication (modified intention-to-treat population). Patients for whom data were missing were classified as not having had a response at that visit but could be classified as having a response at future visits if the lack of response was solely due to the missing HCV RNA measurement. Patients who required rescue therapy were classified as not having had a response at the time of rescue and at all subsequent visits.

Results

Characteristics of the Patients

A total of 211 patients received treatment at 18 centers in the United States between June 2011 and November 2012. A total of 44 were infected with HCV genotype 2 or 3, and 167 had genotype 1 infection (126 untreated patients and 41 patients who did not have a response to prior treatment with protease inhibitors) (Fig. S1 in the Supplementary Appendix). Among patients with genotype 1 infection, the median age ranged from 54 to 59 years, and most had fibrosis of Metavir stage 2 or higher (on a scale from F0 to F4, with higher stages indicating a greater degree of fibrosis) (Table 1). Of the 41 patients who did not have a response to prior treatment with protease inhibitors, 19 (46%) had NS3 polymorphisms conferring resistance to telaprevir or boceprevir (Tables S2 and S3 in the Supplementary Appendix).

Virologic Response

During the initial 48 hours, the slope of the mean viral decline was steeper in groups receiving daclatasvir and sofosbuvir than in those receiving sofosbuvir alone (P<0.001) (Fig. S2 in the Supplementary Appendix). This difference did not persist; all patients had an HCV RNA level of less than 25 IU per milliliter by week 4.

All patients infected with genotype 2 or 3 had an undetectable HCV RNA level during the treatment period. One patient with genotype 3 infection who was treated without ribavirin had a detectable HCV RNA level of less than 25 IU per milliliter at weeks 8 and 10, which, per protocol, was defined as a virologic breakthrough (Table 2). However, before the initiation of rescue therapy at week 12, HCV RNA was undetectable; the patient had a sustained virologic response at 24 weeks after rescue therapy (Table S4 in the Supplementary Appendix). Overall, 91% of the patients infected with genotype 2 or 3 had a sustained virologic response 12 weeks after treatment and 93% had a sustained virologic response 24 weeks after treatment (Table 2). Rates of sustained virologic response 12 weeks after treatment were 92% among patients with genotype 2 infection (24 of 26 patients) and 89% among patients with genotype 3 infection (16 of 18).

None of the patients with genotype 1 infection had a virologic breakthrough, and all had an HCV RNA level of less than 25 IU per milliliter at the end of the treatment period (Table 2). After the treatment period, no patient had a virologic relapse. Overall, 164 of 167 patients with genotype 1 infection (98%) had a sustained virologic response at week 12 after treatment, including 84 of 85 patients who received treatment for 24 weeks (all 44 patients who had not received previous treatment and 40 of 41 patients who had received a protease inhibitor) and 80 of 82 patients who received treatment for 12 weeks. Of the 3 patients who were classified as not having a sustained virologic response 12 weeks after treatment, 2 missed the assessment visit at 12 weeks but had a sustained virologic response at week 24 after treatment, and 1 was lost to follow-up (Table 2, and Tables S2 and S4 in the Supplementary Appendix). Rates of sustained virologic response 12 weeks after treatment were similar in subgroups defined according to viral subtype (genotype 1a, 98% [129 of 132 patients]; genotype 1b, 100% [35 of 35 patients]), IL28B genotype (CC, 93% [57 of 61 patients]; non-CC, 98% [147 of 150 patients]), race (white, 97% [170 of 175 patients]; black, 96% [25 of 26 patients]; and other race, 90% [9 of 10 patients]), ribavirin status (ribavirin, 94% [85 of 90 patients]; no ribavirin, 98% [119 of 121 patients]), and history of treatment failure with protease inhibitors (98% [40 of 41 patients]).

Of 126 patients with previously untreated genotype 1 infection, 120 (95%) had a sustained virologic response at week 24 after treatment (Table 2). Of the 6 patients who were classified as not having a sustained virologic response at week 24 after treatment, 4 missed the assessment visit at week 24 but were classified as having a sustained virologic response at week 36 after treatment, and 1 was lost to follow-up. The remaining patient, whose history included injection-drug use, had a high level of viremia (HCV RNA level, 670,772 IU per milliliter), and viral sequences at week 24 after treatment that differed from the sequences at baseline suggested a new HCV infection. Furthermore, no daclatasvir-resistant or sofosbuvirresistant variants were detected (Fig. S3 in the Supplementary Appendix).

Virologic Breakthrough, Relapse, and Resistance

Virologic relapse was confirmed in 1 patient with genotype 3 infection who received treatment without ribavirin; adherence to the treatment regimen was documented on the basis of pill counts, as well as plasma concentrations of daclatasvir and major sofosbuvir metabolites that were consistent with those in other patients. Resistance analysis showed a preexisting NS5A-A30K polymorphism, associated with daclatasvir resistance, at baseline and at the time of relapse. No other resistance-associated changes were detected at the time of relapse. Of the available baseline samples, pretreatment polymorphisms, including NS5A-A30K and others known to confer loss of susceptibility to daclatasvir in vitro, were observed in 10 of 123 untreated patients with genotype 1 infection (8%), 3 of 40 patients with genotype 1 infection in whom prior treatment with protease inhibitors had failed (8%), 14 of 23 patients with genotype 2 infection (61%), and 5 of 18 patients with genotype 3 infection (28%) (Table S5 in the Supplementary Appendix). Except for the patient described above, all patients with preexisting daclatasvir resistance variants had a sustained virologic response. With respect to sofosbuvir, no preexisting NS5B-S282T polymorphisms were detected. In the only patient with protocol-defined virologic breakthrough, no baseline daclatasvir or sofosbuvir resistance-associated polymorphisms were detected, and the HCV RNA level at the time of virologic breakthrough was too low (<25 IU per milliliter) for resistance testing; the patient had a sustained virologic response after rescue therapy.

Safety

The most common adverse events were fatigue, headache, and nausea (Table 3Table 3, and Table S6 in the Supplementary Appendix). Two patients discontinued treatment because of adverse events (fibromyalgia in one patient and a stroke in one patient); both had a sustained virologic response (Table S7 in the Supplementary Appendix). Serious adverse events during the treatment period (Table 3, and Table S8 in the Supplementary Appendix) included single events of gastroenteritis, colitis, stroke, acute renal failure from dehydration that resolved with administration of fluids, forearm fracture, anxiety and pleuritic pain, exacerbation of psoriasis, and hypokalemia. The most common grade 3 or 4 laboratory abnormalities were low phosphorus and elevated glucose levels. The mean change in the hemoglobin level associated with regimens that contained ribavirin versus those that did not contain ribavirin was -2.2 g per deciliter versus -0.3 g per deciliter after 24 weeks of therapy and -2.8 g per deciliter versus -0.9 g per deciliter after 12 weeks of therapy. The ribavirin dose was reduced in five patients because of anemia. Additional safety findings are listed in Tables S6, S7, and S8 in the Supplementary Appendix.

Discussion

We assessed daclatasvir plus sofosbuvir in untreated patients and patients in whom previous treatment with telaprevir or boceprevir had failed. Overall, most patients had a sustained virologic response, including 98% of patients with genotype 1 infection, regardless of viral subtype or failure of prior treatment with protease inhibitors, and 91% of patients infected with genotype 2 or 3. The most common adverse event was fatigue, which was reported in approximately one third of patients. Our study shows that the combination of an NS5A inhibitor and an NS5B inhibitor was associated with high cure rates in a range of HCV-infected patients, including patients who had persistent HCV variants conferring resistance to protease inhibitors after unsuccessful treatment with telaprevir or boceprevir.

Daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients with characteristics that were previously associated with a poor response to treatment - HCV genotypes 1a and 3, the non-CC IL28B genotype, and black race. Studies evaluating peginterferon alfa-ribavirin plus a single direct-acting antiviral agent11,12,26,27 or different combinations of direct-acting antiviral agents28-30 have shown that patients with genotype 1a infection have a worse response than patients with genotype 1b infection; indeed, some oral regimens are effective primarily in patients with genotype 1b infection. In our study, most of the patients had genotype 1a infection, and the rates of response were high in both these patients and those with genotype 1b infection. Recent evidence suggests that HCV genotype 3 may also be less responsive to treatment than other genotypes.21,31 In our study, 16 of 18 patients with genotype 3 infection had a sustained virologic response at week 12 after treatment. With regard to host factors, lower response rates have been observed with non-CC IL28B genotypes than with the CC genotype in studies of peginterferon alfa-ribavirin with or without telaprevir or boceprevir11,26,32 and in studies of some direct-acting antiviral combinations.29,30 Most patients in our study had non-CC IL28B genotypes, and the rate of response was high among these patients.

Patients with HCV genotype 1 infection who have virologic failure during telaprevir-based or boceprevir-based therapy despite acceptable adherence are frequently infected with HCV genotype 1a, and they often have a poor response to interferon, as indicated by a non-CC IL28B genotype.13,26 In our study, patients in whom prior treatment with protease inhibitors had failed were characterized according to prior virologic response: 71% had virologic breakthrough or nonresponse, indicating poor interferon responsiveness, HCV resistance, or both (Table S2 in the Supplementary Appendix). Furthermore, most of these patients were infected with subtype 1a (80%), had a non-CC IL28B genotype (98%), and had evidence of at least moderate hepatic fibrosis (score ≥2) at baseline (83%) (Table 1). Despite these characteristics, early HCV RNA suppression was similar in previously treated and untreated patients (Fig. S2 in the Supplementary Appendix), and all patients in whom prior treatment with protease inhibitors had failed had a sustained virologic response. This represents proof of concept that a sustained virologic response can be achieved in patients in whom previous treatment with telaprevir or boceprevir had failed, including patients who have persistent HCV variants with resistance to protease inhibitors (Fig. S4 in the Supplementary Appendix).

Virologic breakthrough and relapse were rare in our population and were not observed in any of the 193 patients infected with HCV genotype 1 or 2, despite preexisting daclatasvir-resistant variants in 27 patients. Of the 5 patients infected with HCV genotype 1 or 2 who were classified as not having a sustained virologic response at week 12 after treatment, 3 had missing data at week 12 but had a sustained virologic response at week 24 after treatment (including 1 who returned after the database lock) and 2 were lost to follow-up. Among the 18 patients with HCV genotype 3 infection, virologic relapse occurred in 1 of 5 patients with a preexisting daclatasvir-resistant variant, and in a second patient, who did not have preexisting daclatasvir-resistant variants, an HCV RNA level below 25 IU per milliliter was detected at weeks 8 and 10. Although HCV RNA was undetectable at week 12, this response pattern was predefined in the original protocol as virologic breakthrough, and rescue therapy was initiated. Because of low virus levels during the treatment period and a sustained virologic response at week 12 after treatment, we could not assess the role of viral variants in this patient. Sofosbuvir-resistant variants were not detected in any of the patients. Our observations suggest that the development of resistance is uncommon with daclatasvir plus sofosbuvir.

Many HCV treatment regimens have been assessed with and without ribavirin, and the response rates have been lower in the absence of ribavirin. This has been observed with peginterferon alfa-ribavirin plus a protease inhibitor33 and with interferon-free regimens, including sofosbuvir with or without ribavirin in patients infected with genotype 2 or 3.23,29,34 In our study, response rates were similar among patients treated with ribavirin and those treated without it; however, ribavirin recipients had a greater decrease in the hemoglobin level. Our findings may reflect the antiviral potency and high resistance barrier of the daclatasvir-sofosbuvir combination and suggest that ribavirin is not required with every oral direct-acting antiviral regimen. Ribavirin requires twice-daily dosing, is associated with hemolytic anemia, and is highly teratogenic. Ribavirin-sparing regimens are therefore desirable and warrant further investigation.

In conclusion, once-daily, oral treatment with the NS5A inhibitor daclatasvir plus the NS5B polymerase inhibitor sofosbuvir was associated with high rates of sustained virologic response in untreated patients infected with genotype 1, 2, or 3 and in patients with genotype 1 infection in whom previous treatment with protease inhibitors had failed and who had no current treatment options. The response rate was high across subgroups of patients defined according to IL28B genotype, HCV genotype 1 subtype, receipt of ribavirin, and the presence of HCV protease inhibitor-resistant variants.

Source

Provided by NATAP

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"In this article, we present the results of a phase 2b, open-label, multiple-group study that was designed to determine the safety and efficacy of various combinations of ABT-450/r, ABT-333, ABT-267, and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. The study design enabled multiple comparisons between treatment groups, allowing preliminary comparisons of treatment durations, antiviral-drug combinations, and ABT-450 doses in a single study."

\-- the rate of sustained virologic response .......was 96% in the subgroup of patients who were never before treated that received 12 weeks of therapy with the full regimen - ABT-450/r+ABT-333+ABT-267+RBV, and 95% in the patients who were previously treated with Peg/Rbv. \

"In this phase 2b study of interferon-free antiviral regimens for the treatment of chronic HCV genotype 1 infection without cirrhosis, the treatment regimens were associated with rates of sustained virologic response at 24 weeks after treatment that ranged from 83 to 100%.

The 12-week regimen was also associated with a 93% rate of sustained virologic response at 24 weeks after treatment among patients who had not had a response to prior therapy, with a similar rate among patients treated for 24 weeks, which suggests that 12 weeks may be the preferred duration in this population as well."

Recently released in the Abbvie press releases with updated new results from their ongoing phase 3 studies:

ABBVIE DEMONSTRATES 96 PERCENT SVR(12) IN ITS PHASE III STUDY OF TREATMENT-EXPERIENCED PATIENTS WITH GENOTYPE 1 HEPATITIS C - (12/18/13)

AbbVie Releases First of Six Phase III Results from Investigational All-Oral, Interferon-Free, 12-week Regimen, Showing 96 Percent SVR12 in Genotype 1 Hepatitis C Patients New to Therapy - (11/18/13)

-----------------------------

Phase 2b Trial of Interferon-free Therapy for Hepatitis C Virus Genotype 1

Kris V. Kowdley, M.D., Eric Lawitz, M.D., Fred Poordad, M.D., Daniel E. Cohen, M.D., David R. Nelson, M.D., Stefan Zeuzem, M.D., Gregory T. Everson, M.D., Paul Kwo, M.D., Graham R. Foster, F.C.R.P., Mark S. Sulkowski, M.D., Wangang Xie, Ph.D., Tami Pilot-Matias, Ph.D., George Liossis, B.A., Lois Larsen, Ph.D., Amit Khatri, Ph.D., Thomas Podsadecki, M.D., and Barry Bernstein, M.D.

N Engl J Med January 16, 2014

ABSTRACT

Background

An interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study involving patients with HCV genotype 1 infection. The addition of another potent agent, the NS5A inhibitor ABT-267, may improve efficacy, especially in difficult-to-treat patients. This study was designed to evaluate multiple regimens of direct-acting antiviral agents and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously or who had no response to prior therapy with pegylated interferon and ribavirin.

Methods

\In this phase 2b, open-label study with 14 treatment subgroups, 571 patients without cirrhosis who had not received treatment previously or who had not had a response to prior therapy were randomly assigned to a regimen of ABT-450/r, combined with ABT-267 or ABT-333 or both, for 8, 12, or 24 weeks and received at least one dose of therapy. All the subgroups but 1 also received ribavirin (dose determined according to body weight). The primary end point was sustained virologic response at 24 weeks after the end of treatment. The primary efficacy analysis compared rates between previously untreated patients who received three direct-acting antiviral agents and ribavirin for 8 weeks and those who received the same therapy for 12 weeks.

Results

\Among previously untreated patients who received three direct-acting antiviral agents (with the ABT-450/r dose administered as 150 mg of ABT-450 and 100 mg of ritonavir) plus ribavirin, the rate of sustained virologic response at 24 weeks after treatment was 88% among those who received the therapy for 8 weeks and 95% among those who received the therapy for 12 weeks (difference, -7 percentage points; 95% confidence interval, -19 to 5; P=0.24). The rates of sustained virologic response across all treatment subgroups ranged from 83 to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia. Eight patients (1%) discontinued treatment owing to adverse events.

Conclusions

In this phase 2b study, all-oral regimens of antiviral agents and ribavirin were effective both in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. (Funded by AbbVie; ClinicalTrials.gov number, NCT01464827.)

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis, liver cancer, and end-stage liver disease.1 The current standard of care for chronic HCV genotype 1 infection is pegylated interferon (peginterferon) and ribavirin, with a protease inhibitor (boceprevir or telaprevir).2 Although the addition of a protease inhibitor has been associated with a significant increase in response rates, only approximately one third of patients who had not had a response to prior therapy with peginterferon and ribavirin had a sustained virologic response when re-treated with the addition of a protease inhibitor.3,4 Furthermore, these therapies are associated with adverse effects that can lead to early discontinuation of treatment.5-7 Patient characteristics, such as host genetic factors (e.g., IL28B rs12979860 CT or TT genotype), HCV subtype 1a, black race, and high baseline viral load, are also associated with poor response rates.6-8 New interferon-free therapies with greater activity in difficult-to-treat patients with HCV infection are needed.

ABT-450, a potent inhibitor of the HCV NS3/4A protease, is coadministered with 100 mg of ritonavir (ABT-450/r) to increase ABT-450 plasma levels and half-life, permitting once-daily dosing.9 ABT-333 is a nonnucleoside NS5B polymerase inhibitor. A recent pilot study involving patients with HCV genotype 1 infection who received 12 weeks of treatment with ABT-450/r, ABT-333, and ribavirin showed rates of sustained virologic response 12 weeks after treatment of 93 to 95% among previously untreated patients and 47% among patients who had not had a response or who had had only a partial response to prior therapy with peginterferon and ribavirin.10

The addition of a potent third direct-acting antiviral agent, the NS5A inhibitor ABT-267, may improve efficacy in patients for whom a poor response is predicted, including those who have not had a response to prior therapy. ABT-267 monotherapy for 3 days in previously untreated patients resulted in a mean decrease in the HCV RNA level of 3.10 log10 IU per milliliter.11 Because patients who have not had a response to prior therapy have historically had the lowest levels of response to retreatment, a favorable therapeutic outcome in this population would be likely to extend to other patient populations that have received therapy previously.

In this article, we present the results of a phase 2b, open-label, multiple-group study that was designed to determine the safety and efficacy of various combinations of ABT-450/r, ABT-333, ABT-267, and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. The study design enabled multiple comparisons between treatment groups, allowing preliminary comparisons of treatment durations, antiviral-drug combinations, and ABT-450 doses in a single study.

Methods

Study Population

Eligible patients were 18 to 70 years of age with a plasma HCV RNA level of more than 50,000 IU per milliliter at screening and no evidence of cirrhosis. Previously untreated patients and those who had not had a response to prior therapy (patients who had received peginterferon and ribavirin for at least 12 weeks and did not have a decline in the HCV RNA level of at least 2 log10 IU per milliliter) were eligible. Detailed eligibility criteria are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Study Design

This study was designed as an open-label trial with respect to treatment durations, drug combinations, and doses for each of 14 treatment subgroups (Figure 1. Details of the randomization procedure are provided in the Supplementary Appendix.

ABT-450/r was administered in doses of 100 mg, 150 mg, or 200 mg of ABT-450 with 100 mg of ritonavir daily. The ABT-267 dose was 25 mg daily. The ABT-333 dose was 400 mg twice daily. The daily dose of ribavirin was 1000 mg (divided into doses of 400 mg and 600 mg) if the body weight was less than 75 kg or 1200 mg (600 mg twice daily) if the body weight was 75 kg or more. The treatment duration was 8, 12, or 24 weeks.

Study Oversight

All the patients provided written informed consent. The study was performed in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki, and the study protocol was approved by the relevant institutional review boards and regulatory agencies.

The study was designed jointly by the study investigators and the sponsor (AbbVie). The investigators gathered the data, and the sponsor conducted the data analyses. All the authors had full access to the data and signed confidentiality agreements with the sponsor regarding the data. The first draft of the manuscript was written by a medical writer employed by the sponsor and was edited and revised by the first author, with input from all the authors. All the authors reviewed and provided feedback on all subsequent versions of the manuscript. All the authors vouch for the completeness and accuracy of the data and analyses presented and confirm that the study was conducted and reported with fidelity to the protocol, which is available at NEJM.org.

Virologic and Safety Assessments

\Details on the collection of plasma samples, HCV RNA measurement, resistance testing, and criteria for virologic failure are provided in the Supplementary Appendix. Assessments of adverse events and clinical laboratory testing were performed at each study visit. Events were classified as mild, moderate, or severe by the investigator.

Data on all adverse events were collected from the start of study-drug administration until 30 days after the last dose was administered. Data on serious adverse events were collected throughout the study.

Efficacy Analyses

The primary efficacy end point was sustained virologic response (HCV RNA level below the lower limit of quantitation [25 IU per milliliter]) at 24 weeks after the end of treatment. Analyses were performed on the modified intention-to-treat population, which included patients who had undergone randomization and received at least one dose of study drug. The primary analysis was a comparison of the rate of sustained virologic response at 24 weeks after treatment between previously untreated patients who received three direct-acting antiviral agents (including ABT-450/r administered in daily doses of 150 mg of ABT-450 and 100 mg of ritonavir) with ribavirin for 8 weeks (subgroup A) and those who received the same therapy for 12 weeks (subgroup G). Secondary analyses compared the rate of sustained virologic response at 24 weeks after treatment among other treatment groups and subgroups.

\Virologic breakthrough during treatment was defined as two consecutive HCV RNA measurements of more than 1 log10 IU per milliliter above the nadir HCV RNA level or two consecutive HCV RNA measurements that were higher than the lower limit of quantitation at any time after the HCV RNA level had been less than the lower limit of quantitation. Virologic relapse was defined as a confirmed quantifiable HCV RNA level in a patient who had had an HCV RNA level that was less than the lower limit of quantitation at the end of treatment.

Statistical Analysis

SAS software, version 9.2, for the UNIX operating system (SAS Institute) was used for all analyses. Details of the sample-size determination and interim analysis are provided in the Supplementary Appendix. All statistical tests and confidence intervals were two-sided, with a significance level of 0.05. The stratum-adjusted Mantel-Haenszel method, with adjustment for the stratification variables at baseline (IL28B genotype [CC vs. non-CC] and HCV subgenotype [1a vs. non-1a]), was used to calculate between-group differences in the rates of sustained virologic response at 24 weeks after treatment and the two-sided 95% confidence intervals of the differences.

Results

Study Population

\A total of 1013 patients with chronic HCV genotype 1 infection were screened at 97 sites in nine countries, including the United States. From October 2011 through April 2012, a total of 571 patients (438 previously untreated patients and 133 patients who had not had a response to prior therapy) underwent randomization and received at least one dose of study drug (Fig. S1 and Table S1 in the Supplementary Appendix). The final data collection for the analysis of the rate of sustained virologic response at 24 weeks after treatment occurred in August 2013. Demographic and clinical characteristics of the patients at baseline are shown in Table 1.

Efficacy

Primary Analysis

Across all treatment subgroups, the rates of sustained virologic response at 24 weeks after treatment ranged from 83 to 100% (Table S5 in the Supplementary Appendix). With respect to the primary analysis, among previously untreated patients who received treatment with three direct-acting agents plus ribavirin, with ABT-450/r administered as 150 mg of ABT-450 and 100 mg of ritonavir, the rate of sustained virologic response at 24 weeks after treatment was 88% in the subgroup that received 8 weeks of therapy and 95% in the subgroup that received 12 weeks of therapy (difference between 8-week and 12-week subgroups, -7 percentage points; 95% confidence interval, -19 to 5; P=0.24). Secondary analyses of the rates of sustained virologic response at 24 weeks after treatment are shown in Table S6 in the Supplementary Appendix.

Analysis According to ABT-450/r Dose

In a prespecified analysis comparing subgroups that received ABT-450/r administered as 100 mg of ABT-450 and 100 mg of ritonavir with those that received ABT-450/r administered as 150 mg of ABT-450 and 100 mg of ritonavir in otherwise identical regimens, the rates of sustained virologic response at 24 weeks were similar (93.6% and 94.3%, respectively; P=0.91). Therefore, the subgroups differing only in the dose of ABT-450 were combined, which resulted in nine groups for further analysis. With these groups combined, the rates of sustained virologic response at 24 weeks after treatment ranged from 83 to 96% among previously untreated patients and from 89 to 95% among patients who had not had a response to prior therapy (Figure 2).

Analysis According to Regimen

Across all treatment groups, the rates of sustained virologic response at 24 weeks after treatment were high regardless of host IL28B rs12979860 haplotype, HCV subtype, race, or HCV RNA level at baseline (Table S7 and S8 in the Supplementary Appendix). The rates of sustained virologic response were highest in the groups that received regimens that included three direct-acting agents plus ribavirin, but comparisons of the group that received three direct-acting agents plus ribavirin for 12 weeks with groups that received two direct-acting agents plus ribavirin did not show significant differences (Figure 3). Among patients administered three direct-acting antiviral agents with ribavirin for 12 weeks, the rates of sustained virologic response at 24 weeks after treatment were 96% among previously untreated patients and 93% among those who had not had a response to prior therapy.

Analysis According to Duration of Therapy

The rate of sustained virologic response at 24 weeks after treatment was higher among previously untreated patients who received three direct-acting agents plus ribavirin for 12 weeks than among those who received the same therapy for 8 weeks (96% and 88%, respectively) (Figure 3), but the difference was not significant. Among previously untreated patients who received three direct-acting agents with ribavirin, relapse after treatment occurred in 12%, 1%, and 2% of patients randomly assigned to 8 weeks, 12 weeks, and 24 weeks of therapy, respectively. None of these patients had virologic breakthrough. Among patients who had not had a response to prior therapy and who received this regimen, there were no relapses among patients treated for 12 weeks or for 24 weeks; 7% and 2% of the patients, respectively, had virologic breakthrough. A 24-week duration of therapy, as compared with a 12-week duration, was not associated with an increase in the rate of sustained virologic response, among either previously untreated patients or patients who had not had a response to prior therapy (P=0.24 and P=0.71, respectively). Information on virologic failure in each group is provided in Tables S9 and S10 in the Supplementary Appendix.

Among 166 patients with HCV genotype 1b infection who were previously untreated or who had not had a response to prior therapy and who received 12 or 24 weeks of any treatment regimen in this study, none had virologic failure. Relapse occurred in 1 patient with HCV genotype 1b infection who received 8 weeks of treatment.

No resistance-associated variants emerging during the treatment period were detected in 7 of the 10 samples from patients with relapse in the 8-week treatment group. In the 12-week and 24-week treatment groups, all but 1 of the samples obtained at breakthrough or relapse showed the emergence of variants known to confer resistance to ABT-450, ABT-267, or ABT-333. The most frequently detected variants that developed during the treatment period were at amino acid positions 168 in NS3, 28 and 30 in NS5A, and 556 in NS5B.

\Safety

A total of eight patients (1%) discontinued study-drug therapy owing to adverse events, including six previously untreated patients and two who had not had a response to prior therapy (Table 2). The reasons for discontinuation included affective disorder, homicidal ideation, convulsion, jitteriness, and confusional state. Six of these patients had a sustained virologic response at 24 weeks after treatment, including both patients who had not had a response to prior therapy. Serious adverse events occurred in eight patients (1%) during the study treatment period or the following 30 days (Table 2). One event (arthralgia) was considered by the investigator to be possibly related to a study drug. Adverse events that occurred during treatment in more than 20% of patients in any group are shown in Table 2. The most common adverse events were fatigue, headache, nausea, and insomnia. The nature and frequency of adverse events were similar across treatment groups. Adverse events that occurred during treatment in more than 5% of patients in any subgroup are listed in the Table S12 in the Supplementary Appendix.

Laboratory abnormalities of grade 3 or 4 that occurred in more than 1 patient in any group are shown in Table 2. A total of 11 patients (2%) had grade 3 elevations in the bilirubin concentration (predominantly indirect bilirubin), which normalized during or immediately after treatment. No patient had a grade 4 elevation. These elevations were not associated with elevations in aminotransferase levels. A total of 5 patients (1%) had a grade 3 elevation in the alanine aminotransferase level, with a maximum alanine aminotransferase level of 408 U per liter; there were no grade 4 elevations. Alanine aminotransferase levels normalized in each case without interruption of the study drug. Triglyceride values of grade 3 or 4 were observed in 7 patients (1%); in 4 patients, the samples were not obtained while the patient was fasting. Anemia developed during the treatment period in 5% of previously untreated patients, in 6% of patients who had not had a response to prior therapy, and in 1% of patients who did not receive ribavirin. No grade 3 or 4 decreases in the hemoglobin level were observed. Additional details regarding patients with laboratory abnormalities of grade 3 or 4 are provided in the Supplementary Appendix.

\Discussion

In this phase 2b study of interferon-free antiviral regimens for the treatment of chronic HCV genotype 1 infection without cirrhosis, the treatment regimens were associated with rates of sustained virologic response at 24 weeks after treatment that ranged from 83 to 100%. Among previously untreated patients, the rate of treatment failure was lower among those receiving three direct-acting agents plus ribavirin for 12 weeks than among those who received the same regimen for only 8 weeks and among those who received fewer agents; extending the treatment to 24 weeks offered no further benefit. However, no differences in the rates of sustained virologic response reached statistical significance. The higher number of relapses among patients in the 8-week treatment group (in 10 of 80 patients, vs. in 1 of 79 patients in the 12-week treatment group) and the absence of resistance-associated variants in most patients who had a relapse in the 8-week treatment group suggest that 8 weeks of treatment might not be sufficient to eradicate the susceptible HCV population in these patients. Treatment durations longer than 8 weeks were not associated with a less favorable safety profile.\

The 12-week regimen was also associated with a 93% rate of sustained virologic response at 24 weeks after treatment among patients who had not had a response to prior therapy, with a similar rate among patients treated for 24 weeks, which suggests that 12 weeks may be the preferred duration in this population as well. Previous studies have shown that patients who have not had a response to prior therapy with peginterferon and ribavirin have a poorer response to retreatment than do previously untreated patients, regardless of whether the treatments are interferon-based regimens or interferon-free combinations.10,14-16 In the current study, the rates of sustained virologic response at 24 weeks after treatment were similar among previously treated patients and patients who had not had a response to prior therapy. In addition, the rates in this study were consistently high, even in the presence of baseline characteristics that have been associated historically with poor rates of response to treatment, such as host IL28B non-CC genotype, HCV genotype 1a infection, black race, and high baseline HCV RNA levels.

Response rates to interferon-free, protease inhibitor-containing combination therapy have been reported to be higher among patients with HCV genotype 1b infection than among those with HCV genotype 1a infection.17,18 In this study, among 166 patients with HCV genotype 1b infection who received any 12-week or 24-week regimen and had not received treatment previously or had not had a response to prior therapy, there were no treatment failures, and only 1 of 24 patients who received an 8-week regimen had a relapse. These results suggest that a regimen containing fewer agents (e.g., without ribavirin) may be effective in treating this population, but this possibility would need to be explored in larger studies.

The results of other studies of interferon-free therapies currently in development have recently been published. Various regimens consisting of the investigational protease inhibitor faldaprevir and the nonnucleoside polymerase inhibitor deleobuvir with ribavirin, with treatment duration of 16 to 40 weeks, were associated with rates of sustained virologic response at 12 weeks after treatment of 52 to 69% among previously untreated patients with HCV genotype 1 infection, with low response rates among patients with HCV genotype 1a infection or an IL28B non-CC genotype.19 A 12-week regimen of the nucleotide polymerase inhibitor sofosbuvir with ribavirin was associated with rates of sustained virologic response at 24 weeks after treatment of 84% among 25 previously untreated patients with HCV genotype 1 infection and 10% among 10 patients who had not had a response to prior therapy.16

Preliminary data suggest that the addition of the NS5A inhibitor ledipasvir to sofosbuvir and ribavirin can improve the rates of sustained virologic response among patients who have not had a response to prior therapy.20 That finding is consistent with the similar rates we observed among previously untreated patients and those who had not had a response to prior therapy, suggesting that a regimen that is active against multiple viral targets may provide additional benefit in patients who have not had a response to prior therapy.

In this study, 1% of the patients had a serious adverse event during the study treatment period and the following 30 days; 1% of patients discontinued the study drug owing to an adverse event. Larger studies are needed, but this preliminary assessment of adverse events compares favorably with the findings in studies of treatment with telaprevir or boceprevir plus peginterferon and ribavirin, in which serious adverse events occurred in 9 to 14% of patients, and 10 to 16% of patients discontinued therapy owing to adverse events.5-7,15 The most common laboratory abnormality of grade 3 or 4 in this study, observed in 2% of patients, was a grade 3 elevation in the total bilirubin level. This finding appears to be related to the known inhibitory effect of protease inhibitors on the organic anion-transporting polypeptide 1B1.21,22

This study had several limitations. First, the open-label design could bias the assessment of adverse events. However, the use of objective, laboratory-based efficacy end points and laboratory assessments for safety mitigate this limitation. Second, the small number of patients in each study group limits the power to detect differences between groups. Third, patients with cirrhosis, who are less likely than those without cirrhosis to have a response to peginterferon and ribavirin,5,15 were excluded from this study. Finally, the fibrosis stage at baseline was assessed by means of serum biomarkers, transient elastography, or biopsy. The use of various methods limits the ability to assess the effect of the disease stage at baseline on treatment response.

In conclusion, in this phase 2b study, interferon-free combinations of ABT-450/r, ABT-267, ABT-333, and ribavirin were associated with high rates of sustained virologic response at 24 weeks after treatment among previously untreated patients with chronic HCV genotype 1 infection and among patients who had not had a response to prior therapy. These preliminary data suggest that a 12-week regimen of three direct-acting agents plus ribavirin is efficacious in patients without cirrhosis who either had not received treatment previously or had not had a response to prior therapy.

Source