HCV Resistance 

Hepatitis C has always been extremely difficult to treat effectively because the  virus evolves so quickly and develops
resistance to drugs that are used to treat  it. The new protease inhibitors can elicit resistance even in patients who  follow dosing regimens.

The sites mentioned below are great sources for easy to understand HCV information, although like any site offering continuing medical education (CME), they require a free quick registration.

2012
On May 10 2012 CCO
released a new CME -" Clinical Implications of HCV Resistance ."  This interactive virtual presentation will cover appropriate stopping rules thus avoiding resistance-assoicated variants, missed doses, managing null responders and the risks and benefits of deferring current HCV therapy.

Continuing medical education (CME)  @  CCO
Clinical Implications of HCV Resistance: Laying the Foundation for Optimal Treatment Today and in the
Future
Clinical Implications of HCV Resistance - Graham R. Foster, FRCP, PhD, provides expert opinion on how to avoid the
development of HCV resistance with new direct-acting antiviral regimens through  review of 4  patient cases.
Click  here to view the presentation
*Free registration required

Also at CCO-Released  on: 2/27/12

Jean-Michel Pawlotsky, MD, PhD, emphasizes the  importance of optimal drug  exposure and adherence levels to avoid the  
development of resistant hepatitis C  virus variants, along with strategies to optimize adherence rates.
Click Here To View Module

Learning Objectives
Upon completion of this activity, participants should be able to:
Evaluate the importance of optimal drug exposure for treatment success rates in HCV-infected patients receiving triple
therapy

Explain to colleagues and patients the importance of avoiding protease inhibitor monotherapy for HCV-infected patients

Apply strategies to maximize adherence rates in patients receiving triple therapy for HCV infection 

Importance of Pharmacokinetics and Adherence to Avoid Emergence  of  Resistant  HCV Variants
Introduction
Hepatitis C virus (HCV) resistance to a direct-acting antiviral (DAA) agent corresponds to the selection during treatment of viral variants that bear amino acid substitutions that alter the drug target; therefore, they are less susceptible to the inhibitory activity of the drug. These drug-resistant variants preexist as minor populations within the patient’s HCV quasispecies. Drug
exposure profoundly inhibits replication of the dominant  “wild-type” drug-sensitive viral population, and the resistant variants gradually occupy the vacant replication space. Moreover, viruses with low-level or partial resistance that can continue to replicate in the presence of drug, often favored by suboptimal drug exposure, may accumulate further mutations, leading to stepwise  decreases in drug susceptibility, albeit often at a cost of reduced replicative capacity. If insufficient antiviral activity is provided  because of suboptimal dosing or adherence, inadequate virologic suppression and the selection of resistance is inevitable. Therefore, to reduce the development of resistance, it is essential to achieve optimal drug concentrations through proper dosing and maximal adherence. Resistance to antiviral drugs is classically prevented by combining several  drugs with potent antiviral activity and no  cross-resistance. Indeed, HCV  resistance to DAAs is observed significantly less
frequently when one of these  drugs is administered in combination with peginterferon and  ribavirin.[3,4] Therefore, the triple combination of  peginterferon,  ribavirin, and a PI—telaprevir or boceprevir—has become the new standard-of-care  therapy for both treatment-naive and treatment-experienced patients with  genotype 1 HCV infection.[5-8] For the reasons defined above, it  is crucial that optimal exposure to all 3 drugs in the regimen be achieved for   these patients...
*Again free registration required
Click Here To View Module

In the 2012 April
issue of CLD in an article titled; "Drug resistance: Prevalence and clinical implications during the treatment of chronic hepatitis C infection", the concern is  discussed that resistance may undermine therapy based on DAAs.
Watch the interview with the authors or read the article here.

2011
HCV Advocate has an easy to understand article on drug resistance published in the July 2011 issue of HCV Advocate, written by Ms. Lucinda K. Porter,  RN.  In the article "Resisting Resistance" , viral resistance  and the importance of taking the new protease inhibitors  as directed is discussed.  Another easy to understand source of information is this Patient  video.

In August of 2011 LabCorp begun offering its hepatitis C  GenoSure NS3/4A assay, which is designed to identify NS3 and NS4A mutations and  NS3-associated resistance to the recently FDA approved HCV protease  inhibitors,  Victrelis and Incivek.

HCV GenoSure NS3/4A scans the genetic sequence in a patient’s  blood sample for mutations associated with the  replication of HCV. The test was  developed because previous studies showed that some HCV variants containing the mutations NS3 and NS4A are more resistant  to  Victrelis and Incivek, two new protease inhibitor drugs  approved to treat  HCV. In clinical trials, patients with those mutations  experienced suboptimal response to the drugs.
View the August press release here.
Company Information: www.labcorp.com 

From NATAP:HCV Protease Inhibitor Resistance - New Monogram Resistance Assay: this report  contains relevant information related to HCV telaprevir & boceprevir  resistance and the new assay from LabCorp. 

Nov 30, 2011
Understanding Resistance In HCV
Understanding Resistance in Chronic HCV Infection: Lessons Learned From HIV and HBV
This Medscape CME discusses some of the clinical implications of resistance in HCV therapy. Read the discussion or listen to the audio and view slides here.

The article below from CCO discusses new data presented at the 2011 AASLD meeting on the resistance variants during therapy with boceprevir and telaprevir . It also includes the second-wave/second-generation  protease inhibitors.

Update on HCV Resistance from AASLD 2011

Christoph Sarrazin, MD
Professor of Medicine
Department of Medicine I JW Goethe University Hospital Frankfurt, Germany

Source CCO

Introduction
Due to the high replication turnover of the hepatitis C virus (HCV) and the low fidelity of its NS5B polymerase, numerous variants, named quasispecies, are continuously generated in an infected patient.[1] During treatment with a direct-acting antiviral agent (DAA), an existing variant may confer resistance and can be selected as the dominant quasispecies, which may be associated with treatment failure.

The likelihood of treatment failure with a DAA-containing regimen is mainly a result of preexistent resistant variants in a given patient (HCV genotype, subtype, isolate), the barrier to resistance of a specific DAA (number and replicative fitness of variants required to confer resistance), and features of additional drugs in the combination treatment schedule (antiviral activity and cross-resistance).[2] Potential persistence of selected resistant variants in patients with treatment failure could affect future treatment options.

Boceprevir- and telaprevir-based triple therapies are approved in the United States[3,4] and Europe,[5,6] and the importance of resistance is characterized best with these 2 NS3 protease inhibitors. This article will discuss new data presented at the 2011 American Association for the Study of Liver Diseases (AASLD) meeting on the selection of resistant variants during therapy with boceprevir and telaprevir and long-term follow-up data on the potential persistence of these resistant variants. In addition, new data from AASLD 2011 on resistance to second-wave/second-generation NS3 protease inhibitors, NS5A inhibitors, and NS5B inhibitors will be discussed.

Triple Therapy With Boceprevir
A detailed analysis of resistance-associated variants in patients treated in the phase III boceprevir studies was presented at AASLD 2011.[7] These data confirmed that the overall sustained virologic response (SVR) rate was lower in patients infected with HCV subtype 1a (53% to 64%) than in those infected with HCV subtype 1b (66% to 73%). This difference is mainly explained by the lower genetic barrier to resistance for subtype 1a HCV vs subtype 1b HCV. Indeed, for the main resistance variant R155K, only 1 nucleotide exchange is required for subtype 1a HCV, whereas 2 changes are needed to generate the same amino acid substitution for subtype 1b HCV. The differences between the subtypes resulted in the observation of a typical subtype 1a resistance profile (V36M, T54S, R155K), which varied from the typical subtype 1b resistance profile (T54A, V55A, A156S, I/V170A). Interestingly, phenotypic resistance analysis in the HCV replicon assay showed that resistance-associated variants found in patients with subtype 1b HCV conferred greater levels of resistance (5- to 16-fold loss of susceptibility) to boceprevir than those found in patients with subtype 1a HCV (2- to 4-fold loss).

In addition, long-term follow-up data on resistance-associated variants selected in non-SVR patients during treatment in the boceprevir phase III clinical studies were presented.[8] In this analysis, 155 patients with treatment failure and detectable resistance mutations were followed for 6-14 months after treatment was stopped. Overall, approximately 20% of patients still had resistant variants detectable by population-based sequencing at follow-up. The disappearance rate for the different NS3 protease resistance mutations was variable and is shown in Table 1. Longer follow-up durations and clonal/deep sequence analyses are required for a full understanding of disappearance rates.

Table 1. Proportion of Patients Without Detectable Boceprevir-Resistant Variants at Follow-up (6 -14 Months)

Triple Therapy With Telaprevir

A summary of resistance data from the phase III telaprevir studies was presented at AASLD 2011. At baseline, the main variants conferring resistance to telaprevir in patients with subtype 1a HCV (R155K, V36M) were detectable by population-based sequencing in 0.6% to 1.2% of patients.[9] Variants conferring resistance to telaprevir in patients with subtype 1b HCV were either undetectable (T54A, V36A, and A156T), detectable in a very small percentage of patients (0.07% for A156S, V36M), or detectable in a small percentage of patients (2.1% for T54S).

On-treatment virologic failure rates were found to differ for patients with subtype 1a vs 1b HCV and were dependent on the prior treatment status of the patients. Indeed, among 362 treatment-naive patients, virologic failure was observed in 10% of patients with subtype 1a HCV and 3% of patients with subtype 1b HCV. Among previous nonresponders (n = 244), the on-treatment virologic failure rate was 38% and was again found to be higher in patients with subtype 1a vs subtype 1b HCV. Finally, the on-treatment virologic failure rate for prior relapsers (n = 286) was low at 1%.

The median time to loss of resistant variants V36M and R155K for subtype 1a HCV was approximately 6 and 10 months, respectively, whereas loss of the combination of both mutations required approximately 13 months. For patients with subtype 1b HCV, the median half-life of resistant variants was shorter at 3 months for the common variants T54A, V36A, and A156T and 9 months for the rarely occurring A156S variant.

Additional long-term follow-up data were presented on patients treated in the phase II/III telaprevir clinical trials, after a median duration of 29 months (range, 7 to 49 months) after treatment failure.[10] Overall, resistant variants were no longer detected in 85% of 126 patients at follow-up. The rate of disappearance of resistant variants differed depending on the specific mutation(s), as shown in Table 2. Once again, deep sequencing analyses are required for a complete assessment of variants present in the HCV quasispecies. Furthermore, it would be interesting to know whether resistant variants remain detectable in patients who reached 49 months of follow-up.

Table 2. Proportion of Patients Without Detectable Telaprevir-Resistant Variants at Follow-up (29 Months; Range: 7-49 Months)

Second-Wave Protease Inhibitors Simeprevir (TMC435) and BI 201335

The resistance profiles of simeprevir (TMC435) and BI 201335 overlap with those of boceprevir and telaprevir.[11,12] For simeprevir, a macrocyclic NS3 protease inhibitor, resistance data from the large, treatment-naive, phase II triple-therapy PILLAR study were presented.[13] At baseline, the previously identified variants conferring reduced susceptibility to simeprevir—Q80K, R155K, and D168E—were observed in 10.4% (40 of 385), 0.8% (3 of 385), and 0.3% (1 of 385) of patients, whereas no variants were detected at positions F43 or A156.

The Q80K variant was mainly observed in patients with subtype 1a HCV (38 of 40; 95% of patients harboring Q80K) and conferred low-level resistance in the 1a replicon (approximately 3-fold). However, patients harboring the Q80K variant had slower viral declines than those without this variant, and the higher 150-mg dose (vs the lower 75-mg dose) was required to achieve HCV RNA reductions similar to those in patients not harboring this variant. Indeed, patients without this variant treated with either dose of simeprevir achieved HCV RNA reductions of approximately 5 log10 IU/mL, whereas patients with the Q80K variant treated with 75 mg simeprevir only achieved HCV RNA reductions of approximately 4 log10 IU/mL.

The importance of the Q80K variant was also highlighted by the trend that patients with this variant were more likely to experience virologic breakthrough, relapse, and lower SVR24 rates (Table 3). Overall, virologic breakthrough was observed in only 4.9% of patients during triple therapy with simeprevir. Additional data from other simeprevir studies are required to fully understand the importance of the Q80K variant and the potential need for baseline resistance analysis in patients with subtype 1a HCV.

Table 3. Responses According to the Q80K Mutation in Patients in the PILLAR Study

BI 201335 is another inhibitor of the NS3/4A protease. Despite a linear structure, the resistance profile of BI 201335 is similar to macrocyclic NS3 protease inhibitors.[12] At AASLD 2011, resistance data from the large, phase II SILEN-C1 study of BI 201335 in combination with peginterferon alfa-2a and ribavirin in treatment-naive patients with genotype 1 HCV (N = 452) were presented.[14] At baseline, 6 of 352 patients had dominant variants conferring resistance to BI 201335 (R155K, D168E/N); nevertheless, 5 of these 6 patients completed BI 201335 triple therapy and achieved an SVR. Overall, 4% of patients experienced virologic breakthrough.

On-treatment virologic failure in patients with subtype 1a and 1b HCV was associated predominantly with the R155K and D168V mutations, respectively. In some patients (0.3% to 0.6%), mixed R155/D168 variants were observed. For patients who relapsed, resistance-associated variants could be detected by population-based sequencing in only 32% of cases. Clonal sequence analysis is currently under way to determine whether resistance-associated variants were present in the remainder of these patients. No Q80 variants were selected during exposure to BI 201335. Taken together, the clinical resistance profile of BI 201335 seems to be narrow and restricted to the R155K and D168X variants in patients with subtype 1a and 1b HCV, respectively, which may predict a low frequency of virologic breakthroughs.

Second-Generation Protease Inhibitors (MK-5172)
MK-5172 is a second-generation NS3 protease inhibitor with in vitro antiviral activity against HCV genotypes 1a/b, 2a/b, 3a, 4a, 5a, and 6a NS3 enzymes or replicon chimeras and HCV isolates harboring known first-generation protease inhibitor resistance mutations (V36, T54, Q80, R155).[15] However, reduced antiviral activity was observed against strains harboring the A156V/T and D168 mutations. The in vitro activity of MK-5172 was found to be slightly impaired in HCV 3a isolates, which can be explained by the natural occurrence of the amino acid glutamine (Q) at position 158.

In a subsequent phase I clinical trial, 79 patients with genotype 1/3 HCV received various doses of MK-5172 once daily for 7 days (genotype 1: 50-800 mg once daily for 7 days; genotype 3: 100-800 mg once daily for 7 days).[16] In patients with genotype 1 HCV, the mean maximum HCV RNA declines ranged from 4.6 log10 IU/mL to 5.4 log10 IU/mL, whereas patients with genotype 3 HCV experienced lower HCV RNA declines of 2.5 log10 IU/mL to 5.2 log10 IU/mL. Additionally, the responses appeared to be dose-dependent for patients with genotype 3 HCV, with higher doses required for HCV RNA suppression. No virologic breakthrough was observed during the 7-day treatment period. Longer follow-up data, and studies in patients with other HCV genotypes, are required to confirm the pangenotypic antiviral activity of MK-5172.

Triple Therapy With an NS5A Inhibitor (Daclatasvir)
A Week 24 interim analysis of the COMMAND study of the NS5A inhibitor daclatasvir (BMS-790052) plus peginterferon and ribavirin in treatment-naive patients with genotype 1/4 HCV was presented.[17] The resistance profile of daclatasvir includes variants at positions Q30, L31, H54, H58, and Y93 of the NS5A protein.[18] Virologic breakthrough was observed in 7% to 10% of patients, and the frequencies between patients with genotype 1 and 4 HCV seem to be similar. However, it is well known that resistance to daclatasvir occurs more often in subtype 1a HCV isolates,[18] and this finding was reflected by a lower rapid virologic response rate in patients with subtype 1a HCV vs those with subtype 1b HCV (52% to 56% vs 71%, respectively). Detailed resistance analyses are awaited.

Triple Therapy With a Nucleotide Polymerase Inhibitor (PSI-7977)
HCV replicon studies have shown that the S282T variant in the NS5B polymerase is the principal mutation to confer resistance to the nucleotide polymerase inhibitor PSI-7977.[19] However, in a 7-day monotherapy study, no virologic breakthrough was observed.[20] This high barrier to resistance was confirmed in the large triple-therapy PROTON study of PSI-7977 plus peginterferon/ribavirin in treatment-naive patients with genotype 1 HCV at AASLD 2011.[21] Indeed, no virologic breakthrough was observed during 12 weeks of triple therapy with PSI-7977 at different dosing levels (200 mg and 400 mg once daily). In the lower-dose group, 3 patients experienced virologic breakthrough after the end of the 12 weeks of PSI-7977 dosing during the peginterferon/ribavirin phase of therapy and 1 patient experienced virologic relapse. However, no virologic breakthrough was observed at any point in the 400-mg PSI-7977 arm.

Oral Combination Therapies (PSI-7977 Plus Ribavirin and Daclatasvir Plus Asunaprevir)
Data were reported for treatment-naive, noncirrhotic patients with genotype 2/3 HCV receiving either PSI-7977 alone, PSI-7977 plus ribavirin, or PSI-7977 plus ribavirin in combination with peginterferon, for a total therapy duration of 12 weeks in the ELECTRON study.[22] In addition, a PSI-7977 monotherapy arm was added to the trial.

Investigators reported rapid virologic response and SVR12 rates of 100% for all combination therapy arms, whereas only 6 of 10 patients in the monotherapy arm achieved an SVR4. The 4 patients who did not achieve an SVR4 had undetectable HCV RNA at the end of treatment but experienced a virologic rebound 4 weeks after the end of treatment. Although no on-treatment virologic breakthrough or resistance was reported, it is unclear whether resistant variants were selected in these 4 patients during treatment but, due to replicative impairment, remained below the detection limit of HCV RNA assays. When relapse is assessed, it is possible that such resistant variants may have converted to wild-type and thus may no longer be detectable.

Promising data on combination therapy with the NS5A inhibitor daclatasvir and the NS3 protease inhibitor asunaprevir (BMS-650032) for 24 weeks in prior null responders were presented at the 2011 European Association for the Study of the Liver (EASL) meeting (Capsule Summary).[23] In that analysis, 2 of 2 patients with subtype 1b HCV achieved virologic response, and 6 of 9 patients with subtype 1a HCV experienced virologic breakthrough. The high barrier to resistance of this oral combination therapy regimen in patients with subtype 1b HCV is now confirmed in a study from Japan, presented at AASLD 2011.[24] Indeed, these data showed that 10 of 10 previous nonresponder patients with genotype 1b HCV achieved an SVR24, and no resistance mutations on treatment or virologic breakthroughs were reported.

References 1. Neumann AU, Lam NP, Dahari H, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science. 1998;282:103-107.

2. Rong L, Dahari H, Ribeiro RM, Perelson AS. Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med. 2010;2:30ra32.

3. Victrelis [package insert]. Whitehouse Station, NJ: Merck & Company Incorporated; 2011.

4. Incivek [package insert]. Cambridge, Mass: Vertex Pharmaceuticals Incorporated; 2011.

5. Victrelis [boceprevir]. European Medicines Agency. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002332/WC500109786.pdf. Accessed December 19, 2011.

6. Incivo [telaprevir]. European Medicines Agency. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002313/WC500115529.pdf. Accessed December 19, 2011.

7. Ogert RA, McMonagle P, Black S, et al. Genotypic and phenotypic correlates of resistance in HCV genotype 1a and 1b infected patients treated with boceprevir plus peginterferon alpha and ribavirin. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 927.

8. Barnard RJ, Zeuzem S, Vierling JM, et al. Analysis of resistance-associated amino acid variants (RAVs) in non-SVR patients enrolled in a retrospective long-term follow-up analysis of boceprevir phase III clinical studies. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 164.

9. Bartels DJ, DeMeyer S, Sullivan J, et al. Summary of clinical virology findings from clinical trials of telaprevir. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 1328.

10. Sherman KE, Sulkowski MS, Zoulim F, et al. Follow-up of SVR durability and viral resistance in patients with chronic hepatitis C treated with telaprevir-based regimens: interim analysis from the EXTEND study. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 248.

11. Lenz O, Verbinnen T, Lin TI, et al. In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother. 2010;54:1878-1887.

12. Kukolj G, Bousquet C, Dansereau N, et al. Characterization of resistant mutants selected in vitro by the HCV NS3/4A protease inhibitor BI 201335. Program and abstracts of the 45th Annual Meeting of the European Association for the Study of the Liver; April 14-18, 2010; Vienna, Austria. Abstract 758.

13. Lenz O, Fevery B, Verbeek J, et al. TMC435 in combination with peginterferon alpha-2a/ribavirin in treatment-naive patients infected with HCV genotype 1: virology analysis of the PILLAR study. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 1329.

14. Kukolj G, Lagace L, Cartier M, et al. Characterization of HCV NS3 variants that emerged during virologic breakthrough and relapse from BI 201335 phase 2 SILEN-C1 study. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 1339.

15. Graham D, Acosta A, Guo Z, et al. MK-5172, a second generation HCV NS3/4A protease inhibitor is active against common resistance associated variants (RAVs) and exhibits cross-genotype activity. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 370.

16. Petry AS, Fraser IP, Van Dyck K, et al. Safety and antiviral activity of MK-5172, a next-generation HCV NS3/4a protease inhibitor with a broad HCV genotypic activity spectrum and potent activity against known resistance mutants, in genotype 1 and 3 HCV-infected patients. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 346.

17. Hèzode C, Hirschfield GM, Ghesquiere W, et al. Daclatasvir (DCV; BMS-790052), an NS5A replication complex inhibitor, combined with peginterferon-alfa-2a and ribavirin in treatment-naive HCV-genotype 1 or 4 subjects: phase 2b COMMAND study interim Week 24 results. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 227.

18. Gao M, Nettles RE, Belema M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010;465:96-100.

19. Hang JQ, Yang Y, Harris SF, et al. Slow binding inhibition and mechanism of resistance of non-nucleoside polymerase inhibitors of hepatitis C virus. J Biol Chem. 2009;284:15517-15529.

20. Lawitz E, Rodriguez-Torres M, Denning J, et al. Once daily dual-nucleotide combination of PSI-938 and PSI-7977 provides 94% HCV RNA < LOD at day 14: first purine/pyrimidine clinical combination data (the NUCLEAR study). Program and abstracts of the 46th Annual Meeting of the European Association for the Study of the Liver; March 30 - April 3, 2011; Berlin, Germany. Abstract 1370.

21. Lawitz E, Lalezari JP, Hassanein T, et al. PROTON: PSI-7977 and Peg/RBV in treatment-naive patients with HCV GT1: sustained virologic response. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 225.

22. Gane EJ, Stedman CA, Hyland RH, et al. PSI-7977: ELECTRON. Interferon is not required for sustained virologic response in treatment-naive patients with HCV GT2 or GT3. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract 34.

23. Lok A, Gardiner D, Lawitz E, et al. Quadruple therapy with BMS-790052, BMS-650032 and peg-IFN/RBV for 24 weeks: results in 100% SVR12 in HCV genotype 1 null responders. Program and abstracts of the 46th Annual Meeting of the European Association for the Study of the Liver; March 30 - April 3, 2011; Berlin, Germany. Abstract 1356.

24. Chayama K, Takahashi S, Kawakami Y, et al. Dual oral combination therapy with the NS5A inhibitor daclatasvir (DCV; BMS-790052) and the NS3 protease inhibitor asunaprevir (ASV; BMS-650032) achieved 90% sustained virologic response (SVR12) in Japanese HCV genotype 1b–infected null responders. Program and abstracts of the 62nd Annual Meeting of the American Association for the Study of Liver Diseases; November 5-8, 2011; San Francisco, California. Abstract LB4