Monday, February 9, 2015

Genotype 1-4: Optimal Interferon-free Therapy in Treatment-experienced Chronic Hepatitis C Patients

Joy Peter and David R. Nelson
Liver International. 2015;35(s1):65-70. 

Medscape:
Key Points
  • Current IFN-free regimens offer most treatment-experienced patients SVR rates above 90%.
  • Treatment-experienced patients with cirrhosis benefit from longer duration of therapy and/or the addition of RBV to IFN-free regimens.
  • Several IFN-free options are available to treat HCV-1 patients with prior failure to peg-IFN/RBV and peg-IFN/RBV/PI.
  • Resistant associated variants present at baseline can be overcome by selecting regimens with non-overlapping targets or with longer treatment duration in the setting of a nucleotide inhibitor.
  • SVR12 rates in HCV-3, non-cirrhotic patients are highest with a combination of daclatasvir/sofosbuvir.
Abstract and Introduction
Abstract
Over the past year, interferon (IFN) free dosing regimens have become available to treat chronic hepatitis C. Offering high rates of sustained virological response (SVR), short treatment and improved tolerability, IFN-free treatment now represents the paradigm for both treatment-naïve and -experienced patients. Patients with prior treatment failure, in particular those with cirrhosis, still represent some of the most difficult to treat, but the availability of multiple agents that can interrupt several steps of the HCV lifecycle affords providers and patients with options that can be combined and individually tailored to each patient's unique needs to obtain high rates of SVR.

Introduction
Several recent and ongoing studies show that interferon (IFN)-free, all-oral hepatitis C virus (HCV) regimens using direct-acting antiviral (DAA) combinations can cure most chronically infected HCV patients.[1–11] With the evolution of DAAs, nearly all steps of the HCV life cycle have become sensitive to pharmacological intervention including entry, translation, RNA replication, assembly and export of progeny viruses.[12] This has led to development of highly potent oral therapies characterized by shorter treatment, simplified dosing, a high genetic barrier to resistance, and improved safety profiles, thus making HCV treatment more feasible and attractive for both patients and providers.[13]

Yet even with these rapid advances and all-oral combinations producing sustained virological response (SVR) rates well above 90%, currently there is no one-size-fits-all treatment available. Regimen selection and treatment duration must still be decided by providers and patients. Viral factors including HCV genotype, genome targets and drug resistant variants (RAVs) must be considered in relation to host and disease factors including cirrhosis, prior treatment response, the complexity of the regimen and potential drug interactions to select the optimal regimen for each individual patient.

Overview of Treatment Strategies
Combining therapies to attack multiple targets in the HCV genome is highly effective in eradicating the virus and reducing the risk of viral resistance compared to monotherapy.[14] These targets include NS3/4A protease inhibitors (PI), NS5A inhibitors and NS5B polymerase inhibitors [both nucleoside/tide inhibitors (NI) and non-nucleoside inhibitors (NNI)]. Treatment recommendations for HCV are changing rapidly with several new oral agents with recent or imminent regulatory approval. The FUSION and POSITRON Phase III trials received approval by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) as the first IFN-free therapies for HCV in late 2013.[15,16] As a result of the rapid changes in the field, the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) developed a new guidance protocol to expeditiously provide recommendations for the use of newer regimens as they gain approval.[16] The European Association for the Study of the Liver (EASL) also rapidly published new recommendations on the treatment of HCV for 2014, including the use of all-oral combinations of sofosbuvir (SOF)/simeprevir (SMV) and SOF/daclatasvir (DCV).[15] AASLD/IDSA and EASL will update their recommendations regularly as new therapeutics and regimens become approved by the FDA and EMA. These recommendations are useful starting point for providers to make treatment decisions.

Therapy With or Without Nucleotide/Side Inhibitors
Regimen options can be best stratified by HCV genotype and according to the presence or absence of a NI. Sofosbuvir, a prodrug of a nucleotide analog inhibitor of the HCV NS5B RNA-dependent RNA polymerase, is the only approved NI for HCV. Sofosbuvir is active in all HCV genotypes and its mechanism of action (RNA chain termination) at the active site of the NS5B protein provides a high barrier to resistance.[17] It has a well-known safety profile and offers minimal drug–drug interaction, thus potentially positioning it as a good combination with other DAAs, including PIs and NS5As, or just ribavirin (RBV). A nucleotide/side analog combination, however, is not necessary to achieve high rates of SVR in IFN-free therapy for treatment-experienced patients. Combinations of two or more molecules including PIs, NS5As and NNIs +/−RBV are also highly effective and can produce SVR rates above 90% in multiple genotypes.

HCV Genotype 1
SMV + SOF (+/−RBV): 91% of SVR
Simeprevir, a specific inhibitor of the HCV NS3/4A serine protease, and SOF each received regulatory approval in the USA in late 2013. Although the two molecules were not labelled for combination, AASLD and EASL recommendations include the use of this regimen for patients who are peg-IFN/RBV non-responders, based on results from the phase II COSMOS study in which combined SMV/SOF resulted in an overall SVR12 of 92%.[8] Of the 128 previous non-responders in the study, 117 (91%) achieved SVR12 compared to 97% of the treatment-naïve patients.[8] Sustained virological response rates were not improved with longer treatment (24 weeks) or the addition of RBV in patients with advanced disease, prior non-response, or the presence of Q80K baseline RAVs. However, the AASLD and EASL guidelines recommend the use of RBV in patients with predictors of poor response to HCV therapy.[15,16]


Simeprevir and SOF are well tolerated and no new safety concerns were observed in the COSMOS trial. The most common adverse events (AEs) reported were fatigue (31%), headache (20%) and nausea (16%) and only four patients (2%) discontinued treatment early for AEs. Rash, pruritus and anaemia were reported (17%/11%/14%) more frequently in groups receiving RBV. Transient increases in bilirubin were also seen in 12 patients (7%), 11 were receiving RBV, although bilirubin elevations were not associated with aminotransferase increases. Photosensitivity reactions were observed in 5% of patients in the COSMOS study; thus, patients should be warned about this risk.[8]

Simeprevir/SOF optimal use: SMV 150 mg + SOF 400 mg once daily for 12 weeks in genotype 1 (HCV-1) prior peg-IFN/RBV failures with or without cirrhosis. The addition of weight-based RBV should be considered in patients with poor predictors of response and in HCV-1a in the absence of Q80K testing.

DCV + SOF (+/−RBV): 98–100% of SVR
Daclatasvir is an NS5A inhibitor with a highly potent antiviral effect in several HCV genotypes.[18] The overall AE profile in phase II and III combination studies using DCV has shown that it is well tolerated and the pharmacokinetics allow once daily administration.[4,7,19–21] Analyses of DCV viral resistance profiles show that it does not overlap with other DAAs (PIs/NNIs/NIs) making it a good candidate to suppress emerging RAVs when combined with other DAAs.[21] In an open-label, phase II study, DCV 60 mg plus SOF 400 mg once daily with and without RBV was administered for 24 weeks to patients without cirrhosis, who previously failed therapy with telaprevir or boceprevir in combination with peg-IFN/RBV. Sustained virological response rates were 100% (21/21) in prior triple therapy failure patients receiving RBV and 98% (19/21) without RBV.[4] There was no difference in response based on HCV-1a vs. 1b (HCV-1a has been associated with lower SVR in some regimens) or by IL28B (IFN3L) non-CC genotype. Telaprevir and boceprevir RAVs were present in 46% of the previously treated patients at baseline. This study represented the 'proof of concept' that patients with prior (PI) resistance could be successfully retreated with regimens inhibiting other HCV genome targets.

The most common AEs reported with DCV/SOF are fatigue, nausea, headache and diarrhoea with most AEs being Grade 1 or 2 in severity and rarely leading to treatment discontinuation.[4,7] Although RBV in combination with DCV/SOF results in a greater decline in haemoglobin levels, results suggest that RBV may not be necessary to enhance the antiviral potency of this regimen in HCV-1 patients. The once daily dosing of DCV/SOF, its good tolerability and the high SVR rates in non-responders to prior telaprevir/boceprevir triple therapy make the combination of DCV and SOF highly effective when retreating HCV-1 PI failures.

Daclatasvir/SOF optimal use HCV-1: DCV 60 mg + SOF 400 mg once daily for 24 weeks in HCV-1 peg-IFN/RBV or PI triple therapy failures.

Ledipasvir + SOF (+/−RBV): 94–99% of SVR
Ledipasvir (LDV) is an NS5a inhibitor with potent antiviral activity against HCV-1, and HCV-4–6 and is also effective against variants with the NS5B resistance mutation, 282T, observed with SOF in vitro. [22]

Ledipasvir is combined with SOF in a single, once daily fixed-dosed tablet. HCV-1 treatment-experienced patients, including non-responders to peg-IFN/RBV with a PI (52%) and without a PI (46%), were randomized to 12 and 24 weeks of LDV/SOF (90 mg/400 mg once daily) +/−RBV in one of three phase III studies of this regimen. The population (N = 440) included 20% of patients with cirrhosis and 79% with HCV-1a. Overall, in the 12-week treatment groups, there was 94% SVR without RBV, 96% with RBV and in the 24-week treatment groups, the SVR was 99% with and without RBV.[2] Treatment-experienced patients with cirrhosis had a markedly higher SVR with 24 weeks compared to 12 weeks of treatment prompting the US label for this regimen to recommend a 24-week duration in that subpopulation vs. a 12-week duration for all other populations (naïve with or without cirrhosis and treatment-experienced without cirrhosis).[23] Recent data using LDV/SOF in 155 patients with cirrhosis who did not respond to prior peg-IFN/RBV and subsequent PI triple therapy resulted in a SVR12 in 96% (74/77) with LDV/SOF/RBV for 12 weeks and an SVR12 in 97% (75/77) with LDV/SOF for 24 weeks showing that a 12 week dose of RBV and LDV/SOF in treatment-experienced patients with cirrhosis does not compromise the SVR.[24] The most common AEs with LDV/SOF are fatigue, nausea and headache, and the incidence of AEs was higher in patients receiving 24 weeks of treatment.[2,11,20,24] As in other studies, patients receiving RBV with LDV/SOF had higher rates of AEs associated with RBV: anaemia, fatigue, cough, dyspnoea and rash.

Special Considerations: baseline prevalence of and effects of NS5A, nucleoside inhibitor and PI RAVs on virological response to LDV/SOF were evaluated in a combined analysis of baseline samples from the ION studies. Baseline NS5A RAVs were present in 16% of the samples (318/1752). Lower SVR rates (69.2%) were observed in treatment-experienced patients with baseline NS5A RAVs with >100-fold resistance when patients received 12 weeks of treatment, however, when treatment-experienced patients received 24 weeks of therapy, the SVR was 100%, suggesting that the baseline presence of highly RAVs can be overcome with longer therapy.[25]

Ledipasvir/SOF Optimized: treatment-experienced HCV-1 patients without cirrhosis should be treated with one tablet (90 mg/400), once daily for 12 weeks. Treatment-experienced patients with cirrhosis should be treated for 24 weeks; however, 12 weeks of therapy may be effective with the addition of RBV in treatment-experienced patients with cirrhosis.

3 Direct Acting Antiviral (3-D): Paritaprevir/R-ombitasvir and Dasabuvir (+/−RBV)
More than 2300 patients have participated in six phase III trials using ritonavir boosted paritaprevir + ombitasvir + dasabuvir +/−RBV. Paritaprevir/r is an inhibitor of the HCV non-structural 3/4A (NS3/4A) protease administered with ritonavir as a 'booster' to increase the PI peak and trough exposures.[26] Ombitasvir is an HCV NS5A inhibitor and dasabuvir is a non-nucleoside HCV NS5B RNA polymerase inhibitor. The paritaprevir/r and ombitasvir are supplied as a single, coformulated tablet. The combined triple regimen is referred to as '3-D' and was evaluated in HCV-1, treatment-experienced patients in the SAPPHIRE-II (non-cirrhotic), TURQUOISE-II (cirrhotic) and PEARL-II (non-cirrhotic, HCV-1b) studies.

SAPPHIRE-II included patients without cirrhosis who previously failed treatment with peg-IFN/RBV who were treated for 12 weeks with 3-D + weight-based RBV. The overall SVR was 96.3% (286/297) and the SVR was 95.2% (139/146) in non-responders, typically considered to be a predictor of poor response.[1] Viral breakthrough was observed in one patient and seven patients relapsed (2.4%). TURQUOISE-II is the first phase III study completed in HCV-1 patients with cirrhosis investigating an all-oral, IFN-free regimen. The trial evaluated 12 or 24 weeks of 3-D treatment with RBV in HCV-1a (261) and HCV-1b (119) treatment-naive and treatment-experienced patients with cirrhosis. After 12 weeks of treatment, 92% of patients (n = 191/208) achieved an SVR and in following 24 weeks of treatment, 96% of patients (n = 165/172) achieved an SVR.[3] Viral failure during treatment occurred in four patients (one in the 12 week group/three in the 24-week group) and the relapse rate was higher in the 12 week group 12/203 (5.9%) vs. 1/164 (0.6%) in the 24-week group. The SVR was higher in HCV-1a, prior non-responders, after 24 weeks of treatment (92.2%) vs. 12 weeks (80%).[3] PEARL-II assessed 12 weeks of treatment with 3-D with and without RBV in 179 HCV-1b, treatment-experienced patients without cirrhosis. With 12 weeks of treatment, 97% of patients in the RBV-free arm (n = 85/88) and 100% of patients in the RBV containing arm (n = 91/91) achieved SVR12.[9] Among the three patients who did not achieve SVR, two discontinued treatment because of AEs and one was lost to follow-up. RAVs were detected in most of the patients who failed treatment or relapsed with 3-D and were varied across NS3, NS5A and NS5B positions.[1,3,9]


Headache, fatigue and nausea were the most commonly reported AEs in the three studies and treatment discontinuation because of AEs occurred in no more than 2% of patients.[1,3,9] Fewer AEs and laboratory abnormalities commonly attributed to RBV (insomnia, anaemia, rash and hyperbilirubinemia) were observed in the RBV-free arm of the PEARL-II study. Grade 3/4 bilirubin increases were observed in all three studies. These were predominantly of indirect bilirubin and did not have associated aminotransferase elevations or lead to premature treatment discontinuation.
3 Direct acting antiviral (3-D) optimized: treat for 12 weeks with weight-based RBV if HCV-1a without cirrhosis or HCV-1b with cirrhosis. Treat for 24 weeks with RBV if HCV-1a with cirrhsois. HCV-1b patients without cirrhosis may be treated for 12 weeks without RBV.

Genotype 2
SOF + RBV: 86–94% of SVR
Two clinical trials evaluated SOF in combination with RBV to treat HCV genotype 2 (HCV-2) treatment-experienced patients: FUSION and VALENCE. In the FUSION study, patients were treated with daily SOF (400 mg) and weight-based RBV [1000 mg (<75 kg) to 1200 mg (≥75 kg)] for 12 or 16 weeks. The SVR12 with 12 weeks was 86% and with 16 weeks was 94%.[5] The VALENCE study evaluated SOF/RBV for 12 weeks and reported an overall SVR12 of 93%.[6] The presence of cirrhosis in the VALENCE study led to lower SVR rates, 77.8% in treatment-experienced patients compared to 93.8% in those without cirrhosis. Similarly in the FUSION study, patients with cirrhosis had lower SVR rates than those without cirrhosis, but the SVR was higher in that population when the duration was extended to 16 weeks from 12 weeks (78 and 60% respectively).[5] Patients with cirrhosis may benefit from extending treatment to 16 weeks, while the EASL guidelines recommend up to 20 weeks in this population.[15]


Sofosbuvir/RBV for HCV-2 optimized: SOF 400 mg daily + RBV weight-based 1000 mg or 1200 mg in patients <75 mg or ≥75 mg, respectively, in a divided dose for 12 weeks. Consider extending treatment to 16 weeks in the presence of cirrhosis.

Genotype 3
DCV/SOF: 84–86% of SVR
Daclatasvir (60 mg daily) and SOF (400 mg daily) with and without RBV were studied in combination for 24 weeks in HCV-2 & 3 treatment-naïve patients. In the AI444040 Phase IIb study, the SVR rate was 89% (16/18) in HCV-3 patients.[4] Although the population was treatment-naïve and without cirrhosis (better response predictors), the 2014 EASL treatment guidelines recommended this regimen for 24 weeks in treatment-experienced HCV-3 patients based on the naïve patient SVR rate and on antiviral activity of DCV demonstrated in vitro and in vivo. [15] New data from the phase III ALLY-3 study using DCV/SOF for 12 weeks in HCV-3 treatment-experienced (including prior SOF or alisporivir failures), demonstrated an 86% SVR4.[7] Sustained virological response-4 rates were higher in patients without cirrhosis (94% without cirrhosis vs. 70% with cirrhosis in pooled treatment-naïve & experienced data) and most post-treatment relapses (N = 15) occurred in patients with cirrhosis.

The ALLY-3 study did not explore the addition of RBV or the duration, so it is unknown whether the addition of RBV or longer treatment would improve SVR outcomes in treatment-experienced and patients with cirrhosis treated with this regimen. This regimen offers a much needed option for treatment-experienced HCV-3 patients, including those who previously failed SOF/RBV, and should be proposed instead of SOF/RBV for 24 weeks in areas where DCV/SOF is available.
Daclatasvir/SOF optimal use HCV-3: DCV 60 mg + SOF 400 mg once daily for 12 weeks in patients without cirrhosis. Consider the addition of RBV or extended duration in patients with multiple poor predictors of response.

SOF + RBV: up to 94% of SVR
Two clinical trials evaluated SOF in combination with RBV to treat HCV HCV-3 treatment-experienced patients: FUSION and VALENCE. SVR12 using daily SOF (400 mg) and weight-based RBV [1000 mg (<75 kg) to 1200 mg (≥75 kg)] HCV-3 patients had a lower SVR after 12 and 16 weeks of therapy with 30 and 62%, respectively, compared to HCV-2 patients treated with the same regimen and duration.[5] The VALENCE study evaluated SOF/RBV for 24 weeks and reported an overall SVR12 of 85% in HCV-3 patients, with a higher SVR rate in treatment-naïve (94%) compared to experienced patients (79%).[6] Treatment-experienced patients with cirrhosis had 62% SVR. The 24-week treatment duration using SOF/RBV resulted in a higher response rate than the 12- or 16-week studies, suggesting with this regimen longer is better for HCV-3. Optimal therapy for HCV-3 treatment-experienced patients with this regimen is daily SOF (400 mg) and weight-based RBV [1000 mg (<75 kg) to 1200 mg (≥75 kg)] for 24 weeks. Extending the treatment duration for HCV-3 patients to 24 weeks in the VALENCE study did not lead to increased frequency or severity of AEs.

Sofosbuvir/RBV optimal use HCV-3: SOF 400 mg daily + RBV weight-based 1000 mg or 1200 mg in patients <75 mg or ≥75 mg, respectively, in a divided dose for 24 weeks.

Genotype 4
Sofosbuvir/RBV
In the Egyptian Ancestry study, treatment-experienced HCV-4 (patients (N = 32) were treated with SOF/RBV for 12 or 24 weeks. Patients in the 24-week arm had an SVR12 of 87% compared to 59% with 12 weeks. Although the sample was small, the findings suggest that SOF/RBV therapy may be an effective IFN-free regimen for treatment-experienced HCV-4 patients if given for 24 weeks.

Paritaprevir/R/Ombitasvir + RBV
The PEARL-I study (phase 2) evaluated paritaprevir/r/ombitasivr + RBV for 12 weeks in 49 treatment-experienced (peg-IFN/RBV failure) HCV-4 patients without cirrhosis. All 49 patients achieved an early on treatment response and of the 37 patients who reached the SVR4 time point, SVR4 was 100%.[27]

The regimen was generally well tolerated and there were no discontinuations for AEs. Similar to the HCV-1 studies with this regimen, the most common AEs were headache, asthenia, fatigue and nausea and transient bilirubin elevations were observed but with no associated aminotransferase elevations.

Conclusion
Interferon-free HCV therapy is advancing rapidly. Current all-oral regimens offer SVR rates above 90% as well as 12-week treatment durations for most treatment-experienced patients. This, along with more tolerable side effect profiles, enhances the benefit compared to IFN-based therapies. There are multiple DAA combinations that can be selected to optimize SVR outcomes in the treatment-experienced patient, each of which can be tailored according to HCV genotype/subtype, type of prior regimen and presence of cirrhosis. As more patients are exposed to DAA therapies, the few who fail these regimens will require special attention to select an optimal retreatment strategy when RAVs may be present. Even with resistance testing, providers will have very little data from which to select a therapeutic retreatment option, but preliminary data suggest among the current DAAs an alternate IFN-free therapy will be plausible.

References
  1. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014; 370: 1604–14.
  2. Afdhal N, Reddy KR, Nelson DR, ION-2 Investigators, et al. Ledipasvir and sofosbuvir for previously treated genotype 1 infection. N Engl J Med 2014; 379: 1483–93.
  3. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014; 370: 1973–82.
  4. Sulkowski MS1, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370: 211–21.
  5. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013; 368: 1867–77.
  6. Zeuzem S, Dusheiko GM, Salupere R, VALENCE Investigators, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014; 370: 1993–2001.
  7. Nelson D, Cooper JN, Lalezari JP, et al. All-oral 12-week combination treatment with daclatasvir (DCV) and sofosbuvir (SOF) in patients infected with HCV genotype (GT)3: ALLY-3 phase 3 study (Abstract). Hepatology 2014; 60(Suppl.): 6.
  8. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in nonresponders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014; pii: S0140-6736(14)61036-9.
  9. Andreone P1, Colombo MG2, Enejosa JV3, et al. ABT- 450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection. Gastroenterology 2014; 147: 359–65 e1.
  10. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370: 1879–88.
  11. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014; 370: 1889–98.
  12. Schmidt WN, Nelson DR, Pawlotsky JM, Sherman KE, Thomas DL, Chung RT. Direct acting antiviral agents and the path to interferon independence. Clin Gastroenterol Hepatol 2014; 12: 728–37.
  13. Schinazi R, Halfon P, Marcellin P, Asselah T. HCV directacting antiviral agents: the best interferon-free combinations. Liver Int 2014; 34(Suppl. 1): 69–78.
  14. Rong L, Dahari H, Ribeiro RM, Perelson AS. Rapid emergence of protease inhibitor resistance in hepatitis C virus. Sci Transl Med 2010; 2: 30ra32.
  15. EASL Recommendations on Treatment of Hepatitis C. 2014. Available at http://www.easl.eu/_newsroom/latest--news/easl-recommendations-on-treatment-of-hepatitis-c-2014. Accessed: 5 October 2014.
  16. AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. Available at http://www.hcvguidelines.org. Accessed: 5 October 2014.
  17. Lam AM, Espiritu C, Bansal S, et al. Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus. Antimicrob Agents Chemother 2012; 56: 3359–68.
  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. Lok AS1, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366: 216–24.
  20. Lok AS, Gardiner DF, H_ezode C, et al. Randomized trial of daclatasvir and asunaprevir with or without peg-IFN/RBV for hepatitis C virus genotype 1 null responders. J Hepatol 2014; 60: 490–9.
  21. Lee C. Daclatasvir: potential role in hepatitis C. Drug Des Devel Ther 2013; 7: 1223–33.
  22. Cheng G, Peng B, Corsa A, et al. Antiviral activity and resistance profile of the novel HCV NS5A inhibitor GS-5885. J Hepatol 2012; 56: S464.
  23. Harvoni_. Full Prescribing Information, Foster City, CA: Gilead, 2014.
  24. Bourliere M, Bronowicki J, Ledinghen V, et al. Ledipasvir/Sofosbuvir fixed dose combination is safe and efficacious in cirrhotic patients who have previously failed proteaseinhibitor based triple therapy (Abstract). Hepatology 2014; 60(Suppl.): 13.
  25. Dvory-Sobol H, Doehle B, Svarovskaia E, et al. The prevalence of HCVNS5A, nucleoside and protease inhibitor resistance associated variants and the effects on treatment with ledipasvir/sofosbuvir +/− ribavirin in the phase 3 ION studies. International Workshop on Antiviral Drug Resistance, Berlin, Germany, June 2014.
  26. Menon RM, Klein CE, Lawal AA, et al. Pharmacokinetics and tolerability of the HCV protease inhibitor ABT-450 following single ascending doses in healthy adult volunteers with and without ritonavir. Presented at the annual meeting of HepDART, Kohala Coast, HI, 6–10 December 2009.
  27. Hezode C, Marcellin P, Pol S, et al. Results from the phase 2 PEARL-I study: interferon-free regimens of ABT-450/r+ABT-267 with or without ribavirin in patients with HCV genotype 4 infection. Presented at the annual meeting of EASL, London, UK, 9–13 April.

No comments:

Post a Comment