All-oral combination of ledipasvir, vedroprevir, tegobuvir, and ribavirin in treatment-naïve patients with genotype 1 HCV infection

Abstract

This phase II trial assessed the efficacy and safety of a combination regimen of the nonstructural protein (NS)5A inhibitor ledipasvir (LDV), NS3 protease inhibitor vedroprevir (VDV), non-nucleoside NS5B inhibitor tegobuvir (TGV), and ribavirin (RBV) in treatment-na€ ıve patients with chronic hepatitis C virus (HCV) genotype 1 without cirrhosis. Patients were randomized 1:2 to LDV 30 mg once daily (QD; Arm 1; n 5 46) or LDV 90 mg QD (Arm 2; n 5 94); patients in both arms also received VDV 200 mg QD, TGV 30 mg twice-daily, and RBV 1,000-1,200 mg/day. Patients in Arm 2 with vRVR, defined as HCV RNA below the lower limit of quantification (LLOQ) from treatment weeks 2 to 10, were randomized 1:1 to stop treatment at 12 weeks or continue for 24 weeks. Sustained virologic response 12 weeks after treatment (SVR12) was higher in patients receiving 90 mg of LDV for 24 weeks (63%), compared with LDV 90 mg for 12 weeks (54%) and LDV 30 mg for 24 weeks (48%). In patients with very rapid virologic response (vRVR) in Arm 2, SVR12 was achieved by 68% and 81% of patients treated for 12 and 24 weeks, respectively. Virologic breakthrough was more common in patients with HCV genotype 1a and was associated with resistance-associated variants for all three direct-acting antiviral agents (DAAs); however, in all but 1 patient who relapsed, resistance-associated variants directed against only one or two of the DAAs were detected. The most common adverse events were fatigue, headache, nausea, rash, and diarrhea. Conclusion: In patients with HCV genotype 1, an interferon-free regimen containing LDV/VDV/TGV/RBV was well tolerated and led to SVR12 in up to 63% of patients. LDV 90 mg is currently being investigated in combination with the nucleotide polymerase inhibitor, sofosbuvir. (HEPATOLOGY 2014;60:56-64)

High-Resolution Hepatitis C Virus Subtyping Using NS5B Deep Sequencing and Phylogeny, an Alternative to Current Methods

“…However, both in vitro studies and clinical trials with different classes of direct-acting antiviral (DAA) agents (NS3 protease, NS5A-, and nucleos[t]ide and nonnucleos[t]ide NS5B-polymerase inhibitors), given with PR or in interferon-free combinations, have shown lower response rates for HCV genotype 1a than for HCV genotype 1b (2)(3)(4)(5)(6)(7)(8). Moreover, at least for HCV genotype 1, both the frequency and the pattern of resistance to different DAA classes are subtype specific (9). A striking example is the NS3-Q80K polymorphism, naturally found in Ͼ30% of naive subtype 1a patients but in Ͻ1% of subtype 1b patients (10), which conveys 30%-to-40%-lower sustained-virologic-response (SVR) rates to the macrocyclic protease inhibitor simeprevir (2).…”

In Vitro and In Vivo Antiviral Activity and Resistance Profile of the Hepatitis C Virus NS3/4A Protease Inhibitor ABT-450

“…This finding may explain the low rates of virologic breakthrough seen in the phase 3 clinical trials of ABT-450/r, ombitasvir, and dasabuvir with or without RBV, since similarly constructed drug regimens that did not use pharmacokinetic enhancement have been associated with high rates of virologic breakthrough (51,52). In addition, the lower dosing of ABT-450, facilitated by the boosting effect of ritonavir, may correlate with the low rates of treatment discontinuation and good tolerability seen in these large clinical trials (19)(20)(21)(22)(23).…”

Direct acting anti-hepatitis C virus drugs: Clinical pharmacology and future direction

“…Ledipasvir several studies have shown its value as a combination therapy with other DAA therapies, other than SOF. [18] The current recommendation for LDV use suggests there is no need to combine LDV/SOF with RBV or to prolong the treatment duration for more than 12 weeks. [19] Moreover, a more recent study recommends that a patient with HCV RNA level of < 6 million IU/mL may need LDV/SOF for only an 8-weeks treatment schedule.…”