Multicenter Experience using Ledipasvir/Sofosbuvir ± RBV to Treat HCV GT 1 Relapsers after Simeprevir and Sofosbuvir Treatment

Introduction and aim. Approximately 10%-15% of patients with hepatitis C genotype 1 (HCV GT1) experience virological relapse after all-oral antiviral regimen using simeprevir (SMV) and sofosbuvir (SOF). The efficacy and safety of treating such relapsers using ledipasvir/sofosbuvir (LDV/SOF) with/without ribavirin (RBV) has been limited.Objective. Report the virological response and safety of LDV/SOF with/without RBV for 12-24 weeks in treating HCV GT1 relapsers after SMV + SOF.Material and methods. Patients treated with standardized clinical protocol utilizing LDV/SOF with/without RBV at three transplant centers were retrospectively reviewed.Results. Forty-five patients (29% post-LT, 82% male, 13% non-white, 73% subtype 1a, 86% IL28B CT/ TT, 78% F3-4) started LDV/SOF with/without RBV at a median of 22 weeks (range 7-55 weeks) after the last dose of SMV+SOF treatment. Thirty-seven patients received LDV/SOF for 24 weeks (24/37 patients with RBV) and eight patients received LDV/SOF for 12 weeks (5/8 patients with RBV). RBV dose was adjusted for renal function. Sixteen patients who were RBV-ineligible received LDV/SOF without RBV for 12 or 24 weeks. SVR 12 was achieved in 96% (43/45) of patients. Baseline viral load, RBV use, or GT1 subtype did not impact SVR 12. Minimal adverse events were reported in those without RBV; 45% of patients who received RBV developed significant anemia requiring RBV dose reduction and/or discontinuation. In LT recipients, minimal immunosuppression dose adjustments were required and no biopsy-proven acute rejection occurred.Conclusions. Treatment with LDV/SOF with/without RBV for 12-24 weeks was very well tolerated and resulted in high SVR 12 rates (96%) in HCV GT1 relapsers to SMV + SOF treatment.     

Impact of hepatitis C virus recombinant form RF1_2k/1b on treatment outcomes within the Georgian national hepatitis C elimination program

Aim

Hepatitis C virus (HCV) recombinant form RF1_2k/1b is common in ethnic Georgians. This chimera virus contains genomic fragments of genotype 2 and genotype 1 and is misclassified as genotype 2 by standard genotyping. We aimed to identify RF1_2k/1b strains among genotype 2 patients and assess its impact on treatment outcomes.

Methods

The study included 148 patients with HCV genotype 2 as determined by 5‐untranslated region/core genotyping assay. RF1_2k/1b was identified by sequencing the non‐structural protein 5B region. Patients were treated within the national hepatitis C elimination program with sofosbuvir/ribavirin (SOF/RBV), interferon (IFN)/SOF/RBV, or ledipasvir (LDV)/SOF/RBV.

Results

Of 148 patients, 103 (69.5%) had RF1_ 2k/1b. Sustained virologic response (SVR) data was available for 136 patients (RF1_ 2k/1b, n = 103; genotype 2, n = 33). Sustained virologic response was achieved in more genotype 2 patient than in RF1_2k/1b patients (97.0% vs. 76.7%, P = 0.009). Twelve weeks of LDV/SOF/RBV treatment was highly effective (100% SVR) in both genotypes. Among RF1_2k/1b patients, LDV/SOF/RBV for 12 weeks was superior (100% SVR) to SOF/RBV for 12 weeks (56.4%, P < 0.0001) or 20 weeks (79.2%, P = 0.05). Twelve weeks of IFN/SOF/RBV also showed better response than SOF/RBV for 12 weeks (88.9% vs. 56.4%, P = 0.02) in these patients.

Conclusions

High prevalence of the RF1_2k/1b strain can significantly affect treatment outcomes. Treatment with IFN/SOF/RBV and especially LDV/SOF/RBV ensured significantly higher SVR in patients infected with RF1_2k/1b strain compared to standard HCV genotype 2 treatment with SOF/RBV. There is a need to reassess existing methods for the management of HCV genotype 2 infections, especially in areas with high prevalence of the RF1_2k/1b strain.     

Safety and efficacy of sofosbuvir‐based direct‐acting antiviral regimens for hepatitis C virus genotypes 1‐4 and 6 in Myanmar: Real‐world experience

This open‐label, clinical experience investigated the safety and efficacy of direct‐acting antiviral (DAA) hepatitis C virus (HCV) therapy in Myanmar; 344 patients completed treatment between June 2015 and May 2016. Patients with HCV genotypes 1‐4 and 6 received one of four treatments: (i) Peg‐interferon (PEG‐IFN)+sofosbuvir (SOF)+ribavirin (RBV) for 12 weeks, (ii) SOF+RBV for 24 weeks, (iii) ledipasvir (LDV)+SOF for 12 weeks or (iv) daclatasvir (DCV)+SOF+RBV for 12 or 24 weeks. Genotype 3 was most common (n=133, 38.7%), followed by genotype 6 (n=122, 35.5%) and genotype 1 (n=86, 25%). Overall, 91% of patients achieved sustained virologic response (SVR); 99% in group 1, (n=148/149), 90% in group 2 (n=95/106), 78% in group 3 (n=65/83) and 100% in group 4 (n=6/6). In group 3, SVR rates were 96.8% in genotype 1 (n=30/31) and 64.1% in genotype 6 (n=25/39). Multivariable regression analysis identified advanced fibrosis (F3‐4) (OR=.16 CI: 0.05‐0.57, P=.005), genotype 6 (OR=.35, CI: 0.16‐0.79, P=.012) and diabetes (OR=.29, CI: 0.12‐0.71, P=.007) as negative independent predictors of response. Adverse events were mild with all‐oral therapy. Conclusion: DAA therapy ±PEG‐IFN achieved high SVR rates. Genotype 6 patients had a low SVR to 12 weeks of LDV and SOF raising the need for other regimens, RBV or longer treatment duration in this population.     

Effectiveness and safety of sofosbuvir‐based regimens plus an NS5A inhibitor for patients with HCV genotype 3 infection and cirrhosis. Results of a multicenter real‐life cohort

Patients with HCV genotype 3 (GT3) infection and cirrhosis are currently the most difficult to cure. We report our experience with sofosbuvir+daclatasvir (SOF+DCV) or sofosbuvir/ledipasvir (SOF/LDV), with or without ribavirin (RBV) in clinical practice in this population. This was a multicenter observational study including cirrhotic patients infected by HCV GT3, treated with sofosbuvir plus an NS5A inhibitor (May 2014‐October 2015). In total, 208 patients were included: 98 (47%) treatment‐experienced, 42 (20%) decompensated and 55 (27%) MELD score >10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24 weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count <75×10E9/mL (RR: 3.50, P=.019). In patients with MELD <10, type of NS5A inhibitor did not impact on SVR12 (94% vs 97%; adjusted RR: 0.49). Thirteen patients (6.3%) had serious adverse events, including three deaths (1.4%) and one therapy discontinuation (0.5%), higher in decompensated patients (16.7% vs 3.6%, P<.006). In patients with GT3 infection and cirrhosis, SVR12 rates were high with both SOF+DCV and SOF/LDV, with few serious adverse events.     

Sofosbuvir and ledipasvir improve patient‐reported outcomes in patients co‐infected with hepatitis C and human immunodeficiency virus

A fixed‐dose combination of ledipasvir and sofosbuvir (LDV/SOF) has been approved for treatment of HCV patients. We assessed the effect of LDV/SOF on patient‐reported outcomes (PROs) in HIV–HCV‐co‐infected patients. Patient‐reported outcomes data from HIV–HCV‐co‐infected patients who were treated with LDV/SOF for 12 weeks were collected as a part of a clinical trial (ION‐4). Historical controls were HIV–HCV‐co‐infected patients treated with SOF and ribavirin (RBV) in PHOTON‐1. We included 335 HIV–HCV‐co‐infected patients (SVR‐12 in HCV genotype 1 was 96%) who received LDV/SOF, while 223 patients (SVR‐12 in HCV genotype 1 was 76.3%) received SOF/RBV. During treatment, patients receiving LDV/SOF showed improvement in all of their PRO scores (+6.0% in activity/energy of CLDQ‐HCV, +5.0% in fatigue score of FACIT‐F, +6.8% in physical component of SF‐36; all P < 0.0001) while those receiving SOF+RBV showed moderate decline in some of their PRO scores (?4.8% in physical functioning of SF‐36, ?4.4% in fatigue score of FACIT‐F, both P < 0.001). Patients who achieved sustained virologic response with LDV/SOF also showed improvement of PROs (average +5.1%) while those treated with SOF/RBV showed less or no improvement (average +1.4%). In a multivariate analysis, in addition to depression and fatigue, receiving SOF+RBV (vs LDV/SOF) was independently associated with more PRO impairment during treatment (beta ?6.1 to ?12.1%, P < 0.001). Hence, HIV–HCV patients treated with LDV/SOF show significant improvement of their health‐related quality of life and other patient‐reported outcomes during treatment and after treatment cessation.     

Changes in serum lipid profiles caused by three regimens of interferon‐free direct‐acting antivirals for patients infected with hepatitis C virus

Aim

Serum low‐density lipoprotein cholesterol (LDL‐C) increases during treatment of chronic hepatitis C (CHC) with interferon‐free direct‐acting antivirals (DAAs). We sought to compare the changes of serum lipid profiles caused by three regimens.

Methods

A total of 216 CHC patients were enrolled. Among 170 patients infected with hepatitis C virus (HCV) genotype 1b, 85 received daclatasvir plus asunaprevir (DCV/ASV) and 85 received sofosbuvir plus ledipasvir (SOF/LDV). Forty‐six infected with HCV genotype 2 received sofosbuvir plus ribavirin (SOF/RBV). Serum total cholesterol (TC), LDL‐C, high‐density lipoprotein cholesterol, and triglyceride were measured at baseline and 4, 8, 12 (for all regimens), and 24 weeks (for DCV/ASV) during treatment (4w, 8w, 12w, and 24w, respectively) and 12 and 24 weeks after treatment (p12w and p24w, respectively).

Results

In 69 (81.2%) patients who received DCV/ASV and achieved a sustained virologic response at 24 weeks after the end of treatment (SVR24), TC and LDL‐C increased significantly from baseline to p24w. In 84 (98.8%) treated with SOF/LDV who achieved SVR24, TC and LDL‐C increased significantly from baseline to 8w, and TC decreased significantly from 8w to p12w. The 45 (97.8%) who received SOF/RBV and achieved SVR24 showed no significant changes. At 12w, TC and LDL‐C increased to a greater degree in patients receiving SOF/LDV than in those receiving DCV/ASV or SOF/RBV.

Conclusion

During treatment with DAAs, the serum lipid profile may reflect not only recovery from the disruption of lipid metabolism induced by HCV, but also the pharmacological effects of DAAs. Further investigations are needed to elucidate the effect of DAAs on serum lipid profiles.     

Resistance Analyses of Japanese Hepatitis C‐Infected Patients Receiving Sofosbuvir or Ledipasvir/Sofosbuvir Containing Regimens in Phase 3 Studies

High rates of sustained virologic response (SVR) has been achieved in Japanese patients with chronic hepatitis C virus (HCV) genotype (GT)1 and GT2 infection treated with ledipasvir/sofosbuvir (LDV/SOF) ±ribavirin (RBV) and SOF+RBV, respectively. We evaluated the effect of baseline HCV NS5A and NS5B resistance‐associated variants (RAVs) on treatment outcome and characterized variants at virologic failure. Baseline deep sequencing for NS5A and NS5B genes was performed for all GT1 patients. Deep sequencing of NS5A (GT1 only) and NS5B (GT1 and GT2) was performed for patients who failed treatment or discontinued early with detectable HCV RNA (i.e., >25 IU/mL). In patients with HCV GT1 infection, 22.3% (GT1a: 2/11; GT1b: 74/330) had ≥1 baseline NS5A RAV. The most frequent NS5A RAVs in GT1b were Y93H (17.9%, 59/330) and L31M (2.4%, 8/330). Despite the presence of NS5A RAVs at baseline, 100% and 97% of patients achieved SVR12, compared with 100% and 99% for those with no NS5A RAVs with LDV/SOF and LDV/SOF+RBV, respectively. All patients with NS5B RAVs at baseline achieved SVR12. Of the 153 patients with GT2 infection (GT2a 60.1%, GT2b 39.9%), 3.3% (5/153) experienced viral relapse. No S282T or other NS5B RAVs were detected at baseline or relapse; no change in susceptibility to SOF or RBV was observed at relapse. In conclusion, LDV/SOF and SOF+RBV demonstrate a high barrier to resistance in Japanese patients with HCV GT1 and GT2 infection. The presence of baseline NS5A RAVs did not impact treatment outcome in GT1 Japanese patients treated with LDV/SOF for 12 weeks.     

Hepatitis C virus genotype 3: Meta-analysis on sustained virologic response rates with currently available treatment options

AIM: To address the therapeutic efficacy of various treatment regimens in genotype 3 selecting randomized clinical trials and prospective National Cohort Studies.METHODS:(1) PEG-INF-based therapy including sofosbuvir(SOF) + RBV for 12 wk vs SOF + RBV 24 wk;(2) SOF + RBV therapy 12 wk/16 wk vs 24 wk; and(3) the role of RBV in SOF + daclatasvir(DCV) and SOF + ledipasvir(LDV) combinations. This metaanalysis provides robust information with the intention of addressing treatment strategy for hepatitis C virus genotype 3.RESULTS: A combination treatment including SOF + RBV + PEG-IFN for 12 wk notes better SVR than with only SOF + RBV for 12 wk, although its association with more frequent adverse effects may be a limiting factor. Longer duration therapy with SOF + RBV(24 wk) has achieved higher SVR rates than shorter durations(12 or 16 wk). SOF + LDV are not an ideal treatment for genotype 3. CONCLUSION: Lastly, SOF + DCV combination is probably the best oral therapy option and the addition of RBV does not appear to be needed to increase SVR rates substantially.     

Real-World Data from Turkey: Is Sofosbuvir/Ledipasvir With or Without Ribavirin Treatment for Chronic Hepatitis C Really Effective?

Background: In this study, we aimed to investigate the efficacy and safety of sofosbuvir-based therapies in the treatment of chronic hepatitis C in real-world clinical practice.Methods: Data from patients with chronic hepatitis C treated with SOF/LDV ± RBV or SOF/RBV in 31 centers across Turkey between April 1, 2017, and August 31, 2018, were recorded in a nationwide database among infectious disease specialists. Demographics, clinical, and virological outcomes were analyzed.Results: A total of 552 patients were included in the study. The mean age of the patients was 51.28 ± 14.2, and 293 (55.8%) were female. The majority had HCV genotype 1b infection (65%), 75.04% of the patients underwent treatment, and non-cirrhosis was present at baseline in 381 patients (72.6%). SOF/LDV ± RBV treatment was given to 477 patients and 48 patients received SOF/RBV according to HCV genotype. The total SVR12 rate was 99% in all patients. Five patients experienced disease relapse during the study and all of them were genotype 2. In patients infected with HCV GT2, SVR12 was 77.3%. SVR was 100% in all patients infected with other HCV genotypes. All treatments were well tolerated by patients without causing severe adverse events. Side effects and side effects-associated treatment discontinuation rates were 28.2% and 0.4%, respectively. Weakness (13.7%) was the common side effect.Conclusion: The present real-world data of 525 patients with HCV genotypes 1, 1a, 1b, 3, 4, and 5 who underwent SOF/LDV ± RBV treatment in Turkey demonstrated a high efficacy and safety profile. HCV GT2 patients should be treated with more efficacious treatment.     

Efficacy and safety results of patients with HCV genotype 2 or 3 infection treated with ombitasvir/paritaprevir/ritonavir and sofosbuvir with or without ribavirin (QUARTZ II‐III)

The efficacy and safety of an investigational combination of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) plus sofosbuvir (SOF) ± ribavirin (RBV) in patients with HCV genotype 2 or 3 infection with or without cirrhosis was evaluated. Patients with HCV genotype 3 infection without cirrhosis were randomized to receive OBV/PTV/r + SOF ± RBV for 12 weeks; OBV/PTV/r + SOF + RBV was administered to genotype 3‐infected patients with cirrhosis for 12 weeks and to genotype 2‐infected patients without cirrhosis for either 6 or 8 weeks. Efficacy was assessed by sustained virologic response [HCV RNA <25 IU/mL] 12 weeks post‐treatment (SVR12). Safety was assessed in all treated patients. In patients with genotype 3 infection with or without cirrhosis treated with 12 weeks of OBV/PTV/r + SOF ± RBV, the overall SVR12 rate was 98% (50/51), with no virologic failures. Patients with genotype 2 infection treated with OBV/PTV/r + SOF + RBV had SVR12 rates of 90% (9/10) and 44% (4/9) following 8‐ and 6‐week treatment durations, respectively; failure to achieve SVR12 for these patients was due to relapse without baseline or treatment‐emergent resistance‐associated substitutions. Thus, the investigational combination of OBV/PTV/r with SOF ± RBV was well tolerated and achieved high SVR rates with no virologic failures in patients with genotype 3 infection. Combining direct‐acting antivirals with complementary mechanisms of action and different viral targets may be an effective treatment strategy that may allow for shorter durations of therapy.     

Management of hepatitis C patients with decompensated liver disease

Little is known about the tolerance and effectiveness of novel oral direct acting antivirals (DAA) in hepatitis C patients with decompensated cirrhosis. To examine the studies relevant to the treatment of hepatitis C virus(HCV)-related decompensated liver disease, we performed computer–based searches for English articles between 1947 and August 2015. Fourteen articles including HCV patients with decompensated cirrhosis were reviewed. The combinations of ledipasvir(LDV)/sofosbuvir(SOF)/ribavirin(RBV) for 12 weeks, or daclatasvir/SOF/RBV for 12 weeks are safe and effective for HCV genotype 1 or 4 infection, and daclatasvir/SOF/RBV for 12 weeks or SOF/RBV for 24 weeks might be effective and safe for HCV genotype 2 or 3 infection. In conclusion, current evidence supports the use of all oral DAA regimens in HCV patients with decompensated cirrhosis.     

Augmentation of hepatitis C virus‐specific immunity and sustained virologic response

Treatment for chronic hepatitis C virus (HCV) infection has rapidly evolved into interferon‐free directly acting antiviral regimens (DAA) that result in high sustained virologic response. DAAs primarily work by suppressing HCV replication and rely less on the immune system than interferon‐based therapies. However, it is unclear whether the immune system recovers with suppression of HCV replication and contributes to HCV clearance with DAA therapy. We previously demonstrated HCV clearance is associated with increased HCV‐specific immunity in CHCV‐GT‐1‐infected patients during treatment with sofosbuvir (SOF)+ribavirin (RBV). Here, we aimed to analyse changes in HCV‐specific immunological responses associated with viral clearance with combination DAA therapy of SOF+ledipasvir (LDV) for 12 weeks in CHCV‐GT1 (N=14) patients who relapsed without augmentation of HCV‐specific immunity during treatment with SOF+RBV. Phenotypic and functional changes within the T‐cell compartment of PBMCs pre‐ and post‐treatment were analysed. Retreatment of relapsers with LDV/SOF resulted in all patients attaining SVR₁₂. Suppression of HCV was associated with a decline in T‐cell exhaustion markers (CD57; Tim3; PD1) along with augmented of HCV‐specific T‐cell IFN‐gamma responses post‐treatment. Addition of LDV to SOF was associated with augmentation of HCV‐specific immunity and SVR in patients who previously failed SOF+RBV therapy without increased immunity. These findings demonstrate a novel effect of DAA in inducing host immune responses to aid HCV clearance and achieve SVR.     

Retrospective analysis of hepatitis C infected patients treated through an integrated care model

AIMTo determine if our health system’s integrated model reflects sustained virologic response (SVR) outcomes similar to those in clinical trial data, maximizes adherence, and averts drug interactions.METHODSSubjects with chronic hepatitis C had their medical records reviewed from November 1^st, 2014 through March 1^st, 2016. Patients eligible for treatment were entered into an integrated care model therapy algorithm. The primary outcome was SVR12 based on intention to treat (ITT) analysis. Inclusion criteria consisted of both treatment naïve and experienced patients over the age of 18 who were at least twelve weeks post-therapy completion with any genotype (GT) or METAVIR score. Secondary outcomes included adherence, adverse events, and number of drug interaction interventions.RESULTSAt the time of analysis, 133 patients had reached twelve weeks post therapy with ITT. In the ITT analysis 70 patients were GT 1a, 26 GT 1b, 23 could not be differentiated between GT 1a or 1b, 8 GT 2, 4 GT 3, and 2 patients with multiple genotypes. The ITT treatment regimens consisted of 97 sofosbuvir (SOF)/ledipasvir (LDV), 8 SOF/LDV and ribavirin (RBV), 7 SOF and Simeprevir (SMV), 6 3D and RBV, 1 3D, 11 SOF and RBV, and 1 SOF, peg interferon alpha, and RBV. The overall SVR12 rate was 93% in the ITT analysis with a total of 6 patients relapsing. In patients with cirrhosis, 89% obtained SVR12. All 33 patients who were previous treatment failures achieved SVR12. Drug-drug interactions were identified in 56.4% of our patient population, 69 of which required interventions made by the pharmacist. The most common side effects were fatigue (41.4%), headache (28.6%), nausea (18.1%), and diarrhea (8.3%). No serious adverse effects were reported.CONCLUSIONDean Health System’s integrated care model successfully managed patients being treated for hepatitis C virus (HCV). The integrated care model demonstrates high SVR rates amongst patients with different levels of fibrosis, genotypes, and HCV treatment history.     

Treatment of Chronic HCV Infection with the New Direct Acting Antivirals (DAA): First Report of a Real World Experience in Southern Brazil

Introduction and aimThere is almost no data regarding the efficacy of direct acting antivirals (DAAs) therapy in Brazil. The aim of this historical cohort study is to describe the sustained virologic response (SVR) rate among real-world compensated chronic hepatitis C patients in three hepatology centers from Southern Brazil.Materials and methodsPatients were included if they had at least 12 weeks follow-up after the end of therapy. Patients that were lost to follow-up or had treatment prematurely interrupted for any reason were considered treatment failure in this intention to treat analysis.Results219 patients were analyzed. Mean age was 57.4 ± 10.9 years and 142/219 (64.8%) were male. Genotype 1 was present in 166 patients (75.8%; 1a 29.2%, 1b 46.6%); Genotypes 2, 3 and 4 in 8 (3.7%), 43 (19.6%) and 2 (0.9%), respectively. 96 (43.8%) were cirrhotic. 134 (59.5%) were treatment experienced. DAA therapies were: sofosbuvir (SOF) + ribavirin (RBV) in 10 patients; SOF + simeprevir (SMV) ± RBV in 73; SOF + pegylated interferon (PEG-IFN) + RBV in 6; SOF + daclatasvir (DCV) ± RBV in 51, SOF + ledipasvir (LDV) ± RBV in 61, and par-itaprevir/ritonavir + ombitasvir + dasabuvir (PTVr/OBV/DSV) ± RBV in 18 patients. SVR-12 was achieved in 208/219 (95%). Ten patients had virologic failure: 6 cirrhotic, 7 treatment experienced, and 6 either genotype 3 or 1a. No adverse event was attributed to the DAA therapy.ConclusionsReal world experience with DAA therapy in Southern Brazil showed a high rate of SVR and excellent tolerability. Failure to achieve SVR was mainly observed among patients with at least one negative predictor of response: cirrhosis and/or genotypes 1a or 3.     

Daclatasvir and Peginterferon/Ribavirin for Black/African-American and Latino Patients with HCV infection

Background. Patient race and ethnicity have historically impacted HCV treatment response. This phase 3 study evaluated daclatasvir with peginterferon-alfa-2a/ribavirin (pegIFN alfa-2a/RBV) in treatment-naive black/African American (AA), Latino, and white non-Latino patients with chronic HCV genotype 1 infection.Material and methods. In this single-arm, open-label study, 246 patients received daclatasvir plus pegIFN alfa-2a and weight-based RBV. Patients with an extended rapid virologic response (eRVR; undetectable HCV-RNA at treatment weeks 4 and 12) received 24 weeks of treatment; those without eRVR received an additional 24 weeks of treatment with pegIFN alfa-2a/RBV. The primary endpoint was sustained virologic response at post-treatment week 12 (SVR12; HCV-RNA < 25 IU/mL) compared with the cohort historical rate.Results. Most patients were IL28B non-CC (84.4% black/AA; 77.6% Latino) genotype 1a-infected (72.7%; 81.3%), with HCV-RNA ≥ 800,000 IU/mL (81.3%; 64.5%). SVR12 rates were 50.8% (65/128; 95% confidence interval [CI], 42.1-59.4) for black/AA and 58.9% (63/107; 95% CI, 49.6-68.2) for Latino patients. The majority (55.5%; 58.9%) received 24 weeks treatment; rapid reductions (> 4-log₁₀) in HCV-RNA levels were observed. Only 60.9% (78/128) of black/AA and 63.6% (68/107) of Latino patients completed treatment. On-treatment serious adverse events (SAEs) occurred in 21 patients. Discontinuations due to adverse events (aEs) occurred in 9 black/AA and 6 Latino patients.Conclusion. SVR12 rates for black/AA (50.8%) and Latino (58.9%) cohorts treated with daclatasvir plus pegIFN alfa-2a/RBV and the lower bound of the 95% Cls were higher than the estimated historical control (black/AA, 26% SVR; Latino, 36% SVR) treated with pegIFN alfa-2a/RBV. These data support daclatasvir use in all-oral direct-acting antiviral combinations.     

Real‐world effectiveness of glecaprevir/pibrentasvir and ledipasvir/sofosbuvir for mixed genotype hepatitis C infection: A multicenter pooled analysis in Taiwan

Data on direct‐acting antiviral agent (DAA) treatment for mixed genotype hepatitis C virus (HCV) infection are scant. This study examined the effectiveness of glecaprevir/pibrentasvir (GLE/PIB) and ledipasvir/sofosbuvir (LDV/SOF) for mixed HCV genotype infection in a real‐world setting in Taiwan. We analysed the data from all patients with mixed HCV genotype infections treated with GLE/PIB or LDV/SOF from 2017 to 2019 in three Chang Gung Memorial Hospitals in Taiwan. The primary treatment outcome was sustained virologic response 12 weeks after treatment cessation (SVR12). Adverse events (AEs) were also evaluated. A total of 5190 HCV patients received DAA treatment during this time period. Among them, 116 patients (2.2%) had mixed infections of any 2 or 3 genotypes of 1a, 1b, 2, 3 and 6. Fifty‐four patients received GLE/PIB and 62 received LDV/SOF. SVR12 rates for LDV/SOF vs GLE/PIB therapy were 96.6% (56/58) vs 100% (51/51) by the per‐protocol analysis and 90.3% (56/62) vs 94.4% (51/54) by the evaluable population analysis. Two patients with 1b + 6 and 1b + 2 genotype infections in the LDV/SOF group had relapse. Evaluating the GLE/PIB vs LDV/SOF groups for the most common AEs revealed pruritus (16.7% vs 4.8%), abdominal discomfort (5.6% vs 8%) and fatigue (5.6% vs 4.8%). One patient with AE‐related treatment discontinuation presented with liver decompensation after 4‐week GLE/PIB therapy. DAA‐related significant laboratory abnormalities occurred in two patients with >3× elevated bilirubin level in the GLE/PIB group. GLE/PIB and LDV/SOF are well tolerated and achieve high SVR12 rates for patients with mixed HCV genotype infection.     

Direct-acting antiviral regimens in Egyptian patients with chronic hepatitis C virus infection: A real-world single-center experience

Background and study aims:Chronic hepatitis C virus (HCV) infection has always been identified as a major health threat and a potential cause of liver cirrhosis, portal hypertension, and other associated problems. The introduction of direct-acting antiviral agents (DAAs) has represented a paradigm shift in HCV management. In this study, we aim to observe the rate of sustained virologic response (SVR12) in a large scale of patients at a single center as well as record the post-treatment changes in the hematologic, hepatic, and renal biochemical profiles.Patients and methodsIn total, 1933 chronic HCV genotype 4 mono-infected non-HCC patients who completed the treatment with six different DAA regimens in the Faculty of Medicine, Ain Shams University Research Institute (MASRI), were retrospectively enrolled in this study. The rate of sustained virologic response after 12 weeks off-therapy (SVR12) was assessed. The baseline characteristics to predict the SVR12 were then analyzed. The post-treatment changes in many profiles were recorded and analyzed.ResultsThe overall SVR12 rate was 96.2% (after excluding 84 cases who were lost to follow-up). It was achieved in 346/375 patients (92.3%), 466/477 patients (97.7%), 60/62 patients (96.8%), 11/11 patients (100%), 532/545 patients (97.6%), and 445/463 patients (96.1%) who received sofosbuvir/daclatasvir (SOF/DCV), sofosbuvir/daclatasvir/ribavirin (SOF/DCV/RBV), sofosbuvir/ledipasvir (SOF/LDV), sofosbuvir/ledipasvir/ribavirin (SOF/LDV/RBV), sofosbuvir/simeprevir (SOF/SMV), and ombitasvir/paritaprevir/ritonavir/ribavirin (OBV/PTV/r + RBV), respectively. In total, 73 patients (3.8%) failed to achieve SVR12. The baseline aspartate aminotransferase (AST), cirrhotic status, and treatment regimen were determined to have a significant impact on SVR12. In the overall treated population, the levels of serum AST, alanine aminotransferase, albumin, creatinine, bilirubin, and hemoglobin and platelet count improved significantly after treatment. Furthermore, sustained virologic response was strongly related to cirrhosis and its degree.ConclusionThe interferon-free DAA regimens offered high SVR12 rates in Egyptian patients with chronic HCV infection. They were associated with a significant improvement in the hematologic, hepatic, and renal biochemical profiles. The baseline AST, liver cirrhosis, and treatment regimen might have an impact on achieving SVR.     

Community‐based real‐world treatment outcomes of sofosbuvir/ledipasvir in Asians with chronic hepatitis C virus genotype 6 in the United States

Sofosbuvir/ledipasvir (SOF/LDV) is the first all‐oral ribavirin‐free treatment approved for chronic hepatitis C virus (HCV) genotype 6, offering a safe and highly efficacious treatment option. Large studies evaluating real‐world outcomes of this regimen are lacking. We aim to evaluate real‐world treatment outcomes for HCV genotype 6. A retrospective cohort study evaluated 65 adults (age ≥18) with chronic HCV genotype 6 treated with SOF/LDV without ribavirin at a community gastroenterology clinic in the United States from November 2014 to May 2016. Rates of undetectable virus at week 4 on treatment, at end of treatment (EOT) and SVR12 were stratified by the presence of cirrhosis and prior treatment (treatment naïve vs treatment experienced). Among 65 patients with chronic HCV genotype 6 treated with SOF/LDV (52.3% male, mean age 66.3 years [SD 9.7], 41.5% cirrhosis and 15.4% treatment experienced), 97.3% had undetectable virus at week 4 on treatment, 96.9% had undetectable virus at EOT and 95.3% achieved SVR12. SVR12 was 100% in females vs 91.2% in males, P=.096, and 92.3% in patients with cirrhosis vs 97.4% in those without cirrhosis, P=.347. Resistance testing of treatment failures was attempted but unsuccessful due to lack of conforming primers to define the possible resistance mutations. Among the largest U.S. community‐based real‐world cohort of Asian chronic HCV genotype 6 patients treated with all‐oral SOF/LDV without ribavirin, SVR12 was similar to SVR12 reported in clinical trials, confirming the safety and effectiveness of this regimen and validating current HCV genotype 6 treatment guideline recommendations.     

Real-world efficacy and safety of Ledipasvir + Sofosbuvir and Ombitasvir/Paritaprevir/Ritonavir ± Dasabuvir combination therapies for chronic hepatitis C: A Turkish experience

Background/AimsThis study aimed to evaluate the real-life efficacy and tolerability of direct-acting antiviral treatments for patients with chronic hepatitis C (CHC) with/without cirrhosis in the Turkish population.Material and MethodsA total of 4,352 patients with CHC from 36 different institutions in Turkey were enrolled. They received ledipasvir (LDV) and sofosbuvir (SOF)±ribavirin (RBV) ombitasvir/paritaprevir/ritonavir±dasabuvir (PrOD)±RBV for 12 or 24 weeks. Sustained virologic response (SVR) rates, factors affecting SVR, safety profile, and hepatocellular cancer (HCC) occurrence were analyzed.ResultsSVR12 was achieved in 92.8% of the patients (4,040/4,352) according to intention-to-treat and in 98.3% of the patients (4,040/4,108) according to per-protocol analysis. The SVR12 rates were similar between the treatment regimens (97.2%–100%) and genotypes (95.6%–100%). Patients achieving SVR showed a significant decrease in the mean serum alanine transaminase (ALT) levels (50.90±54.60 U/L to 17.00±14.50 U/L) and model for end-stage liver disease (MELD) scores (7.51±4.54 to 7.32±3.40) (p<0.05). Of the patients, 2 were diagnosed with HCC during the treatment and 14 were diagnosed with HCC 37.0±16.0 weeks post-treatment. Higher initial MELD score (odds ratio [OR]: 1.92, 95% confidence interval [CI]: 1.22–2.38; p=0.023]), higher hepatitis C virus (HCV) RNA levels (OR: 1.44, 95% CI: 1.31–2.28; p=0.038), and higher serum ALT levels (OR: 1.38, 95% CI: 1.21–1.83; p=0.042) were associated with poor SVR12. The most common adverse events were fatigue (12.6%), pruritis (7.3%), increased serum ALT (4.7%) and bilirubin (3.8%) levels, and anemia (3.1%).ConclusionLDV/SOF or PrOD±RBV were effective and tolerable treatments for patients with CHC and with or without advanced liver disease before and after liver transplantation. Although HCV eradication improves the liver function, there is a risk of developing HCC.