A combination of nirmatrelvir and ombitasvir boosts inhibition of SARS-CoV-2 replication.

Antiviral therapeutics are highly effective countermeasures for the treatment of coronavirus disease 2019 (COVID-19). However, development of resistance to antivirals undermines their effectiveness. Combining multiple antivirals during patient treatment has the potential to overcome the evolutionary selective pressure towards antiviral resistance, as well as provide a more robust and efficacious treatment option. The current evidence for effective antiviral combinations to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication is limited. Here, we demonstrate a combination of nirmatrelvir with ombitasvir, to jointly bring about potent inhibition of SARS-CoV-2 replication. We developed an in vitro 384- well plate cytopathic effect assay for the evaluation of antiviral combinations against Calu-3 cells infected with SARS-CoV-2 and found, that a combination of ombitasvir and nirmatrelvir was synergistic; thereby decreasing the nirmatrelvir IC50 by approx. 16-fold. The increased potency of the nirmatrelvir-ombitasvir combination, over nirmatrelvir alone afforded a greater than 3 log10 reduction in viral titre, which is sufficient to fully prevent the detection of progeny SARS-CoV-2 viral particles at 48 h post infection. The mechanism of this potentiated effect was shown to be, in-part, due to joint inhibition of the 3-chymotrypsin-like protease via a positive allosteric modulation mechanism.

Efficacy and safety of ombitasvir/paritaprevir/ritonavir-based therapy in HCV patients with chronic kidney disease.

BACKGROUND AND STUDY AIMS: Hepatitis C virus (HCV) prevalence inchronic kidney disease (CKD) patients is significantly higher than in the general population. This study evaluated the efficacy and safety of combined ombitasvir/paritaprevir/ritonavir-based therapy in HCV patients with renal impairment. PATIENTS AND METHODS: Our study included 829 patients with normal kidney functions (group 1) and 829 patients with CKD (group 2),which were subdivided into patients not requiring dialysis (group 2a) and those on hemodialysis (group2b). Patients received regimens of ombitasvir/paritaprevir/ritonavir with or without ribavirin or sofosbuvir/ombitasvir/paritaprevir/ritonavir with or without ribavirin for 12 weeks. Clinical and laboratory assessment was done before treatment, and patients were followed up for12 weeks after treatment. RESULTS: The sustained virological response (SVR) at week 12 was significantly higher in group 1 than in the other three groups/subgroups, being 94.2% vs 90.2%, 90%, and 90.7%, respectively. The regimen with the highest SVR was ombitasvir/paritaprevir/ritonavir with ribavirin. The most common adverse event was anemia, which was more common in group 2. CONCLUSION: Ombitasvir/paritaprevir/ritonavir-based therapy in chronic HCV patients with CKD is highly effective, with minimal side effects despite ribavirin-induced anemia.

Effectiveness and safety of generic and brand direct acting antivirals for treatment of chronic hepatitis C.

BACKGROUND: Direct acting antivirals (DAAs) are a very effective treatment for hepatitis C virus (HCV). However, brand DAAs are expensive. The licensing of cheaper generic DAAs may address this issue, but there is a lack of clinical studies comparing the efficacy of generic vs brand DAA formulations. AIM: To compare the efficacy and safety of generic against brand DAAs for chronic hepatitis C treatment in Bahrain. METHODS: This was a retrospective observational study involving 289 patients with chronic HCV infection during 2016 to 2018. There were 149 patients who were treated with brand DAAs, while 140 patients were treated with generic DAAs. Commonly used DAAs were Ombitasvir/Paritaprevir/Ritonavir ± Dasabuvir ± Ribavirin, and Sofosbuvir/Daclatasvir ± Ribavirin. SVR at 12 wk post treatment was the main outcome variable. RESULTS: Overall, 87 patients (30.1%) had cirrhosis and 68.2% had genotype 1 HCV infection. At 12 wk post treatment, SVR was achieved by 271 (93.8%) of the patients. In patients who were treated with generic medications, 134 (95.7%) achieved SVR at 12 wk post treatment, compared to 137 (91.9%) among those treated with brand medications (P = 0.19). Having cirrhosis [odds ratio (OR): 9.41, 95% confidence interval (CI): 2.47-35.84] and having HCV genotype 3 (OR: 3.56, 95%CI: 1.03-12.38) were significant independent predictors of not achieving SVR. Alanine transaminase, gamma-glutamyl transpeptidase, and total bilirubin levels decreased significantly following therapy with both generic and brand DAAs. CONCLUSION: Generic and brand DAAs demonstrate comparable effectiveness in the treatment of chronic hepatitis C patients. Both are safe and equally effective in improving biochemical markers of hepatic inflammation.

Effects of a ritonavir-containing regimen on the pharmacokinetics of sirolimus or everolimus in healthy adult subjects.

The immunosuppressive agents sirolimus and everolimus are sensitive CYP3A4 substrates with narrow therapeutic index. Ritonavir is a strong CYP3A inhibitor. A phase 1 study was conducted to evaluate the pharmacokinetics, safety, and tolerability of the co-administration of sirolimus or everolimus with the ritonavir-containing 3D regimen of the direct-acting antiviral agents ombitasvir, ritonavir-boosted paritaprevir, and dasabuvir in healthy subjects. This study had two independent arms, each with a two-period, single-sequence, crossover study design. A single dose of sirolimus 2 mg (N = 12) or everolimus 0.75 mg (N = 12) was administered in Period 1. In Period 2, multiple doses of the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily and dasabuvir 250 mg twice daily) were administered for 34 or 28 days, with a single dose of sirolimus 0.5 mg or everolimus 0.75 mg co-administered on Day 15. Following co-administration with the 3D regimen, the sirolimus dose-normalized maximum observed blood concentration (Cmax ) and area under the blood concentration-time curve from time zero to infinity (AUCinf ) increased to 6.4-fold and 38-fold, respectively. Following co-administration with the 3D regimen, the everolimus Cmax and AUCinf increased to 4.7-fold and 27-fold, respectively. Sirolimus and everolimus half-lives increased from 96 to 249 h, and 42 to 118 h, respectively. There were no major safety or tolerability issues in this study. The ritonavir-containing 3D regimen resulted in a significant increase in sirolimus or everolimus exposure, consistent with the known strong inhibitory effect of ritonavir on CYP3A requiring dose and/or frequency modification when co-administered with each other.

The effectiveness and safety of direct-acting antivirals for hepatitis C virus treatment: A single-center experience in Saudi Arabia.

Background: The introduction of direct-acting antivirals (DAA) to treat the hepatitis C virus (HCV) overcame many drawbacks of interferon-based therapy. DAA achieved sustained viral response (SVR) rates above 90% and overcame many drawbacks of pegylated interferon regimens.The HCV genotype (GT) distribution varies by geographical area, with GT-4 being most prevalent in the Middle East region, including Saudi Arabia. Yet, the real-world evidence about using DAAs in the Saudi population is limited.Thus, the aim of this study to investigate the effectiveness and safety of DAAs in Saudi patients with HCV infection. Methods: A retrospective cohort study included patients treated with DAAs from 2015 to 2017 at a tertiary care hospital in Riyadh, Saudi Arabia. All patients with HCV treated with either ledipasvir plus sofosbuvir (LDS/SOF) ± ribavarin (RBV) or ombitasvir-paritaprevir-ritonavir (OBV/PTV/r) ± dasabuvir (DSV) ± RBV were included. Using a per-protocol analysis, the effectiveness outcome was the end-of-treatment response (EOTr) and Sustained virologic reponce12 weeks after competing the regimen (SVR12). The secondary safety outcome was the adverse event related to the therapy reported by the patients. Results: A total of 97 patients were included; with the majority infected with GT-4 (64 %), followed by GT-1 (18 %), in addition to 8 % having a mixed GT (1 + 4). The EOTr and SVR12 rates were 98 % and 96 %, respectively. SVR12 was 94.4 % within the LDS/SOF ± RBV group and 97.7 % within the OBV/PTV/r ± DSV ± RBV group. Only 4 % had a response failure due to relapse or breakthrough, and all were infected with mixed GT1 + 4. Medications were well tolerated with minimal side effects, including vomiting, nausea, and weakness. Conclusion: DAAs regimens are associated with high rates of SVR12 and are well tolerated with a good safety profile in Saudi HCV-infected patients.

High success rates for the use of ombitasvir/paritaprevir/ritonavir containing regimens in treatment of naïve and experienced chronic hepatitis C genotype 4: Real world results.

INTRODUCTION AND AIMS: Treatment of hepatitis C virus (HCV) genotype 4 patient with fixed dose combination of ombitasvir-paritaprevir-ritonavir plus ribavirin (OBV/rPTV/RBV) has been proven efficacy and safety in many clinical trials. The current study reports the efficacy and safety of OBV/rPTV/RBV (for treatment-naïve), and OBV/rPTV/RBV/sofosbuvir (SOF) (for treatment-experienced), in chronic HCV genotype 4 patients in real life settings. METHODS: Prospective cohort study including all adult chronic HCV genotype 4 patients who were scheduled to receive OBV/rPTV/RBV ± SOF for 12 or 24 weeks in New Cairo Viral Hepatitis Treatment Center. The primary efficacy endpoint was a virologic response at posttreatment week 12 (SVR12). Changes in hematological parameters, liver biochemical profile and fibrosis-4 index (FIB-4), as well as clinical and laboratory adverse events (AEs) across follow up visits (week 4, end of treatment [EOT], and SVR12), were recorded. RESULTS: Our study included 325 patients (age; 47.63 ± 12.63 years, 55.38% [n = 180] men). Most of the included patients (89.85%, n = 292) were treatment naïve and only 7% (n = 23) had liver cirrhosis. Overall, SVR12 was attained by 98.44% (316 of 321) of the patients; 97.15% (307 of 316) of patients who received 12 weeks of OBV/rPTV/RBV ± SOF and 100% (9 of 9) of patients who received 24 weeks of OBV/rPTV/RBV as assessed by modified intention to treat analysis. There was a significant improvement of baseline alanine aminotransferase, aspartate aminotransferase, hemoglobin, FIB-4 at SVR12 (P < 0.05). The most common reported AEs were anemia (n = 106), fatigue (n = 41) and elevated indirect bilirubin (n = 37). CONCLUSION: OBV/rPTV/RBV (±SOF) is a highly effective therapy for chronic HCV patients in real life settings.

Three regimens for re-treatment failure of Sofosbuvir-based therapy for chronic hepatitis-C genotype-4: a cohort study

ABSTRACT Despite the high sustained virologic response (SVR) rates of direct-acting antiviral (DAAs) therapy, a small number of patients does not eradicate the virus, and these patients represent a challenge. This study aims to compare the outcomes of three second-line regimens for DAAs-experienced patients with chronic hepatitis C (CHC). This prospective observational study was conducted at the Damanhur Viral Hepatitis Center from January 2017 to February 2020. We included patients with CHC who did not achieve SVR after the complete course of Sofosbuvir/Daclatasvir±Ribavirin (SOF/DAC±RBV). The primary endpoint was SVR-12 after re-treatment. This study included 360 patients (with a mean age of 51.53±11.38 years). Approximately 51.1% of the patients were males, and 65.5% had liver cirrhosis. All patients of group 1 (45 patients) received SOF/VEL/VOX over 12-weeks; SVR-12 was achieved in 44 patients (97.8%). Group 2 (28 patients) received SOF/DAC/RBV over 24-weeks; (one patient was lost during follow-ups and one patient discontinued treatment due to hepatic decompensation). SVR-12 was achieved in 25 patients (96.2%). Group 3 (287 patients) received SOF/Ombitasvir/Paritaprevir/Ritonavir/RBV) over 12-weeks. Eight patients were lost during follow-ups, and one patient discontinued treatment due to grade 4 adverse events. SVR-12 was achieved in 276 patients (99.3%). There was no difference between the groups regarding their age, gender distribution, baseline viral load or comorbidities. Adverse events (thrombocytopenia, anemia, hyperbilirubinaemia and prolonged INR) were significantly higher in group 3, while group 1 did not experience any. The three studied retreatment regimens can be used for DAAs treatment-experienced patients considering availability. The SOF/VEL/VOX combination had the least adverse events.

Efficacy and Safety of Ombitasvir plus Paritaprevir, Ritonavir and Ribavirin in Non-cirrhotic Treatment-naïve and Treatment-experienced Egyptians with Chronic HCV Genotype-4 Infection.

Hepatitis C virus genotype 4 (HCV-GT4) is a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. A combination of three new direct-acting antivirals ombitasvir, paritaprevir, and ritonavir has been recommended for treatment of HCV-GT4 infection. The current study was aimed to assess the efficacy and safety of this combination plus ribavirin in non-cirrhotic, treatment-naïve and -experienced Egyptians with HCV-GT4 infection in a real-world setting. A total of 255 Egyptians with HCV-GT4 infection were enrolled, including 82 treatment-experienced and 173 treatment-naïve patients. All of them completed 12-week treatment protocol of ombitasvir, paritaprevir and ritonavir as an oral dose combination with ribavirin. Virological response (VR) was measured, as well as the biochemical parameters related to treatment efficacy and adverse events at baseline and after treatment, at 4 (VR4) and 12 (VR12) weeks post-treatment. The results showed that the VR4 rates were 98.8% in both groups, and VR12 rates were 97.7% and 96.3% in treatment-naïve and -experienced patients, respectively, with no significant differences found between the groups concerning VR4 (P=0.9) and VR12 (P=0.3). The most common adverse events were headache and fatigue, which were significantly more common (P=0.001 and 0.003, respectively) in treatment-experienced than in treatment-naïve group. The quadruple regimen was well-tolerated, and the reported adverse events were generally mild to moderate. This real-world setting study confirms that the combination of ombitasvir, paritaprevir, ritonavir, and ribavirin is highly effective in the treatment of HCV- GT4 infection with a good safety and tolerability profile.

Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C.

BACKGROUND & AIMS: We aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections. METHODS: A total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing. RESULTS: Failure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens (p <0.01), which was similar to that seen with L31-RAS and Y93-RAS. The prevalence of patients with RASs in either NS3 or NS5A, or in both, increased significantly with increasing numbers of failed regimens. The P32del, which is unique to patients for whom DAA had failed, was linked to the absence of Y93H, the presence of L31F, and previous exposure to IFN plus protease inhibitor regimens. CONCLUSIONS: Failure of multiple DAA regimens can lead to the generation of multiple RASs in the NS3 and NS5A regions of the HCV 1b genome. These mutations contribute to viral resistance to multiple treatment regimens and, therefore, should be considered during decision making for treatment of chronic HCV. LAY SUMMARY: Resistance-associated substitutions (RAS) in the genome of the hepatitis C virus are 1 of the major causes for failed treatment. We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.

Safety, efficacy and cost of two direct-acting antiviral regimens: A comparative study in chronic hepatitis C Egyptian patients.

WHAT IS KNOWN AND OBJECTIVE: Direct-acting antivirals (DAAs) have become the most widely used treatment of chronic hepatitis C infection. Comparative studies on DAAs regimens approved by the Egyptian Ministry of Health for easy-to-treat genotype 4 (G4) Egyptian patients are still deficient. In this prospective study, we compared the efficacy and cost of two DAA regimens that are used in the treatment of Egyptian chronic hepatitis C virus (HCV) G4. The cost-saving regimen is determined. METHODS: Eligible patients were randomized into 2 groups. Group 1 (Gp 1) received sofosbuvir plus daclatasvir, and group 2 (Gp 2) received ombitasvir, paritaprevir and ritonavir plus ribavirin (RBV) for 12 weeks. Data were collected and evaluated at baseline and at weeks 4, 8 and 12. Sustained virologic response 12 weeks after the end of treatment (SVR12 ) was evaluated. Cost-minimization analysis (CMA) was performed. RESULTS AND DISCUSSION: Eligibility was achieved in 107 patients, Gp1 included 57 patients, and Gp 2 included 50 patients. Two patients dropped out from Gp 2 due to non-compliance. All patients in the two groups showed negative HCV blood levels at the end of treatment. At the 24th week, 3 relapsers (5.2%) were detected in Gp1 and 2 relapsers (4.1%) were detected in Gp 2. SVR12 was 54/57 (94.7%) and 46/48 (95.8%) for Gp 1 and Gp 2, respectively. After the 12th week of treatment, a significant decrease in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and haemoglobin levels were observed in both groups. Albumin levels declined in Gp 2 only. CMA showed higher cost in Gp 2 than Gp 1, although similar efficacy and safety. WHAT IS NEW AND CONCLUSION: The two DAA regimens showed high SVR12 and safety in Egyptian HCV G4 patients. Sofosbuvir plus daclatasvir is the cost-saving regimen.

Comparative effectiveness of 8 versus 12 weeks of Ombitasvir/Paritaprevir/ritonavir and Dasabuvir in treatment-naïve patients infected with HCV genotype 1b with non-advanced hepatic fibrosis.

PURPOSE: Since 2017 treatment-naïve patients infected with genotype 1b of hepatitis C virus and minimal or moderate fibrosis can be treated with Ombitasvir/Paritaprevir/ritonavir + Dasabuvir (OPrD) for 8 weeks according to updated Summary of Product Characteristics. The aim of our study was to assess the comparative efficacy of 8 and 12-weeks therapy with OPrD in large cohort of patients eligible for 8 weeks regimen treated in real-world setting. MATERIALS AND METHODS: We analysed data of 3067 HCV genotype 1b infected patients treated with OPrD between 2015 and 2017. Final analysis included patients with none, minimal or moderate fibrosis (F0-F2). RESULTS: A total of 771 patients were enrolled in the study, including 197 (26%) treated for 8-weeks and 574 patients fulfilling criteria for 8-weeks but assigned to 12-weeks regimen. Majority of patients had no or minimal fibrosis (F0-F1). Longer treatment duration was more often administered in patients with moderate fibrosis, comorbidities, concomitant medications. SVR was achieved in 186 (94%) patients treated for 8 weeks and 558 (97%) for 12 weeks (p = 0.07). After exclusion of lost to follow-up patients, sustained virological response (SVR) rate reached 95% and 99%, respectively (p = 0.01). We were not able to identify factors associated with non-response. CONCLUSIONS: This real-word experience study confirmed similar, high effectiveness of 8 and 12-weeks regimens of OPrD in genotype 1b HCV infected patients with non-advanced fibrosis. Despite of reduced SVR rate after 8-weeks regimen, there is no need to extend therapy to 12-weeks in vast majority of such patients and no need to add ribavirin.

Recurrence rate of hepatocellular carcinoma in patients with treated hepatocellular carcinoma and hepatitis C virus-associated cirrhosis after ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin therapy.

Introduction: Recent studies have suggested a higher recurrence rate of hepatocellular carcinoma (HCC) in patients with a history of HCC and hepatitis C virus (HCV)-associated cirrhosis treated with direct-acting antiviral (DAA) agents. Material and methods: We conducted a prospective analysis of 24 patients with HCV-associated cirrhosis and treated HCC who received ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin for 12 weeks. Prior therapies for HCC included resection (9/24 patients), radiofrequency ablation (RFA) (7/24) and trans-arterial chemoembolization (TACE) (8/24). All patients were eligible for treatment if they had no HCC recurrence 6 months after their last procedure. A control group was defined. All patients were followed every 6 months, with dynamic computed tomography and/or magnetic resonance imaging. Results: The sustained virological response rate per protocol was 21/24 (87.5%). The study group included 14 (59%) males, median age 64 years (51-77), 50% with associated non-alcoholic steatohepatitis and 24% with Child-Pugh A6 points. HCC recurrence rate/100 patient-years was lower in the DAA-HCC group versus control: 5.5 versus 24.6% patient-years for the resection+RFA group (p = 0.044), respectively, and 18.6 versus 72.7% patient-years for TACE group (p = 0.002). Survival without recurrence was higher in the resection+RFA group (45 compared to 18 months (p < 0.001)) and also in the TACE group (44 compared to 11.5 months (p = 0.002)). Conclusions: DAA therapy significantly reduced the recurrence rate of HCC and improved survival without recurrence in patients with treated HCV-associated HCC.

Efficacy and Tolerability of Ombitasvir/Paritaprevir/Ritonavir in HCV Genotype 1-infected Elderly Japanese Patients.

INTRODUCTION AND AIM: We assessed the characteristics of virological response to a combination treatment of ombitasvir, paritaprevir, and ritonavir in hepatitis C virus genotype 1-infected elderly Japanese patients. MATERIAL AND METHODS: This multicenter prospective study was conducted at six locations in Japan. Seventy patients with chronic hepatitis C virus genotype 1b infection were orally administered ombitasvir/paritaprevir/ritonavir once daily for 12 weeks. The primary endpoint was the proportion of elderly patients with sustained virological response (SVR) 12 weeks after the completion of treatment. Adverse events were also recorded to evaluate drug safety and tolerability during the trial period. SVR in elderly patients (age > 65; 94% [47 / 50]) was lower than that in younger patients (100% [20 / 20]). RESULTS: No significant differences in SVR 12 weeks after the completion of treatment were observed between the age groups (P = 0.153). Adverse events were observed in 16 patients (23.3%). Multivariate analysis confirmed that the change or discontinuation of concomitant drugs owing to drug interactions was independent of risk factors for adverse events associated with this drug combination (P = 0.015; odds ratio, 15.9; 95% confidence interval, 1.79 - 148). Ombitasvir/paritaprevir/ritonavir combination treatment was highly effective in elderly patients. CONCLUSION: Tolerability should be monitored in older patients for whom concomitant medications are discontinued or changed because of drug interactions.

Ombitasvir/paritaprevir/ritonavir + dasabuvir +/- ribavirin in real world hepatitis C patients.

BACKGROUND: The hepatitis C virus (HCV) NS5A inhibitor ABT-267 (ombitasvir, OBV), the HCV NS4/4A protease inhibitor ABT-450 (paritaprevir, PTV), the CYP3A inhibitor ritonavir (r) and the non-nucleoside NS5B polymerase inhibitor ABT-333 (dasabuvir, DSV) (OBV/PTV/r + DSV) with or without ribavirin (RBV) is a direct-acting antiviral regimen approved in the United States and other major countries for the treatment of HCV in genotype 1 (GT1) infected patients. Patients with HCV who are considered "hard-to-cure" have generally been excluded from registration trials due to rigorous study inclusion criteria, presence of comorbidities and previous treatment failures. AIM: To investigate the efficacy of this regimen in HCV G1-infected patients historically excluded from clinical trials. METHODS: Patients were ≥ 18 years old and chronically infected with HCV GT1 (GT1a, GT1b or GT1a/1b). Patients were treatment-naïve or previously failed a regimen including pegylated interferon/RBV +/- telaprevir, boceprevir, or simeprevir. One hundred patients were treated with the study drug regimen, which was administered for 12 or 24 wk +/- RBV according to GT1 subtype and presence/absence of cirrhosis. Patients were evaluated every 4 wk from treatment day 1 and at 4 and 12 wk after end-of-treatment. RESULTS: Many of the patients studied had comorbidities (44.2% hypertensive, 33.7% obese, 20.2% cirrhotic) and 16% previously failed HCV treatment. Ninety-six patients completed study follow-up and 99% achieved 12-wk sustained virologic response. The majority (88.4%) of patients had undetectable HCV RNA by week 4. The most common adverse events were fatigue (12%), headache (10%), insomnia (9%) and diarrhea (8%); none led to treatment discontinuation. Physical and mental patient reported outcomes scores significantly improved after treatment. Almost all (98%) patients were treatment compliant. CONCLUSION: In an all-comers HCV GT1 population, 12 or 24-wk of OBV/PTV/r + DSV +/- RBV is highly effective and tolerable and results in better mental and physical health following treatment.

Paritaprevir/ritonavir, ombitasvir plus dasabuvir for East Asian non-cirrhotic hepatitis C virus genotype 1b patients receiving hemodialysis.

BACKGROUND AND AIM: Data regarding the efficacy and safety of paritaprevir/ritonavir, ombitasvir plus dasabuvir (PrOD) for East Asian non-cirrhotic hepatitis C virus genotype 1b (HCV GT1b) patients receiving hemodialysis were limited. METHODS: Forty-six HCV GT1b non-cirrhotic patients receiving hemodialysis who received PrOD for 12 weeks were prospectively enrolled in seven academic centers in Taiwan. The primary efficacy endpoint was sustained virologic response 12 weeks off-therapy (SVR12 ). Patients' baseline characteristics, early virokinetics, and HCV resistance-associated substitutions (RASs) potentially related to SVR12 were analyzed. The safety profiles were also assessed. RESULTS: The SVR12 rate was 100% (46 of 46 patients). Patients' baseline characteristics, on-treatment viral decline, and baseline HCV resistance-associated substitutions did not affect SVR12 . All patients tolerated treatment well. One patient with folliculitis temporarily discontinued treatment, and another two patients had serious adverse events (SAEs), which were considered not related to PrOD treatment. The common adverse events were pruritus (19.6%), fatigue (15.2%), and upper respiratory tract infection (6.5%). Twelve (19.6%) and one (2.2%) patients had hemoglobin levels < 10 and 8.5 g/dL, respectively, which were related to renal impairment. Five (10.9%) patients had on-treatment total bilirubin level of 1.5-3.0 mg/dL, but none developed hepatic decompensation. The bilirubin levels peaked at week 1 of treatment and then declined with continuous treatment. CONCLUSION: Treatment with PrOD for 12 weeks is efficacious and well-tolerated for East Asian non-cirrhotic HCV GT1b patients receiving hemodialysis.

Ritonavir-boosted paritaprevir, ombitasvir plus ribavirin could improve eGFR in patients with renal impairment and HCV: an Egyptian cohort.

BACKGROUND: The present study aimed at evaluation of changes in estimated glomerular filtration rate (eGFR) among chronic Hepatitis C virus (HCV) patients with chronic kidney disease (CKD) Stages 3-5 who were treated with 12 weeks of ritonavir-boosted paritaprevir, ombitasvir plus ribavirin. METHODS: Changes in renal functions were compared across follow up time points (baseline, SVR4, and SVR8). Data on on-treatment adverse events (AEs), serious AEs, laboratory abnormalities, treatment discontinuation were collected. RESULTS: 171 patients were included (females 35%, mean age 53 years). 29 patients had liver cirrhosis. The most common etiologies of CKD were diabetes and/or hypertension (n = 67). All included patient reached the end of treatment (EOT) with no treatment discontinuations. The overall EOT response was 100%. 122/122 (100%) patients who reached 4 weeks post-treatment have achieved SVR4, and 80/80 (100%) have achieved SVR12. No reported SAEs. Ribavirin therapy was interrupted in 25% (43/171) of patients due to anemia; 16 patients required blood transfusions. The median eGFR improved from 33.5 (15) mL/min/1.73 m2 at baseline to 35 (36) mL/min/1.73 m2 at SVR8 (p = 0.0003). CONCLUSIONS: The use of ombitasvir, paritaprevir, and ritonavir for treatment of HCV-infected patients with advanced renal disease was safe and effective, moreover, it was associated with significantly improved eGFR.

Impact of Preexisting Hepatitis C Virus Genotype 6 NS3, NS5A, and NS5B Polymorphisms on the In Vitro Potency of Direct-Acting Antiviral Agents.

HCV genotype 6 (GT-6) is found predominantly in East and Southeast Asia. Clinical studies have focused on patients infected with hepatitis C virus (HCV) GT-6a, where high sustained virologic response (SVR) rates to direct-acting antivirals (DAAs) have been achieved. However, GT-6 is highly diverse, with 29 reported subtypes. We explored the diversity of GT-6 polymorphisms at residues associated with DAA resistance, their impact on DAA in vitro potency when evaluated in a GT-6a consensus replicon, and their association with specific GT-6 subtypes. GT-6 sequences from 25 patient-derived samples and 105 sequences from the U.S. HCV database were compared, and substitutions at resistance-associated residue positions were phenotyped against different DAAs. Preexisting resistance-associated substitutions (RASs) to NS3 protease (A156V and D168E) and NS5B nucleotide (L159F and S282C) inhibitors were rare (<4%). Preexisting RASs to NS5A inhibitors were common, especially at L28 (A/F/G/M/T/V) and R30 (E/N/S). In vitro susceptibilities of NS5A-L28A and -L28T were dramatically reduced against all tested NS5A drugs (90% effective concentration [EC90] range, 119 to 2,032 nM) compared with susceptibilities against a GT-6a consensus replicon (EC90 range, 0.1 to 19 nM). These L28 RASs preexisted in combination with R30S (EC90 [L28A-R30S] of ≥720 nM or EC90 [L28T-R30S] of ≥128 nM against tested DAAs) or as L28T-L31I (EC90 [tested DAAs] of >5,000 nM) and were detected in evaluated GT-6b and -6f sequences. NS5A-L28A-R30A, observed in GT-6r, did not replicate. In conclusion, HCV GT-6b, GT-6f, and GT-6r sequences harbored highly resistant RASs to all evaluated NS5A drugs. Therefore, monitoring SVR in patients infected with these GT-6 subtypes treated with NS5A drug-containing regimens is suggested to confirm any association between noted NS5A polymorphisms and treatment failure.

Three renal failure cases successfully treated with ombitasvir/paritaprevir/ritonavir for genotype 1b hepatitis C virus reinfection after liver transplantation.

We report three cases of genotype 1b hepatitis C virus (HCV) reinfection after liver transplantation. When antiviral treatment was considered, all three patients had renal dysfunction and had been treated with immunosuppressive agents for a long time; one with tacrolimus (TAC) and the others with cyclosporine A (CyA). Therefore, the possible antiviral regimens among direct-acting antivirals (DAA) were limited and so we treated all three patients with ombitasvir/paritaprevir/ritonavir (OBV/PTV/r). Because ritonavir is known to markedly increase the blood concentration of TAC and CyA through drug-drug interactions, close monitoring of blood concentrations of TAC or CyA and dose adjustments of immunosuppressive agents were needed. Sustained virus response was achieved in all the patients treated, and there were no adverse effects or transplant rejection. OBV/PTV/r might be a useful DAA regimen for patients with genotype 1 HCV reinfection in the setting of renal dysfunction.