Adjuvant ribavirin and longer direct‐acting antiviral treatment duration improve sustained virological response among hepatitis C patients at risk of treatment failure

The role of ribavirin (RBV) in the era of direct‐acting antivirals (DAA) is not clear, and DAA studies have been largely genotype‐ and regimen‐specific. Using data from the Chronic Hepatitis Cohort Study, we evaluated the role of RBV and increased DAA treatment duration among patients with chronic hepatitis C (HCV) in routine clinical care. We performed multivariable analysis of data from 4133 patients receiving any of the following: sofosbuvir (SOF); daclatasvir + SOF; grazoprevir + elbasvir; paritaprevir/ritonavir + ombitasvir; simeprevir + SOF; and SOF + ledipasvir; SOF + velpatasvir ± voxilaprevir; and glecaprevir + pibrentasvir—all with/ without RBV. Inverse probability treatment weighting was used to adjust for treatment selection bias. Sustained virological response (SVR) was defined by undetectable HCV RNA 12 weeks after end of therapy. The overall SVR rate was 95%. Mean treatment duration was 12 ± 4.5 weeks. The final model included treatment duration and diabetes, as well as the interaction of RBV with previous treatment status (treatment naïve, interferon treatment failure [TF] or previous DAA TF), cirrhosis status, and HCV genotype (GT). Each one‐month increment of treatment duration increased odds of SVR by 99% (aOR = 1.99). Diabetes, previous DAA TF, and decompensated cirrhosis significantly reduced odds of SVR. RBV significantly increased the likelihood of SVR among patients with decompensated cirrhosis (aOR = 5.05), previous DAA treatment failure (aOR = 5.43), and GT3 (aOR = 13.28). Among RBV‐free regimens, patients with GT3 were less likely to achieve SVR than those with GT1 or 2 (aOR 0.07). Diabetes, decompensated cirrhosis, and prior DAA TF independently reduced the likelihood of SVR. Longer treatment duration increased likelihood of SVR. Conclusion: RBV increased likelihood of SVR among patients with GT3, previous DAA TF, or decompensated cirrhosis.     

Long‐term safety and efficacy results in hepatitis C virus genotype 1‒infected patients receiving ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin in the TOPAZ‐I and TOPAZ‐II trials

The 3‐DAA regimen consisting of ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV) has shown high sustained virologic response rates (~95%) in phase 3 clinical trials including >2300 HCV genotype 1–infected patients. Real‐world evidence studies have confirmed the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with chronic HCV genotype 1 infection and are consistent with clinical trial results. TOPAZ‐I and TOPAZ‐II are ongoing phase 3b trials, assessing safety, efficacy and long‐term progression of liver disease and clinical outcomes for up to 5 years post‐treatment in patients treated with OBV/PTV/r + DSV ± RBV. High rates of sustained virologic response (SVR) were achieved regardless of presence or absence of cirrhosis.In this report, we assessed the long‐term progression of liver disease and incidence of clinical outcomes up to 3 years of post‐treatment follow‐up in patients with chronic HCV GT1 infection who were treated with (OBV/PTV/r + DSV) ± RBV in the TOPAZ‐I and TOPAZ‐II studies. Improvements were observed in liver disease markers including FIB‐4, METAVIR and Child‐Pugh scores as well as platelet counts. Clinical outcomes related to long‐term progression of liver disease such as liver decompensation were infrequent (<1%). Hepatocellular carcinoma (HCC) occurred in 1.4% of cirrhotic patients.     

Real‐world safety and effectiveness of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin in hepatitis C virus genotype 1‐ and 4‐infected patients with diverse comorbidities and comedications: A pooled analysis of post‐marketing observational studies from 13 countries

Ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) regimens show high efficacy and good tolerability in clinical trials for chronic hepatitis C virus (HCV) genotypes (GT) 1 or 4. To evaluate whether these results translate to clinical practice, data were pooled from observational studies across 13 countries. Treatment‐naïve or ‐experienced patients, with or without cirrhosis, received OBV/PTV/r ± DSV ± RBV according to approved local labels and clinical practice. Sustained virologic response at post‐treatment Week 12 (SVR12), adverse events (AEs) and comedication management were assessed for patients initiating treatment before 1 June 2017. The safety population included 3850 patients who received ≥1 dose of study drug. The core population (N = 3808) further excluded patients with unknown GT or cirrhosis status, or who received off‐label treatment. Patients had HCV GT1a (n = 732; 19%), GT1b (n = 2619; 69%) or GT4 (n = 457; 12%). In 3546 patients with sufficient follow‐up data at post‐treatment Week 12, the SVR12 rate was 96% (n/N = 3401/3546 [95% CI 95.2‐96.5]). In patients with or without cirrhosis, SVR12 was comparable (96%). In patients with HCV GT1a, GT1b or GT4, SVR12 rates were 93%, 97% and 94%. In GT1b‐infected patients with planned treatment for 8 weeks, SVR12 was 96%. In patients with ≥1 comorbidity (67%), SVR12 was 95%. 58% of patients received ≥1 comedication, and there was minimal impact on SVR12 rates using comedications for peptic ulcers and gastro‐esophageal reflux disease, statins, antipsychotics or antiepileptics. Most comedications were maintained during treatment although 58% of patients changed their statin medication. AEs and serious AEs occurred in 26% and 3% of patients. Post‐baseline Grade 3‐4 laboratory abnormalities were rare (<3%), and discontinuation rates were low (<4%). Real‐world evidence confirms the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with HCV GT1 or GT4, regardless of common comorbidities or comedications, and is consistent with clinical trial results. Adverse safety outcomes may be limited by underreporting in the real‐world setting.     

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.     

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.     

Real‐world experience with the all‐oral,interferon‐free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus infection in the German Hepatitis C Registry

Real‐world studies are relevant to complement clinical trials on novel antiviral therapies against chronic hepatitis C; however, clinical practice data are currently limited. This study investigated effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±ribavirin (RBV) for treatment of HCV genotype (GT) 1 and GT4 infection in a large real‐world cohort. The German Hepatitis C Registry is an observational cohort study prospectively collecting clinical practice data on direct‐acting antiviral therapies. Patients with GT1/4 infection treated with OBV/PTV/r±DSV±RBV were analysed. Effectiveness was assessed by sustained virologic response in 558 patients who reached post‐treatment week 12 (SVR12). Safety is reported in 1017 patients who initiated treatment. Of the patients, 892 (88%) had GT1 and 125 (12%) had GT4 infection. Prior treatment experience and cirrhosis were reported in 598 (59%) and 228 (22%) patients, respectively. Overall, SVR12 (mITT) was 96% (486/505) in GT1‐ and 100% (53/53) in GT4 patients. SVR12 rates were high across subgroups including patients with cirrhosis (95%, 123/129), patients with moderate to severe renal impairment (100%, 34/34), and subgroups excluded from registrational trials like patients ≥70 years (96%, 64/67) and failures to prior protease inhibitor treatment (96%, 46/48). Adverse events (AEs) and serious AEs were reported in 52% (525/1017) and 2% (21/1017) of patients, respectively, and led to treatment discontinuation in 1.5% (15/1017) of patients. OBV/PTV/r±DSV±RBV was effective and generally well tolerated for treatment of HCV infection in clinical practice.     

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.     

Real‐world effectiveness of ombitasvir/paritaprevir/ritonavir±dasabuvir±ribavirin in patients with hepatitis C virus genotype 1 or 4 infection: A meta‐analysis

The direct‐acting antiviral regimen of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r)±dasabuvir (DSV)±ribavirin (RBV) demonstrated high rates of sustained viral response at post‐treatment week 12 (SVR12) in clinical trials for treatment of hepatitis C virus (HCV) genotypes (GT) 1 and 4. To confirm the effectiveness of this regimen in the real world, we conducted meta‐analyses of published literature on 30 April 2016. Freeman‐Tukey transformation determined the SVR rate within GTs 1a, 1b and 4, as well as specific SVR rates by cirrhosis or prior treatment experience status. Rates of virologic relapse, hepatic decompensation, drug discontinuation and serious adverse events were also analysed. In total, 20 cohorts across 12 countries were identified, totalling 5158 patients. The overall SVR12 rates were 96.8% (95% CI 95.8‐97.7) for GT1 and 98.9% (95% CI 94.2‐100) for GT4. For GT1a patients, the SVR rates were 94% and 97% for those with or without cirrhosis, and 94% overall. For GT1b patients, the SVR rates were 98% and 99% for those with or without cirrhosis, and 98% overall. The virologic relapse rate of GT1 patients was 1.3%, across 3524 patients in nine studies that reported this parameter. The rate of hepatic decompensation was less than 1% across five studies, including 3440 patients, 70% of which had cirrhosis. Conclusions: Real‐world SVR12 rates for OBV/PTV/r±DSV±RBV were consistently high across HCV GT1 and four irrespective of cirrhosis status or prior HCV treatment experience, confirming effectiveness within a diverse patient population across multiple cohorts and countries.     

Efficacy and safety of 12 weeks of elbasvir ± grazoprevir ± ribavirin in participants with hepatitis C virus genotype 2, 4, 5 or 6 infection: The C‐SCAPE study

People with hepatitis C virus (HCV) infection other than genotype 1 represent a heterogeneous group. The aim of the phase 2 C‐SCAPE study was to evaluate elbasvir/grazoprevir (EBR/GZR), with or without ribavirin (RBV), in participants with HCV genotype 2, 4, 5 or 6 infection. This was a part randomised, open‐label, parallel‐group study (NCT01932762; PN047‐03) of treatment‐naive, noncirrhotic participants. Participants with HCV genotype 2 infection received GZR 100 mg + RBV ± EBR 50 mg for 12 weeks and those with genotype 4, 5 or 6 infection were randomized to receive EBR/GZR ± RBV for 12 weeks. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12; HCV RNA <25 IU/mL). Among participants with genotype 2 infection, SVR12 was achieved by 80% (24/30) of those receiving EBR/GZR + RBV and 73% (19/26) of those receiving GZR + RBV. SVR rates were high in participants with HCV genotype 4 infection receiving EBR/GZR with and without RBV (100% [10/10] and 90% [9/10]; respectively). In contrast, the addition of RBV to EBR/GZR appeared to increase SVR12 in participants with genotype 5 infection (EBR/GZR, 25%; EBR/GZR + RBV 100% [4/4]). In participants with genotype 6 infection, SVR12 was 75% (3/4) in both those receiving EBR/GZR and those receiving EBR/GZR + RBV. The safety profile was similar across treatment arms, with adverse events tending to occur more frequently among participants receiving RBV. In conclusion, these data support the inclusion of participants with genotype 4 or 6 infection in the EBR/GZR phase 3 studies. EBR/GZR ± RBV was unsatisfactory for participants with genotype 2 or 5 infection.     

Nonstructural protein 5A resistance profile in patients with chronic hepatitis C treated with ledipasvir‐containing regimens without sofosbuvir

The study aimed to evaluate the effects of baseline hepatitis C virus (HCV) nonstructural protein 5A (NS5A) resistance‐associated substitutions (RASs) on sustained virologic response to ledipasvir (LDV)‐containing regimens in the absence of sofosbuvir (SOF) in patients with HCV genotype (GT) 1 infection across 6 phase 2 clinical studies. We analysed data from 1103 patients who received either LDV + vedroprevir (NS3 protease inhibitor) + tegobuvir (NS5B inhibitor) ± ribavirin or LDV + ribavirin + pegylated interferon. Population sequencing of HCV NS5A was performed at baseline and at virologic failure from patient plasma samples. Of 1045 patients with available baseline sequences, 747 (67.7%) had GT1a, and 298 (26.9%) had GT1b infection. The overall prevalence of NS5A RASs at baseline was 9.4%; 7.6% (57/747) and 13.8% (41/298) of patients with GT1a and GT1b infection, respectively. The majority of GT1a‐infected patients with NS5A RASs at baseline had a single NS5A RAS (78.9%) at NS5A positions K24R, M28T, Q30H/L, L31M and Y93H/N/C/S. The spectrum of NS5A RASs detected in GT1b patients was much less diverse compared to GT1a patients, with all patients harbouring a single NS5A RAS either L31M or Y93H/C. For patients treated with LDV‐containing regimens in the absence of SOF, the presence of baseline NS5A RASs was associated with low SVR rates. In patients with virologic failure, nearly all had either pre‐existing and/or emergent NS5A RASs: 287/287 (100%) and 40/42 (95.2%) patients with GT1a and GT1b infection, respectively. Three novel NS5A substitutions were identified as emergent NS5A RASs: K26E and S38F in GT1a; and L31I in GT1b. In conclusion, the presence of NS5A RASs at baseline reduced the SVR rate in patients treated with LDV in combination vedroprevir + tegobuvir ± ribavirin or ribavirin + pegylated interferon. Virologic failure was associated with the detection of NS5A RASs in nearly all patients. These results suggest that the resistance barrier may differ depending on HCV drug combination and may be more important than that of the individual DAAs.     

Treatment of chronic hepatitis C with direct‐acting antivirals in patients with β‐thalassaemia major and advanced liver disease

Interferon‐based regimens for chronic hepatitis C (CHC ) were often deferred in patients with β‐thalasaemia major (β‐TM ) due to poor efficacy and tolerance. Current guidelines recommend direct‐acting antivirals (DAA s) for these patients. The aim of this study was to assess the safety and efficacy of DAA s in patients with β‐TM and advanced liver disease due to CHC . Patients were recruited from eight liver units in Greece. The stage of liver disease was assessed using transient elastography and/or liver histology. Five regimens were used: sofosbuvir (SOF ) + ribavirin (RBV ); SOF  + simeprevir ± RBV ; SOF  + daclatasvir ± RBV ; ledipasvir/SOF  ± RBV and ombitasvir/paritaprevir‐ritonavir + dasabuvir ± RBV . Sixty‐one patients (median age 43 years) were included. The majority of patients was previously treated for hepatitis C (75%) and had cirrhosis (79%). Viral genotype distribution was: G1a: n  = 10 (16%); G1b: n  = 22 (36%); G2: n  = 2 (3%); G3: n  = 14 (23%); G4: n  = 13 (22%). The predominant chelation therapy was a combination of deferoxamine and deferiprone (35%). Overall sustained virological response rates were 90%. All treatment regimens were well tolerated and no major adverse events or drug‐drug interactions were observed. Approximately half of the patients who received RBV (7/16, 44%) had increased needs for blood transfusion. Treatment of CHC with DAA s in patients with β‐TM and advanced liver disease was highly effective and safe.     

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.     

B.A.R.C.O.S. (Brazilian Argentine Hepatitis C Collaborative Observational Study): Effectiveness and clinical outcomes of HCV treatment with daclatasvir and sofosbuvir with or without ribavirin

Real‐world data evaluating the effectiveness of direct‐acting antivirals (DAAs) in hepatitis C virus (HCV) treatment have been reported from different regions. Our aim was to evaluate the effectiveness and clinical outcomes of daclatasvir (DCV) and sofosbuvir (SOF) ± ribavirin (RBV) in a prospective multicentre cohort study including patients from Argentina and Brazil who received DCV/SOF ± RBV for 12 or 24 weeks from 2015 to 2018. Multivariable logistic regression models were carried out to identify factors associated with failure to achieve sustained virologic response (SVR) as a primary end point, and to death, decompensation, hepatocellular carcinoma (HCC) or liver transplantation (LT) as a composite secondary end point. From a total of 1517 patients treated with DCV/SOF, 906 completed 12 weeks post‐treatment evaluation and were included in the analysis. Overall SVR12 rate was 96.1% (95% CI: 94.6%‐97.2%), and 95% (95% CI: 92.8%‐96.6%) in patients with cirrhosis. LT recipients and presence of cirrhosis were independently associated with failure to achieve SVR. During post‐SVR12 follow‐up, cumulative incidence of the secondary end point was 2.4% (95% CI: 1.5%‐3.6%); two patients died from nonliver‐related causes and two from HCC, five underwent LT, 12 developed HCC and 17 patients developed hepatic decompensation. Independent variables associated with these composite secondary end points were prior to HCV treatment and presence of cirrhosis. In conclusion, although the high pangenotypic effectiveness of DCV/SOF ± RBV was confirmed in our real‐life cohort, patients with compensated and decompensated cirrhosis showed higher risk of non‐SVR and complication appearance during treatment or after achieving SVR.     

Intrapatient viral diversity and treatment outcome in patients with genotype 3a hepatitis C virus infection on sofosbuvir‐containing regimens

Treatment with the direct‐acting antiviral agent (DAA) sofosbuvir (SOF), an NS5B inhibitor, and velpatasvir (VEL), an NS5A inhibitor, demonstrates viral cure rates of ≥95% in hepatitis C virus (HCV) genotypes (GT) 1‐6. Here, we investigated intrapatient HCV diversity in NS5A and NS5B using Shannon entropy to examine the relationship between viral diversity and treatment outcome. At baseline, HCV diversity was lowest in patients infected with HCV GT3 as compared to the other GTs, and viral diversity was greater in NS5A than NS5B (P < .0001). Treatment outcome with SOF/VEL or the comparator regimen of SOF with ribavirin (RBV) was not correlated with baseline diversity. However, among persons treated with SOF/VEL, a decrease in diversity from baseline was observed at relapse in the majority virologic failures, consistent with a viral bottleneck event at relapse. In contrast, an increase in diversity was observed in 27% of SOF+RBV virologic failures. We investigated whether the increase in diversity was due to an increase in the transition rate, one mode of potential RBV‐mediated mutagenesis; however, we found no evidence of this mechanism. Overall, we did not observe that viral diversity at baseline influenced treatment outcome, but the diversity changes observed at relapse can improve our understanding of RBV viral suppression in vivo.     

High sustained virologic response in genotypes 3 and 6 with generic NS5A inhibitor and sofosbuvir regimens in chronic HCV in myanmar

Exclusive HCV therapy clinical trials with genotype 6 patients in high prevalence areas have been sparse. We analysed the safety and efficacy of two generic, pangenotypic NS5A/NS5B combination oral DAA regimens, primarily in genotypes 3 and 6, in a real‐world setting: (a) daclatasvir/sofosbuvir (DCV/SOF) ± ribavirin (RBV) and (b) Velpatasvir/sofosbuvir (VEL/SOF ± RBV). Between December 2015 and November 2017, data from 522 patients were analysed, 311 of whom were treated with DCV/SOF ± RBV for 12/24 weeks (genotype 3: n = 193, genotype 6: n = 89) and 211 were treated with VEL/SOF ± RBV for 12/24 weeks (genotype 3: n = 83, genotype 6: n = 77). Overall SVR rates were high for both DCV/SOF ± RBV (96.1%, n = 299/311) and VEL/SOF ± RBV (95.3%, n = 201/211), and there was a good adverse event profile. Treatment naïve status and inclusion of RBV (in advanced fibrosis/cirrhosis) were significant independent predictors of achieving SVR12, while type of DAA regimen was not predictive. In this large cohort of genotypes 3 (n = 276) and 6 (n = 166; n = 127 unique subtype of 6c‐l), high SVR rates of 94.9% (n = 262/276) and 95.2% (n = 158/166), respectively, were noted. In conclusion, generic and pangenotypic DCV/SOF and VEL/SOF ± RBV regimens were highly effective and safe, in genotypes 3 and 6 chronic HCV in Myanmar. These efficacious pangenotypic regimens suggest that baseline genotype testing can be eliminated moving forward. While RBV may still be needed for those with advanced fibrosis/cirrhosis, in a global elimination strategy it would not be practical even if it does compromise SVR in a minority with difficult to treat characteristics.     

Time to viral suppression is not related to achievement of SVR12 in HCV GT1‐infected patients treated with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin

High rates of sustained virologic response at post‐treatment week 12 (SVR12) were achieved in six phase 3 trials of ombitasvir (OBV, an NS5A inhibitor), paritaprevir (an NS3/4A protease inhibitor) co‐dosed with ritonavir (PTV/r) + dasabuvir (DSV, an NS5B RNA polymerase inhibitor) (ie, 3D regimen) with or without ribavirin (RBV) in adults with chronic genotype (GT) 1 hepatitis C virus (HCV) infection. We assessed whether time to first HCV RNA value below the lower limit of quantification in patients with and without cirrhosis was associated with achievement of SVR12. Data were analysed from GT1‐infected patients enrolled in six phase 3 studies of 3D ± RBV. Patients who experienced non‐virologic failure were excluded from analysis. HCV RNA was determined using the Roche COBAS TaqMan RT‐PCR assay (lower limit of quantification, LLOQ =25 IU/mL). SVR12 was analysed by week of first HCV RNA suppression, defined as HCV RNA <LLOQ. The analysis included a total of 2027 patients. Cumulative proportions of subjects with initial HCV RNA suppression <LLOQ at weeks 1, 2, 4 and 6 were 31%, 81%, 99% and 100%, respectively. SVR12 was achieved by 98%, 97%, 98% and 92% of patients with initial suppression at Weeks 1, 2, 4 and 6, respectively (P=.42, trend test). Across six phase 3 trials of 3D ± RBV, most patients achieved viral suppression by week 2. Time to viral suppression was not associated with subsequent achievement of SVR12, suggesting that on‐treatment virologic monitoring may not be necessary with this regimen.     

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.     

Sustained virological response to ombitasvir/paritaprevir/ritonavir and dasabuvir treatment for hepatitis C: Real‐world data from a large healthcare provider

Treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin (OPrD ± RBV), was the first interferon‐free direct‐acting antiviral for hepatitis C virus (HCV) introduced to Israel's national basket of health services in February 2015. Patients with HCV genotype 1 (GT1) and advanced fibrosis (F3‐F4) were eligible for treatment in 2015. This study aimed to characterize patients initiating OPrD ± RBV and assess sustained virological response (SVR). A retrospective cohort study was performed using the database of Maccabi Healthcare Services (MHS), a 2‐million‐member health plan in Israel. The study population included adults who initiated OPrD ± RBV through December 2015 per health basket criteria. A gap in medication fills (>14 days between a fill's run‐out and the next fill) was used to estimate adherence. SVR was defined by the viral tests at least 12‐week post‐treatment. The study population consisted of 403 patients (56.3% male), with a mean age of 60.7 years (SD 11.0). Overall, 71.0% were naïve to prior HCV treatment, and 95.6% were treated with a 12‐week regimen. A total of 348 patients (86.4%) completed the regimen in the usual time frame (highly adherent), whereas 8.2% completed with a gap, and 4.7% purchased less than the recommended dose. SVR rates overall and among highly adherent patients were 395/403 (98.0%; 95% CI 96.1‐99.1) and 346/348 (99.4%; 95% CI 97.9‐99.9), respectively. GT1b patients on 12‐week regimens attained SVR rates of 194/196 (fibrosis F3) and 170/176 (cirrhosis). After a first year of provision of OPrD ± RBV with good adherence, high SVR rates were achieved in various patient subgroups and comorbidities.     

Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotypes 1 and 4 hepatitis C virus (HCV) infection in patients with severe renal impairment: A multicentre experience

Limited data are available on direct‐acting antivirals for treating hepatitis C virus (HCV) infection in patients with severe renal impairment. The aim of this study was to evaluate the effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) ± dasabuvir (DSV) ± ribavirin (RBV) in patients with stage 4 or 5 chronic kidney disease (CKD) and HCV genotype 1 or 4 infection in real clinical practice, and to investigate pharmacological interactions. This retrospective study included patients treated with OBV/PTV/r+DSV±RBV or OBV/PTV/r+RBV with CKD stage 4 (eGFR: 15‐29 mL/min/1.73m²) or 5 (eGFR<15 mL/min/1.73m² or requiring dialysis) and HCV infection by genotypes 1 and 4 between April 2015 and October 2015 in nine Spanish centres. Sustained virological response at 12 weeks (SVR12) was assessed, and clinical and laboratory data, fibrosis stage, adverse events and pharmacological interactions were reported. Forty‐six patients were included: 10 (21.7%) had CKD stage 4 and 36 (78.2%) CKD stage 5. Seventeen (36.9%) had cirrhosis. SVR12 rate in the intention‐to‐treat population was 95.7%. Twenty‐one (45.6%) received RBV, which was discontinued in two (9.5%) patients. Anaemia (haemoglobin <10 g/dl) occurred in 12 patients (57.1%) with RBV vs 10 (40.0%) without RBV (P=.246). Renal function remained stable during antiviral therapy. Nine patients (19.5%) experienced serious adverse events unrelated to antiviral therapy. Concomitant medication was discontinued or modified in 41.3% of patients. In conclusion, the effectiveness of OBV/PTV/r±DSV±RBV in patients with CKD 4‐5 was similar to that observed in those with normal renal function and was not associated with severe adverse events.     

Efficacy and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir with low‐dose ribavirin in patients with chronic hepatitis C virus genotype 1a infection without cirrhosis

Patients infected with hepatitis C virus (HCV) treated with interferon‐free direct‐acting antivirals may still require ribavirin. However, ribavirin is associated with adverse events that can limit its use. This open‐label, multicentre, Phase 3 study evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir + dasabuvir (OBV/PTV/r + DSV) with low‐dose ribavirin for 12 weeks in genotype 1a‐infected patients without cirrhosis. The primary efficacy endpoint was sustained virologic response at post‐treatment Week 12 (SVR12). The primary safety endpoint was haemoglobin <10 g/dL during treatment and decreased from baseline. Overall, 105 patients enrolled. The SVR12 rate was 89.5% (n/N = 94/105; 95% CI, 83.7‐95.4). The study did not achieve noninferiority versus the historic SVR12 rate for OBV/PTV/r + DSV plus weight‐based ribavirin. Five patients experienced virologic failure, four discontinued, and two had missing SVR12 data. Excluding nonvirologic failures, the SVR12 rate was 94.9% (n/N = 94/99). One patient met the primary safety endpoint. OBV/PTV/r + DSV plus low‐dose ribavirin offers an alternative option for patients in whom full‐dose ribavirin may compromise tolerability, although noninferiority to the weight‐based ribavirin regimen was not met.