Occurrence of late relapse of hepatitis C virus confirmed by molecular analysis after sustained virologic response to interferon–ribavirin‐based therapy

Aim

The optimal duration of follow‐up for patients who achieve sustained virologic responses (SVR) has become an important issue. Reports on long‐term follow‐up of SVR have indicated that 99% of patients maintained SVR. However, the limitations of a majority of studies include small patient numbers, short study periods, and lack of molecular analysis of hepatitis C virus (HCV) genome. The present study sought to evaluate the late relapse rate in long‐term follow‐up of patients who achieved SVR, with molecular analysis of HCV.

Methods

A total of 224 patients with chronic hepatitis C who were treated by interferon and ribavirin‐based therapy and achieved SVR were enrolled. All patients were recommended for follow‐up every 6 or 12 months.

Results

The mean follow‐up period was 6.0 years (range, 1.0–13.6 years). Cumulative 5‐ and 10‐year follow‐up rates of the patients after SVR were 87.8% and 78.8%, respectively. Cumulative 5‐ and 10‐year follow‐up rates of serum HCV RNA after SVR were 85.5% and 52.6%, respectively. Two patients had detectable serum HCV RNA at 20 and 30 months, respectively, after SVR. Phylogenetic analyses of core, non‐structural protein 3, and 5A regions of HCV strains from late relapse patients confirmed the same strain was present at baseline and late relapse.

Conclusions

Two of 224 patients developed late relapse of HCV by the original strain, which was confirmed by direct sequencing analysis. Although few patients may develop late relapse, SVR achieved with interferon and ribavirin‐based therapy is durable for prolonged periods.     

Boceprevir and telaprevir‐based triple therapy for chronic hepatitis C: virological efficacy and impact on kidney function and model for end‐stage liver disease score

Triple therapy using telaprevir or boceprevir [hepatitis C virus (HCV)‐NS3/NS4A protease inhibitors (PI)] in association with PEG‐IFN/ribavirin has recently become the new standard of care (SOC) for treatment of HCV genotype 1 patients. Our objective was to assess the efficacy and tolerance of triple therapy in routine clinical practice. A total of 186 consecutive HCV patients initiating triple therapy were enrolled in a single centre study. Clinical, biological and virological data were collected at baseline and during follow‐up as well as tolerance and side effect details. Among 186 HCV patients initiating triple therapy, 69% received telaprevir and 31% boceprevir. Sixty‐one per cent of patients had cirrhosis. The overall extended rapid virological response (eRVR) rate and sustained virological response (SVR) rate were 57.0% and 59.7%, respectively. IL28B CC phenotype was associated with increased probability of achieving eRVR and SVR, whereas previous non‐response was associated with low eRVR and SVR rates. The SVR rate increased from 30.8% in previously non‐responders to 59.1% in partial non‐responders and 75% in relapsers. SVR rate in naive patients was 62.5%. Glomerular filtration rate assessed by MDRD after 12 weeks of therapy was significantly reduced for both PI (P < 0.001). The model for end‐stage liver disease (MELD) score was significantly increased at W12 for telaprevir (P = 0.008) and at W24 for boceprevir (P = 0.027). PI‐based triple therapy leads to high rates of virological response even in previously non‐responder patients. Renal function after triple therapy is impaired as well as MELD score in all patients. Cautious clinical monitoring should focus not only on haematological and dermatological side effects but also on renal function.     

Efficacy and safety of 6 or 8 weeks of simeprevir,daclatasvir, sofosbuvir for HCV genotype 1 infection

The phase 2, open‐label ACCORDION (ClinicalTrials.gov: NCT02349048) study investigated the efficacy, safety and pharmacokinetics of a 6‐ or 8‐week regimen of simeprevir, daclatasvir and sofosbuvir in treatment‐naïve patients with chronic hepatitis C virus (HCV) genotype (GT) 1 infection and either early‐stage fibrosis or compensated cirrhosis. Patients were assigned to treatment groups according to their fibrosis stage. Early‐stage fibrosis: simeprevir 150 mg, daclatasvir 60 mg, sofosbuvir 400 mg once daily for 6 weeks; compensated cirrhosis: same regimen for 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety, tolerability and pharmacokinetics of simeprevir, daclatasvir and sofosbuvir were investigated. Sixty‐eight patients were treated (6‐week group: n = 59; 8‐week group: n = 9). SVR12 was achieved by 86.4% (51/59) of patients with early‐stage fibrosis and by 100% (9/9) of patients with cirrhosis. The main reason for not achieving SVR12 in the 6‐week group was viral relapse (11.9%; 7/59). One patient had on‐treatment failure due to an early withdrawal (lost to follow‐up due to incarceration). One patient with SVR12 in the 6‐week group had a late viral relapse at post‐treatment week 24. No clinically significant drug‐drug interactions were observed. Adverse events were reported in 63.2% of patients (43/68) and were mainly grade 1/2. None of these led to treatment discontinuation. The 3 direct‐acting antiviral regimens of simeprevir, daclatasvir and sofosbuvir were safe and well tolerated in treatment‐naïve, HCV GT1‐infected patients with early‐stage fibrosis or compensated cirrhosis.     

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.     

Hepatitis C treatment from “response‐guided” to “resource‐guided” therapy in the transition era from interferon‐containing to interferon‐free regimens

Peginterferon/ribavirin has been the standard‐of‐care for chronic hepatitis C virus (HCV) infections: 48 weeks for genotype 1 or 4 (HCV‐1/4) and 24 weeks for HCV‐2/3. Response‐guided therapy recommended shorter 24‐ and 16‐week regimens for HCV‐1 with lower baseline viral loads (< 400 000–800 000 IU/mL) and rapid virological response (RVR, undetectable HCV RNA at week 4) and HCV‐2/3 with RVR, respectively; and extending to 72 and 48 weeks for HCV‐1 slower responders and HCV‐2 non‐RVR patients, respectively, to improve the efficacy. The progress of directly acting antivirals (DAA), moving from interferon‐containing regimens in 2011 to interferon‐free regimens in 2013, has greatly improved the treatment success. Interferon‐containing regimens include boceprevir or telaprevir or simeprevir or daclatasvir plus peginterferon/ribavirin, 24–48 weeks, for HCV‐1 or 4. However, adding these DAA has no benefit for HCV‐1 with lower baseline viral loads/RVR. Instead, 12‐week sofosbuvir plus peginterferon/ribavirin attained sustained virological response rates of > 90% for HCV‐1/3–6. Interferon‐free regimens include two main categories: NS5B nucleotide inhibitor (sofosbuvir)‐based regimens and NS3/4A inhibitor/NS5A inhibitor‐based regimens (daclatasvir/asunaprevir, paritaprevir/r/ombitasvir/dasabuvir and grazoprevir/elbasvir). About 8–24 weeks interferon‐free regimens could achieve sustained virological response rates of 82–99% for corresponding HCV genotypes. Although the newly DAA interferon‐free regimens have high efficacy and safety, the huge budget impact increases the treatment barriers. The current recommendation should, therefore, base on the availability, indication, and cost‐effectiveness in the transition era of DAA. Based on the concept of “resource‐guided therapy,” peginterferon/ribavirin might be applied for easy‐to‐treat interferon‐eligible patients in resource‐constrained areas. Prioritizing patients for interferon‐free regimens according to “time‐degenerative factors” (age and fibrosis) is justified before the regimens becoming available and affordable.     

Effectiveness and safety of daclatasvir plus asunaprevir for patients with hepatitis C virus genotype 1b aged 75 years and over with or without cirrhosis

Aim

The aim of this study was to evaluate the efficacy and safety of 24‐week daclatasvir (NS5A inhibitor) plus asunaprevir (NS3/4 A protease inhibitor) treatment for elderly patients with hepatitis C virus (HCV) genotype 1b infection.

Methods

This prospective, multicenter study consisted of 321 Japanese HCV genotype 1b patients who were interferon‐ineligible/intolerant or non‐responders to interferon‐based regimens, including 103 (32.1%) aged ≥75 years and 127 (39.6%) with cirrhosis. Sustained virological response (SVR) at 24 weeks after the end of treatment and adverse effects were analyzed according to age.

Results

The overall SVR rate was 90.3%. In terms of by age, 94.5% (69/73), 88.3% (128/145), and 90.3% (93/103) of the patients aged <65, 65–74, and ≥75 years, respectively, achieved SVR. For the entire cohort, pre‐existent NS5A resistance‐associated variants and prior simeprevir failure were independently associated with treatment failure. According to the analysis of patients without these unfavorable pretreatment factors, 90.8% (89/98) aged ≥75 years achieved SVR, although this was significantly lower than for those aged <65 years (98.5%, 66/67) (P < 0.05). The frequency of adverse effects was comparable for the <75 and ≥75 age groups, the most common being an elevated alanine aminotransferase level (>150 U/L, 8.7%), however, no decompensating events were seen.

Conclusions

Daclatasvir plus asunaprevir for HCV genotype 1b was well tolerated and effective for patients without pre‐existent NS5A resistance‐associated variants or simeprevir failure, irrespective of fibrosis status. However, it was less effective for very old patients aged ≥75 years compared to those aged <65.

     

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.     

Real‐world effectiveness of sofosbuvir/velpatasvir/voxilaprevir in 573 direct‐acting antiviral experienced hepatitis C patients

Sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) provides a needed hepatitis C virus (HCV) antiviral option for direct‐acting antiviral (DAA)‐experienced patients. We evaluated the effectiveness of SOF/VEL/VOX for 12 weeks in DAA‐experienced patients with genotype 1‐4 treated in clinical practice. In this observational cohort analysis from the Veterans Affairs’ Clinical Case Registry, 573 DAA‐experienced patients initiating SOF/VEL/VOX were included: 490 genotype 1, 20 genotype 2, 51 genotype 3 and 12 genotype 4. Rates of cirrhosis were 32.7%, 30.0%, 49.0% and 58.3%; rates of prior NS5A‐experience were 100.0%, 95.0%, 90.2% and 100.0% for genotypes 1‐4, respectively. Overall SVR rates were 90.7% (429/473), 90.0% (18/20), 91.3% (42/46) and 100.0% (12/12) for genotypes 1‐4, respectively, and were 91.3% (274/300), 88.9% (16/18), 90.2% (37/41) and 100.0% (11/11) for those with prior NS5A + NS5B experience. For genotype 1, SVR rates were similar in patients with prior regimens of ledipasvir/SOF (90.6%, 298/329), elbasvir/grazoprevir (91.2%, 73/80) and ombitasvir/paritaprevir/ritonavir/dasabuvir (90.9%, 70/77). SVR rates in genotype 1, 2 and 3 patients with prior SOF/VEL experience were 78.9% (15/19), 86.7% (13/15) and 84.6% (11/13). In genotype 1‐4 patients completing 12 weeks of SOF/VEL/VOX, overall SVR rates were 95.1% (409/430), 89.5% (17/19), 93.3% (42/45) and 100% (12/12). In this diverse real‐world cohort of heavily NS5A pretreated patients, SOF/VEL/VOX SVR rates in DAA‐experienced patients were high across all genotypes. Genotype 1 patients who had prior experience with the most commonly prescribed NS5A regimens achieved similarly high SVR rates when retreated with SOF/VEL/VOX. For genotypes 1, 2 and 3, patients with prior SOF/VEL experience had lower SVR rates.     

Cost‐effectiveness analyses of anti‐hepatitis C virus treatments using quality of life scoring among patients with chronic liver disease in Hiroshima prefecture,Japan

Aim

We estimated the cost‐effectiveness of direct‐acting antiviral treatment (DAA) compared to triple therapy (simeprevir, pegylated interferon‐α [Peg‐IFN], and ribavirin [RBV]) (scenario 1), Peg‐IFN + RBV (scenario 2), and non‐antiviral therapy (scenario 3).

Methods

Cost‐effectiveness was evaluated as incremental cost‐effectiveness ratios (ICERs) using direct costs and indirect costs, which included loss of wages during the patient's lifetime due to early death caused by viral hepatitis infection. Quality of life (QOL) scores were determined by EQ‐5D‐3L questionnaire survey on 200 HCV patients in Hiroshima.

Results

The QOL scores for chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma were estimated as 0.871, 0.774, and 0.780, respectively. The follow‐up period that the ICER of scenario 1 becomes shortest (cost <¥6 million) was 25 years after treatment in men and women who started treatment at the age of 20–60. In contrast, those of scenarios 2 and 3 was 10 years after treatment in patients who started treatment at age <80 years. Based on the sensitivity analysis in scenario 1, the most significant factor affecting the value of ICER is the QOL score after sustained virologic response (SVR), followed by the SVR rate of DAA or follow‐up period.

Conclusions

Direct‐acting antiviral treatment was estimated to be cost‐effective from 10 to 25 years after treatment, depending on the SVR rate of the drugs and the age of onset of treatment. In order to increase the cost‐effectiveness of DAA treatment, measures or effort to improve the QOL score of patients after SVR are necessary.     

Safety and efficacy of faldaprevir in combination with pegylated interferon α‐2b and ribavirin in Japanese patients with genotype‐1 chronic hepatitis C virus infection

Aim

We evaluated the safety and efficacy of the hepatitis C virus (HCV) NS3/4A A protease inhibitor faldaprevir plus pegylated interferon α‐2b and ribavirin (PegIFNα‐2b/RBV) in Japanese patients with HCV genotype‐1 infection.

Methods

Treatment‐naïve patients were randomized (1:1) to faldaprevir 120 mg q.d. for 12 or 24 weeks (response‐guided therapy [RGT], n = 44), or faldaprevir 240 mg q.d. for 12 weeks (n = 43), each combined with PegIFNα‐2b/RBV for 24 or 48 weeks (RGT). Response‐guided therapy was based on early treatment success (HCV RNA <25 IU/mL at week 4 and <25 IU/mL undetected at week 8). Treatment‐experienced patients received 240 mg q.d. for 24 weeks, plus PegIFNα‐2b/RBV RGT (24 or 48 weeks, prior relapsers, n = 29) or PegIFNα‐2b/RBV (48 weeks, 5 prior partial responders/breakthroughs, 10 prior null responders). The primary objective was safety; sustained virologic response 12 weeks post‐treatment (SVR12) was a secondary end‐point.

Results

All except one patient experienced drug‐related adverse events. Adverse events led to faldaprevir discontinuation in 1 (2%), 13 (20%), and 3 (6.8%) patients on faldaprevir 120 mg, faldaprevir 240 mg 12 weeks, and faldaprevir 240 mg 24 weeks, respectively. The SVR12 rates were: 86% with faldaprevir 120 mg and 74% with faldaprevir 240 mg among treatment‐naïve patients; and 86%, 60%, and 40% among prior relapsers, partial responders/breakthroughs, and null responders, respectively.

Conclusions

In treatment‐naïve Japanese patients, faldaprevir 120 mg q.d. plus PegIFNα‐2b/RBV was better tolerated than faldaprevir 240 mg q.d. plus PegIFNα‐2b/RBV, with at least comparable efficacy. In treatment‐experienced patients, most prior relapsers achieved SVR12 with 24 weeks of faldaprevir 240 mg q.d. plus PegIFNα‐2b/RBV. Clinicaltrials.gov NCT01579474.

     

Daclatasvir/asunaprevir/beclabuvir fixed-dose combination in Japanese patients with HCV genotype 1 infection

Background

DCV-TRIO, a fixed-dose combination of daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (non-nucleoside NS5B inhibitor), has achieved high rates of sustained virologic response at post-treatment Week 12 (SVR12) in phase 3 studies.

Methods

In this phase 3 study, DCV-TRIO for 12 weeks and daclatasvir plus asunaprevir (DUAL) for 24 weeks were studied in Japanese patients infected with HCV genotype 1 (99 % genotype 1b).

Results

SVR12 rates ≥95 % were achieved in both treatment-naive (N = 152) and interferon-experienced (N = 65) cohorts treated with DCV-TRIO for 12 weeks and were comparable across patient subgroups, including patients aged ≥65 years and those with cirrhosis. DUAL recipients (N = 75) had an SVR12 rate of 87 %. In the absence of baseline resistance-associated polymorphisms at positions NS5A-Y93H or -L31, SVR12 rates were 98 % with DCV-TRIO or DUAL. Among genotype 1b-infected patients with baseline Y93H or L31 polymorphisms, 35/38 (92 %) DCV-TRIO recipients, and 7/16 (44 %) DUAL recipients achieved SVR12. Adverse events, mostly liver related, led to treatment discontinuation in 10 % of DCV-TRIO recipients. In this group, SVR12 was achieved by 3/9 patients who discontinued before Week 4 and by 12/12 patients who completed ≥4 weeks of DCV-TRIO. Treatment-related serious adverse events occurred in 4 and 3 % of DCV-TRIO and DUAL recipients, respectively. Seven patients (9 %) discontinued DUAL due to adverse events. No deaths occurred.

Conclusion

SVR12 was achieved by 96 % of Japanese patients with HCV genotype 1 infection after 12 weeks of treatment with the DCV-TRIO regimen. DCV-TRIO and DUAL exhibited comparable safety profiles.

     

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.     

Evolution of fibrosis during HCV recurrence after liver transplantation – influence of IL‐28B SNP and response to peg‐IFN and ribavirin treatment

The IL‐28 gene is associated with sustained viral response (SVR) after treatment with peg‐IFN and ribavirin in liver transplant recipients with chronic hepatitis C genotype 1 infection. We analysed the importance of recipient and donor IL‐28B genotype for response to treatment and fibrosis progression in 54 liver transplant recipients. Fibrosis stage (F) was defined as mild when F ≤ 2 and severe when F ≥ 3 in a liver biopsy or according to liver elasticity analysis. We found a significantly lower prevalence of IL‐28B SNP CC in the recipients (22%) than in the donors (67%), P < 0.0001. SVR was seen in 61% of the recipients with mild and 27% with severe fibrosis pretreatment, P = 0.01. Recipients with IL‐28 CC and non‐CC had mild fibrosis in 64% and 38% prior to treatment, P = 0.13. At follow‐up, after treatment, significantly more recipients with CC had mild fibrosis than non‐CC recipients (75% versus 32%, P = 0.0072), and all with CC and SVR had mild fibrosis. The strongest baseline factor predicting SVR was genotype. Hence, 13/19 (68%) genotype non‐1 patients reached SVR versus only 9/35 (26%) genotype 1 patients, P = 0.0022. In summary, we found that liver transplant recipients with IL‐28B CC tended to have less advanced fibrosis prior to and significantly less after SOC treatment and that all recipients with IL‐28B CC who achieved SVR had mild fibrosis at follow‐up. A significantly higher SVR rate was achieved in recipients with mild than severe fibrosis pretreatment and with genotype non‐1 than 1 infection. Our findings indicate that treatment for post‐transplant HCV recurrence should be offered before advanced fibrosis is seen in the recipient.     

Resistance‐associated substitutions in patients with chronic hepatitis C virus genotype 4 infection

Data on the prevalence of resistance‐associated substitutions (RASs) and their implications for treatment with direct‐acting antivirals (DAAs) are sparse in European patients with HCV genotype 4. This study investigated RASs before and after DAA failure in different genotype 4 subtypes and evaluated retreatment efficacies. Samples of 195 genotype 4‐infected patients were collected in the European Resistance Database and investigated for NS3, NS5A and NS5B RASs. Retreatment efficacies in DAA failure patients were analysed retrospectively. After NS5A inhibitor (NS5Ai) failure, subtype 4r was frequent (30%) compared to DAA‐naïve patients (5%) and the number of NS5A RASs was significantly higher in subtype 4r compared to 4a or 4d (median three RASs vs no or one RAS, respectively, P < .0001). RASsL28V, L30R and M31L pre‐existed in subtype 4r and were maintained after NS5Ai failure. Typical subtype 4r RASs were located in subdomain 1a of NS5A, close to membrane interaction and protein‐protein interaction sites that are responsible for multimerization and hence viral replication. Retreatment of 37 DAA failure patients was highly effective with 100% SVR in prior SOF/RBV, PI/SOF and PI/NS5Ai failures. Secondary virologic failures were rare (n = 2; subtype 4d and 4r) and only observed in prior NS5Ai/SOF failures (SVR 90%). In conclusion, subtype 4r harboured considerably more RASs compared to other subtypes. A resistance‐tailored retreatment using first‐ and second‐generation DAAs was highly effective with SVR rates ≥90% across all subtypes and first‐line treatment regimens.     

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.     

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.     

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.     

Long‐term follow‐up of patients treated with entecavir and peginterferon add‐on therapy for HBeAg‐positive chronic hepatitis B infection: ARES long‐term follow‐up

Addition of peginterferon alpha (PEG‐IFN add‐on) to entecavir (ETV) treatment after a short lead‐in phase results in more response than ETV monotherapy in HBeAg‐positive chronic hepatitis B infection (CHB). This study is the first to assess long‐term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG‐IFN add‐on in a global trial (ARES study) and completed follow‐up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG‐IFN add‐on and 48 patients treated with ETV monotherapy were included. The median follow‐up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non‐responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log₁₀ HBsAg decline in 59% vs 28% (P = 0.02) for PEG‐IFN add‐on and ETV monotherapy, respectively. In 41 initial non‐responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG‐IFN add‐on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow‐up, rates of serological response became comparable between PEG‐IFN add‐on and ETV monotherapy. Although in this LTFU study initial non‐responders were overrepresented in the add‐on arm, PEG‐IFN add‐on possibly leads rather to accelerated HBeAg loss than to increased long‐term HBeAg loss rates.     

Update on Current Evidence for Hepatitis C Therapeutic Options in HCV Mono-infected Patients

Purpose of Review

Therapies for hepatitis C (HCV) are evolving rapidly with the advent of novel direct-acting antiviral agents (DAAs). We review evidence for currently or imminently available regimens to aide clinicians in understanding current therapeutic options.

Recent Findings

A number of DAA combinations have completed clinical trials and are available for use. Current combinations are often genotype-specific, and combine HCV protease inhibitors, NS5A inhibitors and/or NS5B inhibitors to suppress HCV replication, leading to eradication. Current potential combinations for genotype 1 infection include sofosbuvir-ledipasvir, paritaprevir/ritonavir-ombitasvir-dasabuvir, sofosbuvir with daclatasvir, and grazoprevir-elbasvir. These regimens have been associated with sustained virologic response (SVR) rates of over 95 % for treatment naïve individuals after 12 weeks of therapy regardless of cirrhosis, and some sub-groups of patients may be successfully treated with just 8 weeks of sofosbuvir-ledipasvir. Regimens for genotype 2 and 3 include sofosbuvir with ribavirin, sofosbuvir with daclatasvir, or with velpatasvir, which may offer highest SVR rates when available. The development of HCV drug resistance, particularly against NS5A agents, may impact subsequent regimens. The need for baseline screening for resistant variants is unclear for most regimens, but likely would affect only a minority of patients.

Summary

All-oral curative regimens for HCV are now possible for most patients.