Direct‐acting antivirals (DAAs) have transformed traditional treatment options for hepatitis C virus (HCV) infection. DAA combinations have been shown to be highly effective in reducing the burden of ...chronic HCV infection in clinical trials and have been recommended by the European Association for the Study of the Liver (EASL) treatment guidelines. This review examines the results of second‐generation DAA combinations in real‐life clinical practice in patients with genotypes 1‐3 and in those co‐infected with HIV (real‐world data in genotypes 4‐6 are rare). Second generation DAAs (sofosbuvir plus daclatasvir, sofosbuvir/ledipasvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir, sofosbuvir plus velpatasvir, glecaprevir plus pibrentasvir, grazoprevir plus elbasvir) have very high SVR rates and good safety profiles, higher resistance barriers and are more convenient. Real‐world data in all 3 genotypes generally support the EASL guidelines and high overall sustained virological response rates are reported with recommended regimens. However, real‐world data are only available for sofosbuvir plus daclatasvir, sofosbuvir/ledipasvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir. Furthermore, because of the existing level of evidence, it is difficult to define optimal regimens based on real‐world data (ie, treatment duration, when to include ribavirin and options for patients with cirrhosis). The real‐life challenges of managing HIV‐coinfected patients are also discussed showing the additional burden of avoiding drug–drug interactions between DAAs and antiretrovirals.
In clinical trials, treatment with a combination of the nucleotide polymerase inhibitor sofosbuvir and the antiviral drug ribavirin was associated with high response rates among patients with ...hepatitis C virus (HCV) genotype 2 infection, with lower response rates among patients with HCV genotype 3 infection.
We conducted a study involving patients with HCV genotype 2 or 3 infection, some of whom had undergone previous treatment with an interferon-based regimen. We randomly assigned 91 patients with HCV genotype 2 infection and 328 with HCV genotype 3 infection, in a 4:1 ratio, to receive sofosbuvir-ribavirin or placebo for 12 weeks. On the basis of emerging data from phase 3 trials indicating that patients with HCV genotype 3 infection had higher response rates when they were treated for 16 weeks, as compared with 12 weeks, the study was unblinded, treatment for all patients with genotype 3 infection was extended to 24 weeks, the placebo group was terminated, and the goals of the study were redefined to be descriptive and not include hypothesis testing. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.
Of the 419 patients who were enrolled and treated, 21% had cirrhosis and 58% had received previous interferon-based treatment. The criterion for a sustained virologic response was met in 68 of 73 patients (93%; 95% confidence interval CI, 85 to 98) with HCV genotype 2 infection who were treated for 12 weeks and in 213 of 250 patients (85%; 95% CI, 80 to 89) with HCV genotype 3 infection who were treated for 24 weeks. Among patients with HCV genotype 3 infection, response rates were 91% and 68% among those without and those with cirrhosis, respectively. The most common adverse events were headache, fatigue, and pruritus.
Therapy with sofosbuvir-ribavirin for 12 weeks in patients with HCV genotype 2 infection and for 24 weeks in patients with HCV genotype 3 infection resulted in high rates of sustained virologic response. (Funded by Gilead Sciences; VALENCE ClinicalTrials.gov number, NCT01682720.).
Summary Current all-oral interferon-free regimens offer sustained virological response (SVR) rates above 90% as well as 12-week treatment durations for the majority of patients with chronic hepatitis ...C virus (HCV), including treatment-naïve and -experienced patients with or without cirrhosis. There are multiple direct-acting antiviral (DAA) combinations that can be selected to optimize efficacy and safety outcomes. Each of them can be tailored according to different parameters including the use of ribarivin (RBV). For sofosbuvir (SOF)-based combinations, RBV is useful in the following situations: HCV genotype 1, treatment-experienced, cirrhotic patients, or patients with decompensated cirrhosis, and HCV genotype 3, cirrhotic patients. In these situations the addition of RBV allows to shorten the treatment to 12 weeks in the majority of cases and therefore decreases the cost of the treatment. The need of RBV remains to be determined in cirrhotic patients with a SOF plus simeprevir regimen. RBV-containing regimens are recommended in all HCV genotype 1a patients who receive the 3-DAA combination: paritaprevir/r, ombitasvir, dasabuvir. Globally, the addition of RBV to the different combinations of DAA increases slightly the risk of anaemia. However severe anaemia was rare and easily manageable with RBV dose reduction without any impact on SVR. In practice, because RBV is cheap and well tolerated when combined with interferon-free regimen, it remains a useful tool to fine tune anti-HCV treatment regimens and optimize their results.
Summary Background Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor ...tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. Methods In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18–70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10 000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12 ). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT01685203. Findings Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 95% CI 91·6–100) in the ribavirin-containing regimen and 90·9% (40/44 95% CI 78·3–97·5) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference −9·16% 95% CI −19·61 to 1·29; p=0·086). All treatment-experienced patients achieved SVR12 (49/49; 100% 95% CI 92·7–100). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 29% of 49 treatment-experienced patients and 14 33% of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia. Interpretation An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection. Funding AbbVie.
Background. With the advent of highly efficient antiviral therapies for hepatitis C virus (HCV) infection, providing broad access to diagnosis and care is needed. The dried blood spot (DBS) technique ...can be used to collect, store, and ship whole-blood specimens. Our goal was to assess the performance of standardized HCV diagnostic and monitoring tools in the analysis of DBS. Methods. Serum specimens and whole-blood specimens collected using the DBS technique from >500 patients were tested for virological markers used to diagnose and monitor HCV infection. Results. Enzyme immunoassay detection of anti-HCV antibodies in specimens from DBS was reliable after establishment of a new signal-to-cutoff ratio. HCV RNA was detected DBS from the vast majority of patients with active replication, but HCV RNA levels were substantially lower than in serum specimens, implying that only the presence or absence of HCV RNA or changes in the HCV RNA level should be taken into consideration for therapy. Detection of HCV core antigen in specimens from DBS was not a sensitive marker of chronic HCV infection. HCV genotype determination was possible in the vast majority of DBS. Conclusions. This study shows that whole-blood specimens collected using the DBS technique can be confidently used to diagnose and monitor HCV infection. DBS could help improve access to care for HCV infection because they are suitable for use in large-scale screening programs, diagnosis, and therapeutic monitoring.
Hepatitis C virus (HCV) genotype 4 is highly heterogeneous. HCV subtype 4r has been suggested to be less responsive to direct‐acting antiviral (DAA) drug treatment than other genotype 4 subtypes. ...Among 537 DAA‐treated patients who experienced a virological failure (VF) in France between 2015 and 2018, 121 (22.5%) were infected with genotype 4 and 27 of them (22.3%) with subtype 4r; subtype 4r was thus over‐represented as compared to its prevalence in the French general population. Population sequencing of the nonstructural protein (NS) 3, NS5A, and NS5B genes was performed in all subtype 4r patients at treatment failure and in 6 at baseline, whereas full‐length HCV genome sequencing was performed in two baseline and three treatment failure samples by means of an original shotgun metagenomics method based on deep sequencing. At treatment failure, all subtype 4r patients harbored two to three dominant NS5A resistance‐associated substitutions (RASs), including at least L28A/C/I/M/V and L30R. Among 13 patients exposed to sofosbuvir and an NS5A inhibitor (daclatasvir, ledipasvir, or velpatasvir), 5 (38.5%) also harbored NS5B S282C/T RASs at treatment failure. An additional patient harbored S282C/T RASs at treatment failure by deep sequencing. Prevalence of S282C/T RASs at treatment failure was significantly higher in patients infected with genotype 4r than with other genotypes, including other subtypes of genotype 4. Conclusion: The lower rates of sustained virological response in patients infected with subtype 4r are related to the frequent preexistence at treatment baseline and subsequent selection by DAA treatment of both NS5A and NS5B S282 RASs. Our study suggests that these patients should be identified and receive a triple DAA combination regimen as first‐line treatment.
A simple treatment regimen that is effective in a broad range of patients who are chronically infected with the hepatitis C virus (HCV) remains an unmet medical need.
We conducted a phase 3, ...double-blind, placebo-controlled study involving untreated and previously treated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis. Patients with HCV genotype 1, 2, 4, or 6 were randomly assigned in a 5:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir in a once-daily, fixed-dose combination tablet or matching placebo for 12 weeks. Because of the low prevalence of genotype 5 in the study regions, patients with genotype 5 did not undergo randomization but were assigned to the sofosbuvir-velpatasvir group. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.
Of the 624 patients who received treatment with sofosbuvir-velpatasvir, 34% had HCV genotype 1a, 19% genotype 1b, 17% genotype 2, 19% genotype 4, 6% genotype 5, and 7% genotype 6. A total of 8% of patients were black, 19% had cirrhosis, and 32% had been previously treated for HCV. The rate of sustained virologic response among patients receiving sofosbuvir-velpatasvir was 99% (95% confidence interval, 98 to >99). Two patients receiving sofosbuvir-velpatasvir, both with HCV genotype 1, had a virologic relapse. None of the 116 patients receiving placebo had a sustained virologic response. Serious adverse events were reported in 15 patients (2%) in the sofosbuvir-velpatasvir group and none in the placebo group.
Once-daily sofosbuvir-velpatasvir for 12 weeks provided high rates of sustained virologic response among both previously treated and untreated patients infected with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT02201940.).
In small-size and short-term studies of hepatitis C virus-associated cryoglobulinemia vasculitis (HCV-CryoVas), patients had a higher rate of response and tolerance to direct-acting antiviral (DAA) ...agents than interferon-containing regimens. We collected follow-up data from a clinical trial to determine the long-term effectiveness and tolerance of all-oral, interferon-free DAA regimens in patients with CryoVas.
We collected follow-up data from a prospective international multicenter cohort study of 148 patients with symptomatic HCV-CryoVas (53.7% with cirrhosis and 49.3% naive to treatment with DAAs). All patients received DAA (sofosbuvir plus daclatasvir, n = 53; sofosbuvir plus ribavirin, n = 51; sofosbuvir plus ledipasvir, n = 23; or sofosbuvir plus simeprevir, n = 18), for 12 or 24 weeks, from 2014 through 2017; the median follow-up time was 15.3 months. A complete clinical response was defined as improvement of all organs involved at baseline and the absence of clinical relapse; a partial response was defined as improvement in some but not all organs involved at baseline. The primary end point was clinical response of CryoVas symptoms at week 12 after stopping DAA therapy.
A complete response was reported for 106 patients (72.6%), a partial response for 33 patients (22.6%), and no response for 7 patients (4.8%). Cryoglobulins were no longer detected in blood samples from 53.1% of patients, and 97.2% of the patients had a sustained virologic response to therapy. Premature DAA withdrawal was reported for 4.1% of patients. Factors associated with no or partial response to therapy included a severe form of CryoVas (odds ratio, 0.33; 95% CI, 0.12-0.91; P = .03) and peripheral neuropathy (odds ratio, 0.31; 95% CI, 0.11-0.84; P = .02). After a median follow-up time of 15.3 months, 4 patients (2.8%) died. The CryoVas manifestation of purpura was cleared from 97.2% of patients, renal involvement from 91.5% of patients, arthralgia from 85.7% of patients, neuropathy from 77.1% of patients, and cryoglobulinemia from 52.2%.
In a long-term follow-up analysis of data from a clinical trial, we found that more than 95% of patients with HCV-CryoVas have a full or partial response of symptoms to different DAA treatment regimens. Fewer than 5% of patients stop therapy prematurely and less than 3% die. A severe form of CryoVas and peripheral neuropathy were associated with a lack of response of HCV-CryoVas to DAA therapy.
Summary Dermatological adverse events (AEs) are an existing concern during hepatitis C virus (HCV) infection and peginterferon/ribavirin treatment. HCV infection leads to dermatological and ...muco-cutaneous manifestations including small-vessel vasculitis as part of the mixed cryoglobulinemic syndrome. Peginterferon/ribavirin treatment is associated with well-characterized dermatological AEs tending towards a uniform entity of dermatitis. New direct-acting antivirals have led to significant improvements in sustained virologic response rates, but several have led to an increase in dermatological AEs versus peginterferon/ribavirin alone. In telaprevir trials, approximately half of treated patients had rash. More than 90% of these events were Grade 1 or 2 (mild/moderate) and in the majority (92%) of cases, progression to a more severe grade did not occur. In a small number of cases (6%), rash led to telaprevir discontinuation, whereupon symptoms commonly resolved. Dermatological AEs with telaprevir-based triple therapy were generally similar to those observed with peginterferon/ribavirin (xerosis, pruritus, and eczema). A few cases were classified as severe cutaneous adverse reaction (SCAR), also referred to as serious skin reactions, a group of rare conditions that are potentially life-threatening. It is therefore important to distinguish between telaprevir-related dermatitis and SCAR. The telaprevir prescribing information does not require telaprevir discontinuation for Grade 1 or 2 (mild/moderate) rash, which can be treated using emollients/moisturizers and topical corticosteroids. For Grade 3 rash, the prescribing information mandates immediate telaprevir discontinuation, with ribavirin interruption (with or without peginterferon) within 7 days of stopping telaprevir if there is no improvement, or sooner if it worsens. In case of suspicion or confirmed diagnosis of SCAR, all study medication must be discontinued.
The detection and quantification of hepatitis B virus (HBV) DNA are essential for the diagnosis and treatment of chronic HBV infection. The use of real-time PCR assays for HBV DNA quantification is ...strongly recommended. The goal of this study was to evaluate the intrinsic characteristics and clinical performance of version 2.0 (v2.0) of the Cobas AmpliPrep/Cobas TaqMan (CAP/CTM) assay, a fully automated platform for HBV DNA quantification in serum or in plasma with a claimed lower limit of detection of 20 IU/ml and a claimed upper limit of quantification of 1.7 x 10⁸ IU/ml. The specificity of the assay was 99% (95% confidence interval, 94.7 to 100%). Intra-assay and interassay coefficients of variation ranged from 0.21% to 2.67% and from 0.65% to 2.25%, respectively. The calibration of the assay was found to be satisfactory. Study of blood specimens from patients infected with HBV genotypes A to F showed good correspondence between HBV DNA levels measured by the CAP/CTM v2.0 assay, version 1.0 of the same assay, and the third-generation "branched DNA" assay. The CAP/CTM v2.0 assay quantified HBV DNA levels in serum or plasma from the same patients equally. In conclusion, the new version of the CAP/CTM assay is sensitive, specific, and reproducible. It accurately quantifies HBV DNA levels in patients chronically infected with HBV genotypes A to F. Improvements made to ensure equal quantification of HBV DNA in serum and plasma have been successful. Overall, the CAP/CTM assay, version 2.0, is well suited to monitoring clinical HBV DNA levels according to current clinical practice guidelines.
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