Response-guided Therapy Research Articles

Hellenic Association for the Study of the Liver Clinical Practice Guidelines: Autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a relatively rare acute or chronic liver disease of unknown etiology characterized by large heterogeneity. Its distribution is global, covering all ages, both sexes and all ethnic groups. The aim of the present Clinical Practice Guidelines (CPG) of the Hellenic Association for the Study of the Liver was to provide updated guidance and help to gastroenterologists, hepatologists, internists and general practitioners for AIH diagnosis and management. AIH diagnosis is based on clinicopathological characteristics: namely, polyclonal hypergammaglobulinemia, particularly of immunoglobulin G (IgG), circulating autoantibodies, interface hepatitis on liver histology, absence of viral hepatitis, and a favorable response to immunosuppression. Clinical manifestations at disease onset are variable, ranging from asymptomatic to the acute/severe form. Aminotransferase and bilirubin levels vary, while the presence of hepatitis at the histological level is a prerequisite for diagnosis. Autoantibodies are the hallmark for AIH diagnosis; therefore, the CPG describe the appropriate serological algorithm for their detection. AIH therapy should aim to achieve complete biochemical (normalization of IgG and aminotransferases) and histological remission. All patients who have active disease, even those with cirrhosis, should be treated with individualized and response-guided induction therapy using prednisolone in combination with azathioprine or mycophenolate mofetil as first-line therapy. Immunosuppression should be given for at least 3 years and for at least 2 years after the achievement of complete biochemical response, while a liver biopsy should be recommended before treatment discontinuation. Current CPG are also provided for several specific conditions and difficult-to-treat patients.

No one size fits all-Shortening duration of therapy with direct-acting antivirals for hepatitis C genotype 1 infection.

The advent of shorter duration, highly effective and well-tolerated interferon-free therapy now provides an opportunity for virtually all HCV-infected individuals to be cured. However, there continues to be a need to simplify and shorten treatment duration. Shortening therapy to 8weeks with sofosbuvir and ledipasvir can be considered in treatment patients with HCV genotype 1 infection and low baseline viral load. A number of other 8-week dual and triple therapy direct-acting antiviral (DAA) regimens are in advanced clinical development. Several small studies have further demonstrated the feasibility of 6weeks of sofosbuvir therapy in combination with an NS5A inhibitor and a protease inhibitor for HCV genotype 1. Four weeks of therapy with various combinations of the currently available DAAs appears to be suboptimal with poor response rates observed in phase 2 trials. Response-guided therapy is another promising tool that may allow for shorter therapy but require further research. Shortening therapy and retreating relapsers may be a viable cost-saving measure, but requires further cost-benefit analysis and more data on the impact of resistance on retreatment options.

Safety and effectiveness of response-guided therapy using pegylated interferon and ribavirin for chronic hepatitis C virus infection in patients on maintenance dialysis.

Treatment of hepatitis C virus (HCV) infection in patients with end-stage renal disease (ESRD) is difficult. Addition of ribavirin to pegylated-interferon (Peg-IFN) may help to improve the treatment response. Further, treatment duration could be shortened using a response-guided treatment (RGT) approach. We retrospectively reviewed records of treatment-naïve adult patients with ESRD and chronic HCV infection who had been treated with Peg-IFN and low-dose ribavirin using a RGT approach. Rapid responders (undetectable HCV-RNA at 4 weeks) received treatment for 12 weeks, and slow responders (HCV-RNA detectable at 4 weeks, but undetectable or with >2.0 log10 reduction at week 12) for 24 (genotype 3; GT3) or 48 (genotype 1; GT1) weeks. In those without such reduction (null responders), treatment was discontinued. Of 26 non-cirrhotic patients (GT1 15, GT3 11) treated, four (15%; GT1 3, GT3 1) were null responders. Twenty-two (85%) patients had either rapid (n = 14 (54%); GT1 10, GT3 4) or slow response (n = 8 (31%); GT1 2, GT3 6). Of them, 21 patients had undetectable RNA at the end of treatment; one could not complete the treatment and was lost thereafter. There were no deaths during treatment. Three patients relapsed and three others died in 6 months after stopping treatment. Overall, 15/26 (58%) patients attained SVR24. Fourteen patients underwent transplantation beginning one month after treatment completion, and all were relapse-free after 17 (14-24) months of follow-up. RGT using Peg-IFN and ribavirin was effective in ESRD patients on maintenance dialysis. Renal transplant was safely done within one month of completing such treatment.

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: 48weeks for genotype 1 or 4 (HCV-1/4) and 24weeks for HCV-2/3. Response-guided therapy recommended shorter 24- and 16-week regimens for HCV-1 with lower baseline viral loads (<400000-800000IU/mL) and rapid virological response (RVR, undetectable HCV RNA at week 4) and HCV-2/3 with RVR, respectively; and extending to 72 and 48weeks 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, 24-48weeks, 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 8-24weeks 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.

Efficacy of response-guided directly observed pegylated interferon and self-administered ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: The ACTIVATE study

BackgroundThere are few data on treatment for hepatitis C virus (HCV) infection among people with ongoing injecting drug use. This study evaluated the efficacy of response-guided therapy for chronic HCV genotypes 2/3 infection among people with ongoing injecting drug use or receiving opioid substitution therapy (OST). A secondary aim was to identify predictors of HCV treatment response. MethodsACTIVATE was a multicentre clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg-interferon alfa-2b and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Participants were recruited from drug treatment clinics, private practices, hospital clinics and community clinics in Australia, Canada, and five countries in Europe. The primary study outcome was sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment). ResultsAmong 93 people with ongoing injecting drug use or receiving OST treated for HCV genotype 2/3, 59% had recently (past month) injected drugs, 77% were receiving OST and 56% injected drugs during therapy. Overall SVR was 66% (61/93). SVR was 84% in those with undetectable HCV RNA at week 4 (12 weeks) compared to 38% in those without (24 weeks). In adjusted analysis, cirrhosis vs. no/mild fibrosis [adjusted OR (aOR) 0.33, 95% CI 0.13, 0.86] predicted reduced SVR, while response at week 4 was associated with increased SVR [aOR 8.11, 95% CI 2.73, 24.10]. Recent injecting drug use at baseline or during therapy was not associated with SVR. ConclusionThis study demonstrates that people with recent injecting drug use or OST with chronic HCV can achieve responses to interferon-based therapy similar to other populations, despite injecting drugs prior to or during therapy. Cirrhosis was predictive of reduced response to HCV therapy, while response at week 4 (despite shortened therapy) was predictive of improved response.

Adherence to response-guided pegylated interferon and ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: the ACTIVATE study

BackgroundThe aims of this analysis were to investigate treatment completion and adherence among people with ongoing injecting drug use or receiving opioid substitution therapy (OST) in a study of response-guided therapy for chronic HCV genotypes 2/3 infection.MethodsACTIVATE was a multicenter clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg-interferon alfa-2b (PEG-IFN) and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Outcomes included treatment completion, PEG-IFN adherence, ribavirin adherence, and sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment).ResultsAmong 93 people treated, 59% had recently injected drugs (past month), 77% were receiving OST and 56% injected drugs during therapy. Overall, 76% completed treatment. Mean on-treatment adherence to PEG-IFN and ribavirin were 98.2% and 94.6%. Overall, 6% of participants missed >1 dose of PEG-IFN and 31% took <95% of their prescribed ribavirin., Higher treatment completion was observed among those receiving 12 vs. 24 weeks of treatment (97% vs. 46%, P < 0.001) while the proportion of participants with 95% on-treatment ribavirin adherence was similar between groups (67% vs. 72%, P = 0.664). Receiving 12 weeks of therapy was independently associated with treatment completion. No factors were associated with 95% RBV adherence. Neither recent injecting drug use at baseline nor during therapy was associated with treatment completion or adherence to ribavirin. In adjusted analysis, treatment completion was associated with SVR (aOR 23.9, 95% CI 2.9–193.8).ConclusionsThis study demonstrated a high adherence to directly observed PEG-IFN and self-administered ribavirin among people with ongoing injecting drug use or receiving OST. These data also suggest that shortening therapy from 24 to 12 weeks can lead to improved treatment completion. Treatment completion was associated with improved response to therapy.ACTIVATE trial registration number: NCT01364090 - May 31, 2011

Simeprevir with peginterferon \u03b1-2a/ribavirin for chronic hepatitis C virus genotype 1 infection in treatment-experienced patients: an open-label, rollover study

BackgroundThis Phase 3, open-label, rollover study (NCT01323244) investigated the efficacy and safety of simeprevir plus peginterferon α-2a (PegIFNα-2a) and ribavirin (RBV) in a well-characterized population of HCV genotype 1 (GT1)-infected treatment-experienced patients.MethodsPatients who had failed PegIFNα/RBV treatment in the placebo arm of a previous Phase 2/3 simeprevir study (Phase 2/3 group, n = 125), or had been exposed to HCV direct-acting antivirals (simeprevir or other) for up to 14 days in a selected Phase 1 study (Phase 1 group, n = 16), were eligible. Phase 2/3 group patients were classified according to prior relapse, breakthrough, or non-response (null response, partial response, non-classifiable non-response) to PegIFNα/RBV. Eight patients in the Phase 1 group received short-term (≤14 days) simeprevir.Treatment comprised simeprevir 150 mg once daily (QD) plus PegIFNα-2a/RBV for 12 weeks followed by PegIFNα-2a/RBV for 12 or 36 weeks (using response-guided therapy [RGT] to determine total treatment duration in Phase 2/3 prior relapsers or breakthrough) or 36 weeks fixed (Phase 2/3 group non-responders and Phase 1 group). The primary endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12).ResultsPhase 2/3 group: SVR12 rate was 69.6% (87/125) overall; 92.7% (51/55), 60.0% (6/10), 64.3% (18/28), and 36.7% (11/30) in patients with prior relapse, viral breakthrough, partial response, or null response, respectively. SVR12 rates were similar for patients with HCV GT1a (66.0% [33/50]) and GT1b infection (72.0% [54/75]) and among HCV GT1a-infected patients with/without a baseline Q80K polymorphism (66.7% [8/12] and 65.8% [25/38], respectively). The majority of RGT-eligible patients (prior viral relapse or breakthrough) met RGT criteria (89.2% [58/65]); of these, 89.7% (52/58) achieved SVR12. Overall, 16.0% (20/125) of patients experienced on-treatment failure and 14.4% (18/125) experienced post-treatment failure (15 relapses, 3 missing data). Phase 1 group (simeprevir-naïve and -experienced patients combined): SVR12 rate was 37.5% (6/16). Safety and tolerability findings were comparable to those of the feeder studies.ConclusionsThe majority of RGT-eligible patients met criteria for shortening treatment to 24 weeks in total. Simeprevir 150 mg QD with PegIFNα-2a/RBV led to a high SVR rate among prior relapsers with HCV GT1 infection. No new safety signals were noted.Trial registrationNCT01323244. (date of registration: March 24, 2011).

Clinical utility of HCV core antigen detection and quantification in the diagnosis and management of patients with chronic hepatitis C receiving an all-oral, interferon-free regimen.

The introduction of highly potent direct-acting combination therapies for HCV have negated the role of response-guided therapy and reduced the role of treatment monitoring. However, there remains a need to identify patients who are actively infected with HCV and discriminate those who have achieved sustained virological response (SVR) from those who fail to achieve SVR. A total of 1,678 plasma samples from the 631 subjects enrolled in AbbVie's SAPPHIRE I trial (NCT01716585) were tested in a blinded fashion with Abbott HCV core antigen (cAg) assay and results were compared with Roche High-Pure system/COBAS® TaqMan HCV RNA 2.0 assay. Using 10 fmol/l as the clinical cutoff for cAg, the HCV RNA and cAg tests were in 100% agreement for true negative samples and 99.6% agreement for truly positive samples. One discordant (screening) sample was identified. This sample was target not detected by HCV RNA method but positive by anti-HCV and highly positive by ARCHITECT core antigen (7,912 fmol/l). Seventeen samples had cAg levels in the 'grey zone' >3 but <10 fmol/l at initial testing and were re-tested per package insert. All of these samples gave a result of <3 fmol/l upon retest. These results were in alignment with target not detected HCV RNA result. One sample had a cAg >3 but <10 fmol/l when tested on three consecutive occasions (5.8, 5.5 and 4.4) but had a target not detected RNA result. In this study cAg, with a 10 fmol/l cutoff, accurately identified 99.6% of patients with active viraemia and discriminated all subjects who achieved SVR from those who failed therapy.

Junior Doctors’ Knowledge about Chronic Hepatitis B Guideline: A Survey Among 30 Primary Hospitals in Sichuan Province of China

Objectives: This study aimed to assess the knowledge of junior doctors on the 2015 chronic hepatitis B (CHB) guideline recommended by Chinese society of infectious diseases and Chinese society of hepatology, Chinese medical association. Methods: Junior doctors, who were already engaged in the field of CHB, were invited to complete a questionnaire-based survey between May and June 2016. The questionnaire consisted of 28 items focusing on knowledge in the following three sections: mother-to-child transmission (MTCT) prevention, response-guided therapy (RGT) strategies, and special patients’ antiviral therapy. Results: Responses were received from 562 out of 600 participants. Among those 562 junior doctors, about 10%~30% were not familiar with the use of hepatitis B vaccine and hepatitis B immunoglobulin (HBIG), and 18.8% did not know that newborn with HBsAg-positive mother could be breastfed after giving HBIG and vaccine. About 20.6% of junior doctors did not know the possible withdrawal indications recommended by the guideline. For HBeAg-positive patients receiving low genetic barrier drugs, about 30% of junior doctors did not know that the antiviral strategies should be adjusted according to HBV DNA levels at treatment week 24. For CHB patients receiving chemotherapy, about 25% of participants did not know antiviral therapy should be started at least 1 week earlier, and about 20% did not know that adefovir dipivoxil or tenofovir disoproxil fumarate should be avoided in patients with kidney diseases or high-risk of developing kidney diseases. Conclusions: The knowledge on CHB guideline was rather unsatisfactory in junior doctors. Our finding highlights the urgent need for strengthening junior doctors to gain a greater understanding of CHB guideline.

Cost-Effectiveness Comparison Between the Response-Guided Therapies and Monotherapies of Nucleos(t)ide Analogues for Chronic Hepatitis B Patients in China.

Nucleos(t)ide analogue (NA) monotherapies are typically used as the primary treatment for chronic hepatitis B (CHB) patients, including lamivudine (LAM), telbivudine (TBV), adefovir (ADV), entecavir (ETV) and tenofovir (TDF). For high-resistance NAs (LAM, TBV, ADV), they can generate excellent clinical outcomes by using response-guided therapy; however, their pharmacoeconomic profiles remain unclear in China. We aimed to evaluate the cost effectiveness between response-guided therapies and monotherapies of NAs for Chinese hepatitis B e-antigen (HBeAg)-positive and -negative CHB patients. We constructed a Markov model to simulate CHB progression associated with 12 treatment strategies using effectiveness and cost data from the published literature. We measured the lifetime costs, quality adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). One-way sensitivity (especially to extend the range of the TDF price) and probabilistic sensitivity analyses were used to explore the uncertainties of the model. For both HBeAg-positive and -negative patients, no treatment strategy generated the lowest lifetime costs (US$31,185-US$31,338) and QALYs (7.54-7.58). ETV and TDF monotherapies were not dominated by other treatments, whereas, the ICER of ETV monotherapy was the lowest (US$6112/QALY-US$8533/QALY). For each high-resistance NA, compared with its monotherapy, the ICERs of its response-guided therapies were below the willingness-to-pay threshold of US$22,833/QALY. Additionally, TDF monotherapy was the preferred treatment when its price dropped to US$1820/year or lower. Among 12 treatment strategies evaluated, ETV monotherapy is the most cost-effective treatment for treatment-naive CHB patients in China. The response-guided therapies of high-resistance NAs are more cost-effective than their monotherapies.

Predictors for HCV treatment outcome: lower limit of quantification vs. limit of detection

Introduction. In HCV treatment, the early on-treatment virological status is used as guideline for response guided therapy (RGT) and is the key predictor for a sustained virological response (SVR). The response to treatment (RT) is determined by HCV RNA results at week 4 and 12 of treatment. Being ‘undetectable’ at these time points, is a reliable predictor for reaching a SVR. To define an ‘undetectable’ HCV RNA, the lower limit of quantification (LOQ) and not the limit of detection (LOD) is used. This leaves a gray zone between the LOQ and the LOD, which results in a ‘detectable but no quantifiable’ (DNQ) HCV RNA to be reported as ‘undetectable’. The aim of this study is to analyse the reliability of using the LOQ at key decision time points, week 4 (Rapid viral response; RVR) and week 12 ( Early viral response; EVR) to predict treatment outcome. Methods. Retrospective analysis of the response to therapy, treatment outcome and SVR of patients treated for HCV. In the period Oct 2012 – Apr 2013, HCV RNA samples were conducted at week 4, 12, end of treatment (EOT) and 24 weeks after treatment and tested with the Ampliprep/Cobas-Taqman_HCV-test-v1.0. (Limit of detection; LOD: 15 IU/ml, Lower limit of quantification; LOQ: 43 IU/ml). Results. In total, 19 patients were treated, of which 10 relapsed and 9 cleared the virus. In both treatment outcome groups, DNQ HCV RNA statuses were observed. Treatment outcome showed no relation between having a DNQ during treatment (p=0,350) or at decision time points, 4th week (p=0,167) or 12th week (p=0,474). In contrast, a on-treatment viral status &gt;LOQ and &lt;LOD showed a relation with treatment outcome at week 4 (p=0,007), but not at week 12 (p=0,474). In addition, the response to therapy (RVR or EVR) showed a relation with reaching SVR (p=0,023), which was not influenced by the on-treatment viral status; DNQ. Conclusion. Reaching an ‘undetectable’ HCV RNA result at week 4 and/or week 12, is not always a guarantee of achieving SVR. In our study, being ‘detectable but not quantifiable’ at decision time point does not give a higher incidence of relapsing. The HCV RNA being ‘detectable but not quantifiable’ does not influence the predictive value of a Rapid or Early viral response. Therefore, our study suggests that no alterations in the decision-rules for HCV guidelines have to be carried out.

Boceprevir plus pegylated interferon/ribavirin to re-treat hepatitis C virus genotype 1 in HIV–HCV co-infected patients: final results of the Spanish BOC HIV–HCV Study

Boceprevir (BOC) was one of the first oral inhibitors of hepatitis C virus (HCV) NS3 protease to be developed. This study assessed the safety and efficacy of BOC+pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in the retreatment of HIV-HCV co-infected patients with HCV genotype 1. This was a phase III prospective trial. HIV-HCV (genotype 1) co-infected patients from 16 hospitals in Spain were included. These patients received 4 weeks of PEG-IFN/RBV (lead-in), followed by response-guided therapy with PEG-IFN/RBV plus BOC (a fixed 44 weeks was indicated in the case of cirrhosis). The primary endpoint was the sustained virological response (SVR) rate at 24 weeks post-treatment. Efficacy and safety were evaluated in all patients who received at least one dose of the study drug. From June 2013 to April 2014, 102 patients were enrolled, 98 of whom received at least one treatment dose. Seventy-three percent were male, 34% were cirrhotic, 23% had IL28b CC, 65% had genotype 1a, and 41% were previous null responders. The overall SVR rate was 67%. Previous null-responders and cirrhotic patients had lower SVR rates (57% and 51%, respectively). Seventy-six patients (78%) completed the therapy scheme; the most common reasons for discontinuation were lack of response at week 12 (12 patients) and adverse events (six patients). Response-guided therapy with BOC in combination with PEG-IFN/RBV led to an overall SVR rate of 67%, but an SVR rate of only 51% in patients with cirrhosis. The therapy was generally well tolerated. Although the current standards of care do not include BOC+PEG-IFN/RBV, the authors believe that this combination can be beneficial in situations where new HCV direct antiviral agent interferon-free therapies are not available yet.

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.

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. 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. 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. 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.

Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study

To shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor-NS5B nucleotide analogue. In this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until six patients in each group (1:1:1) achieved an ultrarapid virological response (plasma HCV RNA <500 IU/mL by day 2, measured by COBAS TaqMan HCV test, version 2.0). Patients with an ultrarapid virological response received 3 weeks of therapy. Patients who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. The primary endpoint was the proportion of patients with a sustained virological response at 12 weeks (SVR12) after treatment completion, analysed in the intention-to-treat population. All patients who achieved an ultrarapid virological response were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02470858. Between April 5, 2015, and April 15, 2015, 26 eligible patients were recruited. 12 patients were assigned to sofosbuvir, ledipasvir, and asunaprevir; six to sofosbuvir, daclatasvir, and simeprevir; and eight to sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group achieved an ultrarapid virological response (18 [69%]). All patients with an ultrarapid virological response who were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (one [17%] of six patients receiving sofosbuvir, ledipasvir, and asunaprevir; one [17%] of six patients receiving sofosbuvir, daclatasvir, and simeprevir; and two [33%] of six patients receiving sofosbuvir, daclatasvir, and asunaprevir) and headache (one [17%] patient in each group). No patients experienced any serious adverse events. In this proof-of-concept study, all patients with chronic HCV without cirrhosis who achieved an ultrarapid virological response on triple direct-acting antiviral regimens by day 2 and received 3 weeks of treatment were cured, with excellent tolerability. By shortening the duration of therapy from the currently recommended 12 weeks to 3 weeks, we could drastically reduce the cost of therapy and the rate of adverse events. Further large-scale studies should be done to confirm our findings. Center for AIDS Research, National Institutes of Health, US Department of Energy, National Center for Research Resources and the Office of Research Infrastructure Programs, Cheng Si-Yuan (China-International) Hepatitis Research Foundation, and Humanity and Health Medical Group.

Very rapid virologic response and early HCV response kinetics, as quick measures to compare efficacy and guide a personalized response-guided therapy

BackgroundThis is the second and final report for our study designed to compare two generic sofosbuvir products for the degree and speed of virologic response to a dual anti-hepatitis C virus (HCV) treatment protocol. We aimed to test the applicability of the early virus response kinetics and the very rapid virologic response (vRVR) rate as quick outcome measures for accelerated comparative efficacy studies and as a foundation for a personalized response-guided therapy.MethodsFifty eligible chronic HCV patients were randomized to either one of two generic sofosbuvir products (Gratisovir or Grateziano) at a daily dose of one 400 mg tablet plus a weight-based ribavirin dose. Data were compared between the groups for early virus response kinetics and vRVR rates in relation to the rates of final sustained virologic response at week 12 posttreatment (SVR12).ResultsThe Log10 transformed virus load (Log polymerase chain reaction) curves showed fairly similar rapid decline during the first 2 weeks, with no significant difference between the groups at four analysis points throughout the study by repeated-measures factorial analysis of variance test (P=0.48). The SVR12 rates were 96% (95% confidence interval, 79.6%–99.9%) in Gratisovir group (24/25) and 95.7% (95% confidence interval, 78%–99.9%) in Grateziano group (22/23). There was no statistically significant difference found by exact test (P>0.999). There was a significant association between the vRVR and the SVR12, with 100% positive predictive value (38/38 of those who had vRVR, achieved a final SVR12) and 82.6% sensitivity (among the total 46 with SVR12, 38 were having vRVR).ConclusionWe can conclude from our study that the early HCV response kinetics and the vRVR rates could be used as sensitive quick markers for efficacy (with a very high positive predictive value for SVR12), based on our accelerated comparative efficacy research model. This might open the way for new models of accelerated equivalence efficacy studies along with the bioequivalence kinetics studies to test a generic drug against a reference. Also, the early response kinetics and the vRVR might be used as qualifiers for a personalized course of treatment. This could shorten unnecessarily long treatment courses in rapid responders and might help to avoid relapses in slow responders.

Peripheral blood toll-like receptor 4 correlates with rapid virological response to pegylated-interferon and ribavirin therapy in hepatitis C genotype 1 patients.

BackgroundToll-like receptors (TLRs) are effectors of the innate immune system that are able to recognize hepatitis C virus (HCV) and give rise to an immune response. Failure of interferon (IFN)-α-based treatment is related to host immunity. Therefore, we sought to study the clinical importance of TLRs in HCV genotype 1 patients who received pegylated IFN (PEG-IFN) plus ribavirin (RBV) therapy.MethodsWe enrolled 79 treatment-naïve patients with HCV genotype 1. Patients completed a 24- to 48-week course of response-guided therapy. Peripheral blood monocyte (PBMC) expression of mRNA for TLRs 2, 3, 4, 7, and 9 was quantified by real-time PCR before therapy. TLR mRNA expression is shown as a log ratio relative to GAPDH mRNA (log 2 -(∆Ct)).ResultsForty-five patients (57.0 %) showed a rapid virological response (RVR). Univariate analysis revealed that TLR 2, 3, 4, 7, and 9 were significantly lower in the RVR group than in the non-RVR group (P = 0.001, 0.014, < 0.001, 0.008, and 0.001, respectively). Multivariate analysis revealed that TLR 4 < −2 log (OR: 7.17, 95 % CI: 1.70–30.34, P = 0.007) was an independent predictor for RVR. In addition, levels of TLR 2, 3, 4, 7, and 9 were positively correlated with HCV viral load (P = 0.009, 0.013, < 0.001, 0.007, and 0.001, respectively).ConclusionsA low level of TLR 4 mRNA in PMBCs was correlated with RVR, which indicates that TLR4 may play a critical role in HCV recognition and activation of innate immunity. TLR expression levels were correlated with HCV viral load, indicating that TLR activation upon exposure to HCV may subsequently limit HCV replication.Electronic supplementary materialThe online version of this article (doi:10.1186/s12876-016-0492-6) contains supplementary material, which is available to authorized users.

Safety and Effectiveness of Response-Guided Therapy Using Pegylated Interferon and Ribavirin for Chronic Hepatitis C Virus Infection in Patients on Maintenance Dialysis

Safety and Effectiveness of Response-Guided Therapy Using Pegylated Interferon and Ribavirin for Chronic Hepatitis C Virus Infection in Patients on Maintenance Dialysis

Efficacy and safety of grazoprevir + ribavirin for 12 or 24 weeks in treatment-naïve patients with hepatitis C virus genotype 1 infection.

Grazoprevir (GZR) is a second-generation hepatitis C virus NS3/4A protease inhibitor. The aim of this study was to evaluate GZR plus ribavirin (RBV) in patients with HCV GT1 infection. Noncirrhotic, IL28B CC patients with HCV genotype 1 infection were randomized to GZR 100 mg once daily and RBV for 12 or 24 weeks. Patients in the 12-week arm with detectable HCV RNA at treatment week 4 (TW4) had treatment extended to 24 weeks (response-guided therapy, RGT). The primary endpoint was sustained virologic response (SVR12) at follow-up week 12 (HCV RNA <25 IU/mL) in the per-protocol (PP) population (excluding patients with important protocol deviations). Twenty-six patients were randomized and 22 were included in the PP population. SVR12 was 58.3% (7 of 12) and 90% (9 of 10) in the RGT and 24-week arms, respectively. Seven PP patients had virologic failure, including one patient in the 24-week arm who relapsed after follow-up week 12. All three breakthrough patients had wild-type (WT) virus at baseline and developed breakthrough at TW6 or TW12 with Y56H, A156T and D168A/N mutations. Of the five relapse patients, four had WT at baseline (at relapse three had WT and one had V55A and D168A), and one had S122A/T at baseline and S122T at relapse. There were no serious adverse events (AEs), discontinuations due to AEs or grade 3/4 elevations in total and/or direct bilirubin. Grazoprevir plus RBV was associated with a rapid and sustained suppression of HCV RNA. These results support further evaluation of grazoprevir-based regimens (NCT01716156; protocol P039).

Response-guided peginterferon therapy in patients with HBeAg-positive chronic hepatitis B: A randomized controlled study

Response-guided therapy has been confirmed to be an effective strategy for the treatment of chronic hepatitis C in the pegylated interferon (PegIFN) era, but no randomized trial utilizing this strategy has been conducted in chronic hepatitis B. In this open-label, multicenter, randomized trial, HBeAg positive patients were treated with PegIFN (180μg/week) for 24weeks. Early responders (HBsAg <1500IU/ml and HBV DNA <10(5)copies/ml at week 24) received PegIFN for a further 24weeks (arm A), while non-early responders were randomized to PegIFN for another 24weeks (arm B), another 72weeks (arm C) or PegIFN for another 72weeks plus adefovir for 36weeks (arm D). The primary endpoint was the change of quantitative HBsAg from baseline to the end of follow-up (EOF). For non-early responders, 96-week PegIFN monotherapy did not lead to a greater reduction of HBsAg from baseline to EOF, compared with 48-week PegIFN (-0.71 vs. -0.67log10IU/ml, P=0.407). The rate of HBeAg seroconversion with HBV DNA <2000IU/ml at EOF were similar for arms B, C and D (17.9%, 23.9% and 25.0% respectively). For patients with HBsAg <1500IU/ml or HBV DNA <10(5)copies/ml at week 24, 38.4% and 37.0% achieved HBeAg seroconversion with HBV DNA <2000IU/ml at EOF respectively. Patients with HBsAg <1500IU/ml or HBV DNA <10(5)copies/ml at week 24 would benefit from continued PegIFN treatment. Extending the duration of PegIFN with or without adding adefovir did not show superiority over 48weeks PegIFN monotherapy. Extending the duration of pegylated interferon (PegIFN) alfa-2a is not recommended in HBeAg positive patients as treatment extension beyond 48weeks did not show convincing benefit. Patients who achieved HBsAg <1500IU/ml or HBV DNA <10(5)copies/ml after 24-week PegIFNα-2a showed satisfactory outcome after the withdrawal of finite PegIFNα-2a treatment. NCT01086085.

Is response guided therapy dead? Low cure rates in patients with detectable hepatitis C virus at week 4 of treatment.

Historically, chronic hepatitis C virus (HCV) treatment was response-guided. Clinical trials with sofosbuvir indicated on-treatment virologic response was not predictive of sustained virologic response (SVR) and hence response-guided therapy (RGT) was abandoned. The purpose of this study is to examine the association between on-treatment 4-week HCV RNA and SVR in patients treated in real-world practice. The study is a retrospective analysis of consecutive patients started on treatment with a sofosbuvir-containing regimen, January 1, 2014 through August 20, 2014, for HCV genotype 1-6 infection. Patients were treated by HCV specialists at 6 centers in the Project ECHO (Extension for Community Healthcare Outcomes) HCV Collaborative or in the community by primary care clinicians mentored by HCV specialists through Project ECHO. Patients were included if they were over 18years, had evidence of chronic HCV, and were started on a sofosbuvir-containing regimen. The aspartate aminotransferase:platelet ratio index (APRI) was used to estimate fibrosis. The main outcome measures were 4-week HCV RNA and SVR. Overall SVR was 82.5%. At week 4, HCV RNA was detected in 27.4% of patients. Stepwise multivariable logistic-regression analyses identified APRI>1.0, male sex, genotype 3, and detectable on treatment 4-week HCV RNA as independent predictors of failure to achieve SVR. In a real-world setting, a significant proportion of sofosbuvir treated patients have detectable on-treatment 4-week HCV RNA. Detectable on-treatment 4-week HCV RNA is associated with virologic failure. More data are needed to formulate guidance for RGT with newly available HCV therapies.