Combination Antiviral Therapy Research Articles

A prospective study on Foxp3+CD25highCD4+ regulatory T cells in chronic hepatitis C infected patients undergoing direct-acting antiviral combination therapy

A prospective study on Foxp3+CD25highCD4+ regulatory T cells in chronic hepatitis C infected patients undergoing direct-acting antiviral combination therapy

Management of patients with chronic hepatitis C failing repeated courses of interferon‐free direct acting antiviral combination therapy

Management of patients with chronic hepatitis C failing repeated courses of interferon‐free direct acting antiviral combination therapy

The efficacy and safety of antiviral drugs of direct action in liver recipients with recurrence of chronic hepatitis C genotype 1 after transplantation

Aim.To study the efficacy and safety of the use of paritaprevir, ritonavir, ombitasvir and dasabuvir in combination or without ribavirin in liver recipients with recurrence of HCV 1 genotype after transplantation.Materials and methods.The study included 46 patients after orthotopic liver transplantation with recurrence of HCV 1 genotype. 37 patients completed a 24-week course of antiviral therapy, including paritaprevir, ritonavir, ombitasvir and dasabuvir in combination or without ribavirin. The effectiveness of the therapy was calculated as the proportion of patients who achieved aviremia 12 weeks after the end of the course of treatment. The safety of therapy was assessed by the number of adverse events that occurred during the course of antiviral therapy.Results.A sustained virologic response at 12 weeks after the end of the course of antiviral therapy, including paritaprevir, ritonavir, ombitasvir and dasabuvir, reached 100% of the recipients of the liver. Reduction in the intensity of cytolytic and cholestatic syndromes was noted at week 4 of therapy. Adverse events were recorded in 56.7% of the subjects, mostly they were not severe and were stopped on their own. Acute cellular rejection of the transplant developed in 1 patient (2.7%). There have been no cases of irreversible liver transplant dysfunction or death of the recipient.The conclusion.The use of paritaprevir, ritonavir, ombitasvir and dasabuvir is safe and effective in the treatment of relapse of HCV infection of 1 genotype after liver transplantation.

Discovery and Development of Metal-Catalyzed Coupling Reactions in the Synthesis of Dasabuvir, an HCV-Polymerase Inhibitor.

Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three-component direct-acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed sulfonamidation of aryl nonaflate 33 was developed, promoted by electron-rich palladium complexes, including the novel phosphine ligand, VincePhos (50). This made possible a convergent, highly efficient synthesis of dasabuvir that significantly reduced the mutagenic impurity burden of the process.

Комбинированная противовирусная терапия у пациентов с тяжелым течением простого герпеса: клинико-иммунологические особенности и оценка качества жизни

Комбинированная противовирусная терапия у пациентов с тяжелым течением простого герпеса: клинико-иммунологические особенности и оценка качества жизни

Оценка пищевого статуса у детей с хроническим гепатитом С при проведении комбинированной противовирусной терапии

Оценка пищевого статуса у детей с хроническим гепатитом С при проведении комбинированной противовирусной терапии

Durable control of hepatitis C through interferon‐free antiviral combination therapy immediately prior to allogeneic haematopoietic stem cell transplantation

Chronic hepatitis C virus (HCV) infection carries increased risks for morbidity and mortality in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) but has become curable through the advent of directly acting antiviral compounds. Current guidelines of the American Society for Blood and Marrow Transplantation (ASBMT) recommend that HCV-infected HSCT candidates preferably start and complete therapy prior to transplant. However, this is often not feasible due to time constraints or treatment-limiting comorbidities, conditions and treatments. For these reasons, data on the safety of antiviral treatment, its efficacy to achieve durable eradication of the virus until full immune recovery, and late effects of former HCV infection in patients receiving HSCT are unknown. Here, we report the course of two paediatric patients with chronic HCV infection who received a full course of directly acting antivirals prior to allogeneic HSCT and achieved and maintained viral eradication throughout transplantation until complete immune recovery.

COMPLEX THERAPY OF INFECTIOUS CONJUNCTIVITIS, ACCOMPANIED BY AN ALLERGIC REACTION

Complex therapy of infectious conjunctivitis (adenovirus, herpetic, bacterial, chlamydial), complicated by toxic-allergic reaction, developing during the acute infectious process or long-term vigorous treatment, includes several treatment algorithms. The method of therapy consists in the use of systemic and local anti-allergic drugs against the background of a specific etiological antibacterial, antiviral or anti-herpetic therapy in combination with symptomatic therapy (anti-infectious, anti-inflammatory, reparative and tear replacement agents). The use of the developed algorithms of therapy can improve the effectiveness of treatment by 12-25%.

Treatment of Epstein-Barr Virus Associated Central Nervous System Diseases after Allogeneic Hematopoietic Stem Cell Transplantation with Intrathecal Donor Lymphocyte Infusion

▪Allogeneic hematopoietic stem cell transplantation(allo-HSCT) is an effective measure for the treatment of hematological disease. With the progress and widespread use of allo-HSCT, Epstein-Barr virus(EBV) related central nervous system(CNS) diseases have gotten more and more attention because of its poor prognosis and overall survival. Since currently there is no standard treatment for patients with EBV-associated CNS diseases and reported therapies are heterogeneous with mixed results, we attempted to develop a novel therapeutic method. We have applied a regimen of intrathecal donor lymphocyte infusion(IDLI) in 3 patients with EBV-associated CNS diseases after allo-HSCT in addition to immunosuppressants reduction and combined antiviral therapy. All of 3 patients were responsive to this therapy: all clinical symptoms and EBV load in CSF resolved 10, 17 and 12 days after initial IDLI respectively, and magnetic resonance imaging (MRI) showed lesions of case 1 and 2 disappeared 15 and 19 days after initial IDLI respectively. Even more appealing, there were no acute or chronic adverse reactions during the infusion and up to 23 months of follow-up. In conclusion, IDLI seems to be an effective and safe method for EBV-associated CNS diseases in allo-HSCT recipients. We recommend this treatment modality for further investigation. DisclosuresNo relevant conflicts of interest to declare.

The impact of combined postoperative antiviral therapy with adjuvant transarterial chemoembolization in hepatitis B-related hepatocellular carcinoma patients with high risks of recurrence

Objective To investigate the impact of combined postoperative transcatheter arterial chemoembolization (TACE) with antiviral therapy in hepatitis B-related hepatocellular carcinoma (HBV-HCC) patients with high risks of recurrence. Methods Fifty-three consecutive patients who underwent curative resection of HBV-HCC between January 2014 to February 2016 were enrolled. These patients were assigned to either the adjuvant antiviral therapy combined with TACE group (n=32), the treatment group or the no adjuvant treatment group (n=21, the control group). The recurrence-free survival (RFS) and overall survival (OS) were analyzed. Results There was no significant difference between the two groups in clinical characteristics (P>0.05). The recurrence-free survival (RFS) (mean±S.D.) was (20.1±1.8) months in the treatment group and (18.7±2.4) months in the control group (P=0.752). The 1-, 2- and 3-year RFS rates of the treatment group and the control group were 65.6% vs. 57.1%, 31.3% vs. 28.6% and 15.6% vs. 14.3%, respectively (P>0.05). The overall survival (OS) (mean±S.D.) was (26.8±1.7) months in the treatment group and (21.1±2.2) months in the control group (P=0.037). The 1-, 2- and 3-year RFS rates were 65.6% vs. 57.1%, 31.3% vs. 28.6% and 15.6% vs. 14.3% in the treatment group and the control group, respectively. The 1-, 2-, and 3-year OS rates were 87.5% vs. 66.7%, 59.4% vs. 38.1% and 43.8% vs. 19.0% in the treatment group and the control group, respectively. Conclusion Antiviral therapy in combination with TACE did not decrease the RFS rate, but it improved the OS rate in HCC patients with high risks of recurrence. Key words: Transcatheter arterial chemoembolization (TACE); Antiviral; Hepatocelluar carcinoma; Recurrence; Risk factor

Efficacy, Safety and Relapse of Sofosbuvir in Combination with Daclatasvir, Ledipasvir and Simeprevir for Treatment of Hepatitis C Virus in Egypt

AbstractBackground: Hepatitis C Virus infects about 185 million people equating 2.8% of worldwide population and about 500,000 people die annually from hepatitis C related liver diseases. The most common clinical presentation of the disease is the chronic hepatitis and its complications such as: Com-pensated cirrhosis, portal hypertension, decompensated cir-rhosis and Hepatocellular Carcinoma (HCC). Therapeutic management of chronic HCV patients traditionally depended on combination of peg-interferon (IFN) with ribavirin but this regimen showed many serious side effects beside its non-satisfactory efficacy. In 2013, a second generation of Direct Acting Antiviral Agents (DAAs) gave a promising efficacy and safety. Although many IFN free regimens were approved, further evaluations are needed for these regimens.Aim: To compare sofosbuvir in combination with Da-clatasvir, Ledipasvir and Simeprevir in patients with chronic hepatitis C infection according to safety, efficacy, relapse and patient outcomes.Patients and Methods: This is a prospective study con-ducted on 150 patients of chronic HCV who were admitted to the Viral Hepatitis Center in Al-Ahrar Educational Hospital in Zagazig {National Committee for the Control of Viral Hepatitis (NCCVH) during the first 9 months of 2017 and were selected according to the inclusion and exclusion criteria set by the (NCCVH). 58% of overall participants had cirrhosis and 2.7% were treatment-experienced. Patients were assigned into three groups: 50 patients received Sofosbuvir + Daclatasvir ± Ribavirin (SOF/DCV ± RBV) therapy, 50 patients received Sofosbuvir + Ledipasvir ± Ribavirin (SOF/LDV ± RBV) therapy and 50 patients received Sofosbuvir + Simeprevir ± Ribavirin (SOF/SIM±RBV) therapy. Three regimens were given for 12 weeks. Primary end point was the rate of achieving SVR12 by HCV RNA PCR, while secondary end point was the occurrence of virologic relapse.Results: The SVR rate of three groups was 98%, 100% and 100% for SOF/DCV, SOF/LDV and SOF/SIM groups respectively. Only one patient had a virological failure and he was in SOF/DCV group but these results showed no statistical significance. Virological relapse occurred in only 1 patients (.67%) of the 149 patients. The patient who showed virological failure wasn't included, while the only one patient relapsed (2%) was in SOF/SIM therapy group. Results of virological relapse were statistically not significant. RVR showed a predictive value in SVR achievement and relapse occurrence was also confirmed in our study, in SVR (p=>.05) and in relapse (p=.9). Adverse events occurred in (22%) of SOF/DCV group, (26%) of SOF/LDV group and (40%) of SOF/SIM group (p=.153), thus SOF/SIM therapy showed a higher incidence of adverse events occurrence.Conclusions: Sofosbuvir based antiviral combination therapy with (DCV, LDV and SIM) showed a highly safety, tolerability and efficacy for treatment of chronic Hepatitis C Virus.

Effectiveness and Safety of Direct-Acting Antiviral Combination Therapies for Treatment of Hepatitis C Virus in Elderly Patients: Results from the German Hepatitis C Registry.

With the aging of the hepatitis C virus (HCV)-infected patient cohort and the availability of highly effective and tolerable treatment regimens, an increasing number of elderly patients are now eligible for HCV therapy. This study investigated clinical and epidemiologic characteristics of elderly HCV-infected patients as well as the effectiveness and safety of available therapies. Patients were enrolled into the German Hepatitis C Registry (DHC-R), a prospective, multicenter, real-world cohort study. Patients were treated at the discretion of the physician, and data were collected by a web-based system. Of 7133 patients who initiated treatment, 686 (9.6%) were > 70years of age. In patients > 70years, intent-to-treat (ITT) SVR12 was 92.6% (514/555) compared to 90.7% (4521/4985) in patients ≤ 70years of age. Overall, adverse events (AEs) were reported in 374 (54.5%) and 3435 patients (53.3%) > 70 or ≤ 70years of age; 7.6% (52) and 3.6% (235) in the respective age groups had a serious AE. Twenty-two (3.2%) and 62 (1.0%) of the patients > 70 or ≤ 70years discontinued treatment due to AEs. Death was reported in 34 patients, of whom eight were > 70years of age. Frequent comorbidities in patients > 70years of age were cardiac disease, renal disease and diabetes. Psychiatric disorders, substance abuse and viral co-infection were more frequent in younger patients. Direct-acting antiviral therapies were well tolerated in patients older than 70years. SVR12 rates in the elderly patient group were similar to those observed in younger patients. Differences in the prevalence of comorbidities between age groups warrant individualized attention with respect to drug-drug interactions and therapy adherence. The study was registered in the German Clinical Trials Register, DRKS-ID: DRKS00009717.

Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle.

Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition ( Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.

Comparison between Different Lines of Antiviral Combination Therapies against Hepatitis C Virus Genotype 4 in Egyptian Patients

Background: hepatitis C virus (HCV) infection in one of worldwide chief causes chronic liver illness. The extended effect of it is highly inconstant, ranging from least histological changes to broad fibrosis and cirrhosis with possibility of hepatocellular carcinoma (HCC). The morbidity and mortality of this global infection are growing. The estimated worldwide prevalence of HCV is a by the World Health Organization (WHO) affecting >170 million people worldwide. There is a varied distribution of HCV infection with about 23 million people likely to have it in the countries of Eastern Mediterranean Region. This is nearly number of infected people in both Americas and Europe. Egypt is considered to have highest prevalence worldwide with an expected 14.7% of total population seropositive for HCV. Aim of the Work: to compare the different new lines of antiviral combination therapies against hepatitis C virus genotype 4 in Egyptian patients as regards efficacy and safety. Material and Methods: an open label, single-center, parallel-groups, randomized controlled clinical study, comparing the different lines of antiviral combination therapies against hepatitis C virus in Egyptian patients as regards efficacy reflected by the sustained virological response and safety through reporting adverse effects occur with each drug combination. This study was conducted on confirmed HCV chronically infected patients with diagnosis based on HCV-RNA PCR. The cases were collected from viral hepatitis treatment unit in Electricity hospital, one of the centers of National Committee for Control of Viral Hepatitis (NCCVH). All cases in this study were assessed and managed according to updated guidelines by NCCVH in parallel with the European Association for Study of Liver (EASL) and the American European Association for Study of Liver (AASLD). Results: this study was conducted on 1000 patients with confirmed diagnosis of chronic HCV with positive serum HCV RNA by PCR technique. The cases were collected for this study had chronic hepatitis either without cirrhosis or with compensated cirrhosis differentiated by using the FIB-4 score. They could be INF-naive or INF-experienced. The antiviral regimens used were SOF/SIM, SOF/LDV±RBV, SOF/DCV±RBV, PAR/OMB/RBV, and IFN/SOF/RBV. Out of 1737 patients who underwent initial evaluation, 531 patients were not eligible for therapy due to the presence of one or more exclusion criteria. The main causes for treatment exclusion were advanced liver decompensation, inadequately controlled diabetes and HBV co-infection. The total number of patients enrolled and eligible for antiviral treatment was 1206, 1000 of them started the treatment course, while 206 patients did not start it due to receiving treatment in other centres or died before starting the treatment. Conclusion: 1000 patients started antiviral therapy for HCV, they showed good adherence to treatment and high SVR rates compared to other recently published real-life studies. We used seven different treatment regimens, all of which proved to be efficacious and safe with no clear preference for each over others.

Preclinical assessment of antiviral combination therapy in a genetically humanized mouse model for hepatitis delta virus infection.

Chronic delta hepatitis, caused by hepatitis delta virus (HDV), is the most severe form of viral hepatitis, affecting at least 20 million hepatitis B virus (HBV)-infected patients worldwide. HDV/HBV co- or superinfections are major drivers for hepatocarcinogenesis. Antiviral treatments exist only for HBV and can only suppress but not cure infection. Development of more effective therapies has been impeded by the scarcity of suitable small-animal models. We created a transgenic (tg) mouse model for HDV expressing the functional receptor for HBV and HDV, the human sodium taurocholate cotransporting peptide NTCP. Both HBV and HDV entered hepatocytes in these mice in a glycoprotein-dependent manner, but one or more postentry blocks prevented HBV replication. In contrast, HDV persistently infected hNTCP tg mice coexpressing the HBV envelope, consistent with HDV dependency on the HBV surface antigen (HBsAg) for packaging and spread. In immunocompromised mice lacking functional B, T, and natural killer cells, viremia lasted at least 80 days but resolved within 14 days in immunocompetent animals, demonstrating that lymphocytes are critical for controlling HDV infection. Although acute HDV infection did not cause overt liver damage in this model, cell-intrinsic and cellular innate immune responses were induced. We further demonstrated that single and dual treatment with myrcludex B and lonafarnib efficiently suppressed viremia but failed to cure HDV infection at the doses tested. This small-animal model with inheritable susceptibility to HDV opens opportunities for studying viral pathogenesis and immune responses and for testing novel HDV therapeutics.

Restoration of natural killer cell activity by interferon-free direct-acting antiviral combination therapy in chronic hepatitis C patients.

Interferon-free direct-acting antiviral (DAA) therapy is an effective treatment for chronic hepatitis C (CH(C)) patients. Activity of natural killer (NK) cells was reported to be impaired in patients with hepatitis C virus infection. The aim of this study was to examine whether DAA therapy could restore NK activity in patients with CH(C). Direct-acting antiviral therapy was given to 31 CH(C) patients as asunaprevir/daclatasvir (ASV/DCV) (n = 15), ledipasvir/sofosbuvir (n = 7), ombitasvir/paritaprevir/ritonavir (n = 6), or elbasvir/grazoprevir (n = 3). Prior to therapy (0M), at the completion of the therapy (EOT), and at 24weeks after completion (AFTER), NK activity and the frequency of CD56dim NK and CD56bright NK cells in peripheral blood were estimated by Cr release assay and flow cytometry. Statistical analysis was carried out by anova and the Mann-Whitney U-test. In one of the ASV/DCV-treated patients, treatment was stopped 12weeks after initiation of therapy because of viral breakthrough. The anova showed that NK activity significantly improved at EOT (vs. 0M, P < 0.01) and at AFTER (vs. 0M, P < 0.001) in 30 patients with sustained virologic response. It also showed that the frequency of CD56dim NK cells was significantly increased at EOT and at AFTER (vs. 0M, P < 0.05). In addition, the NK activity ratio (AFTER/0M) had no significant difference between patient groups with higher and lower Fibrosis-4 scores. Direct-acting antiviral therapy in CH(C) patients could improve NK activity by increasing the frequency of CD56dim NK cells. Additionally, our results might imply that DAAs therapy could reduce the risk of hepatocarcinogenesis by restoring innate immune responses.

Ombitasvir–Paritaprevir–Ritonavir Therapy in a Kidney Transplant Recipient With Chronic Hepatitis C Virus Genotype 1 Infection: A Case Report on the Importance of Considering Drug–Drug Interactions and Monitoring Cyclosporine Levels

A 74-year-old Japanese man with a history of chronic hepatitis C and kidney transplant (KT) was administered pegylated-interferon plus ribavirin therapy. However, this therapy was ineffective. The patient was then hospitalized to receive ombitasvir (OBV) plus paritaprevir (PTV) plus ritonavir (r) antiviral combination therapy. He tested negative for the virus after 4 weeks, and completed 12 weeks of treatment. The patient ultimately achieved a sustained virological response after the 12 weeks of treatment. Cyclosporine (CyA) trough levels, during the OBV-PTV-r therapy, reached a peak within 5 days of initiating therapy, and increases in serum creatinine and total bilirubin were also observed. However, onset of irreversible nephropathy and hepatopathy were avoided by reducing the CyA dosage. The OBV-PTV-r therapy demonstrated a sufficient antiviral effect and could be safely administered postoperatively to patients having undergone KT. When a combination therapy with interferon-free, direct-acting antivirals is used in patients post-transplantation, consideration of drug-drug interactions with and monitoring CyA are of vital importance.

THE METHOD OF TREATMENT OF GENERALIZED CYTOMEGALOVIRUS INFECTION IN INFANTS

Purpose of the study. Evaluation of the effectiveness of treatment of generalized cytomegalovirus infection (CMVI) in infants with a combination of ganciclovir and VIFERON®. Materials and methods. 52 children of the first months of life were treated with generalized CMV. Patients are divided into 3 groups: the first included 25 children who received ganciclovir for 14—21 days, then — IFN-α-2b in combination with antioxidants vitamins E and C (VIFERON®); The second group consisted of 17 patients receiving only ganciclovir; in the third group included 10 children who had only symptomatic treatment of CMVI: hepatoprotectors, broad-spectrum antibiotics (ceftriaxone, ampicillins) at age dosages. Therapy was carried out under the control of viral load in the blood serum on the 14th and 21st day from the start of treatment. Patients of the 1st group with a decrease in the clinical manifestations of CMV and a decrease in the viral load to 104—103 copies/ml on the 14—21 day were prescribed rectal suppositories of IFN-α-2b (VIFERON®) 150 000 IU according to the original scheme. Results. In the 1st group, all children during 3—6 months had an elimination of the virus from the blood and liquor. Relapse of CMV was not observed. Children of the second group had a decrease in the viral load was observed, but the elimination of the virus from the blood, the cerebrospinal fluid did not occur. Patients of the 3rd group had the viral load remained at the same level, it increased by 102 copies/ml at one patient. The conclusion. Using of combined antiviral therapy with ganciclovir and IFN-α-2b in combination with antioxidants vitamins E and C (VIFERON®) promotes elimination of the virus from blood and liquor, transferring and keeping it in an inactive state, which prevents the development of complications. The proposed method for treatment of CMV can be successfully used in inpatient and outpatient settings.

Population Pharmacokinetics of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin in Hepatitis C Virus-Infected Cirrhotic and Non-cirrhotic Patients: Analyses Across Nine Phase III Studies.

The clinical development program of the direct-acting antiviral (DAA) combination therapy of paritaprevir (coadministered with ritonavir) and ombitasvir, with and without dasabuvir (3-DAA [3D] and 2-DAA [2D] regimens, respectively) used in the treatment of chronic hepatitis C infection has generated a robust dataset across various dosing regimens and patient populations. The current analysis aimed to characterize the population pharmacokinetics in patients without cirrhosis ('non-cirrhotic') and with compensated cirrhosis ('cirrhotic'), while accounting for differences across hepatitis C virus (HCV) genotypes (GT) 1, 2, and 4, multiple regimens (3D regimen±ribavirin for GT1 in global studies, 2D regimen for subgenotype 1b in Japan, 2Dregimen+ribavirin for GT2 in Japan, and 2D regimen+ribavirin for GT4), and ethnicities. Pharmacokinetic data from nine clinical studies (~1850 patients) were used to model the population pharmacokinetics of each component of the DAA regimens. Model development was performed in stages, starting with an initial base model. Covariate-parameter relationships were then assessed using forward inclusion/backward elimination procedures. Model development was guided by goodness-of-fit plots, likelihood ratio tests, plausibility of parameter estimates, and knowledge of DAA, ritonavir, and ribavirin pharmacokinetics. Paritaprevir, ombitasvir, and ritonavir pharmacokinetics were described by a one-compartment model, while dasabuvir and ribavirin pharmacokinetics were characterized by a two-compartment model. The analysis showed generally overlapping exposures between compensated cirrhotic and non-cirrhotic patients or between subgroups of the identified significant covariates. The largest differences were the approximately 30-60% higher dasabuvir and paritaprevir exposures in compensated cirrhotic patients. These differences did not warrant dose adjustments for the DAAs when used in HCV-infected patients with compensated cirrhosis.

Directly observed therapy of chronic hepatitis C with ledipasvir/sofosbuvir in people who inject drugs at risk of nonadherence to direct-acting antivirals.

An important subgroup of people who inject drugs (PWID) receiving opioid agonist therapy (OAT) cannot be treated in the setting of a hepatology centre and would not regularly ingest their medication when handed to them for self-administration. Our hypothesis was that chronic hepatitis C in these patients could be ideally managed if modern, interferon-free regimens were administered together with OAT under direct observation of a physician or nurse at a low-threshold facility. In this open-label, noninterventional, proof-of-concept study (ClinicalTrials.gov number, NCT02638233), 40 PWID at risk of nonadherence to direct-acting antivirals (DAA) and previously untreated chronic hepatitis C virus genotype 1 infection without cirrhosis were treated with ledipasvir/sofosbuvir for 8weeks. Patients received antiviral treatment together with OAT under direct observation of a physician or nurse at a low-threshold facility. By following the concept of directly observed therapy, excellent adherence to antiviral therapy was achieved as follows: only 0.16% (95% CI: 0.03-0.47) of scheduled dates for ingestion of the antiviral therapy in combination with OAT were missed by the 40 patients. The rate of sustained virological response 12weeks after end of therapy was 100% (95% CI: 91.2-100.0). Between week 12 and week 24 of follow-up reinfections were recorded in 2 of 40 patients (5%). Directly observed therapy of chronic hepatitis C is highly effective in PWID at risk of nonadherence to DAA. By this new concept, a group of difficult-to-treat patients can be cured, who could not have been treated in settings of studies published so far.