Interferon-free Treatment Research Articles

Rate of hepatitis C reinfection after successful direct-acting antivirals treatment among people who inject drugs in Spain: the LIVERate study

BackgroundHepatitis C virus (HCV) reinfection following successful treatment threatens the achievement of HCV elimination. The primary aim of this study is to assess reinfection rate three years after sustained virologic response (SVR) in people who inject drugs (PWID) that are on opioid agonist treatment (OAT) who underwent anti-HCV treatment with interferon-free regimens.MethodsObservational, non-interventional, prospective, descriptive study carried out in Spanish tertiary public hospitals between 2017 and 2022. Participants comprised 186 adult HCV infected individuals, 85.5% males with a mean age (Standard Deviation, SD) of 50.1 (5.9). All were enrolled in an OAT program at baseline and had attained SVR 12 weeks after therapy completion with an interferon-free treatment. Baseline data were abstracted from medical chart information collected through the routine clinical practice.ResultsThe overall rate of HCV reinfection three years after SVR12 among PWID was 1.2 new cases per 100 person-years of follow-up at a median of 15.9 months. In the subgroup analyses, those with injection drug practice and without a stable housing had higher reinfection rates.ConclusionAlthough PWID in OAT present a low rate of reinfection by HCV after successful treatment, a closer monitoring in the first year and strengthening inter-consultations with services responsible for monitoring addiction in these patients will be crucial to reduce risky behaviors avoiding HCV reinfection.

Impact of new direct-acting antiviral therapy on the prevalence and undiagnosed proportion of chronic hepatitis C infection.

Patients with chronic hepatitis C (CHC) can be cured with the new highly effective interferon-free combination treatments (DAA) that were approved in 2014. However, CHC is a largely silent disease, and many individuals are unaware of their infections until the late stages of the disease. The impact of wider access to effective treatments and improved awareness of the disease on the number of infections and the number of patients who remain undiagnosed is not known in Canada. Such evidence can guide the development of strategies and interventions to reduce the burden of CHC and meet World Health Organization's (WHO) 2030 elimination targets. The purpose of this study is to use a back-calculation framework informed by provincial population-level health administrative data to estimate the prevalence of CHC and the proportion of cases that remain undiagnosed in the three most populated provinces in Canada: British Columbia (BC), Ontario and Quebec. We have conducted a population-based retrospective analysis of health administrative data for the three provinces to generate the annual incidence of newly diagnosed CHC cases, decompensated cirrhosis (DC), hepatocellular carcinoma (HCC) and HCV treatment initiations. For each province, the data were stratified in three birth cohorts: individuals born prior to 1945, individuals born between 1945 and 1965 and individuals born after 1965. We used a back-calculation modelling approach to estimate prevalence and the undiagnosed proportion of CHC. The historical prevalence of CHC was inferred through a calibration process based on a Bayesian Markov chain Monte Carlo (MCMC) algorithm. The algorithm constructs the historical prevalence of CHC for each cohort by comparing the model-generated outcomes of the annual incidence of the CHC-related health events against the data set of observed diagnosed cases generated in the retrospective analysis. The results show a decreasing trend in both CHC prevalence and undiagnosed proportion in BC, Ontario and Quebec. In 2018, CHC prevalence was estimated to be 1.23% (95% CI: .96%-1.62%), .91% (95% CI: .82%-1.04%) and .57% (95% CI: .51%-.64%) in BC, Ontario and Quebec respectively. The CHC undiagnosed proportion was assessed to be 35.44% (95% CI: 27.07%-45.83%), 34.28% (95% CI: 26.74%-41.62%) and 46.32% (95% CI: 37.85%-52.80%) in BC, Ontario and Quebec, respectively, in 2018. Also, since the introduction of new DAA treatment in 2014, CHC prevalence decreased from 1.39% to 1.23%, .97% to .91% and .65% to .57% in BC, Ontario and Quebec respectively. Similarly, the CHC undiagnosed proportion decreased from 38.78% to 35.44%, 38.70% to 34.28% and 47.54% to 46.32% in BC, Ontario and Quebec, respectively, from 2014 to 2018. We estimated that the CHC prevalence and undiagnosed proportion have declined for all three provinces since the new DAA treatment has been approved in 2014. Yet, our findings show that a significant proportion of HCV cases remain undiagnosed across all provinces highlighting the need to increase investment in screening. Our findings provide essential evidence to guide decisions about current and future HCV strategies and help achieve the WHO goal of eliminating hepatitis C in Canada by 2030.

Pegylated interferon in the treatment of chronic delta hepatitis: the experience from real-world clinical practice

Rationale: The high prevalence of hepatitis D virus (HDV) infection in the Republic of Dagestan, significantly exceeding that in the European part of the Russian Federation, as well as the limited choice of therapeutic options, have led to the need to analyze the accumulated experience of interferon therapy in the real clinical practice to further select possible treatment regimens.
 Aim: To evaluate the efficacy of pegylated interferon alpha (Peg-IFN-) in patients with chronic hepatitis D (CHD) in real world clinical practice.
 Materials and methods: In a retrospective study, the efficacy, safety and tolerability of Peg-IFN- were analyzed in 34 patients with CHD living in the Republic of Dagestan. Main virological parameters (anti-HDV antibodies (anti-HDV), HDV RNA and HBV DNA), alanine aminotransferase levels, changes over time in liver density by elastometry, and clinical parameters (hematology and urine tests, clinical chemistry, thyroid function tests) were assessed at 24 and 48 weeks of therapy, as well as at 48 weeks after its completion.
 Results: The treatment with Peg-IFN- for 48 weeks resulted in a virological response, defined as a HDV RNA decrease by more than 2 lg copies/mL, in 32% (11/34) of the patients. A sustained virological response, defined as undetectable HDV RNA at 48 weeks after the end of therapy, was not observed in any case. Treatment with interferon was associated with a decrease in liver density by average 4.1 kPa by week 48 on therapy. Normalization of alanine aminotransferase levels after 48 weeks of treatment was observed in 59% (20/34) of the patients; however, sustained biochemical response was achieved in none of them. Serious adverse events of high or moderate severity that resulted in the discontinuation of therapy were observed in 12% (4/34) of the cases.
 Conclusion: The results obtained indicate low efficacy of Peg-IFN- in the treatment of CHD in the Dagestan patients. Further research is needed to refine optimal interferon therapy regimens, to search for predictors of treatment response, and to evaluate the impact of interferon treatment regimens on the risk of hepatic complications, clinical outcomes, and patient survival. However, the most obvious solution to the problem of CHD therapy is the development and implementation of interferon-free treatment regimens.

Hepatic Steatosis in Patients with Chronic Viral Hepatitis C Treated with Direct Acting Antivirals

Abstract Hepatic steatosis is a frequent pathological finding in patients with chronic viral C infection (HCV) and can be independently associated with increased alcohol consumption, type 2 diabetes, obesity and hyperlipidemia. All these factors can lead to the development of hepatic steatosis in patients with HCV. There are several noninvasive techniques and scores used for diagnosing and quantifying liver steatosis. Successful eradication of HCV with interferon-free treatment regimens has been suggested to improve the level of hepatic steatosis. The precise mechanisms responsible for these beneficial effects are currently under investigation, but it is thought that the decrease in hepatic inflammation and viral replication contribute to the resolution of hepatic steatosis. Moreover, the overall enhancement in liver health and metabolic factors may also have a significant impact.

Evaluation of carbohydrate and lipid metabolism dynamics in chronic HCV diabetic patients treated with direct antiviral agents

Although Hepatitis C virus (HCV) infection has become a curable disease, the aftermath of the infection remains an important aspect to be evaluated. HCV infection is well known for its extrahepatic manifestations, mostly the tight relationship between HCV, type 2 diabetes mellitus (T2DM) and dyslipidemia. Not only HCV increases the risk of T2DM, but it also affects its control in diabetic patients, increasing the risk of diabetes related complications. Furthermore, HCV hijacks the lipid metabolism resulting in abnormalities in circulating lipids which can lead to multiple complications, such as increased atherosclerotic risk and hepatic steatosis. Objectives. The aim of this study was to evaluate the dynamics of the parameters of carbohydrate and lipid metabolism in HCV-infected diabetic patients compared to non-diabetic patients after viral eradication. Material and methods. This is a prospective study conducted on 100 patients with chronic HVC infection who obtained viral clearance after interferon-free treatment. 58 patients had type 2 diabetes mellitus and 42 were non-diabetic. We evaluated serum total cholesterol, triglycerides, blood glucose and glycosylated hemoglobin in both groups at treatment initiation and 1 year after. Continuous variables were expressed as mean values ± standard deviation or median, categorical variables were represented as relative or absolute frequencies. Characteristics were compared using the Mann-Whitney method or the two-sample Student's T-test method for continuous variables, Chi-square and Fischer's test for categorical variables. A p value < 0.05 was considered statistically significant. Outcomes. The study analyzed and compared lipid and glycemic profiles of diabetic and non-diabetic HVC patients before and after viral cure. Conclusions. 1 year after treatment initiation the changes in lipid metabolism seem to persist, carbohydrate metabolism seems to remain unchanged, with no differences between diabetic and non-diabetic patients.

Reasons for not commencing direct-acting antiviral treatment despite unrestricted access for individuals with HIV and hepatitis C virus: a multinational, prospective cohort study.

Individuals with HIV and hepatitis C virus (HCV) who remain untreated with direct-acting antivirals can contribute to HCV transmission and HCV-related mortality. We aimed to compare rates of uptake of direct-acting antivirals following unrestricted access to this treatment in high-income countries and examine factors associated with remaining untreated. This multinational, prospective cohort study used data from the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC). We analysed data from nine observational cohorts participating in the InCHEHC, including data from six high-income countries (Australia, Canada, France, the Netherlands, Spain, and Switzerland). We included individuals aged 18 years and older, with HIV and HCV (ie, HCV-RNA positive without evidence of spontaneous clearance) during unrestricted access to interferon-free direct-acting antiviral treatment in each country. We calculated the cumulative proportion of participants who remained untreated with direct-acting antivirals, with follow-up starting after the date of unrestricted access or cohort inclusion, whichever occurred most recently. Factors associated with the commencement rate of direct-acting antiviral treatment were assessed using competing-risks regression with the Fine-Gray method. The date of unrestricted access to direct-acting antiviral treatment for people with HIV ranged from Nov 1, 2014, in France to Nov 1, 2017, in Switzerland. We included 4552 individuals with HIV-HCV, mainly men who have sex with men (MSM; n=2156 [47%]) and people who inject or have injected drugs (n=1453 [32%]). 1365 (30%) of 4552 participants remained untreated with direct-acting antivirals. For individuals treated with direct-acting antivirals, median time from start of follow-up to treatment was 5 months (IQR 2-12). For individuals who were not treated with direct-acting antivirals, median follow-up was 22 months (8-30). Being linked to care in Australia, France, or the Netherlands, on antiretroviral therapy, having undetectable HIV RNA, and shorter duration since first positive HCV test were independently associated with higher commencement rate of direct-acting antiviral treatment. Compared with MSM, male heterosexuals and females with unknown or other routes of HIV transmission (ie, neither injection drug use nor heterosexual transmission) had lower rates of commencement. Despite unrestricted access, almost a third of individuals with HIV-HCV remained untreated with direct-acting antivirals during follow-up, with variation in commencement rate of HCV treatment between countries and key populations. Increased efforts are required to reach the remaining individuals with HIV who are HCV-viraemic to achieve HIV-HCV micro-elimination. None.

Risk factors for loss to follow-up after the start of direct-acting antiviral treatment for hepatitis C virus infection.

Direct-acting antivirals (DAAs) have recently been developed to treat hepatitis C virus (HCV) infection. Additionally, interferon-free DAA treatment has improved liver function and reduced the risk of hepatocellular carcinoma (HCC) following HCV eradication. Previous studies on HCV have focused mainly on the treatment rate and the risk of developing HCC, and less attention has been given to loss to follow-up (LTFU) after DAA treatment. Therefore, the present study aimed to identify the definitive risk factors for LTFU after the start of DAA treatment. Between September 2017 and March 2022, 296 patients receiving glecaprevir and pibrentasvir for HCV infection were enrolled in this study. The incidence of LTFU following DAA treatment and the risk factors contributing to LTFU were identified using the patients' clinical characteristics. In the present study, 75 patients (25.3%) interrupted their follow-up visits. Multivariate logistic analysis revealed a history of injection drug use (hazard ratio [HR], 1.81; P=0.017), treatment duration (8 weeks) (HR, 3.51; P=0.0033), and age <70 years (HR, 1.9; P=0.0422) as independent factors associated with LTFU after the start of DAA treatment. Young patients and those with injection drug use are likely to discontinue their follow-up visits after the start of DAA treatment for HCV infection. Therefore, these patients require strict supervision.

Virological failures of primary interferon-free therapy in patients with chronic HCV RNA viremia and successful repeated interferon-free therapy

Objective. Description of clinical forms of chronic HCV infection in the observed patients, clarifications of options and causes of virological failures of primary interferon-free therapy (DAAT/1) and the results of repeated interferon-free treatment (DAAT/2).Materials and methods. 8 patients with chronic RNA HCV viremia (subtypes 1b+/–1a and 3а/3ab) were prospectively observed who suffered a virological failure of primary interferon-free therapy with original inhibitors in the form of relapse of RNA HCV viremia and aviremic low-level replication RNA HCV in PBMCs (peripheral mononuclears), but then achieved HCV eradication with a repeated course of interferon-free therapy.Results. Two variants of virological failures of primary interferon-free therapy were noted — relapse of RNA HCV viremia and aviremic low-level replication of RNA HCV in PBMCs. A number of unfavorable prognosis signs (individual clinical and laboratory syndromes and laboratory parameters) were revealed, which were observed in most patients who did not achieve HCV eradication using primary interferon-free therapy with antiviral drugs: HCV-associated syndromes of low-grade systemic inflammation (LGSI), benign lymphoproliferation and autoantibody production, a high level viral load of HCV RNA viral load in blood plasma, HBV-coinfection without HBsAg and cirrhosis of the liver in the outcome of chronic hepatitis C. The target result of repeated interferon-free therapy, confirmed by the sustainable virological response after 12 weeks after the end of the treatment (SVR12), was achieved in all «losers» of primary interferon-free therapy.Conclusion. The unfavorable prognostic signs identified in the majority of «losers» of primary interferon-free therapy in the form of individual clinical and laboratory syndromes and laboratory parameters may be associated with potential virological inefficiency of therapy. Based on logistic regression analysis, the value of each of the identified features for predicting different outcomes of primary interferon-free therapy in a large group of patients with HCV is shown. Pangenotypic combinations of GLE/PIB+SOF+/–RBV and VEL/SOF+RBV inhibitors have shown their high antiviral efficacy in the treatment of relapse of RNA HCV viremia and aviremic low-level replication of RNA HCV in peripheral mononuclears for all the patients for whom primary interferon-free therapy was unsuccessful.

Alcohol consumption upon direct-acting antiviral therapy for hepatitis C among persons with human immunodeficiency virus in the United States

BackgroundDirect-acting antivirals (DAA) are highly effective against hepatitis C virus (HCV) infection among persons with human immunodeficiency virus (PWH). However, alcohol use post-DAA treatment poses a continued threat to the liver. Whether the focus on liver health alone during HCV treatment can impact alcohol consumption is unclear. Therefore, we examined the change in alcohol use among HCV-coinfected PWH who received DAA therapy by non-addiction medical providers. MethodsIn our longitudinal clinical cohort study, we identified HCV-coinfected PWH who received interferon-free DAA therapy between January 2014 and June 2019 in the Centers for AIDS Research Network of Integrated Clinical Systems. The Alcohol Use Disorders Identification Test—Consumption (AUDIT-C) was the alcohol screening instrument. We used mixed-effects logistic regression models to estimate the longitudinal change in alcohol use upon DAA therapy. ResultsAmong 738 HCV-coinfected PWH, 339 (46 %) reported any alcohol use at the end of HCV treatment, including 113 (15 %) with high-risk use (i.e., AUDIT-C ≥3 for women, ≥4 for men). Concurrently, 280 (38 %) PWH noted active drug use, and 357 (48 %) were currently smoking. We observed no changes in the odds of any alcohol or high-risk alcohol use over time with DAA therapy. Findings were similar in the PWH subgroup with a history of alcohol use before DAA treatment. ConclusionsFor PWH with HCV, alcohol use did not change following interferon-free DAA treatment by non-addiction medical providers. Thus, clinicians should consider integrating targeted alcohol use interventions into HCV care to motivate reduced alcohol consumption and safeguard future liver health.

Outcomes of Interferon-free Treatment of Hepatitis C Virus Infection Seven Years after Approval and Problems with Drop out during and after Treatment: A Retrospective, Single-center Study.

Objective This retrospective, single-center study assessed the effects of interferon (IFN)-free treatment of hepatitis C virus (HCV) infection, which has been approved for seven years; calculated the incidence of hepatocellular carcinoma (HCC) after achieving a sustained virologic response (SVR); and elucidated problems with follow-up for surveillance of post-SVR HCC, particularly the impact of the coronavirus disease 2019 (COVID-19) pandemic. Methods We summarized the SVR achievement rate of 286 HCV-infected patients who received 301 IFN-free treatments and analyzed the cumulative incidence of initial HCC and the cumulative continuation rate of follow-up after SVR in the 253 patients who achieved SVR and did not have a history of HCC. Results Among 286 patients who received IFN-free treatments, 14 dropped out, and the 272 remaining patients achieved an SVR after receiving up to third-line treatment. Post-SVR HCC occurred in 18 (7.1%) of the 253 patients without a history of HCC, with a cumulative incidence at 3 and 5 years after SVR of 6.6% and 10.0%, respectively; the incidence of cirrhosis at those time points was 18.2% and 24.6%, respectively.Of the 253 patients analyzed, 58 (22.9%) discontinued follow-up after SVR. Patients who had no experience with IFN-based therapy tended to drop out after SVR. Notably, the number of dropouts per month has increased since the start of the pandemic. Conclusion Currently, IFN-free treatment is showing great efficacy. However, the incidence of HCC after SVR should continue to be monitored. In this study, the COVID-19 pandemic did not affect treatment outcomes, but it may affect surveillance for post-SVR HCC.

Results of interferon-free treatment for HCV-infected patients with decompensated cirrhosis from a Brazilian real-life cohort

Real-life data on the HCV treatment with direct-acting agents in patients with decompensated cirrhosis are scarce. Study to investigate the effectiveness and safety of sofosbuvir-containing regimens in a prospective cohort of patients with HCV decompensated cirrhosis. A total of 150 patients were enrolled (64% male, 84% genotype 1 with a mean age of 61 ± 9 years). The median MELD was 12, and 79% were Child-PughB. Most patients were treated with sofosbuvir and daclatasvir (98%) with ribavirin in 27%. The overall intention to treat SVR12 was 91% (137/150). The most frequent adverse event was anemia (17%), 73% associated with ribavirin. Twenty-one (14%) patients experienced renal dysfunction, 81% AKI I, and 1 discontinued treatment. Thirty-five (23%) patients presented at least 1 infectious episode, mainly respiratory tract infection (29%). Thirty-three patients (22%) had at least 1 episode of cirrhosis decompensation throughout treatment, particularly worsening of previous ascites in 19%. Nine patients died, and among those, 7 patients died from sepsis. The probability of decompensation in 28, 90 and 180 days was 4%, 19% and 25%. During treatment, infection (OR 2.24; 95 CI 1.09–4.61; P = .03) was a predictor of cirrhosis decompensation, and baseline MELD and CHILD ≥ B8 were both associated with infection. In decompensated cirrhosis, the overall virological response was high with mild adverse events. However, this population had a high frequency of liver-associated decompensation and infections.

Effects of Achieving Sustained Virologic Response after Direct-Acting Antiviral Agents on Long-Term Liver Fibrosis in Diabetics vs. in Non-Diabetic Patients with Chronic Hepatitis C Infection.

Because of the prevalence of HCV worldwide as well as its undiagnosed population due to a lack of screening, HCV can be considered a modern pandemic disease. In 2016, the World Health Organization (WHO) set goals for HCV’s elimination that included a 65 percent reduction in mortality and an 80 percent reduction in newly infected cases by 2030. This study is a follow-up evaluation of 80 patients who received interferon-free treatment with direct-acting agents (DAA) for chronic HCV infection between the second half of 2017 and the end of 2018. They were assessed using a FibroMax test prior to DAA administration. Two pills/day of Ombitasvir 12.5 mg/Paritaprevir 75 mg/Ritonavir 50 mg and two pills/day of Dasabuvir 250 mg were given to the patients for 8 weeks. After treatment, all 80 patients in this study achieved an SVR (sustained virologic response), and the FibroMax test was performed three years later. Our study found that successfully treating HCV infection can play a significant role in reducing fibrosis in T2DM patients. In comparison to those of ActiTest and SteatoTest, FibroMax scores showed a significantly greater reduction in T2DM patients than in treatment-naive patients.

Serum α-fetoprotein level at treatment completion is a useful predictor of hepatocellular carcinoma occurrence more than one year after hepatitis C virus eradication by direct-acting antiviral treatment.

Direct-acting antivirals (DAAs) have recently been developed to treat hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved liver function of HCV patients. The risk of hepatocellular carcinoma (HCC) occurrence following HCV eradication has been previously reported, but HCC may have been missed following imaging diagnosis before DAA administration in previous studies. Therefore, the present study aimed to identify definite predictors of HCC occurrence ≥1year after DAA treatment. Among 956 patients receiving DAAs for HCV infection, 567 patients who achieved sustained virologic response with no history of HCC treatment were enrolled in this study between September 2014 and July 2021. The incidence of HCC in HCV-infected patients ≥1year following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinical characteristics and blood test results. In the present study, 25 patients developed HCC. The incidence of HCC was 1.4%, 3.2%, 4.9% and 6.8% at 2, 3, 4 and 5years, respectively, from the end of treatment with DAAs. Multivariate logistic analysis revealed serum α-fetoprotein level at end of treatment (EOT-AFP) >3.8ng/ml ≥1year following treatment with DAAs (HR, 9.7; p<.0001) as an independent factor that may contribute to HCC occurrence following DAA treatment. In conclusion, serum EOT-AFP level may serve an important role in determining the risk of HCC occurrence ≥1year after DAA treatment. Regular examinations are required even if serum EOT-AFP level is low at treatment completion.

Long-term hepatic function of patients with compensated cirrhosis following successful direct-acting antiviral treatment for hepatitis C virus infection.

Direct-acting antivirals (DAAs) have contributed to the improvement of outcomes for all patients with chronic hepatitis C. The aim of this study was to evaluate the long-term hepatic benefits of hepatitis C virus (HCV) cure by DAAs in patients with compensated cirrhosis. This multicenter cohort study consisted of consecutive patients with compensated cirrhosis who initiated interferon-free DAA treatment before September 2016. The impact of treatment on long-term hepatic function was followed for at least 4years after the end of treatment, and the progression to decompensation was evaluated. The data of 394 patients were available for study. The median age was 70, and 41% had modified albumin-bilirubin (ALBI) grade 2b. During a short-term follow-up 1year after the end of treatment, FIB-4 index and ALBI score significantly improved. The achievement rates of FIB-4<3.25 (40%) and ALBI grade 1 (70%) reached their plateau in the first year; however, there were significant further improvements in platelet count and α-fetoprotein level after the first year. The annual incidence of decompensation was 1.30 (95% confidence interval 0.83-2.02) per 100 person-years. In multivariable analysis, male sex and modified ALBI grade 2b at baseline were associated with decompensation. In a large real-world cohort of patients with compensated cirrhosis treated with a DAA, remarkable improvement in hepatic function was seen after HCV cure, especially during the first year after the end of treatment. Treatment in the early stage of cirrhosis would be of great benefit for preventing liver deterioration to decompensation.

Weight Gain after Interferon-Free Treatment of Chronic Hepatitis C-Results from the German Hepatitis C-Registry (DHC-R).

Chronic hepatitis C can be treated very effectively with direct-acting antivirals (DAA) with only minor side effects compared to an interferon-containing treatment regimen. The significance of metabolic comorbidities after HCV cure is not well defined. This study aims to investigate short- and long-term weight change of patients receiving interferon-free antiviral treatment for chronic hepatitis C. The German Hepatitis C-registry (DHC-R) is a national multicenter real-world cohort. A total of 5111 patients were followed prospectively after DAA treatment for up to 3 years. Weight change compared to baseline was analyzed at end of treatment and at years 1, 2, and 3 after completion of antiviral therapy. Regression analysis was performed to identify baseline predictors for weight change. While there was no relevant mean weight change (−0.2 kg, SD 4.3 kg) at the end of antiviral treatment, weight started to increase during long-term follow-up reaching +1.7 kg (SD 8.0 kg, p < 0.001) compared to baseline at 3 years (follow-up year 3, FU3) after completion of antiviral therapy. 48%, 31%, and 22% of patients had a weight gain greater than 1, 3, and 5 kg at FU3, respectively. During follow-up, a body mass index (BMI) <30 proved to be the only consistent predictor for weight gain. DAA treatment is followed by a substantial weight gain (+3 kg or more) in one-third of the patients during long-term follow-up. Non-obese patients seemed to be most vulnerable to weight gain. The body compartment involved in weight gain as well as the mechanism of weight gain remain to be elucidated.

Direct-Acting Antiviral Use for Genotype 1b Hepatitis C Patients with Associated Hematological Disorders from Romania.

Background and objectives: this study assessed variations in the blood parameters of patients with hematological disorders infected with HCV throughout a 12-week interferon-free treatment regimen. Materials and methods: We followed a total of 344 patients suffering from chronic hepatitis C, infected with the 1b genotype and concomitant hematological disorders, who benefited from the direct-acting antiviral (DAA) therapy in our clinic. Seven of the most routinely checked blood parameters were analyzed, namely, hemoglobin, leucocyte count, neutrophils, erythrocyte count, platelet count, ALT, and total bilirubin level. In total, 129 patients received a treatment scheme comprising ombitasvir, paritaprevir, ritonavir, and dasabuvir, while the 215 other patients received a sofosbuvir and ledipasvir regimen. Results: Patients enrolled in the study showed remarkably increased ALT levels in the first four weeks of DAA treatment, normalizing to levels below 40 U/L by the end of regimen. There were no other blood parameters that worsened throughout the 12-week regimen to levels below our laboratory’s normal range. After 12 weeks of DAA therapy, 309 patients (90%) achieved SVR. Conclusions: Our findings are consistent in evaluating the efficacy and tolerability of direct-acting antivirals for 1b genotype HCV infected patients with associated hematological malignancies under remission, and other hematological disturbances, that were previously unsuccessfully treated with a pegylated interferon regimen. Thus, paving a pathway for government-funded programs being implemented in this direction.

Non-Invasive Indirect Markers of Liver Fibrosis after Interferon-Free Treatment for Hepatitis C.

The effectiveness of interferon-free therapy during the course of HCV infection has already been confirmed. Liver fibrosis can be assessed in several ways, from biopsies to imaging tests. The present study evaluates the usefulness of non-invasive indirect biomarkers of liver fibrosis (APRI, GAPRI, FORNS, FIB-4, the AP index and HUI score) as markers of the effective treatment of HCV with the 3D regimen. Blood samples were collected from 70 patients suffering from chronic hepatitis C. Patients received the 3D AbbVie regimen for hepatitis C. All patients had HCV genotype 1b. The APRI, GAPRI, FIB-4, FORNS, HUI and AP index (age–platelet score) values were calculated with their respective algorithms. The stage of fibrosis was evaluated on the basis of a liver biopsy and confirmed by FibroScan-based transient elastography. An undetectable level of HCV RNA after 12 weeks of treatment with the 3D regimen indicates 100% eradication of hepatitis C virus. After the treatment, non-invasive indirect markers of liver fibrosis achieved levels below the limit for significant fibrosis, Thus, non-invasive indirect biomarkers of hepatic fibrosis failed to detect the presence of significant fibrosis, which was proved in histopathological examination. However, the eradication of hepatitis C virus by means of the 3D regimen treatment does not mean that patients were completely cured.

DEVELOPMENT AND VALIDATION OF HPLC METHOD FOR QUANTIFICATION OF DACLATASVIR IN PURE AND SOLID DOSAGE FORM

Daclatasvir is a novel and highly selective NS5A replication inhibitor of HCV. It is stated to offer the potential for interferon free treatment when used in combination with another direct acting antivirals. The current project is aimed to develop and validate an easy to perform, precise, fast and accurate reverse phase HPLC method for Daclatasvir in the solid dosage form by wielding UV detector, in accordance with ICH Q2 (R1) guidelines. The process was carried out for daclatasvir, utilizing C-18 column (25 cm length, 4.6 mm internal diameter, and 5 µm particle size) in isocratic mode, with mobile phase comprising of acetonitrile and phosphate buffer (40:60 v/v). The flow rate was 1 mL/min and the detection wavelength examined out by UV detector was 304 nm. The retention time for daclatasvir was 3.0 ± 0.1 min. RSD (0.65 %), theoretical plates (1118117) and tailing factor (1) complied within acceptable certified limits. The developed method showed the linearity within a range (1 – 5 µg/mL). The accuracy of the developed method was figured out by recovery analysis and it was 99 %. The precision analysis i.e. interday (0.0.790937 %), intraday (0.364517 %) and repeatability (0.229167 %), were within the acceptance criteria. All the validation parameters were within the acceptable limits. The sample solutions of daclatasvir tablets (Dacriva, 60 mg) developed and correlated its chromatograms with working standard solution and perceived the percentage purity of daclatasvir in the tablet, found within recommended acceptable limit (90 – 110 %). It is concluded that the HPLC method is sensitive, stable, rapid and reliable. It can be deployed for the quantification of daclatasvir of standard and brands available in market in the solid dosage form in the pharmaceutical industry.

Follow-Up of Patients Who Achieved Sustained Virologic Response after Interferon-Free Treatment against Hepatitis C Virus: Focus on Older Patients.

Background and Objectives: Direct-acting antiviral agents (DAAs) have improved sustained virologic response (SVR) rates in patients with chronic hepatitis C virus (HCV) infection. Our aim was to elucidate the occurrence of hepatocellular carcinoma (HCC) and to compare the outcomes of patients aged 75 years or older (older group) with those of patients younger than 75 years (younger group) after SVR. Materials and Methods: Among 441 patients treated with interferon-free DAA combinations, a total of 409 SVR patients were analyzed. We compared the two age groups in terms of HCC incidence and mortality rates. Results: Older and younger groups consisted of 68 and 341 patients, respectively. Occurrence of HCC after SVR did not differ between the two groups of patients with a history of HCC. Occurrence of HCC after SVR was observed more in younger patients without a history of HCC (p < 0.01). Although older patients without a history of HCC had a higher mortality rate (p < 0.01), their causes of death were not associated with liver diseases. Among younger patients without a history of HCC, none died. Conclusions: After SVR, liver disease may not be a prognostic factor in older HCV patients without a history of HCC.

Effect of itraconazole on the pharmacokinetics of faldaprevir in healthy subjects.

Faldaprevir (FDV), a substrate of CYP3A/P-glycoprotein (P-gp), is a selective inhibitor of the hepatitis C virus (HCV) NS3/4 protease. FDV is currently under clinical development for application in interferon-free treatment regimens for patients with chronic HCV infection. Understanding the drug-drug interaction potential of FDV is critical, as certain drug combinations may facilitate the more rapid achievement of steady-state-that is, the ideal drug concentration and balanced metabolic cycle of absorption and elimination that optimize drug efficacy. We thus conducted this study to investigate the effect of itraconazole (ICZ), a strong inhibitor of CYP3A and a moderate inhibitor of P-gp, on the pharmacokinetics (PK) of FDV. Eighteen healthy male and female volunteers participated in this open-label, fixed-sequence study. FDV 120 mg twice daily (BID) was administered on Day 1, followed by 120 mg once daily (QD) from Day 2 until the end of the 10-day study; after 6 days of FDV alone, ICZ 200 mg was added to FDV for an additional 4 days (BID on Day 7 and QD from Day 8 to Day 10). Intensive PK sampling was performed after 6 days of FDV treatment and again after 4 days of combined FDV/ICZ treatment. The adjusted geometric mean (gMean) ratios (%) of area under the concentration curve over dosing interval at steady-state (AUCτ, ss) and maximal concentration at steady-state (Cmax, ss) for combined FDV/ICZ treatment vs. FDV treatment alone were 198.6% and 180.6%, respectively, with 90% confidence intervals (CIs) of 182.4-216.1 and 165.7-196.9. Administration of FDV alone or in combination with ICZ was observed to be safe and well-tolerated. Co-administration with ICZ, however, resulted in an approximately two-fold increase in FDV steady-state exposure. Furthermore, FDV required no dosage adjustment when co-administered with ICZ.