Antiviral HCV Research Articles

PS-160 - No evidence for higher risk of hepatocellular carcinoma occurrence or recurrence following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression

PS-160 - No evidence for higher risk of hepatocellular carcinoma occurrence or recurrence following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression

Viral-Associated GN: Hepatitis C and HIV.

Viruses are capable of inducing a wide spectrum of glomerular disorders that can be categorized on the basis of the duration of active viremia: acute, subacute, or chronic. The variable responses of the adaptive immune system to each time period of viral infection results mechanistically in different histologic forms of glomerular injury. The unique presence of a chronic viremic carrier state with either hepatitis C (HCV) or HIV has led to the opportunity to study in detail various pathogenic mechanisms of viral-induced glomerular injury, including direct viral infection of renal tissue and the development of circulating immune complexes composed of viral antigens that deposit along the glomerular basement membrane. Epidemiologic data show that approximately 25%-30% of all HIV patients are coinfected with HCV and 5%-10% of all HCV patients are coinfected with HIV. This situation can often lead to a challenging differential diagnosis when glomerular disease occurs in this dual-infected population and requires the clinician to be familiar with the clinical presentation, laboratory workup, and pathophysiology behind the development of renal disease for both HCV and HIV. Both of these viruses can be categorized under the new classification of infection-associated GN as opposed to being listed as causes of postinfectious GN as has previously been applied to them. Neither of these viruses lead to renal injury after a latent period of controlled and inactive viremia. The geneses of HCV- and HIV-associated glomerular diseases share a total dependence on the presence of active viral replication to sustain renal injury so the renal disease cannot be listed under "postinfectious" GN. With the new availability of direct-acting antivirals for HCV and more effective combined antiretroviral therapy for HIV, successful remission and even regression of glomerular lesions can be achieved if initiated at an early stage.

Early Experience with Direct-Acting Antivirals for HCV in Kidney Transplant Recipients Receiving HCV+ Allografts

Early Experience with Direct-Acting Antivirals for HCV in Kidney Transplant Recipients Receiving HCV+ Allografts

Risk of End-Stage Liver Disease in HIV-Viral Hepatitis Coinfected Persons in North America From the Early to Modern Antiretroviral Therapy Eras.

Human immunodeficiency virus (HIV)-infected patients coinfected with hepatitis B (HBV) and C (HCV) viruses are at increased risk of end-stage liver disease (ESLD). Whether modern antiretroviral therapy has reduced ESLD risk is unknown. Twelve clinical cohorts in the United States and Canada participating in the North American AIDS Cohort Collaboration on Research and Design validated ESLD events from 1996 to 2010. ESLD incidence rates and rate ratios according to hepatitis status adjusted for age, sex, race, cohort, time-updated CD4 cell count and HIV RNA were estimated in calendar periods corresponding to major changes in antiretroviral therapy: early (1996-2000), middle (2001-2005), and modern (2006-2010) eras. Among 34 119 HIV-infected adults followed for 129 818 person-years, 380 incident ESLD outcomes occurred. ESLD incidence (per 1000 person-years) was highest in triply infected (11.57) followed by HBV- (8.72) and HCV- (6.10) coinfected vs 1.27 in HIV-monoinfected patients. Adjusted incidence rate ratios (95% confidence intervals) comparing the modern to the early antiretroviral era were 0.95 (.61-1.47) for HCV, 0.95 (.40-2.26) for HBV, and 1.52 (.46-5.02) for triply infected patients. Use of antiretrovirals dually activity against HBV increased over time. However, in the modern era, 35% of HBV-coinfected patients were not receiving tenofovir. There was little use of HCV therapy. Despite increasing use of antiretrovirals, no clear reduction in ESLD risk was observed over 15 years. Treatment with direct-acting antivirals for HCV and wider use of tenofovir-based regimens for HBV should be prioritized for coinfected patients.

Daclatasvir plus sofosbuvir, with or without ribavirin, in real-world patients with HIV-HCV coinfection and advanced liver disease.

HIV-HCV-coinfected patients respond just as well to modern direct-acting antiviral HCV therapy as HCV-monoinfected patients. However, clinical data for all-oral HCV treatments are sparse in HIV-HCV-coinfected patients with an advanced stage of liver cirrhosis. A subanalysis of efficacy and safety for a daclatasvir (DCV) and sofosbuvir (SOF) regimen, with or without ribavirin (RBV), was undertaken in HIV-HCV-coinfected patients with advanced liver disease and no other treatment options enrolled into a European DCV compassionate use programme. Fifty five HIV-HCV (mostly genotypes 1, 3, 4) coinfected patients were treated with DCV+SOF with (n=16) or without RBV (n=39), mostly for 24 weeks. Patients were predominantly (95%) cirrhotic (50% were Child-Pugh class B or C) and were receiving a wide range of antiretrovirals; 40% were injection drug users and 25% were receiving oral opioid substitution. Sustained virological response at post-treatment week 12 (SVR12) by modified intention-to-treat analysis (n=52) was 92% overall (95% CI 81.5, 97.9), and was similar with (94% [95% CI 69.8, 99.8]) or without RBV (92% [95% CI 77.5, 98.2]). Only one patient relapsed (Child-Pugh class B). The overall SVR12 rate after excluding non-virological failures (n=49) was 98% (95% CI 89.1, 99.9). Four patients discontinued treatment for adverse events and one died during treatment (not treatment-related). No patient lost opioid maintenance or required a change of antiretrovirals due to drug-drug interactions. DCV+SOF, with or without RBV, showed high SVR12 rates and was well tolerated in this real-world cohort of HIV-HCV-coinfected patients with very advanced liver disease. ClinicalTrials.gov ID NCT02097966 (Study AI444-237).

THU-263 - In the ERA of New Direct Acting Antiviral Agents HCV Sequencing Allows the Most Accurate Subtype and Genotype Assignment

THU-263 - In the ERA of New Direct Acting Antiviral Agents HCV Sequencing Allows the Most Accurate Subtype and Genotype Assignment

SAT-200 - Influence of Proton Pump Inhibitors and H2 Receptor Antagonists on Direct Acting Antiviral HCV Sustained Virologic Response

SAT-200 - Influence of Proton Pump Inhibitors and H2 Receptor Antagonists on Direct Acting Antiviral HCV Sustained Virologic Response

Cascade of Care for Hepatitis C Virus Infection Within the US Veterans Health Administration.

We measured the quality of HCV care using a cascade of HCV care model. We estimated the number of patients diagnosed with chronic HCV, linked to HCV care, treated with HCV antivirals, and having achieved a sustained virologic response (SVR) in the electronic medical record data from the Veterans Health Administration's Corporate Data Warehouse and the HCV Clinical Case Registry in 2013. Of the estimated 233,898 patients with chronic HCV, 77% (181,168) were diagnosed, 69% (160,794) were linked to HCV care, 17% (39,388) were treated with HCV antivirals, and 7% (15,983) had achieved SVR. This Cascade of HCV Care provides a clinically relevant model to measure the quality of HCV care within a health care system and to compare HCV care across health systems.

History and progress of antiviral drugs: From acyclovir to direct-acting antiviral agents (DAAs) for Hepatitis C

The development of antiviral drugs is a very complex process. Currently, around 50 drugs have been approved for human use against viruses such as HSV, HIV-1, the cytomegalo virus, the influenza virus, HBV and HCV. Advancements in this area have been achieved through efforts and technical breakthroughs in different scientific fields. The improvement in the treatment of HCV infection is a good example of what is needed for efficient antiviral therapy. A thorough description of the events that lead to the development of specifically targeted antiviral therapy or HCV (STAT-C) could be useful to further improve research for treating many other viral diseases in the future. Similar to HIV-1 and HBV treatment, combination therapy along with personalized medicine approaches have been necessary to successfully treat HCV patients. This review is focused on what has been done to develop a successful HCV therapy and the drawbacks along the way.

The promise of treatment as prevention for hepatitis C: Meeting the needs of people who inject drugs?

Treatment as prevention (TasP) is a concept common to the HIV sector. In this commentary we draw on the literature addressing HIV and HCV TasP, alongside qualitative HCV research, to critically appraise the promise of TasP for HCV and assess the needs of PWID in the future of HCV care. With the advent of highly effective direct-acting antiviral HCV treatments, TasP is now under consideration for HCV. A growing body of literature documents numerous social structural barriers to HCV treatment access and uptake for PWID, among whom HCV is highly prevalent. Yet these barriers – and suggestions for surmounting them – are rarely included in emergent literature on HCV TasP. Although HCV TasP has important advocacy potential for increasing treatment access among PWID, critical reflection on its implications are warranted. We outline potential limitations of TasP for HCV and the conditions under which it might be optimised. We argue that HCV treatment as a prevention strategy can only be realisable in a context of enhanced harm reduction access, meaningful community engagement, and enabling environment interventions informed by the needs and perspectives of PWID.

Treatment of Hepatitis C in HIV-Infected Patients: Moving Towards an Era of All Oral Regimens.

Hepatitis C (HCV)-related liver disease has become one of the leading causes of death in HIV patients. With the development of new direct-acting antivirals for HCV, treatment regimens have become shorter, more effective, and easier to tolerate without interferon. However, cost may be a significant impediment to the widespread use of these newer agents in both resource-rich and resource-poor settings. In HIV patients, treatment for HCV is not always as straightforward compared with HCV monoinfected patients due to potential drug–drug interactions. In this article, we will examine by genotypes the FDA approved direct-acting antivirals, as well as those in clinical trials that will soon be FDA-approved focusing on data in HCV/HIV co-infection. Preferred agents for HCV treatment and potential drug–drug interactions with antiretroviral therapy (ART) will be highlighted.

Do new HCV antivirals provide good value for money?

Do new HCV antivirals provide good value for money?

G09 : Targeting a host-cell entry factor barricades antiviral resistant HCV variants from on-therapy breakthrough in human-liver mice

G09 : Targeting a host-cell entry factor barricades antiviral resistant HCV variants from on-therapy breakthrough in human-liver mice

Tu1022 Diabetes and Hyperlipidemia Compromise Practical Effectiveness of Direct Acting Antiviral HCV Therapy in Minority Populations

Rationale: Newly approved direct acting antiviral (DAA) regimens for Chronic Hepatitis C (HCV) achieve excellent response rates with unprecedented attainment of sustained virologic response (SVR12) in clinical trials. Real world effectiveness of HCV DAA therapy in special populations, particularly minority populations, is lacking. Aim: To assess SVR12 rates and identify pre treatment predictors of SVR12 in a non-Caucasian cohort.Methods: A prospective cohort study consecutively enrolled mono-infected, non-Caucasian patients undergoing DAA treatment for HCV. Enrolled subjects (N=54) were treated with one of the following: 1) pegylated interferon alfa-2a (IFN) + sofosbuvir (SOF) + ribavirin (RBV) for 12 weeks; 2) SOF + RBV for 12 or 24 weeks; and 3) SOF + simeprevir (SMV) for 12 weeks in accordance with AASLD guidelines and genotype. End of treatment response and SVR12 were defined as HCV RNA undetectable or below the lower limit of detection at regimen completion and at 12 weeks post therapy, respectively. Multivariate logistic regression was conducted to identify significant predictors of SVR12 controlling for age, gender, and BMI. Results: The majority of participants were Hispanic (64.8%) followed by Asian (18.5%) and African American (16.7%). Baseline clinical and viral demographics were recorded [Table 1] and included: 59.3% cirrhotic, 57.5% genotype 1, mean viral load 2,703,207 IU/mL and previous interferon experience: naive, 57.4%; non response 33.3%; and relapse 9.3%. DAA regimens utilized: IFN + SOF + RBV, 27.8%; SOF + RBV, 48.1%; and SOF + SMV, 24.1%. End of treatment response was 96% (52/54). SVR 12 rate was 81.5% (8 relapsers, 2 non responders to DAA therapy). Patients with pretreatment fasting glucose <=126 were 9.8 times (OR= 9.8; 95% CI=1.3-76.4) more likely to achieve SVR12 controlling for age, gender and BMI. Patients without hyperlipidemia were 6.9 times (OR=6.9; 95% CI=1.4-34.0) more likely to achieve SVR12 controlling for age, gender and BMI. Conclusions: Pre-existing diabetes and hyperlipidemia may explain the discrepancy between practical SVR12 and those reported in clinical trials. Optimization of diabetes and lipid control should be considered prior to DAA HCV therapy, particularly in minority populations with HCV.

Final and future frontiers

In hepatology, hepatocellular carcinoma (HCC), not outer space, is the final frontier (sorry, Star Trek fans, https://www.youtube.com/watch?v=S6R3MiAv9ac), given its extremely heterogeneous molecular pathogenesis, dismal prognosis and limited treatment options [1]. Treatment of this neoplasm remains a huge unmet need with no major successes imminent, in contrast to the recent transformative progress in HCV antivirals, and the heightened prospects for antifibrotic therapies. Two articles, by Perra et al.

Ubiquitin-Proteasome Pathway, Alcohol and Hepatitis C Infection (HCV)

About 70% of HCV-infected patients develop chronic hepatitis with significant progression to fibrosis, cirrhosis and hepatocellular carcinoma. Numerous attempts to create an efficient vaccine for the prevention of HCV-infection failed due to extremely high mutagenesis of HCV. However, recently, sufficient progress in the treatment of HCV-infection has been achieved with appearance of highly effective direct HCV antivirals as Sofosbuvir and Ledipasvir on the market [1,2]. Multiple clinical trials are in progress to demonstrate the efficiency of these new medications alone or in a combination with already known ribavirin and interferon alpha. However “the honeymoon period” with the successful treatment by direct antivirals may not be applied to HCV patients that drink alcohol since the pathogenesis of liver disease progression in these patients is different than in alcohol non-consuming HCV patients and requires the involvement of additional therapeutic strategies.

Measuring the Response of Extrahepatic Symptoms and Quality of Life to Antiviral Treatment in Patients with Hepatitis C

Background. HCV infection is associated with musculoskeletal manifestations such as chronic widespread pain, sicca syndrome, polyarthritis, and a reduced HRQOL. Little data is available on the effect of treatment on these manifestations. This study measured changes in extrahepatic symptoms and HRQOL before and after antiviral treatment in a large UK patient cohort. Methods. 118 patients completed HQLQ and rheumatological questionnaires before and after treatment with pegylated interferon-α and ribavirin, with specific regard to chronic widespread pain, sicca syndrome, and sustained virological response. Results. There was significant improvement in HQLQ domains of physical functioning, physical disability, social functioning, limitations and health distress due to hepatitis, and general health. There was significant deterioration in domains of positive well-being, health distress, and mental health. There was a significant decline prevalence of CWP (26.3% versus 15.3%, P = 0.015). Sicca syndrome prevalence fell insignificantly (12.7% versus 11%). SVR was associated positively with all HRQOL changes and significantly with CWP remission. Conclusions. HCV antivirals significantly improve poor HRQOL scores and CWP. Before treatment, both were common, coassociated, and unaccounted for through mixed cryoglobulinemia alone. Although a role of the hepatitis C virus in CWP cannot be deduced by these results, symptomatic improvement via antiviral treatment exists for this subset of patients.

Assessment of Pharmacokinetic Interactions of the HCV Ns5A Replication Complex Inhibitor Daclatasvir with Antiretroviral Agents: Ritonavir-Boosted Atazanavir, Efavirenz and Tenofovir

Approximately one-third of all HIV-infected individuals are coinfected with HCV, many of whom will receive concomitant treatment for both infections. With the advent of direct-acting antivirals (DAAs) for HCV, potential drug interactions between antiretrovirals and DAAs require evaluation prior to co-therapy. Three open-label studies were conducted in healthy subjects to assess potential interactions between the investigational first-in-class HCV NS5A replication complex inhibitor daclatasvir and representative antiretrovirals atazanavir/ritonavir, efavirenz and tenofovir disoproxil fumarate. Target exposure was that of 60 mg daclatasvir alone. Dose-normalized (60 mg) geometric mean ratios of daclatasvir AUCτ for 20 mg ± atazanavir/ritonavir (2.10 [90% CI 1.95, 2.26]) and 120 mg ± efavirenz (0.68 [0.60, 0.78]) showed less than the three-fold elevation and two-fold reduction, respectively, in systemic exposure predicted by prior interaction studies with potent inhibitors/inducers of CYP3A4. Daclatasvir dose adjustment to 30 mg once daily with atazanavir/ritonavir and 90 mg once daily with efavirenz is predicted to normalize AUCτ relative to the target exposure (geometric mean ratios 1.05 [0.98, 1.13] and 1.03 [0.90, 1.16], respectively). Atazanavir exposure (Cmax, AUCτ and C24 trough) and efavirenz Ctrough under coadministration were similar to historical data without daclatasvir. No clinically relevant interactions between daclatasvir and tenofovir disoproxil fumarate were observed for either drug, and no dosing adjustments were indicated. Daclatasvir was well tolerated in all three studies. The pharmacokinetic data support coadministration of daclatasvir with atazanavir/ritonavir, efavirenz and/or tenofovir. A Phase III study in HIV-HCV coinfection has commenced using the described dose modifications.

Peginterferon plus ribavirin and sustained virological response rate in HCV-related advanced fibrosis: a real life study

BackgroundTolerance and response to antiviral HCV treatment is poor in advanced fibrosis. The aim of this study was to assess SVR rate and its predictive factors in HCV advanced fibrosis patients treated in real life with full dose PEG-IFN plus RBV and to evaluate the adverse events related to treatment. MethodsA multicentric, retrospective study was conducted at six university hospitals. METAVIR F3 and F4 HCV monoinfected patients who were treated with PEG-IFN and RBV had their data analyzed. A stepwise logistic regression analysis was performed to identify the variables independently related to SVR. Adverse events were recorded during treatment. Results308 patients were included, 75% genotype 1 and 23% genotype 3. METAVIR F3 was present in 39% and F4 in 61% of patients. The median Child Pugh score for F4 patients was 5 (5–9). The global SVR rate was 34%, 11% were relapsers and 55% were nonresponders. SVR rates were similar between patients treated with PEG-IFN alfa 2a or alfa 2b (p=0.24). SVR rates according to Child–Pugh score were 26% (Child A) and 18% (Child B). The independent factors related to SVR in F4 patients were genotype 3, RVR and fewer Child Pugh score points. Treatment interruption occurred in 31% patients and death occurred in 1.9%, all with liver cirrhosis. ConclusionTreatment of HCV in patients with advanced fibrosis should not be postponed. However, a very careful evaluation of cirrhotic patients must be performed before treatment is indicated and careful monitoring is required during treatment.

Who Needs Direct-Acting Antivirals for HCV? Challenges Faced in Advancing HCV Therapy for HIV–HCV-Coinfected Individuals

The recent availability of new direct-acting antivirals (DAAs) for HCV treatment, which significantly increase sustained virological response rates for genotype 1 HCV infection, has brought new optimism with respect to curative HCV treatment for HIV-HCV-coinfected patients. We describe the characteristics of coinfected patients who could be eligible for DAAs to determine potential challenges facing clinicians and patients hoping to take advantage of these new therapies. We evaluated the sociodemographic and clinical characteristics of the genotype 1 HCV-HIV-infected participants in a Canadian prospective multicentre cohort study at their most recent visit to assess potential eligibility for combination HCV treatment with boceprevir or telaprevir. Of the 1,020 coinfected participants enrolled in the cohort, 707 (85%) had evidence of chronic HCV infection (HCV-RNA-positive), of whom 497 (70%) were infected with genotype 1; 375 (75%) were naive to HCV treatment and 122 (25%) had previously received therapy and failed. Only 143 (38%) of HCV treatment-naive and 39 (32%) of treatment-experienced participants had no absolute contraindications for treatment. Alcohol abuse, active depression and decompensated liver disease were the most frequent reasons for treatment ineligibility. The majority would require alterations in antiretroviral regimens to avoid important drug-drug interactions. Although the need for curative HCV therapy in HIV-HCV coinfection is great, the actual number of patients who could be eligible for DAAs at the present time may be quite low. There remains an urgent need to develop safe, simple and interferon-sparing treatments for coinfected individuals.