Hepatitis C virus genotypes among population with reported risk factors in Assam, north-east India: Emergence of genotype-8.

Background & objectives Hepatitis C virus (HCV) exhibits extensive genetic diversity in infected hosts. There are few published reports of HCV genotype (GT) distribution from the north-east Indian States lying close to the 'Golden Triangle' known for illicit drug trafficking. Real-time knowledge of HCVGT distribution is important for studies on epidemiologic aspects and virus evolution and for the development of new target-specific, direct-acting antiviral drugs. This study aims to examine the distribution of HCVGTs and their subtypes in different risk groups from Assam, north-east India. Methods It is a hospital-based cross-sectional study. Plasma samples reactive for anti-HCV antibody in enzyme-linked immunosorbent assay (ELISA) were subjected to viral load test and genotyping by real-time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) or characterization of non-structural protein NS5B region by nested PCR. Nucleotide sequences were subjected to phylogenetic analysis. Results The most common HCVGT detected was GT-3 (95.89%), followed by GT-1 (3.42%), GT-6xa (0.34%) and GT-8 (0.34%). The mean age of subjects was 30.24 yr, and males outnumbered females. The most commonly associated risk factor was injecting drug use (IDU) (74.31%), followed by tattooing and/or piercing (33.22%), transfusion of blood/blood products (10.27%), and haemodialysis (9.25%). Co-infection with human immunodeficiency virus (HIV) was found in 17.8 per cent, and with Hepatitis B virus (HBV) in 3.42 per cent of the cases. Interpretation & conclusions The detection of HCVGT-8 makes this the first report from Assam and the second from India as per the authors' knowledge. This may indicate strain's endemic nature in India. The increasing trend of HCV infection among young IDUs and HCV-HIV co-infection indicates the need for enhancing surveillance and intensified prevention efforts among young adults.

Expression of CYP2B6 Enzyme in Human Liver Tissue of HIV and HCV Patients.

Background and Objectives: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections present significant public health challenges worldwide. The management of these infections is complicated by the need for antiviral and antiretroviral therapies, which are influenced by drug metabolism mediated by metabolic enzymes and transporters. This study focuses on the gene expression of CYP2B6, CYP3A4, and ABCB1 transporters in patients with HIV, HCV, and HIV/HCV co-infection, aiming to assess their potential association with the choice of therapy, patohistological and clinical parameters of liver damage such as the stage of liver fibrosis, serum levels of ALT and AST, as well as the grade of liver inflammation and other available biochemical parameters. Materials and Methods: The study included 54 patients who underwent liver biopsy, divided into HIV-infected, HCV-infected, and co-infected groups. The mRNA levels of CYP2B6, CYP3A4, and ABCB1 was quantified and compared between the groups, along with the analysis of liver fibrosis and inflammation levels. Results: The results indicated a significant increase in CYP2B6 mRNA levels in co-infected patients, a significant association with the presence of HIV infection with an increase in CYP3A4 mRNA levels. A trend towards downregulation of ABCB1 expression was observed in patients using lamivudine. Conclusions: This study provides insight into gene expression of CYP2B6 CYP3A4, and ABCB1 in HIV, HCV, and HIV/HCV co-infected patients. The absence of correlation with liver damage, inflammation, and specific treatment interventions emphasises the need for additional research to elucidate the complex interplay between gene expression, viral co-infection, liver pathology, and therapeutic responses in these particular patients population.

Evaluation of Hematological, Biochemical Profiles and Molecular Detection of Envelope Gene (gp-41) in Human Immunodeficiency Virus (HIV) among Newly Diagnosed Patients.

The Human Immunodeficiency Virus (HIV) is a highly morphic, retrovirus that rapidly evolves through mutation as well as recombination. Because of the immunocompromised status in HIV patients, there is often a higher chance of acquiring different secondary infections followed by liver cirrhosis, hepatitis B & C, and HIV-associated nephropathy. The current study was conducted to see the prevalence of secondary infections, hematological and biochemical markers for liver and renal associated diseases, and to detect the envelope gene (GP41) in newly diagnosed HIV patients. A total of 37 samples were collected from HIV-positive patients registered in different hospital settings under the National AIDS control program. The collected samples were processed for hepatitis B, hepatitis C, hematological analysis, and biochemical analysis. To identify the envelope gene in newly diagnosed HIV patients, polymerase chain reaction (PCR) was performed using four gene-specific primers. The HIV infections were seen more in male as compared to females. A significant decrease in complete blood count was observed in HIV patients when compared to healthy individuals. There was a significant increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine observed in HIV patients. No significant difference was observed in alkaline phosphatase (ALP), total bilirubin, and albumin levels when compared to healthy control. Anemia was observed in 59.4% of HIV patients. A total of three (8.1%) patients were found to be co-infected with hepatitis B and one (2.7 %) was co-infected with hepatitis C. Out of these 37 tested samples, a total of four showed the successful amplification of the envelope gene. This study provides platform for the health care facilitators to regularly monitor the signs, symptoms and clinical biomarkers of HIV-associated infections to prevent toxicity at an early stage to improve the quality of life (QoL) and minimize the mortality rate in HIV patients. Envelope gene mutating frequently results in drug resistance, and thus future research on polymorphism analysis will reveal points of substitutions to improve drug designing.

HLA-G liver expression and HLA-G extended haplotypes are associated with chronic hepatitis C in HIV-negative and HIV-coinfected patients.

Chronic hepatitis C virus (HCV) infection induces liver damage and the HCV/Human Immunodeficiency Virus (HIV)-coinfection may further contribute to its progression. The HLA-G molecule inhibits innate and adaptive immunity and may be deleterious for chronically virus-infected cells. Thus we studied 204 HCV-mono-infected patients, 142 HCV/HIV-coinfected patients, 104 HIV-mono-infected patients and 163 healthy subjects. HLA-G liver expression was similarly induced in HCV and HCV/HIV specimens, increasing with advanced fibrosis and necroinflammatory activity, and with increased levels of liver function-related enzymes. Plasma soluble HLA-G (sHLA-G) levels were higher in HCV/HIV patients compared to HCV, HIV and to healthy individuals. sHLA-G continued to be higher in coinfected patients even after stratification of samples according to degree of liver fibrosis and necroinflammatory activity when compared to mono-infected patients. Some HLA-G gene haplotypes differentiated patient groups and presented few associations with liver and plasma HLA-G expression. HLA-G thus may help to distinguish patient groups.

Real life results of direct acting antiviral therapy for HCV infection in HIV-HCV-coinfected patients: Epi-Ter2 study.

The aim of this study was to evaluate the baseline demographics and real-life efficacy of direct acting antivirals (DAAs) in HIV-HCV-positive patients as compared to patients with HCV monoinfection. The analysis included 5690 subjects who were treated with DAAs: 5533 were HCV-positive and 157 were HIV-HCV-positive. Patients with HCV-monoinfection were older (p < .0001) and in HIV-HCV group there were more men (p < .0001). Prevalence of genotype 1a (p = .002), as well as of genotypes 3 and 4 (p < .0001) was higher in HIV-HCV-coinfected patients. Genotype 1b was more frequent (p < .0001) in the HCV-mono-infection group. Patients with HCV-monoinfection had a higher proportion of fibrosis F4 (p = .0004) and lower proportion of fibrosis F2 (p < .0001). HIV-HCV-coinfected individuals were more often treatment-naïve (p < .0001). Rates of sustained viral response after 12 weeks did not differ significantly between both groups (95.9% versus 97.3% in coinfection and monoinfection group, respectively; p > .05). They were, however, influenced by HCV genotype (p < .0001), stage of hepatic fibrosis (p < .0001), male sex (p < .0001), BMI (p = .0001) and treatment regimen modifications (p < .0001). Although factors associated with worse response to therapy (male sex, genotype 3) occurred more often in the HIV coinfection group, real-life results of DAAs did not differ significantly between both populations.

Causative factors of liver fibrosis in HIV-infected patients. A single center study.

BACKGROUND: Liver disease is a leading cause of morbidity and mortality among Human Immunodeficiency virus (HIV) infected patients; however no consensus exists on HIV-related risk factors for it. The aim of this study was to identify risk factors for liver fibrosis/cirrhosis in a cohort of Greek HIV-infected patients. METHODS: Patients attending the HIV outpatient clinic of Pathophysiology Department at «Laiko¼ General Hospital in Athens, Greece, between December 2014 and December 2017 were eligible for inclusion. Inclusion criteria were confirmed HIV infection and age > 18 years. Exclusion criteria were Body-Mass index (BMI) > 40, liver metastases of malignant diseases and concurrent or previous chemotherapy. Liver stiffness (LS) was measured using Vibration Controlled Transient Elastography (TE) and laboratory tests were acquired in all patients. Patients were classified in 2 groups: those with mild or no fibrosis (equivalent to Metavir score F0-F2) and those with significant fibrosis (equivalent to Metavir score F3-F4). RESULTS: A total of 187 consecutive patients were included in this study. Median TE value was 5.1 kilopascals (KPa) (range 2.8-26.3), with 92.5% (173/187) of the patients having no/mild fibrosis and 7.4% (14/187) significant fibrosis. On multivariate logistic regression analysis older patient's age, abnormal serum aspartate aminotransferase (AST) value, Hepatitis C virus (HCV) infection, alcohol abuse, CD4/CD8 ratio and an increased number of liver related events (LREs) were significantly correlated with liver fibrosis/cirrhosis. CONCLUSIONS: In our cohort of HIV-infected individuals HCV/HIV co-infection, older age, alcohol abuse and CD4/CD8 ratio seem to correlate with fibrogenesis in the liver.

Comparison of predictive models for hepatitis C co-infection among HIV patients in Cambodia.

BACKGROUND: Hepatitis C virus (HCV) infection is a major global health problem. WHO guidelines recommend screening all people living with HIV for hepatitis C. Considering the limited resources for health in low and middle income countries, targeted HCV screening is potentially a more feasible screening strategy for many HIV cohorts. Hence there is an interest in developing clinician-friendly tools for selecting subgroups of HIV patients for whom HCV testing should be prioritized. Several statistical methods have been developed to predict a binary outcome. Multiple studies have compared the performance of different predictive models, but results were inconsistent. METHODS: A cross-sectional HCV diagnostic study was conducted in the HIV cohort of Sihanouk Hospital Center of Hope in Phnom Penh, Cambodia. We compared the performance of logistic regression, Spiegelhalter-Knill-Jones and CART to predict Hepatitis C co-infection in this cohort. We estimated the number of HCV co-infections that would be missed. To correct for over-optimism, the leave-one-out bootstrap estimator was used for estimating this quantity. RESULTS: Logistic regression misses the fewest HCV co-infections (8%), but would still refer 98% of HIV patients for HCV testing. Spiegelhalter-Knill-Jones (SKJ) and CART respectively miss 12% and 29% of HCV co-infections but would only refer about 30% for HCV testing. CONCLUSIONS: In our dataset, logistic regression has the highest log-likelihood and smallest proportions of HCV co-infections missed but Spiegelhalter-Knill-Jones has the highest area under the ROC curve. The likelihood ratios estimated by Spiegelhalter-Knill-Jones might be easier to interpret for clinicians than odds ratios estimated by logistic regression or the decision tree from CART. CART is the most flexible method, and no model has to be specified regarding presence of interactions and form of the relationship between outcome and predictor variables.

The distinct epidemic characteristics of HCV co-infection among HIV-1-infected population caused by drug injection and sexual transmission in Yunnan, China.

Hepatitis C virus (HCV) infection was frequent in human immunodeficiency virus (HIV) patients in Yunnan province. We studied the epidemic characteristics of HCV in HIV/HCV co-infected patients. Serum from 894 HIV-1 patients was collected, together with basic information and biochemical features. All samples were infected with HIV through injecting drug users (IDUs) and sexual transmission (ST). The NS5B gene was amplified and sequenced to affirm HCV genotype. In total, 202 HIV patients were co-infected with HCV, and most (81.19%) of co-infected patients were IDUs. Genotype 3b was predominant (37.62%) in these samples, and its frequency was similar in patients with IDU and ST. The frequencies of genotypes 1a, 1b, 3a, 6a, 6n, 2a and 6u were 3.96%, 16.34%, 23.76%, 6.93%, 10.40%, 0.50% and 0.50%, respectively. However, genotype 3a showed significantly different frequency in HCV patients with IDU and ST (P = 0.019). When HCV patients were divided into subgroups, the haemoglobin (HGB) level was significantly higher in patients with genotype 3a than in patients with 3b (P = 0.033), 6a (P = 0.006) and 6n (P = 0.007), respectively. Although no difference existed among HCV subgroups, HIV-viral load was identified to be positively correlated with the HGB level and CD4+ cells when dividing HCV/HIV co-infected persons into male and female groups. In conclusion, genotype 3b was the predominant HCV genotype in Yunnan HIV/HCV co-infected persons. The HGB level was higher in patients with genotype 3a than others. HIV-viral load was positively correlated with the HGB level and CD4+ cells in the male or female HCV-infected group.

The Role of Hepatitis C Virus NS5A Region Mutation and SNP IL-28B of Host to Support Successful Pegylated Interferon and Ribavirin Treatment in Patients with HCV-HIV Coinfection: A Prospective Cohort Study.

BACKGROUND: HIV infection in HCV-infected patients accelerates disease progression and reduces the success rate of Peg-IFN/RBV treatment. HCV mutation in NS5A-ISDR/PKR-BD region improved the outcome in HCV monoinfection treated with Peg-IFN/RBV. SNP-IL28B polymorphism is predicted to have an effect on HCV quasispecies evolution. However, the role of NS5A mutation and SNP IL-28B in HIV-HCV coinfection is still unclear. The aim of the study is to determine the role of HCV NS5A-ISDR/PKR-BD mutation and SNP IL-28 polymorphism on the successfulness of Peg-IFN/RBV therapy in HCV-HIV coinfection. METHODS: prospective cohort was performed in this study. Plasma sample were obtained from 30 and 8 patients with HCV-HIV coinfection and HCV monoinfection, respectively. PCR nucleotide sequencing was performed after RNA virus extraction and cDNA synthesis. Protein secondary structure and prediction of mutation function were analyzed using PredictProtein (PP) program. RESULTS: sixteen HCV-HIV coinfected patients and none from eight HCV patients achieved sustained virological response (SVR). ≥1 non-neutral mutation was found in 24/30 HCV-HIV coinfection and more frequent in SVR group (14 patients). ≥1 non-neutral mutation were found statistically significant for overall SVR achievement (p<0.05) in all patients regardless of coinfection or monoinfection status. Of the 27 HCV-HIV coinfected patients with CC-gene, 21 subjects had non-neutral mutation. The structure which was expected as NS5A binding site structure was different from consensus (wild type) in SVR group, while the structure was similar to consensus in non-SVR group. CONCLUSION: having ≥1 non-neutral mutation was associated with SVR achievement in Peg-IFN/RBV therapy, regardless of monoinfection and coinfection status.

IFN-free therapy is associated with restoration of type I IFN response in HIV-1 patients with acute HCV infection who achieve SVR.

Interferon (IFN)-free direct-acting antiviral agents (DAAs) have revolutionized chronic hepatitis C virus (HCV) treatment; early studies suggest excellent efficacy in acute HCV. However, changes in innate immune responses during DAA therapy for acute HCV are unknown. We studied interferon-stimulated gene (ISG) expression and related cytokines/chemokines in HIV-infected patients with acute HCV receiving sofosbuvir plus ribavirin (SOF+RBV) as part of the A5327 clinical trial. ISG expression was determined from PBMCs, and circulating cytokines/chemokines were quantified from serum from study participants. The overall sustained virologic response (SVR) was 57%; all treatment failures were due to virologic relapse. Apart from NOS2a, baseline ISG/chemokine/cytokine levels were similar irrespective of treatment outcome. Downregulation of ISGs was observed at treatment week four and end of treatment (EOT), implicating HCV in establishing elevated ISGs early during HCV infection. Levels of many of these ISGs increased at post-treatment week 12 (PTW12) in relapsers only, coinciding with recurrent HCV RNA. Eleven ISGs were differentially expressed in responders vs relapsers. On-treatment viral suppression was also associated with a reduction in IP-10, CXCL11 and MIP-1ß levels. In contrast, circulating IFN-α levels were significantly higher at EOT and PTW12 in responders vs relapsers. Upregulation of peripheral ISG expression is established early in the course of HCV infection during acute HCV infection, but did not predict subsequent treatment outcome with SOF+RBV. ISGs were downregulated during therapy and increased post-therapy in relapsers. IFN-α levels were higher in responders at EOT/PTW12, suggesting that impaired type I IFN production/secretion may contribute to relapse.

Efficacy and safety of Sofosbuvir-containing regimens in patients co-infected with chronic hepatitis C virus and human immunodeficiency virus: a meta-analysis.

BACKGROUND: The treatment of hepatitis C virus (HCV) in HCV/human immunodeficiency virus (HIV) co-infected patients remains complex. This present meta-analysis evaluated the efficacy and safety of Sofosbuvir (SOF) for treatment in HCV/HIV co-infected patients using the most recent and available data. METHODS: A systematic search of the published data was conducted in PubMed Medline, EMBASE and Cochrane databases. Eligible studies were clinical trials, case-control studies or prospective cohort studies aiming at assessing the efficacy and safety of the SOF-containing regimens in patients co-infected with HCV and HIV. Heterogeneity of results was assessed and a pooled analysis was performed using random effects model with maximum likelihood estimate and 95% confidence intervals (95%CI). Subgroup analysis and assessment of publication bias through Egger's test were also performed. STATA 13.0 software was used to analyze the data. RESULTS: Seven studies (n = 1167 co-infected patients) were included in this analysis. The pooled estimate of sustained virological response at 12 weeks (SVR12) was 94.0% (95%CI: 92.0%-95.0%). Subgroup analysis showed that the treatment-naïve patients had higher SVR12 compared with patients that were treated before (χ2 = 21.39, P < 0.01). The pooled incidence of any adverse events (AEs) was 79.6% (95%CI: 77.1%-82.1%). Publication bias did not exist. CONCLUSION: The results of this study showed that the treatment response of SOF-containing regimens in patients co-infected with HIV and HCV was satisfied. Attention should be paid to the high rates of AEs.

Ultra-Deep Genomic Sequencing of HCV NS5A Resistance-Associated Substitutions in HCV/HIV Coinfected Patients.

BACKGROUND AND AIMS: The prevalence of naturally occurring HCV-NS5A resistance-associated substitutions (RAS) to DAA drugs might affect the response to treatment in HCV/HIV coinfected subjects. There are limited data on the frequency of HCV-NS5A naturally occurring drug-RAS at baseline in HCV/HIV coinfected patients when ultra-deep sequencing methodologies are applied. METHODS: HCV-NS5A-RAS were evaluated among 25 subjects in each group. Patients were matched by age, gender, and hepatic fibrosis stage category to control for selection bias. RESULTS: Within subtype 1a, RAS were observed in 28% of HCV monoinfected and 48% of HCV/HIV coinfected subjects. More patients in the HCV/HIV coinfected group had clinically relevant mutations to DAA directed at NS5A. CONCLUSION: While the clinical significance of this observation may be limited in highly drug adherent populations, some HCV/HIV coinfected persons may be at greater risk of viral resistance if suboptimal dosing occurs.

Sofosbuvir and Velpatasvir for the Treatment of Hepatitis C Virus in Patients Coinfected With Human Immunodeficiency Virus Type 1: An Open-Label, Phase 3 Study.

BACKGROUND: A safe, simple, effective, and pan-genotypic regimen to treat hepatitis C virus (HCV) infection in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains a medical need. We assessed the efficacy and safety of the NS5B polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir for HCV in patients coinfected with HIV-1. METHODS: This phase 3, open-label, single-arm study at 17 sites in the United States enrolled patients with HCV of any genotype and HIV-1 coinfection, including those with compensated cirrhosis. All patients received sofosbuvir-velpatasvir once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Efficacy and safety were assessed in all patients receiving at least 1 dose of treatment. RESULTS: Of 106 patients, 91 (86%) were men, 48 (45%) were black, and 19 (18%) had cirrhosis. SVR12 was achieved by 101 of 106 (95% [95% confidence interval {CI}, 89%-99%]) patients: 74 of 78 (95% [95% CI, 87%-99%]) with genotype 1; all 11 (100% [95% CI, 72%-100%]) with genotype 2; 11 of 12 (92% [95% CI, 62%-100%]) with genotype 3; and all 5 (100% [95% CI, 48%-100%]) with genotype 4. All 19 patients with cirrhosis had SVR12. Two patients relapsed, 2 were lost to follow-up, and 1 withdrew consent. Two discontinued treatment due to adverse events and 2 had serious adverse events. The most common adverse events were fatigue (25%), headache (13%), upper respiratory tract infection (8%), and arthralgia (8%). CONCLUSIONS: Sofosbuvir-velpatasvir for 12 weeks was safe and provided high rates of SVR12 in patients coinfected with HCV and HIV-1. CLINICAL TRIALS REGISTRATION: NCT02480712.

Successful Re-treatment of Hepatitis C Virus in Patients Coinfected With HIV Who Relapsed After 12 Weeks of Ledipasvir/Sofosbuvir.

UNLABELLED: We assessed the efficacy and safety of ledipasvir/sofosbuvir plus ribavirin for 24 weeks in 9 human immunodeficiency virus/hepatitis C virus-coinfected patients who relapsed after receiving 12 weeks of treatment with ledipasvir/sofosbuvir. Eight of 9 (89%) achieved sustained virologic response 12 weeks after the end of treatment. One patient relapsed at posttreatment week 4. These results suggest an effective salvage therapy for patients for whom direct-acting antiviral treatment has failed. CLINICAL TRIALS REGISTRATION: NCT02073656.

Sofosbuvir and Ribavirin for Treatment of Chronic Hepatitis C in Patients Coinfected With Hepatitis C Virus and HIV: The Impact on Patient-Reported Outcomes.

BACKGROUND: Sofosbuvir-containing regimens have been approved for treatment of hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients. We assessed the effect of treatment with sofosbuvir and ribavirin on patient-reported outcomes (PROs) in individuals with HIV/HCV coinfection. METHODS: HIV/HCV-coinfected patients were treated for 12 or 24 weeks with sofosbuvir and ribavirin. Matched HCV-monoinfected controls were also evaluated. All subjects completed standard PRO questionnaires before, during, and after treatment. RESULTS: Included were 497 participants from the PHOTON-1 and PHOTON-2 clinical trials. At baseline, more impairment in PRO scores was noted in HIV/HCV-coinfected patients, compared with HCV-monoinfected patients. During treatment, moderate decrements in PRO scores (change, up to -6.8% on a 0%-100% scale; P = .0053) were experienced regardless of treatment duration and were similar to those for HCV-monoinfected patients (all P > .05). In 413 HIV/HCV-coinfected patients with a virologic response sustained for 12 weeks after treatment cessation, most PRO scores improved (change, up to +7.6%; P < .0001), similar to findings for HCV-monoinfected patients. In multivariate analysis, in addition to clinico-demographic predictors, coinfection with HIV was associated with PRO impairment at baseline (beta, up to -7.6%; P < .002) but not with treatment-emergent changes in PRO scores (all P > .05). CONCLUSIONS: Patients with HIV/HCV coinfection tolerate interferon-free sofosbuvir-based anti-HCV regimens well and, despite the presence of some baseline impairment, have treatment-emergent changes in PRO scores that are similar to those of patients with HCV monoinfection. CLINICAL TRIALS REGISTRATION: NCT01667731 (PHOTON-1), NCT01783678 (PHOTON-2), NCT01604850 (FUSION), and NCT01682720 (VALENCE).

Soraphen A: A broad-spectrum antiviral natural product with potent anti-hepatitis C virus activity.

BACKGROUND & AIMS: Soraphen A (SorA) is a myxobacterial metabolite that inhibits the acetyl-CoA carboxylase, a key enzyme in lipid biosynthesis. We have previously identified SorA to efficiently inhibit the human immunodeficiency virus (HIV). The aim of the present study was to evaluate the capacity of SorA and analogues to inhibit hepatitis C virus (HCV) infection. METHODS: SorA inhibition capacity was evaluated in vitro using cell culture derived HCV, HCV pseudoparticles and subgenomic replicons. Infection studies were performed in the hepatoma cell line HuH7/Scr and in primary human hepatocytes. The effects of SorA on membranous web formation were analysed by electron microscopy. RESULTS: SorA potently inhibits HCV infection at nanomolar concentrations. Obtained EC50 values were 0.70 nM with a HCV reporter genome, 2.30 nM with wild-type HCV and 2.52 nM with subgenomic HCV replicons. SorA neither inhibited HCV RNA translation nor HCV entry, as demonstrated with subgenomic HCV replicons and HCV pseudoparticles, suggesting an effect on HCV replication. Consistent with this, evidence was obtained that SorA interferes with formation of the membranous web, the site of HCV replication. Finally, a series of natural and synthetic SorA analogues helped to establish a first structure-activity relationship. CONCLUSIONS: SorA has a very potent anti-HCV activity. Since it also interferes with the membranous web formation, SorA is an excellent tool to unravel the mechanism of HCV replication.

Molecular characterization of hepatitis C virus for determination of subtypes and detection of resistance mutations to protease inhibitors in a group of intravenous drug users co-infected with HIV.

Modifications in therapeutic regimens for the treatment of hepatitis C virus (HCV) have been observed since the approval of viral protease inhibitors (PI), and the selection of natural drug-resistant variants has been also reported. Thus, it becomes crucial to be aware of consequences of new therapeutic approaches and make available tools for monitoring the infection. The study aimed to apply an "in-house" method for amplification and sequencing of the NS3 region which is the target of PI, and allowing simultaneously the classification of viral subtypes and identification of resistance mutations. Forty-seven samples collected from HIV injecting drug users and drug naive for HCV protease inhibitors were tested for anti-HCV antibodies, 93.6% of them had a positive result and in 70.5% was determined HCV active infection. High frequency of subtype 1a (46.2%), followed by an equal proportion of subtypes 3a, 4a, and 4d (15.4%) was obtained. Two potential recombinants, RF1_2k/1b (3.8%) and 2q/2k (3.8%) were identified. Substitutions V36L/P, T54A, I72L/N/T/V, Q80K/G, S122R/T, D168Q, and I170L/V were observed in 65.4% of the samples. The T54A and Q80K mutations, and the combination V36L + T54A were also identified. Polymorphisms were observed exclusively associated with specific genotypes, particularly, I72L and D168Q with genotype 3, and S122T with genotype 4. The V36L substitution was identified in 92.8% of sequences of non-genotype 1 denoting that this amino acid substitution is a natural polymorphism associated with non-genotype 1 strains. Although no major PI resistance mutations were detected, a more extensive study is needed to evaluate the impact of mutations identified in efficacy of PI treatment.

German cohort of HCV mono-infected and HCV/HIV co-infected patients reveals relative under-treatment of co-infected patients.

BACKGROUND: Current German and European HIV guidelines recommend early evaluation of HCV treatment in all HIV/HCV co-infected patients. However, there are still considerable barriers to initiate HCV therapy in everyday clinical practice. This study evaluates baseline characteristics, "intention-to-treat" pattern and outcome of therapy of HCV/HIV co-infected patients in direct comparison to HCV mono-infected patients in a "real-life" setting. METHODS: A large, single-center cohort of 172 unselected HCV patients seen at the Infectious Diseases Unit at the University Medical Center Hamburg-Eppendorf from 2000-2011, 88 of whom HCV/HIV co-infected, was retrospectively analyzed by chart review with special focus on demographic, clinical and virologic aspects as well as treatment outcome. RESULTS: Antiviral HCV combination therapy with PEG-interferon plus weight-adapted ribavirin was initiated in 88/172 (52%) patients of the entire cohort and in n = 36 (40%) of all HCV/HIV co-infected patients (group A) compared to n = 52 (61%) of the HCV mono-infected group (group B) (p = 0.006). There were no significant differences of the demographics or severity of the liver disease between the two groups with the exception of slightly higher baseline viral loads in group A. A sustained virologic response (SVR) was observed in 50% (n = 18) of all treated HIV/HCV co-infected patients versus 52% (n = 27) of all treated HCV mono-infected patients (p = 0.859). Genotype 1 was the most frequent genotype in both groups (group A: n = 37, group B: n = 49) and the SVR rates for these patients were only slightly lower in the group of co-infected patients (group A: n = 33%, group B: 40% p = 0.626). During the course of treatment HCV/HIV co-infected patients received less ribavirin than mono-infected patients. CONCLUSION: Overall, treatment was only initiated in half of the patients of the entire cohort and in an even smaller proportion of HCV/HIV co-infected patients despite comparable outcome (SVR) and similar baseline characteristics. In the light of newer treatment options, greater efforts to remove the barriers to treatment that still exist for a great proportion of patients especially with HIV/HCV co-infection have to be undertaken.

Impact of a Pharmacist-Led HCV Treatment Program at a Federally Qualified Health Center.

Pharmacists are key players who can help to eliminate the hepatitis C virus (HCV) epidemic in the United States. This pilot retrospective study evaluated the impact of a pharmacist-led HCV treatment program in a federally qualified health center (FQHC) primary care clinic setting. The primary outcome was to assess sustained virologic response (SVR) rates 12 weeks after patients were initiated and completed their oral direct acting antiviral (DAA) treatment regimens. METHODS: This pilot retrospective study included historical analyses of patients who received DAA treatment in the pharmacist-led HCV treatment program in a FQHC clinic between 1 January 2019 and 31 January 2021. SVR was the primary outcome measure for treatment response. RESULTS: Sixty-seven patients with HCV mono- and HIV co-infection were referred, and 59 patients were initiated on DAA regimens after treatment. Fifty of those who were started on DAA regimens completed their treatment, and 38 achieved SVR (modified intention to treat [mITT] SVR rate of 76%). CONCLUSION: Our study's findings demonstrated SVR rates that were comparable with other pharmacist-directed HCV treatment services in the United States despite the impact of the COVID-19 pandemic. Our study included a higher proportion of individuals with HCV/HIV co-infection and of Hispanic ethnicity.

Real-life effectiveness of antiviral therapy for HCV infection with pangenotypic regimens in HIV coinfected patients.

BACKGROUND: The aim of this study was to evaluate the real-life efficacy of pangenotypic antivirals in HIV-HCV-positive patients. RESEARCH DESIGN AND METHODS: The analysis included 5650 subjects who were treated with pangenotypic anti-HCV drugs: 5142 were HCV-positive and 508 were HIV-HCV-positive. RESULTS: Patients with HCV-monoinfection were older (p < 0.0001), however patients with HCV-monoinfection had a higher proportion of advanced fibrosis F4 (p < 0.0001). There were no differences between the study groups in the rate of SVR12 in ITT-analysis (87,6% versus 93,9% in coinfection and monoinfection group, respectively; p > 0.05). However, there was a difference between study groups in PP-analysis, HIV/HCV and HCV, respectively 95.9% vs 97.9%, p = 0.0323. Additionally, there were a higher rate of patients who did not apply for follow-up (SVR12) in coinfected patients (7,9% vs 3,6% respectively p = 0.0001). In multivariante analysis, factors associated with worse response to the pangenotypic anti-HCV therapy included male sex, HCV genotype 3, stage of fibrosis and decompensation of liver function and HIV coinfection. CONCLUSIONS: The real-life results of pangenotypic anti-HCV treatment are veryeffective in the group of HIV-HCV-coinfected patients. However, the finaleffectiveness is slightly lower than that obtained in HCV monoinfectedpatients.