The effectiveness and safety of direct-acting antivirals for hepatitis C virus treatment: A single-center experience in Saudi Arabia.

Background: The introduction of direct-acting antivirals (DAA) to treat the hepatitis C virus (HCV) overcame many drawbacks of interferon-based therapy. DAA achieved sustained viral response (SVR) rates above 90% and overcame many drawbacks of pegylated interferon regimens.The HCV genotype (GT) distribution varies by geographical area, with GT-4 being most prevalent in the Middle East region, including Saudi Arabia. Yet, the real-world evidence about using DAAs in the Saudi population is limited.Thus, the aim of this study to investigate the effectiveness and safety of DAAs in Saudi patients with HCV infection. Methods: A retrospective cohort study included patients treated with DAAs from 2015 to 2017 at a tertiary care hospital in Riyadh, Saudi Arabia. All patients with HCV treated with either ledipasvir plus sofosbuvir (LDS/SOF) ± ribavarin (RBV) or ombitasvir-paritaprevir-ritonavir (OBV/PTV/r) ± dasabuvir (DSV) ± RBV were included. Using a per-protocol analysis, the effectiveness outcome was the end-of-treatment response (EOTr) and Sustained virologic reponce12 weeks after competing the regimen (SVR12). The secondary safety outcome was the adverse event related to the therapy reported by the patients. Results: A total of 97 patients were included; with the majority infected with GT-4 (64 %), followed by GT-1 (18 %), in addition to 8 % having a mixed GT (1 + 4). The EOTr and SVR12 rates were 98 % and 96 %, respectively. SVR12 was 94.4 % within the LDS/SOF ± RBV group and 97.7 % within the OBV/PTV/r ± DSV ± RBV group. Only 4 % had a response failure due to relapse or breakthrough, and all were infected with mixed GT1 + 4. Medications were well tolerated with minimal side effects, including vomiting, nausea, and weakness. Conclusion: DAAs regimens are associated with high rates of SVR12 and are well tolerated with a good safety profile in Saudi HCV-infected patients.

Independent evolution of multi-dominant viral genome species observed in a hepatitis C virus carrier.

The viral genome quasispecies composition of hepatitis C virus (HCV) could have important implications to viral pathogenesis and resistance to anti-viral treatment. The purpose of the present study was to profile the HCV RNA quasispecies. We developed a strategy to determine the full-length HCV genome sequences co-existing within a single patient serum by using next-generation sequencing technologies. The isolated viral clones were divided into the groups that can be distinguished by core amino acid 70 substitution. Subsequently, we determined HCV full-length genome sequences of three independent dominant species co-existing in the sequential serum with a 7-year interval. From phylogenetic analysis, these dominant species evolved independently. Our study demonstrated that multiple dominant species co-existed in patient sera and evolved independently.

Intrahepatic De Novo Tumors in Liver Recipients are Highly Associated With Recurrent Viral Hepatitis.

BACKGROUND/AIMS: Long-term survival of liver transplant recipients is endangered by tumorigenesis at different sites. Little is known about primary de novo tumors developing in the graft. METHODS: We analyzed the follow-up data of 2731 liver recipients that were transplanted between 1988 and 2019 at our institution (Charité - Universitätsmedizin Berlin, Department of Surgery). All cases with new intrahepatic tumors during follow-up were identified. RESULTS: A total of nine patients were diagnosed at a median of 16 years (range, 2-24 years) after surgery. Eight patients presented with hepatocellular carcinoma (HCC), and one patient presented with epithelioid hemangioendothelioma (EHE). All eight HCC patients had a recurrence of the initial disease that had caused liver failure before transplantation. This was associated with viral reinfection with either HCV or HBV in seven cases. Of the nine patients, three underwent surgical resection and only one patient was alive at data abstraction. CONCLUSION: Intrahepatic de novo neoplasms in the liver graft need to be considered in the long-term follow-up of liver recipients and were strongly associated with recurrent viral hepatitis in our study. Although prognosis of this rare complication is generally poor, patients may benefit from surgical resection of localized disease.

Outcomes of Real-World Integrated HCV Microelimination for People Who Inject Drugs: An expansion of the Punjab Model.

BACKGROUND: The prevalence of chronic hepatitis C (CHC) in People Who Inject Drugs (PWID) is 8-10% as compared to 3·6% in the general population in Punjab, India. We assessed the real-world efficacy and safety of free-of-charge generic direct-acting antivirals (DAAs), sofosbuvir with an NS5A inhibitor (ledipasvir, daclatasvir or velpatasvir)±ribavirin in the microelimination of CHC in PWID in a public health setting. METHODS: An integrated care team at 25 sites provided algorithm based DAAs treatment to PWID supervised by telemedicine clinics between 18th June 2016 and 31st July 2019. The primary endpoint was sustained virological response at 12 weeks (SVR-12); the secondary endpoints were treatment completion, adherence, safety, and adverse events. ClinicalTrials.gov number: NCT01110447. FINDINGS: We enrolled 3477 PWID (87·2% men; mean age 33·6±12·5 years; 83·8% rural; 6·8% compensated cirrhosis). While 2280 (65·5%) patients completed treatment, 1978 patients completed 12 weeks of follow up for SVR-12. SVR-12 was achieved in 91·1% of patients per protocol, 49.5% as per intention to treat (ITT) and 90·1% in a modified ITT analysis. Of 546 (15·7%) patients with treatment interruptions, 99 (19·7%) could be traced to test for SVR-12 with a cure rate of 77·8%. There were no major adverse events or consequent treatment discontinuation. INTERPRETATION: Integrated care of PWID with CHC with DAAs is safe and effective. Measures for reducing treatment interruptions will further improve outcomes. FUNDING: The Government of the state of Punjab, India under the Mukh Mantri Punjab Hepatitis C Relief Fund (MMPHCRF) project, funds the project.

Non-alcoholic fatty liver disease is a risk factor for occurrence of hepatocellular carcinoma after sustained virologic response in chronic hepatitis C patients: A prospective four-years follow-up study.

BACKGROUND AND AIM: The incidence of hepatocellular carcinoma (HCC) decreases significantly in chronic hepatitis C (CHC) patients with sustained virologic response (SVR) after pegylated-interferon plus ribavirin (PR) or direct-acting antiviral (DAAs) therapy. We follow-up a single cohort of CHC patients to identify risk factors associated with HCC development post-SVR. METHOD: CHC patients with SVR in Beijing/Hong Kong were followed up at 12-24 weekly intervals with surveillance for HCC by ultrasonography and alpha-fetoprotein (AFP). Multivariate Cox proportional hazards regression analysis was used to explore factors associated with HCC occurrence. RESULTS: Between October 2015 and May 2017, SVR was observed in 519 and 817 CHC patients after DAAs and PR therapy respectively. After a median post -SVR follow-up of 48 months, HCC developed in 54 (4.4%) SVR subjects. By adjusted Cox analysis, older age (≥55 years) [HR 2.4, 95% CI (1.3-4.3)], non-alcoholic fatty liver diseases [HR 2.4, 95%CI (1.3-4.2), higher AFP level (≥20 ng/ml) [HR 3.4, 95%CI (2.0-5.8)], higher liver stiffness measurement (≥14.6 kPa) [HR 4.2, 95%CI (2.3-7.6)], diabetes mellitus [HR 4.2, 95%CI (2.4-7.4)] at pre-treatment were associated with HCC occurrence. HCC patients in the DAAs induced SVR group had a higher prevalence of NAFLD as compared with those in the PR induced SVR group, 62% (18/29) vs 28% (7/25), p = 0.026. A nomogram formulated with the above six independent variables had a Concordance-Index of 0.835 (95% CI 0.783-0.866). CONCLUSION: Underlying NAFLD is associated with increased incidence of HCC in chronic HCV patients post-SVR, particularly in those treated with DAA.

Where are the children in national hepatitis C policies? A global review of national strategic plans and guidelines.

BACKGROUND & AIMS: It is estimated that 3.26 million children and adolescents worldwide have chronic HCV infection. To date, the global response has focused on the adult population, but direct-acting antiviral (DAA) regimens are now approved for children aged ≥3 years. This global review describes the current status of policies on HCV testing and treatment in children, adolescents, and pregnant women in WHO Member States. METHODS: We identified national strategic plans and/or clinical practice guidelines (CPGs) for HCV infection from a World Health Organization (WHO) database of national policies from Member States as of August 2019. A standardised proforma was used to abstract data on polices or recommendations on testing and treatment in children, adolescents and pregnant women. Analysis was stratified according to the country-income status and results were validated through WHO regional focal points through August 2020. RESULTS: National HCV policies were available for 122 of the 194 WHO Member States. Of these, the majority (n = 71/122, 58%) contained no policy recommendations for either testing or treatment in children or adolescents. Of the 51 countries with policies, 24 had specific policies for both testing and treatment, and were mainly from the European region; 18 countries for HCV testing only (12 from high- or upper-middle income); and 9 countries for treatment only (7 high- or upper-middle income). Twenty-one countries provided specific treatment recommendations: 13 recommended DAA-based regimens for adolescents ≥12 years and 6 still recommended interferon/ribavirin-based regimens. CONCLUSIONS: There are significant gaps in policies for HCV-infected children and adolescents. Updated guidance on testing and treatment with newly approved DAA regimens for younger age groups is needed, especially in most affected countries. LAY SUMMARY: To date, the predominant focus of the global response towards elimination of hepatitis C has been on the testing and treatment of adults. Much less attention has been paid to testing and treatment among children and adolescents, although in 2018 an estimated 3.26 million were infected with HCV. Our review shows that many countries have no national guidance on HCV testing and treatment in children and adolescents. It highlights the urgent need for advocacy and updated policies and guidelines specific for children and adolescents.

Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C.

BACKGROUND & AIMS: We aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections. METHODS: A total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing. RESULTS: Failure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens (p <0.01), which was similar to that seen with L31-RAS and Y93-RAS. The prevalence of patients with RASs in either NS3 or NS5A, or in both, increased significantly with increasing numbers of failed regimens. The P32del, which is unique to patients for whom DAA had failed, was linked to the absence of Y93H, the presence of L31F, and previous exposure to IFN plus protease inhibitor regimens. CONCLUSIONS: Failure of multiple DAA regimens can lead to the generation of multiple RASs in the NS3 and NS5A regions of the HCV 1b genome. These mutations contribute to viral resistance to multiple treatment regimens and, therefore, should be considered during decision making for treatment of chronic HCV. LAY SUMMARY: Resistance-associated substitutions (RAS) in the genome of the hepatitis C virus are 1 of the major causes for failed treatment. We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.

New Direct-Acting Antivirals for the Treatment of Patients With Hepatitis C Virus Infection: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: New direct-acting antiviral agents (DAAs) approved for the treatment of patients infected by Hepatitis C virus (HCV) are well tolerated and increase sustained virological response (SVR) rate. We summarize current evidence on the efficacy and safety from comparative randomized controlled trials (RCTs) of DAAs. METHODS: We systematically searched MEDLINE, Embase, Scopus, CENTRAL, and Lilacs as well as a list of reference literature. We included RCTs comparing DAAs with placebo or active control and reporting response rates and adverse events according to antiviral regimens. Risk ratios (RRs) were pooled as appropriate. We assessed the risk of bias of included studies and graded the quality of evidence according to the GRADE method. RESULTS: We included 28 RCTs, enrolling more than 7000 patients. The quality of evidence was generally low. Twelve-week treatment with DAAs in naïve patients significantly increased SVR12 and SVR24 compared with placebo (RR 1.4, 95% CI 1.3-1.6; RR 1.5, 95% CI 1.4-1.6, respectively). This means that for every 1000 patients, 240 or 260 more patients experienced SVR12 or SVR24 if treated with any DAAs. We could not find RCTs assessing progression of liver disease or development of hepatocellular carcinoma. DAAs were not associated with higher incidence of serious adverse events or discontinuation due to adverse events. CONCLUSIONS: This systematic review confirms that new DAAs are more effective in inducing SVR than placebo. Outside clinical trials, in real word, HCV cure with DAA regimens occurs in less than 90% of patients, so further comparative evaluations are needed to establish their long-term effects.

Advances in HCV and Cryoglobulinemic Vasculitis in the Era of DAAs: Are We at the End of the Road?

Hepatitis C Virus (HCV)-related Mixed Cryoglobulinemia (MC) is a unique condition with complex pathogenesis that involves HCV antigen-driven B-lymphocyte clonal proliferation and mutagenesis. Clinical spectrum of MC ranges from asymptomatic state to clinically-apparent vasculitis involving multiple organs. In the era of Direct-Acting Antiviral (DAA) therapy, patients with HCV-related MC achieve high rates of viral clearance that is commonly accompanied by an improvement in clinical symptoms as well as immunological profiles. Rituximab, either alone or in combination with DAA, has also been shown to be effective. Nevertheless, there have been limited and somewhat conflicting data, particularly over the long-term, regarding the rate and degree of clinical response of MC following DAA therapy. It appears that we have come quite a long way in the last decade with this condition. As with non-MC related HCV, undoubtedly long term outcome data will be forthcoming over the next few years. As we move forward successful therapy of HCV is not likely to be a challenge in contrast to access to therapy.

Safety and Efficacy of Sofosbuvir and Daclatasvir for Hepatitis C Virus Infection in Patients with ß-Thalassemia Major.

BACKGROUND AND AIMS: ß-thalassemia major patients are susceptible to Hepatitis C Virus (HCV) infection owing to life-long dependency for blood-transfusion. Moreover, this patient population is at risk of progression of liver fibrosis or development of cirrhosis as a consequence of both iron overload and HCV infection. Hence, this study was carried out to evaluate efficacy and safety of the combination regimen of sofosbuvir and daclatasvir for HCV infection in ß-thalassemia major patients. METHODS: The present study was a prospective observational study which enrolled multi-transfused ß-thalassemia major patients treated with a combination regimen of sofosbuvir (400 mg) and daclatasvir (60 mg) daily for 12 weeks for HCV infection during May 2016 and November 2016 depending upon inclusion and exclusion criteria of the study. Sustained virological response at post-treatment week-12 (SVR-12) was defined as negative HCV-RNA at week-12 after completion of antiviral treatment. RESULTS: A total of 10 multi-transfused patients with ß-thalassemia major were included in the study. Average age of the patient was 13.60 ± 4.38 years. All the included patients were treatment-naïve, non-cirrhotic and infected with HCV genotype-3. All the patients achieved SVR-12. There was significant reduction in aspartate aminotransferase (p = 0.005) and alanine aminotransferase level (p = 0.005) and serum ferritin level (p = 0.028) after completion of the antiviral treatment. The reported adverse events include nausea, vomiting and anorexia which were managed conservatively. None of the patient required dose reduction or termination of antiviral treatment. CONCLUSION: The study reports safety and efficacy of sofosbuvir-based treatment in non-cirrhotic, treatment-naive ß-thalassemia major patients infected with HCV genotype-3. However, further studies with larger patient populations are needed to build up stronger evidence of safety and efficacy of this treatment approach for HCV infection in thalassemic patients.

Impact of Direct Acting Antiviral Therapy for Treatment of Hepatitis C Genotypes 1, 3 and 4: A Real Life Experience from India.

OBJECTIVE: To assess impact of Direct Acting Antiviral (DAA) therapies for treatment of Hepatitis C Virus (HCV) genotypes 1, 3 and 4 in a real-world cohort from India. METHODS: Adults with chronic HCV infection treated with Sofosbuvir (SOF) and Ledipasvir (LDV) (genotypes 1 and 4) or SOF and Daclatasvir (DCV) (genotype 3), with or without Ribavirin (RBV) between December 2015 and December 2016 were included. The primary endpoint was Sustained Virological Response at Post-treatment Week 12 (SVR12). RESULTS: Of the 648 patients, 181 received SOF/LDV (65 with RBV) and 467 received SOF/DCV (135 with RBV). Most patients were males (65.4%), aged 41-60 years (49.4%) and treatment-naïve (92.6%). Genotype 3 (72.1%) was most common, followed by genotypes 1 (22.4%) and 4 (5.6%). Forty two percent patients (n = 271) had cirrhosis (112 patients were decompensated). SVR12 (modified intention-to-treat) was achieved by 98.1% of patients (512/522) (100% in genotypes 1 and 4, and 97.3% (362/372) in genotype 3). On intention to treat analysis, SVR12 was 88.1% (512/581) [genotype 1-96.8% (121/125), genotype 3-85.2%, genotype 4-93.5% (29/31)]. Seventy patients had treatment failure (non response in 6, virological breakthrough in 2, 10 patients relapsed, 2 died and 50 were lost to follow up). High SVR was observed regardless of HCV genotype, presence of cirrhosis or past history of treatment. No major adverse events warranting discontinuation of treatment were noted. CONCLUSIONS: DAA therapy for HCV genotypes 1, 3 and 4 achieves high SVR rates in all patients, including those with cirrhosis and previous non-responders.

Sofosbuvir and Ribavirin for 24 Weeks Is An Effective Treatment Option for Recurrent Hepatitis C Infection After Living Donor Liver Transplantation.

BACKGROUND: Recurrent hepatitis C virus (HCV) has been a serious problem after liver transplantation (LT). We report our experience of 24-week therapy with sofosbuvir (SOF) and ribavirin (RBV) in post-LT recurrent HCV in living donor liver transplantation (LDLT) setting in South Asia. METHODS: Data from all patients treated for post-transplantation HCV recurrence in a single center were analyzed. Treatment regimen was 24 weeks of SOF 400 mg daily and RBV (starting at 800 mg daily, increased as tolerated). Sustained virological response (SVR) was assessed 12 weeks and 24 weeks after completion of treatment. RESULTS: 63 patients (median age 52 [range 30-69] years; 80% males) were treated. Most (76.2%) were treatment experienced and predominant HCV genotype was 3 (77.7%) followed by 1 (20.6%). Median transient elastography (Fibroscan) score was 7 (range 3-11) kPa and none of the patients had cirrhosis. SVR12 was achieved in 60 of 63 patients (95.2%) while SVR24 was noted in 59 (93.7%). SVR12 rates were as good in genotype-3 as in genotype-1. Older age, longer period after transplantation, higher Fibroscan value and higher need for erythropoietin were likely to be associated with relapse. Adverse effects were noted in 34 patients and weakness and fatigue were the commonest side effects. Significant drop in hemoglobin (<8 g/dL) was seen in 6 patients. CONCLUSIONS: SOF + RBV combination therapy for 24 weeks was safe and effective in treatment of for post-LT recurrent HCV in a single LT center and remains relevant due to its low cost and lack of drug interactions.

Potential Liver Transplant Recipients with Hepatitis C: Should They Be Treated Before or After Transplantation?

Treatment of hepatitis C virus (HCV) with newer directly acting antivirals (DAAs) and lead to sustained viral response (SVR) in majority of patients and SVR has been documented to be associated with reversal of liver cirrhosis. The improved SVR rates and safety profiles of DAAs have led to the treatment of patients with decompensated cirrhosis awaiting liver transplantation (LT). Several clinical trials of DAAs in decompensated HCV patients have recently demonstrated SVR rates above 80%, which have been associated with significant improvements, in the Child-Pugh-Turcotte scores/or model for end-stage liver disease scores in a proportion of patients. Moreover, it has been shown that HCV RNA becomes negative after 2-4 weeks of treatment, and those who are transplanted after becoming HCV RNA negative will be have very low the risk of HCV recurrence after transplantation. Some of the patients may have reached the "point of no return" and may proceed to worsening of decomposition over time. To avoid the risk of worsening, there is an additional option of treating these patients after LT should they develop recurrent HCV infection. Currently there are no guidelines as to select patients who would benefit from treatment prior to LT as opposed to those who will be better off being treated after the transplant surgery. The article discusses a possible approach for such selection.

Chronic Hepatitis C: Do Generics Work as Well as Branded Drugs?

India has a large share of the hepatitis C virus (HCV) burden of the world. Unsafe medical practices and blood transfusions are the leading modes of transmission of HCV in India. The commonest HCV genotype in India is genotype 3 followed by genotype 1. While directly acting antivirals (DAAs) agents have become available at reasonable rates in India, cost of therapy remains a major barrier for control of HCV in India. Generic DAAs have been proven to be cost-saving in prior studies. We examined data from various studies in India and elsewhere using generic DAAs, and evaluated whether they are equally efficacious as the branded drugs. Since the availability of generic DAAs in the Indian market, there is a lot of real life data as well as prospective studies in special patient populations such as hematological disorders (thalassemia and hemophilia), chronic kidney disease, hemodialysis patients, post liver and renal transplant patients on immunosuppression, intravenous drug users, confections and other high risk groups. Control of HCV infection in India requires multi pronged approach. There is a need to formulate a health educational curriculum targeting not only the high-risk population but also the general population regarding the transmission of HCV. Adopting the dual approach of treating the old cases (decreasing the reservoir pool of HCV) and decreasing the incidence of new ones would help curtail the disease and decrease liver related mortality. In this scenario, the role of efficacious low cost generic medications is essential.

Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016.

India contributes significantly to the global burden of HCV. While the nucleoside NS5B inhibitor sofosbuvir became available in the Indian market in March 2015, the other directly acting agents (DAAs), Ledipasvir and Daclatasvir, have only recently become available in the India. The introduction of these DAA in India at a relatively affordable price has led to great optimism about prospects of cure for these patients as not only will they provide higher efficacy, but combination DAAs as all-oral regimen will result in lower side effects than were seen with pegylated interferon alfa and ribavirin therapy. Availability of these newer DAAs has necessitated revision of INASL guidelines for the treatment of HCV published in 2015. Current considerations for the treatment of HCV in India include the poorer response of genotype 3, nonavailability of many of the DAAs recommended by other guidelines and the cost of therapy. The availability of combination DAA therapy has simplified therapy of HCV with decreased reliance of evaluation for monitoring viral kinetics or drug related side effects.

Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection in 2015.

Overall prevalence of HCV infection in India has been estimated to be approximately 1.3% in the general population. Recent introduction of sofosbuvir in India at a relatively affordable price has led to great optimism about prospects of cure for these patients. This drug is likely to form the backbone of current and future treatment regimes for HCV infection, displacing pegylated interferon. Availability of directly acting antiviral drugs (DAAs) has necessitated revision of INASL guidelines for the treatment of HCV published in 2014, as has happened across the world. Current considerations for the treatment of HCV in India include the poorer response of genotype 3, nonavailability of many of the DAAs recommended by other guidelines and the cost of therapy. Since only one DAA, sofosbuvir, is available in India, only two sofosbuvir-based regimes are possible: either dual drug therapy in combination with ribavirin alone for 6 months or triple drug therapy in combination with ribavirin and pegylated interferon for 3 months. The utility of these regimes in various situations has been discussed. Availability of a few other newer DAAs, expected in 2016, is expected to lead to more widespread use of these agents. Current guidance will be updated once newer DAAs, newer evidence with DAAs and 'real-life experience' with use of DAAs accumulate in India.

Oxidized Low-Density Lipoprotein Is a Novel Predictor of Interferon Responsiveness in Chronic Hepatitis C Infection.

BACKGROUND & AIMS: Hepatitis C virus (HCV) cell entry is mediated by several cell surface receptors, including scavenger receptor class B type I (SR-BI). Oxidized low density lipoprotein (oxLDL) inhibits the interaction between HCV and SR-BI in a noncompetitive manner. We tested whether serum oxLDL levels correlate with sustained virologic response (SVR) rates after interferon-based treatment of chronic hepatitis C. METHODS: Baseline oxLDL was determined in 379 participants with chronic HCV genotype 1 infection from the INDIV-2 study using a commercial enzyme-linked immunosorbent assay. The mechanistic in vitro studies used full-length and subgenomic HCV genomes replicating in hepatoma cells. RESULTS: In the multivariate analysis, oxLDL was found to be an independent predictor of SVR. Oxidized LDL did not correlate with markers of inflammation (alanine transaminase, ferritin), nor was serum oxLDL affected by exogenous interferon administration. Also, oxLDL did not alter the sensitivity of HCV replication to interferon. However, oxLDL was found to be a potent inhibitor of cell-to-cell spread of HCV between adjacent cells in vitro. It could thus reduce the rate at which new cells are infected by HCV through either the cell-free or cell-to-cell route. Finally, serum oxLDL was significantly associated with the estimated infected cell loss rate under treatment. CONCLUSIONS: Oxidized LDL is a novel predictor of SVR after interferon-based therapy and may explain the previously observed association of LDL with SVR. Rather than being a marker of activated antiviral defenses it may improve chances of SVR by limiting spread of infection to naive cells through the cell-to-cell route.

Most Patients of Hepatitis C Virus Infection in India Present Late for Interferon-Based Antiviral Treatment: An Epidemiological Study of 777 Patients from a North Indian Tertiary Care Center.

BACKGROUND: Interferon-based antiviral therapy is offered only to those HCV patients who have either chronic hepatitis or early cirrhosis. Advanced cirrhotics do not tolerate interferon-based therapy. Since HCV is asymptomatic in early stages and usually presents late, the eligibility for interferon-based therapy is thus limited. There are scarce studies from India, which looked specifically the eligibility of interferon-based therapy in HCV patients. AIM: To study the spectrum of presentation of HCV infection, determine their eligibility for interferon-based therapy, and follow for SVR. METHODS: The records of all consecutive patients of HCV, >14 years age, who presented to our department between 2008 and 2014, were analyzed for categorization into chronic hepatitis, cirrhosis and hepatocellular carcinoma. Patients with detectable HCV RNA who have chronic hepatitis or Child A cirrhosis were considered eligible for Peg-interferon and ribavirin. Patients who received treatment were followed for SVR. RESULTS: 777 patients (median age 49 [range 15-95] years, males 69%) were included. Cirrhosis was the most common presentation (56%, 439/777) followed by chronic hepatitis (37%, 287/777) and HCC (7%, 51/777). Of patients who had cirrhosis (including those with HCC), 36% (174/490) were Child A; 51% (250/490) were Child B and 14% (66/490) were Child C. Only 347/777 (45%) were eligible for Peg-interferon-alpha and Ribavirin. Among the remaining 430 patients, in 326 (76%) the disease was far too advanced. Of eligible patients only 54% actually received Peg-interferon-alpha and Ribavirin and 81% patients could complete the course. Of them only 70% could achieve SVR. CONCLUSIONS: Most HCV patients in India present late and only about 45% are eligible for Interferon-based antiviral treatment. At presentation 56% patients already have cirrhosis and 7% have HCC. Since HCV is usually asymptomatic in early stages, awareness about screening should be increased so that more patients are diagnosed early before they develop cirrhosis or HCC.

Hepatitis C virus treatment in the 'real-world': how well do 'real' patients respond?

BACKGROUND: Published clinical trials of the treatment of HCV are largely multicentre prospective pharmaceutical trials. Patients in clinical trials tend to have more favorable outcomes than patients in the 'real-world', due to strict patient selection and differences in treatment conditions and available resources. OBJECTIVES: To assess the outcomes of Hepatitis C infected patients treated at the Barwon Health Liver Clinic with combination Pegylated interferon (PEG-IFN) and Ribavirin (RBV) therapy and to determine factors associated with a treatment response. METHODS: Retrospective review of patients who received treatment for Hepatitis C at our institution's Liver Clinic from January 2001-September 2011. Patient demographics, comorbidities, treatment-related parameters and side effects were extracted from medical records and analyzed. RESULTS: A total of 190 patients (120 male, 70 female) with a mean age of 42.8 years (range 20-68 years) commenced treatment. The most common genotype was genotype 3 (48.9%), followed by genotype 1 (42.6%). 150 of 190 patients (78.9%) completed treatment and had end of treatment data available. 107 of 182 patients, (58.8%) for whom sustained virologic response (SVR) rate data was available achieved an SVR. Overall response rates were; 46.9%, 68.8% and 62.4% in genotypes 1, 2 and 3 respectively. The response rate was significantly lower in 29 patients with documented cirrhosis (20.7%). Age, diabetes and alcohol abuse did not predict treatment response in our cohort. Side effects reported in 81.6% of patients included general malaise, hematological disturbance and psychiatric issues, and necessitated cessation of therapy in 16 patients (8.4%) and dose reduction in 26 patients (13.7%). CONCLUSIONS: Response rates to combination PEG-IFN and RBV therapy at our institution are comparable to other 'real-world' and pharmaceutical registration trials. Side effects of combination therapy were prominent but resulted in fewer discontinuations of therapy compared to pharmaceutical trials.

The antiviral effect of jiadifenoic acids C against coxsackievirus B3.

Coxsackievirus B type 3 (CVB3) is one of the major causative pathogens associated with viral meningitis and myocarditis, which are widespread in the human population and especially prevalent in neonates and children. These infections can result in dilated cardiomyopathy (DCM) and other severe clinical complications. There are no vaccines or drugs approved for the prevention or therapy of CVB3-induced diseases. During screening for anti-CVB3 candidates in our previous studies, we found that jiadifenoic acids C exhibited strong antiviral activities against CVB3 as well as other strains of Coxsackie B viruses (CVBs). The present studies were carried out to evaluate the antiviral activities of jiadifenoic acids C. Results showed that jiadifenoic acids C could reduce CVB3 RNA and proteins synthesis in a dose-dependent manner. Jiadifenoic acids C also had a similar antiviral effect on the pleconaril-resistant variant of CVB3. We further examined the impact of jiadifenoic acids C on the synthesis of viral structural and non-structural proteins, finding that jiadifenoic acids C could reduce VP1 and 3D protein production. A time-course study with Vero cells showed that jiadifenoic acids C displayed significant antiviral activities at 0-6 h after CVB3 inoculation, indicating that jiadifenoic acids C functioned at an early step of CVB3 replication. However, jiadifenoic acids C had no prophylactic effect against CVB3. Taken together, we show that jiadifenoic acids C exhibit strong antiviral activities against all strains of CVB, including the pleconaril-resistant variant. Our study could provide a significant lead for anti-CVB3 drug development.