Antiviral Agent Therapy Research Articles

FRI-237 - HepCom: impact of co-morbidities on the final success of direct antiviral agents therapy in hepatitis C

FRI-237 - HepCom: impact of co-morbidities on the final success of direct antiviral agents therapy in hepatitis C

Effectiveness and safety of daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: Systematic review and meta-analysis.

Daclatasvir plus asunaprevir (DCV + ASV) has demonstrated potent antiviral activity in patients with hepatitis C virus (HCV) genotype 1b infection. A definite conclusion about efficacy and safety of DCV + ASV in patients with HCV genotype 1b is not available. A meta-analysis was conducted to evaluate outcomes of all-oral treatment with DCV + ASV in terms of sustained virological response at 12 (SVR12 ) and 24 (SVR24 ) weeks and adverse effects after the end of treatment. PUBMED, MEDLINE, and EMBASE databases were searched in May 2016. The data were analyzed with Review Manager 5.3. Nine trials (n = 1690) met entry criteria. SVR12 was achieved by 89.9% of treatment-naïve patients, 84.7% of interferon-ineligible/intolerant patients, and 81.9% of nonresponder patients. Moreover, 89.0% of interferon-ineligible/intolerant patients and 83.1% of nonresponder patients achieved SVR24 . Baseline characteristics, including gender, race, advanced age, non-CC IL28B genotype, and cirrhosis, did not appear to impact SVR rates. However, the rate of SVR12 in all patients with viral load < 8 × 105 was higher than that of all those with viral load ≥ 8 × 105 (151/162 vs 625/753). Moreover, pre-existing nonstructural protein 5A resistance-associated variants (RAVs) were associated with virological failure during DCV + ASV therapy, resulting in the emergence of multiple RAVs. Treatment with DCV + ASV was well tolerated, with low incidences of serious adverse effects, discontinuations, and grade 3 or 4 laboratory abnormalities in all patients. Daclatasvir plus asunaprevir provides a highly effective and well-tolerated treatment option for patients with HCV genotype 1b. However, patients with nonstructural protein 5A RAVs at baseline should be assessed to optimize more potent direct antiviral agent therapies.

Considerations on Direct Antiviral Agent Therapy in Patients Having Chronic Hepatitis C from Constanta County

Abstract Introduction: Direct-acting antiviral agents (DAA) have a direct action in chronic hepatitis C, their addition to the standard therapy with interferon alfa2 (IFN) and ribavirin (RBV) significantly improving the sustained virologic response (SVR) in this disease. Objective: The study analyses the results of triple therapy inclduign DAA in terms of tolerability and efficiency. Material and method: We selected a lot of 24 patients who concluded the DAA administration period, being in the period of finalization of standard therapy at the time of the study. In all the patients clinical and paraclinical assesment was performed including laboratory tests, fibroscan, echography, etc. Results: The duration of the therapy consisting in association of DAA to the standard treatment was 3 months and led to a remarkable result represented by a high rate of negativation of viremia (83.3%). Among the adverse reactions recorded, the most important were: anemia 17 patients (70.8%), leucopenia 10 patients (41.6%), thrombocitopenia 14 patients (58.3%), hyperbilirubinemia 3 patients (12,5%); hyperuricemia 8 patients (33,3%), hypocalcemia 4 patients (16.6%), loss of weight 4 patients (16,6%), anal pruritus (16,6%); among the 24 patients, 2% did not exhibit any adverse reactions. Conclusions: Despite of the various adverse reactions recorded, the triple therapy consisting in DAA added to the standard treatment proves its utility, and the high rates of sustained viral reaction justifies its utilization. It is necessary to increase the number of patients who benefit from the advantages of triple therapy, which, after becoming larger available, could become a new standard therapy in patients with viral chronic hepatitis.

Once-daily simeprevir in combination with pegylated-interferon and ribavirin: a new horizon in the era of direct-acting antiviral agent therapy for chronic hepatitis C

Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC), and it is estimated that infected individuals total 185 million people worldwide. In Japan, around 2 million are infected with HCV, and more than 20 thousand die from HCV-induced HCC annually. Though viral eradication with antiviral therapies is the most important and effective choice for decreasing HCC-related deaths induced by HCV, complete viral eradication has been quite difficult till recently, especially in patients with genotype-1 HCV infection because of the low response rate to interferon (IFN)-based therapy [1, 2]. In this background, development of novel direct-acting antiviral agents (DAAs) specific for HCV was truly a revolutionary event. In 2011, two first-generation NS3 protease inhibitors (PIs), telaprevir and boceprevir, were firstly approved among all the DAAs for clinical use in USA and Europe for genotype-1 HCV in combination with pegylated-interferon and ribavirin (PR), while telaprevir was approved in Japan in the same 2011 period. As expected, a regimen including telaprevir in combination with pegylated-interferon and ribavirin dramatically improved the sustained viral response (SVR) rate to as high as 80 % in genotype-1 HCV infection. On the other hand, telaprevir has several undesirable problems. Among all, adverse events (AEs) of anemia and skin rash are serious problems of telaprevir, and Grade 3/4 skin disorders, including Stevens–Johnson syndrome and drug rashes with eosinophilia and systemic symptoms, as well as Grade 3 anemia (\8.0 g/dL), might occur [3, 4]. Moreover, cumbersome frequent dosing three times a day (every 7–9 h) could induce poor medication adherence. Under the circumstances, it has been quite stressful for patients as well as clinicians to introduce and monitor this telaprevir-based regimen. Simeprevir (SMV, TMC435) is classified as a secondgeneration PI with the macrocyclic structure having an advantage in the binding affinity and specificity for NS3 protease compared to the first-generation PI with the linear structure. Due to the difference in the structure, the drugresistance profile is somewhat different from that of telaprevir. Though simeprevir shows cross-resistance with telaprevir at amino acid positions of 155 and 156, most of the resistant mutation occurs at the simeprevir-specific amino acid position of 168 [5]. Though simeprevir is effective in all viral genotypes (genotype 1–6), it has the strongest antiviral activity for genotype-1a and -1b HCV infection. In particular, low AE rate and its patient-friendly once-daily dosing are the important characters of simeprevir aside from its strong antiviral activity. In the international phase II trials of simeprevir in combination with PegIFNa-2a/RBV for treatment-naive (PILLAR study) [6] and treatment-experienced patients (ASPIRE study) [7] for HCV genotype 1-infected patients, it was demonstrated that simeprevir was generally well tolerated and had a pharmacokinetic profile supporting once-a-day (QD) dosing resulting in high virologic response rates. In this issue of the Journal of Gastroenterology, Hayashi et al. [8] reported the important results of the phase II Dose and duration Ranging study of Antiviral agent TMC435 in Genotype One HCV treatment-Naive patients (DRAGON study; TMC435-C215) evaluating once-daily simeprevir This comment refers to the article available at doi:10.1007/s00535013-0875-1.

Corticosteroids for viral myocarditis

Myocarditis is defined as inflammation of the myocardium accompanied by myocellular necrosis. Experimental evidence suggests that autoimmune mechanisms follow viral infection, resulting in inflammation and necrosis in the myocardium. However, the use of corticosteroids as immunosuppressives for this condition remains controversial. The existing review was updated. The primary objective of this review is to assess the beneficial and harmful effects of treating acute or chronic viral myocarditis with corticosteroids. The secondary objective is to determine the best dose regimen. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 7 of 12, 2012) on The Cochrane Library, MEDLINE OVID (1946 to July Week 2, 2012), EMBASE OVID (1980 to Week 29, 2012), BIOSIS Previews (1969 to 20 July 2012), ISI Web of Science (1970 to 20th July, 2012), and LILACS (from its inception to 25 July, 2012) , Chinese Biomed Database, CNKI and WANFANG Databases (from their inception to 31 December 2012). We applied no language restrictions. Randomised controlled trials (RCTs) of corticosteroids for viral myocarditis compared with no intervention, placebo, supportive therapy, antiviral agents therapy or conventional therapy, including trials of corticosteroids plus other treatment versus other treatment alone, irrespective of blinding, publication status, or language. Two review authors extracted data independently. Results were presented as risk ratios (RRs) and mean differences (MDs), both with 95% confidence intervals (CIs). Eight RCTs (with 719 participants) were included in this update. The trials were small in size and methodological quality was poor. Viral detection was performed in 38% of participants, among whom 56% had positive results. Mortality between corticosteroids and control groups was non-significant (RR, 0.93, 95% CI 0.70 to 1.24). At 1 to 3 months follow-up, left ventricular ejection fraction (LVEF) was higher in the corticosteroids group compared to the control group (MD 7.36%, 95% CI 4.94 to 9.79), but there was substantial heterogeneity. Benefits were observed in LVEF in two trials with 200 children given corticosteroids (MD 9.00%, 95% CI 7.48 to 10.52). New York Heart Association (NYHA) class and left ventricular end-stage systole diameter (LVESD) were not affected. Creatine phosphokinase (CPK) (MD -104.00 U/L, 95% CI -115.18 to -92.82), Isoenzyme of creatine phosphate MB (CKMB) (MD 10.35 U/L, 95% CI 8.92 to 11.78), were reduced in the corticosteroids group compared to the control group, although the evidence is limited to small participant numbers. There were insufficient data on adverse events. For people diagnosed with viral myocarditis and low LVEF, corticosteroids do not reduce mortality. They may improve cardiac function but the trials were of low quality and small size so this finding must be regarded as uncertain. High-quality, large-scale RCTs should be careful designed to determine the role of corticosteroid treatment for viral myocarditis. Adverse events should also be carefully evaluated.

The science of direct-acting antiviral and host-targeted agent therapy

Direct-acting antiviral drugs targeting two major steps of the HCV life cycle, polyprotein processing and replication, and cyclophilin inhibitors, that target a host cell protein required to interact with the replication complex, have reached clinical development. In order to achieve a sustained virological response, that is, a cure of the HCV infection, it is necessary to shut down virus production, to maintain viral inhibition throughout treatment and to induce a significant, slower second-phase decline in HCV RNA levels that leads to definitive clearance of infected cells. Recent findings suggest that the interferon era is coming to an end in hepatitis C therapy and HCV infection can be cured by all-oral interferon-free treatment regimens within 12 to 24 weeks. Further results are awaited that will allow the establishment of an ideal first-line all-oral, interferon-free treatment regimen for patients with chronic HCV infection.

NS5A阻害剤とNS3プロテアーゼ阻害剤併用投与における早期の抗ウイルス効果

To further improve therapeutic effect on chronic hepatitis C, we have administered NS3 inhibitor and NS5A inhibitor together, and examined effects of early antiviral agent therapy. The subjects were five cases where interferon is ineffective (null responders). The NS5A and NS3 inhibitors are oral drugs and were daily administered for 24 weeks. Figure 1 shows time-dependent change of the number of viruses after the therapy started, and rapid decrease of viruses is recognized. Within 12 hours, HCV-RNA decreased by more than 2 log IU/ml in every patient. Two patients became negative for the virus by the 15th day after the therapy started. Furthermore, 80% of cases by the 28th day and all the cases by the 56th day became negative. The new therapy has manifested excellent early antiviral effect.

Intravitreal Ganciclovir Treatment in Progressive Outer Retinal Necrosis

To report two patients with progressive outer retinal necrosis, which is presumed to be caused by the varicella-zoster virus in patients with acquired immunodeficiency syndrome (AIDS). Case report. The patients were treated with intravenous foscarnet, 60 mg per kg of body weight three times per week, without response. Remission of retinal necrosis occurred with the commencement of intravitreal ganciclovir treatment, 400 mg two times per week. Laser photocoagulation was performed in both cases. Neither patient developed retinal detachment. Intravitreal ganciclovir treatment combined with systemic antiviral agent therapy in patients with progressive outer retinal necrosis may delay progress of the disease. Early photocoagulation may prevent the development of retinal detachment if retinal necrosis is controlled.

帯状ほう疹後神経痛に対するＰＧＥ１の治療効果

Sympathetic nerve block, periganglionic methylprednisolone injection and antiviral agent therapy have been adopted for treatment of herpetic neuralgia and prevention of post-herpetic neuralgia. Although such therapies are applied at the early stages of the disease, many aged patients suffer from post herpetic neuralgia. During the past five years, 24 post-herpetic neuralgia patients were treated with intravenous prostaglandin E1 (120-180 μg/week) . The pain was reduced at various degrees in all cases. While 13 patients out of 24 had neuralgia in the trigeminal region (group T), the other 11 patients were suffering in the spinal nerve region (group S) . 11 cases in group T and 5 cases in group S exhibited excellent improvement. 2 cases in group T and 6 in group S showed in moderate improvement. Among all 24 cases, 5 cases in group T (group Tp) and 4 in group S (group Sp) received intravenous prostaglandin E1 only. All of group Tp responded excellently to prostaglandin E1, however 3 cases in group Sp revealed only moderate improvement and one case showed no improvement at all. There was a significant difference between group Tp and Sp.The results indicate there is a correlation between the area being treated and the effectiveness of the treatment. Notably the treatment of intravenous prostaglandin E1 was extremely effective when applied to the trigeminal area.