Interferon-Associated Retinopathy During the Treatment of Chronic Hepatitis C

Journal of Viral Hepatitis

A Systematic Review

A. Raza, S. Mittal, G. K. Sood

J Viral Hepat. 2013;20(9):593-599.

Abstract and Introduction

Abstract

The incidence of retinopathy in patients with chronic hepatitis C treated with interferon-based regimens has been variably reported in the literature. There is no consensus regarding ophthalmologic screening before and during treatment with interferon-based therapy. To assess the incidence of retinopathy in patients with chronic hepatitis C being treated with interferon-based regimens and estimate the rate of resolution. A systematic literature search was performed to locate all relevant publications. Pooled incidence of retinopathy was calculated in patients treated with interferon or pegylated interferon. We also estimated the rate of discontinuation of treatment and resolution after the treatment was stopped. A total of 21 studies fulfilled the inclusion criteria. The overall incidence of retinopathy using random effect model was 27.7% (95% confidence interval [CI] 20.9–34.5%). The pooled incidence of retinopathy in 10 studies that only used pegylated interferon was 20.9% (95% CI: 11.6–29.8). The incidence of retinopathy with pegylated interferon in diabetic and hypertensive patients (high-risk group) was 65.32% and 50.7%, respectively. This was significantly higher compared with the incidence of retinopathy (11.7%) in patients without these risk factors. Overall pooled estimate for the resolution of retinopathy was 87% (95% CI 75.7–98.4%). The rate of discontinuation of treatment was 6.3%. The incidence of retinopathy with pegylated interferon in patients without hypertension and diabetes is low, but the risk is higher in patients with diabetes and hypertension. Routine pretreatment fundoscopic screening may not be warranted in all patients and can be limited to the patients with these risk factors.

Introduction

In recent years, there have been significant advances in the treatment of chronic hepatitis C virus (HCV) infection. There are many new agents on horizon, and the novel interferon (IFN)-free regimens are being explored. But IFN-based regimens along with the new direct acting antiviral agents are likely to stay as part of hepatitis C treatment for the next few years.^[1–3] Currently, pegylated interferon alpha (PegIFNα) is a part of all the standard regimens for the treatment of HCV. The development of retinopathy is a well-known side effect of the PegIFNα therapy.^[4] However, the data report discordant results about the frequency and clinical significance of retinopathy seen during PegIFNα-based therapy. Retinopathy has been reported in 18–86% of patients with chronic HCV who received IFN-based treatment regimens, and the risk is even higher in diabetic and hypertensive patients.^[4–6] The wide range of frequency reported in the literature reflects the limitations of small studies, which are heterogeneous in selection of the patients and screening protocols for retinopathy. Given the inconvenience and cost associated with the ophthalmological screening, significance of IFN-associated retinopathy during HCV treatment and lack of screening or surveillance protocols, we conducted a systematic review to estimate the incidence of retinopathy in patients with chronic HCV being treated with PegIFNα or IFNα and its outcomes. We specifically reviewed incidence in various high-risk groups, pertinently in patients with associated diabetes mellitus (DM) and hypertension (HTN). We also studied the rate of discontinuation of the treatment due to the development of severe retinopathy and the outcomes of retinopathy after the treatment was completed or discontinued.

Methods

Electronic databases (PubMed and Scopus EMBASE, ISI Web of Science) were searched for the studies between January 1991 and December 2012 by two independent investigators (AR and SM). The search terms used were hepatitis C, HCV, Interferon, interferon alpha, pegylated interferon, pegylated interferon alpha and retinopathy and their Boolean combination. The search was limited to the studies published in English. Related abstracts presented at meetings were also reviewed. In addition, a manual search was performed for cross-references from publications.

Study Selection

We selected the studies reporting the incidence of retinopathy in patients with chronic HCV, who were treated with IFNα or PegIFNα with or without ribavirin. We included both retrospective and prospective observational studies.

Following inclusion criteria were used:

1. Retinal examination performed at baseline, which is prior to the initiation of treatment or within 1 week of the initiation of treatment.

2. Retinal examination performed at least once during treatment and at least once after the discontinuation or finishing the treatment.

Studies were excluded if:

1. The patient population had co-infection with hepatitis B (HBV) or human immunodeficiency virus (HIV).

2. History of liver transplantation.

3. Studies that did not meet the inclusion criteria for ophthalmological examination.

Outcome Measures

Following outcome measures were assessed

1. The pooled incidence of retinopathy in patients with chronic HCV treated with PegIFNα or IFNα.

2. The pooled Incidence of retinopathy in high-risk (patients with DM or HTN) and low-risk (patients without HTN or DM) groups treated with PegIFNα for chronic HCV.

3. The rate of resolution of retinopathy in patients treated with PegIFNα and IFNα.

4. The rate of discontinuation of PegIFNα and IFNα treatment.

Data Extraction

The data were systematically extracted and entered into the tables. The data included study type, year of publication, type of interferon used, retinopathy prior to the treatment, incidence of retinopathy on active treatment and the rate of resolution of retinopathy after discontinuation of the treatment. Retinopathy was defined as the presence of cotton wool spots, retinal haemorrhages or microaneurysm. Resolution of retinopathy was defined as disappearance of cotton wool spots, retinal haemorrhages or microaneurysms on the surveillance fundoscopic examination.

Data Synthesis and Statistical Analysis

The incidence of retinopathy for each study was calculated using the number of patients who developed retinopathy and the total number of patients treated with IFN. Data analysis was performed in Microsoft Excel using methodology described in details by Neyeloff et al.^[7] Proportions were compared using chi-squared test, and a P-value <0.05 was considered significant. Summary pooled incidence with 95% confidence interval (CI) was obtained. Heterogeneity was evaluated using Q statistic and I ² index. To take the effect of heterogeneity into consideration, random effects model was used for analysis.

Results

After careful review of the literature and applying the inclusion and exclusion criteria, only 21 studies were selected (see Table 1 for all the citations). There was wide geographical spread; seven studies from Asia, six from Europe, five from USA, two from Africa and one study from Canada. Ten studies used PegIFNα, eight studies used IFNα, and three studies used a combination of PegIFNα and IFNα to treat the patients with chronic HCV (Table 1). Overall incidence of retinopathy was calculated in studies that used PegIFNα or IFNα either alone or in combination with ribavirin. Incidence of retinopathy was calculated in diabetic and hypertensive patients^{[4, 10, 11, 18, 25]} as well as nonhypertensive and nondiabetic patients^{[4, 10, 18, 25]} in the PegIFNα treatment studies that provided pertinent clinical information.

Overall Incidence of Retinopathy

There were a total of 1382 patients in 21 studies that received either IFNα or PegIFNα. The incidence of retinopathy ranged from 2.6% to 61.1% among studies using random effect model (heterogeneity I ² = 17.9%). The overall incidence of retinopathy using random effect model was 27.7% (95% confidence interval [CI] 20.9–34.5%).

PegIFNα vs IFNα

The pooled incidence of retinopathy in 10 studies (Fig. 1, 608 patients) that exclusively used PegIFNα was 20.7% (95% CI: 19.8–21.6). The pooled incidence of retinopathy in eight studies that exclusively used IFNα was 41.6% (95% CI: 28.8%–54.5%), which was significantly higher than PegIFNα-treated group (P < 0.0001).

Figure 1. The incidence of retinopathy in PegIFNα treated patients.

Incidence of Retinopathy in High-risk and Low-Risk Groups With PegIFNα Treatment

Only five of the ten studies^{[4, 10, 11, 18, 25]} looked at the incidence of retinopathy in diabetic and hypertensive patients (Table 2). Among these patients, 84 had HTN and 38 had DM. Some of these high-risk patients had overlap of both diseases, but the information about this was not provided in all studies. The incidence of retinopathy in diabetic and hypertensive patients was 65.32% (95% CI: 39.6–91) and 50.7% (95% CI: 39.6–61.8), respectively (Table 3). Four of these five studies looked at the incidence of retinopathy in patients without HTN or DM.^{[4, 10, 18, 25]} The incidence of retinopathy in this low-risk group was 11.7% (95% CI: 6.4–17). The incidence of retinopathy in diabetic and hypertensive patients (high-risk group) was significantly higher compared with the patients without these risk factors (P < 0.0001 and P < 0.0001, respectively).

Resolution of Retinopathy in Patients Treated With IFNα/PegIFNα

Estimates of resolution of retinopathy were reported in 17 studies (Table 1). Pooled data from these studies included 260 patients that developed retinopathy, of which retinopathy resolved in 233 patients. Pooled estimate for resolution of retinopathy was 87% (95% CI 75.7–98.4%). Data on resolution of retinopathy were reported in eight studies that used PegIFNα. Among 92 patients that developed retinopathy with PegIFNα, retinopathy resolved in 77 patients after completion or discontinuation of treatment. The pooled estimate of resolution was 81.9% (95% CI 63.4–100%). Resolution rate in subgroups (high-risk vs low-risk) was not performed due to small sample size.

The Rate of Treatment Discontinuation

Overall, 6.3% (n = 8) and 1.9% (n = 3) of the patients discontinued treatment in PegIFNα and non-PegIFNα groups, respectively. Reasons to discontinue the PegIFNα treatment included patient request (n = 4), retinal vein occlusion (n = 2), transient visual loss (n= 1) and per study protocol (n = 1). The reason to discontinued IFNα treatment was related with worsening retinopathy.

Discussion

Interferons belong to a large group of glycoproteins with antiviral, anti-tumour and immune modulatory effects. Upon contact with a virus, innate immune system activates and produces cytokines, chemokines and IFNs. IFNs turn on hundreds of interferon-stimulating genes (ISGs) through JAK-STAT pathway. The products of ISGs act on multiple steps of viral life cycle to counter replication. Side effects of IFNs include influenza-like syndrome, haematological, psychiatric, cardiovascular, endocrine and ophthalmological abnormalities. The exact mechanism of IFN-associated retinopathy is not known. Ikebe and colleagues reported the first case of IFN-associated retinopathy in a 39-year-old woman who developed cotton wool spots and retinal haemorrhages after intravenous administration of IFN in 1990.^[26] In 1993, Miller et al.^[27] showed that systemic administration of IFNα successfully inhibited angiogenesis in an experimental model of iris neovascularization. For its antiangiogenic effects, IFNα has been used to stop the subretinal neovascularization in the treatment of age-related macular degeneration.^[28] Later, Guyer et al.^[29] used fluorescein angiography in patients who developed retinopathy after IFN administration for reasons other than HCV and showed areas of retinal ischaemia and poor perfusion. Nishiwaki et al.^[30] showed increased trapping of leucocytes in the retinal microcirculation of rats after the administration of IFNα. The trapping of leucocytes was dose dependent; the authors postulated that this might be related to impairment of the retinal microcirculation. Nagaoka et al.^[13] studied the effects of IFN on retinal microcirculation in patients with chronic HCV receiving treatment. They showed that wall shear stress increased significantly within 2 weeks of treatment initiation. Their findings suggested endothelial dysfunction as a cause of IFN-associated retinopathy. IFN-associated retinopathy was more frequent in patients with DM or HTN in the previously reported studies.

Abe et al.^[31] demonstrated that patients with chronic HCV infection had a higher incidence of retinopathy compared with the age- and sex-matched controls, independent of the IFN treatment. Similarly, Purtscher-like retinopathy was reported in a chronic HCV patient with cryoglobulinemia who was not on IFN treatment. Authors of the above two studies suggested an immune complex mediated ischaemic injury to the retina. HCV has been isolated from the lacrimal secretions and tears of the patients with chronic HCV infection,^[32] but we do not know of any study demonstrating active replication of HCV in the retinal epithelial cells causing retinopathy.

The incidence of retinopathy related to IFNα or PegIFNα has been variably reported in the literature, and there is no consensus on screening and surveillance protocols in such patients.^{[4, 8, 9]} A recent study by Vujosevic et al.^[4] reported a very high incidence (30%) of retinopathy in 97 patients with chronic HCV during PegIFNα and ribavirin treatment. The frequency of the development of retinopathy was even higher among hypertensive patients (68%) during serial ophthalmological examination. Based on these findings, the authors not only recommended baseline ophthalmological examination in all patients with HTN but also serial fundoscopic examinations at 3-month intervals during the treatment period. They further suggested continuing the fundoscopic examination 3 months after the end of treatment if the patient developed any retinopathy during the treatment period, regardless of any visual symptoms. On the contrary, Panetta et al.^[9] reported a very low incidence (3.8%) of retinopathy among 183 patients with chronic HCV treated with PegIFNα and ribavirin. Moreover, patients with HTN and DM were not at higher risk of IFN-associated retinopathy. The authors concluded that pretreatment and during treatment, fundoscopic examinations were not necessary in asymptomatic patients, even in the presence of HTN and DM. The study by Vujosvic et al. was prospective and evaluated both symptomatic and asymptomatic patients, while the study by Panetta et al. was retrospective and ophthalmological examinations were only carried out in symptomatic patients. This wide variation in the frequency of retinopathy is due to the differences in study designs, patient population and protocols for evaluation of retinopathy.^{[4, 9]}

The result of this systematic review highlights some important points (i) The overall incidence of retinopathy during IFN (IFNα and PegIFNα) treatment and ribavirin is around 27%. The risk is higher in patients treated with standard IFNα but much lower in patients treated with the current standard of care, PegIFNα. The precise mechanism by which IFN causes retinopathy is unknown, but it is thought to be related to microvascular changes in the retinal circulation.^[4] The difference between the incidence of retinopathy between PegIFNα and IFNα may be explained by their pharmacokinetics. PegIFNα is a once a week subcutaneous injection with a steady release, and IFNα is administered at least three times a week with a shorter half-life and higher peak concentration. (ii) The risk of development of retinopathy in patients without DM and HTN is low, and the frequency of retinopathy increases with coexisting DM and HTN. (iii) The IFN-related retinopathy is not a progressive disease, and most of the patients had spontaneous resolution of retinopathy after finishing the treatment. (iv) A significant number of patients developed retinopathy on treatment with IFN, but only a few patients discontinued treatment. In our literature review, only three patients in the PegIFNα group had to discontinue treatment due to worsening retinopathy, and all three of them developed visual symptoms during the treatment. The other five patients in the PegIFNα group discontinued treatment due to nonmedical reasons (patient preference and per study protocol). Even in the study of Vujosevic et al., despite a very high incidence of the retinopathy, only one patient had to stop treatment. This patient came to medical attention because he developed significant visual symptoms. It appears that the development of visual symptoms is a key finding during the treatment and necessitates a complete fundoscopic examination regardless of co-morbidities or pre-existing retinopathy.

The current study has limitations. Studies included had variable design and patient population giving rise to incidence rates with wide dispersion. We used random effects model for all our analysis to account for this heterogeneity. All the studies did not provide information about the presence of risk factors such as HTN and DM. Most of the studies also did not provide information regarding which patients had both HTN and DM.

In conclusion, pooled analysis of studies suggests that incidence of retinopathy with PegIFNα is low, especially among patients without underlying DM or HTN. Results also highlight that retinopathy is mostly a temporary and asymptomatic complication, if it is not associated with visual symptoms. Based on these findings, we recommend that baseline screening for retinopathy should only be performed in high-risk group (with HTN and DM) prior to the initiation of the treatment. Low-risk group does not need any baseline screening evaluation. Also, we recommend against the serial fundoscopic examinations in both high-risk and low-risk groups during the treatment. We recommend complete ophthalmological evaluation in any patient who develops visual symptoms during treatment.

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ICAAC to Feature Higher Cure Rate Options for Hepatitis C

Medscape Medical News > Conference News

Jim Kling

Aug 28, 2013

DENVER, Colorado — New therapeutic regimens are in the works to permanently curb many hepatitis C infections. Delegates attending the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) will be privy to the latest, cutting-edge information.

"There will be a symposium on what every infectious disease physician should know about treating hepatitis C," Robin Patel, MD, vice chair of the ICAAC program committee, told Medscape Medical News.

Current hepatitis C therapy consists of a protease inhibitor, pegylated interferon, and ribavirin, but the adverse effects of flu-like symptoms and anemia are poorly tolerated by some patients and disqualify others because of comorbidities. "Response rates are very good, but we are limited in who we can treat because of side effects and required length of therapy," explained session comoderator Kimberly Brown, MD, chief of gastroenterology and hepatology at the Henry Ford Hospital in Detroit, Michigan.

New therapies are shorter in duration and eliminate interferon but still lead to high cure rates. New therapies will be administered orally and target hepatitis C genotypes 2 and 3; genotype 1 will be treated with an oral agent, interferon, and ribavirin, but for a shorter period of time. The new regimens should have a higher cure rate than the current regimen, and be applicable to a wider patient population, according to Dr. Brown.

More Cures

The developments are good news for patients. "Cures have been associated with improved liver histology, better liver function, reduced rates of liver cancer, and overall improved survival," said Dr. Brown. "Patients who have previously not been candidates for treatment because of their other medical conditions are looking forward to access to therapies they can tolerate."

The new drugs and regimens have been in development for years, but they are coming to the market more rapidly now because the shorter treatment duration makes it possible to test them more quickly for safety and efficacy.

“This is really a huge change in clinical practice.”

"This is really a huge change in clinical practice," said Dr. Patel.

The ICAAC, which runs from September 9 to 13, will host delegates from 80 different countries. Of the 5000 people expected to attend, about 3000 will be from outside the United States.

"Over the years, the ICAAC has become a very international meeting," said Dr. Patel. "There are people literally from everywhere around the globe. I always learn so much from all the attendees, but especially the international attendees. I think our big international presence is a bit different from other meetings."

Because infections spread from country to country and continent to continent, it is important to stay up to date on current research, pointed out Dr. Patel, who is professor of medicine and microbiology at the Mayo Clinic in Rochester, Minnesota. A microbial agent that is currently absent in the United States could arrive any time, she cautioned.

The meeting will feature plenaries, oral sessions, and posters. In all, more than 1500 abstracts will be presented. Studies will outline which treatment regimens have been modified so that existing drugs can be applied to novel infectious agents.

Pharmacology will have a big presence at the meeting. "You can come up with new ways of giving an old drug that will make it work better or will work against organisms that we didn't traditionally think it would work against, " said Dr. Patel. "This can include a novel way of administering the drug — for instance, using prolonged infusion."

Updates on novel vaccines and vaccine trials will cover various disease organisms, including some with no current vaccines, such as tuberculosis.

There will be a keynote lecture on the future of antimicrobial therapies by Fernando Baquero, MD, from Ramón y Cajal Institute for Health Research in Madrid, Spain. There will also be a lecture on the importance of innovation in the treatment of infectious diseases in developing countries by Trevor Mundel, MD, president of global health at the Bill and Melinda Gates Foundation.

In a special session on Escherichia coli, James Johnson, MD, professor of medicine at the University of Minnesota in Minneapolis, will describe 3 pathotypes of E coli and changes in E coli populations that can lead to increased virulence and antimicrobial resistance.

The ICAAC will have an extensive online presence. Six sessions will be streamed live and, after the meeting, more than 125 sessions will be available online.

For entertainment, conference organizers will host a game show. Infectious disease experts from around the world will be pitted against one another to answer trivia questions. In addition to fun, the show will provide "interesting and educational pieces about infectious diseases," Dr. Patel noted.

Dr. Patel has disclosed no relevant financial relationships. Dr. Brown reports being a consultant for Janssen, Merck, Vertex, Gilead, Salix, and Genentech; being on the speakers' bureau for Gilead; and receiving research support from Merck, Gilead, Mass Biologics, Vertex, and Eisai.

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New protease inhibitors showing promise for HIV/HCV coinfection

Provided by Healio

August 28, 2013

This is an exciting time in the treatment of chronic hepatitis C virus infections. As opposed to the antibiotic pipeline, there are a number of new antiviral agents for treatment of hepatitis C in development that may transform the way these patients are treated.

Chronic infection with HCV has emerged as a major cause of morbidity and mortality in those living with HIV infection. Approximately 15% to 30% of patients with HIV in the United States are estimated to be coinfected with HIV and HCV. All patients with HIV/HCV coinfection should be evaluated for HCV therapy because of the more rapid progression of liver disease in those with HCV alone, and because the successful treatment of HCV may also reduce the risk for hepatotoxicity from the use of HAART in these patients.

The treatment for HCV has become increasingly successful, but it is complex, particularly in the HIV coinfected patient who is often on multiple medications and has other barriers to care. Treatment of both HIV and HCV is feasible, although it can be complicated because of the high pill burden, drug interactions and overlapping adverse effects that require careful monitoring.

Available treatment options

The currently available treatment regimens for HCV leave much to be desired. They have poor safety profiles, tolerability issues and low success rates, particularly in the HIV/HCV coinfected patients. While the treatment of HIV has led to reduced mortality during the past 15 years, the treatment of HCV has essentially remained unchanged with pegylated interferon alfa plus ribavirin (PegIFN/RBV).

PegIFN/RBV is recommended for those HIV/HCV coinfected patients who are at the greatest risk for developing liver disease. Pegylated interferon has covalently bound molecules of polyethylene glycol that slow the metabolism of interferon, which permits a weekly dosing schedule, increased serum levels, and improved activity against HCV. The primary goal in HCV treatment is to achieve a sustained viral response, which is defined as an undetectable HCV RNA 24 weeks after the end of therapy. HCV treatment in HIV/HCV coinfected patients is complicated by low rates of treatment initiation, higher rates of contraindications to the medications and a low sustained virologic response in those who are treated for HCV.

The two newest agents available are boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex Pharmaceuticals), which are protease inhibitors specific for HCV. They were approved in the United States and Europe in 2011 for use in combination with PegIFN/RBV among HIV-negative patients with HCV genotype-1 infection only. The approval was based on randomized trials demonstrating that patients achieved a greater sustained viral response with triple therapy compared with standard dual therapy in those who were either treatment-naive or were treated previously, but were nonresponders. Despite not being FDA-approved for treatment of HIV/HCV coinfected patients, use of these agents in this patient population is evolving because of the disappointing success with standard treatment.

Evolving therapies for HIV/HCV

A newly published controlled trial conducted by Sulkowski and colleagues randomly assigned 60 patients with HIV and HCV genotype-1 infection to 12 weeks of pegylated interferon alfa-2a and ribavirin, plus either placebo or telaprevir, followed by 36 weeks of peginterferon with ribavirin. After 4 weeks of therapy, 68% of the patients in the telaprevir group had undetectable HCV RNA, whereas 0% of those in the control arm had this response. The sustained viral response was achieved in 74% of patients in the telaprevir treatment group vs. 45% of those in the control group. Reported adverse effects were more common with telaprevir-treated patients, specifically pruritus, dizziness, headache, nausea, rash and anemia. Telaprevir is a substrate and an inhibitor of CYP3A4 and p-glycoprotein enzymes, so interactions with antiretrovirals metabolized by these pathways may occur.

Drug interactions possible

To date, there is less published data available for treatment of HIV/HCV coinfected patients with boceprevir. A phase 2a study was presented at the 19th CROI meeting comparing boceprevir or placebo combined with PegIFN/RBV for the treatment of chronic HCV genotype-1 infection in adults. Ninety-eight patients were given 4 weeks of lead-in treatment with PegIFN/RBV, followed by 44 weeks of combination therapy of boceprevir 800 mg every 8 hours, plus PegIFN/RBV. Patients assigned efavirenz (Sustiva, Bristol-Myers Squibb) or other non-nucleoside reverse transcriptase inhibitors were not enrolled based on previous drug interaction studies.

The sustained viral response at week 12 was higher in the boceprevir treatment group (67.7%) compared with PegIFN/RBV alone (26.5%). Reported adverse effects were common among patients who received boceprevir, with a greater frequency of anemia, neutropenia, pyrexia, decreased appetite, diarrhea, vomiting, and taste disturbances. Boceprevir is metabolized by aldo-keto reductase, but it is also a substrate and inhibitor of CYP3A4/5 and p-glycoprotein enzymes, so drug-drug interactions may occur. When boceprevir is administered with efavirenz, and ritonavir-boosted regimens of atazanavir, darunavir (Prezista, Janssen Therapeutics), lopinavir and raltegravir (Isentress, Merck), bidirectional interactions occur, so concomitant use is not recommended. If patients are taking an HIV protease inhibitor along with boceprevir, then consideration should be given to changing the HIV protease inhibitor or efavirenz to raltegravir.

Telaprevir and boceprevir are the first generation of direct-acting antiviral agents that have improved the sustained viral response for HCV genotype-1 infections. However, PegIFN/RBV treatment is still required. Although use of telaprevir or boceprevir in the HIV/HCV coinfected patient would be considered off-label, consideration should be given to utilizing these agents when HCV treatment is desired because the current evidence shows a substantial improvement in treatment success.

However, use of these medications along with PegIFN/RBV presents several challenges such as substantial side effects, drug-drug interactions and increased costs. There are several direct-acting antiviral agents in the pipeline that will likely yield higher sustained viral response, shorter treatment durations, lower pill burden and improved safety profiles. Until they are available, careful selection of patients who may benefit from a HCV-specific protease inhibitor may help improve the outcomes of the HIV/HCV infected patient.

- By Jeff Brock, PharmD

References:

Ghany MG. Hepatology. 2011;54:1433-1444.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
Sulkowski MS. Ann Intern Med. 2013;159:86-96.
Sulkowski MS. J Infect Dis. 2013;207(suppl 1):s26-s32.

Disclosure: Brock reports no relevant financial disclosures.

Source

Here's Why Mosquitoes Can't Transmit HIV

By Christina Sterbenz | Business Insider – Thu, Aug 22, 2013 11:45 AM EDT

Getty Images/Tom Ervin

HIV/AIDS kills about 1.6 million people every year, according to the most recent World Health Organization data. Hopefully, high school health classes taught us all how to avoid contraction: Don't have random, unprotected sex or use dirty needles.

Mosquitoes function the same way as hypodermic needles though — They can both inject chemicals and extract blood. And if mosquitoes carry West Nile Virus and other blood-borne diseases, shouldn't they logically be able to transmit HIV, too?

Thankfully, we were reassured that that's not the case. Mosquitoes can not transmit HIV.

"It's definitely not a stupid question," Joe Conlon, former Navy entomologist and current technical advisor for the American Mosquito Control Association, told Business Insider.

Conlon explained that first of all, when a mosquito bites you, it draws your blood into its gut. Acids there kill the HIV virus. Plain and simple.

Even if the mosquito's stomach acids didn't render the virus harmless, it wouldn't be able to get back out of the insect.

That's because mosquitoes use two different tubes to suck up blood and to inject you with saliva that stops your blood from clotting up while it's drinking. Even if a mosquito had virus-containing blood from another human inside it, the blood would never exit the bug through its salivary glands and into your blood stream.

"For a mosquito to transmit a disease, it's gotta pick up the virus. The virus has to survive in the gut and then get outside the gut into the body cavity and then eventually into the salivary glands to be injected into something else. It's a very complicated process, and with HIV, it just doesn't happen," Conlon said.

Malaria parasites, on the other hand, are able to grow in the mosquito gut, then migrate specifically to the salivary glands to continue their lifecycle in another human.

Thank goodness HIV doesn't have that ability. If mosquitoes spread HIV the way they spread Malaria, we'd have a million more deaths every year on our hands.

Source

Japan conducts first operation of liver cells transplant to baby

English.news.cn   2013-08-23 21:18:06

TOKYO, Aug. 23 (Xinhua) -- Japan's National Center for Child Health and Development (NCCHD) said here Friday that it has successfully transplanted liver cells to a baby boy for the first time in Japan.

Akira Matsui, the NCCHD hospital chief, said they have safely conducted the operation that could develop into regenerative medicine using embryo-stem or induce pluripotent stem cells, according to Japan's Kyodo News Agency.

The center used some surplus liver cells left frozen after 14 living liver transplantations it conducted in and after May 2011 in the globally rare case.

The baby, whose liver failed to function properly, received the transplantation on Aug. 10, when he was 11 days old, and on Aug. 13.

The baby could be discharged from the hospital in a month and a half.

Editor: Yang Yi

Source

Janssen’s Simeprevir: Hep C Patients Hope It Is Worth the Wait

Randi Hernandez, MS, Associate Editor/Online

Published Online: Monday, July 8, 2013

Recent actions by the FDA to accelerate simeprevir’s journey to market may be instrumental in helping close the treatment gap for genotype 1 hepatitis C patients in need.

---

The hepatitis C (HCV) patient population is incredibly complex and diverse. Patients with genotype 1 chronic HCV—especially patients who have relapsed after prior interferon-based treatment—can be particularly difficult to cure.

The current standard of care for genotype 1 chronic HCV involves treatment with pegylated interferon and ribavirin plus a protease inhibitor, but a number of new agents in the pipeline have been creating a great deal of buzz in the HCV community. In fact, many physicians are encouraging their HCV patients to defer treatment (a practice known as “warehousing”) until these new, potentially more effective drugs are approved by the FDA.

These investigational agents reportedly have fewer side effects than the interferon-based therapies and appear to produce significantly higher sustained virologic response (SVR) rates in clinical trials. In addition, most of the new therapies can be taken orally. Before 2011, all HCV treatments required weekly injections.

If these new interferon-free medications are approved, their impact could be widespread. Indeed, uptake of the new therapies is expected to quadruple spending on HCV over the next 3 years, according to a recent drug trend forecast from Express Scripts.

Simeprevir, a protease inhibitor developed by Janssen and Medivir, is 1 of the prospective agents that has been creating a stir in the HCV community The FDA recently granted the drug priority review, which may accelerate its journey to market and help close the treatment gap for patients in need. Janssen is seeking approval for simeprevir administered once daily along with pegylated interferon and ribavirin to treat adult patients with genotype 1 chronic HCV with compensated liver disease.

Janssen’s HCV clinical development program has investigated simeprevir’s potential use in a number of different treatment combinations and HCV patient populations. Specialty Pharmacy Times recently corresponded with Gaston Picchio, hepatitis disease area leader at Janssen, to learn more about the development of simeprevir.

———————————————————-

SPT: What is novel about simeprevir?

GP: Currently available protease inhibitors are administered 3 times daily in the United States and 2 or 3 times daily in the European Union. If simeprevir is approved by the FDA, it would offer the option of a protease inhibitor–based regimen that includes simeprevir taken once daily for 12 weeks in combination with 24 or 48 weeks of pegylated interferon and ribavirin.

SPT: How does simeprevir compare with other protease inhibitors already on the market in terms of sustained virologic response?

GP: Simeprevir has not been investigated in a head-to-head study with other PIs already on the market.

In the QUEST-1 and QUEST-2 Phase 3 trials, the use of simeprevir led to sustained virologic response 12 weeks after the end of treatment (SVR12) in 80% and 81%, respectively, of treatment-naïve genotype 1 chronic hepatitis C adult patients with compensated liver disease, including all stages of liver fibrosis, when administered once daily with pegylated interferon and ribavirin. In the PROMISE Phase 3 trial, the use of simeprevir led to SVR12 in 79% of treatment-experienced genotype 1 chronic hepatitis C adult patients with compensated liver disease, including all stages of liver fibrosis, when administered once daily with pegylated interferon and ribavirin.

SPT: What is the anticipated FDA approval date for simeprevir? Will the drug’s Priority Review status affect this date?

GP: On March 28, 2013, Janssen announced it had submitted a New Drug Application (NDA) to FDA seeking approval for simeprevir with pegylated interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C in adult patients. In May, the FDA granted Priority Review to the NDA for simeprevir. 

Under the Prescription Drug User Fee Act, FDA review will begin approximately 60 days after receipt of the application and will aim to be complete within 6 months from when the review period begins, which for simeprevir is expected to be in late November.

SPT: Tell us something about the drug that may not have been included in the press releases from Janssen that you think is important to note.

GP: Simeprevir is being studied in combination with several direct-acting antiviral agents with different mechanisms of action, with and without ribavirin, as part of multiple interferon-free regimens. These include:

1. The Phase 2 COSMOS study of simeprevir and Gilead’s nucleotide inhibitor sofosbuvir (GS-7977) in treatment-naïve and previous null-responder genotype 1 HCV patients, including patients with cirrhosis;
2. A Phase 2 study of simeprevir and Bristol-Myers Squibb's NS5A replication complex inhibitor daclatasvir in treatment-naïve and previous null-responder genotype 1 HCV patients; and
3. A Phase 2a trial of simeprevir and TMC647055, Janssen R&D Ireland’s non-nucleoside polymerase inhibitor, with and without ribavirin in treatment-naïve genotype 1a and 1b HCV patients.

SPT: Were pegylated interferon and ribavirin added to therapy in both of the QUEST trials and the PROMISE trial?

GP: In QUEST-1, QUEST-2, and PROMISE, patients were randomized to receive one 150 mg capsule of simeprevir or placebo once daily plus pegylated interferon and ribavirin for 12 weeks, followed by pegylated interferon and ribavirin alone for either 12 or 36 weeks based on response-guided therapy. 

SPT: NDAs were submitted in both United States and Japan for simeprevir. What factors went into filing in these 2 areas in particular?

GP: In February, Janssen submitted a regulatory application to Japanese authorities for approval of simeprevir administered with pegylated interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C patients who are treatment-naïve, prior non-responders, or relapsed following treatment with pegylated interferon with or without ribavirin. This was the first worldwide regulatory application for simeprevir.

In March, Janssen submitted a New Drug Application to the FDA seeking approval of simeprevir administered once daily with pegylated interferon and ribavirin for the treatment of adult patients with genotype 1 chronic HCV with compensated liver disease.

Additionally, in April, Janssen submitted a Marketing Authorisation Application to the European Medicines Agency seeking approval for simeprevir administered as 1 capsule once daily with pegylated interferon and ribavirin for the treatment of genotype 1 or genotype 4 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis), with or without HIV-1 co-infection, who are treatment-naïve or who have failed previous interferon-based therapy.

SPT: It has been said that simeprevir treatment will be part of an “interferon-free regimen.” Could you please explain what this means and the benefit of not using an interferon regimen to treat HCV?

GP: As a result of the complexity and diversity of the patient population, a proportion of patients with HCV do not tolerate interferon-containing regimens. Therefore, physicians need multiple treatment options, including interferon-free ones, in order to provide their patients the best possible chance at successful therapy.

Source

Medivir announces interim results from Cohort 2 of the COSMOS study evaluating Simeprevir and Sofosbuvir in HCV patients with METAVIR scores F3-F4

Press Release 28 August 2013

Medivir announces interim results from Cohort 2 of the COSMOS study evaluating Simeprevir and Sofosbuvir in HCV patients with METAVIR scores F3-F4

• In Hepatitis C patients with advanced liver fibrosis or cirrhosis (METAVIR  F3 or F4) 12 weeks all oral treatment with simeprevir and sofosbuvir with or without ribavirin led to SVR4 rates of 96% and 100%, respectively
• Once-daily simeprevir and sofosbuvir with or without ribavirin was generally safe and well tolerated

Stockholm, Sweden — Medivir AB (OMX: MVIR) today announced interim results from the second Cohort in the ongoing COSMOS study evaluating a once daily combination of simeprevir and sofosbuvir in hard to cure hepatitis C (HCV) patients.

SVR4 results from the 12 week arms of Cohort 2, including treatment naïve or previous null responder HCV patients all with METAVIR score F3-F4 were reported. Treatment for 12 weeks with simeprevir and sofosbuvir, with or without ribavirin, led to SVR4 rates of 96% and 100%, respectively.

Interim results from Cohort 1 of the COSMOS study, which include only prior null responder HCV patients (METAVIR F0-F2) have been reported earlier and demonstrated SVR8 rates of 96% and 93% after 12 weeks treatment simeprevir and sofosbuvir with and without ribavirin, respectively.

“The high SVR rates seen in genotype 1 prior null responders and treatment-naïve patients with advanced liver disease, in the COSMOS study and the safety profile of the combination are highly encouraging. We look forward to the final results of this study in difficult to cure patients.” says Charlotte Edenius, EVP Development, Medivir AB.

COSMOS - Study Design

COSMOS is a randomized, open label, phase IIa clinical trial evaluating a once-daily combination of the HCV protease inhibitor simeprevir and the nucleotide sofosbuvir with and without ribavirin (RBV) for 12 and 24 weeks. Cohort 1 (n=80) evaluates prior null responder genotype 1 hepatitis C (HCV) patients with METAVIR scores F0-F2 and Cohort 2 (n=87) evaluates prior null responder and treatment-naïve genotype 1 hepatitis C patients with METAVIR scores F3-F4. The METAVIR score is used to quantify the degree of inflammation and fibrosis of the liver. Liver fibrosis is scored on a four-point scale.

At the time of the interim analysis, SVR4 results were available for all patients (n=41) in the 12 week arms of Cohort 2. In this Cohort, 78.2% of patients had GT1a subtype with 40% of those having a Q80K baseline polymorphism, 79.3% had IL28B CT or TT genotype, 47.1% had Metavir score F4 (cirrhosis) and 54.0% were prior null responders.

In the previously reported Cohort 1, 77.5% of the patients had GT1a subtype with 50% of those having a Q80K baseline polymorphism, 93.7%, had IL28B CT or TT genotype and 58.8% had METAVIR score F2.

COSMOS - Summary Interim Results: Efficacy

Efficacy results with 150 mg simeprevir (SMV) and 400 mg sofosbuvir (SOF) once daily for 12 weeks with or without ribavirin (RBV). Intent-to-treat (ITT) population.

Cohort 1* Prior null responder HCV patients (METAVIR score F0-F2)		Cohort 2 Prior null responder and treatment naïve HCV patients (METAVIR scores F3 or F4)
	SMV / SOF+ RBV (n=27)	SMV / SOF (n=14)	SMV / SOF + RBV (n=27)	SMV / SOF(n=14)
SVR4	26/27(96%)	13/14(93%)	26/27(96%)	14/14(100%)
SVR8	26/27(96%)	13/14(93%)	-	-

* Data reported at the 20th Conference on Retroviruses and Opportunistic Infections (CROI) in March 2013 in Atlanta, USA. SVR: Sustained Virologic Response 4 or 8 weeks (SVR4 or SVR8) after end of treatment.

There were no viral breakthroughs in either Cohort. At the time of respective cut-off there was 1 relapse in Cohort 2, which was detected 4 weeks after end of treatment. As previously reported there were 2 relapses detected in Cohort 1 both at the 4 week time point after end of treatment.

COSMOS - Summary Interim Results: Safety
Once-daily simeprevir and sofosbuvir with or without ribavirin for 12 weeks was generally considered safe and well tolerated. Among events defined in the protocol as being of special interest, increased bilirubin was observed in 9.3% of the patients in the ribavirin containing arms, compared with 0%, for the non-ribavirin containing arms. Anemia was observed in 13.0% of the patients in the ribavirin containing arms, compared with 0% for the non-ribavirin containing arms.   

For more information please contact:
Rein Piir, EVP Corporate Affairs & IR Mobile: +46 708 537 292.

About Simeprevir
Simeprevir is a new generation NS3/4A protease inhibitor jointly developed by Medivir and Janssen R&D Ireland, part of the Janssen Pharmaceutical Companies for the treatment of chronic hepatitis C in adult patients with compensated liver disease.

For additional information about simeprevir clinical trials, please visit www.clinicaltrials.gov.

About Sofosbuvir
Sofosbuvir (formerly referred to as GS-7977) is a once-daily nucleotide analog polymerase inhibitor for the treatment of HCV infection being developed by Gilead Sciences, Inc. Sofosbuvir is being evaluated as part of multiple therapeutic regimens, including programs with RBV alone and in combination with peg-IFN and RBV.

About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease and liver transplants, is a rapidly evolving treatment area with a clear need for innovative treatments. Approximately 150 million people are infected with hepatitis C worldwide, and 350,000 people per year die from the disease.

About Medivir
Medivir is an emerging research-based pharmaceutical company focused on infectious diseases.

Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor in late phase III clinical development for hepatitis C that is being developed in collaboration with Janssen R&D Ireland. Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

For more information about Medivir AB, please visit the Company’s website: www.medivir.com

Source

HCV: Interferon-Free Regimen Works in Hard-to-Treat Patients

Medscape Medical News

Nancy A. Melville

Aug 27, 2013

Patients with chronic hepatitis C (HCV) in a traditionally difficult-to-treat population respond well to an interferon-free oral treatment regimen of sofosbuvir and ribavirin, according to research published in the August 28 issue of JAMA.

"Because treatment of HCV is evolving from an interferon-based combination therapy to an all-oral, interferon-free directly acting antiviral agent regimen, these results are encouraging and provide important information regarding the expected treatment responses in a population representative of the US epidemic," Anuoluwapo Osinusi, MD, MPH, from the National Institutes of Health, Bethesda, Maryland, write.

The 2-part, open-label phase 2 study involved 60 treatment-naive patients with HCV genotype 1. Among the participants, 83% were black, 66% were men, 23% had advanced liver disease, 48% had a body mass index of 30 kg/m² or higher, 70% had HCV genotype 1a, and 62% had baseline HCV RNA levels of 800,000 or higher.

In the first part of the study, 10 patients with early to moderate liver fibrosis were treated with 400 mg/day sofosbuvir and ribavirin dosage based on weight for 24 weeks. The 50 participants in the second part of the study had all stages of liver fibrosis and were randomly assigned 1:1 to receive 400 mg sofosbuvir with either weight-based ribavirin or low-dose 600 mg/day ribavirin for 24 weeks.

Nine participants (90%) in the first part of the study achieved a sustained virologic response (SVR), defined as an undetectable HCV viral load for 24 weeks after the completion of treatment. In the second part of the study, 68% (95% confidence interval, 46% - 85%) of the patients in the weight-based dosage group achieved SVR for 24 weeks compared with 48% (95% confidence interval, 28% - 69%) of the patients in the low-dose group (P = .20).

Seven (28%) participants in the weight-based group and 10 (40%) participants in the low-dose group relapsed after completing treatment. Baseline factors most associated with relapse included male sex, advanced liver disease, and high baseline HCV RNA levels.

The most common adverse events included headache, anemia, fatigue, and nausea. Although most adverse events were described as mild to moderate, 7 patients developed grade 3 adverse events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. There were no deaths or discontinuation of treatment resulting from adverse events, and the combination regiment was considered safe and well-tolerated.

"This study demonstrates the efficacy of an interferon-free regimen in a traditionally difficult-to-treat population while exploring the reasons for treatment relapse," the authors write.

"As new direct-acting antiviral agent regimens are being evaluated, it is important that these studies involve populations most affected by the disease."

Interferon has, among its disadvantages, weekly injections and fatigue from influenza-like symptoms, and it is furthermore contraindicated in patients with HCV who have advanced liver disease, making the findings on the new all-oral regimen even more encouraging, said Michael Saag, MD, clinical director for the Center for AIDS Research and the Division of Infectious Diseases at the University of Alabama at Birmingham.

"Anything that allows these people to have success without the injection is an important step forward," he told Medscape Medical News.

Although the overall rate of 68% achieving sustained virologic response was lower than that observed in populations with more favorable treatment predictors, it is still higher than is typically seen in the black male population, Dr. Saag noted.

"The SVR rate in this population is usually in the 40% to 50% range, due to some [genotype differences], so 68% is relatively good," added Dr. Saag, who is also a spokesperson for the Infectious Disease Society of America's hepatitis task force. "I think we're on the verge of a very exciting revolution in HCV care, and this is the first of what I believe will be several landmark articles that will change how we approach the treatment of this disorder over the next 5 years."

The study was funded by the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the German Research Foundation. One coauthor has reported serving as research consultant for Roche Pharma and Novartis. One coauthor has reported serving on the Gilead and Merck Advisory Boards and as a speaker for Gilead. One coauthor has reported serving as a speaker for Merck and performing research funded by Vertex pharmaceuticals. One coauthor has reported being a member of the Regional Advisory Boards for Abbott and Gilead. Three coauthors are employees of Gilead Pharmaceuticals. Dr. Saag disclosed that he has consulted for Gilead Pharmaceuticals in the past but was not involved in the current study.

JAMA. 2013;310:804-811.

Source

Also See:

Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics: A Randomized Clinical Trial (Journal of the American Medical Association-Abstract)

Investigational oral regimen for hepatitis C shows promise in NIH trial (NIH Press Release)

Vertex’s VX-135 partial hold signals heightened FDA scrutiny toward HCV drugs

August 27, 2013 3:35 pm

By Christine Livoti in New York

This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com

--------------------------------------------------------------------------------

Vertex Pharmaceuticals’ (NASDAQ:VRTX) hepatitis C virus (HCV) drug VX-135 and the recent partial clinical hold placed on it signal heightened FDA scrutiny toward HCV drugs, experts said.

Still, most experts expressed optimism the partial hold will be removed and that the 200mg dose will advance.

On 25 July, the company announced the FDA had issued a partial clinical hold on Vertex’s ongoing Phase II US study of VX-135, a nucleotide (nuc) pyrimidine analogue. The agency’s decision prevents evaluation of the 200mg dose, following observation of reversible elevated liver enzymes in patients receiving 400mg VX-135 in combination with ribavirin in a Phase II study in Europe. Evaluation of a 100mg dose in combination with ribavirin in the 12-week Phase II US study is continuing as planned, according to the press release.

Vertex recently completed dosing of 100mg and 200mg VX-135 in combination with ribavirin in the 12-week Phase II European study, and both doses were well tolerated with no discontinuations. No serious adverse events (SAEs) have been reported and no liver or cardiac safety issues have been identified, according to the release. An adverse event is any undesirable experience associated with a medical product. The event is considered serious when the outcome is death, hospitalization, disability or permanent damage and/or congenital anomaly, among other important medical events, according to the FDA. Following completion of enrollment in the 100mg and 200mg arms of the European study, the study was amended to evaluate a 400mg dose in combination with ribavirin in 10 patients. Elevated liver enzymes were observed in three patients in this dose group, including one SAE, and the study’s 400mg arm was discontinued. After discontinuation, liver enzyme levels returned to baseline in all three patients, according to the same release.

Continue reading full article here …..

Santaris Pharma A/S Completes Enrollment in Phase 2 Clinical Trial of Miravirsen

Santaris Pharma A/S Completes Enrollment in Phase 2 Clinical Trial of Miravirsen In Null Responders to Pegylated Interferon and Ribavirin for the Treatment of the Hepatitis C Virus

-- Enrollment also begins in study investigating miravirsen in combination with telaprevir and ribavirin in null responders to pegylated interferon and ribavirin --

Hørsholm, Denmark/San Diego, California, August 27, 2013 — Santaris Pharma A/S, a clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies, today announced the completion of enrollment of its Phase 2 miravirsen 12-week monotherapy study of miravirsen, a host-targeted, pan-HCV genotype antiviral agent, in subjects who were "null responders" to pegylated interferon alpha and ribavirin (peg-IFNα/RBV). The company also announced the enrollment of the first patient into another Phase 2 study of miravirsen in combination with telaprevir and ribavirin, also in null responders to peg-IFNα/RBV.

"The current standard of treatment for HCV is a combination of a direct acting-antiviral agent protease inhibitor with pegylated-interferon plus ribavirin. However, there remains a pressing need for therapeutic regimens that can attain high sustained virologic responses without peg-IFNα/RBV, which is poorly tolerated, and without drug-drug interactions. Miravirsen’s unique mode-of-action has shown potential in providing antiviral activity in patients who have failed previous treatment regimens for the hepatitis C virus," said Maribel Rodriguez-Torres, M.D., president of Fundacion de Investigacion and the study’s Principal Investigator. "We are excited to have completed enrollment and look forward to following the enrolled patients and reporting the data from this study. So far, the emerging viral load data suggest that miravirsen might be a unique treatment option, in combination with other antivirals, for the treatment of this type of difficult to treat patients."

The Phase 2, open-label study assesses the safety, antiviral activity and pharmacokinetics of miravirsen monotherapy over a total of 12 weeks of treatment. Patients enrolled in the study were chronically infected with HCV genotype 1 and had previously failed treatment with peg-IFNα/RBV therapy. Miravirsen was given as a total of five doses over five weeks, followed by a further four doses once every other week over seven weeks.

Developed using Santaris Pharma A/S proprietary Locked Nucleic Acid (LNA) Drug Platform, miravirsen is an inhibitor of miR-122, a liver specific microRNA that the hepatitis C virus requires for replication. Miravirsen is designed to recognize and sequester miR-122, making it unavailable to the hepatitis C virus. As a result, the replication of the virus is effectively inhibited and the levels of HCV RNA are profoundly reduced.

Santaris Pharma A/S has also enrolled its first patient into another Phase 2 clinical trial that will assess the safety, tolerability and antiviral activity of miravirsen given for 12 weeks in combination with telaprevir (TVR) and ribavirin (RBV) in patients with HCV infection who are non-responders to peg-IFNα/RBV.

"We are pleased to report on the progress in the miravirsen clinical program," said Michael R. Hodges, MD, Vice President and Chief Medical Officer at Santaris Pharma A/S. "We hope that data from these two 12-week studies in the hard to treat patients will confirm the earlier promising efficacy and safety data from the four-week monotherapy study in treatment naïve patients that was recently published in the New England Journal of Medicine. We continue to believe that miravirsen given in combination with direct acting-antiviral agent(s) has the potential to cure chronic HCV infection in hard-to-treat patients."

The first series of non-clinical and clinical studies demonstrated the following key attributes for miravirsen:

• Miravirsen has a novel mechanism of action, inhibits a well conserved hepatic host target thus has an high barrier to resistance with predicted activity against all HCV genotypes, is not metabolized by cytochrome P450 enzymes therefore drug interactions are unlikely
• In in vitro studies, miravirsen was active against all six HCV genotypes, additive activity to direct acting antiviral agents (DAAs), active against DAA resistant virus and a showed a high barrier to resistance
• In clinical trials with four weeks of monotherapy, miravirsen was well tolerated, showed dose dependent antiviral activity that can be maintained weeks after the end of therapy
• In two separate drug-drug interaction clinical trials, miravirsen showed no interactions with peg-IFNα/RBV or with telaprevir

About Hepatitis C

Hepatitis C infection is a viral disease caused by the hepatitis C virus that leads to inflammation of the liver. The World Health Organization estimates that approximately 3 percent of the world’s population have been infected with HCV and that some 170 million have chronic hepatitis C and are at risk of developing liver cirrhosis and/or liver canceri. Approximately 3-4 million Americans are chronically infected with an estimated 40,000 new infections per yearii. In Europe, there are about 4 million carriersi. The current standard of care treatment for genotype 1 is a protease inhibitor given with pegylated-interferon α and ribavirin. This triple combination is effective in about 70-80% of those treatedii. Even though in Europe and the United States genotype 1 is the most prevalent, there are 50-70 million people worldwide that are infected with a non-genotype 1 virus. In these patients, the combination of pegylated-interferon α and ribavirin remains the currently approved standard of care treatmentiii. Patients that are not effectively treated have an increased risk for the progression of liver disease. By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion^iv.

About microRNAs

MicroRNAs have emerged as an important class of small RNAs encoded in the genome. They act to control the expression of sets of genes and entire pathways and are thus thought of as master regulators of gene expression. Recent studies have demonstrated that microRNAs are associated with many disease processes. Because they are single molecular entities that dictate the expression of fundamental regulatory pathways, microRNAs represent potential drug targets for controlling many biologic and disease processes.

About Locked Nucleic Acid (LNA) Drug Platform

The LNA Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combines the company’s proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver LNA-based drug candidates against RNA targets, both mRNA and microRNA, for a range of diseases including cardiometabolic disorders, infectious and inflammatory diseases, cancer and rare genetic disorders. LNA is also sometimes referred to as BNA (Bicyclic or Bridged Nucleic Acid). LNA-based drugs are a promising new class of therapeutics that enable scientists to develop drugs that work through previously inaccessible clinical pathways. The LNA Drug Platform overcomes the limitations of earlier antisense and siRNA technologies to deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The unique combination of small size and very high affinity allows this new class of drugs candidates to potently and specifically inhibit RNA targets in many different tissues without the need for complex delivery vehicles. The most important features of LNA-based drugs include excellent specificity providing optimal targeting; increased affinity to targets providing improved potency; and favorable pharmacokinetic and tissue-penetrating properties that allow systemic delivery of these drugs without complex and potentially troublesome delivery vehicles.

About Santaris Pharma A/S

Santaris Pharma A/S is a privately held, clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies. The Locked Nucleic Acid (LNA) Drug Platform and Drug Discovery Engine developed by Santaris Pharma A/S combine the company’s proprietary LNA chemistry with its highly specialized and targeted drug development capabilities to rapidly deliver potent single-stranded LNA-based drug candidates across a multitude of disease states. The company’s research and development activities focus on infectious diseases and cardiometabolic disorders, while partnerships with major pharmaceutical companies address a range of therapeutic areas including cancer, cardiovascular disease, infectious and inflammatory diseases, and rare genetic disorders. The company has strategic partnerships with RaNA Therapeutics, Bristol-Myers Squibb, miRagen Therapeutics, Shire, Pfizer, GlaxoSmithKline, and Enzon Pharmaceuticals. As part of its broad patent estate, the company holds exclusive worldwide rights to manufacture and sell products that comprise LNA as active ingredient for studies performed with a view to obtaining marketing approval. Santaris Pharma A/S, founded in 2003, is headquartered in Denmark with operations in the United States. Please visit www.santaris.com for more information.

Santaris Pharma A/S® is a registered trademark of Santaris Pharma A/S. Santaris^TM, Santaris Pharma^TM, Cureon^TM and LNA-antimiR™ are trademarks of Santaris Pharma A/S.

Media Contacts: Liz Narrillos Roux, Edelman (liz.narrillosroux@edelman.com) - Office: (323)202-1074

Source

Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients With Unfavorable Treatment Characteristics: A Randomized Clinical Trial

Journal of the American Medical Association

Preliminary Communication | August 28, 2013

Anuoluwapo Osinusi, MD, MPH^1,2; Eric G. Meissner, MD, PhD¹; Yu-Jin Lee¹; Dimitra Bon, MS³; Laura Heytens, RN⁴; Amy Nelson, RN¹; Michael Sneller, MD¹; Anita Kohli, MD¹; Lisa Barrett, MD, PhD¹; Michael Proschan, PhD⁵; Eva Herrmann, PhD³; Bhavana Shivakumar, MS¹; Wenjuan Gu, PhD⁶; Richard Kwan, PAC⁴; Geb Teferi, MD⁷; Rohit Talwani, MD⁸; Rachel Silk, RN²; Colleen Kotb, RN²; Susan Wroblewski, RN¹; Dawn Fishbein, MD⁹; Robin Dewar, PhD⁶; Helene Highbarger, MS⁶; Xiao Zhang, MS¹; David Kleiner, MD¹⁰; Brad J. Wood, MD¹¹; Jose Chavez, MD⁷; William T. Symonds, PharmD¹²; Mani Subramanian, MD, PhD¹²; John McHutchison, MD¹²; Michael A. Polis, MD, MPH¹; Anthony S. Fauci, MD¹; Henry Masur, MD⁴; Shyamasundaran Kottilil, MD, PhD¹

[+-] Author Affiliations

¹Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
²Clinical Research Directorate/Clinical Monitoring Research Program, Science Applications International Corp (SAIC)–Frederick Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland
³Institute of Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe University, Frankfurt, Germany
⁴Critical Care Medicine Department, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, Maryland
⁵Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
⁶SAIC-Frederick Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland
⁷Unity Health Care Inc, Washington, DC
⁸Department of Infectious Diseases, University of Maryland, Baltimore
⁹Department of Infectious Diseases, MedStar Washington Hospital Center, Washington, DC
¹⁰Department of Pathology, National Cancer Institute, Bethesda, Maryland
¹¹Center for Interventional Oncology, Radiology and Imaging Sciences, NIH Clinical Center and National Cancer Institute, Bethesda, Maryland
¹²Gilead Sciences, Foster City, California

JAMA. 2013;310(8):804-811. doi:10.1001/jama.2013.109309.

Abstract

Objective  To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics.

Design, Setting, and Patients  Single-center, randomized, 2-part, open-label phase 2 study involving 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 enrolled at the National Institutes of Health (October 2011-April 2012).

Interventions  In the study’s first part, 10 participants with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. In the second part, 50 participants with all stages of liver fibrosis were randomized 1:1 to receive 400 mg of sofosbuvir with either weight-based or low-dose 600 mg/d of ribavirin for 24 weeks.

Main Outcomes and Measures  The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response of 24 weeks [SVR₂₄]).

Results  In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR_24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR₂₄ rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events.

Conclusion and Relevance  In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR₂₄ rates of 68% and 48%, respectively.

Trial Registration  clinicaltrials.gov Identifier: NCT01441180

Source

Also See: Investigational oral regimen for hepatitis C shows promise in NIH trial

Investigational oral regimen for hepatitis C shows promise in NIH trial

Embargoed for Release: Tuesday, August 27, 2013, 4 p.m. EDT

Side effects minimized with combination therapy in hard-to-treat patients

In a study of an all-oral drug regimen, a majority of volunteers with liver damage due to hepatitis C virus (HCV) infection were cured following a six-month course of therapy that combined an experimental drug, sofosbuvir, with the licensed antiviral drug ribavirin. The results showed that the regimen was highly effective in clearing the virus and well tolerated in a group of patients who historically have had unfavorable prognoses.

Scientists from the National Institute of Allergy and Infectious Diseases (NIAID) and the NIH Clinical Center, parts of the National Institutes of Health, led the Phase II trial. The findings appear in the Aug. 28 issue of the Journal of the American Medical Association (JAMA).

More than 3 million Americans have chronic HCV infection, a condition that is a major cause of cirrhosis (liver tissue scarring) and liver cancer, and a leading reason for liver transplantation. Deaths from HCV-related liver disease number about 15,000 every year. Standard treatment for HCV can last up to a year and usually involves weekly injections of pegylated interferon-alpha given with the oral drug ribavirin and an HCV protease inhibitor. Side effects from this treatment can be severe, notably from interferon-alpha, and can include depression, flu-like symptoms and anemia.

“There is a pressing need for hepatitis C virus treatments that are less burdensome to the patient, have fewer side effects and take less time to complete. Building on previous work, this trial provides compelling evidence that interferon-free regimens can be safe and effective,” said NIAID Director and study co-author Anthony S. Fauci, M.D.

The current study involved 60 volunteers with genotype-1 HCV, which tends to be less responsive to interferon-based treatment. Fifty of the 60 participants were African-American.

“While African-Americans make up about 13 percent of the U.S. population, they represent more than 22 percent of people with chronic HCV infection and, compared to whites, have lower cure rates with traditional HCV therapy,” said NIAID researcher Shyam Kottilil, M.D., Ph.D., the principal investigator of the trial. “Several recently completed trials testing interferon-free regimens have yielded promising results, but most volunteers in those studies were white.”

The new study also differs from many previous trials because it enrolled people with severe liver damage as well as those with mild or moderately scarred livers.

The study was divided into two parts. The first part enrolled 10 people with mild or moderate liver fibrosis. Volunteers received oral ribavirin at a dosage based on their weight along with the experimental drug sofosbuvir, also in pill form, taken daily for six months. Gilead Sciences, Inc., of Foster City, Calif., manufactures sofosbuvir and supplied it to the study physicians.

Nine volunteers completed the course of therapy. Virus was undetectable in all nine volunteers 12 weeks after the end of therapy and continued undetectable when they were tested again 24 weeks after finishing therapy. HCV does not integrate itself into human DNA. If the virus cannot be detected for a period of 12 weeks after stopping therapy, the patient is considered cured, Dr. Kottilil said.

The second part of the trial enrolled 50 volunteers, 13 of whom had liver damage rated as serious. Twenty-five received ribavirin based on their weight, and 25 received a low dose (600 milligrams per day). All received sofosbuvir.

“Because ribavirin can cause serious side effects, including anemia, we wanted to compare response rates in patients taking low-dose ribavirin with results from patients on a weight-based dosage,” said Dr. Kottilil.

At four, 12 and 24 weeks after the end of treatment, volunteers were tested for the presence of HCV. HCV levels were undetectable in 24 of the volunteers in the weight-based arm when treatment ended. Of those, 17 continued to have undetectable virus levels 24 weeks later and were considered cured of infection. In the low-dose arm, three volunteers dropped out of the study. Of the remaining 22, all responded to the treatment, but only 12 were considered cured at 24 weeks after the end of treatment.

“We saw an overall cure rate of about 70 percent using regimens that did not include interferon,” said Dr. Kottilil. “This is an encouraging result, especially considering the proportion of volunteers who had characteristics — such as being male, having HCV genotype-1 infection, being African-American and having advanced liver damage — that are recognized as predictors of poor response to treatment.”

Additional trials are underway to further determine if regimens without interferon or ribavirin can help people with chronic HCV infection, particularly those who have both HIV and HCV infections said Dr. Kottilil. These trials include two studies in which volunteers with or without HIV infection take a combination of HCV drugs (but no interferon or ribavirin) for periods of three months or less. Information about these trials is available at clinicaltrials.gov using the identifiers NCT01805882 and NCT01878799.

Further information about the HCV trial described in the current issue of JAMA is available at clinicaltrials.gov using the trial identifier NCT01441180.

NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website at http://www.niaid.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH...Turning Discovery Into Health^®

Reference

A Osinusi et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: A randomized clinical trial. JAMA DOI: 10.1001/JAMA.2013.109309 (2013).

Source

Also See: Investigational oral regimen for hepatitis C shows promise in NIH trial