November 1, 2013

Provided by The Motley Fool

By Amy Ho | More Articles
November 1, 2013

Following significant moves toward FDA approval for two hepatitis C agents last week -- sofosbuvir by Gilead Sciences  (NASDAQ: GILD ) and simeprevir by Johnson & Johnson (NYSE: JNJ )  -- competitor Vertex Pharmaceuticals (NASDAQ: VRTX ) is cutting jobs associated with its hepatitis C drug and changing focus to the hopefully more profitable and less competitive cystic fibrosis space.

Vertex knew this day was coming, as the race to a new hepatitis C treatment has had major players Gilead, Bristol-Myers Squibb, AbbVie, and Johnson & Johnson long vying for a new interferon-free agent.

Vertex's Incivek is a first-generation oral agent against hepatitis C that is still used in combination with interferon and thus is not completely interferon-free (which is the ultimate goal for new therapeutics, given the unpleasant flu-like side effects of interferon). Incivek, as well as Merck's Victrelis were both approved in 2011 as protease inhibitors to stop replication of the hepatitis C virus; the new agents coming down the pipeline work under a similar mechanism, but better and with potential to be independent of interferon.

While now clearly a short-term asset, Incivek was quite successful at initial release. Sales peaked at $456.8 million in 2011 and helped Vertex reach profitability. However, as physicians stopped starting new patients on the agent, waiting for newer agents to gain approval, Incivek sales quickly declined. This past quarter alone, sales were down 66%. The company is on a $124.1 million loss this quarter, and the 15% workforce cut and restructuring is expected to product a $150 million to $200 million reduction in operating expenses this year.

Meanwhile, Gilead is investing $47 million and 80 jobs for the manufacturing of sofosbuvir, which achieved a unanimous recommendation from a panel of experts at the FDA last week. While sofosbuvir was tested in conjunction with interferon, it is expected to be the first-in-class oral, interferon-free hepatitis C treatment. Peak annual sales are estimated at $7 billion.

J&J's simeprevir also got unanimous support from an FDA panel, although it targets a narrower class of genotypes for hepatitis C. Both drugs will likely gain FDA approval this year. To seal the coffin, Bristol-Myers Squibb and AbbVie are both expected to file New Drug Applications next year and around 20 agents are in the hepatitis C pipeline.

It is no wonder Vertex is moving away for this quickly crowded space. In the release announcing the cost-cutting measures, CEO Jeffrey Leiden indicated his vision for opportunity in cystic fibrosis. Most likely he was referring to Kalydeco, a treatment for the genetic disease that was approved last year. So far, its 2013 total sales are growing at $261 million, already well surpassing the $171 million in total 2012 sales. Sales more than doubled for Kalydeco this quarter, to $101.1 million and Vertex's force for 2013 is $365 million in sales.

While a smart move, the shift will still likely take a toll just due to the smaller market for cystic fibrosis. Around 170 million people are infected worldwide with hepatitis C, as opposed to about 70,000 worldwide for cystic fibrosis. Patients can live a normal lifespan with hepatitis C, whereas cystic fibrosis is longevity-limiting -- the median age of survival for cystic fibrosis is in the 30s.

One big growth stock you need to watch
This incredible tech stock is growing twice as fast as Google and Facebook, and more than three times as fast as Amazon.com and Apple. Watch our
jaw-dropping investor alert video today to find out why The Motley Fool's chief technology officer is putting $117,238 of his own money on the table, and why he's so confident this will be a huge winner in 2013 and beyond. Just click here to watch!

Fool contributor Amy Ho has no position in any stocks mentioned. The Motley Fool recommends Gilead Sciences, Johnson & Johnson, and Vertex Pharmaceuticals. The Motley Fool owns shares of Johnson & Johnson. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.

Source

Gilead's Hepatitis C Drug Continues to Impress

Fri, 11/01/2013 - 12:00pm

ddd1310-gilead

Gilead's new drug therapies continue to show promise for some hepatitis C sufferers whose transplanted livers are threatened by a recurrence of the disease, including some patients who have had no treatment options.

These encouraging findings are contained in two new studies by a collaboration of researchers across the U.S.—as well as in Spain and New Zealand—including Dilip Moonka, MD, medical director of Liver Transplant at Henry Ford Hospital. Both studies are being presented at the annual meeting of the American Association for the Study of Liver Disease being held in Washington, DC, Nov. 1-5.

The studies focused on Gilead Pharmaceutical’s experimental anti-viral drug sofosbuvir, a direct-acting oral medication that may take the place of injectable interferon, which causes severe side effects in some patients.

The U.S. Food and Drug Administration is expected to decide in early December whether to approve its use for treating hepatitis C. Last week, the Antiviral Drugs Advisory Committee of the FDA voted unanimously in support of approval for sofosbuvir-based therapies for the treatment of chronic hepatitis C.

Chronic hepatitis C is a blood-borne viral disease that leads to scarring and deterioration of the liver. It is particularly insidious because patients usually don't develop symptoms until the scarring—or cirrhosis—is well underway.

Sofosbuvir, which belongs to a class of drugs known as nucleotide analogue polymerase inhibitors, acts at the molecular level by interfering with the RNA of the hepatitis C virus.

Interferon alternative
In the first newly released study, researchers tested it as an alternative to interferon, a naturally occurring protein that plays a role in fighting viral infections, but commonly produces a range of serious side effects.

The researchers used it in combination with ribavirin, which also inhibits the hepatitis C virus by interfering with its RNA to stem the replication of the virus and slow the progression of the disease. They sought to test the drug combination's effectiveness in preventing recurrence of hepatitis C in liver transplant recipients.

A total of 61 chronic hepatitis C patients with liver cancer were enrolled in the study and given both sofosbuvir and ribavirin daily for up to 48 weeks before liver transplant. All of the patients had well-compensated cirrhosis, meaning their bodies were still functioning without too much trouble despite liver scarring.

The researchers found that the new drug combination was both safe and effective in such patients and prevented post-transplant recurrence of the hepatitis C virus in more than 60 percent of them.

No other option
In the second newly released study, researchers focused on liver transplant recipients whose severe hepatitis C recurred after surgery and who either couldn't tolerate or didn't respond to approved antiviral therapies—leaving them with no other effective treatment options.

In such cases, experimental drugs can sometimes be tested under "compassionate use" protocols.

The researchers reported that as of April, 115 patients were approved for compassionate use of sofosbuvir combined with ribavirin and/or the anti-viral drug peginterferon. At the time of their report, 63 had started treatment.

After several weeks of treatment and study, the researchers concluded that patients with severe recurrence of hepatitis C after receiving transplanted livers were able to tolerate the drug regimen, which produced strong anti-viral effects.

Date: October 31, 2013
Source: Henry Ford Health System

Source

Also See:

Prison needle exchange programs rare despite evidence

October 29, 2013

119078180

Although the UN and WHO advocate for needle and syringe exchanges for inmates, only 60 prisons of more than 10 000 worldwide have programs.

Photo Credit: © 2013 Thinkstock

Clean needle distribution in prisons is "poor and patchy" around the world, despite evidence that it reduces the spread of infectious diseases and does not increase drug use, an international expert told a panel discussion in Toronto, Ontario.

"There's a big gap between what is being recognized at the UN [United Nations] level and what is going on, on the ground," Heino Stöver, a professor at the University of Applied Sciences in Frankfurt, Germany, recently told an audience at the Dalla Lana School of Public Health.

Although the United Nations Office on Drugs and Crime and the World Health Organization (WHO) both advocate for needle and syringe exchanges for inmates, only 60 prisons out of more than 10 000 worldwide have launched programs since Switzerland set up the first one in 1994, said Stöver. Switzerland, Spain, Kyrgyzstan, Moldova, Romania, Portugal and Luxembourg all have needle exchange programs in at least one prison.

Germany ended six of its seven programs in the past decade. "They were politically controversial but not professionally controversial. We have very fine evidence that they were working," said Stöver, who has advocated for prison needle exchanges since he was "a young man … throwing syringes over the prison walls."

A WHO review of 55 European prison needle exchange programs found no reported increase in drug use and no negative unintended consequences. No needles were used as weapons, for example.

Among Canadian inmates, 30% of males and 34.9% of females have contracted Hepatitis C, compared to .95% of men and .61% of women in the general population. The figures for inmates are based on Correctional Service Canada's 2008 statistics, the most recent available, compared with 2007 figures for the general population. For HIV, the rates are 1.7% (males) and 4.7% (females), compared to 0.2% in the Canadian population.

Canada does not offer needle exchange programs in any prison. The absence of such programs is the subject of a current lawsuit that prisoner, HIV/AIDS and Aboriginal advocacy groups have launched. They hope a successful suit will force federal prisons to implement needle exchanges.

Correctional Service Canada "has a comprehensive anti-drug strategy ... providing needles for illicit drug use run counter to that strategy," spokesperson Melissa Hart writes in an email.

The lawsuit argues that prisoners are entitled to the same standards of essential health care as in the wider community, and that the 200 needle exchange programs available across Canada are part of this essential health package, says Lisa Kerr, a lawyer and academic who studies approaches to incarceration and justice.

In addition, lawyers have pointed to the Canadian Charter of Rights and Freedoms, arguing dirty needles in prisons makes life worse for indigenous people, for women, and for people with disabilities, Kerr told the panel in Toronto. Indigenous people, who make up 4% of the Canadian population, account for 23% of the prison population.

Current methods of reducing infections have shortcomings. Machines that dispense bleach and condoms, for example, are sometimes located near cameras and prisoners worry about increased surveillance if they use them. The dispensing machines are also frequently empty, said Seth Clarke, the community development coordinator for the Prisoners' HIV/AIDS Support Action Network.

Furthermore, bleach is not 100% effective in eliminating Hepatitis C, and the "best practice" method of cleaning, rinsing and cleaning again is not pragmatic for the "quite hastily" way prisoners  use needles, Clarke said. After all, drug use and tattooing are both illegal in prisons.

In addition to providing needle exchange programs, prison authorities should help rather than punish addicts, argued Clarke. For example, when a prisoner recently turned in his needle because he wanted to stop using, he was slapped with an institutional charge. "This kind of thing happens all the time," he said.

In a taped interview aired during the presentation, one former prisoner said that inmates construct needles out of "markers, light bulb filaments [and] the inside of a pen tube," and often share them. Injectable drugs are popular, he said, because "it's the biggest bang for your buck."

As to how the drugs are getting into prisoners, Clarke answered indirectly, noting that family members and friends often face drug dogs and careful searches but "they're not doing that for staff a lot of the time."

DOI:10.1503/cmaj.109-4644

— Wendy Glauser, Toronto, Ont

Source

Review

J?rgen K Rockstroh1* and Sanjay Bhagani23

* Corresponding author: Jurgen K Rockstroh juergen.rockstroh@ukb.uni-bonn.de

Author Affiliations

1 Department of Medicine I, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany

2 Department of Infectious Diseases/HIV Medicine, Royal Free London, NHS Foundation Trust, London, UK

3 Research Department of Infection, UCL, London, UK

For all author emails, please log on.

BMC Medicine 2013, 11:234  doi:10.1186/1741-7015-11-234

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1741-7015/11/234

Received: 21 August 2013
Accepted: 3 October 2013
Published: 1 November 2013

© 2013 Rockstroh and Bhagani; licensee BioMed Central Ltd.

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Morbidity and mortality from co-morbid hepatitis C (HCV) infection in HIV co-infected patients are increasing; hence, the management of hepatitis co-infection in HIV is now one of the most important clinical challenges. Therefore, the development of direct acting antivirals (DAAs) for treatment of HCV has been eagerly awaited to hopefully improve HCV treatment outcome in co-infected individuals. Indeed, the availability of the first HCV protease inhibitors (PI) boceprevir and telaprevir for HCV genotype 1 patients has changed the gold standard of treating hepatitis C allowing for substantially improved HCV cure rates under triple HCV-PI/pegylated interferon/ribavirin therapy. Moreover, numerous other new DAAs are currently being studied in co-infected patient populations, also exploring shorter treatment durations and interferon-free treatment approaches promising much easier and better tolerated treatment regimens in the near future. Nevertheless, numerous challenges remain, including choice of patients to treat, potential for drug-drug interactions and overlapping toxicities between HIV and HCV therapy. The dramatically improved rates of HCV cure under new triple therapy, however, warrant evaluation of these new treatment options for all co-infected patients.

Keywords:  HIV; Hepatitis C; Direct acting antivirals; Interferon; Ribavirin

Introduction

The introduction of highly active antiretroviral therapy (HAART) in 1996 and the resultant sustained control of HIV replication and consequent immune reconstitution, has decreased HIV associated morbidity and mortality dramatically. Consequently, liver disease, mostly as a result of chronic viral hepatitis co-infection, has emerged as one of the most important causes of non-AIDS associated morbidity and mortality in HIV infected patients [1]. HIV and hepatitis C viruses share similar rules of transmission leading to a high rate of hepatitis C co-infection among patients with HIV. Overall it is estimated that around 25% of all European HIV patients have concomitant hepatitis C virus (HCV) co-infection [2,3]).

In the natural course of hepatitis C in HIV, in the absence of antiretroviral therapy, a faster progression of hepatic fibrosis has been observed. This is particularly true in patients who develop CD4 counts below 200 cells/mm3 or develop AIDS [4]. This enhanced fibrosis progression may be a result of the direct fibrogenetic effect of HIV in the liver and a likely consequence of HIV induced impairment of the innate and adaptive immune system leading to more inflammation, apoptosis and fibrosis [5]). Importantly, successful anti-HIV therapy can slow down the accelerated cause of fibrosis progression in HIV/HCV co-infected patients, emphasizing the importance of maintaining high CD4 counts in these patients [6]). However, despite attenuation of faster fibrosis progression with successful HAART, some patients continue to develop hepatocellular carcinoma and advanced liver disease. Therefore, the treatment of HCV is of the utmost clinical importance. Although the introduction of pegylated interferon (pegIFN) and ribavirin (RBV) combination therapy simplified HCV treatment and was associated with improved response rates, the outcome of treatment remained unsatisfying particular for genotype 1 and 4 patients where cure rates defined as sustained virological response (negative HCV PCR 24 weeks after stopping therapy) (SVR) was not higher than 22 to 35% [7-9]. The development of direct acting antivirals (DAAs) against HCV promising higher cure rates in this challenging patient population have led to substantial hope that better treatment options have finally arrived. In 2011, the Food and Drug Administration (FDA) approved the use of the first two DAAs, boceprevir and telaprevir, for the treatment of HCV genotype 1 infection in mono-infected patients. Subsequently, the first pilot trials with the use of these compounds in HCV treatment na?ve as well as HCV treatment experienced HIV/HCV co-infected patients have been presented. To date, the results of the studies suggest excellent treatment response rates with SVRs in the range of 60 to 80% and an increase in SVRs by 29 to 35% when pegIFN and RBV were used as comparators [10-13]. Despite this, treatment of HCV in HIV remains complex with multiple challenges, including high pill burden, higher rates of adverse events (AEs) and difficult drug-drug-interactions commonly seen between HIV drugs and HCV protease inhibitors that need to be addressed. From a clinician?s perspective this calls for practical clinical algorithms which could help in the day-to-day management of these patients. This review aims at summarizing the currently available data on treatment of chronic HCV with DAA-based therapy and to provide guidance and whom to treat now and where to wait for improved options in the near future. Management of acute HCV is outside the scope of this article.

Pegylated interferon and ribavirn therapy in HIV/HCV co-infection

Until recently, dual therapy with pegIFN and RBV has been the gold standard for HCV therapy in HIV co-infected individuals. Overall SVR rates have been between 25 to 50%, with cure rates approaching 70 to 80% in HCV genotype 2 or 3 infection and considerably lower at between 18 to 38% in HCV genotype 1 and 4 patients [14]. Treatment uptake, however, was very low, mostly due to the fear of high adverse event rates (in particular, central nervous system (CNS) toxicity) associated with pegIFN/RBV combination therapy, a high rate of comorbid medical and psychiatric conditions representing a contraindication for dual HCV therapy coupled with high cost of therapy and a high proportion of genotype 1 infections with low SVR rates. Indeed, data from the EuroSIDA cohort suggest that not more than 25% of all European HIV/HCV co-infected patients have ever received anti-HCV therapy [15]). However, it needs to be emphasized that cohort studies evaluating the clinical outcome of HCV therapy have demonstrated that achieving SVR is associated with a significant decline in risk of liver-specific and all-cause mortality in patients with HCV mono-infection as well as in HIV/HCV co-infection. In the Veterans Affairs HCV mono-infection population, SVR was associated with a marked reduction in all-cause mortality [16]). Similarly, in the Spanish GESIDA HCV/HIV cohort, SVR was accompanied by a significant decrease in liver-related complications and mortality as well as non-liver-related mortality [17,18]. Interestingly, in more recent analyses, HIV/HCV co-infected patients with end-of-treatment response but relapse after stopping dual HCV therapy developed less liver-related mortality, decompensations and liver stiffness progression than treatment non-responders, suggesting a benefit from successful HCV viremia suppression to the end of a finite treatment course, even if a cure was not achieved [19]. Therefore, for HIV patients with genotype 2,3 and 4 where no licensed DAAs are currently available, dual HCV therapy with pegIFN and RBV remains the gold standard. The current treatment algorithm for these HCV genotypes is summarized in Figure?1.

1741-7015-11-234-1

Figure 1. Optimal duration of dual HCV therapy in HCV/HIV co-infected patients not eligible for triple therapy. (adapted with permission from http://www.europeanaidsclinicalsociety.org/). Legend: i) Where no access to DAA is available or high chances of cure even with dual therapy (favorable IL28B genotype, low HCV viral load and no advanced fibrosis). ii) In patients with baseline low viral load (<600,000 IU/mL) and minimal liver fibrosis. DAA, direct acting antivirals; HCV, hepatitis C virus.

Direct Acting Antivirals (DAA) in HIV/HCV co-infection

Resolution of the three-dimensional structures of several HCV proteins, together with the development of replicative cell culture systems, has led to the identification of a number of potential targets for DAAs [20]. Numerous families of drugs that potently inhibit the HCV life cycle in vitro have been identified, and many of these molecules have reached early to late clinical development. Two NS3-4A protease inhibitors, telaprevir and boceprevir, were the first DAAs to become approved in Europe and the United States in 2011 in combination with pegIFN-? and RBV for the treatment of HCV genotype 1 infection. Numerous other DAAs are at the clinical developmental stage in combination with pegIFN and RBV or with other DAAs in IFN-free regimens, with or without ribavirin. They include first-generation, second-wave and second-generation NS3-4A protease inhibitors, NS5B polymerase inhibitors, inhibitors of non-structural protein 5A and host-targeted agents, such as cyclophilin A inhibitors and microRNA-122 antagonists.

Currently licensed DAAs for HCV therapy in treatment-naive HIV/HCV patients

Recently, two pilot studies, one with boceprevir- and one with telaprevir-based HCV therapy, have been published with full SVR24 results in treatment-na?ve HIV/HCV co-infected patients and are briefly summarized below [10,11].

A phase IIa, double-blind study in 98 HCV/HIV co-infected patients investigated the safety and efficacy of boceprevir in combination with PegIFN-?-2b and weight-based dose ribavirin [10]. Patients were randomly allocated (1:2) according to a computer generated sequence, stratified by Metavir score and baseline HCV RNA level, to receive pegIFN-alpha-2b 1.5 ?g/kg per week with weight-based RBV (600 to 1,400 mg per day) for four weeks, followed by pegIFN/RBV plus either placebo (control group) or 800 mg boceprevir three times per day (boceprevir group) for 44 weeks. All patients were HCV-treatment na?ve and had genotype 1 HCV infection. The majority of patients included in the study were male (69%), Caucasian (82%), non-cirrhotic (95%) and had a HCV viral-load >800,000 IU/ml (88%). In addition, they were mostly on HAART, with an undetectable HIV viral load and CD4 cell count >500 cells/mm3. The antiretroviral therapeutic combinations used in the study were predominately based on boosted protease inhibitor (PI) (>90%). Non-nucleoside reverse-transcriptase inhibitors, zidovudine and didanosine were not permitted. A total of 40 (63%) of 64 patients in the boceprevir group had an SVR at follow-up Week 24, compared with 10 (29%) of 34 control patients (difference 33.1%, 95% CI 13.7 to 52.5; P?=?0.0008). Adverse events were more common in patients who received boceprevir than in control patients: 26 (41%) versus 9 (26%) had anemia, 23 (36%) versus 7 (21%) pyrexia, 22 (34%) versus 6 (18%) had decreased appetite, 18 (28%) versus 5 (15%) dysgeusia, 18 (28%) versus 5 (15%) vomiting, and 12 (19%) versus 2 (6%) neutropenia. Three patients who received boceprevir plus pegIFN/RBV and four controls had HIV virological breakthrough.

A phase IIa, randomized, double-blind, placebo-controlled study in 62 HCV/HIV co-infected patients investigated the safety and efficacy of telaprevir in combination with PegIFN-?-2a and 800 mg RBV (US) and weight-based dose RBV in France and Germany [11]). A total of 62 patients with HCV genotype 1 infection and HIV-1 infection who were HCV treatment-naive were enrolled in the study. Patients were required to be receiving no antiretrovirals (part A) or one of two specified antiretroviral regimens (part B), including either efavirenz or ritonavir boosted atazanavir. Patients in part A were randomly assigned in a 1:1 ratio and patients in part B were randomly assigned in a 2:1 ratio to receive telaprevir or placebo, both in combination with PEG-IFN-?-2a and ribavirin for 12 weeks, plus 36 weeks of PEG-IFN-?-2a and ribavirin. Analyses of all patients from the different treatment arms showed that SVR occurred in 74% (28 in 38) of patients receiving telaprevir plus PEG-IFN-?2a/RBV and 45% (10 in 22) of patients receiving placebo plus PEG-IFN-?-2a/RBV. Rapid HCV suppression was seen with telaprevir plus PEG-IFN-?-2a?+?ribavirin (68% (26 in 38 patients) vs. 0% (0 in 22 patients) undetectable HCV RNA levels by Week 4). Two patients had on-treatment HCV breakthrough with telaprevir-resistant variants. Patients treated with antiretroviral drugs had no HIV breakthroughs; antiretroviral exposure was not substantially modified by telaprevir. Pruritus, headache, nausea, rash and dizziness were higher with telaprevir plus pegIFN-?2a/RBV during the first 12 weeks. During this period, serious adverse events occurred in 5% (2 in 38) of those receiving telaprevir plus pegIFN-?-2a in combination with RBV and 0% (0 in 22) of those receiving placebo plus pegIFN-?-2a and RBV; the same number in both groups discontinued treatment due to adverse events.

In summary, both pilot trials in na?ve HIV/HCV co-infected patients have demonstrated statistically superior treatment outcome responses in patients receiving DAA-based HCV therapy over dual therapy with pegIFN/RBV alone. Therefore, within the European AIDS Clinical Society (EACS) hepatitis co-infection guidelines (please also see http://www.europeanaidsclinicalsociety.org/), HCV treatment in HCV genotype 1 patients is recommended with triple therapy, including either of the HCV protease inhibitors boceprevir or telaprevir in combination with pegIFN and RBV where available.

First licensed DAAs in HCV treatment experienced HIV/HCV patients

At the Conference on Retroviruses and Opportunistic Infections (CROI) 2013 meeting in Atlanta, first results were presented from two Agence Nationale de Recherche sur la SIDA (ANRS) studies which looked at the efficacy and safety of triple HCV therapy (either with telaprevir or boceprevir) in previous non-responders to dual pegIFN/RBV therapy [12,13]. Patients with previous null-response and cirrhosis were excluded because of the overall low probability of treatment response. Both studies were presented as pre-planned interim analyses at Week 16 of therapy. In the telaprevir ANRS HC26 study at the interim analyses, 69 patients who received at least one dosage were included [12]. Background HIV therapy contained atazanavir (ATV), ritonavir-boosted atazanavir (ATV/r), efavirenz (EFV), raltegravir (RAL), tenofovir (TDF), emtricitabine (FTC) or lamivudine (3TC). Patients started with a four-week lead-in of pegIFN/RBV. This approach, which is outside the labeling of telaprevir, was chosen so the investigators could compare the results to the boceprevir study, which had a lead-in period of four weeks and because data from telaprevir studies in HCV mono-infection in treatment experienced patients had potentially promised some benefit for this approach. After Week 4, telaprevir was added for12 weeks. Patients who achieved a complete rapid virological response at Week 8 (RVR8) defined as HCV-RNA <15 IU/mL received 32 weeks of pegIFN/RBV after stopping telaprevir at Week 16 following12 weeks of triple therapy (full treatment: 48 weeks). Whereas patients who only obtained a partial RVR8 (15 IU/mL?<?HCV-RNA <1,000 IU/mL) received an additional 56 weeks of pegIFN/RBV (full treatment: 72 weeks). Telaprevir was administered as 750 mg q8h (1,125 mg q8h with EFV) and pegIFN ?-2a as 180 ?g sc/week. Ribavirin was dosed as 1,000 mg/day (?75 kg) and 1,200 mg/day (>75 kg). Futility rules for telaprevir were HCV-RNA >1,000 IU/mL at Week 8 or Week 12 or virological breakthrough at any time. For study inclusion patients needed to have CD4 ?200 cells/mm3 and ?15%, as well as plasma HIV-RNA levels <50 copies/mL. At baseline, the median CD4-count was 630 cells/mm3 (range 459 to 736) and HIV-RNA was below 50 c/ml in 99% of patients. Eleven (18%) patients had Metavir F3 fibrosis and 16 (23%) had F4 fibrosis at inclusion into the study. A total of 39% of patients were previous relapsers to dual therapy, 9% had previous viral breakthrough, 22% were partial responders and 30% null-responders. With 88% achieving an undetectable HCV-RNA at Week 16 in this patient population comprising of 30% previous null-responders and 40% with F3/F4 fibrosis, this study has achieved surprising high early efficacy results. Most interestingly, efficacy remained high independent of a previous response to dual HCV therapy (early virological response at Week 16 (EVR16) was 86% in relapsers versus 86% in previous null-responders) or baseline fibrosis stage (EVR16 was 92% in F1 and 94% in F4 patients). Concomitant antiretroviral therapy (ART) also had no impact on early virological response. Adverse events were frequent (99% of patients developed an AE) but were mostly related to pegIFN side effects. A total of 4% (n?=?3) of patients discontinued study drugs because of psychiatric adverse events and cutaneous adverse events, respectively. Noteworthy, in contrast to the pilot trial in HCV treatment-na?ve patients where no telaprevir discontinuation because of rash was recorded, a few discontinuations because of rash did occur in this study. Grade 3 to 4 anemia, erythropoietin (EPO) use, transfusion or RBV dose reduction was recorded in 61% of patients.

The second ANRSstudy looked at the efficacy and safety of a boceprevir containing triple therapy in 64 previous IFN/RBV non-responders [13]. Following a lead-in with dual therapy, boceprevir was added at Week 4. Boceprevir was discontinued in all patients with a HCV viral load above 1,000 IU/ml at Week 8 and/or at Week 12. All HCV drugs were discontinued if HCV viral load was >1,000 IU/ml at Week 16 or still detectable at Week 28 or in case of virological breakthrough. Patients who achieved a complete rapid virological response at Week 8 (RVR8) defined as HCV-RNA <15 IU/mL received another 40 weeks of triple therapy. Patients who at Week 8 had an HCV viral load >15 IU/mL but <1,000 IU/mL triple therapy continued for four more weeks. If their HCV viral load at Week 12 was again >15 IU/mL but <1,000 IU/mL, they received an additional 36 weeks of triple therapy followed by a further 12 weeks of pegIFN/RBV. Patients recruited for the trial had to be on stable ART for at least three months, with at least three molecules among ATV (ritonavir boosted or not), RAL, TDF, ABC, FTC or 3TC. Again, only previous non-responders to dual therapy with HCV genotype 1 infection were included. Overall, 17% of patients had Metavir F4 fibrosis at baseline and 33% were previous null-responders. Overall, 63% achieved undetectability at Week 16, which was slightly higher in the RAL-treated patients than in patients on other ART regimens. Response rates at Week 16 were best for previous relapsers (with 90% <15 IU/ml) versus patients with previous breakthrough (60% <15 IU/ml), partial responders (60% <15 IU/ml) and null-responders (38% <15 IU/ml), respectively. Response rates according to fibrosis at baseline in contrast were comparable between the different fibrosis stages (62% <15 IU/ml at Week 16 with F1, 67% for F2, 50% for F3 and 73% for F4). Anemia occurred in 42% of patients but only 5% developed grade 3 to 4 anemia. A total of 42% of the patients received concomitant EPO.

Both of these studies show very impressive early treatment response rates independent of baseline fibrosis stage (please note that patients with prior null-response and F4 fibrosis, however, were excluded from the trial). Whether the good early response rates can be maintained and translate into good SVR rates remains to be seen, as at this time these studies are still ongoing. It is noteworthy, however, that triple therapy studies in HCV treatment-experienced patients (see the ANRS CO20-CUPIC trial) also showed good early treatment response rates, which, however, did not translate to high SVR rates after the end of therapy [21]. Moreover, similar to CUPIC, significant hematological toxicity was observed in these studies despite proactive management of anemia. However, significant drop-out rates as a result of SAEs were not seen by Week 16. Moreover, in the CUPIC trial, there was a considerable incidence of severe complications and death, especially in patients with low platelet counts and low albumin. This has not as yet been reported in the early results from the ANRS co-infection trials but needs to be borne in mind with respect to treating patients with advanced fibrosis/cirrhosis with currently available triple therapy. These patients should be managed withincenters with experience in looking after co-infected patients with advanced liver disease.

Trial results with new DAAs in HIV/HCV co-infected individuals

At present, several other HCV trials are currently taking place in the HIV/HCV co-infected patient population and early treatment response rates from these studies have already been presented at conferences. Among the DAA anti-HCV drugs, the three most likely to be licensed in 2014 is the once-daily nucleotide analogue HCV polymerase inhibitor sofosbuvir, as well as the second-wave, once-daily HCV protease inhibitors simeprevir and faldaprevir. For both HCV protease inhibitors, data from co-infection trials are available and summarized below [22,23].

STARTVerso4 is an open-label, sponsor-blinded study in HCV/HIV co-infected patients who were HCV treatment-na?ve (TN) or relapsed after previous HCV therapy to assess the efficacy and safety of faldaprevir q.d. plus pegIFN/RBV, and to evaluate 24-week treatment duration in HIV/HCV co-infected patients [22]. Patients in arm A were treated with faldaprevir at 120 mg/pegIFN/RBV for 24 weeks; Arm B: faldaprevir at 240 mg/PegIFN/RBV for 12 weeks then re-randomization at Week 12 to a further 12 weeksof faldaprevir/pegIFN/RBV or pegIFN/RBV alone. For response-guided therapy, early treatment success (ETS) was defined as a HCV RNA below the limit of quantitation at Week 4 and below the limit of detection at Week 8. At Week 24, ETS were re-randomized to stop treatment at Week 24 or continue pegIFN/RBV through Week 48. Patients without ETS received pegIFN/RBV through Week 48. Patients on HIV protease-based ART or efavirenz were allocated to faldaprevir 120 mg or 240 mg q.d., respectively; those receiving other allowed ART (raltegravir or maraviroc) or no ART were randomized to either dose. The primary endpoint of the study is SVR12. Overall, 304 (239 treatment na?ve and 69 relapsers) patients were included, making this the largest co-infection DAA study so far. Importantly, 17% of the patients included had F4 fibrosis, 78% GT1a and baseline HCV RNA was ?800,000 IU/mL in 80% of patients.

Early virological treatment response up to Week 12 was excellent in na?ve as well as in previous relapsers. ETS was observed in 80% of patients with half of these patients being able to stop treatment at Week 24. This study will provide very interesting data on potentially shorter treatment durations in HIV/HCV co-infected subjects for the first time in the near future. The adverse event profile was comparable to adverse events observed with faldaprevir and pegIFN/RBV in HCV mono-infected patients [23]. A total of 18% of patients developed anemia and 18% a rash. Two rashes were documented as SAEs.

The other second wave HCV protease inhibitor study evaluated efficacy and safety of simeprevir based triple therapy in HIV/HCV co-infection in study C212. C212 is a phase III, open-label, single-arm, international trial assessing simeprevir (150 mg q.d.) plus pegIFN/RBV in treatment-naive and -experienced patients (N?=?106) co-infected with genotype-1 HCV and HIV-1 [24]. Patients who were treatment-na?ve and non-cirrhotic (n?=?50) or prior relapsers (n?=?14) received a response-guided treatment (RGT) regimen of simeprevir (150 mg once daily) for 12 weeks plus pegIFN/RBV for 24 or 48 weeks. Prior partial (n?=?10) or null (n?=?28) responders and patients with cirrhosis (three treatment-na?ve patients and one relapser) received treatment for 48 weeks. The primary endpoint of the study was again SVR12, as well as safety and tolerability. Combination HCV therapy with simeprevir 150 mg q.d. + pegIFN/RBV led to high virologic response rates in co-infected patients, regardless of prior response (SVR12 77% in treatment-na?ve and prior relapsers). Relapse occurred only in patients infected with HCV genotype-1a: 5/31 overall population; 3/22 treatment-naive; 2/9 prior relapsers. A total of 64% of all prior null responders had not experienced failure at the time of the interim analysis. Of the 88% of patients who met RVR, 75% achieved SVR 12; 30% of patients developed grade 3 or 4 events. A rash was reported for 17% of the patients. Hyperbilirubinemia (a known side effect of simeprevir) was noted in 5% of study subjects. However, only 4% of patients discontinued simeprevir because of adverse events. Overall, simeprevir was well tolerated, with a safety profile similar to that in HCV mono-infected patients.

In summary, these trials suggest that simplified DAA-based HCV therapy will become available very shortly, promising for a smaller tablet burden, with at least equal efficacy compared to the current triple therapy regimens but with better tolerability. Further co-infection studies include studies with daclatasvir, a NS5A inhibitor, as well as the first interferon-free studies with sofosbuvir. No interim results from these studies, however, have been publically presented to date.

Who to treat now, where to wait?

With the rapid advances in HCV therapy making simplified and better tolerated HCV therapy with higher cure rates a realistic vision within the next two years, current treatment algorithms need to balance the need for preventing liver disease progression and occurrence of hepatocellular carcinoma against the side effects of current therapies and improved treatment options in the near future. Therefore, the first essential step in HCV treatment decision-making is fibrosis stage assessment, as the current fibrosis stage of a patient reliably predicts subsequent clinical risk of developing relevant liver disease. In patients with low fibrosis stages, treatment can be safely deferred as risk of liver disease progression, particularly in the setting of controlled HIV replication, is low and, therefore, patients could wait for newer treatment options. Patients with more advanced liver fibrosis stages, however, are at risk of developing more severe liver disease associated complications and can be potentially cured now with the currently available DAA-based treatment regimens. Figure?2 shows the management algorithm of persons with newly diagnosed HCV infection, which is adapted from the EACS guidelines [25]). Besides the fibrosis stage, previous response to interferon- and ribavirin-based dual HCV therapy is also important information in the decision making process. All studies to date have shown that relapsers, in particular, are most likely to benefit from DAA-based HCV re-treatment and, therefore, are preferred candidates, whereas patients with previous null-response (defined as less than 2 log drop in HCV-RNA levels under pegIFNIFN/RBV) therapy are much less likely to respond. Waiting for more potent DAA combinations is probably the best strategy for this group if fibrosis stage allows this (see Figure?3). It is important to bear in mind that if this is the case, careful monitoring of fibrosis progression would be essential.

1741-7015-11-234-2

Figure 2. Management of newly diagnosed HIV/HCV co-infected genotype 1 patients (adapted with permission from [[25]]). Legend: Metavir fibrosis score: F0?=?no fibrosis; F1?=?portal fibrosis, no septae; F2?=?portal fibrosis, few septae; F3?=?bridging fibrosis; F4?=?cirrhosis; Peg, pegylated interferon; RBV, ribavirin.

1741-7015-11-234-3

Figure 3. Management of HIV-HCV co-infected genotype-1 patients by fibrosis stage/prior treatment (adapted with permission from [[25]]).

While a number of new DAA-based therapies and IFN-free therapies, including combinations within fixed-drug combination tablets are in phase 2 and phase 3 clinical trials for mono-infected patients, there are an increasing number of studies underway or in the planning stage for co-infected patients. These include the IFN-free combination of sofosbuvir and ribavirin for G1, 2, 3 and 4 patients, a combination of Peg-IFN-lamda (a potentially better tolerated IFN) with ribavirin and the NS5a inhibitor daclatasvir also for G1, 2, 3 and 4 infections and ABT-450/r, a ritonavir-boosted protease inhibitor together with NS5a inhibitor ABT-267, non-nucleoside polymerase inhibitor ABT-333 combined with ribavirin for G1 patients. There is no doubt that better-tolerated, more efficacious and potentially IFN-free regimens are on the horizon for co-infected patients.

Practical recommendations: CD4-count level and drug-drug interactions

Cure rates of HCV therapy in HIV co-infection have been demonstrated to increase with higher CD4 relative percentage above 25%, and undetectable HIV-RNA has been suggested to be independently associated with improved SVR rates ([26]. Therefore, in patients with a CD4-count <500 cells/mm3 early ART initiation is recommended to optimize HCV treatment outcome. Only in patients with a CD4-count above 500/?l without HIV therapy should HCV treatment in the absence of HIV therapy be considered. This strategy offers the advantage of decreased pill burden, lack of overlapping toxicities between HIV and HCV drugs and no drug-drug interactions.

As HCV protease inhibitors, as well as HIV protease inhibitors and NNRTIs, are all metabolized by the cytochrome p450 pathway, multiple complex drug-drug interactions exist between HCV and HIV drugs. Table?1 summarizes the corresponding drug interactions. Telaprevir can currently only be safely combined with boosted atazanavir, raltegravir, maraviroc, rilpivirine, etravirine or efavirenz (with EFV, telaprevir doses need to be increased to 1,125 mg every eight hours) in combination with tenofovir or abacavir and FTC or 3TC (please also check http://www.hep-druginteractions.com). Due to drug-drug interactions, boceprevir can only be currently safely combined with raltegravir, rilpivirine or etravirine in combination with tenofovir or abacavir and FTC or 3TC. The European Medicines Agency (EMEA) has also suggested considering boceprevir in combination with boosted atazanavir in patients with no previous HIV treatment failure and no drug resistance who have suppressed HIV-RNA when starting HCV therapy as boceprevir exposure is not impacted by concomitant boosted atazanavir, whereas atazanavir area under the curve (AUC) decreased significantly but trough levels remained above the recommended IC90 in all patients. It is not possible to co-administer simeprevir with HIV protease inhibitors. Faldaprevir can be combined with ritonavir boosted darunavir but the dose needs to be reduced to 120 mg once a day. So far, first results from interaction studies with sofosbuvir, which is not metabolized by the cytochrome p450 pathway, indicate that this compound can be combined with darunavir/r, atazanavir/r or efavirenz [27], thereby apparently offering more HIV treatment choices along with HCV therapy.

Table 1

Summary of key drug-drug interactions between HIV drugs and the licensed DAAs and dosing recommendations
Telaprevir Boceprevir
ATV/r Monitoring for hyperbilirubinemia recommended Consider on a case by case basis if deemed necessary
DRV/r/, FPV/r LPV/r Not recommended Not recommended
EFV Increase TVR to 1,250 mg q8h Not recommended
ETR No dose adjustment needed No dose adjustment needed
RPV No dose adjustment needed No dose adjustment needed
RAL No dose adjustment needed No dose adjustment needed
TDF Increased monitoring is warranted No dose adjustment needed

Rockstroh and Bhagani

Rockstroh and Bhagani BMC Medicine 2013 11:234   doi:10.1186/1741-7015-11-234

Taking into consideration all the complex issues surrounding anti-HCV treatment in this group of patients, particularly drug-drug interactions and side-effects, it is important that these patients are managed in centers with experience in managing HCV/HIV co-infected patients. Many physicians may want to start HCV/HIV co-infected patients on cART therapies that will have the least potential for drug-drug interactions, although it would be possible to switch cART during the period of DAA-based therapy. It is important to ensure that all co-medications, and not just cART components, that patients are on are documented and scrutinized for potential drug-drug interactions with the new DAAs. It is also imperative that as many patients as possible are included in the forthcoming clinical trials.

Conclusion

HCV therapy has also dramatically changed with the advent of the first DAAs in the HIV/HCV co-infected population with the promise of much higher cure rates and potentially shortened treatment durations. Nevertheless, complex drug interactions as well as significant additional toxicities and challenging overall management issues have limited the uptake of these new treatment strategies to date. With easier to take, better tolerated and optimally interferon-free HCV treatment approaches on the horizon in the very near future, HCV treatment initiation can be delayed in all patients with low fibrosis stages. For patients with more advanced fibrosis, however, the new treatment modalities should at least be discussed in order not to miss out on further liver disease progression and HCC development.

Competing interests

In the last five years, J?rgen Rockstroh has received honoraria for speaking at educational events or for consulting for Abbott, Abbvie, Astella, Bionor, BMS, Boehringer Ingelheim, Gilead, Janssen, Merck, Novartis, Pfizer, Vertex and ViiV.

In the last five years, Sanjay Bhagani has received honoraria for speaking at educational meetings, attending advisory meetings or travel support for attending conferences from Abbvie, BMS, Boehringer Ingelheim, Gilead, Janssen, MSD and Roche.

Authors contributions

JKR and SB have both written this review and both authors read and approved the final manuscript.

Authors information

JKR is a Professor of Medicine at the University of Bonn where he heads the HIV outpatient clinic. Sanjay Bhagani is a Consultant Physician in Infectious Diseases and HIV Medicine at the Royal Free Hospital, London where he leads a multi-disciplinary HIV/hepatitis co-infection clinic and is an honorary Senior Lecturer at UCL.

Acknowledgements

The authors would like to thank Drs. Christoph Boesecke and Jan-Christian Wasmuth for the feedback each provided on this manuscript and/or the concepts therein. Funding for this research project was provided primarily by funding through the German Centre for Infection Research (DZIF), partner site Bonn-K?ln.

Note

This article is part of the cross journal collection HIV 30 years on. Other articles in this series can be found at http://www.biomedcentral.com/series/HIV_30.

References

Source

Posted on: 01 Nov 13

Nimbus Discovery LLC a biotechnology company discovering novel medicines against exciting but previously inaccessible drug targets will present preclinical data at The Liver Meeting® the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) that show the company has optimized a unique series of Acetyl Co-A Carboxylase (ACC) allosteric inhibitors that bind to the BC domain of ACC and demonstrate excellent potency drug-like properties and preclinical efficacy. The novel internally-developed small molecules ND-654 and ND-630 demonstrated desirable in vitro and in vivo efficacy in experimental models of metabolic disease diabetes and hepatic steatosis. In an iterative design fashion over 16 months the potency of this family of compounds were improved >1000x utilizing the company’s proprietary small molecule computational drug discovery technology and drug-like properties were optimized to efficiently deliver development candidate quality molecules.

Simultaneous inhibition of both isoforms of ACC decreases fatty acid synthesis and stimulates fatty acid oxidation and has the potential to favorably affect the morbidity and mortality associated with obesity diabetes and fatty liver diseases including non-alcoholic steatohepatitis (NASH). Nimbus’ ACC inhibitors including ND-654 and ND-630 are believed to be the first drug-like allosteric inhibitors to bind the biotin carboxylase (BC) domain of ACC with high potency and selectivity.

Key findings of the Nimbus compounds presented at the conference include:

  • ND-654
    • Liver specific ND-654 has favorable drug-like properties with a 2700:1 liver to muscle exposure
    • Proof-of-mechanism: ND-654 acutely inhibits ACC with virtually no effect on muscle resulting in focused pharmacological effects on the liver
    • Proof-of-concept: ND-654 demonstrated target engagement in the liver and dose dependently decreased fatty acid production in the liver
  • NC-630
    • Liver selective ND-630 has favorable drug-like properties with a 100:1 liver to muscle exposure
    • Proof-of-mechanism: ND-630 acutely inhibits ACC demonstrating efficacy in both liver and muscle by preventing malonyl Co-A production
    • Proof-of-concept: ND-630 demonstrated target engagement in the liver and muscle
    • Dosing of ND-630 in high sucrose fed diet-induced obesity (DIO) rats showed improvement in insulin sensitivity improvement in hepatic cholesterol and normalization of hepatic triglycerides dose dependent decrease of plasma triglycerides and FFAs and decrease in plasma cholesterol

“Within 16 months Nimbus has become the first company to identify and optimize a broad portfolio of liver directed small molecule inhibitors of ACC -- a previously intractable disease target” said Rosana Kapeller M.D. Ph.D. Chief Scientific Officer of Nimbus. “We are now preparing for ND-630 to enter the clinic in 2015 for the treatment of NASH and diabetes while we continue to progress ND-654 in preclinical models of hepatocellular carcinoma.”

About Nimbus

Nimbus Discovery a biotechnology company harnesses cutting-edge computational technologies to uncover breakthroughs in small molecule pharmacology. We focus on medically important and highly sought-after disease targets that have proven inaccessible to traditional industry approaches. Our robust pre-clinical pipeline includes novel agents for the treatment of cancer metabolic disease and inflammation. Nimbus is organized as a constellation of small nimble teams of experienced drug-hunters deployed across program-focused subsidiary companies. Each team is freed from conventional barriers to scientific success chartered to create solutions and geared for program asset deals with leading pharmaceutical companies. Founded in 2009 Nimbus partnered with Schrödinger to invent and apply a physics-based approach that establishes a new standard for rational drug design. Nimbus is backed by world-class life science investors including Atlas Venture SR One Lilly Ventures and Bill Gates. The company has been named by FierceBiotech as one of 2013's Fierce 15 designating it as one of the most promising private biotechnology companies in the industry. For more information please visit www.nimbusdiscovery.com.

Business Wire
http://www.businesswire.com/

Source

Sugar Intake Is Not Directly Related to Liver Disease

Provided by AGA Pressroom

Bethesda, MD (Nov. 1, 2013) — Despite current beliefs, sugar intake is not directly associated with nonalcoholic fatty liver disease, according to a new study in Gastroenterology, the official journal of the American Gastroenterological Association. Rather, high-calorie diets promote the progression of this serious form of liver disease.

Researchers conducted a double-blind study of healthy, but centrally overweight men to compare the effects of high intakes of two types of sugar, glucose and fructose, in two conditions — weight-maintaining (moderate-calorie diet) and weight-gaining (high-calorie diet). In the weight-maintaining period, men on neither diet developed any significant changes to the liver. However, in the weight-gaining period, both diets produced equivalent features of nonalcoholic fatty liver disease, including steatosis (fatty liver) and elevated serum transaminase and triglycerides. These findings indicate that fructose and glucose have comparable effects on one’s liver, and calorie intake is the factor responsible for the progression of liver disease.

“Based on the results of our study, recommending a low-fructose or low-glycemic diet to prevent nonalcoholic fatty liver disease is unjustified,” said Professor Ian A. Macdonald, study author and faculty of medicine and health sciences, University of Nottingham, UK. “The best advice to give a patient is to maintain a healthy lifestyle with diet and exercise. Our study serves as a warning that even short changes in lifestyle can have profound impacts on your liver.”

During the period of increased calorie intake, all study participants experienced significant increases in body weight, waist circumference and total body fat, as expected. Interestingly, satiety was unaltered in spite of weight gain during the high-calorie diet; this reinforces the notion of “hidden calories” in drinks since participants consumed a portion of their calories in liquid form.

Fructose is a simple sugar commonly found in fruits and vegetables. Glucose, also known as grape or blood sugar, is present in all major carbohydrates, such as starch and table sugar.

Nonalcoholic fatty liver disease, the most prevalent liver problem in the U.S. and most Western countries, is the buildup of extra fat in liver cells that is not caused by alcohol. For more on how a low-calorie diet is the best prescription for this form of liver disease, read the article “NAFLD Treatment: Is there More to Talk About Other than Diet and Exercise?” from the October/November issue of AGA Perspectives, the AGA Institute’s most prominent non-scientific publication.

###

About the AGA Institute

The American Gastroenterological Association is the trusted voice of the GI community. Founded in 1897, the AGA has grown to include 17,000 members from around the globe who are involved in all aspects of the science, practice and advancement of gastroenterology. The AGA Institute administers the practice, research and educational programs of the organization. www.gastro.org.

About Gastroenterology

Gastroenterology, the official journal of the AGA Institute, is the most prominent scientific journal in the specialty and is in the top 1 percent of indexed medical journals internationally. The journal publishes clinical and basic science studies of all aspects of the digestive system, including the liver and pancreas, as well as nutrition. The journal is abstracted and indexed in Biological Abstracts, Current Awareness in Biological Sciences, Chemical Abstracts, Current Contents, Excerpta Medica, Index Medicus, Nutrition Abstracts and Science Citation Index. For more information, visit www.gastrojournal.org.

Like AGA and Gastroenterology on Facebook.
Join AGA on LinkedIn.
Follow us on Twitter @AmerGastroAssn.
Check out our videos on YouTube.

Source

PRESS RELEASE

Oct. 31, 2013, 9:33 a.m. EDT

RenderImage

Harry Shum, Jr., Jabbawockeez and Dancers from Around the World Invite People to Get Up and Dance to Help End Mother-To-Child Transmission of HIV

ATLANTA, Oct 31, 2013 (BUSINESS WIRE) -- Your favorite dance move could help save lives. Coca-Cola and (RED) have enlisted the help of Harry Shum, Jr. (Mike Chang, "Glee") and the world-famous dance crew Jabbawockeez, as well as other notable dancers to harness the power of dance and inspire people to participate in a global dance movement with the goal of helping end mother-to-child transmission of HIV by 2015. Every day, 700 babies are born with HIV. By supporting programs that offer prevention, treatment, counseling, HIV testing and care services for pregnant women, that number can be near zero.

Being part of the movement couldn't be easier. Step to the left, then step to the right or do whatever moves come naturally to you and then upload a video of the dance to YouTube or Instagram, using #CokeREDMoves in the title or as the hashtag. For the first 1,000 videos submitted, Coca-Cola will make a donation to buy life-saving medicine for someone living with HIV. This is in addition to the $1 million donation Coca-Cola made earlier this year to the Global Fund to help finance HIV/AIDS programs in Africa.

"We hold a fundamental belief that more movement brings more happiness, for everyone," said Wendy Clark, SVP Sparkling Brand Center, The Coca-Cola Company. "Partnering with (RED) to connect people through the universal language of dance is a meaningful way to show our support."

In collaboration with The DanceOn Network - the leading dance channel on YouTube - and Recreation Worldwide, Coca-Cola worked with Shum, Jabbawockeez, Nappy Tabs, Brian Puspos and Ian Eastwood, 8 Flavahz, Tyanna Padilla aka "Tiny Miney", Jasmine Meakin from "Mega Jam" and Les Twins. The dancers came together to support the cause in the official music video for Celebrate (Tommy Trash Remix) by Empire of the Sun & Tommy Trash, which was created exclusively for (RED) and launched today on YouTube www.youtube.com/watch?v=9lWhVii3D24. The track will be featured on the upcoming DANCE (RED) SAVE LIVES(2)compilation album.

To help inspire people to show their moves, Shum and the Jabawockeez developed an easy-to-follow dance that anyone can learn that is featured in the music video. Consumers can visit www.CokeREDMoves.com to download a free clip of the Celebrate remix, view a tutorial for the dance move and find instructions on how to upload a dance video and to learn more about how their moves could help support this important cause.

"This cause and this program really spoke to me," said Shum. "Dancing is such a huge part of my life and I believe in its power to bring people from all walks of life together for a singular purpose. It's inspiring to know that my generation has the power to help eliminate mother-to-child transmission of HIV. I'm excited to work with Coca-Cola and (RED) to help make that goal a reality."

Coca-Cola has made a commitment of more than $5 million USD from 2011 to 2015, and over the next two years the partnership with (RED) will raise awareness and money to help eliminate mother-to-child transmission of HIV. This money will help fund up to 7.5 million doses of antiretroviral treatment for people affected by HIV/AIDS in Africa.

"Raising awareness and heat around the AIDS fight is so critical to winning the battle against this disease," said Deborah Dugan, Chief Executive Officer for (RED). "Coca-Cola has the unique ability to motivate and inspire young people around the world to get involved and show their support through great initiatives like this. We're so excited to have such extraordinary support for this year's DANCE (RED), SAVE LIVES campaign."

About The Coca-Cola Company

The Coca-Cola Company /quotes/zigman/222647/delayed/quotes/nls/ko KO +0.18% is the world's largest beverage company, refreshing consumers with more than 500 sparkling and still brands. Led by Coca-Cola, one of the world's most valuable and recognizable brands, our Company's portfolio features 16 billion-dollar brands including Diet Coke, Fanta, Sprite, Coca-Cola Zero, vitaminwater, Powerade, Minute Maid, Simply, Georgia and Del Valle. Globally, we are the No. 1 provider of sparkling beverages, ready-to-drink coffees, and juices and juice drinks. Through the world's largest beverage distribution system, consumers in more than 200 countries enjoy our beverages at a rate of more than 1.8 billion servings a day. With an enduring commitment to building sustainable communities, our Company is focused on initiatives that reduce our environmental footprint, support active, healthy living, create a safe, inclusive work environment for our associates, and enhance the economic development of the communities where we operate. Together with our bottling partners, we rank among the world's top 10 private employers with more than 700,000 system associates. For more information, visit Coca-Cola Journey at www.coca-colacompany.com, follow us on Twitter at twitter.com/CocaColaCo, visit our blog, Coca-Cola Unbottled, at www.coca-colablog.com or find us on LinkedIn at www.linkedin.com/company/the-coca-cola-company.

About (RED)(TM)

(RED) was founded in 2006 by Bono and Bobby Shriver to engage businesses and people in the fight against AIDS.

(RED) partners with the world's most iconic brands who contribute up to 50% of profits from (RED) branded goods and services to the Global Fund. (RED) Proud Partners include: Apple, Starbucks, The Coca-Cola Company, Beats by Dr. Dre, Belvedere, Claro, SAP and Telcel. (RED) Special Edition partners include: Shazam, Girl Skateboards, Mophie, FEED, Nanda Home, Bottletop, Tourneau, Fatboy USA, Bed Bath & Beyond, HEAD. To date, (RED) has generated more than $215 million for the Global Fund to fight AIDS, Tuberculosis and Malaria, to support HIV/AIDS grants in Ghana, Lesotho, Rwanda, South Africa, Swaziland, Zambia, Kenya and Tanzania. 100 percent of that money goes to work on the ground - no overhead is taken. Global Fund grants that (RED) supports have impacted more than 14 million people with prevention, treatment, counseling, HIV testing and care services. (RED) is a division of The ONE Campaign. Learn more at www.red.org.

About The Global Fund to Fight AIDS, Tuberculosis and Malaria

The Global Fund is an international financing institution dedicated to attracting and disbursing resources to prevent and treat HIV and AIDS, TB and malaria. The Global Fund promotes partnerships between governments, civil society, the private sector and affected communities, the most effective way to help reach those in need. This innovative approach relies on country ownership and performance-based funding, meaning that people in countries implement their own programs based on their priorities and the Global Fund provides financing where verifiable results are achieved.

Since its creation in 2002, the Global Fund has approved funding of US$ 22.9 billion for in 140 countries. To date, programs supported by the Global Fund have provided AIDS treatment for 5.3 million people, anti-tuberculosis treatment for 11 million people and 340 million insecticide-treated nets for the prevention of malaria. The Global Fund works in close collaboration with other bilateral and multilateral organizations to supplement existing efforts in dealing with the three diseases.

NOTE TO EDITORS:

Visuals to accompany this release can be viewed at: http://www.coca-colacompany.com/press-center/

Photos/Multimedia Gallery Available: http://www.businesswire.com/multimedia/home/20131031005895/en/

SOURCE: The Coca-Cola Company

Source

Published on: 2013-11-01

Morbidity and mortality from co-morbid hepatitis C (HCV) infection in HIV co-infected patients are increasing; hence, the management of hepatitis co-infection in HIV is now one of the most important clinical challenges. Therefore, the development of direct acting antivirals (DAAs) for treatment of HCV has been eagerly awaited to hopefully improve HCV treatment outcome in co-infected individuals.

Indeed, the availability of the first HCV protease inhibitors (PI) boceprevir and telaprevir for HCV genotype 1 patients has changed the gold standard of treating hepatitis C allowing for substantially improved HCV cure rates under triple HCV-PI/pegylated interferon/ribavirin therapy. Moreover, numerous other new DAAs are currently being studied in co-infected patient populations, also exploring shorter treatment durations and interferon-free treatment approaches promising much easier and better tolerated treatment regimens in the near future.

Nevertheless, numerous challenges remain, including choice of patients to treat, potential for drug-drug interactions and overlapping toxicities between HIV and HCV therapy. The dramatically improved rates of HCV cure under new triple therapy, however, warrant evaluation of these new treatment options for all co-infected patients.

Author: J?rgen K RockstrohSanjay Bhagani
Credits/Source: BMC Medicine 2013, 11:234

Source

The 64th Annual Meeting of the AASLD Starts Today

Washington, DC - Walter E. Washington Convention Center
November 1 - 5, 2013

ALEXANDRIA, Va., Oct. 15, 2013 /PRNewswire/ -- The Liver Meeting® is the premier Annual Meeting in the science and practice of hepatology, including the latest findings on new drugs, novel treatments, and the results from pilot and multicenter studies.

Approximately 10 percent of Americans have some form of liver disease, but fortunately, the research community has made great strides in recent years in developing new treatments for patients. 

At this year's meeting, 2306 abstracts addressing these issues that will be presented, including 270 abstracts that will be presented in oral sessions. Those abstracts are available to members of the press at our website (www.aasld.org).

Washington, DC:  November 1 – 5, 2013

  • Poster Presentations:    November 2 – 5
  • Oral Presentations:       November 3 – 5 

An AASLD President's press conference highlighting key abstracts and issues presented at The Liver Meeting® is scheduled for Saturday, November 2 at 4:00 pm.

The following two programs will highlight the latest in viral hepatitis treatment:

  • The HCV Symposium will discuss the integration of new therapies for the treatment of chronic hepatitis
  • The Hepatitis Debrief will provide a synthesis of new data on the treatment of viral hepatitis presented at The Liver Meeting®

Founded in 1950, AASLD is the leading organization of scientists and healthcare professionals committed to preventing and curing liver disease. AASLD has grown into an international society responsible for all aspects of hepatology, and our annual meeting attracts more than 9,500 physicians, surgeons, researchers, and allied health professionals from around the world.

Please contact AASLD at 703-299-9766 for information about the above presentations, or to receive any additional information about The Liver Meeting® – or visit our website at www.aasld.org

Please visit our website to register as press for the meeting, or contact Ann Haran at aharan@aasld.org with any questions.

This release was issued through The Xpress Press News Service, merging e-mail and satellite distribution technologies to reach business analysts and media outlets worldwide. For more information, visit http://www.XpressPress.com.

SOURCE American Association for the Study of Liver Diseases (AASLD)

RELATED LINKS
http://www.aasld.org

Source

PRESS RELEASE

Nov. 1, 2013, 7:00 a.m. EDT

RALEIGH, N.C., Nov 01, 2013 (BUSINESS WIRE) -- Salix Pharmaceuticals, Ltd. /quotes/zigman/87125/delayed/quotes/nls/slxp SLXP -0.02% today announced that presentations related to the investigation of rifaximin are scheduled to take place during the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). AASLD is being held in Washington, DC November 1-5 2013.

Rifaximin Presentations

Poster #1344: Flamm et al. "Impact of Liver Disease Status and Treatment with Rifaximin on Complications of Cirrhosis in a Randomized, Placebo-Controlled Trial"

Poster #374: Neff et al. "Hospital Costs, Length of Stay and Readmission Rates in a Cohort of Cirrhotic Patients Discharged with Hepatic Encephalopathy"

Important Safety Information about XIFAXAN 550 mg

XIFAXAN(R) (rifaximin) 550 mg tablets are contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis.

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

There is increased systemic exposure in patients with more severe hepatic dysfunction. The clinical trials were limited to patients with MELD scores < 25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C).

Based on animal data, XIFAXAN may cause fetal harm. Discontinue in nursing mothers after taking into account the importance of the drug to the mother.

The most common adverse reactions occurring in greater-than or equal to 10% of patients and at a higher incidence than placebo in the clinical study were edema peripheral (15%), nausea (14%), dizziness (13%), fatigue (12%), and ascites (11%).

Xifaxan 550 mg is licensed by Alfa Wassermann S.p.A. to Salix Pharmaceuticals, Inc.

Please see complete Prescribing Information for XIFAXAN.

About Salix

Salix Pharmaceuticals, Ltd., headquartered in Raleigh, North Carolina, develops and markets prescription pharmaceutical products and medical devices for the prevention and treatment of gastrointestinal diseases. Salix's strategy is to in-license late-stage or marketed proprietary therapeutic products, complete any required development and regulatory submission of these products, and market them through the Company's gastroenterology specialty sales and marketing team.

Salix markets XIFAXAN(R) (rifaximin) tablets 200 mg and 550 mg, MOVIPREP(R) (PEG 3350, Sodium Sulfate, Sodium Chloride, Potassium Chloride, Sodium Ascorbate and Ascorbic Acid for Oral Solution), OSMOPREP(R) (sodium phosphate monobasic monohydrate, USP and sodium phosphate dibasic anhydrous, USP) Tablets, APRISO(R) (mesalamine) extended-release capsules 0.375 g, GIAZO(TM) (balsalazide disodium) tablets, COLAZAL(R) (balsalazide disodium) Capsules, METOZOLV(R) ODT (metoclopramide HCl), RELISTOR(R) (methylnaltrexone bromide) Subcutaneous Injection, FULYZAQ(TM) (crofelemer) delayed-release tablets, SOLESTA(R), DEFLUX(R), PEPCID(R) (famotidine) for Oral Suspension, DIURIL(R) (Chlorothiazide) Oral Suspension, AZASAN(R) (Azathioprine) Tablets, USP, 75/100 mg, ANUSOL-HC(R) 2.5% (Hydrocortisone Cream, USP), ANUSOL-HC(R) 25 mg Suppository (Hydrocortisone Acetate), PROCTOCORT(R) Cream (Hydrocortisone Cream, USP) 1% and PROCTOCORT(R) Suppository (Hydrocortisone Acetate Rectal Suppositories) 30 mg. Budesonide foam, RELISTOR(R) , LUMACAN(TM) and rifaximin for additional indications are under development.

For full prescribing information and important safety information on Salix products, including BOXED WARNINGS for OSMOPREP, AZASAN and METOZOLV, please visit www.salix.com where the Company promptly posts press releases, SEC filings and other important information or contact the Company at 919 862-1000.

Salix trades on the NASDAQ Global Select Market under the ticker symbol "SLXP".

For more information, please visit our Website at www.salix.com or contact the Company at 919-862-1000. Follow us on Twitter (@SalixPharma) and Facebook (www.facebook.com/SalixPharma). Information on our Twitter feed, Facebook page and web site is not incorporated in our SEC filings.

Please Note: The materials provided herein that are not historical facts are or might constitute forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Although we believe the expectations reflected in such forward-looking statements are based on reasonable assumptions, our expectations might not be attained. Forward-looking statements involve known and unknown risks that could cause actual results to differ materially from expected results. Factors that could cause actual results to differ materially from our expectations expressed in the report include, among others: the high cost and uncertainty of the research, clinical trials and other development activities involving pharmaceutical products; the unpredictability of the duration and results of regulatory review of New Drug Applications and Investigational New Drug Applications; the uncertainty of market acceptance of our products; intense competition, including from generics in an increasingly global market; the possible impairment of, or inability to obtain intellectual property rights and the costs of obtaining such rights from third parties in an increasingly global market; general economic conditions; our need to maintain profitability; the uncertainty of obtaining, and our dependence on, third parties to manufacture and sell our products; results of ongoing and any future litigation and investigations and other risk factors detailed from time to time in our other SEC filings.

SOURCE: Salix Pharmaceuticals, Ltd.

Source