Monday, June 2, 2014

Monday HCV News Ticker - Does Cancer Treatment Bring Back HCV and Hepatitis C therapies: Dawn of a new age

 AGA Journals:

Does Cancer Treatment Bring Back HCV Infection?

Treated hepatitis C virus (HCV) infections do not return after patients receive chemotherapy or immunosuppressive therapy, researchers report in the June issue of Clinical Gastroenterology and Hepatology.

Cancer chemotherapy leads to HCV reactivation in patients with chronic infections, but little is known about the effect of chemotherapy on HCV infections that have been cured among patients with sustained viral responses (SVRs). Immunosuppressive therapies could also reverse SVRs.
Parag Mahale et al. investigated whether cancer treatments led to relapse of HCV infection among 30 patients who achieved SVRs before they were diagnosed with and treated for cancer.

Half of the patients studied had hematologic malignancies and half had solid tumors; 60% had received HCV therapy with interferon and ribavirin. Chemotherapy was started at a median of 72 months after patients achieved their SVRs, and included rituximab (27%), cyclophosphamide (23%), cisplatin (17%), or corticosteroids (37%).  The authors defined HCV infection relapse based on detection of HCV RNA in serum using commercially available assays.

Mahale et al. found that none of the patients had viral relapse after any form of cancer therapy. The authors conclude that SVRs are not affected by chemo- or immunosuppressive therapies.
Some studies have reported detection of HCV RNA in liver cells and peripheral blood mononuclear cells (PBMCs) from patients who already achieved SVRs, but little is known about the clinical significance of these observations. Mahale et al. were not able to determine whether PBMCs from patients included in their study hid some residual HCV.

Further studies are therefore needed to evaluate larger groups of patients, treated with other types of HCV therapies, to determine if these findings can be generalized to all cancer patients with a history of successfully treated HCV infection.


Hepatitis C therapies: dawn of a new age
New treatments from the likes of Merck & Co, Janssen and Gilead offer significant treatment advances

The hepatitis C virus (HCV) is a highly mutable, heterogeneous, enveloped RNA virus transmitted through the blood of infected carriers. Classified into eleven major genotypes, genotypes 1-3 have a worldwide distribution, with subtypes 1a and 1b accounting for approximately 60 per cent of infections. Due to its long latency period and constantly mutating genome, the highly infectious blood-borne pathogen has proven particularly difficult to control; worldwide, more than 170 million chronic carriers are estimated to be at risk of developing liver cirrhosis or hepatocellular carcinoma.

For more than a decade, standard of care has been based on the combination of pegylated versions of the immunomodulator interferon-alpha (IFN) and the ribonucleoside antiviral agent ribavirin (RBV), administered for 24 or 48 weeks. While these regimens can achieve viral eradication in 40-50 per cent of patients with HCV genotype 1 infection, and in approximately 80 per cent of patients with genotypes 2 and 3, they are limited by significant side effects and contraindications in a high proportion of patients.

In 2011, a new class of HCV therapeutics specifically targeting key viral growth and replication mechanisms, called direct-acting antivirals (DAAs), entered the market. HCV protease inhibitors boceprevir (Victrelis; Merck) and telaprevir (Incivo; Vertex, Janssen) were first and, while both remained dependent on the IFN + RBV backbone, the agents significantly improved virologic response rates in the genotype 1 patient population. In 2013, the approvals of the HCV NS3/4A protease inhibitor simeprevir (Olysio; Medivir, Janssen) and the HCV NS5B inhibitor sofosbuvir (Sovaldi; Gilead) signalled the beginning of a new wave of DAAs. Sofosbuvir became the first ever IFN-free HCV treatment to be approved.

Convenient all-oral treatments
Research has been driven by the need for a convenient, all-oral treatment that improves the tolerability profile of IFN-based regimens and provides efficacy across all HCV genotypes and in difficult-to-treat subpopulations, such as patients with advanced cirrhosis and those co-infected with HIV. To this end, the HCV pipeline has advanced with speed and success. Over the coming year, several IFN-free, DAA-based regimens and fixed-dose combinations (FDCs) are expected to reach the market.

Bristol-Myers Squibb's (BMS) NS5A inhibitor daclatasvir is fast approaching the finish line, with regulatory approval pending in the European Union (EU), the United States (US) and Japan for its use in combination with other antiviral agents, including sofosbuvir or the NS3 inhibitor asunaprevir (BMS). Already, the daclatasvir + sofosbuvir combination regimen is available on a compassionate-use basis in the EU. The ongoing phase 3 ALLY trials are evaluating this combination across genotypes 1-6 in both treatment-naïve and -experienced patients, as well as in cirrhotic patients and in those having undergone liver transplantation.

The asunaprevir + daclatasvir combination is currently being assessed in the phase 3 Hallmark studies. Results to date have shown that sustained virologic response at 12 weeks post-treatment (SVR12), considered to be an end-point reflective of a functional cure, was achieved in 90 per cent of treatment-naïve patients and in 82 per cent of patients unresponsive to or ineligible for IFN + RBV therapy. The dual regimen is also performing well with the addition of the NS5B inhibitor BMS 791325 (BMS). This triple DAA combination is being evaluated as an FDC in the phase 3 UNITY trials. Interim phase II results reported an SVR12 rate of 94 per cent in treatment-naïve patients with genotype 1 infection treated for 12 weeks.

The cost of novel HCV drugs remains a significant concern ... and the milestone launch of Sovaldi was dampened by controversy over its price tag 

The FDC comprising the NS5A inhibitor ledipasvir (Gilead) and sofosbuvir is also awaiting regulatory approval. Submissions were made in the EU, the US and Canada in February 2014 for its use as an IFN-free treatment for HCV genotype 1 infection, and included positive results from the phase 3 ION programme. Across the three ION studies, 1,952 patients with genotype 1 HCV infection were randomised to receive ledipasvir/sofosbuvir once daily, with or without RBV, for 8, 12 or 24 weeks. The rates of SVR12 were exceptionally high, despite more than half the study population having infection compounded by compensated cirrhosis. An intent-to-treat analysis showed that SVR12 was achieved in up to 97.7 per cent of treatment-naïve patients who received the FDC without RBV. In treatment-experienced patients, 96.4 per cent and 99 per cent achieved SVR12 when RBV was added to the 12- and 24-week regimens, respectively.

AbbVie is developing a DAA-based, IFN-free regimen centred on the protease inhibitor ABT 450. Regulatory filings were submitted in the US in April 2014, with EU submissions planned for the following month. This regimen comprises the once-daily FDC of ABT 450 (pharmacologically enhanced with ritonavir) and the NS5A inhibitor ABT 267, administered with the twice-daily non-nucleoside polymerase inhibitor ABT 333. The entire regimen is being trialled in more than seven phase 3 clinical studies, which include treatment-naïve and -experienced patients with genotype 1a or 1b HCV infection, with and without cirrhosis or co-infection with HIV. Virologic response rates to date have been impressive; in genotype 1b treatment-naïve and treatment-experienced patients, SVR12 was achieved in 99 per cent and 100 per cent of participants, respectively, when the regimen was administered without RBV. The TURQUOISE II study in cirrhotic patients has recently demonstrated SVR12 rates as high as 91.8 per cent following 12 weeks' treatment and 95.9 per cent after 24 weeks' treatment.

An IFN-free FDC comprising the NS3/4A protease inhibitor MK 5172 and the NS5A inhibitor MK 8742 is being developed by Merck. With pan-genotypic activity and improved resistance profiles compared with their first-generation counterparts, both compounds can be considered second-generation variants in their respective DAA classes. Results from the phase 2 C-WORTHY study showed promising virologic response rates in a number of patient subpopulations. According to an intent-to-treat analysis, a virologic response was observed in 98 per cent of treatment-naïve, genotype 1 patients given once-daily MK 5172/MK 8742 without RBV for 12 weeks. Of 29 patients co-infected with HCV/HIV, 100 per cent achieved a virologic response after 12 weeks' treatment. The phase 3 C-EDGE programme, scheduled to commence in June 2014, will evaluate the FDC across multiple HCV genotypes, as well as in patients with chronic kidney disease, cirrhosis, co-infection with HIV, and those on opiate substitution therapy.

Direct-acting antivirals
In addition to these late-stage regimens vying for approval, the number of DAAs in phase 2 development indicates that research remains committed to continual improvement. AbbVie is co-formulating its next-generation compounds ABT 530 and ABT 493, its ritonavir-free protease inhibitor, and Gilead has GS 5816 poised for phase 3 development with sofosbuvir. Achillion Pharmaceuticals has DAAs sovaprevir, neceprevir and ACH 3102 in the works, Idenix and Janssen are collaborating on samatasvir and TMC 647055, and phase 2 development of JNJ 56914845 (Janssen) is also underway. While the majority of DAAs in the pipeline act on the HCV NS3/4A serine protease, NS5A polymerase or NS5B polymerase, additional targets are also emerging. The HCV p7 protein is being targeted by BIT 225 (Biotron) and the HCV NS4B protein has also been identified for its potential druggability.

If HCV research has indeed been directed toward the creation of a well-tolerated, pan-genotypic, all-oral, IFN-free regimen with minimal contraindications and a high barrier to drug resistance, the late-stage results from these DAA regimens are certainly a testament to the success of these efforts. However, despite the vast improvements in efficacy and tolerability over their standard-of-care counterparts, these regimens will arrive with their own limitations.

The cost of novel HCV drugs in the marketplace remains a significant concern. The milestone launch of sofosbuvir, for example, was dampened by controversy over its $1,000 per pill price tag. With a number of regimens approaching commercialisation, an atmosphere of competition may help to mitigate this issue. In any event, access to these drugs is likely to remain a hot topic due to the proportion of the HCV population residing in developing countries. As well as its geographic dispersal, this population is characteristically diverse within itself. For this reason, it cannot be assumed that a 'boxed set' FDC product will be as efficacious for one patient as it is for another. Individual patient needs and economic factors may drive a 'mix and match' approach to tailor inter-company drug cocktails for maximal efficacy and cost-effectiveness. It is certainly hoped that in time collaborative drug-interaction studies may clinically validate such uses.

Aside from any lingering question marks or potential limitations, it cannot be denied that these are exciting times in the field of HCV therapeutics. It remains to be seen whether one or more of the aforementioned DAA-based, IFN-free regimens succeeds in providing a long-term, clinically meaningful, true 'miracle cure' for the millions of patients infected with HCV worldwide. This promising pipeline is, without doubt, one to watch.


NASH expected to top indications for liver transplantation in HCC patients
Nonalcoholic steatohepatitis is the most rapidly progressing indication for liver transplantation among patients with hepatocellular carcinoma, a recent study determined.
In a retrospective study, researchers assessed trends in the etiology of hepatocellular carcinoma (HCC) among 61,868 patients who underwent liver transplantation (LT) in the US. The cohort, drawn from the 2002 to 2012 United Network for Organ Sharing registry, included 10,061 patients with HCC.
Full Story »

Diabetes mellitus increased risk for HCC mortality among middle-aged, elderly
June 2, 2014
Middle-aged and elderly Taiwanese patients with diabetes mellitus had an increased risk for death from hepatocellular carcinoma, according to new study results.
Researchers conducted a cohort study of 50,080 Taiwanese patients (mean age, 53.9 years; 53% women) without chronic hepatitis B or C virus infection and cirrhosis between January 1998 and December 2008, to determine any associations between diabetes mellitus (DM), dyslipidemia and hepatocellular carcinoma (HCC). The follow-up period was 10 years and completed by 88% of the cohort.
Full Story »

Alimentary Pharmacology & Therapeutic

UK consensus guidelines on hepatitis C management
The latest Alimentary Pharmacology & Therapeutics reports on the 2014 UK consensus guidelines for hepatitis C management and direct-acting anti-viral therapy.


Alcoholic Hepatitis: Current Challenges and Future Directions
Alcoholic cirrhosis is the eighth most common cause of mortality in the United States and the second leading cause of mortality among all gastrointestinal diseases.[1] This may come as no surprise because the majority of the U.S. population consumes alcohol, with 1 in 10 reporting "heavy" drinking (≥3 drinks/day).[2] Fortunately, only a minority of these heavy drinkers develop significant liver disease.[2,3,4] The reasons for this are unclear, although demographic and genetic factors such as gender, ethnicity, binge drinking (5 or more drinks at a time), nutrition status including obesity, coexisting liver diseases such as hepatitis C virus (HCV) infection, and patatin-like phospholipase-3 gene polymorphism clearly play a role.[2,5–8] A recent study by Becker et al[4] indicates that younger people, women, and binge drinkers are more prone to develop alcoholic hepatitis (AH). This clinical decision meeting should take these factors into account, rather than focusing only on a precise level of alcohol consumption. AH is a clinical syndrome among subjects with chronic and active alcohol abuse characterized clinically by hepatic decompensation and portal hypertension.[9,10] Owing to the high mortality associated with this condition as well as the lack of adequate pharmacologic treatments, increasing efforts have been directed toward developing new therapies.[11] This review focuses on the challenges related to management of AH as well as future directions in the field.

FDA Okays First Device for Restless Legs Syndrome
Susan Jeffrey
The US Food and Drug Administration (FDA) today granted commercial clearance of the first device to help improve quality of sleep in patients with primary restless legs syndrome (RLS), the company announced.

The device (Relaxis, Sensory Medical Inc) is a low-profile pad; the patient lies in bed and places his or her legs on the pad, which provides vibratory counterstimulation that gradually ramps down and shuts off. The approval is based on a meta-analysis and a pooled analysis of 2 randomized, multicenter clinical trials that showed the device was superior to a placebo pad for improving sleep quality in patients with RLS, the company noted in a statement...

BMA Commends NAM’s New Hepatitis C Leaflets, Funded by Wandsworth Oasis
June 2, 2014
by Gill P

Wandsworth Oasis has been contributing towards NAM’s highly regarded information resources for people living with HIV for the last two years. Some of the funds from our first grant went towards the production of four illustrated leaflets on hepatitis C.

We were delighted to hear that the four leaflets were commended by the British Medical Association (BMA) in the recent BMA Patient Information Awards!

Hepatitis is one of the most common co-infections affecting people with HIV. It is passed on in many of the same ways as HIV and can be the cause of serious health problems. But it is treatable, and at the moment, there’s a lot of promising research in newer, better treatments for hepatitis C.

There isn’t much easy-to-read information on hepatitis C for people with HIV. In particular, there’s almost no clear and practical information about the sexual transmission of hepatitis C although it’s an increasing concern for gay men with HIV. And making a decision about whether to start hepatitis C treatment now can be difficult, with a number of pros and cons to weigh up.

The leaflets aim to explain these topics, breaking down complex health information. Each title covers a few key facts and the simple language and pictures bring the information to life.

You can find the four leaflets by following these links:
Hepatitis C
Hepatitis C treatment
How hepatitis C is passed on
How hepatitis C is passed on during sex

The project is a great example of how Wandsworth Oasis is supporting projects that are responding to important, emerging needs.

The BMA Patient Information Awards

The awards have been running since 1997, with the aim of encouraging, “excellence in the production and dissemination of accessible, well-designed and clinically balanced patient information”.

Caspar Thomson, NAM’s Executive Director, told us: ‘We are really thrilled. We could never have produced these leaflets without Wandsworth Oasis’s support and I am really pleased that they have received this praise from the BMA. Hepatitis C co-infection is a complex issue and it is vital people living with HIV have access to good quality information about it. Wandsworth Oasis has made this possible.” 

Weekend Updates -
HCV Weekend Reading; Behind evolving treatments for hepatitis C and progress toward a cure
Updated June 1 2014: Sofosbuvir Based Hepatitis C Clinical Trials - Recruiting

Healthy You
NEJM Featured Multimedia
Nut Consumption and Mortality
Y. Bao and Others
Quick Take Animation 

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