Wednesday, January 18, 2017

Scaling-up HCV treatment to achieve WHO targets by 2030

Accepted Articles

Scaling-up HCV treatment to achieve WHO targets by 2030
Graham Cooke

Accepted manuscript online: 10 January 2017
DOI: 10.1111/tmi.12837

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WHO recently launched a new strategy for tackling viral hepatitis with ambitious goals for reducing both deaths and new infections by 2030 [1]. Antiviral therapy is one only part of a multi-faceted strategy needed to tackle viral hepatitis, but for hepatitis C (HCV), the absence of an effective vaccine means that achieving these targets is going to require substantial scale-up of HCV treatment. Reaching the target of treating 80% of those in need by 2030 will require reaching at least 70 million people [2].....

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Article Of Interest
HCV Universal Treatment Access /Global Elimination - Targeted direct-acting antiviral treatment for chronic hepatitis C: A financial reality or an obstacle to elimination? - Editorial

Researchers discover a protein that protects against fatty liver

Researchers discover a protein that protects against fatty liver

A team co-headed by scientists at the Institute for Research in Biomedicine (IRB Barcelona) and the IDIBAPS Biomedical Research Institute (part of the Hospital Clínic de Barcelona) has revealed the capacity of the CPEB4 protein to prevent fatty liver disease.

This condition generally leads to chronic inflammation (non-alcoholic steatohepatitis), which can trigger fibrosis, cirrhosis and ultimately liver cancer. This study on the basic biology of the liver paves the way to examine therapeutic strategies to fight and prevent fatty liver disease. The results have appeared in Nature Cell Biology this week.

CPEB4 and fatty liver

Non-alcoholic fatty liver is characterised by the accumulation of fat deposits in hepatocytes. The development of this condition is determined by many factors that have not been well described to date. However, obesity and lifestyle, as well as aging, are associated with an increase in the incidence of this disease. Also, a number of large-scale genomics studies have linked variants of the CPEB4 gene with the impairment of fat metabolism.

The scientists at IRB Barcelona depleted CPEB4 expression in mouse livers in order to study the function of this protein. They observed that the mice developed fatty liver as they aged. Furthermore, young CPEB4-depleted mice fed a high-fat diet also developed this condition in a more pronounced manner.

Carlos Maíllo, first author of the article and PhD student at IRB Barcelona funded by a “la Caixa” grant, has described the molecular function of CPEB4. He reveals that this protein is essential to drive the liver stress response.

Specifically, under stress, caused by uncontrolled ingestion of fats for example, the endoplasmic reticulum—a cell organelle associated with protein synthesis and folding and lipid metabolism—stops its activity in order to re-establish cell equilibrium. This “clean-up” mechanism is orchestrated by CPEB4 and varies in function of the time of day—being more active in humans during the day (when the liver has most work) and dropping off at night.

Without CPEB4, the endoplasmic reticulum is unable to activate the stress response, thus causing hepatocytes to accumulate the lipids produced by the fatty liver.

New treatments?
Raúl Méndez, ICREA researcher at IRB Barcelona and co-leader of the study, explains that “knowledge of the hepatic function of CPEB4 could be useful as a predictive marker for those people with variants of this protein, thus serving to prevent this condition, for example, through improvements in diet and better choice of eating times. Such knowledge could also contribute to the development of treatments that boost the clean-up process”.

The researchers have managed to reverse fatty liver disease in mice by treatment with a drug called Tudca, which is currently used for other disorders. This drug exerts the same function as the proteins that are activated by CPEB4 and that are responsible for cleaning up the cell, namely chaperones. “In the future it may be possible to design molecules like Tudca that specifically target CPEB4, thus enhancing the liver clean-up process,” proposes Méndez.

“This basic research study does not have a direct and immediate clinical application, but it lays down the foundation for the applied science that follows,” says Mercedes Fernández, co-leader of the study and head of the group at IDIBAPS and the Biomedical Research Networking Center of Hepatic and Digestive Diseases (CIBEREHD).

Fernández warns, “Given the obesity epidemic in the US and worldwide, an increase in those affected by non-alcoholic fatty liver disease is expected in the coming decades and we still do not have a suitable treatment for this condition; A fundamental understanding of this medical problem is therefore essential for development of novel treatment strategies.”

It is estimated that between 80 and 100 million people in the US alone suffer from fatty liver disease. People with this disease have an increased risk of cirrhosis and liver cancer. Moreover, liver cancer incidence has more than tripled since 1980 and is the primary cause of death in patients with cirrhosis.

This study has received funding from the Worldwide Cancer Research Foundation in the UK, the Spanish Association Against Cancer (AECC), the Fundación Botín by Banco Santander through its Santander Universities Global Division, the Spanish Ministry of Economy and Competitiveness/ERDF and the Government of Catalonia.

Reference article:
Carlos Maillo, Judit Martín, David Sebastián, Maribel Hernández-Alvarez, Mar García-Rocha, Oscar Reina, Antonio Zorzano, Mercedes Fernandez and Raúl Méndez

Circadian- and UPR-dependent control of CPEB4 mediates a translational response to counteract hepatic steatosis under ER stress

Nature Cell Biology (2017) DOI: 10.1038/ncb3461
Article Source

Hepatitis C Treatment: What to Expect in 2017

ARC Journal of Hepatology and Gastroenterology
Volume-1 Issue-1, 2016, Page No: 9-16

Hepatitis C Treatment: What to Expect in 2017
Andreia Gi1, Ana Miguel Matos1,2, Cristina Luxo1,2

Hepatitis C virus infection is a substantial health problem on a global scale [1] It is estimated that approximately 185 million people live with hepatitis C worldwide, with 350,000–500,000 patients dying each year from liver disease associated with hepatitis C[2]. However, something is about to change. In the latest years, there has been a shift in treatment paradigm due to the discovery and approval of direct-acting antiviral agents [3]. Nevertheless, these regimens still included ribavirin, which increased side effects, cost, and inconvenience of treatment. Moreover, improved treatment options for patients who did not respond to prior direct-acting antiviral agents (and may have drug-resistant virus) and for hepatitis C virus genotype 3 infection, with or without cirrhosis, were desirable. Thus, three new promising direct-acting antiviral agents were developed to fulfill these significant unmet medical needs [4,5]

In many countries, sustainability has been the buzzword across all stakeholders. Still, direct-acting antiviral agents have demonstrated a favorable cost-effectiveness profile [6] and their exceptional cure rates have already helped establish the concept that chronic hepatitis C virus infection can be cured in most, if not all, affected individuals.

This review summarizes the clinical potential of velpatasvir-sofosbuvir, velpatasvir-voxilaprevir-sofosbuvir and glecaprevir-pibrentasvir, discussing key results and future directions. Its aim is to highlight the significance of a future free from hepatitis C.

Keywords: Hepatitis C Virus, Direct-Acting Antiviral Agents, Sustained Virologic Response, Cure, Difficult-To- Treat Populations

HCV - Hepatitis C virus
HCC - Hepatocellular carcinoma
SVR - Sustained Virologic Response
IFN - Interferon
RBV - Ribavirin
DAAs - Direct-acting antiviral agents
SOF – Sofosbuvir
VEL – Velpatasvir
VOX - Voxilaprevir

The Hepatitis C virus (HCV) is a small-enveloped virus of the Flaviridae family and genus Hepacivirus, [7] with a single-stranded positive RNA molecule of approximately 9.6 kb [8]. Prior to the discovery of the viral agent, HCV was mainly transmitted via blood products. Since then, injection drug use has arisen as the major mode of transmission in developed countries [2]

The main problem is that, following exposure to HCV, only a minority of patients clears the acute infection, whereas 80% persist with life-long chronic viremia[9] Chronic HCV infection is a serious, progressive, and potentially life-threatening disease [10,11] If left untreated, over time it can cause liver damage or failure due to the development of cirrhosis. This liver complication can lead patients at substantial risk of decompensated disease and hepatocellular carcinoma (HCC), [12] which impose a considerable burden on affected people, healthcare systems and society [13,14] Early diagnosis could help prevent these consequences, but HCV infection is often undiagnosed because it is usually asymptomatic during decades and so, the majority of HCV-infected individuals are unaware of their infection [15].

The goal of treatment in all infected individuals, regardless of which of the six major genotypes are present, remains the achievement of a sustained virologic response (SVR) in which circulating HCV RNA is undetectable (with the use of a highly sensitive assay) following treatment. When a SVR is achieved, there is a 99% chance that the hepatitis C infection is cured [13,16]. Historically, SVR was defined as HCV RNA levels below a designated threshold of quantification 24 weeks after completion of treatment (SVR24)[17]. However, more recent data shows that viral clearance 12 weeks post-treatment (and sometimes, even 8 weeks) correlates closely to SVR24[18]. Therefore, an undetectable HCV RNA at 12 weeks after treatment (SVR12) is considered an appropriate primary efficacy endpoint [19] and translates into “cure” for nearly all patients[13]

2. Direct-Acting Antiviral Agents Versus Interferon-Based Therapies
The new regimens for HCV mean a breakthrough novelty in the history of anti-HCV treatment. Previous treatments for HCV were often long and difficult. Many lasted from 24 to 48 weeks and showed suboptimal efficacy in viral response with a range of commonly occurring significant side effects, which impaired therapeutic compliance[20]. Nowadays, HCV patients can benefit from a less complex administration schedule and expect interferon (IFN) and even ribavirin (RBV)-free combinations. This results in a reduction of the incidence and severity of adverse events, optimizing quality of life during therapy and improving adherence to direct-acting antiviral agents (DAAs).

3. Sofosbuvir-Velpatasvir
Sofosbuvir-velpatasvir (EPCLUSA®) is a prescription medicine used to treat adults with chronic (lasting a long time) hepatitis C genotype 1, 2, 3, 4, 5, or 6 infection with or without cirrhosis (compensated). In clinical studies, sofosbuvir-velpatasvir (SOF-VEL) had high overall cure rates. (Table 1) The most common side effects were headache and tiredness [21].

Clinical Study (Reference)Number of patients (% cirrhosis)HCV genotype (%)Treatment HistorySVR12 by Genotype, Cirrhosis and Treatment Experience
ASTRAL-1 (22)740 (19%)1
Treatment-naïve and treatment- experiencedSOF - VEL, 12 weeksGenotype 1a98% (206/210)
Genotype 1b99% (117/118)
Genotype  2100% (104/104)
Genotype  4100% (116/116)
Genotype  597% (34/35)
Genotype  6100% (41/41)
Without Cirrhosis99% (496/501)
With Cirrhosis99% (120/121)
Treatment- naïve99% (418/423)
Treatment- experienced99% (200/201)
ASTRAL-2 (23)266(14%)2(100%)Treatment-naïve and treatment- experienced SOF - VEL, 12weeksTreatment- naïve without cirrhosis99% (99/100)
SOF + RBV, 12 weeksTreatment- naïve without cirrhosis96% (92/96)
SOF - VEL, 12 weeksTreatment- naïve with cirrhosis100% (15/15)
SOF + RBV, 12 weeksTreatment- naïve with cirrhosis93% (14/15)
SOF - VEL, 12 weeksTreatment- experienced without cirrhosis100% (15/15)
SOF + RBV, 12 weeksTreatment- experienced without cirrhosis81% (13/16)
SOF - VEL, 12 weeksTreatment- experienced with cirrhosis100% (4/4)
SOF + RBV, 12 weeksTreatment- experienced with cirrhosis100% (4/4)
ASTRAL-3 (23)552(30%)3(100%)Treatment-naïve and treatment- experiencedSOF - VEL, 12 weeksTreatment- naïve without cirrhosis98% (160/163)
SOF + RBV, 24 weeksTreatment- naïve without cirrhosis90% (141/156)
SOF - VEL, 12 weeksTreatment- naïve with cirrhosis93% (40/43)
SOF + RBV, 24 weeksTreatment- naïve with cirrhosis73% (33/45)
SOF - VEL, 12 weeksTreatment- experienced without cirrhosis91% (31/34)
SOF + RBV, 24 weeksTreatment- experienced without cirrhosis71% (22/31)
SOF - VEL, 12 weeksTreatment- experienced with cirrhosis89% (33/37)
SOF + RBV, 24 weeksTreatment- experienced with cirrhosis

4. Sofosbuvir-Velpatasvir-Voxilaprevir
Four Phase 3 clinical studies (POLARIS-1, POLARIS-2, POLARIS-3 and POLARIS-4) evaluated a once-daily, fixed-dose combination of sofosbuvir (SOF), a nucleotide analog NS5B polymerase inhibitor; velpatasvir (VEL), a pangenotypic NS5A inhibitor; and voxilaprevir (VOX; GS-9857), an investigational pangenotypic NS3/4A protease inhibitor, for the treatment of genotype 1,2,3,4,5 and 6 chronic HCV infection. (Table 3)

The most common adverse events among patients who received SOF-VEL-VOX were headache, fatigue, diarrhea and nausea. The overall incidence of adverse events was similar to placebo or SOF- VEL. Among the 1,056 patients who received SOF-VEL-VOX in the four studies, only a patient receiving SOF-VEL-VOX for 12 weeks discontinued due to an adverse event[26]. These results show that this new three-drug co-formulation with different mechanisms of action and high barrier to resistance can provide high cure rates for patients who had previously failed treatment with other DAAs.

Table 2. Summary of clinical studies of sofosbuvir-velpatasvir in special populations

3. Summary of clinical studies of sofosbuvir-velpatasvir-voxilaprevir

5. Glecaprevir-Pibrentasvir

Glecaprevir-pibrentasvir is an investigational, pan-genotypic regimen that is being evaluated (table 4) not only as a potential cure in 8 weeks for HCV patients without cirrhosis and who are new to treatment, but also in patients with specific treatment challenges, such as genotype 3, patients who were not cured with previous DAA treatment and those with chronic kidney disease, including patients on dialysis.

This investigational, pan-genotypic regimen of glecaprevir-pibrentasvir is showing to be well tolerated with a favorable safety profile in these difficult-to-treat populations. The most commonly reported adverse events included fatigue and nausea.

Table 4. Summary of clinical studies of glecaprevir-pibrentasvir

6. Discussion
Although the post-marketing phase always requires a careful evaluation of data from the “everyday” clinical practice experience, clinical trials have showed that these new DAA combinations have resolved most issues related to HCV treatment compared with the past regimens. Despite the approval of the first DAAs which have provided high cure rates and simplified treatment for most HCV patients, HCV genotype 3-infected patients with cirrhosis, patients with chronic kidney disease and those who have failed previous treatment with DAAs continued to represent an unmet medical need. In the era of velpatasvir-sofosbuvir, velpatasvir-voxilaprevir-sofosbuvir and glecaprevir- pibrentasvir, DAA therapy provides a new way to manage these difficult-to-treat HCV-infected patients, who are at a high risk of serious conditions[30]. They are now contemplated and are therefore expected to have a much better prognosis than they have had until very recently. Perhaps, soon, we may no longer have difficult-to-treat populations.

The advent of new generation oral antiviral therapy has led to major improvements in efficacy and tolerability but has also resulted in an explosion of data with increased treatment choice complexity [31].

Thus, clinicians need more detailed, accurate and timely information in order to choose the right regimen for individual patients and educate them. When they counsel and guide their patients, these ones are less likely to be anxious or resistant about taking steps toward possible cure. However, cure does not prevent reinfection and so, it is crucial to advise patients on measures that will reduce their risk (avoid alcohol intake and sexual and injection risk behaviors, eat a balanced diet and take exercise are some examples).

7. Conclusion
DAAs have shown that it is possible to minimize the spread of HCV and the morbidity and mortality associated with HCV infection[32].

Despite the financial controversy around their high costs, which have served as a major barrier for more widespread use, many stakeholders recognize now their long-term cost-benefits and the advantages of a future free from hepatitis C are manifest.

It is true that patients undergoing treatment need systematic monitoring before, during and after therapy, but these new treatment options have offered them hope and re-awakening. It is a clear evolution compared with the previous IFN-based therapies.

8. Future Directions
At a future time, treatment failure and resistance can occur and become a clinical challenge to be solved[30,33].

However, before them, there are already some questions that should concern us. First one is why is the association of RBV with DAAs, in some cases, increasing the SVR12 rate and shortening the duration of treatment? Then, at what point is it no longer worth treating a patient? Will we have the financial capacity to treat reinfected-patients? Will this simplicity of therapeutic regimen encourage risk behaviors in the future?

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AASLD and IDSA  clinical guidelines fall short of conflict of interest standards

Prominent clinical guidelines fall short of conflict of interest standards
From Twitter To Treatment Guidelines, Industry Influence Permeates Medicine
Two committees that developed guidelines for the management of high cholesterol and hepatitis C did not fully comply with standards set by the Institute of Medicine in 2011 to limit the number of industry-funded panelists. The Institute of Medicine required that fewer than half of guideline writers have commercial ties and that all chairs and co-chairs have no conflicts. But in both cases, at least one chairperson received money from industry and, in the case of the hepatitis C guidelines, a substantial majority of panelists also received money.

Moreover, the authors noted, when separate committees with no commercial conflicts developed guidelines for cholesterol and hepatitis C, the recommendations were more conservative and called for less expensive first-line treatments.
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Increased conflict of interest policies needed for guideline committees, advocacy organizations
The guideline for cholesterol by the American College of Cardiology and American Heart Association, as well as the guideline for hepatitis C virus treatment by the American Association for the Study of Liver Diseases and Infectious Diseases Society of America did not fully meet the Institute of Medicine standards for commercial conflict of interest management, according to studies published in JAMA Internal Medicine. The authors noted that modest or substantial industry support was common among many patient advocacy organizations, and that such support could influence their positions.
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Tuesday, January 17, 2017

Forbes - The U.S. Government Should Buy Gilead For $156 Billion To Save Money On Hepatitis C

Guest post written by
Peter B. Bach and Mark Trusheim
The U.S. government could cure most Americans suffering from hepatitis C infections if it simply bought drug maker Gilead Sciences on the stock market rather than purchasing its products in the drug market.
Gilead has drawn fire for the high price of its hepatitis C drugs, Sovaldi and Harvoni, which currently cost more than $500 per pill but cure the underlying hepatitis C liver infection. But, counterintuitively, buying Gilead outright on the open market could lower hepatitis C drug costs per patient to one-third their current level. That would make it affordable to rapidly treat the 2.7 million Americans the CDC estimates still have hepatitis C....

HCV Next Cover Story - 2017 A Year in Transition
2017: A Year in Transition

"HCV Next" features cutting edge news on the latest HCV research developments. With in-depth articles on a range of topics; diagnosis, hepatitis c treatment regimens, side effects, drug/drug interaction, guidelines, practice management issues, to name a few.

The following articles appeared in the January 2017 print edition of HCV NEXT, provided online at Healio.

Table of Contents
5 Questions
A Conversation With Robert Gish, MD

Cover Story
2017: A Year in Transition
Cover Story     
Throughout 2016, the remarkable success of direct-acting agents was confirmed and extended. Several new drugs — including Epclusa (Gilead), Zepatier (Merck), Daklinza (Bristol-Myers Squibb), Technivie (AbbVie), Viekira Pak (AbbVie) and Viekira XR (AbbVie) — were approved, representing continued remarkable potency of the DAA agents with the added bonus of extension into more pangenotypic activity. While there are still many other new drugs in development with the same trend toward increased potency and pangenotypic activity, it seems that drug development is starting to plateau. This ultimately will leave us with a strong armamentarium from which to choose the best agents for each of our individual patients.

Michael S. Saag, MD
Drug Pipeline
HCV 2016 Timeline