Friday, July 21, 2017

Perspective for those who want to dig deeper on prescription drug costs

Perspective for those who want to dig deeper on prescription drug costs
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Study to better understand how rapidly hepatitis C virus (HCV) clears the bloodstream

PLOS ONE

The purpose of the current study was to better understand how rapidly hepatitis C virus (HCV) clears the bloodstream. As the only ethical way to infect a human liver in a human patient is by transplanting an HCV-uninfected liver into an HCV-infected recipient, we calculated the rates of viral clearance from the bloodstream during liver transplant as a surrogate for viral entry.

Research Article

Rate of hepatitis C viral clearance by human livers in human patients: Liver transplantation modeling primary infection and implications for studying entry inhibition
Michael G. Hughes Jr. , William W. Tucker, Sreelatha Reddy, Michael E. Brier, David Koch, Craig J. McClain, Colleen B. Jonsson, Nobuyuki Matoba, Donghoon Chung

Published: July 21, 2017 https://doi.org/10.1371/journal.pone.0180719

Abstract
To better understand the dynamics of early hepatitis C virus (HCV) infection, we determined how rapidly non-cirrhotic HCV-uninfected liver allografts clear HCV from the circulation of cirrhotic HCV-infected patients at the time of transplantation but before administration of immunosuppression. Specifically, we characterized serum HCV kinetics during the first 90 min of reperfusion for 19 chronically HCV-infected patients transplanted with an HCV-uninfected liver by measuring serum viral load immediately prior to reperfusion (t = 0) and then every 15 min for a total of 90 min (t = 90). Immunosuppression was withheld until all samples were taken to better model primary infection. During this period, rates of viral clearance varied more than 20-fold with a median rate constant of 0.0357 1/min, range 0.0089–0.2169; half-life (minutes) median 19.4, range 3.2–77.8. The majority of viral clearance occurred within the first 60 min. The amount of blood transfused during this 90-min period (a potential confounding variable of this human liver transplant model of primary infection) accounted for 53% and 59% of k (r = 0.53, p = 0.05) and half-life (r = 0.59, p = 0.03) variability, respectively. No other clinical variables tested (age, allograft weight, and degree of reperfusion injury as assessed by peak postoperative ALT or AST) accounted for the remaining variability (p>0.05).

Conclusion: In a human liver transplant model of primary infection, HCV rapidly clears the bloodstream. With approximately 90% of clearance occurring in the first 90 minutes of reperfusion, studies of HCV entry inhibition could utilize rate of clearance during this early period as an outcome measure.

Discussion Only
View Full Text Article
The purpose of the current study was to better understand how rapidly hepatitis C virus (HCV) clears the bloodstream. As the only ethical way to infect a human liver in a human patient is by transplanting an HCV-uninfected liver into an HCV-infected recipient, we calculated the rates of viral clearance from the bloodstream during liver transplant as a surrogate for viral entry. To more accurately model primary infection, immunosuppression was withheld during the study period. This is a key difference from other published studies on HCV kinetics during liver transplantation.

We hypothesized that the rate of viral clearance (and likely entry) varies widely during initial infection and focused our investigation on the first 90 min of reperfusion to ensure that the dynamics of initial infection were captured. Decreasing serum viral levels over the 90 min of initial reperfusion were considered to represent viral clearance by allografts, as it has been previously demonstrated that serum viral levels dramatically decrease with transition from the anhepatic phase to the reperfusion phase of liver transplant [7, 12]. The current study significantly adds to existing knowledge regarding this transition by 1) evaluating earlier time points and 2) excluding immunosuppression as a confounding variable.

We elected to use an in-house HCV qRT-PCR assay rather than utilize a commercial assay to minimize variability. The internal controls for the commercial assays were qualitative rather than quantitative and therefore could not be used for calibration. For our study, we anticipated that we would need to detect potentially very small changes in viral load as we were going to sample every 15 minutes. We therefore used a quantitative internal control (Armored HIV RNA quant) that could be used to calibrate our HCV levels and reduce variability. Compared with commercially available assays, our variability was lower [13], though we did sacrifice some sensitivity. For this study, we prioritized minimizing variability over maximizing sensitivity.

In our current study of 19 patients who were viremic at the time of reperfusion, the rate of viral clearance by allografts varied more than 20-fold but demonstrated first order kinetics for all patients but one (patient 5). The linearity of the process throughout the 90 min of the study suggests that virus may be cleared at a rate greater than production. Most viral clearance occurred in the first 60 min of reperfusion. Of the tested clinical variables, only blood transfusion could account for any of the observed variability. Patient 5 deviated from log-linear towards the end of the 90-minute period. Though this could be due the newly infected liver supporting rapid viral replication and release back into the bloodstream, this plateau could rather represent the intermediate phase of a biphasic decline consistent with what has been described in other studies [7, 14]. If the minimal intra-cellular delay time is truly 6 hours [14], then this more likely represents a second, extra-hepatic replication compartment that generated a more significant contribution to HCV levels for patient 5 than for the other patients [14]. The duration of our study was too short to calculate the contribution of a second compartment for these patients.

Bleeding and resulting blood transfusion is a likely a confounding variable for this model of primary infection. Virus is lost during bleeding with a reduction in circulating blood volume. Restoring blood volume with transfusion of HCV-uninfected blood and fluids then dilutes out circulating viral levels. However, blood transfusion could not fully account for the observed differences in this study. The amount of blood transfused during this 90-min period accounted for 53% and 59% of k (r = 0.53, p = 0.05) and half-life (r = 0.59, p = 0.03) variability, respectively. It may be that blood transfusion is an imperfect marker for blood loss and volume replacement. Patients transfused just 1 or 2 units of blood were observed to clear virus twice as quickly as those that did not. It seems unlikely that a <500 cc/unit blood transfusion could dilute viral levels to this degree when circulating blood volumes are typically 3–5 liters. Measuring actual blood loss in real-time during reperfusion was not possible as this process is too dynamic. We therefore propose that the intrinsic rate viral clearance would be best estimated by the median rate of clearance for those patients not transfused (0.0287 1/min). However, this still likely overestimates the true rate of viral clearance as it cannot separate out the contribution of degradation or other non-hepatic clearance mechanisms. If we had determined the rate of clearance during the anhepatic phase, then we could have used these data to more accurately determine hepatic clearance. This represents a limitation of our study design.

The study was designed to carefully and prospectively analyze a very discrete period during the transplant event and follow up on the findings of Garcia-Retortillo et al. [7] and Powers et al. [12]. In a study of 20 patients undergoing liver transplantation, Garcia-Retortillo et al. showed that virus decreased with reperfusion despite having a longer half-life (3.4 hours compared with 2.2 hours during the anhepatic phase). This discrepancy is likely because they did not measure any circulating viral levels during the first 4 hours of reperfusion. By evaluating the first 90 min of reperfusion in 15-min intervals, the current study shows that clearance occurs much earlier and faster (t1/2 19.4 min). The half-life of HCV during reperfusion (as calculated by Garcia-Retortillo et al.) was likely longer than the anhepatic phase because viral production by the newly infected allograft was starting to increase relative to clearance.

In a smaller study of 6 patients, Powers et al. (9) sampled serum during reperfusion earlier than Garcia-Retortillo et al. (10). However, the Powers’ study still did not capture the first hours of reperfusion, missing most clearance, and calculated viral clearance by lumping the anhepatic phase within the first 4 hours of reperfusion. The purpose and design of their study was not to evaluate viral clearance, but rather to characterize viral resurgence following initial reperfusion. They calculated a similar half-life during reperfusion (3.4 hours) as Garcia-Retortillo et al., likely because they also started 4 hours after reperfusion. Their graphical depiction of viral levels does show, like Garcia-Retortillo et al., that the largest decrease in viral levels occurred between the last anhepatic and the first reperfusion samples drawn. Therefore, viral clearance during initial reperfusion (as described in the current study) links viral decay during the anhepatic phase and viral resurgence during later reperfusion (as described by these two prior studies). We have included the viral kinetics following the 90-minute reperfusion phase from 4 patients to show that our findings are similar to the other cited studies when measured over the same time period.

It appears that the clearance mechanism was not saturated in any of the patients studied. This was determined by the observation that the concentrations fall in a linear fashion (on the straight line of natural log of HCV concentration over time). It is therefore unlikely that cell surface receptors for the virus (such as CD81 [15], SR-BI [16], Claudin-1 [17] and Occludin [18]) were present at low enough levels to become saturated. With such high titer inoculum relative to other primary infections (e.g. needle stick transmission), it is unlikely other modes of transmission would result in receptor saturation either. During the first 90 min of reperfusion, new viral production was minimal relative to clearance due to the HCV concentration over time not departing from linearity. Therefore, studies of viral evolution during this time period are unlikely to be significantly confounded by production of new mutations [19, 20].

The large variation in rates of viral clearance not fully accounted for by the tested clinical variables must be explained by other factors. As clearance is determined by blood flow and extraction efficiency, variable perfusion pressure during reperfusion will contribute to the observed differences. This is a likely contributor as hemodynamic instability occurs frequently during reperfusion. Furthermore, differences in extraction efficiency could be due to differences in allograft or viral factors. Allografts may differ in HCV receptor density and/or turnover [20, 21] and therefore may vary in susceptibility to infection. In a study of liver transplant recipients in the first year following transplantation, Mensa et al. found that higher concentrations of SR-BI in the allograft correlated with more rapid clearance of HCV in the early reperfusion phase (first 24 hours), whereas higher levels of occludin and claudin-1 correlated with faster rate of viral production in the following week [22]. Alternatively, a study targeting SR-BI showed that an SR-BI antagonist, ITX5061, had no impact on rates of viral clearance in the first 24 hours, but may have limited subsequent viral rebound [23]. Additionally, viral populations have been shown to differ between patients, leading to variable levels of infectivity [19, 20, 24]. The same study of ITX5061 showed that SR-BI blockade limited viral quasispecies evolution at hypervariable region 1 of E2 [23], further supporting that SR-BI may bind HCV at HVR1 [25]. Patients therefore may differ in viral inoculum fitness.

We believe that the data presented herein can provide background to design clinical studies measuring the efficacy of HCV entry inhibitors. Entry inhibitors can play a role during liver transplant by preventing transmission of recipient bloodstream derived HCV into the newly transplanted uninfected liver without damaging vulnerable hepatocytes [8, 10]. Given that secondary non-hepatic compartments for viral production may exist, such inhibitors may need to address these compartments through anti-viral activity, either through an intrinsic mechanism or when given in combination with direct acting anti-viral agents [23]. Rates of viral clearance over the first 90 minutes of reperfusion would be relevant outcome measure for entry inhibitors that target either the virus or host-entry factors. Liver transplantation could be used to study the impact of these inhibitors on viral entry prior to testing them in chronically infected patients.

Conclusion
With most HCV clearance occurring in the first 90 minutes of transplantation, we believe that liver transplantation represents a prime opportunity to study the impact of HCV entry inhibitors.

View Full Text Article......

Engineered liver tissue expands after transplant


Researchers have developed a new way to engineer liver tissue by organizing tiny subunits that contain three types of cells embedded into a biodegradable tissue scaffold. This image shows vascularized engineered human liver tissue that has self-organized into a lobule-like microstructure.

Engineered liver tissue expands after transplant

Tiny implantable “seeds” of tissue produce fully functional livers.
                              



Many diseases, including cirrhosis and hepatitis, can lead to liver failure. More than 17,000 Americans suffering from these diseases are now waiting for liver transplants, but significantly fewer livers are available.

To help address that shortage, researchers at MIT, Rockefeller University, and Boston University have developed a new way to engineer liver tissue, by organizing tiny subunits that contain three types of cells embedded into a biodegradable tissue scaffold. In a study of mice with damaged livers, the researchers found that after being implanted in the abdomen, the tiny structures expanded 50-fold and were able to perform normal liver tissue functions.

“There are just not enough organs to go around. Our goal is that one day we could use this technology to increase the number of transplants that are done for patients, which right now is very limited,” says Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.

These engineered livers could also help the millions of people who suffer from chronic liver disease but don’t qualify for a liver transplant, says Bhatia, the senior author of the study, which appears in the July 19 issue of Science Translational Medicine.

“These patients never really are transplant candidates, but they suffer from liver disease, and they live with it their whole lives. In that population you could imagine augmenting their liver function with a small engineered liver, which is an idea we’re pretty excited about,” she says.

The paper’s lead author is Kelly Stevens, a former Koch Institute postdoc.

Liver regeneration

The new implantable liver builds on previous work by Bhatia’s lab. In 2011, she developed an engineered tissue scaffold, about the size and shape of a contact lens, that could be implanted into the abdomen of a mouse. There, the liver cells would integrate with the mouse’s circulatory system, allowing it to receive a blood supply and begin performing normal liver functions.

However, those implants contained fewer than 1 million hepatocytes (the cells that perform most of the liver’s critical functions). A healthy human liver has about 100 billion hepatocytes, and Bhatia believes that at least 10 to 30 percent of that number would be necessary to help most patients.

To boost their hepatocyte population, the researchers decided to take advantage of a key trait of liver cells, which is that they can multiply to generate new liver tissue. “The liver is one of the only organs that can regenerate, and it’s the mature cells that divide, without an intermediate stem cell. That’s extraordinary,” Bhatia says.

Working with Christopher Chen, a professor of biomedical engineering at Boston University, Bhatia’s team designed microfabricated structures that incorporate spherical “organoids” made of hepatocytes and fibroblasts, as well as cords of endothelial cells, which are the building blocks of blood vessels. These two types of structures are organized into patterns and embedded into fibrin, a tough protein normally involved in blood clotting.

Once the constructs are implanted into a mouse, they receive regenerative signals from the surrounding environment. These signals, which include growth factors, enzymes, and molecules, are naturally produced when liver damage occurs. These signals stimulate the endothelial cells to form blood vessels and to release factors that stimulate hepatocyte proliferation, resulting in 50-fold expansion of the original tissue.

“The idea is that it’s the seed of an organ, and you organize it in a way that it can be responsive to these regenerative signals, but it’s a minimal unit of what you eventually want to end up with,” Bhatia says. “What’s really exciting about this is that the architecture of the tissue that emerges looks a lot like the liver architecture in the body.”

In this case, the researchers worked with Charles Rice, a virology professor at Rockefeller University, to implant the tissue into mice with a genetic liver disorder called tyrosinemia. When treated with a repair-inducing drug, the livers of these mice begin produce regenerative signals, and the researchers expect that patients receiving the transplants would produce similar signals. They are also looking into the possibility of embedding the implant with additional regeneration-promoting chemicals that they discovered in 2013.

Fully functional

The liver performs hundreds of functions for the body, most of which are related to regulation of metabolism, detoxification of harmful substances, and bile production. Tests of the implanted human livers showed that examples of all of these functions were occurring normally in the host mice.

“This work is very innovative,” says Inder Verma, a professor of molecular biology at the Salk Institute, who was not involved in the research. “The use of primary hepatocytes, endothelial cells, and stromal cells, leading to a 50-fold increase, is impressive and could pave the way for the growth of other organoids currently being employed by other labs.”

Intriguingly, the researchers also found that after implantation, the tissue began forming tiny precursors to bile ducts, which they had not designed. “The next step for us is to find out how they got there, whether we can make it happen faster and in a more organized way, and whether they’re functional,” Bhatia says.

The researchers are also exploring the best source of cells for these implants. Currently they are using liver cells from human organs that can’t be transplanted because they were on ice for too long after being removed from the donor or had some unusual anatomy. Other possibilities include using liver cells taken from the patient who will be receiving the tissue, which would avoid the need for immunosuppressive drugs, or using liver cells generated from induced pluripotent stem cells.

The research was funded by the National Institutes of Health, the Howard Hughes Medical Institute, the Skolkovo Institute of Science and Technology, and the National Institute of Environmental Health Sciences.

WHO prequalifies first generic hepatitis C medicine and first HIV self-test

In the lead-up to Paris AIDS conference, WHO prequalifies first generic hepatitis C medicine and first HIV self-test

Hepatitis C

WHO today prequalified the first generic version of sofosbuvir, a critical medicine for the treatment of hepatitis C. The development could expand access to treatment by increasing the number of quality-assured generic medicines on the market. Sofosbuvir, 400 mg tablet, is manufactured by Mylan Laboratories Ltd., India.

“This is a break-through medicine with a 95% cure,” said Dr Suzanne Hill, Director, Essential Medicines and Health Products at WHO. “The first WHO-prequalified generic of this product will give large procurers and countries the assurance of quality for an affordable product.”

WHO prequalification means the product can now be procured by the United Nations and financing agencies such as UNITAID, which has recently introduced hepatitis C in the portfolio of diseases it covers. Countries such as Indonesia, Vietnam, Cambodia, Myanmar, Mongolia, Nepal, Rwanda, Uganda, Kenya, Zambia, Ethiopia, Pakistan and Egypt are already procuring generic versions of sofosbuvir. The fact that WHO has prequalified one of those generics will give them extra guarantee of the product’s quality, safety and efficacy.

“Direct acting antiviral medicines such as sofosbuvir are highly effective for treating and curing chronic hepatitis C infection. But, at best, 1 out of 10 people in need had access to these medicines in 2015,” said Dr Gottfried Hirnschall, WHO’s Director of the HIV Department. “Prequalification of the hepatitis C medicine for the first-time is therefore exciting news, ahead of World Hepatitis Day next week.”

The average price of the required three-month treatment course of Mylan’s sofosbuvir is around US$ 260, a small fraction of the medicine’s market entry price in late 2013, and of the price set in the majority of high-income countries. The medicine remains highly expensive in many countries, but licensing agreements between Gilead Sciences, who developed sofosbuvir, and a number of generic manufacturers have made it possible for low-income and some middle-income countries to provide the medicine at more affordable prices.

HIV self-test
WHO today prequalified the first HIV self-test in a move to increase HIV diagnosis and treatment. The product, OraQuick ® HIV Self-Test (manufactured by OraSure Technologies Inc.) uses oral fluid as a specimen and provides results in as little as twenty minutes.

“The prequalification of this product means that countries with poor laboratory infrastructure will be able to safely increase testing capacity, thereby facilitating treatment of people living with HIV,” said Dr Suzanne Hill, Director, Essential Medicines and Health Products, WHO.

The move also marks a significant step in allowing countries to implement WHO guidelines, released in 2016, recommending HIV self-testing as a complementary approach to reach those who remain undiagnosed due to fear of stigma and discrimination.

“Over the past year, the number of countries incorporating HIV self-testing into their policies has increased from 16 to 40. This is impressive progress,” said Dr Gottfried Hirnschall, WHO’s Director of the HIV Department. “Having quality-assured self-tests is essential to enable countries to implement more rapidly. It is a positive step towards making innovative HIV self-testing accessible to all those who would benefit from it.”

In 2016, an estimated 30% of all people living with HIV remained unaware of their HIV status, many from higher risk populations who are either less likely to approach a health facility or are unable to do so.

“As the first HIV self-testing product to obtain WHO prequalification, this is a major step that will help give governments the confidence they need to adopt and scale up use of self-testing,” said Philippe Duneton, Deputy Executive Director of Unitaid.

There is currently great interest from the international community in deploying tests intended for HIV self-testing, with numerous countries having developed national guidelines and plans for implementation. Support for procurement and deployment of these tests has been pledged by most major international financing and procurement agencies, including a specific agreement on affordable pricing for 50 lower-middle income countries in Africa and Asia between the manufacturer and the Bill and Melinda Gates Foundation, a funder of WHO Prequalification.

Medscape TV - Episode 2: Considerations Before HCV Therapy

Medscape TV - Hepatitis C Virus: Containing the Threat

July 17, 2017

June 21, 2017
EPISODE 1 - Strides and Obstacles

Six Episode Series
In the past few years, a new class of direct-acting antiviral agents has made the treatment of HCV easier and more effective than ever before, with cure rates nearing 100%, even among HIV-positive patients. But not all patients with HCV who are eligible for antiviral treatment are identified, and even fewer are being referred for care. Thus, HCV infection remains a significant risk for progression to cirrhosis, liver failure, and hepatocellular carcinoma. Liver specialists at two prestigious Chicago medical centers confront the key issues in the management of patients with chronic HCV infection.

Coming Soon
Episode 3 - Hope and Uncertainty
Episode 4 - New Regimens
Episode 5 - Dealing With Chronic Disease
Episode 6 - Strategies for Prevention
Free registration may be required

Primary Care Providers Can Treat Hep C

AGA Reading Room

Primary Care Providers Can Treat Hep C
by Liz Highleyman
Contributing Writer, MedPage Today

Primary care physicians and nurse practitioners can achieve cure rates matching those of liver disease specialists
Primary care providers can successfully manage direct-acting antiviral (DAA) treatment for hepatitis C, though some complicated cases should still be referred to specialists, experts say.
Recent studies have shows that hepatitis C treatment by primary care physicians and nurse practitioners can result in cure rates similar to those achieved by hepatologists and infectious disease specialists. Increasing the number of providers is key to expanding access to effective new therapies.
 Continue reading...

Free registration may be required

Chemical analysis of counterfeit hepatitis C drug found in Japan.

Chemical analysis of counterfeit hepatitis C drug found in Japan.
Uchiyama N1, Kamakura H1, Masada S1, Tsujimoto T1, Hosoe J1, Tokumoto H1, Maruyama T1, Goda Y1, Hakamatsuka T1.
Author information 1National Institute of Health Sciences (NIHS). Citation Yakugaku Zasshi. 2017 Jul 19. doi: 10.1248/yakushi.17-00136. [Epub ahead of print]

Advance Publication July 19, 2017

In January 2017, counterfeits of the hepatitis C drug 'HARVONI® Combination Tablets' (HARVONI®) were found at a pharmacy chain through unlicensed suppliers in Japan. A total of five lots of counterfeit HARVONI® (samples 1-5) bottles were found, and the ingredients of the bottles were all in tablet form. Among them, two differently shaped tablets were present in two of the bottles (categorized as samples 2A, 2B, 4A, and 4B). We analyzed the total of seven samples by high-resolution LC-MS, GC-MS and NMR. In samples 2A, 3 and 4B, sofosbuvir, the active component of another hepatitis C drug, SOVARDI® Tablets 400 mg (SOVARDI®), was detected. In sample 4A, sofosbuvir and ledipasvir, the active components of HARVONI®, were found. A direct comparison of the four samples and genuine products showed that three samples (2A, 3, 4B) are apparently SOVARDI® and that sample 2A is HARVONI®. In samples 1 and 5, several vitamins but none of the active compounds usually found in HARVONI® (i.e., sofosbuvir and ledipasvir) were detected. Our additional investigation indicates that these two samples are likely to be a commercial vitamin supplement distributed in Japan. Sample 2B, looked entirely different from HARVONI® and contained several herbal constitutents (such as ephedrine and glycyrrhizin) that are used in Japanese Kampo formulations. A further analysis indicated that sample 2B is likely to be a Kampo extract tablet of Shoseiryuto which is distributed in Japan. Considering this case, it is important to be vigilant to prevent a recurrence of distribution of counterfeit drugs.

Full website
https://www.ncbi.nlm.nih.gov/m/pubmed/28724837/?i=7&from=hepatitis c

BVHG/BASL/BSG/BHIVA/BIA/CVN Guidelines for management of chronic HCV infection

HCV consensus treatment guidelines

BVHG/BASL/BSG/BHIVA/BIA/CVN Guidelines for management of chronic HCV infection

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Preface
These guidelines were generated following a consensus meeting held in Birmingham on the 30th of June 2017 of representatives from the above organisations as well as representatives from the operational delivery networks in England. They are intended to reflect best practice rather than what is currently commissioned for HCV treatment.
 
Headline Recommendations


1. We recommend that NHSE considers commissioning pan-genotypic regimens for use in the community for patients who are treatment naïve and do not have cirrhosis to avoid the need for genotyping and facilitate rapid access to care.  

2. We recommend that ribavirin be avoided whenever possible.

3. We recommend that 8 week regimens without ribavirin are first choice for treatment naïve non-cirrhotic patients treated in community or prison settings regardless of genotype.

4. We reiterate that transplantation is not contra-indicated in patients with HCV even in the presence of ‘difficult’ drug resistant mutations.

5 Drug-drug interactions should continue to be assessed and therapy should take account of potential interactions.

Genotype Specific Recommendations

Non-cirrhotic

G1a
Sofosbuvir/ledipasvir 8 weeks (treatment naïve) or 12 weeks (treatment experienced) Grazoprevir/elbasvir 12 weeks OR 16 weeks + ribavirin  for patients with viral load >800,000 and resistance associated substitutions(16 weeks + ribavirin is NOT a preferred regimen) Paritaprevir/ritonavir/ombitasvir+dasabuvir+ribavirin 12 weeks – should be discarded when Glecaprevir/pibrentasvir is available. Sofosbuvir/velpatasvir 12 weeks Sofosbuvir/velpatasvir/voxilaprevir - 8 weeks Glecaprevir/pibrentasvir - 8 weeks 

G1b
Sofosbuvir/ledipasvir 8 weeks (treatment naïve) or 12 weeks (treatment experienced) Grazoprevir/elbasvir 12 weeks Paritaprevir/ritonavir/ombitasvir+dasabuvir 12 weeks– should be discarded when Glecaprevir/pibrentasvir is available. Sofosbuvir/velpatasvir 12 weeks Sofosbuvir/velpatasvir/voxilaprevir 8 weeks Glecaprevir/pibrentasvir 8 weeks

Compensated cirrhosis

G1a
Sofosbuvir/ledipasvir 12 weeks Grazoprevir/elbasvir 12 weeks OR 16 weeks + ribavirin for patients with viral load >800,000 and resistance associated substitutions (16 weeks + ribavirin is NOT a preferred regimen) Paritaprevir/ritonavir/ombitasvir+dasabuvir+ribavirin 12-24 weeks - should be discarded when Glecaprevir/pibrentasvir is available. Sofosbuvir/velpatasvir 12 weeks Sofosbuvir/velpatasvir/voxilaprevir 12 weeks  Glecaprevir/pibrentasvir 12 weeks

G1b
Sofosbuvir/ledipasvir 12 weeks Grazoprevir/elbasvir 12 weeks  Paritaprevir/ritonavir/ombitasvir+dasabuvir 12 weeks - should be discarded when Glecaprevir/pibrentasvir is available. Sofosbuvir/velpatasvir 12 weeks
Sofosbuvir/velpatasvir/voxilaprevir 12 weeks Glecaprevir/pibrentasvir 12 weeks

Decompensated cirrhosis

G1a &1b
Sofosbuvir/ledipasvir +/- ribavirin 12 weeks  Sofosbuvir/velpatasvir + ribavirin 12 weeks

Re-treatment for DAA failures Requires pre-treatment virological sequencing to identify resistance associated variants whose presence/absence should be used to guide treatment decisions.

Sofosbuvir/velpatasvir/voxilaprevir 12 weeks Glecaprevir/pibrentasvir  12 weeks (no prior NS5A) or 16 weeks (prior NS5A)

Decompensated cirrhosis – retreatment requires Sof/vel +/- riba 24 weeks 

G2
Non cirrhotic
Strongly recommend that IFN is removed and ribavirin free regimens are preferred. Sof/Vel 12 weeks Sof/Vel/Vox 8 weeks Glecaprevir/pibrentasvir 8 weeks

G2
Cirrhosis
Sof/Vel 12 weeks Sof/vel/vox 12 weeks Glecaprevir/pibrentasvir 12 weeks
Decompensated cirrhosis Sof/vel +/- riba 12 weeks 

Re-treatment of DAA failures Requires pre-treatment virological sequencing to identify resistance associated variants whose presence/absence should be used to guide treatment decisions.

Sofosbuvir/velpatasvir/voxilaprevir 12 weeks Glecaprevir/pibrentasvir  16 weeks

G3
Non cirrhotic
Sof/Vel 12 weeks Sof/Vel/Vox 8 weeks Glecaprevir/pibrentasvir 8 weeks

Cirrhotic
Sof/Vel 12 weeks Sof/Vel/Vox 12 weeks Glecaprevir/pibrentasvir 16 weeks

Decompensated cirrhosis 12 weeks sofosbuvir/velpatasvir +ribavirin. Consideration should be given to the use of sof/vel for 24 weeks in patients deemed unlikely to respond or intolerant of ribavirin.  

Re-treatment for DAA failures Requires pre-treatment virological sequencing to identify resistance associated variants whose presence/absence should be used to guide treatment decisions.

Sofosbuvir/velpatasvir/voxilaprevir 12 weeks
Decompensated cirrhosis – retreatment requires Sof/vel +/- riba 24 weeks 

G4
Non Cirrhotic 
Given the paucity of data and the availability of better-validated regimens we recommend that the use of sofosbuvir/ledipasvir for patients with Genotype 4 HCV should be discontinued. 

Grazoprevir/elbasvir 12   Paritaprevir/ritonavir/ombitasvir 12 weeks - should be discarded when Glecaprevir/pibrentasvir is available. Sofosbuvir/velpatasvir/voxilaprevir 8 weeks  Sofosbuvir/velpatasvir 12 weeks Glecaprevir/pibrentasvir 8 weeks Cirrhosis Grazoprevir/elbasvir 12 OR 16 weeks  Sofosbuvir/velpatasvir 12 weeks Paritaprevir/ritonavir/ombitasvir 12 weeks - should be discarded when Glecaprevir/pibrentasvir is available. Sofosbuvir/velpatasvir/voxilaprevir 12 weeks Glecaprevir/pibrentasvir 12 weeks

Decompensated cirrhosis
12 weeks sofosbuvir/velpatasvir +ribavirin.
Re-treatment for DAA failures Requires pre-treatment virological sequencing to identify resistance associated variants whose presence/absence should be used to guide treatment decisions.

Sofosbuvir/velpatasvir/voxilaprevir 12 weeks Glecaprevir/pibrentasvir 16 weeks

 G5/6
The small number of patients G5/6 infection in trials reported to date was noted. 
Non cirrhotic
Sof/Vel 12 weeks Glecaprevir/pibrentasvir 8-12weeks Sof/Vel/Vox 8 weeks

Cirrhotic
Sofosbuvir/velpatasvir 12 weeks Glecaprevir/pibrentasvir 12 weeks Sof/vel/vox 8 weeks

Decompensated cirrhosis
12 weeks sofosbuvir/velpatasvir +ribavirin.

Re-treatment for DAA failures Requires pre-treatment virological sequencing to identify resistance associated variants whose presence/absence should be used to guide treatment decisions.

Sofosbuvir/velpatasvir/voxilaprevir 12 weeks Glecaprevir/pibrentasvir 16 weeks (note that in patients with both NS5A and NS3 resistance associated variants this regimen is likely to be inadequate)

 Special Patient Categories

Patients with renal impairment We recommend treatment as above but recommend that sofosbuvir be avoided in patients with GFR <45 ml/min.

HIV-hepatitis C coinfection

We recommend that patients with HIV-hepatitis C coinfection are treated for chronic hepatitis C with the same DAA-based treatment regimens as patients
with hepatitis C mono-infection, although consideration of drug-drug interactions between DAAs and antiretrovirals should be taken into account.   We recommend that where HIV therapy cannot be switched to avoid drug-drug interactions, an appropriate alternate DAA-based regimen is identified.

Acute hepatitis C infection

We note emerging data shows public health benefits with early DAA therapy for patients with acute HCV who are at high risk of transmission. We recognize that pegylated interferon and ribavirin (the only current treatment option) is unlikely to be acceptable to patients and we therefore recommend that DAA-based treatment is made available for the treatment of acute and early hepatitis C infection, replacing pegylated-interferon +/- ribavirin 24 to 48 weeks

 Re-infection following successful DAA-based hepatitis C treatment

We recommend that DAA-based treatment is made available for the treatment of  hepatitis C re-infection following successful DAA-based hepatitis C treatment.

Solid Organ Transplantation

HCV infection acquired from a donor organ can be readily treated with currently available drug regimens.  We recommend that patients without HCV infection should be offered an opportunity to receive an organ infected with HCV and we recommend that such recipients are offered antiviral therapy as soon as practicable post transplantation; with usual practice being to initiate treatment within the first month.

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Thursday, July 20, 2017

WHO urges action against HIV drug resistance threat

WHO urges action against HIV drug resistance threat

20 July 2017 | GENEVA - WHO alerts countries to the increasing trend of resistance to HIV drugs detailed in a report based on national surveys conducted in several countries. The Organization warns that this growing threat could undermine global progress in treating and preventing HIV infection if early and effective action is not taken.

The WHO HIV drug resistance report 2017 shows that in 6 of the 11 countries surveyed in Africa, Asia and Latin America, over 10% of people starting antiretroviral therapy had a strain of HIV that was resistant to some of the most widely used HIV medicines. Once the threshold of 10% has been reached, WHO recommends those countries urgently review their HIV treatment programmes.
HIV drug resistance report 2017

“Antimicrobial drug resistance is a growing challenge to global health and sustainable development,” said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. “We need to proactively address the rising levels of resistance to HIV drugs if we are to achieve the global target of ending AIDS by 2030.”

HIV drug resistance develops when people do not adhere to a prescribed treatment plan, often because they do not have consistent access to quality HIV treatment and care. Individuals with HIV drug resistance will start to fail therapy and may also transmit drug-resistant viruses to others. The level of HIV in their blood will increase, unless they change to a different treatment regimen, which could be more expensive – and, in many countries, still harder to obtain.

Of the 36.7 million people living with HIV worldwide, 19.5 million people were accessing antiretroviral therapy in 2016. The majority of these people are doing well, with treatment proving highly effective in suppressing the HIV virus. But a growing number are experiencing the consequences of drug resistance.

WHO is therefore issuing new guidelines to help countries address HIV drug resistance. These recommend that countries monitor the quality of their treatment programmes and take action as soon as treatment failure is detected.

"We need to ensure that people who start treatment can stay on effective treatment, to prevent the emergence of HIV drug resistance," said Dr Gottfried Hirnschall, Director of WHO’s HIV Department and Global Hepatitis Programme. “When levels of HIV drug resistance become high we recommend that countries shift to an alternative first-line therapy for those who are starting treatment.”

Increasing HIV drug resistance trends could lead to more infections and deaths. Mathematical modelling shows an additional 135 000 deaths and 105 000 new infections could follow in the next five years if no action is taken, and HIV treatment costs could increase by an additional US$ 650 million during this time.

Tackling HIV drug resistance will require the active involvement of a broad range of partners. A new five-year Global Action Plan calls on all countries and partners to join efforts to prevent, monitor and respond to HIV drug resistance and to protect the ongoing progress towards the Sustainable Development Goal of ending the AIDS epidemic by 2030. In addition, WHO has developed new tools to help countries monitor HIV drug resistance, improve the quality of treatment programmes and transition to new HIV treatments, if needed.

The WHO HIV drug resistance report 2017 was co-authored by the Global Fund to Fight AIDS, Tuberculosis and Malaria, and the Centers for Disease Control and Prevention, USA.

“This new report shows a worrying picture of increasing levels of HIV drug resistance and, if unchecked, it will be a major risk to program impact,” said Dr Marijke Wijnroks, Interim Executive Director of the Global Fund. “We strongly recommend implementing WHO recommendations for early warning indicators and HIV drug resistance surveys in every national plan for antiretroviral therapy, and to consider funding them through Global Fund grants or reprogramming.”

Dr Shannon Hader, Director of CDC’s Division of Global HIV and Tuberculosis, US Centers for Disease Control and Prevention, added: “The new report pulls together key HIV drug resistance survey findings from across the globe that, taken together with other national-level data, confirm we must be forward-thinking in our efforts to combat resistance: scaling up viral load testing, improving the quality of treatment programs, and transitioning to new drugs like dolutegravir.“

Dr. Hader continued, stating that “Overall high rates of viral suppression across three recent national Population-based HIV Impact Assessments showed that present first-line regimens remain largely effective. However, special attention to populations at risk for higher resistance, such as pediatrics, adolescents, pregnant women and key populations, will be critical to target more urgent interventions. We call on the global community for continued vigilance and responsiveness.”

TAG HCV Pipeline Report: DAAs and Diagnostics in the Pangenotypic Era

In Case You Missed It - TAG Pipeline Report HIV, TB, and HCV

Treatment Action Group (TAG) is an independent, activist and community-based research and policy think tank fighting for better treatment, prevention, a vaccine, and a cure for HIV, tuberculosis, and hepatitis C virus.

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The 2017 Pipeline Report
July 2017

HIV, TB, and HCV
Drugs, Diagnostics, Vaccines, Preventive Technologies, Research Toward a Cure, and Immune-Based and Gene Therapies in Development
Written by Mike Frick, Annette Gaudino, Mark Harrington, Tim Horn, Richard Jefferys, Jeremiah Johnson, Erica Lessem, Marcus Low, and Lindsay McKenna

Hepatitis C
Annette Gaudino
AbbVie, Gilead, Merck, and Janssen have presented data at international congresses on efficacy across the six major genotypes; in difficult-to-treat populations, including patients with genotype 3 and cirrhosis; and patients with advanced kidney disease. Gilead also recently received approval for previously untreated adolescents, and presented data on ongoing clinical trials in young children. It would not be hyperbole to state that science has solved chronic HCV infection for all but individuals with decompensated cirrhosis—yet another powerful argument for early treatment. It must be noted that, as historically has been the case, all clinical trial data is based on majority male patient populations, with few people of color, particularly African Americans, taking part in clinical trials....

Updates On This Blog
Gilead's VoseviTM (Sofosbuvir/Velpatasvir/Voxilaprevir FDA Approved
On July 18, 2017 Gilead's VoseviTM (Sofosbuvir/Velpatasvir/Voxilaprevir) was FDA approved,
last month CHMP - the scientific committee of the European Medicines Agency adopted a positive opinion on the company’s marketing authorization application for Vosevi.


In this year's report:

Towards supporting greater and lower cost access to direct acting antiviral treatment for hepatitis C for all patients

Saudi J Gastroenterol [serial online] 2017 [cited 2017 Jul 20];23:263-4. Available from: http://www.saudijgastro.com/text.asp?2017/23/4/263/210834

LETTER TO EDITOR
Towards supporting greater and lower cost access to direct acting antiviral treatment for hepatitis C for all patients

Said A Al-Busafi1, Heba Omar2

Sir,
It is with great interest that we read the Saudi Association for the Study of Liver diseases and Transplantation (SASLT) position statement [1] and guidelines [2] on direct-acting antiviral agents (DAAs) for the treatment of hepatitis C virus (HCV) infection. The position statement and the guidelines, which were clearly influenced by the limited availability of highly priced DAAs, recommend that HCV treatment should be prioritized to patients at higher risk for developing HCV-related complications.

The introduction of the curative DAAs to the global market caused worldwide celebration because it is expected to save millions of lives and control if not eliminate one of the major infectious disease worldwide.[3] Unfortunately, for the majority of HCV patients, these costly medications are not readily available, accessible, or affordable even for those in the developed countries.[3] This is likely going to affect many countries in their ability to minimize the burden of this disease.[4]

On the other hand, generic DAAs (sofosbuvir, ledipasvir, and daclatasvir) are being produced in India and other countries with permission of the concerned pharmaceutical agencies and priced less than 1% of their current actual price in USA and Europe. The evidence for the clinical safety and efficacy of these generics is compelling including the recent interim results from international REDEMPTION trial presented by Freeman et al.[5] The results of this trial, which was supported by the European Association for the Study of the Liver (EASL), are important in indicating that generic DAAs are highly effective and safe comparable to those reported in clinical trials of branded DAAs. Another abstract presented by Hill et al. at the same meeting showed that the active pharmaceutical ingredient for the combination of sofosbuvir and daclatasvir was approximately $200 for 12 weeks' course of treatment per patient.[6]

Oman, with an estimated HCV prevalence of 1%, is one such country where access to those important agents is also limited.[7] This has led many of our patients to self-import these drugs from India giving them hope instead of waiting for years to be treated from this debilitating disease.

At the Sultan Qaboos University Hospital, using the EASL 2016 guidelines,[8] we have treated 58 HCV patients [28% genotype 3, 26% cirrhotic with 40% of them decompensated, and 3% severe chronic kidney disease (CKD)] with generic DAAs including (sofosbuvir, ledipasvir, and daclatasvir). Sustained virological response was achieved in 57 patients (98%), the remaining one patient with severe CKD discontinued treatment due to worsening renal function. All patients with decompensated cirrhosis were delisted from transplantation.

Therefore, healthcare leaders and policy makers at the national and international level should adopt strategies to ensure that these DAAs are made available and are accessible and affordable for all in need.
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Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.

   References

1.
Alghamdi AS, Alqutub A, Abaalkhail F, Sanai FM, Alghamdi H, Altraif I, et al. SASLT position statement on the direct-acting antiviral agents for the treatment of hepatitis C virus infection. Saudi J Gastroenterol 2015;21:60-3.
[PUBMED]  [Full text]  
2.
Alghamdi AS, Alghamdi M, Sanai FM, Alghamdi H, Aba-Alkhail F, Alswat K, et al. SASLT Guidelines: Update in Treatment of Hepatitis C Virus Infection. Saudi J Gastroenterol 2016;22(Suppl 2):S25-S57.
    
3.
Freeman JA, Hill A. The use of generic medications for hepatitis C. Liver Int 2016;36:929-32.
    
4.
Edwards DJ, Coppens DG, Prasad TL, Rook LA, Iyer JK. Access to hepatitis C medicine. Bull World Health Organ 2015;93:799-805.
    
5.
Freeman J, Sallie R, Kennedy A, Hieu PT, Jeffreys G, Hill AM. High sustained virological response rates using generic Direct Acting Antiviral treatment for Hepatitis C, imported into Australia. J Hepatol 2016;2:S209.
    
6.
Hill A, Gotham D, Fortunak J. Significant Reductions in Costs of Generic Production of Sofosbuvir and Daclatasvir for Hepatitis C Treatment in Low- and Middle-Income Countries. J Hepatol 2016;2:S209.
    
7.
Alnaqdy A, Alfahdi A, Alkobaisi M, Kaminski GZ. Prevalence of autoantibodies in patients with hepatitis C virus infection in Oman. Ann Saudi Med 2003;23:127-31.
    
8.
European Association of the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol 2017;66:153-94.  

Impact of alcohol consumption among patients in hepatitis C virus treatment

Impact of alcohol consumption among patients in hepatitis C virus treatment

Arquivos de Gastroenterologia
Print version ISSN 0004-2803On-line version ISSN 1678-4219
ahead of print

Full Text
Impact of alcohol consumption among patients in hepatitis C virus treatment. Arq. Gastroenterol. [online]. In press. . Epub July 13, 2017. ISSN 0004-2803. http://dx.doi.org/10.1590/s0004-2803.201700000-33.

BACKGROUND:
Recent studies have questioned the recommendation of abstinence from alcohol for at least 6 months for alcoholic patients to be treated for hepatitis C.

OBJECTIVE:

The present study aimed to assess the impact of alcohol consumption among patients undergoing hepatitis C treatment.

METHODS:
In this cross-sectional study, 121 patients [78 (64.5%) men; 28-70 years] were evaluated. They were divided as follows: patients who consumed <12 g of ethanol/day throughout life (Group 1), 12-59 g/day (Group 2) and ≥60 g/day (Group 3). Patients were treated with pegyla­ted-interferon plus ribavirin.

RESULTS:
These three groups could not be distinguished in terms of the severity of liver fibrosis and frequency of HCV genotype-1 infection. In Group 3, treatment discontinuation (32.4%) was higher than in the Group 1 (9.4%) or Group 2 (0%), it was higher among patients who drank during treatment (66.7% vs 21.4%) and among those who had not been abstinent for at least 6 months (72.7% vs 15.4%). Moderate alcohol drinkers showed good adherence and did not discontinue the treatment. The frequencies of sustained viral response among patients in Group 3 (44.4%) were similar to those in Group 1 (61%) and Group 2 (68.4%).

CONCLUSION:

Heavy drinkers more often discontinued treatment for hepatitis C, but those that received this treatment had acceptable sustained viral response rates. These results suggest that heavy drinkers should not be systematically excluded from the treatment, but they should be monitored to avoid drinking and abandoning treatment, mainly those who have not been abstinent for at least 6 months.

Keywords : Alcoholism; Patient compliance; Hepatitis C; Therapeutics. 

Wednesday, July 19, 2017

Gilead Vosevi’s (Sofosbuvir/Velpatasvir/Voxilaprevir) price at $24,920 per bottle

Investment Commentary

Gilead gets its go-ahead for blockbuster hopeful Vosevi, but will 12-week dosing give it trouble?
by Carly Helfand |
Jul 19, 2017 11:15am 
Gilead has set Vosevi’s price at $24,920 per bottle, putting it “at parity” with Epclusa at $74,760 for the 12-week course, Porges wrote in a note to clients. “Effectively Gilead is giving the third component of Vosevi free of charge to maintain the price point of their 12-week treatment course,” he said, noting that “ given this label and position in the treatment hierarchy, Gilead could have priced Vosevi higher and probably not lost significant share.”
Continue reading .. http://www.fiercepharma.com/pharma/gilead-wins-blockbuster-approval-for-hep-c-trio-vosevi-but-will-12-week-dosing-give-it

Investment Commentary
How AbbVie Could Hammer Gilead's Hepatitis C Franchise 
  • 7/19/2017
  • Meanwhile, AbbVie's combination of glecaprevir and pibrentasvir looks likely to gain approval as an eight-week regimen in all genotypes of hepatitis C and in patients who've never undergone treatment. Gilead's Harvoni is approved as an eight-week regimen, but only in one subset of patients.Gilead is pricing its triple-pill, which will be branded as Vosevi, at $24,920 per bottle. At one bottle per month, that runs up to a 12-week price of about $75,000. That is less costly than Gilead's Harvoni and Sovaldi, but more expensive than Zepatier
     Continue reading.....

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    Gilead's VoseviTM (Sofosbuvir/Velpatasvir/Voxilaprevir) FDA Approved for Re-Treatment of Adults with HCV