Showing posts with label HCV-Editorial. Show all posts
Showing posts with label HCV-Editorial. Show all posts

Sunday, November 25, 2018

In a Critical State: Ongoing Barriers to Treatment for Hepatitis C Virus (HCV)

In a Critical State: Ongoing Barriers to Treatment for Hepatitis C Virus (HCV)
Jorge Mera, MD, Brigg Reilley, MPH, Jessica Leston, David Stephens, RN


The American Journal of Medicine
Publication History
Published online: November 24, 2018

Recent advances in Hepatitis C Virus HCV treatment could be described as revolutionary: for uncomplicated patients, treatment is nearly 100% effective, oral-only, has a low pill burden, minimal side effects, and results in a cure.1 Comparisons we have heard from clinicians are that HCV is now easier to treat than either diabetes or hypertension. Unfortunately for many patients, their state of residence is the decisive factor for whether they will receive lifesaving treatment. As part of a tribal telehealth network for HCV, we support several rural clinics successfully treating HCV and see this dilemma all too frequently.

Consider a patient with chronic HCV infection who presents with a recent history of marijuana use and has been late picking up hypertension medication. The patient has cirrhosis and is at high risk of HCV related mortality. He is enrolled in state Medicaid and highly motivated for treatment. What is the treatment plan? It depends on the state. A resident of New Mexico can start treatment without delay. If instead the patient lives in Montana, a state that determines treatment eligibility based on advanced liver fibrosis, documented sobriety, and compliance with existing medications, the consultation is effectively moot; treatment will be denied. Montana is far from alone in its HCV treatment restrictions. Patients in South Dakota, Oregon, and several other states we serve face similar hurdles …

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Current Issue
November 2018
Volume 131, Issue 11 

Wednesday, January 17, 2018

Treating Chronic Hepatitis C Infection: A Call to Action for Primary Care Providers

Experts And Viewpoints, January 2018
Treating Chronic Hepatitis C Infection in Primary Care
New treatment guidelines aim to support primary care clinicians in the treatment of hepatitis C infection. 

Treating Chronic Hepatitis C Infection: A Call to Action for Primary Care Providers

Christine A. Kerr, MD; Josh S. Aron, MD
January 17, 2018

Despite a revolutionary opportunity to end the global HCV epidemic, there clearly is a need for a concerted effort to help many more people benefit from curative therapy. It is evident that we, as healthcare providers, must step up our efforts to reach and treat patients who can benefit from DAA therapy. Only 9% of the 4 million Americans living with HCV have been successfully treated.

Thursday, August 31, 2017

NEJM A Tale of Two Epidemics — HCV Treatment among Native Americans and Veterans

A Tale of Two Epidemics — HCV Treatment among Native Americans and Veterans
Brigg Reilley, M.P.H., and Jessica Leston, M.P.H.

N Engl J Med 2017; 377:801-803
August 31, 2017DOI: 10.1056/NEJMp1705991

Full Text Journal Article 

In light of ongoing debates about health care budgets and rising drug prices, a current public health crisis can provide useful insights. For patients who get their health care through two separate federal agencies, the hepatitis C virus (HCV) epidemic is unfolding in vastly different ways. In recent years, the Department of Veterans Affairs (VA) health care system has mounted a response to HCV that should be the envy of any health system, public or private. On the other hand, the Indian Health Service (IHS), an agency that serves American Indians and Alaska Natives, is struggling to meet the needs of its patients with HCV.

Wednesday, August 30, 2017

Editorial: Health-Related Quality of Life in Chronic Hepatitis C

View Original Journal Article - Health-Related Quality of Life in Portuguese Patients with Chronic Hepatitis C, editorial provided below.

GE Port J Gastroenterol 2017;24:55-57

Health-Related Quality of Life in Chronic Hepatitis C
Cardoso H. · Silva M.                       

Hepatitis C virus (HCV) infection is one of the main causes of liver disease and has a great impact on patient outcomes. The estimate of chronically infected persons is about 160 million worldwide, but most of them are unaware of the disease. The clinical impact of HCV infection is highly variable, from minimal changes to cirrhosis and hepatocellular carcinoma, with or without extrahepatic manifestations. Nevertheless, the outcome of HCV infection is not restricted to the clinical endpoints, as it can affect multiple health and psychosocial dimensions.

In recent years, HCV infection has become increasingly noticeable for different reasons. On the one hand, the development of highly effective antiviral therapy has enabled the actual treatment and cure of most diagnosed patients, but on the other hand, the burden from the most severe complications, such as hepatocellular carcinoma, keeps increasing [1,2].

A comprehensive assessment of overall outcomes would include, besides clinical hepatic and extrahepatic manifestations, patient-reported outcomes (PRO) and economic consequences. A PRO is any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else. It reflects patient experience using surrogate markers such as health-related quality of life (HRQoL), functional status, perceived stigma, and work productivity [3,4]. In this context, the study by Rei et al. [5] addresses an important topic and contributes to improve the scarce available Portuguese data. The main self-administered instruments used were the SF-12 (generic) and CLDQ (disease-specific) HRQoL questionnaires.

The first studies on the effects of HCV infection on patients' quality of life, using the short form SF-36 Health Survey, revealed that patients were polysymptomatic and had diminished quality of life with significant reductions in all domains. The reduction in quality of life could not be attributed to the degree of liver inflammation or to the mode of acquisition of the infection. Hence, the authors conclude that chronic HCV infection gives rise to physical symptoms that reduce the quality of life of infected patients [6]. Also, studies with matched controls demonstrated that work productivity is significantly impaired [7]. Regarding cognitive performance, a meta-analysis of studies in HIV-infected patients demonstrated a higher level of cognitive impairment associated with HCV infection [8].

One of the most frequent extrahepatic manifestations is depression. A review of neuropsychiatric symptoms commonly associated with HCV infection showed that major depression was related to illness perception, functional disability, impaired quality of life, fatigue severity, and the presence of psychiatric comorbidity [9]. Likewise, in the study of Rei et al. [5], there was a high prevalence of mood disorders (namely depression) with a negative impact on HRQoL, and the authors therefore recommend screening and suitable psychosocial interventions in a multidisciplinary setting.

Regarding the impact of antiviral therapy on PRO, there were several concerns regarding interferon-based regimens, which negatively affected quality of life during treatment [4,10,11]. Recent studies with antiviral regimens without interferon or ribavirin demonstrated an improvement of quality of life during treatment coinciding with viral suppression within the first month of therapy [12]. Also, Rei et al. [5] reported that oral antiviral treatment could be correlated with HRQoL increases in some domains, which provides growing evidence for the multiple benefits of appropriate HCV treatment.

The achievement of a sustained virological response is associated with an improvement of clinical outcomes, namely a reduction of all-cause mortality [13]. The impact on PRO following successful HCV therapy is also significant; several studies with paired HRQoL assessments demonstrated an overall improvement of all domains of SF-36. Viral eradication leads to HRQoL improvement, regardless of fibrosis stage. HCV patients with early fibrosis experience similar improvement of PRO as those with advanced fibrosis [12,14,15]. Curiously, the HRQoL improvement was progressive over time after the end of treatment, with scores after 24 weeks greater than at 12 weeks [15]. It might be interesting to study what will be the time frame for an extensive recovery of HRQoL after sustained virological response, in relation to healthy controls. Another issue that would benefit from research is the extent of recovery of other PRO, such as perceived stigma and work productivity.

In this era of widespread HCV antiviral therapy, it is important to recognize the comprehensive burden of this disease as well as the value of achieving HCV cure, which translates into benefits at different levels for the patient and society.

Friday, July 21, 2017

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

Monday, April 24, 2017

Solving the hepatitis C epidemic among people with substance abuse disorders

Solving the hepatitis C epidemic among people with substance abuse disorders
Innovations in HCV treatment at methadone clinics, corrections facilities
Date:April 24, 2017
Source:University at Buffalo
One of the most dramatic medical success stories in recent years has been the introduction of new drugs that eradicate hepatitis C virus (HCV). But it's a different story among HCV patients with substance use disorders. This population typically does not have easy access to conventional health care so it is difficult to screen, diagnose and treat these individuals.

One of the most dramatic medical success stories in the past few years has been the introduction of new drugs that eradicate hepatitis C virus (HCV). But it's a different story among HCV patients with substance use disorders.

As an editorial published online on April 25 in the Annals of Internal Medicine notes, this population typically does not have easy access to conventional health care so it is difficult to screen, diagnose and treat these individuals.

"People with substance use disorders can account for as much as 80 percent of infected individuals in developed countries, a direct result of the opioid epidemic in the U.S.," said Andrew H. Talal, MD, the lead author of the editorial and professor, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo.

Talal, a leading expert in liver disease, is a researcher with the Clinical and Translational Science Institute at the University at Buffalo, funded by a National Institutes of Health Clinical and Translational Science Award. He is currently principal investigator with other UB faculty on a $7 million Patient-Centered Outcomes Research Institute award dedicated to developing innovative ways to treat HCV in persons with substance use disorders. The award funds efforts with these patients throughout New York State, including New York City, Buffalo, Rochester, Syracuse and the Hudson Valley.

According to Talal, a combination of factors all work to prevent these patients from receiving the diagnoses and care they need. Such factors range from discomfort in conventional health care settings and lack of HCV-related knowledge to fear of stigmatization that can result from an HCV diagnosis. That's in addition to insurance barriers and physicians' general reluctance to treat this population.

According to the editorial, "New approaches for persons with substance use disorders are required at every step in the HCV care paradigm."

The reason is that following a decade of fairly steady declines in this population, there have been recent sharp increases in HCV.

"We're seeing infection hotspots," Talal said, noting that this is partly a result of the opioid epidemic, particularly where needle exchange programs, for example, are not available.

Such programs are key, Talal said, citing a report issued earlier this month by the National Academies that found that people who inject drugs account for approximately 75 percent of all new HCV infections.

To better reach persons with substance use disorders, the editorial states, HCV screening and linkage to care must improve. Screening can be especially problematic because it typically requires two steps: confirmation that the person has been exposed to HCV through an antibody test followed by additional blood work to determine if the infection is active. Currently, the second step must be conducted in a conventional laboratory, a setting these patients rarely access. Recent advances, however, are designed to assess whether all of required analyses could be done onsite.

Once a diagnosis is made, getting patients connected with providers is another major hurdle.

"At best, only 20 percent of these patients connect with a provider for treatment," Talal explained, "and often it's far less than that."

Talal and his colleagues at UB and other institutions and care facilities have been developing promising ways to better connect these patients with the care that they need by integrating HCV screening and treatment into methadone clinics that these patients already regularly attend and by reaching patients in the corrections system via telehealth techniques.

Story Source:
Materials provided by University at Buffalo. Note: Content may be edited for style and length.

Journal Reference:
Gregory J. Dore, Frederick Altice, Alain H. Litwin, Olav Dalgard, Edward J. Gane, Oren Shibolet, Anne Luetkemeyer, Ronald Nahass, Cheng-Yuan Peng, Brian Conway, Jason Grebely, Anita Y.M. Howe, Isaias N. Gendrano, Erluo Chen, Hsueh-Cheng Huang, Frank J. Dutko, David C. Nickle, Bach-Yen Nguyen, Janice Wahl, Eliav Barr, Michael N. Robertson, Heather L. Platt. Elbasvir–Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy. Annals of Internal Medicine, 2016; DOI: 10.7326/M16-0816

Monday, December 7, 2015

HCV genotype 3: a wolf in sheep’s clothing

Journal: Expert Review of Anti-infective Therapy

HCV genotype 3: a wolf in sheep’s clothing

José-R. Blancoa* & Antonio Rivero-Juarez
1a Infectious Diseases Area. Hospital San Pedro - Center for Biomedical Research of La Rioja (CIBIR) . Piqueras 98, 26006 Logroño , La Rioja ( Spain ).
2b Infectious Diseases Unit. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC) . Hospital Universitario Reina Sofía de Córdoba. Universidad de Córdoba . Avda. Menendez Pidal s/n, 14004 Córdoba , Córdoba ( Spain ).

Publishing models and article dates explained

Received: 16 Sep 2015
Accepted: 30 Nov 2015
Accepted author version posted online: 03 Dec 2015

Keywords: Hepatitis C, Genotype 3, Metabolic syndrome, Hepatocellular carcinoma

Download as PDF or Interactive PDF

HCV genotype 3: a wolf in sheep’s clothing

"All truths are easy to understand once they are discovered; the point is to discover them". Galileo Galilei"

At present, the hepatitis C virus (HCV) is a major cause of morbidity and mortality affecting over 185 million people worldwide,[1] equivalent to a global prevalence of about 2.5% in 2015. Genotype 3 (HCV G3) is one of the seven recognized genotypes.[2] HCV G3 is the second most common genotype overall and is estimated to account for 54.3 million cases throughout the world (30.1%).[1] Although three-quarters of them occur in South Asia where it is endemic, the 3a subtype is an “epidemic subtype“ widely distributed geographically, probably associated with injecting drug use.[3]

 In the last two years, the history of HCV infection has changed radically with the appearance of the new direct-acting antiviral agents (DAAs).[4] Although HCV G3 was one of those genotypes who achieved a better sustained viral response (SVR) using pegylated interferon and ribavirin (PEG-IFN/Rbv) therapy,[5] the current effectiveness of the new DAAs against HCV G3 leaves a lot to be desired compared with the results obtained with other genotypes.[6] This is a major problem since, compared to other genotypes, HCV G3 is associated with faster progression of fibrosis,[7,8] a greater risk for hepatocellular carcinoma (HCC),[8-10] and a higher mortality.[11] Why is it so pathogenic and resistant to treatment? The reasons for this “aggressiveness” are without doubt multiple, complex and not well known.

First, it is important to remember that the host immune response plays an important role in HCV G3 infection because of its potential to contribute to viral clearance. So, acutely HCV-infected patients are much more likely to spontaneously clear HCV if they are infected with HCV G3 than HCV G1.[12] Indeed, chronically infected HCV G3 patients had higher SVR rates after shorter treatment with PEG-IFN/Rbv therapy when compared to those with chronic HCV G1 infection.[13] One of the possible reasons could be that in monocytic cell and plasmacytoid dendritic cell lines and in macrophages differentiated from monocytes with macrophage colony-stimulating factor, HCV G3 induces greater interferon transcription than either genotype 1a or 1b.[14] However, this apparent benefit may backfire because of the increased rate of fibrosis progression of HCV G3, probably due to the higher non-parenchymal cell transcription of IFN genes following intracellular HCV G3 sensing.[14]

It has been reported previously that HCV G3 is associated with a significantly increased risk of developing cirrhosis and HCC compared to HCV G1, and association that is independent of the patients’ age, diabetes, body mass index, or antiviral treatment.[8] The high viremia observed in HCV G3-infected patients may be a marker of rapid disease damage, reflecting either the inability of the immune system to control the infection or the existence of some escape mechanisms in HCV G3 which prevents the immune system response from being effective.[15]

Secondly, another problem that is not well understood is the interaction between HCV and lipid metabolism.[16] So, HCV G3 selectively interferes with the late cholesterol synthesis pathway,[17] although this interference is resolved after the SVR. Other mechanisms that alter lipid metabolism are increased the novo lipogenesis and the inhibition of mitochondrial fatty acid degradation.[18] At what level of lipid metabolism does HCV G3 work? Is the damage the consequence of the virus or of its proteins in infected hepatocytes? Given that, in previous studies, the variables independently associated with SVR were high LDL levels,[19,20] low HDL levels [19] and statin use,[19] one might think that statins would be a useful option for such patients. Nonetheless, this is not actually the case with HCV G3. In one analysis of patients with HCV 1-3 genotypes who received combination therapy with PEG-IFN/Rbv, the significant impact of statin use was only observed among the HCV G1 patients.[20] Similar findings were reported by Selic Kurincic et al.[21]

Steatosis is a common histologic finding in patients infected by HCV G3, independently of the presence of fibrosis, diabetes, hepatic inflammation, ongoing alcohol abuse, higher body mass index, and older age.[22] Indeed, steatosis in HCV G3 infected patients is not the result of overexpression of genes involved in lipogenesis.[23] The higher rates of hepatic steatosis in HCV G3 patients, even in absence of other metabolic complications, suggest that some specific viral sequences may be involved in the etiology of steatosis.[18] In fact, after reaching SVR, hepatic steatosis in these patients had disappeared.[24,25] Another possible explanation for the high presence of steatosis could be that HCV G3 steatosis induces the liberation of proinflammatory chemokines that increase the recruitment of inflammatory cells to the liver.[14] In support of this idea, the depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance.[26]

It is important to bear in mind that there is a significant correlation between the steatosis score and the titer of intrahepatic HCV RNA in patients with HCV G3, providing virological and some clinical evidence that steatosis is the morphological expression of a viral cytopathic effect in patients infected with this genotype.[27] This finding has important implications, such as lower SVR rates or higher relapse rates after HCV treatment.[28,29] Is steatosis a marker of rapid progression or bad prognosis in HCV G3 infected patients?

Non-alcoholic fatty liver disease (steatosis/steatohepatitis) is similarly recognized as the hepatic manifestation of metabolic syndrome (MS). HCV virus genotype 3 infection increases the risk of insulin resistance and diabetes, probably due to the direct effect of the virus on intracellular insulin signaling.[30] This situation not only increases the cardiovascular risk but also reduces the likelihood of achieving a SVR.[31] Another common manifestation of MS is obesity, a problem that also increases the expression of some inflammatory cytokines and activates several signaling pathways involved in the pathogenesis of insulin resistance.[32] The inflammation may also contribute to the pathogenesis of liver damage.[33] Obesity has also been correlated with a lower SVR rate.[34] Once again, this opens up an interesting way to research the mechanisms involving MS and SVR in these patients. Are insulin resistance and/or obesity indicators of the the existence of an established liver damage, even though we are unable to diagnose it? Is there some symbiotic relationship between the adipocytes and HCV G3 that reduces the efficacy of the DAAs? In view of the higher rates of SVR using the new DAAs, is the presence of MS still important in chronic HCV infection?.[35] Probably not, but there is as yet no concrete answer for this question and so the controversy about steatosis and HCV remains. Valenti et al also reported that the rs738409 genotype, a polymorphism that influences liver fat without affecting insulin resistance and body composition, was associated with severe hepatic steatosis in patients infected with a non-3 HCV genotype, and also with fibrosis stage and cirrhosis (OR = 1.47; P = 0.002).[36] Similarly, Cai et al [37] reported that rs738409 was associated with an increased risk of steatosis in patients infected with a non-3 HCV genotype. These results suggest distinct pathogenic mechanisms in the 3 and non-3 genotypes.

Moving on to the third point, and so concluding this topic, it is necessary to understand the clinical implications of the different HCV G3 subtypes (in other words, immunity, inflammation, prognosis, response to DAAs). This is something we already known for HCV G1a and 1b.[38] At least 10 HCV G3 subtypes have been described so far.[39] Are some of these HCV G3 subtypes able to evade the immune response? Can we expect the same SVR for different subtypes? The correct identification of HCV G3 subtypes would probably be necessary because they are crucial in clinical trials evaluating the new DAAs. No data have so far stratified the response of HCV G3 to the new DAAs, which could be an essential issue that requires further investigation.

In summary, given the aggressiveness of HCV G3, it is increasingly necessary to initiate antiviral treatment as soon as possible in all patients, including those with steatosis and/or MS. In these patients, even those with SVR, continued surveillance is necessary, paying careful attention to patients with cirrhosis. There is no doubt that better knowledge of HCV G3 should be a priority for us all.

Financial & competing interests disclosure
JR Blanco has carried out consulting work for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV Healthcare; has received compensation for lectures from Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV Healthcare, as well as grants and payments for the development of educational presentations for Gilead Sciences and BristolMyers Squibb. A Rivero-Juarez is the recipient of a Postdoctoral Perfection Grant from Fundación Progreso y Salud, Consejería de Salud y Políticas Sociales, Junta de Andalucia (0024-RH-2013). He has received compensation for lectures from Bristol-Myers Squibb, Janssen, Merck, and ViiV Healthcare.The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. 

1. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57(4):1333-1342.
2. Smith DB, Bukh J, Kuiken C, Muerhoff AS, Rice CM, Stapleton JT, et al. Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource. Hepatology. 2014;59(1):318-327.
3. Pybus OG, Cochrane A, Holmes EC, Simmonds P. The hepatitis C virus epidemic among injecting drug users. Infect. Genet. Evol. 2005;5(2):131- 139.
4. Gentile I, Buonomo AR, Zappulo E, Borgia G. Interferon-free therapies for chronic hepatitis C: toward a hepatitis C virus-free world? Expert. Rev. Anti. Infect. Ther. 2014;12(7):763-773.
5. Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. N. Engl. J. Med. 2006;355(23):2444-2451.
6. AASLD/IDSA HCV Guidance Panel Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology. 2015;62(3):932-54.
7. Probst A, Dang T, Bochud M, Egger M, Negro F, Bochud PY. Role of hepatitis C virus genotype 3 in liver fibrosis progression--a systematic review and meta-analysis. J. Viral Hepat. 2011;18(11):745-759.
8. Kanwal F, Kramer JR, Ilyas J, Duan Z, El-Serag HB. HCV genotype 3 is associated with an increased risk of cirrhosis and hepatocellular cancer in a national sample of U.S. Veterans with HCV. Hepatology. 2014;60(1):98- 105.
9. Nkontchou G, Ziol M, Aout M, Lhabadie M, Baazia Y, Mahmoudi A, et al. HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis. J. Viral Hepat. 2011;18(10):e516-522.
10. McCombs J, Matsuda T, Tonnu-Mihara I, Saab S, Hines P, L'italien G, et al. The risk of long-term morbidity and mortality in patients with chronic hepatitis C: results from an analysis of data from a Department of Veterans Affairs Clinical Registry. JAMA Intern. Med. 2014;174(2):204-212.
11. van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308(24):2584-2593.
12. Lehmann M, Meyer MF, Monazahian M, Tillmann HL, Manns MP, Wedemeyer H. High rate of spontaneous clearance of acute hepatitis C virus genotype 3 infection. J. Med. Virol. 2004;73(3):387-391.
13. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann. Intern. Med. 2004;140(5):346-355.
14. Mitchell AM, Stone AE, Cheng L, Ballinger K, Edwards MG, Stoddard M, et al. Transmitted/founder hepatitis C viruses induce cell-type- and genotypespecific differences in innate signaling within the liver. MBio. 2015;6(2):e02510.
15. Buti M, Esteban R. Hepatitis C virus genotype 3: a genotype that is not 'easy-to-treat'. Expert Rev. Gastroenterol. Hepatol. 2015;9(3):375-385.
16. Clement S, Peyrou M, Sanchez-Pareja A, Bourgoin L, Ramadori P, Suter D, et al. Down-regulation of phosphatase and tensin homolog by hepatitis C virus core 3a in hepatocytes triggers the formation of large lipid droplets. Hepatology. 2011;54(1):38-49.
17. Clark PJ, Thompson AJ, Vock DM, Kratz LE, Tolun AA, Muir AJ, et al. Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner. Hepatology 2012;56(1):49-56.
18. Negro F. Hepatitis C virus-induced steatosis: an overview. Dig Dis. 2010;28(1):294-299.
19. Harrison SA, Rossaro L, Hu KQ, Patel K, Tillmann H, Dhaliwal S, et al. Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy. Hepatology 2010;52(3):864-874.
20. Pandya P, Rzouq F, Oni O. Sustained virologic response and other potential genotype-specific roles of statins among patients with hepatitis Crelated chronic liver diseases. Clin. Res. Hepatol. Gastroenterol. 2015;39(5):555-565.
21. Selic Kurincic T, Lesnicar G, Poljak M, Meglic Volkar J, Rajter M, Prah J, et al. Impact of added fluvastatin to standard-of-care treatment on sustained virological response in naive chronic hepatitis C patients infected with genotypes 1 and 3. Intervirology. 2014;57(1):23-30.
22. Leandro G, Mangia A, Hui J, Fabris P, Rubbia-Brandt L, Colloredo G, et al. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology, 2006;130(6):1636-1642. Downloaded by [] at 12:46 07 December 2015
23. Ryan MC, Desmond PV, Slavin JL, Congiu M. Expression of genes involved in lipogenesis is not increased in patients with HCV genotype 3 in human liver. J. Viral Hepat. 2011;18(1):53-60.
24. Poynard T, Ratziu V, McHutchison J, Manns M, Goodman Z, Zeuzem S, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology. 2003;38(1):75-85.
25. Kumar D, Farrell GC, Fung C, George J. Hepatitis C virus genotype 3 is cytopathic to hepatocytes: Reversal of hepatic steatosis after sustained therapeutic response. Hepatology 2002;36(5):1266-1272.
26. Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ, et al. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 2010;59(2):347-357.
27. Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Malé PJ, Mentha G, et al. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J. Hepatol. 2000;33(1):106-115.
28. Aziz H, Gill U, Raza A, Gill ML. Metabolic syndrome is associated with poor treatment response to antiviral therapy in chronic hepatitis C genotype 3 patients. Eur. J. Gastroenterol. Hepatol. 2014;26(5):538-543.
29. Restivo L, Zampino R, Guerrera B, Ruggiero L, Adinolfi LE. Steatosis is the predictor of relapse in HCV genotype 3- but not 2-infected patients treated with 12 weeks of pegylated interferon-alpha-2a plus ribavirin and RVR. J. Viral Hepat. 2012;19(5):346-352.
30. Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 31. Am. J. Pathol. 2004;165(5):1499-1508. 31. Poustchi H, Negro F, Hui J, Cua IH, Brandt LR, Kench JG, et al. Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3. J. Hepatol. 2008;48(1):28-34.
32. Chen L, Chen R, Wang H, Liang F. Mechanisms linking inflammation to insulin resistance. Int. J. Endocrinol. 2015;2015:508409.
33. Szabo G, Petrasek J. Inflammasome activation and function in liver disease. Nat. Rev. Gastroenterol. Hepatol. 2015;12(7):387-400.

All truths are easy to understand once they are discovered
; the point is to
discover them
Galileo Galilei

Friday, September 4, 2015

TGIF Rewind - Free HCV Helpline With App and Big Questions about Hepatitis C

Welcome to TGIF rewind, a digest of this weeks publications, news and updates from around the web. 

In The News

Sept 5
Anger at hepatitis C trial with call for money to be spent on cures
A MEDICAL trial to teach hepatitis C sufferers how to avoid infecting their children with the virus has been criticised as fearmongering and a waste of desperately needed health funding.

The Program
New hepatitis C program to teach sufferers basic skills
A new program being trialled later this year will teach parents with hepatitis C how to reduce the chances of infecting their child.

The program, called Families Living Healthily with Hepatitis C, will teach sufferers how to better prevent the transmission of the blood borne disease to their children and families.

Sept 4
Free Helpline and App for Hepatitis C Patients Offer Peer Support and Self-Care Tools
Viral hepatitis is known as the silent epidemic, because it is a disease that is both under-recognized and underdiagnosed

Mechanism for air pollution-induced liver disease discovered
A research team led by Kezhong Zhang, Ph.D., at the Wayne State University School of Medicine's Center for Molecular Medicine and Genetics, has discovered that exposure to air pollution has a direct adverse health effect on the liver and causes liver fibrosis, an illness associated with metabolic disease and liver cancer.

Webinar: What Soaring Drug Prices Mean for Patients
Concerns over soaring drug prices have grown in recent months, and doctors have become increasingly outspoken about the extremely high prices of drugs used to treat diseases such as cancer, hepatitis C and cystic fibrosis.

We talk about the impact of Hepatitis C on future Medicaid drug trends, as well as options states have to address Hepatitis C now.

The pharmaceutical industry is feeling rising heat from all directions as a result of its excessive price increases that reflect a contempt for consumers and the nation's economy. In response, pharma has been mobilizing its defenders in the media and academia to deploy the industry's standard mixture of half-truths and outright distortions.

Therapy for Hepatitis C Genotype 3: Moving Forward
This article reviews the available therapy and the new treatment agents under development for patients with chronic hepatitis C GT3 infection.

This Editorial discusses three recent original papers related to direct-acting antivirals (DAAs) for the treatment of chronic genotype (GT) 4 HCV infection, published in this issue of the Journal of Hepatology

Hepatitis C - Fibrosis index based on four factors better predicts advanced fibrosis or cirrhosis than aspartate aminotransferase/platelet ratio index
Hepatic fibrosis is one of the important factors associated with the long-term prognosis of CHC patients. If noninvasive methods could accurately predict the severity of hepatic fibrosis, the majority of liver biopsies could be avoided.

Can vaccination contribute to hepatitis C elimination efforts?  Q+A 
In a recent research article published in BMC Medicine, Nick Scott and colleagues used a mathematical modeling approach to show that vaccination is likely to play a role in reducing hepatitis C prevalence. Dr Scott answers our questions about the ...

What Hepatitis C Patients Need to Know When Starting Sovaldi Regimen
Published on Sep 4, 2015 Specialty Pharmacy Times
Michael Sofia, PhD, the inventor of the groundbreaking hepatitis C drug Sovaldi, discusses what patients can expect when they begin a therapeutic regimen with the drug.

In Case You Missed It - Hepatitis C treatment and quality of life You can’t always get what you want, but you might get what you need

Published in Journal Of Hepatology
Published online: May 13 2015


Key Words - Antiviral therapy; Hepatitis C; Ledipasvir; Quality of life; Ribavirin; Sofosbuvir

Hepatitis C treatment and quality of life – You can’t always get what you want, but you might get what you need
Gautam Mehta, Geoffrey Dusheiko UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Campus, London NW3 2PF, United Kingdom 

As shown in this study, symptoms are in fact associated with the presence of the virus, and a treatment effect and effect of cure on HRQL is evident. Will curing hepatitis C, and the symptomatic improvements observed in these trials, translate into improved work productivity and economic gain with these high cost regimens? Presently payers seek improvements in “hard” measurable outcomes such as hospitalisation for hepatic decompensation, transplantation rates, a reduction in hepatocellular carcinoma, and deaths attributable to hepatitis C. Whether these discernible improvements, in quality of life and productivity, will persuade payers to fund treatment for those with minimal fibrosis remains to be seen. The situation is akin to the words of a famous rock band of the 1960s, ‘You can’t always get what you want, but if you try sometimes, you just might get what you need...’
Continue reading @ J Hepatol

This Week In The News

World Hepatitis Summit harnesses global momentum to eliminate viral hepatitis
Around 400 million people are currently living with viral hepatitis, and the disease claims an estimated 1.45 million lives each year, making it one of the world’s leading causes of death. Hepatitis B and C together cause approximately 80% of all liver cancer deaths, yet most people living with chronic viral hepatitis are unaware of their infection.

More than 200,000 Brits chronically infected with HCV
Around 214,000 individuals are chronically infected with hepatitis C (HCV) in the UK, national estimates from Public Health England (PHE) suggest Hide related content: Show related content read more (Source: Nursing in Practice)

The Next HCV Drugs
10 promising new treatments are currently in development.


In a September 2 editorial, The New York Times Editorial Board concludes that “competitive market forces and hard-nosed bargaining” make “tremendously effective” new hepatitis C medicines not just more accessible to ailing patients – but also offer good value to the U.S. health care system.
Continue reading @

Editorial: When is the high cost of prescription drugs too high?
Friday, September 4, 2015 4:51pm
Other countries establish formulas that force drug treatments to prove cost effectiveness. By their nature, these systems place a dollar value on human life and suffering, an unpleasant prospect that America has so far avoided. Somehow, though, Congress must allow Medicare to find ways to limit costs — including allowing Medicare to negotiate with the drug companies. 
Continue reading @ Tampa Bay Times 

Costly Hepatitis C Drugs for Everyone?
September 2, 2015, Wednesday - BY THE EDITORIAL BOARD
Competition and discounts are going a long way toward resolving the problem of expensive hepatitis C drugs.
Key clinical point: Ledipasvir-sofosbuvir plus ribavirin for 12 weeks achieved high SVR rates among patients with hepatitis C virus infection and advanced liver disease.

Meta-analysis- SVR and its Treatment Predictors in HCV Genotype 4 Compared to Genotypes 1, 2, and 3
Does treatment with pegylated interferon and ribavirin bring about sustained virological response in HCV genotype 4 as compared to genotypes 1, 2, and 3?

Patients With Renal Disease: One of the Remaining Challenges in HCV Therapy
Nancy Reau MD
A recent patient discussion highlighted important questions about how to approach HCV infection in renal disease.

Updates Around The Web

Big Questions about Hepatitis C

HCV Advocate September Newsletter
Hepatitis C in Children
by Alan Franciscus, Editor-in-Chief
Find out what the prevalence of hepatitis C is in children, what the consequences are and what can be done about it.

HealthWise: Big Questions about Hepatitis C
by Lucinda K. Porter, RN
Lucinda answers the “Big Questions about Hepatitis C” including what does “not detected” mean when treatment is finished, what does “cured” mean and a recurring question about treatment and toothbrushes and many more questions….and answers!

by Alan Franciscus, Editor-in-Chief
This month’s column includes a brief overview of the antihistamine that is purported to have antiviral properties against hepatitis C, and a couple of brief overviews of Baby Boomer testing initiatives at two different hospitals.

Consumer Reports Best Buy Drugs Booklet
by Alan Franciscus, Editor-in-Chief
I discuss my experience shopping around for the best buy for a generic drug for my dog—Buddy—and a very good resource for people from Consumer Reporters that is free of charge.

Download September Newsletter

What’s New!
by Alan Franciscus, Editor-in-Chief
What’s New features two of our new Easy C fact sheets as well as our Training Workshop schedule for the rest of the year!

HCV Advocate Eblast: September 1, 2015
Attention: There are many insurance companies that are denying coverage of HCV medications to only the sickest of patients. I am working on a brief

Blog Updates

Karen Hoyt
You've wondered where I’ve been, so here’s the truth. I’m working on a post transplant nervous breakdown. It kind of started a few weeks ago. I was seated at my fave outdoor restaurant (to avoid germs) typing away from my notes. It was a blog titled “I Can Do Anything”. I’ve always said that, and I’ve always tried. Really tried. Hard. Always. Anyway, here I was looking at my own thoughts through a microscope when I realized that I can’t do everything. POW! Sucker punched, right there on the patio.

Hep is an award-winning print and online brand for people living with and affected by viral hepatitis. Offering unparalleled editorial excellence since 2010, Hep Blogs and are the go-to source for educational and social support for people living with hepatitis.

David Pieper
HIV/Hep C Co-infection activist; on treatment
4 September: The tip of the iceberg
There are 25 million people living with viral hepatitis in Indonesia. This is a tragedy. It puts my treatment experience into context and I realise that I am the merest tip of the iceberg
click here to enter

Grace Campbell
A nom de guerre for a person living with hepatitis C on Viekira Pak + Ribavirin
My Year of Living With Hepatitis C
I have four more days of treatment. Four more days of thinking about treatment. Then I can switch to thinking about treatment in the past tense. And no doubt I'll find something else to obsess over
click here to enter

National Viral Hepatitis Roundtable
 First-Ever World Hepatitis Summit meeting this week in Glasgow
An invite-only, exclusive event that will be the first of its kind to directly address the overwhelming global burden of viral hepatitis.
click here to enter

Connie M. Welch
Passionate Encourager for Christ, Writer, Speaker, and Hep C Warrior
Living Beyond Hep C with Faith and Trust
Hep C knows no boundaries, it does not hold back from race, sex, religion, social status, rich or poor, or country. Hep C like any other serious health condition causes you to look on the inside out of life.
click here to enter

Matt Starr
Hepatitis, Liver Disease Support Coach
 Hep C Meds - The Home Stretch
But, it's not easy sometimes to stay positive as effects of meds and liver disease compromise you.
click here to enter

Greg Jefferys
My Hep C Travel Diary, Hepatitis C Advocate
Hepatitis C Headlines, Hacking, and Scams
I need to again mention that there are a LOT of Harvoni scams going around now. I make the point again that there is no generic Harvoni in India at the moment, or anywhere else in the world.
click here to enter

Stay well, see you soon...

Tuesday, August 25, 2015

Hepatitis C treatment: Back to the warehouse

Hello folks, the August issue of Clinical Liver Disease is available online, here.
An excerpt of this months editorial is included below followed by the August index.

This journal is an official digital educational resource from the American Association for the Study of Liver Diseases. Along with full text access, each article includes a video presentation and author interview.

Clinical Liver Disease
Special Issue: Editorial, Palliative Care & Non-Viral Liver Infections
Volume 6, Issue 2, pages 27–29, August 2015

Hepatitis C treatment: Back to the warehouse
John P. Rice M.D

Article first published online: 24 AUG 2015
DOI: 10.1002/cld.490

Hepatitis C treatment: Back to the warehouse
Like many physicians that specialize in hepatitis C virus (HCV) treatment, I have spent the last few years advising many of my patients with chronic HCV infection to defer treatment and wait for new therapies. For those without advanced fibrosis or an extraintestinal manifestation of HCV, this process of “warehousing” patients for future HCV treatment made perfect sense. Why undergo interferon-based therapy, with all of the side effects and marginal results, when it was becoming clear that highly efficacious, interferon-free therapy was close to becoming a reality? Patients, advocacy groups, and physicians closely followed the development of sofosbuvir (Sovaldi), simeprevir (Olysio), sofosbuvir/ledipasvir (Harvoni), and paritaprevir/ritonavir/ombitasvir/dasabuvir (Viekira Pak) among others in eager anticipation of US Food and Drug Administration (FDA) approval and, for most patients, the possibility of a cure of their HCV infection.
Watch a video presentation of this article

Hepatitis C treatment: Back to the warehouse (pages 27–29)
Overview of palliative care and hospice services (pages 30–32)
Issues in the end-stage liver disease patient for which palliative care could be helpful (pages 33–36)
Working with palliative care services (pages 37–40)
Amebic liver abscess (pages 41–43)
Recognizing clonorchiasis: A foodborne illness leading to significant hepatobiliary disease (pages 44–46)
Hepatosplenic candidiasis (pages 47–50)
Pyogenic liver abscess (pages 51–54)

Saturday, August 22, 2015

HCV: The Best Cure Possible or the Best Possible Cure?

Journal of Viral Hepatitis

HCV: The Best Cure Possible or the Best Possible Cure?

L. Craxí; C. Cammá; A. Craxí

J Viral Hepat. 2015;22(8):627-629. 

 Is a regimen combining interferon (IFN) with a highly effective direct-acting antiviral agents (DAA) still an acceptable choice in 2015? The ultimate goal for society as a whole is to obtain what is best for each individual, but in doing so, it should aim not towards the best possible cure, but the best cure possible. This basic assumption is essential, even though it often leads to a conflict with the desires and aspirations of individuals, especially because immediate access to information about new and potentially effective treatments is available to anyone. In some instances, the high price tag on treatments and devices is unquestionably related to industrial costs (research, development, licensing, production and distribution), while in others finding any kind of justification is extremely hard. In the instance of HCV treatment, Are we really sure that IFN-free therapies cannot be both the best possible cure and the best cure possible for everyone?[2] These therapies are unquestionably more effective than the others, and the only obstacle towards a sustainable generalized distribution is their extremely high cost, which looks artificially inflated even considering the high R&D costs. The cost of fabricating all the new DAAs does not exceed 300 $ for a 12 weeks course of treatment, a more than 200-fold difference from their retail price.

Progress in medicine goes along with an exponential growth of the cost of drugs and devices. While any person has the right to obtain the best possible benefit from medical care, a state needs to strike a balance between granting the optimal personal benefit to each individual and the needs of the society as a whole. Health systems in all countries therefore are facing a huge problem of distributive justice, as while they should guarantee individual rights, among which the right to health in its broader sense, including physical, psychological and social well-being (therefore not limited to healing, but extending to compliance and quality of life), they must also grant equal access to the healthcare resources and keep the distribution system sustainable.

The new generation of highly effective direct acting antivirals (DAAs) to treat HCV infection brings major promises to infected patients in terms of exceedingly high rates of sustained virological response (SVR) but also of tolerability, allowing even the sickest patients to be treated.[1] However in most countries throughout the world, the exceedingly high prices of DAAs are hampering their integration into the HCV treatment programmes. A similar situation arose at the outset of the HIV/AIDS epidemics until the availability of generic compounds removed the price obstacle. The current costs of DAA combinations active against HCV mean that on a global level far less patients than needed are being treated and that no population-wide public health benefit can be expected for some of the most heavily affected countries.[2]

Direct acting antivirals in all-oral regimens need to be used in combination to get SVR rates beyond 90%, except for the easiest to treat patients such as those with HCV genotype 2, where sofosbuvir with ribavirin will suffice. A need to prolong therapy to 24 weeks when treatment is given to patients with cirrhosis emerged at least with some regimens. Need for combination and longer treatment duration will cause a further rise of costs, in a context where the prices of DAAs are already deemed to be exceedingly high.[3] Although in an ideal world everybody would like to get rid of interferon and of its complications and inherent limitations, its relatively low price tag still keeps it as an option to partner with one DAA to reduce costs while still obtaining high SVR rates, at least among patients without cirrhosis. Another currently popular option is to allow IFN-free DAA treatment only in patients with advanced fibrosis or cirrhosis, while keeping on hold persons with lesser stages of liver disease (so-called 'informed deferral' policies).[4] The net balance of these attitudes has never been quantified.

In this issue of JVH, Pho et al.[5] perform a cost–utility analysis aimed to quantify the trade-offs of immediate, interferon-containing therapy versus delayed, interferon-free therapy for interferon-eligible patients with HCV genotype 1 chronic infection. The evaluation, addressing a lifelong time horizon, was performed using a decision-analytic approach, and the natural history of progression of chronic hepatitis C was projected by Markov's model. Using grouped data derived from phase III studies, Pho et al. have tested the incremental cost-effectiveness ratio (ICER) of four different antiviral treatment scenarios stratified by the presence or absence of cirrhosis: (i) no treatment, (ii) immediate, one-time treatment with sofosbuvir interferon-containing regimen, (iii) immediate treatment as above with the opportunity for retreatment in patients who fail to achieve sustained virologic response with interferon-free therapy in 1 year and (iv) delayed therapy with interferon-free therapy in 1 year. They found that waiting 1 year for interferon-free therapy resulted in superior health benefits compared with one-time immediate therapy with interferon. This superiority in health benefits was however lost when the wait-time for an interferon-free therapy was >3 years. Time dependency of this choice was consistent across a broad range of disease variables, and more evident in subjects without cirrhosis. As a message, HCV-infected patients facing the decision of whether to accept to be treated immediately, with a less costly IFN-containing (but still sofosbuvir based) regimen, or wait until more relaxed rules and reduced costs will allow them to be eligible for an IFN-free treatment should opt for the IFN-containing regimen if they have severe disease (but not severe enough to prevent the use of IFN) if the projected waiting time for IFN-free DAAs exceeds 1 year.

The issue tackled by Pho et al.[5] is of practical relevance, given that due to costs, many countries are unable to effectively deliver this innovation.[2] One wonders however how large will be the reduction of costs, given that sofosbuvir, a highly priced drug except in Egypt and in some non-Western countries, is still the backbone of the regimen. If new DAA combos are priced in the same fascia of sofosbuvir, the advantage of an IFN-containing combination becomes far less relevant. Moreover, the indirect costs generated by the use of IFN (growth factors, EPO, transfusions, medical care) could offset the sparing obtained.[6] Also, the option of using only PEG IFN and ribavirin in patients with a high likelihood of response[7] as a way to reduce costs has not been explored in the model.

Albeit Pho's analysis is conducted rigorously, its conclusions cannot be fully transferred to clinical practice without considering some methodological issues. Decision models are often designed using summary data hampering more detailed treatment comparisons that could be achieved with a prognostic model using individual patient data. These summary results describe only between-population, not between-patient, variation because they reflect group averages rather than individual data. Therefore, conventional quality-adjusted life years (QALYs) are population-level tools and fail to take into account important interindividual differences that might affect the value of a particular intervention.[8] The choice that maximizes the population's health or has the best cost/effectiveness overall is not always the same as the best choice for a specific individual. Moreover, the best choices may differ for different individuals. There is thus interest in how to modify the ICER concept for applications in individual decision-making.[9] While for any person it would be more desirable to receive immediately a highly effective IFN-free regimen, at a societal level, it is important to know that an informed deferral strategy, to be carefully agreed with the patient, allows waiting 1 year for interferon-free therapy with superior health benefits as compared to one-time immediate therapy with interferon. According to Aronsohn,[4] deferring treatment is justifiable and appropriate for many patients, and an informed deferral is needed considering risks related to inaccurate staging of liver disease, inability to predict progression of fibrosis and comorbidity changes over time. Obviously, the clinical value and ethical impact of treatment or deferral should not be compromised by any economic analysis.

Moreover, in a prognostic setting, predictions are used to plan therapeutic choices based on the risk of a specific outcome, and estimates of probabilities are seldom based on a single predictor. In fact, physicians naturally integrate several patient's characteristics and symptoms to make a prediction. Prediction is therefore inherently multivariable.[9] Although deterministic and probabilistic analyses try to take these aspects into consideration, these analyses often fail to capture the full complexity of the clinical decision on the individual patient. In this setting, more detailed treatment comparisons could be achieved by combining the different variables affecting the achievement of SVR using multivariate risk modeling.[10] Pho's model adopts the same expected SVR rate regardless of the type of patient to be treated (naïve or P/R experienced, a relevant issue when dealing with IFN-based regimens).

In the end, a major question mark remains: Is a regimen combining IFN with a highly effective DAA still an acceptable choice in 2015? The ultimate goal for society as a whole is to obtain what is best for each individual, but in doing so, it should aim not towards the best possible cure, but the best cure possible. This basic assumption is essential, even though it often leads to a conflict with the desires and aspirations of individuals, especially because immediate access to information about new and potentially effective treatments is available to anyone. In some instances, the high price tag on treatments and devices is unquestionably related to industrial costs (research, development, licensing, production and distribution), while in others finding any kind of justification is extremely hard. In the instance of HCV treatment, Are we really sure that IFN-free therapies cannot be both the best possible cure and the best cure possible for everyone?[2] These therapies are unquestionably more effective than the others, and the only obstacle towards a sustainable generalized distribution is their extremely high cost, which looks artificially inflated even considering the high R&D costs. The cost of fabricating all the new DAAs does not exceed 300 $ for a 12 weeks course of treatment, a more than 200-fold difference from their retail price.[11] Even allowing for other industrial costs, this rate of amplification is totally unheard in any field of medical care. The basics of modern free market economics dictate that pharmaceutical industries have the right to set the price they like and seek the profit they deem appropriate, while facing supply and demand dynamics. But, Are we sure that both the parties in the negotiation game are playing by the same rules? Are pharmaceutical industries (private, profit-driven enterprises) and public healthcare services really peers? Can we really consider drugs market a free market when it has the dynamics of a monopoly or a cartel? The focal point therefore is increasing the state's negotiating power, which originates from the state's economic force and from the raw number of potential users. It is utterly absurd that despite the focus on European community, and on international trade treaties at large, each individual state negotiates the price of drugs and treatments individually based on its numerical needs. States could and most surely should join forces to apply more pressure on the industry. Possible means of pressure are generic drugs, treatment scale up and chiefly drugs patenting, which has often seen the granting of patents for drugs whose originality and potential benefits wee questionable to say the least. Last, but not the least, health technology assessment should give a strict guidance on the margins of negotiation available to provide the therapy to everyone.

In conclusion, an assessment of the possible timing of deferral of IFN-free treatments without prejudice for a patient's health is a useful tool, but cannot be used to justify the status quo and the adoption of a double track for treatment.

Of Interest
In The News

Thursday, March 19, 2015

Hepatitis C: only a step away from elimination?

Editorial - The Lancet

Hepatitis C: only a step away from elimination?
Volume 385, No. 9973, p1045, 21 March 2015


Globally, an estimated 185 million people are infected with hepatitis C virus (HCV). Acute HCV infections are usually asymptomatic. However, about 75% of patients develop chronic infection, which can lead to liver cirrhosis and hepatocellular carcinoma. 700 000 deaths worldwide could be attributed to HCV in 2013. While most people affected live in low-income and middle-income countries in Asia, Africa, and the Middle East, in the UK an estimated 200 000 individuals are infected with HCV, and annual deaths from HCV have quadrupled since 1996. These figures are appalling, surely. But the extraordinary recent developments in treatment for hepatitis C offer substantial grounds for optimism. A series of new drugs—more effective in viral clearance with fewer side-effects—are changing the landscape for hepatitis C.

Today's Lancet gives a sense of the remarkable past few years it has been for hepatitis C. As described in Paul Webster and colleagues' comprehensive Seminar, until recently interferon in combination with ribavirin was the main treatment for hepatitis C, but eligibility, safety, tolerability, and effectiveness were limited. The development of direct-acting antiviral drugs towards NS3/4A protease, NS5B polymerase, and NS5A replication complex has progressed tremendously and now allows for interferon-free therapies. Four clinical trials with new regimens are published in today's issue. The C-WORTHY trial assessed a single-tablet once-daily regimen of grazoprevir (protease inhibitor) and elbasivir (NS5A inhibitor) with or without ribavirin for patients with HCV genotype 1. Eric Lawitz and colleagues report a sustained virological response (SVR) at 12 weeks, irrespective of ribavirin and duration of treatment. Similarly, Mark Sulkowski and colleagues report very encouraging results (SVR at 12 weeks: 87–97%) in patients co-infected with HIV. With about 25% of individuals infected with HIV being co-infected with HCV, inclusion of this group of patients in trials is also of utmost importance. In the PHOTON-2 trial, Jean-Michel Molina and colleagues specifically assessed the recently approved regimen sofosbuvir (NS5B inhibitor) plus ribavirin in patients infected with HCV genotypes 1–4 co-infected with HIV. They confirm the pan-genotypic potential of sofosbuvir (SVR 12 weeks: 84–89%), offering HIV co-infected patients a useful interferon-free option. The fourth trial published in today's issue goes a step further and assesses whether the addition of a third direct-acting antiviral drug to an interferon-free, ribavirin-free combination (sofosbuvir and ledipasvir) would allow shorter treatment duration—an important factor for a patient population in which treatment compliance and adherence can be an issue.

These trials are important because they offer new effective treatment options for HCV infection. “An opportunity now exists to almost eliminate this infection from the UK”, wrote Roger Williams and colleagues in The Lancet Commission on Addressing liver disease in the UK. Highly effective new antiviral drugs not only can cure those treated but also can reduce transmission of HCV and therefore its prevalence. The Commission estimated that with these new antiviral drugs we could contemplate the “eradication of infections from chronic hepatitis C virus in the UK by 2030”. Indeed, modelling studies for England showed that increasing diagnostic and number of people treated by 27 times would result in a 95% reduction in the prevalence of HCV infection, an 80% reduction in hepatocellular carcinoma, and avert 5200 deaths by 2030.

While new drugs offer new opportunities, new challenges also arise. Scaling-up treatment—in any country—will face important cost issues. But the high costs of these new medicines, which should be robustly scrutinised and, where appropriate, challenged, must not inhibit a careful and comprehensive analysis of the broader benefits they might bring. For example, as Melanie Calvert and colleagues argue this week, patient-reported outcomes offer the opportunity to have the patient's voice more forcefully heard in health policy decision making. The self-reported benefits to patients from these new anti-HCV regimens might prove to be substantial. And the financial returns from reduced health-care costs and higher economic activity might easily outweigh the expense of the medicines themselves. This kind of broader cost-effectiveness work needs to be urgently completed.

Next month, The Lancet Infectious Diseases is hosting its inaugural Viral Hepatitis Summit in Shanghai (April 10–12). We look forward to this meeting addressing the increasingly urgent need for a global plan to eliminate hepatitis C. With no vaccine in sight, if we are truly to contemplate elimination of hepatitis C by 2030, ensuring that treatments reach marginalised groups and are accessible to all those living with HCV will be crucial.

PDF Lancet

Linked Articles
New kids on the block—step by step to an ideal HCV therapy

PHOTON-2: hope for patients with HIV and HCV co-infection?

Shorter treatments for hepatitis C: another step forward?

Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial

Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial

Sofosbuvir plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV (PHOTON-2): a multicentre, open-label, non-randomised, phase 3 study

Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study

Hepatitis C

Putting patients at the heart of health-care research

Thursday, October 9, 2014

Delivering on the Promise: Maximizing SVR in the Real World

New at Clinical Care Options

Delivering on the Promise: Maximizing SVR in the Real World
Free registration is required to view links provided in this article.

With the promise of curing up to 75% of patients infected with genotype 1 HCV, the approval of the first-generation protease inhibitors (PIs) in May 2011 led to rapid uptake of these then-new agents. Despite the difficult treatment algorithms, less than optimal adverse event (AE) profiles, risk for drug–drug interactions, and the ongoing need for peginterferon, clinicians and patients were motivated by the high SVR rates reported in phase III clinical trials. Unfortunately, the real world proved to be very different from a controlled trial. We all experienced a rude awakening with higher rates of AEs, poorer tolerability, and much lower rates of SVR than we had quoted our patients based on the published data.

With the highly effective new agents now available—and more on the horizon—we need to make sure we do not repeat history.

To achieve excellent results in the real world, we will have to do many things right. The first thing we should probably do is to temper expectations, at least somewhat. The remarkable results reported in phase III trials have appropriately garnered an enormous amount of publicity in the medical and lay press. When more than 95% of patients in multiple trials achieve SVR, it is hard for clinicians and patients not to be incredibly optimistic. However, before assuring our patients that they will almost certainly be cured, we have to make sure that the results apply to them specifically. I remember seeing patients who had anticipated that they had a 75% chance of responding to telaprevir and were disappointed when I pointed out that as a previous null responder with cirrhosis, the likelihood of SVR was closer to 15%. The differences in treatment response rates by baseline characteristics with the new agents are not nearly as stark as with the first-generation PIs. But as an example, the presence of cirrhosis is still quite relevant, affecting the response rates and possibly the duration of therapy. In addition, many of the patients we treat in practice have comorbidities that would have prevented their entry into the highly selected trial populations. Until we have more data on treating specific subpopulations, such as those with renal disease and those older than 65 years of age, we should probably temper our SVR estimates, at least to some degree.

Patients’ Experiences Differ and Can Shape Expectations
Beyond setting realistic expectations, there are other issues for clinicians to consider in relation to the use of these new agents in the real world. The outstanding results reported in clinical trials may leave us with the sense that treatment is easy and everyone should be treated right away. Treatment is certainly easier, but that is a relative term. For our patients who have struggled through peginterferon and ribavirin for 48 weeks or longer, possibly on more than 1 occasion, these new treatments sound like a cakewalk—and from that perspective, they are. However, for those who have never considered HCV therapy, 3 months of treatment still sounds very daunting. “Interferon free” is only a positive feature if you know the alternative. Getting patients through 8 or 12 weeks of even the best tolerated therapy can still be a challenge, particularly as the patient population expands. To date, we have tackled mostly the low-hanging fruit. Patients had to have been diagnosed, meaning that they had access to some type of healthcare coverage, they had to have been referred to a specialist and to show up to that appointment, the specialist had to deem them acceptable candidates for treatment, and then they had to be willing to take very difficult treatment. The 10% to 15% of the population we have treated up until now is a highly selected, motivated, and relatively comorbidity-free population. Many practitioners have shied away from treating people with active substance use and mental health issues with the easy argument that interferon may complicate these other problems. With the new therapies, this “excuse” is no longer valid, and we will have to deal with the challenges that come along with treating harder-to-access populations. This is not a small point and not a small challenge. Without expanding treatment dramatically, the benefits of the remarkable recent advances in HCV therapy will have little effect at a population level. However, for many hepatologists, treating more marginalized populations will not be easy.

Like everyone else, those with mental health, substance use, and other comorbidities first need to be evaluated to decide whether treatment is the right thing for them. The presence of effective therapy in and of itself is not necessarily an indication for treatment, particularly with treatment that is evolving so quickly. It is still important to first evaluate the stage of liver disease. Fortunately, this is made easier by transient elastography and serum panels, meaning that most patients no longer require a liver biopsy. At the minimum, knowing whether a patient has cirrhosis is critical. Even those cirrhotic patients who achieve SVR will require long-term follow-up to screen for liver cancer. For those without experience of managing advanced liver disease, this is the type of patient who may merit referral. As we have noted, cirrhosis may affect the type and duration of therapy. For example, caution should be used with simeprevir in patients with any signs of decompensation (Child’s B or greater) because of unreliable pharmacokinetics. In my clinic, we have seen a few patients with advanced liver disease experience problems while receiving sofosbuvir/simeprevir therapy that needed specialist management. With the coming regimen of ritonavir-boosted paritaprevir plus ombitasvir and dasabuvir, previous null cirrhotics with genotype 1a HCV should probably receive 24 weeks of therapy and will definitely require ribavirin. Similarly, for cirrhotic patients, 8 weeks of sofosbuvir/ledipasvir is not an option, and for those who failed previous treatment, 24 weeks might be of benefit. The improved simplicity of the new regimens can sometimes tempt us to jump to therapy before completing these evaluations.

For patients with minimal or no liver damage and no significant extrahepatic disease, treatment is not an urgent matter. This is not to say we should deny therapy for those patients seeking treatment, but it is important to note that patients with mild disease have time on their side. Hepatitis C disease evolves slowly and treatment options are evolving quickly. Current and near-future 8-week and 12-week regimens will likely be replaced by treatments of just 6 weeks, 4 weeks, or even shorter in the not-too-distant future. Particularly for patients for whom adherence may be a challenge, rushing into therapy can lead to poor outcomes. Even for those with more advanced liver damage, including cirrhosis, treatment is not urgent in terms of weeks or even months. Making sure that patients are able to attend clinic reliably, that they have a good rapport with their treating team, and that important comorbidities and concomitant medications have been reviewed and any issues addressed will ensure much better outcomes on therapy. Even though we will likely have salvage therapies for those who fail initial regimens, it is preferable on all levels to maximize the chance of SVR on the first attempt.

Monitoring Has Multiple Roles to Play
One practical challenge that has arisen is how often to see patients. In the absence of rigid stopping rules and with almost every patient achieving undetectable HCV RNA on therapy, there may be a tendency to hand patients a prescription for 3 months of treatment with a follow-up appointment 12 weeks after they finish. However, even for those who cruise through therapy with no problems, follow-up visits are very important. For many patients, knowing that the virus is undetectable, sometimes for the first time after multiple previous treatment attempts, is a huge motivating factor. We have had many patients tell us that our nurses’ reminders and encouragement kept them taking their pills when treatment exhaustion set in around Week 8. For stable patients, monthly monitoring is likely adequate, but for those in whom adherence may be an issue, more frequent contact is definitely helpful. In addition, assessing our patients on therapy may bring to light new issues; it was only in clinical practice that anemia was recognized as a problem with telaprevir.

Another practical consideration, which will hopefully soon become less relevant, is treatment access. Coverage for sofosbuvir/simeprevir has been an issue with many payers. The high cost and lack of robust phase III data with this combination have led to denials of coverage for some patients in my clinic. We are hopeful that coverage requests will be more straightforward with the approval of coming regimens; however, the decisions in certain US states to limit therapy for those still using injection drugs must be challenged. Studies have clearly shown that patients who inject drugs can be successfully treated even with interferon-based therapy and the risks of reinfection are surprisingly low. In my opinion, limiting access to therapy based on behaviors is entirely inappropriate and would be akin to refusing to cover statin therapy in patients who smoke or lead sedentary lifestyles. The challenge of access will hopefully be less of an issue because the new regimens will have FDA approval and solid phase III data behind them. However, if access is limited, we as healthcare providers will have a duty to advocate strongly for our patients, particularly for those who do not advocate well for themselves.

The advances in treatment for HCV are nothing short of remarkable. Delivering the successes from clinical trials to the real world is achievable but will take some work. We need to start with realistic expectations and then move forward with therapy for those who need it. Access may be a challenge, but we need to work hard to ensure that everyone who needs therapy gets it. We will need to support patients through treatment, with attention to the stage of liver disease, comorbidities, and treatment adherence. With attention to detail, we can realize the potential of these new therapies, but we have to do it right because we cannot afford—both literally and figuratively—to get it wrong the first time.

Your Thoughts
I am interested to hear about your thoughts on what is needed to ensure that we maximize the effects of these powerful new agents in clinical practice. What has been your early experience of treating patients with new direct-acting antivirals, and what lessons have you learned for the future? Please use the comments section below to provide your insights.

Topics: HCV - Treatment

Satellite Symposium
All-Oral Therapy for HCV: A New Era Begins
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Join us for a live symposium highlighting the use of all-oral therapy for the treatment of hepatitis C. The program will include a review of key data and discussion by expert faculty as well as perspectives from patients receiving all-oral HCV therapy.
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Sunday, November 9, 2014
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All-Oral Therapy for HCV: A New Era Begins (Coming soon)
Register now for this CME/CE-certified webcast.
Join us for a live webcast highlighting the use of all-oral therapy for the treatment of hepatitis C. The program will include a review of key data and discussion by expert faculty as well as perspectives from patients receiving all-oral HCV therapy.
Available Dates:
Sunday, November 9, 2014