June 12, 2012

Ascites Care Suboptimal at Some Veterans Affairs Facilities

By: DENISE NAPOLI, Family Practice News Digital Network

06/11/12

Quality of care for ascites, the most common complication of cirrhosis, was found to be suboptimal at several Veterans Affairs medical centers, reported Dr. Fasiha Kanwal and colleagues in the July issue of Gastroenterology.

"In general, care targeted at diagnosis and treatment was more likely to meet standards than preventive care," wrote Dr. Kanwal, of the Michael E. DeBakey Veterans Affairs Medical Center, Houston.

"We also found a trend towards improved outcomes in patients who met recommended quality indicators," added the investigators, although these findings "can only be regarded as preliminary."

The authors studied records from 774 patients (mean age 54.7 years, 99% male) in a database comprising 3 VA medical centers and 15 affiliated clinics in the Midwest (Gastroenterology 2012 [doi: 10.1053/j.gastro.2012.03.038]).

All patients had at least two ICD-9 codes for cirrhosis or at least one code for cirrhosis with either a code for complications of cirrhosis or an aspartate aminotransferase to platelet ratio greater than 2. The patients were seen between January 2000 and December 2007.

The authors compared data on these patients to a set of class 1 ascites care quality indicators (QIs). These indicators were derived by using the RAND/University of California, Los Angeles (UCLA), Appropriateness Method, which had been previously published elsewhere (Clin. Gastroenterol. Hepatol. 2010;8:709-17).

If a patient had been hospitalized more than once, only the first hospitalization was assessed. The rate of adherence to each QI was expressed as a percentage of subjects who received the recommended care, among those who were eligible for the QI.

The first QI assessed the percentage of new-onset ascites patients who underwent abdominal paracentesis within 30 days of diagnosis. On this measure, the VA scored 50.6%. The second indicator was whether known ascites patients admitted with either ascites or hepatic encephalopathy underwent abdominal paracentesis during the index hospitalization. Just over half (57.6%) of patients met this criterion.

The next QI was more likely to be met: 89.3% of patients who underwent abdominal paracentesis received ascitic fluid cell count and differential. Another indicator that was met for a high percentage of patients addressed whether ascites patients with normal renal function received diuretics within 30 days of diagnosis – 82.8% met this criterion.

Similarly, among hospitalized patients with spontaneous bacterial peritonitis (SBP), 72.0% received antibiotics within 24 hours before or after ascitic fluid analysis.

However, just 30% of patients with SBP who survived and were discharged from the facility received long-term outpatient antibiotics (for secondary prophylaxis) within 30 days. And just under half (49.2%) of patients admitted with a GI bleed received antibiotics during the index hospitalization.

The final QI was associated with the worst compliance rate: just 22.2% of patients with ascitic fluid total protein levels less than 1 g/dL and serum bilirubin of greater than 2.5 mg/dL received long-term outpatient antibiotics (for primary prophylaxis) within –3 to 30 days of that test result.

Next, the authors assessed which demographic or other independent factors were associated with higher QI compliance. In general, they reported that better care was inversely related to a worsening liver disease. More specifically, they found that patients who saw a gastroenterologist received higher-quality care than those who did not (odds ratio, 1.33), as did patients who were seen at a VA facility with academic affiliation, versus unaffiliated centers (OR, 1.73).

Finally, in two exploratory analyses, the authors examined how adherence to the ascites QIs affected patient outcomes.

Not surprisingly, "we found that after adjusting for age, liver disease severity, and comorbidity, patients receiving suboptimum care had 37% higher odds of death and 35% higher odds of readmission during the 12-month follow-up compared to patients who received optimum ascites care," although these figures did not reach statistical significance.

This study was supported by the 2008 American Society of Gastrointestinal Endoscopy Quality of Care Award and by the 2009 American College of Gastroenterology Clinical Research Award. The authors stated that they had no personal conflicts of interest.

Source

Public release date: 11-Jun-2012

Contact: David Eve
celltransplantation@gmail.com
Cell Transplantation Center of Excellence for Aging and Brain Repair

Tampa, Fla. (June 11 , 2012) –Researchers in Japan have found that hepatocytes, cells comprising the main tissue of the liver and involved in protein synthesis and storage, can assist in tissue engineering and create a "new liver system" in mouse models when donor mouse liver hepatocytes are isolated and propagated for transplantation. Their study is published in a recent issue of Cell Transplantation (21:2/3), now freely available on-line at http://www.ingentaconnect.com/content/cog/ct/,

"In light of a serious shortage of donor livers that can be used for hepatocyte isolation, it has become important to establish an efficient way for hepatocytes to be retrieved and propagated for the purposes of tissue engineering," said study lead author Dr. Kazuo Ohashi of Tokyo's Institute of Advanced Biomedical Engineering and Science at Tokyo Women's medical Hospital. "Our study demonstrated the feasibility of propagating mouse hepatocytes by creating a vascularized platform using a growth factor releasing device, and also by creating uniform hepatocyte "sheets" using the isolated individual donor hepatocytes in culture."

Using these approaches and implementing assessment eight weeks following hepatocyte transplantation, the researchers confirmed the functionality of the engineered liver system by documenting the production of liver-specific proteins, by analyzing chemical uptake in the mouse livers and observing subsequent metabolic activity, and by assessing regenerative growth.

The researchers note that the risk of cancer derived from transplanted hepatocytes needs to be addressed because of the "active level of proliferation" following transplantation. In their research, however, and in similar studies they reviewed, it appears that the "risk of cancer cell development is minimal," they concluded.

"The ability to regenerate and expand hepatocytes has potential clinical value when small amounts of tissue can be expanded to sufficient quantities prior to their use in hepatocyte transplantation or other hepatocyte-based therapies," said the researchers.

###

This study highlights some of the pioneering work stemming from the Japan Society for Organ Preservation and Medical Biology. The impact of this work on liver regeneration by cell transplantation ranks favorably with other studies and its usefulness will be revealed once all the necessary contributing factors for liver regeneration are understood.

Contact: Kazuo Ohashi, MD, PhD, Institute of Advanced Biomedical Engineering Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo, 162-8666, Japan
Tel. +81-3-3353-8112 ext. 66220 954468004
Fax. +81-3-3359-6046 954461664
Email ohashi@abmes.twmu.ac.jp

Citation: Ohashi, K.; Tatsumi, K.; Tateno, C.; Kataoka, M.; Utoh, R.; Yoshizato, K.; Okano, T. Liver Tissue Engineering Utilizing Hepatocytes Propagated in Mouse Livers In Vivo. Cell Transplant. 21 (2/3):429-436; 2012.

The Coeditor-in-chief's for CELL TRANSPLANTATION are at the Diabetes Research Institute, University of Miami Miller School of Medicine and Center for Neuropsychiatry, China Medical University Hospital, TaiChung, Taiwan. Contact, Camillo Ricordi, MD at ricordi@miami.edu or Shinn-Zong Lin, MD, PhD at shinnzong@yahoo.com.tw or David Eve, PhD at celltransplantation@gmail.com

Source

Mortality Due to HCV-Related Disease in HIV+

Provided by NATAP

Download the PDF here

"During this year, death due to ESLD represented 28% of all non AIDS-related deaths in the HIV-positive population. These findings are in accordance with recent studies from Europe.....the progression to cirrhosis and HCC in patients with chronic HCV infection occurs over an average of two or three decades [5,6], potentially leading to a burden of disease over time......Our multi-centre, national study demonstrates that ESLD, predominantly due to HCV coinfection, is now a leading cause of mortality in the HIV-infected population. Five years after the introduction of HAART, the importance of liver disease as a cause of death has increased progressively"....(from Jules: if anything liver disease deaths & hospitalizations have gotten worse over time because coinfected response less well to peg/rbv and have a hard time with tolerability(although this study is from 2003 liver disease has gotten worse in coinfected in many ways since 2003).....HCV appears to cause inflammation & may contribute to other comorbidities....with the HIV aging patient population other comorbidities are emerging but liver disease remains a predominant cause of death & hospitalization because with aging liver disease progresses without successful treatment.....this recently published study linked to immediately below reports untreated HCV increases HIV comorbidities & consequent deaths thus these deaths or hospitalizations are NOT reported to be associated with HCV!)

HCV Sustained Viral Response in HIV Coinfected Reduces Non-Liver Related Mortality & Liver-Related Disease: cancers/CVD - (06/01/12)

"We found that failure to achieve an SVR was associated with increased risk of liver decompensation, hepatocellular carcinoma, liver transplantation, and liver-related death; findings consistent with our previous observations [11]. Interestingly, we also found that failure to achieve an SVR was associated with an increased risk of HIV progression and non-liver-related mortality. Most non-liver-related deaths were due to non-AIDS-defining cancers, cardiovascular events, and bacterial infections. Of note, both the risk of non-liver-related death, and non-liver-related non-AIDS-related death was significantly higher for nonresponders than for responders after adjustment......may be explained by several factors, including immune activation, defective immunity, systemic inflammation, and liver disease itself"

060312-11

Mortality due to hepatitis C-related liver disease in HIV-infected patients in France (Mortavic 2001 study)

AIDS: 15 August 2003

Rosenthal, Eric; Poiree, Marilyne; Pradier, Christiana; Perronne, Christianb; Salmon-Ceron, Dominiquec; Geffray, Loicd; Myers, Robert Pe; Morlat, Philippef; Pialoux, Gillesg; Pol, Stanislash; Cacoub, Patricei; for the GERMIVIC Joint Study Group

From the Service d'Hematologie Clinique, Hopital Archet, Nice, aCISIH, Hopital Archet, the bService des Maladies Infectieuses, Hopital Raymond Poincare, Garches, the cService de Medecine Interne, Groupe Hospitalier Cochin, Paris, the dService de Medecine Interne, Centre Hospitalier General Bisson, Lisieux, the eService d'Hepato-Gastro-enterologie, Groupe Hospitalier Pitie-Salpetriere, Paris, the fService de Medecine Interne, Hopital Saint-Andre, Bordeaux, the gService des Maladies Infectieuses, Hopital Tenon, the hService d'Hepatologie, Hopital Necker, and the iService de Medecine Interne, Groupe Hospitalier Pitie-Salpetriere, Paris, France. *Joint Study Group on Hepatitis C virus of the French National Society of Internal Medicine and the French Society of Infectious Diseases;

Abstract

Objective: To determine mortality due to end-stage liver disease (ESLD) in a nationwide cohort of HIV-infected patients 5 years after the introduction of highly active antretroviral therapy (HAART) and to compare this with that observed before and during the early years of HAART.

Design: and methods: All departments of internal medicine and infectious diseases from the GERMIVIC Study Group prospectively recorded all deaths in HIV-infected patients during 2001. Sixty-five departments, following a total of 25 178 HIV-infected patients, participated in the study. Results were compared with those of previous surveys conducted using similar methodology in 1995 and 1997.

Results: Among 265 deaths observed during 2001, 129 (48.7%) were related to AIDS, 38 (14.3%) to ESLD, and 98 (36.7%) to other causes. Mortality due to ESLD represented 28% of non AIDS-related deaths; 36 of the 38 patients (95%) dying from ESLD had chronic hepatitis C virus (HCV) infection. In 2001, deaths due to ESLD (14.3%) were significantly more frequent than in 1995 (1.5%; P < 0.01) and 1997 (6.6%; P < 0.01). During this interval, the prevalence of hepatocellular carcinoma as a cause of death increased (1995, 4.7%; 1997, 11%; 2001, 25%; P < 0.05), as did alcohol consumption (P < 0.01).

Conclusions: In the post-HAART era, ESLD due to HCV is a growing cause of mortality in HIV-infected patients. Increased longevity attributable to HAART, and a higher prevalence of alcohol consumption, are probably involved in this trend.

Introduction

Coinfection with hepatitis C virus (HCV) and HIV is common as both viruses are transmitted by parenteral routes, i.e., injecting drug use and blood transfusion. In the USA, it is estimated that 30% of the 800 000 HIV-infected individuals are coinfected with HCV [1,2]; similar rates have been reported in Western Europe [3]. Among certain subgroups of HIV-infected patients, such as in injecting drug users and haemophiliacs, the prevalence of coinfection approaches 70-90% [2-4]. HCV infection leads to chronic hepatitis in 85% of HIV-negative patients; approximately 20% will eventually develop cirrhosis of the liver [5,6]. In HIV-positive individuals, chronic hepatitis C is more severe, particularly in those with advanced immunosuppression [7-10]. Regardless of HIV serostatus, time represents a critical factor in determining mortality due to end-stage liver disease (ESLD). In HIV-positive patients, longer survival observed since the introduction of highly active antiretroviral therapy (HAART) may permit the progression of HCV-related liver disease and increase mortality due to complications including liver failure and hepatocellular carcinoma (HCC). Moreover, HAART itself may accelerate the progression of HCV-related liver disease [11]. Several studies have suggested an increased risk of mortality caused by ESLD in HIV-HCV coinfected patients [12-21]. However, most of these studies examined cohorts of haemophilic patients [12,13] or single-centre cohorts of HIV seropositive patients and compared mortality rates during the pre-HAART era with that during the early years of HAART.

Five years following the introduction of HAART, we have examined the mortality associated with HCV-related ESLD in a nationwide cohort of HIV-infected patients in France. The objective of the study was to assess trends in mortality by comparing current data to two previous surveys conducted by our study group in the pre-HAART era (1995) and during the first few years of this therapy (1997) [20].

Discussion

As in our previous surveys [20], our current study analysed approximately half of the HIV-related deaths reported to the French Public Health Network (Institut de Veille Sanitaire) in 2001 [23]. During this year, death due to ESLD represented 28% of all non AIDS-related deaths in the HIV-positive population. These findings are in accordance with recent studies from Europe showing the growing importance of liver disease as a cause of mortality in HIV-infected patients [24,25]. For example, Camino et al. reviewed the causes of death among 1600 HIV-infected patients in Spain during a 21-month period in 1998 and 1999 [24]. Of the 44 deaths registered during this interval, liver disease was responsible for 25%. In another multicentre study from France, 422 deaths were reported among HIV-infected patients during the year 2000 [25]. HCV coinfection was the most frequent non AIDS-related cause of death, representing 10% of all cases.

Combining our contemporary data with our previous surveys from 1995 and 1997 [20], has allowed us to evaluate temporal trends in the mortality of HIV-infected patients in France. Importantly, unlike previous studies addressing this issue [14-16,18,24], our data were derived from a large population of HIV-infected patients from a national network. All participating centres were involved in three consecutive surveys conducted with similar methodology. Although the annual incidence of death decreased between 1995 and 2001, mortality attributable to ESLD (expressed as a percentage of the total number of deaths) increased progressively from 1.5% in 1995, to 6.6% in 1997, and 14.3% in 2001. These findings confirm those of previous studies of predominantly single-centre cohorts in Europe and North America [14-16,18,24] (Table 5), emphasizing the growing importance of ESLD in HIV-infected patients. Several factors may be implicated in this evolution. First, prior to the HAART era, early mortality due to opportunistic infections probably precluded future deaths related to associated chronic viral hepatitis. Moreover, the progression to cirrhosis and HCC in patients with chronic HCV infection occurs over an average of two or three decades [5,6], potentially leading to a burden of disease over time. Increased longevity of HIV-infected patients in the era of HAART, along with accelerated progression of HCV-related liver disease [26] places this group of patients at extremely high risk for liver disease and its complications in future years.

In the current study, mortality due to ESLD in HIV-infected patients was predominantly related to HCV coinfection (95%). However, additional factors, such as alcohol consumption (66%), HBV coinfection (21%), and the use of hepatotoxic medications, must be considered as potential cofactors in accelerating the progression of chronic liver disease or promoting decompensation in some of these patients. In particular, the use of alcohol was more prevalent among patients who died from ESLD in 2001 (66%) than in those during previous years (1995, 38%; 1997, 33%). In parallel, the proportion of injecting drug users, whom are often co-dependent on alcohol, was higher in 2001 (76%) than in 1995 (29%) and 1997 (39%). As observed in HIV-negative patients with chronic hepatitis C [27], the incidence of HCC as a cause of death increased over the study interval (1995, 4.7%; 2001, 25%). Regardless of its aetiology, cirrhosis per se is an important risk factor for HCC [28]. Thus, longer survival of HIV-infected patients with HCV-related cirrhosis may be implicated in the higher rate of HCC observed in 2001. Similarly, a higher prevalence of alcohol abuse probably played a major factor in the rising proportion of HCC-related deaths [29]. These data emphasize the importance of abstinence from alcohol due to its role in accelerating fibrosis progression [30] and promoting hepatocarcinogenesis in HCV-infected patients.

060312-12

Our data demonstrate that approximately three-quarters of patients who died from ESLD in 2001 were receiving HAART. This is significantly higher than in 1997 (44%), and parallels the rising prescription of HAART in France during the period. The association of chronic HCV infection with hepatotoxicity during HAART constitutes a potential concern for morbidity and mortality in HIV-HCV coinfected patients [31,32]. In particular, HCV infection is an independent risk factor for HAART-related hepatotoxicity [33], and it has been reported that HAART may increase the severity of hepatic necroinflammatory lesions in patients with chronic hepatitis C [9]. However, other studies have suggested that the use of protease inhibitors may be protective with respect to the progression of HCV-related liver disease [26]. Unfortunately, the design of our study did not allow us to determine the role of HAART in overall or liver-related mortality in our patient population. Nevertheless, a recent study demonstrating that HAART is the strongest predictor of survival in HIV-positive patients [34] suggests that treatment for HIV is more important in terms of overall survival than concerns regarding the potential exacerbation of HCV-related liver disease by these medications.

Our multi-centre, national study demonstrates that ESLD, predominantly due to HCV coinfection, is now a leading cause of mortality in the HIV-infected population. Five years after the introduction of HAART, the importance of liver disease as a cause of death has increased progressively. This finding probably relates to prolonged longevity attributable to HAART, and possibly due to an increased prevalence of alcohol use. These findings emphasize the importance of developing effective strategies for the prevention and treatment of chronic HCV infection and the moderation of alcohol intake in HIV-positive patients.

Results

Study population


Eighty-two questionnaires were distributed to French departments of internal medicine and infectious diseases; a total of 65 departments (79%) responded. During the year 2001, these departments followed 25 178 HIV-infected patients. The modes of HIV infection were homosexual transmission (31%), injecting drug use (21%), heterosexual transmission (38%), transfusion of blood products (3%), and other or unknown (7%) (Table 1).

Mortality rates

Among the 25 178 HIV-infected patients followed in 2001, 265 deaths were observed, representing a mortality rate of 1.05%. Causes of death were as follows (Table 2): AIDS (n = 129, 48.7%), ESLD (n = 38, 14.3%) and other (n = 98, 37.0%). ESLD represented 27.9% of the non AIDS-related deaths.

Mortality due to ESLD in relation to hepatitis viruses

The main characteristics of the 38 patients who died due to ESLD are outlined in Table 3. These patients were predominantly male (79%) and the mean age was 42 years (range, 32-69 years). HIV transmission occurred predominantly via injecting drug use (76%). Among the 38 cases with death due to ESLD, 19 (50%) were considered definite and 19 (50%) probable. Thirty of these patients had HCV-related cirrhosis (including HCC in seven cases), six had cirrhosis due to HBV-HCV coinfection (including HCC in one case), and two had HBV-related cirrhosis (including HCC in one case and HDV coinfection in another). Of the 30 patients who died due to HCV-related cirrhosis (without HBV coinfection), 25 (83%) consumed alcohol. In these patients, daily alcohol consumption was high (> 60 g) in 11 (44%), moderate (30-60 g) in eight (32%), and low (< 30 g) in six (24%). Ten of the 38 patients (26.3%) who died as a result of ESLD had previously received treatment with IFN-α alone (n = 6) or in combination with ribavirin (n = 3). HIV category according to the 1993 revised CDC classification system was determined in 34 patients: seven (21%) were asymptomatic (stage A), nine (26%) were symptomatic (stage B), and 18 (53%) had AIDS (stage C). At the time of death, the mean CD4 lymphocyte count was 200 x 106/l (range, 3-700 x 106/l), and 28 patients (74%) were receiving HAART.

Comparison with the 1995 and 1997 surveys

The distribution of risk factors for HIV transmission differed between 2001 and the previous cohorts (Table 1). Whereas heterosexual transmission was more common in 2001 (1995, 25% versus 2001, 38%; P < 0.01), transmission due to homosexual activity (1995, 39% versus 2001, 31%; P < 0.01) and injecting drug use decreased (1995, 25% versus 2001, 21%; P < 0.01). Although overall mortality decreased from 1995 to 2001 (8.15% versus 1.05%; P < 0.01), the proportion of deaths attributable to cirrhosis and/or HCC increased (1995, 1.5%; 1997, 6.6%; 2001, 14.3%; P < 0.01) (Table 2). During the same interval, the percentage of patients who died because of AIDS decreased from 91.6% in 1995 to 48.7% in 2001 (P < 0.01). Among the patients who died from ESLD, the percentage of patients with HCV infection (without HBV or HDV coinfection) was higher in 2001 (78.9%) than in 1995 (57.1%) and 1997 (55.5%) (P < 0.05; Table 4). HCC as a cause of death also increased over this time interval (1995, 4.7%; 1997, 11.1%; 2001, 25%; P < 0.05). The percentages of injecting drug use and alcohol consumption were also higher in 2001 (76% and 66%, respectively) when compared with that observed in the 1995 (29% and 38%, respectively; P < 0.05) and 1997 surveys (39% and 33%, respectively; P < 0.05). Finally, prescription of HAART was more frequent in 2001 (74%) than in 1997 (42%, P < 0.01), and there was a non-significant increase in median CD4 cell counts at death between these time points.

Source

 

Gilead HCV SVR Registries

Provided by NATAP

Gilead Sustained Virologic Response (SVR) Registry

Purpose

This Registry is designed to provide long term clinical and virologic follow up in subjects who have achieved sustained virologic response (SVR) while participating in a previous Gilead sponsored Hepatitis C Virus (HCV) study.

A Gilead Sequence Registry of Subjects Who Did Not Achieve Sustained Virologic Response

Purpose

This Registry is designed to obtain long term data on subject who have failed to achieve sustained virologic response (SVR) while receiving at least one Gilead oral antiviral agent (OAV) in a previous Gilead-sponsored hepatitis C study.

Download the PDF Here

Download the PDF Here

The Lancet Infectious Diseases, Early Online Publication, 29 May 2012

Brian L Pearlman MD
Center for Hepatitis C, Atlanta
Medical Center, Atlanta, GA,
USA; Medical College of
Georgia, Augusta, GA, USA; and
Emory School of Medicine,
Atlanta, GA, USA
Summary

For the past decade, the standard treatment for chronic hepatitis C infection has been pegylated-interferon plus ribavirin. With US Food and Drug Administration approval of boceprevir and telaprevir-two protease inhibitors-the standard-of-care treatment for genotype-1 infection, the main genotype worldwide, is now peginterferon plus ribavirin and a protease inhibitor. Rates of sustained virological response or cure with triple combination treatment have improved substantially, both in patients who have had previous treatment and in those who have not. Improvements have been most substantial in populations regarded as difficult to treat, such as individuals with cirrhosis. However, despite improved response rates, protease inhibitors have incremental toxic effects, high costs, increased pill burden, and many drug interactions. Moreover, because new antiviral drugs directly inhibit hepatitis C virus, viral resistance has become an important issue, essentially precluding use of protease inhibitor monotherapy, and potentially restricting future treatment options for patients who consequently do not achieve sustained virological response. Protease inhibitors are the first of many antiviral medications that will probably be combined in future interferon-free regimens.

Introduction

Hepatitis C virus is a leading cause of liver failure and hepatocellular carcinoma1 and infects about 3% of the population worldwide.2 Treatment with pegylated interferon and ribavirin cures only about 45% of patients with hepatitis C genotype-1, the main strain in Europe and the USA.3

The virus is a single-stranded linear RNA virus with a genome encoding a polyprotein of about 3000 aminoacids. Cellular and viral proteases cleave this large polyprotein into several structural and non-structural polypeptides that assist in viral replication within hepatocytes. A crucial cleavage step involves the serine protease NS3-NS4A, a protein composed of the N-terminus of the NS3 protein and a small NS4A protein cofactor.4 Polyprotein cleavage is not the only function of NS3-NS4A. The protease subverts its host's innate immune response by preventing the phosphorylation, and thus activation, of interferon regulatory factor 3, a key antiviral signalling molecule. This factor induces expression of interferon ß, which leads to the expression of many interferon-stimulated genes, thus producing an antiviral state in infected and surrounding cells.5 NS3-4A also reduces the intrahepatic production of interferon γ, which might impair the hepatic inflammatory response and contribute to viral persistence.6 Hence, inhibition of NS3-4A might block viral replication and potentially restore suppressed interferon pathways. Small peptides derived from the cleavage products of NS3A can competitively inhibit this enzyme.7 Peptidomimetic molecules with specific activity against NS3-NS4A have subsequently been formulated.

In 2011, the US Food and Drug Administration (FDA) and European Medicines Agency approved the first two linear protease inhibitors, boceprevir and telaprevir. Although these approvals mark an important advance in treatment of hepatitis C, the drugs have many limitations and additional toxic effects beyond those of pegylated interferon and ribavirin, with which they must be combined.

Clinical trials

Boceprevir


The SPRINT-2 study8 was a randomised, double-blind, phase 3 trial that compared safety and efficacy of combination treatment with pegylated interferon alfa plus ribavirin (the previous standard of care) with or without boceprevir (800 mg three times a day with food) in groups of previously untreated black and non-black patients with genotype-1 hepatitis C (figure 1 and table 1). Patients were randomly assigned to one of three groups: group one (control group), group two (response-guided treatment), or group three (fixed-duration treatment). The primary endpoint was sustained virological response defined by undetectable hepatitis C RNA at week 24 after treatment (lower limit of detection 9 IU/mL). For both races, patients in the boceprevir group had significantly higher rates of sustained virological response than did those in the pegylated interferon plus ribavirin control group (table 1). For black patients, rates of sustained virological response were 23% in group one, 42% (p=0·04) in group two, and 53% (p=0·004) in group three versus 40%, 67% (p<0·001), and 68% (p<0·001), respectively, for non-black patients.

Findings from this trial resulted in response-guided treatment recommendations in the product label for boceprevir. Patients in the fixed-duration group (48 weeks of treatment) and the response-guided group (28 weeks of treatment) who were so-called early responders, defined by undetectable virus between week 8 and week 24, had similar rates of sustained virological response (96% vs 97%). However, late responders (detectable serum hepatitis C RNA at week 8, but undetectable at week 24) had lower rates of sustained virological response with response-guided treatment than did those who received the full treatment course (66% vs 75%; p=0·16).12 The final 20 weeks of response-guided treatment contained pegylated interferon plus ribavirin and placebo, compared with the fixed-duration treatment, which was triple therapy (pegylated interferon plus ribavirin with boceprevir) in the same period.

The RESPOND-2 trial10 was a randomised, double-blind, phase 3 trial that enrolled 403 patients with genotype-1 infection, in whom pegylated interferon plus ribavirin had previously been ineffective. 64-65% of enrolled patients had relapsed after previous hepatitis C treatment and 36% had had a partial response; no previous null-responders were enrolled (figure 1 and appendix). Overall efficacy rates were significantly higher (p<0·001) in the two boceprevir groups than in the control group (table 1). As expected, rates of sustained virological response were better in patients with previous relapse than in those with prior partial response (figure 2).

Telaprevir

The ADVANCE trial10 was a randomised, double-blind, placebo-controlled phase 3 study assessing the efficacy of telaprevir combined with peginterferon alfa-2a plus ribavirin. 1088 previously untreated patients with chronic hepatitis C genotype-1 were randomly assigned (1:1:1) to one of three groups: placebo with peginterferon alfa-2a plus ribavirin for 12 weeks followed by peginterferon alfa-2a plus ribavirin for 36 weeks (control group), and two telaprevir groups with telaprevir 750 mg three times a day for 8 or 12 weeks, and peginterferon alfa-2a plus ribavirin for 24 or 48 weeks (figure 3 and table 1). The assay for measurement of viral load had a lower limit of detection of 25 IU/mL. The primary endpoint was sustained virological response. 58% of patients in the telaprevir groups were eligible for shortened (24 weeks) treatment duration, because they achieved extended rapid virological response, defined by undetectable hepatitis C RNA at treatment week 4 and week 12. These patients had higher rates of sustained virological response than did those who were not eligible for 24 weeks of treatment (83-97% vs 39-54%); thus, the likelihood of sustained virological response was determined by the rate of the viral RNA decline.

The ILLUMINATE trial13-a randomised, open-label, phase 3 non-inferiority trial of previously untreated patients-strongly supported shortening of treatment duration for patients who achieved extended rapid virological response. Patients with an extended rapid virological response after 12 weeks of triple therapy with telaprevir and peginterferon plus ribavirin were randomly assigned (1:1) after week 20 to receive dual treatment with peginterferon plus ribavirin for another 4 weeks or 28 weeks (figure 3). The overall rate of sustained virological response was 72%. 92% of patients in the 24 week group and 88% in the 48 week group had sustained virological response (absolute difference 4%; 95% CI -2 to 11), which confirmed non-inferiority. As in ADVANCE,10 the likelihood of sustained virological response was determined by rate of viral decline: patients who did not achieve extended rapid virological response, but continued treatment to week 48, had a rate of response of only 64%.

The randomised, phase 3 REALIZE trial11 assessed the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with genotype-1 hepatitis C in whom previous treatment with peginterferon alfa-2a plus ribavirin had been ineffective. Unlike the RESPOND-2 trial,9 REALIZE included patients who were null-responders to previous treatment (figure 3). Overall, rates of sustained virological response were significantly higher in the two telaprevir groups than in the control group (p<0·0001). Rates of response were highest in patients with previous relapse, followed by those with a partial response, and the lowest rates of response were in those with previous null-response (figure 2).

The effect of fibrosis in REALIZE was crucial. Patients with cirrhosis who were previous null-responders had only a 14% chance of achieving sustained virological response; whereas, null-responders with mild fibrosis scores (F0-F2) had response rates of 41%, and even previously null-responders bridging fibrosis (F3) had rates of 42%. Moreover, cirrhosis was not always associated with poor response. Patients with cirrhosis who had previously relapsed achieved sustained virological response 86% of the time.14 Both previous response and fibrosis severity are important considerations when deciding whether to retreat previously treated patients with triple therapy.

Limitations of clinical trials

Telaprevir and boceprevir are indicated only in patients with compensated cirrhosis in the Child Pugh class A. Although findings from the ADVANCE trial10 showed that rates of sustained virological response were much higher when patients with cirrhosis were treated with a protease inhibitor than with peginterferon plus ribavirin, especially in previously untreated patients (telaprevir 62% vs control 33%), few of these patients were studied and the rates were still lower than in those with milder disease (62% for patients with cirrhosis vs 81% for those with minimal or no fibrosis).

A general limitation of the phase 3 discussed trials was that few black (African American) patients enrolled (table 1). Black patients have lower rates of sustained virological response than do non-black patients, especially with peginterferon plus ribavirin treatment, and should have represented a greater percentage of patients than they did. In the REALIZE trial,11 only 3-4% of patients enrolled were African American. Even in SPRINT-2,8 despite a separate analysis, the black cohort was only 14% of patients studied.

A limitation of RESPOND-2 was the exclusion of patients with classic null-response to previous treatment (defined as less than a 2 log10 decline in virus after 12 weeks of treatment), because they have the lowest rates of sustained virological response among non-responsive patients when retreated with triple therapy. Despite this exclusion, the FDA has still approved boceprevir for use in patients with previous null-response to pegylated interferon plus ribavirin on the basis of interim results from the PROVIDE study.15 In this study, patients with previous null-response in the control groups of phase 3 trials RESPOND-2 and SPRINT-2, and in one additional phase 2 study16 received a 4 week pegylated interferon plus ribavirin lead-in followed by 44 weeks of triple therapy with boceprevir. The end-of-treatment response of 39% was roughly comparable to that of 44% among patients with less than 1 log10 decrement in hepatitis C RNA at week 4 in the groups receiving boceprevir in the phase 3 trials. Furthermore, a decline in viral load of less than 1 log10 at 4 weeks of pegylated interferon plus ribavirin correlates with the definition of classic null-response.17

The complexity and disparate designs of phase 3 clinical trials hampers comparison of protease inhibitors without a head-to-head study. The American Association for the Study of Liver Disease guidelines provide further information about the trials.18

FDA-approved dosing

The recommended regimen for boceprevir in previously untreated patients is triple therapy with a 4 week lead-in with pegylated interferon plus ribavirin, followed by the addition of boceprevir (figure 4 and table 2).19 Patients who are difficult to treat, including any with cirrhosis or previous null-responders, should receive the maximum duration of protease inhibitor-ie, 4 week lead-in followed by 44 weeks of triple therapy. Furthermore, 48 weeks of treatment (44 weeks of triple therapy) should be considered for previously untreated patients who respond poorly to interferon in the lead-in period (<1 log10 decline in hepatitis C RNA from baseline). None of these groups qualify for response-guided treatment, and treatment time should not be shortened, irrespective of virological response. For patients with cirrhosis, fewer in the response-guided treatment group (41%) had sustained virological response than in the fixed dosing group (52%). Response rates were particularly disparate in patients who had received previous treatment (response-guided treatment 14 [44%] of 32 patients vs full-treatment course 21 [68%] of 31 patients); however, these numbers were small and did not differ significantly.

According to the boceprevir package label,19 all treatment should be stopped if the serum hepatitis C RNA is either 100 IU/mL or more at 12 weeks, or detectable (at any level) at week 24. Not only was the likelihood of sustained virological response extremely low for patients with insufficient viral suppression in the phase 3 trials, but also, patients with serum virus concentrations greater than these thresholds had an increased chance of having drug-resistant variants.

No lead-in phase is needed for regimens containing telaprevir, and all patients begin triple therapy from day 1 of treatment with peginterferon plus ribavirin and telaprevir for 12 weeks. The US FDA-approved regimen for telaprevir allows for response-guided treatment if a patient is either previously untreated or had had a past relapse to pegylated interferon plus ribavirin (previous partial responders are not candidates for shortened treatment duration with telaprevir; figure 4, table 2).20

According to the telaprevir package label, when either previously untreated or therapy-experienced patients are treated, pegylated interferon, ribavirin, and telaprevir should all be discontinued if the serum concentration of hepatitis C RNA is 1000 IU/mL or more at treatment week 4 or week 12, or detectable (at any level) at week 24.20 These futility rules are based on findings from the phase 3 trials in which patients with serum concentrations of hepatitis C RNA greater than these thresholds had extremely low chances of achieving sustained virological response. The FDA recommends 1000 IU/mL, rather than 100 IU/mL, as the stopping threshold for telaprevir, because in the ADVANCE, ILLUMINATE, and REALIZE trials, five of 19 untreated, and one of seven previously treated patients achieved sustained virological responses after having concentrations of 100-1000 IU/mL of serum hepatitis C RNA at week 4 of treatment.21

Response-guided treatment for patients who had previously relapsed was not prospectively assessed in the REALIZE trial. The FDA based this recommendation on supportive data from two phase-2 trials of telaprevir, in which 52 patients who had previously relapsed after pegylated interferon plus ribavirin, achieved a sustained virological response rate of 94% when treated with 12 weeks of triple therapy containing telaprevir, followed by 12 weeks of peginterferon plus ribavirin alone.22, 23

Approved dosing for both boceprevir and telaprevir (table 2) is three times a day (7-9 h apart). Boceprevir is taken as 800 mg (four capsules) and telaprevir as 750 mg (two capsules). Although a phase 2 study24 showed non-inferiority for a regimen of telaprevir 1125 mg twice a day, the study was small and enrolled patients who were easy to treat. The larger ongoing phase 3 OPTIMIZE trial25 is likely to confirm the non-inferiority question. Both telaprevir and boceprevir should be taken with food, but telaprevir needs a meal or a snack containing at least 20 g of fat (systemic exposure to telaprevir is increased by 237% when taken with a standard fat meal compared with exposure when fasting).20 Frequent assessment with complete blood counts are needed with telaprevir and boceprevir, as is pregnancy testing every month for women of childbearing age, which is the same as assessment for pegylated interferon plus ribavirin. Because both drugs must be combined with ribavirin, a known teratogen, patients and their sexual partners must continue to use two effective contraceptive methods during treatment, and up to 6 months after treatment cessation.

Importance of the lead-in phase

The lead-in phase of pegylated interferon plus ribavirin with no protease inhibitor was intended to minimise resistance and treatment failure by reducing viral replication before addition of the third molecule. In the phase 2 SPRINT-1 trial16 with separate groups for boceprevir, with or without a lead-in phase, the rate of viral breakthrough was slightly lower with lead-in than without it (4% vs 9%; p=0·057). Because no control group without a lead-in phase was used in SPRINT-2, findings could not confirm the significance of this phase; however, the predictive value of the virological response was high during lead-in. In all treatment groups of non-black patients, those with a decline of 1 log10 of more in hepatitis C RNA had higher rates of sustained virological response than did those without it (82% vs 29-39%; p<0·0001). Thus, a patient's interferon responsiveness or sensitivity is crucial to successful treatment outcome, despite the addition of a protease inhibitor.

In the REALIZE trial,11 rate of sustained virological response did not differ between the group with the lead-in phase (66%) compared with that without (64%). However, a lead-in period might still be useful with telaprevir for previous non-responders. Preliminary data14 from an analysis of the REALIZE trial showed that patients with no previous response and decline in hepatitis C RNA of less than 1 log10 from baseline (59%) had only a 15% chance of achieving sustained virological response with triple therapy compared with those with at least a decline of 1 log10 from baseline who achieve a response 54% of the time. Thus, a lead-in period might help clinicians make a better decision about treatment cessation than when no lead-in is used, particularly in patients who respond poorly to interferon treatment, previous null-responders, and those with mild fibrosis scores. In previous non-responders with mild liver disease who achieve less than a log10 decline in virus at week 4, treatment can potentially be stopped while awaiting more effective treatment.

By contrast, a rapid virological response-an undetectable concentration of hepatitis C RNA after the lead-in phase of pegylated interferon plus ribavirin-has excellent positive predictive value for success. Patients with genotype-1 infection who achieve this outcome have an 88% chance of sustained virological response.26 Patients with genotype-1 infection, no cirrhosis, a low baseline viral load (<600 000 IU/mL), and a rapid virological response can be treated with pegylated-interferon plus ribavirin with a shortened treatment duration of 24 weeks, according to European Guidelines.27 For these patients, addition of a protease inhibitor might not be beneficial because of increased cost and side-effects, despite similar effectiveness. In an ongoing trial, we have randomised patients with genotype-1 infection and low viral loads who achieve rapid virological response, to either 24 weeks of pegylated interferon plus ribavirin, or to a further 24 weeks of triple therapy with the addition of boceprevir. Interim results are expected by November, 2012.

Safety and adverse effects

Because boceprevir and teleprevir must be combined with pegylated-interferon plus ribavirin, which are usually accompanied by adverse effects, toxic effects associated with these protease inhibitors will be in addition to those of the previous standard of care. If patients have absolute contraindications for either pegylated-interferon or ribavirin, they are not candidates for protease inhibitors. Dose of protease inhibitors should crucially not be lowered, because this reduction could engender treatment failure via resistance.

In pooled phase 3 trials19 of boceprevir treatment (n=1548), the most common adverse events with a frequency of 5% and greater than those with placebo (listed in order of occurrence) were anaemia, nausea, dysgeusia (altered sense of taste), chills, neutropenia, and vomiting. In SPRINT-2,8 serious adverse events occurred in 11-12% of patients in the boceprevir groups versus 9% of those in the control groups, compared with 10-14% versus 5%, respectively, in RESPOND-2.9

In SPRINT-2,8 boceprevir was associated with a significantly higher incidence of anaemia than was the control regimen (49% vs 29%; p<0·001); similar findings were shown in RESPOND-2 (43-46% vs 20%; p<0·001). In patients receiving boceprevir, haemoglobin concentrations were less than 8·5 g/dL in 6% of those who had had no previous treatment and 10% in those who had, versus 1-3% of those in the control groups.9 In both trials, 41-46% of patients receiving boceprevir who became anaemic were given erythropoietin (an off-label drug used for mono-infected patients with hepatitis C) compared with 24% of those in control groups. In the telaprevir trials,8, 9 growth factors were prohibited.

Additional adverse events more common in the boceprevir groups of both phase 3 trials compared with the control groups were neutropenia (absolute neutrophil count 500-750/μL, previously untreated patients 24-25% vs 14% control, p<0·001 and previously treated patients 19-20% vs 9% control; response-guided treatment group vs control group p=0·06, fixed-duration group vs control group p=0·03) and dysgeusia (previously untreated patients 37-43% vs control 18%, p<0·001; previously treated patients 43-45% vs control 11%, p<0·001). Dysgeusia was not a major dose-limiting adverse event in either trial.8, 9

In pooled phase 3 trials20 of telaprevir (n=1787), the most common adverse effects with a frequency of 5% and greater than that of placebo (listed in order of occurrence) were rash, fatigue, pruritus, nausea, anaemia, diarrhoea, vomiting, haemorrhoids, anorectal discomfort or pruritus, and dysgeusia. In the ADVANCE trial,10 treatment discontinuation because of adverse events occurred in 10% of patients in the telaprevir groups versus 7% of those in the control group. In the ILLUMINATE trial,13 18% of patients discontinued all study drugs because of serious adverse events, although response-guided treatment resulted in fewer adverse events and treatment discontinuations in those for whom duration of treatment was shortened. In the REALIZE trial,11 5% of patients in the telaprevir groups stopped treatment because of adverse events versus 3% in the control group. 29% of patients given telaprevir had anorectal discomfort compared with 7% of those in the control groups; however, less than 1% of patients stopped treatment because of anorectal complaints. Anorectal symptoms associated with telaprevir include burning, itching, and haemorrhoids, and rarely lead to treatment cessation. For intolerable symptoms, perianal topical lidocaine or zinc oxide might give partial relief. Although most rashes were mild to moderate in the phase 3 trials of telaprevir, severe rashes occurred in only 6% of patients; telaprevir was stopped in many cases and pegylated-interferon plus ribavirin were continued. Three patients (<1%) developed Stevens-Johnson syndrome and 11 (<1%) developed drug rash with eosinophilia and systemic symptoms.20 Although the mechanism for rash due to telaprevir is unknown, the histology of most rashes is a spongiotic pattern with lymphocytic perivascular infiltration.28

Rash associated with telaprevir typically occurs in the first 8 weeks of treatment, but severe rash can occur anytime during the drug's 12 week dosing period. Strict management rules have been established because of findings from clinical trials. For patients with mild to moderate rash (up to 50% of body surface area), patients should be managed with topical steroids and antihistamines. For those with systemic signs or symptoms associated with a rash, so-called red-flag features, such as mucosal involvement or a rash progressing to 50% or more of body surface area, telaprevir should be stopped and dermatological referral sought. Pegylated-interferon plus ribavirin can be continued if the rash abates within 7-10 days. Rash typically resolves within 7-10 days after telaprevir cessation. Once the drug is withdrawn, it cannot be restarted, and patients need to be reassessed regularly. Although pruritus due to telaprevir is generally present with a rash, it can present in the absence of any other dermatological symptoms. Treatment is similar to that for a rash and rarely warrants treatment discontinuation.

Although anaemia was common in the boceprevir trials, it was also important in the telaprevir trials. With telaprevir, the main mechanism of anaemia in the first 8 weeks of treatment is haemolysis; thereafter, myelosuppression can have an additional role.28 In a pooled analysis of phase 3 data,20 14% of patients in the telaprevir groups, versus 5% of those in the control groups, had haemoglobin nadirs of less than 8·5 g/dL. In the ADVANCE study,10 rates of anaemia were about two times higher in patients in the telaprevir group than in those in the control groups (37-39% vs 19%), and more than two times higher in the SPRINT-2 trial8 of boceprevir compared with those in the control group (49% vs 20%). In the ADVANCE trial, 12% of patients with anaemia who were given telaprevir needed blood transfusions compared with 3% of those with anaemia who were previously untreated and given boceprevir;29 however, growth factors used in previously untreated patients could have been transfusion sparing.

Anaemia is a common side-effect with either boceprevir or telaprevir. In accord with ribavirin package labelling, for haemoglobin concentrations of less than 10 gm/dL, ribavirin dose should be reduced, and, for those of less than 8·5 gm/dL, it should be stopped and the protease inhibitor discontinued. How providers should treat anaemia is unclear when using these new molecules either to use growth factors (off-label prescribing) or to reduce ribavirin dose. Past experience with pegylated-interferon plus ribavirin showed that changes in ribavirin dose early in treatment had the most substantial effect on relapse rate.30 A retrospective pooled analysis31 from the ADVANCE and ILLUMINATE trials showed that reductions in ribavirin dose had no apparent effect on sustained virological response in the groups given telaprevir, but seemed to have a deleterious effect on response in those without it. Preliminary evidence from a prospective trial32 showed that with boceprevir-associated anaemia, reduction of the ribavirin dosage or addition of a growth factor were reasonable approaches; both methods produced similar rates of sustained virological response.

Drug interactions

Boceprevir and telaprevir are strong inhibitors of cytochrome P450 3A4 (CYP3A4) and potential inhibitors of p-glycoprotein.19, 20 Thus, drugs metabolised mainly by CYP3A4 might have increased exposure when given with either protease inhibitor, thereby prolonging or increasing therapeutic events and toxic effects (appendix).

The most important and commonly prescribed classes of drug that interact with the first-generation protease inhibitors are hormonal contraceptives, statins, dihydropiridine calcium channel blockers, and phosphodiesterase-5 inhibitors. Because serum concentrations can change, systemic hormonal contraceptives can no longer be relied upon to provide contraception during interferon-based treatment that includes boceprevir or telaprevir; thus, only barrier methods and intrauterine devices are recommended.

Importance of ribavirin

Because haemolytic anaemia is a major side-effect of ribavirin, initial hopes were that this drug could be eliminated from any treatment regimen containing a protease inhibitor. Unfortunately, rates of sustained virological response are lower in groups treated with pegylated-interferon and a protease inhibitor, than in people given pegylated interferon and ribavirin. For example, in the PROVE3 phase 2 trial22 of telaprevir for previously treated patients, the triple-therapy group had a rate of sustained virological response of 53% compared with 24% in those given pegylated-interferon alfa and telaprevir, half that of those given pegylated-interferon plus ribavirin.3 In another phase 2 trial33 of telaprevir, 60% of patients achieved sustained virological response in a triple-therapy group; however, those in a double-therapy group without ribavirin had a rate of only 36%.

Genotypes and subgenotypes

Although telaprevir was active in patients with genotype-2 infection in a phase 2 study,34 and has shown activity against genotype-6 in vitro,35 both telaprevir and boceprevir have poor antiviral activity against genotype-3 virus.36 With no findings from large clinical trials to support the use of telaprevir or boceprevir in patients with infections other than genotype-1, both molecules should be prescribed only for genotype-1 infection.

Subtypes of genotype-1 have different susceptibility to protease inhibitors. In the REALIZE trial,11 37% of previous null-responders with genotype-1b infection achieved sustained virological response compared with 27% of those with genotype-1a; among those with previous partial responses 68% with genotype 1b and 47% with genotype 1a achieved sustained virological response. The most probable reason for disparity in rates of response between subtypes is the genetic barrier to the development of protease inhibitor resistance. Genotype-1b virus has a higher barrier to resistance than does genotype-1a, because it needs two nucleotide substitutions at position 155 in its protease to confer resistance to telaprevir or boceprevir; whereas, genotype-1a needs one substitution in the same position to become resistant.37, 38

Special groups

Providers might be tempted to begin regimens containing a protease inhibitor in patients with hepatitis C who could benefit from improved cure rates, such as liver transplant recipients, patients with decompensated cirrhosis, young (aged <18 years) or old (>65 years) patients, or those who are renally impaired; no available safety or efficacy data support this decision, thus, providers should avoid this practice. Nonetheless, promising interim results are available from a study39 of patients with genotype-1 infection who also had HIV treated with triple therapy, including telaprevir. 12 weeks after treatment was completed, 74% of previously untreated patients with co-infection had undetectable hepatitis C RNA when treated with a telaprevir-based regimen, compared with 45% of patients treated with pegylated-interferon plus ribavirin and placebo. Tolerability was comparable to that of telaprevir treatment in patients with hepatitis C mono-infection.

Interleukin-28B polymorphism

rs12979860, a single-nucleotide polymorphism near the interleukin-28B gene, which encodes interferon-λ3, has been associated with responsiveness to treatment with pegylated-interferon plus ribavirin.40-42 The interleukin-28B genotype test is commercially available (Laboratory Corporation of America, Burlington, NC, USA). The CC genotype predicts interferon responsiveness, whereas the non-CC genotypes TT and TC predict poor interferon response.40, 43 The interleukin-28B polymorphism could explain at least half the disparity between treatment responses in white and black patients given pegylated interferon plus ribavirin.40 In both the previously untreated and the treated groups of the ADVANCE and REALIZE trials of telaprevir, rates of sustained virological response were increased for all interleukin-28B genotypes in patients receiving telaprevir.44, 45 Unlike in the telaprevir trials, in the SPRINT-2 trial, patients with the CC genotype had similarly high rates of sustained virological response in all groups, including the control group (80-82% vs 78%); however, in the patients with non-CC genotypes, rates were significantly higher (data not shown) in the groups given boceprevir than in the control group (55-71% vs 27-28%).46 Overall, the predictive value of the interleukin-28B genotype for sustained virological response has been attenuated by the introduction of the protease inhibitors, and measurement of interferon responsiveness is improved with the 4 week lead-in period, as is standard with boceprevier regimens. The best use of the interleukin-28B test might be to predict treatment duration, because about 90% of patients with the CC genotype will qualify for a shortened duration of treatment.46

Resistance

Because the RNA-dependent RNA polymerase of hepatitis C is prone to error, and the rate of virion production is high (up to 1013 particles per day),47 the emergence of resistant variants is frequent. Investigators have estimated that every possible viral variant is produced daily in an infected patient.48, 49 Naturally occurring dominant mutations resistant to the hepatitis C protease inhibitors are present even in previously untreated patients with genotype-1 infection.50, 51 Patients infected with genotype 1a have a higher prevalence (8·6%) of resistance mutations than do those with genotype 1b (1·4%).50 Despite harbouring baseline resistance mutations, many patients still achieve sustained virological response, because baseline resistance does not correlate with treatment response.19, 20 Phenotypic resistance profiles have no known correlates, and baseline resistance testing has no clinical indication as per current guidelines.25

Because of the shallow substrate binding pocket of NS3, even minute structural changes can promote resistance.52 Monotherapy with protease inhibitors selects for resistance mutations rapidly.53-55 Several resistant mutations in the NS3 protein have been identified, including Val36Met, Thr54Ala, Arg155Lys, Ala156Ser, Ala156Thr, and Val170Ala (boceprevier only). With ongoing monotherapy with telaprevir, single mutations increase and are eventually replaced by double resistant mutations; compared with single-mutation variants, double mutations confer very high-level resistance to telaprevir (eg, Val36 and Arg155 >50 times compared with Val36 alone less than eight times relative to wild-type).56 Although the Ala156Ser mutation confers the highest resistance to boceprevir and telaprevir, it renders the virus substantially less fit than wild-type virus.57

In phase 1 studies,49, 53, 56 monotherapy with boceprevir and telaprevir engendered emergence of resistance mutations, which were reduced when these molecules were combined with pegylated-interferon. Patients treated with telaprevir in the PROVE2 trial33 with pegylated-interferon and no ribavirin developed more resistant mutations than did those given triple therapy. In the SPRINT-2 trial,8 previously untreated patients who were interferon sensitive (decline of <1 log10 in hepatitis C RNA at end of lead-in) had more resistant mutations and lower rates of sustained virological response than did those who were interferon sensitive. Moreover, population sequencing has shown that occurrence of high-level resistance is increased when virological failure occurs during the first 12 weeks of triple therapy with telaprevir compared with the development of low-level resistant variants during the subsequent pegylated-interferon plus ribavirin phase of treatment.18

Because similar variants are detected in patients treated with either boceprevir or telaprevir, cross-resistance between these drugs is expected; thus, virological failure with triple therapy containing a protease inhibitor is a contraindication for a change from one drug to another. With virological failure and ongoing exposure to protease inhibitors, resistance mutations are more likely to develop than when these inhibitors are not used; consequently, strict stopping rules have been developed to circumvent further resistance.

Most patients in whom triple therapy containing pegylated-interferon plus ribavirin plus a protease inhibitor is ineffective have a dominant resistant virus population, which, at the time of relapse, is resistant to the protease inhibitor proper.34 In fact, 80-90% of patients with virological failure or relapse after termination of treatment containing protease inhibitor harbour resistant variants, compared with 5-7% in those at baseline.20, 58 These variants are replaced by wild-type virus within weeks to months.59 Nonetheless, variants resistant to the protease inhibitors remain as minor viral populations replicating at low concentrations. If in the future, patients are rechallenged with protease inhibitors with similar resistance profiles, whether resistant virus will re-emerge is uncertain. Moreover, how these resistant variants might affect future treatment options is unclear.

Selection of patients

Identified patients with hepatitis C should be referred to providers experienced in the use of these new molecules. Unfortunately, many of those infected are not identified or referred for treatment.60 Primary-care providers must understand that hepatitis C is not only treatable, but is also curable, and cure results in reduced rates of hepatic decompensation events and decrements in liver-related deaths.60-62 Thus, the improved rates of sustained virological response with these drugs could potentially reduce the substantial disease burden of hepatitis C.63 Patients with previous null-response to pegylated-interferon plus ribavirin, particularly those with mild liver disease who are interferon insensitive, can benefit from deferral of this first phase of direct-acting antiviral treatment. Previously untreated patients who are interferon insensitive with mild fibrosis scores might also be a group for whom treatment should be deferred. These patients have rates of sustained virological response between 28% and 38% with triple therapy containing boceprevir.8 New treatment options will be needed with improved effectiveness.

Findings from a preliminary modelling analysis comparing two strategies have provided guidance about how to treat previous null-responders. The first strategy was to treat patients immediately with triple therapies and the second was to withhold treatment until more effective antiviral becomes available. For patients with mild fibrosis and cirrhosis, awaiting better treatment was more reasonable; those with intermediate fibrosis scores would benefit from immediate triple therapy.64 Patients intolerant of or with substantial contraindications to interferon can benefit from regimens with no interferon, whether approved or in clinical trials, irrespective of fibrosis stage on their baseline liver biopsy.

Cost-effectiveness

The retail cost of boceprevir is US$1100 per week of treatment, and for telaprevir is $4100 per week of treatment (needs only 12 weeks of treatment);65 however, these costs do not include that of pegylated-interferon plus ribavirin with which the protease inhibitors must be combined. Access to these drugs can be difficult, especially in resource-poor settings. Protease inhibitors are cost effective, and improved cure rates will engender substantial improvements in lifetime clinical outcomes.66-69

Future directions

Use of triple combination treatment containing either boceprevir or telaprevir will engender a new population of non-responders in whom this new standard of care did not work. This first regimen will be ineffective in 24-31% of previously untreated patients given triple therapy, as will retreatment with protease inhibitors and pegylated-interferon plus ribavirin in two-thirds of those who had no previous response. Additional treatments are warranted.

In the clinical development pathway for direct-acting antiviral treatment, the next phase of treatment will probably combine pegylated-interferon plus ribavirin with a third molecule that is distinct from the available protease inhibitors. This molecule might have an improved side-effect profile or one with improved dosing schedules compared with those of boceprevir and telaprevir. For example, simeprevir (TMC-435) and BI201335 are both NS3-4A protease inhibitors in phase 3 trials70, 71 that offer once-a-day dosing and possibly improved side-effect profiles compared with presently approved protease inhibitors. Because of common resistance mutations, such as Arg155, patients in whom boceprevir and telaprevir are ineffective cannot be switched to these drugs; however, late-generation protease inhibitors, such as MK5172, which is still in phase 2 trials, might be active in the presence of mutations associated with early-generation failure of protease inhibitor-eg, Arg155, Gln80Lys).72

Other molecules that might be combined with pegylated-interferon and ribavirin as triple therapy include nucleoside polymerase inhibitors,73 and NS5a inhibitors.74 An important treatment goal is to prevent development of resistance by combining of direct-acting antiviral drugs that target distinct components of the hepatitis C life cycle without any cross-resistance; patients who are interferon intolerant or poorly responsive might benefit from treatments that do not include interferon, which can be regarded as the third phase of an overall clinical development programme for direct-acting antiviral drugs. The INFORM trial75 used 2 week regimens of the nucleoside polymerase inhibitor mericitabine, and a second generation protease inhibitor danopevir, resulting in a substantial decline in serum hepatitis C RNA; however, all patients eventually received pegylated-interferon plus ribavirin. With use of a protease plus a polymerase inhibitor (eg, telaprevir plus MS-0608) for 4 weeks, investigators successfully eradicated hepatitis C from human hepatocyte chimeric mice followed up for 20 weeks after treatment.76 SOUND-C277 -the largest interferon-free trial so far- was a phase 2b open-label study of 362 previously untreated patients with genotype-1 infection given a combination of a protease inhibitor, non-nucleoside polymerase inhibitor, and ribavirin. Preliminary rates of sustained virological response were 83% for genotype-1b infections, and 43% for genotype-1a infections. Other promising interferon-free regimens in human beings are underway.78, 79 To raise an effective barrier to emergence of resistance, and to achieve sustained virological response without interferon, more than two direct-acting antiviral drugs might be needed, especially in patients with genotype 1a.78, 80

Despite their limitations, the hepatitis C protease inhibitors mark important progress towards achievement of a cure with interferon-free regimens.

Source

 

Scientists Sequence Genome Of Liver Cancer Caused By Hepatitis B, C

Hepatitis-B

By Tang Yew Chung | Featured Research
June 1, 2012

Two teams of Asian researchers have independently completed whole-genome sequencing studies of a type of liver cancer commonly caused by hepatitis virus infection.

AsianScientist (Jun. 1, 2012) - Two teams of Asian researchers, one Japanese and the other from China and Singapore, have independently completed large-scale, whole-genome sequencing studies of a type of liver cancer commonly caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infection.

Both studies were published this week in Nature Genetics, providing important insights into how hepatitis viral infection causes hepatocellular carcinoma (HCC), the most common form of liver cancer worldwide, and may lead to improvements in diagnosis and treatment.

Individuals infected with HBV and HCV are known to have a significantly higher risk of developing HCC. In countries like China and other parts of Asia where hepatitis B is endemic, HBV infection is the predominant cause of HCC.

In Japan, which has the highest HCC rates of any industrialized country in the world, HCV infection is thought to be responsible for the majority of cases.

It is thought that the HBV and HCV genomes are integrated into the genome of the human host in a manner that promotes the accumulation of genetic abnormalities, leading to cancer development.

The China-Singapore team studied tumor samples and adjacent normal tissues from 81 HBV-positive and 7 HBV-negative HCC patients while the Japanese team collected tumor and blood samples from 11 HBV-positive HCCs, 14 HCV-positive HCCs, and 2 HCCs that were not associated with hepatitis infection.

Both teams used whole-genome sequencing technologies to identify novel gene mutations that may be responsible for HCC development and pinpoint locations where the viral genome has been integrated into the host genome.

In particular, the China-Singapore team identified characteristics of HBV integrations that may help the virus to control specific genes in the host tumor, providing new insights into the mechanisms through which HBV integration promotes cancer.

“A deep understanding of the recurring HBV insertions in HCC will help the research community identify novel molecular targets in liver cancer, for which effective treatments are still limited,” said John Luk, a leader of the China-Singapore collaboration.

The articles can be found at: Fujimoto et al. (2012) Whole-genome Sequencing Of Liver Cancers Identifies Etiological Influences On Mutation Patterns And Recurrent Mutations In Chromatin Regulators and Sung et al. (2012) Genome-wide Survey Of Recurrent HBV Integration In Hepatocellular Carcinoma.

Source

All-oral hep. C combos threaten interferon

ImageResizer

Marc Iskowitz June 01, 2012

Scientists are getting closer to finding the killer app in treating hepatitis C, but it may be too soon to pick a winner.

Bristol-Myers Squibb and Gilead say that an all-oral therapy joining daclatasvir from BMS and Gilead's GS-7977 suppressed the virus in more than 95% of patients across a broad spectrum of genotypes.

The two drugs reached a 100% sustained virologic response (SVR), or cure rate, at week four in a common subgroup, genotype 1 patients not previously treated with interferon.

The 100% rate held when ribavirin, another traditional treatment mainstay, was not in the mix, bettering the roughly 90% SVR rate seen in trials for an Abbott triple therapy.

The direct-acting antivirals (DAAs) from BMS, Gilead and Abbott showed the best efficacy and tolerability of those presented at the European Association of the Study of Liver Disease (EASL) in April.

The findings accelerated momentum in a fast-moving category. Not that there haven't been speed bumps. In February, Gilead's ‘7977 came under assault when data showed that six out of six subjects treated with the pipeline drug, all prior “null” responders to an interferon-containing regimen, experienced viral relapse within four weeks of completing an all-oral regimen of ‘7977 and ribavirin. Gilead's stock fell after the news.

Several analysts now believe daclatasvir, an NS5a inhibitor, and ‘7977, a nucleotide analog (or “Nuc”), may form the best treatment “backbone” option across all genotypes.

“The ‘killer app' in HCV is probably an NS5a plus a nuc without ribavirin,” ISI analyst Mark Schoenebaum declared.

The newer protease inhibitors—Vertex's Incivek and Merck's Victrelis—appear vulnerable to the all-oral regimens, but not for a few years.

“These results obviously reinforce the expectation that DAA-only (IFN and RBV-sparing) regimens will likely quickly supplant current HCV treatments when they become available in the 2015/2016 timeframe,” wrote Deutsche Bank's Barbara Ryan in a note.

In a dispatch to investors, Credit Suisse's Catherine Arnold said the data “takes a little shine off” Abbott's HCV program, “but we still view it as a competitive presence.” The triple therapy combines the firm's protease inhibitor ABT-450 + NS5B inhibitor ABT-333 + ribavirin. Another three-drug regimen including NS5B inhibitor ABT-072 also showed a high HCV cure rate.

The Gilead/BMS combo “represents the most compelling all-oral, interferon-free data in the highly visible [HCV] marketplace,” noted Arnold.

Gilead has many HCV compounds to pair its nuc with, including an NS5a like daclatasvir. That makes a Gilead-BMS partnership far from a given.

Ryan also cautioned that other factors—side effects, dosing convenience and cost—“will be important considerations in determining market share.”

Results from a mix of Gilead's ‘7977 and ribavirin hit an SVR rate of 88%—above the 50% the Street had expected, according to Schoenebaum. Abbott's all-oral triple combo may be another good backbone option, while daclatasvir looks like a solid add-on option and BMS is exploring multiple pairing options.

Other nucs in development include Vertex's ALS-2200 and ALS-2158, and biotech firm Idenix's IDX184, which can be combined with its NS5a inhibitor, IDX719.

From the June 2012 Issue of MMM

Source

Bristol urges combo hepatitis C study with Gilead

By Ransdell Pierson

Thu May 31, 2012 5:24pm EDT

(Reuters) - Bristol-Myers Squibb Co renewed calls for biotechnology company Gilead Sciences Inc to test one of its hepatitis C drugs in late-stage trials alongside Bristol's own promising medicine, following impressive results from a mid-stage trial that combined the experimental products.

Bristol's daclatasvir is from a new class of drugs known as NS5A inhibitors. Gilead's GS-7977 is a million to 180 million people worldwide believed to be infected with the virus. Transmitted by blood transfusions, sexual contact or shared drug needles, the virus invades the liver and can steadily destroy the organ over decades. It is the most common reason for liver transplants in the United States.

Data from the mid-stage trial combining Gilead's GS-7977 and Bristol's daclatasvir showed a 100 percent response rate in previously untreated patients with the most common form of hepatitis C.

Shares of Gilead jumped 11 percent on April 19 when the data were released, showing the profound benefits of combining its 7977 -- acquired through Gilead's $11 billion purchase of Pharmasset -- with daclatasvir.

At the time, Bristol said Gilead had balked at further collaboration on the combination under study, which was begun while 7977 was owned by Pharmasset.

The results of the mid-stage study were accomplished without interferon, an injected drug that causes flu-like symptoms and other side effects that often lead patients to discontinue or delay treatment. Nor did the study use ribavirin, an older antiviral drug that is also currently part of all treatment regimens.

Instead of working with Bristol-Myers, Gilead is forging ahead with a study of 7977 in combination with its own experimental NS5A inhibitor. In the meantime, Bristol-Myers is testing daclatasvir with a drug similar to 7977 that it acquired with its $2.5 billion purchase of Inhibitex, as well as with other experimental drugs in its development pipeline.

In other remarks at the Sanford Bernstein meeting on Thursday, Andreotti said he expects some form of U.S. healthcare reform to emerge, even if the U.S. Supreme Court rules against extensive reforms approved by Congress and signed into law by President Obama.

The High Court is expected next month to render a decision on the sprawling legislation, which would greatly expand healthcare coverage to uninsured Americans but require bigger fees and rebates from drugmakers and medical device makers.

Andreotti said the enacted reforms "started out on the right foot" but became too complicated for Bristol-Myers and the American people.

The Bristol-Myers CEO said he expects rapidly declining sales of Plavix, a blood-clot preventer which has long been the company's biggest product, due to loss of U.S. patent protection earlier this month and ensuing competition from a number of cheaper generics. The pill, sold in partership with French drugmaker Sanofi, had revenue last year of more than $7 billion -- making it one of the world's top-selling medicines.

Despite expected plunging sales of Plavix, Andreotti said Bristol-Myers has no plans to "downsize" its research spending, having already closed down many company facilities in previous cost-cutting efforts.

Bristol-Myers will adjust future R&D spending in accordance with company performance, and expects significant sales gains to come from Asia but not from Europe, Andreotti said.

He said the company plans over the next few years to concentrate on developing medicines to treat cancer, viral infections and blood clots -- calling those therapeutic areas "the three pillars" of company growth.

(Reporting By Ransdell Pierson; Additional reporting by Bill Berkrot; Editing by Maureen Bavdek and Gunna Dickson)

Source

Quality of Life Undiminished by Telaprevir in Chronic Hepatitis C

By: DIANA MAHONEY, Family Practice News Digital Network

SAN DIEGO – Although the addition of telaprevir to peginterferon/ribavirin therapy for treatment of chronic hepatitis C exacerbates treatment-related side effects, the triple combination does not diminish patient quality of life relative to treatment with the peginterferon/ribavirin regimen alone, a study has shown.

In other words, adding the protease inhibitor "does not further diminish patient quality of life," lead investigator Dr. Zobair Younossi explained at the annual Digestive Disease Week. "The most important contributor to the quality of life measurement in interferon therapy is interferon itself, which is so overwhelming in terms of side effects, especially grade 4 and 5 effects, that it probably overshadows everything else," he said.

RTEmagicC_3s10dqzf_hepatitis_c_jpg

Photo courtesy US Dept. of Veterans Affairs

Adding the protease inhibitor telaprevir to the treatment for hepatitis C "does not further diminish patient quality of life," lead investigator Dr. Zobair Younossi explained at the annual Digestive Disease Week.

Studies have shown that the addition of telaprevir to standard peginterferon alfa-2a/ribavirin (PR) significantly improves treatment efficacy in treatment-naive patients with genotype 1 hepatitis C virus (HCV), but there is a perception that the additional side effect burden from adding telaprevir is prohibitive in some patients, said Dr. Younossi, chairman of the department of medicine at Inova Health System in Falls Church, Va.

Dr. Younossi and colleagues conducted post hoc analyses of data from the ADVANCE trial, in which adding telaprevir to the treatment mix significantly improved patients’ sustained virologic response compared with standard PR therapy.

In the ADVANCE study, 1,088 treatment naive HCV genotype 1 patients were assigned to one of three treatment arms: 48 weeks of standard PR therapy; 12 weeks of telaprevir plus 24 weeks PR; or 12 weeks of telaprevir plus 48 weeks of PR. Nearly 80% of patients in both telaprevir groups achieved sustained virologic response, compared with 46% of patients in the standard PR treatment group (N. Engl. J. Med. 2011;364:2405-16).

In terms of side effects, "across all phase III studies, the incidence of rash and anemia (which are the effects we’re talking about with the protease inhibitors) was 56% and 34%, respectively, among telaprevir-treated patients, and 36% and 17% in patients receiving standard treatment," Dr. Younossi said.

To assess whether and to what degree these increases played a role in patient quality of life, Dr. Younossi and colleagues analyzed the results of EQ-5D quality of life questionnaires completed at baseline and at weeks 4, 12, 24, 36, 48, and 72 by 722 patients. They derived a summary index by calculating the percentages of patients reporting problems for each of the five health-related quality of life dimensions measured (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression).

After adjustment for age and sex, the baseline mean index values for the EQ-5D were 0.92 for the telaprevir plus 24-week PR group, 0.90 for the telaprevir plus 48-week PR group, and 0.91 for the 48-week PR-only group. The percentages of patients reporting any problems in each of the five qualitative dimensions at baseline were 8.2% for mobility, 2.0% for self-care, 12.9% for usual activities, 25.7% for pain/discomfort, and 25.6% for anxiety/depression, he said.

Across all the treatment groups, the EQ-5D index scores worsened during the first 12 weeks of treatment initiation. Specifically, mean values were 0.80 for the pooled-telaprevir groups and 0.83 for the PR-only group, according to Dr. Younossi.

Also, the respective percentages of patients in the pooled-telaprevir and PR-only groups reporting any problems at week 12 were 56% and 50% for usual activities, 51% and 42% for anxiety/depression, and 60% and 63% for pain/discomfort, he said. Change from baseline in terms of reported impact on mobility and self-care were small and not reported.

At week 48, the corresponding mean EQ-5D values were 0.93 for the telaprevir plus 24-week PR group, 0.83 for the telaprevir plus 48-week PR group, and 0.84 for the PR-only group.

By week 72 the EQ-5D index values returned to baseline levels, Dr. Younossi said.

Adjusted for age and sex, the mean EQ-5D index at week 72 was higher among the patients achieving sustained virologic response (SVR) compared with those who did not, with respective values of 0.90 and 0.86. "The 4% difference is within the range of published values for the minimal clinically important difference for the EQ-5D," he said.

Furthermore, at week 72, there were fewer patients among those who experienced SVR and reported problems in each dimension, compared with those who did not experience SVR.

At week 72, after adjustment for the index at baseline, patient age, sex, race, advanced liver disease, self-reported comorbidities, and the number of adverse events during treatment, only SVR was a positive predictor of the EQ-5D index. "We saw that [SVR] was a statistically significant and meaningful predictor of health-related quality of life," he said.

The study findings are consistent with the published research on the impacts of interferon-based regimens on health-related quality of life in this patient population, "and support the value of shorter treatment duration and [SVR] from a patient-reported outcomes perspective," said Dr. Younossi.

"We certainly cannot say that adding telaprevir causes fewer side effects. It’s clear there are more side effects, but it appears that the most troublesome side effects are related to the interferon therapy," he explained. When considered in the context of the improved SVR, "the burden of the increased incidence of anemia and rash associated with telaprevir, of which few cases are severe, appears to be outweighed by the overall treatment response."

This study was sponsored by Vertex. Dr. Younossi disclosed relationships with Biolex, Vertex, Salix, GlaxoSmithKline, and Tibotec.

Source

Time to get hep C out of the closet

By: Don Marks - Winnipeg Free Press

Posted: 06/5/2012 1:00 AM

In many ways, living with hepatitis C is similar to living with HIV -- both are viruses that begin with a dormant stage, but then they attack the human body and eventually kill you unless they are treated.

Treatments for hep C and HIV are quite similar, too. Both are highly invasive, but there is a 55 to 70 per cent success rate in ridding the body of the hep C virus entirely, while there is no "cure" for HIV. In other words, you live with the HIV virus and keep it under control with a drug, hoping it won't eventually become full-blown AIDS (and now there are even plenty of people living with AIDS because of a "prescription drug cocktail" which prevents the body's immune system from failing)

But I am told a big difference has developed between the experiences of HIV and hep C patients recently.

According to one of Manitoba's top liver specialists, Dr. Kelly Kaita, people who have hep C are living with a social stigma people with other treatable illnesses have been able to manage or overcome more effectively. Kaita says people with hep C are especially reluctant to talk about their illness. And that's what is making it a stigma.

About 250,000 Canadians have hepatitis C. The virus is spread through the blood so most victims got the illness from blood transfusions, before we started testing for it, and many were infected by sharing needles. No matter how you got it, you are sick and should be treated as such.

The most effective treatment for is a 48-week regimen that consists of a weekly injection of interferon and daily ribavirin pills (two or three in the morning and the same at night). The big problem is this treatment is a monster that knocks you on your arse.

There are about 150 possible side-effects. Most patients can expect to experience about 35 of them, and the most common are flu-like symptoms. Not just feeling "light-headed" or "off your game" but knock 'em down and drag 'em out influenza -- painful, aching joints, nausea that keeps you flat on your back in bed, fever, chills, dry heaves, headaches of the migraine kind and so on.

The more exotic side-effects include something called lichen planis, a horrible fungal infection that literally slices your tongue to shreds and turns your cheeks and gums red with a painful pimply rash.

Most people who decide to undergo this treatment have to make arrangements to take an extended leave from work or have a big enough savings account to cover living expenses for six months to a year. All of this becomes more difficult because, according to Dr. Kaita, patients with hep C are extremely reluctant to talk about it.

Maybe it's because AIDS attracted such high-profile support after it became known how devastating the effects of this killer illness were. At first it was "confined" to the gay community. Hollywood stars such as Elizabeth Taylor (and others who knew how powerful gays are in the film and television industry) created awareness and raised funds for research.

And when AIDS began to spread to heterosexuals, basketball star Magic Johnson jumped up and educated people about the dangers of unprotected sex while also making people aware of how simple it can be to prevent the spread of AIDS if you take some basic precautions.

Somehow hepatitis C got lost in the shuffle.

Hep C is only spread through the blood. Since it is socially accepted that people should protect themselves during sex, and there are sanitary reasons for not sharing a razor blade or even a toothbrush, it is easy to keep hep C to yourself in every way.

Some patients have said they have experienced budding romantic or sexual relationships cool as soon as they tell their prospective partner they have the virus. Co-workers and casual, even close friends, start to whisper about you if you share your experience.

So they suffer in silence. And isolation.

The hep C virus can lie dormant for years -- 20 to 30 is the average -- but inevitably it will attack your liver until this vital organ is so damaged you need a transplant or you die from liver disease or cancer.

When hep C becomes active, you stop being active, because along with all the other hepatitis symptoms (jaundice, tender abdomen, etc.), you are extremely tired all the time.

And the treatment makes you just as sick, and it is just as debilitating.

You become undependable, and you can only make so any excuses for missing work or the social events you used to attend so reliably.

Dr. Kaita feels there is a need to remind people that hep C affects a lot of our fellow Canadians and they are going through hell trying to deal with it.

They don't need a social stigma on top of all of that.

Don Marks is a freelance writer based in Winnipeg who is presently being treated for hep C but asks for no sympathy or understanding because he is routinely unreliable and has been blessed with some good friends.

Source