June 28, 2010

The risk jumped especially among people undergoing transplants since 2005, study found

MONDAY, June 28 (HealthDay News) -- Cyclosporine, a drug commonly used to prevent organ rejection following a transplant, has been linked to a significantly increased risk of developing cancer after liver transplant, new Dutch research reveals.

The study was done in part to examine what role drugs that suppress the immune system might play in the development of cancer in liver transplant patients, whose long-term survival rates have improved little over the past three decades. Cancer is one of the leading causes of late death, and appears to be directly related to the intensity and cumulative doses of immunosuppressive drugs, according to researchers.

The Dutch study compared cyclosporine and tacrolimus -- the cornerstone of immunosuppressive drug therapy -- in the occurrence of de novo (new) malignancies after transplantation. To do so, researchers analyzed the records of 385 liver transplant patients who had the procedure between 1986 and 2007, and tracked all the patients through 2008 for signs of de novo cancer (defined as the onset of cancer other than a recurrence of primary liver cancer).

Of the study participants, 13 percent were found to have developed at least one de novo cancer.

Lead author Dr. Herold Metselaar and his colleagues found that compared to TAC therapy, cyclosporine appeared to be the most important risk factor for new cancer following a liver transplant. The higher cancer risk was not found in all patients treated with cyclosporine, however; it was specific to patients who had undergone a transplant more recently (2005 to 2007) and to those under the age of 50.

In addition, compared to tacrolimus, cyclosporine was more likely to spark aggressive types of cancer, those with a one-year survival rate of less than 30 percent.

Metselaar and his team theorized that the increased risk among patients transplanted since 2005 may have something to do with a change in the way cyclosporine dose monitoring was structured from that year onward.

"Strikingly, [cyclosporine-treated] patients transplanted from 2005 on showed a 9.9-fold higher de novo cancer risk in the early phase after liver transplant compared to patients treated with [tacrolimus]," he noted in a news release. In addition, cyclosporine was associated with cancer types that had a worse prognosis, Metselaar said in a news release.

The study, conducted by researchers from the Erasmus MC University Medical Center in The Netherlands, appears in the July issue of Liver Transplantation.

More information

For more on liver transplants, visit the National Digestive Diseases information Clearinghouse.

--Alan Mozes

SOURCE: Wiley Medical News, June 24, 2010, news release

http://www.businessweek.com/lifestyle/content/healthday/640544.html
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Gastroenterology June 2010

Jeanette J. McCarthy, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina Josephine H. Li, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina Alexander Thompson, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina Sunil Suchindran, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina Xiang Qian Lao, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina Keyur Patel, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina Hans L. Tillmann, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina Andrew J. Muir, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina John G. McHutchison, Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina

Received 20 October 2009; accepted 10 February 2010. published online 22 February 2010.

ABSTRACT

Background & Aims

Patients with chronic hepatitis C virus (HCV) infections are treated with pegylated interferon and ribavirin (PEG-IFN/RBV), which is effective in less than 50% of those infected with HCV genotype 1. Genome-wide association studies have linked response to PEG-IFN/RBV with common single nucleotide polymorphisms in the vicinity of interferon (IFN)-λ genes on chromosome 19. We investigated the association between the polymorphism rs12979860 and treatment response in a diverse cohort of chronic HCV patients.

Methods

A cross-sectional study of 1021 consecutive patients enrolled in the Duke Hepatology Clinic Research Database and Biorepository. We analyzed DNA, clinical and demographic data, along with validated data of the response of 231 subjects to PEG-IFN/RBV. The study included Caucasians (n = 178), African Americans (n = 53), and HCV genotypes 1 (n = 186) and 2/3 (n = 45). The rs12979860 genotype was tested for an association with sustained virologic response, defined as undetectable levels of HCV RNA 24 weeks after treatment ended.

Results

The rs12979860 CC genotype (found in -40% of Caucasians) predicted a sustained virologic response to therapy among Caucasians (odds ratio, 5.79; 95% confidence interval, 2.67-12.57; P = 9.0 x 10-6), independent of HCV genotype and other covariates. Rs12979860 CC predicted a sustained response with 78% specificity and 65% sensitivity in patients infected with HCV genotype 1).

Conclusions

rs12979860 genotype is a significant independent predictor of response to PEG-IFN/RBV in patients with chronic HCV infection; tests for this genotype might be used to determine the best course of treatment for patients considering antiviral therapy.

Infection with the hepatitis C virus (HCV) is a global health problem, with worldwide estimates of 120-130 million carriers.1 In the United States alone, 3-4 million people are thought to be infected, representing 1.6% of the population.2, 3 Chronic HCV infection can lead to progressive liver disease, resulting in cirrhosis and complications including decompensated liver disease and hepatocellular carcinoma leading to the need for transplantation.2, 3 The current standard-of-care treatment for suitable patients with chronic HCV infection consists of pegylated interferon alfa 2a or 2b (PEG-IFN) given by injection in combination with oral ribavirin (RBV), for 24 or 48 weeks, dependent on HCV genotype. This treatment is not only costly, but is associated with significant side effects resulting in reduced compliance and fewer patients completing treatment. Only about half of treated subjects achieve a sustained virologic response (SVR).4, 5, 6 For all these reasons, decisions regarding treatment with current standard-of-care IFN-based therapy are complex and based on the balanced assessment of host and viral determinants that aid in predicting virologic response. HCV genotype, in particular, is used in making treatment decisions: patients with HCV genotype 2/3 have a relatively high rate of SVR (70%-80%) with 24 weeks of treatment, whereas those infected with HCV genotype 1 (representing about 70%-75% of infected persons in the United States) have a much lower rate of SVR (40%) despite 48 weeks of treatment.6

Recently, several highly correlated common single nucleotide polymorphisms (SNPs) on a linkage disequilibrium block in the vicinity of 3 IFN-λ genes on chromosome 19, encoding interferon λ1 (IL29), λ2 (IL28A), and λ3 (IL28B), have been implicated in response to PEG-IFN/RBV among patients infected with HCV genotype 1 from 3 genome-wide association studies.7, 8, 9 The risk genotype associated with nonresponse to therapy was more common in African Americans and thought to account for half of the observed ethnic variation in treatment response. Paradoxically, the responder genotype was associated with higher viral load.

We sought to confirm and extend our understanding of this recently reported genetic association in a cohort of patients with chronic HCV infection from a large tertiary care setting, including subjects infected with HCV genotypes 2 and 3.

Results

Association of rs12979860 Genotype With SVR to PEG-IFN/RBV by Race

A description of the cohort used in our analysis of response to PEG-IFN/RBV is shown in Table 1. Patients predominantly were Caucasian, infected with HCV genotype 1, and broadly representative of a tertiary care chronic HCV cohort. Among patients treated with PEG-IFN/RBV, those included in this analysis differed only slightly from those excluded, with more HCV genotype 2/3-infected subjects (20% vs 11%; P = .02). As expected, responders to standard-of-care PEG-IFN/RBV treatment were characterized as having significantly lower viral load, being younger, of Caucasian race, infected with HCV genotype 2 or 3, and being treatment-naive. Rs12979860 allele frequencies differed by race and were consistent with those previously reported (Caucasian C, 0.63; T, 0.37; African American C, .40; T, .60). In the overall cohort, a nominal deviation in Hardy-Weinberg equilibrium was found for Caucasians (P = .02), which could not be attributed to genotyping error, but possibly reflects an underlying association between genotype and chronic HCV infection.

Figure 2 illustrates how, among Caucasians, rs12979860 genotype was associated significantly with response to PEG-IFN/RBV, with the greatest effect seen when comparing subjects with two copies of the C allele (CC genotype) with those with one or no copies. Therefore, all subsequent analyses considered the CC genotype vs CT/TT. This association remained significant in multivariable analysis controlling for age, sex, HCV genotype, treatment history, and fibrosis, where presence of the CC genotype conferred a nearly 6-fold increased odds of SVR relative to the CT/TT genotype (odds ratio, 5.79; 95% confidence interval, 2.67-12.57; P = 9.0 x 10-6). Among Caucasians, there was no difference in the effect of rs12979860 on SVR comparing subjects with HCV genotype 1 and 2/3, or between those with a prior treatment history and those treatment naive at baseline (rs12979860 genotype by trait interactions, P > .05).

Figure 2. Association between rs12979860 genotype and PEG-IFN/RBV treatment response in Caucasian and African American chronic HCV patients from our cohort. (A) Caucasians, (B) African Americans. Numbers with SVR out of all with that genotype are shown below each rs12979860 genotype. Chi-squared P values for Caucasians are adjusted for age, sex, HCV genotype, treatment history, and fibrosis. P values in African Americans are from the Fisher exact test and are not adjusted because of the small sample sizes.



African Americans comprised only 23% of our cohort and predominantly were infected with genotype 1 HCV (98%), and 57% were treatment-naive. As illustrated in Figure 2, no association was found between rs12979860 genotype and treatment response in African Americans in our study, and the difference in the rs12979860 treatment response association between African Americans and Caucasians did not reach significance (rs12979860 by race interaction, P = .34). However, it should be noted that the estimated proportion of SVR among patients with the CC genotype, 0.125 (1 of 8), is unstable because of the small sample size, resulting in a wide confidence interval (0.003-0.53), and thus making it difficult to draw inference.

To assess the relative contribution of important covariates to treatment response, we examined the effect of each covariate in a multivariable model. Table 2 shows the relative effect of all covariates on treatment response in univariable and multivariable models. HCV genotype was the strongest predictor of treatment response in univariable and multivariable analyses that did not include the rs12979860 genotype. Inclusion of rs12979860 in the model attenuated the effects of HCV genotype and enhanced the association with viral load. Rs12979860 genotype emerged as the strongest factor associated with treatment response; other independently associated factors included HCV genotype, viral load, age, and treatment history. Inclusion of rs12979860 genotype in the model improved the C statistic (from 0.75 to 0.82) as well as the Nagelkerke R2 (from 0.25 to 0.38). In the current study, inclusion of the IL28B genotype in the model resulted in reclassification of responders (30%) and nonresponders (56%), for an overall Net Reclassification Improvement (0.86) that was highly significant (P = 2.3 x 10-7).

To assess the relative value of rs12979860 compared with HCV genotype, we calculated sensitivity, specificity, and likelihood ratios in our cohort of Caucasian subjects (Table 3). Comparing rs12979860 CC genotype with HCV genotype 2/3 revealed HCV genotype as having somewhat better specificity, but rs12979860 genotype has better sensitivity and is more common, found in 38% of chronic HCV patients (compared with -25% prevalence of HCV genotypes 2/3). Performance of rs12979860 among the subset of HCV genotype 1 subjects, or among the subset of treatment-naive subjects, mirrors that in all subjects with HCV genotypes 1, 2, and 3 combined.

Effect of rs12979860 on Treatment Relapse Among Caucasians

Among 111 (62%) Caucasian subjects who failed to achieve SVR to PEG-IFN/RBV, 29 (26%) were classified as relapsers. The frequency of the rs12979860 CC genotype in this group was between that observed for the SVR and end-of-treatment nonresponder groups. However, only the difference found between relapsers and end-of-treatment nonresponders was significant, suggesting that rs12979860 CC genotype influences end-of-treatment response and does not distinguish accurately between patients with a relapse response and those with a SVR (Figure 3).

Association With HCV Genotype

HCV genotype data were available for a larger group of patients than were used for analysis of treatment response (n = 649 Caucasians). We compared the rs12979860 genotype frequencies between Caucasians infected with HCV genotypes 1, 2, and 3 (Figure 4). Rs12979860 CC was most common in genotype 3 patients (55%), followed by genotype 2 (46%) and genotype 1 (33.5%; P = .0007). To correct for possible referral bias, we examined this association in the subset of naive patients undergoing treatment with PEG-IFN/RBV and observed the same trend (data not shown).

Association With Viral Load

Off-treatment viral load measures were available for 301 Caucasians with chronic HCV infection from our cohort, 277 of whom had complete data on covariates as well and could be used in our analysis to determine the association between rs12979860 genotype and viral load. The odds of having a higher quantitative viral load in patients with rs12979860 CC genotype were twice that of patients with genotype CT/TT in analysis controlling for age, sex, HCV genotype, and fibrosis (odds ratio, 2.13; 95% confidence interval, 1.24-3.66; P = .0061).

Discussion

Treatment decisions in patients with chronic hepatitis C infection currently are based on clinical, demographic, and virologic characteristics of infected patients. Although these may be helpful from a population point of view, for any individual patient and provider, these baseline pretreatment characteristics are inaccurate in predicting treatment response in hepatitis C patients infected with genotype 1, the most common genotype found in the United States. We have confirmed in this study that the recently identified common genetic variant in the IFN-λ gene region is associated strongly with response to standard-of-care PEG-IFN/RBV in a tertiary care setting. The association among Caucasians thus was validated outside of the clinical trial setting. Because of the limited sample size of African Americans and other racial groups in this current study, we had inadequate power to detect statistical association in these groups, as was observed by Ge et al.7 Nonetheless, inclusion of rs12979860 genotype and race in a multivariable model caused an attenuation of the effect of race on treatment response, indicating that the effect of race may be mediated in part through this polymorphism.

Our results extend the observations of Ge et al7 and indicate that, among Caucasians, rs12979860 has a high specificity, similar to HCV genotype, the current best baseline indicator used for identifying patients who will achieve a SVR to antiviral therapy. Used in conjunction with HCV genotype, rs12979860 may provide additional discriminatory power to identify likely responders to treatment.

Another interesting observation was the significantly different frequency of the rs12979860 genotype according to HCV genotype in Caucasian patients. HCV genotype 1-infected patients were less likely to have the rs12979860 response genotype than were patients infected with HCV genotypes 2 or 3. Although interesting, this relationship does not fully explain why patients infected with HCV genotypes 2 or 3 have significantly higher sustained response rates compared with those infected with HCV genotype 1; both the gene variant and HCV genotype remain independently associated with treatment response in the multivariable models we ran. Nonetheless, this observation theoretically could have some biological bearing on the development of persistent or chronic (vs spontaneously cleared) HCV infection. The data could be interpreted in the context of a case-only study design, where an association between 2 factors (rs12979860 and HCV genotype) among cases of chronic HCV may reflect interaction between rs12979860 and HCV genotype in the development of chronic HCV.18, 19 Based on these results, we would hypothesize that subjects with both HCV genotype 2/3 and rs12979860 CC would be more likely to develop chronic HCV and hence less likely to clear the virus spontaneously than those with HCV genotype 1 and rs12979860 CT/TT. Although this relationship may seem counterintuitive on account of HCV genotype 2/3 subjects having a significantly higher rate of treatment-induced viral clearance, it warrants further exploration in appropriate prospective studies of spontaneous clearance. We also considered that the association could have been due to referral bias, whereby chronic HCV patients who are difficult to treat may be overrepresented among the Duke cohort, and these patients would be more likely to be HCV genotype 1 and rs12979860 CT/TT genotype. This bias could lead to an overestimate of the association between rs12979860 genotype and HCV genotype. However, when we analyzed a subset of treatment-eligible patients with no prior treatment history we found a similar trend of association.

Although the rs12979860 SNP showed a remarkably strong association with treatment response in both the study by Ge et al7 and our replication study, the exact causal variant underlying the observed genetic association has not been identified. This SNP lies closest to 2 genes encoding for IFN-λ proteins, λ2 and λ3. IFN-λ have been studied previously in the context of HCV infection and shown to suppress HCV replication in vitro.20, 21, 22 It is possible that the causal variant affects expression or function of one of these antiviral genes, which may in turn affect viral control.

Interestingly, Ge et al7 reported a paradoxic relationship to viral load in that the responder allele of rs12979860 was associated statistically with a higher baseline viral load, inconsistent with the clinical observation that higher baseline viral load typically is associated with a poorer treatment response.4, 5, 6 We also confirmed this paradoxic association with off-treatment viral load in our expanded cohort of Caucasian patients from a tertiary care setting. The exact mechanism underlying this genetic association with high viral load and yet increased likelihood of treatment response remains to be determined.

There are several important clinical implications of this genetic association originally reported by Ge et al7 in a clinical trial population and confirmed in the present study in a tertiary care population. First, the rs12979860 SNP may be useful in determining which chronic HCV genotype 1 patients would be most likely to respond to treatment with PEG-IFN/RBV. Given the high prevalence of the rs12979860 responder genotype in Caucasians (-40%), this could have a substantial impact on treatment decision making. Our data support the potential utility of rs12979860 in predicting SVR in Caucasians, regardless of treatment history. However, additional prospective studies are needed to determine the true predictive value of this marker among all treatment-eligible patients, including those from other racial/ethnic and HCV genotype groups, and taking into account noncompliant and relapsing patients as well. Ultimately, chronic HCV patients with the rs12979860 responder genotype may be more motivated to comply with treatment, or to undergo treatment in the presence of mild underlying liver disease, knowing that they have a higher likelihood of SVR.

These important genetic findings related to treatment response in patients with chronic hepatitis C infection suggest the possibility of personalized medicine for the treatment of this disease. Clinical trials are now necessary to determine whether HCV genotype 1-infected patients with the favorable rs12979860 responder genotype would benefit equally from shorter treatment duration with our current therapies or future therapies, thus reducing the cost and side effects associated with longer-term treatment. How the rs12979860 responder genotype influences the outcomes to future antiviral strategies, including those based on protease and polymerase inhibition, requires immediate attention and investigation. Understanding the clinical implications of this genetic, biologically plausible finding will be a major research agenda and priority.
 
http://www.natap.org/2010/HCV/062810_04.htm
Jnl of Hepatology

from Jules: these data are compelling that earlier HCV therapy is better in general but of course other factors must also be considered. Ongoing HCV replication does damage including to the liver and perhaps in other ways as well.

"A total of 871 patients were enrolled, randomized (1:1) to induction and standard therapy, and received study drug (intention to treat analysis population)......Eligible subjects included treatment naïve adults aged 18-75years with chronic HCV genotype 1 infection and compensated liver disease (Child-Pugh Score <7)........These further analyses within the CHARIOT study provide robust evidence for the influence of fibrosis stage on treatment response. SVR was as high as 70% among patients with no fibrosis, declining in a step-wise fashion to rates of 31% for those with bridging fibrosis (n=97), and only 10% for those with cirrhosis (n=30) ......the influence of fibrosis stage on PEG-IFN and ribavirin therapy outcomes in other studies has been based on two disease stage groupings only (generally advanced fibrosis and earlier disease) [2], [3], [18]. Further, key studies have not provided genotype-specific SVR by disease stage, including the pivotal studies of PEG-IFN and ribavirin therapy by Fried et al. [18] and Manns et al. [3]......A marked step-wise decline in SVR was evident by fibrosis stage: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001). Early virological responses were lower among F3/4 patients, including rapid virological response (RVR) (21% vs. 34% for F3/4 and F0-2, respectively) (p=0.0072), and the RVR positive predictive value was also lower (63% vs. 80%). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001)......A rapid virological response (RVR) was achieved in 25% and 18% of F3/4 patients on induction and standard therapy, respectively, compared to 39% and 28% in F0-2 patients...... A lower proportion of F3/4 patients reached undetectable HCV RNA by week 4 (21% vs. 34%) and week 8 (19% vs. 26%) (p<0.0001 for comparison of time to undetectable HCV RNA) (Fig. 3A). Furthermore, the SVR rates for each treatment response group were lower for F3/4 patients compared to F0-2 patients, including the rapid virological response group (week 4, 63% vs. 80%) (Fig. 3B). Thus, patients with advanced fibrosis had both slower initial viral decline and lower likelihood of SVR within each early treatment response group......

.....A potential explanation for our findings is the relationships between fibrosis stage, intrahepatic HCV RNA replication, and HCV clearance. Although patients with advanced fibrosis do not have higher serum HCV RNA levels, they have a higher percentage of hepatocytes with evidence of HCV RNA replication [19]. Viral kinetic studies have shown that patients with HCV genotype 1 and advanced fibrosis have slower second phase HCV RNA decline than those with less fibrosis [20], consistent with our week 4 and 8 response findings. Further, recent HCV modeling based on HCV genotype 1 patients indicates that patients with cirrhosis have lower SVR rates due to a higher percentage of HCV-infected hepatocytes [21]. An additional explanation would relate to potential immunological differences by extent of liver disease. Immunological characteristics including up-regulation of intrahepatic Th1-like cytokines and interferon-stimulated genes (ISGs) are known to influence both fibrosis progression and IFN-based treatment response [22], [23]. Finally, the recently reported association, between IL28B genetic polymorphisms and PEG-IFN/RBV treatment outcome in treatment naïve patients with chronic HCV genotype 1, indicates that host genetic characteristics are important for treatment responsiveness [24], [25]. If IL28B genetic polymorphisms associated with poor HCV treatment response are also found to be linked to liver disease progression, host genetic characteristics could explain the differential response by fibrosis stage......

......A further feature of the virological response patterns, between patients with and without advanced fibrosis, was the differential outcomes within similar virological response groupings. Patients with advanced fibrosis with initial undetectable HCV RNA at week 4, 8, 12, were less likely to achieve an SVR compared to those in the corresponding virological response group without advanced fibrosis. Among patients without advanced fibrosis and a RVR, the proportion with a SVR (PPV) was 80%, within the 77-90% RVR PPV range from other studies [26], [27], [28]. However, only 63% of patients with advanced fibrosis and RVR achieved a SVR. The high NPV of RVR for SVR among patients with advanced fibrosis (84%) makes extension of therapy a potential strategy for evaluation in this group. Extension of PEG-IFN and ribavirin therapy, from 48 to 72weeks among patients with HCV genotype 1 and non-RVR, has reduced relapse rates and increased SVR [29], [30], but data on this specific strategy among patients with advanced fibrosis is not available.....

.....Although combination therapy with PEG-IFN, ribavirin, and direct acting antivirals (DAA) such as protease or polymerase inhibitors has shown great promise in phase I and II evaluation, most of these trials have enrolled relatively few patients with advanced fibrosis (patients with established cirrhosis have generally been excluded) and disease stage-specific response data is not available [31], [32]. Pivotal studies among genotype 1 patients for the protease inhibitors telaprevir and boceprevir have included individuals with advanced fibrosis, therefore data on efficacy and safety in this sub-group is eagerly awaited."

Articles in Press

Low virological response and high relapse rates in hepatitis C genotype 1 patients with advanced fibrosis despite adequate therapeutic dosing

Journal of Hepatology

June 2010

Wendy S.C. Cheng1, Stuart K. Roberts2, Geoffrey McCaughan3, William Sievert4, Martin Weltman5, Darrell Crawford6, William Rawlinson7, Philippa S. Marks8, James Thommes9, Bishoy Rizkalla10, Motoko Yoshihara10, Gregory J Dore811, on behalf of the CHARIOT Study Group 1 Royal Perth Hospital, Perth, Australia, 2 Alfred Hospital, Melbourne, Australia, 3 Royal Prince Alfred Hospital, Sydney, Australia, 4 Monash Medical Centre and Monash University, Melbourne, Australia, 5 Nepean Hospital, Sydney, Australia, 6 Greenslopes Hospital, Brisbane, Australia, 7 SEALS Microbiology, Prince of Wales Hospital, Sydney, Australia, 8 National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia, 9 Roche Products, Nutley, NJ, USA, 10 Roche Products, Sydney, Australia, 11 St. VincentÕs Hospital, Sydney, Australia Received 12 November 2009; received in revised form 19 March 2010; accepted 11 April 2010. published online 23 June 2010.

Uncorrected Proof

ABSTRACT

Background & Aims

The impact of fibrosis stage on chronic hepatitis C virus (HCV) treatment response was explored in CHARIOT, a study of high dose peginterferon alfa-2a (PEG-IFNα-2a) induction therapy in treatment naïve genotype 1 infection.

Methods

Eight hundred and ninety-six patients were randomised 1:1 to 360µg (n=448) or 180µg (n=448) PEG-IFNα-2a weekly with RBV 1000-1200mg/day for 12weeks followed by 36weeks of 180µg PEG-IFNα-2a weekly plus RBV 1000-1200mg/day. Virological responses were assessed at week 4, 8, 12, 24, 48 (end of therapy), and 24weeks following therapy (sustained virological response, SVR). As previously reported, there was no significant difference in SVR in the induction (53%) and standard (50%) arms, therefore the pooled study population was used for analysis of SVR and relapse.

Results

A marked step-wise decline in SVR was evident by fibrosis stage: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001). Early virological responses were lower among F3/4 patients, including rapid virological response (RVR) (21% vs. 34% for F3/4 and F0-2, respectively) (p=0.0072), and the RVR positive predictive value was also lower (63% vs. 80%). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001). Cumulative PEG-IFNα-2a and ribavirin doses were similar among patients with F3/4 and F0-2 within treatment arms through week 4, 8, 12, and week 24.

Conclusion

Low virological response in hepatitis C genotype 1 patients with advanced fibrosis is not explained by inadequate cumulative PEG-IFN and ribavirin doses.

Introduction

Pegylated interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection achieves a sustained virological response (SVR) in 70-80% in genotype 2/3, but only 40-55% in genotype 1 infected patients [1], [2], [3]. Treatment response rates are particularly poor among patients with genotype 1 infection and advanced fibrosis (bridging fibrosis and compensated cirrhosis), with SVR rates of 15-40% [2], [3], [4], [5], [6], [7] reported from generally small study populations.

HCV-related cirrhosis is associated with a high risk of progression to hepatic decompensation, hepatocellular carcinoma (HCC), and liver-related mortality [8], [9], [10]. Although interferon-based HCV viral clearance is more difficult to achieve in patients with advanced fibrosis, there are clear benefits for those who do, with lower risk of progression to advanced liver disease complications [11], [12], [13], and regression of fibrosis in many [14], [15].

The CHARIOT trial was a large international randomized controlled trial of peginterferon (PEG-IFN) alfa-2a induction dosing in combination with ribavirin in treatment of naïve patients with chronic HCV genotype 1 infection [16]. Despite enhanced early virological responses, induction therapy provided no improvement in SVR (53% and 50% in induction and standard therapy arms, respectively). Preliminary analyses of the influence of fibrosis stage on treatment outcomes, following induction and standard therapy, demonstrated poor SVR rates among patients with advanced fibrosis (28% and 24%) compared to those with moderate (51% and 50%) and no or minimal fibrosis (64% and 60%) [16]. The aim of this analysis was to further evaluate the impact of fibrosis stage on treatment response within CHARIOT, including the predictive value of week 4, 8, and 12 responses, and virological relapse. In particular, the contribution of cumulative PEG-IFNα-2a and ribavirin dose to the lower virological responses observed in patients with advanced fibrosis was explored.

Results

Patient characteristics

A total of 871 patients were enrolled, randomized (1:1) to induction and standard therapy, and received study drug (intention to treat analysis population). Baseline liver histology was obtained in 625 of 871 patients (71.8%). Fibrosis stage was F3/4 in 127 patients (14.6%), F0-2 in 498 patients (57.2%), and missing in 246 patients (28.2%). F3/4 patients were older with higher body weight and baseline ALT levels compared to F0-2 patients (Table 1). All F3/4 patients had compensated liver disease (Child-Pugh Score 5 in 124 and 6 in 3 patients). The distribution of patient characteristics for those with biopsy staging were similar to those with missing staging, apart from a lower proportion of Caucasians (80% vs. 90%), and a higher baseline ALT level (median: 54 vs. 44U/L) in those with biopsy (Table 1). Laboratory markers of advanced fibrosis were similar among those with and without biopsy staging including AST/ALT ratio, serum albumin, serum total bilirubin, INR, and platelet count (Table 1). Only six (2.4%) patients with missing biopsy had a Child-Pugh Score of >5.

Virological responses

Induction therapy provided approximately 10% higher early virological responses including undetectable HCV RNA proportions at week 4, 8, and 12 for both F3/4 and F0-2 groups (Fig. 1). However, early virological responses were lower among F3/4 patients in both induction and standard groups compared to corresponding F0-2 patient groups; this difference was apparent by week 4. A rapid virological response (RVR) was achieved in 25% and 18% of F3/4 patients on induction and standard therapy, respectively, compared to 39% and 28% in F0-2 patients.

A similar disparity in virological response between F3/4 and F0-2 groups was seen at week 24 and week 48 (ETR), however, this disparity widened considerably by week 72, with SVR rates of 24-28% in F3/4 patients compared with 55-58% among F0-2 patients (p<0.0001) (Fig. 1).

The randomized groups were combined (given similar SVR rates) to explore the impact of individual fibrosis stage on treatment responses. A marked trend in SVR by fibrosis stage was evident with progressive declines in response with increasing fibrosis: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001) (Fig. 2A). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001) (Fig. 2B). Among patients without SVR, the percentage with non-response at week 12, virological breakthrough, and virological relapse was similar for patients with F0-2 (n=216; 27%, 36%, 37%, respectively) and patients with F3/4 (n=94; 30%, 28%, 42%, respectively).

The impact of early treatment response was further characterized in the overall population by determining SVR among fibrosis groups (F0-2, F3/4) within four mutually exclusive response groups based on the week of initial undetectable HCV RNA (week 4, 8, 12, 24). A lower proportion of F3/4 patients reached undetectable HCV RNA by week 4 (21% vs. 34%) and week 8 (19% vs. 26%) (p<0.0001 for comparison of time to undetectable HCV RNA) (Fig. 3A). Furthermore, the SVR rates for each treatment response group were lower for F3/4 patients compared to F0-2 patients, including the rapid virological response group (week 4, 63% vs. 80%) (Fig. 3B). Thus, patients with advanced fibrosis had both slower initial viral decline and lower likelihood of SVR within each early treatment response group.

In a multivariate analysis among patients with all baseline parameters available for inclusion (n=507), METAVIR fibrosis score was associated with SVR (p=0.0194). Adjusted odds ratios for SVR in comparisons with F4 patients were 8.9 (1.8-43.8), 6.3 (1.5-26.6), 5.7 (1.4-23.6), and 2.7 (0.6-11.5) for patients with F0, F1, F2, and F3, respectively.

Predictors of response

The predictive value of early virological response in determination of SVR was also examined, among fibrosis groups and randomized arms (Table 2). The positive predictive value (PPV) of RVR for SVR was lower among F3/4 patients in induction (60%) and standard (67%) arms compared to F0-2 patients (79% and 82%, respectively). Of note, the negative predictive value (NPV) of RVR for SVR was considerably higher among F3/4 patients (83-84%) compared to F0-2 patients (55-57%) (Table 2). Among F3/4 patients the PPV for SVR was lower and NPV higher at week 8. Also, the PPV of week 12 response for SVR, both EVR and cEVR, were considerably lower among F3/4 patients compared to F0-2 patients (Table 2), while NPV of EVR was 100% for all groups (note that patients in both arms without an EVR, continued therapy to week 24 then to week 48 if HCV RNA was undetectable at week 24).

Cumulative therapeutic dosing

The proportions of patients receiving >80% and >95% of planned PEG-IFNα-2a dose by week 12 and 24 were lower among patients on induction therapy, but similar among patients with F3/4 and F0-2 (Table 3). There was a marginally lower proportion with >95% cumulative dosage of PEG-IFNα-2a among F3/4 patients compared to F0-2 patients in the standard arm by week 12 (83.6% vs. 89.3%) and 24 (76.1% vs. 81.0%). The proportions with receipt of >80% and .95% of planned ribavirin dose were similar across randomized and fibrosis groupings, including >95% receipt by week 12 (F0-2: induction 80.1%, standard 83.9%; F3/4: induction 83.3%, standard 83.6%) and week 24 (F0-2: induction 74.6%, standard 74.8%; F3/4: induction 75.0%, standard 73.1%) (Table 3).

Methods

CHARIOT study population

The CHARIOT trial methods and patient population have been described in detail [16]. Eligible subjects included treatment naïve adults aged 18-75years with chronic HCV genotype 1 infection and compensated liver disease (Child-Pugh Score <7). Initial recruitment (in Australia from August 2004) excluded patients with cirrhosis. The protocol was revised in mid-2006 to allow inclusion of patients with normal serum ALT level and absence of liver biopsy staging of disease consistent with changes to Australian subsidized treatment requirements for serum ALT elevation (December 2005) and pre-treatment liver biopsy (April 2006). In addition, patients with compensated cirrhosis were able to enroll. Also, from mid-2006, recruitment commenced through several other countries (New Zealand, Thailand, Canada, Mexico, Argentina), with pre-treatment liver biopsy staging required in all these countries apart from New Zealand.

Patients meeting screening eligibility criteria were randomly assigned 1:1 to receive PEG-IFNα-2a either in an induction dose or standard dose regimen. The induction regimen consisted of 360µg of PEG-IFNα-2a weekly, for the first 12weeks, followed by 180µg of PEG-IFNα-2a weekly, for 36weeks and 1000/1200mg of ribavirin daily for 48weeks. The standard dose regimen involved 180µg of PEG-IFNα-2a weekly and 1000/1200mg of ribavirin daily for 48weeks. Patients in both arms without an early virological response (EVR) at week 12 continued therapy to week 24; patients with detectable HCV RNA at week 24 ceased therapy.

Cumulative exposure to PEG-IFNα-2a and ribavirin was determined by calculation of the percentage of planned dose received through week 4, 8, 12, 24, and 48. Reductions from maximum dose occurred through both clinician-directed dose modification and patient non-adherence, with adherence assessed via recording the injections and doses of PEG-IFNα-2a and ribavirin at each visit according to the patientÕs detailed statements, and via documentation of drugs dispensed through pharmacy records.

Assessments and efficacy endpoints

Quantitative serum HCV RNA levels were measured at baseline and at weeks 4, 8, 12, 24, 48, and 72 (Roche Ampliprep/Cobas TaqMan HCV Test with a detection limit of 15IU/ml). Treatment response endpoints were defined as undetectable HCV RNA, including the primary endpoint at week 72, and were based on Taqman results below the level of detection (both undetectable and detectable <15IU/ml).

Liver biopsies were taken within 36months of treatment and scored by local pathologists. Fibrosis stage was classified according to the METAVIR system [17] as F0 (no), F1 (mild), F2 (moderate), F3 (severe), and F4 (cirrhosis). Advanced fibrosis included patients with either F3 or F4 fibrosis stage.

Statistical analysis

The intent-to-treat analysis population was defined as all patients randomized who received at least one dose of study medication. Percentages are calculated for categorical parameters. Means are calculated for the continuous variables. Area under the curve (AUC) of HCV RNA through week 24 is calculated and has been analyzed with F3/4 vs. F0-2 and treatment groups as factors in ANCOVA. A logistic regression analysis was conducted for SVR with METAVIR score as a prognosis factor. A multivariate logistic regression analysis was also conducted to evaluate the independent impact of fibrosis stage on SVR, with the following baseline variables included: treatment group, age, gender, race, body weight, METAVIR fibrosis score, screening HCV RNA level, subtype (1b or non-1b), ALT, AST/ALT ratio, hemoglobin, white blood cell count, platelet count, serum creatinine, serum albumin, total bilirubin, alkaline phosphatase, gamma-glutamyl transferase (GGT), and international normalized ratio (INR). Due to the exploratory nature of the analyses, no alpha-adjustments were applied to account for multiple significance testing.
 
http://www.natap.org/2010/HCV/062810_03.htm
Gastroenterology May 2010

Raymond T. Chung (Associate Editor)

Much fanfare heralded the successful sequencing of the human genome in 2003. Newly armed with a comprehensive understanding of the human genetic map, investigators proclaimed that personalization of medicine was imminent. Now, 7 years after this signal discovery, where do we stand in the delivery on this promise to clinical care?

In the past several years, there has been a breathtaking flurry of genome-wide association studies (GWAS) designed to identify susceptibility loci for complex, polygenic diseases. These studies have succeeded in identifying single nucleotide polymorphisms (SNPs) that increase predisposition to conditions incrementally (usually with odds ratios well under 1.5). For these disorders, which include Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, and type 2 diabetes mellitus, it is likely that only a small fraction of the genetic risk for these conditions has been identified. Although doubtless much will be learned regarding the functional significance of these susceptibility loci through fundamental biological investigation, and ultimately insight gained into new therapeutic targets or biomarkers, the dividends may be some years in the making. Furthermore, it seems that the probable requirement for interaction of several predisposition loci with environmental factors to trigger disease makes the prospect of a "slam dunk" genetic test to predict risk for complex disorders a somewhat remote one.

There are, however, notable exceptions to the premise that a given phenotype represents a complex interaction of genotypes. One such example was the recent discovery of an extraordinarily strong relationship between a SNP in the IL28B gene, which encodes IL28B, or interferon lambda-3 (IFNλ-3), and responsiveness to IFN-α-based antiviral therapy for hepatitis C virus (HCV) in persons harboring genotype 1 infection. In a recently published GWAS study of patients with chronic hepatitis C who had entered a clinical trial of pegylated IFN-α and ribavirin, possession of a favorable genotype (CC) at the rs12979860 SNP in the IL28B locus was associated with a 2.5-fold improved likelihood of experiencing sustained virologic clearance compared with the unfavorable genotype (CT or TT).1 To put this finding into genomics perspective, the significance threshold for GWAS studies is typically about 10-8. In the case of the IL28B allele, the overall significance level was a staggering 10-28. This level of significance may be as close as we get to a bankable finding.

More important, to put this finding into clinical perspective, the impact of IL28B genotype is on par with viral genotype as a determinant of IFN and ribavirin responsiveness, and eclipses viral load, liver histology, and ethnic group and race as a predictive factor. Indeed, the frequency of the favorable IL28B SNP explains in large measure (but not completely) the known, observed decrease in sustained virologic response in African Americans compared with Caucasians and Hispanics. To reinforce the strength of this data, these findings have been replicated in at least 2 other clinical cohorts of Asian and Caucasian descent.2, 3 Not surprisingly, the favorable IL28B genotype was also associated among persons with acute hepatitis C infection with a significant likelihood of spontaneous clearance compared with those who developed chronic infection.4

Is the finding of such a strong association with a single polymorphism surprising? Perhaps not, if one considers that, unlike complex disease traits, susceptibility to an infection that does not produce immediate life-threatening illness may not be under intensive selection pressure. The finding that a polymorphism in a gene that encodes a member of the type III IFN family (as IL28B is) raises a whole raft of fundamental biological questions that relate to the antiviral properties of IL28B and its interaction with type I IFNs, which include IFN-α. We can therefore anticipate that the uncovering of these interactions will remain an active area of investigation for years to come.

Although further investigation of much larger numbers of subjects will likely yield additional meaningful determinants of treatment-induced or spontaneous viral clearance, the fact remains that these findings are striking, and are likely to have implications for clinical practice among gastroenterologists and hepatologists who care for persons with HCV infection. How might such a gene test be used in practice? For starters, the use of an a priori test that can stratify response likelihood among persons with genotype 1 HCV will represent an important tool that will lead to the minimization of exposure of patients to IFN and ribavirin and their attendant toxicities. Possession of an unfavorable (non-CC) genotype will be taken as a measure of a very low likelihood of sustained virologic response, and, among those patients with limited liver disease who can afford to wait, could justify deferral until cocktails of direct antiviral agents become available, possibly as early as the next 5-10 years. On the other hand, those patients with the favorable IL28B genotype might be viewed as having a high likelihood of responding, and be encouraged to consider initiating therapy with current standard of care. In other words, genotype 1-infected patients with favorable IL28B genotype may behave clinically as do genotype 2- or 3-infected persons. Trials to examine the value of truncating therapy in this group of patients (as is the case for patients experiencing rapid virologic responses on pegylated IFN and ribavirin therapy) will no doubt also be warranted.

It is also not difficult to imagine combining this pharmacogenomic data with more conventional clinical variables (such as liver histology or viral load) to further refine our prediction rules for response. With this pharmacogenomic breakthrough, we in gastroenterology and hepatology will now firmly enter the arena of predictive medicine.

These findings have additional downstream implications for clinical trial design. It is highly conceivable that patients entering clinical trials of new therapies for HCV will be stratified by IL28B genotype. Furthermore, studies examining strategies of therapies thought to be of somewhat higher risk (such as combining direct acting antiviral agents without IFN) could be restricted to those with a favorable IL28B genotype who might then be "rescued" with IFN-based regimens in the event of treatment failure.

On the other hand, the counterargument could be made that those persons who have an unfavorable IL28B genotype should attempt to enter trials with oral cocktail therapy in light of their poor responsiveness to IFN. Either way, we seem to be poised to be able to dictate therapeutic choices in the management of HCV based on genetic information.

Although pharmacogenomics has already been productive in identifying alterations in the metabolism of some therapeutic agents (eg, azathioprine or 6-mercaptopurine), the power of the IL28B pharmacogenomic data lies in its potential ability to influence the subsequent choice of therapeutic agents themselves. Of course, an additional possible major benefit attending the IL28B gene discovery is that IFN-λ3 could itself become a useful therapeutic agent against HCV, either alone or in conjunction with IFN-α.

As we turn the corner on the first decade of the 21st century, the exploration of genomics in medicine has been made possible by efforts to pool very large numbers of patients into informative cohorts. Even so, we have only begun to peel away the outer, more apparent layers of risk, since it is clear that ever larger numbers of subjects will be required to identify less obvious but contributory loci to complex diseases. Yet as we embark on these lofty efforts, we can now be gratified that picking some of the lowest-hanging fruit of all has positioned us for a bountiful yield.

References

1. Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399-401

2. Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy. Nat Genet. 2009;41:1100-1104

3. Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105-1109

4. Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461:798-801
 
http://www.natap.org/2010/HCV/062810_01.htm

Caffeine, a drug for all seasons

Journal of Hepatology

Bruce N. Cronstein
NYU School of Medicine, 550 First Ave., NBV16N1, New York, NY 10016, USA

Received 3 February 2010; received in revised form 16 February 2010; accepted 18 February 2010. published online 02 April 2010.

COMMENTARY ON: Increased caffeine consumption is associated with reduced hepatic fibrosis. Apurva A. Modi, Jordan J. Feld, Yoon Park, David E. Kleiner, James E. Everhart, T. Jake Liang, Jay H. Hoofnagle. Hepatology, 2010 Jan;51(1):201-9.

Caffeine is the most widely used drug in the world and the most common caffeine delivery vehicle is coffee. Additional vehicles for caffeine delivery include carbonated soft drinks and "energy drinks." Interestingly, high doses of caffeine are banned from competitive sports as a performance enhancing drug, caffeine is included in a number of over-the-counter pain relievers and there are at least four psychiatric diagnoses associated with caffeine use. Thus, it comes as quite a surprise to most people that drinking coffee is associated with diminished mortality and that protection from death due to liver disease is the best documented contributor to reduced mortality. Although caffeine is the most extensively characterized pharmacologic agent in coffee, there are other active agents as well, and it has been difficult to capitalize on the hepatoprotective qualities of coffee without knowing which ingredient mediates the protective effect.

The recent demonstration by Modi and colleagues [1] that caffeine appears to protect from severe liver fibrosis in a case control study of patients seen at the NIH for treatment of chronic liver disease, primarily hepatitis C, offers at least a partial explanation for the protective effects of coffee. In their study Modi and co-workers observed that patients who consumed more than the 75th percentile of caffeine for the cohort (about 300mg/day which is equivalent to the caffeine found in 2.25 cups of coffee) were significantly less likely to have severe hepatic fibrosis as defined by Ishak stage 3 (OR 0.33). Evidence for a protective effect of caffeine persisted even after correction for age, sex, race, type of liver disease, body mass index, and alcohol ingestion (OR 0.25); and the protective effect was no less marked in the patients with HCV infection (OR 0.19). Although prior work had suggested that other agents (kahwol and cafestol) found in coffee might afford protection from hepatic fibrosis by altering the expression of hepatic enzymes involved in activation of agents (e.g. CCl4) that cause fibrosis in animals [2], the authors were unaware of prior work indicating the direct effects of caffeine on hepatic fibrosis in vivo. In this series, coffee was the greatest single source of caffeine and other sources contributed far less caffeine. Because coffee was the dominant source of caffeine in this group of patients, there was only a trend towards an impact for the contribution of other sources of caffeine toward the protection from fibrosis.

The pharmacologic properties of caffeine have been explored for many years and a variety of different pharmacologic mechanisms have been ascribed to caffeine. The most well known and better understood pharmacologic effect of caffeine is the antagonism of adenosine receptors. Adenosine receptors were first described by Sattin and Rall [3], and it has subsequently become clear that there are four different types of adenosine receptors (A1, A2A, A2B and A3), all of which are members of the G protein coupled family of receptors [4]. Adenosine receptors are ubiquitous in their expression and they regulate a large number of physiologic functions.

Adenosine is a short-lived but abundant purine nucleoside that is released as a result of adenine nucleotide catabolism. Although hypoxia is the most well known stimulus for increasing extracellular adenosine levels, it has long been acknowledged that other types of cellular injury also induce adenosine release as adenine nucleotides are turned over and released. In the liver, adenosine is released as a result of the exposure to toxins, including ethanol and the hepatic fibrosing agents CCl4 and thioacetamide [5]. Recent work from our laboratory has demonstrated that adenosine and its receptors (A1 and A2B receptors) play a central role in the development of hepatic steatosis in mice that chronically ingest high doses of ethanol [6]. In prior work, we and others have used a combination of specific adenosine receptor antagonists and adenosine receptor knockout mice to demonstrate a critical role for adenosine A2A receptors in murine models of hepatic fibrogenesis [5], [7]. Indeed, caffeine itself prevented hepatic fibrosis in response to CCl4 and thioacetamide by, presumably, blocking adenosine receptor-mediated fibrosis [7]. Adenosine A2A receptors are expressed in hepatic stellate cells and hepatocytes where they directly stimulate collagen production and induce activation of TGFβ and stimulate CTGF production by hepatocytes [8], [9], [10]. Interestingly, all four adenosine receptors are expressed in human liver and the expression of adenosine A2A and A2B receptors is markedly increased in cirrhotic and steatotic livers [6].

Thus, the demonstration by Modi and colleagues [1] that caffeine ingestion prevents advanced liver fibrosis provides further supportive evidence for a role for adenosine receptors in hepatic fibrosis. Moreover, these findings suggest that more selective adenosine receptor antagonists with more favorable pharmacokinetics might offer even greater protection from the development of hepatic fibrosis and cirrhosis (Fig. 1).


Fig. 1 Adenosine, generated primarily extracellularly from adenine nucleotides, stimulates hepatic fibrosis via A2A receptors on hepatocytes and stellate cells. Caffeine reduces fibrosis by blocking adenosine A2A receptors.

Dr. Cronstein holds or has filed applications for patents on the use of adenosine A2A receptor agonists to promote wound healing and use of A2A receptor antagonists to inhibit fibrosis; use of adenosine A1 receptor antagonists to treat osteoporosis and other diseases of bone; the use of adenosine A1 and A2B Receptor antagonists to treat fatty liver, and; the use of adenosine A2A receptor agonists to prevent prosthesis loosening. Consultant (within the past two years) King Pharmaceutical (licensee of patents on wound healing and fibrosis above). CanFite Biopharmaceuticals, Savient Pharmaceuticals, Bristol-Myers Squibb, Roche Pharmaceuticals, Cellzome, Tap (Takeda) Pharmaceuticals, Prometheus Laboratories, Regeneron (Westat, DSMB), Sepracor, Amgen, Endocyte, Protalex, Allos, Inc.,Combinatorx, Kyowa Hakka. Honoraria/Speakers' Bureaus: Tap (Takeda) Pharmaceuticals. Stock: CanFite Biopharmaceuticals received for membership in Scientific Advisory Board.

References

[1]. Modi AA, Feld JJ, Park Y, Kleiner DE, Everhart JE, Liang TJ, et al. Increased caffeine consumption is associated with reduced hepatic fibrosis. Hepatology. 2010;51:201-209.

[2]. Lee KJ, Choi JH, Jeong HG. Hepatoprotective and antioxidant effects of the coffee diterpenes kahweol and cafestol on carbon tetrachloride-induced liver damage in mice. Food Chem Toxicol. 2007;45:2118-2125. CrossRef

[3]. Sattin A, Rall TW. The effect of adenosine and adenine nucleotides on the cyclic adenosine 3',5'-phosphate content of guinea pig cerebral cortex slices. Mol Pharmacol. 1970;6:13-23.

[4]. Fredholm BB, AP IJ, Jacobson KA, Klotz KN, Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev. 2001;53:527-552.

[5]. Peng Z, Fernandez P, Wilder T, Yee H, Chiriboga L, Chan ES, et al. Ecto-5'-nucleotidase (CD73) -mediated extracellular adenosine production plays a critical role in hepatic fibrosis. FASEB J. 2008;22:2263-2272.

[6]. Peng Z, Borea PA, Wilder T, Yee H, Chiriboga L, Blackburn MR, et al. Adenosine signaling contributes to ethanol-induced fatty liver in mice. J Clin Invest. 2009;119:582-594. CrossRef

[7]. Chan ES, Montesinos MC, Fernandez P, Desai A, Delano DL, Yee H, et al. Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol. 2006;148:1144-1155.

[8]. Gressner OA, Lahme B, Rehbein K, Siluschek M, Weiskirchen R, Gressner AM. Pharmacological application of caffeine inhibits TGF-beta-stimulated connective tissue growth factor expression in hepatocytes via PPARgamma and SMAD2/3-dependent pathways. J Hepatol. 2008;49:758-767.

[9]. Che J, Chan ES, Cronstein BN. Adenosine A2A receptor occupancy stimulates collagen expression by hepatic stellate cells via pathways involving protein kinase A, Src, and extracellular signal-regulated kinases 1/2 signaling cascade or p38 mitogen-activated protein kinase signaling pathway. Mol Pharmacol. 2007;72:1626-1636.

[10]. Hashmi AZ, Hakim W, Kruglov EA, Watanabe A, Watkins W, Dranoff JA, et al. Adenosine inhibits cytosolic calcium signals and chemotaxis in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2007;292:G395-G401.

http://www.natap.org/2010/HCV/062810_02.htm

Yale Researchers Awarded $3.5 Million to Study Hepatitis C

Published: June 28, 2010

New Haven, Conn. — Two Yale scientists have received a $3.5 million grant from the National Institutes of Health to study hepatitis C virus (HCV), a deadly pathogen that attacks the liver and afflicts about 170 million people worldwide.

Anna Marie Pyle, the William Edward Gilbert Professor of Molecular Biophysics and Biochemistry and an investigator for the Howard Hughes Medical Institute, and Brett Lindenbach, assistant professor of microbial pathogenesis, will use the money to study the molecular underpinnings of HCV.

Current treatments for HCV are poorly tolerated in patients and effective only in a minority. The team hopes to dissect the critical features of viral replication in hopes of laying the groundwork for a new generation of therapies.

The team goal is to develop a functional replication complex for HCV in the lab, which in turn can be used to identify targets for new drugs.

“The success of the work will depend upon the coordinated efforts of chemists, biochemists, and viral geneticists,” Pyle said.

Nearly 2 percent of the U.S. population has been infected by HCV, which can cause chronic liver disease, cirrhosis, liver cancer and liver failure.

http://opa.yale.edu/news/article.aspx?id=7639

Safety records of surgery centers found lacking

In the wake of several hepatitis outbreaks, a JAMA study found frequent lapses in infection management.

By Kevin B. O'Reilly, amednews staff. Posted June 28, 2010.

Ambulatory surgical centers' safety practices are under scrutiny as a study in the Journal of the American Medical Association found that problems in infection control are common at such centers.

The study came on the heels of a 28-count criminal indictment filed June 4 against Las Vegas gastroenterologist Dipak K. Desai, MD, and two of his endoscopy clinic nurse anesthetists. They were charged in connection with unsafe injection practices that led to a 2008 hepatitis C outbreak infecting 115 patients in southern Nevada.

The felony counts include criminal neglect of patients, racketeering, insurance fraud and "performance of an act of reckless disregard of persons or property." The Clark County indictment says Dr. Desai pressured employees to reuse single-use vials, syringes and needles to save costs.

Dr. Desai, who surrendered his medical license in February, following health problems, pleaded not guilty. His trial is set for March 2011.

The Nevada outbreak, one of at least a half dozen hepatitis B and C outbreaks at hospitals and outpatient clinics in the last three years, led to the JAMA study, which was published June 9. The Centers for Medicare & Medicaid Services paid state surveyors to conduct unannounced, on-site assessments of ambulatory surgical centers' compliance with safety standards.

Sixty-eight ambulatory surgical centers in Maryland, North Carolina and Oklahoma were examined in 2008, and 46 had at least one infection-control lapse, the study said. Twelve centers had lapses in three or more of five infection-control categories, such as injection safety, hand hygiene and equipment reprocessing. Nearly 30% of centers reused single-dose medication vials for more than one patient.

The results "suggest that infection control practices in ASCs might be lacking and were not specific to a given state," the study said. Authors of the paper were not available for interview by this article's deadline.

Nicole Coffin, a spokeswoman for the Centers for Disease Control and Prevention's Division of Healthcare Quality Promotion, said the article shows that physicians must ensure that their nurses and other medical staff are adhering to safe infection-control practices. "Not only do you have to have the right policies in place, but you have to make sure people are following those policies and make sure the staff understands what those policies are," Coffin said.

One and done

In late May, the Safe Injection Practices Coalition released a 10-minute CDC training video as part of the group's One and Only Campaign.

"The overall message -- use one needle, one syringe, only one time -- is the main thrust of the video, and it's done in the hopes of dispelling some of these misperceptions that it's safe to administer medications from single-dose vials to multiple patients," Coffin said.

Organizations representing ambulatory surgical centers objected to the JAMA paper, arguing that it is based on old data, does not look at outcomes and does not compare the clinics' performance with that of hospitals and other health care organizations.

"There's no comparison data, and [the study] doesn't contextualize what's going on," said David Shapiro, MD, chair of the Ambulatory Surgery Center Assn., which represents more than 2,600 surgical centers. "The implication is that they were surveying ambulatory surgical centers because it is the only setting in which infection control is a problem. The data out there suggest that, because of the high-quality patient care we provide in our settings, ASCs are where a patient would go to avoid getting a health care-associated infection."

The ASC Quality Collaboration, launched in 2006, monitors outcomes from more than 650 ambulatory surgical centers. The initiative has found that 80% of ASCs report fewer than 1.5 postsurgical wound infections per 1,000 patients.

Coffin, the CDC spokeswoman, rejected the notion that the agency is singling out ambulatory surgical centers for safety scrutiny. "We expect people to be following our infection-control recommendations in all facilities, whether they are hospitals or ambulatory surgical centers."

Dr. Shapiro said the negative publicity surrounding unsafe injection practices has had an upside. "This has just reminded everyone about the importance of very, very, very basic stuff," he said. "This is physician 101 and nursing 101, and has to do with the basic tenet s of professionalism."

The print version of this content appeared in the July 5 issue of American Medical News.

http://www.ama-assn.org/amednews/2010/06/28/prsa0628.htm

Experts urge reform of global drug policy

By VERONIKA OLEKSYN (AP) – 15 minutes ago

VIENNA — Policies that criminalize drug users fuel the spread of AIDS and should be reformed, experts preparing for an international conference said Monday.

Instead, governments, international organizations and the U.N. should promote policies that include opiate substitution therapy and needle and syringe programs that have been shown to reduce HIV rates without increasing rates of drug use, said the experts from groups such as the International AIDS Society, the International Center for Science in Drug Policy and the British Columbia Center for Excellence in HIV/AIDS. They also want compulsory drug treatment centers to be scrapped, saying they are ineffective and violate human rights.

"The criminalization of illicit drug users is fueling the HIV epidemic and has resulted in overwhelmingly negative health and social consequences. A full policy reorientation is needed," the experts said in a declaration issued ahead of an AIDS conference that gets under way in the Austrian capital on July 18.

Among other things, the declaration says there is no evidence that increasing the "ferocity" of law enforcement reduces the prevalence of drug use and claims that the number of countries in which people inject illegal drugs is growing.

"Many of us in AIDS research and care confront the devastating impacts of misguided drug policies every day," Julio Montaner, president of the International AIDS Society and director of the BC Center for Excellence in HIV/AIDS, said in a statement.

"As scientists, we are committed to raising our collective voice to promote evidence-based approaches to illicit drug policy that start by recognizing that addiction is a medical condition, not a crime," added Montaner, who will serve as chairman of the Vienna conference.

The declaration urges governments, international organizations and the United Nations to carry out a transparent review of the effectiveness of current drug policies and to implement a science-based public health approach.

While legal barriers to needle programs and opiate substitution therapy mean hundreds of thousands of people become infected with HIV and hepatitis C every year, the criminalization of drug users has resulted in record incarceration rates, the experts said in joint statement.

They added that opiate substitution therapy, and needle and syringe programs, are cost-effective, help drug users access health care and have not been shown to have negative consequences.

"The current approach to drug policy is ineffective because it neglects proven and evidence-based interventions, while pouring a massive amount of public funds and human resources into expensive and futile enforcement measures," said Evan Wood, founder of the International Center for Science in Drug Policy.

"It's time to accept the war on drugs has failed and create drug policies that can meaningfully protect community health and safety using evidence, not ideology."

Wood appeared to be echoing a comment made by U.S. drug czar Gil Kerlikowske last month. In an interview with The Associated Press, he said that after 40 years the United States' $1 trillion war on drugs has not been successful.

Online:
The Vienna Declaration: http://www.viennadeclaration.com/
Copyright © 2010 The Associated Press.

Source

Drug Discovery & Development - June 28, 2010

Inovio Pharmaceuticals, Inc., a leader in the development of therapeutic and preventive vaccines against cancers and infectious diseases, announced that the peer-reviewed journal Molecular Therapy has published a paper entitled "Comparative Analysis of Immune Responses Induced by Vaccination With SIV Antigens by Recombinant Ad5 Vector or Plasmid DNA in Rhesus Macaques." The paper, co-authored by researchers from Merck, University of Pennsylvania School of Medicine, and Inovio Pharmaceuticals, notes that significant advances in the design, formulation, and delivery of DNA plasmid-based vaccines have dramatically increased their ability to induce antigen-specific immune responses. In this head-to-head comparison with an adenovirus serotype 5 (Ad5) vaccine considered to be the most immunogenic among viral vectors, Inovio's optimized SynCon(TM) DNA vaccine delivered using its proprietary electroporation technology demonstrated numerous advantages in both magnitude and breadth of immune responses produced in non-human primates.

Compared to Ad5, the SynCon DNA vaccine resulted in:

• Significantly stronger antigen-specific cellular immune responses, in particular CD8+ T cells. T cells are considered instrumental in clearing cancerous or infected cells from the body. Such responses are therefore imperative to achieving sufficient potency in new vaccines against cancers and chronic infectious diseases such as HIV and hepatitis C virus. Importantly, Ad5 immunizations failed to boost immune responses following the first immunization, whereas immune responses from DNA vaccination were continually boosted even after four immunizations.

• Increased breadth of T cell-based immune responses. CD4+ and CD8+ T cell immune responses produced with DNA vaccination were broader and produced multiple immune molecules called cytokines (IFN, IL-2, TNF-a, and CD107a). Broad immune responses are considered an important potential marker for vaccine efficacy.

Immune responses that were long-lasting and maintained at high levels.

Dr. David Weiner, Professor, Department of Pathology & Laboratory Medicine and Chair, Gene Therapy and Vaccines Program at the University of Pennsylvania, and the lead author of the paper, commented: "While Ad5 is particularly potent after a single immunization, its apparent susceptibility to pre-existing immune responses is a concerning limitation. We were pleased to see the superior magnitude and quality of immune responses generated by Inovio's SIV DNA vaccine delivered using electroporation. Moreover, the ability of this technology to continuously boost immune responses after multiple immunizations is an accomplishment that bodes well for the application of this vaccine platform for diseases requiring strong T cell responses, such as HIV, hepatitis C virus, and cancers." Dr. Weiner is also chairman of Inovio's scientific advisory board.

Dr. J. Joseph Kim, Inovio's CEO and also a co-author of the paper, said: "This study highlights that Inovio's DNA vaccine platform has achieved levels of immune responses previously not achievable and is playing an important role in further advancing this important new generation of vaccines. These results have more recently been supported by the human data reported from our HPV clinical trial, which demonstrated unprecedented levels of cellular and humoral (antibody) responses."

Inovio's PENNVAX-B HIV vaccine is currently being tested in two separate Phase I clinical studies (preventive and therapeutic settings). Inovio is developing two additional globally targeted HIV vaccine candidates, PENNVAX(TM)-G and PENNVAX(TM)-GP, in a collaboration with the US Military HIV Vaccine Research Program and via a multi-year $23.5 million NIAID HIV vaccine development contract, respectively.

Date: June 22, 2010

Source: Inovio Pharmaceuticals, Inc.

http://www.dddmag.com/news-Inovio-DNA-Vaccine-Shows-Advantages-Over-Viral-Methods-62810.aspx

Outdated Meds Pose Problems If Kept or Tossed

Health, environmental experts suggest safe disposal methods

FRIDAY, June 25 (HealthDay News) -- It's a common find in medicine cabinets and bathroom drawers: a prescription vial containing years-old medication or an over-the-counter cold remedy that's embarrassingly past its sell-by date.

But unless they're spring-cleaning, many people don't bother throwing away these items. And when they do, people often turn to the toilet and flush the products away.

Both behaviors are big mistakes.

Keeping out-of-date medications in the house poses dangers to everyone in the family. And flushing old medications down the toilet can be harmful to the environment.

Old drugs and remedies kept moldering in the medicine cabinet may not be able to help you when you need them the most.

"The big reason to dispose of these medications would be that they may be ineffective. They lose potency over time," said Jeffrey C. Delafuente, an associate dean and professor in the School of Pharmacy at Virginia Commonwealth University. "After the expiration date, there's no guarantee they'll be of any benefit."

Someone with severe asthma, for instance, might reach for an inhaler during an asthma attack only to find that it's full of expired medication, Delafuente said. "That could put them in the emergency department, or they could die from the attack," he said.

Old medications also pose an overdose hazard. Statistics from the American Association of Poison Control Centers show that most childhood poisonings are due to ingestion of over-the-counter medicines or prescription drugs.

So, if you should get rid of medications after their expiration date, why not flush them?

Because biologists have found that flushed medications are getting into the ecosystem and have the potential to cause environmental damage, said Tiffany Parson, a biologist with the U.S. Fish & Wildlife Service.

"We're concerned about aquatic habitats, and medications getting into them," Parson said. "We don't want medications flushed directly into the sewer system. If they are flushed, there is that potential that they could get more directly into an aquatic ecosystem, compared with putting them in the landfill."

The chemicals in medications can cause hormonal changes and affect aquatic organisms at the cellular level, Parson said. Drugs intended to lower people's cholesterol, for instance, can retard metabolism and growth in fish, and antipsychotic and anxiety medications can impact behavior, growth and reproduction.

"Fish may be expressing different hormones that they wouldn't normally," Parson said. "We don't want any kind of impurity in any of our waters. Pharmaceuticals are just one of those potential substances."

However, people shouldn't depend on a waste treatment plant to remove pharmaceutical chemicals from wastewater, either. "Most treatment facilities don't have the technology to filter out these substances from sewage," Parson said.

That's led experts to suggest that the best way to get rid of expired medications is to throw them away in the household trash.

Take-back programs do exist -- with expired drugs being collected and disposed of by pharmacies, government agencies or community groups -- but most aren't meant for consumers, Delafuente said.

"At the retail or pharmacy level, they can have a pick-up service come, collect the old medications and dispose of them, usually by incineration," he said.

However, some medications are just too risky to be put in the trash and should, instead, be flushed, according to the U.S. Food and Drug Administration. These include controlled substances such as methadone, OxyContin, Percocet and Dilaudid. Flushing such drugs, the agency says, ensures that they won't fall into the wrong hands. Some drugs on the list could be fatal if taken by someone who doesn't need the medication, the FDA warns.

Medications disposed of in the trash, though, can be disguised, Delafuente said. Simply crush the pills or tablets or add kitty litter, coffee grounds or sawdust to the trash bag. "That way it doesn't look attractive to anyone or any thing," he said.

The FDA also suggests putting the mixture in a sealed container as an extra measure of protection against animals ingesting the drugs should they scrounge through the trash.

SOURCES: Jeffrey C. Delafuente, M.S., associate dean for professional education and professor, School of Pharmacy, Virginia Commonwealth University, Richmond, Va.; Tiffany Parson, biologist, U.S. Fish & Wildlife Service, Arlington, Va.; American Association of Poison Control Centers (www.aapcc.org)

http://www.nlm.nih.gov/medlineplus/news/fullstory_100407.html
EDMONTON, June 28 /CNW/ - Cyplasin Biomedical (CPBM: OTCBB and XYI1:FRA) is a product-oriented, specialty pharmaceutical company focused on developing products for the multi-billion dollar hepatitis C virus (HCV) market. Cyplasin has amassed a portfolio of key products for the prevention and treatment of HCV infection, which affects over 4 million people in the U.S. and several hundred million people worldwide.

One such anti HCV product is known as Interferon-alpha which was approved by the FDA for treatment of HCV infection in 1997. This drug is administered to HCV-infected patients three-times-a-week by injection, for a period up to 1-2 years to achieve a clinical effect. In 2001, a newer, longer-lasting formulation of interferon-alpha called Pegylated interferon-alpha2A and -alpha2B (Roche Pegasys(R) and Schering-Plough Pegintron(R), respectively) were approved for use. The longer-acting version of interferon-alpha only needs to be administered once-per-week for 1-2 years.

Cyplasin recently signed an agreement with Minapharm Pharmaceuticals to distribute and market their version of the long-acting pegylated interferon-alpha product (to be marketed and sold under Cyplasin's brand name C-Pegferon(TM)) within the North American and South American markets as well as Mexico, Latin America, Korea, Russia, China, India and other countries. Cyplasin will be one of the first companies with a biosimilar long-acting interferon-alpha formulation for treatment of hepatitis C patients in North America. Minapharm's pegylated interferon-alpha product is currently sold in the Middle East and Northern Africa region.

The combined market for ribavirin and the long-acting interferon-alpha therapy is estimated to be over $2 Billion annually and Cyplasin now has generic versions of both drugs. Cyplasin will start the process to acquire regulatory marketing approvals to sell the generic drugs in territories outside of North America this July and expects to be on track for other regulatory approvals for the North American market by 2012.

Garth Likes, the CEO of Cyplasin, stated "There are generic drug companies, such as the Israeli company Teva and the Indian companies Dr. Reddy and Wockhardt, that have programs seeking approval of biosimilar or generic short-acting interferon-alpha. Where we can make a difference to our market and revenue stream is that we have partnered with Minapharm who are already selling a commercially viable form of the much improved, long-acting interferon-alpha product. It places us strategically well ahead of a small but elite group of companies in the hepatitis C product area. In combination with our ribavirin product, C-Virin(TM), we anticipate we will be able to start the market application process and submit our dossier to the various regulatory authorities for approval to begin selling C-Pegferon(TM) to governments and healthcare providers who are looking for more reasonably priced HCV drug products".

Mr Likes went on to state "Minapharm will also be our partner to manufacture, test and commercialize our HCV vaccine (C-Vaxin(TM)) in the same territory covered by the C-Virin(TM) distribution agreement."

The Middle East /MENA (Middle East/North Africa) territory includes: the Middle East, Africa and other industrialized regions: Afghanistan, Algeria, Armenia, Azerbaijan, Bahrain, Cyprus, Egypt, Georgia, Indonesia, Kazakhstan, Kyrgyzstan, Iraq, Iran, Israel, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Pakistan, Palestine, Qatar, Saudi Arabia, Sudan, Syria, Tajikistan, Tunisia, Turkey, Turkmenistan, United Arab Emirates, Uzbekistan and Yemen. By latest census, the MENA region comprises approximately 6 - 7% of the world's population (ca. 380 million people), a population equivalent to the European Union, or about one quarter larger than the U.S.

ABOUT CYPLASIN: http://www.c-pharma.net/

Cyplasin Biomedical is a publically-traded specialty pharmaceutical company (OTCBB:CPBM - News) with headquarters in Edmonton, Alberta. Cyplasin's technology encompasses the use of recombinant DNA technology to manufacture recombinant cytokines and virus like particles (VLPs). VLPs can be engineered to incorporate various viral and non-viral antigens for use as vaccines against many different types of targets such as hepatitis C. Cyplasin is using the technology to develop a hepatitis C vaccine (C-Vaxin(TM)) to prevent hepatitis C viral infection. The Company is also pursuing a revenue generation strategy by commercializing highly profitable therapeutic drugs (C-Virin(TM) & C-Pegferon(TM)) for use in the hepatitis C market.

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http://www.newswire.ca/en/releases/archive/June2010/28/c8570.html

Indonesia looking to work with China for liver transplants

Dina Indrasafitri, The Jakarta Post, Jakarta
Mon, 06/28/2010 9:37 AM
 
National Indonesia is looking to work with other hepatitis-endemic countries including China in its fight against liver diseases, the Health Ministry says.
 
“As nations in the Asia-Pacific region, Indonesia and China share the same burden, which is that they are in a hepatitis-B-endemic region. Thus, cooperation between the two countries, ranging from prevention to treatment needs, needs to be developed further,” Health Minister Endang Rahayu Sedyaningsih said during the China Indonesia Hepatobiliary Medicine and Surgery symposium recently.

Since Indonesia initiated a hepatitis B immunization program in 1997 the prevalence of the disease has declined among children under four, from 6.2 percent to 1.4 percent, ministry data shows.

Hepatitis B infections affect the liver and in some cases can require patients to undergo liver transplant operations.

In terms of human resources Indonesia is currently capable of conducting such operations, but lacks the necessary equipment, Rahayu said on the sidelines of the symposium.

Earlier this year, a 3-year-old boy in East Java died from organ failure after having undergone a liver transplant operation to receive his mother’s liver.

China, meanwhile, has a reputation for having carried out successful liver transplants.

Data from the 2007 Basic Health Research report, which includes analysis of blood samples collected from 30,000 households in 294 regencies and cities, shows that around 34 percent of residents were infected with hepatitis B, and the infection rate tended to increase with age.

Endang said the 55-to-59-year-old age group was the most vulnerable group to hepatitis C.

There are currently 22 million people in Indonesia infected with hepatitis B and/or hepatitis C. Ten percent of these are carriers and half of that 10 percent have chronic cases.

Indonesian Liver Research Association (PPHI) chairman Unggul Budihusodo said most infections occurred from the virus being passed from mothers to infants.

Besides a low success rate — around half for hepatitis B and 65 percent for hepatitis C — curing hepatitis is a long and costly process, which can cost the patient millions of rupiah or even their job, Unggul said.

Reports had emerged of hepatitis carriers being discriminated against in the workplace, being deemed unfit even though the virus does not have a significant impact on the quality of life.

Indonesia has pushed for global awareness on viral hepatitis, and last month the annual WHO meeting in Geneva adopted a resolution declaring July 28 World Hepatitis Day.

In January 2010 during the WHO Executive Board meeting, as a representative of the Southeast Asian region Indonesia suggested (along with Brazil and Columbia) that viral hepatitis be recognized as a global issue.

The World Health Assembly agreed on the suggestion and established it as the assembly resolution on viral hepatitis, Endang said.

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