Optimization of Comorbidity Therapy to Achieve Sustained Viral Response in HCV Patients

Optimization of Comorbidity Therapy to Achieve Sustained Viral Response in HCV Patients

Claudio Ucciferri1,2, Jacopo Vecchiet2, Eligio Pizzigallo2 and Katia Falasca2
1Infectious Disease Unit, University of Molise, Campobasso, Italy
2Department of Medicine and Aging, Clinic of Infectious Diseases, “G. d’Annunzio”
University Cheti, Pescara, Italy
Corresponding author: Prof. Vecchiet Jacopo, Clinic of Infectious Diseases, Dept. of Medicine and Aging,
University “G. d’Annunzio” School of Medicine, Via dei Vestini, 66100 Chieti, Italy

KEY WORDS: Sartan; Hepatitis; Insulin-resistance; Hypertension.

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SUMMARY
Several studies indicate that insulin resistance and diabetes influence sustained viral response in treatment for chronic HCV infection. We describe the case of a relapsed patient with HCV infection who achieved a sustained viral response due to an improvement in insulin resistance through modification of antihypertensive therapy. By improving insulin resistance with telmisartan, an ARB with PPAR gamma agonist propriety, sustained viral response was obtained with the same antiviral therapy. Optimization of comorbidity therapy is useful for improving the possibility of achieving a sustained viral response.


INTRODUCTION
Hepatitis C virus (HCV) infection is the major cause of chronic liver disease worldwide,evolving in cirrhosis and increasing the risk of developing hepatocellular carcinoma (1,2). Effective antiviral therapy can cure HCV infection and prevent HCV infection complications (3,4).

Currently the most effective treatment for chronic HCV infection is the combination of pegylated interferon (peg-IFN) and ribavirin (RBV). This therapy obtains sustained virological response (SVR), especially genotype 2 (5). However, achieving SVR is influenced by several factors, such as viral factor, dose of RBV (6,7), cirrhosis and IL28b (8). An interesting issue is the role of obesity and insulin resistance in influencing SVR (9). Recent evidence shows that insulin resistance and obesity reduce SVR by 25-50% less than the otherwise expected rates (10). Insulin resistance and obesity are important risk factors for diabetes and metabolic syndrome. Their implications may be considerable in HCV infected individuals, increasing the risk of developing diabetes and cardiovascular diseases and leading to increased necroinflammatory activity of chronic liver disease (11). An increased rate of SVR is observed in subjects who obtain reduction of obesity and/or insulin resistance (12). Improving insulin resistance with changes in lifestyle or pharmacological approaches, such as metformin or PPAR gamma agonist, is an interesting and encouraging view. However, more definite data are still needed before translation of this approach in clinical practice (13). We describe the case of a chronically HCV infected patient treated with peg-IFN and RBV who obtained SVR by improving insulin resistance with the use of telmisartan, an antihypertensive drug with properties of PPAR gamma agonist.


CASE REPORT
M.M. is a 63 year-old Caucasian female with HCV infection detected by chance by presurgical screening in 2005. At first clinical examination the patient showed aspartate aminotransferases (AST) and alanine aminotransferases (ALT) serum levels in the normal range, WBC 5900cell/m3 and normal leukocyte formula, Hb 14.5g/dL, PLT 198000cell/m3 and HCV-RNA 1198130UI/mL, genotype 2. Moreover, she had body mass index (BMI) 33.1 and insulin resistance assessed by HOMA-IR 5.3 (Figure 1); total cholesterol (TCh) 251mg/dL, HDL cholesterol (HDL) 75mg/dL, LDL cholesterol (LDL) 155mg/dL and triglycerides (TG) 103mg/dL. She was taking antihypertensive therapy with 8mg candesartan daily with good control of blood pressure values and propafenone 150mg bis in die for previous episodes of arrhythmia.

Anti HCV treatment was started with peg-IFN 2A 180μg weekly plus RBV 1200mg/die (13.7mg/Kg/die) for 24 weeks. After one month of therapy HCV-RNA became negative, Hb dropped out at 10.5g/dL and HOMA-IR was 5.4. Therapy was continued without changes and
at the end of treatment HCV-RNA was persistently negative and Hb was 10.1g/dL. However, 3 months after the end of antiviral treatment she relapsed with HCV-RNA 559000 UI/mL. After a further 4 months, the patient had HCV-RNA 3360000UI/mL, Hb 13.9g/dL, TCh 221mg/dL, HDL 71mg/dL, TG 106mg/dL, LDL 129mg/dL, HOMA-IR 6.8, BMI 33.9 and suboptimal hypertension control. Thus, we decided to discontinue candesartan, introduce 40mg telmisartan daily in order to improve blood pressure control and reduce insulin resistance and start antiviral treatment after one mouth.

One month after the antihypertensive drug change, the patient showed good blood pressure control and improved metabolic conditions with HOMA-IR 5.2, TCh 211mg/dL, HDL 83mg/dL, LDL 110mg/dL and Tg 91mg/dL. Continuing treatment with telmisartan, it was decided to re-treat the patient with a new therapy of peg-IFN 2A 180μg weekly plus RBV 1200mg/die for 24 weeks. After four weeks of antiviral treatment, HCV-RNA was negative and patient showed Hb 10.3g/dL, TCh 153mg/dL, HDL 57mg/dL, LDL 75mg/dL, TG 103mg/dL and HOMA-IR 4.2. At the end of treatment, clinical parameters showed HCVRNA negative, Hb 9.8g/dL, TCh 182mg/dL, HDL 70mg/dL, LDL 87mg/dL, TG 122mg/dL,HOMA-IR 4.1 and good blood pressure control.

Six months after the end of anti-HCV treatment, the patient showed a sustained viral response with normal aminotransferases serum levels and negative viremia, persisting good blood pressure control and improved metabolic profile.


DISCUSSION
This case is particular, showing that improving insulin resistance is crucial for achieving the goal of SVR. In clinical practice, the approach to improving insulin resistance is still unclear. In this case, we used an antihypertensive drug, telmisartan, to influence insulin resistance.

Antihypertensive drugs are not all the same, since some of these molecules may have several
metabolic actions. In particular, telmisartan has the strongest PPAR gamma activating properties at the plasma concentration usually used. Several studies have shown that telmisartan, acting as a PPAR gamma agonist, improves insulin resistance and lipid profile both in the general population (14,15) and in special populations, such as HIV or HCV infected patients (16,17). In our patient the switch to telmisartan improved insulin resistance and achieved SVR without modification or discontinuation of anti HCV therapy.

This case demonstrated that optimizing the comorbidity therapy is useful for improving SVR. Thus, if further data confirm this observation, telmisartan may become the first choice therapy
in hypertensive HCV positive subjects with insulin resistance, since it improves metabolic profile steatohepatitis (16). Furthermore, telmisartan may be particularly useful in HCV patients who undergo antiviral treatment with peg-IFN and RBV, since its use seems to increase the possibility of achieving SVR.


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2. Kumada T, Toyoda H, Kiriyama S, et al.: Incidence of hepatocellular carcinoma in hepatitis
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cirrhosis: a seventeen-year prospective cohort study. Hepatology 2007; 46:1350-6.
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chronic hepatitis C. J Gastroenterol Hepatol 2009; 24:531-6.
5. Zeuzem S, Berg T, Moeller B, et al.: Expert opinion on the treatment of patients with
chronic hepatitis C. J Viral Hepat 2009; 16:75-90.
6. Falasca K, Ucciferri C, Mancino P, Gorgoretti V, Pizzigallo E, Vecchiet J: Use of epoetin
beta during combination therapy of infection with hepatitis c virus with ribavirin improves a
sustained viral response. J Med Virol 2010; 82:49-56.
7. Ucciferri C, Falasca K, Mancino P, De Tullio D, Pizzigallo E, Vecchiet J: High dose of
erythropoietin in management of interferon/ribavirin induced anemia. Hepato-gastroenterol
2007; 54:2181-3.
8. Ge D, Fellay J, Thompson AJ, et al.: Genetic variation in IL28B predicts hepatitis C
treatment-induced viral clearance. Nature 2009; 461:399-401.
9. Dai CY, Huang JF, Hsieh MY, et al.: Insulin resistance predicts response to peginterferonalpha/
ribavirin combination therapy in chronic hepatitis C patients. J Hepatol 2009; 50:712-8.
10. Diago M, Shiffman ML, Bronowicki JP, et al.: Identifying hepatitis C virus genotype 2/3
patients who can receive a 16-week abbreviated course of peginterferon alfa-2a (40KD) plus
ribavirin. Hepatology 2010; 51:1897-903.
11. Hui JM, Sud A, Farrell GC, et al.: Insulin resistance is associated with chronic hepatitis C
virus infection and fibrosis progression [corrected]. Gastroenterology 2003; 125:1695-704.
12. Hickman IJ: Obesity management in liver clinics: what's your style of lifestyle intervention?
J Gastroenterol Hepatol 2009; 24:327-8.
13. Wang CC, Kao JH: Metformin improves sustained virologic response in difficult-to-cure
hepatitis C: more questions than answers. Hepatology 2010; 51:1082; author reply 1082-3.
14. Benndorf RA, Rudolph T, Appel D, et al.: Telmisartan improves insulin sensitivity in
nondiabetic patients with essential hypertension. Metabolism 2006; 55:1159-64.
15. Kurtz TW: Treating the metabolic syndrome: telmisartan as a peroxisome proliferatoractivated
receptor-gamma activator. Acta Diabetol 2005; 42(1):S9-16.
16. Georgescu EF, Ionescu R, Niculescu M, Mogoanta L, Vancica L: Angiotensin-receptor
blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic
steatohepatitis. World J Gastroenterol 2009; 15:942-54.
17. Ucciferri C, Mancino P, Vecchiet J, Falasca K: Beneficial effects of telmisartan in an HIV+
diabetic insulin-dependent patient. Int J Immunopathol Pharmacol 2009; 22:853-7.
FIGURE 1.

Recent Trends of Japanese Hepatocellular Carcinoma due to HCV

Recent Trends of Japanese Hepatocellular Carcinoma due to HCV in Aging Society;

Hiraoka A, Hidaka S, Shimizu Y, Utsunomiya H, Imai Y, Tatsukawa H, Tazuya N, Yamago H, Yorimitsu N, Tanihira T, Hasebe A, Miyamoto Y, Ninomiya T, Kawasaki H, Hirooka M, Abe M, Hiasa Y, Matsuura B, Onji M, Michitaka K; Hepato-Gastroenterology 59 (118), (Dec 2011)


Abstract

Background/Aims: The mean age of hepatocellular carcinoma (HCC) patients has increased (more then 65 years old). We want to identify the recent trend of the clinical features of HCC patients due to hepatitis C virus (HCV) (HCV-HCC).

Methodology: From 2000 to 2009, 855 naive HCC patients were admitted. HCV-HCC patients were divided into two groups, first period group (2000-04, n=270) and second period group (2005-09, n=343) and the clinical features of HCV-HCC were investigated.

Results: There was no difference in gender, TNM stage and percentages of HCV-HCC between the periods. On the other hand, the ratio of HCV-HCC patients with worse liver function (Child-Pugh B or C), elderly (more then 75 years old) and the population of patients treated with low invasive radiofrequency ablation were increased (30.0% to 42.0%, 17.2% to 35.8% and 25.1% to 36.2%, respectively; p<0.01). The 1y-, 3y- and 5y-survival rate of HCV-HCC did not show differences (82.1%, 60.5% and 44.7% vs. 81.8%, 56.9% and 37.7%, respectively; p=0.219).

Conclusions: The ratio of aged HCV-HCC as well as HCV-HCC patients with worse liver function was increased. The less invasive treatment for HCC in these patients and the quick anti-viral treatment for HCV patients should be considered to avoid occurrence of HCC in Japan.

DISCUSSION ONLY
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A rapidly aging society is occurring not only in Japan, but also in other Asian and Western countries. Although surgical resection is an effective therapy for HCC, its invasiveness and difficulty to be performed repeatedly are serious obstacles, especially for elderly patients and patients with LC. In addition, liver transplantation is an important therapy for HCC. However, the shortage of donors is a major issue and such therapy is not suitable for elderly patients.

RFA, which has a low level of invasiveness, is now used as therapy for HCC worldwide. In addition to developments in US and CEUS methods (14) the increasing number of elderly patients with HCC in Japan is considered to be the reason for the increasing number of RFA procedures performed as initial treatment for HCC. Although there were larger percentages of elderly patients and patients with poor Child-Pugh class results in HCV-HCC in our study, no significant difference in regard to survival rate of HCV-HCC was seen between the periods (Figure 2). It is thought that low invasive RFA contributed to keep the high survival rate in the second period.

HCV is a major basal hepatic disease related to HCC in Japan. Tsukuma et al. reported that age over 60 years increased the odds ratio for occurrence of HCC in chronic liver disease in a series of cases treated in the 1990s (15). Nishiguchi et al. reported that interferon therapy reduced the risk for HCC and improved the survival rate in patients with LC related to HCV (LC-C) (16,17). In that regard, Yoshida et al. reported that interferon therapy for LC-C reduced the occurrence rate of HCC, especially in cases with sustained viral response (SVR) (18) and Arase et al. also reported the efficacy of interferon therapy for preventing HCC in aged patients with HCV (19).

In the past decade, the aging of society accelerated in Japan. Although the frequency of HCV-HCC in total cases did not change statistically from the first to the second period in our study, the frequencies of elderly HCV-HCC patients without LC and those with advanced LC (Child-Pugh B or C) doubled, respectively. Interferon therapy should be used more aggressively in patients with HCV for preventing HCC and the progression of LC. Interferon therapy for extermination of HCV to prevent progression of LC and avoid the occurrence of HCC should be considered in patients with HCV as early as possible. The background of HCC is rapidly changing with the progression of aging society in Japan.

Click here for introduction/results/ figures and tables

REFERENCES
1. Bruix J, Sherman M: Management of hepatocellular carcinoma. Hepatology 2005;
42:1208-36.
2. Saito K, Kotate F, Ito N, et al.: Gd-EOB-DTPA enhanc

Tailor-Made Therapy for Viral Hepatitis

Paper

Tailor-Made Therapy for Viral Hepatitis: Recent Advances
Masatoshi Kudo

Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Japan

Address of Corresponding Author

Digestion 2011;84 (Suppl. 1):1-4 (DOI: 10.1159/000333207)

Published online: December 2, 2011

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Key Words

• Hepatitis C
• Hepatitis B
• Interleukin-28B
• Inosine triphosphatase
• Pegylated interferon ribavirin therapy
• Double-filtration plasmapheresis

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Abstract

Combination therapy of pegylated interferon-α with ribavirin (PEG-IFN/RBV) is a standard of care for chronic hepatitis C (CHC). The majority of CHC patients are infected with HCV genotype I.

The recent discovery revealed by a genome-wide association study technology provides the important role of interleukin-28B (IL28B) and inosine triphosphatase (ITPA) in HCV infection. In addition, response to PEG-IFN/RBV therapy is correlated with insulin resistance, hepatic steatosis, and hepatic fibrosis in CHC patients. Double-filtration plasmapheresis together with IFN therapy has proved to be effective in the reduction of viral load during the early stage of treatment. In CHC patients, not only IL28B status, but also the treatment period of PEG-IFN/RBV is important.

Even when new polymerase/protease inhibitors are introduced in the treatment of CHC, tailor-made treatment for CHC using IL28B, inosine triphosphatase testing or double-filtration plasmapheresis treatment prolonged treatment strategy is highly recommended. The relative etiologic role of prior hepatitis B virus infection in the development of non-B non-C hepatocellular carcinoma is also known in hepatitis B-endemic areas.

Copyright © 2011 S. Karger AG, Basel

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Introduction

The 8th Japan-Korea Liver Symposium, the main theme of which was ‘Tailor-made therapy of viral hepatitis’, was held in Kobe, Japan, on July 17, 2011, to focus on and discuss current topics in viral hepatitis. The symposium was full of enlightening lectures by world’s leading scientists, followed by extensive discussions. This supplement issue of Digestion contains the most important articles presented at this meeting.

Insulin Resistance

Insulin resistance (IR) has been reported to be an independent predictor of treatment outcome in chronic hepatitis C (CHC) patients.

Associations among IR, steatosis and liver fibrosis have been observed in CHC patients [1,2,3,4,5]. IR has been suggested as the cause, more than a consequence, of hepatic steatosis and fibrosis in patients with HCV, particularly in those with genotype 1 infection [6]. The mechanisms of the more obvious and crucial influence of IR, more than steatosis and fibrosis, need further study. IR seems to be at least associated with body mass index and steatosis, but not with hepatic fibrosis [7].

Double-Filtration Plasmapheresis

The use of double-filtration plasmapheresis (DFPP), approved in Japan in April 2008 for the retreatment of chronic CHC patients with genotype 1b and high viral loads, together with IFN administration has produced a substantial reduction in the viral load during the early stages of treatment and has effected a high sustained virological response (SVR) [8,9], suggesting that this treatment is a new modality for difficult-to-treat CHC patients.

Recent reports have revealed factors associated with response to pegylated interferon-α with ribavirin (PEG-IFN/RBV) therapy such as single nucleotide polymorphisms (SNPs), as host genetic factors, located in interleukin-28B (IL28B; rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917, rs7248668, and rs12979860) on chromosome 19 [10,11,12,13]; amino acid (aa) substitutions in nonstructural protein 5a, especially those in the IFN/RBV resistance-determining region [14] and the IFN sensitivity-determining region (ISDR) [15], and the core regions of HCV [16], as viral genetic polymorphisms.

Kim et al. [17] reported that early viral dynamics with DFPP + IFN-β/RBV then PEG-IFN/RBV therapy is superior to the previous PEG-IFN/RBV combination therapy. There was a significant difference in viral reduction at 24 and 48 h, and 1, 2, 4, 8 and 12 weeks between non-viral response (NVR) and relapse patients. The rate of rapid viral response (RVR) and complete early viral response (cEVR) showed a significant difference between NVR and relapse patients: among the 20 patients, RVR was obtained in 75% (6/8) of relapse patients but in 0% (0/12) of NVR patients, and cEVR in 88% (7/8) of relapse patients but in only 8% (1/12) of NVR patients. On the basis of the above results, DFPP + IFN-β/RBV then PEG-IFN/RBV therapy is indicated more for relapse than for NVR patients. We could conclude that relapse patients would be better candidates than NVR patients [17].

IL28B and Inosine Triphosphatase

The recent discovery revealed by a genome-wide association study (GWAS) technology provides the unexpected role of IL28B and inosine triphosphatase (ITPA) in HCV infection. The former SNPs around the IL28B gene could improve the diagnostics on the prediction of spontaneous clearance and the response to anti-HCV treatment, suggesting that these findings could be strong evidence to enhance the development of a novel therapeutic strategy and the basic study of IFN-λs. Interestingly, the discovered IL28B SNPs revealed the enigma that the viral clearance rate was dependent on ethnic type. The latter functional SNP in ITPA locus was the most significant SNP associated with RBV-induced anemia as well as IFN-induced thrombocytopenia. Note that severe Hb decline, which is mainly found in ITPA-CC patients, was inversely correlated with platelet reduction, contributing to an association between severe anemia and relative reactive increase in platelet count.

The efficacy of triple therapy of telaprevir/PEG-IFN/RBV was high in the patients with genotype TT (rs8099917), who achieved SVR (84%), irrespective of substitution of core aa70. In the patients having genotype non-TT, those of Arg70 gained high SVR rate (50%), and SVR rate (12%) was the worst in patients who possessed both genotype non-TT and Gln70 (His70), suggesting genetic variation near the IL28B gene and aa substitution of the core region as predictors of SVR to a triple therapy in Japanese patients infected with HCV genotype 1b [18].

Genetic variants leading to ITPA deficiency, a condition not thought to be clinically important, protect against hemolytic anemia in CHC patients receiving RBV [19]. Results obtained in one GWAS study need to be evaluated in the context of different geographical and racial populations and independent cohorts. Tanaka confirmed that ITPA SNP (rs1127354) was a useful predictor of RBV-induced anemia in Japanese patients [20]. Excluding those with genotype 1b and high viral load, patients with ITPA minor variant A achieved significantly higher SVR rates than those with the major variant (CC; 96 vs. 70%, respectively, p = 0.0066) [20]. Because the typical PEG-IFN/RBV treatment period is shorter (24 weeks) in genotype 1 low viral load and genotype 2 patients than in genotype 1 high viral load (48 weeks) patients, early dose reduction in RBV may be more critical for the final outcome.

The recent discovery revealed by GWAS technology provides the unexpected role of IL28B and ITPA in HCV infection. These data may provide a valuable pharmacogenetic diagnostic tool for tailoring PEG-IFN/RBV dosing to minimize drug-induced adverse events and for further optimization of clinical anti-HCV chemotherapeutics.

Total PEG-IFN Dose, Core 70 Substitution and ISDR Substitution

Takita et al. [21] showed in their multivariate analysis that rs8099917 genotype and total PEG-IFN dose contribute to the successful outcome of PEG-IFN plus ribavirin combination treatment for infection with HCV genotype 1. The study indicated the value of a combination of the rs8099917 genotype and core 70 substitutions for prediction of SVR. The patients with the rs8099917 genotype TT had high rates of SVR (67.9%). SVR was achieved by 30.7% of patients with the rs8099917 genotype non-TT and core 70 wild type. The SVR rate was worst in patients with rs8099917 genotype non-TT and core 70 mutant type. These results indicate the effects of both host and viral factors on IFN responsiveness. However, a combination of the IL28 genotype and ISDR substitutions for prediction of SVR was not useful.

Etiologic Role of Prior Hepatitis B Infection and Nonalcoholic Steatohepatitis on Hepatocellular Carcinoma Occurrence

A previous study on 1,145 Korean patients showed that the prevalence of cryptogenic hepatocellular carcinoma (HCC) was significantly increased during the last decade, and patients with cryptogenic HCC had a tendency to have risk factors for nonalcoholic fatty liver disease (NAFLD) such as DM, hypertension and obesity than those with virus or alcohol-related HCC [22]. It can be assumed that the increased proportion of risk factors for NAFLD may contribute to the development of cryptogenic HCC. However, there has been no study to compare the relative etiological role of prior HBV infection and NAFLD in the development of NBNC-HCC in HBV-endemic areas. Cho et al. [23] show in their study that the relative proportion of NAFLD-related HCC increased more than three times during the past 10 years, while that of prior HBV infection-related HCC decreased. A growing trend towards a rise in NAFLD-related HCC is expected in the near future, while the prevalence of new HBV infection has definitely decreased due to universal vaccination programs but that of NAFLD has increased recently [24].

Predictions of HBsAg Seroclearance

In chronic HBV infections, HBsAg seroclearance reportedly occurs at a rate of 0.50–2.26%. Several factors have been suggested to be associated with seroclearance including age and HBeAg negativity. However, there are few studies evaluating whether HBV DNA levels are an independent predictor of HBsAg seroclearance.

Old age, a sustained inactive phase, and low levels of HBV DNA were the independent predictors of HBsAg seroclearance [25]. The authors showed that HBsAg seroclearance occurred at a rate of 1.8% per year in HBeAg-negative chronic hepatitis B patients. In addition, multivariable analysis suggested that low HBV DNA levels, old age, and sustained inactive phase were independent predictors of HBsAg seroclearance, but use of antiviral agents was not. Therefore, spontaneous HBsAg seroclearance takes place in elderly patients with low serum HBV DNA levels (<2,000 IU/ml) who remain in a sustained inactive phase.

Non-B Non-C HCC

NBNC-HCC is associated with several etiologic factors such as alcoholic liver diseases (ALD) autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and NAFLD/nonalcoholic steatohepatitis. In addition, a variety of clinical factors are also involved in the development and progression of NBNC-HCC, including age, sex, alcohol consumption, and diabetes mellitus [26,27]. There are only a few reports, however, on the clinical characteristics of NBNC-HCC, and the actual state of NBNC-HCC has not been fully elucidated [28,29,30,31].

Although the number of patients with NBNC-HCC has been increasing annually, many features of NBNC-HCC remain unknown. Based on the present study, the most common etiologic factor for NBNC-HCC was alcohol, and diabetes may be related to the occurrence of HCC in patients with non-alcohol-related liver disease. The comparison between groups revealed that non-ALD-HCC tended to be detected at a more advanced stage, whereas liver function in ALD-HCC was worse. Finally, the prognosis was equivalent between groups [32].

Conclusion

Tailor-made treatment for chronic hepatitis is a very important issue to be addressed even when new polymerase/protease inhibitors are available.

Disclosure Statement

The author has no conflict of interest to declare.

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Masatoshi Kudo

Department of Gastroenterology and Hepatology
Kinki University School of Medicine
Ohno-Higashi, Osaka-Sayama 589-8511 (Japan)
Tel. +81 72 366 0221, E-Mail m-kudo@med.kindai.ac.jp

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Source

Hospital sued for improper sterilization of equipment; Fear of disease claimed

Hospital sued for improper sterilization of equipment; Fear of disease claimed
12/27/2011 7:59 AM
By Kyle Barnett

A New Orleans woman is suing a local hospital that reported an instrument used in a procedure on her husband had not been properly sterilized and exposed him to infectious diseases.

Carol Domio, on behalf of the estate of Clifford Domio, filed suit in Orleans Parish Civil District Court on Dec. 14 against Tulane Medical Center.

The suit claims Tulane Medical Center sent the Domio family a letter stating a medical device used in a recent endoscopic procedure on Clifford was not sterilized to the proper degree and could have resulted in the transmission of HIV, Hepatitis B and Hepatitis C.

Domio claims the mishap by the hospital resulted in injury to her family including reasonable fear and fright of contracting infectious diseases, need for medical monitoring, medical expenses, loss of enjoyment of life, loss of earnings and earning capacity, mental anguish and emotional distress. Damages sought are to cover all injuries to the Domio family.

The defendant is accused of negligence that led to the Domio family's alleged injuries.

New Orleans-based attorney Kevin P. Riche is representing Domio.

The case has been assigned to Division M Judge Paulete R. Irons.

Case number 2011-12889

Tattoos and Piercings: A Review for the Emergency Physician

Complications of Tattoos

Tattoo complication rates show a prevalence of approximately 2% to 3%. Table 3 summarizes the complications associated with tattoos, many of which will be encountered by EPs. Most complications are related to infection that can be traced back to individual tattooist practicing a nonsterile technique. In particular, the jail and intravenous drug-using population is at risk for hepatitis B and C and methicillinresistant Staphylococcus aureus infection.^[10–12] Even syphilis has been transmitted by a tattoo artist licking the tattoo needle.^[13] Failure to recognize a tattoo as the source of a complication leads to incorrect therapy. In many cases the tattoo is not correctly linked to the medical problem because the patient may have multiple risky behaviors.

From Western Journal of Emergency Medicine

Tattoos and Piercings
A Review for the Emergency Physician

Michael Urdang; Jennifer T. Mallek; William K. Mallon

Posted: 12/19/2011; Western J Emerg Med. 2011;12(4):393-398. © 2011 Western Journal of Emergency Medicine

Abstract and Introduction
Abstract

Tattoos and piercings are increasingly part of everyday life for large sections of the population, and more emergency physicians are seeing these body modifications (BM) adorn their patients. In this review we elucidate the most common forms of these BMs, we describe how they may affect both the physical and psychological health of the patient undergoing treatment, and also try to educate around any potential pitfalls in treating associated complications.

Introduction

Tattoos and piercings (T&P) are ancient practices of body modification. The word tattoo comes from Polynesia and was first described by Captain Cook in 1769. The art form was named for the tapping noise made by a tattoo needle on the skin, which in the native tongue was tatau or tatu.^[1] Piercing, including the ear lobe, is also an ancient process, defined as the insertion of a needle to create a fistula for decorative ornaments. First recorded in the Middle East more than 5 thousand years ago, the practice is mentioned in Genesis 24:22 when Abraham asks his older servant to find a wife for his son Isaac. One of the gifts given to Rebecca, Isaac's new wife, by the servant was a golden earring. Since then, ear piercing has become so well accepted that most scientific literature excludes the ear lobe in the definition of body piercing.

Social acceptability of these practices varies widely from culture to culture. Catholicism and Judaism have banned the practice of tattooing.^[2] Esthetics, personal expression, religious views, communication, and style are all motivations for obtaining a tattoo or a piercing. Once relegated to the margins of society (bikers, military, sailors), tattoos and piercings are now common across all ages and both genders in what has been described as an epidemic. For the emergency physician (EP), tattoos and piercings have become important nonverbal clues about the patient's lifestyle and, furthermore, are increasingly the cause of an emergency department visit.^[3,4]

This review provides EPs with the tools to be able to assess the lifestyle or social background of their patients, to be able to understand the medical complications that may arise as a result of body modification, and to have a deeper understanding of the psychologic associations of tattooing and, when necessary, the relevance of the body modification to the current chief complaint.

Epidemiology

Within Western society there has been a shift from the stereotype of the tattooed sailors, who used tattoos to communicate their travel and services, the outsider biker of the 1960s (Hell's angels), and the gang members of the 1980s to the ornamental tattoo, which is now part of a collection of body modifications among women as much as men. Recent surveys completed in 2002 and again in 2006 have shown an increase in prevalence in tattoos within the US population.^[5,6] In 2002, a Harris poll showed a tattoo prevalence of 16%, whereas in 2006 a North American survey of 18 to 50 year olds found that 24% had tattoos and 14% had body piercings (excluding the ear). The surveys found that those who were tattooed were more likely to be less well educated, to have a high recreational drug use, and were less likely to show any religious affiliation.

Tattooing can be used to camouflage intravenous drug abuse, where it involves the antecubital fossa, and has an important place within generalized medical therapy. Its use is seen as a camouflage for dermatologic disease, can be added as a final stage in many plastic reconstructive procedures, and is also used for guidance in radiation therapy, endoscopic surgery, and ophthalmologic procedures.

Studies, which have looked at the epidemiology of piercings, have found that 2% of Americans report having piercings (not including the ear lobe) and that females get more piercings than men. Among young adults who have piercings there is a high rate of associated eating disorders.^[7] Studies also show that persons who get piercings are more likely to partake in risky activities, including drug taking and sexual promiscuity, and have a higher risk of incarceration. The educational status and income of persons with T&P are generally lower, although these educational and economic disparities are lessening as T&P becomes more mainstream (Table 1).^[8,9]

Medical Relevance for the Emergency Practitioner

There are several ways that T&P are relevant to the practicing emergency practitioner (Table 2).

Interpretive Relevance

For the EP, T&P presents a window to the lifestyle and life experience of the patient. Many questions relevant to the history can be answered by a review of the T&P present. Figures 1 through 4 show examples of information obtained from T&P. While interpretation is not as simple as it was 30 years ago, when sailors, military members, and gangs had the most tattoos, relevant information is often within reach of the observant EP.

Figure 1. "LW" is a gang affiliation meant to be seen when wearing sandals.

Figure 2. Mi vida Loca = My crazy life also seen as [ in many patients; in this case, "LOWCA" is a reference to low riders and the automotive culture associated with them. The gang is "Lowell Street," indicating a traditional Hispanic "turf gang" that is "loco"—crazy or brave.

Figure 3. Jiminy Cricket shown (a derogatory reference to the Crips, when called crickets or crabs), with the lipstick mark from a woman who loves him. The N and the E probably refer to northeast and the Chinese characters are of uncertain reference.

Figure 4. "Brown Pride" for racial identity as Hispanic or Latin; the anticubital fossa tattoos often cover intravenous drug abuse tracks, and the woman (right arm) is often the woman who "waits for him" during jail time. Yolanda is his girlfriend, and the left anticubital fossa tattoo is a tribute to a family member in the military, killed in service with "R.I.P.", or rest in peace, noted above.

Complications of Tattoos

Tattoo complication rates show a prevalence of approximately 2% to 3%. Table 3 summarizes the complications associated with tattoos, many of which will be encountered by EPs. Most complications are related to infection that can be traced back to individual tattooist practicing a nonsterile technique. In particular, the jail and intravenous drug-using population is at risk for hepatitis B and C and methicillinresistant Staphylococcus aureus infection.^[10–12] Even syphilis has been transmitted by a tattoo artist licking the tattoo needle.^[13] Failure to recognize a tattoo as the source of a complication leads to incorrect therapy. In many cases the tattoo is not correctly linked to the medical problem because the patient may have multiple risky behaviors.

Complications of Piercings

Complications of piercings are more common than those of tattoos and studies show rates as high as 9%. The types of complications include local or systemic infections, traumatic insertion, poor cosmesis, and rejection of foreign body, as well as migration and embedding.^[14] These are summarized in Table 4.

Jewelry is mainly body-site specific and made from metal. Metals used include stainless steel, gold, titanium, and various alloys. When these alloys contain nickel, there are associated allergic skin reactions and contact dermatitis. Specific complications relevant to the EP are summarized in Table 5. Rarer complications of piercings include bacterial endocarditis, tetanus, piercing migration with embedding, and even a case reported of appendicitis from a swallowed piercing that occluded the appendiceal aperture.^[15–18]

Psychologic Associations of Body Modifications

The EP should be more concerned about illnesses and suicidal behavior in those with body modifications. Tattooing correlates with the perception of decreased mental health, and tattooing and body piercing together correlate highly with increased "sensation-seeking" behavior.^[19] A study of young tattooed Korean males conducted in Korea, where body modification is considered part of counterculture, used the Minnesota Multiphasic Personality Inventory personality test and found high scores in items of psychopathic deviance and schizophrenia, suggesting that those with tattoos were impulsive, hostile, and prone to delinquent behavior.^[20] A data analysis of 4,700 individuals who responded to a Web site (www.bmezine.com) for body modification found a high frequency of abuse in the background of those who participated. This survey also found that 36.6% of the males had suicidal ideation and 19.5% had attempted suicide. For the females, a statistically significant higher suicidality rate was found, with percentage values of 40.8% and 33.3% respectively.^[21] Skegg^[22] noted that piercing was more common among women rated as having low constraint or high negative emotionality and was less common among those with high positive emotionality. Therefore, one can conclude that body piercing and tattoos, especially in females, could be a sign of suicidal behavior. However, no association has been found with eating disorders.^[7]

Some authors have attempted to show positive association for these body modifications. In a study of women with eating disorders, the authors suggested that body piercing could be seen as reflecting a positive attitude towards the body, an expression of care.^[23] In addition people with piercings are more likely to give attention to their physical appearance and are less likely to be overweight than people without piercings.^[22]

Removal of Tattoos and Piercings

Burris and Kim^[24] found that 50% of persons with tattoos express regret and wish for tattoo removal. The quest for tattoo removal reflects earlier poor decision making and an embarrassing stigma often perceived by the age of 40 years. Tattoos may cause immediate and delayed hazard to health and are not easy to remove. Delayed complications include development of allergic, hypersensitivity, or granulomatous reactions that require tattoo removal.^[25] On average, tattoo regret occurs 14 years after tattooing and has spawned a whole new industry. Nonprofit organizations also provide tattoo removal to gang members wishing to remove their tattoos (www.homeboy-industries.org). Tattoos can be removed by mechanical, chemical, or thermal methods.

Alternatives to permanent tattoos include the Indian technique of staining the skin with henna. This will fade over a period of 7 to 10 days. In the past year there has been the development of nonpermanent tattoo ink. This technique uses ink-containing beads that are deployed in the same method as used previously. However, the ink can be fully removed by single-pass laser treatment (www.freedom2ink.com) that dissolves the bead, allowing the dye to be exposed to enzymes, laser, and UV rays.

Source Medscape

Summary

Tattoos and piercings have become widespread practices that enjoy greater social acceptance than ever before. Body modification is important to the EP because it provides information about the "patient." The physician can learn a great deal about these patients via their body modification, including information of immediate relevance to their medical evaluation. Secondarily, T&P are directly responsible for an increasing number of emergency department visits due to both immediate and delayed complications. The EP armed with knowledge about T&P/body modifications can forge more functional doctorpatient relationships, obtain critical historical data, and provide better treatment and referral for this patient population.

*
1. Tattoos By Design. History of tattoos. Tattoos By Design Web site. Available at: www.tattoos-by-design.co.uk/history.html. Accessed April 23, 2008.
2. Gennaro J. A brief tattoo history. Religious Tattoos Web site. Available at: http://www.religioustattoos.net/tattoos-history/index. Accessed April 23, 2008.
3. Scheinfeld N. Tattoos and religion. Clin Dermatol. 2007;25:362–365.
4. Vassileva S, Hristakieva E. Medical applications of tattooing. Clin Dermatol. 2007;25:367–374.
5. Laumann A, Derick A. Tattoos and body piercings in the United States: a national data set. J Am Acad Dermatol. 2006;55:413–421.
6. Sever J. The Harris Poll No. 58, October 8, 2003. Harris Interactive Web site. Available at: http://harrisinteractive.com/harris_poll/printerfriend/index.asp?PID¼407. Accessed April 23, 2008.
7. Preti A, Pinna C, Nocco S, et al. Body of evidence: tattoos, body piercing, and eating disorder symptoms among adolescents. J Psychosom Res. 2006;61:561–566.
8. Armstrong ML, Roberts AE, Koch JR, et al. Investigating the removal of body piercings. Clin Nurs Res. 2007;16:103–118.
9. Panconesi E. Body piercing: psychosocial and dermatologic aspects. Clin Dermatol. 2007;25:412–416.
10. Samuel MC, Doherty PM, Bulterys M, et al. Association between heroine use, needle sharing and tattoos received in prison with hepatitis B and C positivity among street-recruited injecting drug users in New Mexico, USA. Epidemiol Infect. 2001;127:475–484.
11. Zeuzem S, Teuber G, Lee JH, et al. Risk factors for the transmission of hepatitis C. J Hepatol. 1996;24:3–10.
12. Stemper ME, Brady JM, Qutaishat SS, et al. Shift in Staphylococcus aureus clone linked to an infected tattoo. Emerg Infect Dis. 2006;12:1444–1446.
13. Long GE, Rickman LS. Infectious complications of tattoos. Clin Infect Dis. 1994;18:610–619.
14. Meltzer DI. Complications of body piercing. Am Fam Physician. 2005;72:2029–2034.
15. Ochsenfahrt C, Friedl R, Hannekum A, et al. Endocarditis after nipple placement in a patient with bicuspid aortic valve. Ann Thorac Surg. 2001;71:1365–1366.
16. Lick SD, Edozie SN, Woodside KJ, et al. Streptococcus viridans endocarditis from tongue piercing. J Emerg Med. 2005;29:57–59.
17. O'Malley CD, Smith N, Braun R, et al. Tetanus associated with body piercing. Clin Infect Dis. 1998;27:1343–1344.
18. Hadi HI, Quah HM, Maw A. A missing tongue stud: an unusual appendicular foreign body. Int Surg. 2006;91:87–89.
19. Stuppy DJ, Armstrong ML, Casals-Ariet C. Attitudes of health care providers and students toward tattooed people. J Adv Nurs. 1998;27:1165–1170.
20. Kim JJ. A cultural psychiatric study on tattoos of young Korean males. Yonsei Med J. 1991;32:255–262.
21. Hicinbothem J, Gonsalves S, Lester D. Body modification and suicidal behavior. Death Stud. 2006;30:351–363.
22. Skegg K, Nada-Raja S, Paul C, et al. Body piercing, personality, and sexual behavior. Arch Sex Behav. 2007;36:47–54.
23. Claes L, Vandereycken W, Vertommen H. Self-care versus self-harm: piercing, tattooing, and self-injuring in eating disorders. Eur Eat Disord Rev. 2004;13:11–18.
24. Burris K, Kim K. Tattoo removal. Clin Dermatol. 2007;25:388–392.
25. Stirn A. Trauma and tattoo-piercing, tattooing and related forms of body modification between self-care and self-destruction of traumatized individuals. Psychotraumatologie. 2002;2:45.
26. Van Sciver AE. Hepatitis from ear piercing. JAMA. 1969;207:2285.
27. Perkins CS, Meisner J, Harrison JM. A complication of tongue piercing. Br Dent J. 1992;182:147–148.
28. Fischer T, Fregert S, Gruvberger B, et al. Nickel release from ear piercing kits and earrings. Contact Dermatitis. 1984;10:39–41.
29. McCarthy VP, Peoples WM. Toxic shock syndrome after ear piercing. Pediatr Infect Dis J. 1988;7:741–742.
30. Lane JE, Waller JL, Davis LS. Relationship between age of ear piercing and keloid formation. Pediatrics. 2005;115:1312–1314.
31. Turkeltab SH, Habal MB. Acute Pseudomonas chondritis as a sequel to ear piercing. Ann Plast Surg. 1990;24:279–281.
32. Hanif J, Frosh A, Marnane C, et al. Lesson of the week: "High" ear piercing and the rising incidence of perichondritis of the pinna. BMJ. 2001;322:906–907.
33. Gazzeri R, Mercuri S, Galarza M. Atypical trigeminal neuralgia associated with tongue piercing. JAMA. 2006;296:1840–1842.
34. Hadi HI, Quah HM, Maw A. A missing tongue stud: an unusual appendicular foreign body, Int Surg. 2006;91:87–89.
35. Maheu-Robert LF, Andrian LE, Grenier D. Overview of complications secondary to tongue and lip piercings. J Can Dent Assoc. 2007;73:327–331.
36. Simplot TC, Hoffman HT. Comparison between cartilage and soft tissue ear piercing complications. Am J Otolaryngol. 1998;19:305–310.
37. Gokhale R, Hernon M, Ghosh A. Genital piercing and sexually transmitted infections. Sex Transform Infect. 2001;77:393–394.

Natural Variation in Drug Susceptibility to HCV Polymerase Inhibitors in Treatment-naïve HCV Patient Isolates

Source Medscape

From Journal of Viral Hepatitis

Natural Variation in Drug Susceptibility to HCV Polymerase Inhibitors in Treatment-naïve HCV Patient Isolates

S.-C. C. Sun; A. Bae; X. Qi; J. Harris; K. A. Wong; M. D. Miller; H. Mo

Posted: 12/27/2011; J Viral Hepat. 2011;18(12):861-870. © 2011 Blackwell Publishing

Abstract and Introduction

Abstract

To assess the natural variation in drug susceptibility among treatment-naïve hepatitis C virus (HCV) patient isolates, the susceptibilities of chimeric replicons carrying the HCV NS5B polymerase from up to 51 patient isolates against a panel of diverse HCV nonnucleoside polymerase inhibitors were evaluated using a replicon-based transient replication assay. Some patient to patient variation in susceptibility to the panel of three HCV nonnucleoside polymerase inhibitors was observed. Linear regression and correlation analyses revealed no correlations among the susceptibilities to the polymerase inhibitors tested. Our results suggest that variable antiviral responses to HCV nonnucleoside polymerase inhibitors may be observed because of the natural variation in baseline susceptibility. In addition, the lack of correlation among the susceptibilities to three classes of HCV polymerase inhibitors evaluated here supports their possible combined use in a combination therapy strategy

Discussion Only
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In this study, the sensitivity of up to 51 clinical baseline isolates from untreated HCV GT-1-infected patients to a panel of nonnucleoside HCV polymerase inhibitors was determined to investigate the effect of HCV genetic diversity on the inhibitor's antiviral potency. Some natural variation in susceptibility among these isolates was observed with all three different classes of HCV polymerase inhibitors tested (benzofuran, benzothiadiazine and thiophene carboxylic acid). The degree of the variation in EC₅₀ was slightly different among these three drug classes of nonnucleoside HCV polymerase inhibitors. The EC₅₀ values in the 95th percentile were 4.5-, 6.0- and 7.5-fold higher than the 5th percentile EC₅₀ values for the thiophene carboxylic acid, benzofuran and benzothiadiazine, respectively. Interestingly, no significant difference in sensitivity between GT-1a and GT-1b was observed for the tested benzofuran and thiophene carboxylic acid. In contrast, the benzothiadiazine was significantly more potent against GT-1b than GT-1a. The differential potency against GT-1a vs GT-1b for only the benzothiadiazine, and the high assay reproducibility for the reference standard suggests that the natural variation in drug susceptibility observed among baseline clinical isolates is not caused by assay variation. In addition, the results in the study are consistent with the findings of previous reports that described variable activity for HCV nonnucleoside polymerase inhibitors among clinical baseline isolates using similar phenotypic analysis assays.^[38,39]

Given the observation of the natural variation in drug susceptibility to these three classes of nonnucleoside inhibitors, it is possible that this natural variation may cause variable antiviral response among different patients. For example, one dose may be optimal for patients containing more sensitive variants, but this same dose may be suboptimal for patients who have less susceptible variants. Indeed, variable response to some of the HCV nonnucleoside polymerase inhibitors among different patients has been observed in clinical studies, especially in lower-dose groups. Furthermore, consistent with the in vitro findings of less potent activity against GT-1a than GT-1b for the benzothiadiazines in this study, the response in HCV GT-1a-infected patients was poorer than the GT-1b-infected patients during monotherapy with ABT-333 and ANA-598 (both benzothiadiazines).^[9,10] In addition to the susceptibility of baseline isolates, the pharmacokinetics of the drug also influences response. The natural variation in drug susceptibility coupled with pharmacokinetic information could be used to predict the response to drug treatment and provide guidance on the drug concentration needed for achieving a maximal response. If sufficiently high levels of drug exposure relative to the cluster of EC₅₀ values is achieved, the natural variation in drug susceptibility would be of less concern. Finally, the natural variation in baseline susceptibility could provide a threshold for defining abnormal reductions in drug susceptibility and serve as an indicator for an increased probability of drug resistance.

Sequence analysis of NS5B revealed C316N and S556G double mutants in 2 of the 14 GT-1b isolates. Phenotypic analysis of the one isolate with sufficient replication capacity to test drug susceptibility had the highest EC₅₀ against the benzofuran. This finding is consistent with previous reports, demonstrating that C316N confers a low-level of resistance to the benzofuran.^[26] However, the benzofuran susceptibility of this isolate was well within the natural variation of the GT-1a isolates and it had wild-type susceptibility to the benzothiadiazine tested in this study. Similarly, no significant change in EC₅₀ to the benzothiadiazine was seen in the isolate containing S556S/G. Previous studies showed that both C316N and S556G were associated with reduced susceptibility to other compounds of the benzothiadiazine class.^[23,24,26] The discrepancy may be due to the fact that the benzothiadiazine compound tested in this study has subtle differences in chemical structure with the benzothiadiazine compounds in previous studies resulting in a slightly different interaction with the NS5B polymerase.

In contrast to the above three GT-1b isolates, NS5B sequence analysis did not identify any of the mutations that are known to confer resistance to the tested compounds in 52 of 55 patient samples (41 GT-1a and 11 of 14 GT-1b). In addition, no clear pattern of the NS5B sequence was revealed in baseline clinical isolates with higher EC₅₀ values (data not shown). Thus, the natural variation in drug susceptibility observed in this study may be caused by the intrinsic genetic diversity of HCV.

The mean EC₅₀ values derived from each baseline clinical isolate against the benzofuran, benzothiadiazine and thiophene carboxylic acid were compared between drugs using the statistical regression analysis of correlation. Overall, the correlation was poor between any of the three compounds. These results suggest that the HCV variants which are less susceptible to one of these three classes of nonnucleoside polymerase inhibitors may not be less sensitive to the other two different classes of nonnucleoside polymerase inhibitors. Therefore, a combination of two or three different classes of nonnucleoside polymerase inhibitors may be advantageous for maximal antiviral response and reducing the selection of resistance. However, other aspects including synergistic/antagonistic inhibitory effects, drug–drug interactions and overlapping toxicity profiles should be taken into consideration for potential combination therapy strategies. The lack of correlation between two different classes of nonnucleotide polymerase inhibitors agrees with the fact that these three nonnucleoside inhibitors target different sites of the HCV polymerase and also exhibit different resistance profiles.

In summary, the activity of three classes of nonnucleoside polymerase inhibitors (benzofuran, benzothiadiazine and thiophene carboxylic acid) against a panel of baseline clinical isolates was evaluated using a replicon-based transient replication assay. Some variation in drug susceptibility was observed for all three classes of nonnucleoside polymerase inhibitors. However, there was no correlation between susceptibilities from one compound to another among those tested. Our findings suggest that the existing natural variation in baseline susceptibility should be taken into account for the optimal dose selection for the development of future nonnucleoside polymerase inhibitors. The lack of correlation between drug susceptibilities supports the combination of these different classes of HCV nonnucleotide polymerase inhibitors in the clinic.

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Management of Hepatitis C Infection

From CCO

Hepatology - Management of Hepatitis C Infection

Authors: Jordan J. Feld, MD, MPH, Hemant Shah, MD, FRCPC

Released: 12/13/11

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Preview Of Topics

Management of Acute Hepatitis C Virus Infection

Goals of Therapy
In patients with chronic hepatitis C virus (HCV) infection, the goal of therapy is virologic cure. Eradication of HCV RNA, which persists long-term off therapy, is referred to as a sustained virologic response (SVR). Although SVR is equivalent to virologic cure, the term cure has traditionally been avoided. Initially, there was concern that despite undetectable HCV RNA following treatment, there might potentially be dormant virus that could return in the future. However, long-term follow-up data show that patients with an SVR following treatment with peginterferon and ribavirin have a relapse rate < 1% after a mean of 1.8 years from the end of antiviral treatment.....

Types of Therapy
Peginterferon Alfa
Ribavirin
Protease Inhibitors
Combination therapy is necessary to optimize hepatitis C virus treatment response rates. Currently recommended treatment options include pegylated interferon, ribavirin, and (for patients with genotype 1 HCV infection) the protease inhibitors boceprevir and telaprevir.

Treatment Candidacy
Several factors must be considered when deciding to treat a patient with hepatitis C virus (HCV) infection, including stage of disease, natural history, treatment efficacy, the potential for adverse events, and response to previous treatment. In general, all patients with histologic and serologic evidence of HCV infection should be considered as treatment candidates

Pretreatment Evaluation
A thorough patient history should be obtained before prescribing hepatitis C virus (HCV) therapy. Several issues need to be explored to aid decision-making, including the patient’s medical history, socioeconomic status, and any psychiatric comorbidities.

History
Table covers-cardiac history, thyroid history, autoimmune history and more.

Physical Examination
A thorough physical examination is necessary before initiating hepatitis C virus (HCV) therapy This is partly to identify health issues that need to be addressed before therapy, but it also is to serve as a baseline for comparison once therapy is initiated.

Laboratory Testing
Pretreatment laboratory testing is essential in patients commencing hepatitis C virus (HCV) therapy and serves to rule out coexistent liver disease, ensure safety parameters before therapy, and aid in posttreatment monitoring

Role of Liver Biopsy and Noninvasive Tests in Determining Fibrosis
An assessment of hepatic fibrosis is needed before commencing hepatitis C virus (HCV) therapy and selected noninvasive markers commonly used in the setting of hepatitis C are summarized

The degree of fibrosis has an impact on treatment duration and response. In addition, cirrhotic patients should be surveyed for hepatocellular carcinoma even if they go on therapy and ultimately achieve sustained virologic response. Until recently, most patients with HCV had liver biopsies to assess fibrosis. However, there are now several other modalities available to assess fibrosis by noninvasive means. In many patients, the use of noninvasive measures for hepatic fibrosis assessment is sufficient.

Pretreatment Optimization of the Cirrhotic Patient
Although cirrhotic patients have lower response rates to hepatitis C virus (HCV) therapy than noncirrhotic patients, achievement of sustained virologic response in this group has a marked effect on the risk of liver-related mortality.

Therapeutic Regimens: Which Therapy for Which Patient?
Non–Genotype 1 Patients
For non–genotype 1 patients, standard-of-care hepatitis C virus (HCV) therapy is a combination of peginterferon alfa-2a or peginterferon alfa-2b and ribavirin

Genotype 1 Patients
For patients with genotype 1 HCV, standard-of-care treatment is now a triple-therapy combination of peginterferon alfa-2a or peginterferon alfa-2b, ribavirin, and a protease inhibitor (either boceprevir or telaprevir). Recommended dosing for ribavirin is weight-based only according to the guidelines used for the peginterferon of choice. ©2003-2011 Clinical Care Options, LLC. All Rights Reserved.

Treatment Efficacy
Peginterferon and Ribavirin
Monitoring and Determining Treatment Efficacy With Peginterferon/Ribavirin Dual Therapy
Boceprevir (Genotype 1 Only)
Telaprevir (Genotype 1 Only)
Any discussion of treatment efficacy must be considered according to hepatitis C virus (HCV) genotype, the most important determinant of treatment outcome with interferon-based therapy. Genotype 1 is the least interferon-responsive HCV genotype and has therefore been the primary focus for the development of direct-acting antiviral agents (DAAs). First-generation DAAs were specifically developed for genotype 1 HCV, and although telaprevir and boceprevir may have some efficacy against other genotypes (particularly genotype 2), they are only approved for use in genotype 1 infection.

Using Protease Inhibitors
Pretreatment Predictors of Response
Viral Factors
Host Factors
This section provides practical information about using approved protease inhibitors (PIs) in patients with hepatitis C virus (HCV) infection
Note that the approved indications for use of telaprevir and boceprevir in Europe differ somewhat from those approved by the US FDA

On-Treatment Predictors of Response
Once hepatitis C virus (HCV) treatment is started, initial viral kinetics are helpful in predicting treatment outcome. Patients who have cleared viremia by Week 4 of therapy, whether with protease inhibitor (PI)–based triple therapy or with peginterferon/ribavirin alone, are very likely to achieve sustained virologic response (SVR). By contrast, those who still have detectable HCV RNA levels by Week 12 of therapy have very low likelihood of obtaining SVR

Protease Inhibitor Resistance
Mechanisms of Resistance
Significance of Resistance
Current Understanding of Protease Inhibitor Resistance
Prevention of Resistance
The development of direct-acting antiviral agents (DAAs) has been a major therapeutic advance in the treatment of hepatitis C virus (HCV) infection, but it has also introduced new challenges. True viral resistance to peginterferon and ribavirin has not been described (although host resistance to interferon is well characterized). By contrast, resistance-associated variants have been identified for all DAAs and have been shown to emerge rapidly with the use of DAA monotherapy. This section will discuss resistance to telaprevir and boceprevir.

Adverse Effects and Management Strategies
Peginterferon/Ribavirin
Protease Inhibitors: Boceprevir and Telaprevir
The use of either peginterferon/ribavirin dual therapy or in combination with direct-acting antiviral agents can lead to significant adverse effects that necessitate dose reduction or discontinuation of treatment. Early recognition and intervention can help clinicians ensure patients are able to complete therapy where possible and achieve the goal of viral eradication. Although every patient will experience adverse effects to differing degrees, a systematic approach to their management can be very helpful.

Posttreatment Management
Sustained virologic response (SVR) is determined with measurement of HCV RNA using a highly sensitive assay 24 weeks following the end of treatment. For patients who obtain an SVR and do not have cirrhosis, no long-term monitoring is necessary. In some centers, such patients undergo hepatitis C virus (HCV) RNA testing 1 year after completion of treatment to confirm that HCV RNA remains undetectable.
For patients who obtain an SVR and have cirrhosis, long-term follow-up is required

Successful Therapy
Unsuccessful Therapy

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Hepatitis C News Ticker: Following response-guided therapy guidelines with boceprevir and telaprevir

"Reading the Paper" Lynne Crumpacker

Hepatitis Journal Options – Volume 5, Issue 1

Now Available! CCO Hepatology inPractice™

This special edition includes all the pivotal phase III studies of the HCV protease inhibitors, with a range of commentaries exploring key aspects of the use of these agents, plus Capsule Summaries of each study and downloadable slidesets.

Topics include:

• Following response-guided therapy guidelines with boceprevir and telaprevir
• Understanding futility rules and their importance
• Outcomes and management of anemia
• Strategies for managing telaprevir rash and anorectal symptoms
• Using boceprevir and telaprevir in patients with advanced fibrosis or cirrhosis
• Effect of telaprevir on cyclosporine and tacrolimus pharmacokinetics
• Antiviral activity with telaprevir in patients with genotype 2 or 3 HCV
• Evaluation of HBV screening cost effectiveness

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