P- Reviewer: Pavlidis C S- Editor: Song XX L- Editor: O’Neill M E- Editor: Ma S
Published online Nov 7, 2013. doi: 10.3748/wjg.v19.i41.6947
Revised: July 27, 2013
Accepted: August 16, 2013
Published online: November 7, 2013
The high rate of sustained viral response (SVR) to boceprevir or telaprevir-based triple therapy in hepatitis C (HCV)-related, non-cirrhotic naïve patients or relapsers to previous antiviral treatment leads clinicians to believe that the impact of metabolic host factors on SVR is minimal when triple therapy is used, unlike what is observed with the peginterferon and ribavirin schedules. This concept is strongly expressed by some opinion leaders on the basis of the data derived from sub-analyses of registrative trials as well as from a post-hoc analysis of the phase II C208 clinical trial. The perception of unrestrainable therapeutic success with the use of newer, more powerful antivirals is now reinforced by the brilliant results obtained with sofosbuvir, an HCV NS5B polymerase inhibitor, as well as by the data from the phase II and III studies on the various combinations of second-generation NS3/4A inhibitors and NS5A and/or NS5B inhibitors. However, a great deal of concern has emerged from the real world scenario in which patients are often older and have more comorbidities than patients in the “world of trials”. Furthermore, many of them have advanced fibrosis and previous failure with peginterferon and ribavirin treatment. Some data from the recent literature suggest that the host metabolic factors may play a minor but non-negligible role in these difficult-to-treat patients, an issue that will hopefully be investigated in further studies. This editorial aims to provide a detailed analysis of the role that host metabolic factors played in the past and what role they may play in the era of direct antiviral agents.
Core tip: This editorial explores the past and present role of metabolic factors by analyzing the data that has emerged from the post hoc analysis of registrative trials of direct antiviral-based treatment. Low-density lipoprotein-cholesterol and statin use proved to be predictors of sustained viral response (SVR) in both boceprevir and telaprevir-treated patients, respectively. Furthermore, HOMA-IR negatively influenced SVR in prior partial and null responders treated with telaprevir-based schedules. By transferring these data to the real world scenario in which patients have comorbidities, advanced fibrosis and prior failure to antiviral treatment, we believe that metabolic factors might play a non-negligible role in influencing antiviral response, even in triple therapy.
- Citation: Grasso A, Malfatti F, Testa R. Are metabolic factors still important in the era of direct antiviral agents in patients with chronic hepatitis C? World J Gastroenterol 2013; 19(41): 6947-6956
- URL: https://www.wjgnet.com/1007-9327/full/v19/i41/6947.htm
- DOI: https://dx.doi.org/10.3748/wjg.v19.i41.6947
More than 170 million people are chronically infected with the hepatitis C virus (HCV) worldwide, thus HCV has become the main cause of chronic liver disease leading to death from liver failure or hepatocellular carcinoma (HCC) in many Western countries and in Japan. Viral eradication resulting from antiviral treatment has led to a decrease in these complications. However, treatment with pegylated interferon and ribavirin, which has been the standard-of-care therapy for chronic hepatitis C for the last decade, has been able to cure only about 40%-50% of patients with hepatitis C genotype 1, the main strain in Europe and the United States[3-6].
Genotype 1 is the main viral-related variable associated with treatment failure[3,4]. However, a number of other pretreatment variables related to the virus (high viral load) and to the host (interleukin 28b polymorphism, age, overweight, metabolic factors), as well as on-treatment variables (4-wk negativization of viral load) have been shown to affect the response to anti-viral dual therapy[7-10].
Epidemiological data suggest that HCV interferes with glucose and lipid metabolism. Patients with diabetes show a greater prevalence of HCV as compared to the non-diabetic population. Moreover, the prevalence of diabetes is significantly higher in chronic hepatitis C patients than in those with chronic liver disease other than HCV. Furthermore, it is well known that HCV infection is an independent risk factor for developing diabetes. These data suggest that HCV, rather than liver disease per se, predisposes patients to diabetes. The link between HCV and diabetes is the development of insulin resistance (IR), a metabolic prerogative of HCV (i.e., IR is more than six fold higher in HCV patients than in those with HBV). IR, hepatic steatosis and body mass index (BMI) are related in a genotype-dependent fashion. In fact, HCV genotype 3 exerts a direct cytopathic and steatogenic effect on hepatocytes, thus resulting in a higher prevalence of steatosis and a lower prevalence of IR compared with HCV genotype 1, which very quickly induces IR and some steatosis[15-17]. IR occurs very early in transgenic mice expressing the HCV core protein and may even precede the occurrence of hepatic steatosis, thus indicating that IR is not a consequence of hepatic steatosis, similarly to what is observed in humans. Furthermore, IR is a pro fibro genetic stimulus, thus patients with high IR show more advanced liver fibrosis than patients with low IR. Finally, the association between IR and high HCV RNA levels suggests a complex interplay between viral replication and insulin action. HCV may induce over-expression of the suppressor of the cytokine signaling-3 (SOCS3) gene in liver tissue. This gene is involved in the interferon signaling pathway and is associated with poorer treatment outcome[20,21]. HCV core-induced SOCS3 may promote proteosomal degradation of the insulin receptor substrates 1 and 2 (IRS1/2), thus inducing severe hepatic IR[22,23]. Both SOCS3 over-expression and hepatic steatosis promote intra-hepatic and systemic lipid oxidation, thus leading to an imbalance of total glucose disposal in the muscles and resulting in peripheral (and not only hepatic) IR.
Direct involvement of HCV in glucose metabolism has also been demonstrated “in vivo”. In fact, there is robust evidence showing that IR improved significantly in patients with HCV genotype 1 who achieved SVR compared with patients who did not obtain viral clearance after treatment[25,26]. Furthermore, achieving viral clearance is demonstrated to significantly reduce the risk of both type 2 diabetes in retrospective cohorts and of de novo IR in non-diabetic HCV patients.
Hepatic steatosis is also related, in a genotype-specific manner, to a decrease in serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB), thus demonstrating the close link between HCV and lipids. A variable fraction of HCV in the serum circulates in lipo viro particles (LVP), with very-low-density-lipoprotein (VLDL) containing apoB and apoE. LVP reach the highest levels in the post prandial phase, suggesting that their formation is a dynamic process. Very recently, a strong correlation between the maximum amount of LVP in vivo and both IR and metabolic syndrome was reported, suggesting that lipids may play a role in HCV-induced IR. ApoE is considered the central component of the HCV-host lipid interaction, mediating HCV infectivity via lipoprotein receptors. Lipoproteins (LP) are easily endocytosed, thus supporting the hypothesis that HCV can use this association with LP to adhere to the cell and subsequently enter the host cell by endocytosis. Various cell surface receptors, including tetraspanin CD814, scavenger receptor class B member I, tight-junction proteins claudin-1 and occludin, and clathrin-mediated endocytosis have been proposed as entry factors for HCV, but the role each of them plays remains controversial. Recently, the Niemann-Pick type C1-like 1 (NPC1L1) gene receptor has come to the attention of researchers in the view of a potentially new therapeutic antiviral strategy since it is the possible target of the receptor-blocker drug ezetimibe[34,35].
Few and inconsistent data have been reported on serum lipid level modifications during interferon therapy. Increased total cholesterol and triglyceride levels have been observed with interferon treatment, with a subsequent drop to pretreatment levels of both after discontinuing therapy, but with different trends depending on the HCV genotype[36,37]. In a small population of patients with genotype 2 and 3, viral clearance induced serum level modifications of lanosterol, a cholesterol precursor, suggesting a direct viral interference with the enzymes of sterol synthesis.
Patients with high IR show a slower decay of HCV viral load than patients with low IR, even in the very early phase of treatment (first 24 h), suggesting that hyperinsulinemia reduces the cellular response to pegylated-interferon. Furthermore, high IR has been associated with a low rate of rapid viral response (RVR) in genotypes 1, 3 and 4.
Whether or not IR influences SVR rate has been a question of debate since 2005. Two meta-analyses assessing the impact of IR on treatment outcome, both of which included fourteen studies with more than 2700 patients, were published in 2011[42,43]. However, among the studies which failed to find an association between IR and SVR, the main baseline HOMA value, an indirect measurement of IR[44,45], was < 3 and the prevalence of advanced fibrosis or cirrhosis was also low or even absent. This observation supports the hypothesis that the HOMA value is predictive of response to antiviral treatment mainly in patients with advanced disease stage. Liver fibrosis is an event which may occur as a consequence of HCV-related chronic necroinflammatory activity or via HCV related IR, or probably both. However, non-HCV related IR (genetic, or related to true metabolic syndrome) may also occur since almost 25% of the general population has the metabolic syndrome stigmata. On the basis of these data, we can assume that a proportion of patients with prevalent virus-related IR (likely those with lower fibrosis as well as a lower incidence of cardio-metabolic comorbidities) have lower HOMA values and a higher likelihood of SVR after antiviral treatment, whereas other HCV patients with prevalent metabolic IR (likely those with the phenotype of metabolic syndrome) have a higher probability of advanced fibrosis as well as higher HOMA levels and a lower probability of achieving SVR[28,42,47].
Obesity is another important metabolic cofactor that can affect antiviral response. It may induce IR and hepatic steatosis, both of which are associated with poor antiviral response either directly or by ultimately promoting liver fibrosis. However, it has been demonstrated that obesity is an independent negative predictor of response to antiviral treatment regardless of genotype and cirrhosis.
Obesity is now considered an inflammatory condition, resulting in an abnormal immune response to therapy. Adipose tissue secretes many proteins, including adipokines, which regulate hepatic and peripheral glucose and lipid metabolism. One of the adipokines secreted by adipose cells is leptin, whose expression is regulated by interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α) and insulin. Although leptin secretion from adipocytes provides antiobesity signals, obese patients have elevated levels of leptin. This suggests an intrinsic leptin resistance in the obese, a complex phenomenon involving increased levels of SOCS3, which impairs post-receptor signaling and leads to reduced adenosine monophosphate-activated protein kinase (AMPK) activation[48,49].
Increased SOCS3 expression, which is associated with nonresponse to antiviral treatment, has been demonstrated to be independently associated with obesity in patients with chronic HCV viral genotype 1.
Regarding the role of circulating lipid levels on the efficacy of antiviral treatment, there are few, but concordant, data. Higher pretreatment total cholesterol and LDL-C[51,52], as well as lower triglyceride levels are independent variables associated with higher SVR rates.
The relationship between IL28b polymorphisms and metabolic variables has been reported in several studies, thus emerging as a new and challenging issue. There is a close association between IL28b and lipid levels. In HCV genotype 1 patients, low apoE levels and higher LDL-C were associated with IL28b rs12979860 CC rather than CT/TT[54,55]. Both IL28CC and LDL-C were good predictors of SVR, but the predictive power of IL28CC was higher. Thus, the LDL-C level was found to be a significant predictor of SVR, mainly for IL28 heterozygous CT patients.
Furthermore, lower steatosis as well as lower IR have been seen in genotype 1 patients with IL28b rs12979860 CC. In a recent, large cohort of genotype 1 patients from Italy, IL28b rs12979860 CC was associated with higher levels of total and LDL-C, lower levels of triglycerides, lower prevalence of IR and moderate-to-severe steatosis. However, only IR and steatosis were associated with IL28b rs12979860 CC after correcting for BMI and lipid profile, suggesting an indirect role of LDL-C status on IL28b polymorphism. IR was found to have a predictive power for SVR which is independent of IL28 genotype, although the likelihood of achieving SVR progressively increases from the lowest probability in patients carrying both negative predictors (IR and rs12979860 TT/TC; SVR = 20.7%) to the highest probability in patients with no IR and rs12979860 CC (SVR = 78.4%). These data give rise once again to the thorny question concerning the intimate pathogenetic interplay between metabolic and genetic host factors.
One of the most intriguing and challenging tasks was to transfer the information regarding the predictive power of a metabolic variable for SVR to a practical ground. This gave rise to a series of studies aimed at improving SVR by correcting the metabolic factors before or during antiviral treatment.
Some studies with very small cohorts have explored the effect of a lifestyle intervention in obese and insulin-resistant subjects with chronic hepatitis C. BMI, HOMA values and leptin levels, but not TNF-α and IL-6, decreased significantly after aerobic exercise. A more structured intervention based on 24-wk dietary and physical activity regimens significantly reduced BMI and HOMA values and could be an interesting baseline strategy in difficult-to-treat chronic hepatitis C patients who are obese and insulin-resistant prior to starting peginterferon and ribavirin. However, to date, no studies have demonstrated the efficacy of this strategy. Tarantino et al demonstrated that a low-calorie diet for 3 mo before starting antiviral therapy in patients with genotype 1-chronic hepatitis C resulted in a significant improvement in IR as well as a 60% “end-of-treatment” response rate in the low-calorie diet group as compared to the control group (17.6%).
More data have been reported on insulin sensitizing agents used in combination with peginterferon and ribavirin. The randomized, double-blind TRIC-1 trial by Romero-Gómez et al analyzed 125 naive genotype 1 patients treated with peginterferon alpha-2a and ribavirin plus metformin or placebo on an intention-to-treat basis. Their final results showed that there was a significant decrease in both HOMA value and viral load during the first 12 wk, as well as an improvement in SVR rate in the metformin group as compared with the placebo group, but only in females. While metformin failed to improve overall SVR, conflicting results have been obtained with other insulin sensitizing agents, mainly pioglitazone. Although comforting results have been obtained in genotype 4, no improvement in SVR was observed by adding pioglitazone (30 mg/d) to peginterferon and ribavirin as compared with the standard of care of dual therapy[65,66]. Similar negative results have been shown by Harrison et al in a randomized controlled trial which compared pioglitazone plus standard of care vs standard of care alone. This study definitively demonstrated that even when pioglitazone was administered at an appropriate dose (45 mg/d), it failed to improve SVR, regardless of administration timing (i.e., prior to starting the standard of care or during the peginterferon and ribavirin course).
In recent years, several antiviral drugs that directly target HCV have been developed. These new drugs, known as direct-acting antiviral agents (DAAs), are designed to interfere directly with the HCV life cycle by inhibiting enzymes such as HCV NS3/4A protease and HCV NS5B polymerase, or other proteins such as NS5A. Two NS3/4A protease inhibitors, boceprevir and telaprevir, have become the first new drugs approved for the treatment of patients with genotype 1 HCV who have either not previously received treatment or who failed to achieve SVR with previous therapy. These new drugs, however, must be given with peginterferon and ribavirin because of their low barrier to viral resistance when they are used as monotherapy, and this may limit efficacy. A further limitation is due to overall side effects resulting in higher discontinuation rates. However, when candidates for this treatment are carefully selected, the overall SVR rates can almost double in naïve and even triple in relapsers to previous double therapy[69-75]. Thus, triple therapy is the new standard treatment for HCV genotype 1 chronic liver disease.
One of the questions under debate is whether the predictors of treatment failure that are observed when using dual therapy in HCV genotype 1 also exert a negative influence in triple therapy.
Among the variables which have shown predictive power for SVR in dual therapy, some of them, such as IL28b polymorphism, fibrosis and the 4-wk viral response in both naive or previously treated patients, have also been highlighted in triple therapy on the basis of data emerging from registrative trials. Metabolic factors seem to play either no role at all, or only a minor one in influencing SVR in the context of triple treatment. However, some considerations have to be made when looking carefully at the post-hoc analysis of landmark phase-III trials.
In the boceprevir-based SPRINT-2 trial, two metabolic variables were associated with SVR, but only statin use proved to be an independent predictor of SVR (OR = 3.4; 95%CI: 1.1-10.7; P = 0.04), whereas BMI was not retained in the multivariate model after adjustment for other variables.
In RESPOND-2, a boceprevir-based trial focusing on previously treated patients, both the response-guided treatment (RGT) group and the 48-wk triple treatment group had a significantly higher SVR rate compared with dual treatment. However, in obese patients (BMI ≥ 30), a 10% lower SVR rate was observed in the RGT group compared with the 48-wk triple treatment group (56% vs 65%).
A sub-analysis of baseline predictors in the SPRINT-2 and RESPOND-2 trials showed that a BMI ≤ 30 was significantly associated with SVR and with a ≥ 1 log10 HCV-RNA decline at week 4 in untreated patients but not in patients previously treated with peginterferon and ribavirin.
In the two telaprevir-based studies carried out on untreated patients, both ADVANCE and ILLUMINATE showed a higher SVR rate in the RGT arms compared with the double treatment arm, regardless of diabetes and obesity. In the ADVANCE study, although a 30% greater improvement in the SVR rate of patients receiving telaprevir for 12 wk was achieved in all 3 BMI groups (< 25, 25-30 and > 30) as compared to the control group, a 12%-16% lower SVR rate was observed in overweight and obese patients compared to normal weight patients.
An important contribution was provided by Serfaty et al in their post-hoc analysis of the phase II C208 clinical trial. In this study, which is the first to focus on the influence of baseline metabolic variables on SVR in patients treated with triple therapy, only LDL-C was associated with SVR (even in multivariate analysis), thus confirming its predictive role for SVR even in the telaprevir-based triple regimen and not only in dual therapy. However, this is not the case for baseline IR measured by the HOMA index, which did not show any relationship with SVR. Furthermore, the HOMA index did not influence the 4-wk HCV RNA decline, nor were the rates of HCV RNA undetectability at week 4 found to differ among patients with or without IR. However, this is not surprising since baseline HOMA values were not found to be associated with SVR in many European studies in which the study population had a low prevalence of advanced fibrosis and a relatively low BMI[39,40,80,81]. This may suggest that a higher prevalence of “viral” IR, which can easily be counteracted by antivirals, actually does exist in this population of patients. The significant association between HCV RNA and HOMA values in the study of Serfaty et al, as well as the improvement of HOMA in patients who achieved SVR compared with those who did not, further confirm the direct “in vivo” involvement of HCV in IR pathways. On the other hand, a powerful, combined effect on suppressing HCV viremia and rapidly lowering IR was previously observed using a 14-d course of danoprevir monotherapy, i.e., another powerful, selective inhibitor of NS3/4A HCV serine protease. Interestingly, overweight patients had a greater decrease in HOMA values than patients with normal BMI, despite a similar decrease in serum HCV RNA, suggesting a complex interplay between these two variables. The authors hypothesize an anti-inflammatory or insulin sensitizing effect of danoprevir.
Other important data concerning IR were obtained from a post-hoc analysis of the REALIZE phase III study which was carried out to assess the impact of IR on virological response to a telaprevir-based regimen in previously treated patients. Baseline HOMA values were found to be associated with SVR at univariate analysis (TVR: OR = 0.76; 95%CI: 0.60-0.96) but not after adjustment for other baseline prognostic factors (TVR: OR = 0.95; 95%CI: 0.71-1.29). SVR decreased as HOMA values increased, both in the control group and in the pooled T12-PR48 group where, however, this trend was observed only in prior partial and null responders, but not in prior relapsers.
In summary, on the basis of all these data we can say that LDL-C and statin use proved to be predictors of SVR in telaprevir and boceprevir-treated patients, respectively. Obesity may negatively influence rapid virologic decline as well as SVR in previously naive patients treated with a boceprevir-based regimen. To the best of our knowledge, no sub-analysis regarding the impact of obesity on SVR has ever been carried out for telaprevir. No data on HOMA are available for boceprevir. HOMA values were reported as being univariately associated with SVR in a telaprevir-based trial on previously treated patients. In naive patients treated with a telaprevir-based regimen, the HOMA value was not a predictor of SVR, nor was it found to be associated with rapid virological response.
However, some comments have to be made. First, we have no data on the real weight of baseline metabolic factors in patients with less favorable probability of response, such as those with advanced fibrosis and/or non-CC IL28b. It is reasonable to suppose that in patients with advanced fibrosis or cirrhosis, as well as in prior partial or null responders to dual therapy and in whom non-CC IL28b is highly prevalent, metabolic IR, metabolic syndrome and obesity may be significant cofactors of nonresponse to triple therapy. Hopefully, this will be an issue for further studies. Secondly, in a real world setting we have to face a change in the epidemiology of candidates to triple therapy compared with the “world of trials”. In the “real world scenario” we have to expect a higher prevalence of patients over 65 years of age who have often previously been treated with dual therapy and have a higher prevalence of comorbidities, including hypertension, dyslipidemia and diabetes. In this context, many patients might experience either a worsening in the sensitivity to interferon as well as a higher probability of side effects when a protease-inhibitor is added to therapy.
These points seem to have been taken into consideration by United Kingdom consensus guidelines for the use of protease inhibitors in the treatment of HCV genotype 1 infected patients. These guidelines recommend evaluating the presence of factors predictive of poor response to therapy, such as BMI and type 2 diabetes among others.
Currently, an enormous effort is being made by researchers and companies to provide physicians with new and more powerful drugs with a high genetic barrier and able to work on several HCV genotypes. Recently, phase II and III studies on sofosbuvir, a new nucleotide analogue HCV NS5B polymerase inhibitor used in combination with peginterferon and ribavirin in genotypes 1, 4, 5 and 6 or in combination with ribavirin in genotypes 2 and 3, showed a high rate of SVR, up to 90% in untreated genotype 1 patients after a 12-wk regimen, with no additional side effects to those occurring with peginterferon and ribavirin[85-87].
New combinations of drugs with interferon-free schedules are under evaluation in phase II or III studies[88-91]. Hopefully, by the end of the decade the holy grail of a pangenotypic oral association of highly powerful drugs will be able to cure virtually all patients. In this scenario, the role of predictors of SVR will rapidly fade, but we have to keep in mind that in the short amount of time that separates us from the availability of new and more powerful treatment schedules, many patients will have to be treated with boceprevir and telaprevir-based triple therapy. Furthermore, many patients around the world have no, or only limited access to DAAs. With this in mind, SVR predictors remain important tools that are available to us in order to assign patients to the best treatment schedules.
Baseline metabolic factors seem to have a minor, though likely not negligible, role in influencing antiviral response to direct antiviral agent-based treatment in patients with genotype 1 chronic hepatitis C. Further studies aimed at clarifying their role in a subpopulation of unfavorable candidates to this treatment, such as patients with advanced fibrosis or prior partial or null responders to peginterferon and ribavirin, are needed.
|2.||Verna EC, Brown RS. Hepatitis C virus and liver transplantation. Clin Liver Dis. 2006;10:919-940. [PubMed] [DOI]|
|3.||Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet. 2001;358:958-965. [PubMed] [DOI]|
|4.||Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL, Häussinger D, Diago M, Carosi G, Dhumeaux D. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982. [PubMed]|
|5.||Hadziyannis SJ, Sette H, Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H, Bernstein D, Rizzetto M, Zeuzem S, Pockros PJ, Lin A, Ackrill AM, PEGASYS International Study Group. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346-355. [PubMed] [DOI]|
|6.||McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER, Galati JS, Bacon BR, Davis MN, Mukhopadhyay P, Koury K, Noviello S, Pedicone LD, Brass CA, Albrecht JK, Sulkowski MS, IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593. [PubMed] [DOI]|
|7.||Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology. 2003;38:639-644. [PubMed] [DOI]|
|8.||Yu ML, Dai CY, Huang JF, Chiu CF, Yang YH, Hou NJ, Lee LP, Hsieh MY, Lin ZY, Chen SC. Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial. Hepatology. 2008;47:1884-1893. [PubMed] [DOI]|
|9.||Romero-Gómez M, Del Mar Viloria M, Andrade RJ, Salmerón J, Diago M, Fernández-Rodríguez CM, Corpas R, Cruz M, Grande L, Vázquez L. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128:636-641. [PubMed] [DOI]|
|10.||Thompson AJ, Muir AJ, Sulkowski MS, Ge D, Fellay J, Shianna KV, Urban T, Afdhal NH, Jacobson IM, Esteban R. Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology. 2010;139:120-9.e18. [PubMed] [DOI]|
|11.||Ozyilkan E, Arslan M. Increased prevalence of diabetes mellitus in patients with chronic hepatitis C virus infection. Am J Gastroenterol. 1996;91:1480-1481. [PubMed]|
|12.||Lecube A, Hernández C, Genescà J, Simó R. Glucose abnormalities in patients with hepatitis C virus infection: Epidemiology and pathogenesis. Diabetes Care. 2006;29:1140-1149. [PubMed] [DOI]|
|13.||Wang CS, Wang ST, Yao WJ, Chang TT, Chou P. Hepatitis C virus infection and the development of type 2 diabetes in a community-based longitudinal study. Am J Epidemiol. 2007;166:196-203. [PubMed] [DOI]|
|14.||Moucari R, Asselah T, Cazals-Hatem D, Voitot H, Boyer N, Ripault MP, Sobesky R, Martinot-Peignoux M, Maylin S, Nicolas-Chanoine MH. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134:416-423. [PubMed] [DOI]|
|15.||Rubbia-Brandt L, Quadri R, Abid K, Giostra E, Malé PJ, Mentha G, Spahr L, Zarski JP, Borisch B, Hadengue A. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol. 2000;33:106-115. [PubMed] [DOI]|
|16.||Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33:1358-1364. [PubMed] [DOI]|
|17.||Fartoux L, Poujol-Robert A, Guéchot J, Wendum D, Poupon R, Serfaty L. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut. 2005;54:1003-1008. [PubMed] [DOI]|
|18.||Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, Moriya K, Koike K. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126:840-848. [PubMed]|
|19.||Muzzi A, Leandro G, Rubbia-Brandt L, James R, Keiser O, Malinverni R, Dufour JF, Helbling B, Hadengue A, Gonvers JJ. Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients. J Hepatol. 2005;42:41-46. [PubMed] [DOI]|
|20.||Huang Y, Feld JJ, Sapp RK, Nanda S, Lin JH, Blatt LM, Fried MW, Murthy K, Liang TJ. Defective hepatic response to interferon and activation of suppressor of cytokine signaling 3 in chronic hepatitis C. Gastroenterology. 2007;132:733-744. [PubMed] [DOI]|
|21.||Persico M, Capasso M, Persico E, Svelto M, Russo R, Spano D, Crocè L, La Mura V, Moschella F, Masutti F. Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: Insulin resistance and response to antiviral therapy. Hepatology. 2007;46:1009-1015. [PubMed] [DOI]|
|22.||Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T, Taniguchi E, Kumemura H, Hanada S, Maeyama M. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165:1499-1508. [PubMed] [DOI]|
|23.||Kawaguchi T, Ide T, Taniguchi E, Hirano E, Itou M, Sumie S, Nagao Y, Yanagimoto C, Hanada S, Koga H. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol. 2007;102:570-576. [PubMed] [DOI]|
|24.||Vanni E, Abate ML, Gentilcore E, Hickman I, Gambino R, Cassader M, Smedile A, Ferrannini E, Rizzetto M, Marchesini G. Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C. Hepatology. 2009;50:697-706. [PubMed] [DOI]|
|25.||Delgado-Borrego A, Jordan SH, Negre B, Healey D, Lin W, Kamegaya Y, Christofi M, Ludwig DA, Lok AS, Chung RT, Halt-C Trial Group. Reduction of insulin resistance with effective clearance of hepatitis C infection: results from the HALT-C trial. Clin Gastroenterol Hepatol. 2010;8:458-462. [PubMed] [DOI]|
|26.||Thompson AJ, Patel K, Chuang WL, Lawitz EJ, Rodriguez-Torres M, Rustgi VK, Flisiak R, Pianko S, Diago M, Arora S. Viral clearance is associated with improved insulin resistance in genotype 1 chronic hepatitis C but not genotype 2/3. Gut. 2012;61:128-134. [PubMed] [DOI]|
|27.||Arase Y, Suzuki F, Suzuki Y, Akuta N, Kobayashi M, Kawamura Y, Yatsuji H, Sezaki H, Hosaka T, Hirakawa M. Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C. Hepatology. 2009;49:739-744. [PubMed] [DOI]|
|28.||Aghemo A, Prati GM, Rumi MG, Soffredini R, D’Ambrosio R, Orsi E, De Nicola S, Degasperi E, Grancini V, Colombo M. Sustained virological response prevents the development of insulin resistance in patients with chronic hepatitis C. Hepatology. 2012;56:1681-1687. [PubMed] [DOI]|
|29.||Clark PJ, Thompson AJ, Vock DM, Kratz LE, Tolun AA, Muir AJ, McHutchison JG, Subramanian M, Millington DM, Kelley RI. Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner. Hepatology. 2012;56:49-56. [PubMed] [DOI]|
|30.||Felmlee DJ, Sheridan DA, Bridge SH, Nielsen SU, Milne RW, Packard CJ, Caslake MJ, McLauchlan J, Toms GL, Neely RD. Intravascular transfer contributes to postprandial increase in numbers of very-low-density hepatitis C virus particles. Gastroenterology. 2010;139:1774-183, 1774-183. [PubMed] [DOI]|
|31.||Sheridan J, Felmlee DJ, Bridge SH, Fenwick1 F, Askew B, Neely D, Crossey MME, Taylor-Robinson SD, Toms GL, Bassendine MF. Metabolic syndrome and insulin resistance are associated with maximum hepatitis C lipoviral particles in genotype 1 infection. J Hepatol. 2013;58 Suppl 1:S202. [DOI]|
|32.||Owen DM, Huang H, Ye J, Gale M. Apolipoprotein E on hepatitis C virion facilitates infection through interaction with low-density lipoprotein receptor. Virology. 2009;394:99-108. [PubMed] [DOI]|
|33.||André P, Komurian-Pradel F, Deforges S, Perret M, Berland JL, Sodoyer M, Pol S, Bréchot C, Paranhos-Baccalà G, Lotteau V. Characterization of low- and very-low-density hepatitis C virus RNA-containing particles. J Virol. 2002;76:6919-6928. [PubMed] [DOI]|
|34.||Del Campo JA, Rojas Á, Romero-Gómez M. Entry of hepatitis C virus into the cell: a therapeutic target. World J Gastroenterol. 2012;18:4481-4485. [PubMed] [DOI]|
|35.||Sainz B, Barretto N, Martin DN, Hiraga N, Imamura M, Hussain S, Marsh KA, Yu X, Chayama K, Alrefai WA. Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor. Nat Med. 2012;18:281-285. [PubMed] [DOI]|
|36.||Naeem M, Bacon BR, Mistry B, Britton RS, Di Bisceglie AM. Changes in serum lipoprotein profile during interferon therapy in chronic hepatitis C. Am J Gastroenterol. 2001;96:2468-2472. [PubMed] [DOI]|
|37.||Hamamoto S, Uchida Y, Wada T, Moritani M, Sato S, Hamamoto N, Ishihara S, Watanabe M, Kinoshita Y. Changes in serum lipid concentrations in patients with chronic hepatitis C virus positive hepatitis responsive or non-responsive to interferon therapy. J Gastroenterol Hepatol. 2005;20:204-208. [PubMed] [DOI]|
|38.||Bortoletto G, Scribano L, Realdon S, Marcolongo M, Mirandola S, Franceschini L, Bonisegna S, Noventa F, Plebani M, Martines D. Hyperinsulinaemia reduces the 24-h virological response to PEG-interferon therapy in patients with chronic hepatitis C and insulin resistance. J Viral Hepat. 2010;17:475-480. [PubMed] [DOI]|
|39.||Grasso A, Malfatti F, De Leo P, Martines H, Fabris P, Toscanini F, Anselmo M, Menardo G. Insulin resistance predicts rapid virological response in non-diabetic, non-cirrhotic genotype 1 HCV patients treated with peginterferon alpha-2b plus ribavirin. J Hepatol. 2009;51:984-990. [PubMed] [DOI]|
|40.||Fattovich G, Covolo L, Pasino M, Perini E, Rossi L, Brocco G, Guido M, Cristofori C, Belotti C, Puoti M, Gaeta GB, Santantonio T, Raimondo G, Bruno R, Minola E, Negro F, Donato F, Italian Hepatitis C Cohort Study Collaborative Group. The homeostasis model assessment of the insulin resistance score is not predictive of a sustained virological response in chronic hepatitis C patients. Liver Int. 2011;31:66-74. [PubMed] [DOI]|
|41.||Khattab M, Eslam M, Sharwae MA, Shatat M, Ali A, Hamdy L. Insulin resistance predicts rapid virologic response to peginterferon/ribavirin combination therapy in hepatitis C genotype 4 patients. Am J Gastroenterol. 2010;105:1970-1977. [PubMed] [DOI]|
|42.||Eslam M, Aparcero R, Kawaguchi T, Del Campo JA, Sata M, Khattab MA, Romero-Gomez M. Meta-analysis: insulin resistance and sustained virological response in hepatitis C. Aliment Pharmacol Ther. 2011;34:297-305. [PubMed] [DOI]|
|43.||Deltenre P, Louvet A, Lemoine M, Mourad A, Fartoux L, Moreno C, Henrion J, Mathurin P, Serfaty L. Impact of insulin resistance on sustained response in HCV patients treated with pegylated interferon and ribavirin: a meta-analysis. J Hepatol. 2011;55:1187-1194. [PubMed] [DOI]|
|44.||Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-419. [PubMed] [DOI]|
|45.||Ikeda Y, Suehiro T, Nakamura T, Kumon Y, Hashimoto K. Clinical significance of the insulin resistance index as assessed by homeostasis model assessment. Endocr J. 2001;48:81-86. [PubMed] [DOI]|
|46.||Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol. 2008;28:629-636. [PubMed] [DOI]|
|47.||Fattovich G, Baroni GS, Pasino M, Pierantonelli I, Covolo L, Ieluzzi D, Passigato N, Tonon A, Faraci MG, Guido M. Post-load insulin resistance does not predict virological response to treatment of chronic hepatitis C patients without the metabolic syndrome. Dig Liver Dis. 2012;44:419-425. [PubMed] [DOI]|
|48.||Charlton MR, Pockros PJ, Harrison SA. Impact of obesity on treatment of chronic hepatitis C. Hepatology. 2006;43:1177-1186. [PubMed] [DOI]|
|50.||Walsh MJ, Jonsson JR, Richardson MM, Lipka GM, Purdie DM, Clouston AD, Powell EE. Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1. Gut. 2006;55:529-535. [PubMed] [DOI]|
|51.||Gopal K, Johnson TC, Gopal S, Walfish A, Bang CT, Suwandhi P, Pena-Sahdala HN, Clain DJ, Bodenheimer HC, Min AD. Correlation between beta-lipoprotein levels and outcome of hepatitis C treatment. Hepatology. 2006;44:335-340. [PubMed] [DOI]|
|52.||Economou M, Milionis H, Filis S, Baltayiannis G, Christou L, Elisaf M, Tsianos E. Baseline cholesterol is associated with the response to antiviral therapy in chronic hepatitis C. J Gastroenterol Hepatol. 2008;23:586-591. [PubMed] [DOI]|
|53.||Ramcharran D, Wahed AS, Conjeevaram HS, Evans RW, Wang T, Belle SH, Yee LJ, Virahep-C Study Group. Associations between serum lipids and hepatitis C antiviral treatment efficacy. Hepatology. 2010;52:854-863. [PubMed] [DOI]|
|54.||Sheridan DA, Bridge SH, Felmlee DJ, Crossey MM, Thomas HC, Taylor-Robinson SD, Toms GL, Neely RD, Bassendine MF. Apolipoprotein-E and hepatitis C lipoviral particles in genotype 1 infection: evidence for an association with interferon sensitivity. J Hepatol. 2012;57:32-38. [PubMed] [DOI]|
|55.||Li JH, Lao XQ, Tillmann HL, Rowell J, Patel K, Thompson A, Suchindran S, Muir AJ, Guyton JR, Gardner SD. Interferon-lambda genotype and low serum low-density lipoprotein cholesterol levels in patients with chronic hepatitis C infection. Hepatology. 2010;51:1904-1911. [PubMed] [DOI]|
|56.||Clark PJ, Thompson AJ, Zhu M, Vock DM, Zhu Q, Ge D, Patel K, Harrison SA, Urban TJ, Naggie S. Interleukin 28B polymorphisms are the only common genetic variants associated with low-density lipoprotein cholesterol (LDL-C) in genotype-1 chronic hepatitis C and determine the association between LDL-C and treatment response. J Viral Hepat. 2012;19:332-340. [PubMed] [DOI]|
|57.||Tillmann HL, Patel K, Muir AJ, Guy CD, Li JH, Lao XQ, Thompson A, Clark PJ, Gardner SD, McHutchison JG. Beneficial IL28B genotype associated with lower frequency of hepatic steatosis in patients with chronic hepatitis C. J Hepatol. 2011;55:1195-1200. [PubMed] [DOI]|
|58.||Petta S, Rosso C, Leung R, Abate ML, Booth D, Salomone F, Gambino R, Rizzetto M, Caviglia P, Smedile A. Effects of IL28B rs12979860 CC genotype on metabolic profile and sustained virologic response in patients with genotype 1 chronic hepatitis C. Clin Gastroenterol Hepatol. 2013;11:311-7.e1. [PubMed] [DOI]|
|59.||Del Campo JA, Ampuero J, Rojas L, Conde M, Rojas A, Maraver M, Millán R, García-Valdecasas M, García-Lozano JR, González-Escribano MF. Insulin resistance predicts sustained virological response to treatment of chronic hepatitis C independently of the IL28b rs12979860 polymorphism. Aliment Pharmacol Ther. 2013;37:74-80. [PubMed] [DOI]|
|60.||Konishi I, Hiasa Y, Tokumoto Y, Abe M, Furukawa S, Toshimitsu K, Matsuura B, Onji M. Aerobic exercise improves insulin resistance and decreases body fat and serum levels of leptin in patients with hepatitis C virus. Hepatol Res. 2011;41:928-935. [PubMed] [DOI]|
|61.||Pattullo V, Duarte-Rojo A, Soliman W, Vargas-Vorackova F, Sockalingam S, Fantus IG, Allard J, Heathcote J. A 24-week dietary and physical activity lifestyle intervention reduces hepatic insulin resistance in the obese with chronic hepatitis C. Liver Int. 2013;33:410-419. [PubMed] [DOI]|
|62.||Tarantino G, Conca P, Ariello M, Mastrolia M. Does a lower insulin resistance affect antiviral therapy response in patients suffering from HCV related chronic hepatitis? Gut. 2006;55:585. [PubMed]|
|63.||Romero-Gómez M, Diago M, Andrade RJ, Calleja JL, Salmerón J, Fernández-Rodríguez CM, Solà R, García-Samaniego J, Herrerías JM, De la Mata M, Moreno-Otero R, Nuñez O, Olveira A, Durán S, Planas R, Spanish Treatment of Resistance to Insulin in Hepatitis C Genotype 1 Group. Treatment of insulin resistance with metformin in naïve genotype 1 chronic hepatitis C patients receiving peginterferon alfa-2a plus ribavirin. Hepatology. 2009;50:1702-1708. [PubMed] [DOI]|
|64.||Khattab M, Emad M, Abdelaleem A, Eslam M, Atef R, Shaker Y, Hamdy L. Pioglitazone improves virological response to peginterferon alpha-2b/ribavirin combination therapy in hepatitis C genotype 4 patients with insulin resistance. Liver Int. 2010;30:447-454. [PubMed] [DOI]|
|65.||Overbeck K, Genné D, Golay A, Negro F, Swiss Association for the Study of the Liver (SASL). Pioglitazone in chronic hepatitis C not responding to pegylated interferon-alpha and ribavirin. J Hepatol. 2008;49:295-298. [PubMed]|
|66.||Conjeevaram H, Burant CF, McKenna B, Harsh D, Kang H, Das AK, Everett L, White D, Lok ASF. A randomized, double-blind, placebo-controlled study of ppar-gamma agonist pioglitazone given in combination with peginterferon and ribavirin in patients with genotype-1 chronic hepatitis C. Hepatology. 2008;48 Suppl 1:384A.|
|67.||Harrison SA, Hamzeh FM, Han J, Pandya PK, Sheikh MY, Vierling JM. Chronic hepatitis C genotype 1 patients with insulin resistance treated with pioglitazone and peginterferon alpha-2a plus ribavirin. Hepatology. 2012;56:464-473. [PubMed] [DOI]|
|68.||Jacobson IM, Pawlotsky JM, Afdhal NH, Dusheiko GM, Forns X, Jensen DM, Poordad F, Schulz J. A practical guide for the use of boceprevir and telaprevir for the treatment of hepatitis C. J Viral Hepat. 2012;19 Suppl 2:1-26. [PubMed] [DOI]|
|69.||McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ, PROVE1 Study Team. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360:1827-1838. [PubMed] [DOI]|
|70.||McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, Heathcote EJ, Zeuzem S, Reesink HW, Garg J, Bsharat M, George S, Kauffman RS, Adda N, Di Bisceglie AM, PROVE3 Study Team. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362:1292-1303. [PubMed]|
|71.||Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, Pound D, Davis MN, Galati JS, Gordon SC, Ravendhran N. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;376:705-716. [PubMed] [DOI]|
|72.||Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206. [PubMed] [DOI]|
|73.||Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217. [PubMed] [DOI]|
|74.||Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z, Foster GR, Horban A, Ferenci P, Nevens F, Müllhaupt B, Pockros P, Terg R, Shouval D, van Hoek B, Weiland O, Van Heeswijk R, De Meyer S, Luo D, Boogaerts G, Polo R, Picchio G, Beumont M, REALIZE Study Team. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428. [PubMed] [DOI]|
|75.||Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson GT, Fried MW, Adler M, Reesink HW, Martin M, Sankoh AJ, Adda N, Kauffman RS, George S, Wright CI, Poordad F, ILLUMINATE Study Team. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365:1014-1024. [PubMed]|
|76.||Poordad F, Bronowicki JP, Gordon SC, Zeuzem S, Jacobson IM, Sulkowski MS, Poynard T, Morgan TR, Molony C, Pedicone LD. Factors that predict response of patients with hepatitis C virus infection to boceprevir. Gastroenterology. 2012;143:608-18.e1-5. [PubMed] [DOI]|
|77.||Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S, ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416. [PubMed] [DOI]|
|78.||Serfaty L, Forns X, Goeser T, Ferenci P, Nevens F, Carosi G, Drenth JP, Lonjon-Domanec I, DeMasi R, Picchio G. Insulin resistance and response to telaprevir plus peginterferon α and ribavirin in treatment-naive patients infected with HCV genotype 1. Gut. 2012;61:1473-1480. [PubMed] [DOI]|
|79.||Marcellin P, Forns X, Goeser T, Ferenci P, Nevens F, Carosi G, Drenth JP, Serfaty L, De Backer K, Van Heeswijk R. Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or -2b to patients with chronic hepatitis C. Gastroenterology. 2011;140:459-468.e1; quiz e14. [PubMed]|
|80.||Petta S, Cammà C, Di Marco V, Cabibi D, Ciminnisi S, Caldarella R, Licata A, Massenti MF, Marchesini G, Craxì A. Time course of insulin resistance during antiviral therapy in non-diabetic, non-cirrhotic patients with genotype 1 HCV infection. Antivir Ther. 2009;14:631-639. [PubMed]|
|81.||Prati GM, Rumi MG, Aghemo A, D’Ambrosio R, De Nicola S, Olgiati L, Donato MF, Colombo M. Insulin resistance does not predict a response to pegylated interferon plus ribavirin in chronic hepatitis C patients: a sub-analysis of the MIST study. J Hepatol. 2010;52 Suppl1:S122. [DOI]|
|82.||Moucari R, Forestier N, Larrey D, Guyader D, Couzigou P, Benhamou Y, Voitot H, Vidaud M, Seiwert S, Bradford B. Danoprevir, an HCV NS3/4A protease inhibitor, improves insulin sensitivity in patients with genotype 1 chronic hepatitis C. Gut. 2010;59:1694-1698. [PubMed] [DOI]|
|83.||Younossi ZM, Negro F, Serfaty L, Pol S, Diago M, Zeuzem S, Andreone P, Lawitz E, Roberts SK, Focaccia R. Impact of insulin resistance on virologic response to a telaprevir-based regimen in patients with HCV genotype 1 and prior peginterferon/ribavirin treatment failure: post-hoc analysis of the realize phase III study. Hepatology. 2011;54 Suppl 1:1008A.|
|84.||Ramachandran P, Fraser A, Agarwal K, Austin A, Brown A, Foster GR, Fox R, Hayes PC, Leen C, Mills PR. UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients. Aliment Pharmacol Ther. 2012;35:647-662. [PubMed] [DOI]|
|85.||Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, Schultz M, Davis MN, Kayali Z, Reddy KR. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887. [PubMed] [DOI]|
|86.||Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, DeMicco M, Bernstein DE, Afdhal N, Vierling JM, Gordon SC. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. 2013;381:2100-2107. [PubMed] [DOI]|
|87.||Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, Afdhal NH, Bernstein DE, Dejesus E, Freilich B. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis. 2013;13:401-408. [PubMed] [DOI]|
|88.||Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson D, Zeuzem S, Everson GT, Kwo P, Foster GR, Sulkowski M. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 /− ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. J Hepatol. 2013;58 Suppl 1:S2. [DOI]|
|89.||Everson GT, Sims KD, Rodriguez-Torres M, Hezode C, Lawitz E, Bourliere M, Loustaud-Ratti V, Rustgi V, Schwartz H, Tatum H. Interim analysis of an interferon (IFN)- and ribavirin (RBV)-free regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 in treatment-naive, hepatitis C virus genotype 1-infected patients. J Hepatol. 2013;58 Suppl 1:S573. [DOI]|
|90.||Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ, Schwartz H, Nelson DR, Everson GT, Eley T, Wind-Rotolo M, Huang SP, Gao M, McPhee M, Hernandez D, Sherman D, Hindes R, Symonds W, Pasquinelli C, Grasela DM, AI444040 Study Group. Sustained virologic response with daclatasvir plus sofosbuvir ± ribavirin (RBV) in chronic HCV genotype (gt) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC). J Hepatol. 2013;58 Suppl 1:S570. [DOI]|