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Abd El-Wahab EW, Mikheal A, Sidkey F, Shatat HZ. Insulin resistance as a predictor of early virologic response to HCV therapy among chronic HCV Egyptian patients. J Med Virol 2015; 87:428-40. [PMID: 25583244 DOI: 10.1002/jmv.24092] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/01/2014] [Indexed: 12/19/2022]
Abstract
Prior assessment of insulin resistance by HOMA-IR is emerging as an important milestone in the treatment of patients with chronic hepatitis C. This cost-effective tool is recommended to individualize treatment duration, or to exclude those with low insulin sensitivity from being treated until ameliorating their state of insulin resistance (IR). The present work aims to elucidate further the effect IR state on early viral kinetic response to Chronic hepatitis C virus (HCV) therapy and the impact of HCV treatment and viral eradication on insulin sensitivity. Insulin sensitivity was assessed using the HOMA-IR method. All enrolled patients were treated with a dual therapy (pegylated interferon-alpha plus ribavirin) for 48 weeks and evaluated using qRT-PCR for early virologic response as well as the impact of treatment on insulin sensitivity throughout the early period of therapy. Of a total 392 chronic HCV cases, early virologic response was achieved by 318 (81.1%). IR was detected in 241 (61.5%) chronic HCV patient of which 73.4% responded to treatment. Early virologic response among patients with > 2.18 HOMA-IR value were significantly lower than those with HOMA-IR values ≤2.18 (P < 0.0001). IR was significantly associated with high baseline BMI. Steatosis and fibrosis correlated with IR but neither independently predicted early virologic response. Pretreatment IR < 2.18, low fasting blood glucose, low and intermediate HCV viral load, normal BMI, and non-smoking were independent factors associated with early virologic response. IR interferes with early virologic response to the antiviral care. Clinical application of pretreatment HOMA-IR assessment could help in predicting early treatment outcome and thus enable treatment regimens to be optimized and individually tailored.
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Affiliation(s)
- Ekram W Abd El-Wahab
- Tropical Health Department, High Institute of Public Health, Alexandria University, Egypt
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Congly SE, Doucette KE, Coffin CS. Outcomes and management of viral hepatitis and human immunodeficiency virus co-infection in liver transplantation. World J Gastroenterol 2014; 20:414-424. [PMID: 24574710 PMCID: PMC3923016 DOI: 10.3748/wjg.v20.i2.414] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Revised: 10/22/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation for human immunodeficiency virus (HIV) positive patients with viral hepatitis co-infection is increasingly offered in many North American and European liver transplant centers. Prior studies have demonstrated acceptable post-transplant outcomes and no increased risk of HIV complications in patients co-infected with hepatitis B virus (HBV). However, liver transplantation in HIV positive patients with hepatitis C virus (HCV) has poorer outcomes overall, requiring careful selection of candidates. This review aims to summarize the published literature on outcomes after transplant in HIV patients with HBV or HCV related end-stage liver disease and recommendations for management. In particular the pre-transplant factors impacting outcomes in HCV/HIV co-infected candidates and importance of multidisciplinary management will be discussed.
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Mandorfer M, Reiberger T, Payer BA, Breitenecker F, Aichelburg MC, Obermayer-Pietsch B, Rieger A, Puoti M, Zangerle R, Trauner M, Peck-Radosavljevic M. Revisiting predictors of virologic response to PEGIFN + RBV therapy in HIV-/HCV-coinfected patients: the role of metabolic factors and elevated GGT levels. J Viral Hepat 2014; 21:33-41. [PMID: 24329855 DOI: 10.1111/jvh.12118] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Accepted: 03/26/2013] [Indexed: 12/26/2022]
Abstract
Evaluation of metabolic factors and elevated γ-glutamyltransferase (GGT) levels as independent predictors of treatment failure in a thoroughly documented cohort of HIV-/HCV-coinfected patients (HIV/HCV). Sixty-four HIV/HCV patients treated with pegylated interferon-α-2a plus ribavirin (PEGIFN + RBV) at the Medical University of Vienna within a prospective trial were included in this study. In addition, 124 patients with HIV/HCV from the AIFA-HIV and AHIVCOS cohorts were included as a validation cohort. Advanced liver fibrosis, GGT elevation, insulin resistance (IR) and low CD4+ nadir were defined as METAVIR F3/F4, GGT levels >1.5× sex-specific upper limit of normal, homoeostasis model assessment of insulin resistance >2 and CD4+ nadir <350 cells/μL, respectively. HCV-genotype 1/4 (OR26.3; P = 0.006), advanced liver fibrosis (OR20.2; P = 0.009), interleukin 28B rs12979860 non-C/C SNP (OR8.27; P = 0.02) and GGT elevation (OR7.97; P = 0.012) were independent predictors of treatment failure, while both IR (OR3.51; P = 0.106) and low CD4 + nadir (OR2.64; P = 0.263) were not independently associated with treatment failure. A statistically significant correlation between GGT elevation and prior alcohol abuse (r = 0.259; P = 0.039), liver steatosis (r = 0.301; P = 0.034) and low-density lipoprotein-cholesterol (r = -0.256; P = 0.041) was observed. The importance of GGT elevation as an independent predictor of treatment failure was confirmed in a validation cohort (OR2.76; P = 0.026). While GGT elevation emerged as an independent predictor of treatment failure in both the derivation and the validation cohort, no independent associations between metabolic factors and treatment failure were observed. Thus, our findings suggest that GGT elevation is an independent predictor of treatment failure in HIV/HCV that can easily be incorporated into predictive algorithms.
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Affiliation(s)
- M Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna HIV & Liver Study Group, Vienna, Austria
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Ezzat WM, Elhosary YA, Abdulla NA, Raslan HM, Saleh OM, Ibrahim MH, Rasheed MA, El-Hariri H. Insulin resistance and early virological response in chronic HCV infection. J Genet Eng Biotechnol 2013. [DOI: 10.1016/j.jgeb.2012.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Butt AA, Umbleja T, Andersen JW, Sherman KE, Chung RT. Impact of peginterferon alpha and ribavirin treatment on lipid profiles and insulin resistance in Hepatitis C virus/HIV-coinfected persons: the AIDS Clinical Trials Group A5178 Study. Clin Infect Dis 2012; 55:631-8. [PMID: 22563020 DOI: 10.1093/cid/cis463] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The effect of peginterferon alpha/ribavirin (PEG-IFN/RBV) and hepatitis C virus (HCV) clearance on lipid and insulin resistance (IR) profiles in HCV/human immunodeficiency virus (HIV) coinfection is unknown. METHODS We measured fasting total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoproteins (HDL-C), triglycerides (TG), glucose, and insulin at defined intervals in the A5178 study (N = 329), a prospective treatment trial in HCV/HIV coinfection. Changes from baseline and the relation between baseline values of these variables to sustained virologic response (SVR) were determined. RESULTS Of 182 subjects with metabolic data, 98 achieved early virologic response (EVR) and continued PEG-IFN/RBV. Among those, median pretreatment HCV RNA was 6.6 log(10 )IU/mL; 73% had HCV genotype 1. Median pretreatment TC was 176 mg/dL (interquartile range [IQR],150-205]; median LDL-C was 99 mg/dL (IQR, 79-123); median HDL-C was 40 mg/dL (IQR, 31-47); and median TG was 147 mg/dL (IQR, 101-221). Median homeostasis model assessment of IR (HOMA-IR) was 3.3 (IQR, 1.7-5.3). The EVRs demonstrated a decline in TC, LDL-C, and HDL-C, whereas TG increased on treatment but returned to near baseline 24 weeks after end of treatment (EOT). The HOMA-IR decline from entry to 24 weeks after EOT was significant among non-sustained virologic responders and nonsignificant among sustained virologic responders; this difference was offset after adjusting for higher HOMA-IR at baseline among the former. Among all 182 subjects, entry LDL-C was associated with SVR in a joint logistic model adjusted for HCV genotype, race, and prior IFN (odds ratio, 1.17 per 10 mg/dL increase; 95% confidence interval, 1.03-1.32), but TC, HDL, TG, and IR were not. CONCLUSIONS Peginterferon alpha and RBV can significantly affect lipid profile and IR in HCV/HIV-coinfected persons. Although the lipid profile returns to near pretreatment levels after completion of treatment, our data suggest persistent modest improvement in IR with treatment. Clinical Trials Registration. NCT00078403.
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Affiliation(s)
- Adeel A Butt
- University of Pittsburgh School of Medicine, PA 15213, USA.
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Eslam M, López-Cortés LF, Romero-Gomez M. The role of insulin resistance in HIV/hepatitis C virus-coinfected patients. Curr Opin HIV AIDS 2011; 6:553-558. [PMID: 21934619 DOI: 10.1097/coh.0b013e32834bd21d] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
PURPOSE OF REVIEW Insulin resistance, HIV, antiviral drugs and hepatitis C virus (HCV) infection contribute to a complex interaction involving the metabolic syndrome. The objective of this review was to explore the meaning of insulin resistance in HIV-HCV-coinfected patients and how it may impact on sustained virological response (SVR) and disease progression. RECENT FINDINGS In the HIV/HCV coinfection setting, insulin resistance seems to be associated with a reduction in rapid virological response and SVR to pegylated interferon and ribavirin, both in naive and treatment experienced patients. A recent meta-analysis demonstrated insulin resistance impairs SVR rate with an odds ratio 0.47 (95% confidence interval 0.31-0.71). However, many confounding factors may promote contradictory results. Prevalence of insulin resistance depends on surrogate markers of insulin resistance and the threshold for defining impaired insulin sensitivity. For example, homeostasis model for the assessment of insulin resistance may be influenced by both methods of insulin measurement and interpretation. Insulin sensitizers, lifestyle changes and improvement in the use of protease inhibitors should be evaluated in the management of coinfected patients. SUMMARY Insulin resistance is common finding in patients with HIV/HCV coinfection, with wide clinical consequences including progression of hepatic fibrosis and reduction in the response to antiviral treatment. Our understanding of this relationship continues to improve. More prospective studies are required to improve future management.
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Affiliation(s)
- Mohammed Eslam
- Unit for The Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, Ctra de Cadiz s/n, Spain
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Kaddai V, Negro F. Current understanding of insulin resistance in hepatitis C. Expert Rev Gastroenterol Hepatol 2011; 5:503-16. [PMID: 21780897 DOI: 10.1586/egh.11.43] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Important breakthroughs have been made in recent years into understanding the close interaction between hepatitis C virus (HCV) infection and glucose homeostasis. Both cross-sectional and longitudinal studies have demonstrated that infection with HCV is associated with an increased risk of developing insulin resistance and Type 2 diabetes. A direct effect of HCV on hepatocyte insulin signaling has been shown in experimental models. Some preliminary observations seem to suggest that indirect mechanisms involving extrahepatic organs might also play a role. The interaction between HCV and glucose metabolism has significant clinical consequences. Insulin resistance and Type 2 diabetes not only accelerate the histological and clinical progression of chronic hepatitis C, but also reduce the virological response to IFN-α-based therapy. Thus, understanding the mechanisms underlying HCV-associated glucose metabolism derangements is of paramount interest in order to improve the clinical management of chronic hepatitis C. This article will focus on the studies that consistently argue in favor of an interrelation between HCV and insulin resistance and will highlight the latest discoveries in this field.
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Affiliation(s)
- Vincent Kaddai
- Department of Pathology and Immunology, Centre Médical Universitaire, Rue Michel-Servet 1, Geneva, Switzerland
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Abstract
Hepatitis C (HCV) treatment is on the cusp of change with the approval of the first direct-acting antivirals: telaprevir and boceprevir. Drug-drug interactions with HIV antiretrovirals, increased toxicity, and rapid selection of HCV-resistant mutants are among the treatment complexities expected in this difficult-to-treat population. Until the current standard of care changes, focus should be on strategies to optimize management of HIV/HCV-coinfected patients with currently available options. This article reviews the latest predictive factors of response to HCV treatment with the current standard of care in HIV-coinfected patients, and new treatment options.
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Affiliation(s)
- Marie-Louise C Vachon
- Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA
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Abstract
Insulin resistance (IR) was one of the first metabolic complications reported with highly active antiretroviral therapy for HIV infection. It continues to be of concern despite the introduction of newer antiretrovirals with safer metabolic profiles and is associated with inflammation and the development of diabetes mellitus. As the HIV-infected population ages, the prevalence of IR is likely to rise. Specific antiretrovirals can increase insulin resistance through two principal mechanisms, either directly by interfering with insulin signalling at the cellular level or indirectly as a consequence of defects in lipid metabolism (lipotoxocity) arising from antiretroviral toxicities such as the IR observed in those with HIV-associated lipodystrophy. There is considerable overlap between different antiretrovirals in their propensity to cause IR making it more difficult to attribute development of IR to a particular antiretroviral medication. In addition, in the setting of a generalised epidemic of obesity that exists in many populations worldwide, HIV-infected patients may be more prone to the consequences of antiretroviral-induced insulin resistance and diabetes mellitus. Optimal screening and treatment strategies for IR in treated HIV infection have not been established. In this article we review current opinion on insulin resistance in HIV and identify potential areas for future research.
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Affiliation(s)
- E R Feeney
- HIV Molecular Research Group, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
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Fattovich G, Covolo L, Bibert S, Askarieh G, Lagging M, Clément S, Malerba G, Pasino M, Guido M, Puoti M, Gaeta GB, Santantonio T, Raimondo G, Bruno R, Bochud PY, Donato F, Negro F. IL28B polymorphisms, IP-10 and viral load predict virological response to therapy in chronic hepatitis C. Aliment Pharmacol Ther 2011; 33:1162-72. [PMID: 21443535 DOI: 10.1111/j.1365-2036.2011.04635.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma and the identification of the predictors of response to antiviral therapy is an important clinical issue. AIM To determine the independent contribution of factors including IL28B polymorphisms, IFN-gamma inducible protein-10 (IP-10) levels and the homeostasis model assessment of insulin resistance (HOMA-IR) score in predicting response to therapy in chronic hepatitis C (CHC). METHODS Multivariate analysis of factors predicting rapid (RVR) and sustained (SVR) virological response in 280 consecutive, treatment-naive CHC patients treated with peginterferon alpha and ribavirin in a prospective multicentre study. RESULTS Independent predictors of RVR were HCV RNA <400 000 IU/mL (OR 11.37; 95% CI 3.03-42.6), rs12980275 AA (OR 7.09; 1.97-25.56) and IP-10 (OR 0.04; 0.003-0.56) in HCV genotype 1 patients and lower baseline γ-glutamyl-transferase levels (OR=0.02; 0.0009-0.31) in HCV genotype 3 patients. Independent predictors of SVR were rs12980275 AA (OR 9.68; 3.44-27.18), age <40 years (OR=4.79; 1.50-15.34) and HCV RNA <400 000 IU/mL (OR 2.74; 1.03-7.27) in HCV genotype 1 patients and rs12980275 AA (OR=6.26; 1.98-19.74) and age <40 years (OR 5.37; 1.54-18.75) in the 88 HCV genotype 1 patients without a RVR. RVR was by itself predictive of SVR in HCV genotype 1 patients (OR 33.0; 4.06-268.32) and the only independent predictor of SVR in HCV genotype 2 (OR 9.0, 1.72-46.99) or genotype 3 patients (OR 7.8, 1.43-42.67). CONCLUSIONS In HCV genotype 1 patients, IL28B polymorphisms, HCV RNA load and IP-10 independently predict RVR. The combination of IL28B polymorphisms, HCV RNA level and age may yield more accurate pre-treatment prediction of SVR. HOMA-IR score is not associated with viral response.
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Affiliation(s)
- G Fattovich
- Clinic of Gastroenterology, Department of Medicine, University of Verona, Piazzale L.A. Scuro 10, Verona, Italy.
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Vachon MLC, Factor SH, Branch AD, Fiel MI, Rodriguez-Torres M, Bräu N, Sterling RK, Slim J, Talal AH, Dieterich DT, Sulkowski MS. Insulin resistance predicts re-treatment failure in an efficacy study of peginterferon-α-2a and ribavirin in HIV/HCV co-infected patients. J Hepatol 2011; 54:41-7. [PMID: 20974502 PMCID: PMC2994950 DOI: 10.1016/j.jhep.2010.06.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2010] [Revised: 06/11/2010] [Accepted: 06/16/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. The aim of this study is to evaluate the safety and efficacy of pegylated interferon-α-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response, including insulin resistance, and the relationship between insulin resistance and liver histology. METHODS This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-α-2a and ribavirin for 48 weeks. Serum HCV RNA was measured 24 weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR >2. Correlations between baseline insulin resistance and steatosis, and/or cirrhosis were determined. RESULTS Sustained virological response was achieved in 14/96 (15%) patients. 35% of patients with HOMA-IR < 2 (6/17) achieved sustained virological response vs 14% (5/36) of those with HOMA-IR between 2-4, and 7% (3/41) of those with HOMA-IR > 4 (p = 0.01). In multivariable analysis, insulin resistance and log₁₀ HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95% CI 0.05-0.64, p = 0.009, and AOR 0.36; 95% CI 0.14-0.93, p = 0.04, respectively]. Steatosis and cirrhosis correlated with insulin resistance (p = 0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% of cases, and 2 patients died of unrelated causes. CONCLUSIONS In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those patients without insulin resistance are significantly more likely to achieve sustained virological response.
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Insulin resistance impairs response to interferon plus ribavirin in patients coinfected with HIV and hepatitis C virus. J Acquir Immune Defic Syndr 2010; 55:176-81. [PMID: 20577091 DOI: 10.1097/qai.0b013e3181e5b1f0] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND/AIMS Controversy exists about whether insulin resistance (IR) affects response to treatment of hepatitis C. We evaluated the effect of IR on sustained virologic response (SVR) in HIV/hepatitis C virus (HCV)-coinfected patients treated with interferon plus ribavirin. METHODS We reviewed the clinical records of HIV/HCV-coinfected patients who received interferon plus ribavirin at our institution between July 2000 and March 2007. IR was defined as a homeostasis model assessment ≥ 3.8. SVR was defined as an undetectable HCV RNA at 24 weeks after the end of treatment. Efficacy was evaluated using an on-treatment (OT) analysis. Multivariate logistic regression analysis was used to evaluate factors associated with SVR. RESULTS During the study period, 218 patients were treated with interferon plus ribavirin; IR at baseline was available for 162 patients, and 134 were included in the OT analysis; HCV genotype (G) 1/4, 67%; F3-F4 fibrosis, 36%; IR 31%. SVR was achieved in 67 patients (50%) (79% in G 2/3 vs. 38% in G 1/4). IR was associated with a lower SVR [odds ratio (OR), 0.33; 95% confidence interval (CI): 0.15-0.72; P = 0.006). The independent variables related to SVR were genotype 2/3 (OR, 6.7; 95% CI: 2.71-16.98; P < 0.001), absence of IR at baseline (OR, 3.3; 95% CI: 1.36-8.26; P = 0.008), and nadir CD4 T-cell count (OR, 1.002; 95% CI: 1.00-1.00; P = 0.047). CONCLUSIONS Our data suggest that IR is an important determinant of SVR in HIV/HCV-coinfected patients treated with interferon plus ribavirin. Strategies to modify IR should be explored to enhance SVR during anti-HCV therapy.
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Petit JM, Carrat F, Duong M, Halfon P, Duvillard L, Bani-Sadr F, Chavanet P, Cacoub P, Piroth L. Response to anti-HCV therapy in HIV–HCV-coinfected patients: does the lipid profile really have an effect? Antivir Ther 2010; 15:797-800. [DOI: 10.3851/imp1582] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Cammà C, Petta S. Insulin resistance in HCV mono-infected and in HIV/HCV co-infected patients: Looking to the future. J Hepatol 2009; 50:648-51. [PMID: 19231012 DOI: 10.1016/j.jhep.2009.01.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Cacoub P, Carrat F, Bedossa P, Lambert J, Penaranda G, Pol S, Halfon P. Insulin resistance impairs sustained virological response rate to pegylated interferon plus ribavirin in HIV–hepatitis C virus-coinfected patients: HOMAVIC-ANRS HC02 Study. Antivir Ther 2009; 14:839-45. [DOI: 10.3851/imp1298] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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