Comunicación cortaWe assessed the relationship between atazanavir (ATV)-based antiretroviral treatment (ART) and plasma hepatitis C virus (HCV) viral load in a population of HIV/HCV-coinfected patients. HIV/HCV-coinfected patients who received ART based on a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) were included. Patients were stratified by ART drug [ATV/rtv, lopinavir (LPV/rtv), efavirenz (EFV), nevirapine (NVP), and other PIs], HCV genotype (1/4 and 2/3), and IL28B genotype (CC and non-CC). The Kruskal-Wallis test and chi-squared test were used to compare continuous and categorical variables, respectively. Multivariate analysis consisted of a stepwise linear regression analysis. Six hundred and forty-nine HIV/HCV-coinfected patients were included. HCV genotype 1/4 patients who received ATV had higher HCV RNA levels [6.57 (5.9-6.8) log IU/ml] than those who received LPV [6.1 (5.5-6.5) log IU/ml], EFV [6.1 (5.6-6.4) log IU/ml], NVP [5.8 (5.5-5.9) log IU/ml], or other PIs [6.1 (5.7-6.4) log IU/ml] (p=0.014). This association held for the IL28B genotype (CC versus non-CC). The association was not found in patients carrying HCV genotypes 2/3. The linear regression model identified the IL28B genotype and ATV use as independent factors associated with HCV RNA levels. ATV-based therapy may be associated with a higher HCV RNA viral load in HIV/HCV-coinfected patients

Girón-González, José-Antonio

López Cortés, Luis Fernando

Mira, Jose A.

Márquez, Manuel

Rivero-Juarez, Antonio

Santos-Gil, Ignacio De Los

English

Rivero-Juárez, Antonio

idUS. Depósito de Investigación Universidad de Sevilla

Short CommunicationAtazanavir-Based Therapy Is Associatedwith Higher Hepatitis C Viral Loadin HIV Type 1-Infected Subjects with Untreated Hepatitis CAntonio Rivero-Juarez,1,2 Jose A. Mira,3,4 Ignacio Santos-Gil,5 Luis F. Lopez-Cortes,6,7Jose A Giro´n-Gonzalez,8 Manuel Marquez,9 Dolores Merino,10 Francisco Tellez,11Antonio Caruz,12 Juan A Pineda,2 and Antonio Rivero,1,2on behalf of the Grupo Andaluz para el Estudio de las Hepatitis Vı´ricas (HEPAVIR)de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI)AbstractWe assessed the relationship between atazanavir (ATV)-based antiretroviral treatment (ART) and plasma hepatitisC virus (HCV) viral load in a population of HIV/HCV-coinfected patients. HIV/HCV-coinfected patients whoreceived ART based on a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) wereincluded. Patients were stratified by ART drug [ATV/rtv, lopinavir (LPV/rtv), efavirenz (EFV), nevirapine (NVP),and other PIs], HCV genotype (1/4 and 2/3), and IL28B genotype (CC and non-CC). The Kruskal–Wallis test andchi-squared test were used to compare continuous and categorical variables, respectively. Multivariate analysisconsisted of a stepwise linear regression analysis. Six hundred and forty-nine HIV/HCV-coinfected patients wereincluded. HCV genotype 1/4 patients who received ATV had higher HCV RNA levels [6.57 (5.9–6.8) log IU/ml]than those who received LPV [6.1 (5.5–6.5) log IU/ml], EFV [6.1 (5.6–6.4) log IU/ml], NVP [5.8 (5.5–5.9) log IU/ml],or other PIs [6.1 (5.7–6.4) log IU/ml] ( p= 0.014). This association held for the IL28B genotype (CC versus non-CC).The association was not found in patients carrying HCV genotypes 2/3. The linear regression model identified theIL28B genotype and ATV use as independent factors associated with HCV RNA levels. ATV-based therapy may beassociated with a higher HCV RNA viral load in HIV/HCV-coinfected patients.Hemoglobin catabolism is closely related to the repli-cation of the hepatitis C virus (HCV).1 Heme oxygenase-1 (HO-1) catalyzes the breakdown of the heme molecule toyield equimolar quantities of biliverdin (BV), iron, and carbonmonoxide. The oxidation of heme by HO-1 releases at leasttwo antiviral agents, iron and BV.2 Lehman et al. reported thatBV has antiviral activity in replicon cells, noting that antiviralactivity was accompanied by a rise in specific interferon-stimulated gene (ISG) products.2 Likewise, Zhu et al. recentlydemonstrated that BV has potent antiviral activity againstHCV, with inhibitory action over HCV NS3/4A protease.3Iron has also been shown to inhibit HCV replication by pre-venting divalent caption binding to RdRp.4Atazanavir (ATV) is a protease inhibitor used in HIV ther-apy. ATV interfereswith hemoglobin catabolism because of itscompeting inhibitory activity against the uridine diphosphateglucuronosyltransferase 1A1 (UGT1A1) enzyme, responsiblefor bilirubin (BR) conjugation.5 This inhibition is directly1Unit of Infectious Diseases, Hospital Universitario Reina Sofia, Cordoba, Spain.2Maimonides Institute for Biomedical Research (IMIBIC), Cordoba, Spain.3Unit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Seville, Spain.4Internal Medicine Department, Hospital Universitario de Valme, Seville, Spain.5Unit of Infectious Diseases, Hospital Universitario de la Princesa, Madrid, Spain.6Unit of Infectious Diseases, Hospitales Universitarios Virgen del Rocio, Seville, Spain.7Instituto de Biomedicina de Sevilla (IBIS), Seville, Spain.8Unit of Infectious Diseases, Hospital Universitario Puerta del Mar, Cadiz, Spain.9Unit of Infectious Diseases, Hospital Universitario Virgen de la Victoria, Malaga, Spain.10Internal Medicine Service, Hospital Juan Ramo´n Jime´nez, Huelva, Spain.11Unit of Infectious Diseases, Hospital de La Lı´nea de la Concepcio´n, Ca´diz, Spain.12Immunogenetics Unit, Faculty of Sciences, Universidad de Jae´n, Jaen, Spain.AIDS RESEARCH AND HUMAN RETROVIRUSESVolume 29, Number 2, 2013ª Mary Ann Liebert, Inc.DOI: 10.1089/aid.2012.0126223associated with hyperbilirubinemia, the most common sideeffect of patients treated with ATV boosted with ritonavir(ATV/rtv). We hypothesize that this inhibition could modifythe modulatory effect of the products of hemoglobin catabo-lism on HCV replication.The aim of this study therefore was to assess the relation-ship between the use of ATV-based antiretroviral treatment(ART) and plasma HCV viral load in a population of HIV/HCV-coinfected patients.The study population was 829 HCV treatment-naive pa-tientswho had been consecutively enrolled fromOctober 2004to December 2011 in the Spanish HEPAVIR prospective co-hort of HIV/HCV-coinfected patients. Further details of thesecohorts have been reported elsewhere.6 Patients who receivedART based on two ITIAN plus a protease inhibitor (PI) ornonnucleoside reverse transcriptase inhibitors (NNRTI) wereincluded in the study. Patients who received estavudine, di-danosine, or zidovudine were excluded from the study. Onlypatients maintained for a minimum of time of 12 months onan unchanged regimen were included. HCV RNA levels inplasmawere measured using a commercial PCR assay (CobasTaqman; Roche Diagnostic Systems Inc., Pleasanton, CA:detection limit of 50 IU/ml).Liver fibrosis stage was determined by biopsy or livertransient elastography (FibroScan, Echosen, Paris). Significantfibrosis was defined as a METAVIR fibrosis score of F3–F4 inliver biopsy or a liver stiffness (LS) value of ‡ 8.9. SNPrs129679860, located 3 kilobases upstream of the IL28B gene,was genotyped using a custom Taqman assay (Applied Bio-systems, Foster City, CA) on DNA isolated from whole bloodsamples. The bilirubin data of those patients on ATV/rtvtreatment were also collected. Patients were stratified by ARTdrug [ATV/rtv, lopinavir (LPV), efavirenz (EFV), nevirapine(NVP), or other PI (saquinavir, nelfinavir, darunavir, or in-dinavir)], HCV genotype (1/4 and 2/3), and IL28B genotype(CC and non-CC). The Kruskal–Wallis test and chi-squaredtest were used to compare continuous and categorical vari-ables, respectively. Post hoc comparisons between groupswere carried out using the Mann–Whitney U test and the chi-squared test. To test our hypothesis, we used the Pearson orthe bivariate Spearman’s rank correlation coefficient to ana-lyze the relationship between HCV viral load and bilirubinlevels among patients treated with ATV/rtv. Associationswith p values of < 0.05 were considered significant for com-parisons between groups. Multivariate analysis consisted of astepwise linear regression analysis.Six hundred and forty-nine HIV/HCV-coinfected patientswere included in the analysis. Forty patients (7.3%) weretreated with ATV/rtv, 128 (23.4%) with LPV/rtv, 225 (41.2%)with EFV, 41 (7.5%) with NVP, and 112 (20.5%) received someother PI. Only nine patients who might have been included inthe analysis and fulfilled the criteria for inclusion in the studywere receiving darunavir/r. Given the low number of pa-tients, we decided not to include them as an independentgroup for analysis The most significant characteristics areshown in Table 1.Median HCV RNA levels of HCV genotypes 1/4 and 2/3were 6.13 (5.6–6.7) log IU/ml and 5.7 (5.3–6.2) log IU/ml,respectively ( p< 0.001). HCV genotype 1/4 patients who re-ceived ATV/rtv had higher HCV RNA levels [6.57 (6.2–6.8)log IU/ml] than those receiving LPV/rtv [6.1 (5.5–6.5) logIU/ml], EFV [6.1 (5.6–6.4) log IU/ml], NVP [5.8 (5.5–5.9) logIU/ml], or another PI drug [6.1 (5.7–6.4) log IU/ml( p= 0.014)]. However, this association was not found inpatients bearing HCV genotype 2/3 [ATV/rtv: 5.74 (5.4–5.9)log IU/ml], LPV/rtv [5.7 (5.2–5.8) log IU/ml], EFV [5.8 (5.6–6)log IU/ml], NVP [5.3 (4.9–5.5) log IU/ml], and other PI drug[5.6 (5.4–5.9) log IU/ml, p= 0.34].The IL28B-CC genotype was associated with a higher HCVviral load than the non-CC genotype [6.3 (6.2–6.6) log IU/mlversus 6 (5.9–6.3) log IU/ml, p = 0.001]. There were no dif-ferences in HCV viral load found on the basis of detectableHIV viral load [detectable, 6.1 (5.8–6.4) versus undetectable6 (5.4–6.2), p= 0.247] or liver fibrosis stage [advanced liverfibrosis: 6.2 (5.8–6.5) versus absence of liver fibrosis stage: 6.1(5.9–6.3), p= 0.472]. When HCV RNA viral loads wereanalyzed in terms of the drug used for ART, patients withIL28B-CC receiving ATV/rtv had higher viral loads thanthose receiving another drug [ATV/rtv: 7.3 (6.9–7.4) logIU/ml; LPV/rtv: 6.6 (6.2–6.8) log IU/ml; EFV: 6.6 (6.3–6.8) logIU/ml; other PI: 6.4 (6.2–6.9) log IU/ml, p= 0.038]. Patientswith IL28B non-CC receiving ATV had higher baseline HCVviral loads than those receiving another ART regimen [ATV/rtv: 6.15 (6–6.4) log IU/ml; LPV/rtv: 5.9 (5.8–6.2) log IU/ml;EFV: 5.8 (5.6–6) log IU/ml; other PIs: 5.9 (5.8–6.1) log IU/ml,p = 0.032]. The mean ( – SD) bilirubin level among thosepatients who received ATV/rtv was 2.31 – 0.87. In thesepatients, HCV viral load correlated positively with bilirubinlevels (r= 0.39; p = 0.0129).Table 2 shows the linear regression model. Independentfactors associatedwithHCVRNA levels were IL28B genotypeTable 1. Baseline Population CharacteristicsCharacteristicsN 649Age (years), mean (SD) 40.8 (5.56)Male gender, n (%) 537 (82.7)AIDS criteria, n (%) 192 (29.6)HbsAg positive, n (%) 8 (1.2)Undetectable HIV viral load, n (%) 472 (72.7)CD4 cell count (cells/mm3), mean (SD) 518 (266)HCV genotype 1/4, n (%) 452 (69.6)Liver cirrhosis stage, n (%) 154 (23.7)IL28B-CC genotype, n (%)a 115 (38.1)aAvailable for 302 patients.SD, standard deviation; AIDS, acquired immunodeficiency syn-drome criteria in the past; HbsAg, hepatitis B surface antigen; IL28B,interleukin 28B.Table 2. Linear Regression Model for Hepatitis CVirus Baseline Viral Load in Patients Bearingthe Hepatitis C Virus Genotype 1Variable Condition B pIL28B CC 0.7 0.033ATV/rtv Use 0.8 0.017Liver fibrosis stage Significant 0.075 0.884HIV viral load Undetectable 0.18 0.321R2 = 0.22.B, adjusted coefficient; IL28B, interleukin 28B; ATV/rtv, atazana-vir boosted with ritonavir; HIV, human immunodeficiency virus.224 RIVERO-JUAREZ ET AL.(B = 2.7; p = 0.033) and use of ATV (B = 2.8; p = 0.017). R2 was0.22.This is the first study to show the association betweenATV/rtv use and HCV RNA viral load. Since a high HCVRNA viral load is a risk factor for nonresponse to treatment,this may be an important issue in conditioning the response topegylated-interferon (PEG-IFN) with ribavirin (PEG-IFN/RBV) or to therapy based on NS3 protease inhibitors in HIV/HCV genotype 1-coinfected patients.7–9 However, the rela-tionship between ATV/rtv and treatment response has notyet been analyzed.The reason ATV use might be associated with higher HCVRNA viral loads is unknown. In vitro studies have reportedthat BR and BV show antiviral activity against HIV, the herpesvirus, and HCV.3 More specifically, the antiviral actionagainst HCV is due to both recombinant and endogenousNS3/4A protease from replicon microsomes being inhibitedby BR and BV.3 HO-1, on the other hand, potentiates inter-feron (IFN)-a, and so enhances antiviral activity.2 Hyperbi-lirubinemia and ATV use are directly associated because ofATV’s competing inhibitory activity against UGT1A1, re-sponsible for BR conjugation in the liver. Inhibition maymodify hemoglobin catabolism by suppressing various en-zymes with antiviral activity against HCV (BR-R, BV-S, andHO-1) due to the enhancement of the resulting metabolite(BR) or reduced ISG activity (from the inhibition or down-regulation of HO-1). There is no evidence that ATV blocks theactivity of HO-1, in addition to inhibiting UGT1A1. However,a clinical trial is currently in progress whose secondary ob-jective is to determine the effect of atazanavir-induced hy-perbilirubinemia on HO-1 induction (NCT00916448), whichmay clarify this question. On the other hand, our studyshowed that NVP use was associated with lower HCV viralload, as has previously been reported by our group.10Our study has several limitations. First, the number ofpatients with ATV-based therapy was relatively low. Second,the design was not a randomized study, which may have ledto bias not being recognized. Third, no concomitant drugswere considered in the analysis. Fourth, although BR is closelyrelated to ATV/rtv use, BR levels were not collected. Fifth, noconcomitant diseases were analyzed in our study, and it isknown that several liver pathologies may condition BR levels,as Gilbert’s syndrome.In conclusion, on the basis of our results, ATV-based ther-apy may be associated with higher HCV RNA viral loadsamong HIV/HCV-coinfected patients, a finding that couldhave an important impact on the outcome of HCV therapy.Studies are needed to confirm the relationship found in ourstudy, as well to analyze this association in HCV treatmentresponse.AcknowledgmentsThis work was partly supported by grants from the Fun-dacio´n Progreso y Salud, Consejerı´a de Salud de la Junta deAndalucı´a (grants for health research projects: 0036/2010, PI-0247-2010, PI-0208, and 0124/2008) and the Spanish HealthMinistry (ISCIII-RETIC RD06/006 and projects PI10/0164and PI10/01232). A.R. is the recipient of a research extensiongrant from the Fundacio´n Progreso y Salud, Consejerı´a deSalud de la Junta de Andalucı´a (AI-0011-2010); J.A.P. is therecipient of an extension grant from the Instituto de SaludCarlos III (Programa-I3SNS).Author Disclosure StatementThe authors have received consulting fees from Bristol-Myers Squibb, Abbott, Gilead, Roche, and BoehringerIngelheim. They have received research support from Glaxo-SmithKline, Roche, Bristol-Myers Squibb, Schering-Plough,Abbott, and Boehringer Ingelheim and lecture fees fromGlaxoSmithKline, Roche, Abbott, Bristol-Myers Squibb,Boehringer Ingelheim, and Schering-Plough.References1. Choi J and Ou JHJ: Mechanism of liver injury. III. Oxidativestress in the pathogenesis of hepatitis C virus. Am J PhysiolGastrointest Liver Physiol 2006;290:G847–851.2. Lehmann E, EL-Tantawy WH, Ocker M, et al.: The hemeoxygenase 1 product biliverdin interferes with hepatitis Cvirus replication by increasing antiviral interferon response.Hepatology 2010;51:398–404.3. Zhu Z, Wilson AT, Luxon BA, et al.: Biliverdin inhibitshepatitis C virus NS3/4A protease activity: Mechanism forthe antiviral effects of heme oxygenase? Hepatology 2010;52:1897–1905.4. Fillebeen C, Rivas-Estilla AM, Bisaillon M, et al.: Iron inac-tivates the RNA polymerase NS5B and suppresses sub-genomic replication of hepatitis C virus. J Biol Chem 2005;280:9049–9057.5. Brierly C and Burchell B: Human UDP-glucoronosyl trans-ferases: Chemical defence, jaundice and gene therapy.Bioessays 1993;15:749–754.6. Neukam K, Mira JA, Ruiz-Morales J, et al.: Liver toxicityassociated with antiretroviral therapy including efavirenz orritonavir-boosted protease inhibitors in a cohort of HIV/hepatitis C virus co-infected patients. J Antimicrob Che-mother 2011;66:2605–2614.7. Dore GJ, Torriani FJ, Rodriguez-Torres M, et al.: Baselinefactors prognostic of sustained virological response inpatients with HIV-hepatitis C virus co-infection. AIDS 2007;21:1555–1559.8. Poordad F, McCone J, Bacon BR, et al.: Boceprevir for un-treated chronic HCV genotype 1 infection. N Engl J Med2011;364:1195–1206.9. Jaconson IM, Mchutchison JG, Dusheiko G, et al.: Telaprevirfor previously untreated chronic hepatitis C virus infection.N Engl J Med 2011;364;25:2405–2416.10. Mata RC, Mira JA, Rivero A, et al.: Nevirapine-based anti-retroviral therapy is associated with lower plasma hepatitisC virus viral load among HIV/hepatitis C virus-coinfectedpatients. J AIDS Clinic Res 2010;1:110.Address correspondence to:Antonio RiveroHospital Universitario Reina Sofia de Co´rdobaEdificio ProvincialHospital de dı´a de Enfermedades InfecciosasAvd. Menendez Pidal s/n14004 CordobaSpainE-mail: ariveror@gmail.comATAZANAVIR INCREASES HCV VIRAL LOAD 225

Atazanavir-Based Therapy Is Associated with Higher Hepatitis C Viral Load in HIV Type 1-Infected Subjects with Untreated Hepatitis C

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Atazanavir-Based Therapy Is Associated with Higher Hepatitis C Viral Load in HIV Type 1-Infected Subjects with Untreated Hepatitis C

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