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1. 48 week outcomes of maraviroc-containing regimens following the genotypic or Trofile assay in HIV-1 failing subjects: the OSCAR Study.

Author

Nozza S, Pignataro AR, Galli L, Svicher V, Alteri C, Boeri E, Ripa M, Castagna A, Sampaolo M, Clementi M, Perno CF, and Lazzarin A

Subjects
Adult, Anti-HIV Agents administration & dosage, Cyclohexanes administration & dosage, Drug Administration Schedule, Female, Humans, Male, Maraviroc, Middle Aged, Treatment Failure, Triazoles administration & dosage, Viral Tropism, Anti-HIV Agents therapeutic use, Cyclohexanes therapeutic use, Genotype, HIV Infections drug therapy, HIV-1 genetics, Triazoles therapeutic use
Abstract

This study assessed the 48-week efficacy of an antiretroviral therapy including maraviroc following the assessment of co-receptor tropism by use of Geno2Pheno algorithm or the Trofile phenotypic assay in failing treatment-experienced HIV-1 patients. This was a multicenter, randomized, open-label, non-inferiority trial. Treatment-experienced subjects with HIV-RNA ≥500 copies/mL were randomized (1:1) to undergo co-receptor tropism testing by the Geno- 2Pheno algorithm (with a false positive rate >10%) or the Trofile assay before starting a new antiretroviral treatment which included maraviroc. The primary endpoint was the 48 week proportion of patients with treatment success (TS). Intention-to-treat analyses are also reported. One hundred and fifty-five experienced patients were analysed: 77 patients in the Trofile arm and 78 in the Genotype arm. The 48-week proportion of TS was 87% in the Trofile arm and 89% in the Genotype arm (difference: 1.5%, 95%CI: -8.9% to 11.8%) suggesting non-inferiority. In the Trofile arm, 10 patients had treatment failure: 5 viral rebound, 5 discontinuations. In the Genotype arm, 9 patients had treatment failure: 7 viral rebound, 2 lost to follow-up. CD4+ significantly increased from baseline to week 48 in both arms. 48-week treatment success was similar for maraviroc-including therapy prescribed following the Trofile phenotypic assay or Geno2Pheno algorithm.

Published
2016

2. Performance of genotypic tropism testing on proviral DNA in clinical practice: results from the DIVA study group.

Author

Svicher V, Alteri C, Montano M, D'Arrigo R, Andreoni M, Angarano G, Antinori A, Antonelli G, Allice T, Bagnarelli P, Baldanti F, Bertoli A, Borderi M, Boeri E, Bon I, Bruzzone B, Callegaro AP, Capobianchi MR, Carosi G, Cauda R, Ceccherini-Silberstein F, Clementi M, Chirianni A, Colafigli M, D'Arminio Monforte A, De Luca A, Di Biagio A, Di Nicuolo G, Di Perri G, Di Pietro M, Di Santo F, Fabeni L, Fadda G, Galli M, Gennari W, Ghisetti V, Giacometti A, Gori C, Gori A, Gulminetti R, Leoncini F, Maffongelli G, Maggiolo F, Manca G, Gargiulo F, Martinelli C, Maserati R, Mazzotta F, Meini G, Micheli V, Monno L, Mussini C, Narciso P, Nozza S, Paolucci S, Pal G, Parisi S, Parruti G, Pignataro AR, Pollicita M, Quirino T, Re MC, Rizzardini G, Santangelo R, Scaggiante R, Sterrantino G, Turriziani O, Vatteroni ML, Vecchi L, Viscoli C, Vullo V, Zazzi M, Lazzarini A, and Perno CF

Subjects
Female, Genotyping Techniques standards, HIV Envelope Protein gp120 genetics, HIV Infections diagnosis, Humans, Leukocytes, Mononuclear virology, Male, Reproducibility of Results, Viral Load, Genotype, HIV Infections virology, HIV-1 genetics, Proviruses, Viral Tropism
Abstract

Objective: The DIVA study is aimed at setting up a standardized genotypic tropism-testing on proviral-DNA for the routine clinical diagnostic-laboratory., Methods: Twelve local centres and 5 reference centres (previously cross-validated) were identified. For inter-center validation-procedure, 60 peripheral-blood mononuclear cells (PBMCs) aliquots from 45 HAART-treated patients were randomly chosen for population V3 sequencing on proviral-DNA at local HIV centre and at reference-laboratory. Viral tropism was predicted by Geno2Pheno algorithm (False Positive Rate [FPR] = 20%) as proposed by the European-Guidelines. Quantification of total HIV-1 DNA was based on a method described by Viard (2004)., Results: Quantification of HIV-1 DNA was available for 35/45 (77.8%) samples, and gave a median value of 598 (IQR:252- 1,203) copies/10 PBMCs. A total of 56/60 (93.3%) samples were successfully amplified by both the reference and the local virological centers. The overall concordance of tropism prediction between local and reference centers was 54/56 (96.4%). Results of tropism prediction by local centers were: 33/54 (61.1%) R5 and 21/54 (38.9%) X4/DM., Conclusion: There was high concordance in the genotypic tropism prediction based on proviral DNA among different virological centers throughout Italy. Our results are in line with other European studies, and support the use of genotypic tropism testing on proviral DNA in patients with suppressed plasma HIV-1 RNA candidate to CCR5-antagonist treatment.

Published
2012

3. Resistance analysis and treatment outcomes in hepatitis C virus genotype 3-infected patients within the Italian network VIRONET-C

Author

Di Maio, V. C., Barbaliscia, S., Teti, E., Fiorentino, G., Milana, M., Paolucci, S., Pollicino, T., Morsica, G., Starace, M., Bruzzone, B., Gennari, W., Micheli, V., Yu La Rosa, K., Foroghi, L., Calvaruso, V., Lenci, I., Polilli, E., Babudieri, S., Aghemo, A., Raimondo, G., Sarmati, L., Coppola, N., Pasquazzi, C., Baldanti, F., Parruti, G., Perno, C. F., Angelico, M., Craxi, A., Andreoni, M., Ceccherini-Silberstein, F., Andreone, P., Aragri, M., Bertoli, A., Boeri, E., Brancaccio, G., Brunetto, M., Callegaro, A. P., Cenderello, G., Cento, V., Ciaccio, A., Ciancio, A., Cuomo, N., De Santis, A., Di Biagio, A., Di Marco, V., Di Perri, G., Di Stefano, M. A., Gaeta, G. B., Ghisetti, V., Gulminetti, R., Lampertico, P., Landonio, S., Lichtner, M., Lleo, A., Maida, I., Marenco, S., Masetti, C., Mastroianni, C., Minichini, C., Milano, E., Monno, L., Novati, S., Pace Palitti, V., Paternoster, C., Pellicelli, A., Pieri, A., Puoti, M., Rizzardini, G., Ruggiero, T., Rossetti, B., Sangiovanni, V., Santantonio, T., Taliani, G., Toniutto, P., Vullo, V., Zazzi, M., Di Maio, V, Barbaliscia, S, Teti, E, Fiorentino, G, Milana, M, Paolucci, S, Pollicino, T, Morsica, G, Starace, M, Bruzzone, B, Gennari, W, Micheli, V, Yu La Rosa, K, Foroghi, L, Calvaruso, V, Lenci, I, Polilli, E, Babudieri, S, Aghemo, A, Raimondo, G, Sarmati, L, Coppola, N, Pasquazzi, C, Baldanti, F, Parruti, G, Perno, C, Angelico, M, Craxi, A, Andreoni, M, Ceccherini-Silberstein, F, Andreone, P, Aragri, M, Bertoli, A, Boeri, E, Brancaccio, G, Brunetto, M, Callegaro, A, Cenderello, G, Cento, V, Ciaccio, A, Ciancio, A, Cuomo, N, De Santis, A, Di Biagio, A, Di Marco, V, Di Perri, G, Di Stefano, M, Gaeta, G, Ghisetti, V, Gulminetti, R, Lampertico, P, Landonio, S, Lichtner, M, Lleo, A, Maida, I, Marenco, S, Masetti, C, Mastroianni, C, Minichini, C, Milano, E, Monno, L, Novati, S, Pace Palitti, V, Paternoster, C, Pellicelli, A, Pieri, A, Puoti, M, Rizzardini, G, Ruggiero, T, Rossetti, B, Sangiovanni, V, Santantonio, T, Taliani, G, Toniutto, P, Vullo, V, Zazzi, M, Di Maio, Vc, Perno, Cf, Craxì, A, Di Maio V.C., Barbaliscia S., Teti E., Fiorentino G., Milana M., Paolucci S., Pollicino T., Morsica G., Starace M., Bruzzone B., Gennari W., Micheli V., Yu La Rosa K., Foroghi L., Calvaruso V., Lenci I., Polilli E., Babudieri S., Aghemo A., Raimondo G., Sarmati L., Coppola N., Pasquazzi C., Baldanti F., Parruti G., Perno C.F., Angelico M., Craxi A., Andreoni M., Ceccherini-Silberstein F., Andreone P., Aragri M., Bertoli A., Boeri E., Brancaccio G., Brunetto M., Callegaro A.P., Cenderello G., Cento V., Ciaccio A., Ciancio A., Cuomo N., De Santis A., Di Biagio A., Di Marco V., Di Perri G., Di Stefano M.A., Gaeta G.B., Ghisetti V., Gulminetti R., Lampertico P., Landonio S., Lichtner M., Lleo A., Maida I., Marenco S., Masetti C., Mastroianni C., Minichini C., Milano E., Monno L., Novati S., Pace Palitti V., Paternoster C., Pellicelli A., Pieri A., Puoti M., Rizzardini G., Ruggiero T., Rossetti B., Sangiovanni V., Santantonio T., Taliani G., Toniutto P., Vullo V., and Zazzi M.

Subjects
Male, Sofosbuvir, Sustained Virologic Response, Drug Resistance, Hepacivirus, Viral Nonstructural Proteins, Gastroenterology, Settore MED/06, direct-acting antivirals, failure, genotype 3, HCV, resistance, chemistry.chemical_compound, 0302 clinical medicine, Medicine, Viral, Chronic, Phylogeny, Dasabuvir, hcv, virus diseases, Hepatitis C, Pibrentasvir, Italy, 030220 oncology & carcinogenesis, Combination, Drug Therapy, Combination, 030211 gastroenterology & hepatology, Female, medicine.drug, Ledipasvir, medicine.medical_specialty, Daclatasvir, Genotype, Antiviral Agents, Drug Resistance, Viral, Humans, Hepatitis C, Chronic, 03 medical and health sciences, Drug Therapy, Internal medicine, Antiviral Agent, direct-acting antiviral, Hepaciviru, Hepatology, business.industry, Viral Nonstructural Protein, Glecaprevir, direct acting antivirals, Regimen, chemistry, Paritaprevir, business
Abstract

Aim: This study aimed to investigate the role of resistance-associated substitutions (RASs) to direct-acting-antivirals (DAAs) in HCV genotype 3 (GT3). Methods: Within the Italian VIRONET-C network, a total of 539 GT3-infected patients (417 DAA-naïve and 135 DAA-failures, of them, 13 at both baseline and failure) were analysed. Sanger sequencing of NS3/NS5A/NS5B was performed following home-made protocols. Results: The majority of patients were male (79.4%), 91.4% were injection drug users, 49.3% were cirrhotic and 13.9% were HIV co-infected. Phylogenetic analysis classified sequences as GT3a-b-g-h (98%-0.4%-0.2%-1.2%) respectively. Overall, 135 patients failed a DAA regimen: sofosbuvir (SOF)/daclatasvir (DCV) or velpatasvir (VEL)±ribavirin (RBV) (N=91/15) and glecaprevir (G)/pibrentasvir (P) (N=9). Moreover, 14.8% of patients were treated with suboptimal regimens for GT3: 3D±RBV (Paritaprevir/r+Ombitasvir+Dasabuvir, N=15), SOF+Simeprevir (SIM) (N=1) or SOF/Ledipasvir (LDV)±RBV (N=4). RAS prevalence was 15.8% in DAA-naïve patients. At failure, 81.5% patients showed at least one RAS: 11/25 (44.0%) in NS3, 109/135 (80.7%) in NS5A, 7/111 (6.3%) in NS5B SOF-failures. In NS5A-failures, Y93H RAS was the most prevalent (68.5% vs 5.1% DAA-naïve, P&nbsp

Published
2021

4. Prevalence of acquired resistance mutations in a large cohort of perinatally infected HIV-1 patients

Author

Ungaro, R., Taramasso, L., Bruzzone, B., Vicenti, I., Galli, L., Borghi, V., Francisci, D., Pecorari, M., Zoncada, A., Callegaro, A. P., Paolini, E., Monno, L., Bonora, S., Di Biagio, A., ARCA Study Group, Giacometti, A., Butini, L., del Gobbo, R., Bagnarelli, P., Tacconi, D., Corbelli, G., Zanussi, S., Punzi, G., Maggiolo, F., Calza, L., Carla Re, M., Pristera, R., Turconi, P., Mandas, A., Tini, S., Amadio, G., Sighinolfi, L., Corsi, P., Di Pietro, M., Colao, G., Tosti, A., Setti, M., Cenderello, G., Trezzi, M., Orani, A., Arcidiacono, I., Degiuli, A., De Gennaro, M., Chiodera, A., Scalzini, A., Palvarini, L., Todaro, G., Rusconi, S., Gismondo, M. R., Micheli, V., Biondi, M. L., Capetti, A., Meraviglia, P., Boeri, E., Mussini, C., Soria, A., Vecchi, L., Santirocchi, M., Brustia, D., Ravanini, P., Dal Bello, F., Romano, N., Mancuso, S., Calzetti, C., Maserati, R., Filice, G., Baldanti, F., Parruti, G., Polilli, E., Sacchini, D., Martinelli, C., Consolini, R., Vatteroni, L., Vivarelli, A., Nerli, A., Lenzi, L., Magnani, G., Ortolani, P., Andreoni, M., Fimiani, C., Palmisano, L., Di Giambenedetto, S., Vullo, V., Turriziani, O., Montano, M., Antinori, A., Zaccarelli, M., Dentone, C., Gonnelli, A., De Luca, A., Palumbo, M., Ghisetti, V., Delle Foglie, P., Rossi, C., Mondino, V., Malena, M., Grossi, P., Seminari, E., Poletti, F., Ungaro R., Taramasso L., Bruzzone B., Vicenti I., Galli L., Borghi V., Francisci D., Pecorari M., Zoncada A., Callegaro A.P., Paolini E., Monno L., Bonora S., Di Biagio A., Giacometti A., Butini L., del Gobbo R., Bagnarelli P., Tacconi D., Corbelli G., Zanussi S., Punzi G., Maggiolo F., Calza L., Carla Re M., Pristera R., Turconi P., Mandas A., Tini S., Amadio G., Sighinolfi L., Corsi P., Di Pietro M., Colao G., Tosti A., Setti M., Cenderello G., Trezzi M., Orani A., Arcidiacono I., Degiuli A., De Gennaro M., Chiodera A., Scalzini A., Palvarini L., Todaro G., Rusconi S., Gismondo M.R., Micheli V., Biondi M.L., Capetti A., Meraviglia P., Boeri E., Mussini C., Soria A., Vecchi L., Santirocchi M., Brustia D., Ravanini P., Dal Bello F., Romano N., Mancuso S., Calzetti C., Maserati R., Filice G., Baldanti F., Parruti G., Polilli E., Sacchini D., Martinelli C., Consolini R., Vatteroni L., Vivarelli A., Nerli A., Lenzi L., Magnani G., Ortolani P., Andreoni M., Fimiani C., Palmisano L., Di Giambenedetto S., Vullo V., Turriziani O., Montano M., Antinori A., Zaccarelli M., Dentone C., Gonnelli A., De Luca A., Palumbo M., Ghisetti V., Delle Foglie P., Rossi C., Mondino V., Malena M., Grossi P., Seminari E., and Poletti F.

Subjects
Male, antiretroviral treatment, Infectious Disease Transmission, genotype, Human immunodeficiency virus (HIV), Drug Resistance, HIV Infections, Drug resistance, medicine.disease_cause, Retrospective Studie, Genotype, pol Gene Products, Human Immunodeficiency Viru, Prevalence, Medicine, Vertical, HIV Infection, Viral, pol Gene Products, Young adult, General Medicine, Infectious Diseases, Italy, Mutation (genetic algorithm), Female, Human Immunodeficiency Virus, Human, Microbiology (medical), Adult, Settore MED/17 - Malattie Infettive, Adolescent, Anti-HIV Agents, Young Adult, Acquired resistance, Drug Resistance, Viral, Humans, vertical HIV transmission, HIV-1, Mutation, Retrospective Studies, pol Gene Products, Human Immunodeficiency Virus, Infectious Disease Transmission, Vertical, HIV perinatally infection, business.industry, Anti-HIV Agent, Retrospective cohort study, Virology, Large cohort, business
Published
2019

5. Declining Prevalence of HIV-1 Drug Resistance in Antiretroviral Treatment-exposed Individuals in Western Europe

Author

De Luca, A, Dunn, D, Zazzi, M, Camacho, R, Torti, C, Fanti, I, Kaiser, R, Sönnerborg, A, Codoñer, Fm, Van Laethem, K, Vandamme, Am, Bansi, L, Ghisetti, V, van de Vijver DA, Asboe, D, Prosperi, Mc, Di Giambenedetto, S, Collaborators: Giacometti A, SEHERE collaboration in C. h. a. i. n., Butini, L, del Gobbo, R, Menzo, S, Tacconi, D, Corbelli, G, Zanussi, S, Monno, L, Punzi, G, Maggiolo, F, Callegaro, A, Calza, L, Pristerà, R, Turconi, P, Mandas, A, Tini, S, Zoncada, A, Paolini, E, Amadio, G, Sighinolfi, L, Zuccati, G, Morfini, M, Manetti, R, Corsi, P, Galli, L, Di Pietro, M, Bartalesi, F, Colao, G, Tosti, A, Di Biagio, A, Setti, M, Bruzzone, B, Penco, G, Trezzi, M, Orani, A, Pardelli, R, De Gennaro, M, Chiodera, A, Scalzini, A, Palvarini, L, Almi, P, Todaro, G, Monforte, Ad, Cicconi, P, Rusconi, S, Gismondo, Mr, Micheli, V, Biondi, Ml, Gianotti, N, Capetti, A, Meraviglia, P, Boeri, E, Mussini, C, Pecorari, M, Soria, A, Vecchi, L, Santirocchi, M, Brustia, D, Ravanini, P, Dal Bello, F, Romano, N, Mancuso, S, Calzetti, C, Maserati, R, Filice, G, Baldanti, F, Francisci, D, Parruti, G, Polilli, E, Sacchini, D, Martinelli, C, Consolini, Rita, De Luca, A, Dunn, D, Zazzi, M, Camacho, R, Torti, C, Fanti, I, Kaiser, R, Sönnerborg, A, Codoñer, F, Van Laethem, K, Vandamme, A, Bansi, L, Ghisetti, V, Van De Vijver, D, Asboe, D, Prosperi, M, Di Giambenedetto, S, Mancuso, S, and Virology

Subjects
Male, Multivariate analysis, Databases, Factual, Drug Resistance, HIV Infections, Drug resistance, 0302 clinical medicine, Retrospective Studie, Risk Factors, Epidemiology, Genotype, pol Gene Products, Human Immunodeficiency Viru, Odds Ratio, Prevalence, Immunology and Allergy, HIV Infection, 030212 general & internal medicine, pol Gene Products, Viral, Multivariate Analysi, media_common, 0303 health sciences, Drug Resistance Prevalence HIV-1, Middle Aged, Resistance mutation, 3. Good health, Reverse Transcriptase Inhibitor, Europe, Infectious Diseases, Reverse Transcriptase Inhibitors, epidemiology, Female, Multiple, Human Immunodeficiency Virus, Human, Drug, Adult, medicine.medical_specialty, Evolution, media_common.quotation_subject, Sexual Behavior, antiretroviral therapy, Infectious Disease, Biology, Settore MED/17 - MALATTIE INFETTIVE, Evolution, Molecular, 03 medical and health sciences, Databases, SDG 3 - Good Health and Well-being, Drug Resistance, Multiple, Viral, medicine, Humans, HIV Protease Inhibitor, Factual, Retrospective Studies, 030306 microbiology, Risk Factor, Molecular, Retrospective cohort study, Odds ratio, HIV Protease Inhibitors, CD4 Lymphocyte Count, drug resistance, genotyping, HIV-1, Multivariate Analysis, Mutation, pol Gene Products, Human Immunodeficiency Virus, Immunology, Demography
Abstract

HIV-1 drug resistance represents a major obstacle to infection and disease control. This retrospective study analyzes trends and determinants of resistance in antiretroviral treatment (ART)-exposed individuals across 7 countries in Europe. Of 20 323 cases, 80% carried at least one resistance mutation: these declined from 81% in 1997 to 71% in 2008. Predicted extensive 3-class resistance was rare (3.2% considering the cumulative genotype) and peaked at 4.5% in 2005, decreasing thereafter. The proportion of cases exhausting available drug options dropped from 32% in 2000 to 1% in 2008. Reduced risk of resistance over calendar years was confirmed by multivariable analysis. © 2013 The Author.

Published
2013
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6. Rules-based HIV-1 genotypic resistance interpretation systems predict 8 week and 24 week virological antiretroviral treatment outcome and benefit from drug potency weighting

Author

Zazzi, M, Prosperi, M, Vicenti, I, Di Giambenedetto, S, Callegaro, A, Bruzzone, B, Baldanti, F, Gonnelli, A, Boeri, E, Paolini, E, Rusconi, S, Giacometti, A, Maggiolo, F, Menzo, S, De Luca, A, ARCA Collaborative Group, Butini, L, del Gobbo, R, Tacconi, D, Corbelli, G, Zanussi, S, Monno, L, Punzi, G, Calza, L, Re, Mc, Pristerà, R, Turconi, P, Mandas, A, Tini, S, Carnevale, G, Amadio, G, Sighinolfi, L, Zuccati, G, Morfini, M, Manetti, R, Corsi, P, Galli, L, Di Pietro, M, Bartalesi, F, Colao, G, Tosti, A, Di Biagio, A, Setti, M, Penco, G, Trezzi, M, Orani, A, Pardelli, R, De Gennaro, M, Chiodera, A, Scalzini, A, Palvarini, L, Almi, P, Todaro, G, Cicconi, P, Gismondo, Mr, Micheli, V, Biondi, Ml, Gianotti, N, Capetti, A, Meraviglia, P, Mussini, C, Pecorari, M, Santirocchi, M, Brustia, D, Ravanini, P, Dal Bello, F, Romano, N, Mancuso, S, Calzetti, C, Maserati, R, Filice, G, Francisci, D, Parruti, G, Polilli, E, Sacchini, D, Martinelli, C, Consolini, Rita, Zazzi, M, Prosperi, M, Vicenti, I, Di Giambenedetto, S, Callegaro, A, Bruzzone, B, Baldanti, F, Gonnelli, A, Boeri, E, Paolini, E, Rusconi, S, Giacometti, A, Maggiolo, F, Menzo, S, De Luca, A, Mancuso, S, Zazzi M, Prosperi M, Vicenti I, Di Giambenedetto S, Callegaro A, Bruzzone B, Baldanti F, Gonnelli A, Boeri E, Paolini E, Rusconi S, Giacometti A, Maggiolo F, Menzo S, De Luca A, ARCA Collaborative Group: [.., Butini L, del Gobbo R, Tacconi D, Corbelli G, Zanussi S, Monno L, Punzi G, Calza L, Re M C, Pristerà R, Turconi P, Mandas A, Tini S, and ]

Subjects
Male, interpretation system, HIV Infections, Drug resistance, Logistic regression, Retrospective Studie, HIV Infection, Pharmacology (medical), Microbial Sensitivity Test, Middle Aged, Prognosis, genotype, drug resistance, algorithm, Algorithm, Treatment Outcome, Infectious Diseases, Italy, RNA, Viral, Female, Cohort study, Human, Microbiology (medical), Adult, medicine.medical_specialty, Genotype, Logistic Model, Anti-HIV Agents, Prognosi, antiretroviral, Microbial Sensitivity Tests, Internal medicine, medicine, Potency, Animals, Humans, Retrospective Studies, Pharmacology, Receiver operating characteristic, business.industry, Animal, Anti-HIV Agent, Retrospective cohort study, Odds ratio, genotype, drug potency weighting, Weighting, Logistic Models, ROC Curve, Immunology, HIV-1, business
Abstract

Objectives: To test retrospectively the ability of four freely available rules-based expert systems to predict short- and medium-term virological outcome following an antiretroviral treatment switch in pre-treated HIV-1 patients. Methods: The HIV-1 genotype interpretation systems (GISs) HIVdb, ANRS, Rega and AntiRetroScan were tested for their accuracy in predicting response to highly active antiretroviral therapy using 8 week (n = 765) and 24 week (n = 634) follow-up standardized treatment change episodes extracted from the Italian Antiretroviral Resistance Cohort Analysis (ARCA) database. A genotypic sensitivity score (GSS) was derived for each genotype-treatment pair for the different GISs and tested as a predictor of virological treatment outcome by univariable and multivariable logistic regression as well as by receiver operating characteristic curve analysis. The two systems implementing drug potency weights (AntiRetroScan and Rega) were evaluated with and without this correction factor. Results: All four GSSs were strong predictors of virological treatment outcome at both 8 and 24 weeks after adjusting for baseline viro-immunological parameters and previous drug exposure (odds ratios ranging from 2.04 to 2.43 per 1 unit GSS increase; P < 0.001 for all the systems). The accuracy of AntiRetroScan and Rega was significantly increased by drug potency weighting with respect to the unweighted versions (P ≤ 0.001). HIVdb and ANRS also increased their performance with the same drug potency weighting adopted by AntiRetroScan and Rega, respectively (P < 0.001 for both analyses). Conclusions: Currently available GISs are valuable tools for assisting antiretroviral treatment choices. Drug potency weighting can increase the accuracy of all systems. © The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Published
2009

7. Genotypic resistance profiles associated with virological failure to darunavir-containing regimens: a cross-sectional analysis

Author

Sterrantino, G, Zaccarelli, M, Colao, G, Baldanti, F, Di Giambenedetto, S, Carli, T, Maggiolo, F, Zazzi, M, Giacometti, A, Butini, L, Del Gobbo, R, Bagnarelli, P, Tacconi, D, Corbelli, G, Zanussi, S, Monno, L, Punzi, G, Callegaro, A, Calza, L, Re, MC, Pristera, R, Turconi, P, Mandas, A, Tini, S, Zoncada, A, Paolini, E, Amadio, G, Sighinolfi, L, Zuccati, G, Morfini, M, Manetti, R, Corsi, P, Galli, L, Di Pietro, M, Bartalesi, F, Tosti, A, Di Biagio, A, Setti, M, Bruzzone, B, di Biagio, A, Penco, G, Trezzi, M, Orani, A, Pardelli, R, Arcidiacono, I, Degiuli, A, de Gennaro, M, Chiodera, A, Scalzini, A, Palvarini, L, Almi, P, Todaro, G, Cicconi, P, Rusconi, S, Gismondo, MR, Micheli, V, Biondi ML, Gianotti, N, Capetti, A, Meraviglia, P, Boeri, E, Mussini, C, Pecorari, M, Soria, A, Vecchi, L, Gerardo, AO, Santirocchi, M, Brustia, D, Maggiore, AO, Ravanini, P, Bello, FD, Romano, N, MANCUSO, Salvatrice, Calzetti, C, Maserati, R, Filice, G, Francisci, D, Parruti, G, Polilli, E, Sacchini, D, Martinelli, C, Consolini, R, Vatteroni, L, Vivarelli, A, Nerli, A, Lenzi, L, Magnani, G, Ortolani, P, Andreoni, M, Palamara, G, Fimiani, C, Palmisano, L, di Giambenedetto, S, Colafigli, M, Vullo, V, Turriziani, O, Montano, M, Antinori, A, Dentone, C, Gonnelli, A, de Luca, A, Palumbo, M, Ghisetti, V, Bonora, S, Foglie, PD, Rossi, C, Mondino, V, Malena, M, Grossi, P, Seminari, E, Poletti, F., Sterrantino, G, Zaccarelli, M, Colao, G, Baldanti, F, Di Giambenedetto, S, Carli, T, Maggiolo, F, Zazzi, M, Giacometti, A, Butini, L, Del Gobbo, R, Bagnarelli, P, Tacconi, D, Corbelli, G, Zanussi, S, Monno, L, Punzi, G, Callegaro, A, Calza, L, Re, MC, Pristera, R, Turconi, P, Mandas, A, Tini, S, Zoncada, A, Paolini, E, Amadio, G, Sighinolfi, L, Zuccati, G, Morfini, M, Manetti, R, Corsi, P, Galli, L, Di Pietro, M, Bartalesi, F, Tosti, A, Di Biagio, A, Setti, M, Bruzzone, B, di Biagio, A, Penco, G, Trezzi, M, Orani, A, Pardelli, R, Arcidiacono, I, Degiuli, A, de Gennaro, M, Chiodera, A, Scalzini, A, Palvarini, L, Almi, P, Todaro, G, Cicconi, P, Rusconi, S, Gismondo, MR, Micheli, V, Biondi ML, Gianotti, N, Capetti, A, Meraviglia, P, Boeri, E, Mussini, C, Pecorari, M, Soria, A, Vecchi, L, Gerardo, AO, Santirocchi, M, Brustia, D, Maggiore, AO, Ravanini, P, Bello, FD, Romano, N, Mancuso, S, Calzetti, C, Maserati, R, Filice, G, Francisci, D, Parruti, G, Polilli, E, Sacchini, D, Martinelli, C, Consolini, R, Vatteroni, L, Vivarelli, A, Nerli, A, Lenzi, L, Magnani, G, Ortolani, P, Andreoni, M, Palamara, G, Fimiani, C, Palmisano, L, di Giambenedetto, S, Colafigli, M, Vullo, V, Turriziani, O, Montano, M, Antinori, A, Dentone, C, Gonnelli, A, de Luca, A, Palumbo, M, Ghisetti, V, Bonora, S, Foglie, PD, Rossi, C, Mondino, V, Malena, M, Grossi, P, Seminari, E, and Poletti, F

Subjects
Male, Time Factors, Cross-sectional study, Human immunodeficiency virus (HIV), Drug Resistance, HIV Infections, Drug resistance, medicine.disease_cause, Cohort Studies, Antiretroviral Therapy, Highly Active, Ritonavir-boosted darunavir, Genotype, HIV Infection, Treatment Failure, Viral, Genotypic resistance, Darunavir, Sulfonamides, General Medicine, Middle Aged, Virological failure, Infectious Diseases, Female, Human, medicine.drug, Adult, Microbiology (medical), Logistic Model, Time Factor, Antiretroviral Therapy, Settore MED/17 - MALATTIE INFETTIVE, Sulfonamide, Drug Resistance, Viral, medicine, Humans, Highly Active, Protease inhibitors, Cross-Sectional Studies, HIV Protease Inhibitors, HIV-1, Logistic Models, Mutation, HIV Protease Inhibitor, Cross-Sectional Studie, business.industry, Antiretroviral therapy, Virology, Protease inhibitor, Cohort Studie, business
Abstract

Introduction: This study aimed at defining protease (PR) resistance mutations associated with darunavir (DRV) failure and PR resistance evolution at DRV failure in a large database of treatment-experienced human immunodeficiency virus (HIV) patients. Results: Overall, 1,104 patients were included: 118 (10.7%) failed at a median observation time of 16 months. The mean number of PR mutations at baseline was 2.7, but it was higher in patients who subsequently failed DRV. In addition, the number of PR mutations increased at failure. The increase in the mean number of mutations was completely related to mutations considered to be associated with DRV resistance following the indications of the main DRV clinical trials. Discussion The higher statistical difference at baseline between failing versus non-failing patients was observed for the V32I and I84V mutations. At DRV failure, the major increase was still observed for V32I; I54L, V11I, T74P and I50V also increased. Despite the increment in the mean number of mutations per patient between baseline and failure, in 21 patients (17.8%) at baseline and 36 (30.5%) at failure, no PR mutation was detected. Conclusion: The HIV-DB interpretation algorithm identified few patients with full DRV resistance at baseline and few patients developed full resistance at DRV failure, indicating that complete resistance to DRV is uncommon. © Springer-Verlag 2011.

Published
2012

8. Characterization of GBV-C infection in HIV-1 infected patients

Author

Canducci, F., Foppa, C. U., Boeri, E., Racca, S., Gallotta, G., Grasso, M. A., Calori, G., Adriano LAZZARIN, Clementi, M., Canducci, F, UBERTI FOPPA, Caterina, Boeri, E, Racca, S, Gallotta, G, Grasso, Ma, Calori, G, Lazzarin, A, and Clementi, Massimo

Subjects
Adult, Male, Genotype, Reverse Transcriptase Polymerase Chain Reaction, GB virus C, HIV Infections, Sequence Analysis, DNA, Flaviviridae Infections, Middle Aged, Viral Load, Blotting, Northern, CD4 Lymphocyte Count, HIV Long-Term Survivors, Italy, Antiretroviral Therapy, Highly Active, HIV-1, Humans, RNA, Viral, Female, Databases, Nucleic Acid, Sequence Alignment, Phylogeny
Abstract

Background. GB virus C, a positive-stranded RNA virus, is classified in the family Flaviviridae. It is currently believed that persistent infection occurs in 25-50% of infected individuals, however, it still remains an "orphan" virus in search of a role in human pathology. Molecular epidemiological studies have demonstrated that GBV-C infection is present in about 1-1.4% of the healthy population in developed countries, that it shares routes of transmission with HIV and HCV and that the prevalence of GBV-C in these populations is higher than in blood donors. On the basis of the sequence variation among the isolates, GBV-C is classified into at least four major genotypes. Preliminary evidence has suggested that GBV-C is a lymphotropic virus that replicates mainly in the spleen and bone marrow. Recently, several reports have investigated the possible beneficial effect of GBV-C co-infection on HIV disease progression to AIDS, reduced mortality in HIV infected individuals and lower HIV viral loads, not leading to a definitive conclusion yet. Aim. To investigate the role of GBV virus C co-infection in two different subsets of HIV-infected patients, and to evaluate the prevalence of GBV-C genotypes in Northern Italy. Methods. A total of 86 HIV positive patients were examined for GBV-C viremia (years after HIV sera conversion: 12 +/- 5). Control population (Group A): 46 patients (mean age 42 years) with 500 CD4/ml for at least 8 years and never treated with HAART. After extraction of viral RNA from plasma samples, amplification of a highly conserved region of 5'UTR was performed by nested RT-PCR. All positive samples were genotyped by sequencing, alignment with published sequences and phylogenetic analysis. CD4 cell count, HIV plasma levels were also evaluated. Results. 9 out of 46 (19.56%) in Group A and 15 out of 40 (37.5%) in Group B had detectable GBV-C viremia (p=0.064, OR 2.47, percent confidence interval 0.94 to 6.51). No statistical difference was observed when disease stage was evaluated between the two groups. In Group B, after regression analysis for CD4 cell count decrease over the period observed, no significant difference was detected between GBV-C positive and negative patients. No significant difference was observed in Group B in HIV viremia and CD4 cell count at time of GBV-C detection between GBV-C infected patients and GBV-C negative patients. All Italian patients were genotype 2, the only African patient carried GBV-C genotype 1. Conclusions. Although previous results suggest that GBV-C virus may be a favorable marker for long term non progression of HIV disease, whether it plays a direct anti-HIV role or just takes advantage of non progessors' higher CD4 cell count to replicate more efficiently, still remains to be answered. Follow up of untreated patients and further evaluation of virological interactions, between the viruses and the host immune system, will be helpful to shed some light on these observations, offering new prognostic and eventually therapeutical tools for the management of HIV patients.

Published
2003

9. Detection of drug resistance mutations at low plasma HIV-1 RNA load in a European multicentre cohort study

Author

Prosperi, Mc1, Mackie, N, Di Giambenedetto, S, Zazzi, M, Camacho, R, Fanti, I, Torti, C, Sönnerborg, A, Kaiser, R, Codoñer, Fm, Van Laethem, K, Bansi, L, van de Vijver DA, Geretti, Am, De Luca, A, Giacometti A, SEHERE c. o. n. s. o. r. t. i. u. m., Butini, L, del Gobbo, R, Menzo, S, Tacconi, D, Corbelli, G, Zanussi, S, Monno, L, Punzi, G, Maggiolo, F, Callegaro, A, Calza, L, Carla Re, M, Pristerà, R, Turconi, P, Mandas, A, Tini, S, Zoncada, A, Paolini, E, Amadio, G, Sighinolfi, L, Zuccati, G, Morfini, M, Manetti, R, Corsi, P, Galli, L, Di Pietro, M, Bartalesi, F, Colao, G, Tosti, A, Di Biagio, A, Setti, M, Bruzzone, B, Penco, G, Trezzi, M, Orani, A, Pardelli, R, De Gennaro, M, Chiodera, A, Scalzini, A, Palvarini, L, Almi, P, Todaro, G, d'Arminio Monforte, A, Cicconi, P, Rusconi, S, Gismondo, Mr, Micheli, V, Biondi, Ml, Gianotti, N, Capetti, A, Meraviglia, P, Boeri, E, Mussini, C, Pecorari, M, Soria, A, Vecchi, L, Santirocchi, M, Brustia, D, Ravanini, P, Bello, Fd, Romano, N, Mancuso, S, Calzetti, C, Maserati, R, Filice, G, Baldanti, F, Francisci, D, Parruti, G, Polilli, E, Sacchini, D, Martinelli, C, Consolini, R, Vatteroni, L, Vivarelli, A, Dionisio, D, Nerli, A, Lenzi, L, Magnani, G, Ortolani, P, Andreoni, M, Palamara, G, Fimiani, C, Palmisano, L, Fadda, G, Vullo, Vincenzo, Turriziani, O, Montano, M, Cenderello, G, Gonnelli, A, Palumbo, M, Ghisetti, V, Bonora, S, Foglie, Pd, Rossi, C, Grossi, P, Seminari, E, Poletti, F, Mondino, V, Malena, M, Lattuada, E, Lengauer, T, Däumer, M, Hoffmann, D, Schülter, E, Müller, C, Oette, M, Reuter, S, Esser, S, Fätkenheuer, G, Rockstroh, J, Incardona, F, Rosen Zvi, M, Clotet, B, Thalme, A, Svedhem, V, Bratt, G, Gargiulo, F, Lapadula, G, Manca, N, Paraninfo, G, Quiros Roldan, E, Carosi, G, Castelnuovo, F, Vandamme, Am, Van Wijngaerden, E, Ainsworth, J, Anderson, J, Babiker, A, Dunn, D, Easterbrook, P, Fisher, M, Gazzard, B, Garrett, N, Gilson, R, Gompels, M, Hill, T, Johnson, M, Leen, C, Orkin, C, Phillips, A, Pillay, D, Porter, K, Post, F, Sabin, C, Sadiq, T, Schwenk, A, Walsh, J, Delpech, V, Palfreeman, A, Glabay, A, Lynch, J, Hand, J, de Souza, C, Perry, N, Tilbury, S, Churchill, D, Nelson, M, Waxman, M, Mandalia, S, Kall, M, Korat, H, Taylor, C, Ibrahim, F, Campbell, L, James, L, Brima, N, Williams, I, Youle, M, Lampe, F, Smith, C, Grabowska, H, Chaloner, C, Puradiredja, Di, Weber, J, Ramzan, F, Carder, M, Wilson, A, Dooley, D, Asboe, D, Pozniak, A, Cameron, S, Cane, P, Chadwick, D, Clark, D, Collins, S, Lazarus, L, Dolling, D, Fearnhill, E, Castro, H, Coughlin, K, Zuckerman, M, Booth, C, Goldberg, D, Hale, A, Kaye, S, Kellam, P, Leigh Brown, A, Smit, E, Templeton, K, Tilston, P, Tong, W, Zhang, H, Ushiro Lumb, I, Oliver, T, Bibby, D, Mitchell, S, Mbisa, T, Wildfire, A, Tandy, R, Shepherd, J, Maclean, A, Bennett, D, Hopkins, M, Garcia Diaz, A, Kirk, S, Sloot, P. M., Virology, Prosperi, M, Mackie, N, di Giambenedetto, S, Zazzi, M, Camacho, R, Fanti, I, Torti, C, Sönnerborg, A, Kaiser, R, Codoñer, F, van laethem, K, Bansi, L, van de Vijver, D, Geretti, A, de luca, A, and Mancuso, S

Subjects
Male, Drug Resistance, HIV Infections, Drug resistance, Cohort Studies, 0302 clinical medicine, Genotype, HIV Infection, Pharmacology (medical), 030212 general & internal medicine, Viral, 0303 health sciences, Proteolytic enzymes, Genotypic testing, HIV, Viral load, Adult, Anti-HIV Agents, CD4 Lymphocyte Count, Europe, Female, HIV-1, Humans, RNA, Viral, Viral Proteins, Drug Resistance, Viral, Mutation, Missense, Viral Load, Pharmacology, Infectious Diseases, 3. Good health, Cohort, Cohort study, Human, Microbiology (medical), Biology, Settore MED/17 - MALATTIE INFETTIVE, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Viral Protein, 030306 microbiology, Anti-HIV Agent, Virology, Reverse transcriptase, Regimen, genotypic testing, viral load, Immunology, Mutation, RNA, Missense, Cohort Studie
Abstract

Background and objectives: Guidelines indicate a plasma HIV-1 RNA load of 500-1000 copies/mL as the minimal threshold for antiretroviral drug resistance testing. Resistance testing at lower viral load levels may be useful to guide timely treatment switches, although data on the clinical utility of this remain limited. We report here the influence of viral load levels on the probability of detecting drug resistance mutations (DRMs) and other mutations by routine genotypic testing in a large multicentre European cohort, with a focus on tests performed at a viral load

Published
2011

10. Prevalence of mutations and determinants of genotypic resistance to etravirine (TMC125) in a large Italian resistance database (ARCA)

Author

Di Vincenzo, P, Rusconi, S, Adorni, F, Vitiello, P, Maggiolo, F, Francisci, D, Di Biagio, A, Monno, L, Antinori, A, Boeri, E, Punzi, G, Perno, Cf, Callegaro, A, Bruzzone, B, Zazzi, M, on behalf of the ARCA Collaborative Group, and Consolini, Rita

Subjects
Adult, Male, Nevirapine, Efavirenz, Genotype, Drug Resistance, Etravirine, HIV Infections, Drug resistance, viral, male, retrospective studies, multivariate analysis, mutation, HIV infections, female, HIV reverse transcriptase, Italy, genotype, treatment failure, humans, prevalence, HIV-1, pyridazines, adult, anti-retroviral agents, Drug resistance, Biology, computer.software_genre, chemistry.chemical_compound, Drug Resistance, Viral, Nitriles, medicine, Prevalence, Humans, Pharmacology (medical), TMC125, ARCA, Anti-Retroviral Agents, Female, HIV Reverse Transcriptase, Multivariate Analysis, Pyridazines, Retrospective Studies, Treatment Failure, Mutation, Viral, Database, Health Policy, Odds ratio, Settore MED/07 - Microbiologia e Microbiologia Clinica, Virology, Infectious Diseases, Pyrimidines, chemistry, Cohort, computer, Viral load, medicine.drug
Abstract

To evaluate whether etravirine (TMC125) might be effective in patients failing therapy with current nonnucleoside reverse transcriptase inhibitors (NNRTIs), we analysed the prevalence of TMC125 mutations and the possible determinants of genotypic resistance to this drug among sequences reported to a large database in Italy [Antiretroviral Resistance Cohort Analysis (ARCA)].We analysed the prevalence of TMC125 resistance-associated mutations (RAMs) and the TMC125 weighted genotypic score (WGS) together with the determinants of genotypic resistance. A total of 5011 sequences from 2955 patients failing NNRTI therapy were evaluated.Among the sequences in ARCA, 68% had at least one and 9.8% at least three TMC125 RAMs, whereas 31% had a WGS2. Frequent RAMs were Y181C, G190A, K101E and A98G, whereas V179F, Y181V and G190S appeared in5% of sequences. Multivariate analysis revealed a higher risk of developing at least three TMC125 RAMs associated with both nevirapine and efavirenz exposure, whereas CD4 countsor = 200 cells/microL retained their protective effect. An increased risk of WGS2 was linked to higher HIV RNA values (maximum risk at5 log(10) copies/mL) and nevirapine exposure; CD4 countsor = 200 cells/microL were protective.The prevalence of TMC125 resistance mutations in the ARCA cohort was 68%. The DUET studies showed that at least three TMC125-associated mutations were required to impair the efficacy of the drug and Y181C/V, V179F and G190S had the greatest effect on response. The prevalence of these mutations among the patients examined in our study was low. However, WGS2 was found for one-third of our sequences. Previous nevirapine exposure was associated with an increased risk of having WGS2 (adjusted odds ratio 1.76).

Published
2010

11. Rules-based HIV-1 genotypic resistance interpretation systems predict 8 week and 24 week virological antiretroviral treatment outcome and benefit from drug potence weightening

Author

Zazzi, Maurizio, Prosperi, Mattia, Vicenti, I, Di Giambenedetto, Simona, Callegaro, A, Bruzzone, Bianca, Baldanti, F, Gonnelli, A, Boeri, E, Paolini, E, Rusconi, Stefano, Giacometti, Antonio, Maggiolo, Franco, Menzo, S, and De Luca, Andrea

Subjects
genotype, interpretation system, antiretroviral, drug potency weighting, Settore MED/17 - MALATTIE INFETTIVE
Published
2009

12. Comparison of a rule-based algorithm with a phenotype-based algorithm for the interpretation of HIV genotypes in guiding salvage regimens in HIV-infected patients by a randomized clinical trial: The mutations and salvage study

Author

Gianotti, N., Mondino, V., Rossi, M. C., Chiesa, E., Mezzaroma, Ivano, Ladisa, N., Guaraldi, G., Torti, C., Tarquini, P., Castelli, P., Di Carlo, A., Boeri, E., Keulen, W., Kenna, P. M., Lazzarin, A., Mutations, and Study Group Salvage Musa

Subjects
Microbiology (medical), Adult, Male, Genotype, Anti-HIV Agents, phenotype, genotype, HIV Infections, law.invention, Randomized controlled trial, Acquired immunodeficiency syndrome (AIDS), law, Antiretroviral Therapy, Highly Active, Medicine, Humans, Protease inhibitor (pharmacology), Sida, Genotyping, Salvage Therapy, Intention-to-treat analysis, algorithm, biology, business.industry, Proteolytic enzymes, HIV, HIV Protease Inhibitors, mutation, Middle Aged, Viral Load, medicine.disease, biology.organism_classification, Regimen, Infectious Diseases, Phenotype, Italy, Mutation, RNA, Viral, Reverse Transcriptase Inhibitors, Female, business, Algorithm, Algorithms
Abstract

BACKGROUND There is still considerable uncertainty as to the best algorithm for interpreting human immunodeficiency virus (HIV) genotyping results. METHODS A total of 318 subjects with HIV RNA levels of >1000 copies/mL were enrolled in 41 centers throughout Italy from 2001 through 2003, stratified on the basis of their drug history, randomized (1:1) to 2 arms to have their treatments modified on the basis of the results of HIV genotyping (as interpreted by virtual phenotype analysis or with use of a rule-based interpretation system), and followed up for 48 weeks. At least 1 nucleoside reverse-transcriptase inhibitor and 1 protease inhibitor had to be included in any new regimen; nonnucleoside reverse-transcriptase inhibitor-naive patients were also prescribed a nonnucleoside reverse-transcriptase inhibitor. Only drugs licensed in Italy were allowed. The primary end point was a decrease in HIV RNA level to

Published
2006

13. Performance of genotypic tropism testing in clinical practice using the enhanced sensitivity version of Trofile as reference assay: Results from the OSCAR Study Group

Author

Svicher V, D'Arrigo R, Alteri C, Andreoni M, Angarano G, Antinori A, Antonelli G, Bagnarelli P, Baldanti F, Bertoli A, Boeri E, Bruzzone B, Callegaro AP, Cammarota R, Canducci F, Ceccherini Silberstein F, Clementi M, Monforte AD, De Luca A, Di Biagio A, Di Gianbenedetto S, Di Perri G, Di Pietro M, Fabeni L, Fadda G, Galli M, Gennari W, Ghisetti V, Giacometti A, Gori A, Leoncini F, Maggiolo F, Maserati R, Mazzotta F, Micheli V, Meini G, Monno L, Mussini C, Nozza S, Paolucci S, Parisi S, Pecorari M, Pizzi D, Quirino T, Rizzardini G, Santangelo R, Soria A, Stazi F, Sterrantino G, Turriziani O, Viscoli C, Vullo V, Lazzarin A, Perno CF, OSCAR Study Group, BORDERI, MARCO, BON, ISABELLA, RE, MARIA CARLA, Svicher V, D'Arrigo R, Alteri C, Andreoni M, Angarano G, Antinori A, Antonelli G, Bagnarelli P, Baldanti F, Bertoli A, Borderi M, Boeri E, Bonn I, Bruzzone B, Callegaro AP, Cammarota R, Canducci F, Ceccherini-Silberstein F, Clementi M, Monforte AD, De Luca A, Di Biagio A, Di Gianbenedetto S, Di Perri G, Di Pietro M, Fabeni L, Fadda G, Galli M, Gennari W, Ghisetti V, Giacometti A, Gori A, Leoncini F, Maggiolo F, Maserati R, Mazzotta F, Micheli V, Meini G, Monno L, Mussini C, Nozza S, Paolucci S, Parisi S, Pecorari M, Pizzi D, Quirino T, Re MC, Rizzardini G, Santangelo R, Soria A, Stazi F, Sterrantino G, Turriziani O, Viscoli C, Vullo V, Lazzarin A, Perno CF, and OSCAR Study Group.

Subjects
Male, Protein Structure, trafile, Receptors, CCR5, Genotype, Settore MED/17 - Malattie Infettive, HIV, viral load, AIDS, hiv, HIV Infections, HIV Envelope Protein gp120, v3 loop, Receptors, Humans, Viral Tropism, Protein Structure, Tertiary, HIV-1, Female, Receptors, Virus, tropism, virus diseases, genotypic tropism testing, OSCAR Study Group, Settore MED/07 - Microbiologia e Microbiologia Clinica, Virus, genotypic tropism, CCR5 Receptor Antagonists, CCR5, Tertiary
Abstract

Objective: The goal of the OSCAR programme is to evaluate the performances of genotypic HIV-1 tropism testing in clinical practice using the enhanced sensitivity version of Trafile (ESTA) as reference-assay. Methods: HIV-1 coreceptor-usage was assessed using plasma samples from 406 HIV-1 infected patients by ESTA and by gp120 V3 population-sequencing followed by Geno2pheno (set at a False Positive Rate [FPR] of 10% and 5%). Results: ESTA was successful in 365 (89.9%) samples indicating R5 in 254 (69.6%), and DM/X4 in 111 (30.4% of samples (104 [28.5%] DM and 7 [1.9%] X4). Genotypic-testing successfully assessed viral tropism for all 406 samples, including the 41 with undetermined result by ESTA. Genotypic-tropism testing at a FPR of 5% and 10% was 81.1% and 78.4% concordant with ESTA, respectively. Despite a sensitivity of 48.7% and 55.9% at a FPR of 5% and 10%, respectively, a high concordance (specificity: 95.3% for FPR of 5% and 88.2% for FPR of 10%) between genotypic-tropism testing and ESTA was reached in the detection of R5-tropic viruses. Conclusion: Our results are in line with other European studies, and support the routine use of genotypic tropism testing in clinical-settings for monitoring of HIV-1 infected patients candidate to or failing CCR5-antagonists.

14. Phylogenetic internal control for HIV-1 genotypic antiretroviral testing

Author

Boeri, E., Canducci, F., Carrera, P., Massimo Clementi, Grasso, M. A., Presi, S., Racca, S., Boeri, E, Canducci, E, Grasso, Ma, Presi, S, Carrera, P, Racca, S, and Clementi, Massimo

Subjects
Quality Control, Base Sequence, Genotype, Anti-HIV Agents, Sequence Homology, HIV Infections, Microbial Sensitivity Tests, HIV Reverse Transcriptase, HIV Protease, Drug Resistance, Viral, HIV-1, Humans, Amino Acid Sequence, Phylogeny
Abstract

Genotypic testing includes several steps (RNA purification, RT-PCR amplification, DNA sequencing, sequence editing and analysis) that should be individually controlled. In our laboratory, we have added to this step-by-step internal control a final phylogenetic quality control: this is performed every time a sequence is obtained from a patient previously subjected to the same test. Each sequence with this characteristic is routinely compared with sequences from previous samples of the same patient by multiple alignment and a neighbor-joining tree by using Kimura two-parameter method is constructed. To validate the quality control procedure, we have aligned and calculated the mean similarity of the reverse transcriptase (first 984 nucleotides) and protease (whole gene) sequences from 30 patients whose virus was completely wild-type for both reverse transcriptase and protease. In the same tree, we have added the sequences obtained from 5 out of the 30 patients, tested at a second time point. The wild type sequences have shown a mean inter-sample divergence of 2.9%, and all the sequence pairs from individual patients clustered together in the tree constructed with the nucleotide sequences, while the tree constructed with the inferred aminoacid sequences did not always permit to cluster the sequences from the same patients. This indicates that: 1) the phylogenetic analysis of nucleic acid sequences can be useful to rule out sample mix-up; 2) the belonging of a sequence to each individual patient can efficiently be assessed also in the cases of extreme divergence in terms of drug resistance mutations.

15. 48 week outcomes of maraviroc-containing regimens following the genotypic or Trofile assay in HIV-1 failing subjects: The OSCAR study

Author

Nozza, S., Pignataro, A. R., Laura Galli, Svicher, V., Alteri, C., Boeri, E., Ripa, M., Castagna, A., Sampaolo, M., Clementi, M., Pemo, C. F., Lazzarin, A., Nozza, Silvia, Pignataro, Angela Rosa, Galli, Laura, Svicher, Valentina, Alteri, Claudia, Boeri, Enzo, Ripa, Marco, Castagna, Antonella, Sampaolo, Michela, Clementi, Massimo, Perno, Carlo Federico, and Lazzarin, Adriano

Subjects
Adult, Male, Genotype, Anti-HIV Agents, Genotypic tropism assay, HIV Infections, Drug Administration Schedule, Settore MED/07, Maraviroc, Failing patients, Cyclohexanes, Cyclohexane, Trofile, Humans, HIV Infection, Treatment Failure, Failing patient, Anti-HIV Agent, Female, HIV-1, Middle Aged, Triazoles, Viral Tropism, Settore MED/07 - Microbiologia e Microbiologia Clinica, Triazole, Human
Abstract

This study assessed the 48-week efficacy of an antiretroviral therapy including maraviroc following the assessment of co-receptor tropism by use of Geno2Pheno algorithm or the Trofile phenotypic assay in failing treatment-experienced HIV-1 patients. This was a multicenter, randomized, open-label, non-inferiority trial. Treatment-experienced subjects with HIV-RNA ≥500 copies/mL were randomized (1:1) to undergo co-receptor tropism testing by the Geno- 2Pheno algorithm (with a false positive rate >10%) or the Trofile assay before starting a new antiretroviral treatment which included maraviroc. The primary endpoint was the 48 week proportion of patients with treatment success (TS). Intention-to-treat analyses are also reported. One hundred and fifty-five experienced patients were analysed: 77 patients in the Trofile arm and 78 in the Genotype arm. The 48-week proportion of TS was 87% in the Trofile arm and 89% in the Genotype arm (difference: 1.5%, 95%CI: -8.9% to 11.8%) suggesting non-inferiority. In the Trofile arm, 10 patients had treatment failure: 5 viral rebound, 5 discontinuations. In the Genotype arm, 9 patients had treatment failure: 7 viral rebound, 2 lost to follow-up. CD4+ significantly increased from baseline to week 48 in both arms. 48-week treatment success was similar for maraviroc-including therapy prescribed following the Trofile phenotypic assay or Geno2Pheno algorithm.

16. Prevalence of etravirine ( ETR)- RAMs at NNRTI failure and predictors of resistance to ETR in a large Italian resistance database ( ARCA).

Author

Rusconi, S., Adorni, F., Bruzzone, B., Di Biagio, A., Meini, G., Callegaro, A., Punzi, G., Boeri, E., Pecorari, M., Monno, L., Gianotti, N., Butini, L., Galli, L., Polilli, E., and Galli, M.

Subjects
*DRUG resistance, *ETRAVIRINE (Drug), *NON-nucleoside reverse transcriptase inhibitors, *ANTI-HIV agents, *ANTIRETROVIRAL agents, *MULTIVARIATE analysis
Abstract

The prevalence of drug resistance associated with the failure of non-nucleoside reverse transcriptase inhibitor ( NNRTI)-based regimens and the predictors of resistance to Etravirine ( ETR) were assessed in 2854 subjects: 39 < 18 (paediatric) and 2815 ≥ 18 (adult) years old. These subjects failed to respond to their current NNRTI treatment, were three-class experienced and had been exposed to NNRTI for ≥3 months. A total of 1827 adult (64.9%) and 32 paediatric subjects (82.1%) harboured the virus with at least one ETR mutation. V179I, Y181C and G190A were the most frequent mutations in both groups. A significantly increased risk of ETR resistance with all three algorithms (Monogram ( MGR) >3, Tibotec ( TBT) >2 and enhanced MGR ( ENH) ≥4) emerged in the paediatric population. Multivariate analysis revealed an increased risk of developing TBT >2 for NNRTI exposure, ENH ≥4 for NNRTI and EFV exposure in paediatric subjects; NVP exposure and higher (≥3.5 log10) HIV- RNA values for all three algorithms in adult subjects, whereas CD4 ≥ 200/μL appeared to be protective. The risk of being ETR resistant was more than doubled for paediatric vs. adult subjects, probably due to a more extensive use of NNRTI and an incomplete virological control. [ABSTRACT FROM AUTHOR]

Published
2013
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17. Evolution patterns of raltegravir-resistant mutations after integrase inhibitor interruption.

Author

Canducci, F., Barda, B., Ceresola, E., Spagnuolo, V., Sampaolo, M., Boeri, E., Nozza, S., Cossarin, F., Galli, A., Gianotti, N., Castagna, A., Lazzarin, A., and Clementi, M.

Subjects
*HIV, *RALTEGRAVIR, *RNA, *GENOTYPE-environment interaction, *GENETIC mutation, *VIROLOGY, *IMMUNOLOGY
Abstract

The objective of this study was to address the evolution of human immunodeficiency virus type 1 (HIV-1) mutations resistant to the integrase inhibitor raltegravir after drug interruption. Thirteen HIV-1 infected patients undergoing virological failure due to the selection of raltegravir-resistant variants, who had interrupted raltegravir treatment, were enrolled. For all patients, the virological failure was associated with the selection of variants, with mutations conferring resistance to all of the drugs present in their regimens. Patients were prospectively monitored at baseline (raltegravir interruption) and every 4–24 weeks for clinical, virological and immunological parameters, including HIV-1 viraemia, CD4+ T-cell counts, and sequence analysis of the HIV-1 integrase sequence. Reversion to the wild-type HIV-1 integrase sequence genotype was observed between 4 and 36 weeks after raltegravir withdrawal in eight out of the 13 patients. Reversion was not observed in three patients. In two patients, reversion was partial at week 24 from raltegravir interruption. These results highlight that in eight out of 13 patients under treatment with raltegravir and experiencing a virological failure, HIV-1variants harbouring mutations associated with raltegravir resistance become undetectable after drug interruption within a few weeks (in some cases, very rapidly). This occurs under different therapy regimens and in patients receiving 3TC mono-therapy. In the other patients, complete reversion of the integrase sequence is not observed, and either primary or secondary resistance mutations are fixed in the replication competent viral population in vivo also for long time, suggesting that other factors may influence this dynamic process. [ABSTRACT FROM AUTHOR]

Published
2011
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18. Genotypic/phenotypic patterns of HIV-1 integrase resistance to raltegravir

Author

Enzo Boeri, Nicola Gianotti, Stefania Paolucci, Fausto Baldanti, Maria Chiara Marinozzi, Antonella Castagna, Vincenzo Spagnuolo, Michela Sampaolo, Massimo Clementi, Adriano Lazzarin, Filippo Canducci, Canducci, F, Marinozzi, Mc, Sampaolo, M, Boeri, E, Spagnuolo, Vincenzo, Gianotti, N, Castagna, Antonella, Paolucci, S, Baldanti, F, Lazzarin, A, and Clementi, Massimo

Subjects
CD4-Positive T-Lymphocytes, Microbiology (medical), Genotype, Anti-HIV Agents, Mutation, Missense, Integrase inhibitor, HIV Infections, HIV Integrase, Microbial Sensitivity Tests, Drug resistance, Virus Replication, medicine.disease_cause, Raltegravir Potassium, Inhibitory Concentration 50, Drug Resistance, Viral, medicine, Humans, Pharmacology (medical), Cells, Cultured, Pharmacology, Genetics, Mutation, biology, Sequence Analysis, DNA, Raltegravir, Virology, Pyrrolidinones, Integrase, Phenotype, Infectious Diseases, Amino Acid Substitution, Viral evolution, HIV-1, biology.protein, medicine.drug
Abstract

To understand the dynamic viral evolution observed during failure on raltegravir-containing regimens, we studied the genotypic and phenotypic patterns of resistance to raltegravir and the residual replication capacity (rRC) of HIV-1 variants selected in vivo.Clonal genotypic analyses were performed on sequential HIV-1 integrase sequences amplified from 11 failing patients and sampled every 4-24 weeks for up to 64 weeks. Fully replicating recombinant viruses were generated using modified vectors in which selected viral integrase genes amplified from patients' plasma were cloned. rRC was measured by a novel multiple cycle competition assay. Resistance to raltegravir and the rRC of resistant HIV-1 variants selected in vivo were evaluated in purified CD4+ T cells.In all of the patients but one, failure was associated with selection of mutations in positions 143, 148 or 155. Unlike mutations at position 143 (Y143S/K/R), identified alone or in combination with others, mutations at position 148 and 155 were always found in combination. A wide range of resistance levels to raltegravir [from 10- to 770-fold change in 50% inhibitory concentration (IC(50)) compared with baseline] was observed using recombinant viral clones. Finally, rRC was not significantly altered in highly resistant variants.Two patterns of viral evolution were observed in the resistant viral populations, driving the variants towards a fast (most of them with G140S + Q148H mutations) or progressive increase in resistance to raltegravir. These results may have implications either for the evaluation of genotypic results, or for the correct clinical use of the compound.

Published
2010

19. Performance of genotypic tropism testing on proviral DNA in clinical practice: Results from the DIVA study group

Author

Svicher, Valentina, Alteri, Claudia, Montano, Marco, D Arrigo, Roberta, Andreoni, Massimo, Angarano, Gioacchino, Antinori, Andrea, Antonelli, Guido, Allice, Tiziano, Bagnarelli, Patrizia, Baldanti, Fausto, Bertoli, Ada, Borderi, Marco, Boeri, Enzo, Bon, Isabella, Bruzzone, Bianca, Callegaro, Anna Paola, Capobianchi, Maria Rosaria, Carosi, Giampiero, Cauda, Roberto, Ceccherini-Silberstein, Francesca, Clementi, Massimo, Chirianni, Antonio, Manuela Colafigli, Monforte, Antonella D. Arminio, Luca, Andrea, Di Biagio, Antonio, Di Nicuolo, Giuseppe, Di Perri, Giovanni, Di Pietro, Massimo, Di Santo, Fabiola, Fabeni, Lavinia, Fadda, Giovanni, Galli, Massimo, Gennari, William, Ghisetti, Valeria, Giacometti, Andrea, Gori, Caterina, Gori, Andrea, Gulminetti, Roberto, Leoncini, Francesco, Maffongelli, Gaetano, Maggiolo, Franco, Manca, Giuseppe, Gargiulo, Franco, Martinelli, Canio, Maserati, Renato, Mazzotta, Francesco, Meini, Genny, Micheli, Valeria, Monno, Laura, Mussini, Cristina, Narciso, Pasquale, Nozza, Silvia, Paolucci, Stefania, Palu, Giorgio, Parisi, Saverio, Parruti, Giustino, Pignataro, Angela Rosa, Pollicita, Michela, Quirino, Tiziana, Re, Maria Carla, Rizzardini, Giuliano, Santangelo, Rosaria, Scaggiante, Renzo, Sterrantino, Gaetana, Turriziani, Ombretta, Vatteroni, Maria Linda, Vecchi, Laura, Viscoli, Claudio, Vullo, Vincenzo, Zazzi, Maurizio, Lazzarin, Adriano, Perno, Carlo Federico, Diva, Grp, Svicher V, Alteri C, Montano M, D'Arrigo R, Andreoni M, Angarano G, Antinori A, Antonelli G, Allice T, Bagnarelli P, Baldanti F, Bertoli A, Borderi M, Boeri E, Bon I, Bruzzone B, Callegaro AP, Capobianchi MR, Carosi G, Cauda R, Ceccherini-Silberstein F, Clementi M, Chirianni A, Colafigli M, D'Arminio Monforte A, De Luca A, Di Biagio A, Di Nicuolo G, Di Perri G, Di Pietro M, Di Santo F, Fabeni L, Fadda G, Galli M, Gennari W, Ghisetti V, Giacometti A, Gori C, Gori A, Gulminetti R, Leoncini F, Maffongelli G, Maggiolo F, Manca G, Gargiulo F, Martinelli C, Maserati R, Mazzotta F, Meini G, Micheli V, Monno L, Mussini C, Narciso P, Nozza S, Paolucci S, Pal G, Parisi S, Parruti G, Pignataro AR, Pollicita M, Quirino T, Re MC, Rizzardini G, Santangelo R, Scaggiante R, Sterrantino G, Turriziani O, Vatteroni ML, Vecchi L, Viscoli C, Vullo V, Zazzi M, Lazzarini A, Perno CF., Svicher, V, Alteri, C, Montano, M, D'Arrigo, R, Andreoni, M, Angarano, G, Antinori, A, Antonelli, G, Allice, T, Bagnarelli, P, Baldanti, F, Bertoli, A, Borderi, M, Boeri, E, Bon, I, Bruzzone, B, Callegaro, Ap, Capobianchi, Mr, Carosi, G, Cauda, R, Ceccherini Silberstein, F, Clementi, Massimo, Chirianni, A, Colafigli, M, Monforte, Ad, De Luca, A, Di Biagio, A, Di Nicuolo, G, Di Perri, G, Di Pietro, M, Di Santo, F, Fabeni, L, Fadda, G, Galli, M, Gennari, W, Ghisetti, V, Giacometti, A, Gori, C, Gori, A, Gulminetti, R, Leoncini, F, Maffongelli, G, Maggiolo, F, Manca, G, Gargiulo, F, Martinelli, C, Maserati, R, Mazzotta, F, Meini, G, Micheli, V, Monno, L, Mussini, C, Narciso, P, Nozza, S, Paolucci, S, Palu, G, Parisi, S, Parruti, G, Pignataro, Ar, Pollicita, M, Quirino, T, Re, Mc, Rizzardini, G, Santangelo, R, Scaggiante, R, Sterrantino, G, Turriziani, O, Vatteroni, Ml, Vecchi, L, Viscoli, C, Vullo, V, Zazzi, M, Lazzarin, Adriano, Perno, Cf, Callegaro, A, Capobianchi, M, Clementi, M, D'Arminio Monforte, A, Pal, G, Pignataro, A, Re, M, Vatteroni, M, Lazzarini, A, and Perno, C

Subjects
Male, Genotype, Genotyping Techniques, IMPACT, Mononuclear, HIV-1 TROPISM, Proviral DNA, Reproducibility of Result, HIV Infections, CORECEPTOR SWITCH, HIV Envelope Protein gp120, FREQUENCY, Tropism, CXCR4-USING HIV, HIV, AIDS, DNA provirale, ANTIRETROVIRAL THERAPY, Proviruses, INFECTION, Leukocytes, Humans, HIV Infection, CD4 CELL COUNT, PLASMA RNA, MARAVIROC, Proviruse, hiv, tropism, proviral dna, virus diseases, Reproducibility of Results, Viral Load, Settore MED/07 - Microbiologia e Microbiologia Clinica, Viral Tropism, HIV-1, Leukocytes, Mononuclear, Female, Genotyping Technique, Human
Abstract

"Objective: The DIVA study is aimed at setting up a standardized genotypic tropism-testing on proviral-DNA for the routine clinical diagnostic-laboratory Methods: Twelve local centres and 5 reference centres (previously cross-validated) were identified. For inter-center validation-procedure, 60 peripheral-blood mononuclear cells (PBMCs) aliquots from 45 HAART-treated patients were randomly chosen for population V3 sequencing on proviral-DNA at local HIV centre and at reference-laboratory Viral tropism was predicted by Geno2Pheno algorithm (False Positive Rate [FPR] = 20%) as proposed by the European-Guidelines. Quantification of total HIV-1 DNA was based on a method described by Viard (2004). Results: Quantification of HIV-1 DNA was available for 35\/45 (77.8%) samples, and gave a median value of 598 (IQR:252-1,203) copies\/10(6) PBMCs. A total of 56\/60 (93.3%) samples were successfully amplified by both the reference and the local virological centers. The overall concordance of tropism prediction between local and reference centers was 54\/56 (96.4%). Results of tropism prediction by local centers were: 33\/54 (61.1%) R5 and 21\/54 (38.9%) X4\/DM. Conclusion: There was high concordance in the genotypic tropism prediction based on proviral DNA among different virological centers throughout Italy. Our results are in line with other European studies, and support the use of genotypic tropism testing on proviral DNA in patients with suppressed plasma HIV-1 RNA candidate to CCR5-antagonist treatment."

20. Redistribution of human immunodeficiency virus type 1 variants resistant to protease inhibitors after a protease inhibitor-sparing regimen

Author

Anna Danise, Enzo Boeri, Elena Seminari, Stefania Salpietro, Giuliana Fusetti, Nicola Gianotti, Antonella Castagna, Massimo Clementi, Adriano Lazzarin, Gianotti, N, Seminari, E, Lazzarin, A, Boeri, E, Clementi, Massimo, Danise, A, Salpietro, S, Fusetti, G, and Castagna, Antonella

Subjects
medicine.medical_specialty, Genotype, Anti-HIV Agents, medicine.medical_treatment, Immunology, HIV Infections, Gastroenterology, Virus, Drug Administration Schedule, HIV Protease, Interquartile range, Virology, Internal medicine, Immunopathology, Drug Resistance, Viral, medicine, Humans, Sida, Protease, biology, Genetic Variation, HIV Protease Inhibitors, biology.organism_classification, CD4 Lymphocyte Count, Regimen, Infectious Diseases, Lentivirus, Mutation, HIV-1, RNA, Viral, Reverse Transcriptase Inhibitors, Drug Therapy, Combination, Viral disease
Abstract

The redistribution of mutations related to protease inhibitor (PI) resistance after a PI-sparing regimen in human immunodeficiency virus (HIV)-infected, highly PI-experienced patients was prospectively assessed. Twenty-five patients failing a PI-including regimen were given PI-sparing antiretroviral therapy, and then followed for 24 weeks after PI resumption. Genotyping was performed by direct sequencing before and during the PI-sparing regimen. The median (interquartile range, IQR) baseline CD4+ T-lymphocyte count was 198 (120-255) cells/microl, and the median HIV-RNA level was 82,000 (41,000-300,000) copies/ml. Patients had experienced a median of 4.5 (4-5.25) PIs. The median number of PI mutations was eight (6-9). The PI-sparing regimen consisted of a median of three (3-4) drugs and lasted for a median of 53 (24-67) weeks. At the end of the study, the median number of PI mutations was 6.5 (6-9). The median change in the number of PI mutations was -1 (IQR from -1 to 0). A reduction from baseline was observed in 13 cases (52%); nine (36%) showed no change and three (12%) showed an increased number of PI substitutions. In highly PI-experienced patients, a PI-sparing regimen may lead to a reduction, no change, or increase in the number of PI mutations. The reduction is negligible in most cases.

Published
2005

21. Impact of a treatment including tenofovir plus didanosine on the selection of the 65R mutation in highly drug-experienced HIV-infected patients

Author

Giuliana Fusetti, Andrea Galli, Enzo Boeri, Antonella Castagna, Nicola Gianotti, Adriano Lazzarin, Elena Seminari, Massimo Clementi, Stefania Salpietro, Gianotti, N, Seminari, E, Fusetti, G, Salpietro, S, Boeri, E, Galli, A, Lazzarin, A, Clementi, Massimo, and Castagna, Antonella

Subjects
medicine.medical_specialty, Genotype, Anti-HIV Agents, Immunology, Organophosphonates, HIV Infections, Drug resistance, Biology, Gastroenterology, Virus, Acquired immunodeficiency syndrome (AIDS), Drug Resistance, Multiple, Viral, Internal medicine, Antiretroviral Therapy, Highly Active, Databases, Genetic, medicine, Immunology and Allergy, Humans, heterocyclic compounds, Sida, Tenofovir, Didanosine, Reverse-transcriptase inhibitor, Adenine, medicine.disease, biology.organism_classification, Virology, Infectious Diseases, Mutation (genetic algorithm), DNA, Viral, Mutation, HIV-1, Viral disease, Gene Deletion, medicine.drug
Abstract

Data from 20 highly drug-experienced HIV-infected patients receiving tenofovir plus didanosine as part of a salvage regimen were analysed. At baseline, all but one patient harboured a virus bearing at least one nucleoside excision mutation (NEM); in 13 cases (65%) three or more NEM were detectable. After a median of 26 weeks of treatment, two patients (10%) selected the 65R mutation. These results support the hypothesis that NEM hinder the selection of this mutation.

Published
2004

22. Evolution patterns of raltegravir-resistant mutations after integrase inhibitor interruption

Author

Nicola Gianotti, Andrea Galli, Vincenzo Spagnuolo, Adriano Lazzarin, Enzo Boeri, Filippo Canducci, Beatrice Barda, F. Cossarin, Massimo Clementi, Michela Sampaolo, Antonella Castagna, Elisa Rita Ceresola, Silvia Nozza, Canducci, F, Barda, B, Ceresola, E, Spagnuolo, Vincenzo, Sampaolo, M, Boeri, E, Nozza, S, Cossarin, F, Galli, A, Gianotti, N, Castagna, Antonella, Lazzarin, Adriano, and Clementi, Massimo

Subjects
Adult, Male, Microbiology (medical), Genotype, Anti-HIV Agents, Population, Reversion, Mutation, Missense, Integrase inhibitor, HIV Infections, HIV Integrase, Virus, Antiretroviral Therapy, Highly Active, Raltegravir Potassium, Drug Resistance, Viral, medicine, Humans, Longitudinal Studies, Prospective Studies, Treatment Failure, education, education.field_of_study, biology, General Medicine, Middle Aged, Viral Load, Raltegravir, biology.organism_classification, Virology, Pyrrolidinones, Integrase, CD4 Lymphocyte Count, Infectious Diseases, integrase inhibitors, resistance mutations, Lentivirus, Immunology, biology.protein, HIV-1, Female, raltegravir, medicine.drug
Abstract

The objective of this study was to address the evolution of human immunodeficiency virus type 1 (HIV-1) mutations resistant to the integrase inhibitor raltegravir after drug interruption. Thirteen HIV-1 infected patients undergoing virological failure due to the selection of raltegravir-resistant variants, who had interrupted raltegravir treatment, were enrolled. For all patients, the virological failure was associated with the selection of variants, with mutations conferring resistance to all of the drugs present in their regimens. Patients were prospectively monitored at baseline (raltegravir interruption) and every 4–24 weeks for clinical, virological and immunological parameters, including HIV-1 viraemia, CD4 + T-cell counts, and sequence analysis of the HIV-1 integrase sequence. Reversion to the wild-type HIV-1 integrase sequence genotype was observed between 4 and 36 weeks after raltegravir withdrawal in eight out of the 13 patients. Reversion was not observed in three patients. In two patients, reversion was partial at week 24 from raltegravir interruption. These results highlight that in eight out of 13 patients under treatment with raltegravir and experiencing a virological failure, HIV-1 variants harbouring mutations associated with raltegravir resistance become undetectable after drug interruption within a few weeks (in some cases, very rapidly). This occurs under different therapy regimens and in patients receiving 3TC mono-therapy. In the other patients, complete reversion of the integrase sequence is not observed, and either primary or secondary resistance mutations are fixed in the replication competent viral population in vivo also for long time, suggesting that other factors may influence this dynamic process.

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