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

2019; Elsevier BV; Volume: 25; Issue: 11 Linguagem: Inglês

10.1016/j.cmi.2019.07.004

1469-0691

Ryan C. Ungaro, Lucia Taramasso, Bianca Bruzzone, Ilaria Vicenti, Laura Galli, Vanni Borghi, Daniela Francisci, Monica Pecorari, Alessia Zoncada, A.P. Callegaro, Elisabetta Paolini, Laura Monno, Stefano Bonora, Antonio Di Biagio, Maria Carla Re, Luca Butini, Romana del Gobbo, Maria Carla Re, Danilo Tacconi, Giovanni Corbelli, Stefania Zanussi, Laura Monno, Grazia Punzi, Franco Maggiolo, Leonardo Calza, Maria Carla Re, R. Pristerà, Paola Turconi, Antonella Mandas, Sauro Tini, Alessia Zoncada, Elisabetta Paolini, Giorgio Amadio, Laura Sighinolfi, Paola Corsi, Laura Galli, Massimo Di Pietro, G Colao, Andrea Tosti, Maurizio Setti, Bianca Bruzzone, Antonio Di Biagio, Giovanni Cenderello, Michele Trezzi, Anna Orani, Irene Arcidiacono, Alberto Degiuli, Michele De Gennaro, Alessandro Chiodera, Alfredo Scalzini, Loredana Palvarini, Giovanni Todaro, Stefano Rusconi, Maria Rita Gismondo, Valeria Micheli, Maria Luisa Biondi, Amedeo Capetti, Paola Meraviglia, Enzo Boeri, Cristina Mussini, Monica Pecorari, Alessandro Soria, Laura Vecchi, Maurizio Santirocchi, Diego Brustia, Paolo Ravanini, Federico Dal Bello, Nino Romano, Salvatrice Mancuso, Carlo Calzetti, Renato Maserati, G. Filice, Fausto Baldanti, Daniela Francisci, Giustino Parruti, Ennio Polilli, D. Sacchini, Chiara Martinelli, Rita Consolini, Linda Vatteroni, A Vivarelli, Alessandro Nerli, Lucia Lenzi, G. Magnani, P Ortolani, Massimo Andreoni, Caterina Fimiani, Lucia Palmisano, Simona Di Giambenedetto, Vincenzo Vullo, Ombretta Turriziani, Marco Aurélio Echart Montano, Andrea Antinori, Mauro Zaccarelli, Chiara Dentone, Angela Gonnelli, Andrea De Luca, Michele Palumbo, Valeria Ghisetti, Stefano Bonora, Palma Delle Foglie, Cristina Rossi, Vincenzo Mondino, Marina Malena, Paolo Grossi, Elena Seminari, Federica Poletti,

HIV/AIDS Research and Interventions

Data of drug resistance mutations (DRMs) within the Italian vertically infected population are scarce. The aim of the present work was to assess the prevalence of DRMs in this setting. We retrospectively analysed HIV-1 pol sequences of vertically infected patients obtained from the Italian Antiviral Response Cohort Analysis (ARCA) database (https://www.dbarca.net/). Our queries were restricted to adults. DRMs were interpreted using the Stanford HIVDB resistance interpretation algorithm (https://hivdb.stanford.edu/hivdb/by-mutations/). Any modification of antiretroviral therapy after initiation was considered a change in the therapeutic regimen. Data from a total of 94 patients were analysed (Fig. 1). Patient clinical characteristics are summarized in Table 1. The population was exposed to a median of five different antiretroviral regimens (range, 1–35 regimens). Data about the ongoing antiretroviral regimen were recovered for 73 patients (78%). Fourteen (15%) had no DRMs. At least one major DRM to nucleos(t)ide reverse transcriptase inhibitors (N(t)RTIs) was found in 74 cases (79%), to nonnucleoside reverse transcriptase inhibitors (NNRTIs) in 61 (65%) cases, to protease inhibitors (PIs) in 33 cases (35%) and to integrase strand transfer inhibitor (INSTIs) in 7 (7%).Table 1Demographics of 94 perinatal HIV-infected patients in ARCA cohortCharacteristicValueAge 18–24 years30 (32) 25–29 years34 (36) ≥30 years30 (32)Ethnicity White88 (94) African4 (4) Hispanic2 (2)Sex Male46 (49) Female48 (51)Serology HCV-AbaPercentages calculated on total of available HCV serology (n = 88).10 (11) HBsAgbPercentages calculated on total of available HBV serology (n = 91).1 (1)Last virus load ≤50 copies/mL56 (60) >50 copies/mL38 (40)Virus load zenith >100 000 copies/mLcPercentage calculated on total of available HIV virus load zenith values (n = 83).49 (59)Last CD4+ count <200 cells/mm³8 (8) 200–499 cells/mm³25 (27) ≥500 cells/mm³61 (65) CD4+ nadir <200 cells/mm³dPercentage calculated on total of available CD4+ nadir values (n = 93).15 (16)No. of regimen switches (ART and cART) 1–555 (58) 6–1024 (25) ≥1115 (16)Last available ART regimenePercentages calculated on total of last available ART regimen (n = 73). Monotherapy6 (8) Dual therapy4 (5) 2 N(t)RTIs16 (22) 2 N(t)RTI + INSTI5 (7) 2 N(t)RTI + PI17 (23) 2 N(t)RTI + NNRTI17 (23) Multiregimen8 (11)ART, antiretroviral therapy; cART, combined antiretroviral therapy; HCV, hepatitis C virus; HBsAg, hepatitis B surface antigen; INSTI, integrase strand transfer inhibitors; N(t)RTI, nucleos(t)ide inhibitors; NNRTI, nonnucleoside inhibitors; PI, protease inhibitor.a Percentages calculated on total of available HCV serology (n = 88).b Percentages calculated on total of available HBV serology (n = 91).c Percentage calculated on total of available HIV virus load zenith values (n = 83).d Percentage calculated on total of available CD4+ nadir values (n = 93).e Percentages calculated on total of last available ART regimen (n = 73). Open table in a new tab ART, antiretroviral therapy; cART, combined antiretroviral therapy; HCV, hepatitis C virus; HBsAg, hepatitis B surface antigen; INSTI, integrase strand transfer inhibitors; N(t)RTI, nucleos(t)ide inhibitors; NNRTI, nonnucleoside inhibitors; PI, protease inhibitor. The most common DRM in the N(t)RTI class was M184V/I (62/94, 66%); in NNRTIs, K103N/S (39/94, 41%); in PI, M46I/L (26/94, 28%); and in INSTI, Q148H (3/94, 3%) (Fig. 2). Dual class resistance was seen in 39 (41%) of 94 patients, including simultaneous DRMs to N(t)RTI and NNRTI in 30 (32%), to N(t)RTI and PI in 8 (9%) and to N(t)RTI and INSTI in 1 (1%). Susceptibility to one or fewer class of drugs was seen in 25 (27%) of 94 cases, including concomitant DRMs to N(t)RTI, NNRTI and PI in 19 (20%) and N(t)RTI, NNRTI, PI and INSTI in 6 (6%) of 94 patients. More than half (50/94, 53%) of patients had concomitant DRMs that conferred moderate to high resistance to all N(t)RTIs, 33 (35%) to all NNRTIs, 11 (12%) to all PIs and 3 (3%) to all INSTIs. One quarter of patients (25/94, 27%) had concomitant moderate to high resistance to N(t)RTI and NNRTI, while 8 (8%) had concomitant moderate to high resistance to N(t)RTIs, NNRTIs and PIs. According to univariate analysis, patients with limited treatment options were more likely to have a CD4 nadir <200 cells/mm³ (hazard ratio (HR) 3.1; 95% confidence interval (CI) 1.2–8.1; p 0.021), last available CD4 cell count 50 copies/mL (HR 3.0; 95% CI 1.2–7.7; p 0.023). They were also more likely to have a history of exposure to more than ten different antiretroviral regimens (HR 5.9; 95% CI 1.8–19.0; p 0.003) and to be receiving current treatment with a salvage multiple-class drug regimen (HR 13.2; 95% CI 2.3–73.8; p 0.003). In multivariate analysis, limited treatment options, i.e. susceptibility to one or fewer classes of antiretrovirals, remained significantly associated with previous exposure to more than ten antiretroviral regimens (HR 4.4; 95% CI 1.0–18.0; p 0.049) and with last available HIV RNA >50 copies/mL (HR 3.0; 95% CI 1.1–10; p 0.032). In this retrospective analysis of the prevalence and characteristics of HIV-1 pol mutations in a cohort of Italian patients with vertically acquired HIV-1 infection, major DRMs to N(t)RTIs, NNRTIs and PIs were present in 79%, 65% and 35% of cases, respectively, thus showing higher DRM prevalence than in the adult population [1Zazzi M. Hu H. Prosperi M. The global burden of HIV-1 drug resistance in the past 20 years.PeerJ. 2018; 6: e4848Google Scholar, 2Franzetti M. De Luca A. Ceccherini-Siberstein F. Spagnuolo V. Nicastri E. Mussini C. et al.ICONA Foundation Study GroupEvolution of HIV-1 transmitted drug resistance in Italy in the 2007–2014 period: a weighted analysis.J Clin Virol. 2018; 106: 49-52Crossref PubMed Scopus (6) Google Scholar]. Similarly, dual-, triple- and all-class resistance was observed in 41%, 20% and 6% of our patients, respectively. Genotyping results may not be available for the perinatally infected population, particularly for those born and managed in the mid-1990s through the mid-2000s, which could lead to an underestimation of DRM prevalence in the cohort. In high-income settings, 30% to 40% of vertically infected children develop virologic failure over time, however [[3]Van Dyke R.B. Patel K. Siberry G.K. Burchett S.K. Spector S.A. Chernoff M.C. et al.Pediatric HIV/AIDS Cohort Study. Antiretroviral treatment of US children with perinatally acquired HIV infection: temporal changes in therapy between 1991 and 2009 and predictors of immunologic and virologic outcomes.J Acquir Immune Defic Syndr. 2011; 57: 165-173Crossref PubMed Scopus (65) Google Scholar]. In our study, a quarter of patients had limited treatment options. They were more likely to have had more than ten previous antiretroviral regimens and were about three times more likely than others to have detectable HIV RNA at the last follow-up. Notably, 7% of the cohort already harboured at least an INSTI resistance mutation. This study highlights how patients vertically infected with HIV-1 develop a high prevalence of DRMs at long-term follow-up, as has been shown in other studies [4de Mulder M. Yebra G. Navas A. de Jose M.I. Gurbindo M.D. Gonzalez-Tome M.I. et al.Madrid cohort of HIV-infected childrenHigh drug resistance prevalence among vertically HIV-infected patients transferred from pediatric care to adult units in Spain.PLoS One. 2012; 7: e52155Crossref PubMed Scopus (27) Google Scholar, 5Judd A. Lodwick R. Noguera-Julian A. Gibb D.M. Butler K. Costagliola D. et al.Pursuing Later Treatment Options II (PLATO II) Project Team for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoordHigher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe.HIV Med. 2017; 18: 171-180Crossref PubMed Scopus (36) Google Scholar, 6de Mulder M. York V.A. Wiznia A.A. Michaud H.A. Nixon D.F. Holguin A. et al.HIV-1 drug resistance prevalence, drug susceptibility and variant characterization in the Jacobi Medical Center paediatric Cohort, Bronx, NY, USA.HIV Med. 2014; 15: 135-143Crossref PubMed Scopus (8) Google Scholar, 7Fofana D.B. de Almeida M. Lambert-Niclot S. Peytavin G. Girard P.M. Lafia B. et al.Resistance profile and treatment outcomes in HIV-infected children at virological failure in Benin, West Africa.J Antimicrob Chemother. 2018; 73: 3143-3147Google Scholar]. Such patients pose a therapeutic challenge, which highlights the need for new therapies as well as new strategies aimed at preserving drug susceptibility to current and upcoming antiretroviral classes and at optimizing adherence to therapy [[8]Rosso R. Di Biagio A. Maggiolo F. Nulvesu L. Callegaro A.P. Taramasso L. et al.Patient-reported outcomes and low-level residual HIV-RNA in adolescents perinatally infected with HIV-1 after switching to one-pill fixed-dose regimen.AIDS Care. 2012; 24: 54-58Google Scholar]. All authors report no conflicts of interest relevant to this article. Members of the ARCA Study Group are as follows: Andrea Giacometti (ANCONA-Clinica di Malattie Infettive), Luca Butini (ANCONA-Immunologia Clinica), Romana del Gobbo (ANCONA-Malattie Infettive), Patrizia Bagnarelli (ANCONA-Virologia), Danilo Tacconi (AREZZO-Malattie Infettive), Giovanni Corbelli (ASCOLI PICENO-Malattie Infettive), Stefania Zanussi (AVIANO Centro di Riferimento Oncologico), Laura Monno (BARI Clinica Malattie Infettive Universita'), Grazia Punzi (BARI-Virologia), Franco Maggiolo (BERGAMO-Malattie Infettive), Leonardo Calza (BOLOGNA-Malattie Infettive S. Orsola), Maria Carla Re (BOLOGNA-UO Microbiologia, Lab. Retrovirus), Raffaele Pristera' (BOLZANO-Malattie Infettive), Paola Turconi (BRESCIA-Fleming Labs), Antonella Mandas (CAGLIARI Centro S.I.D.A., Policlinico Universitario), Sauro Tini (CITTA′ DI CASTELLO-Medicina Generale), Alessia Zoncada (CREMONA-Malattie Infettive), Elisabetta Paolini (CREMONA-Servizio Immunoematologia e Medicina Trasfusionale), Giorgio Amadio (FERMO-Malattie Infettive), Laura Sighinolfi (FERRARA-Malattie Infettive AOU S. Anna), Paola Corsi FIRENZE-Malattie Infettive CAREGGI), Luisa Galli (FIRENZE-Malattie Infettive Pediatria Meyer), Massimo Di Pietro (FIRENZE-Malattie Infettive SM Annunziata), Grazia Colao (FIRENZE-Virologia CAREGGI), Andrea Tosti (FOLIGNO-Malattie Infettive/SERT), Maurizio Setti (GENOVA Clinica Medica Immunologia), Bianca Bruzzone (GENOVA-Laboratorio di Igiene Ospedale S. Martino), Antonio Di Biagio (GENOVA-Malattie Infettive Ospedale S. Martino), Giovanni Cenderello (GENOVA-Malattie Infettive Ospedali Galliera), Michele Trezzi (GROSSETO-Malattie Infettive), Irene Arcidiacono (LODI-Malattie Infettive), Alberto Degiuli (LODI-Virologia Lodi), Michele De Gennaro (LUCCA Malattie Infettive), Alessandro Chiodera (MACERATA Malattie Infettive), Alfredo Scalzini (MANTOVA-Malattie Infettive Ospedale 'C. Poma'), Loredana Palvarini (MANTOVA-Virologia), Giovanni Todaro (MESSINA-Malattie Infettive), Stefano Rusconi (MILANO Dipart. Scienze Cliniche, Sez. Malattie Infettive-Universita' degli Studi), Maria Rita Gismondo (MILANO-Laboratorio Microbiologia Ospedale L. Sacco (Prima Divisione Malattie Infettive)), Valeria Micheli (MILANO-Laboratorio Microbiologia Ospedale L. Sacco (Seconda Divisione Malattie Infettive)), Maria Luisa Biondi (MILANO Laboratorio di diagnostica molecolare infettivologica AO S. Paolo), Amedeo Capetti (MILANO-Prima Divisione Malattie Infettive Ospedale L. Sacco), Paola Meraviglia (MILANO-Seconda Divisione Malattie Infettive Ospedale L. Sacco), Enzo Boeri (MILANO-Virologia HSR), Cristina Mussini (MODENA-Clinica Malattie Infettive), Monica Pecorari (MODENA-Virologia), Alessandro Soria (MONZA-Malattie Infettive), Laura Vecchi (MONZA-UO Microbiologia AO S. Gerardo), Maurizio Santirocchi (NARNI-SERT), Diego Brustia (NOVARA Malattie Infettive AO Maggiore), Paolo Ravanini (NOVARA-Virologia), Federico Dal Bello (PADOVA Virologia), Nino Romano PALERMO-Centro Riferimento AIDS Universita'), Salvatrice Mancuso (PALERMO Servizio Riferimento Regionale Diagnosi AIDS), Carlo Calzetti (PARMA-Divisione Malattie Infettive ed Epatologia Azienda Ospedaliera), Renato Maserati (PAVIA Ambulatorio Clinica Malattie Infettive S. Matteo), Gaetano Filice (PAVIA-Clinica Malattie Infettive e Tropicali), Fausto Baldanti (PAVIA-Virologia S. Matteo), Daniela Francisci (PERUGIA-Malattie Infettive), Giustino Parruti (PESCARA-Malattie Infettive), Ennio Polilli (PESCARA Virologia Pescara), Daria Sacchini (PIACENZA-Malattie Infettive), Chiara Martinelli (PISA-Malattie Infettive), Rita Consolini (PISA-Pediatria I Universita), Linda Vatteroni (PISA-Virologia), Angela Vivarelli (PISTOIA-Malattie Infettive), Alessandro Nerli (PRATO-Malattie Infettive), Lucia Lenzi (PRATO-Virologia), Giacomo Magnani (REGGIO EMILIA-Malattie Infettive), Patrizia Ortolani (RIMINI-Malattie Infettive RIMINI), Massimo Andreoni (ROMA-Cattedra Malattie Infettive Tor Vergata), Caterina Fimiani (ROMA-Immunologia Clinica Umberto I), Lucia Palmisano (ROMA-Istituto Superiore di Sanita'), Simona Di Giambenedetto (ROMA-Istituto di Clinica Malattie Infettive Cattolica), Vincenzo Vullo (ROMA-Malattie Infettive e Tropicali La Sapienza-Umberto I), Ombretta Turriziani (ROMA-Medicina Sperimentale e Patologia-Sezione Virologia-La Sapienza), Marco Montano (ROMA Virologia per Malattie Infettive Tor Vergata), Andrea Antinori (ROMA, IRCCS Spallanzani), Mauro Zaccarelli (ROMA, IRCCS Spallanzani), Chiara Dentone (SAN REMO-Malattie Infettive), Angela Gonnelli (SIENA-Malattie Infettive), Andrea De Luca (SIENA-Malattie Infettive 2), Michele Palumbo (TERNI-Malattie Infettive), Valeria Ghisetti (TORINO-Laboratorio di Virologia, Ospedale Amedeo di Savoia), Stefano Bonora (TORINO-Malattie Infettive Amedeo di Savoia), Palma Delle Foglie (TRENTO-Malattie Infettive), Cristina Rossi (TREVISO-Malattie Infettive; VERBANIA Malattie Infettive), Vincenzo Mondino (VERBANIA-Virologia), Marina Malena (VERONA-Centro di Medicina Preventiva), Paolo Grossi (VARESE-Clinica Malattie Infettive e Tropicali), Elena Seminari (VARESE-Virologia), Federica Poletti (VERBANIA-Malattie ULSS 20).