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1. Effectiveness of Once/Day Dolutegravir Plus Boosted Darunavir as a Switch Strategy in Heavily Treated Patients with Human Immunodeficiency Virus.

Author

Navarro, Jordi, Santos, José Ramón, Silva, Ana, Burgos, Joaquin, Falcó, Vicenç, Ribera, Esteban, Imaz, Arkaitz, and Curran, Adrian

Subjects
*DARUNAVIR, *HIV, *VIROLOGY, *COHORT analysis, *CD4 antigen
Abstract

Study Objective: Dual therapy with once/day dolutegravir (DTG) plus boosted darunavir (DRV/b) may be a suitable and effective strategy with a high genetic barrier to resistance in patients infected with human immunodeficiency virus (HIV). Our aim was to evaluate the effectiveness of DTG plus DRV/b (DTG+DRV/b) as a switch strategy in HIV‐infected patients, irrespective of their history of virologic failure (VF). Design: Multicenter retrospective cohort study. Setting: Human immunodeficiency outpatient treatment clinics at three university hospitals in Spain. Patients: Fifty HIV‐infected adults who had a stable antiretroviral treatment (ART) regimen and an undetectable viral load for at least 6 months, and whose ART was switched to once/day DTG+DRV/b between January 2015 and January 2018 were included in the analysis. Historical genotype at the time of VF was available in 44 patients. Measurements and Main Results: Patients were followed until VF or treatment discontinuation for any reason. The primary outcome was the percentage of patients with a viral load of 50 copies/mL or lower at the last follow‐up visit. Secondary outcomes included changes in CD4+ cell count, lipid profile, and renal function. Of the 50 patients included, median time of viral suppression was 52 months (interquartile range [IQR] 18–103 mo) and nadir CD4+ 89 cells/mm3 (IQR 37–241 cells/mm3). Patients had a history of a median of 8 ART combinations (IQR 4–11 combinations) and 3 VFs (IQR 2–8 VFs). The historical genotypes from 44 patients showed 41 patients (93.2%) with nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance‐associated mutations (RAMs), 32 (72.7%) with nonnucleoside reverse transcriptase inhibitor (NNRTI) RAMs, and 12 (27.3%) with primary protease inhibitor (PI) RAMs; 7 (15.9%) had darunavir RAMs, and no patients had baseline integrase strand transfer inhibitor RAMs. Thirty‐seven patients (84.1%) had resistance to at least two antiretroviral classes. After a median of 25 months (IQR 17–28 mo) of follow‐up, 49 patients (98%) maintained a viral load of 50 copies/mL or lower, and 1 patient (2%) had VF. No new RAMs emerged at VF. At week 4, serum creatinine concentration increased a median of 0.12 mg/dl (0.03–0.23 mg/dl). At last visit, total cholesterol and low‐density lipoprotein cholesterol levels increased by a median of 9 mg/dl (IQR −18 to 40 mg/dl) and 16 mg/dl (IQR −9 to 40 mg/dl), respectively, whereas CD4+ cell count remained stable (median +13 cell/mm3). Conclusion: In this cohort of heavily treated HIV‐infected patients with virologic suppression, switching to the combination of DTG+DRV/b was a convenient regimen that was highly effective and had good tolerability. [ABSTRACT FROM AUTHOR]

Published
2019
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2. Prevalence and determinants of resistance mutations in HIV‐1‐infected patients exposed to integrase inhibitors in a large Italian cohort.

Author

Rossetti, B, Modica, S, Maffeo, M, De Luca, A, Francisci, D, Penco, G, Sacchini, D, Di Biagio, A, Vicenti, I, Zazzi, M, Lombardi, F, Lagi, F, D'Autilia, R, Pecorari, M, Bruzzone, B, Magnani, G, and Paolucci, S

Subjects
*CHI-squared test, *DRUG resistance, *HIV, *HIV infections, *HIV-positive persons, *GENETIC mutation, *LOGISTIC regression analysis, *DISEASE prevalence, *HIV integrase inhibitors, *DESCRIPTIVE statistics, *SEQUENCE analysis, *GENOTYPES, *PHARMACODYNAMICS
Abstract

Objectives: The aim of the study was to analyse the prevalence of integrase resistance mutations in integrase strand transfer inhibitor (INSTI)‐experienced HIV‐1‐infected patients and its predictors. Methods: We selected HIV‐1 integrase sequences from the Antiviral Response Cohort Analysis (ARCA) database, derived from INSTI‐experienced patients between 2008 and 2017. Differences in the prevalence of resistance to raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) were assessed by χ2 test and predictors of resistance were analysed by logistic regression. Results: We included 462 genotypes from INSTI‐exposed individuals: 356 'INSTI‐failing' patients and 106 'previously INSTI‐exposed' patients (obtained a median of 42 weeks after INSTI discontinuation [interquartile range (IQR) 17–110 weeks]). Overall, at least low‐level resistance (LLR) to any INSTI (Stanford 8.5 algorithm) was detected in 198 (42.9%) cases. The most frequent INSTI resistance mutation was N155H, followed by Q148H/K/R, G140A/C/S, E138A/K/T and Y143C/H/R. Y143R and E138A were more prevalent in viral subtype B versus non‐B [5.2 versus 1.5%, respectively (P = 0.04), and 3.1 versus 0%, respectively (P = 0.02)]. Overall, the Q148H/K/R plus G140A/C/S and/or E138A/K/T pattern, defining an intermediate level of resistance to DTG, was detected in 70 (15%) cases. Independent predictors of at least LLR to any INSTI were current use versus past use of INSTIs, a lower genotypic sensitivity score (GSS) for contemporary antiretroviral drugs used, and having an integrase sequence obtained in calendar year 2016 as compared to 2008–2009. Conclusions: The results support integrase resistance testing in INSTI‐experienced patients. Emergence of INSTI resistance is facilitated by the reduced genetic barrier of the regimen as a consequence of resistance to companion drugs. However, INSTI resistance may become undetectable by standard population sequencing upon INSTI discontinuation. [ABSTRACT FROM AUTHOR]

Published
2019
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3. Durability, safety, and efficacy of rilpivirine in clinical practice: results from the SCOLTA Project.

Author

Bagella, Paola, Socio, Giuseppe VL De, Ricci, Elena, Menzaghi, Barbara, Martinelli, Canio, Squillace, Nicola, Maggi, Paolo, Orofino, Giancarlo, Calza, Leonardo, Carenzi, Laura, Celesia, Benedetto Maurizio, Penco, Giovanni, Biagio, Antonio Di, Valsecchi, Laura, Vichi, Francesca, Colombo, Valeria, Parruti, Giustino, Dentone, Chiara, Falasca, Katia, and Bonfanti, Paolo

Subjects
RILPIVIRINE, MEDICATION safety, DRUG efficacy, ANTIRETROVIRAL agents, THERAPEUTICS, HIV infections, DRUG side effects
Abstract

Rilpivirine is associated with a good efficacy and safety profile. However, data from real-life settings are scarce. Methods: We investigated the durability, safety and efficacy of Rilpivirine-based antiretroviral therapy in a prospective, observational, multicenter study. Results: We enrolled 499 HIV-infected patients, 360 (72.1%) males, mean age 43.4 ± 10.5 years, mean CD4 600 ± 327 cell/µL, mean HIV-RNA 3.80 ± 1.15 log10 cp/mL. After a median follow up of 16 months, 81 (16.2%) interruptions were reported, 36 (7.2%) of which for adverse events (16 of grade =3), most commonly neurological and gastrointestinal. We observed virological failures in only 8 (1.6%) patients. Naive patients showed a significant reduction in eGFR at week 24, 48 and 72 and in total cholesterol (TC)/HDL ratio at week 48 (p=0.007). In patients switching from PI we found a significant decrease at week 24 and 48 in TC and triglycerides at week 24, 48 and 72. eGFR showed a significant decrease at week 48 and 72. TC/HDL ratio showed a statistically significant decrease at week 24 (p=0.0008) and 72 (p=0.04). A significant increase at week 24 and 48 in AST and ALT values was observed. Patients switching from TDF/FTC/EFV showed a reduction in HDL, total cholesterol and triglycerides at week 24 and 48 and in eGFR at all follow up times. TC/HDL ratio showed a significant decrease at week 48 (p=0.01). CDC stage C and antiretroviral-experience (especially Protease Inhibitors) were associated with RPV discontinuation. Conclusion: In conclusion, our data confirm Rilpivirine efficacy, safety and tolerability with improvement in lipid profile. Although hepatic and renal events rarely caused discontinuation, liver and kidney parameters should be monitored. [ABSTRACT FROM AUTHOR]

Published
2018
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4. Etravirine plasma exposure is associated with virological efficacy in treatment-experienced HIV-positive patients.

Author

Calcagno, A., Marinaro, L., Nozza, S., Aldieri, C., Carbone, A., Ghisetti, V., Trentalange, A., D'Avolio, A., Castagna, A., Di Perri, G., and Bonora, S.

Subjects
*ETRAVIRINE (Drug), *REVERSE transcriptase inhibitors, *ANTIRETROVIRAL agents, *HIV-positive persons, *COMBINATION drug therapy, *VIRAL load, *MEDICAL virology, *THERAPEUTICS
Abstract

Etravirine is a non-nucleoside reverse transcriptase inhibitor used in combination with other antiretrovirals for the treatment of HIV infection. Given previous conflicting results aim of this study was to investigate whether etravirine plasma exposure was associated with virological outcome. Adult HIV-positive patients starting etravirine with detectable HIV viral loads were included if highly adherent (<90% of the doses) and if steady-state plasma concentrations were available (measured through a validated HPLC-PDA method). Virological success was defined as reaching and maintaining viral suppression (HIV RNA <50 copies/mL) during follow up. Fifty-nine (84.7% male) patients were included: baseline CD4+ T-lymphocyte and HIV RNA were 276 cells/μ L (101-419) and 3.99Log10copies/mL (3.11-4.91), respectively. Darunavir/ritonavir (n=21, 35.6%) and raltegravir plus maraviroc (n=33, 55.9%) were the most common associated antiretrovirals. 240 trough samples were available (3-7 per patient); etravirine trough concentrations (Ctrough) and weighted genotypic inhibitory quotients (wgIQ) were 426 ng/mL (266-763) and 408ng/mL/mutation (227-663), respectively. Virological success was observed in 49 patients (83.1%). Genotypic sensitivity of associated drugs (GSS) ≥2 (p=0.03), etravirine Ctrough >300 ng/mL (p=0.02) and etravirine wgIQ >276 ng/mL/mutation (p=0.02) were associated with virological success; at multivariate Cox proportional analysis etravirine wgIQ <276 ng/mL/mutation (p=0.012) and baseline CD4 <200 cell/μ L (p=0.043) were independently associated with virological failure. In a cohort of experienced patients etravirine exposure as well as immune status were associated with virological success; two cut off values (300 ng/mL and 276 ng/mL) were proposed for etravirine Ctrough and wgIQ and need to be confirmed in prospective studies. [ABSTRACT FROM AUTHOR]

Published
2014
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5. Antiretroviral adherence for adolescents growing up with HIV: understanding real life, drug delivery and forgiveness

Author

Sara Ayers, Sarah Fidler, Caroline Foster, and Imperial College Healthcare NHS Trust- BRC Funding

Subjects
0301 basic medicine, DOLUTEGRAVIR, Forgiveness, viral suppression, media_common.quotation_subject, 030106 microbiology, antiretroviral therapy, Human immunodeficiency virus (HIV), MEDLINE, MULTICENTER, Review, Infectious and parasitic diseases, RC109-216, medicine.disease_cause, THERAPY, 03 medical and health sciences, DOUBLE-BLIND, 0302 clinical medicine, PERINATAL HIV, YOUNG-ADULTS, INFECTION, Medicine, Pharmacology (medical), 030212 general & internal medicine, Viral suppression, adherence, adolescents, media_common, Developmental stage, Science & Technology, business.industry, HIV, Cognition, CARE, Antiretroviral therapy, Infectious Diseases, Drug delivery, EXPERIENCED PATIENTS, business, Life Sciences & Biomedicine, Clinical psychology, INTERVENTIONS
Abstract

Poorer adherence to medication is normal in adolescence and is one of a range of risk-taking behaviours common during a developmental stage that encompasses enormous cognitive, physical, sexual, social and emotional change. For adolescents living with human immunodeficiency virus (HIV) infection, poor adherence to antiretroviral therapy (ART) confers two significant challenges: poor health, but also the specific additional burden of onward transmission to partners. Late adolescence (15–19 years) is the only age group where HIV-associated mortality is rising, driven by poor adherence to ART and lack of access to second-line therapy, particularly amongst surviving perinatally infected young people. A previous lack of well-powered randomised multimodal behavioural ART adherence interventions specifically targeting adolescents is now being addressed and ongoing studies registered to ClinicalTrials.gov are described in the context of previous data. Accepting that despite enhanced support, some adolescents will continue to struggle with adherence, we must address how best to use existing ART agents to reduce mortality and allow adolescents the time to mature into adult life. Single-tablet regimens with a high genetic barrier to resistance based on integrase inhibitors and boosted protease inhibitors exist, but global access, in resource limited settings of young people living with HIV reside, is limited. Pragmatically, such regimens tolerate the intermittent adherence so characteristic of adolescence, preserving immune function, without the rapid evolution of resistance. The potential role of long-acting injectable ART, specifically cabotegravir and rilpivirine, is discussed and future strategies including ultra-long-acting drug-delivery systems and broadly neutralising monoclonal antibodies explored.

Published
2020

6. Prevalence and determinants of resistance mutations in HIV-1-infected patients exposed to integrase inhibitors in a large Italian cohort

Author

Daniela Francisci, Giovanni Penco, Filippo Lagi, Ilaria Vicenti, M Maffeo, Stefania Paolucci, Maurizio Zazzi, Bianca Bruzzone, A. Di Biagio, D Sacchini, A. De Luca, G. Magnani, Sara Modica, Barbara Rossetti, Roberto D'Autilia, Monica Pecorari, and Francesca Lombardi

Subjects
Male, 0301 basic medicine, Integrase inhibitor, HIV Infections, integrase strand transfer inhibitor, HIV Integrase, Quinolones, Piperazines, chemistry.chemical_compound, 0302 clinical medicine, experienced patients, HIV-1, resistance mutations, Interquartile range, Prevalence, Pharmacology (medical), 030212 general & internal medicine, biology, Elvitegravir, Health Policy, Middle Aged, Resistance mutation, Integrase, Infectious Diseases, Italy, Dolutegravir, Female, Heterocyclic Compounds, 3-Ring, medicine.drug, Adult, medicine.medical_specialty, Genotype, Pyridones, 03 medical and health sciences, Raltegravir Potassium, Internal medicine, Drug Resistance, Viral, Oxazines, medicine, Humans, HIV Integrase Inhibitors, business.industry, Raltegravir, 030112 virology, Discontinuation, Logistic Models, chemistry, Mutation, biology.protein, business
Abstract

OBJECTIVES The aim of the study was to analyse the prevalence of integrase resistance mutations in integrase strand transfer inhibitor (INSTI)-experienced HIV-1-infected patients and its predictors. METHODS We selected HIV-1 integrase sequences from the Antiviral Response Cohort Analysis (ARCA) database, derived from INSTI-experienced patients between 2008 and 2017. Differences in the prevalence of resistance to raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) were assessed by χ2 test and predictors of resistance were analysed by logistic regression. RESULTS We included 462 genotypes from INSTI-exposed individuals: 356 'INSTI-failing' patients and 106 'previously INSTI-exposed' patients (obtained a median of 42 weeks after INSTI discontinuation [interquartile range (IQR) 17-110 weeks]). Overall, at least low-level resistance (LLR) to any INSTI (Stanford 8.5 algorithm) was detected in 198 (42.9%) cases. The most frequent INSTI resistance mutation was N155H, followed by Q148H/K/R, G140A/C/S, E138A/K/T and Y143C/H/R. Y143R and E138A were more prevalent in viral subtype B versus non-B [5.2 versus 1.5%, respectively (P = 0.04), and 3.1 versus 0%, respectively (P = 0.02)]. Overall, the Q148H/K/R plus G140A/C/S and/or E138A/K/T pattern, defining an intermediate level of resistance to DTG, was detected in 70 (15%) cases. Independent predictors of at least LLR to any INSTI were current use versus past use of INSTIs, a lower genotypic sensitivity score (GSS) for contemporary antiretroviral drugs used, and having an integrase sequence obtained in calendar year 2016 as compared to 2008-2009. CONCLUSIONS The results support integrase resistance testing in INSTI-experienced patients. Emergence of INSTI resistance is facilitated by the reduced genetic barrier of the regimen as a consequence of resistance to companion drugs. However, INSTI resistance may become undetectable by standard population sequencing upon INSTI discontinuation.

Published
2018
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7. Incidence of cancer and overall risk of mortality in individuals treated with raltegravir-based and non-raltegravir-based combination antiretroviral therapy regimens

Author

Cozzi-Lepri, A., Zangerle, R., Machala, L., Zilmer, K., Ristola, M., Pradier, C., Kirk, O., Sambatakou, H., Fatkenheuer, G., Yust, I., Schmid, P., Gottfredsson, M., Khromova, I., Jilich, D., Flisiak, R., Smidt, J., Rozentale, B., Radoi, R., Losso, M. H., Lundgren, J. D., Mocroft, A., Kundro, M., Schmied, B., Karpov, I., Vassilenko, A., Mitsura, V. M., Paduto, D., Clumeck, N., De Wit, S., Delforge, M., Florence, E., Vandekerckhove, L., Hadziosmanovic, V., Begovac, J., Sedlacek, D., Kronborg, G., Benfield, T., Gerstoft, J., Katzenstein, T., Moller, N. F., Pedersen, C., Ostergaard, L., Wiese, L., Nielsen, L. N., Aho, I., Viard, J. -P., Girard, P. -M., Fontas, E., Duvivier, C., Rockstroh, J., Schmidt, R., Degen, O., Stellbrink, H. J., Stefan, C., Bogner, J., Chkhartishvili, N., Gargalianos, P., Xylomenos, G., Lourida, P., Szlavik, J., Mulcahy, F., Turner, D., Burke, M., Shahar, E., Hassoun, G., Elinav, H., Haouzi, M., Elbirt, D., Sthoeger, Z. M., D'Arminio Monforte, A., Esposito, R., Mazeu, I., Mussini, C., Mazzotta, F., Gabbuti, A., Vullo, V., Lichtner, M., Zaccarelli, M., Antinori, A., Acinapura, R., Plazzi, M., Lazzarin, A., Castagna, A., Gianotti, N., Galli, M., Ridolfo, A., Uzdaviniene, V., Matulionyte, R., Staub, T., Hemmer, R., Reiss, P., Ormaasen, V., Maeland, A., Bruun, J., Knysz, B., Gasiorowski, J., Inglot, M., Horban, A., Bakowska, E., Grzeszczuk, A., Parczewski, M., Maciejewska, K., Aksak-Was, B., Beniowski, M., Mularska, E., Smiatacz, T., Gensing, M., Jablonowska, E., Malolepsza, E., Wojcik, K., Mozer-Lisewska, I., Caldeira, L., Mansinho, K., Maltez, F., Oprea, C., Panteleev, A., Panteleev, O., Yakovlev, A., Trofimora, T., Kuzovatova, E., Borodulina, E., Vdoushkina, E., Jevtovic, D., Tomazic, J., Gatell, J. M., Miro, J. M., Moreno, S., Rodriguez, J. M., Clotet, B., Jou, A., Paredes, R., Tural, C., Puig, J., Bravo, I., Domingo, P., Gutierrez, M., Mateo, G., Sambeat, M. A., Laporte, J. M., Falconer, K., Thalme, A., Sonnerborg, A., Blaxhult, A., Flamholc, L., Scherrer, A., Weber, R., Cavassini, M., Calmy, A., Furrer, H., Battegay, M., Kuznetsova, A., Kyselyova, G., Sluzhynska, M., Gazzard, B., Johnson, A. M., Simons, E., Edwards, S., Phillips, A., Johnson, M. A., Orkin, C., Weber, J., Scullard, G., Clarke, A., Leen, C., Thiebaut, R., Burger, D., Peters, L., Matthews, C., Fischer, A. H., Bojesen, A., Raben, D., Kristensen, D., Gronborg Laut, K., Larsen, J. F., Podlekareva, D., Shepherd, L., Schultze, A., Amele, S., Cozzi-lepri, A, Zangerle, R, Machala, L, Zilmer, K, Ristola, M, Pradier, C, Kirk, O, Sambatakou, H, Fätkenheuer, G, Yust, I, Schmid, P, Gottfredsson, M, Khromova, I, Jilich, D, Flisiak, R, Smidt, J, Rozentale, B, Radoi, R, Losso, M. H, Lundgren, J. D, Mocroft, A, Eurosida Study, Group, Castagna, A, Lazzarin, A, AII - Infectious diseases, APH - Aging & Later Life, Infectious diseases, Global Health, Amsterdam institute for Infection and Immunity, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Clinicum, Department of Medicine, and HUS Inflammation Center

Subjects
Male, 0301 basic medicine, observational treatment comparison, HIV Infections, Rate ratio, propensity scores, 0302 clinical medicine, Antiretroviral Therapy, Highly Active, Neoplasms, Medicine and Health Sciences, Risk of mortality, AIDS-DEFINING, Pharmacology (medical), Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Original Research, EXPERIENCED, ddc:616, IMMUNODEFICIENCY, Incidence, Health Policy, Incidence (epidemiology), risk of cancer, Middle Aged, 3. Good health, Infectious Diseases, Anti-Retroviral Agents, SAFETY, EXPERIENCED PATIENTS, Cohort, AIDS-DEFINING CANCERS, Female, Historical Cohort, medicine.drug, Adult, Alnæmi, medicine.medical_specialty, animal structures, CANCERS, HIV INTEGRASE INHIBITORS, 030106 microbiology, Antiretroviral Therapy, survival, Risk Assessment, HIV-1-INFECTED PATIENTS, MALIGNANCIES, 03 medical and health sciences, Lyf, Raltegravir Potassium, Internal medicine, PATIENTS, medicine, Humans, COHORT, Highly Active, propensity score, Krabbamein, OPTIMIZED BACKGROUND THERAPY, business.industry, observational treatment, Raltegravir, Survival Analysis, Odds ratio, INFECTED INDIVIDUALS, comparison, 3121 General medicine, internal medicine and other clinical medicine, business
Abstract

Publisher's version (útgefin grein), Objectives There are currently few data on the long‐term risk of cancer and death in individuals taking raltegravir (RAL). The aim of this analysis was to evaluate whether there is evidence for an association. Methods The EuroSIDA cohort was divided into three groups: those starting RAL‐based combination antiretroviral therapy (cART) on or after 21 December 2007 (RAL); a historical cohort (HIST) of individuals adding a new antiretroviral (ARV) drug (not RAL) to their cART between 1 January 2005 and 20 December 2007, and a concurrent cohort (CONC) of individuals adding a new ARV drug (not RAL) to their cART on or after 21 December 2007. Baseline characteristics were compared using logistic regression. The incidences of newly diagnosed malignancies and death were compared using Poisson regression. Results The RAL cohort included 1470 individuals [with 4058 person‐years of follow‐up (PYFU)] compared with 3787 (4472 PYFU) and 4467 (10 691 PYFU) in the HIST and CONC cohorts, respectively. The prevalence of non‐AIDS‐related malignancies prior to baseline tended to be higher in the RAL cohort vs. the HIST cohort [adjusted odds ratio (aOR) 1.31; 95% confidence interval (CI) 0.95–1.80] and vs. the CONC cohort (aOR 1.89; 95% CI 1.37–2.61). In intention‐to‐treat (ITT) analysis (events: RAL, 50; HIST, 45; CONC, 127), the incidence of all new malignancies was 1.11 (95% CI 0.84–1.46) per 100 PYFU in the RAL cohort vs. 1.20 (95% CI 0.90–1.61) and 0.83 (95% CI 0.70–0.99) in the HIST and CONC cohorts, respectively. After adjustment, there was no evidence for a difference in the risk of malignancies [adjusted rate ratio (RR) 0.73; 95% CI 0.47–1.14 for RALvs. HIST; RR 0.95; 95% CI 0.65–1.39 for RALvs. CONC] or mortality (adjusted RR 0.87; 95% CI 0.53–1.43 for RALvs. HIST; RR 1.14; 95% CI 0.76–1.72 for RALvs. CONC). Conclusions We found no evidence for an oncogenic risk or poorer survival associated with using RAL compared with control groups., EuroSIDA was supported by the European Union's Seventh Framework Programme for research, technological development and demonstration under EuroCoord grant agreement no. 260694. Current support includes unrestricted grants from Bristol‐Myers Squibb, Gilead, GlaxoSmithKline LLC, Janssen R&D, Merck and Co. Inc. and Pfizer Inc. The participation of centres from Switzerland was supported by The Swiss National Science Foundation (Grant 108787). The study is also supported by a grant (grant number DNRF126) from the Danish National Research Foundation.

Published
2017
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8. Durability, safety, and efficacy of rilpivirine in clinical practice: results from the SCOLTA project

Author

Bagella, P., De Socio, Gvl., Ricci, E., Menzaghi, B., Martinelli, C., Squillace, N., Maggi, P., Orofino, G., Calza, L., Carenzi, L., Belesia, B. M., Penco, G., Di Biagio, A., Valsecchi, L., Vichi, F., Colombo, V., Parruti, G., Dentone, C., Falasca, K., Bonfanti, P., Madeddu, G., Study Group Italy, On behalf of the C. I. S. A. I., Nunnari, G., Pellicano', Giovanni Francesco, Bagella, P, De Socio, G, Ricci, E, Menzaghi, B, Martinelli, C, Squillace, N, Maggi, P, Orofino, G, Calza, L, Carenzi, L, Celesia, B, Penco, G, Di Biagio, A, Valsecchi, L, Vichi, F, Colombo, V, Parruti, G, Dentone, C, Falasca, K, Bonfanti, P, Madeddu, G, Bagella, Paola, De Socio, Giuseppe V. L., Ricci, Elena, Menzaghi, Barbara, Martinelli, Canio, Squillace, Nicola, Maggi, Paolo, Orofino, Giancarlo, Calza, Leonardo, Carenzi, Laura, Celesia, Benedetto Maurizio, Penco, Giovanni, Di Biagio, Antonio, Valsecchi, Laura, Vichi, Francesca, Colombo, Valeria, Parruti, Giustino, Dentone, Chiara, Falasca, Katia, Bonfanti, Paolo, and Madeddu, Giordano

Subjects
0301 basic medicine, safety, Combination antiretroviral therapy, NNRTI, medicine.medical_specialty, Cohort study, Experienced patients, HIV-1, Naive, efficacy, Infectious Disease, Experienced patient, Gastroenterology, lcsh:Infectious and parasitic diseases, rilpivirine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Median follow-up, Internal medicine, medicine, Pharmacology (medical), lcsh:RC109-216, 030212 general & internal medicine, Adverse effect, HIV-1, combination antiretroviral therapy, NNRTI, cohort study, naive, experienced patients, Original Research, Pharmacology, medicine.diagnostic_test, business.industry, 030112 virology, Antiretroviral therapy, Discontinuation, combination antiretroviral therapy, Infectious Diseases, Tolerability, chemistry, Infection and Drug Resistance, Rilpivirine, Lipid profile, business
Abstract

Paola Bagella,1 Giuseppe VL De Socio,2 Elena Ricci,3 Barbara Menzaghi,4 Canio Martinelli,5 Nicola Squillace,6 Paolo Maggi,7 Giancarlo Orofino,8 Leonardo Calza,9 Laura Carenzi,3 Benedetto Maurizio Celesia,10 Giovanni Penco,11 Antonio Di Biagio,12 Laura Valsecchi,3 Francesca Vichi,13 Valeria Colombo,14 Giustino Parruti,15 Chiara Dentone,16 Katia Falasca,17 Paolo Bonfanti,18 Giordano Madeddu1 On behalf of the C.I.S.A.I. Study Group, Italy 1Unit of Infectious Diseases, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy; 2Infectious Diseases Unit, Department of Medicine, Azienda Ospedaliero-Universitaria di Perugia, Santa Maria Hospital, Perugia, Italy; 3Department of Infectious Diseases, ASST Fatebenefratelli Sacco, Milan, Italy; 4Unit of Infectious Diseases, ASST della Valle Olona, Busto Arsizio, Italy; 5Unit of Infectious and Tropical Diseases, Careggi Hospital Florence, Florence, Italy; 6Infectious Diseases Unit, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy; 7Infectious Diseases Clinic, University of Bari, Policlinico Consorziale, Bari, Italy; 8Amedeo di Savoia Hospital Unit of Infectious Diseases, Torino, Italy; 9University of Bologna, Department of Infectious Diseases, S. Orsola Malpighi Hospital, Bologna, Italy; 10Unit of Infectious Diseases, Garibaldi Hospital, Catania, Italy; 11Infectious Diseases Unit, Galliera Hospital, Genoa, Italy; 12Unit of Infectious Diseases, IRCCS San Martino Hospital – IST, Genoa, Italy; 13Infectious Diseases Unit, Santa Maria Annunziata Hospital, Florence, Italy; 14Infectious Diseases Unit, University of Milan, DIBIC Luigi Sacco, Milan, Italy; 15Unit of Infectious Diseases, Pescara Hospital, Pescara, Italy; 16Unit of Infectious Diseases, Sanremo Hospital, Sanremo, Italy; 17Infectious Diseases Unit, University of Chieti, Chieti, Italy; 18Unit of Infectious Diseases, A. Manzoni Hospital, Lecco, Italy Abstract: Rilpivirine is associated with a good efficacy and safety profile. However, data from real-life settings are scarce. Methods: We investigated the durability, safety and efficacy of Rilpivirine-based antiretroviral therapy in a prospective, observational, multicenter study. Results: We enrolled 499 HIV-infected patients, 360 (72.1%) males, mean age 43.4 ± 10.5years, mean CD4 600 ± 327 cell/μL, mean HIV-RNA 3.80 ± 1.15 log10 cp/mL. After a median follow up of 16 months, 81 (16.2%) interruptions were reported, 36 (7.2%) of which for adverse events (16 of grade ≥3), most commonly neurological and gastrointestinal. We observed virological failures in only 8 (1.6%) patients. Naive patients showed a significant reduction in eGFR at week 24, 48 and 72 and in total cholesterol (TC)/HDL ratio at week 48 (p=0.007). In patients switching from PI we found a significant decrease at week 24 and 48 in TC and triglycerides at week 24, 48 and 72. eGFR showed a significant decrease at week 48 and 72. TC/HDL ratio showed a statistically significant decrease at week 24 (p=0.0008) and 72 (p=0.04). A significant increase at week 24 and 48 in AST and ALT values was observed. Patients switching from TDF/FTC/EFV showed a reduction in HDL, total cholesterol and triglycerides at week 24 and 48 and in eGFR at all follow up times. TC/HDL ratio showed a significant decrease at week 48 (p=0.01). CDC stage C and antiretroviral-experience (especially Protease Inhibitors) were associated with RPV discontinuation. Conclusion: In conclusion, our data confirm Rilpivirine efficacy, safety and tolerability with improvement in lipid profile. Although hepatic and renal events rarely caused discontinuation, liver and kidney parameters should be monitored. Keywords: HIV-1, combination antiretroviral therapy, NNRTI, cohort study, naive, experienced patients

Published
2018

9. Comparison between rules-based human immunodeficiency virus type 1 genotype interpretations and real or virtual phenotype

Subjects
INDIVIDUALS, ANTIRETROVIRAL THERAPY, EXPERIENCED PATIENTS, LABORATORY GUIDELINES, MANAGEMENT, SUSCEPTIBILITY, HIV DRUG-RESISTANCE, FOLLOW-UP, RANDOMIZED TRIAL, RECOMMENDATIONS
Abstract

We compared 2 rules-based genotype interpretation systems and real or virtual phenotype through a retrospective analysis of a prospective trial. Genotypes were determined with VircoGEN II (VIRCO) and were interpreted with either RetroGram 1.4 or TRUGENE HIV-1 ( guidelines 3.0) or original virtual phenotype ( Virtual Phenotype; VIRCO), as available in the year 2000. Among 188 human immunodeficiency virus (HIV) type 1 isolates, overall concordance (kappa agreement) was observed for the 2 rules-based systems, whereas striking discordances were noted between them and real and virtual phenotype interpretations for stavudine, didanosine, zalcitabine, abacavir, and amprenavir (kappa

Published
2003

10. Comparison between Rules‐Based Human Immunodeficiency Virus Type 1 Genotype Interpretations and Real or Virtual Phenotype: Concordance Analysis and Correlation with Clinical Outcome in Heavily Treated Patients

Author

Sergio Lo Caputo, Giampiero Carosi, Carlo Torti, A. M. M. Been-Tiktak, Francesco Castelli, Luigia Scudeller, Carmine Tinelli, Wilco Keulen, Eugenia Quiros-Roldan, M. Gennaro, Francesco Mazzotta, Giovanni Buccoliero, Piera Pierotti, Charles A. Boucher, and University of Groningen

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Genes, Viral, Genotype, Anti-HIV Agents, Concordance, HIV Infections, SUSCEPTIBILITY, HIV DRUG-RESISTANCE, RANDOMIZED TRIAL, RECOMMENDATIONS, Amprenavir, ANTIRETROVIRAL THERAPY, Risk Factors, Abacavir, Internal medicine, Drug Resistance, Viral, Odds Ratio, MANAGEMENT, medicine, Humans, Immunology and Allergy, Didanosine, Salvage Therapy, business.industry, Odds ratio, Confidence interval, INDIVIDUALS, Phenotype, Treatment Outcome, Infectious Diseases, EXPERIENCED PATIENTS, Immunology, HIV-1, LABORATORY GUIDELINES, Female, FOLLOW-UP, business, Kappa, medicine.drug
Abstract

We compared 2 rules-based genotype interpretation systems and real or virtual phenotype through a retrospective analysis of a prospective trial. Genotypes were determined with VircoGEN II (VIRCO) and were interpreted with either RetroGram 1.4 or TRUGENE HIV-1 (guidelines 3.0) or original virtual phenotype (Virtual Phenotype; VIRCO), as available in the year 2000. Among 188 human immunodeficiency virus (HIV) type 1 isolates, overall concordance (kappa agreement) was observed for the 2 rules-based systems, whereas striking discordances were noted between them and real and virtual phenotype interpretations for stavudine, didanosine, zalcitabine, abacavir, and amprenavir (kappa

Published
2003
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11. Prevalence and determinants of resistance mutations in HIV-1-infected patients exposed to integrase inhibitors in a large Italian cohort.

Author

Modica S, Rossetti B, Lombardi F, Lagi F, Maffeo M, D'Autilia R, Pecorari M, Vicenti I, Bruzzone B, Magnani G, Paolucci S, Francisci D, Penco G, Sacchini D, Zazzi M, De Luca A, and Di Biagio A

Subjects
Adult, Female, Genotype, HIV Infections virology, HIV Integrase Inhibitors therapeutic use, Heterocyclic Compounds, 3-Ring therapeutic use, Humans, Italy epidemiology, Logistic Models, Male, Middle Aged, Oxazines, Piperazines, Prevalence, Pyridones, Quinolones therapeutic use, Raltegravir Potassium therapeutic use, Drug Resistance, Viral, HIV Infections drug therapy, HIV Integrase genetics, HIV-1 genetics, Mutation
Abstract

Objectives: The aim of the study was to analyse the prevalence of integrase resistance mutations in integrase strand transfer inhibitor (INSTI)-experienced HIV-1-infected patients and its predictors., Methods: We selected HIV-1 integrase sequences from the Antiviral Response Cohort Analysis (ARCA) database, derived from INSTI-experienced patients between 2008 and 2017. Differences in the prevalence of resistance to raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) were assessed by χ 2 test and predictors of resistance were analysed by logistic regression., Results: We included 462 genotypes from INSTI-exposed individuals: 356 'INSTI-failing' patients and 106 'previously INSTI-exposed' patients (obtained a median of 42 weeks after INSTI discontinuation [interquartile range (IQR) 17-110 weeks]). Overall, at least low-level resistance (LLR) to any INSTI (Stanford 8.5 algorithm) was detected in 198 (42.9%) cases. The most frequent INSTI resistance mutation was N155H, followed by Q148H/K/R, G140A/C/S, E138A/K/T and Y143C/H/R. Y143R and E138A were more prevalent in viral subtype B versus non-B [5.2 versus 1.5%, respectively (P = 0.04), and 3.1 versus 0%, respectively (P = 0.02)]. Overall, the Q148H/K/R plus G140A/C/S and/or E138A/K/T pattern, defining an intermediate level of resistance to DTG, was detected in 70 (15%) cases. Independent predictors of at least LLR to any INSTI were current use versus past use of INSTIs, a lower genotypic sensitivity score (GSS) for contemporary antiretroviral drugs used, and having an integrase sequence obtained in calendar year 2016 as compared to 2008-2009., Conclusions: The results support integrase resistance testing in INSTI-experienced patients. Emergence of INSTI resistance is facilitated by the reduced genetic barrier of the regimen as a consequence of resistance to companion drugs. However, INSTI resistance may become undetectable by standard population sequencing upon INSTI discontinuation., (© 2018 British HIV Association.)

Published
2019
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12. Study of Genotypic and Phenotypic HIV-1 Dynamics of Integrase Mutations During Raltegravir Treatment: A Refined Analysis by Ultra-Deep 454 Pyrosequencing

Author

Valeria Cento, Francesca Ceccherini-Silberstein, Daniele Armenia, Roberta D'Arrigo, Fernanda Scopelliti, Carlo Federico Perno, Andrea Antinori, Pasquale Narciso, Valeria Micheli, Herwig Van Marck, Valerio Tozzi, Liesbeth Van Wesenbeeck, Lieven J. Stuyver, Lavinia Fabeni, Ina Vandenbroucke, Giuliano Rizzardini, Bianca Bruzzone, Sergio Lo Caputo, and Jeroen Aerssens

Subjects
Male, HIV Infections, HIV Integrase, medicine.disease_cause, ANTIRETROVIRAL THERAPY, Genotype, INFECTION, Immunology and Allergy, MAXIMUM-LIKELIHOOD, Phylogeny, Genetics, VIRUS TYPE-1 INTEGRASE, 0303 health sciences, education.field_of_study, Mutation, Settore MED/07 - Microbiologia e Microbiologia Clinica, Phenotype, Pyrrolidinones, 3. Good health, Integrase, Infectious Diseases, EXPERIENCED PATIENTS, Female, medicine.drug, Adult, Anti-HIV Agents, Molecular Sequence Data, Population, Mutation, Missense, Microbial Sensitivity Tests, Viral quasispecies, Biology, REVERSE-TRANSCRIPTASE INHIBITORS, DRUG-RESISTANCE MUTATIONS, TREATMENT-NAIVE PATIENTS, MINORITY VARIANTS, FREQUENCY, Major Articles and Brief Reports, 03 medical and health sciences, Raltegravir Potassium, Drug Resistance, Viral, medicine, Humans, education, 030304 developmental biology, Salvage Therapy, 030306 microbiology, Sequence Analysis, DNA, Raltegravir, Virology, HIV-1, biology.protein, Pyrosequencing
Abstract

Background. The dynamics of raltegravir-resistant variants and their impact on virologic response in 23 HIV-1‐ infected patients, who started a salvage raltegravir-containing regimen, were investigated. Methods. Integrase population sequencing and Ultra-Deep-454 Pyrosequencing (UDPS) were performed on plasma samples at baseline and at raltegravir failure. All integrase mutations detected at a frequency $1% were considered to be reliable for the UDPS analyses. Phylogenetic and phenotypic resistance analyses were also performed. Results. At baseline, primary resistance mutations were not detected by both population and UDPS genotypic assays; few secondary mutations (T97A-V151I-G163R) were rarely detected and did not show any statistically association either with virologic response at 24-weeks or with the development of resistant variants at failure. At UDPS, not all resistant variants appearing early during treatment evolved as major populations during failure; only specific resistance pathways (Y143R-Q148H/R-N155H) associated with an increased rate of fitness and phenotypic resistance were selected. Conclusions. Resistance to raltegravir in integrase strand transfer inhibitor‐naive patients remains today a rare event, which might be changed by future extensive use of such drugs. In our study, pathways of resistance at failure were not predicted by baseline mutations, suggesting that evolution plus stochastic selection plays a major role in the appearance of integrase-resistance mutations, whereas fitness and resistance are dominant factors acting for the late selection of resistant quasispecies.

Published
2012

13. In vitro cytotoxicity and mitochondrial toxicity of tenofovir alone and in combination with other antiretrovirals in human renal proximal tubule cells

Author

Universitat Rovira i Virgili, Vidal, F; Domingo, JC; Guallar, J; Saumoy, M; Cordobilla, B; de la Rosa, RS; Giralt, M; Alvarez, ML; López-Dupla, M; Torres, F; Villarroya, F; Cihlar, T; Domingo, P, Universitat Rovira i Virgili, and Vidal, F; Domingo, JC; Guallar, J; Saumoy, M; Cordobilla, B; de la Rosa, RS; Giralt, M; Alvarez, ML; López-Dupla, M; Torres, F; Villarroya, F; Cihlar, T; Domingo, P

Abstract

We assessed the in vitro toxicity of tenofovir (TFV) and compared it with those of zidovudine (AZT), didanosine (ddI), ritonavir (RTV), and lopinavir (LPV) alone and in combination in human renal proximal tubule epithelial cells (RPTECs). The cells were treated with various concentrations and combinations of the tested antiretrovirals for up to 22 days, and cytotoxicity was determined. In addition, we assessed the levels of mitochondrial DNA (mtDNA) and cytochrome oxidase II (COII) mRNA in RPTECs treated with reverse transcriptase inhibitors. TFV alone was not associated with significant cytotoxicity. ddI showed pronounced cytotoxicity that was greater than those of AZT (P = 0.002) and TFV (P = 0.0001). The combination of 10 mu M RTV and 40 mu M LPV significantly reduced RPTEC viability (P < 0.0001), and TFV tended to partially reduce this effect. TFV alone affected neither mtDNA nor COII mRNA levels, whereas ddI caused a profound depletion of mtDNA and a parallel reduction in COII mRNA expression. The effects of ddI, but not those of AZT, on mtDNA and COII mRNA were further enhanced in the presence of TFV, a finding consistent with the inhibition of ddI clearance by TFV. The addition of TFV to ddI or AZT appeared to slightly increase the COII mRNA/mtDNA ratio relative to that in cells treated with ddI or AZT alone. Together, these in vitro results indicate that combination with other antiretrovirals does not significantly increase the toxic potential of TFV in RPTECs.

Published
2006

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