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1. Long-term safety and efficacy of rilpivirine in combination with nucleoside/nucleotide reverse transcriptase inhibitors in HIV-1 infected patients: 336-week rollover study of phase 2b and 3 clinical studies.

Author

Molina JM, Ene L, Cahn P, Fätkenheuer G, Van Wijngaerden E, Lombaard J, Zakharova N, Van Eygen V, Vanveggel S, and Van Solingen-Ristea R

Subjects
Humans, Nucleosides therapeutic use, Nucleotides therapeutic use, Reverse Transcriptase Inhibitors adverse effects, Rilpivirine adverse effects, Anti-HIV Agents adverse effects, HIV Infections drug therapy, HIV-1
Abstract

Background: To evaluate the long-term safety and efficacy of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in human immunodeficiency virus (HIV)-infected patients., Methods: RPV-treated HIV-infected patients from phase 2b or 3 studies rolled-over into this phase 3, open-label study and received RPV 25 mg once daily (QD) with choice of two NRTIs. Adverse events (AEs), plasma viral load, CD4 + cell count, and antiviral resistance were evaluated., Results: Of the 482 patients treated, 437 (>90%) patients discontinued study treatment; 371 (77%) had switched to commercially available RPV, 14 (2.9%) discontinued due to AEs, and 6 (1.2%) had virologic failure. In this rollover study, patients were followed up to week 336, although data was limited beyond 288 weeks. Forty-five (9.3%) patients were still undergoing treatment at the time of data cut-off for the current analysis (8 February 2018). The most frequently reported AEs were pregnancy in 7 (1.5%) patients and syphilis in 5 (1.0%) patients. Grade 3-4 AEs were reported in 17 (3.5%) patients, and AEs possibly related to RPV in 23 (4.8%) patients. Over 288 weeks of treatment, 80.1% (95% CI: 74.9%; 84.3%) of patients maintained virologic suppression (HIV-1 RNA <50 copies/mL). The absolute CD4 + cell count increased over time until week 192 and remained constant thereafter., Conclusions: RPV 25 mg QD in combination with an investigator-selected background regimen of two NRTIs demonstrated sustained long-term virologic suppression. The treatment was well-tolerated with no new safety findings.

Published
2021
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2. Long-term use of darunavir/ritonavir-containing regimens in daily practice in Belgium: retrospective observational cohort data of 1701 HIV-patients.

Author

De Wit S, Florence E, Vandekerckhove L, Vandercam B, Goffard JC, Van Wijngaerden E, Moutschen M, Demeester R, Thilakarathne P, and Piryns H

Subjects
Adult, Anti-HIV Agents therapeutic use, Antiretroviral Therapy, Highly Active, Belgium epidemiology, Darunavir therapeutic use, Female, HIV Infections epidemiology, Humans, Male, Retrospective Studies, Ritonavir therapeutic use, Anti-HIV Agents administration & dosage, Darunavir administration & dosage, HIV Infections drug therapy, Ritonavir administration & dosage
Abstract

Background Once daily (QD) ritonavir or cobicistat-boosted darunavir (DRV/b), in combination with other antiretrovirals (ARVs), is recommended as a first-line option for human immunodeficiency virus-infected patients in European and USA guidelines. The objective of this study was to analyse the outcomes of DRV/r QD-based antiretroviral therapy (ART) regimens in real-life settings. Methods This is an observational, non-interventional, non-comparative, retrospective, multicentre cohort study. Data were collected from the databases of eight Belgian AIDS Reference Centres. All patients who received at least one dose of DRV/r QD, regardless of background ARV regimen, with a minimum follow-up of 6 months were included. Results Data from 1701 subjects were collected. Most were male (66.5%) with a mean age of 42.9 years, 33.1% were treatment-naïve and 66.9% were ART experienced. During a median follow-up of 2.45 years (95% CI: 1.50-3.34), the probability to remain on treatment was 87% for the first year, 79% for the second year. DRV/r was well tolerated with few discontinuations due to adverse events (6.9%) or virological failure (0.8%). Among the 1138 treatment-experienced patients, 111 (9.8%) patients received DRV/r QD monotherapy. Conclusions This retrospective cohort analysis confirms the long-term effectiveness and good tolerability of DRV/r QD in a real-life setting. No unexpected adverse events were reported.

Published
2018
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3. Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe.

Author

Hofstra LM, Sauvageot N, Albert J, Alexiev I, Garcia F, Struck D, Van de Vijver DAMC, Åsjö B, Beshkov D, Coughlan S, Descamps D, Griskevicius A, Hamouda O, Horban A, Van Kasteren M, Kolupajeva T, Kostrikis LG, Liitsola K, Linka M, Mor O, Nielsen C, Otelea D, Paraskevis D, Paredes R, Poljak M, Puchhammer-Stöckl E, Sönnerborg A, Staneková D, Stanojevic M, Van Laethem K, Zazzi M, Zidovec Lepej S, Boucher CAB, Schmit JC, Wensing AMJ, Puchhammer-Stockl E, Sarcletti M, Schmied B, Geit M, Balluch G, Vandamme AM, Vercauteren J, Derdelinckx I, Sasse A, Bogaert M, Ceunen H, De Roo A, De Wit S, Echahidi F, Fransen K, Goffard JC, Goubau P, Goudeseune E, Yombi JC, Lacor P, Liesnard C, Moutschen M, Pierard D, Rens R, Schrooten Y, Vaira D, Vandekerckhove LPR, Van den Heuvel A, Van Der Gucht B, Van Ranst M, Van Wijngaerden E, Vandercam B, Vekemans M, Verhofstede C, Clumeck N, Van Laethem K, Beshkov D, Alexiev I, Lepej SZ, Begovac J, Kostrikis L, Demetriades I, Kousiappa I, Demetriou V, Hezka J, Linka M, Maly M, Machala L, Nielsen C, Jørgensen LB, Gerstoft J, Mathiesen L, Pedersen C, Nielsen H, Laursen A, Kvinesdal B, Liitsola K, Ristola M, Suni J, Sutinen J, Descamps D, Assoumou L, Castor G, Grude M, Flandre P, Storto A, Hamouda O, Kücherer C, Berg T, Braun P, Poggensee G, Däumer M, Eberle J, Heiken H, Kaiser R, Knechten H, Korn K, Müller H, Neifer S, Schmidt B, Walter H, Gunsenheimer-Bartmeyer B, Harrer T, Paraskevis D, Hatzakis A, Zavitsanou A, Vassilakis A, Lazanas M, Chini M, Lioni A, Sakka V, Kourkounti S, Paparizos V, Antoniadou A, Papadopoulos A, Poulakou G, Katsarolis I, Protopapas K, Chryssos G, Drimis S, Gargalianos P, Xylomenos G, Lourida G, Psichogiou M, Daikos GL, Sipsas NV, Kontos A, Gamaletsou MN, Koratzanis G, Sambatakou H, Mariolis H, Skoutelis A, Papastamopoulos V, Georgiou O, Panagopoulos P, Maltezos E, Coughlan S, De Gascun C, Byrne C, Duffy M, Bergin C, Reidy D, Farrell G, Lambert J, O'Connor E, Rochford A, Low J, Coakely P, O'Dea S, Hall W, Mor O, Levi I, Chemtob D, Grossman Z, Zazzi M, de Luca A, Balotta C, Riva C, Mussini C, Caramma I, Capetti A, Colombo MC, Rossi C, Prati F, Tramuto F, Vitale F, Ciccozzi M, Angarano G, Rezza G, Kolupajeva T, Vasins O, Griskevicius A, Lipnickiene V, Schmit JC, Struck D, Sauvageot N, Hemmer R, Arendt V, Michaux C, Staub T, Sequin-Devaux C, Wensing AMJ, Boucher CAB, van de Vijver DAMC, van Kessel A, van Bentum PHM, Brinkman K, Connell BJ, van der Ende ME, Hoepelman IM, van Kasteren M, Kuipers M, Langebeek N, Richter C, Santegoets RMWJ, Schrijnders-Gudde L, Schuurman R, van de Ven BJM, Åsjö B, Kran AB, Ormaasen V, Aavitsland P, Horban A, Stanczak JJ, Stanczak GP, Firlag-Burkacka E, Wiercinska-Drapalo A, Jablonowska E, Maolepsza E, Leszczyszyn-Pynka M, Szata W, Camacho R, Palma C, Borges F, Paixão T, Duque V, Araújo F, Otelea D, Paraschiv S, Tudor AM, Cernat R, Chiriac C, Dumitrescu F, Prisecariu LJ, Stanojevic M, Jevtovic D, Salemovic D, Stanekova D, Habekova M, Chabadová Z, Drobkova T, Bukovinova P, Shunnar A, Truska P, Poljak M, Lunar M, Babic D, Tomazic J, Vidmar L, Vovko T, Karner P, Garcia F, Paredes R, Monge S, Moreno S, Del Amo J, Asensi V, Sirvent JL, de Mendoza C, Delgado R, Gutiérrez F, Berenguer J, Garcia-Bujalance S, Stella N, de Los Santos I, Blanco JR, Dalmau D, Rivero M, Segura F, Elías MJP, Alvarez M, Chueca N, Rodríguez-Martín C, Vidal C, Palomares JC, Viciana I, Viciana P, Cordoba J, Aguilera A, Domingo P, Galindo MJ, Miralles C, Del Pozo MA, Ribera E, Iribarren JA, Ruiz L, de la Torre J, Vidal F, Clotet B, Albert J, Heidarian A, Aperia-Peipke K, Axelsson M, Mild M, Karlsson A, Sönnerborg A, Thalme A, Navér L, Bratt G, Karlsson A, Blaxhult A, Gisslén M, Svennerholm B, Bergbrant I, Björkman P, Säll C, Mellgren Å, Lindholm A, Kuylenstierna N, Montelius R, Azimi F, Johansson B, Carlsson M, Johansson E, Ljungberg B, Ekvall H, Strand A, Mäkitalo S, Öberg S, Holmblad P, Höfer M, Holmberg H, Josefson P, and Ryding U

Subjects
Adult, Europe, Female, HIV Infections drug therapy, HIV Protease Inhibitors pharmacology, HIV-1 genetics, Humans, Male, Microbial Sensitivity Tests, Middle Aged, Mutation, Prevalence, Reverse Transcriptase Inhibitors pharmacology, Anti-HIV Agents pharmacology, Drug Resistance, Viral genetics, HIV Infections virology, HIV-1 drug effects
Abstract

Background: Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001., Methods: Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0., Results: The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones., Conclusions: Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.)

Published
2016
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4. Pharmacy refill adherence outperforms self-reported methods in predicting HIV therapy outcome in resource-limited settings.

Author

Sangeda RZ, Mosha F, Prosperi M, Aboud S, Vercauteren J, Camacho RJ, Lyamuya EF, Van Wijngaerden E, and Vandamme AM

Subjects
Adolescent, Adult, Female, Humans, Male, Medically Underserved Area, Middle Aged, Outcome and Process Assessment, Health Care methods, Prospective Studies, Self Report, Tanzania, Viral Load, Young Adult, Anti-HIV Agents administration & dosage, HIV Infections drug therapy, HIV-1 isolation & purification, Health Resources supply & distribution, Medication Adherence, Pharmaceutical Services statistics & numerical data
Abstract

Background: Optimal adherence to antiretroviral therapy is critical to prevent HIV drug resistance (HIVDR) epidemic. The objective of the study was to investigate the best performing adherence assessment method for predicting virological failure in resource-limited settings (RLS)., Method: This study was a single-centre prospective cohort, enrolling 220 HIV-infected adult patients attending an HIV/AIDS Care and Treatment Centre in Dar es Salaam, Tanzania, in 2010. Pharmacy refill, self-report (via visual analog scale [VAS] and the Swiss HIV Cohort study-adherence questionnaire), pill count, and appointment keeping adherence measurements were taken. Univariate logistic regression (LR) was done to explore a cut-off that gives a better trade-off between sensitivity and specificity, and a higher area under the curve (AUC) based on receiver operating characteristic curve in predicting virological failure. Additionally, the adherence models were evaluated by fitting multivariate LR with stepwise functions, decision trees, and random forests models, assessing 10-fold multiple cross validation (MCV). Patient factors associated with virological failure were determined using LR., Results: Viral load measurements at baseline and one year after recruitment were available for 162 patients, of whom 55 (34%) had detectable viral load and 17 (10.5%) had immunological failure at one year after recruitment. The optimal cut-off points significantly predictive of virological failure were 95%, 80%, 95% and 90% for VAS, appointment keeping, pharmacy refill, and pill count adherence respectively. The AUC for these methods ranged from 0.52 to 0.61, with pharmacy refill giving the best performance at AUC 0.61. Multivariate logistic regression with boost stepwise MCV had higher AUC (0.64) compared to all univariate adherence models, except pharmacy refill adherence univariate model, which was comparable to the multivariate model (AUC = 0.64). Decision trees and random forests models were inferior to boost stepwise model. Pharmacy refill adherence (<95%) emerged as the best method for predicting virological failure. Other significant predictors in multivariate LR were having a baseline CD4 T lymphocytes count < 200 cells/μl, being unable to recall the diagnosis date, and a higher weight., Conclusion: Pharmacy refill has the potential to predict virological failure and to identify patients to be considered for viral load monitoring and HIVDR testing in RLS.

Published
2014
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5. Increase in transmitted resistance to non-nucleoside reverse transcriptase inhibitors among newly diagnosed HIV-1 infections in Europe.

Author

Frentz D, Van de Vijver DA, Abecasis AB, Albert J, Hamouda O, Jørgensen LB, Kücherer C, Struck D, Schmit JC, Vercauteren J, Åsjö B, Balotta C, Beshkov D, Camacho RJ, Clotet B, Coughlan S, Griskevicius A, Grossman Z, Horban A, Kolupajeva T, Korn K, Kostrikis LG, Liitsola K, Linka M, Nielsen C, Otelea D, Paraskevis D, Paredes R, Poljak M, Puchhammer-Stöckl E, Sönnerborg A, Stanekova D, Stanojevic M, Van Wijngaerden E, Wensing AM, and Boucher CA

Subjects
Adult, Europe epidemiology, Female, Genotype, HIV Infections epidemiology, HIV Infections transmission, HIV-1 classification, HIV-1 drug effects, HIV-1 isolation & purification, Humans, Male, Mutation, Phylogeny, Prevalence, Anti-HIV Agents therapeutic use, Drug Resistance, Viral, HIV Infections drug therapy, HIV Infections virology, HIV-1 genetics
Abstract

Background: One out of ten newly diagnosed patients in Europe was infected with a virus carrying a drug resistant mutation. We analysed the patterns over time for transmitted drug resistance mutations (TDRM) using data from the European Spread program., Methods: Clinical, epidemiological and virological data from 4317 patients newly diagnosed with HIV-1 infection between 2002 and 2007 were analysed. Patients were enrolled using a pre-defined sampling strategy., Results: The overall prevalence of TDRM in this period was 8.9% (95% CI: 8.1-9.8). Interestingly, significant changes over time in TDRM caused by the different drug classes were found. Whereas nucleoside resistance mutations remained constant at 5%, a significant decline in protease inhibitors resistance mutations was observed, from 3.9% in 2002 to 1.6% in 2007 (p = 0.001). In contrast, resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) doubled from 2.0% in 2002 to 4.1% in 2007 (p = 0.004) with 58% of viral strains carrying a K103N mutation. Phylogenetic analysis showed that these temporal changes could not be explained by large clusters of TDRM., Conclusion: During the years 2002 to 2007 transmitted resistance to NNRTI has doubled to 4% in Europe. The frequent use of NNRTI in first-line regimens and the clinical impact of NNRTI mutations warrants continued monitoring.

Published
2014
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6. Clinical evaluation of Rega 8: an updated genotypic interpretation system that significantly predicts HIV-therapy response.

Author

Vercauteren J, Beheydt G, Prosperi M, Libin P, Imbrechts S, Camacho R, Clotet B, De Luca A, Grossman Z, Kaiser R, Sönnerborg A, Torti C, Van Wijngaerden E, Schmit JC, Zazzi M, Geretti AM, Vandamme AM, and Van Laethem K

Subjects
Adult, Anti-HIV Agents pharmacology, Databases as Topic, Female, Genotype, HIV-1 drug effects, Humans, Male, ROC Curve, Sensitivity and Specificity, Treatment Outcome, Algorithms, Anti-HIV Agents therapeutic use, HIV Infections drug therapy, HIV Infections virology, HIV-1 genetics
Abstract

Introduction: Clinically evaluating genotypic interpretation systems is essential to provide optimal guidance in designing potent individualized HIV-regimens. This study aimed at investigating the ability of the latest Rega algorithm to predict virological response on a short and longer period., Materials Methods: 9231 treatment changes episodes were extracted from an integrated patient database. The virological response after 8, 24 and 48 weeks was dichotomized to success and failure. Success was defined as a viral load below 50 copies/ml or alternatively, a 2 log decrease from the baseline viral load at 8 weeks. The predictive ability of Rega version 8 was analysed in comparison with that of previous evaluated version Rega 5 and two other algorithms (ANRS v2011.05 and Stanford HIVdb v6.0.11). A logistic model based on the genotypic susceptibility score was used to predict virological response, and additionally, confounding factors were added to the model. Performance of the models was compared using the area under the ROC curve (AUC) and a Wilcoxon signed-rank test., Results: Per unit increase of the GSS reported by Rega 8, the odds on having a successful therapy response on week 8 increased significantly by 81% (OR = 1.81, CI = [1.76-1.86]), on week 24 by 73% (OR = 1.73, CI = [1.69-1.78]) and on week 48 by 85% (OR = 1.85, CI = [1.80-1.91]). No significant differences in AUC were found between the performance of Rega 8 and Rega 5, ANRS v2011.05 and Stanford HIVdb v6.0.11, however Rega 8 had the highest sensitivity: 76.9%, 76.5% and 77.2% on 8, 24 and 48 weeks respectively. Inclusion of additional factors increased the performance significantly., Conclusion: Rega 8 is a significant predictor for virological response with a better sensitivity than previously, and with rules for recently approved drugs. Additional variables should be taken into account to ensure an effective regimen.

Published
2013
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7. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study.

Author

Stellbrink HJ, Orkin C, Arribas JR, Compston J, Gerstoft J, Van Wijngaerden E, Lazzarin A, Rizzardini G, Sprenger HG, Lambert J, Sture G, Leather D, Hughes S, Zucchi P, and Pearce H

Subjects
Absorptiometry, Photon, Adenine administration & dosage, Adenine adverse effects, Adolescent, Adult, Aged, Anti-HIV Agents administration & dosage, Bone and Bones pathology, Bone and Bones physiopathology, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Dideoxynucleosides administration & dosage, Drug Combinations, Emtricitabine, Europe, Female, Humans, Lamivudine administration & dosage, Male, Middle Aged, Organophosphonates administration & dosage, Tenofovir, Young Adult, Adenine analogs & derivatives, Anti-HIV Agents adverse effects, Bone Density drug effects, Bone Density physiology, Deoxycytidine analogs & derivatives, Dideoxynucleosides adverse effects, HIV Infections drug therapy, Lamivudine adverse effects, Organophosphonates adverse effects
Abstract

Background: Abacavir-lamivudine and tenofovir DF-emtricitabine fixed-dose combinations are commonly used as first-line antiretroviral therapies. However, few studies have comprehensively compared their relative safety profiles., Methods: In this European, multicenter, open-label, 96-week study, antiretroviral-naive adult subjects with human immunodeficiency virus (HIV) infection were randomized to receive either abacavir-lamivudine or tenofovir-emtricitabine with efavirenz. Primary analyses were conducted after 48 weeks of treatment. Bone mineral density (BMD), a powered secondary end point, was assessed by dual energy x-ray absorptiometry. Bone turnover markers (osteocalcin, procollagen 1 N-terminal propeptide, bone specific alkaline phosphatase, and type 1 collagen cross-linked C telopeptide [CTx]) were assessed in an exploratory analysis., Results: A total of 385 subjects were enrolled in the study. BMD loss was observed in both treatment groups, with a significant difference in the change from baseline in both total hip (abacavir-lamivudine group, -1.9%; tenofovir-emtricitabine group, -3.6%; P < .001) and lumbar spine (abacavir-lamivudine group, -1.6%; tenofovir-emtricitabine group, -2.4%; P = .036). BMD loss of >or=6% was more common in the tenofovir-emtricitabine group (13% of the tenofovir-emtricitabine group vs 3% of the abacavir-lamivudine group had a loss of >or=6% in the hip; 15% vs 5% had a loss of >or=6% in the spine). Bone turnover markers increased in both treatment groups over the first 24 weeks, stabilizing or decreasing thereafter. Increases in all markers were significantly greater in the tenofovir-emtricitabine treatment group than in the abacavir-lamivudine group at week 24. All but CTx remained significantly different at week 48 (eg, osteocalcin: abacavir-lamivudine group, +8.07 mg/L; tenofovir-emtricitabine group, +11.92 mg/L; P < .001)., Conclusions: This study demonstrated the impact of first-line treatment regimens on bone. Greater increases in bone turnover and decreases in BMD were observed in subjects treated with tenofovir-emtricitabine than were observed in subjects treated with abacavir-lamivudine.

Published
2010
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8. Evolution of genotypic resistance to enfuvirtide in HIV-1 isolates from different group M subtypes.

Author

Covens K, Kabeya K, Schrooten Y, Dekeersmaeker N, Van Wijngaerden E, Vandamme AM, De Wit S, and Van Laethem K

Subjects
Amino Acid Sequence, Amino Acid Substitution genetics, Enfuvirtide, HIV-1 classification, HIV-1 isolation & purification, Humans, Molecular Sequence Data, Mutation, Missense, Salvage Therapy methods, Sequence Analysis, DNA, Treatment Failure, Anti-HIV Agents pharmacology, Drug Resistance, Viral, Evolution, Molecular, HIV Envelope Protein gp41 genetics, HIV Envelope Protein gp41 pharmacology, HIV Infections drug therapy, HIV Infections virology, HIV-1 drug effects, HIV-1 genetics, Peptide Fragments pharmacology
Abstract

Background: Enfuvirtide is active against isolates from different HIV-1 subtypes. In vitro and in vivo studies reveal that resistance mutations are primarily found within the region spanning amino acid 36-45 of gp41. However, most studies include only subtype B strains, while it is known that especially the env region is very divergent among subtypes., Objectives: To analyze the gp41 HR1 genetic evolution during failure of enfuvirtide-containing salvage regimens in 19 HIV-1 patients infected with strains from different group M subtypes., Study Design: The gp41 sequence was determined at baseline and upon failure in 19 patients. For a subset of 7 patients, samples were available after discontinuation of enfuvirtide., Results: Our results confirmed the conserved nature of the HR1 region. Escape mutants during chronic treatment with enfuvirtide were mainly observed within region 36-45. One novel mutation was identified, i.e. S42G in a subtype A1 strain., Conclusions: Different subtypes escape enfuvirtide selective pressure through similar mutational patterns, however a new S42G variant was observed. The in vivo selection of S42G suggests that it might play a role in enfuvirtide resistance. Therefore, it could be considered as a candidate mutation to be included within drug resistance interpretation systems.

Published
2009
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10. The effect of highly active antiretroviral treatment on viral load and antiretroviral drug levels in breast milk.

Author

Colebunders R, Hodossy B, Burger D, Daems T, Roelens K, Coppens M, Van Bulck B, Jacquemyn Y, Van Wijngaerden E, and Fransen K

Subjects
Adult, Female, HIV Infections metabolism, Humans, Pregnancy, Pregnancy Complications, Infectious drug therapy, Viral Load, Anti-HIV Agents metabolism, Antiretroviral Therapy, Highly Active, HIV Infections drug therapy, Milk, Human chemistry
Abstract

Viral load and drug levels were measured in the plasma and breast milk of nine mothers treated with highly active antiretroviral therapy (HAART) and one woman treated only with zidovudine during delivery. In all HAART-treated women after delivery the viral load was less than 400 copies/ml in plasma and breast milk. Compared with the plasma concentration, the breast milk concentration was between 68 and 90% for nevirapine, 6 and 24% for nelfinavir and 90 and 540% for indinavir.

Published
2005
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11. Current levels of drug resistance among therapy-naive HIV-infected patients have significant impact on treatment response.

Author

Derdelinckx I, Van Laethem K, Maes B, Schrooten Y, De Wit S, Florence E, Fransen K, Ribas SG, Marissens D, Moutschen M, Vaira D, Zissis G, Van Ranst M, Van Wijngaerden E, and Vandamme AM

Subjects
Anti-HIV Agents pharmacology, Female, HIV Infections virology, HIV-1 genetics, Humans, Male, Mutation, Reverse Transcriptase Inhibitors pharmacology, Treatment Outcome, Anti-HIV Agents therapeutic use, Drug Resistance, Viral genetics, HIV Infections drug therapy, HIV Infections epidemiology, HIV-1 drug effects, Reverse Transcriptase Inhibitors therapeutic use
Published
2004
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12. Performance of the VERSANT HIV-1 resistance assays (LiPA) for detecting drug resistance in therapy-naive patients infected with different HIV-1 subtypes.

Author

Derdelinckx I, Van Laethem K, Maes B, Schrooten Y, De Schouwer K, De Wit S, Fransen K, García Ribas S, Moutschen M, Vaira D, Zissis G, Van Ranst M, Van Wijngaerden E, and Vandamme AM

Subjects
Anti-HIV Agents therapeutic use, Belgium epidemiology, Female, Genotype, HIV Infections drug therapy, HIV Infections virology, HIV Protease genetics, HIV Reverse Transcriptase genetics, HIV-1 genetics, HIV-1 isolation & purification, Humans, Male, Mutation, Nucleic Acid Hybridization, Sequence Analysis, DNA methods, Anti-HIV Agents pharmacology, Drug Resistance, Viral genetics, HIV-1 classification, HIV-1 drug effects, Microbial Sensitivity Tests methods
Abstract

In this study we evaluated the performance of the VERSANT HIV-1 Resistance Assays (LiPA) in detecting drug resistance in therapy-naive HIV-infected patients diagnosed in Belgium in 2000. We compared the results with population sequencing and found concordance to be in line with previous studies in treatment-experienced patients (86.87% for reverse transcriptase (RT); 92.77% for protease (PRO)). Discordance was mainly due to indeterminate reactions on LiPA (8.45% for RT; 6.85% for PRO) and minor discordances (4.13% for RT; 0.25% for PRO). Major discordances were rare (0.46% for RT; 0.12% for PRO). Indeterminate reactions were significantly associated with strains belonging to non-B subtypes.

Published
2003
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13. Prevalence and characteristics of multinucleoside-resistant human immunodeficiency virus type 1 among European patients receiving combinations of nucleoside analogues.

Author

Van Vaerenbergh K, Van Laethem K, Albert J, Boucher CA, Clotet B, Floridia M, Gerstoft J, Hejdeman B, Nielsen C, Pannecouque C, Perrin L, Pirillo MF, Ruiz L, Schmit JC, Schneider F, Schoolmeester A, Schuurman R, Stellbrink HJ, Stuyver L, Van Lunzen J, Van Remoortel B, Van Wijngaerden E, Vella S, Witvrouw M, Yerly S, De Clercq E, Destmyer J, and Vandamme AM

Subjects
Amino Acid Substitution, CD4 Lymphocyte Count, Codon, Drug Resistance, Microbial, Drug Resistance, Multiple genetics, Drug Therapy, Combination, Europe, Female, Gene Frequency, Genotype, HIV Infections drug therapy, HIV Infections immunology, HIV Reverse Transcriptase genetics, HIV Reverse Transcriptase metabolism, HIV-1 enzymology, HIV-1 genetics, Humans, Male, Microbial Sensitivity Tests, Mutagenesis, Insertional, Nucleosides chemistry, Nucleosides pharmacology, Nucleosides therapeutic use, Phenotype, Anti-HIV Agents pharmacology, HIV Infections virology, HIV-1 drug effects
Abstract

The prevalence and the genotypic and phenotypic characteristics of multinucleoside-resistant (MNR) human immunodeficiency virus type 1 (HIV-1) variants in Europe were investigated in a multicenter study that involved centers in nine European countries. Study samples (n = 363) collected between 1991 and 1997 from patients exposed to two or more nucleoside analogue reverse transcriptase inhibitors (NRTIs) and 274 control samples from patients exposed to no or one NRTI were screened for two marker mutations of multinucleoside resistance (the Q151M mutation and a mutation with a 2-amino-acid insertion at codon 69, T69S-XX). Q151M was identified in six of the study samples (1. 6%), and T69S-XX was identified in two of the study samples (0.5%; both of them T69S-SS), but both patterns were absent among control samples. Non-NRTI (NNRTI)-related changes were observed in viral strains from two patients, which displayed the Q151M resistance pattern, although the patients were NNRTI naive. The patients whose isolates displayed multinucleoside resistance had received treatment with zidovudine and either didanosine, zalcitabine, or stavudine. Both resistance patterns conferred broad cross-resistance to NRTIs in vitro and a poor response to treatment in vivo. MNR HIV-1 is found only among multinucleoside-experienced patients. Its prevalence is low in Europe, but it should be closely monitored since it seriously limits treatment options.

Published
2000
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14. Presence of 2',5'-Bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"-oxath iole-2",2"-dioxide) (TSAO)-resistant virus strains in TSAO-inexperienced HIV patients.

Author

Van Laethem K, Schmit JC, Pelemans H, Balzarini J, Witvrouw M, Pérez-Pérez MJ, Camarasa MJ, Esnouf RM, Aquaro S, Cenci A, Perno CF, Hermans P, Sprecher S, Ruiz L, Clotet B, Van Wijngaerden E, Van Ranst M, Desmyter J, De Clercq E, and Vandamme AM

Subjects
Base Sequence, DNA Primers genetics, Drug Resistance, Microbial genetics, Genes, Viral, Genetic Variation, HIV Reverse Transcriptase chemistry, HIV Reverse Transcriptase genetics, HIV-1 enzymology, HIV-1 genetics, Humans, Models, Molecular, Phenotype, Point Mutation, Protein Conformation, Reverse Transcriptase Inhibitors pharmacology, Thymidine pharmacology, Anti-HIV Agents pharmacology, HIV Infections drug therapy, HIV Infections virology, HIV-1 drug effects, Spiro Compounds pharmacology, Thymidine analogs & derivatives
Abstract

HIV-1 samples from six patients undergoing diverse anti-HIV therapies possessed the E138A mutation in their reverse transcriptase (RT) genome. Patients were receiving the following therapies: TIBO monotherapy (one patient); zidovudine plus didanosine combination therapy (one); zidovudine monotherapy (one); sequential therapy with zidovudine, then stavudine and finally zalcitabine plus didanosine (one); and two were drug naive. E138K, not E138A, is a known TSAO-specific resistance mutation, emerging under selective pressure in vitro. Our phenotypic data on the patient isolates, confirmed by data on an E138A mutant acquired through in vitro mutagenesis, indicated that an alanine substitution for glutamate at codon 138 of the HIV-1 RT renders the virus TSAO resistant, confirming the importance of this amino acid residue in the activity of TSAO derivatives. In addition, we have demonstrated through phenotypic analysis of the E138A and A98S mutants (after in vitro mutagenesis) that the mutation A98S, found in one of these patients, could be partially responsible for the phenotypic reversal of TSAO resistance. This reversal could be explained by the restoration of a hydrogen bond between 98S and the main-chain residue L349, which compensates for the loss of the E138-G99 main-chain hydrogen bond. As TSAO derivatives have not been used in the clinical setting, the presence of the E138A mutation at a frequency of 6.7% in our study of 90 TSAO-inexperienced HIV-seropositive individuals implies that 138A of the RT must be a natural variant and that the mutant virus is replication competent. Our observations suggest that the E138A mutation may likely arise in patients under the selective pressure of TSAO or related compounds that show a decreased antiviral potency toward the E138A variant.

Published
2000
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15. Safe and effective use of combination antiretroviral treatment.

Author

Colebunders R, Clumeck N, Florence E, Vandercam B, Van Wanzeele F, Van Wijngaerden E, Lacor P, Demonty J, and De Wit S

Subjects
Anti-HIV Agents administration & dosage, Anti-HIV Agents adverse effects, Clinical Protocols, Drug Combinations, Drug Interactions, Drug Monitoring, Drug Resistance, Microbial, HIV Infections virology, HIV Protease Inhibitors administration & dosage, HIV Protease Inhibitors adverse effects, Humans, Patient Compliance, Physician-Patient Relations, Safety, Treatment Failure, Viral Load, Anti-HIV Agents therapeutic use, HIV Infections drug therapy, HIV Protease Inhibitors therapeutic use
Published
1999
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16. Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials

Author

Lathouwers, Erkki, Wong, Eric Y, Brown, Kimberley, Baugh, Bryan, Ghys, Anne, Jezorwski, John, Mohsine, El Ghazi, Van Landuyt, Erika, Opsomer, Magda, De Meyer, Sandra, De Wit, S, Florence, E, Vandekerckhove, L, Vandercam, B, Brunetta, J, Klein, M, Murphy, D, Rachlis, A, Walmsley, S, Ajana, F, Cotte, L, Girard, P-M, Katlama, C, Molina, J-M, Poizot-Martin, I, Raffi, F, Rey, D, Reynes, J, Teicher, E, Yazdanpanah, Y, Arasteh, K, Bickel, M, Bogner, J, Esser, S, Faetkenheuer, G, Jessen, H, Kern, W, Rockstroh, J, Spinner, C, Stellbrink, H-J, Stoehr, A, Antinori, A, Castelli, F, Chirianni, A, De Luca, A, Di Biagio, A, Galli, M, Lazzarin, A, Maggiolo, F, Maserati, R, Mussini, C, Garlicki, A, Gasiorowski, J, Halota, W, Horban, A, Parczewski, M, Piekarska, A, Belonosova, E, Chernova, O, Dushkina, N, Kulagin, V, Ryamova, E, Shuldyakov, A, Sizova, N, Tsybakova, O, Voronin, E, Yakovlev, A, Antela, A, Arribas, JR, Berenguer, J, Casado, J, Estrada, V, Galindo, MJ, Garcia Del Toro, M, Gatell, JM, Gorgolas, M, Gutierrez, F, Gutierrez, MDM, Negredo, E, Pineda, JA, Podzamczer, D, Portilla Sogorb, J, Rivero, A, Rubio, R, Viciana, P, De Los Santos, I, Clarke, A, Gazzard, BG, Johnson, MA, Orkin, C, Reeves, I, Waters, L, Benson, P, Bhatti, L, Bredeek, F, Crofoot, G, Cunningham, D, DeJesus, E, Eron, J, Felizarta, F, Franco, R, Gallant, J, Hagins, D, Henry, K, Jayaweera, D, Lucasti, C, Martorell, C, McDonald, C, McGowan, J, Mills, A, Morales-Ramirez, J, Prelutsky, D, Ramgopal, M, Rashbaum, B, Ruane, P, Slim, J, Wilkin, A, deVente, J, Moutschen, M, Van Wijngaerden, E, Vekerckhove, L, Vercam, B, Conway, B, Shafran, S, Janssen Pharmaceutica [Beerse], Janssen Pharmaceutical Research and Development Titusville, AMBER and EMERALD Study Groups: S De Wit, E Florence, L Vandekerckhove, B Vandercam, J Brunetta, M Klein, D Murphy, A Rachlis, S Walmsley, F Ajana, L Cotte, P-M Girard, C Katlama, J-M Molina, I Poizot-Martin, F Raffi, D Rey, J Reynes, E Teicher, Y Yazdanpanah, K Arastéh, M Bickel, J Bogner, S Esser, G Faetkenheuer, H Jessen, W Kern, J Rockstroh, C Spinner, H-J Stellbrink, A Stoehr, A Antinori, F Castelli, A Chirianni, A De Luca, A Di Biagio, M Galli, A Lazzarin, F Maggiolo, R Maserati, C Mussini, A Garlicki, J Gasiorowski, W Halota, A Horban, M Parczewski, A Piekarska, E Belonosova, O Chernova, N Dushkina, V Kulagin, E Ryamova, A Shuldyakov, N Sizova, O Tsybakova, E Voronin, A Yakovlev, A Antela, J R Arribas, J Berenguer, J Casado, V Estrada, M J Galindo, M Garcia Del Toro, J M Gatell, M Gorgolas, F Gutierrez, Mdm Gutierrez, E Negredo, J A Pineda, D Podzamczer, J Portilla Sogorb, A Rivero, R Rubio, P Viciana, I De Los Santos, A Clarke, B G Gazzard, M A Johnson, C Orkin, I Reeves, L Waters, P Benson, L Bhatti, F Bredeek, G Crofoot, D Cunningham, E DeJesus, J Eron, F Felizarta, R Franco, J Gallant, D Hagins, K Henry, D Jayaweera, C Lucasti, C Martorell, C McDonald, J McGowan, A Mills, J Morales-Ramirez, D Prelutsky, M Ramgopal, B Rashbaum, P Ruane, J Slim, A Wilkin, J deVente, S De Wit, E Florence, M Moutschen, E Van Wijngaerden, L Vandekerckhove, B Vandercam, J Brunetta, B Conway, M Klein, D Murphy, A Rachlis, S Shafran, S Walmsley, F Ajana, L Cotte, P-M Girard, C Katlama, J-M Molina, I Poizot-Martin, F Raffi, D Rey, J Reynes, E Teicher, Y Yazdanpanah, J Gasiorowski, W Halota, A Horban, A Piekarska, A Witor, J R Arribas, I Perez-Valero, J Berenguer, J Casado, J M Gatell, F Gutierrez, M J Galindo, Mdm Gutierrez, J A Iribarren, H Knobel, E Negredo, J A Pineda, D Podzamczer, J Portilla Sogorb, F Pulido, C Ricart, A Rivero, I Santos Gil, A Blaxhult, L Flamholc, M Gisslèn, A Thalme, J Fehr, A Rauch, M Stoeckle, A Clarke, B G Gazzard, M A Johnson, C Orkin, F Post, A Ustianowski, L Waters, J Bailey, P Benson, L Bhatti, I Brar, U F Bredeek, C Brinson, G Crofoot, D Cunningham, E DeJesus, C Dietz, R Dretler, J Eron, F Felizarta, C Fichtenbaum, J Gallant, J Gathe, D Hagins, S Henn, K W Henry, G Huhn, M Jain, C Lucasti, C Martorell, C McDonald, A Mills, J Morales-Ramirez, K Mounzer, R Nahass, H Olivet, O Osiyemi, D Prelutsky, M Ramgopal, B Rashbaum, G Richmond, P Ruane, A Scarsella, A Scribner, P Shalit, D Shamblaw, J Slim, K Tashima, G Voskuhl, D Ward, A Wilkin, J de Vente, and Malbec, Odile

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], efficacy, Human immunodeficiency virus (HIV), HIV Infections, darunavir, medicine.disease_cause, VIRALLY SUPPRESSED ADULTS, PLUS LAMIVUDINE, DOUBLE-BLIND, 0302 clinical medicine, INFECTION, Medicine and Health Sciences, Emtricitabine, 030212 general & internal medicine, Darunavir, Emtricitabine tenofovir alafenamide, Alanine, Cobicistat, Single tablet regimen, virus diseases, Viral Load, OPEN-LABEL, 3. Good health, [SDV] Life Sciences [q-bio], Drug Combinations, Infectious Diseases, NON-INFERIORITY, INITIAL TREATMENT, Reverse Transcriptase Inhibitors, Life Sciences & Biomedicine, Tablets, medicine.drug, Adult, TENOFOVIR DISOPROXIL FUMARATE, Anti-HIV Agents, Darunavir/Cobicistat, Immunology, archived RAMs, Tenofovir alafenamide, Drug Administration Schedule, single-tablet regimen, resistance, 03 medical and health sciences, deep sequencing, Virology, Drug Resistance, Viral, medicine, darunavir/cobicistat/emtricitabine/TAF, Humans, Clinical Trials/Clinical Studies, Tenofovir, emtricitabine, DRUG-RESISTANCE, Science & Technology, TREATMENT-NAIVE PATIENTS, business.industry, Adenine, cobicistat, 030104 developmental biology, TAF, HIV-1, business
Abstract

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) ≥400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL

Published
2019
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17. Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe

Author

Moutschen, M., Hofstra, Laura Marije Arije, Sauvageot, Nicolas, Albert, Jan, Alexiev, Ivailo, Garcia, Federico, Struck, Daniel, Van, de Vijver, Åsjö, Birgitta, Beshkov, Danail, Coughlan, Suzie, Descamps, Diane, Griskevicius, Algirdas, Hamouda, Osamah, Horban, Andrzej, Van Kasteren, Marjo, Kolupajeva, Tatjana, Kostrikis, Leontios G., Liitsola, Kirsi, Linka, Marek, Mor, Orna, Nielsen, Claus, Otelea, Dan, Paraskevis, Dimitrios N., Paredes, Roger, Poljak, Mario, Puchhammer-Stöckl, Elisabeth, Sönnerborg, Anders, Staneková, Danica, Stanojevic, Maja, Van Laethem, Kristel, Zazzi, Maurizio, Zidovec Lepej, Snjezana, Boucher, Charles A. B., Schmit, Jean-Claude, Wensing, Annemarie M. J., Puchhammer-Stockl, E., Sarcletti, M., Schmied, B., Geit, M., Balluch, G., Vandamme, A. M., Vercauteren, J., Derdelinckx, I., Sasse, A., Bogaert, M., Ceunen, H., De Roo, A., De Wit, S., Echahidi, F., Fransen, K., Goffard, J. -C, Goubau, P., Goudeseune, E., Yombi, J. -C, Lacor, P., Liesnard, C., Pierard, D., Rens, R., Schrooten, Y., Vaira, D., Vandekerckhove, L. P. R., Van, den Heuvel, Van, Der Gucht, Van Ranst, M., Van Wijngaerden, E., Vandercam, B., Vekemans, M., Verhofstede, C., Clumeck, N., Van Laethem, K., Lepej, S. Z., Begovac, J., Demetriades, Ioannis, Kousiappa, Ioanna, Demetriou, Victoria L., Hezka, Johana, Linka, M., Maly, M., Machala, L., Nielsen, C., Jørgensen, L. B., Gerstoft, J., Mathiesen, L., Pedersen, C., Nielsen, H., Laursen, A., Kvinesdal, B., Liitsola, K., Ristola, M., Suni, J., Sutinen, J., Descamps, D., Assoumou, L., Castor, G., Grude, M., Flandre, P., Storto, A., Hamouda, O., Kücherer, C., Berg, T., Braun, P., Poggensee, G., Däumer, M., Eberle, J., Heiken, H., Kaiser, R., Knechten, H., Korn, K., Müller, H., Neifer, S., Schmidt, B., Walter, H., Gunsenheimer-Bartmeyer, B., Harrer, T., Hatzakis, Angelos E., Zavitsanou, Assimina, Vassilakis, A., Lazanas, Marios C., Chini, Maria C., Lioni, A., Sakka, V., Kourkounti, Sofia, Paparizos, Vassilios A., Antoniadou, Anastasia C., Papadopoulos, Antonios I., Poulakou, Garyphallia G., Katsarolis, I., Protopapas, K., Chryssos, Georgios, Drimis, Stylianos, Gargalianos, Panagiotis, Xylomenos, Georgios, Lourida, G., Psichogiou, Mina A., Daikos, George L., Sipsas, N. V., Kontos, Athanasios N., Gamaletsou, M. N., Koratzanis, Georgios, Sambatakou, H., Mariolis, H., Skoutelis, A., Papastamopoulos, V., Georgiou, O., Panagopoulos, Periklis, Maltezos, E., Coughlan, S., De Gascun, C., Byrne, C., Duffy, M., Bergin, C., Reidy, D., Farrell, G., Lambert, J., O'Connor, E., Rochford, A., Low, J., Coakely, P., O'Dea, S., Hall, W., Mor, O., Levi, I., Chemtob, D., Grossman, Z., Zazzi, M., de Luca, A., Balotta, Claudia, Riva, C., Mussini, C., Caramma, I., Capetti, A., Colombo, M. C., Rossi, C., Prati, F., Tramuto, F., Vitale, F., Ciccozzi, M., Angarano, G., Rezza, G., Kolupajeva, T., Vasins, O., Griskevicius, A., Lipnickiene, V., Schmit, J. C., Struck, D., Hemmer, R., Arendt, V., Michaux, C., Staub, T., Sequin-Devaux, C., Wensing, A. M. J., Boucher, C. A. B., van, de Vijver, van Kessel, A., van Bentum, P. H. M., Brinkman, K., Connell, B. J., van, der Ende, Hoepelman, I. M., van Kasteren, M., Kuipers, M., Langebeek, N., Richter, C., Santegoets, R. M. W. J., Schrijnders-Gudde, L., Schuurman, R., van, de Ven, Kran, A. -M B., Ormaasen, V., Aavitsland, P., Horban, A., Stanczak, J. J., Stanczak, G. P., Firlag-Burkacka, E., Wiercinska-Drapalo, A., Jablonowska, E., Maolepsza, E., Leszczyszyn-Pynka, M., Szata, W., Camacho, Ricardo J., Palma, C., Borges, F., Paixão, T., Duque, V., Araújo, F., Otelea, D., Paraschiv, S., Tudor, A. M., Cernat, R., Chiriac, C., Dumitrescu, F., Prisecariu, L. J., Stanojevic, M., Jevtovic, Dj, Salemovic, D., Stanekova, D., Habekova, M., Chabadová, Z., Drobkova, T., Bukovinova, P., Shunnar, A., Truska, P., Poljak, M., Lunar, M., Babic, Dunja Z., Tomazic, J., Vidmar, L., Vovko, T., Karner, P., Garcia, F., Paredes, R., Monge, S., Moreno, S., del Amo, J., Asensi, V., Sirvent, J. L., de Mendoza, C., Delgado, R., Gutiérrez, F., Berenguer, J., Garcia-Bujalance, S., Stella, Natalia C., de, los Santos, Blanco, J. R., Dalmau, D., Rivero, M., Segura, F., Elıás, Marıá Jesús Pérez, Alvarez, M., Chueca, N., Rodríguez-Martín, C., Vidal, C., Palomares, J. C., Viciana, I., Viciana, P., Cordoba, J., Aguilera, A., Domingo, P., Galindo, M. J., Miralles, C., del Pozo, M. A., Ribera, E., Iribarren, J. A., Ruiz, L., de, la Torre, Vidal, F., Clotet, B., Heidarian, A., Aperia-Peipke, K., Axelsson, M., Mild, M., Karlsson, A., Sönnerborg, A., Thalme, A., Navér, L., Bratt, G., Blaxhult, A., Gisslén, M., Svennerholm, B., Bergbrant, I., Björkman, Per, Säll, C., Mellgren, Å., Lindholm, A., Kuylenstierna, N., Montelius, R., Azimi, F., Johansson, B., Carlsson, M., Johansson, E., Ljungberg, B., Ekvall, H., Strand, A., Mäkitalo, S., Öberg, S., Holmblad, P., Höfer, M., Holmberg, H., Josefson, P., Ryding, U., Van Kessel, A., Clinical sciences, Microbiology and Infection Control, Supporting clinical sciences, Clinicum, Department of Medicine, Virology, Cohorte de Adultos de la Red de Investigación en SIDA, Spain., SPREAD Program, [Hofstra,LM, Sauvageot,N, Struck,D, Schmit,JC ] Luxembourg Institute of Health, Luxembourg. [Hofstra,LM, Wensing,AMJ] Department of Virology, University Medical Center Utrecht, The Netherlands. [Albert,J, Sönnerborg,A] Karolinska Institute, Solna. Karolinska University Hospital, Stockholm, Sweden. [Alexiev,I, Beshkov,D] National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria. [Garcia,F] Complejo Hospitalario Universitario de Granada. Instituto de Investigación IBS Granada, Spain. [Van de Vijver,DAMC, Boucher,CAB] Erasmus MC, University Medical Center, Rotterdam, The Netherlands. [Åsjö,B] University of Bergen, Norway. [Coughlan,S] University College Dublin, Ireland. [Descamps,D] AP-HP Groupe hospitalier Bichat-Claude Bernard. IAME INSERM UMR 1137. Université Paris Diderot Sorbonne Paris Cité, Paris, France. [Griskevicius,A] Lithuanian AIDS Center, Vilnius, Lithuania. [Hamouda,O] Robert Koch Institute, Berlin, Germany. [Horban,A] Hospital of Infectious Diseases, Warsaw, Poland. [Van Kasteren,M] St Elisabeth Hospital, Tilburg, The Netherlands. [Kolupajeva,T] Infectiology Center of Latvia, Riga. [Kostrikis,LG] University of Cyprus, Nicosia. [Liitsola,K] Department of Infectious Diseases, National Institute for Health and Welfare, Helsinki, Finland. [Linka,M] National Reference Laboratory for HIV/AIDS, National Institute of Public Health, Prague, Czech Republic. [Mor,O] National HIV Reference Laboratory, Chaim Sheba Medical Center, Tel-Hashomer, Israel. [Nielsen,C] Statens Serum Institut, Copenhagen, Denmark. [Otelea,D] National Institute for Infectious Diseases 'Prof. dr. Matei Bals', Bucharest, Romania. [Paraskevis,D] National Retrovirus Reference Center, University of Athens, Greece. [Paredes,R] IrsiCaixa Foundation, Badalona, Spain. [Poljak,M] Faculty of Medicine, Slovenian HIV/AIDS Reference Centre, University of Ljubljana, Slovenia. [Puchhammer-Stöckl,E] Medical University Vienna, Austria. [Staneková,D] Slovak Medical University, Bratislava, Slovakia. [Stanojevic,M] Faculty of Medicine, University of Belgrade, Serbia. [Van Laethem,K] Rega Institute for Medical Research, KU Leuven, Belgium. [Zazzi,M] University of Siena, Italy. [Zidovec Lepej,S] University Hospital for Infectious Diseases 'Dr. Fran Mihaljevic', Zagreb, Croatia., This work was supported by a CORE grant of Fond National de la Recherche Luxembourg (grant number C12/BM/4011111–HIV molecular epidemiology in Europe). This work has been partially supported by the European Commission (fifth framework, grant number QLK2-CT-2001-01344, sixth framework, grant number LSHP-CT-2006-518211, DynaNets grant number 233847, seventh framework, CHAIN grant number 223131), Belgium: Belgian AIDS Reference Laboratory Fund, Belgian Fonds voor Wetenschappelijk Onderzoek (grant number G.0692.14), Cyprus: Cyprus Research Promotion Foundation (grant number Health/0104/22), Denmark: Danish AIDS Foundation, France: Agence Nationale de Recherches sur le SIDA et les Hepatites Virales, Germany: Ministry of Health (grant number 1502-686-18), Ministry of Education and Research (grant number 01KI501), Italy: Fifth National Program on HIV/AIDS, Instituto Superiore di Sanità (grant numbers 40F.56 and 20D.1.6), Luxembourg: Fondation Recherche sur le SiDA and Ministry of Health, Republic of Serbia: Ministry of Education and Science (grant number 175024), Slovakia: project 'Center of Excellence of Environmental Health,' ITMS number 26240120033, based on supporting operational research and development program financed from the European Regional Development Fund, and Sweden: Swedish Research Council and Swedish Civil Contingencies Agency., APH - Health Behaviors & Chronic Diseases, Graduate School, Hofstra, LM, Sauvageot, N, Albert, J, Alexiev, I, Garcia, F, Struck, D, Van de Vijver, DA, Åsjö, B, Beshkov, D, Coughlan, S, Descamps, D, Griskevicius, A, Hamouda, O, Horban, A, Van Kasteren, M, Kolupajeva, T, Kostrikis, LG, Liitsola, K, Linka, M, Mor, O, Nielsen, C, Otelea, D, Paraskevis, D, Paredes, R, Poljak, M, Puchhammer-Stöckl, E, Sönnerborg, A, Staneková, D, Stanojevic, M, Van Laethem, K, Zazzi, M, Lepej, SZ, Boucher, CA, Schmit, JC, Wensing, AM, SPREAD program investigators, including Vitale F and Tramuto, F, Vandamme, Annemie, Vercauteren, Jurgen, Schrooten, Yoeri, Van Ranst, Marc, Van Wijngaerden, Eric, Derdelinckx, Inge, Camacho, Ricardo Jorge, Kostrikis, Leontios G. [0000-0002-5340-7109], and Paraskevis, Dimitrios [0000-0001-6167-7152]

Subjects
Male, Human immunodeficiency virus 1, Etravirine, RNA directed DNA polymerase inhibitor, darunavir, HIV Infections, Settore MED/42 - Igiene Generale E Applicata, Disciplines and Occupations::Health Occupations::Medicine::Public Health [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Salud pública, genetics, Inhibidores de proteasas, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Morbidity::Prevalence [Medical Subject Headings], atazanavir, media_common, transmission, Geographicals::Geographic Locations::Europe [Medical Subject Headings], 3. Good health, microbial sensitivity test, priority journal, Europe, HIV-1, antiretroviral therapy, drug resistance, HIV/AIDS, lamivudine, Reverse Transcriptase Inhibitors/pharmacology, anti human immunodeficiency virus agent, Drug, Microbiology (medical), medicine.medical_specialty, antiviral susceptibility, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings], media_common.quotation_subject, 030106 microbiology, HIV Infections/drug therapy, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agents::Anti-Retroviral Agents::Reverse Transcriptase Inhibitors [Medical Subject Headings], Microbial Sensitivity Tests, RILPIVIRINE, Article, EFAVIRENZ, 03 medical and health sciences, transmitted drug resistance, SDG 3 - Good Health and Well-being, Humans, Transmission, human, Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Drug Resistance [Medical Subject Headings], REVERSE-TRANSCRIPTASE INHIBITORS, Rilpivirina, INTEGRASE, MUTATIONS, abacavir, major clinical study, Virology, Infecciones por VIH, Regimen, Antiretroviral therapy, Drug resistance, Medicine (all), Infectious Diseases, chemistry, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Oxazines::Benzoxazines [Medical Subject Headings], Mutation, 0301 basic medicine, nevirapine, Communicable diseases, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Confidence Intervals [Medical Subject Headings], chemistry.chemical_compound, antiviral therapy, INFECTION, Medicine and Health Sciences, Prevalence, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Surveys and Questionnaires [Medical Subject Headings], Viral, Non-U.S. Gov't, Reverse-transcriptase inhibitor, antiretrovirus agent, Research Support, Non-U.S. Gov't, Human immunodeficiency virus infected patient, Middle Aged, virology, PREVALENCE, Encuestas y Cuestionarios, ANTIRETROVIRAL TREATMENT, HIV-1/drug effects, HIV Protease Inhibitors/pharmacology, Rilpivirine, Reverse Transcriptase Inhibitors, Diseases::Immune System Diseases::Immunologic Deficiency Syndromes::HIV Infections [Medical Subject Headings], Female, HIV drug resistance, medicine.drug, Adult, Human immunodeficiency virus proteinase inhibitor, Chemicals and Drugs::Organic Chemicals::Nitriles::Rilpivirine [Medical Subject Headings], Efavirenz, Anti-HIV Agents, Research Support, Resistencia a medicamentos, Settore MED/17 - MALATTIE INFETTIVE, antiviral resistance, Internal medicine, Anti-HIV Agents/pharmacology, Drug Resistance, Viral, Journal Article, medicine, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protease Inhibitors [Medical Subject Headings], abacavir plus lamivudine, Europa (Continente), HIV Protease Inhibitors, emtricitabine, nonhuman, Intervalos de confianza, Mutación, business.industry, HIV, prediction, Inhibidores de la transcriptasa inversa, Human immunodeficiency virus 1 infection, tenofovir, INDIVIDUALS, Drug Resistance, Viral/genetics, Benzoxazinas, ETRAVIRINE, drug effects, 3121 General medicine, internal medicine and other clinical medicine, Prevalencia, business
Abstract

Transmitted human immunodeficiency virus drug resistance in Europe is stable at around 8%. The impact of baseline mutation patterns on susceptibility to antiretroviral drugs should be addressed using clinical guidelines. The impact on baseline susceptibility is largest for nonnucleoside reverse transcriptase inhibitors., Background. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. Methods. Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)–infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. Results. The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%–9.5%) in 2008–2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. Conclusions. Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected.

Published
2016
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18. Increase in transmitted resistance to non-nucleoside reverse transcriptase inhibitors among newly diagnosed HIV-1 infections in Europe

Author

Moutschen, M., Frentz, D., Van de Vijver, D. A. M. C., Abecasis, A. B., Albert, Jan, Hamouda, O., Jørgensen, L. B., Ku¨cherer, C., Struck, D., Schmit, J. -C, Vercauteren, J., A˚sjo¨, B., Balotta, Claudia, Beshkov, Danail, Camacho, Ricardo J., Clotet, B., Coughlan, S., Griskevicius, A., Grossman, Z., Horban, A., Kolupajeva, T., Korn, K., Kostrikis, Leontios G., Liitsola, K., Linka, M., Nielsen, C., Otelea, D., Paraskevis, Dimitrios N., Paredes, R., Poljak, M., Puchhammer, Stockl E., So¨nnerborg, A., Stanekova, D., Stanojevic, M., Van Wijngaerden, E., Wensing, A. M. J., Boucher, C. A. B., Sarcletti, M., Schmied, B., Geit, M., Balluch, G., Vandamme, A. -M, Derdelinckx, I., Sasse, A., Bogaert, M., Ceunen, H., De Roo, A., De Wit, S., Echahidi, F., Fransen, K., Goffard, J. -C, Goubau, P., Goudeseune, E., Yombi, J. -C, Lacor, P., Liesnard, C., Pierard, D., Rens, R., Schrooten, Y., Vaira, D., Vandekerckhove, L. P. R., Van den Heuvel, A., Van Der Gucht, B., Van Ranst, M., Vandercam, B., Vekemans, M., Verhofstede, C., Clumeck, N., Van Laethem, K., Demetriades, Ioannis, Kousiappa, Ioanna, Demetriou, Victoria L., Hezka, Johana, Bruckova, M., Machala, L., Gerstoft, J., Mathiesen, L., Pedersen, C., Nielsen, H., Laursen, A., Kvinesdal, B., Salminen, M., Ristola, M., Suni, J., Sutinen, J., Berg, T., Braun, P., Poggensee, G., Da¨umer, M., Eberle, J., Heiken, H., Kaiser, R., Knechten, H., Mu¨ller, H., Neifer, S., Schmidt, B., Walter, H., Gunsenheimer-Bartmeyer, B., Harrer, T., Hatzakis, Angelos E., Magiorkinis, Emmanouil N., Hatzitheodorou, Eleni, Haida, Catherine, Zavitsanou, Assimina, Magiorkinis, Gkikas, Lazanas, Marios C., Chini, Maria C., Magafas, N., Tsogas, Nickolaos, Paparizos, Vassilios A., Kourkounti, Sofia, Antoniadou, Anastasia C., Papadopoulos, Antonios I., Panagopoulos, Periklis, Poulakou, Garyphallia G., Sakka, V., Chryssos, Georgios, Drimis, Stylianos, Gargalianos, Panagiotis, Lelekis, Moyssis I., Chilomenos, G., Psichogiou, Mina A., Daikos, George L., Panos, George, Haratsis, G., Kordossis, Theodore, Kontos, Athanasios N., Koratzanis, Georgios, Theodoridou, Maria C., Mostrou, Glykeria J., Spoulou, Vana I., De Gascun, C., Byrne, C., Duffy, M., Bergin, C., Reidy, D., Farrell, G., Lambert, J., O'Connor, E., Rochford, A., Low, J., Coakely, P., O'Dea, S., Hall, W., Levi, I., Chemtob, D., Riva, C., Mussini, C., Caramma, I., Capetti, A., Colombo, M. C., Rossi, C., Prati, F., Tramuto, F., Vitale, F., Ciccozzi, M., Angarano, G., Rezza, G., Schmit, J. C., Hemmer, R., Arendt, V., Staub, T., Schneider, F., Roman, F., van Kessel, A., van Bentum, P. H. M., Brinkman, K., op de Coul, E. L., van der Ende, M. E., Hoepelman, I., van Kasteren, M., Juttmann, J., Kuipers, M., Langebeek, N., Richter, C., Santegoets, R., Schrijnders-Gudde, L., Schuurman, R., van de Ven, B. J. M., Ormaasen, V., Aavitsland, P., Stanczak, J. J., Stanczak, G. P., Firlag-Burkacka, E., Wiercinska-Drapalo, A., Jablonowska, E., Malolepsza, E., Leszczyszyn-Pynka, M., Szata, W., Palma, C., Borges, F., Paixa&tild, o, T., Duque, V., Araújo, F., Jevtovic, D., Salemovic, D., Habekova, M., Mokráš, Miloš, Truska, P., Lunar, M., Babic, Dunja Z., Tomazic, J., Vidmar, L., Vovko, T., Karner, P., Domingo, P., Galindo, M. J., Miralles, C., del Pozo, M. A., Ribera, E., Iribarren, J. A., Ruiz, L., de la Torre, J., Vidal, F., Garcia, F., Heidarian, A., Aperia-Peipke, K., Axelsson, M., Mild, M., Karlsson, A., Thalme, A., Nave´r, L., Bratt, G., Blaxhult, A., Gissle´n, M., Svennerholm, B., Bergbrant, I., Björkman, Per, Sa¨ll, C., Mellgren, A˚, Lindholm, A., Kuylenstierna, N., Montelius, R., Azimi, F., Johansson, B., Carlsson, M., Johansson, E., Ljungberg, B., Ekvall, H., Strand, A., Ma¨kitalo, S., o¨berg, S., Holmblad, P., Ho¨fer, M., Holmberg, H., Josefson, P., Ryding, U., Van Kessel, A., Kostrikis, Leontios G. [0000-0002-5340-7109], Paraskevis, Dimitrios [0000-0001-6167-7152], Virology, Erasmus MC other, Frentz, Dineke, Van de Vijver, David A.M.C., Abecasis, Ana B., Albert, Jan, Hamouda, Osamah, Jørgensen, Louise B., Ku¨cherer, Claudia, Struck, Daniel, Schmit, Jean-Claude, Vercauteren, Jurgen, A˚sjo¨, Birgitta, Balotta, Claudia, Beshkov, Danail, Camacho, Ricardo J., Clotet, Bonaventura, Coughlan, Suzie, Griskevicius, Algirda, Grossman, Zehava, Horban, Andrzej, Kolupajeva, Tatjana, Korn, Klau, Kostrikis, Leondios G., Liitsola, Kirsi, Linka, Marek, Nielsen, Clau, Otelea, Dan, Paraskevis, Dimitrio, Paredes, Roger, Poljak, Mario, Puchhammer-Sto¨ckl, Elisabeth, So¨nnerborg, Ander, Stanekova, Danica, Stanojevic, Maja, Van Wijngaerden, Eric, Wensing, Annemarie M.J., Boucher, Charles A.B., SPREAD programme investigators, including Vitale F and Tramuto F., Graduate School, UCL - SSS/IREC/MBLG - Pôle de Microbiologie médicale, UCL - (SLuc) Service de microbiologie, UCL - (SLuc) Service de médecine interne générale, UCL - (SLuc) Service d'hématologie, Clinicum, and Department of Medicine

Subjects
Male, virus strain, Resistance, HIV Infections, Drug resistance, THERAPY, Nucleoside Reverse Transcriptase Inhibitor, ANTIRETROVIRAL DRUG-RESISTANCE, 0302 clinical medicine, Medical microbiology, Genotype, Medicine and Health Sciences, Prevalence, HIV Infection, 030212 general & internal medicine, UNITED-KINGDOM, Phylogeny, 0303 health sciences, Communicable disease, Transmission (medicine), adult, virus mutation, UPDATED RECOMMENDATIONS, virus transmission, 3. Good health, Europe, Infectious Diseases, female, risk factor, virus resistance, Female, NAIVE PATIENTS, SOCIETY-USA PANEL, Research Article, Human, Adult, medicine.medical_specialty, Anti-HIV Agents, Virus, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, male, MOLECULAR EPIDEMIOLOGY, Drug Resistance, Viral, medicine, proteinase inhibitor, Humans, Transmission, controlled study, human, molecular phylogeny, 030304 developmental biology, nonhuman, MUTATIONS, business.industry, Anti-HIV Agent, nucleotide sequence, nonnucleoside reverse transcriptase inhibitor, Human immunodeficiency virus 1 infection, Virology, major clinical study, unindexed sequence, Parasitology, 3121 General medicine, internal medicine and other clinical medicine, Mutation, HIV-1, business
Abstract

Background: One out of ten newly diagnosed patients in Europe was infected with a virus carrying a drug resistant mutation. We analysed the patterns over time for transmitted drug resistance mutations (TDRM) using data from the European Spread program.Methods: Clinical, epidemiological and virological data from 4317 patients newly diagnosed with HIV-1 infection between 2002 and 2007 were analysed. Patients were enrolled using a pre-defined sampling strategy.Results: The overall prevalence of TDRM in this period was 8.9% (95% CI: 8.1-9.8). Interestingly, significant changes over time in TDRM caused by the different drug classes were found. Whereas nucleoside resistance mutations remained constant at 5%, a significant decline in protease inhibitors resistance mutations was observed, from 3.9% in 2002 to 1.6% in 2007 (p = 0.001). In contrast, resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) doubled from 2.0% in 2002 to 4.1% in 2007 (p = 0.004) with 58% of viral strains carrying a K103N mutation. Phylogenetic analysis showed that these temporal changes could not be explained by large clusters of TDRM.Conclusion: During the years 2002 to 2007 transmitted resistance to NNRTI has doubled to 4% in Europe. The frequent use of NNRTI in first-line regimens and the clinical impact of NNRTI mutations warrants continued monitoring. © 2014 Frentz et al. licensee BioMed Central Ltd. 14 Cited By :16

Published
2014

19. Trends and predictors of transmitted drug resistance (TDR) and clusters with TDR in a local Belgian HIV-1 epidemic

Author

Pineda-Peña, A. -C, Schrooten, Y., Vinken, L., Ferreira, F., Li, G., Trovão, N. S., Khouri, R., Derdelinckx, I., De Munter, P., Kuc̈herer, C., Kostrikis, Leontios G., Nielsen, C., Littsola, K., Wensing, A., Stanojevic, M., Paredes, R., Balotta, Claudia, Albert, Jan, Boucher, C., Gomez-Lopez, A., Van Wijngaerden, E., Van Ranst, M., Vercauteren, J., Vandamme, A. M., Van Laethem, K., Kostrikis, Leontios G. [0000-0002-5340-7109], López-Galíndez, Cecilio, Erasmus MC other, and Virology

Subjects
Male, Epidemiology, Human immunodeficiency virus type 1 subtype B, Drug Resistance, Human immunodeficiency virus 1, Proteinase Inhibitor, Anti-Hiv Agents, HIV Infections, Men Who Have Sex With Men, Men who have sex with men, Immunodeficiency Viruses, Belgium, Pregnancy, Salud pública, Trend Study, Medicine, Epidemias, Phylogeny, education.field_of_study, Health Survey, 3. Good health, Transmitted Drug Resistance, Medical Microbiology, HIV epidemiology, Viral Pathogens, Cohort, Infection, Viral load, Human, medicine.medical_specialty, Genotype, Science, HIV prevention, Epidemic, Microbial Sensitivity Tests, Disease Surveillance, Microbiology, Article, SDG 3 - Good Health and Well-being, Genetics, Humans, Transmission, Risk factor, education, Microbial Pathogens, Retrospective Studies, Aged, Medicine and health sciences, Preventive medicine, Biology and Life Sciences, Public and occupational health, Immunology, Virus 1 Infection, HIV-1, Viral Diseases, Anti Human Immunodeficiency Virus Agent, Drug resistance, 1 Subtype B, Risk Factors, Prevalence, Cluster Analysis, Public Health Surveillance, Virus Transmission, Viral, Univariate analysis, Multidisciplinary, Microbial Sensitivity Test, Hiv Infections, HIV diagnosis and management, Middle Aged, Infectious Diseases, young adult, Female, Sequence Analysis, Cohort Analysis, Research Article, Antiviral Resistance, Adult, Rna Directed Dna Polymerase Inhibitor, Anti-HIV Agents, Disease Association, Population, Major Clinical Study, Drug Effects, Resistencia a medicamentos, Young Adult, Retrospective Study, Internal medicine, Immunodeficiency Virus Type, Virology, Drug Resistance, Viral, business.industry, Risk Factor, HIV, Gender, Human immunodeficiency virus 1 infection, Confidence interval, Diagnostic medicine, Virus Load, business, Prediction
Abstract

We aimed to study epidemic trends and predictors for transmitted drug resistance (TDR) in our region, its clinical impact and its association with transmission clusters. We included 778 patients from the AIDS Reference Center in Leuven (Belgium) diagnosed from 1998 to 2012. Resistance testing was performed using population-based sequencing and TDR was estimated using the WHO-2009 surveillance list. Phylogenetic analysis was performed using maximum likelihood and Bayesian techniques. The cohort was predominantly Belgian (58.4%), men who have sex with men (MSM) (42.8%), and chronically infected (86.5%). The overall TDR prevalence was 9.6% (95% confidence interval (CI): 7.7-11.9), 6.5% (CI: 5.0-8.5) for nucleoside reverse transcriptase inhibitors (NRTI), 2.2% (CI: 1.4-3.5) for non-NRTI (NNRTI), and 2.2% (CI: 1.4-3.5) for protease inhibitors. A significant parabolic trend of NNRTI-TDR was found (p = 0.019). Factors significantly associated with TDR in univariate analysis were male gender, Belgian origin, MSM, recent infection, transmission clusters and subtype B, while multivariate and Bayesian network analysis singled out subtype B as the most predictive factor of TDR. Subtype B was related with transmission clusters with TDR that included 42.6% of the TDR patients. Thanks to resistance testing, 83% of the patients with TDR who started therapy had undetectable viral load whereas half of the patients would likely have received a suboptimal therapy without this test. In conclusion, TDR remained stable and a NNRTI up-and-down trend was observed. While the presence of clusters with TDR is worrying, we could not identify an independent, non-sequence based predictor for TDR or transmission clusters with TDR that could help with guidelines or public health measures. ispartof: PLoS One vol:9 issue:7 ispartof: location:United States status: published

Published
2014

20. Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients

Author

Moutschen, M., Theys, K., Deforche, K., Vercauteren, J., Libin, P., van de Vijver, D. A. M. C., Albert, Jan, Åsjö, Birgitta, Balotta, Claudia, Bruckova, M., Camacho, Ricardo J., Clotet, B., Coughlan, S., Grossman, Z., Hamouda, O., Horban, A., Korn, K., Kostrikis, Leontios G., Kücherer, C., Nielsen, C., Paraskevis, Dimitrios N., Poljak, M., Puchhammer-Stockl, E., Riva, C., Ruiz, L., Liitsola, K., Schmit, J. -C, Schuurman, R., Sönnerborg, A., Stanekova, D., Stanojevic, M., Struck, D., Van Laethem, K., Wensing, A. M. J., Boucher, C. A. B., Vandamme, A. M., Sarcletti, M., Schmied, B., Geit, M., Balluch, G., Derdelinckx, I., Sasse, A., Bogaert, M., Ceunen, H., De Roo, A., De Wit, S., Echahidi, F., Fransen, K., Goffard, J. -C, Goubau, P., Goudeseune, E., Yombi, J. -C, Lacor, P., Liesnard, C., Pierard, D., Rens, R., Schrooten, Y., Vaira, D., Van den Heuvel, A., Van Der Gucht, B., Van Ranst, M., Van Wijngaerden, E., Vandercam, B., Vekemans, M., Verhofstede, C., Clumeck, N., Demetriades, Ioannis, Kousiappa, Ioanna, Demetriou, Victoria L., Hezka, Johana, Linka, M., Machala, L., Jrgensen, L. B., Gerstoft, J., Mathiesen, L., Pedersen, C., Nielsen, H., Laursen, A., Kvinesdal, B., Ristola, M., Suni, J., Sutinen, J., K̈ucherer, C., Berg, T., Braun, P., Poggensee, G., Däumer, M., Eberle, J., Heiken, H., Kaiser, R., Knechten, H., Müller, H., Neifer, S., Schmidt, B., Walter, H., Gunsenheimer-Bartmeyer, B., Harrer, T., Hatzakis, Angelos E., Magiorkinis, Emmanouil N., Hatzitheodorou, Eleni, Issaris, C., Haida, Catherine, Zavitsanou, Assimina, Magiorkinis, Gkikas, Lazanas, Marios C., Chini, Maria C., Magafas, N., Tsogas, Nickolaos, Paparizos, Vassilios A., Kourkounti, Sofia, Antoniadou, Anastasia C., Papadopoulos, Antonios I., Panagopoulos, Periklis, Poulakou, Garyphallia G., Sakka, V., Chryssos, Georgios, Drimis, Stylianos, Gargalianos, Panagiotis, Lelekis, Moyssis I., Xilomenos, G., Psichogiou, Mina A., Daikos, George L., Panos, George, Haratsis, G., Kordossis, Theodore, Kontos, Athanasios N., Koratzanis, Georgios, Theodoridou, Maria C., Mostrou, Glykeria J., Spoulou, Vana I., Hall, W., De Gascun, C., Byrne, C., Duffy, M., Bergin, C., Reidy, D., Farrell, G., Lambert, J., O'Connor, E., Rochford, A., Low, J., Coakely, P., Levi, I., Chemtob, D., Mussini, C., Caramma, I., Capetti, A., Colombo, M. C., Rossi, C., Prati, F., Tramuto, F., Vitale, F., Ciccozzi, M., Angarano, G., Rezza, G., Schmit, J. C., Hemmer, R., Arendt, V., Staub, T., Schneider, F., Roman, F., van Bentum, P. H. M., Brinkman, K., op de Coul, E. L., van der Ende, M. E., Hoepelman, I. M., van Kasteren, M., Juttmann, J., Kuipers, M., Langebeek, N., Richter, C., Santegoets, R. M. W. J., Schrijnders-Gudde, L., van de Ven, B. J. M., Ormaasen, V., Aavitsland, P., Stanczak, J. J., Stanczak, G. P., Firlag-Burkacka, E., Wiercinska-Drapalo, A., Jablonowska, E., Malolepsza, E., Leszczyszyn-Pynka, M., Szata, W., Palma, C., Borges, F., Paix̃ao, T., Duque, V., Araújo, F., Jevtovic, D. J., Salemovic, D., Habekova, M., Mokráš, Miloš, Truska, P., Babic, Dunja Z., Tomazic, J., Vidmar, L., Karner, P., Gutíerrez, C., deMendoza, C., Erkicia, I., Domingo, P., Camino, X., Galindo, M. J., Blanco, J. L., Leal, M., Masabeu, A., Guelar, A., Llibre, J. M., Margall, N., Iribarren, J. A., Gutierrez, S., Baldov́i, J. F., Pedreira, J. D., Gatell, J. M., Moreno, S., de Mendoza, C., Soriano, V., Blaxhult, A., Heidarian, A., Karlsson, A., Aperia-Peipke, K., Bergbrant, I. -M, Gissĺen, M., Svennerholm, M., Björkman, Per, Bratt, G., Carlsson, M., Ekvall, H., Ericsson, M., Ḧofer, M., Johansson, B., Sonnerb̈org, A., Kuylenstierna, N., Ljungberg, B., Mäkitalo, S., Strand, A., Öberg, S., Virology, Erasmus MC other, Van Wijngaerden, Eric, Clinicum, Department of Medicine, Infektiosairauksien yksikkö, Centro de Malária e outras Doenças Tropicais (CMDT), Graduate School, Kostrikis, Leontios G. [0000-0002-5340-7109], Paraskevis, Dimitrios [0000-0001-6167-7152], UCL - SSS/IREC/MBLG - Pôle de Microbiologie médicale, UCL - (SLuc) Service de microbiologie, UCL - (SLuc) Service de médecine interne générale, Theys, K, Deforche, K, Vercauteren, J, Libin, P, van de Vijver, DA, Albert, J, Asjö, B, Balotta, C, Bruckova, M, Camacho, RJ, Clotet, B, Coughlan, S, Grossman, Z, Hamouda, O, Horban, A, Korn, K, Kostrikis, LG, Kücherer, C, Nielsen, C, Paraskevis, D, Poljak, M, Puchhammer Stockl, E, Riva, C, Ruiz, L, Liitsola, K, Schmit, JC, Schuurman, R, Sönnerborg, A, Stanekova, D, Stanojevic, M, Struck, D, Van Laethem, K, Wensing, AM, Boucher, CA, Vandamme, AM, Tramuto, F, and Vitale, F

Subjects
Adult, Male, lcsh:Immunologic diseases. Allergy, Anti-HIV Agents, education, Virulence, HIV Infections, Drug resistance, Biology, Settore MED/42 - Igiene Generale E Applicata, Virus, polymorphism, 03 medical and health sciences, Viral Proteins, SDG 3 - Good Health and Well-being, Virology, Genotype, Drug Resistance, Viral, drug-naive, medicine, Humans, Prospective Studies, 030304 developmental biology, 0303 health sciences, Polymorphism, Genetic, 030306 microbiology, Research, protease, Viral Load, Reverse transcriptase, 3. Good health, CD4 Lymphocyte Count, Drug-naïve, Infectious Diseases, 3121 General medicine, internal medicine and other clinical medicine, Immunology, biology.protein, HIV-1, Female, Antibody, lcsh:RC581-607, Viral load, HIV-1 infected patient, medicine.drug, Peptide Hydrolases
Abstract

Background: The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore expected to revert quickly. Compensatory mutations, often already polymorphic in wild-type viruses, do not tend to revert after transmission. While compensatory mutations increase fitness during treatment, their presence may also modulate viral fitness and virulence in absence of therapy and major resistance mutations. We previously designed a modeling technique that quantifies genotypic footprints of in vivo treatment selective pressure, including both drug resistance mutations and polymorphic compensatory mutations, through the quantitative description of a fitness landscape from virus genetic sequences. Results: Genotypic correlates of viral load and CD4 cell count were evaluated in subtype B sequences from recently diagnosed treatment-naive patients enrolled in the SPREAD programme. The association of surveillance drug resistance mutations, reported compensatory mutations and fitness estimated from drug selective pressure fitness landscapes with baseline viral load and CD4 cell count was evaluated using regression techniques. Protease genotypic variability estimated to increase fitness during treatment was associated with higher viral load and lower CD4 cell counts also in treatment-naive patients, which could primarily be attributed to well-known compensatory mutations at highly polymorphic positions. By contrast, treatment-related mutations in reverse transcriptase could not explain viral load or CD4 cell count variability. Conclusions: These results suggest that polymorphic compensatory mutations in protease, reported to be selected during treatment, may improve the replicative capacity of HIV-1 even in absence of drug selective pressure or major resistance mutations. The presence of this polymorphic variation may either reflect a history of drug selective pressure, i.e. transmission from a treated patient, or merely be a result of diversity in wild-type virus. Our findings suggest that transmitted drug resistance has the potential to contribute to faster disease progression in the newly infected host and to shape the HIV-1 epidemic at a population level. ispartof: Retrovirology vol:9 issue:1 ispartof: location:England status: published

Published
2012

21. 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

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