bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patterns of drug resistance among newly diagnosed HIV‐1 infected patients in Greece during the last decade: the crucial role of transmission networks
Authors: Paraskevis Dimitrios , Zavitsanou Assimina , Magiorkinis Emmanouil , Gargalianos Panagiotis , Xylomenos Georgios , Lazanas Marios , Chini Maria , Skoutelis Athanasios , Papastamopoulos Vasileios , Antoniadou Anastasia , Papadopoulos Antonios , Psichogiou Mina , Daikos Georgios , Vassilakis Alexis , Chrysos Georgios , Paparizos Vasilis , Kourkounti Sofia , Sambatakou Helen , Kordossis Theodoros , Koratzanis Georgios , Panagopoulos Periklis , Maltezos Evangelos , Drimis Stylianos , Hatzakis Angelos 
Published: November 2014

IntroductionThe prevalence of drug resistance is approximately 10% in Europe and North America among newly infected patients. We aim to investigate the temporal patterns of resistance among drug naive HIV‐infected individuals in Greece and also to determine transmission networking among those with resistant strains.Materials and MethodsProtease (PR) and partial reverse transcriptase (RT) sequences were determined from 2499 newly diagnosed HIV‐1 patients, in Greece, during 2003–2013. Genotypic drug resistance was estimated using the HIVdb: Genotypic Resistance Interpretation Algorithm. We identified transmission clusters of resistant strains on the basis of a large collection of HIV‐1 sequences from 4024 seropositives in Greece. Phylodynamic analysis was performed using a Bayesian method.ResultsWe estimated drug resistance levels among naïve patients on the basis of all resistance mutations in PR and partial RT. The overall prevalence of resistance was 19.6% (490/2499). Resistance to NNRTIs was the most common (397/2499, 15.9%) followed by PIs (116/2499, 4.6%) and NRTIs (79/2499, 3.2%). We found a significant trend for decreasing resistance to NRTIs over time (6.7%–1.6%). There was no time trend for the overall PI and NNRTI resistance. The most frequently observed major resistant sites in PR were V82 (2.0%) and L90 (1.8%). In RT, we found E138 (58.6%), K103 (13.1%), V179 (8.4%) and T215 (7.1%), M41 (4.7%) associated with resistance to NNRTIs and NRTIs, respectively. The prevalence of K103N and E138Q were significantly increased during 2003–2013. Crucially, we found that both K103N, E138Q are associated with transmission networking within men having sex with men (MSM) and intravenous drug user (IDU) local networks. The K103N network included seropositives across Greece, while the latter only from the recent IDU outbreak in Athens metropolitan area (1). Phylodynamic analyses revealed that the exponential growth for K103N network started in 2009 (Figure 1) and for the E138Q in 2010.ConclusionsThe overall resistance has been stable in Greece over time; however, specific NNRTI resistance patterns are increasing. Notably, they are associated with local transmission networking, thus suggesting that this is the cause for the increased patterns of NNRTI resistance and not multiple transmissions of resistant strains from different sources among treated individuals. Our study highlights the advance of molecular epidemiology for understanding the dynamics of resistance.
Improved therapy‐success prediction with GSS estimated from clinical HIV‐1 sequences
Authors: Pironti Alejandro , Pfeifer Nico , Kaiser Rolf , Walter Hauke , Lengauer Thomas 
Published: November 2014

IntroductionRules‐based HIV‐1 drug‐resistance interpretation (DRI) systems disregard many amino‐acid positions of the drug's target protein. The aims of this study are (1) the development of a drug‐resistance interpretation system that is based on HIV‐1 sequences from clinical practice rather than hard‐to‐get phenotypes, and (2) the assessment of the benefit of taking all available amino‐acid positions into account for DRI.Materials and MethodsA dataset containing 34,934 therapy‐naïve and 30,520 drug‐exposed HIV‐1 pol sequences with treatment history was extracted from the EuResist database and the Los Alamos National Laboratory database. 2,550 therapy‐change‐episode baseline sequences (TCEB) were assigned to test set A. Test set B contains 1,084 TCEB from the HIVdb TCE repository. Sequences from patients absent in the test sets were used to train three linear support vector machines to produce scores that predict drug exposure pertaining to each of 20 antiretrovirals: the first one uses the full amino‐acid sequences (DEfull), the second one only considers IAS drug‐resistance positions (DEonlyIAS), and the third one disregards IAS drug‐resistance positions (DEnoIAS). For performance comparison, test sets A and B were evaluated with DEfull, DEnoIAS, DEonlyIAS, geno2pheno[resistance], HIVdb, ANRS, HIV‐GRADE, and REGA. Clinically‐validated cut‐offs were used to convert the continuous output of the first four methods into susceptible‐intermediate‐resistant (SIR) predictions. With each method, a genetic susceptibility score (GSS) was calculated for each therapy episode in each test set by converting the SIR prediction for its compounds to integer: S=2, I=1, and R=0. The GSS were used to predict therapy success as defined by the EuResist standard datum definition. Statistical significance was assessed using a Wilcoxon signed‐rank test.ResultsA comparison of the therapy‐success prediction performances among the different interpretation systems for test set A can be found in Table 1, while those for test set B are found in Figure 1. Therapy‐success prediction of first‐line therapies with DEnoIAS performed better than DEonlyIAS (p<10–16).ConclusionsTherapy success prediction benefits from the consideration of all available mutations. The increase in performance was largest in first‐line therapies with transmitted drug‐resistance mutations.
Transmitted antiretroviral drug resistance in treatment naïve HIV‐infected persons in London in 2011 to 2013
Authors: McFaul Katie , Lim Charlotte , Jones Rachael , Asboe David , Pozniak Anton , Sonecha Sonali , Boffito Marta , Nwokolo Nneka 
Published: November 2014

IntroductionPreviously published UK data on HIV transmitted drug resistance (TDR) shows that it ranges between 3 and 9.4% [1,2]. However, there are no recent data from populations where HIV transmission rates are increasing. The aim of this study was to assess the prevalence of TDR in untreated HIV‐infected individuals attending three HIV specialist clinics under the HIV Directorate, Chelsea and Westminster Hospital and based throughout London – the Kobler Clinic, 56 Dean Street and West London Centre for Sexual Health.MethodsWe included all patients with a HIV diagnosis, no history of antiretroviral therapy (ART) intake, attending one of the three clinics (Kobler (K), 56 Dean Street (DS) and West London (WL)), between 2011 and 2013 who started antiretrovirals. Reverse transcriptase (RT) and protease region sequencing was performed using Vircotype virtual phenotype resistance analysis. Drug resistance mutations were identified according to Stanford University HIV Drug Resistance Database (http://hivdb.stanford.edu/).ResultsAmong 1705 HIV‐1‐infected patients enrolled in the study, 1252 were males (919 were MSM), 107 were females and 346 had no gender recorded. Ethnicity was 51.1% white British/Irish/other, 6.1% African, 2.1% Caribbean, 2.8% Asian, 1.3% Indian/Pakistani/Bangladeshi, 4.2%, other, 3.2% not stated, and 29.2% unknown. 547 were from K (84.3% males, 48.3% MSM), 826 were from DS (84.3% males, 71.9% MSM), and 109 from WL (87.2% males, 56.0% MSM), 223 from other sites not specified. 77.5% (1321 of 1705) of patients had baseline viral resistance testing performed. Prevalence of primary resistance in those with a baseline viral resistance test was 13.5% overall: 19.3% in K, 14.9% in DS, and 14.7% in WL. The most common mutations detected were: NRTI: 184V, 215F, 41L; NNRTI 103N, 179D, 90I; PI 90M, 46I, and 82A. Among patients who tested with TDR, 79.1% had one single mutation, 18.7% and 2.2% exhibited dual or triple class‐resistant viruses, respectively.ConclusionsThis study across a large HIV Medicine Directorate reported an overall TDR prevalence which is higher than that previously published and with significant rates of NNRTI resistance at baseline.
Resistance remains a problem in treatment failure
Authors: Obermeier Martin , Ehret Robert , Wienbreyer Andreas , Walter Hauke , Berg Thomas , Baumgarten Axel 
Published: November 2014

IntroductionProven resistance against HIV drugs, either by phenotyping or genotyping is a rare event in clinical trials. The overall assumption of drug resistance disappearing is additionally driven by the recommendations to screen for transmitted drug resistance, leading to large numbers of examinations with relatively low rates of resistance. Goal of our analysis was to assess if drug resistance in treatment failure is also decreasing outside of clinical trials.Materials and MethodsThe MIB database at timepoint of analysis consists of data from 2876 HIV infected patients. Besides various laboratory parameters, clinical data and treatment history is included. HIV‐1 protease and reverse transcriptase sequences were analyzed using the HIV‐GRADE drug resistance algorithm. As in only a small number of patients genotypic resistance testing for integrase inhibitors was performed, mainly due to reimbursement reasons, it was assumed that failing treatment on a previous integrase inhibitor containing regimen is equate to resistance.ResultsOf the 2876 patients in the database, 220 had a treatment change due to treatment failure between 2009 and 2012, a genotypic resistance testing at an appropriate timepoint of maximum four weeks before treatment change and a treatment duration of at least six months before treatment failure. In 2009, 61% of patients showed no drug resistance while 39% showed resistance against one or more drug classes (two or more drug classes: 19.5%; three or more drug classes: 2.4%, four drug classes 2.4%). In 2012, no resistance was found in 52% of patients while resistance against three or more drug classes was found in nearly 14% of patients (one or more: 48%; two or more 23%; four classes: 4.5%).ConclusionsTreatment failure with viral load sufficiently high for drug resistance testing was not frequently observed in our database. Nevertheless, treatment failure was often associated with drug resistance against at least one drug class. With more use of the newer drug classes, resistance against those new classes will become more common and rates of multiclass resistance will be increasing.
Potential drug–drug interactions in HIV‐perinatally infected adolescents on antiretroviral therapy in Buenos Aires, Argentina
Authors: Cordova Ezequiel , Cecchini Diego , Rodriguez Claudia 
Published: November 2014

IntroductionAn increasing number of treatment‐experienced perinatally HIV‐infected adolescents (PHA) are being transitioned from paediatric centres to adult HIV‐care [1]. Most of them had been heavily exposed to antiretroviral drugs (ARVs), harbour drug‐resistant viruses and require non‐antiretroviral medication due to comorbidities [2]. This may predispose for clinically significant drug–drug interactions (CSDDIs) [3]. There are no studies concerning CSDDIs in PHA. We aimed to evaluate the prevalence of concomitant medications and CSDDIs in PHA who were transitioned for adult HIV‐care to the Infectious Diseases Unit, Cosme Argerich Hospital, Buenos Aires City, Argentina.Materials and MethodsDescriptive pilot cross‐sectional study (March to June 2014). PHA under ARVs at the time of the study were assessed for concomitant medication. CSDDIs were screened and categorized using the University of Liverpool Drug Interactions Program (www.hiv‐druginteractions.org) [4].ResultsForty‐five patients were included. Female sex: 53%. Median (IQR) age: 20 years (18–22). CDC‐stage C was observed in 27 (79%); 50% had ≥1 comorbidities including 3 with HCV co‐infection. Drug abuse was observed in 6 (13%). The median of prior ARV regimens was 3 (3–5). Current ARV regimen included: PI: 87%, NNRTI: 27%, INSTI: 20%, enfuvirtide: 7% and CCR5 inhibitor: 4%. Median CD4 T‐cell count: 568 cells/mL (279–771). Viral load <50 copies/mL: 80%. Sixty percent (27/45) had ≥1 co‐medications (median 1). The most frequent co‐medications were NSAIDs (40%), hormonal therapy (19%) and antimicrobials (19%). Use of herbal supplements was observed in 10 (22%). Overall, 23 (51%) had ≥ 1 CSDDIs: 19/27 (70%) with co‐medication (orange flag=18 and red flag=1); and 2/10 (20%) with herbal supplements. ARV–ARV interactions were observed in 4/45 (9%): unboosted atazanavir+tenofovir (n=2), unboosted atazanavir+efavirenz (n=1) and lopinavir/ritonavir+efavirenz (n=1) (all orange flag). Considering patients with CSDDIs, 6 (26%) had a CSDDI that could reduce ARV levels.ConclusionsIn this pilot study, a high prevalence of comorbidities, co‐medications and CSDDIs was observed in PHA. A considerable proportion of patients had CSDDIs with a potential to cause sub‐therapeutic ARV levels, what could be a concern in patients harbouring drug‐resistance viruses. Therefore, clinicians should be aware of comorbid conditions pharmacologic management in order to avoid CSDDIs with ARVs agents.
Tolerability is more important than simplicity for treatment durability
Authors: Trottier Benoit , Machouf Nima , Huchet Emmanuelle , Lavoie Stephane , Vezina Sylvie , Boissonnault Michel , Charest Louise , Munoz Marie , Legault Danielle , Longpré Daniele , Thomas Réjean 
Published: November 2014

IntroductionMany studies have shown the superiority of single tablet regimens (STRs) of antiretrovirals for the treatment of HIV in terms of efficacy, adherence and rate of hospitalisation as they offer a low pill burden and once daily dosing. Our objective was to compare the duration of first‐line STRs to multi‐tablet regimens.MethodsFrom our clinical database, we selected patients initiating any of the major first‐line regimens between 2007 and 2013. Two STRs, Atripla (ATP) and Complera (CPLR), were compared to three non‐STRs: two NRTIs and raltegravir (RAL), atazanavir/ritonavir (ATV/r) or darunavir/ritonavir (DRV/r). The primary outcome was time to discontinuation of the first‐line regimen. The association between regimen type and duration was estimated using Cox proportional hazards models adjusted for age, gender, baseline CD4, baseline viral load, risk factor, site and year of treatment initiation.ResultsA total of 743 patients (281 on STRs and 462 on non‐STRs) were included. 693 (93%) were male and median age was 43 years. Median length of follow‐up was 3.2 years. 56% of patients were MSM, 6% IDU and 6% from endemic countries. Patients on an STR were less likely to be IDU (p<0.024) and have a baseline HIV‐RNA ≥100,000 copies/mL (p<0.011). Overall, 321 (43%) patients discontinued their regimen during the study period. The rate of discontinuation one year after starting ARV depends on the regimen: 29% for patients on 2NRTIs+DRV/r, 26% on ATP, 25% on 2NRTIs+ATV/r, 17% on 2NRTIs+RAL and 10% on CPLR (p<0.001). In the adjusted model, durability for STR and non‐STR was equivalent (aHR=0.83, p=0.108). Compared to patients on ATP, patients on CPLR were less likely to discontinue (HR=0.58, p=0.070). No difference between ATP and the other regimens was observed: HR for 2NRTIs+RAL=0.92 (p=0.66), 2NRTIs+ DRV/r=1.16 (p=0.36), 2NRTIs+ATV/r=1.11 (p=0.46).ConclusionsOur findings suggest that STRs do not necessarily result in a more durable treatment. Even with a higher pill burden and/or twice daily dosing, patients initiating therapy with RAL or boosted‐PI based regimens were not more likely to discontinue the first‐line regimen compared to patients on an STR. Among the STR subgroups, the regimen with better known tolerability conferred more durable treatment. Limitations included our inability to adjust for the patient's adherence to a given regimen.
Treatment modification in HIV‐Infected individuals starting antiretroviral therapy between 2011 and 2014
Authors: Rappold Michaela , Rieger Armin , Steuer Andrea , Geit Maria , Sarcletti Mario , Haas Bernhard , Taylor Ninon , Kanatschnig Manfred , Leierer Gisela , Ledergerber Bruno , Zangerle Robert 
Published: November 2014

IntroductionWhile antiretroviral therapy (ART) has increased the survival of HIV patients and turned HIV infection into a chronic condition, treatment modifications and poor adherence might limit this therapeutic success.MethodsPatients from the Austrian HIV Cohort Study, who started their first ART after Rilpivirine became available in February 2011, were analyzed for factors associated with treatment modification which could be either a change of drugs or a stop of the regimen. A drug was considered as stopped when the regimen was interrupted for more than eight days. Drugs of particular interest were Darunavir (DRV), Atazanavir (ATV), Raltegravir (RAL), Rilpivirine (RPV) and Efavirenz (EFV). RPV and EFV were analyzed only when taken as single tablet regimen. Other drugs were summarized as “other.” Proportional hazards regression methods were used to identify predictors of discontinuation and Kaplan–Meier estimates were used to calculate probabilities of discontinuation. Patients who died were censored at the date of death.Results965 patients started ART, 282 with DRV, 161 with ATV, 96 with RAL, 108 with RPV and 118 with EFV. Median time for taking initial ART is 11.6 months. 322 (33.4%) patients modified their initial ART. The overall probability of modification at one year was 28.7%, at two years 40.0% and at three years 49.8%. In a multivariable proportional hazards regression analysis, AIDS diagnosis at baseline and injecting drug use (IDU) of men compared with men who have sex with men (MSM) have a higher risk of switch/stop. Compared with DRV, RPV showed a much lower and ATV and particularly “other” a higher risk for discontinuation (Table 1).Availability of more effective/convenient treatment (28.9%) was the main reason for discontinuation, especially in the group “other” (43.5%), RAL (34.6%) and DRV (31.6%). Non‐specified patient or physician wish to modify therapy was revealed in 17.4% and 9.3% respectively. EFV was modified in 52.8% due to central nervous system toxicity and ATV in 27.8% for gastrointestinal toxicity including hyperbilirubinemia.ConclusionRates of modification and interruption were still high in recent years, particularly in the first year of ART. The decreased rate of modification found in patients treated with Rilpivirine may be attributed to selection of patients according to guidelines.
Phase IIIb, open‐label single‐arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV‐1‐infected treatment‐nave adults
Authors: Tashima Karen , Crofoot Gordon , Tomaka Frank L , Kakuda Thomas N , Brochot Anne , Vanveggel Simon , Opsomer Magda , Garner William , Margot Nicolas , Custodio Joseph M , Fordyce Marshall W , Szwarcberg Javier 
Published: November 2014

IntroductionCOBI, a PK enhancer with no ARV activity is a more selective cytochrome P450 (CYP)3A inhibitor than ritonavir (RTV), does not induce CYP isozymes, and thus has less potential for drug‐drug interactions. COBI boosts DRV PK as effectively as RTV in healthy volunteers.Materials and MethodsThis 48‐week, phase IIIb, open‐label, single‐arm, US multicentre study (NCT01440569) included HIV‐infected treatment‐nave and experienced adults with no DRV RAMs, viral load (VL) ≥1000 c/mL, eGFR ≥80 mL/min and genotypic sensitivity to investigator‐selected N[t]RTIs. Patients received DRV/COBI 800/150 mg qd (as single agents) plus two fully active N[t]RTIs. The primary endpoint was any treatment‐emergent grade 3 or 4 AEs through Week 24. We report 48‐week safety, efficacy and PK/PD results in treatment‐nave patients.ResultsOf 313 ITT patients, 295 were treatment‐nave (94%). In the treatment‐nave cohort, 90% were male, 60% white and 294 (99.7%) received a TDF‐containing regimen. Median baseline (BL) VL was 4.8 log10 c/mL and CD4+ 370 cells/mm3. Treatment‐emergent grade 3 or 4 AEs regardless of causality were reported in 21 (7%) patients. AEs regardless of causality (any grade; ≥10% of patients) were: diarrhoea (27%), nausea (23%), URTI (15%) and headache (12%). Sixteen (5%) patients had AEs leading to study drug discontinuation, most frequently rash (three patients), hypersensitivity and nausea (two patients each). Consistent with the known inhibition of tubular creatinine secretion by COBI, there was a mean increase from BL in serum creatinine by week 2 (0.09 mg/dL), remaining stable through week 48 (mean 0.10 mg/dL increase from BL). At week 48, 83% of patients achieved VL<50 c/mL; FDA Snapshot); median increase in CD4+ was 169 cells/mm3. Eight patients met the criteria for resistance testing. M184V was detected in one pt receiving FTC. New primary RAMs were not detected in the other seven patients. The mean population PK‐derived DRV AUC24h was 100,620 ng.h/mL and C0h 2,105 ng/mL (n=281). There were no clinically relevant relationships between DRV exposure and virologic response, AEs or laboratory parameters.ConclusionsThe DRV PK of DRV/COBI was consistent with historical data for DRV/RTV. DRV/COBI 800/150 mg qd plus two N(t)RTIs had an 83% response and was well tolerated through Week 48. These results are similar to published data for DRV/RTV 800/100 mg qd, and support the use of DRV/COBI 800/150 mg qd in treatment‐nave patients.
Efficacy and tolerability of Etravirine in HIV‐1 adult patients: Results of a large French prospective cohort
Authors: Allavena Clotilde , Katlama Christine , Cotte Laurent , Roger Pierre‐Marie , Delobel Pierre , Cheret Antoine , Duvivier Claudine , Poizot‐Martin Isabelle , Hoen Bruno , Cabié Andre , Cheret Arnaud , Lahoulou Rima , Raffi Francois , Pugliese Pascal 
Published: November 2014

BackgroundIEtravirine (ETR) was approved in France in Sept 2008, to be used in combination with a ritonavir‐boosted protease inhibitor (bPI) and others antiretrovirals (ARV) in HIV‐infected pre‐treated patients.ObjectivesTo describe in a real life setting efficacy and tolerability of ETR‐including regimen and factors associated with virologic response.MethodIn the French DatAIDS cohort including 18,647 patients, we selected patients who initiated an ETR‐including regimen between September 2008 and July 2013. Demographic data and clinico‐biological data were collected from the standardized electronic medical record Nadis®. Analyses were done in patients starting ETR and sub‐analyses were performed in pre‐treated patients starting ETR for virologic failure (VF) or maintenance (MT) therapy, with or without bPI.Results2083 patients (ARV‐naïve n=77, VF n=1014, MT n=992) were included: median age 47 years, 73.3% male, median duration of HIV infection 15.7 years, CDC stage C 38.7%, HBV/HCV co‐infection 25.7%. In pre‐treated patients, 75.5% previously received NNRTIs (median duration on EFV and NVP of 480 and 396 days, respectively), 94.3% bPIs, 30.8% raltegravir (RAL) and 19.4% enfuvirtide. The most frequent ARVs associated with ETR were two NRTIs in 37.2% of the cases (21.9% in VF, 52.9% in MT), 1 bPI+RAL in 10.1% (13.5% in VF, 6.6% in MT), RAL in 6.2% (2% in VF, 10.5% in MT). Median duration on ETR was 3.7 and 2.2 years in the VF and MT group, respectively. In the VF group, HIV RNA was <50 c/ml in 71.7% (71.1% without bPI, 72% with bPI) of the patients at M12, 72.8% (71% without bPI, 73.3% with bPI) of the patients at M24. In the MT group, HIV RNA was<50 c/ml in 90.5% of the patients at M12 and 93.1% at M24. ETR was discontinued in 8.8% of the patients (12.8% in VF, 5.4% in MT) for adverse events in 23.9% of cases (21.5% in VF, 29.5% in MT), treatment failure in 15.2% (16.2% in VF, 7.4% in MT) or simplification in 5.4% (4.6% in VF, 7.4% in MT). In the VF group, factors associated with virologic failure in multivariate analysis were a longer duration of HIV infection (OR 2.6; 95% CI 1.7–4.0) and baseline HIV RNA >5 log10 c/ml (OR: 2.0; 95% CI 1.3–3.2) but not the association with a bPI.ConclusionThis large study shows that in ARV‐pre‐treated patients ETR is well tolerated with a high efficacy when combined with other active drugs, even when the regimen does not include a bPI.