bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of natural polymorphic sites of the HIV‐1 integrase before the introduction of HIV‐1 integrase inhibitors in Germany
Authors: Meixenberger Karolin , Pouran Yousef Kaveh , Somogyi Sybille , Fiedler Stefan , Bartmeyer Barbara , von Kleist Max , Kücherer Claudia 
Published: November 2014

IntroductionThe aim of our study was to analyze the occurrence and evolution of HIV‐1 integrase polymorphisms during the HIV‐1 epidemic in Germany prior to the introduction of the first integrase inhibitor raltegravir in 2007.Materials and MethodsPlasma samples from drug‐naïve HIV‐1 infected individuals newly diagnosed between 1986 and 2006 were used to determine PCR‐based population sequences of the HIV‐1 integrase (amino acids 1–278). The HIV‐1 subtype was determined using the REGA HIV‐1 subtyping tool. We calculated the frequency of amino acids at each position of the HIV‐1 integrase in 337 subtype B strains for the time periods 1986–1989, 1991–1994, 1995–1998, 1999–2002, and 2003–2006. Positions were defined as polymorphic if amino acid variation was >1% in any period. Logistic regression was used to identify trends in amino acid variation over time. Resistance‐associated mutations were identified according to the IAS 2013 list and the HIVdb, ANRS and GRADE algorithms.ResultsOverall, 56.8% (158/278) amino acid positions were polymorphic and 15.8% (25/158) of these positions exhibited a significant trend in amino acid variation over time. Proportionately, most polymorphic positions (63.3%, 31/49) were detected in the N‐terminal zinc finger domain of the HIV‐1 integrase. Motifs and residues essential for HIV‐1 integrase activity were little polymorphic, but within the minimal non‐specific DNA binding region I220‐D270 up to 18.1% amino acid variation was noticed, including four positions with significant amino acid variation over time (S230, D232, D256, A265). No major resistance mutations were identified, and minor resistance mutations were rarely observed without trend over time. E157Q considered by HIVdb, ANRS, and GRADE algorithms was the most frequent resistance‐associated polymorphism with an overall prevalence of 2.4%.ConclusionsDetailed knowledge of the evolutionary variation of HIV‐1 integrase polymorphisms is important to understand the development of resistance in the presence of the drug. Our results will contribute to define the relevance of integrase polymorphisms in HIV‐strains resistant to integrase inhibitors and to improve resistance interpretation algorithms.
Use of deep sequencing data for routine analysis of HIV resistance in newly diagnosed patients
Authors: Fernández‐Caballero Jose‐Angel , Chueca Natalia , Alvarez Marta , Gonzalez Dimitri , García Federico 
Published: November 2014

IntroductionUse of deep sequencing is becoming a critical tool in clinical virology, with an important impact in the HIV field for routine diagnostic purposes. Here, we present the comparison of deep and Sanger sequencing in newly diagnosed HIV patients, and the use of DeepChek v1.3 & VisibleChek for their interpretation and integration with virological and clinical data.Patients and MethodsPlasma samples from 88 newly diagnosed HIV‐1‐infected patients were included in the study. Median age (IQR) was 37 (27–47), median CD4 count (IQR) was 387 (220–554), and 85% were males. Median Viral Load (Log, IQR) was 5.03 (4.51–5.53). Deep sequencing was obtained using a GS‐Junior (Roche). Sequences were preprocessed with the 454 AVA software; aligned reads were uploaded into the DeepChek v1.3 system (ABL SA). Sanger sequences (Trugene), were uploaded in parallel. Stanford algorithm (version 7.0) resistance interpretation to first line drugs and all the mutations (score≥5) were analyzed. For deep sequencing, 1%, 5% and 10% thresholds were chosen for resistance interpretation.ResultsUsing VisibleChek for analysis, we were able to describe the detection of any mutation using Sanger in 37/88 patients, with a total number of 50 Stanford ≥5 mutations, K103N and E138A being the most prevalent (n=4). Using UDS‐1%, we found 72/88 patients with at least one mutation (total of 206 Stanford ≥5 mutations). Using Sanger data, 9/88 patients (10.22%) showed any resistance to NNRTIs, while none showed resistance to NRTIs or PIs. Using UDS‐10% increased resistance to NRTIs [3/88 (3.40%)], to NNRTIs 12/88 (13.63%), and to a lesser extent to PIs [1/88 (1.13%)]. Using UDS‐5% increased resistance to NRTIs [4/88 (4.54%)] and to NNRTIs [12/88 (13.63%)], but not to PIs. Using UDS‐1% increased resistance to all classes: NRTIs [14/88 (15.90%)], NNRTIs [26/88 (30.68%)], and PIs [6/88 (6.81].ConclusionsDeepChek and VisibleChek allow for an easy, reliable and rapid analysis of UDS data from HIV‐1. Compared to Sanger data, UDS detected a higher number of resistance mutations. UDS with a 5 &10% threshold resulted in an increase in the number of patients with any degree of resistance mainly to NRTI, NNRTIs. Going down as low as 1% increased resistance to all classes. A correct definition of clinically relevant thresholds for the interpretation of minor variant detection for different classes of ARVs is needed.
Time to virologic failure for patients taking their first antiretroviral regimen and the subsequent resistance profiles
Authors: Crouzat Frederic , Benoit Anita , Kovacs Colin , Smith Graham , Taback Nathan , Sandler Ina , Brunetta Jason , Chang Benny , Merkley Barry , Tilley David , Fletcher David , Kalaria Dipen , Loutfy Mona 
Published: November 2014

IntroductionThe resistance profiles of first‐line antiretroviral therapy (ART) regimens after virologic failure have yet to be studied in a clinic setting in the modern treatment era. Time to virologic failure among three standard first‐line regimens and the resistance profiles of these failures were compared.Materials and MethodsAll HIV‐positive persons aged 16 and over starting a three‐drug first‐line ART regimen were retrospectively identified at a Toronto community clinic (1 January 2006–1 January 2013). The regimens included a backbone of two NRTIs and a third agent; a PI, an NNRTI, or an II. Patients must have been on treatment for at least 14 days and have at least one VL test within 6 months after starting treatment. The primary outcome was virologic failure defined as either: no suppression by 6 months, or after suppression, two consecutive, detectable VL200 copies/mL at least 14 days apart or one VL>200 copies/mL. Time to failure was compared using a proportional hazards model adjusting for demographic and clinical factors. Resistance profiles of NRTIs and third agents are described in patients with virologic failure who had both baseline and virologic failure genotypes.ResultsSix hundred sixty patients (93% male) were included with a mean age of 38.9 and a median follow‐up period of 35.3 (32.2–39.3) months. Distribution of third agent use was: PI 37.3% (n=246), NNRTI 55.9% (n=369) and II 6.8% (n=45). Virologic failures occurred in 81/246 (33%) with PI, 87/369 (24%) with NNRTI and 11/45 (24%) with II. Compare to PIs, time to failure was longer with NNRTIs (p=0.0013) and similar for IIs (p=0.1562). No evidence that failure with NNRTIs was different from IIs (p=0.9139). Of the 660 patients, 567 (86%) had a baseline genotype. Of the 567 patients, 179 had virological failure. Of the 179, 145(81%) had a baseline genotype and only 37 (21%) had both a baseline and follow‐up genotype. Upon failure, emerging ART resistance was rare. No new PI or II mutations were identified and one new NNRTI (Y181C) mutation was identified. Three patients taking PI‐based regimens developed NRTI mutations (M184V, M184I, T215Y).ConclusionsTime to virologic failure was significantly greater in the NNRTI group compared to the PI group. If failure did occur, ART resistance rarely developed with no PI mutations but a few NRTI mutations in those taking PI‐based regimens, and NNRTI mutations in those taking NNRTI‐based regimen.
Resistance mutations in protease gene at baseline are not related to virological failure in patients treated with darunavir/ritonavir monotherapy
Authors: Gutierrez‐Liarte Angela , Gomez‐Berrocal Ana , Saez Carmen , Valencia Jorge , Santos Ignacio , Sanz Jesus 
Published: November 2014

IntroductionMonotherapy with darunavir plus ritonavir (DRV/r) is a good maintenance strategy for suppressed HIV‐infected patients. The clinical trials designed to prove the efficacy of PI/r do not include patients with resistance mutation in protease gene [1,2]. Sometimes in routine practice, basically to avoid NRTIs toxicity, monotherapy with DRV/r is used despite PI resistance mutations. The aim of this study is to know the effect of previous protease resistance mutation on DRV/r monotherapy efficacy.Materials and MethodsWe designed an observational cohort study of adults in treatment with DRV/r monotherapy in a tertiary Spanish hospital since 2011 to 2014. Demographic data and clinical outcomes were described. The analysis of efficacy was done according to the snapshot algorithm (defining virological failure as viral load >50 copies/mL, ITTe, at 48 and 96 weeks). We analyzed the difference of efficacy between patients with and without baseline resistance mutations at 48 and 96 weeks by using the χ2 test; and during the follow‐up by using the Kaplan–Meier test. The statistical analysis was done with SPSS 17.0.ResultsEighty‐nine patients were included in the cohort but 14 were excluded because they had not reached more than six months with monotherapy. The cohort was composed mainly by men (78%), the medium age was 51 years (SD±10), 35% were MSM and 19% were former IDU. Twenty‐four patients (35%) had a previous diagnosis of AIDS. The mean time taking NRTIs was 10.5 years (SD±5.4). Sixty‐four patients (85%) had been treated with PI in the past. Previous failure with PI had been reported in 15 (20%). A resistance mutation test had been done at baseline in 45 patients (51%). Twenty‐two patients (29%) had some mutations in protease gene, 10 patients (13%) had major mutations and 1 patient had some mutations of resistance for darunavir (I64V). At 48 weeks, 93% (CI 95% 86–98%) had VL<50 copies/mL, and 79% (CI 95% 67–89%) at 96 weeks. There were not differences between patients with or without resistance mutations (p=0.53). After a median follow‐up of 70 weeks, 88% of patients remain free of virological failure and there were not differences between both groups.ConclusionsAccording to these data, previous resistance mutations in the protease gene, which do not affect darunavir, are not related with the efficacy in patients treated with DRV/r monotherapy.
Can we trust the guidelines? Comparison between the data presented and the recommendations of the International Antiviral Society‐USA Panel
Authors: Jan Piso Rein 
Published: November 2014

IntroductionClinicians often do not have the time and possibilities to read all scientific evidence necessary to maintain high quality patient care. They rely on guidelines made by experts to help them in their daily work.MethodsWe compared the 2012 recommendations and the arguments of the IAS‐USA Panel with the data referenced and presented with the original data of the studies. Special topic was the timing of antiretroviral therapy. Only studies included in the guideline text were analyzed.ResultsThere is a large discrepancy between the data and the recommendations concerning early antiviral therapy. The studies are either not designed to answer this question or the data is not sufficient to support the arguments. The authors highlight benefits without mention of side effects or other problems. Neither in transmission rates, nor mortality, AIDS events, co‐morbidities (hepatitis B and C excluded) or decreasing the risk of malignancy, the data presented support early therapy.ConclusionsA large discrepancy between the underlining data and the recommendation made by the IAS‐USA Panel exists concerning early antiviral therapy.
Treatment outcome in HIV+ patients receiving 3‐ or 4‐drug regimens during PHI
Authors: Maria Bottani Giulia , Letizia Oreni Maria , Orofino Giancarlo , Tau Pamela , Di Nardo Stuppino Silvia , Colella Elisa , Carosella Sinibaldo , Guastavigna Marta , Ghisetti Valeria , Micheli Valeria , Galli Massimo , Rusconi Stefano 
Published: November 2014

IntroductionThe optimal timing and modality of therapeutic intervention during early phases of HIV infection is still debated; in our prospective observational study we evaluated immunological and virological outcome in HIV+ patients treated during acute or recent HIV infection.Materials and MethodsA total of 25 naïve patients with acute (detectable HIV‐RNA, immature Western Blot) or recent (documented infection within six months) HIV infection were recruited at the Infectious Diseases Units of the University of Milan and Turin from 2009 to 2014. Patients received treatment with two NRTIs+one NNRTI/bPI, with or without an induction phase with an additional fourth drug (raltegravir or maraviroc) until HIV‐RNA undetectability maintained for six months. Blood samples for HIV‐RNA, lymphocyte subsets and tropism assessment were obtained at the beginning of the treatment (BL). Patients underwent subsequent six‐monthly follow up for clinical outcome, CD4 cell count and HIV‐RNA up to 18 months.ResultsMedian increase in CD4 cells from 0 to 12 months was greater in patients treated during acute (n=18) versus recent (n=7) infection [284/µL, IQR (227–456) versus 176/µL, IQR (70–235); Mann‐Whitney test, p=0.046]. This higher value was maintained through 18 months, although failing to reach statistical significance. Patients with acute or recent infection did not significantly differ in virological success (83.3% versus 85.7% at 12 months). We considered CD4 cells gains at six months (multivariate analysis, ANCOVA; Figure 1) and detected an inverse correlation with CD4 levels at BL (r=−0.517; p=0.008) and a direct correlation with the status of acute infection (r=0.234, p NS). This last correlation reached statistical significance at 12 months (r=0.418, p=0.035), whereas the inverse correlation with CD4 levels at BL was still present without a statistical significance (r=−0.350; p=0.072). Patients treated with three or four drugs did not show any significant difference in immunological nor virological response (Mann‐Whitney and χ2 test). Modification or interruption of therapy for tolerability took place in 4 out of 25 patients, all while receiving four drugs; two patients underwent STI between 12 and 18 months following virological success.ConclusionsTreatment of primary infection appeared to be effective in preserving the pool of CD4 cells in acute more than recent infection. There was no evidence of a different outcome through the addition of a fourth drug to the standard treatment.
An indirect comparison of efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir and dolutegravir + abacavir/lamivudine
Authors: Rogatto Felipe , Bouee Stephane , Jeanbat Vivianne , Piontkowsky David , Aragao Filipa , Bosse Matthew 
Published: November 2014

BackgroundIntegrase strand transfer inhibitors (INSTI) are the standard of care for naïve HIV‐infected individuals due to their favourable efficacy and safety profile. The newest INSTIs, elvitegravir and dolutegravir, have not been evaluated in a head to head study; however, both have been compared to efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF) in phase III trials. Elvitegravir/cobicistat/emtricitabine/tenofovir DF (E/C/F/TDF) was compared to EFV/FTC/TDF for 144 weeks in Gilead Study 102 (GS‐102), while dolutegravir (DTG) with the abacavir/lamivudine fixed‐dose combination (ABC/3TC) was compared to EFV/FTC/TDF for 96 weeks in the SINGLE study. The objective of this analysis is to perform an indirect comparison at 48 and 96 weeks of E/C/F/TDF to DTG+ABC/3TC by using the two trials evaluating each of these regimens compared to EFV/FTC/TDF.MethodsAn indirect comparison was performed by using Bucher's methodology to calculate risk differences based on the two phase III clinical trials described above.ResultsAt week 48 (snapshot analysis), 88% of the patients on E/C/F/TDF and DTG+ABC/3TC had HIV RNA <50 c/mL, while 84% and 81% of patients on EFV/FTC/TDF were suppressed in GS‐102 and SINGLE, respectively. At week 96, 84% of patients receiving E/C/F/TDF compared with 80% of patients receiving DTG+ABC/3TC remained suppressed, while 82% and 72% on EFV/FTC/TDF maintained HIV RNA <50 c/mL in GS‐102 and SINGLE. At week 144 80% of patients on E/C/F/TDF remained suppressed (vs. 75% of the patients on EFV/FTC/TDF). Results of indirect comparison showed a risk difference of HIV RNA <50 copies per mL between E/C/F/TDF compared with DTG+ABC/3TC of −4% (CI 95%=−11 to 3) for the ITT 48 weeks (p=0.3) and −5% (95% CI=−13 to 3) for the ITT 96 weeks (p=0.2). In regards to safety, there was no significant difference between E/C/F/TDF and DTG+ABC/3TC for any adverse event (AE) (p=0.3), serious AEs (0.13), drug related AEs (0.7), or drug‐related serious AEs (0.6).ConclusionsIn GS‐102 and SINGLE, 88% of the patients on E/C/F/TDF and DTG+ABC/3TC were virologically suppressed at week 48. At week 96, these proportions were 84% for E/C/F/TDF and 80% for DTG+ABC/3TC. The indirect efficacy comparisons between EVG/COBI/FTC/TDF and DTG+ABC/3TC at week 48 and 96 revealed no statistically significant differences.
Impact of etravirine use on hospitalization rates among highly pre‐treated failing HIV‐1 infected individuals between 2005 and 2011
Authors: Lacombe Jean‐Marc , Goujard Cecile , Valantin Marc‐Antoine , Cheret Arnaud , Lahoulou Rima , Girard Pierre‐Marie , Costagliola Dominique 
Published: November 2014

IntroductionEtravirine (ETR), a non‐nucleoside reverse transcriptase inhibitor available in France since 2006, is indicated for the treatment of HIV‐1 infection in combination with a ritonavir boosted protease inhibitor (PI) in antiretroviral treatment‐experienced adult patients. To assess its impact in routine clinical care, our objective was to compare hospitalization rates in highly pre‐treated failing HIV‐1 infected individuals between 2005 and 2011 depending on whether or not they received ETR+PI.MethodsFrom the French Hospital Database on HIV (ANRS CO4), we selected highly pre‐treated individuals (prior exposure to at least 2NRTI, 2PI and 1 NNRTI) with a viral load (VL)>50 copies/mL initiating a new regimen between 2005 and 2011. Hospitalization rates were calculated for each calendar month and depending on whether patients never received ETR+PI at any time or during months before initiating ETR+PI (no ETR+PI) or during months after initiating ETR+PI (ETR+PI), using an intention to continue treatment approach. Poisson regression models were used to compare incidence between the two groups, after adjustment for potential confounders (age, transmission group, origin, AIDS, PCP prophylaxis, viral load, CD4, nb of previous ARV).ResultsOverall 3884 patients fulfilled inclusion criteria. Among them 838 (21.6%) received ETR+PI at least once. Among all enrolled patients, 35.8% had CD4 <200/mm3, 17.5% had VL >100,000 copies/ml, 42.8% had had an AIDS event and 47.8% had received more than 10 different antiretroviral drugs. There were 2484 hospitalizations in 808 individuals over 13,986 patient‐years. The hospitalization rates for 1000 P‐Y were 169.0 for the ETR+PI group and 179.3 for the no ETR+PI group. After adjustment, the corresponding figures were 144.8 for 1000 P‐Y and 192.7 for 1000 P‐Y respectively, with a relative risk estimated as 0.75 (95% CI 0.67–0.84).ConclusionsAccess to ETR+PI between 2005 and 2011 was associated with a 25% reduction in the hospitalization rate among highly pre‐treated failing HIV‐1 infected individuals.
Darunavir‐based dual therapy in HIV experienced patients
Authors: Sterrantino Gaetana , Zaccarelli Mauro , Di Biagio Antonio , Rosi Andrea , Bruzzone Bianca , Cicconi Paola , Carli Tiziana , Luisa Biondi Maria , Antinori Andrea , Bartolozzi Dario , Penco Giovanni 
Published: November 2014

BackgroundWe assessed the virological response of DRV/r‐based dual therapy in drug‐experienced patients included in the Italian antiretroviral resistance database (ARCA).Materials and MethodsPatients included in the study were treated with DRV/r in association with raltegravir (RAL), etravirine (ETV) or maraviroc (MAR) following treatment failure(s) and with a resistance test and at least one follow‐up visit available. Observation was censored at last visit under dual therapy and survival analysis and proportional hazard models were used, taking virological failure (confirmed >50 c/mL HIV‐RNA) as the end‐point.ResultsOf the total 221 patients included, 149 (67.4%) started DRV/r with RAL, 45 (20.4%) with ETV, 27 (12.2%) with MAR. Patients characteristics at the start of dual regimen were as follows: mean number of previous regimens, nine (IQR: 5–13); non‐B subtype, 17 (7.7%); median CD4 count, 347 (IQR: 246–544); undetectable viral load, 74 (33.5%). Full DRV/r resistance was detected in one (0.5%, HIV‐DB interpretation system), 13 (5.9%, ANRS) and 17 patients (7.7%, Rega). 69 virological failures (31.2%) were observed during follow‐up. At survival analysis, the overall proportion of failure was 29.2% at one year and 33.8% at two years. The proportion of failure was lower in patients starting with undetectable versus detectable viral load (13.3% and 25.2% versus 37.4% and 38.8% at one and two years, respectively, p=0.001 for both analyses) and in patients treated with DRV 600 BID versus 800 QD (HR: 0, 56; 95% CI 0.31–0.99; p<0.05). By regimen, patients treated with DRV/r‐RAL showed a non‐significant lower proportion of failure (27.7% at one year, 32.0% at two years) if compared with DRV/r‐MAR (35.9%, 47.1%) and DRV/r‐ETV (34.1%, 34.1% at one and two years). In the adjusted proportional model, no significant difference among the three regimens was detected. A significant lower risk of failure was associated with higher overall GSS (HIV‐DB HR: 0.53, 95% CI 0.32–0.88, p=0.014; Rega 0.60, 0.40‐0.88, p<0.01; ANRS 0.55, 0.34–0.90, p=0.017), while a higher risk of failure was associated with detectable HIV‐RNA (3.02, 1.70–5.72, p<0.001).ConclusionsAmong experienced patients, the best candidates to dual‐therapy regimens including DRV/r are those with undetectable viral load and higher GSS. The association with RAL is the most commonly used but no clear advantage with respect to ETV or MAR was observed in our dataset, possibly due to the limited sample size.