bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV‐1 drug resistance testing at low viral load may help to differentiate between ongoing replication and release from reservoirs
Authors: Obermeier M , Ehret R , Kaiser R , Berg T 
Published: November 2012

Purpose of the studyLow level viraemia in HIV‐infected patients treated with anti‐retroviral therapy (ART) is a phenomenon still not fully understood. If the observed viraemia is a result of ongoing replication or if virus is released from cellular reservoirs remains unclear. We analysed our database of genotypic resistance and interpretations to screen for an effect of viral load on frequency of detected drug resistance.Methods1939 viral load and protease and reverse transcriptase sequence pairs from the years 2009 to 2011 were analysed. Drug resistance interpretation was performed by the HIV‐GRADE resistance interpretation rule set. Pairs were split up into viral load categories of below 200 cop/ml, 200–400, 400–1000, 1000–10,000, 10,000–100,000 and more than 100,000 cop/ml. Resistance interpretation was stratified in the following categories: no resistance, resistance against one, two or three drug classes. The collected data were then analysed using chi‐squared test (R Core Team; 2012; R: A language and environment for statistical computing).Summary of results1390 sequences showed no relevant drug resistance, while 336 sequences showed resistance against one drug class (two classes: 145, three classes: 38). In 25 samples viral load was below 200 cop/ml (200–400: 29, 400–1000: 63, 1000–10,000: 275, 10,000–100,000: 526, above 100,000: 472). In both groups below 400 cop/ml no significant increase of resistant variants was observed compared to the mean distribution, while in the groups with 400–1000 cop/ml and 1000–10,000 cop/ml significant more resistant variants were found than expected (p < 0.001). This reverses above 100,000 cop/ml, where significantly (p < 0.001) more susceptible variants were observed.ConclusionsAs in most of the samples with a viral load below 400 cop/ml, no mutations leading to resistance could be found, we conclude that virus in these cases is released from cellular reservoirs. Viral loads between 400 cop/ml and 10,000 cop/ml under ART are a clear sign for ongoing replication, because in this group the highest rate of drug resistance was observed. Viral loads above 100,000 cop/ml seems here to be a sign of missing selective pressure due to incompliance of the patients and thus no drug resistance was observed.
Integrase resistance variants among integrase inhibitor treatment‐naïve and treated patients from Northwestern Poland
Authors: Parczewski M , Leszczyszyn‐Pynka M , Urbanska A , Bander D , Boron‐Kaczmarska A 
Published: November 2012

Purpose of the studyHIV integrase inhibitor use is limited by low genetic barrier to resistance and possible cross‐resistance among representatives of the class. The aim of this study was to analyse the sequence variability in the integrase region in treatment‐naïve and experienced patients with no prior integrase inhibitor (InI) exposure and to investigate the development of the InI drug resistance mutations following the virologic failure of the raltegravir (RAL)‐containing regimen.MethodsSequencing of HIV‐1 integrase region (866 base pair, HXB2 genome location: positions 4230–5096) from plasma samples of 80 integrase treatment‐naïve patients and treatment failing subjects from a group of the 46 RAL‐treated patients were analysed. Drug resistance mutations were called with Stanford DB database and grouped into major and minor mutations. For subtyping, bootstrapped phylogenetic analysis (1000 replicates) with under the GTR + I+gamma model with reference sequences.imageResultsMajority of the integrase region sequences were classified as subtype B; the remaining ones being subtype D, C, G, and CRF01_AE, CRF02_AG and CRF13_cpx recombinants. No major integrase drug resistance mutations have been observed in InI‐treatment naïve patients. In 30 (38.5%) cases polymorphic variation, with predominance of the E157Q mutation was observed. This mutation was more common among subtype B (26 cases, 54.2%) than non‐B sequences (5 cases, 16.7%), p = 0.00099, OR: 5.91 (95% CI: 1.77–22.63)] (Figure 1a, 1b). Other variants included L68V, L74IL, T97A, E138D, V151I, R263. Of the RAL‐treated patients in 12 cases (26.1%) treatment failure was observed. In 4 cases major the following InI drug resistance mutations were found: N155H, V151I, E92EQ, V151I, G163R (3 cases) and Q148H, G140S mutant (one case). Time to the development of drug resistance ranged from 2.6 to 16.3 months with mean increase of HIV viral load of 4.34 (95% CI: 1.86–6.84) log HIV‐RNA copies/ml at the time of emergence of the major mutations. Baseline polymorphisms, including E157Q were not associated with the virologic failure on RAL (p = 0.5).ConclusionsIn InI treatment‐naïve patients polymorphic integrase sequence variation was common, with no major resistance mutants observed. In the failing patients selection of drug resistance occur rapidly, and follows the typical drug resistance pathways accumulation of mutations. Pre‐existing integrase polymorphisms were not associated with the treatment failure.
Genotypic susceptibility to etravirine‐assessment in a population of NNRTI‐experienced patients
Authors: Piñeiro C , Xerinda S , Figueiredo C , Santos A , Soares J , Serrão R , Sarmento A 
Published: November 2012

BackgroundWith the availability of the 2nd‐generation non‐nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (ETR), it is possible to obtain undetectable plasma viral load in HIV‐1‐infected treatment experienced patients with resistance mutations to NNRTIs. The purpose of this study is to determine the proportion of patients with prior exposure to NNRTIs who may benefit from a therapeutic regimen including ETR.Patients and methodsAnalysis of the genotypic resistance tests of patients having failed efavirenz (EFV) or nevirapine (NVP) antiretroviral‐based regimens, in a 5‐year period (2007–2011). Susceptibility to ETR was assessed using four different algorithms: HIVdb Stanford University HIV Drug Resistance Database, ANRS score, REGA score and Tibotec weighted genotypic score.ResultsOf 170 patients with a history of failure or abandonment of regimens containing EFV or NVP, 68 (40%) had mutations conferring resistance to these NNRTIs (RAMs). Resistance tests were carried out from seven months before to 3 years after (X=48±207 days) the NNRTIs discontinuation. Of the HIV‐1 subtypes identified (n=67), most were were subtype B (53.7%) and G (34.3%) RAMs found in the 68 samples successfuly genotyped: V90I (n=2), A98G (n=1), L100I (n=7), K101E (n=5), K103N (n=38), K103S (n=2), V106A (n=1), V106M (n=1), V108I (n=4), V179D (n=4), Y181C (n=18), Y188C (n=1), Y188H (n=1), G190A (n=11), G190E (n=1), G190S (n=1), H221Y (n=6), P225H (n=1), F227L (n=3) and K238T (n=2). In 27 (39.7%) patients only one RAM was detected, 30 (44.1%) had 2, 6 had three mutations and 5 other patients had more than three RAMs to NNRTIs. Susceptibility to ETR varied depending on the used algorithm:

Susceptible
Intermediate resistance
Resistant

ANRS
60 (88.2%)
3 (4.4%)
5 (7.4%)

HIVdb
49 (72.0%)
17 (25.0%)
2 (3.0%)

REGA
40 (58.8%)
27 (39.7%)
1 (1.5%)

Tibotec
44 (64.7%)
23 (33.8%)
1 (1.5%)

ConclusionIn this population with resistant virus to EFV and NVP, we found a low frequency of mutations conditioning severely impacting on susceptibility to ETR. Based on these results, ETR could be a useful component of effective treatment regimens for the majority of these patients with prior exposure to 1st‐generation NNRTIs.
Analysis of HIV‐1 primary drug resistance in Kazakhstan
Authors: Lapovok I , Laga V , Vasilyev A , Kazennova E , Ludvikova E , Kovtunenko N , Dzisyuk N , Tukeev M , Bobkova M 
Published: November 2012

Purpose of the studyMonitoring of primary resistance in HIV‐1 variants circulating in Russia and FSU countries is the important task of HIV infection molecular epidemiology. The data of HIV molecular epidemiology are absent or limited in many FSU countries. IDU‐A variant of HIV‐1 subtype A has been dominating in Russia (>90%) and other FSU countries since 1996. Additionally, the Central Asian region (e.g. Kazakhstan and Uzbekistan) is characterized by relatively wide spread of CRF02_AG recombinant. The aim of our study was the analysis of HIV primary drug resistance in HIV‐1 variants from Kazakhstan.MethodsBlood collection from the HIV‐infected naïve patients was carried out by local specialists. The study was performed with the informed consent of patients. All sequences of pol gene were analyzed by COMETv0.1 and HIVdb on‐line programs. The phylogenetic analysis and tropism testing were carried out by MEGA4.0 and geno2pheno.Summary of results51 PBMC samples were analyzed. According to pol gene phylogenetic analysis and genotyping 24 (47.0%) samples belonged to recombinant CRF02_AG; 25 (49.0%)‐to subtype A1; 2 (3.9%)‐to CRF03_AB circulating in Russia and some FSU countries. Only one subtype A1 sample had D30N mutation in Pro‐region that cause high‐level resistance to NFV. All AG‐samples had K20I substitution which is characteristic for HIV‐1 subtype A and G and is believed to be associated with resistance to LPV and NFV. In addition, we found that 2 AG‐samples had L10V and L76I substitutions, accordingly. Two A1‐subtype samples studied had L10I and K43T, accordingly. A62V characteristic mutation in RT‐region was found in 12 (48%) subtype A1‐samples. One of them had M184I mutation as well. Besides, we found 3 A1‐samples harboring NNRTIs resistance mutations‐K103N, G190S, K238N, accordingly. Further we analyzed IN region of pol‐gene in 16 and env‐gene in 23 samples studied. We found only one E157Q mutation (in CRF03_AB sample) in IN region. As to tropism, only two subtype A1 and 1 CRF03_AB samples belonged to X4/X4R5 variant, all these A1‐subtype samples harbored A62V and one of them‐G190S in RT region of pol‐gene; the other samples were treated as R5 variants.ConclusionsOur data demonstrated the low level of HIV primary drug resistance in Kazakhstan. HIV‐1 subtype A variant dominates on this territory, but CRF02_AG recombinant is rather widespread as well. CRF02_AG variant studied has characteristic features in Pro region compared with IDU‐A.
Effectiveness of first‐line antiretroviral therapy based on NNRTIs vs ritonavir‐boosted PIs in HIV‐1 infected patients with high plasma viral load
Authors: Imaz A , Llibre J , Navarro J , Curto J , Clotet B , Crespo M , Murillo O , Ferrer E , Saumoy M , Tiraboschi J , Podzamczer D 
Published: November 2012

Purpose of the studyFew clinical trials have compared non‐nucleoside reverse transcriptase inhibitors (NNRTI) and ritonavir‐boosted protease inhibitors (PI/r) as initial combined antiretroviral therapy (cART) for HIV‐1‐infected patients with high plasma viral load (pVL), and non‐conclusive results have been reported. We compared the effectiveness between NNRTI and PI/r as first‐line cART for HIV‐1‐infected patients with high pVL.MethodsObservational retrospective study of 664 consecutive treatment‐naïve HIV‐1‐infected patients with pVL (HIV‐1 RNA) >100,000 copies/mL who initiated NNRTI or PI/r‐based cART between 2000–2010 in three University hospitals. Only currently preferred or alternative regimens in clinical guidelines were included. Primary endpoint: percentage of therapeutic failures at week 48. Virologic failure was defined as: a) lack of virologic response (<1 log RNA HIV‐1 decrease in first 3 months); b) RNA HIV‐1 >50 c/mL at week 48; c) confirmed rebound >50 c/ml after a previous value <50 c/mL. Intent‐to‐treat (ITT noncompleter=failure) and on‐treatment (OT) analyses were performed.Results62% of patients initiated NNRTI‐regimens (83% efavirenz) and 38% PI/r‐regimens (62% lopinavir/). Baseline characteristics: male 83%; median age 39 yrs; median CD4 count: 212/µL (NNRTI 232 vs PI/r 177, p=0.028); pVL 5.83 log10 c/mL (NNRTI 5.43 vs PI/r 5.55, p=0.007); AIDS 24% (NNRTI 21% vs PI/r 29%, p=0.015). NRTI backbones were tenofovir plus 3TC or FTC in 72%. The percentage of therapeutic failure was higher in the PI/r group (ITT NC=F 26% vs 18%, p=0.012) with no differences in virologic failures (PI/r 5%, NNRTI 6%, p=0.688). The rate of treatment changes due to toxicity and/or voluntary discontinuations was higher in the PI/r group (15% vs 8%, p=0.008). A multivariate analysis adjusted for age, gender, CD4 count, VL and AIDS showed NNRTI vs PI/r as the only variable associated with treatment response (OR 0.61, 95% CI 0.41–0.88). Median pVL and rate of resistance at virologic failure were higher in patients receiving NNRTI (3.97 vs 2.49 log copies/mL, p<0.001 and 62% vs 12%, p=0.004, respectively).ConclusionsInitial NNRTI‐regimens showed higher effectiveness compared with PI/r‐regimens in HIV‐1‐infected patients with high pVL, although virologic failure rates were low and comparable. Resistance emergence was more frequent and pVL higher in patients failing NNRTI. However, more patients initiating PI/r‐based regimens changed or discontinued therapy.
Increasing subject compliance in pivotal phase III clinical trials of dolutegravir (DTG, S/GSK1349572) in HIV‐infected, ART‐naïve subjects
Authors: Harris J , Bomar M , Campbell M 
Published: November 2012

To maximise the application of results of large‐scale clinical trials, recruitment and retention of a diverse subject population is key. With commonly used algorithms (Snapshot, TLOVR, missing = failure), all withdrawals in HIV studies, regardless of reason, are classed as failures in efficacy analyses. Good subject compliance therefore improves statistical power and the quality of trial results. In four recent GSK/ViiV‐sponsored phase IIIB/IV HIV ART‐naïve studies (HEAT, KLEAN, APV109141 and ARIES), 24% of subjects withdrew and approximately 2/3 of these withdrawals (16%) potentially were avoidable (i.e. not treatment related) [1]. To increase subject compliance in the phase III, treatment‐naïve studies of DTG (ING113086 “SPRING‐2” and ING114467 “SINGLE”), a more robust subject compliance program focussing on understanding subject needs and building sponsor‐site and site‐subject relationships was implemented. The compliance program included opt‐in study visit reminders, late study visit tracking, subject compliance support materials, subject transportation support, on‐going site training, relationship management and presentations on prior withdrawal rates and associated risk factors for attrition at investigator meetings. Week 48 withdrawals, both overall and for potentially avoidable reasons, were considerably lower in SPRING‐2 and SINGLE than historical HIV trials. Comparison of withdrawal rates prior to, and after implementation of robust patient compliance program. Addressing individual study subject needs with a customized approach in SPRING‐2 and SINGLE contributed to considerably lower percentages of withdrawals than in historical HIV studies. Identifying the specific impact of a single subject compliance initiative is difficult as study compliance can be influenced by overall study design, investigational product tolerability profile, current standard of care and treatment access for the disease under study. However, consistently reducing the number of avoidable withdrawals has the potential to lead to improved quality of trial results and smaller, quicker studies in the future, benefitting the whole HIV population.

Study
N
Week
Withdrawals from study n (%)
Withdrawals for unavoidable reasons*
Withdrawals for potentially avoidable reasons#

HEAT/KLEAN/APV109141/ARIES~
2290
36–96
552 (24%)
179 (8%)
373 (16%)…

SPRING‐2
822
48
103 (13%)
57 (7%)
46 (6%)

SINGLE
833
48
135 (16%)
79 (9%)
56 (7%)

Due to adverse events, lack of efficacy, protocol‐defined stopping criteria.
Due to lost to follow‐up, withdrew consent, protocol deviation, investigator discretion.
Pooled data from HEAT (EPZ104057), KLEAN (ESS100732), APV109141, ARIES (EPZ108859).
Week 48 Kaplan‐Meier estimates=15%, 13% and 9% respectively for HEAT, KLEAN and APV109141.
Long‐term durability of nevirapine‐based ART in a cohort of 82 patients after induction with protease inhibitor treatment
Authors: Rump J , Hoehl J , Rosenberg C 
Published: November 2012

Purpose of the studyThere is still an open question how to start antiretro‐viral therapy (ART). This retrospective study shows results of a de‐escalation strategy starting with a protease inhibitor (PI), followed by a nevirapine‐based regimen over a period of five years.MethodsAll patients were ART‐naïve and received PI in combination with two NRTIs. The PI was changed to nevirapine, when viral load (VL) stayed at least 12 months below the detection limit (50 or 40 copies/ml plasma). The median time to negative VL was measured. CD4, VL and liver tests were followed in 82 patients over at least 5 years before ART, during PI phase and over a median of 48 months after change to nevirapine. Resistance tests were performed ‐ if possible ‐ in patients before initiating ART.Summary of results20 female and 62 male patients were treated for an average of 28 months with PI (43×lopinavir, 5×indinavir, 6×invirase/r and 3×fortovase/r, 8×nelfinavir, 14×atazanavir/r, 3×norvir‐mono plus two backbone NRTI in various combinations). There were 2 cases of hepatitis B and 5 HCV positives in the cohort. The mean CD4 before starting ART was 246/µl and the average VL was 421,038 copies/ml plasma (ranging from 1,050–9,000,000 copies/ml plasma). The median time to negative VL was 188 days. CD4 cells were rising by 364/µl during PI treatment to 610/µl. This was followed by a steady increase of another 70 cells/µl during the first year after changing to nevirapine. The median follow up after de‐escalation to nevirapine was 48 months. Although the median CD4 was above 400/µl in all patients when changed to nevirapine, no severe liver toxicity was seen in the cohort. Change to NNRTI was safe in the group of 20 women with CD4 cells above 400/µl. Allergic skin reactions where seen in 7 out of 82 patients during the first 3 months after changing to nevirapine. No events of resistancies were seen in the group of 82 patients before and under treatment.ConclusionsLong‐term durability of nevirapine containing ART regimens following an induction phase with PIs is very high. No risk of treatment failure by resistance mutations was seen in a follow up of more than 48 months. Liver toxicity was not seen when ART was changed to nevirapine neither in female nor in male patients. The study was supported by Boehringer Ingelheim Pharma GmbH.
Causes for switch‐infected patients: the NEXT study
Authors: Casado J , Domingo P , Gutiérrez F , Hevia H , Ledesma F , Palazuelos M 
Published: November 2012

Purpose of the studyNNRTIs are commonly used to initiate HAART. Despite their demonstrated efficacy, tolerability and resistance issues could lead to a treatment change. The objective of the NEXT study was to evaluate the reasons for switching an initial non‐nucleoside based regimen in the clinical setting, and the alternative regimen selected.MethodsA retrospective multicentre study was undertaken between April and October 2009. Patients from 38 Spanish centres who had changed the initial EFV or NVP‐based regimen in the previous six‐month period were included. Social‐demographic and HIV‐related data was collected from medical records. Responsible physicians were interviewed about reasons for switching the non‐nucleoside and the alternative regimen of choice.Summary of resultsA total of 391 HIV‐1 infected patients had changed the initial EFV or NVP‐based regimen in the previous six months. Data were available for 316 (80.8%) of them. 245/316 patients received EFV as first line (77.5%). Median time to switch the NNRTI regimen was 16.9 months, shorter in case of EFV‐based regimen, 15.4 months, than NVP‐based regimen, 20.8 months. Most of changes were observed in the first month after initiation, representing 51.3% of the discontinuations, especially in case of EFV (57.1% EFV; 31% NVP). 9.2% of the patients switched due to chronic toxicity (after the first month of treatment). CNS toxicity was the most common reason for switching therapy in the acute term in 63% of the patients. Other tolerability issues that led to treatment discontinuation in the short term were lipid abnormalities due to EFV (4.1%) and liver enzyme elevations related to NVP (7%). Rash led to a similar rate discontinuation with both NNRTIs (12%). The second reason to discontinue the first‐generation NNRTI was virological/immunological failure in 40.5% of the patients (128/316). The new regimen selected was a boosted PI regimen in 52% of the cases, and was another NNRTI based regimen in 62.3%. Physicians marked safety/tolerability as the main reason for switching in 58.5% of cases (185/316).imageConclusionsIn the clinical setting, both acute and chronic intolerance/toxicity represents the main cause of the first line treatment change based on a first generation NNRTI, mainly EFV. CNS toxicity was the most common reason for switching therapy in the acute term. Therefore, the tolerability profile of the alternative regimen played a relevant role when switching regimens.
Switching to darunavir/ritonavir monotherapy (DRV/r mx): effect on kidney function and lipid profile
Authors: Martinez‐Colubi M , Pérez Elías M , Sanz J , Gomez C , Estrada V , Sepúlveda M , Moreno A , Muriel A , Carranza M , De Palacio M , Dronda F , Gómez‐Ayerbe C , Casado J , Moreno S 
Published: November 2012

Purpose of the studyDRV/r mx is proposed as a therapeutic option for patients with NNRTI toxicity. We aimed to evaluate the impact of switching to DRV/r mx in kidney function and lipid profile.MethodsFrom March 2009 to June 2012 we conducted an observational, retrospective multicenter study evaluating patients switching to DRV/r mx. Kidney function and lipid levels were measured at baseline and at 48 weeks of DRV/r mx. Renal function was estimated by MDRD GFR. Comparative analyzes were performed using Student's t test for paired samples.Summary of resultsWe identified 147 patients: women 30.6%, age 49±7yr, 45% IDU, 27.9% heterosexuals, AIDS 41.5%, Caucasian 58.5%, HCV‐coinfected 48%, baseline HIV‐RNA <1.7 log 93.2%, nadir and baseline CD4 count 180±150 and 663±297 cells/mm3, length of antiretroviral therapy 12.83±4.6 years and of HIV‐RNA <1.7 62±43 months. The rate of HIV‐RNA <1.7 at week 48 were 78.9% ITT; 92.6% OTT. Improvement was observed in kidney function after 48 w of DRV/r mx, mean 0 w vs 48 w MDRD (84.43±22.32 vs. 87.88±23.24; p=0.001). Subgroup analysis demonstrated significantly higher increases in MDRD in patients with a prior tenofovir‐based regimen (TDF), 83.14±21.86 and 48 w 88.97±21.23; p=0.000, and those with a protease inhibitor plus TDF‐based regimen (mean 0 w vs 48 w MDRD 80.66±22.53 87.09±23.37; p=0.002). Lipid profile improved significantly in terms of reduction in total cholesterol (mean 0 w col: 192.47±42.44 vs mean 48 w col 170.48±70.79; p=0.013) with an improvement in the ratio total cholesterol/ HDL (0 w 4.46±1.62 vs 48 w ratio 3.97±2.12; p=0.000). There were no significant changes in lipid profile in subgroup analysis according to previous antiretroviral treatment change.ConclusionsPatients switching to DRV/r monotherapy showed significant improvement in kidney function and lipid profile at 48 w, both implied on cardiovascular risk.