bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Introduction

The 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 Methods

All 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.

Results

Six 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).

Conclusions

Time 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

Introduction

Monotherapy 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 Methods

We 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.

Results

Eighty‐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.

Conclusions

According 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

Introduction

Clinicians 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.

Methods

We 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.

Results

There 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.

Conclusions

A 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

Introduction

The 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 Methods

A 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.

Results

Median 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.

Conclusions

Treatment 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

Background

Integrase 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.

Methods

An indirect comparison was performed by using Bucher's methodology to calculate risk differences based on the two phase III clinical trials described above.

Results

At 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).

Conclusions

In 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

Introduction

Etravirine (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.

Methods

From 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).

Results

Overall 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).

Conclusions

Access 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

Background

We assessed the virological response of DRV/r‐based dual therapy in drug‐experienced patients included in the Italian antiretroviral resistance database (ARCA).

Materials and Methods

Patients 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.

Results

Of 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).

Conclusions

Among 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.
Efficacy and safety of rilpivirine‐based regimens in treatment‐experienced HIV‐1 infected patients: a prospective cohort study
Authors: Gazaignes Sandrine , Resche‐Rigon Matthieu , Yang Chloe , Gatey Caroline , Munier Anne‐Lise , Desseaux Kristell , Rozenbaum Willy , Molina Jean‐Michel
Published: November 2014

Introduction

Rilpivirine (RPV) is a new once‐daily, non‐nucleoside, reverse transcriptase inhibitor (NNRTI). In treatment‐naïve patients, RPV has shown non‐inferior antiviral activity to efavirenz but data in treatment‐experienced patients are more limited. We assessed the efficacy and safety of RPV in treatment‐experienced patients switching to a RPV‐based regimen.

Methods

Between September 2012 and June 2013, all antiretroviral therapy (ART) experienced HIV‐1 infected patients with a plasma HIV‐RNA level <50 cp/mL, and switching to a RPV‐based regimen, were enrolled in this prospective monocentric cohort study. Clinical and laboratory data were collected every 3 months to assess safety and efficacy. The primary endpoint was the proportion of patients with virologic success (HIV‐RNA load <50 cp/mL) at 12 months using the FDA snapshot algorithm.

Results

A total of 281 patients (76% male, median age: 47 years, 56% MSM) were enrolled in this study. Median lymphocyte CD4 count at baseline was 640/mm3. Patients have received ART for a median of 7 years and viral replication was fully suppressed for a median of 3 years. Before the switch, 39% patients were treated with NNRTI, 52% with protease inhibitor and 7% with integrase inhibitor‐based regimens. Reasons for switch were simplification (176 cases), adverse events (AEs) (93 cases) and others (12 cases). At month 12 (database frozen on June 2014) in the snapshot analysis, 56% of patients met virologic success, 5% experienced virologic failure (n=14) and 39% had no data in the window period. In the LOCF analysis (using data from the previous available visit before month 12), 89% patients were suppressed, 5% had virologic failure and 6% had no data. Genotypic resistance analysis was performed in 7/14 patients at the time of virologic failure (3 of whom had previous NRTI/NNRTI resistance‐associated mutations (RAMs)), and new NNRTI and NRTI RAMs emerged in 4 patients. RPV‐based regimen was generally well tolerated and only 6% of patients discontinued treatment for AEs. Grade 2–4 treatment‐related AEs occurred in 39 patients: 6 had rashes, 13 neuropsychiatric symptoms, 10 GI symptoms, 10 biological abnormalities. At month 12, significant changes from baseline were seen for total and LDL cholesterol (−0.5 and −0.28 mmol/L, respectively, p<0.05 for both), and plasma creatinine (+5.8 µmol/L, p<10–4).

Conclusions

In patients fully suppressed on ART, switching to a RPV‐based regimen in clinical practice was well tolerated and associated with few virologic failures.
Renal safety profile of STB in virologically suppressed subjects from two randomized phase 3b switch trials
Authors: Reeves Iain , Fisher Martin , Kegg Stephen , Arribas Jose , Dau Lauren , Garner Will , Walker Ivan , Nguyen Thai
Published: November 2014

Introduction

Cobicistat, a component of stribild (STB), is known to inhibit renal creatinine secretion. A detailed analysis of the renal safety profile of STB in two Phase 3b switch studies of virologically‐suppressed individuals on stable therapy: STRATEGY(S)‐PI (STB vs a RTV‐boosted protease inhibitor [PI] with emtricitabine and tenofovir DF [FTC/TDF]); and STRATEGY(S)‐NNRTI (STB versus a non‐nucleoside reverse transcriptase inhibitor [NNRTI] with FTC/TDF) is herein described.

Materials and Methods

Baseline eGFR ≥70 mL/min was an inclusion criterion. The renal safety profile of STB was examined by baseline eGFR through week 48 (i.e., changes in eGFR, renal tubular laboratory abnormalities, investigator‐reported renal adverse events leading to discontinuation and unreported subclinical proximal renal tubulopathy [PRT]). Subclinical PRT was defined as a confirmed serum‐creatinine increase ≥0.4 mg/dL and two or three markers of renal tubular dysfunction (hypophosphatemia, normoglycemic glycosuria, proteinuria) occurring at the same visit at least once and with no alternative etiologies.

Results

In S‐PI, 433 subjects (STB 293; PI 140) and in S‐NNRTI, 434 subjects (STB 291; NNRTI 143) were randomized and treated. Most (>85%) STB subjects had a baseline eGFR ≥90 mL/min. STB subjects with baseline eGFR <90 mL/min had smaller declines in eGFR compared to those with baseline eGFR ≥90 mL/min and similar occurrences of renal tubular laboratory abnormalities (Table 1). Rate of renal adverse events leading to study drug discontinuation were similar for the STB group (one PRT in a subject with baseline tubular laboratory abnormalities consistent with underlying PRT and one isolated increase in serum creatinine) and PI group (one isolated decrease in eGFR); none in the NNRTI group. The case of PRT improved after study drug discontinuation. There were no cases of unreported subclinical PRT in any group.

Conclusions

In this virologically suppressed patient population, the renal safety of STB did not differ by baseline eGFR. The renal discontinuation rate was low in the STB group, similar to the RTV‐boosted PI group, and consistent with published historical rates.
Removing inactive NRTIs in a salvage regimen is safe, maintains virological suppression and reduces treatment costs: 96 weeks post VERITAS study
Authors: Trottier Benoit , Longpré Daniele , Dion Harold , Vezina Sylvie , Lavoie Stephane , Galanakis Chrissi , Machouf Nima , Thomas Réjean
Published: November 2014

Introduction

In HIV+ patients exhibiting multidrug resistance (MDR), NRTIs often have little activity, increased toxicity, drug interactions and add unnecessary treatment costs. The 48 week VERITAS study demonstrated that these patients can have a safe and effective simplification of salvage regimen by removing inactive NRTIs as determined by genotypic data. Virological, immunological, clinical and financial outcomes were evaluated at an additional 96 weeks of follow‐up.

Materials and Methods

MDR patients with an undetectable viral load (VL) on a stable regimen containing at least four ARVs (including one inactive NRTI) were enrolled in an open‐label, prospective simplification trial, where one inactive NRTI was removed at baseline (BL). A second NRTI could be removed at week 24 if the regimen contained at least five ARVs at enrolment.

Results

31 male patients participated. The mean length of treatment was 14 years, with a median CD4 count of 525. The BL regimen consisted of 4 ARVs in 22 patients (71%) and 5 ARVs in 9 patients (29%). 3TC or FTC was removed in 29 patients (94%), and either AZT or TDF was interrupted in 2 others. Four patients had a second NRTI stopped. One patient was removed at W26 as an active NRTI was removed for creatinine elevation. 30 well‐controlled patients continued follow‐up after W48. At W144, six patients had additional changes in their ARV regimen. Half were due to toxicity (jaundice, neuropathy and nephrotoxicity) while the other half were the result of treatment simplification. None of the patients exhibited virologic failure at the time of treatment change and maintained undetectable VLs throughout the entire follow‐up. These six patients had a mean gain of 79 CD4 (p=0.17) compared to baseline. 22 of the 24 patients (92%) with no changes in ARV therapy after W48 had undetectable VLs. The other two had confirmed virologic failure, one with genotypic resistance. All 24 had elevated CD4 counts (mean +118 CD4, p<0.0001). No deaths or serious adverse events were observed. One or two ARV removals translated to a mean annual saving of $3319 CDN (11%) and $8630 (24%) respectively.

Conclusions

Final results indicate that removing one or two inactive NRTIs from a regimen in patients taking four or more ARVs with controlled VL appears to be safe, maintains virological suppression through 144 weeks and significantly reduces treatment costs.
Nuke‐sparing regimens as a main simplification strategy and high level of toxicity resolution after antiretroviral switch: the SWITCHART Study
Authors: Carrero‐Gras Ana , Antela Antonio , Muñoz‐Rodríguez Jessica , Díaz‐Menéndez Marta , Viciana Pompeyo , Torrella‐Domingo Adriadna , Sanz‐Moreno José , Jesús Téllez‐Molina María , Moreno Javier , Hernández‐Quero José , Pérez‐Hernández Isabel A , Domingo‐Pedrol Pere
Published: November 2014

Background

The advent of combined antiretroviral therapy (ART) in the past decade has led to HIV suppression in most cases. Virological failure was the main reason for ART switch a few years ago; however, toxicity and treatment simplification have now gained importance due to the availability of more effective and convenient drugs. This study assessed the reasons for ART switch in daily practice.

Material and Methods

Observational retrospective study that included patients whose ART was switched between January 2011 and July 2012. Patients with any other switch during the follow‐up period (until September 2013) were excluded.

Results

A total of 246 patients were included. Main reasons for ART switch were simplification (33%) and toxicity (31%), followed by clinical trial inclusion (13%), virological failure (6%), drug interaction (4%), patient decision (3%), lack of adherence (2%), pregnancy (1%) and other (8%). Eighty patients switched to a simpler regimen (median age 48 [40–53], mean CD4 count 608±265 cells/cl, 89% <50 copies/ml, mean number of previous regimens 6±5, mean time on previous ART 3±2 years). In this case, previous ART mostly included 2NRTI+1PI/r (54%) (Figure 1). The simplification strategy mainly contained nuke‐sparing regimens (60%) based on PI (DRV/r 48%): monotherapy 46%, dual therapy 13% (PI/r+maraviroc 9%, PI/r+NNRTI 4%) and triple therapy 1% (PI/r+maraviroc+raltegravir). The second preferred simplification option was 2NRTI+1NNRTI (24%). Seventy‐seven patients switched due to toxicities (median age 47 [43–53], mean CD4 count 606±350 cells/μl, <50 copies/ml 82%, mean number of previous regimens 4±3, mean time on previous ART 3±3 years). Renal (25%) and CNS (18%) toxicities were the main reasons for ART switch, followed by diarrhoea (16%), liver enzyme elevation (ALT 10%; AST 9%; bilirubin 7%), lipid elevation (cholesterol 5%; triglycerides 8%), nausea (7%) and other (=5%) (Figure 2). All patients with renal toxicity were under TDF and in most cases this drug was removed from the new regimen (with 3TC/ABC or nuke‐sparing). Among patients with CNS toxicity, 79% were taking EFV; the main new treatment was a second‐generation NNRTI (ETR)+2NRTI. Toxicities were completely resolved in 66% of patients, partially resolved in 22% and not resolved in only 12%; the median time from ART switch to toxicity resolution was 4 (2–8) months.

Conclusions

The main reasons for ART switch in daily practice are simplification and toxicities, renal and CNS toxicities being the most prevalent. The preferred simplification strategies are nuke‐sparing regimens, mainly DRV/r‐based monotherapy and dual therapy. ART switch leads to a complete resolution of toxicities in most cases in the short term.
Switching from ritonavir to cobicistat in HIV patients with renal impairment who are virologically suppressed on a protease inhibitor
Authors: Fisher Martin , McDonald Cheryl , Moyle Graeme , Martorell Claudia , Ramgopal Moti , Laplante Francois , Curley Joanne , Graham Hiba , Tran‐Muchowski Cecilia , Liu Yapei , Rhee Martin , Szwarcberg Javier
Published: November 2014

Introduction

Cobicistat (COBI) is a pharmacoenhancer and one of the components of ECF/TDF (elvitegravir/cobicistat/emtricitabine/tenofovir DF), which is approved in treatment‐naïve HIV patients with creatinine clearance (CrCl) ≥70 mL/min. Study 118 assessed the renal safety of COBI‐containing regimens in HIV patients with mild to moderate renal impairment.

Material and Methods

Phase 3, open label study in HIV‐1‐infected patients with CrCl 50–89 mL/min who are virologically suppressed on a stable regimen containing ritonavir (RTV)‐boosted atazanavir (ATV) or darunavir (DRV). Patients switched RTV to COBI, while keeping the rest of their regimen unchanged. We present the 96‐week (Wk) data.

Results

Seventy‐three patients were enrolled. Mean age was 54 years; male 82%; white 77%; hypertension 38%; diabetes 18%; baseline proteinuria (≥trace) 51%; median CrCl 71 mL/min (range: 42–98). At Wk 96, 89% maintained virologic suppression (95% CI 77.4–95.8%). No emergent resistance developed. Reductions in CrCl (median [IQR]) were observed as early as Wk 2, after which they were nonprogressive through Wk 96 (Wk 48: −3.8 [−9–0.8]; Wk 96: −5.0 [−13.0–0.1]). Changes in CrCl by baseline CrCl (<70 vs ≥70) at Wk 96 were: −3.1 [−5.1–0.5] vs −7.6 [−15.2 to −3.6], respectively. Cystatin C‐based eGFR remained stable through Wk 96 (median [IQR]: −2.8 [−7.4–8.9 mL/min/1.73 m2). Actual GFR assessment using CLiohexol (n=14) was unaffected over 24 Wks (median at baseline: 82.5, median changes from baseline at Wks 2, 4, and 24: 1.6, 7.0, −4.1 mL/min, respectively). Three renal discontinuations occurred (two worsening CrCl and one proteinuria/hematuria); none had proximal renal tubulopathy [PRT]. No patient had laboratory evidence of PRT (>1 confirmed renal laboratory abnormalities [increase in serum Cr≥0.4 mg/dL, ≥2‐grade increase in proteinuria,≥1‐grade increase in normoglycemic glycosuria or hypophosphatemia]).

Conclusions

In HIV‐infected patients with CrCl 50–89 mL/min, on ATV‐ or DRV‐based regimen switching to COBI from RTV, demonstrated that COBI was well tolerated with no cases of PRT through 96 Wks. The renal safety profile of COBI in patients with mild to moderate renal impairment was consistent with the long‐term data in patients without renal impairment (CrCl≥70 mL/min) from the phase 3 studies of COBI‐containing regimens.
Hypovitaminosis D in HIV‐infected patients in Lisbon: a link with antiretroviral treatment
Authors: Boura Márcia , Filipa Sutre Ana , Badura Robert , Zagalo Alexandra , Afonso Cláudia , Caldeira Luís , Valadas Emília
Published: November 2014

Introduction

Recent data indicates that low vitamin D (25(OH)D) levels can lead to a worst prognosis in HIV‐infected individuals, even in those on successful antiretroviral therapy (ART) [1]. Portugal is the European country that has the largest average sun exposure time but prevalence of hypovitaminosis D is mostly unknown. Our aim was to determine the prevalence of hypovitaminosis D in HIV patients in Lisbon and the possible association with ART.

Methods

From 2012 to January 2014, plasma samples from 518 HIV‐infected patients were collected to 25(OH)D levels determination. Data on demographic features (age, ethnicity, country of origin) and clinical/laboratory parameters were collected from clinical files (HIV subtype, CD4+ cell count, CD4+ nadir, viral load (VL), HBV/HCV co‐infection and ART). 25(OH)D status was defined as: deficiency <20 ng/mL, insufficiency 20–30 ng/mL, optimal >30 ng/mL.

Results

Median age was 46 years old (±11); 62.0% (321/518) were male; 81.3% (421/518) were Caucasian and 78.6% (407/518) were Portuguese. Most patients (96.1%; 498/518), were HIV‐1 infected, 22.9% (114/498) and 4.0% (20/498) of them were HCV and/or HBV co‐infected, respectively. Mean CD4+ cell count was 648 cells/µL (±333) and nadir was 219 cells/µL (±179). On treated patients VL was <40 HIV RNA/mL in 86.7% (417/481). The median levels of 25(OH)D was 20.0 ng/mL (range 4.1–99.7) and we found differences between values observed during Winter (median 16.7 ng/mL) and Summer (median 24.9 ng/mL) (p<0.0001). Low 25(OH)D levels were not correlated to ethnicity (p=0.066). 25(OH)D level was <30 ng/mL in 80.1% (415/518) of the patients, from which 30.9% (160/518) and 49.2% (255/518) had insufficiency and deficiency levels, respectively. Most (92.9%; 481/518) were on ART: regimens containing PI (47.5%), NNRTI (40.3%; 41.3% on NVP and 58.7% on EFV), II (1.2%), PI+NNRTI (3.9%). Comparing the 25(OH)D level along the different ART regimens (PI vs NVP; PI vs EFV; PI vs no ART) there were differences between PI and EFV (p=0.044).

Conclusions

In this study, 80.1% of the HIV‐infected patients had hypovitaminosis D and ART regimens with EFV were more often associated with low 25(OH)D levels. Understanding the impact of the different antiretroviral drugs on 25(OH)D status could help to decide in clinical practice whether 25(OH)D supplementation or drug switch are the best options for each patient.
Recreational drugs and HIV in Europe: current use of recreational drugs and principal HIV guidelines related recommendations
Authors: Garin Escriva Noe , Velasco Muñoz Cesar , Thomas De Pourcq Jan , Lopez Garcia Belen , Maria Haro Abad Josep , Antonia Mangues Bafalluy Maria , Trilla Garcia Antoni
Published: November 2014

Introduction

Recreational drug consumption has been associated with both higher rates of risk activities related to HIV transmission and also worse adherence and management of HIV patients under HAART treatment. Moreover, relevant interactions may be present in patients under HAART treatment. Our aim is to present the European trends of drug consumption per country and age groups and assess the way drug consumption is addressed in general HIV guidelines.

Materials and Methods

Last 12‐month prevalence drug use was obtained from the European Monitoring Centre for Drugs and Drug Addiction for the four most consumed drugs (cannabis, cocaine, amphetamines, ecstasys). Consumption rates were collected and analyzed by country and age. Principal HIV guidelines were assessed to identify the degree of incorporation of drug use issues at three levels: transmission risk, adherence to the HAART and management of interactions. Guidelines: (a) WHO; (b) EACS; (c) BHIVA; (d) US DHHS; (e) IAS‐USA; (f) GESIDA; (g) French CPG; (h) Italian CPG.

Results

Data on drugs of abuse consumption was obtained from 29 European countries, with results showing relevant drug utilization in Europe. Cannabis was the most frequent drug across all countries, with 10 countries over 5% of prevalence over the last year. Other drugs prevalence accounted for about 0.5–1%, reaching up to: 2.1% for cocaine in Spain, 1.4% for ecstasy in the Netherlands and 1.1% for amphetamines in Estonia. 15–24 and 25–34 years old subgroups had the highest prevalence, although notable use of cannabis and cocaine was also found in the 35–44 and 45–54 subgroups. From the eight guidelines assessed, six considered recreational drugs at any point. Recommendations for specific drugs were given in 50% of the guidelines. From those guidelines addressing drug consumption: three assessed risk habits which related to transmission risk, six appraised issues on adherence to HAART and five comprised data on interactions between recreational drugs and HAART. Additionally, five guidelines mentioned drugs in the context of other issues, such as sexual dysfunction or HIV‐associated neurocognitive impairment.

Conclusions

Use of recreational drugs is frequent in Europe, not only in the younger population but also in other unexpected older subgroups. The scarce information found in the guidelines has a potential implication for patients and clinicians; therefore, there is a need to include specific recommendations about the clinical management of people living with HIV who use recreational drugs.
Isolation of Thymic Epithelial Cells and Analysis by Flow Cytometry
Authors: Jain Reema , Gray Daniel H.D.
Published: November 2014

The epithelial cells of the thymus govern the differentiation of hematopoietic precursors into T cells, which are critical for acquired immunity. Thymic epithelial cells (TEC) provide molecular cues that direct precursor recruitment, commitment to the T cell lineage, thymocyte proliferation, and the processes of positive and negative selection. Despite the importance of TEC to the immune system, fundamental questions regarding their differentiation, turnover, and function throughout life remain unanswered. This knowledge gap is largely due to technical difficulties in isolating, quantifying, and purifying this rare cell type. Here, we describe methods for the enzymatic digestion of the thymus to obtain single‐cell suspensions of TEC, their analysis by flow cytometry, enrichment using magnetic beads, and purification for a variety of downstream applications. © 2014 by John Wiley & Sons, Inc.
Isolation and Purification of Proteasomes from Primary Cells
Authors: Steers Nicholas J. , Peachman Kristina K. , Alving Carl R. , Rao Mangala
Published: November 2014

Proteasomes play an important role in cell homeostasis and in orchestrating the immune response by systematically degrading foreign proteins and misfolded or damaged host cell proteins. We describe a protocol to purify functionally active proteasomes from human CD4+ T cells and dendritic cells derived from peripheral blood mononuclear cells. The purification is a three‐step process involving ion‐exchange chromatography, ammonium sulfate precipitation, and sucrose density gradient ultracentrifugation. This method can be easily adapted to purify proteasomes from cell lines or from organs. Methods to characterize and visualize the purified proteasomes are also described. © 2014 by John Wiley & Sons, Inc.
Global estimate of submarine groundwater discharge based on an observationally constrained radium isotope model
Authors: Kwon Eun Young , Kim Guebuem , Primeau Francois , Moore Willard S. , Cho Hyung‐Mi , DeVries Timothy , Sarmiento Jorge L. , Charette Matthew A. , Cho Yang‐Ki
Published: November 2014

Along the continental margins, rivers and submarine groundwater supply nutrients, trace elements, and radionuclides to the coastal ocean, supporting coastal ecosystems and, increasingly, causing harmful algal blooms and eutrophication. While the global magnitude of gauged riverine water discharge is well known, the magnitude of submarine groundwater discharge (SGD) is poorly constrained. Using an inverse model combined with a global compilation of 228Ra observations, we show that the SGD integrated over the Atlantic and Indo‐Pacific Oceans between 60°S and 70°N is (12 ± 3) × 1013 m3 yr−1, which is 3 to 4 times greater than the freshwater fluxes into the oceans by rivers. Unlike the rivers, where more than half of the total flux is discharged into the Atlantic, about 70% of SGD flows into the Indo‐Pacific Oceans. We suggest that SGD is the dominant pathway for dissolved terrestrial materials to the global ocean, and this necessitates revisions for the budgets of chemical elements including carbon.
Generation of Mammalian Offspring by Haploid Embryonic Stem Cells Microinjection
Authors: Shuai Ling , Li Wei , Wan Haifeng , Zhao Xiao‐Yang , Wang Liu , Zhou Qi
Published: November 2014

In this unit we introduce the derivation and genetic modification of mouse haploid embryonic stem (ES) cells. We detail how to produce haploid embryos and the subsequent ES derivation and cell culture. We further introduce readers to the intracytoplasmic injection processes of two types of haploid ES cells [androgenetic haploid ES (ahES) and parthenogenetic ES (phES)], both of which possess potential to produce fertile progenies by microinjection. This unit will be interesting to researchers who focus on recessive screens and transgenic animal model production with haploid stem cells. © 2014 by John Wiley & Sons, Inc.
In Situ Reinforcement of Ti6Al4V Matrix Composites by Polymer‐Derived‐Ceramics Phases
Authors: Fabrizi Alberto , Bonollo Franco , Colombo Paolo , Biasetto Lisa
Published: November 2014

Ti6Al4V‐based metal matrix composites (MMCs) are successfully synthesized via a novel process route. Ti6Al4V powder is premixed with a solid preceramic polymer used as precursor for the in situ formation of a ceramic phase dispersed at the micrometer range. Ball‐milling is used to intimately mix the powders. After the pyrolysis and sintering step, a Ti5Si3 and TiC dispersion within the Ti6Al4V equiaxed grains matrix is formed. The effect of the volume fraction of the polymer‐derived ceramic phase in the Ti6Al4V matrix is investigated in terms of Vickers hardness and wear resistance. The introduction of 10 vol% of ceramic reinforcement produces a homogeneous structure and results in a compact material with improved integrity and enhanced mechanical properties compared to standard cast alloy or Ti6Al4V‐based composites reported in the literature.
Aggregation‐Induced Emission Features of Organometal Halide Perovskites and Their Fluorescence Probe Applications
Authors: Niu Yuwei , Zhang Feng , Bai Zelong , Dong Yuping , Yang Jian , Liu Ruibin , Zou Bingsuo , Li Jingbo , Zhong Haizheng
Published: November 2014

Organometal hybrid perovskites exhibit tunable absorption and photoluminescence spectra that originate from the adjustable excitons of the self‐assembled quantum‐well structures. The aggregation‐induced emission (AIE) features of (RNH3)2PbI4 (R = alkyl, CnH2n+1, n = 4, 12, 16, 18) as well as their reversible photoluminescence response to pH value are demonstrated. This interesting phenomenon correlates with the formation of quantum‐well structure, which is a novel AIE mechanism. The temperature sensors based on organometal hybrid perovskites are also investigated. The combination of high sensitivity (1.3% K−1) and good reversibility (>500 cycles) of organometal halide perovskites to temperature in a large temperature range (0–80 °C) makes them to be versatile systems for the temperature sensor applications. Furthermore, as a proof of concept, the application of organometal hybrid perovskites in 2D spatial imaging and NIR light detection is also presented.
Visible‐Light‐Mediated Radical Aryldifluoroacetylation of N‐Arylacrylamides to give Difluoroacetylated Oxindoles
Authors: Fu Weijun , Zhu Mei , Zou Guanglong , Xu Chen , Wang Zhiqiang
Published: November 2014

A simple and practical approach to oxindole derivatives via visible‐light‐photocatalyzed aryldifluoroacetylation of N‐arylacrylamides with BrCF2CO2Et has been developed. This method provides convenient access to a variety of difluoroester‐substituted oxindoles under mild conditions.
Reversing the Stereoselectivity of a Palladium‐Catalyzed O‐Glycosylation through an Inner‐Sphere or Outer‐Sphere Pathway
Authors: Xiang Shaohua , Hoang Kim Le Mai , He Jingxi , Tan Yu Jia , Liu Xue‐Wei
Published: November 2014

An efficient and concise method for the construction of various O‐glycosidic bonds by a palladium‐catalyzed reaction with a 3‐O‐picoloyl glucal has been developed. The stereochemistry of the anomeric center derives from either an inner‐sphere or outer‐sphere pathway. Harder nucleophiles, such as aliphatic alcohols and sodium phenoxides give β‐products, and α products result from using softer nucleophiles, such as phenol.
Introducing an In Situ Capping Strategy in Systems Biocatalysis To Access 6‐Aminohexanoic acid
Authors: Sattler Johann H. , Fuchs Michael , Mutti Francesco G. , Grischek Barbara , Engel Philip , Pfeffer Jan , Woodley John M. , Kroutil Wolfgang
Published: November 2014

The combination of two cofactor self‐sufficient biocatalytic cascade modules allowed the successful transformation of cyclohexanol into the nylon‐6 monomer 6‐aminohexanoic acid at the expense of only oxygen and ammonia. A hitherto unprecedented carboxylic acid capping strategy was introduced to minimize the formation of the dead‐end intermediate 6‐hydroxyhexanoic acid. For this purpose, the precursor ε‐caprolactone was converted in aqueous medium in the presence of methanol into the corresponding methyl ester instead of the acid. Hence, it was shown for the first time that esterases—specifically horse liver esterase—can perform the selective ring‐opening of ε‐caprolactone with a clear preference for methanol over water as the nucleophile.
Lay Personality Theories in Interactive Decisions: Strongly Held, Weakly Supported
Authors: Cooper Dylan A. , Connolly Terry , Kugler Tamar
Published: November 2014

In interactive decisions, cues to what others will do are important in forming a strategy. Information about others' personalities appears to be potentially valuable for this purpose. We report a series of four studies examining how information about another actor's personality influences people's own choices in interactive decisions. The studies found widespread beliefs that others' personality characteristics are strongly predictive both of broad classes of decision behavior (competition/cooperation, risk‐seeking/risk‐aversion) (Study 1) and of specific choices (Study 2) in single‐agent settings. These beliefs extended to predicting others' choices in interactive decisions (Study 3) and to shaping the predictor's own decisions in interactive play in Chicken and Assurance games (Study 4). Overall, we found extensive evidence that laypeople believe that the personality traits we selected (angry‐hostility, anxiety, assertiveness, excitement‐seeking, and warmth) have substantial effects on behavior in interactive decisions and they act on those beliefs when making their own decisions. The empirical evidence supporting the predictive validity of these traits was, however, quite weak. Copyright © 2014 John Wiley & Sons, Ltd.