bluuebunny/crossref_metadata_2025 huggingface dataset:
Possible association between the stage of HIV disease, antiretroviral treatment and the nutrient composition of breast milk in the Mangaung area, South Africa
Authors: van den Heever Wilhelmina , de Wet Geta , Hattingh Moira
Published: November 2014

Introduction

In South Africa where replacement feeding may not be affordable, feasible or sustainable, HIV‐infected women are recommended to exclusively breastfeed their infants during the first six months of life. The question arises whether HIV disease progression and its metabolic impact on the mother will affect the nutrient composition of breast milk. The aim was to determine the possible association between HIV disease progression, as measured by the immunological markers, and the nutrient composition of breast milk.

Methods

The nutrient composition of breast milk of 100 HIV‐infected and 50 non‐infected volunteered (control group) lodging/day visiting mothers at Paediatric/Neonatal wards of National, Pelonomi and Universitas hospitals, Bloemfontein, were measured. The HIV‐infected group was subdivided into HIV‐naïve and HIV‐ARV treatment group. Breast milk and blood samples were obtained. Macronutrients namely lactose, proteins, fat, total solids and the energy content of the breast milk and micronutrient namely calcium and phosphate were measured. Blood and immunological parameters comprised of CD4/CD8+T cell counts, viral loads and full blood counts.

Results

Protein levels amongst the HIV‐infected group showed a significant elevation (p<0.0001) compared to the control group. The calcium levels of the HIV‐infected group were significantly lower (p=0.0081) than the control group. No statistically significant differences were recorded of the measured nutrients between mothers receiving treatment and the HIV‐naïve group. All the HIV patients were anaemic with haemoglobin, haematocrit and RDW below the normal range. The Spearman Correlation Coefficient was used to determine if HIV disease progression have an influence on the nutrient composition. For the HIV‐naïve group, a significant correlation was found between the viral load and percentage total solids in breast milk. A correlation between the CD4+T cell count, the percentage total solids and energy content of the breast milk was determined in the HIV‐ARV treatment group. No strong positive correlation could be established between the immunological markers, HIV disease progression and the nutrient composition in the breast milk.

Conclusions

HIV mothers can breastfeed their babies even at a more advanced stage of HIV disease progression, but emphasis has been placed on exclusive breastfeeding.
The potential impact of new national guidance on primary prevention of cardiovascular disease in people living with HIV
Authors: Ahmed Nadia , Bradley Sarah , Pearson Patrick , Edwards Simon , Waters Laura
Published: November 2014

Introduction

Cardiovascular disease (CVD) is the leading cause of death in England and Wales. As people living with HIV (PLWH) age, proactive management of CVD risk factors is crucial. The long‐awaited draft guidelines for CVD from the National Institute of Clinical Excellence (NICE) propose lipid modification (with statins) and lifestyle modification for 40–74 year olds with >10% (previously >20%) 10‐year risk of CVD using QRISK2. We currently use Framingham so compared 3 CVD risk calculators in our cohort and analyzed the impact of a change in CVD threshold on the proportion of our patients who would need intervention.

Materials and Methods

Framingham, QRISK2 and JBS3 cardiovascular risk calculators were compared in a group of randomly selected patients. Then, to analyze the impact of a change in primary prevention threshold on our cohort, we interrogated a prospectively collected database to identify all individuals who had a documented Framingham risk assessment and applied the current/proposed thresholds accordingly. We performed the same analysis for the three calculator subgroup (recalculating Framingham risk). Finally we surveyed HIV services in England & Wales regarding their choice of calculator.

Results

We compared the 3 CVD risk calculators in 100 patients, see Table 1.

In terms of eligibility for primary prevention 20.9% (916/4383) had documented Framingham risk assessment as part of routine care. Using a 20% threshold, 8.8% (81/916) would require intervention, increasing to 35.2% (322/916) with a threshold for intervention of 10%. Restricting analysis to the 100 patients to whom we applied all three calculators resulted in the following proportion requiring intervention with a 20%/10% threshold, respectively: Framingham 28%/76%, QRISK2 20%/53%, JBS3 15%/42% (four patients were excluded due to incomplete data).

Conclusions

Reducing the threshold for cardiovascular preventative measures to 10% vastly increases the number of patients requiring primary intervention, from two‐ to fourfold depending on risk calculator used. This may have significant implications, including cost, drug–drug interactions and patient experience, that HIV physicians and general practitioners will need to address, ideally in a coordinated and patient‐focused manner.
Association between abdominal aortic calcifications, bone mineral density and vertebral fractures in a cohort of HIV‐positive patients
Authors: Iannotti Nathalie , Gazzola Lidia , Savoldi Alessia , Suardi Elisa , Cogliandro Viola , Bai Francesca , Magenta Alberto , Peri Mauro , Bini Teresa , Marchetti Giulia , d'Arminio Monforte Antonella
Published: November 2014

Introduction

Evidence from HIV‐negative cohorts suggests a link between osteoporosis and cardiovascular disease. We evaluated the presence and distribution of abdominal aortic calcifications (AAC) and its correlation with bone mineral density (BMD) and vertebral fractures (VF) in a cohort of HIV‐positive patients.

Materials and Methods

In this cross‐sectional study, 280 asymptomatic HIV‐positive patients from the SPID (“San Paolo” Infectious Diseases) cohort were submitted to lateral spine X‐ray and DXA. AAC was identified using the AAC‐8 score, which estimates the total length of calcification of the anterior and posterior aortic walls in front of vertebrae L1–L4. Low BMD was defined by T‐score or Z‐score <−1 at lumbar spine or femoral neck. VF were identified by morph‐metric analysis of X‐ray and were defined by the “spine deformity index” (SDI) ≥1 according to semiquantitative method by Genant. Associations between AAC, BMD and SDI were evaluated by univariate and multivariate logistic regression models. The relationship between the grade of AAC and SDI was evaluated by Spearman's correlation.

Results

AAC≥1 was present in 65 patients (23.2%); of these 15 patients showed moderate/severe calcifications (AAC>2). Low BMD was found in 163 patients (58.2%) and VF (SDI≥1) in 47/274 patients (17.1%). By univariate analysis, factors associated with AAC>=1 were: age (for additional 10 years older HR 3.81 [IC95% 2.64–5.51], p<0.0001) lower CD4 nadir (for additional 50 CD4 HR 0.89 [IC95% 0.82–0.97], p=0.01) AIDS‐diagnosis (HR 2.13 [IC95 % 1.11–4.08], p=0.02) and being on HAART (HR 2.75 [IC95% 1.28–5.90], p=0.009). In multivariate analysis, only age (OR 2.62, IC95% 1.72–3.99, p<0.0001) resulted significantly associated with AAC≥1. Patients with AAC≥1 had twofold increase in the risk of low BMD (HR 2.45 [IC95% 1.32–4.45], p=0.004) and VF (SDI>=1: HR 2.17 [IC95% 1.1–4.2], p=0.02) compared to patients without AAC. The grade of AAC was directly correlated with the grade of SDI (rho=0.16; p=0.008): AAC>2 determines a sixfold increase in the risk of VF (HR 6.44 [IC95% 2.21–18.79], p=0.0006). AAC≥1 predict VF independently from BMD, vitamin D status and bone turnover marker (Table 1).

Conclusions

In our HIV population, AAC resulted a strong predictor of both low BMD and VF, irrespective of factors involved in bone formation. The grade of AAC was directly correlated with the grade of VF.
Depression in HIV‐positive women is associated with changes in antiretroviral treatment regimens
Authors: Philippe Küpper‐Tetzel Claus , Göpel Siri , Khaykin Pavel , Wolf Timo , Stephan Christoph , Herrmann Eva , Brodt Hans‐Reinhard , Haberl Annette
Published: November 2014

Introduction

Depression is a co‐morbidity of clinical significance in HIV‐positive patients with an estimated prevalence of more than 20%. Sex and gender‐related differences in depression are well described in HIV‐negative populations, demonstrating that more women are being affected. So far little is known about frequency and characteristics of depression in HIV‐positive men and women.

Materials and Methods

Primary objective of our prospective epidemiological study was the evaluation of the Beck score for depression in male and female patients of the Frankfurt HIV Cohort. The Beck Depression Inventory (BDI‐II) is a self‐report symptom inventory made up of 21 questions, each with 4 possible answers, correlating with a certain point value. Interpretation: score 14–19: mild depression; score 20–28: moderate depression; score ≥29: severe depression. Secondary objectives of the analysis were factors that might possibly influence the disposition for depression in HIV‐positive patients, e.g. age, antiretroviral treatment history, co‐morbidities and socioeconomic status.

Results

Between January and October 2013, 348 patients were enrolled in the study, 161 women and 187 men of the Frankfurt HIV Cohort, who had a routine appointment at the HIV‐Center of the University Clinic Frankfurt. The mean age of all study participants was 45 years (range 22–80). The majority of patients were on antiretroviral therapy (91%) at study entrance. The median BDI‐II score in all patients was 8 (0–49); in female patients 10 (0–42), in male patients 6 (0–49), respectively (Table 1). Significant more women than men showed a score for moderate depression (p=0.006). Factors associated with a BDI‐II score ≥20 in women were older age (>45 years), living alone, unemployment and the number of prior changes in antiretroviral therapy.

Conclusions

Depression in people living with HIV shows sex and gender‐related differences that might also influence antiretroviral treatment strategies. HIV specialists should be aware of these gender‐specific aspects and consider routine screening for depression especially in female patients of older age or those with multiple therapy changes in history.
HIV‐1 tat and rev upregulates osteoclast bone resorption
Authors: Chew Nicholas , Tan Eemin , Li Lei , Lim Ryan
Published: November 2014

Introduction

Disruption in bone homeostasis with increased osteoclastic resorption may lead to osteoporosis. HIV tat has been found to increase differentiation of precursor cells into osteoclast (OC) [1]. Presence of soluble HIV proteins in virally suppressed HIV patients on ART may drive a bone resorption phenotype. We investigated the role of soluble HIV proteins (tat, gp120 Mn and Bal, rev and p55‐gag) on osteoclastogenesis and OC resorptive capacity.

Methods

Mouse monocyte RAW 264.7 cells were cultured in vitro and induced to differentiate into OCs with 50 ng/mL RANKL and 25 ng/mL mCSF. Medium was supplemented with 100 ng/mL of recombinant HIV tat, gp120 (Mn and Bal), rev, nef and p55‐gag, respectively, with zolendronate as negative control. Differentiated OCs were stained for TRAP and counted. OC resorption function was examined by culturing differentiated OCs (in the presence of respective HIV proteins) on dentin‐coated plates and examining the following (i) sealing zone formation, (ii) volume of resorption pits and (iii) area of resorption pits per field using confocal microscopy. Expression of OC specific genes including NFATc1 and cathepsin K was investigated by qPCR. Reactive oxygen species (ROS) production is essential in RANKL‐induced OC differentiation [2,3]; effect of these proteins on ROS production was assessed using the fluorescent H2DCFH‐DA. Mean fluorescence intensity was then measured by flow cytometry. TNFα production by OC precursors when incubated with tat and rev was measured by ELISA.

Results

Tat and rev treatment was associated with increased OC formation by 70 and 26%, respectively (p<0.01), relative to control, while zolendronate significantly inhibited OC formation by 75%. Gp120 Mn and Bal, nef and p55‐gag treatment had no effect on OC differentiation. Interestingly, neither tat nor rev treatment caused significant increases in sealing zone formation but increased dentin resorption pit area by 28 and 19%, respectively, and resorption pit volume by 11 and 6%, respectively. Tat protein treatment was associated with upregulation of NFATc1 and cathepsin K mRNA expression by 20 and 15%, respectively. Incubation with tat and rev led to a dose‐dependent increase in intracellular ROS production in the monocytes and OC precursors and significant upregulation in TNFα cytokine production by the OC precursors.

Conclusions

In addition to their effect of OC differentiation, we demonstrated the effects of tat and rev on OC resorption. HIV tat and rev are both biologically active in driving a pro‐osteoclastic phenotype.
Failure of daily tenofovir to prevent HIV transmission or the establishment of a significant viral reservoir despite continued antiretroviral therapy
Authors: Davies Olubanke , Alexander Hannah , Robinson Nicola , Pace Matthew , Brady Michael , Frater John , Fox Julie
Published: November 2014

Introduction

Truvada is licenced for HIV‐1 prevention in the USA and is available in the private sector. Tenofovir performed as well as Truvada in the PARTNERS PrEP study and is used as HIV pre‐exposure prophylaxis (PreP) in some settings. The clinical efficacy of Tenofovir for PrEP outside a clinical trial is unknown. Antiretroviral therapy (ART) at acute HIV‐1 infection (AHI) limits the size of the reservoir, optimizing the chance of maintaining viral control off therapy. As such ART at acute HIV infection is proposed to offer a functional cure in a minority of subjects. We present two cases where Tenofovir PrEP failed to prevent HIV acquisition and failed to limit viral reservoir.

Materials and Methods

Two individuals receiving tenofovir monotherapy for Hepatitis B monoinfection were diagnosed with AHI as defined by a negative HIV antibody test within three months of a positive HIV test following unsafe sex with casual male partners. In‐depth histories were taken. Viral genotypes and Tenofovir drug levels were measured from samples taken as close to HIV seroconversion as possible and subsequent samples were analyzed for proviral Total HIV‐1 DNA by qPCR.

Results

Patient A had received tenofovir for the preceding six years and always maintained an undetectable Hepatitis B viral load with no concerns about adherence. Two weeks preceding the positive HIV antibody test, he experienced mild symptoms (fever, pharyngitis) of HIV seroconversion. HIV status was confirmed by a repeat fourth generation HIV antibody test and by Western Blot and an HIV viral load was undetectable. Tenofovir trough level at HIV diagnosis was within normal limits. The regimen was intensified to Eviplera and a total HIV‐1 DNA was 1381 copies/million CD4 T cells. Patient B received four regimens for hepatitis B treatment before starting tenofovir monotherapy in 2011 and subsequently maintained an undetectable hepatitis B viral load. After three years of tenofovir monotherapy he developed a severe symptomatic seroconversion illness and tested HIV antibody positive. The baseline HIV viral load was 103,306 copies/mL. The regimen was intensified and total HIV‐1 DNA was 2746 copies/million CD4 T cells.

Conclusions

Further investigation into the efficacy of tenofovir for PrEP outside a clinical trial is required. ART at AHI does not always lead to a low viral reservoir. To explore the possibility of replication incompetent virus, viral outgrowth assays are underway.
Protease mutations emerging on darunavir in protease inhibitor‐naïve and experienced patients in the UK
Authors: El Bouzidi Kate , White Ellen , Mbisa Jean L , Phillips Andrew , Mackie Nicola , Pozniak Anton , Dunn David
Published: November 2014

Introduction

Darunavir (DRV) is a preferred agent in treatment guidelines for ART‐naïve and experienced patients [1]. It is considered to have a high genetic barrier to resistance and 11 resistance‐associated mutations (RAMs) are recognized by IAS‐USA [2]. These have largely been identified by analyses examining the correlation between baseline genotype and virological response [3]. However, there is little information on RAMs that are directly selected by DRV, outside of short‐term clinical trials. We aimed to identify emerging mutations by comparing the genotypes of individuals before and after DRV exposure.

Materials and Methods

The UK HIV Drug Resistance Database was used to identify patients aged over 16 who had received at least 30 days of a DRV‐containing regimen. Patients were included if they had a “baseline” resistance test, prior to DRV exposure, and a “repeat” test, either on DRV or within 30 days of stopping this agent. To avoid attributing the effects of other PIs on emerging RAMs to DRV, patients were excluded if they had received another PI for greater than 90 days between the baseline genotype and the start of DRV. The baseline and repeat tests were compared to determine the nature of mutations stratified by PI history.

Results

A total of 5623 patients had DRV, of whom 306 met the inclusion criteria. A total of 228 (74.5%) were male, median age at the start of DRV was 42 years (IQR 37–47), and half had subtype B infection. The mode of transmission was homosexual contact for 50%, heterosexual for 38%, and 3% were injection drug users. The median CD4 count at the start of DRV was 257 cells/mm3 (IQR 94–453). A total of 149 patients (49%) had a history of PI use prior to DRV, and 157 (51%) were PI‐naïve. The most common previous PIs were lopinavir, atazanavir, and saquinavir. Baseline DRV RAMs were present in 1 (0.6%) PI‐naïve and 20 (13.4%) PI‐experienced patients. Mutations emerged under DRV pressure in a further 3 (1.9%) PI‐naïve patients, and in 7 (4.7%) PI‐experienced patients, 5 of whom had other DRV RAMs present at baseline (Table 1). The median time from the start of DRV to the repeat test was 196 days for PI‐naïve patients and 296 days for PI‐experienced.

Conclusions

PI‐experienced patients had a greater prevalence of DRV RAMs at baseline than PI‐naïve individuals, probably due to the fact that some DRV RAMs can be selected by other PIs. This group also accumulated more RAMs during DRV exposure, possibly because previous PIs had caused minority variants which then emerged on DRV therapy. Overall, only 10 patients accumulated 16 RAMs, which supports the perception that DRV has a high genetic barrier to resistance. Repeat genotyping in the case of virological failure on DRV may still be warranted to detect emerging resistance and guide management decisions.
Improved therapy‐success prediction with GSS estimated from clinical HIV‐1 sequences
Authors: Pironti Alejandro , Pfeifer Nico , Kaiser Rolf , Walter Hauke , Lengauer Thomas
Published: November 2014

Introduction

Rules‐based HIV‐1 drug‐resistance interpretation (DRI) systems disregard many amino‐acid positions of the drug's target protein. The aims of this study are (1) the development of a drug‐resistance interpretation system that is based on HIV‐1 sequences from clinical practice rather than hard‐to‐get phenotypes, and (2) the assessment of the benefit of taking all available amino‐acid positions into account for DRI.

Materials and Methods

A dataset containing 34,934 therapy‐naïve and 30,520 drug‐exposed HIV‐1 pol sequences with treatment history was extracted from the EuResist database and the Los Alamos National Laboratory database. 2,550 therapy‐change‐episode baseline sequences (TCEB) were assigned to test set A. Test set B contains 1,084 TCEB from the HIVdb TCE repository. Sequences from patients absent in the test sets were used to train three linear support vector machines to produce scores that predict drug exposure pertaining to each of 20 antiretrovirals: the first one uses the full amino‐acid sequences (DEfull), the second one only considers IAS drug‐resistance positions (DEonlyIAS), and the third one disregards IAS drug‐resistance positions (DEnoIAS). For performance comparison, test sets A and B were evaluated with DEfull, DEnoIAS, DEonlyIAS, geno2pheno[resistance], HIVdb, ANRS, HIV‐GRADE, and REGA. Clinically‐validated cut‐offs were used to convert the continuous output of the first four methods into susceptible‐intermediate‐resistant (SIR) predictions. With each method, a genetic susceptibility score (GSS) was calculated for each therapy episode in each test set by converting the SIR prediction for its compounds to integer: S=2, I=1, and R=0. The GSS were used to predict therapy success as defined by the EuResist standard datum definition. Statistical significance was assessed using a Wilcoxon signed‐rank test.

Results

A comparison of the therapy‐success prediction performances among the different interpretation systems for test set A can be found in Table 1, while those for test set B are found in Figure 1. Therapy‐success prediction of first‐line therapies with DEnoIAS performed better than DEonlyIAS (p<10–16).

Conclusions

Therapy success prediction benefits from the consideration of all available mutations. The increase in performance was largest in first‐line therapies with transmitted drug‐resistance mutations.
Transmitted antiretroviral drug resistance in treatment naïve HIV‐infected persons in London in 2011 to 2013
Authors: McFaul Katie , Lim Charlotte , Jones Rachael , Asboe David , Pozniak Anton , Sonecha Sonali , Boffito Marta , Nwokolo Nneka
Published: November 2014

Introduction

Previously published UK data on HIV transmitted drug resistance (TDR) shows that it ranges between 3 and 9.4% [1,2]. However, there are no recent data from populations where HIV transmission rates are increasing. The aim of this study was to assess the prevalence of TDR in untreated HIV‐infected individuals attending three HIV specialist clinics under the HIV Directorate, Chelsea and Westminster Hospital and based throughout London – the Kobler Clinic, 56 Dean Street and West London Centre for Sexual Health.

Methods

We included all patients with a HIV diagnosis, no history of antiretroviral therapy (ART) intake, attending one of the three clinics (Kobler (K), 56 Dean Street (DS) and West London (WL)), between 2011 and 2013 who started antiretrovirals. Reverse transcriptase (RT) and protease region sequencing was performed using Vircotype virtual phenotype resistance analysis. Drug resistance mutations were identified according to Stanford University HIV Drug Resistance Database (http://hivdb.stanford.edu/).

Results

Among 1705 HIV‐1‐infected patients enrolled in the study, 1252 were males (919 were MSM), 107 were females and 346 had no gender recorded. Ethnicity was 51.1% white British/Irish/other, 6.1% African, 2.1% Caribbean, 2.8% Asian, 1.3% Indian/Pakistani/Bangladeshi, 4.2%, other, 3.2% not stated, and 29.2% unknown. 547 were from K (84.3% males, 48.3% MSM), 826 were from DS (84.3% males, 71.9% MSM), and 109 from WL (87.2% males, 56.0% MSM), 223 from other sites not specified. 77.5% (1321 of 1705) of patients had baseline viral resistance testing performed. Prevalence of primary resistance in those with a baseline viral resistance test was 13.5% overall: 19.3% in K, 14.9% in DS, and 14.7% in WL. The most common mutations detected were: NRTI: 184V, 215F, 41L; NNRTI 103N, 179D, 90I; PI 90M, 46I, and 82A. Among patients who tested with TDR, 79.1% had one single mutation, 18.7% and 2.2% exhibited dual or triple class‐resistant viruses, respectively.

Conclusions

This study across a large HIV Medicine Directorate reported an overall TDR prevalence which is higher than that previously published and with significant rates of NNRTI resistance at baseline.
Resistance remains a problem in treatment failure
Authors: Obermeier Martin , Ehret Robert , Wienbreyer Andreas , Walter Hauke , Berg Thomas , Baumgarten Axel
Published: November 2014

Introduction

Proven resistance against HIV drugs, either by phenotyping or genotyping is a rare event in clinical trials. The overall assumption of drug resistance disappearing is additionally driven by the recommendations to screen for transmitted drug resistance, leading to large numbers of examinations with relatively low rates of resistance. Goal of our analysis was to assess if drug resistance in treatment failure is also decreasing outside of clinical trials.

Materials and Methods

The MIB database at timepoint of analysis consists of data from 2876 HIV infected patients. Besides various laboratory parameters, clinical data and treatment history is included. HIV‐1 protease and reverse transcriptase sequences were analyzed using the HIV‐GRADE drug resistance algorithm. As in only a small number of patients genotypic resistance testing for integrase inhibitors was performed, mainly due to reimbursement reasons, it was assumed that failing treatment on a previous integrase inhibitor containing regimen is equate to resistance.

Results

Of the 2876 patients in the database, 220 had a treatment change due to treatment failure between 2009 and 2012, a genotypic resistance testing at an appropriate timepoint of maximum four weeks before treatment change and a treatment duration of at least six months before treatment failure. In 2009, 61% of patients showed no drug resistance while 39% showed resistance against one or more drug classes (two or more drug classes: 19.5%; three or more drug classes: 2.4%, four drug classes 2.4%). In 2012, no resistance was found in 52% of patients while resistance against three or more drug classes was found in nearly 14% of patients (one or more: 48%; two or more 23%; four classes: 4.5%).

Conclusions

Treatment failure with viral load sufficiently high for drug resistance testing was not frequently observed in our database. Nevertheless, treatment failure was often associated with drug resistance against at least one drug class. With more use of the newer drug classes, resistance against those new classes will become more common and rates of multiclass resistance will be increasing.
Potential drug–drug interactions in HIV‐perinatally infected adolescents on antiretroviral therapy in Buenos Aires, Argentina
Authors: Cordova Ezequiel , Cecchini Diego , Rodriguez Claudia
Published: November 2014

Introduction

An increasing number of treatment‐experienced perinatally HIV‐infected adolescents (PHA) are being transitioned from paediatric centres to adult HIV‐care [1]. Most of them had been heavily exposed to antiretroviral drugs (ARVs), harbour drug‐resistant viruses and require non‐antiretroviral medication due to comorbidities [2]. This may predispose for clinically significant drug–drug interactions (CSDDIs) [3]. There are no studies concerning CSDDIs in PHA. We aimed to evaluate the prevalence of concomitant medications and CSDDIs in PHA who were transitioned for adult HIV‐care to the Infectious Diseases Unit, Cosme Argerich Hospital, Buenos Aires City, Argentina.

Materials and Methods

Descriptive pilot cross‐sectional study (March to June 2014). PHA under ARVs at the time of the study were assessed for concomitant medication. CSDDIs were screened and categorized using the University of Liverpool Drug Interactions Program (www.hiv‐druginteractions.org) [4].

Results

Forty‐five patients were included. Female sex: 53%. Median (IQR) age: 20 years (18–22). CDC‐stage C was observed in 27 (79%); 50% had ≥1 comorbidities including 3 with HCV co‐infection. Drug abuse was observed in 6 (13%). The median of prior ARV regimens was 3 (3–5). Current ARV regimen included: PI: 87%, NNRTI: 27%, INSTI: 20%, enfuvirtide: 7% and CCR5 inhibitor: 4%. Median CD4 T‐cell count: 568 cells/mL (279–771). Viral load <50 copies/mL: 80%. Sixty percent (27/45) had ≥1 co‐medications (median 1). The most frequent co‐medications were NSAIDs (40%), hormonal therapy (19%) and antimicrobials (19%). Use of herbal supplements was observed in 10 (22%). Overall, 23 (51%) had ≥ 1 CSDDIs: 19/27 (70%) with co‐medication (orange flag=18 and red flag=1); and 2/10 (20%) with herbal supplements. ARV–ARV interactions were observed in 4/45 (9%): unboosted atazanavir+tenofovir (n=2), unboosted atazanavir+efavirenz (n=1) and lopinavir/ritonavir+efavirenz (n=1) (all orange flag). Considering patients with CSDDIs, 6 (26%) had a CSDDI that could reduce ARV levels.

Conclusions

In this pilot study, a high prevalence of comorbidities, co‐medications and CSDDIs was observed in PHA. A considerable proportion of patients had CSDDIs with a potential to cause sub‐therapeutic ARV levels, what could be a concern in patients harbouring drug‐resistance viruses. Therefore, clinicians should be aware of comorbid conditions pharmacologic management in order to avoid CSDDIs with ARVs agents.
Tolerability is more important than simplicity for treatment durability
Authors: Trottier Benoit , Machouf Nima , Huchet Emmanuelle , Lavoie Stephane , Vezina Sylvie , Boissonnault Michel , Charest Louise , Munoz Marie , Legault Danielle , Longpré Daniele , Thomas Réjean
Published: November 2014

Introduction

Many studies have shown the superiority of single tablet regimens (STRs) of antiretrovirals for the treatment of HIV in terms of efficacy, adherence and rate of hospitalisation as they offer a low pill burden and once daily dosing. Our objective was to compare the duration of first‐line STRs to multi‐tablet regimens.

Methods

From our clinical database, we selected patients initiating any of the major first‐line regimens between 2007 and 2013. Two STRs, Atripla (ATP) and Complera (CPLR), were compared to three non‐STRs: two NRTIs and raltegravir (RAL), atazanavir/ritonavir (ATV/r) or darunavir/ritonavir (DRV/r). The primary outcome was time to discontinuation of the first‐line regimen. The association between regimen type and duration was estimated using Cox proportional hazards models adjusted for age, gender, baseline CD4, baseline viral load, risk factor, site and year of treatment initiation.

Results

A total of 743 patients (281 on STRs and 462 on non‐STRs) were included. 693 (93%) were male and median age was 43 years. Median length of follow‐up was 3.2 years. 56% of patients were MSM, 6% IDU and 6% from endemic countries. Patients on an STR were less likely to be IDU (p<0.024) and have a baseline HIV‐RNA ≥100,000 copies/mL (p<0.011). Overall, 321 (43%) patients discontinued their regimen during the study period. The rate of discontinuation one year after starting ARV depends on the regimen: 29% for patients on 2NRTIs+DRV/r, 26% on ATP, 25% on 2NRTIs+ATV/r, 17% on 2NRTIs+RAL and 10% on CPLR (p<0.001). In the adjusted model, durability for STR and non‐STR was equivalent (aHR=0.83, p=0.108). Compared to patients on ATP, patients on CPLR were less likely to discontinue (HR=0.58, p=0.070). No difference between ATP and the other regimens was observed: HR for 2NRTIs+RAL=0.92 (p=0.66), 2NRTIs+ DRV/r=1.16 (p=0.36), 2NRTIs+ATV/r=1.11 (p=0.46).

Conclusions

Our findings suggest that STRs do not necessarily result in a more durable treatment. Even with a higher pill burden and/or twice daily dosing, patients initiating therapy with RAL or boosted‐PI based regimens were not more likely to discontinue the first‐line regimen compared to patients on an STR. Among the STR subgroups, the regimen with better known tolerability conferred more durable treatment. Limitations included our inability to adjust for the patient's adherence to a given regimen.
Treatment modification in HIV‐Infected individuals starting antiretroviral therapy between 2011 and 2014
Authors: Rappold Michaela , Rieger Armin , Steuer Andrea , Geit Maria , Sarcletti Mario , Haas Bernhard , Taylor Ninon , Kanatschnig Manfred , Leierer Gisela , Ledergerber Bruno , Zangerle Robert
Published: November 2014

Introduction

While antiretroviral therapy (ART) has increased the survival of HIV patients and turned HIV infection into a chronic condition, treatment modifications and poor adherence might limit this therapeutic success.

Methods

Patients from the Austrian HIV Cohort Study, who started their first ART after Rilpivirine became available in February 2011, were analyzed for factors associated with treatment modification which could be either a change of drugs or a stop of the regimen. A drug was considered as stopped when the regimen was interrupted for more than eight days. Drugs of particular interest were Darunavir (DRV), Atazanavir (ATV), Raltegravir (RAL), Rilpivirine (RPV) and Efavirenz (EFV). RPV and EFV were analyzed only when taken as single tablet regimen. Other drugs were summarized as “other.” Proportional hazards regression methods were used to identify predictors of discontinuation and Kaplan–Meier estimates were used to calculate probabilities of discontinuation. Patients who died were censored at the date of death.

Results

965 patients started ART, 282 with DRV, 161 with ATV, 96 with RAL, 108 with RPV and 118 with EFV. Median time for taking initial ART is 11.6 months. 322 (33.4%) patients modified their initial ART. The overall probability of modification at one year was 28.7%, at two years 40.0% and at three years 49.8%. In a multivariable proportional hazards regression analysis, AIDS diagnosis at baseline and injecting drug use (IDU) of men compared with men who have sex with men (MSM) have a higher risk of switch/stop. Compared with DRV, RPV showed a much lower and ATV and particularly “other” a higher risk for discontinuation (Table 1).

Availability of more effective/convenient treatment (28.9%) was the main reason for discontinuation, especially in the group “other” (43.5%), RAL (34.6%) and DRV (31.6%). Non‐specified patient or physician wish to modify therapy was revealed in 17.4% and 9.3% respectively. EFV was modified in 52.8% due to central nervous system toxicity and ATV in 27.8% for gastrointestinal toxicity including hyperbilirubinemia.

Conclusion

Rates of modification and interruption were still high in recent years, particularly in the first year of ART. The decreased rate of modification found in patients treated with Rilpivirine may be attributed to selection of patients according to guidelines.
Phase IIIb, open‐label single‐arm trial of darunavir/cobicistat (DRV/COBI): Week 48 subgroup analysis of HIV‐1‐infected treatment‐nave adults
Authors: Tashima Karen , Crofoot Gordon , Tomaka Frank L , Kakuda Thomas N , Brochot Anne , Vanveggel Simon , Opsomer Magda , Garner William , Margot Nicolas , Custodio Joseph M , Fordyce Marshall W , Szwarcberg Javier
Published: November 2014

Introduction

COBI, a PK enhancer with no ARV activity is a more selective cytochrome P450 (CYP)3A inhibitor than ritonavir (RTV), does not induce CYP isozymes, and thus has less potential for drug‐drug interactions. COBI boosts DRV PK as effectively as RTV in healthy volunteers.

Materials and Methods

This 48‐week, phase IIIb, open‐label, single‐arm, US multicentre study (NCT01440569) included HIV‐infected treatment‐nave and experienced adults with no DRV RAMs, viral load (VL) ≥1000 c/mL, eGFR ≥80 mL/min and genotypic sensitivity to investigator‐selected N[t]RTIs. Patients received DRV/COBI 800/150 mg qd (as single agents) plus two fully active N[t]RTIs. The primary endpoint was any treatment‐emergent grade 3 or 4 AEs through Week 24. We report 48‐week safety, efficacy and PK/PD results in treatment‐nave patients.

Results

Of 313 ITT patients, 295 were treatment‐nave (94%). In the treatment‐nave cohort, 90% were male, 60% white and 294 (99.7%) received a TDF‐containing regimen. Median baseline (BL) VL was 4.8 log10 c/mL and CD4+ 370 cells/mm3. Treatment‐emergent grade 3 or 4 AEs regardless of causality were reported in 21 (7%) patients. AEs regardless of causality (any grade; ≥10% of patients) were: diarrhoea (27%), nausea (23%), URTI (15%) and headache (12%). Sixteen (5%) patients had AEs leading to study drug discontinuation, most frequently rash (three patients), hypersensitivity and nausea (two patients each). Consistent with the known inhibition of tubular creatinine secretion by COBI, there was a mean increase from BL in serum creatinine by week 2 (0.09 mg/dL), remaining stable through week 48 (mean 0.10 mg/dL increase from BL). At week 48, 83% of patients achieved VL<50 c/mL; FDA Snapshot); median increase in CD4+ was 169 cells/mm3. Eight patients met the criteria for resistance testing. M184V was detected in one pt receiving FTC. New primary RAMs were not detected in the other seven patients. The mean population PK‐derived DRV AUC24h was 100,620 ng.h/mL and C0h 2,105 ng/mL (n=281). There were no clinically relevant relationships between DRV exposure and virologic response, AEs or laboratory parameters.

Conclusions

The DRV PK of DRV/COBI was consistent with historical data for DRV/RTV. DRV/COBI 800/150 mg qd plus two N(t)RTIs had an 83% response and was well tolerated through Week 48. These results are similar to published data for DRV/RTV 800/100 mg qd, and support the use of DRV/COBI 800/150 mg qd in treatment‐nave patients.
Efficacy and tolerability of Etravirine in HIV‐1 adult patients: Results of a large French prospective cohort
Authors: Allavena Clotilde , Katlama Christine , Cotte Laurent , Roger Pierre‐Marie , Delobel Pierre , Cheret Antoine , Duvivier Claudine , Poizot‐Martin Isabelle , Hoen Bruno , Cabié Andre , Cheret Arnaud , Lahoulou Rima , Raffi Francois , Pugliese Pascal
Published: November 2014

Background

IEtravirine (ETR) was approved in France in Sept 2008, to be used in combination with a ritonavir‐boosted protease inhibitor (bPI) and others antiretrovirals (ARV) in HIV‐infected pre‐treated patients.

Objectives

To describe in a real life setting efficacy and tolerability of ETR‐including regimen and factors associated with virologic response.

Method

In the French DatAIDS cohort including 18,647 patients, we selected patients who initiated an ETR‐including regimen between September 2008 and July 2013. Demographic data and clinico‐biological data were collected from the standardized electronic medical record Nadis®. Analyses were done in patients starting ETR and sub‐analyses were performed in pre‐treated patients starting ETR for virologic failure (VF) or maintenance (MT) therapy, with or without bPI.

Results

2083 patients (ARV‐naïve n=77, VF n=1014, MT n=992) were included: median age 47 years, 73.3% male, median duration of HIV infection 15.7 years, CDC stage C 38.7%, HBV/HCV co‐infection 25.7%. In pre‐treated patients, 75.5% previously received NNRTIs (median duration on EFV and NVP of 480 and 396 days, respectively), 94.3% bPIs, 30.8% raltegravir (RAL) and 19.4% enfuvirtide. The most frequent ARVs associated with ETR were two NRTIs in 37.2% of the cases (21.9% in VF, 52.9% in MT), 1 bPI+RAL in 10.1% (13.5% in VF, 6.6% in MT), RAL in 6.2% (2% in VF, 10.5% in MT). Median duration on ETR was 3.7 and 2.2 years in the VF and MT group, respectively. In the VF group, HIV RNA was <50 c/ml in 71.7% (71.1% without bPI, 72% with bPI) of the patients at M12, 72.8% (71% without bPI, 73.3% with bPI) of the patients at M24. In the MT group, HIV RNA was<50 c/ml in 90.5% of the patients at M12 and 93.1% at M24. ETR was discontinued in 8.8% of the patients (12.8% in VF, 5.4% in MT) for adverse events in 23.9% of cases (21.5% in VF, 29.5% in MT), treatment failure in 15.2% (16.2% in VF, 7.4% in MT) or simplification in 5.4% (4.6% in VF, 7.4% in MT). In the VF group, factors associated with virologic failure in multivariate analysis were a longer duration of HIV infection (OR 2.6; 95% CI 1.7–4.0) and baseline HIV RNA >5 log10 c/ml (OR: 2.0; 95% CI 1.3–3.2) but not the association with a bPI.

Conclusion

This large study shows that in ARV‐pre‐treated patients ETR is well tolerated with a high efficacy when combined with other active drugs, even when the regimen does not include a bPI.
Efficacy of a dual therapy based on darunavir/ritonavir and etravirine in ART‐experienced patients
Authors: Ignacio Bernardino Jose , Xavier Zamora Francisco , Valencia Eulalia , Moreno Victoria , Vergas Jorge , Jesus Tellez Maria , Estrada Vicente , Gonzalez‐Garcia Juan
Published: November 2014

Introduction

Nucleoside reverse transcriptase inhibitors (NRTI)‐sparing regimens have been studied in antiretroviral therapy (ART)‐naïve patients but data with ART‐experienced are scarce. NRTI‐sparing regimens may be an option in patients with toxicities and for simplification reasons.

Methods

Retrospective multicentre analysis including ART‐experienced patients starting treatment with darunavir/ritonavir and etravirine (DRV/r 800 mg/100 mg QD or 600 mg/100 mg BID and ETV 400 mg QD or 200 mg BID) with at least six months of follow‐up. Primary endpoint was proportion of patients with VL<50 copies/mL at 48 weeks with an ITT analysis (missing or switch equals failure). Secondary endpoints were safety, CD4 count and lipid changes over 48 weeks.

Results

Seventy‐five patients were included of whom 44 (58.6%) had HIV RNA<50 copies/mL. Baseline characteristics: median age 50 years (IQR 34–65), 72% males, 93% Caucasians, 38.6% hepatitis C, and 45.4% with CDC C stage. Median HIV duration and time on ART were 20 (IQR 7–28) and 14 years (IQR 5–21) respectively. Reasons for switching were virologic failure in 27 (36%), simplification in 25 (33.3%), toxicity in 20 (26.6%) and other 3 (4.1%). Most of them received DRV/r and ETV QD. Thirty‐nine patients had NNRTI resistance mutations [28 K103N (37.3%), 6 Y181I/C (8%), 3 G190A (4%)] and 29 patients had ≥1 primary PI mutations. Main analysis (ITT) showed that 67 (89.3%) had a VL undetectable at 24 weeks (95% CI 83.1–95.5) and 57 (76%) at 48 weeks (95% CI 68.4–83.6). On treatment analysis showed that 94.3% and 89% had a viral load<50 copies at 24 and 48 weeks, respectively. 11 (14.6%) patients discontinued the regimen (three virologic failures, three switching to darunavir/ritonavir monotherapy, two to salvage regimen and three due to toxicity). No significant changes in CD4+ count and lipid changes were observed at 48 weeks.

Conclusions

Dual therapy with Darunavir/ritonavir and etravirine is an efficacious and safety option in ART‐experienced HIV patients even in patients on virologic failure.
The efficacy, pharmacokinetics, safety and cardiovascular risks of switching nevirapine to rilpivirine in HIV‐1 patients: the RPV switch study
Authors: Rokx Casper , Blonk Maren , Verbon Annelies , Burger David , JA Rijnders Bart
Published: November 2014

Introduction

Nevirapine (NVP) induces cytochrome P450 3A4 by which rilpivirine (RPV) is metabolized. Switching NVP to RPV could result in decreased RPV exposure with subsequent virological failure and dyslipidemia because NVP is regarded as the least dyslipidemic, non‐nucleoside, reverse transcriptase inhibitor. This trial evaluated the efficacy, pharmacokinetics, safety and cardiovascular risks of switching NVP to RPV.

Materials and Methods

Prospective open label controlled trial. HIV‐1 patients with HIV‐1 RNA <50 copies/mL on once daily NVP, emtricitabine/tenofovir (FTC/TDF) switched to single tablet RPV/FTC/TDF. Eligible patients on NVP, FTC/TDF were controls. Primary endpoint was week 12 HIV‐1 RNA <50 copies/mL by intention to treat analysis. Secondary endpoints were week 24 HIV‐1 RNA <50 copies/mL, NVP and RPV pharmacokinetics, safety and fasting lipids, Framingham risk scores (FRS) and Adult Treatment Panel III (ATP‐III) lipid goals.

Results

Of 189 eligible patients, we included 50 RPV switchers and 139 NVP controls. Week 12 HIV‐RNA was <50 copies/mL in 46/50 switchers (92.0%) which was not different from the hypothesized 90% week 12 suppression rate (p=.431). Forty‐four of 50 switchers had week 24 HIV‐1 RNA <50 copies/mL compared to 126/139 controls (difference: 2.6%, 95% CI −7.6% to 12.8%, p=.593). NVP plasma concentrations were below detection level in all at week 3. Mean week 1 RPV trough concentration was 0.083 mg/L and comparable to phase III trial data (p=0.747). Adverse events occurred in 36 switchers, the majority (82.0%) were grade one. Two switchers discontinued RPV for side effects. Significant changes over 24 weeks (p<0.001) were observed in switchers on total cholesterol (TC, −0.67 mmol/L, 95% CI −0.50 to 0.83), low density lipoprotein (LDL)‐C (−0.36, 95% CI −0.21 to −0.51) and high density lipoprotein (HDL)‐C (−0.28, 95% CI −0.20 to −0.35). The TC/HDL‐C ratio increased 0.20 (95% CI 0.02 to 0.37; p=.029) and systolic blood pressure decreased 6.0 mmHg (95% CI −1.7 to −10.3; p=.007). The median FRS did not change over 24 weeks (8.4% vs. 7.7%; p=.119). More patients achieved LDL‐C (+15%; p=.016) and TC (+25%; p<0.001) ATP‐III treatment goals at week 24 on RPV.

Conclusions

A NVP to RPV switch does not influence RPV exposure and results in adequate ongoing HIV‐1 suppression. RPV could be an option for patients at risk for cardiovascular diseases.
Switch to Stribild versus continuation of NVP or RPV with FTC and TDF in virologically suppressed HIV adults: a STRATEGY‐NNRTI subgroup analysis
Authors: Stellbrink Hans‐Juergen , Antinori Andrea , Pozniak Anton , Flamm Jason , Bredeek Fritz , Patel Kiran , Garner Will , Piontkowsky David
Published: November 2014

Introduction

Switch to Stribild (STB) was non‐inferior to continuation of a non‐nucleoside reverse transcriptase inhibitor (NNRTI) with emtricitabine and tenofovir DF (FTC/TDF) at week 48 in virologically suppressed HIV adults [1]. We report the Week 48 efficacy and safety of STB versus nevirapine (NVP) or rilpivirine (RPV) with FTC/TDF in suppressed subjects.

Materials and Methods

Virologically suppressed subjects on an NNRTI with FTC/TDF regimens for ≥6 months were randomized (2:1) to switch to STB versus continue their NNRTI regimen. Eligibility criteria included no documented resistance to FTC and TDF, no history of virologic failure and eGFR ≥70 mL/min. The primary endpoint was the proportion of subjects in the modified ITT population who maintained HIV‐1 RNA <50 copies(c)/mL at Week 48 by FDA snapshot algorithm (12% non‐inferiority margin). Subgroup analysis by non‐EFV NNRTI use (NVP [74]; RPV [19]; etravirine [3]) at screening was pre‐specified.

Results

The mITT population included 433 subjects who were randomized and treated. In the non‐EFV NNRTI subgroup, 59 switched to STB; 37 continued a non‐EFV NNRTI (27 NVP, 10 RPV) with FTC/TDF. At week 48, 97% STB versus 95% non‐EFV NNRTI maintained HIV‐1 RNA <50 c/mL. No emergent resistance was detected in either group. No difference in median increases from baseline in CD4 count at week 48 (cells/µL): 25 STB versus 55 non‐EFV NNRTI (p=0.78). No discontinuation due to adverse events; no cases of proximal renal tubulopathy. As expected, there were no significant changes in the frequency of neuropsychiatric symptoms (i.e. anxiety, insomnia, dizziness, vivid dreams, weird/intense dreams, and nightmares) reported on the HIV Symptom Index at week 48 compared to baseline after switching to STB. There was a greater but non‐progressive decrease from baseline in eGFR in the STB versus non‐EFV NNRTI group; median changes (mL/min) at week 48: −9.1 versus −1.4. Switch to STB was associated with a higher treatment ease (convenience, flexibility, demand, lifestyle, understanding) score (range: −15 to 15) at week 4 (median: 14 vs 11; p=0.047) and week 24 (median: 14 vs 12.5; p=0.038).

Conclusions

In this small group of virologically suppressed subjects, switch to STB vs continuation of NVP or RPV with FTC/TDF was safe, well‐tolerated, and associated with a high rate of virologic suppression at week 48. There was more treatment ease with STB use.