bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nephrolithiasis and renal failure among patients exposed to atazanavir, other PIs and PI‐free regimens
Authors: Nkhoma Ella , Kumar Monica , Hines Patricia , Moorthy Vidya , Klauck Isabelle , Villasis Keever Angelina 
Published: November 2014

IntroductionRecent single‐site studies and case reports have linked atazanavir (ATV) with the occurrence of nephrolithiasis. The purpose of this study was to estimate and compare the incidence rate of nephrolithiasis and to characterize the occurrence of subsequent renal failure among patients on ATV, other protease inhibitors (PIs) and PI‐free regimens using real world data.Materials and MethodsThis was a retrospective cohort analysis using claims data from a US commercial and a US public health insurance database (Medicaid) spanning 2003–2011 and 2006–2011, respectively. We identified adult HIV patients who were prescribed ATV, other PIs or PI‐free regimens with at least 6 months of continuous enrolment prior to the index claim. Nephrolithiasis was defined as an inpatient or outpatient ICD‐9 diagnosis code for nephrolithiasis or an associated condition, plus an imaging/corrective procedure code. Renal failure was also identified using diagnosis codes among patients experiencing nephrolithiasis. Hazard ratios were estimated using propensity score (PS) adjusted Cox regression, crude and adjusted for demographics, baseline comorbidities and comedications.ResultsA total of 14,477 patients (ATV: 4,150; other PIs: 4,153; PI‐free: 6,174) were identified in the commercial database: 83% male and 20% age ≥50 years. In the Medicaid database, 9,104 patients (ATV: 3,460; other PIs: 3,117; PI‐free: 2,527) were identified: 53% male and 25% age ≥50 years. There were significant baseline differences in demographics, comorbidities and concomitant medications among the three cohorts. In adjusted analyses, ATV use was not significantly associated with nephrolithiasis when compared to other PIs. When ATV was compared to PI‐free regimens, a positive association was observed in the commercial insurance but not the Medicaid database. In both databases, previous history of nephrolithiasis was the strongest predictor of nephrolithiasis in the ATV/PI‐free regimens contrast, but not the ATV/other PIs contrast. For the renal failure outcomes, there were insufficient cases across all cohorts to conduct crude or adjusted analyses (see Table 1).ConclusionsIn this analysis of two large real world databases, we did not find evidence of an increased risk of nephrolithiasis among patients on ATV compared to other PIs. However, when ATV was compared to PI‐free regimens, the results differed across the two databases, requiring further study. Additionally, renal failure following nephrolithiasis was infrequent and not significantly different across the three cohorts.
Prevalence and European AIDS Clinical Society (EACS) criteria evaluation for proximal renal tubular dysfunction diagnosis in patients under antiretroviral therapy in routine setting
Authors: Pitisci Lorenzo , Demeester Rémy , Legrand Jean‐Claude 
Published: November 2014

IntroductionTenofovir (TDF) is an antiretroviral drug often used in combination regimen in HIV‐positive patients. Adverse effects affecting kidneys consist in an increase or a new onset proteinuria, a decrease of glomerular filtration rate (GFR), and/or a proximal renal tubular dysfunction (PRTD) that rarely leads to Fanconi's syndrome. EACS guidelines propose to screen PRTD in patients with chronic renal insufficiency, with a sudden decrease of eGFR, with hypophosphataemia (if non‐renal causes such as vitamin D deficiency are excluded) and with a new onset proteinuria. We aim to evaluate the prevalence of PRTD by comparing the group of patients under TDF to the group free of TDF, in our cohort of 300 patients. We also aim to evaluate the accuracy of EACS criteria for screening PRTD in routine settings and to assess the utility of urinary samples in PRTD diagnosis.Materials and MethodsDuring two consecutive years, we collected annually blood and urine samples at the same time in our outpatient clinic. We assessed kidney function, plasma levels and fractional excretion of phosphate, uric acid, potassium, plasma glucose and proteinuria. PRTD was defined by the presence of at least two out of the five following criteria: fractional excretion (FE) of phosphate >20% (or >10% when serum phosphate <0.8 mmol/L), non‐diabetic glycosuria (positive urine glucose with plasma glucose <70 mg/dL), renal tubular acidosis (urinary pH >5.5 and serum bicarbonate <21 mmol/L), uric acid FE >10% or potassium FE >10%. After the first year, patients with TDF regimen who were diagnosed with PRTD were shifted to TDF‐free regimen and included again in the study.ResultsFor PRTD (first line), they are expressed in number of diagnoses/total number of patients in this group. The second line resumes the number of PRTD diagnose patients who should have been screened according to EACS criteria.ConclusionsPRTD screening according to EACS criteria is not sufficient to diagnose every case, especially minor PRTD, mainly because the prevalence is low and its diagnosis remains difficult in routine settings. We recommend performing a urine test including proteinuria every year for patients undergoing TDF treatment. The next step will be to follow PRTD patients to evaluate the time laps until full recovery after TDF shift.
Prevalence of osteoporosis and predictors of low BMD in a cohort of HIV‐1‐infected patients in Rome: features of a population at high risk
Authors: D'Avino Alessandro , Lassandro Annapia , Lamonica Silvia , Piccoli Benedetta , Fabbiani Massimiliano , Mondi Annalisa , Gagliardini Roberta , Borghetti Alberto , Fanti Iuri , Pallavicini Federico , Cauda Roberto , Di Giambenedetto Simona 
Published: November 2014

IntroductionAgeing of HIV‐infected patients led to an increasing rate of osteopenia and osteoporosis. The cause is multifactorial, including virus activity, drug toxicity and host factors. The aim of our analysis is to quantify this issue according to our department experience and to evaluate predictors of low BMD.Materials and MethodsHIV‐1‐infected patients, on stable HAART, were consecutively enrolled in this cross‐sectional study and underwent DEXA. We analyzed the prevalence and evaluated predictors of low BMD in our population.ResultsWe collected data from 208 patients, 148 of whom were male, with 49 years median age (IQR 24.1–68.3). About 39% of patients were heterosexuals, 33.7 MSM and 12.5% were IDU, 40.4% were smokers. Caucasians were 93.3%, and 13.9% were co‐infected with HCV virus. Around 6.7% of patients were on their first HAART regimen and all of them started TDF. Their median time of HAART exposure was 1.17 years (IQR 0.8–1.6). Conversely, median time of HAART exposure of multi‐experienced patients was 8.5 years (IQR 3.1–12.0). We stratified DEXA results for patients on first‐line regimen versus multi‐experienced one. We found that 42.9% of patients on first‐line HAART had low BMD of lumbar spine and 7.1% had osteoporosis. Regarding the multi‐experienced group of patients, lumbar spine osteopenia was observed in 36.6% of patients and 15.5% of them had osteoporosis. Median age of patients with low BMD of lumbar spine was 45.6 (IQR 24.1–68.3) for patients on first‐line regimen and 49.8 years for multi‐experienced (IQR 44.2–54.0) regimen. We found similar data for BMD of hip, but no patients in the first group had hip osteoporosis. We also analyzed predictors of low BMD in our population. MSM patients showed a 3.4‐fold higher risk to have osteoporosis of lumbar spine (OR 3.41, CI 1,105–9,269, p=0.03). As expected, we found that non‐Caucasian patients had 13.5‐fold higher risk to have osteoporosis of the hip (OR 13.52, CI 1.5–122.7, p=0.02). Exposure to HAART was also evaluated, but no predictors were found.ConclusionsOur data confirm how osteoporosis is highly prevalent and occurs earlier in HIV‐infected patients. Antiretrovirals play a crucial role. In our experience loss of BMD can occur within a year of treatment, when almost half of our patients starting TDF had a low BMD. MSM patients have a higher risk to develop spine osteoporosis and non‐Caucasian patients are more likely to have hip osteoporosis. We remark the importance of BMD assessment for HIV‐infected patients especially during their first months of treatment.
Co‐administration of ritonavir‐boosted protease inhibitors and rate of tenofovir discontinuation in clinical practice
Authors: Costarelli Silvia , Cozzi‐Lepri Alessandro , Lapadula Giuseppe , Bonora Stefano , Madeddu Giordano , Maggiolo Franco , Antinori Andrea , Gori Andrea , D'Arminio‐Monforte Antonella 
Published: November 2014

IntroductionIn clinical trials, toxicity leading to discontinuation of tenofovir (TDF) is a rare occurrence (3% by two years)[1, 2]; however, in clinical practice it seems to be higher. Previous studies suggested that TDF toxicity is higher when it is co‐administered with ritonavir‐boosted protease inhibitors (PI/r)[3, 4]. The aim of this study is to assess the rate of TDF discontinuations in clinical practice and to explore associated factors.MethodsAll previously antiretroviral‐naïve patients initiating a TDF‐containing regimen were selected from the ICONA cohort, unless they were positive for hepatitis B. The primary outcome was TDF discontinuation (>30 days) regardless of the reason, the secondary was TDF discontinuation due to toxicity. All analyses were repeated for the isolated stop of TDF (no stop of associated drugs). The main reason for discontinuation as reported by the treating physicians was used to classify stops. Kaplan–Meier (KM) analysis and Cox proportional hazards model were used.ResultsA total of 3,303 naïve patients were enrolled: 674 (20.4%) were female, the median age was 38 years (32–45), 55% were on PI/r‐based regimen and 45% on NNRTI; 80% of calculated estimated glomerular filtration rates (eGFR) were >90 ml/min. The probability of discontinuation of TDF regardless of the reason was 10% (95% CI 8–11) at two years, 20% by eight years. The causes of discontinuation were: toxicity (33%), failure (10%), non‐adherence (21%), simplification (16%) and other/unknown causes (20%). The five‐year KM estimates in the PI/r vs. not PI/r groups were 23% vs. 10%, respectively (log‐rank p=0.0001), for the outcome of stopping regardless of the reason, and 8% vs. 4% (p=0.18) for discontinuation due to toxicity. In a multivariable Cox model, PI/r use and lower body weight were associated with increased risk of discontinuing TDF regardless of the reason; lower eGFR at baseline was associated with TDF discontinuation for toxicity and PI/r use was associated with isolated stop of TDF (Figure). No differences in rates of TDF discontinuations between PIs were found.ConclusionIn our cohort, the observed frequency of TDF discontinuations was low although higher than estimated in clinical trials (10% by two years). Co‐administration of TDF with PI/r was associated with an increased rate of TDF discontinuations. This finding should guide further investigations of the mechanism that may have led to discontinuation of TDF in patients using PI/r.
Efficacy and safety of etravirine‐containing regimens in a large cohort of HIV/HCV coinfected patients according to liver fibrosis
Authors: Luis Casado Jose , Mena Alvaro , Bañón Sara , Moreno Ana , Castro Angeles , Perez‐Elías María J , Pedreira JD , Moreno Santiago 
Published: November 2014

IntroductionEtravirine has become an alternative in HIV/HCV coinfected patients because of safety and lack of interactions with anti‐HCV drugs. The aim of this study was to establish the risk of liver toxicity in HIV/HCV coinfected patients receiving etravirine in the clinical setting, according to the degree of liver fibrosis and different accompanying drugs.Material and MethodsCohort study of 211 patients initiating etravirine as part of their antiretroviral regimen. HCV coinfection was defined as a positive RNA‐HCV, whereas baseline liver fibrosis was assessed by transient elastography at baseline. Hepatotoxicity was defined as an increased AST/ALT, 5‐fold higher over upper, normal limits for patients with normal baseline values, or 3.5‐fold if altered at baseline.ResultsHCV coinfection was observed in 145 patients (69%) with a longer time of HIV infection and time on HAART than mono‐infected patients, and a lower nadir (182 vs 227 cells/mL; p=0.02) and baseline CD4+ count (446 vs 552 cells/mL; p=0.02). Etravirine was used with two nucleoside analogues in 62%, with boosted darunavir in 17%, with raltegravir in 10%, and with darunavir plus raltegravir or maraviroc in 10% of patients without differences according to HCV serostatus. Transient elastography in 117 patients performed at etravirine initiation (median, 33 days) showed fibrosis 1 and fibrosis 4 in 37% and 24% of cases, and median stiffness value was 8.25 kPa (3.5–69). During an accumulated follow‐up of 449.3 patient‐years (median, 611 days), only one coinfected patient with fibrosis 4 (stiffness value, 50.1 kPa), receiving a rescue regimen including darunavir/r plus maraviroc plus two nucleoside analogues, developed a grade 3‐4 of liver toxicity (0.5%). There were no other episodes of liver toxicity, as defined, and only 6 (3%) and 9 patients (4%) had a grade 1 and 2 of toxicity, respectively, in most cases related to HCV coinfection (6 and 6 cases). Moreover, HCV coinfection or advanced fibrosis was not associated to a higher risk of etravirine discontinuation (26% vs 21%; p=0.27, log‐rank test) or virologic failure (9% vs 11%, p=0.56). CD4+ cell count increase was lower in HCV patients (+23 vs +86 at 6 month; p=0.02).ConclusionsEtravirine is safe in HIV/HCV coinfected patients, even in presence of moderate and advanced liver fibrosis and as part of different antiretroviral regimens.
Cerebral volumes, neuronal integrity and brain inflammation measured by MRI in patients receiving PI monotherapy or triple therapy
Authors: Pérez Valero Ignacio , Gonzalez Baeza Alicia , Antonio Hernandez‐Tamames Juan , Monge Susana , Arnalich Francisco , Ramon Arribas Jose 
Published: November 2014

IntroductionPenetration of protease inhibitors (PI) in the central nervous system (CNS) is limited. Therefore, there are concerns about the capacity of PI monotherapy (MT) to control HIV in CNS and preserve brain integrity.MethodsExploratory case‐control study designed to compare neuronal integrity and brain inflammation in HIV‐suppressed patients (>2 years) with and without neurocognitive impairment (NI), treated with MT or triple therapy (TT), 3‐Tesla cerebral magnetic resonance image (MRI) and spectroscopy (MRS) were used to evaluate neuronal integrity (volume of cerebral structures and MRS levels of N‐acetyl‐aspartate (NAA)) and brain inflammation (MRS levels of myo‐inositol (MI) and choline (CHO)). MRS biomarkers were measured in 4 voxels located in basal ganglia, frontal (2) and parietal lobes. A comprehensive battery of tests (14 tests ‐ 7 domains) was used to diagnose neurocognitive impairment [1].ResultsWe included 18 neurocognitively impaired patients (MT: 10, TT: 8) and 21 without NI (MT: 9; TT: 12, Table 1). Subset of patients with NI: cerebral volumes and MRS biomarkers were mostly similar between MT and TT with exception of the right cingulate nucleolus volume (MT: 8854±1851 vs TT: 10482±1107 mm3; p<0.04), CHO levels in basal ganglia (MT: 0.44±0.05 vs TT: 0.37±0.03 MMOL/L; p<0.01) and the NAA levels in parietal lobe (MT: 1.49±0.12 vs 1.70±0.13 MMOL/L; p<0.01). Subset of patients without NI: cerebral volumes and MRS biomarkers were mostly similar between MT and TT with exception of MI levels in frontal lobe (MT: 1.20±0.36 vs 0.81±0.25 MMOL/L; p=0.01).ConclusionsWe did not find significant differences in cerebral volumes or MRS biomarkers in most areas of the brain. However, we found higher levels of inflammation and neuronal damage in some brain areas of patients who received MT. This observation has to be taken into caution while we could not adjust our results by potential confounders. Further investigation is needed to confirm these preliminary results.
Quality of life of people living with HIV, preliminary results from IANUA (Investigation on Antiretroviral Therapy) study
Authors: Venturini Alberto , Giannini Barbara , Montefiori Marcello , Di Biagio Antonio , Mazzarello Giovanni , Cenderello Giovanni , Giacomini Mauro , Merlano Caterina , Orcamo Patrizia , Setti Maurizio , Viscoli Claudio , Cassola Giovanni 
Published: November 2014

IntroductionThe introduction of combined antiretroviral treatment (cART) has reduced HIV‐associated morbidity and mortality, and changed the patients’ perspective of life. As a result, Health Related Quality of Life (HRQOL) has become a crucial clinical issue.ObjectiveAssessment of HRQOL in a sample of Italian patients from IANUA study. Investigate correlation between CD4 cell counts, viral load and changes in HRQOL.Materials and MethodsEQ‐5D‐3L self‐reported questionnaire has been used in the evaluation of HRQOL. It assesses five dimensions: “mobility,” “self care,” “usual activities,” “pain/discomfort” and “anxiety/depression.” Each dimension has three levels: no problems, some problems and extreme problems. In addition, it includes a Visual Analogue Scale (VAS) where one's own health “today” is rated from 0 “worst imaginable health” to 100 “best imaginable health.” The respondents provide information on marital status, education, employment/unemployment, other treatments used in addition to HAART (1,2,3,4,5 or more) and number of hospitalizations due to HIV/AIDS.Results684 patients completed the questionnaire: 231 females and 453 males. The mean age of the sample was 51 years (range 21–78). The mean VAS score was 69.9. 558 patients (81.5%) reported no problems in mobility. 642 patients (93.5%) had no problems in self care. 423 patients (61.8%) had no pain/discomfort while 219 had some problems. 326 patients (46.1%) had some problems in anxiety/depression.ConclusionsThe analysis of self‐reported questionnaires indicates that HRQOL in our sample group is not deeply affected by HIV/AIDS. The dimensions that are affected in the least are “mobility” and “self care” while the major problem is “anxiety/depression” with half of the sample reporting moderate or high level.
Potential implications of CYP3A4, CYP3A5 and MDR‐1 genetic variants on the efficacy of Lopinavir/Ritonavir (LPV/r) monotherapy in HIV‐1 patients
Authors: Berno Giulia , Zaccarelli Mauro , Gori Caterina , Tempestilli Massimo , Pucci Luigia , Antinori Andrea , Perno Carlo Federico , Paolo Pucillo Leopoldo , D'Arrigo Roberta 
Published: November 2014

IntroductionSeveral genetic single nucleotide polymorphisms (SNPs) in biotransformation enzymes (CYP3A4, CYP3A5) or transporter proteins (multidrug resistance MDR1 gene product, P‐gp) are involved in PI metabolism so that PI pharmacokinetics is characterized by a large inter‐individual variability. The aim of this study was: (i) to develop an in‐house PCR/direct sequencing, based on DNA purification of full‐length CYP3A4 and CYP3A5 genes (SNPs) and MDR1 C3435T variant; (ii) to investigate association of CYP3A4 and CYP3A5 reported or unreported genetic polymorphisms and MDR1‐C3435T (CC homozygote, CT heterozygote, TT homozygote) with clinical outcome of HIV‐1 infected subjects treated with PI.MethodsOverall, 39 HIV‐1 infected patients receiving boosted Lopinavir (LPV/r) monotherapy after virological suppression were genotyped and analyzed through PCR and direct sequencing of full‐length CYP3A4 and CYP3A5 gene sequences [1] and MDR1 gene (C3435T). CD4+T‐cell counts and plasma viral load were analyzed before and after LPV/r initiation; LPV/r therapeutic drug monitoring (TDM) was determined at 12‐hours.ResultsLPV/r TDM (ng/ml) did not show significant differences among CYP3A4 or CYP3A5 SNPs, although a mean lower level of LPV/r was associated with detection of several SNPs: CYP3A5*3 rs776746; CYP3A5 rs28365088, CYP3A5 rs15524, CYP3A4 rs2687116, and a not already described polymorphism CYP3A4 nt20338. In follow‐up analysis, <90% adherence was the main factor associated with virological failure of LPV/r monotherapy (83.3% of failure vs 34.4%, p<0.001 at log‐rank test). Adjusting for adherence, the detection of a single CYP3A5*3 rs776746 and CYP3A5 rs15524 SNPs was associated with higher probability of LPV/r monotherapy failure (p<0.01), and in general, detection of any CYP3A5 SNP was associated with failure (26.2% vs 58.3%, p=0.067). No‐association with detection of any CYP3A4 SNPs was found. MDR1 TT variants showed significant lower frequency of treatment failure (0.0% vs 47.7%, p=0.026), since non‐TT homozygote patient failed LPV/r monotherapy.ConclusionsEfficacy of PI monotherapy is strongly dependent from patient adherence, but, in adherent patients, genetic factors, such as CYP3A5 and MDR1‐C3435T gene variants, may affect the response to treatment, though their role, as well of other genetic variants, need further investigation.
Efficacy, safety, and lack of interactions with the use of raltegravir in HIV‐infected patients undergoing antineoplastic chemotherapy
Authors: Bañón Sara , Machuca Isabel , Araujo Susana , Moreno Ana , Perez‐Elías María J , Moreno Santiago , Casado Jose Luis 
Published: November 2014

IntroductionConcomitant use of combination antiretroviral regimen (cART) and cancer chemotherapy is difficult due to complex interactions and increased toxicity. Raltegravir could be an adequate option through its favourable drug‐drug interaction profile.MethodsProspective longitudinal study of HIV patients with cancer, AIDS related or not, undergoing chemotherapy. Patients without resistance or previous failure were switched or initiated raltegravir plus two nucleoside analogues. Plasma trough levels of raltegravir were measured.ResultsOverall, 28 patients receiving a raltegravir‐based regimen (4 naive) with tenofovir‐emtricitabine (18 cases) or abacavir‐lamivudine (10 cases) were included. Mean age was 46.2 years (IQR, 39–52.7), and 79% were male. Median time of HIV was 201.7 months, CD4+ nadir was 268 cells/mm3, and 75% had previous AIDS. At the diagnosis of neoplasia, 17 were on protease inhibitors and 4 with efavirenz. Ten patients had a non‐HIV‐related cancer (three breast, two pancreatic, one Ewing sarcoma, one myeloblastic leukemia, one melanoma, one parotid adenocarcinoma, one lung), and 18 had an HIV‐related cancer (nine non‐Hodgkin lymphoma, seven Hodgkin disease, two anal). Overall, 43% of patients received more than one line of chemotherapy, including antimetabolites in 12 patients (5‐FU, capecitabine, methotrexate, gemcitabine), alkylating agents in 12 cases (ciclophosphamide, iphosphamide), vinca alkaloids in 20 patients (vincristine, vinblastine, vindesine), antitumor antibiotics in 16 cases (adriamycin), cisplatin o carboplatin in six and monoclonal antibodies in six patients (rituximab, trastuzumab, cetuximab). Six patients modified the doses of antineoplastic agents due to toxicity (four neutropenia), not related to raltegravir. During a median follow up of 12.7 patients‐year in concomitant therapy, there was only 1 case of virological failure and no patient discontinued raltegravir. Plasma concentrations of raltegravir in eight patients showed a median concentration of 143 ng/mL (79–455). Four patients (14%) died during the study, not related to AIDS progression. Raltegravir was continued after chemotherapy in all the cases.ConclusionsA raltegravir‐based therapy is safe and effective in HIV patients undergoing antineoplastic chemotherapy, regardless of the type of tumour, and type and duration of chemotherapy. Pharmacokinetic data show adequate raltegravir levels.