bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proton 1H‐ and Phosphorus 31P‐MR spectroscopy (MRS) in asymptomatic HIV‐positive patients
Authors: Schuettfort Gundolf , Hattingen Elke , Pilatus Ulrich , Stephan Christoph , Wolf Timo , Goepel Siri , Haberl Annette , Blasel Stella , Zanella Freidhelm , Brodt Hans‐Reinhard , Bickel Markus 
Published: November 2014

IntroductionHIV infection is accompanied by a variety of neurological disorders. Depression of cell‐mediated immunity is followed by the development of central nervous system opportunistic infections/tumours, and frequently by the occurrence of the AIDS dementia complex (ADC). However, the pathophysiology of the emergence of neuro‐AIDS is still unknown. Despite the development of cognitive impairments, the early diagnosis, objectification and quantification of the existence and extent of this impairment during infection are difficult to recognize in each individual case. To support the early diagnosis of ADC, there is a need for additional, non‐invasive diagnostic methods. In this study, it is of interest to answer the clinically relevant question of whether magnetic resonance spectroscopy can detect changes in the cerebral metabolism of asymptomatic HIV‐positive patients and is possibly suitable for the early diagnosis and prevention of HIV encephalopathy.MethodsA group of 13 asymptomatic, HIV‐positive patients with combined antiretroviral therapy (cART) and 13 healthy controls were examined with 2D 1H‐MRS and 3D 31P‐MRS at 3T. The patients were treated with cART for at least 12 months. Changes in the absolute concentrations of phosphorylated metabolites (ATP), N‐acetyl‐aspartate, creatine, myo‐Isonitol, glutamate/glutamine and choline‐containing compounds were compared with that of control subjects.ResultsAsymptomatic HIV‐positive patients had significantly lower N‐acetyl‐aspartate in the white matter in a frontal and parietal target region. The other evaluated metabolites in the 1H MRS showed no significant difference between the HIV‐positive patients and healthy controls. The 31P‐MRS detected significant elevated values regarding the choline‐containing compounds PEth, GPE and PCho.ConclusionsThis spectroscopic study revealed a significantly lower N‐acetyl‐aspartate in the white matter in a frontal and parietal cerebral target region in asymptomatic, HIV‐positive patients as an early sign of neuronal disintegration. The 31P‐MRS detected significant elevated values regarding the choline‐containing compounds PEth, GPE and PCho as an early sign of gliosis. Furthermore we could show that with the use of 1H‐MRS and 31P‐MRS cerebral metabolites can be reliably detected and measured in HIV‐positive patients. The 1H‐MRS and 31P‐MRS is therefore suited as a diagnostic tool for early cerebral metabolic changes in HIV‐positive patients.
The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects
Authors: Zong Jian , Borland Julie , Jerva Fred , Wynne Brian , Choukour Mike , Song Ivy 
Published: November 2014

IntroductionDolutegravir (DTG) is an HIV integrase strand transfer inhibitor approved for use in combination with other antiretrovirals for the treatment of HIV‐infection in adults and adolescents. Metformin is a drug frequently used in diabetic HIV‐infected patients, which requires titration to optimize dosing. In vitro, DTG inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE 1) which are known to be involved in the disposition of metformin. The objective of this study was to assess the drug interaction between DTG and metformin.Materials and MethodsThis was an open‐label, parallel‐group, three‐period crossover study in healthy adult subjects. Eligible subjects were enrolled into one of the two treatment cohorts (15 subjects/cohort). Subjects received metformin 500 mg q12h for 5 days in Period 1; metformin 500 mg q12h plus DTG 50 mg q24h (Cohort 1) or 50 mg q12h (Cohort 2) for 7 days in Period 2; and metformin 500 mg q12h for 10 days in Period 3. There were no washout periods between treatments. All doses of study drug were taken with a moderate‐fat meal. Serial plasma PK samples and safety assessments were obtained throughout the study. Non‐compartmental PK analysis was performed and geometric least squares (GLS) mean ratios and 90% confidence intervals (CI) were generated by the mixed effect model for within‐subject treatment comparisons for each cohort.ResultsFourteen and thirteen subjects completed study in Cohort 1 and Cohort 2, respectively. Plasma exposures of metformin were significantly increased when co‐administered with DTG (Table 1).There were no apparent changes in metformin half‐life and tmax. Increased metformin plasma exposure returned to normal levels observed in Period 1 after DTG was discontinued in Period 3. No Grade 3 or 4 adverse events (AEs), deaths or serious AEs were reported during the study. Most frequently reported drug‐related AEs were headache (9), loose stools (8), and nausea (7). All AEs were mild or Grade 1 with the exception of one Grade 2 headache.ConclusionsCo‐administration of DTG and metformin was well tolerated, yet significantly increased metformin plasma exposure; effects were DTG dose dependent. Though metformin has a wide therapeutic index and alone is not associated with hypoglycemia, close monitoring is recommended when co‐administering metformin and DTG. Dose adjustments of metformin may be considered.
Simulation of the impact of rifampicin on darunavir/ritonavir PK and dose adjustment strategies in HIV‐infected patients: a population PK approach
Authors: Dickinson Laura , Winston Alan , Boffito Marta , Khoo Saye , Back David , Siccardi Marco 
Published: November 2014

IntroductionTreatment of HIV/TB co‐infection is challenging due to high drug–drug interaction potential between antiretrovirals and rifamycins, such as rifampicin (RIF). The PK interaction between darunavir/ritonavir (DRV/RTV) and RIF has not been studied. Utilizing other protease inhibitor data, population PK modelling and simulation was applied to assess the impact of RIF on DRV/RTV PK and generate alternative dosing strategies to aid future clinical trial design.Materials and MethodsA previously developed model describing DRV/RTV PK including data from three studies in HIV patients was used [n=51, 7 female, DRV/RTV 800/100 mg (n=32) or 900/100 mg once daily (qd; n=19) [1]. The PK interaction between DRV/RTV and RIF was assumed to mimic that observed in HIV‐infected, TB negative patients receiving lopinavir (LPV)/RTV (n=21) [2]. Simulations of DRV/RTV 800/100 mg qd (n=1000) were performed (‐RIF). The model was adapted to increase the typical value of apparent oral clearance (CL/F) by 71% and 36% and decrease relative bioavailability (F) by 20% and 45% for DRV and RTV, respectively [2]; 1000 simulations were generated (+RIF). Dose adjustments of DRV/RTV 1200/200 mg qd, 800/100 mg and 1200/150 mg twice daily (bid) were simulated to overcome the interaction. DRV trough (Ctrough) for each dosing scenario was compared to the reference (‐RIF) by GMR (90% CI).ResultsDRV and RTV were described by a 1 and 2‐compartment model, respectively. A maximum effect model, with RTV inhibiting DRV CL/F, best described the relationship between the drugs. Compared to the reference (‐RIF), simulated DRV Ctrough was 70%, 46% and 20% lower for 800/100 mg qd, 1200/200 mg qd and 800/100 mg bid all +RIF, respectively. Ctrough was 38% higher with 1200/150 mg bid +RIF (Table 1).ConclusionsModelling and simulation was used to investigate the theoretical impact of RIF on DRV/RTV PK. Based on simulations, 800/100 mg and 1200/150 mg both bid could largely overcome the impact of the interaction. However, the risk of increased RTV‐related side effects and higher pill burden should be considered. In vitro work is ongoing to develop a physiologically based model characterizing the interaction and informing simulations.
HIV test: which is your best? A National survey on testing preferences among MSM in Italy
Authors: Mattioli Sandro , Maria Corbelli Giulio , Pieralli Stefano , Degli Esposti Michele 
Published: November 2014

IntroductionHIV testing opportunities in Italy are frequently limited to the hospital setting. Experiences in other countries show that offering HIV testing in other facilities could improve HIV testing uptake.MethodsAn internet‐based survey was conducted between March 10 and April 3, 2014.ResultsA total number of 348 questionnaires were collected. Responders were 88% male. Most represented age groups were 25–34 (35%) and 35–44 (25%). Most of the responders identify themselves as homosexual (81%) or bisexual (9%). Half of responders had an HIV test within 2 years (56%) while 18% never tested for HIV. Among all responders, 61% had more than 2 sexual partners in the past year. Reported condom use in the past year was: always 39%, always but once 11%, sometimes 27%, never 14%. Most known places to have an HIV test is the hospital (95%), STI clinic (58%) and chemical analysis laboratory (54%); most used places are hospital (73%), STI clinic (30%), laboratory (22%) while 5 responders reported having had a self‐test at home. Preferred places where to have an HIV test is self‐testing at home (53%), hospital (36%), pharmacy (32%) and headquarter of an organization (31%). Most known testing method is draw blood from vein (97%), which is also most used (80%) but the least preferred (31%) while saliva (65%) and finger prick (56%) are the preferred choices. Most responders know that physicians (84%) and nurses (77%) are those who perform HIV tests and most of them had an HIV test with them (60% and 65% respectively). Physicians are the preferred operators (54%) followed by self‐testing (46%), nurses (46%) and peer‐volunteers (39%). The ideal HIV test should be: reliable (86%), with no medical prescription (75%), free (63%), rapid (55%), with no personal information collected (45%), with the opportunity to speak with a peer‐counsellor (36%).ConclusionsChanging HIV testing policies in Italy is urgently needed in order to grant a better access to the service: waiting for the results and bureaucratic obligations represent the major barriers to be removed. Home‐testing and community‐based testing seem to be among the best ways to offer new opportunities though they may require a change in the legal, social and cultural context to be implemented and home testing will not allow any kind of support for newly diagnosed people.
Reducing turnaround time for laboratory test results does not improve retention of stable HIV‐infected adults on POV program: experience from Uganda
Authors: Maselle Edna , Muhanguzi Asaph , Muhumuza Simon , Nansubuga Jeniffer , Nawavvu Cecilia , Namusobya Jeniffer , Kamya Moses R , Semitala Fred C 
Published: November 2014

IntroductionHIV/ AIDS clinics in resource limited settings (RLS) face increasing numbers of patients and workforce shortage [1, 2]. To address these challenges, efficient models of care like pharmacy only visits (POV) and nurse only visits (NOV) are recommended [3]. The Makerere University Joint AIDS Program (MJAP), a PEPFAR funded program providing care to over 42,000 HIV infected adults has implemented the POV model since 2009. In this model, stable patients on antiretroviral therapy (ART) with adherence to ART >95% and Karnofsky score >90% are reviewed by a doctor every four months but visit pharmacy for ART re‐fills every two months. A study conducted in August 2011 showed low retention on the POV program with symptomatic diseases, pending CD4 count, complete blood count results, and poor adherence to ART as the major reasons for the non‐retention in the POV program. To improve retention on POV, the TAT (Turnaround Time) for laboratory results (the main reason for non‐retention in the previous study) was reduced from one month to one week. In August 2012, the study was repeated to assess the effect of reducing TAT on improving retention one year after patients were placed on POV.Materials and MethodsA cohort analysis of data from patients in August 2011 and in August 2012 on POV was done. We compared retention of POV before and after reducing the TAT for laboratory results.ResultsRetention on POV was 12.0% (95% CI 9.50–14.7) among 619 patients in 2011, (70% Females), mean age was 33 years, Standard Deviation (SD) 8.5 compared to 11.1% (95% CI 9.15–13.4) among 888 patients (70% Females), mean age 38.3 years, SD 8.9 in 2012 (p=0.59). The main reasons for non‐retention on the POV program in 2012 were poor adherence to ART (23%) and missed clinic appointments (14%).ConclusionsReducing TAT for laboratory test results did not improve retention of stable HIV‐infected adults on POV in our clinic. Strategies for improving adherence to ART and keeping clinic appointments need to be employed to balance workload and management of patients without compromising quality of care, patients’ clinical, immunological and adherence outcome.
Haemophagocytic syndrome and elevated EBV load as initial manifestation of Hodgkin lymphoma in a HIV patient: case report and review of the literature
Authors: Sculier Delphine , Doco‐Lecompte Thanh , Rougemont Mathieu , Calmy Alexandra 
Published: November 2014

IntroductionIn HIV patients, haemophagocytic syndrome (HPS) may occur in the presence of cancer, concomitant viral infection, HIV primo‐infection or at the initiation of highly active antiretroviral therapy (HAART). Hodgkin lymphoma remains a rare cause of HPS. We describe a case of HPS with very high Epstein Barr virus (EBV) load in a HIV patient as initial manifestation of Hodgkin lymphoma.Materials and MethodsA 29‐year‐old HIV positive man, successfully treated with HAART with an undetectable viral load and CD4 cells count of 438/µl, was admitted for high fever of unknown origin. Laboratory results showed a pancytopenia with haemoglobin at 82 g/l, lymphocyte count at 0.36G/l and platelets count at 47G/l; a highly elevated ferritine >7500 µg/l; increased lactate dehydrogenase at 885U/l and soluble IL2 receptor (CD25) >60 ng/ml. EBV load was measured and confirmed at 2,600,000 copies/ml. A PET‐CT imaging showed diffuse elevated metabolic activity in the bone marrow and in two lesions in the spleen without lymphadenopathy. Bone marrow and liver biopsies revealed images of haemophagocytosis and lymphocyte depleted Hodgkin lymphoma. Treatment consisted in etoposid, steroids, and R‐ABVD (rituximab, doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy. The patient completed six cycles of chemotherapy. We reviewed the literature in PubMed with the following keywords: HPS, HIV, EBV, Hodgkin lymphoma.ResultsWe identified four publications and two reviews reporting cases of HPS associated with Hodgkin lymphoma in HIV patients with either a positive EBV load either the presence of encoded EBV RNA in tumour cells. Twenty‐two cases (including one pediatric case) were described. Among adults, mostly men, the median age was <50 years and immune suppression was marked with a median CD4 cell count<100 cells/µl, even in patients receiving HAART. When measured, EBV load in the serum was high. Prognosis was poor with a high mortality despite adequate treatment consisting in steroids and chemotherapy, with or without etoposide (Table 1).ConclusionsOur case report and the review of literature suggest that physicians should be aware of the association between EBV infection/reactivation and Hodgkin lymphoma as a cause of HPS in HIV patients, even if successfully treated with HAART. The pathogenesis of these three interrelated conditions (viral infection, oncogenesis and immunologic reaction) remains unclear.
The absolute lymphocyte count accurately estimates CD4 counts in HIV‐infected adults with virologic suppression and immune reconstitution
Authors: Young Barnaby , Lye David , Tek Ng Oon , Sin Leo Yee 
Published: November 2014

IntroductionThe clinical value of monitoring CD4 counts in immune reconstituted, virologically suppressed HIV‐infected patients is limited. We investigated if absolute lymphocyte counts (ALC) from an automated blood counting machine could accurately estimate CD4 counts.Materials and MethodsCD4 counts, ALC and HIV viral load (VL) were extracted from an electronic laboratory database for all patients in HIV care at the Communicable Diseases Centre, Tan Tock Seng Hospital, Singapore (2008–13). Virologic suppression was defined as consecutive HIV VLs <400 days apart, <200 copies/mL. CD4 counts and same day ALCs were collected during virologic suppression from the first CD4> 300 cells/mm3. CD4 counts were estimated using the CD4% from the first value >300 and an ALC 181–540 days later.ResultsA total of 1215 periods of virologic suppression were identified from 1183 patients, with 2227 paired CD4‐ALCs available for analysis. 98.3% of CD4 estimates were within 50% of the actual value. 83.3% within 25% and 40.5% within 10%. The error pattern was approximately symmetrically distributed around a mean of −6.5%, but significant peaked and with mild positive skew (kurtosis 4.45, skewness 1.07). Causes for these errors were explored. Variability between lymphocyte counts measured by ALC and flow cytometry did not follow an apparent pattern, and contributed to 32% of the total error (median absolute error 5.5%, IQR 2.6–9.3). The CD4% estimate was significantly lower than the actual value (t‐test, p<0.0001). The magnitude of this difference was greater for lower values, and above 25%, there was no significant difference. Precision of the CD4 estimate was similar as baseline CD4% increased, however accuracy improved significantly: from a median 16% underestimation to 0% as baseline CD4% increased from 12 to 30. Above a CD4% baseline of 25, estimates of CD4 were within 25% of the actual value 90.2% of the time with a median 2% underestimation. A robust (bisqaure) linear regression model was developed to correct for the rise in CD4% with time, when baseline was 14–24 (coefficients: intercept=3.30, CD4=0.939). This improved accuracy from 82.0% to 85.4%, and median error from 11% underestimation to 1% (p<0.0001). Adding time since baseline CD4% into the model increased complexity without significantly improving accuracy.ConclusionIn virologically suppressed hosts with CD4 ≥300 cells/mm3 and percentage ≥14, CD4 counts can be predicted with 85–90% confidence to within 25% of the actual value using the ALC.
Intermittent viraemia and immune reconstitution in patients with more than 10–15 years of antiretroviral therapy: baseline values still matter
Authors: Erdbeer Gesa , Sabranski Michael , Sonntag Ina , Stoehr Albrecht , Horst Heinz‐A , Plettenberg Andreas , Schewe Knud , Unger Stefan , Stellbrink Hans‐J , Fenske Stefan , Hoffmann Christian 
Published: November 2014

IntroductionData on patients with long‐term exposure to ART is scarce because controlled studies usually do not follow up patients for more than five to seven years. We were interested whether baseline parameters such as CD4 T‐cell nadir or pre‐treatment viraemia do have an impact on ART success after more than a decade of treatment.MethodsELBE is a cross‐sectional study on adult HIV+ patients presenting consecutively with viral suppression (<50 HIV RNA copies/mL) and with ART exposure of at least five years. In this sub‐analysis, all patients with more than 10 years of ART exposure were evaluated for immune reconstitution and for intermittent transient viraemia (50–1000 copies/mL, defined as “blips”) during the last five years.ResultsFrom a total of 894 patients included in the three participating ELBE centres, 524 patients had an ART exposure of at least 10 years and had been treated continuously during the last 5 years. Of these, 33.4% had at least one “blip” while 63.5% did not show any transient viraemia of more than 50 copies/mL. Patients with at least one blip had a higher pre‐treatment viraemia compared to patients without blips (5.30 versus 5.06 log copies/mL, p=0.0003). In patients with a pre‐treatment viraemia of more than 100,000, 50,000–100,000 and less than 50,000 copies/mL, the proportions of patients with blips during the last five years were 39.5%, 30.5% and 21.8% (p=0.007), respectively. The history of an AIDS‐defining illness or the CD4 T‐cell nadir was not associated with a higher frequency of blips. However, CD4 T‐cell nadir was a strong predictor for current CD4 T‐cell counts. In patient groups with a CD4 T‐cell nadir of 0–99, 100–199, 200–349, 350+ cells/µL, the median current CD4 T cells were 571, 667, 710 and 890 cells/µL, respectively. These differences remained significant when the analysis was restricted to patients with more than 15 years of ART exposure (n=268).ConclusionsIn this large group of positively selected HIV+ patients with long‐term exposure to ART of at least 10–15 years, high pre‐treatment viraemia was still associated with a higher frequency of intermittent transient viraemia (“blip”). A low CD4 T‐cell nadir remained associated with a lower CD4 cell recovery. The clinical implications of these findings remain to be evaluated.
The effect of tenofovir on renal function in HIV‐positive pregnant women
Authors: Flanagan Stuart , Barnes Lynne , Anderson Jane , Barber Tristan 
Published: November 2014

IntroductionTenofovir is a commonly used component of antiretroviral therapy (ART) to reduce vertical transmission of HIV. Although systematic review of tenofovir use in pregnancy concluded it to be low risk for foetal abnormalities [1], data is limited on its impact on renal function in pregnant women. A recent South African study [2] concluded that renal dysfunction in HIV‐infected pregnant women is significantly less common than in other HIV‐infected adults, however there is currently no UK data. We aimed to investigate the effect of tenofovir on renal function in HIV‐1 positive pregnant women in a UK clinic.MethodsWe retrospectively analyzed data on renal function in pregnancy from a cohort of women attending a busy inner city London antenatal clinic. All women were screened for renal function throughout pregnancy via serum creatinine and estimated glomerular filtration rate (eGFR) calculated using modification of diet in renal disease (MDRD) and corrected for ethnicity.ResultsNinety‐seven HIV‐1 positive women were registered at Homerton Hospital antenatal service of a total of 105 pregnancies between January 2010 and September 2013. Tenofovir was prescribed in 71/105 pregnancies (67.6%). Of the 71 pregnancies, 41 were prescribed tenofovir pre‐conception (57.7%). Of the pregnant women who started tenofovir in pregnancy, 21/31 (67.7%) were initiated before week 24 of pregnancy, in line with British HIV association (BHIVA) guidelines [3]. There was no deterioration in median serum creatinine or decline in eGFR in women prescribed tenofovir during pregnancy. At six weeks after delivery, in the 42 women who continued tenofovir therapy and had eGFR measured, one woman had eGFR=60, all others eGFR >90 (Table 1).ConclusionsConsistent with current guidelines and experience, this study shows tenofovir did not cause decline in renal function in pregnancy in our cohort of HIV‐1 positive women, whether started during pre‐conception or during pregnancy. More evidence should be prospectively collected looking at effects of tenofovir on other measures of tubular renal function in pregnancy such as proteinuria and protein‐creatinine ratio.