Carine Greib

Increased risk of abnormal proximal renal tubular function with HIV infection and antiretroviral therapy

Abnormal kidney function is common in the course of human immunodeficiency virus (HIV) infection. Here, we performed a cross-sectional analysis using 399 patients within the Aquitaine cohort (a hospital-based cohort of HIV-1-infected patients receiving routine clinical management) to estimate the prevalence of proximal renal tubular dysfunction (PRTD) associated with HIV infection. These patients did not differ statistically by sociodemographics, median age, years since HIV diagnosis, AIDS stage, or median CD4 cell count from the entire 3080 patient cohort. Antiretroviral therapy was received by 352 patients, with 256 given tenofovir (TDF); 325 had undetectable HIV plasma viral load, and 26 were diagnosed with PRTD. In multivariate analysis, significant independent associations were found between PRTD and age (odds ratio (OR) 1.28 per 5-year increase), atazanavir (OR 1.28 per year of exposure), and TDF (OR 1.23 per year) treatment. Among patients having received TDF-containing regimens over a 5-year period, PRTD remained significantly associated with TDF exposure when treatment was ongoing (OR 5.22) or had been discontinued (OR 11.49). Thus, cumulative exposure to TDF and/or atazanavir was associated with an increased risk of PRTD, with concern about its reversibility in patients with HIV.

Cognitive disorders in HIV-infected patients: are they HIV-related?

Objectives:Large unselected studies on representative samples of HIV-infected patients with a whole battery of neuropsychological tests and cerebral MRI scan are required to assess the frequency of neurocognitive impairment (NCI), the determinants of mild neurocognitive disorders (MNDs), or HIV-associated dementia (HAD) and the relationship between NCI and MRI scan findings. Methods:Investigation of 400 consecutively enrolled HIV-1-infected adults from the ANRS CO3 Aquitaine Cohort, using standardized neurocognitive tests chosen to achieve consistency with Frascatis criteria. Half of the patients had a cerebral MRI scan allowing gray and white matter volume measurement. Factors associated with NCI were studied by logistic regression models. Results:Median age of participants was 47 years, 79% were male and 89% received combination antiretroviral treatment (cART), of whom 93% had plasma HIV RNA below 500u200acopies/ml. Median CD4 cell count was 515 cells/&mgr;l. Prevalence of NCI was 59%, including 21% of asymptomatic NCI, 31% of MND, and 7% of HAD. A low level of education, prior neurologic AIDS-defining disorders event, anxiety, depressive symptoms, and prior history of brain damage were independently associated with MND or HAD, but neither HIV nor cART-related variables. The presence of NCI was significantly associated with lower gray matter fraction. Interpretation:In this large unselected cohort, a high prevalence of symptomatic neurocognitive disorders was mainly related to its traditional determinants and associated with gray matter atrophy at early stages of the disease.

High frequency of poor locomotor performance in HIV-infected patients.

Objectives:To provide up-to-date assessments of locomotor function in HIV-infected patients and to identify potential determinants of impaired function. Design:Cross-sectional study in 324 HIV-1-infected adults from the French Agency for AIDS and Hepatitis Research (ANRS) CO3 Aquitaine Cohort using standardized locomotor tests. Methods:Patients underwent standardized testing assessing balance, walking ability, functional capacity and lower limb muscle performance. Poor test performance was defined by cut-offs based on age-specific data of the general population. Factors associated with poor test performance were studied by logistic regression. Results:Median age was 48 years, 80% were men and 89% were on antiretroviral treatment. The most frequently altered locomotor test was the five-times sit-to-stand (5STS) test, assessing lower limb muscle performance (poor performance: 53%). In multivariable analysis, time since HIV diagnosis was associated with poor 5STS performance [odds ratio (OR) = 1.08 per year; 95% confidence interval (CI): 1.03, 1.13]. In patients below 30 years, elevated BMI was associated with higher likelihood of good performance (OR = 0.81 per kg/m2; 95% CI: 0.69, 0.93), whereas in those above 70 years this association was reversed (OR = 1.30 per kg/m2; 95% CI: 1.10, 1.53; P < 10−3 for interaction). We found no association with antiretroviral treatment. Conclusion:One of two adults with controlled HIV infection had poor lower limb muscle performance, which might put this population at risk of falls and fracture. The 5STS test is a simple test that should be recommended to assess muscular performance in HIV care.

Steady-state mycophenolate mofetil pharmacokinetic parameters enable prediction of systemic lupus erythematosus clinical flares: an observational cohort study.

IntroductionThe aim of this study was to determine whether mycophenolate mofetil (MMF) pharmacokinetics (PK) under combined MMF and prednisone remission-maintenance therapy can predict systemic lupus erythematosus (SLE) clinical flares.MethodsAt inclusion, steady-state PK parameters of the MMF active form, mycophenolic acid (MPA), and its glucuronide metabolite (MPAG) were determined for 25 stable SLE patients without renal manifestations. Disease activity was assessed during 6 months of follow-up. Potential relationships between those entry MMF-PK variables and clinical outcome were analyzed.ResultsMMF controlled disease activity in 17 patients (successes) and failed to do so for 8 others (failures). For failures and successes, respectively, entry MPA areas under the time-concentration curve between 0 and 12 hours (AUC0-12 h) (medians: 37.7 vs 73.1 mg/h/L, P = 0.003) and MPA 12-hour trough concentrations (C12 h) (medians: 1.5 vs 3.7 mg/L, P = 0.008) were significantly lower, and inclusion MPAG/MPA C12 h ratios (medians: 18.7 vs 10.2, P = 0.02) were significantly higher. According to our receiver operating characteristics curve analysis, MPA C12 h was best able to discriminate a flare during follow-up (93% sensitivity, 85% specificity). A 3-mg/L cut-off had 92% negative-predictive value for developing a flare during follow-up.ConclusionsFor our SLE patients without renal manifestations, clinical flares developing under maintenance therapy were associated with steady-state inclusion MPA C12 h < 3 mg/L.

AIDS and non-AIDS severe morbidity associated with hospitalizations among HIV-infected patients in two regions with universal access to care and antiretroviral therapy, France and Brazil, 2000–2008: hospital-based cohort studies

BackgroundIn high-income settings, the spectrum of morbidity and mortality experienced by Human Immunodeficiency Virus (HIV)-infected individuals receiving combination antiretroviral therapy (cART) has switched from predominantly AIDS-related to non-AIDS-related conditions. In the context of universal access to care, we evaluated whether that shift would apply in Brazil, a middle-income country with universal access to treatment, as compared to France.MethodsTwo hospital-based cohorts of HIV-infected individuals were used for this analysis: the ANRS CO3 Aquitaine Cohort in South Western France and the Evandro Chagas Research Institute (IPEC) Cohort of the Oswaldo Cruz Foundation in Rio de Janeiro, Brazil. Severe morbid events (AIDS- and non-AIDS-related) were defined as all clinical diagnoses associated with a hospitalization of ≥48xa0hours. Trends in the incidence rate of events and their determinants were estimated while adjusting for within-subject correlation using generalized estimating equations models with an auto-regressive correlation structure and robust standard errors.ResultBetween January 2000 and December 2008, 7812 adult patients were followed for a total of 41,668 person-years (PY) of follow-up. Throughout the study period, 90% of the patients were treated with cART. The annual incidence rate of AIDS and non-AIDS events, and of deaths significantly decreased over the years, from 6.2, 21.1, and 1.9 AIDS, non-AIDS events, and deaths per 100 PY in 2000 to 4.3, 14.9, and 1.5/100 PY in 2008. The annual incidence rates of non-AIDS events surpassed that of AIDS-events during the entire study period. High CD4 cell counts were associated with a lower incidence rate of AIDS and non-AIDS events as well as with lower rates of specific non-AIDS events, such as bacterial, hepatic, viral, neurological, and cardiovascular conditions. Adjusted analysis showed that severe morbidity was associated with lower CD4 counts and higher plasma HIV RNAs but not with setting (IPEC versus Aquitaine).ConclusionsAs information on severe morbidities for HIV-infected patients remain scarce, data on hospitalizations are valuable to identify priorities for case management and to improve the quality of life of patients with a chronic disease requiring life-long treatment. Immune restoration is highly effective in reducing AIDS and non-AIDS severe morbid events irrespective of the setting.

Therapeutic drug monitoring of mycophenolate mofetil and enteric-coated mycophenolate sodium in patients with systemic lupus erythematosus

Objective: Mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), is used to treat systemic lupus erythematosus (SLE). MMF and EC-MPS pharmacokinetics were examined to devise guidance for therapeutic drug monitoring (TDM) for SLE patients with normal renal function. Research design and methods: This observational study included 21 patients receiving MMF (1000 mg twice daily) and 14 taking EC-MPS (720 mg twice daily). MPA AUC between 0 and 12 h (AUC0–12h), Cmax, Tmax, and 12-h trough concentrations (C12h) were determined. Results: Means of dose-normalized MMF– or EC-MPS–MPA Cmax were 64.6 ± 25 and 61.4 ± 27.1 h mg/l, respectively. MPA Tmax for EC-MPS was longer and more variable than for MMF. MMF-MPA AUC0–12h and C12h were correlated (r = 0.78, p = 0.0001), but EC-MPS–MPA Cmax and single concentrations were weakly correlated. A limited-sampling strategy (LSS) combining Cmax and C12h gave satisfactory predictive performance to estimate MPA AUC0–12h after EC-MPS administration. Conclusions: For TDM in SLE patients with GFR >u200960 ml/min/1.73 m2, C12h after MMF ingestion could predict MPA AUC0–12h, while an LSS around Tmax should be used for patients on EC-MPS.

Romiplostim as early treatment for refractory primary immune thrombocytopenia

AbstractnRomiplostim is a thrombopoietin-receptor agonist approved to treat chronic immune thrombocytopenia (ITP). We treated eight patients with acute or persistent primary ITP, severe clinical bleeding, and resistance to corticosteroids and/or intravenous immunoglobulins (IVIg). Romiplostim, initially administered at 2 or 3xa0μg/kg/week, was subsequently increased to achieve and maintain platelet-count responses and control bleeding. Seven patients’ platelet counts rose above 30xa0G/L, representing ≥twofold increases, within a median of 14xa0days after 1–5 infusions. The weekly dose reached 9xa0μg/kg at week 5 for three patients; the other patients’ ITPs were controlled with ≤6xa0μg/kg/week. No thromboembolic events occurred. Five patients received rituximab concomitantly with romiplostim, four of whom could stop romiplostim within 2xa0months, thereby demonstrating rituximab efficacy. All three patients treated with romiplostim alone required maintenance therapy. Thus, romiplostim represents an alternative for patients with severe acute or persistent ITP refractory to conventional therapy.

Pre-dose plasma concentration monitoring of mycophenolate mofetil in patients with autoimmune diseases

AIMnTo date, neither the benefit of mycophenolic acid (MPA) therapeutic drug monitoring (TDM), the prodrug of mycophenolate mofetil (MMF), nor the optimal monitoring technique have been established in autoimmune diseases. This study was undertaken to confirm, in a cohort of new patients, the plasma MPA thresholds previously published in patients with systemic lupus erythematosus (SLE) or vasculitis.nnnMETHODSnMPA areas under the concentration-time curves between 0 and 12u2009h, 12u2009h trough concentrations and pre-dose concentrations (C0 ) were determined for 23 patients with SLE and 21 with systemic vasculitis. The relationship between patients pharmacokinetic (PK) variables and their clinical outcomes during follow-up were analyzed.nnnRESULTSnIn both autoimmune diseases, at PK assessment, median MPA C0 for patients with uncontrolled disease was significantly lower than that of patients with stable disease or in remission, 1.6u2009mg l(-1) (IQR 0.9-2.1u2009mg l(-1)) vs. 2.95u2009mg l(-1) (IQR 1.38-3.73u2009mg l(-1)) for SLE (P = 0.048) and 1.55u2009mg l(-1) (IQR 0.98-2.18u2009mg l(-1)) vs. 3u2009mg l(-1) (IQR 2.2-4.4u2009mg l(-1)) for vasculitis (P = 0.016). According to our receiver operating characteristics curve analysis, a C0 threshold of 2.5-3u2009mg l(-1) was best able to discriminate a flare (SLE: 88% sensitivity, 80% specificity; vasculitis: 100% sensitivity, 90% specificity). Patients with C0 ≥ 2.5-3u2009mg l(-1) at inclusion had better clinical outcomes during the 12 months following PK assessment.nnnCONCLUSIONnProvided that the benefit of TDM in patients with autoimmune diseases could be confirmed by randomized, controlled trials, it might be based on the C0 measured approximately 12u2009h post-dose.

Absence of Decline of Kidney Function in Human Immunodeficiency Virus-Infected Patients Under Routine Clinical Management

Background: Since the introduction of antiretroviral therapy (ART), human immunodeficiency virus (HIV)-infected patients have a drastically improved prognosis but at the same time they are also more affected by non-HIV related complications, such as chronic kidney disease. The objective of our study was to investigate the effect of proteinuria and tenofovir (TDF)-containing ART regimens on the temporal evolution of estimated glomerular filtration rate (eGFR). Methods: Between April 2008 and October 2012, we enrolled 395 patients with a complete renal evaluation among patients from the ANRS C03 Aquitaine cohort, a prospective hospital-based cohort of HIV-1-infected patients under routine clinical management in southwestern France. eGFR was estimated at each patient follow-up visit. A linear mixed model was used to analyze eGFR dynamics, accounting for change in TDF by modeling eGFR trajectory according to treatment periods. Results: At inclusion, 56.7% of patients were treated with TDF-containing ART regimens; prevalence of glomerular and tubular proteinuria was 7.9 and 10.8% respectively. A 1-year increase of cumulative exposure to TDF was significantly associated with a mean eGFR decrease of 1.27 mL/min/1.73 m2 (95% CI [-2.14 to -0.41]). Only a urine protein to creatinine ratio >100 mg/mmol and/or a urine albumin to creatinine ratio >70 mg/mmol were associated with eGFR trajectory (mean slope 6.18 mL/min/1.73 m2 per year; 95% CI [2.71 to 9.65]), whereas TDF use was not associated with such eGFR temporal evolution. Conclusion: Decline in kidney function is limited under routine clinical management with monitoring of renal function and interventions including decision to continue or discontinue TDF.