[Show abstract][Hide abstract] ABSTRACT: Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice.
A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with ≥3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR ≤ 60 ml/min/1.73 m2. Poisson regression was used to develop a risk score, externally validated on two independent cohorts. In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1:393 chance of developing CKD in the next 5 y in the low risk group (risk score < 0, 33 events), rising to 1:47 and 1:6 in the medium (risk score 0-4, 103 events) and high risk groups (risk score ≥ 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria.
Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.
PLoS Medicine 03/2015; 12(3):e1001809. DOI:10.1371/journal.pmed.1001809 · 14.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 10(9) cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate.
To identify the optimal CD4 cell count at which cART should be initiated.
Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 10(9) cells/L.
HIV clinics in Europe and the Veterans Health Administration system in the United States.
20, 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 10(9) cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 10(9) cells/L and were included in the analysis.
Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death.
Compared with initiating cART at the CD4 cell count threshold of 0.500 × 10(9) cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death. Limitations: CD4 cell count at cART initiation was not randomized. Residual confounding may exist.
Initiation of cART at a threshold CD4 count of 0.500 × 10(9) cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 × 10(9) cells/L.
Annals of internal medicine 04/2011; 154(8):509-15. DOI:10.1059/0003-4819-154-8-201104190-00001 · 17.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND OBJECTIVES:
Bacterial pneumonia still contributes to morbidity/mortality in HIV infection despite effective combination antiretroviral therapy (cART). Evaluation of Subcutaneous Interleukin-2 in a Randomized International Trial (ESPRIT), a trial of intermittent recombinant interleukin-2 (rIL-2) with cART vs. cART alone (control arm) in HIV-infected adults with CD4 counts ≥300cells/μL, offered the opportunity to explore associations between bacterial pneumonia and rIL-2, a cytokine that increases the risk of some bacterial infections.
Baseline and time-updated factors associated with first-episode pneumonia on study were analysed using multivariate proportional hazards regression models. Information on smoking/pneumococcal vaccination history was not collected.
IL-2 cycling was most intense in years 1-2. Over ≈7 years, 93 IL-2 [rate 0.67/100 person-years (PY)] and 86 control (rate 0.63/100 PY) patients experienced a pneumonia event [hazard ratio (HR) 1.06; 95% confidence interval (CI) 0.79, 1.42; P=0.68]. Median CD4 counts prior to pneumonia were 570cells/μL (IL-2 arm) and 463cells/μL (control arm). Baseline risks for bacterial pneumonia included older age, injecting drug use, detectable HIV viral load (VL) and previous recurrent pneumonia; Asian ethnicity was associated with decreased risk. Higher proximal VL (HR for 1 log(10) higher VL 1.28; 95% CI 1.11, 1.47; P<0.001) was associated with increased risk; higher CD4 count prior to the event (HR per 100 cells/μL higher 0.94; 95% CI 0.89, 1.0; P=0.04) decreased risk. Compared with controls, the hazard for a pneumonia event was higher if rIL-2 was received <180 days previously (HR 1.66; 95% CI 1.07, 2.60; P=0.02) vs.≥180 days previously (HR 0.98; 95% CI 0.70, 1.37; P=0.9). Compared with the control group, pneumonia risk in the IL-2 arm decreased over time, with HRs of 1.41, 1.71, 1.16, 0.62 and 0.84 in years 1, 2, 3-4, 5-6 and 7, respectively.
Bacterial pneumonia rates in cART-treated adults with moderate immunodeficiency are high. The mechanism of the association between bacterial pneumonia and recent IL-2 receipt and/or detectable HIV viraemia warrants further exploration.
HIV Medicine 04/2011; 12(4):219-227. · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Used in combination with antiretroviral therapy, subcutaneous recombinant interleukin-2 raises CD4+ cell counts more than does antiretroviral therapy alone. The clinical implication of these increases is not known.
We conducted two trials: the Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy (SILCAAT) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). In each, patients infected with the human immunodeficiency virus (HIV) who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone. The interleukin-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals. The SILCAAT study involved six cycles and a dose of 4.5 million IU of interleukin-2 twice daily; ESPRIT involved three cycles and a dose of 7.5 million IU twice daily. Additional cycles were recommended to maintain the CD4+ cell count above predefined target levels. The primary end point of both studies was opportunistic disease or death from any cause.
In the SILCAAT study, 1695 patients (849 receiving interleukin-2 plus antiretroviral therapy and 846 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4111 patients (2071 receiving interleukin-2 plus antiretroviral therapy and 2040 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled. Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the interleukin-2 group than in the group receiving antiretroviral therapy alone--by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively. Hazard ratios for opportunistic disease or death from any cause with interleukin-2 plus antiretroviral therapy (vs. antiretroviral therapy alone) were 0.91 (95% confidence interval [CI], 0.70 to 1.18; P=0.47) in the SILCAAT study and 0.94 (95% CI, 0.75 to 1.16; P=0.55) in ESPRIT. The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (P=0.73) and 1.10 (P=0.35), respectively, in the SILCAAT study and 0.90 (P=0.42) and 1.23 (P=0.003), respectively, in ESPRIT.
Despite a substantial and sustained increase in the CD4+ cell count, as compared with antiretroviral therapy alone, interleukin-2 plus antiretroviral therapy yielded no clinical benefit in either study. (ClinicalTrials.gov numbers, NCT00004978 [ESPRIT] and NCT00013611 [SILCAAT study].)
New England Journal of Medicine 10/2009; 361:1548-59. · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: High dose chemotherapy with autologous stem cell transplantation (ASCT) is increasingly used in the treatment of patients with lymphoma. As previously shown with conventional treatments, second neoplasms are emerging as a long term complication of the procedure. In this study, we investigate the incidence of second neoplasm in a cohort of 171 patients treated with BEAM or BEAC regimens for Hodgkin's disease (n = 62) and non-Hodgkin's lymphomas (n = 109) followed up for a median of 52 months post ASCT. Six patients developed six second malignancies 12 to 105 months after ASCT: fibrolamellar carcinoma of the liver, malignant fibrous histiocytoma, pancreatic carcinoma, squamous cell carcinoma of the lung, invasive carcinoma of the vulva and acute myelogenous leukemia. The cumulative actuarial risk for developing second malignancy is 16.7 % (95% confidence interval: 5.9-39.3%) 13 years after transplant. The age-adjusted incidence of cancer in the study group is 4.1 times higher than that of primary cancer in the general population. These data confirm that ASCT recipients are at increased risk of later malignancies. This complication adds significant morbidity and mortality to the transplant process and therefore, needs to be taken into account in long term evaluation of new strategies which involve early intensification in the treatment of lymphomas.
Leukemia and Lymphoma 06/2009; 31(1-2):187-194. DOI:10.3109/10428199809057598 · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We previously reported a beneficial effect of benfluorex (BFL) on oral glucose tolerance test (OGTT) and visceral fat mass in an open-label study conducted in 60 HIV-infected patients. The objective of this study was to assess whether administration of BFL compared to placebo (PBO) improves insulin resistance (IR) in HIV+ patients with HAART- induced lipodystrophy.
22 HIV-infected patients with IR or impaired glucose tolerance were double-blind randomly assigned to receive BFL 3 tablets/day or PBO for 24 weeks. Efficacy assessments included OGTT, abdominal computed tomography, and the measurement of fasting lipids.
Change of median insulin AUC was -53.0 microIU/mL (IQR, -126.0 to -12.7) in the BFL group vs. +33.6 microIU/mL (IQR, 7.0 to 115.6) (p = .01) in PBO group. Weight decreased significantly in the BFL group (-2 kg +/- 2.6; IQR, -6.8 to 2.0) compared to the PBO group (0.8 kg +/- 1.7; IQR, -2.0 to 0.5) (p = .02). No significant changes in visceral or subcutaneous fat mass and plasma lipid level were observed between the two groups.
Added to antiretroviral therapy, a 6-month therapy with BFL improved insulin sensitivity but is not sufficient to reduce significantly visceral fat mass.
HIV Clinical Trials 01/2009; 10(1):33-40. DOI:10.1310/hct1001-033 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IntroductionChronic lymphocytic leukemia (CLL) is the most common leukaemia in the Western world. Recent advancement in the aetiology, pathophysiology and the development of new therapeutics tools have significantly modified the current management of CLL.
La Revue de Médecine Interne 05/2008; 29(5):424-435. DOI:10.1016/j.revmed.2007.10.414 · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: or allogeneic 4 transplantation has been suggested. We report the first case of a woman with a non Hodgkin lymphoma (NHL) who developed PML after a combination of rituximab with chemotherapy as first line treatment. A 67-year-old woman suffered from a mantle cell lymphoma diagnosed on splenomegaly and hyperlym- phocytosis. Staging showed a stage IV with bone mar- row involvement. The patient was treated with a com- bination of rituximab (375 mg/m 2 ) and chemotherapy with standard CHOP: cyclophosphamide 750 mg/m 2 , doxorubicin 50 mg/m 2 , vincristin 2 mg, and oral predni- son 100 mg given in 3-week cycles. She received eight cycles of treatment. Evaluation after the eight cycles showed a complete remission. One month after the last chemotherapy, the patient rapidly presented psychiatric disturbances with speech dysfunction and paranoia delirium. PML was suspected on magnetic resonance imaging showing frontal and temporal leukoen- cephalopathy. JC viral DNA was detected in the cere- brospinal fluid. HIV serology was negative. Her total lymphocyte count was 470/∝L with 110/∝L CD4 + and 310/∝L CD8 + . Peripheral B cells were decreased with
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:
ESPRIT is a randomized trial comparing the clinical impact of interleukin (IL)-2 plus antiretrovirals vs antiretrovirals alone. Identification of factors that influence the relationship between IL-2 and CD4 count recovery will enable better personalization of treatment with IL-2 in HIV-1-positive individuals. The IL-2 induction phase consists of three dosing cycles over 6-8 months (7.5 MIU twice a day, for 5 days every 8 weeks).
We included patients initiating IL-2 at the 7.5 MIU dose with an 8-month CD4 count, measured at least 30 days after their last cycle. We identified baseline predictors of CD4 count changes over 8 months using linear regression.
Of 2090 patients assigned IL-2, 1673 (80%) were included in the analysis. The median (interquartile range) baseline CD4 count was 461 (370, 587) cells/microL with a median increase of 233 (90, 411) cells/microL at month 8. After adjustments, significant predictors of CD4 count change included CD4 nadir (29.8 cells/microL greater increase per 100 cells/microL higher; P<0.0001), last CD4 count before baseline (mean 36.0 cells/microL greater increase per 100 cells/microL higher; P<0.0001), time from antiretroviral start to baseline (8.3 cells/microL smaller increase per year longer; P=0.001), age (11.7 cells/microL smaller increase per 5 years older; P=0.005) and race (79.7 cells/microL greater increase for black patients vs white patients; P=0.003). A linear relationship existed between total IL-2 dose in the first cycle and CD4 count change (73.1 cells/microL greater increase per 15 MIU higher; P<0.0001).
Prior nadir and current CD4 counts, age and IL-2 dose are major determinants of CD4 increases induced by with intermittent administration of IL-2 in HIV-1-positive individuals on antiretrovirals. The clinical function of these induced CD4 cells is under study.
HIV Medicine 03/2007; 8(2):112-123. · 3.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The potential benefit of rituximab as adjuvant to high-dose therapy (HDT) has been investigated in patients under 60 years with poor-risk (age-adjusted international prognostic index at 2-3) CD20+ diffuse large B-cell lymphoma (DLBCL). The treatment consisted of four cycles of high-dose CEOP (cyclophosphamide, epirubicin, vincristine, prednisone), plus etoposide and cisplatin during the two last cycles. Peripheral blood stem cells were collected after cycle 1, and reinfused after cycles 3 and 4. Four weekly rituximab infusions were subsequently delivered. Among the 36 patients included, 30 could complete chemotherapy schedule, and 24/36 received rituximab. A complete response occured in 26/36 patients (72%). With a median follow-up of 30 months, the estimated 5-year overall survival (OS) and event-free survival (EFS) rates (mean +/- s.d.) were 65 +/- 16 and 63 +/- 15%, respectively. For the 24 patients who received both chemotherapy and rituximab, the estimated 5-year OS and EFS rates were 86 +/- 14 and 82 +/- 15%. These data suggest that rituximab after HDT is feasible. Both complete remission rate and survival curves compare favorably with the poor outcome usually observed in high-risk DLBCL patients managed with HDT without rituximab.
Bone Marrow Transplantation 09/2006; 38(3):217-22. DOI:10.1038/sj.bmt.1705414 · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. We obtained estimates of the incidence of tuberculosis (TB) among patients receiving HAART and identified determinants of the incidence. Methods. We analyzed the incidence of TB during the first 3 years after initiation of HAART among 17,142 treatment-naive, AIDS- free persons starting HAART who were enrolled in 12 cohorts from Europe and North America. We used univariable and multivariable Poisson regression models to identify factors associated with the incidence. Results. During the first 3 years (36,906 person-years), 173 patients developed TB (incidence, 4.69 cases per 1000 person-years). In multivariable analysis, the incidence rate was lower for men who have sex with men, compared with injection drug users (relative rate, 2.46; 95% confidence interval [CI], 1.51-4.01), heterosexuals (relative rate, 2.42; 95% CI, 1.64-3.59), those with other suspected modes of transmission (relative rate, 1.66; 95% CI, 0.91-3.06), and those with a higher CD4(+) count at the time of HAART initiation (relative rate per log(2) cells/mL, 0.87; 95% CI, 0.84-0.91). During 28,846 person-years of follow-up after the first 6 months of HAART, 88 patients developed TB (incidence, 3.1 cases per 1000 person-years of follow-up). In multivariable analyses, a low baseline CD4(+) count (relative rate per log(2) cells/mL, 0.89; 95% CI, 0.83-0.96), 6-month CD4(+) count (relative rate per log(2) cells/mL, 0.90; 95% CI, 0.81-0.99), and a 6-month HIV RNA level 1400 copies/mL (relative rate, 2.21; 95% CI, 1.33-3.67) were significantly associated with the risk of acquiring TB after 6 months of HAART. Conclusion. The level of immunodeficiency at which HAART is initiated and the response to HAART are important determinants of the risk of TB. However, this risk remains appreciable even among those with a good response to HAART, suggesting that other interventions may be needed to control the TB epidemic in the HIV-infected population.
[Show abstract][Hide abstract] ABSTRACT: This retrospective and longitudinal study evaluated the long-term hepatic tolerance of a nelfinavir (NFV)-antiretroviral combined regimen in 82 patients of the HCV-HIV Cohort of CISIH-Sud of Marseilles. Follow-up data (liver enzyme levels, CD4 cell count, HIV viral load, and metabolic parameters) of patients treated with NFV on inclusion or during the follow-up of the cohort were analyzed under treatment over 24 months. Comparisons were performed with X2 or Kruskal-Wallis tests. At baseline (n = 82), the median exposure to NFV was 4.1 months; 58 patients received NFV combined with NRTI and 24 with NNRTI. The median CD4 cell count was 337/mm3 [interquartile range (IR): 216-480) and 39.7% had an undetectable HIV RNA level. Qualitative HCV PCR was positive in 91% of the patients and 19/51 patients with liver biopsy were F3-F4. Median alanine and aspartate aminotransferase (ALAT, ASAT), gamma-glutamyltransferase (GT), and alkaline phosphatase (ALP) were 46 UI/liter (IR: 36-76), 55 UI/liter (IR: 32-97), 97 UI/liter (IR: 50-194), and 88 UI/liter (IR: 72-104), respectively, with 76% of the patients with ALAT/ASAT grade <2. Median follow-up was 23 months (IR: 13.8-37). No significant difference was observed in the distribution of ALAT, ASAT, GT, and ALP as well as of ALAT/ASAT grades over the 24-month study period. Patients treated with NFV + NNRTI had significantly higher GT and ALP levels at baseline with no significant increase during follow-up. Cholesterol, triglyceride, and glycemia distributions remained stable over time. In conclusion, this study showed a good hepatic and metabolic tolerance of a long-term NFV-combined regimen in HIV-HCV coinfected patients.
AIDS Research and Human Retroviruses 11/2005; 21(10):841-4. DOI:10.1089/aid.2005.21.841 · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: T-cell lymphoma is an aggressive lymphoma that cannot be cured despite aggressive therapy, including autologous stem cell transplantation. Thalidomide is an immunomodulatory drug with numerous properties that has proven effective in relapsed multiple myeloma and, to a lesser extent, in other hematologic diseases. We report three cases of relapsed refractory T-cell lymphoma treated with thalidomide with a good tumor response.
European Journal Of Haematology 03/2005; 74(2):169-71. DOI:10.1111/j.1600-0609.2004.00362.x · 2.07 Impact Factor