Fabrice Bonnet

Changes in Causes of Death Among Adults Infected by HIV Between 2000 and 2005 : The Mortalité 2000 and 2005 Surveys (ANRS EN19 and Mortavic)

Background:The multicenter national Mortalité 2005 survey aimed at describing the distribution of causes of death among HIV-infected adults in France in 2005 and its changes as compared with 2000. Methods:Physicians involved in the management of HIV infection notified deaths and documented the causes using a standardized questionnaire similar to the previous survey performed in 2000. Results:Overall, 1042 deaths were notified in 2005 (vs 964 in 2000): with median age, 46 years (vs 41 years); men, 76%; and median last CD4 cell count, 161/mm3 (vs 94). The proportion of underlying causes of death due to AIDS decreased (36% in 2005 vs 47% in 2000), and the proportion of cancer not related to AIDS or hepatitis (17% vs 11%), liver related disease (15% vs 13%: hepatitis C, 11%, and hepatitis B, 2%), cardiovascular disease (8% vs 7%), or suicide (5% vs 4%) increased. Among the 375 AIDS-related deaths, the most frequent event was non-Hodgkin lymphoma (28%). Among cancers not related to AIDS or hepatitis, the most frequent localizations were lung (31%) and digestive tract (14%). Among the 154 liver-related deaths, 24% were due to hepatocarcinoma. Conclusions:The heterogeneity of causes of death among HIV-infected adults was confirmed and intensified in 2005, with 3 causes following AIDS: cancers and liver-related and cardiovascular diseases.

Excessive body weight as a new independent risk factor for clinical and pathological progression in primary IgA nephritis

Experimental evidence suggests a role for obesity in the formation and progression of some glomerular lesions, but data for human glomerulonephritis are lacking. In a cohort of 162 incident patients with biopsy-proven immunoglobulin A (IgA) nephropathy, we assessed whether the presence of an elevated body mass index (BMI >/= 25 kg/m(2)) at the time of the first renal biopsy (RB1) correlated with clinical data at RB1 (24-hour proteinuria, arterial hypertension, and renal function), pathological data (global optical score [GOS] with detailed pathological indices), and clinical progression to both arterial hypertension and chronic renal failure (CRF). In both univariate and multivariate analyses, the presence of an elevated BMI at RB1 was significantly associated with the severity of pathological renal lesions (GOS and vascular, tubular, and interstitial indices). Hypertension-free survival was significantly less in overweight patients (P: < 0.0001) compared with those with normal weight. In a Cox regression analysis for hypertension-free survival including 24-hour proteinuria greater than 1 g, GOS, and metabolic parameters, only elevated BMI and GOS were independent factors for the development of arterial hypertension. CRF-free survival was also significantly less in patients with an excessive BMI. In a multivariate Cox regression analysis for CRF-free survival, hypertension, GOS, and BMI at RB1 were independent risk factors for CRF. In IgA nephropathy, excessive body weight and/or BMI are underestimated predictive factors for the development of arterial hypertension and, ultimately, CRF.

Irbesartan normalises the deficiency in glomerular nephrin expression in a model of diabetes and hypertension.

Aims/hypothesis. The location of nephrin has been identified as the slit-diaphragm of the glomerular podocyte. Recent evidence suggests that nephrin could play a key role in the function of the glomerular filtration barrier and the development of proteinuria but its status in long-term diabetes is still not understood. We studied the expression of nephrin in a hypertensive model of diabetic nephropathy and investigated the potential influence of angiotensin II blockade on nephrin gene and protein expression. Methods. Streptozotocin-diabetic spontaneously hypertensive rats were given either no treatment or the angiotensin II antagonist, irbesartan, at a dose of 15 mg/kg per day by gavage for 32 weeks. Non-diabetic spontaneously hypertensive rats were used as a control group. Real time RT-PCR and immunohistochemistry were used to assess and quantify gene and protein expression of nephrin. Results. Diabetic spontaneously hypertensive rats developed albuminuria and had a reduction in both gene and protein expression of nephrin when compared with control rats. Irbesartan treatment prevented the development of albuminuria and completely abrogated the down regulation of nephrin in diabetic rats. Conclusion/interpretation. Long-term diabetes in spontaneously hypertensive rats is associated with a reduction in both gene and protein expression of nephrin within the kidney. These changes in nephrin levels were completely prevented by angiotensin II antagonist treatment, suggesting a potential novel mechanism to explain the antiproteinuric effect of agents which interrupt the renin-angiotensin system. [Diabetologia (2001) 44: 874–877]

Associations Between Anxiety, Depression, and the Metabolic Syndrome

BACKGROUND There is limited evidence as to whether the metabolic syndrome (MetS) is associated with depression or anxiety and, if so, whether this association is gender-specific. This study investigated in each gender whether the MetS is associated with anxiety or depression and whether these relationships are independent of age, obesity, smoking status, socioeconomic factors, and lifestyle. METHODS Metabolic syndrome (American Heart Association/National Heart, Lung, and Blood Institute criteria), depression, and anxiety (Hospital Anxiety and Depression Scale) were assessed in 1598 subjects at risk of cardiovascular disease. RESULTS In both men and women, the MetS was associated with an increased prevalence of depression but not anxiety. The number of components of the MetS increased with increasing levels of depression but not anxiety. This association between the MetS and depressive symptoms was independent of age, smoking status, socioeconomic factors, and lifestyle. The relationship was observed across body mass index categories and was independent of anxiety. CONCLUSIONS The MetS is associated with depression and depressive symptoms but not anxiety irrespective of gender and overweight/obesity status in subjects at risk of cardiovascular disease. These findings suggest a potential importance of screening for depression in patients with the MetS.

Mechanisms of diabetic vasculopathy: an overview

Diabetes is commonly associated with both microvascular and macrovascular complications. These vascular complications are accelerated in the context of systemic hypertension. During the past few years the underlying molecular mechanisms responsible for diabetic vascular complications have begun to be clarified. It appears that both metabolic and hemodynamic factors interact to stimulate the expression of cytokines and growth factors in the various vascular trees. Overexpression of the prosclerotic cytokine transforming growth factor-beta has been observed in glomeruli and tubules from the diabetic kidney. In the retina the angiogenic cytokine vascular endothelial growth factor and its receptor, vascular endothelial growth factor R-2 are increased in experimental diabetes. These changes in growth factors are viewed to be responsible for the extracellular matrix accumulation in the diabetic kidney and new vessel formation in the diabetic retina. Changes in cytokines have also been observed at other vascular sites including the mesenteric vascular tree. Vasoactive hormones, such as angiotensin II and endothelin, are potent stimulators of cytokines with recent studies showing that inhibitors of these vasoactive hormone pathways may confer organ protection in diabetes by inhibition of growth factor expression. Glucose-dependent factors, such as the formation of advanced glycation end products that interact with specific receptors and lead to overexpression of a range of cytokines, may play an important role in diabetic vascular complications including atherosclerosis. It is likely that the effects of inhibitors of this pathway such as aminoguanidine on cytokine production may play a pivotal role in mediating the renal, retinal, and vasoprotective effects observed with this agent in experimental diabetes. It is anticipated that the advent of specific inhibitors of cytokine formation or action will provide new approaches for the prevention and treatment of diabetic vascular complications.

HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies

Objective:To evaluate deaths from AIDS-defining malignancies (ADM) and non-AIDS-defining malignancies (nADM) in the D:A:D Study and to investigate the relationship between these deaths and immunodeficiency. Design:Observational cohort study. Methods:Patients (23 437) were followed prospectively for 104 921 person-years. We used Poisson regression models to identify factors independently associated with deaths from ADM and nADM. Analyses of factors associated with mortality due to nADM were repeated after excluding nADM known to be associated with a specific risk factor. Results:Three hundred five patients died due to a malignancy, 298 prior to the cutoff for this analysis (ADM: n = 110; nADM: n = 188). The mortality rate due to ADM decreased from 20.1/1000 person-years of follow-up [95% confidence interval (CI) 14.4, 25.9] when the most recent CD4 cell count was <50 cells/μl to 0.1 (0.03, 0.3)/1000 person-years of follow-up when the CD4 cell count was more than 500 cells/μl; the mortality rate from nADM decreased from 6.0 (95% CI 3.3, 10.1) to 0.6 (0.4, 0.8) per 1000 person-years of follow-up between these two CD4 cell count strata. In multivariable regression analyses, a two-fold higher latest CD4 cell count was associated with a halving of the risk of ADM mortality. Other predictors of an increased risk of ADM mortality were homosexual risk group, older age, a previous (non-malignancy) AIDS diagnosis and earlier calendar years. Predictors of an increased risk of nADM mortality included lower CD4 cell count, older age, current/ex-smoking status, longer cumulative exposure to combination antiretroviral therapy, active hepatitis B infection and earlier calendar year. Conclusion:The severity of immunosuppression is predictive of death from both ADM and nADM in HIV-infected populations.

Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease

The worldwide epidemic of obesity and insulin resistance favors nonalcoholic fatty liver disease (NAFLD). Insulin resistance (IR) in the adipose tissue increases lipolysis and the entry of nonesterified fatty acids (NEFAs) in the liver, whereas IR‐associated hyperinsulinemia promotes hepatic de novo lipogenesis. However, several hormonal and metabolic adaptations are set up in order to restrain hepatic fat accumulation, such as increased mitochondrial fatty acid oxidation (mtFAO). Unfortunately, these adaptations are usually not sufficient to reduce fat accumulation in liver. Furthermore, enhanced mtFAO without concomitant up‐regulation of the mitochondrial respiratory chain (MRC) activity induces reactive oxygen species (ROS) overproduction within different MRC components upstream of cytochrome c oxidase. This event seems to play a significant role in the initiation of oxidative stress and subsequent development of nonalcoholic steatohepatitis (NASH) in some individuals. Experimental investigations also pointed to a progressive reduction of MRC activity during NAFLD, which could impair energy output and aggravate ROS overproduction by the damaged MRC. Hence, developing drugs that further increase mtFAO and restore MRC activity in a coordinated manner could ameliorate steatosis, but also necroinflammation and fibrosis by reducing oxidative stress. In contrast, physicians should be aware that numerous drugs in the current pharmacopoeia are able to induce mitochondrial dysfunction, which could aggravate NAFLD in some patients. (Hepatology 2013;58:1497–1507)

Phase II Trial of CHOP Plus Rituximab in Patients With HIV-Associated Non-Hodgkin's Lymphoma

PURPOSE To evaluate the safety and efficacy of rituximab adjunction to the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen in patients with newly diagnosed AIDS-related non-Hodgkins lymphoma. PATIENTS AND METHODS HIV-seropositive patients with high-grade lymphoma of B-cell origin were eligible if they had no more than one of the following characteristics: CD4 cell count less than 100/microL, prior AIDS, or performance status less than 2. This multicenter phase II trial evaluated the response rate and disease-free survival after six courses of rituximab plus CHOP. Results Sixty-one patients were enrolled. All the patients were assessable for safety and 52 were assessable for the tumor response after treatment completion. Characteristics of patients were median age, 41 years; median CD4 cells, 172/microL; histology, diffuse large B-cell lymphoma (n = 42), immunoblastic (n = 2), Burkitt lymphoma (n = 16), and plasmablastic (n = 1); 42 patients with stage III to IV; International Prognostic Index 0 to 1 (n=31), and 2 to 3 (n = 27). Grade 3 or 4 toxicity consisted of febrile neutropenia in nine patients, anemia in 16 patients, and thrombocytopenia in five patients. Complete remission (CR) or unconfirmed CR was achieved in 40 of the 52 assessable patients, partial remission was achieved in five patients, and seven patients experienced progression. Forty-three patients were alive after a median follow-up of 33 months. The estimated 2-year overall survival rate was 75% (95% CI, 64% to 86%). Eighteen patients died: 16 as a result of lymphoma, one as a result of infection, and one as a result of encephalitis. CONCLUSION Rituximab adjunction to CHOP produced a CR rate of 77% and a 2-year survival rate of 75% in patients with AIDS-related non-Hodgkins lymphoma, without increasing the risk of life-threatening infections.

Malignancy-related causes of death in human immunodeficiency virus-infected patients in the era of highly active antiretroviral therapy: Malignancy-Related Death in Patients with HIV

Before the introduction of highly active antiretroviral therapy (HAART), malignancies accounted for less than 10% of all deaths among human immunodeficiency virus (HIV)‐infected patients. This figure may have increased, and the observed types of malignant disease may have been modified, as a result of decreased occurrence of opportunistic infections, the chronicity of HIV infection, the possible oncogenic role of HIV itself, and the aging of the HIV‐infected population.

Changes in Cancer Mortality among HIV-Infected Patients: The Mortalité 2005 Survey

BACKGROUND The goal of the current study was to describe the distribution and characteristics of malignancy related deaths among human immunodeficiency virus (HIV)-infected patients with use of data obtained from a national survey conducted in France in 2005 and to compare with results obtained from a similar survey conducted in 2000. METHOD The underlying cause of death was documented using a standardized questionnaire fulfilled in French hospital wards and networks that were involved in the treatment of HIV-infected patients. RESULTS Among the 1042 deaths reported in 2005 (964 were reported in 2000), 344 were cancer related (34%), which represented a significant increase from 2000 (29% of deaths were cancer related) (P=.02); 134 of the cancer-related deaths were AIDS related and 210 were not AIDS related. Among the cancer-related causes of death, the proportion of hepatitis-related cancers (6% in 2000 vs. 11% in 2005) and non-AIDS/hepatitis-related cancers (38% in 2000 vs 50% in 2005) significantly increased from 2000 to 2005 (P=.03 and P=.01, respectively), compared with the proportion of cancer that was AIDS related and adjusting for age and sex. Among cases involving AIDS, the proportion of non-Hodgkin lymphoma-associated deaths did not change statistically significantly between 2000 and 2005 (11% and 10% of deaths, respectively). CONCLUSIONS In this study, an increasing proportion of lethal non-AIDS-related cancers was demonstrated from 2000 to 2005; meanwhile, the proportion of lethal AIDS-related cancers remained stable among HIV-infected patients. Thus, cancer prophylaxis, early diagnosis, and improved management should be included in the routine long-term follow-up of HIV-infected patients.