Impaired health-related quality of life in the HCV cure era: who is concerned? (ANRS CO22 HEPATHER French cohort).

PURPOSE: Hepatitis C virus (HCV) cure after treatment with direct-acting antivirals (DAAs) can improve health-related quality of life (HRQoL). However, specific groups with chronic HCV may still exhibit worse post-cure HRQoL because of persisting severe liver fibrosis or social vulnerability factors (e.g. unhealthy alcohol use, living in poverty). We assessed the effect of such factors on longitudinal measures of HRQoL in chronic HCV patients. METHODS: ANRS CO22 HEPATHER is a prospective cohort of chronic HCV patients receiving DAAs, which included notably patients with social vulnerability factors, a population usually under-represented in clinical trials. Multivariable mixed-effects linear regression models helped identify factors associated with longitudinal measures of HRQoL (PROQOL-HCV scores). RESULTS: At enrolment, 52.4% of the 2740 participants were men, median age was 56 years [interquartile range 50-64], and 21.5% had severe liver fibrosis (FIB-4 > 3.25). Twenty-eight per cent reported current or past unhealthy alcohol use [> 2(3) alcohol units per day for women (men)], and 28.1% were living in poverty (standard of living under 1015€/month per household consumption unit). At first PROQOL-HCV completion, 54.0% of patients were HCV-cured. After multivariable adjustment, people with current or past unhealthy alcohol use, individuals living in poverty, those with severe liver fibrosis, and women had worse HRQoL in the dimensions explored. Conversely, HCV cure was associated with better HRQoL. CONCLUSIONS: Specific socially vulnerable groups of patients with chronic HCV infection still experience impaired HRQoL, independently of HCV cure. Patient-centred interventions, including social support and referral for comorbidities, should be prioritized for them. Trial registration with ClinicalTrials.gov NCT01953458.

Direct, indirect and total effect of HIV coinfection on the risk of non-liver-related cancer in hepatitis C virus-infected patients treated by direct-acting antivirals: a mediation analysis.

OBJECTIVES: HIV-coinfected patients experience higher incidences of non-liver-related cancers than HCV-monoinfected patients. Chronic inflammation, immunosuppression, but also higher tobacco or alcohol consumption and metabolic dysregulation could explain this higher risk. We aimed to estimate the direct, indirect and total effects of HIV coinfection on the risk of non-liver-related cancers in HCV participants treated with direct-acting antivirals (DAAs). METHODS: Up to four HCV-monoinfected participants from the ANRS CO22 HEPATHER cohort were matched by age and sex to HIV/HCV-coinfected participants from the ANRS CO13 HEPAVIH cohort. Participants were followed from DAA initiation until the occurrence of a non-liver-related cancer. Counterfactual mediation analysis was carried out to estimate the direct (chronic inflammation and immunosuppression), indirect (tobacco and alcohol consumption and metabolic syndrome) and total effect of HIV coinfection on the risk of non-liver-related cancers. RESULTS: 548 HIV/HCV-coinfected and 2016 monoinfected participants were included. Overall, HIV coinfection was associated with a 3.7-fold [95% confidence interval (CI): 1.7-7.0] higher risk of non-liver-related cancers in HCV participants. This increased risk was explained by significant direct effect [hazard ratio (HR) = 3.4, 95% CI: 1.7-6.6] but not indirect effect (HR = 1.1, 95% CI: 0.8-1.5) of HIV coinfection. CONCLUSIONS: In HCV participants treated with DAAs, the direct effect of HIV coinfection, reflecting chronic inflammation and immunosuppression, was associated with a 3.7-fold higher risk of non-liver-related cancer. By contrast, the indirect effect of HIV coinfection, reflecting higher tobacco and alcohol consumption and metabolic dysregulation, was not significantly associated with the risk of non-liver-related cancers.

External validation of LCR1-LCR2, a multivariable HCC risk calculator, in patients with chronic HCV.

BACKGROUND & AIMS: The Liver Cancer Risk test algorithm (LCR1-LCR2) is a multianalyte blood test combining proteins involved in liver cell repair (apolipoprotein-A1 and haptoglobin), known hepatocellular carcinoma (HCC) risk factors (sex, age, and gamma-glutamyl transferase), a marker of fibrosis (alpha2-macroglobulin) and alpha-fetoprotein (AFP), a specific marker of HCC. The aim was to externally validate the LCR1-LCR2 in patients with chronic HCV (CHC) treated or not with antivirals. METHODS: Pre-included patients were from the Hepather cohort, a multicentre prospective study in adult patients with CHC in France. LCR1-LCR2 was assessed retrospectively in patients with the test components and AFP, available at baseline. The co-primary study outcome was the negative predictive value (NPV) of LCR1-LCR2 for the occurrence of HCC at 5 years and for survival without HCC according to the predetermined LCR1-LCR2 cut-offs. The cut-offs were adjusted for risk covariables and for the response to HCV treatment, and were quantified using time-dependent proportional hazards models. RESULTS: In total, 4,903 patients, 1,026 (21.9%) with baseline cirrhosis, were included in the study. Patients were followed for a median of 5.7 (IQR 4.2-11.3) years. A total of 3,788/4,903 (77.3%) patients had a sustained virological response. There were 137 cases of HCC at 5 years and 214 at the end of follow-up. HCC occurred at 5 years in 24/3,755 patients with low-risk LCR1-LCR2 compared with 113/1,148 patients with high-risk LCR1-LCR2. The NPV was 99.4% (95% CI 99.1-99.6). Similar findings (hazard ratio, 10.8; 95% CI, 8.1-14.3; p <0.001) were obtained after adjustment for exposure to antivirals, age, sex, geographical origin, HCV genotype 3, alcohol consumption, and type 2 diabetes mellitus. CONCLUSIONS: The results showed that LCR1-LCR2 can be used to successfully identify patients with HCV at very low risk of HCC at 5 years. LAY SUMMARY: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide and the fastest growing cause of cancer death in many countries. We constructed and internally validated a new multianalyte blood test to assess this Liver Cancer Risk (LCR1-LCR2). This study confirmed the performance of LCR1-LCR2 in patients with chronic HCV in the national French cohort Hepather, and its ability to identify patients at a very low risk of HCC at 5 years. CLINICAL TRIALS REGISTRATION: The study is registered at ClinicalTrials.gov (NCT01953458).

Impact of Antiretroviral Drugs on Fracture Risk in HIV-Infected Individuals: A Case-Control Study Nested Within the French Hospital Database on HIV (FHDH-ANRS CO4).

BACKGROUND: HIV-infected patients have lower bone mineral density and a higher incidence of fractures than the general population of the same age and sex. To assess the impact of antiretroviral (ARV) drugs exposure on the risk of osteoporotic fractures, we conducted a nested case-control study. METHODS: Cases were individuals enrolled while ARV-naive, with a first prospectively recorded fracture between 2000 and 2010. Controls were randomly selected after matching for sex, age (±3 years), period of HIV diagnosis (<1997/≥1997), and clinical center. The risk of fracture was analyzed with conditional logistic regression models, using different ways to model ARV exposure. All exposure variables and potential confounders were included in multivariable models. RESULTS: Among 861 reviewed cases, 261 fractures were osteoporotic and 254 of cases were matched to at least one control (376 controls). The median year of fracture diagnosis was 2007 (interquartile range 2004-2009): 49% of patients had been exposed to tenofovir disoproxil fumarate (TDF) and 82% to protease inhibitors (PIs). After taking into account the transmission group, AIDS status, geographic origin, body mass index, current smoking status, alcohol consumption, exposure to systemic glucocorticoids, and the period of enrollment, there was no association between the risk of fracture and exposure to TDF [odds ratio for cumulative exposure: 1.04 (0.86-1.27), similar results for ever-exposed subjects], to nucleoside reverse transcriptase inhibitors, or to PIs [odds ratio for cumulative PI exposure: 1.02 (0.92-1.12)]. CONCLUSIONS: We found no evidence of an excess risk of fracture after exposure to TDF or PIs. This has important implications for the debate concerning tenofovir alafenamide versus generic TDF.

CD4+ cell count recovery after combined antiretroviral therapy in the modern combined antiretroviral therapy era.

OBJECTIVE: To assess CD4 recovery after combined antiretroviral therapy (cART) initiation with sustained virologic control. DESIGN: Cohort study based on the French Hospital Database on HIV (FHDH-ANRS CO4). METHODS: We selected naive HIV-1-infected individuals initiating cART between 2006 and 2014 with CD4 cell counts less than 500 cells/µl who achieved virologic control, defined as two consecutive viral loads less than 50 copies/ml. We estimated the cumulative incidence of CD4 recovery at least 500 cells/µl and identified associated factors, considering 'virologic failure,' 'loss to follow-up' and 'death' as competing events. RESULTS: We analyzed 6050 individuals with a median follow-up of 14.2 months since virologic control. The cumulative incidence for CD4 recovery after 6 years of virologic control reached 69.7%. The main factor associated with CD4 recovery was the CD4 count at treatment initiation [subdistribution hazard ratio (sHR) 9.64, 95% confidence interval (95% CI) 8.12-11.43 for CD4 cell counts between 350 and 500 cells/µl compared with CD4 cell counts <100 cells/µl). A higher CD4/CD8 ratio at initiation was also independently associated with a higher probability of CD4 recovery [sHR 1.67; 95% CI 1.34-2.09] for a CD4/CD8 ratio ≥1.00 vs. < 0.30). Higher viral load at initiation was also associated with a higher probability of CD4 recovery, whereas time to viral suppression was not. CONCLUSION: After 6 years of sustained virologic control, a large majority of the population achieved CD4 recovery. A higher CD4 cell count at initiation was a strong predictor of CD4 recovery and, to a lesser extent, a higher CD4/CD8 ratio at initiation. These results confirm the necessity of early treatment.

Impact of etravirine on hospitalization rate between 2005 and 2011 among heavily treated HIV-1-infected individuals on failing regimens.

BACKGROUND: Etravirine (ETR), a non-nucleoside reverse transcriptase inhibitor (NNRTI) available in France since 2006, is indicated for antiretroviral-experienced HIV-infected adults, in combination with a ritonavir-boosted protease inhibitor (PI). To assess its clinical impact in routine care, we compared hospitalization rates according to ETR + PI prescription or not, among heavily treated HIV-1 infected individuals on failing regimens between 2005 and 2011. METHODS: From the French Hospital Database on HIV (ANRS CO4), we selected heavily treated individuals (prior exposure to at least 2 nucleoside reverse transcriptase inhibitor (NRTI), 2PI and 1 NNRTI) with viral load (VL) > 50 copies/mL who started a new antiretroviral (ARV) regimen between 2005 and 2011. Using an intention-to-continue-treatment approach, hospitalization rates were calculated for the individuals who received ETR + PI, during the months after initiating ETR + PI (ETR + PI) or for the individuals who received ETR + PI, in the months before ETR + PI initiation and for the individuals who never received ETR + PI (no ETR + PI). hospitalization from an AIDS-defining cause and hospitalization from a non-AIDS defining cause rates were also calculated. Poisson regression models were used to compare the incidences between the two groups, with adjustment for potential confounders. RESULTS: Of 3884 patients who met the inclusion criteria, 838 (21.6%) received ETR + PI. During 13,986 person-years (P-Y) of follow-up, there were 2484 hospitalizations in 956 individuals. The hospitalization rates per 1000 P-Y were 169.0 among individuals exposed to ETR + PI and 179.3 among those not exposed to ETR + PI. After adjustment, the respective hospitalization rates were 148.8 and 186.7 per 1000 P-Y, with an estimated relative risk of 0.80 (95%CI: 0.71-0.90), AIDS hospitalization rates were 11.5 and 22.7 per 1000 P-Y, with an estimated relative risk of 0.51(95%CI: 0.39-0.66) and non-AIDS hospitalization rates were 139.5 and 152.2 per 1000 P-Y, with an estimated relative risk of 0.92 (95%CI: 0.80-1.05). CONCLUSIONS: Between 2005 and 2011, access to ETR + PI was associated with a 20% reduction in the hospitalization rate among heavily treated HIV-1-infected individuals. This reduction was mainly due to a reduction in the AIDS hospitalization rate.

Switching to Raltegravir From a Virologically Effective Boosted Protease Inhibitor Regimen: A Comparative Effectiveness Analysis From the French Hospital Database on HIV (FHDH-ANRS CO4).

BACKGROUND: In individuals with viral load (VL) suppression on a boosted protease inhibitor (PI) regimen, a switch to raltegravir (RAL) can be an option in case of comorbidities, but the SWITCHMRK trials challenged this strategy. Here, among individuals with VL suppression on a boosted PI, we compared outcomes between those who continued on the same regimen and those who switched to RAL. METHODS: In this cohort study from the French Hospital Database on HIV, each individual who switched to RAL was matched with up to 3 individuals who continued PI, were being followed up during the calendar period of the switch, and had the same duration of VL suppression (both ±6 months). The primary endpoint was a composite endpoint of hospitalization, or AIDS event or death, and secondary endpoints the immunovirologic responses. To control for measured confounders, the inverse probability treatment weighting (IPTW) method was applied to estimate hazards ratios between the 2 groups. RESULTS: We matched 282 RAL switchers with 838 nonswitchers. Although several variables differed significantly between the groups, including a higher prevalence of comorbidities in the RAL group, the IPTW method yielded standardized differences <10% for all variables. After IPTW, there was no difference in the risk of hospitalization or AIDS event or death between the 2 groups (13.6% and 10.5%, respectively; hazard ratio, 1.16 [95% confidence interval, .74-1.83]) and no difference in the likelihood of virologic failure or CD4 cell gain. CONCLUSIONS: In individuals with controlled VL on a boosted PI regimen who switched to RAL, none of the endpoints differed with nonswitchers after IPTW.

Looking Beyond the Cascade of HIV Care to End the AIDS Epidemic: Estimation of the Time Interval From HIV Infection to Viral Suppression.

BACKGROUND: Ensuring early universal access to HIV treatment is critical to reach the end of AIDS. The cascade of HIV care has become a critical metric to assess the coverage of treatment and viral suppression, but it does not provide any information on the elapsed times between becoming HIV-infected and reaching viral suppression. METHODS: We estimated the cascade of care, the distribution of times between steps of the care continuum, in France, in 2010, at the national level, overall and by HIV exposure groups, using statistical modelling and large datasets: the national HIV surveillance system, the general social insurance scheme, and the French Hospital Database on HIV. RESULTS: We found that the overall rate of viral suppression was high, with an estimated value of 52% (95% confidence interval: 49 to 54). However, the time intervals from HIV infection to viral suppression were long; overall, the median value was 6.1 years (inter quartile range: 3.6-9.2), and it ranged from ∼5.6 years among men who have sex with men and heterosexual women to 9.6 years among injection drug users. Time lost in achieving viral suppression was mainly due to delays in HIV testing (overall median of 3.4 years), except for injection drug users where it was also due to delayed care entry once diagnosed (∼1 year in median versus <1 month for other groups). CONCLUSIONS: High viral suppression rate can hide large gaps between time of HIV infection and time of viral suppression. Estimates of the flow-time between steps of the care continuum should become priority indicators to identify these gaps and monitor whether interventions are successful in closing them.

Is Impact of Statin Therapy on All-Cause Mortality Different in HIV-Infected Individuals Compared to General Population? Results from the FHDH-ANRS CO4 Cohort.

BACKGROUND: The effect of statins on all-cause mortality in the general population has been estimated as 0.86 (95%CI 0.79-0.94) for primary prevention. Reported values in HIV-infected individuals have been discordant. We assessed the impact of statin-based primary prevention on all-cause mortality among HIV-infected individuals. METHODS: Patients were selected among controls from a multicentre nested case-control study on the risk of myocardial infarction. Patients with prior cardiovascular or cerebrovascular disorders were not eligible. Potential confounders, including variables that were associated either with statin use and/or death occurrence and statin use were evaluated within the last 3 months prior to inclusion in the case-control study. Using an intention to continue approach, multiple imputation of missing data, Cox's proportional hazard models or propensity based weighting, the impact of statins on the 7-year all-cause mortality was evaluated. RESULTS: Among 1,776 HIV-infected individuals, 138 (8%) were statins users. During a median follow-up of 53 months, 76 deaths occurred, including 6 in statin users. Statin users had more cardiovascular risk factors and a lower CD4 T cell nadir than statin non-users. In univariable analysis, the death rate was higher in statins users (11% vs 7%, HR 1.22, 95%CI 0.53-2.82). The confounders accounted for were age, HIV transmission group, current CD4 T cell count, haemoglobin level, body mass index, smoking status, anti-HCV antibodies positivity, HBs antigen positivity, diabetes and hypertension. In the Cox multivariable model the estimated hazard ratio of statin on all-cause mortality was estimated as 0.86 (95%CI 0.34-2.19) and it was 0.83 (95%CI 0.51-1.35) using inverse probability treatment weights. CONCLUSION: The impact of statin for primary prevention appears similar in HIV-infected individuals and in the general population.

Significant reduction in HIV virologic failure during a 15-year period in a setting with free healthcare access.

BACKGROUND: Calendar trends in virologic failure (VF) among human immunodeficiency virus (HIV)-infected patients can help to evaluate the performance of healthcare systems and the need for new antiretroviral therapy (ART). We examined the time trend in the rate of VF beyond 6 months of ART between 1997 and 2011 in France. METHODS: We included patients from the French Hospital Database on HIV who received at least 6 months of ART. VF was defined as 2 consecutive plasma HIV-RNA values >500 copies/mL or as 1 value >500 copies/mL followed by a treatment switch. We adjusted for patients' characteristics by fitting a multivariable generalized estimating equation logistic regression model with an exchangeable covariance matrix. RESULTS: A total of 81 738 patients were enrolled, and median follow-up was 112.4 months. Median CD4 count was 333 cells/µL, and 23% of patients had HIV infection classified as Centers for Disease Control and Prevention stage C. Overall, 29.3% of patients received single/dual-drug ART initially, and 45.4% of patients experienced at least 1 episode of VF during follow-up. The percentage of patients with VF fell from 61.5% in 1997-1998 to 9.7% in 2009-2011 (P < .0001). Factors associated with the lower frequency of VF were recent calendar period, a higher contemporary CD4 cell count, and first-line regimens based on nonnucleoside reverse transcriptase inhibitors or integrase inhibitors. CONCLUSIONS: The proportion of HIV-infected patients experiencing VF during routine care fell markedly between 1997 and 2009-2011, to only 9.7%. This was attributed to the advent of fully active and better-tolerated antiretroviral drugs, and to national guidelines recommending rapid management of VF after mid-2000.

Impact of etravirine use on hospitalization rates among highly pre-treated failing HIV-1 infected individuals between 2005 and 2011.

INTRODUCTION: Etravirine (ETR), a non-nucleoside reverse transcriptase inhibitor available in France since 2006, is indicated for the treatment of HIV-1 infection in combination with a ritonavir boosted protease inhibitor (PI) in antiretroviral treatment-experienced adult patients. To assess its impact in routine clinical care, our objective was to compare hospitalization rates in highly pre-treated failing HIV-1 infected individuals between 2005 and 2011 depending on whether or not they received ETR+PI. METHODS: From the French Hospital Database on HIV (ANRS CO4), we selected highly pre-treated individuals (prior exposure to at least 2NRTI, 2PI and 1 NNRTI) with a viral load (VL)>50 copies/mL initiating a new regimen between 2005 and 2011. Hospitalization rates were calculated for each calendar month and depending on whether patients never received ETR+PI at any time or during months before initiating ETR+PI (no ETR+PI) or during months after initiating ETR+PI (ETR+PI), using an intention to continue treatment approach. Poisson regression models were used to compare incidence between the two groups, after adjustment for potential confounders (age, transmission group, origin, AIDS, PCP prophylaxis, viral load, CD4, nb of previous ARV). RESULTS: Overall 3884 patients fulfilled inclusion criteria. Among them 838 (21.6%) received ETR+PI at least once. Among all enrolled patients, 35.8% had CD4 <200/mm(3), 17.5% had VL >100,000 copies/ml, 42.8% had had an AIDS event and 47.8% had received more than 10 different antiretroviral drugs. There were 2484 hospitalizations in 808 individuals over 13,986 patient-years. The hospitalization rates for 1000 P-Y were 169.0 for the ETR+PI group and 179.3 for the no ETR+PI group. After adjustment, the corresponding figures were 144.8 for 1000 P-Y and 192.7 for 1000 P-Y respectively, with a relative risk estimated as 0.75 (95% CI 0.67-0.84). CONCLUSIONS: Access to ETR+PI between 2005 and 2011 was associated with a 25% reduction in the hospitalization rate among highly pre-treated failing HIV-1 infected individuals.

CD4+ cell count recovery in naïve patients initiating cART, who achieved and maintained plasma HIV-RNA suppression.

INTRODUCTION: A key objective of combined antiretroviral therapy (cART) is to reach and maintain high CD4 cell counts to provide long-term protection against AIDS-defining opportunistic infections and malignancies, as well as other comorbidities. However, a high proportion of patients present late for care. Our objective was to assess CD4 cell count recovery up to seven years in naïve patients initiating cART with at least three drugs in usual clinical care. METHODS: From the French Hospital Database on HIV, we selected naïve individuals initiating cART from 2000 with at least two years of follow-up. Participants were further required to have achieved viral load suppression by six months after initiating cART and were censored in case of virological failure. We calculated the proportion of patients (Kaplan-Meier estimates) who achieved CD4 recovery to >500/mm(3) according to baseline CD4 cell count. RESULTS: A total of 15,025 patients were analyzed with a median follow-up on ART of 65.5 months (IQR: 42.3-96.0). At cART initiation, the median age was 38.6 years (IQR: 32.2-46.0), 9734 (64.8%) were men, median CD4 cell count was 239 (IQR: 130-336) and 2668 (17.8%) had a prior AIDS event. RESULTS are presented in the Table 1. CONCLUSIONS: This study shows that CD4 cell counts continue to increase seven years after cART initiation, whatever the baseline CD4 cell count. Failing to achieve CD4 recovery with continuous viral load suppression is rare for naïve patients initiating cART in routine clinical practice, but takes substantially longer in patients who initiate antiretroviral therapy at low CD4 cell counts.

Cohort Profile: French hospital database on HIV (FHDH-ANRS CO4).

The French Hospital Database on HIV (FHDH) is a hospital-based multicentre open cohort with inclusions ongoing since 1989. The research objectives focus mainly on mid- and long-term clinical outcomes and therapeutic strategies, as well as severe AIDS and non-AIDS morbidities, and public health issues relative to HIV infection. FHDH also serves to describe HIV-infected patients receiving hospital care in France. FHDH includes data on more than 120,000 HIV-infected patients from 70 French general or university hospitals distributed throughout France. Patients are eligible for inclusion if they are infected by HIV-1 or HIV-2 and give their written informed consent. Standardized variables are collected at each outpatient visit or hospital admission during which a new clinical manifestation is diagnosed, a new treatment is prescribed or a change in biological markers is noted, and/or at least every 6 months. Since its inception, variables collected in FHDH include demographic characteristics, HIV-related biological markers, the date and type of AIDS and non AIDS-defining events, antiretroviral treatments and the date and causes of death, as reported in the medical records. Since 2005, data have also been collected on: co-infection with hepatitis B or C virus; alcohol and tobacco use; and non HIV-related biomarkers. Anyone can submit a research project by completing a standardized form available on the FHDH website (http://www.ccde.fr/_fold/fl-1385734776-429.pdf) or from the corresponding author, describing the context and objectives of the study. All projects are reviewed by the scientific committee.

Risk of Kaposi sarcoma during the first months on combination antiretroviral therapy.

OBJECTIVE: To determine whether incident AIDS-defining Kaposi sarcoma or Pneumocystis jiroveci pneumonia (PJP) is associated with combination antiretroviral therapy (cART) initiation. DESIGN: Compare risk for Kaposi sarcoma and PJP by time on cART and CD4 reconstitution. METHODS: : In the FHDH-ANRS CO4 cohort (N = 66 369), Kaposi sarcoma (N = 1811) and PJP (N = 1718) incidence rates were computed by demographic and HIV strata. Crude and adjusted relative risk (RR) with 95% confidence intervals (CIs) following cART initiation were calculated by Poisson regression with untreated patients during 1996-2009 as reference. CD4 cell counts were compared by Wilcoxon rank sum tests. RESULTS: The risk of Kaposi sarcoma was very high during months 1-3 on cART (N = 160, RRCrude 3.94, 95% CI 3.26-4.76), which was incompletely attenuated by adjustment for demographics and contemporaneous CD4 cell count (RRAdj 1.25, 95% CI 1.02-1.53). Corresponding PJP risk was minimally elevated (N = 84, RRCrude 1.80, 95% CI 1.42-2.30) and markedly reduced with adjustment on the same variables and PJP prophylaxis (RRAdj 0.52, CI 0.41-0.67). HIV load had no added effect. Median CD4 cell count at cART initiation was much lower in patients with incident Kaposi sarcoma (82 cells/µl) or PJP (61 cells/µl) within 3 months than in those who did not develop these conditions (>250 cells/µl). Notably, median CD4 cell count change was +44 cells/µl per month with incident Kaposi sarcoma within 3 months of cART initiation versus 0 cells/µl per month with incident PJP (P = 0.0003). CONCLUSION: Failure of CD4 cell count reconstitution during months 1-3 on cART fully accounted for incident PJP. In contrast, there were 1.6 additional Kaposi sarcoma cases per 1000 person-years during months 1-3 on cART, suggesting that immune reconstitution may contribute to the risk for AIDS-defining Kaposi sarcoma.

Depression history, depressive symptoms, and incident dementia: the 3C Study.

The aim of our study was to investigate whether depression assessed by different markers predicts the risk of incident dementia in elderly individuals. Data was derived from the 3C cohort study conducted in community-dwelling individuals aged 65 years and over, randomly recruited from electoral rolls of three French areas and followed up for four years (1999-2001 through 2004) with assessments every 2 years. The study sample comprised 7989 dementia-free individuals (mean age, 74.0 years; 61% women) assessed at baseline for current or past Major Depressive Episodes (MDE) based on MDE module of the Mini International Neuropsychiatric Interview, self-reported lifetime treated depression, and level of depressive symptoms using the Center for Epidemiologic Studies-Depression Scale. Fully adjusted Cox proportional hazards models were applied to examine the risk of incident dementia associated with these markers of depression. MDE and self-reported lifetime treated depression did not increase incident dementia risk. Conversely, high level of depressive symptoms at baseline was associated with a 50% increased risk of dementia (adjusted Hazard Ratio [HR], 1.5; 95% Confidence interval [CI], 1.2-2.2). This result was driven by a five-fold increased risk of vascular dementia (HR, 4.8; 95% CI, 2.2-10.7; p < 0.0001), whereas there was no increased risk of Alzheimer's disease (1.0; 0.7-1.6). In elderly individuals, high level of depressive symptoms is predictive of vascular dementia within a few years. This close temporal association suggests that depression is less a risk factor for than a prodromal symptom of vascular dementia.

Relationship between blood pressure and outdoor temperature in a large sample of elderly individuals: the Three-City study.

BACKGROUND: Seasonal variations of blood pressure-related diseases have been described in several populations. However, few studies have examined the seasonal variations of blood pressure in the elderly, a segment of the population particularly exposed to vascular diseases. The association of blood pressure with season and outdoor temperature was examined in 8801 subjects 65 years or older from the Three-City study, a population-based longitudinal study. METHODS: Blood pressure was measured at baseline and 2-year follow-up examinations. Daily outdoor temperature measured at 11 am was provided by the local meteorological offices. RESULTS: Both systolic and diastolic blood pressure values differed significantly across the 4 seasons and across the quintiles of the distribution of outdoor temperature. Systolic blood pressure decreased with increasing temperature, with an 8.0-mm Hg decrease between the lowest (< 7.9 degrees C) and the highest (> or = 21.2 degrees C) temperature quintile. Intraindividual differences in blood pressure between follow-up and baseline examinations were strongly correlated with differences in outdoor temperature. The higher the temperature at follow-up compared with baseline, the greater the decrease in blood pressure. Longitudinal changes in blood pressure according to difference in outdoor temperature were larger in subjects 80 years or older than in younger participants. CONCLUSIONS: Outdoor temperature and blood pressure are strongly correlated in the elderly, especially in those 80 years or older. During periods of extreme temperatures, a careful monitoring of blood pressure and antihypertensive treatment could contribute to reducing the consequences of blood pressure variations in the elderly.

Evaluation of the impact of memantine treatment initiation on psychotropics use: a study from the French national health care database.

BACKGROUND: Clinical studies reported that treatments for Alzheimer's disease may have an impact on behavioral and psychiatric disorders. We tested the hypothesis that memantine treatment initiation modifies psychotropic medication in real-life practice patients. METHODS: A 2-year follow-up cohort study was performed. A sample of patients treated in the general population, extracted from the database of the French national healthcare system (CNAM-TS), was examined. The sample included 4,600 memantine-treated patients (mean age 79.8 years, 69% women) randomly selected from the database of the CNAM-TS covering 69% of the French population aged 65 years and over. The follow-up rate was 95.0%. This database includes exhaustive data on drug consumption. We used interrupted time series analysis of the proportion of psychotropics users (all psychotropic drugs and specific categories) before and after onset of memantine. RESULTS: There was a 39-50% regular increase in patients treated with psychotropic drugs before memantine initiation This increasing trend stopped after memantine initiation, the proportion of psychotropic users remaining stable around 53% up to the end. The trends before and after memantine onset were significantly different (p < 0.001). CONCLUSIONS: Our results suggest a temporal relationship between the onset of memantine and the stabilization of psychotropic drugs use in this large sample of elderly patients.

Relationship between blood pressure and depression in the elderly. The Three-City Study.

OBJECTIVE: To examine the relationship between blood pressure and depression in a large sample of noninstitutionalized elderly people. METHODS: Cross-sectional community-based study in 9294 participants aged 65 years and over, living at home, in three French cities (Bordeaux, Dijon and Montpellier). Participants were categorized as depressive, based on three different markers of depression. Multiple linear regression analyses of the relation between depression and mean systolic and diastolic blood pressure values were conducted, taking into account potential confounders like age, sex, education, smoking, alcohol consumption, body mass index and history of cardiovascular events. RESULTS: Our working sample had a mean age (SD) of 73.7 (5.0) years, and included 60.7% of women. Overall, 31% of participants met the criteria for depression, 77.5% had hypertension, and 49.5% were on antihypertensive drugs. Analyses showed lower systolic and diastolic blood pressure values in depressive individuals compared with nondepressive ones, in both men (systolic blood pressure 148.2 versus 151.8 mmHg, P < 0.002; diastolic blood pressure 83.0 versus 84.7 mmHg, P = 0.003) and women (systolic blood pressure 141.7 versus 144.7 mmHg, P < 0.0001; diastolic blood pressure 80.7 versus 81.4 mmHg, P < 0.02). These associations were independent of age and of use of antihypertensive or psychotropic agents. CONCLUSION: In a large sample of elderly individuals from the general population, depressive individuals had lower blood pressure values than nondepressive ones, independent of medications and of history of cardiovascular events.

Memantine therapy for Alzheimer disease in real-world practice: an observational study in a large representative sample of French patients.

Clinical trials have shown modest effects of memantine, an N-methyl-D aspartate receptor antagonist, in Alzheimer disease patients and memantine effectiveness in routine clinical practice needs to be established further. In 2003, memantine was recommended in France for Alzheimer disease patients with disease severity ranging from 15 to 3 on the mini-mental state examination at the first prescription. Our study aimed at describing memantine use in real-world practice in a cohort of 5283 memantine-treated patients (mean age: 80.1 y; women: 69.4%) randomly selected from the database of the national healthcare insurance, which covers 70% of the French elderly population. Mean follow-up after starting memantine prescription was 10.4 months (range: 1 to 20 mo). Patients were older and had a less severe cognitive impairment than patients included in the first controlled clinical trials. Memantine was prescribed with a cholinesterase inhibitor in 53.3% of cases. At 6 months, 26% of the patients had stopped memantine therapy (36% at 12 mo); conversely, patients who continued treatment were highly compliant. The 1-year mortality rate (12.5%) was similar for a comparative cohort of untreated demented patients and the memantine-treated ones. Approximately one-third of the memantine-treated patients did not strictly fit with the French summary of product characteristic recommendations for the first memantine prescription.

Prevalence, awareness, treatment, and control of hypertension in the elderly: the Three City study.

OBJECTIVE: To study management of hypertension in the elderly in a large population-based study and to evaluate the prevalence of hypertension and factors related to awareness, treatment, and control. DESIGN: The Three City study, a population-based study among 9693 non-institutionalized individuals aged 65 years and over. METHODS: Blood pressure was measured with an automated electronic device, and treatment assessed, during home interview. Hypertension was defined by a mean blood pressure of two measurements superior to or equal to 160/95 mmHg and/or the intake of antihypertensive medications. RESULTS: In the final working sample of 9090 people, 62% were hypertensive. More than two-thirds were aware of their hypertension and 81% were treated with antihypertensive drugs. Among 4573 treated hypertensive participants, 35% had a blood pressure over 160/95 mmHg and 69% over 140/90 mmHg. Women were more frequently aware of their hypertension, more frequently treated, and more frequently controlled than men. A history of cardiovascular disease, high body mass index, diabetes and high frequency of visits to the general practitioner were related to higher percentages of awareness and treatment. Among treated hypertensive patients, those with a history of cardiovascular events or who visited their general practitioner more often or who more often had their blood pressure measured were more frequently controlled. Awareness was strongly associated with treatment, but was inversely related to control of hypertension among treated hypertensive patients. CONCLUSIONS: Management of hypertension, and particularly its control among treated hypertensive patients, needs to be improved in people aged 65 years and over.