Sophie Grabar

Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies

BACKGROUND Combination antiretroviral therapy has led to significant increases in survival and quality of life, but at a population-level the effect on life expectancy is not well understood. Our objective was to compare changes in mortality and life expectancy among HIV-positive individuals on combination antiretroviral therapy. METHODS The Antiretroviral Therapy Cohort Collaboration is a multinational collaboration of HIV cohort studies in Europe and North America. Patients were included in this analysis if they were aged 16 years or over and antiretroviral-naive when initiating combination therapy. We constructed abridged life tables to estimate life expectancies for individuals on combination antiretroviral therapy in 1996-99, 2000-02, and 2003-05, and stratified by sex, baseline CD4 cell count, and history of injecting drug use. The average number of years remaining to be lived by those treated with combination antiretroviral therapy at 20 and 35 years of age was estimated. Potential years of life lost from 20 to 64 years of age and crude mortality rates were also calculated. FINDINGS 18 587, 13 914, and 10 854 eligible patients initiated combination antiretroviral therapy in 1996-99, 2000-02, and 2003-05, respectively. 2056 (4.7%) deaths were observed during the study period, with crude mortality rates decreasing from 16.3 deaths per 1000 person-years in 1996-99 to 10.0 deaths per 1000 person-years in 2003-05. Potential years of life lost per 1000 person-years also decreased over the same time, from 366 to 189 years. Life expectancy at age 20 years increased from 36.1 (SE 0.6) years to 49.4 (0.5) years. Women had higher life expectancies than did men. Patients with presumed transmission via injecting drug use had lower life expectancies than did those from other transmission groups (32.6 [1.1] years vs 44.7 [0.3] years in 2003-05). Life expectancy was lower in patients with lower baseline CD4 cell counts than in those with higher baseline counts (32.4 [1.1] years for CD4 cell counts below 100 cells per muL vs 50.4 [0.4] years for counts of 200 cells per muL or more). INTERPRETATION Life expectancy in HIV-infected patients treated with combination antiretroviral therapy increased between 1996 and 2005, although there is considerable variability between subgroups of patients. The average number of years remaining to be lived at age 20 years was about two-thirds of that in the general population in these countries.

Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy.

Objective:To describe the cases of anal cancer that appeared in the French Hospital Database on HIV between 1992 and 2004 and to study risk factors of anal cancer. Methods:We examined the incidence rates of anal cancer between 1992 and 2004 and the risk associated among 86 322 HIV-infected patients included in the French Hospital Database on HIV. Results:We identified 132 cases of anal cancer, including 124 cases in men (94%), of whom 75% had sex with men. Median age at diagnosis was 42.8 years (interquartile range: 36.9–49.4). At diagnosis, 103 patients (78%) were receiving combination antiretroviral therapy for a median of 37.1 months (interquartile range: 4.5–59.8). Median survival after anal cancer diagnosis was 5 years. The respective overall incidence rates of anal cancer per 100 000 person-years between 1992 and March 1996, April 1996 to 1998 and between 1999 and 2004 were 11 (95% confidence interval, 4–17), 18 (95% confidence interval, 10–27) and 40 (95% confidence interval, 32–47). The risk of anal cancer was higher among men who have sex with men. After adjustment for age at inclusion in the study, as well as gender, the HIV transmission group, the nadir CD4 cell count and AIDS status, the incidence was higher in the years 1999–2004 than in between 1992 to March 1996 (hazard ratio, 2.5; 95% confidence interval, 1.2–5.3), with no change in the years 1999–2004. Conclusion:The incidence of anal cancer has increased among HIV-infected patients in France since 1996. Although an ascertainment bias cannot be excluded, data indicate that combination antiretroviral therapy does not prevent anal cancer in these patients. This supports the urgent need for developing anal cancer screening programs for HIV-infected men who have sex with men.

TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs)

Oncogenic pathways underlying in the development of myelodysplastic syndromes (MDS) remain poorly characterized, but mutations of the ten-eleven translocation 2 (TET2) gene are frequently observed. In the present work, we evaluated the prognostic impact of TET2 mutations in MDS. Frameshift, nonsense, missense mutations, or defects in gene structure were identified in 22 (22.9%) of 96 patients (95% confidence interval [CI], 14.5-31.3 patients). Mutated and unmutated patients did not significantly differ in initial clinical or hematologic parameters. The 5-year OS was 76.9% (95% CI, 49.2%-91.3%) in mutated versus 18.3% (95% CI, 4.2%-41.1%) in unmutated patients (P = .005). The 3-year leukemia-free survival was 89.3% (95% CI, 63.1%-97.0%) in mutated versus 63.7% (95% CI, 48.2%-75.4%) in unmutated patients (P = .035). In univariate analysis (Cox proportional hazard model), the absence of TET2 mutation was associated with a 4.1-fold (95% CI, 1.4-12.0-fold) increased risk of death (P = .009). In multivariate analysis adjusted for age, International Prognostic Scoring System, and transfusion requirement, the presence of TET2 mutation remained an independent factor of favorable prognosis (hazard ratio, 5.2; 95% CI, 1.6-16.3; P = .005). These results indicate that TET2 mutations observed in approximately 20% of patients, irrespective of the World Health Organization or French-American-British subtype, represent a molecular marker for good prognosis in MDS.

Incidence of tuberculosis among HIV-Infected patients receiving highly active antiretroviral therapy in Europe and North America

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 log2 cells/microL, 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 log2 cells/microL, 0.89; 95% CI, 0.83-0.96), 6-month CD4+ count (relative rate per log2 cells/microL, 0.90; 95% CI, 0.81-0.99), and a 6-month HIV RNA level >400 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.

Immunologic and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV

Objective: To study immunologic and clinical responses to HAART in patients over 50 years old. Design and methods: A prospective cohort study which included 68 hospitals in France. A total of 3015 antiretroviral-naive patients, 401 of whom were aged 50 years or over, were enrolled following initiation of HAART. The influence of age on the mean CD4 cell count increase on HAART was studied by using a two-slope mixed model. Progression, defined by the occurrence of a new AIDS-defining event (ADE) or death, was studied by Cox multivariate analyses. Results: Among patients with baseline HIV RNA above 5 log copies/ml, CD4 mean increase during the first 6 months on HAART was +42.9 × 106 cells/l per month in patients under 50 years and +36.9 × 106 cells/l per month in patients over 50 years (P < 0.0001); subsequently, the respective monthly changes were +17.9 and +15.6 × 106 cells/l per month (P < 0.0001). Similar trends were observed in patients with baseline HIV RNA below 5 log copies/ml, and also after stratification for the baseline CD4 cell count. After a median follow-up of 31.5 months, 263 patients had a new ADE and 44 patients died. After adjustment for baseline characteristics, older patients had a significantly higher risk of clinical progression (hazard ratio (HR) = 1.52 [95% confidence interval (CI), 1.15–2.00]) and were more likely to achieve a viral load below 500 copies/ml [HR = 1.23, (95% CI, 1.11–1.38)]. Conclusion: Patients over 50 years of age have an immunologic response to HAART. However, their CD4 cell reconstitution is significantly slower than in younger patients, despite a better virologic response. This impaired immunologic response may explain their higher risk of clinical progression.

Use of observational databases to evaluate the effectiveness of antiretroviral therapy for HIV infection: comparison of cohort studies with randomized trials. EuroSIDA, the French Hospital Database on HIV and the Swiss HIV Cohort Study Groups.

OBJECTIVES It is important to assess the extent of bias when comparing the clinical efficacy of antiretroviral regimens in observational databases because, with the current lack of planned large trials, such analyses may represent the only means of assessing the risk of serious clinical events associated with new regimens. We aimed to compare the results from observational databases with those from randomized trials. METHODS Three treatment comparisons from randomized trials [Delta, AIDS Clinical Trials Group (ACTG) 175, Community Programs for Clinical Research on AIDS (CPCRA) 007 and ACTC 320] were mimicked in cohorts: (i) zidovudine monotherapy versus combination regimens of two nucleoside analogues; (ii) zidovudine combined with either didanosine or zalcitabine; and (iii) a dual combination versus a triple regimen including a protease inhibitor. Data for over 10 000 patients from the French Hospital Database on HIV, the EuroSIDA study and the Swiss HIV cohort study were analysed for each of the comparisons. Progression to AIDS disease or death was analysed in Cox models, adjusting for baseline differences, and results compared with randomized trials. RESULTS For comparison (i) the adjusted relative risk estimates from cohorts were between 0.61 and 0.84, favouring combinations over monotherapy, compared with 0.57 to 0.63 for trials. For comparison (ii) relative risk estimates from cohorts ranged from 0.81 to 1.01 compared with 0.77 to 0.92 for trials. For comparison (iii), two of the cohorts showed similar results to the ACTG 320 trial but one indicated a higher risk of progression on triple therapy [relative risk 1.20, 95% confidence interval (CI) 1.01-1.441, in direct contrast to the trial result (relative risk 0.50, 95% CI 0.33-0.76). CONCLUSION Serious biases can be present when comparing outcomes from the use of antiretroviral regimens in observational studies. However, such bias is not inevitable and careful interpretation of the results from several observational studies considered together is likely to be informative, guiding the design of new trials.

Prevalence and comparative characteristics of long-term nonprogressors and HIV controller patients in the French Hospital Database on HIV.

Objective:To estimate the prevalence and characteristics of long-term nonprogressor (LTNP) and HIV controller patients in a very large French cohort of HIV1-infected patients. Methods:In the French Hospital Database on HIV [FHDH, Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS) CO4], we selected patients who had been seen in 2005, who had been infected for more than 8 years, who were treatment-naive, and who remained asymptomatic. Patients with these characteristics then categorized as follows: LTNP (≥8 years of HIV infection and CD4 cell nadir ≥500/μl), elite LTNP (≥8 years of HIV infection, CD4 cell nadir ≥600/μl, and a positive CD4 slope), HIV controllers (>10 years of HIV infection with 90% of plasma viral load values ≤500 copies/ml), and elite controllers (same as HIV controllers, but with last plasma viral load value ≤50 copies/ml in 2005). Results:Among the 46 880 HIV1-infected patients followed in 2005 in the French Hospital Database on HIV, 0.4% (N = 202) were LTNP, 0.05% (N = 25) were elite LTNP, 0.22% (N = 101) were HIV controllers, and 0.15% (N = 69) were elite controllers. Ten elite LTNP patients (40%) were also HIV controllers, eight (32%) were elite controllers, and 60% had detectable plasma viral load (>50 copies/ml). Among the elite controllers, 32 (46%) were LTNP, eight (12%) were elite LTNP, and one-quarter had a last CD4 cell count less than 500/μl. Conclusion:LTNP, elite LTNP, HIV controller, and elite controller patients are rare phenotypes. Elite LTNP patients are less frequent than HIV controllers. There is little overlap among the four subgroups of patients.

Incidence of HIV-Related Anal Cancer Remains Increased Despite Long-Term Combined Antiretroviral Treatment: Results From the French Hospital Database on HIV

PURPOSE To study recent trends in the incidence of anal cancer in HIV-infected patients receiving long-term combined antiretroviral treatment (cART) compared with the general population. PATIENTS AND METHODS From the French Hospital Database on HIV, we identified 263 cases of invasive anal squamous cell carcinoma confirmed histologically between 1992 and 2008. We compared incidence rates of anal cancer across four calendar periods: 1992-1996 (pre-cART period), 1997-2000 (early cART period), and 2001-2004 and 2005-2008 (recent cART periods). Standardized incidence ratios (SIRs) were calculated by using general population incidence data from the French Network of Cancer Registries. RESULTS In HIV-infected patients, the hazard ratio (HR) in the cART periods versus the pre-cART period was 2.5 (95% CI, 1.28 to 4.98). No difference was observed across the cART calendar periods (HR, 0.9; 95% CI, 0.6 to 1.3). In 2005-2008, HIV-infected patients compared with the general population had an excess risk of anal cancer, with SIRs of 109.8 (95% CI, 84.6 to 140.3), 49.2 (95% CI, 33.2 to 70.3), and 13.1 (95% CI, 6.8 to 22.8) for men who have sex with men (MSM), other men, and women, respectively. Among patients with CD4 cell counts above 500/μL for at least 2 years, SIRs were 67.5 (95% CI, 41.2 to 104.3) when the CD4 nadir was less than 200/μL for more than 2 years and 24.5 (95% CI, 17.1 to 34.1) when the CD4 nadir was more than 200/μL. CONCLUSION Relative to that in the general population, the risk of anal cancer in HIV-infected patients is still extremely high, even in patients with high current CD4 cell counts. cART appears to have no preventive effect on anal cancer, particularly in MSM.

CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE

Using data from the Collaboration of Observational HIV Epidemiological Research Europe, Jim Young and colleagues show that in successfully treated patients the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression.

β-Catenin Activation Is Associated with Specific Clinical and Pathologic Characteristics and a Poor Outcome in Adrenocortical Carcinoma

Purpose: Activation of the Wnt/β-catenin signaling pathway is frequent in adrenocortical carcinoma (ACC) and might be associated with a more aggressive phenotype. The objective of this study was to assess the prognostic value of β-catenin immunohistochemistry and CTNNB1 (β-catenin gene)/APC (adenomatous polyposis coli gene) mutations in patients with resected primary ACC. Experimental design: In 79 patients with resected primary ACC from a French cohort (Cochin-COMETE), β-catenin expression was assessed on tumor specimens by immunohistochemistry. For patients with available DNA (n = 49), CTNNB1, and APC hotspot (mutation cluster region), were sequenced. Association between these results and the clinicopathologic characteristics of the ACC and overall and disease-free survival were studied. Results were confirmed on a tissue microarray from an independent multicentric cohort of 92 ACC from Germany (German-ENSAT cohort). Results: In the Cochin-COMETE cohort, the presence of a β-catenin nuclear staining was significantly associated with a higher ENSAT tumor stage (i.e., stages III and IV), higher Weiss score, more frequent necrosis, mitoses, and CTNNB1/APC mutations. β-Catenin nuclear staining and the presence of CTNNB1/APC mutations were both associated with decreased overall and disease-free survival, and were independent predictive factors of survival in multivariate analysis. The same results were observed in the German-ENSAT cohort. Conclusions: Wnt/β-catenin activation, confirmed by the presence of β-catenin nuclear staining, is an independent prognostic factor of overall and disease-free survival in patients with resected primary ACC. Clin Cancer Res; 17(2); 206–11. ©2010 AACR. Clin Cancer Res; 17(2); 328–36. ©2010 AACR.