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The absolute risk reduction by prophylaxis in chemotherapy-induced febrile neutropenia (FN) is largest in patients at highest underlying risk. Therefore, reliable predictive models are needed. Here, we develop and validate such a model for risk of FN during chemotherapy cycles 2-6. A prediction score for risk of FN during the first cycle has recently been published. Patients with solid cancers initiating first-line chemotherapy in 2010-2016 were included. Cycle-specific risk factors were assessed by Poisson regression using generalized estimating equations and random split sampling. The derivation cohort included 4,590 patients treated with 15,419 cycles, wherein 326 (2.1%) FN events occurred. Predictors of FN in multivariable analyses were: higher predicted risk of FN in the first cycle, platinum- or taxane-containing therapies, concurrent radiotherapy, treatment in cycle 2 compared to later cycles, previous FN or neutropenia and not receiving granulocyte colony-stimulating factors. Each predictor added between -2 and 8 points to each patient's score (median score 4; interquartile range, 1-6). The incidence rate ratios for developing FN in the intermediate (score 1-4), high (score 5-6) and very high risk groups (score ≥7) were 7.8 (95% CI, 2.4-24.9), 18.6 (95% CI, 5.9-58.8) and 51.7 (95% CI, 16.5-162.3) compared to the low risk group (score ≤0), respectively. The score had good discriminatory ability with a Harrell's C-statistic of 0.78 (95% CI, 0.76-0.80) in the derivation and 0.75 (95% CI, 0.72-0.78) in the validation cohort (patient n = 2,295, cycle n = 7,670). The Cycle-Specific Risk of FEbrile Neutropenia after ChEmotherapy score is the first published method to estimate cycle-specific risk of FN.

Objectives Chronic obstructive pulmonary disease (COPD) is underdiagnosed in the general population and possibly also in people living with HIV (PLWH). We evaluated the diagnostic performance of symptoms and risk factors for assessment of airflow limitation in PLWH and in uninfected controls. Methods Spirometry was performed in the Copenhagen Comorbidity in HIV Infection (COCOMO) study and Copenhagen General Population Study (CGPS), and airflow limitation was defined by forced expiratory volume in 1 s/forced vital capacity < lower limit of normal. We calculated the sensitivity, specificity, predictive values and area under the curve (AUC) of symptoms and risk factors for assessment of airflow limitation in PLWH and uninfected controls. Results A total of 1083 PLWH and 12 074 uninfected controls were included in the study. The sensitivity for sputum, chronic cough, breathlessness, wheezing, current and cumulative smoking and self‐reported COPD was higher, but the specificity lower, in PLWH than in uninfected controls. The negative and positive predictive values were largely similar between the groups. The AUCs were similar or slightly higher in PLWH and highest for > 20 pack‐years smoked [0.65; 95% confidence interval (CI) 0.58–0.72] and wheezing (0.64; 95% CI 0.57–0.71). A summed score for five variables was associated with slightly higher AUC in PLWH compared with uninfected controls [0.71 (95% CI 0.63–0.79) versus 0.65 (95% CI 0.63–0.68), respectively; P = 0.06]. Conclusions Clinical variables were relatively poor discriminators of airflow limitation in PLWH and uninfected controls. Active COPD case finding by screening for symptoms and relevant exposures, as recommended in the general population, is likely to yield similar diagnostic power in PLWH.

OBJECTIVES: The long-term side effects of stavudine (d4T) led to recommendations in 2009 to phase out use of this drug. We aimed to describe temporal patterns of d4T use across Europe. METHODS: Patients taking combination antiretroviral therapy (cART) in EuroSIDA with follow-up after 1 January 2006 were included in the study. cART was defined as d4T-containing [d4T plus at least two other antiretrovirals (ARVs) from any class] or non-d4T-containing (at least three ARVs from any class, excluding d4T). Poisson regression was used to describe temporal changes in the prevalence of d4T use and factors associated with initiating d4T. RESULTS: A total of 5850 patients receiving cART on 1 January 2006 were included in the current analysis, rising to 7768 patients on January 1 2013. During this time, the prevalence of d4T use fell from 11.2% to 0.7%, with an overall decline of 19% per 6 months [95% confidence interval (CI) 19-20%]. d4T use declined fastest in Northern Europe [26% (95% CI 23-29%) per 6 months], and slowest in Eastern Europe [17% (95% CI 16-19%) per 6 months]. In multivariable Poisson regression models, new d4T initiations decreased by 14% per 6 months [adjusted incidence rate ratio (aIRR) 0.86; 95% CI 0.80-0.91]. Factors associated with initiating d4T were residence in Eastern Europe (aIRR 4.31; 95% CI 2.17-9.98) versus other European regions and HIV RNA > 400 copies/mL (aIRR 3.11; 95% CI 1.60-6.02) versus HIV RNA < 400 copies/mL. CONCLUSIONS: d4T use has declined sharply since 2006 to low levels in most regions; however, a low but persistent level of d4T use remains in Eastern Europe, where new d4T initiations post 2006 are also more common. The reasons for the regional differences may be multifactorial, but it is important to ensure that all clinicians treating HIV-positive patients are aware of the potential harmful effects associated with d4T.

Objectives HIV infection has been associated with an increased risk of chronic kidney disease (CKD). Little is known about the prevalence of CKD in individuals with high CD4 cell counts prior to initiation of antiretroviral therapy (ART). We sought to address this knowledge gap. Methods We describe the prevalence of CKD among 4637 ART-naive adults (mean age 36.8 years) with CD4 cell counts > 500 cells/μL at enrolment in the Strategic Timing of AntiRetroviral Treatment (START) study. CKD was defined by estimated glomerular filtration rate (eGFR) 500 cells/μL.

Objectives Knowledge about advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) in HIV-positive persons is limited. The aim of this study was to investigate incidence, predictors and outcomes for advanced CKD/ESRD and renal death. Methods Advanced CKD was defined as confirmed (two consecutive measurements ≥ 3 months apart) estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2 using Cockcroft−Gault, and ESRD as haemodialysis or peritoneal dialysis for ≥ 1 month or renal transplant. Renal death was death with renal disease as the underlying cause, using Coding Causes of Death in HIV (CoDe) methodology. Follow-up was from 1 January 2004 until last eGFR measurement, advanced CKD, ESRD or renal death, whichever occurred first. Poisson regression was used to identify predictors. Results Of 9044 individuals included in the study, 58 (0.64%) experienced advanced CKD/ESRD/renal death [incidence rate 1.32/1000 person-years of follow-up (PYFU); 95% confidence interval (CI) 0.98–1.66]; 52% of those who experienced the endpoint had a baseline eGFR ≤ 60 mL/min/1.73 m2 compared with 3% of those who did not. Using Kaplan−Meier methods, at 6 years from baseline, 0.83% (95% CI 0.59–1.07%) were estimated to have experienced the endpoint overall and 11.26% (95% CI 6.75–15.78%) among those with baseline eGFR ≤ 60 mL/min/1.73 m2. Independent predictors of the endpoint included any cardiovascular event [incidence rate ratio (IRR) 2.16; 95% CI 1.24–3.77], lower eGFR (IRR 0.64 per 5 mL/min/1.73 m2; 95% CI 0.59–0.70) and lower CD4 count (IRR 0.77 per doubling; 95% CI 0.62–0.95). One year after experiencing advanced CKD or ESRD, an estimated 19.21% (95% CI 7.84–30.58%) of patients had died, mostly from extra-renal causes. Conclusions The incidence of advanced CKD/ESRD/renal death was low and predictors included traditional renal risk factors, HIV-related factors and pre-existing renal impairment. The prognosis following advanced CKD/ESRD was poor. Larger studies should address possible contributions of specific antiretrovirals.

Objectives Across Europe, almost a third of individuals infected with HIV do not enter health care until late in the course of their infection. Surveillance to identify the extent to which late presentation occurs remains inadequate across Europe and is further complicated by the lack of a common clinical definition of late presentation. The objective of this article is to present a consensus definition of late presentation of HIV infection. Methods Over the past year, two initiatives have moved towards a harmonized definition. In spring 2009, they joined efforts to identify a common definition of what is meant by a ‘late-presenting’ patient. Results Two definitions were agreed upon, as follows. Late presentation: persons presenting for care with a CD4 count below 350 cells/μL or presenting with an AIDS-defining event, regardless of the CD4 cell count. Presentation with advanced HIV disease: persons presenting for care with a CD4 count below 200 cells/μL or presenting with an AIDS-defining event, regardless of the CD4 cell count. Conclusion The European Late Presenter Consensus working group believe it would be beneficial if all national health agencies, institutions, and researchers were able to implement this definition (either on its own or alongside their own preferred definition) when reporting surveillance or research data relating to late presentation of HIV infection.

BACKGROUND: In the combined antiretroviral therapy (cART) era, non-acquired immunodeficiency syndrome (AIDS)-defining malignancies account for more morbidity and mortality in human immunodeficiency virus-infected patients than AIDS-defining malignancies. However, conflicting data have been reported on the relationship between immunodeficiency and the development of some non- AIDS-defining malignancies. METHODS: A total of 14, 453 patients from the prospective, multinational EuroSIDA cohort were included. Malignancies were classified as virus-related, non-virus-related epithelial, and other. The incidence of non-AIDS-defining malignancies was calculated stratified by current CD4 count. Poisson regression was used to investigate factors associated with the development of non-AIDS- defining malignancies. RESULTS: A total of 356 non-AIDS-defining malignancies occurred, with an incidence rate of 4.3 per 1000 person years of follow-up (95% confidence interval [CI], 3.8-4.7) ; 172 (48.3%) were virus-related, 135 (37.9%) were non-virus-related epithelial, and 49 (13.7%) were classified as other. Anal (69 cases), lung (31 cases), and melanoma (13 cases), respectively, were the most common non-AIDS-defining malignancies within each group. After adjustment, current CD4 was associated with virus-related non- AIDS-defining malignancies (incidence rate ratio [IRR], 0.81 per doubling ; 95% CI, 0.75-0.88 ; P < .0001) and non-virus-related epithelial non-AIDS- defining malignancies (IRR, 0.84 ; 95% CI, 0.75- 0.95 ; P = .004), but not with other non-AIDS- defining malignancies (IRR, 1.04 ; 95% CI, 0.83- 1.31 ; P = .73). Current CD4 count was also associated with anal cancer (IRR, 0.86 ; 95% CI, 0.75-0.99 ; P = .03), Hodgkin lymphoma (n = 52 ; IRR, 0.83 ; 95% CI, 0.73-0.95 ; P = .005), and lung cancer (IRR, 0.76 ; 95% CI, 0.64-0.90 ; P = .0002). CONCLUSIONS: A low current CD4 count was associated with an increased incidence of certain non-AIDS-defining malignancies. Starting cART earlier to reduce the proportion of patients with a low CD4 count may decrease the rate of developing many common non-AIDS-related malignancies. A randomized trial to explore this strategy is urgently needed. Cancer 2010 ; 116:5306-15. (c) 2010 American Cancer Society.

Objective The D:A:D study group reported a 1.9-fold increased relative risk (RR) of myocardial infarction (MI) associated with current or recent use of abacavir. The number needed to harm (NNH) incorporates information about the underlying risk of MI and the increased RR of MI in patients taking abacavir. Methods NNH was calculated as the reciprocal of the difference between the underlying risks of MI with and without abacavir use. A parametric statistical model was used to calculate the underlying risk of MI over 5 years. Results The relationship between NNH and underlying risk of MI is reciprocal, resulting in wide variation in the NNH with small changes in underlying risk of MI. The smallest changes in NNH are in the medium- and high-risk groups of MI. The NNH changes as risk components are modified; for example, for a patient who smokes and has a systolic blood pressure (sBP) of 160 mmHg and a 5-year risk of MI of 1.3% the NNH is 85, but the NNH increases to 277 if the patient is a nonsmoker and to 370 if sBP is within the normal range (120 mmHg). Conclusions We have illustrated that the impact of abacavir use on risk of MI varies according to the underlying risk and it may be possible to increase considerably the NNH by decreasing the underlying risk of MI using standard of care interventions, such as smoking cessation or control of hypertension

Regional differences across Europe in triple class failure (TCF; the failure of each of the three separate main classes of antiretrovirals (ARVs) with a viral load >1000 HIV-1 RNA copies/mL for >4 months) have not been described. A total of 1956 patients started combination ARV therapy after 1 January 1999, of whom 123 patients developed TCF [6.3%; incidence 16.7 per 1000 person-years of follow-up; 95% confidence interval (CI) 13.7–19.6]. After adjustment, patients from Eastern Europe had a significantly increased incidence of TCF compared with patients from Southern Europe/Argentina (3.05; 95% CI 1.36–6.82; P=0.0067) while patients taking either a boosted protease inhibitor regimen (0.33; 95% CI 0.15–0.74; P=0.0072) or a nonnucleotide reverse transcriptase inhibitor (NNRTI)-based regimen (0.59; 95% CI 0.37–0.94; P=0.026) had a reduced incidence of TCF.

Objectives Following resolution of hepatitis C virus (HCV) infection, recurrence has been shown to occur in some persons with repeated exposure to HCV. We aimed to investigate the rate and factors associated with HCV RNA recurrence among HIV-1-infected patients with prior spontaneous HCV RNA clearance in the EuroSIDA cohort. Methods All HIV-infected patients with documented prior spontaneous HCV clearance, and at least one subsequently collected plasma sample, were examined. The last sample was tested for HCV RNA and those with HCV RNA ≥ 615 IU/mL were defined as having HCV recurrence and their characteristics were compared with those of patients who were still aviraemic. Logistic regression was used to identify factors associated with HCV recurrence. Results Of 191 eligible patients, 35 [18.3%; 95% confidence interval (CI) 12.8–23.8%] had HCV recurrence. Thirty-three (94.3%) were injecting drug users (IDUs). The median time between the first and last samples was 3.6 years (interquartile range 2.0–5.8 years). After adjustment, those on combination antiretroviral therapy [odds ratio (OR) 0.44; 95% CI 0.20–0.99; P = 0.046] and older persons (OR 0.51 per 10 years older; 95% CI 0.28–0.95; P = 0.033) were less likely to have HCV RNA recurrence, whereas IDUs were over 6 times more likely to have HCV RNA recurrence compared with non-IDUs (OR 6.58; 95% CI 1.48–29.28; P = 0.013). Conclusions Around 1 in 5 HIV-infected patients with prior spontaneous HCV RNA clearance had detectable HCV RNA during follow-up. Our findings underline the importance of maintaining focus on preventive measures to reduce IDU and sharing of contaminated needles. Clinicians should maintain a high degree of vigilance to identify patients with new HCV infection early.

1Royal Free Centre for HIV Medicine, Department of Primary Care and Population Sciences, Royal Free and University College Medical School, London, UK,2NPMS-HHC, St. Stephen's Centre, Chelsea and Westminster Hospital, London, UK,3Global Health Outcomes, Glaxo Wellcome R and D, Greenford, Middlesex, UK,4Royal Free Centre for HIV Medicine, Department of Thoracic Medicine, Royal Free Hospital, London, UK and Joint Departments of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada Objective To assess the cost-effectiveness of highly active antiretroviral therapy (HAART) compared with two nucleoside reverse transcriptase inhibitors (NRTIs) for HIV infected individuals. Design Different data sources on the clinical effects and costs of treatments were combined using a Markov model. Setting English HIV treatment centres. Perspective UK public finance. Interventions HAART – dual NRTI therapy plus a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor – vs. dual NRTI therapy. Participants Hypothetical cohorts of 1000 individuals infected with HIV. Outcome measures Projected life expectancy, cost-effectiveness in UK£ per life-year saved and per quality-adjusted life-years (QALYs) saved. Results Assuming a 2-year additional treatment effect of therapy with HAART produced incremental cost-effectiveness ratios of £14 602 per life-year saved and £17 698 per QALY saved. Conclusions The results were sensitive to a number of assumptions including the cost of HAART and the discount rate, but they suggest that the use of HAART in England is at least moderately cost-effective compared with treatment with two NRTIs alone.

Adenoviruses have been described as a cause of diarrhoea in patients infected with the human immunodeficiency virus (HIV). The prevalence of adenoviruses was studied in all HIV-positive patients presenting with diarrhoea at the Royal Free Hospital in London between 1991 and 1995. In addition, all postmortems carried out in HIV-positive individuals registered at the same centre between 1990 and 1997 were reviewed for evidence of adenovirus infection. Adenovirus was detected in 16.1% of patients presenting with diarrhoea. These individuals had a significantly lower CD4 count and were more likely to have had a diagnosis of acquired immunodeficiency syndrome (AIDS) than patients with diarrhoea in whom adenovirus was not detected. The median survival was 1 year compared with 2.4 years for those without adenoviruses; this difference remained significant (P = .008) after controlling for differences in CD4 counts between the groups. Gastrointestinal adenovirus excretion occurs at an advanced stage of HIV disease, and is associated with a poor prognosis. We suggest that adenoviruses may contribute to mortality in this population. J. Med. Virol. 58:280–285, 1999. © 1999 Wiley-Liss, Inc.

Purpose of the study: To investigate the impact of ART, HIV viremia and immunosuppression on triglyceride (TG), total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) levels. Methods: We considered the cross-sectional associations between TG, TC and HDL-C (mmol/l; first available measurement on/after enrolment in the D:A:D study) and use of ART, HIV viral load (VL; copies/ml), and CD4 count (cells/mm 3 ) measured at the same time. TG was log 10 transformed to ensure normality. Analyses were performed using linear regression and adjusted for other factors known to impact lipid levels (table footnote). ART and VL status were combined (off ARTV IQR 1.52; 1.00-2.45), 45,169 (90.8%) a TC measurement (4.80; 4.00-5.70) and 38,604 (77.6%) a HDL-C measurement (1.12; 0.90-1.40). Most participants were male (74%), of white ethnicity (51%), without AIDS (78%), were not receiving lipid-lowering drugs (4%) and were ART experienced (61%) with 47% previously exposed to PIs, 61% previously exposed to NRTIs and 29% previously exposed to NNRTIs. The median (IQR) age, current CD4 count and CD4 nadir were 38 (36-45) years, 400 (242-590) cells/μl and 240 (100-410) cells/μl respectively. Compared to those on ART with a suppressed VL, all lipids were lower for those off ART (Table); non-suppressive ART was also associated with lower TC and HDL-C levels (no impact on TG). A low current CD4 count was associated with lower lipid levels, whereas a low nadir CD4 count was associated with higher TC and TG levels. Prior AIDS diagnosis was associated with higher TG and TC, but lower HDL-C levels Conclusion: Although specific drug classes were not considered, lipid levels are considerably higher in those on a suppressive ART regimen. The higher TC/TG and lower HDL-C levels seen among those with low nadir CD4 count and with a prior AIDS diagnosis suggests severe immunosuppression may be associated with dyslipidaemia over the long-term. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Kamara D et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18280 http://www.jiasociety.org/index.php/jias/article/view/18280 | http://dx.doi.org/10.7448/IAS.15.6.18280

Background : In the last decade, several outbreaks of sexually acquired acute HCV have been described in men who have sex with men (MSM) infected with HIV in Australia, Europe, and North America. The aims of this study were to determine the incidence of acute HCV within the large EuroSIDA cohort and to explore possible regional differences throughout Europe and in different HIV transmission risk groups. Methods : Baseline was defined as 1st Jan of 2002 or entry into EuroSIDA, whichever comes later. All patients from EuroSIDA who were HCV antibody-negative at baseline and had at least 2 HCV antibody test results available were included into the study. HCV seroconversion was defined as change from negative to positive HCV-antibody test within the observation period from 2002 onwards. Follow-up was counted from baseline to HCV antibody positivity for seroconverters and to the last HCV antibody-negative test result for those that did not seroconvert for HCV. Poisson regression analyses were performed to identify predictive factors for HCV seroconversion. Results : A total of 150 HCV seroconversions (95 [63.3%] in MSM) occurred in 4295 patients during 18,928 person years of follow-up (PYFU), overall incidence of 0.79 acute infections per 100 PYFU (95% CI: 0.67-0.92) (see figure). The incidence of HCV seroconversions increased from 0.47 (CI: 0.19–0.74) in 2002 to 2.34 (CI: 1.24-3.44) in 2010. Similar patterns were observed across all European regions (p=0.89, test for interaction). In multivariate analysis, IDU was associated with a higher incidence rate ratio (IRR) than MSM: 4.59 (2.40-8.80; p

Many studies have focused on chronic kidney disease in HIV-positive individuals, but few have studied the less frequent events, advanced renal disease (ARD) and end-stage renal disease (ESRD). The aim of this study was to investigate incidence, predictors and outcomes for ARD/ESRD and renal death in EuroSIDA. ARD was defined as confirmed eGFR 3 months apart) using Cockcroft-Gault. ESRD was defined as hemo- or peritoneal dialysis >1 month/renal transplant. Renal deaths were defined as renal failure as the underlying cause of death, using CoDe methodology. Patients were followed from baseline (first eGFR after 1/1/2004) until last eGFR, ARD/ESRD/renal death; whichever occurred first. Poisson regression was used to identify predictors. 8817 persons were included, the majority were white (87.3%), males (73.9%) infected though homosexual contact (41.5%) and with a median age of 42 years (IQR 36-49). 45 persons (0.5%) developed the composite endpoint; ARD (24), ESRD (19) and renal death (2) during a median follow up (FU) of 4.5 years (IQR 2.7-5.8), incidence rate (IR) 1.21/1000 PYFU (95% CI 0.86-1.57). Of 312 persons (3.5%) with baseline eGFR

Persistent immunosuppression despite viral suppression (immunovirological discordance, ID) has been associated with higher risk of AIDS and death, although the risk for AIDS seems to decrease with longer time of suppressed viral load (sVL). The impact of ID on a composite endpoint of AIDS/serious non-AIDS/death has not been thoroughly investigated. Patients in EuroSIDA starting ≥1 new antiretroviral drugs after January 2001, when CD4 was 500 copies/mL, and who achieved a sVL ≤50 copies/mL within 1 year were included. Person-years of follow-up (PYFU) accrued from the date of sVL until the first of a new AIDS or severe non-AIDS (SNA) event or death, viral rebound >50 copies/mL (first of 2 consecutive values) or last visit. Rate ratios (RR) were calculated using Poisson regression according to whether or not patient's current CD4 count was still below 200 cells/mm 3 (ID). Models were stratified according to whether or not persons were ART-naive at baseline. Multivariable models included age, HBV/HCV status, mode of HIV transmission, race, cohort, anemia, diabetes, hypertension or current eGFR, current cART, number of previous antiretrovirals, and time to viral suppression. 994 patients satisfied the inclusion criteria and contributed 4520 PYFU. Median age was 41 (IQR 34-47) years and 72.8% were male. 36.5% of patients were ART-naive and started a median of 3 (IQR 2-3) new drugs. 31 AIDS and 58 non-AIDS events occurred, and 31 patients died (7 due to AIDS, 24 due to SNA). The rate of the combined endpoint in patients with ID (50.3 per 1000 PYFU [95% CI 35.2-69.9]) was higher than in patients recovered from ID (22.1 [17.6-27.3], adjusted RR 2.08 [1.32-3.28]; table). This was similar regardless of whether or not people were ART-naive before starting a new drug (interaction test p=0.47). In ID, rate was highest in the first 6 months of sVL (63.1 [33.6-107.9]) and declined thereafter (month 6-12: 60.5 [26.1-119.2],>12 months: 39.8 [22.2-65.6], adjusted RR compared to month 0-6 0.52 [0.24-1.13]). In analyses with endpoints AIDS/death due to AIDS and SNA/death due to SNA separately, the adjusted RR of ID vs. non ID was 4.11 ([1.76-9.60]; p=0.001) and 1.46 ([0.81-2.61]; p=0.207), respectively. ID is a risk factor for clinical disease progression particularly related to AIDS events. In patients with ID, we found a trend for a declining incidence of events with longer periods of sVL, suggesting that sustained viral suppression might be of benefit. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Zoufaly A et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18194 http://www.jiasociety.org/index.php/jias/article/view/18194 | http://dx.doi.org/10.7448/IAS.15.6.18194

A drastic decrease in incidence has been observed for most human immunodeficiency virus (HIV)-related opportunistic manifestations after use of highly active antiretroviral therapy (HAART). We assessed the trend of incidence of central nervous system (CNS) diseases in a prospective multicenter observational study involving 9,803 patients across Europe in the period 1994 to 2002 and analyzed patient and treatment variables associated with these conditions. Overall, 568 patients (5.8%) received a diagnosis of a new CNS disease. Incidence decreased significantly from 5.9 per 100 person-year in 1994 to 0.5 in 2002. Overall, the decrease was 40% per calendar year, and it was similar to that of non-CNS diseases and less evident after year 1998. In multivariable models, low CD4 cell count and high plasma viral load, but not HAART or calendar year, were significantly associated with risk to develop CNS disease, indicating that the effect of HAART was likely mediated by both improved immunological conditions and inhibition of viral replication. In contrast, use of nucleoside reverse transcriptase inhibitors, irrespective of use of protease inhibitors or non-nucleoside reverse transcriptase inhibitors, appeared to protect specifically against acquired immunodeficiency disease syndrome dementia complex, suggesting that, in this condition, therapy might have a direct, additive effect in the CNS.

Introduction : Development of a simple, widely applicable risk score for chronic kidney disease (CKD) allows comparisons of risks or benefits of starting potentially nephrotoxic antiretrovirals (ARVs) as part of a treatment regimen. Materials and Methods : A total of 18,055 HIV-positive persons from the Data on Adverse Drugs (D:A:D) study with >3 estimated glomerular filtration rates (eGFRs) >1/1/2004 were included. Persons with use of tenofovir (TDF), atazanavir (ritonavir boosted (ATV/r) and unboosted (ATV)), lopinavir (LPV/r) and other boosted protease inhibitors (bPIs) before baseline (first eGFR >60 ml/min/1.73 m 2 after 1/1/2004) were excluded. CKD was defined as confirmed (>3 months apart) eGFR 5 points) risk of developing CKD. Increased incidence of CKD associated with starting ARVs was modelled by including ARVs as time-updated variables. The risk score was externally validated on two independent cohorts. Results : A total of 641 persons developed CKD during 103,278.5 PYFU (incidence 6.2/1000 PYFU, 95% CI 5.7–6.7). Older age, intravenous drug use, HCV+ antibody status, lower baseline eGFR, female gender, lower CD4 nadir, hypertension, diabetes and cardiovascular disease predicted CKD and were included in the risk score (Figure 1). The incidence of CKD in those at low, medium and high risk was 0.8/1000 PYFU (95% CI 0.6–1.0), 5.6 (95% CI 4.5–6.7) and 37.4 (95% CI 34.0–40.7) (Figure 1). The risk score showed good discrimination (Harrell's c statistic 0.92, 95% CI 0.90–0.93). The number needed to harm (NNTH) in patients starting ATV or LPV/r was 1395, 142 or 20, respectively, among those with low, medium or high risk. NNTH were 603, 61 and 9 for those with a low, medium or high risk starting TDF, ATV/r or bPIs. The risk score was externally validated on 2603 persons from the Royal Free Hospital clinic cohort (94 events, incidence 5.1/1000 PYFU; 95% CI 4.1–6.1) and 2013 persons from the control arms of SMART/ESPRIT (32 events, incidence 3.8/1000 PYFU; 95% CI 2.5–5.1). External validation showed consistent CKD rates across risk groups (Figure 2). Interpretation : Traditional and HIV-related risk factors were predictive of CKD; all are routinely available, making the risk score easy to incorporate into clinical practise and of direct relevance for clinical decision making. NNTH in persons starting potentially nephrotoxic ARVs at high risk of CKD were low, and alternative ARVs may be more appropriate. (Published: 2 November 2014) Citation : Abstracts of the HIV Drug Therapy Glasgow Congress 2014 Mocroft A et al. Journal of the International AIDS Society 2014, 17(Suppl 3) :19514 http://www.jiasociety.org/index.php/jias/article/view/19514 | http://dx.doi.org/10.7448/IAS.17.4.19514

Introduction : There is a lack of data on potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD) in HIV-positive individuals. We investigated whether such differences exist in the D:A:D study. Material and Methods : Follow-up was from 01/02/99 until the earliest of death, 6 months after last visit or 01/02/13. Rates of initiation of lipid-lowering drugs (LLDs), angiotensin-converting enzyme inhibitors (ACEIs), anti-hypertensives and receipt of invasive cardiovascular procedures (ICPs; bypass, angioplasty, endarterectomy) were calculated in those without a myocardial infarction (MI) or stroke at baseline, overall and in groups known to be at higher CVD risk: (i) age >50, (ii) total cholesterol >6.2 mmol/l, (iii) triglyceride >2.3 mmol/l, (iv) hypertension, (v) previous MI, (vi) diabetes, or (vii) predicted 10-year CVD risk >10%. Poisson regression was used to assess whether rates of initiation were higher in men than women, after adjustment for these factors. Results : At enrolment, women ( n =13,039; median (interquartile range) 34 (29–40) years) were younger than men ( n =36,664, 39 (33–46) years, p =0.001), and were less likely to be current smokers (29% vs. 39%, p =0.0001), to have diabetes (2% vs. 3%, p =0.0001) or to have hypertension (7% vs. 11%, p =0.0001). Of 49,071 individuals without a MI/stroke at enrolment, 0.6% women vs. 2.1% men experienced a MI while 0.8% vs. 1.3% experienced a stroke. Overall, women received ICPs at a rate of 0.07/100 person-years (PYRS) compared to 0.29/100 PYRS in men. Similarly, the rates of initiation of LLDs (1.28 vs. 2.46), anti-hypertensives (1.11 vs. 1.38) and ACEIs (0.82 vs. 1.37) were all significantly lower in women than men (Table 1). As expected, initiation rates of each intervention were higher in the groups determined to be at moderate/high CVD risk; however, within each high-risk group, initiation rates of most interventions (with the exception of anti-hypertensives) were generally lower in women than men. These gender differences persisted after adjustment for potential confounders (Table 1). Conclusion : Use of most CVD interventions was lower among women than men in the D:A:D study. Our findings suggest that actions should be taken to ensure that both men and women are monitored for CVD and, if eligible, receive appropriate CVD interventions. (Published: 2 November 2014) Citation : Abstracts of the HIV Drug Therapy Glasgow Congress 2014 Hatleberg CI et al. Journal of the International AIDS Society 2014, 17(Suppl 3) :19516 http://www.jiasociety.org/index.php/jias/article/view/19516 | http://dx.doi.org/10.7448/IAS.17.4.19516

Introduction : Although prostate cancer (PCa) incidence is lower in HIV+ men than in HIV− men, the usefulness of prostate-specific antigen (PSA) screening in this population is not well defined and may have higher false negative rates than in HIV− men. We aimed to describe the kinetics and predictive value of PSA in HIV+ men. Methods : Men with PCa ( n =21) and up to two matched controls ( n =40) with prospectively stored plasma samples before PCa (or matched date in controls) were selected. Cases and controls were matched on date of first and last sample, age, region of residence and CD4 count at first sample date. Total PSA (tPSA), free PSA (fPSA), testosterone and sex hormone binding globulin (SHBG) were measured. Conditional logistic regression models investigated associations between markers and PCa. Sensitivity and specificity of using tPSA >4 µg/L to predict PCa was calculated. Mixed models were used to describe kinetics. Results : Sixty-one men were included with a median six (IQR 2–9) years follow-up. Time between last sample and PCa was seven (4–11) months. Cases and controls were well matched at first sample, with a median age of 51 (IQR 48–57) and CD4 of 437 (243–610) cells/mm 3 . Median tPSA [2.8 (IQR: 1.6–4.6) and 0.8 (0.5–1.2) µg/L] and fPSA [0.4 (0.2–0.8) and 0.3 (0.2–0.4) µg/L] levels were higher in cases than controls at first sample. Both tPSA and fPSA increased significantly over time in cases (Figure 1), to a median at last sample of 6.1 (4.7–9.5) and 0.9 (0.6–1.3) µg/L, respectively, but were stable in controls, with a median at last sample of 0.8 (0.5–1.4) and 0.2 (0.2–0.4) µg/L (Figure). Higher levels of tPSA and fPSA were associated with higher odds of PCa at first sample [OR for 2-fold higher 4.7 (CI: 1.7–12.9) and 5.4 (1.7–17.4)]. Elevated tPSA values in cases were detectable ≥5 years before PCa ( p 0.7). The most informative predictor of PCa was tPSA (AUC=0.9), followed by fPSA (0.8). Testosterone (AUC=0.5) and SHBG (0.5) were poor predictors of PCa. Overall, tPSA level >4 µg/L had 99% specificity and 37% sensitivity. Performance was best in the year prior to PCa (specificity: 99%, sensitivity: 88%). Conclusions : PSA was highly predictive of PCa in HIV+ men. Our results indicate that PSA screening in HIV+ men may be useful, and further work is needed to identify potentially age-related cut-offs to maximize sensitivity and specificity to identify those for further evaluation at early stages of PCa. (Published: 2 November 2014) Citation : Abstracts of the HIV Drug Therapy Glasgow Congress 2014 Shepherd L et al. Journal of the International AIDS Society 2014, 17(Suppl 3) :19510 http://www.jiasociety.org/index.php/jias/article/view/19510 | http://dx.doi.org/10.7448/IAS.17.4.19510

Introduction : A recent meta-analysis of 4 RCTs showed an increased rate of suicidality events (suicidal ideation or attempted/completed suicide) associated with efavirenz (EFV) compared to other regimens, but only a trend towards a higher rate of completed/attempted suicides, as only 17 events occurred. We investigated the association between EFV use and completed suicide. Materials and Methods : All D:A:D participants were followed from study entry to the first of death, last study visit or 1 February 2013. Deaths are centrally validated using cause of death methodology, which assigns underlying, immediate and up to four contributing causes of death. Two endpoints were considered: 1) suicide or psychiatric disease as the underlying cause, and 2) suicide or psychiatric disease mentioned as an underlying, immediate or contributing cause of death (anywhere). Adjusted rate ratios were calculated using Poisson regression. Results : A total of 4420 deaths occurred in 49,717 people over 371,333 person-years (PY) (rate 11.9 per 1000 PY; 95% CI 11.6–12.3). A total of 193 deaths (rate 0.52; 0.45–0.59) had an underlying cause of suicide or psychiatric disease, and 482 deaths (1.30; 1.18–1.41) had suicide or psychiatric disease mentioned anywhere. A strong association with current CD4 count was seen: for suicide or psychiatric disease mentioned anywhere, rates were: 3.18 (2.55–3.80) for 500 cells/uL and 1.30 (1.18–1.41) for unknown. Highest rate of suicide or psychiatric deaths were seen in ART-experienced people currently off ART, but no differences were seen according to current ART regimen, which remained after adjustment (Table 1). Consistent results were obtained when considering additional endpoints of suicide alone as the underlying cause and death from suicide or any possibly related cause (psychiatric disease, drug overdose, alcohol related, accidental or violent), as well as considering recent EFV use in the previous 3 and 6 months. Conclusions : The finding of no higher death rates from suicide amongst those receiving EFV is reassuring. However, there is likely confounding by indication in our observational study. In light of conflicting results from RCTs, this potentially could suggest that in clinical practice EFV may be less frequently prescribed in those with underlying psychiatric conditions. (Published: 2 November 2014) Citation : Abstracts of the HIV Drug Therapy Glasgow Congress 2014 Smith C et al. Journal of the International AIDS Society 2014, 17(Suppl 3) :19512 http://www.jiasociety.org/index.php/jias/article/view/19512 | http://dx.doi.org/10.7448/IAS.17.4.19512

Introduction: The risk of uncontrolled viral replication in HIV+ patients who are not immune compromised on the development of serious clinical events is not fully understood. We aimed to compare the incidence of fatal and non-fatal AIDS and non-AIDS events occurring at CD4 counts >350 cells/mm3 in different viral load strata (≤500, 501-10000, >10000 copies/ml). Methods: Patients contributed person years at risk if the most recent CD4 count was >350 cells/mm3 and viral load was measured in the 6 months prior. Poisson regression investigated the relationship between viremia and clinical events, after adjustment for confounding variables. Results: 10998 patients were included contributing 43524 person-years of follow-up (PYFU). The majority of follow-up (80%) was with a viral load ≤500, 12% between 501-10000 and 8% >10000. 95%, 72% and 64% of the follow-up in each strata respectively was in patients who had started cART. 379 AIDS events (14 deaths) occurred. There was a lower incidence of AIDS events in patients with a viral load ≤500 (IR 0.69 per 100 PYFU, 95%CI 0.60-0.78) compared to a viral load >10000 (IR 2.38 per 100 PYFU, 95%CI 1.87-2.89). 532 non-AIDS events (131 deaths) occurred. Patients with a viral load ≤500 had an incidence of non-AIDS events of 1.50 per 100 PYFU (95%CI 1.36-1.64), and 1.43 per 100 PYFU (95%CI 0.96-1.89) when viral load >10000. As shown in Figure ​Figure1,1, after adjustment, patients with a viral load >10000 had a 3 times higher incidence of AIDS events than those with a viral load ≤500(p 10000 (p=0.05) respectively, compared to a viral load ≤500. The effect of viral load was independent of current CD4 count and was similar in different CD4 count strata (test for interaction p>0.05 for both endpoints). Conclusions: In patients with a CD4 count >350 cells/mm3 an increased incidence of fatal and non-fatal AIDS and non-AIDS events was found in patients with uncontrolled viral replication, even after adjustment for current CD4 count and use of cART. The association between viral replication and AIDS events was clear and consistent with a biological effect, but with non-AIDS events was less clear without a difference between intermediate and high viral replication. Supplement: Abstracts of the Tenth International Congress on Drug Therapy in HIV Infection http://www.biomedcentral.com/content/pdf/1758-2652-13-S4-info.pdf Conference: Tenth International Congress on Drug Therapy in HIV Infection 7-11 November 2010 Glasgow, UK (Published: 8 November 2010) doi:10.1186/1758-2652-13-S4-O39 Cite this article as: Reekie et al.: Fatal and non-fatal AIDS and non-AIDS events in HIV-1 infected patients with high CD4 counts. Journal of the International AIDS Society 2010 13(Suppl 4):O39. Full text: PubMed Central: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3112853/

Address: 1Royal Free and University College Medical School, London, UK, 2University Hospital, Zurich, Switzerland, 3Medizinische Poliklinik, Munich, Germany, 4Hospital Saint-Antoine, Paris, France, 5Medical University, Bialystok, Poland, 6Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam, Netherlands, 7Copenhagen HIV Programme, Panum Institute, Copenhagen, Denmark and 8Copenhagen HIV Programme, Panum Institute and Centre for Viral Disease KMA, Rigshospitale, Copenhagen, Denmark * Corresponding author