[Atypical mycocutaneous manifestation of Leishmania tropica in a refugee].

In this case report a male 19-year-old Syrian refugee presented with a sore throat. A biopsy from larynx detected Leishmania tropica compatible with leishmaniasis, although L. tropica does not normally cause mucosal leishmaniasis (CL). An immunodeficiency was detected, and the patient was treated for hypogammaglobulinaemia and CL three times, before the symptoms disappeared. Leishmaniasis is a disease, which should be taken into consideration, when refugees present with atypical clinical manifestations, especially in immunosuppressed patients.

CD4 cell count response to first-line combination ART in HIV-2+ patients compared with HIV-1+ patients: a multinational, multicohort European study.

Background: CD4 cell recovery following first-line combination ART (cART) is poorer in HIV-2+ than in HIV-1+ patients. Only large comparisons may allow adjustments for demographic and pretreatment plasma viral load (pVL). Methods: ART-naive HIV+ adults from two European multicohort collaborations, COHERE (HIV-1 alone) and ACHIeV2e (HIV-2 alone), were included, if they started first-line cART (without NNRTIs or fusion inhibitors) between 1997 and 2011. Patients without at least one CD4 cell count before start of cART, without a pretreatment pVL and with missing a priori-defined covariables were excluded. Evolution of CD4 cell count was studied using adjusted linear mixed models. Results: We included 185 HIV-2+ and 30321 HIV-1+ patients with median age of 46 years (IQR 36-52) and 37 years (IQR 31-44), respectively. Median observed pretreatment CD4 cell counts/mm3 were 203 (95% CI 100-290) in HIV-2+ patients and 223 (95% CI 100-353) in HIV-1+ patients. Mean observed CD4 cell count changes from start of cART to 12 months were +105 (95% CI 77-134) in HIV-2+ patients and +202 (95% CI 199-205) in HIV-1+ patients, an observed difference of 97 cells/mm3 in 1 year. In adjusted analysis, the mean CD4 cell increase was overall 25 CD4 cells/mm3/year lower (95% CI 5-44; P = 0.0127) in HIV-2+ patients compared with HIV-1+ patients. Conclusions: A poorer CD4 cell increase during first-line cART was observed in HIV-2+ patients, even after adjusting for pretreatment pVL and other potential confounders. Our results underline the need to identify more potent therapeutic regimens or strategies against HIV-2.

Initial Serological Response after Prime-boost Pneumococcal Vaccination in Rheumatoid Arthritis Patients: Results of a Randomized Controlled Trial.

OBJECTIVE: To evaluate the initial serological responses to pneumococcal vaccination with the 13-valent protein-conjugated pneumococcal vaccine (PCV13) followed by the 23-valent polysaccharide pneumococcal vaccine (PPV23) among patients with rheumatoid arthritis (RA) treated with biological disease-modifying antirheumatic drugs (bDMARD) according to dosing and intervals between immunizations. METHODS: Investigator-initiated clinical trial. Patients with RA receiving bDMARD were randomized (1:1:1) to immunization with single dose PCV13 followed by PPV23 after 16 or 24 weeks, or double dose PCV13 followed by PPV23 after 16 weeks. A comparison group of patients with RA treated with conventional synthetic (cs)DMARD received single dose PCV13 followed by PPV23 16 weeks later. Pneumococcal antibodies were collected before and 4 weeks after each vaccination. The primary endpoint was the proportion of participants responding to ≥ 6/12 pneumococcal serotypes 4 weeks after both vaccinations. RESULTS: Sixty-five participants receiving bDMARD and 35 participants receiving csDMARD were included. After PPV23 vaccination, 87% (95% CI 0.76-0.94) and 94% (95% CI 0.77-0.99), respectively, of participants treated with bDMARD and csDMARD had reached the primary endpoint. There was no significant difference in primary endpoint between the 3 randomization arms. The response for rituximab-treated participants was 25% compared to ≥ 89% in participants treated with bDMARD with other mode of action. CONCLUSION: The early serological response to prime-boost vaccination with PCV13 followed by PPV23 was very similar among participants receiving bDMARD and csDMARD. However, notable differences in response were observed according to individual bDMARD. It is important to consider the RA treatment when planning pneumococcal vaccination in patients with RA.

Inadvertent yellow fever vaccination of a patient with Crohn's disease treated with infliximab and methotrexate.

We present a case of a 56-year-old woman with Crohn's disease, treated with methotrexate and infliximab, who inadvertently received yellow fever vaccination (YFV) prior to a journey to Tanzania. She was not previously vaccinated against YF. YFV contains live-attenuated virus, and is contraindicated in patients treated with immunosuppressive drugs. Following vaccination, the patient fell ill with influenza-like illness. Elevated transaminase levels and YF viremia were detected. Despite being immunocompromised, the patient did not develop more severe adverse effects. Neutralising antibodies to YF virus were detected on day 14 following vaccination and remained protective at least 10 months after vaccination. Limited data is available on outcomes of YFV in patients receiving immunosuppressive therapy, including biologics, and we report this case as a reminder of vigilance of vaccine recommendations in this population.

Hypertension Is a Key Feature of the Metabolic Syndrome in Subjects Aging with HIV.

With widespread and effective antiretroviral therapy, the life expectancy in the HIV population has dramatically improved over the last two decades. Consequently, as patients are aging with HIV, other age-related comorbidities, such as metabolic disturbances and cardiovascular disease (CVD), have emerged as important causes of morbidity and mortality. An overrepresentation of traditional cardiovascular risk factors (RF), toxicities associated with long exposure to antiretroviral therapy, together with residual chronic inflammation and immune activation associated with HIV infection are thought to predispose to these metabolic complications and to the excess risk of CVD observed in the HIV population. The metabolic syndrome (MS) represents a clustering of RF for CVD that includes abdominal obesity, hypertension, dyslipidemia and insulin resistance. Hypertension is a prevalent feature of the MS in HIV, in particular in the aging population, and constitutes an important RF for CVD. Physicians should screen their patients for metabolic and cardiovascular risk at the regular visits to reduce MS and the associated CVD risk among people aging with HIV, since many of RF are under-diagnosed and under-treated conditions. Interventions to reduce these RF can include lifestyle changes and pharmacological interventions such as antihypertensive and lipid-lowering therapy, and treatment of glucose metabolism disturbances. Changes in antiretroviral therapy to more metabolic neutral antiretroviral drugs may also be considered.

Body Mass Index and Risk of Infections Among Women in the Danish National Birth Cohort.

We investigated the possible association between body mass index (BMI; weight (kg)/height (m)(2)) and hospitalization or treatment for acute infection in a prospective cohort study. We linked 75,001 women enrolled in the Danish National Birth Cohort from 1996 to 2002, who had information on BMI and a broad range of confounders, to data on infectious diseases and use of antimicrobial agents from the National Patient Register and the Danish Prescription Register. Associations were tested using Cox proportional hazards models. During 12 years of follow-up, we observed a U-shaped association between baseline BMI and later hospitalization for 1) any infectious disease and 2) infections of the respiratory tract, whereas a dose-response relationship was seen for skin infections. The most pronounced associations were seen for acute upper respiratory infections at multiple and unspecified sites (underweight (BMI <18.5): hazard ratio (HR) = 4.26, 95% confidence interval (CI): 1.69, 10.7; obesity (BMI ≥30): HR = 3.64, 95% CI: 1.62, 8.18), erysipelas (obesity: HR = 5.19, 95% CI: 3.38, 7.95), and fungal infections (underweight: HR = 3.19, 95% CI: 1.53, 6.66). Slightly greater use of antimicrobials was observed among overweight (BMI 25-<30; HR = 1.08, 95% CI: 1.06, 1.10) and obese (HR = 1.21, 95% CI: 1.17, 1.24) women. Among Danish women, underweight and obesity were associated with increased risk of community-acquired infectious diseases, especially infections of the upper respiratory tract and skin.

An updated prediction model of the global risk of cardiovascular disease in HIV-positive persons: The Data-collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study.

BACKGROUND: With the aging of the population living with HIV, the absolute risk of cardiovascular disease (CVD) is increasing. There is a need to further facilitate the identification of persons at elevated risk in routine practice. METHODS AND RESULTS: Prospective information was collected on 32,663 HIV-positive persons from 20 countries in Europe and Australia, who were free of CVD at entry into the Data-collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study. Cox regression models (full and reduced) were developed that predict the risk of a global CVD endpoint. The predictive performance of the D:A:D models were compared with a recent CVD prediction model from the Framingham study, which was assessed recalibrated to the D:A:D dataset. A total of 1010 CVD events occurred during 186,364.5 person-years. The full D:A:D CVD prediction model included age, gender, systolic blood pressure, smoking status, family history of CVD, diabetes, total cholesterol, high-density lipoprotein, CD4 lymphocyte count, cumulative exposure to protease- and nucleoside reverse transcriptase-inhibitors, and current use of abacavir. A reduced model omitted antiretroviral therapies. The D:A:D models statistically significantly predicted risk more accurately than the recalibrated Framingham model (Harrell's c-statistic of 0.791, 0.783 and 0.766 for the D:A:D full, D:A:D reduced, and Framingham models respectively; p < 0.001). The D:A:D models also more accurately predicted five-year CVD-risk for key prognostic subgroups. CONCLUSIONS: An updated, easily recalibrated, global CVD-risk equation tailored to HIV-positive persons was developed using routinely collected CVD risk parameters and incorporating markers on immune function (CD4 lymphocyte count), and exposure to antiretroviral therapies. The estimated CVD risk can be used to quantify risk and to guide preventive care.

Association between tumour necrosis factor-α inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study.

OBJECTIVE: To investigate whether people with inflammatory bowel disease treated with tumour necrosis factor-α (TNF-α) inhibitors are at increased risk of serious infections. DESIGN: Nationwide register based propensity score matched cohort study. SETTING: Denmark, 2002-12. PARTICIPANTS: The background cohort eligible for matching comprised 52,392 people with inflammatory bowel disease, aged 15 to 75 years, of whom 4300 were treated with TNF-α inhibitors. To limit confounding, a two stage matching method was applied; firstly matching on age, sex, disease duration, and inflammatory bowel disease subtype, and secondly matching on propensity scores (1:1 ratio); this yielded 1543 people treated with TNF-α inhibitors and 1543 untreated to be included in the analyses. MAIN OUTCOME MEASURES: The main outcome was any serious infection, defined as a diagnosis of infection associated with hospital admission. Cox regression was used to estimate hazard ratios for two risk periods (90 and 365 days after the start of TNF-α inhibitor treatment). Hazard ratios of site specific serious infections were obtained solely for the 365 days risk period. RESULTS: Within the 90 days risk period, 51 cases of infection were observed in users of TNF-α inhibitors (incidence rate 14/100 person years), compared with 33 cases in non-users (9/100 person years), yielding a hazard ratio of 1.63 (95% confidence interval 1.01 to 2.63). Within the risk period of 365 days, the hazard ratio was 1.27 (0.92 to 1.75). In analyses of site specific infections, the hazard ratio was above 2 for several of the subgroups but only reached statistical significance for skin and soft tissue infections (2.51, 1.23 to 5.12). CONCLUSIONS: This nationwide propensity score matched cohort study suggests an increased risk of serious infections associated with use of TNF-α inhibitors within the first 90 days of starting treatment and a subsequent decline in risk. This calls for increased clinical awareness of potential infectious complications among people with inflammatory bowel disease using these drugs, especially early in the course of treatment.

Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration.

BACKGROUND: With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. METHODS: Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. FINDINGS: 3909 of the 49,731 D:A:D study participants died during the 308,719 person-years of follow-up (crude incidence mortality rate, 12.7 per 1000 person-years [95% CI 12.3-13.1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17.5 in 1999-2000 to 9.1 in 2009-11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5.9 to 2.0), deaths from liver disease (2.7 to 0.9), and cardiovascular disease deaths (1.8 to 0.9). However, non-AIDS cancers increased slightly from 1.6 per 1000 person-years in 1999-2000 to 2.1 in 2009-11 (p=0.58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009-11 vs 1999-2000: 0.92 [0.70-1.22]). However, all-cause (0.72 [0.61-0.83]), liver disease (0.48 [0.32-0.74]), and cardiovascular disease (0.33 [0.20-0.53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999-2000 and 141/627 [22%] in 2009-11) and liver-related (40/256 [16%] in 1999-2000 and 64/627 [10%] in 2009-11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999-2000 to 142/627 [23%] in 2009-11). INTERPRETATION: Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. FUNDING: Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.

Predicting the short-term risk of diabetes in HIV-positive patients: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study.

INTRODUCTION: HIV-positive patients receiving combination antiretroviral therapy (cART) frequently experience metabolic complications such as dyslipidemia and insulin resistance, as well as lipodystrophy, increasing the risk of cardiovascular disease (CVD) and diabetes mellitus (DM). Rates of DM and other glucose-associated disorders among HIV-positive patients have been reported to range between 2 and 14%, and in an ageing HIV-positive population, the prevalence of DM is expected to continue to increase. This study aims to develop a model to predict the short-term (six-month) risk of DM in HIV-positive populations and to compare the existing models developed in the general population. METHODS: All patients recruited to the Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) study with follow-up data, without prior DM, myocardial infarction or other CVD events and with a complete DM risk factor profile were included. Conventional risk factors identified in the general population as well as key HIV-related factors were assessed using Poisson-regression methods. Expected probabilities of DM events were also determined based on the Framingham Offspring Study DM equation. The D:A:D and Framingham equations were then assessed using an internal-external validation process; area under the receiver operating characteristic (AUROC) curve and predicted DM events were determined. RESULTS: Of 33,308 patients, 16,632 (50%) patients were included, with 376 cases of new onset DM during 89,469 person-years (PY). Factors predictive of DM included higher glucose, body mass index (BMI) and triglyceride levels, and older age. Among HIV-related factors, recent CD4 counts of <200 cells/µL and lipodystrophy were predictive of new onset DM. The mean performance of the D:A:D and Framingham equations yielded AUROC of 0.894 (95% CI: 0.849, 0.940) and 0.877 (95% CI: 0.823, 0.932), respectively. The Framingham equation over-predicted DM events compared to D:A:D for lower glucose and lower triglycerides, and for BMI levels below 25 kg/m(2). CONCLUSIONS: The D:A:D equation performed well in predicting the short-term onset of DM in the validation dataset and for specific subgroups provided better estimates of DM risk than the Framingham.

Inflammation predicts changes in high-density lipoprotein particles and apolipoprotein A1 following initiation of antiretroviral therapy.

BACKGROUND: The effects of HIV infection and antiretroviral therapy (ART) on usual lipid levels have been reported. The effects of initiating versus deferring ART on high-density and low-density lipoprotein particle (HDL-P and LDL-P, respectively) concentrations and apolipoprotein (Apo) levels are not well described. METHODS: In a subgroup of participants not taking ART at study entry who were randomized in the Strategies for Management of Antiretroviral Therapy (SMART) trial to immediately initiate ART ('viral suppression group') or to defer it ('drug conservation group'), lipoprotein particle concentrations and ApoA1 and ApoB levels were measured at baseline and at 2 and 6 months following randomization. RESULTS: Compared with drug conservation group (n = 126), HDL-P and ApoA1 levels increased among viral suppression participants (n = 128) after starting ART. At 6 months, viral suppression participants had 13% higher total HDL-P (P < 0.001) and 9% higher ApoA1 (P < 0.001). LDL-P, very low density lipoprotein particle, and ApoB did not differ significantly between the viral suppression and drug conservation groups. Among viral suppression participants, predictors of HDL-P and ApoA1 increases included baseline levels of high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6), but not HIV RNA level, CD4 cell count, or traditional cardiovascular disease risk factors. The effect of starting ART on changes in HDL-P and ApoA1 was greater for those with higher versus lower baseline levels of IL-6 (P = 0.001 and 0.08, respectively, for interaction) or hsCRP (P = 0.01 and 0.04, respectively, for interaction). CONCLUSION: HDL-P and ApoA1 increase following ART initiation, to a degree that depends on the degree of inflammation present at entry. These findings suggest that activation of inflammatory pathways contribute to HIV-associated changes in HDL.

The Coding Causes of Death in HIV (CoDe) Project: initial results and evaluation of methodology.

BACKGROUND: The Coding Causes of Death in HIV (CoDe) Project aims to deliver a standardized method for coding the underlying cause of death in HIV-positive persons, suitable for clinical trials and epidemiologic studies. METHODS: The project incorporates detailed data collection, a classification system, and a centralized adjudication process performed by 2 independent reviewers. The methodology was tested in the Data Collection on Adverse events of Anti-HIV Drugs Study , and independent reviews of causes of death were compared. Logistic regression models identified factors associated with initial agreement by reviewers on underlying cause of death. RESULTS: A total of 491 reported fatal cases were adjudicated; in only 5% of cases the cause of death remained undetermined after adjudication. Reviewers initially agreed on the underlying cause for 339 (69%) deaths. As compared with deaths due to AIDS-related causes, the odds of agreement were more than 80% lower when deaths were ultimately deemed to be due to non-AIDS-related causes (odds ratio = 0.17 [95% confidence interval = 0.08-0.37]) or undetermined causes (0.11 [0.04-0.36]). The odds of initial agreement were also lower for deaths occurring in subjects with hypertension (0.43 [0.22-0.85]) and depression (0.43 [0.23-0.80]). CONCLUSIONS: The extent and format of data collected in the CoDe Project appear to be sufficient for an informed review, and the proposed coding scheme is adequate for obtaining an underlying cause of death.

The prevalence and clinical significance of intestinal parasites in HIV-infected patients in Denmark.

To investigate the prevalence and clinical significance of intestinal parasites in human immunodeficiency virus (HIV)-infected patients, faecal specimens from 96 HIV-infected patients were submitted to microbiological analyses, including microscopy and polymerase chain reaction for protozoa and enteropathogenic bacteria. Results of microbiological analyses were compared with self-reported gastrointestinal complaints collected using a validated questionnaire. Thirty-two (33%) patients were positive for parasites. However, opportunistic parasites (Isospora and Cryptosporidium) were detected in only 2 instances. Entamoeba dispar was detected in 10 cases, 9 of which represented men who have sex with men (MSM). Despite generally low HIV RNA loads and high CD4+ T-cell counts, 42% of the 76 patients reporting symptoms complained of diarrhoea, 31% of whom were parasite-positive. The presence of diarrhoea was not associated with the presence or absence of parasites; neither was it associated with receiving highly active anti-retroviral therapy (HAART) in general, or protease inhibitors (PI) in particular. A CD4+ T-cell count <200 cells/mm³ was not associated with parasitic infection or with diarrhoea. The data show that diarrhoea is a common symptom among HIV-infected patients in Denmark, but do not indicate that the diarrhoea is due to intestinal parasites.

Changes in lipids and lipoprotein particle concentrations after interruption of antiretroviral therapy.

BACKGROUND: The effect of interruption of antiretroviral therapy (ART) on lipoprotein particle subclasses has not been studied. We examined short-term changes in lipids and lipoprotein particles among 332 HIV-infected individuals randomized to interrupt or continue ART in the "Strategies for Management of Antiretroviral Therapy" trial. METHODS: Lipids and lipoprotein particles measured by nuclear magnetic resonance spectroscopy were compared between randomized groups at month 1; associations with inflammatory and coagulation markers (high sensitivity C-reactive protein; interleukin 6; amyloid A; amyloid P; D-dimer; prothrombin fragment 1 + 2) were assessed. RESULTS: Compared with continuation of ART, treatment interruption resulted in substantial declines in total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, and triglyceride, at month 1 but had little net effect on total/HDL cholesterol ratio [baseline-adjusted mean difference [95% confidence interval (CI)] interruption versus continuation arms: -0.10 (-0.59 to 0.38); P = 0.67]. ART interruption resulted in declines in total, large, and medium very low density lipoprotein (VLDL) particle concentrations (VLDL-p) and total and medium HDL-p. However, there was no change in small HDL-p [baseline-adjusted percentage difference between arms: -4.6% (-13.1%, +5.1% ); P = 0.35], small LDL-p [-5.0% (-16.9%, +8.6%); P = 0.45], or other LDL-p subclasses. Changes in lipid parameters on ART interruption did not differ according to baseline ART class (protease inhibitor versus non-nucleoside reverse transcriptase inhibitor) but were negatively associated both with changes in HIV viral load and with changes in inflammatory and coagulation markers, particularly D-dimer. CONCLUSIONS: These results suggest that ART interruption does not favorably influence overall lipid profile: there was little net effect on total/HDL cholesterol ratio, and no change in small LDL-p or small HDL-p, the lipoprotein particle subclasses most consistently linked to coronary risk. Short-term declines in lipid parameters after ART interruption were not associated with class of ART and may be linked to increases in viral replication, inflammation and coagulation.

Predicting the risk of cardiovascular disease in HIV-infected patients: the data collection on adverse effects of anti-HIV drugs study.

AIMS: HIV-infected patients receiving combination antiretroviral therapy may experience metabolic complications, potentially increasing their risk of cardiovascular diseases (CVDs). Furthermore, exposures to some antiretroviral drugs seem to be independently associated with increased CVD risk. We aimed to develop cardiovascular risk-assessment models tailored to HIV-infected patients. METHODS AND RESULTS: Prospective multinational cohort study. The data set included 22,625 HIV-infected patients from 20 countries in Europe and Australia who were free of CVD at entry into the Data collection on Adverse Effects of Anti-HIV Drugs Study. Using cross-validation methods, separate models were developed to predict the risk of myocardial infarction, coronary heart disease, and a composite CVD endpoint. Model performance was compared with the Framingham score. The models included age, sex, systolic blood pressure, smoking status, family history of CVD, diabetes, total cholesterol, HDL cholesterol and indinavir, lopinavir/r and abacavir exposure. The models performed well with area under the receiver operator curve statistics of 0.783 (range 0.642-0.820) for myocardial infarction, 0.776 (0.670-0.818) for coronary heart disease and 0.769 (0.695-0.824) for CVD. The models estimated more accurately the outcomes in the subgroups than the Framingham score. CONCLUSION: Risk equations developed from a population of HIV-infected patients, incorporating routinely collected cardiovascular risk parameters and exposure to individual antiretroviral therapy drugs, might be more useful in estimating CVD risks in HIV-infected persons than conventional risk prediction models.

Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D Study.

OBJECTIVE: To investigate any emerging trends in causes of death amongst HIV-positive individuals in the current cART era, and to investigate the factors associated with each specific cause of death. DESIGN: An observational multicentre cohort study. METHODS: All HIV-positive individuals included in one of the cohorts in the Data Collection on Adverse Events of Anti-HIV drugs (D:A:D) Study were included. The association between HIV-specific and non HIV-specific risk factors and death were studied using multivariable Poisson regression. RESULTS: We observed 2482 deaths in 180,176 person-years (PY) on 33,308 individuals [rate/1000 PY = 13.8 (95% CI 13.2-14.3)]. Primary causes of death were: AIDS (n = 743; rate/1000 PY = 4.12), liver-related (341; 1.89), CVD-related (289; 1.60), non-AIDS malignancy (286; 1.59). The overall rate of death fell from 16.9 in 1999/2000 to 9.6/ 1000 PY in 2007/2008. Smoking was associated with CVD and non-AIDS cancers, HBV and HCV co-infection with liver-related deaths, and hypertension with liver-related and CVD deaths. Diabetes was a risk factor for all specific causes of death except non-AIDS cancers, and higher current HIV RNA for AIDS-related deaths. Lower CD4 cell counts were associated with a higher risk of death from all specific causes of death. CONCLUSION: Multiple potentially modifiable traditional and HIV-specific risk factors for death of HIV-infected persons were identified. The maximum reduction in mortality in HIV-infected populations will require that each of these factors be appropriately addressed. No trends in terms of emerging causes of unexpected deaths were observed, although monitoring will continue.

High prevalence of the metabolic syndrome in HIV-infected patients: impact of different definitions of the metabolic syndrome.

INTRODUCTION: This study describes the characteristics of the metabolic syndrome in HIV-positive patients in the Data Collection on Adverse Events of Anti-HIV Drugs study and discusses the impact of different methodological approaches on estimates of the prevalence of metabolic syndrome over time. METHODS: We described the prevalence of the metabolic syndrome in patients under follow-up at the end of six calendar periods from 2000 to 2007. The definition that was used for the metabolic syndrome was modified to take account of the use of lipid-lowering and antihypertensive medication, measurement variability and missing values, and assessed the impact of these modifications on the estimated prevalence. RESULTS: For all definitions considered, there was an increasing prevalence of the metabolic syndrome over time, although the prevalence estimates themselves varied widely. Using our primary definition, we found an increase in prevalence from 19.4% in 2000/2001 to 41.6% in 2006/2007. Modification of the definition to incorporate antihypertensive and lipid-lowering medication had relatively little impact on the prevalence estimates, as did modification to allow for missing data. In contrast, modification to allow the metabolic syndrome to be reversible and to allow for measurement variability lowered prevalence estimates substantially. DISCUSSION: The prevalence of the metabolic syndrome in cohort studies is largely based on the use of nonstandardized measurements as they are captured in daily clinical care. As a result, bias is easily introduced, particularly when measurements are both highly variable and may be missing. We suggest that the prevalence of the metabolic syndrome in cohort studies should be based on two consecutive measurements of the laboratory components in the syndrome definition.

Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study.

BACKGROUND. The risk of myocardial infarction (MI) in patients with human immunodeficiency virus (HIV) infection has been assessed in 13 anti-HIV drugs in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. METHODS. Poisson regression models were adjusted for cardiovascular risk factors, cohort, calendar year, and use of other antiretroviral drugs and assessed the association between MI risk and cumulative (per year) or recent (current or in the past 6 months) use of antiretroviral drugs, with >30,000 person-years of exposure. RESULTS. Over 178,835 person-years, 580 patients developed MI. There were no associations between use of tenofovir, zalcitabine, zidovudine, stavudine, or lamivudine and MI risk. Recent exposure to abacavir or didanosine was associated with an increased risk of MI. No association was found between MI risk and cumulative exposure to nevirapine, efavirenz, nelfinavir, or saquinavir. Cumulative exposure to indinavir and lopinavir-ritonavir was associated with an increased risk of MI (relative rate [RR] per year, 1.12 and 1.13, respectively). These increased risks were attenuated slightly (RR per year, 1.08 [95% confidence interval {CI}, 1.02-1.14] and 1.09 [95% CI, 1.01-1.17], respectively) after adjustment for lipids but were not altered further after adjustment for other metabolic parameters. CONCLUSIONS. Of the drugs considered, only indinavir, lopinavir-ritonavir, didanosine, and abacavir were associated with a significantly increased risk of MI. As with any observational study, our findings must be interpreted with caution (given the potential for confounding) and in the context of the benefits that these drugs provide.

Lipoprotein particle subclasses, cardiovascular disease and HIV infection.

OBJECTIVE: To study the association of lipoprotein particles with CVD in a subgroup of HIV-infected patients who were enrolled in the Strategies for Management of Anti-Retroviral Therapy (SMART) study. SMART was a trial of intermittent use of ART (drug conservation [DC]) versus continuous of ART (viral suppression [VS]). METHODS: In a nested case-control study, lipoprotein particles (p) by nuclear magnetic resonance were measured at baseline and at the visit prior to the CVD event (latest levels) for 248 patients who had a CVD event and for 480 matched controls. Odds ratios (ORs) were estimated using conditional logistic models. RESULTS: Total, large and small HDL-p, but not VLDL-p nor LDL-p, were significantly and inversely associated with CVD and its major component, non-fatal coronary heart disease. The HDL-p associations with CVD were reduced after adjustment for high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer. Latest levels of total HDL-p were also significantly inversely associated with CVD; treatment interruption led to decrease of total HDL-p; adjusting for latest HDL-p did not explain the greater risk of CVD that was observed in the DC versus VS group. CONCLUSIONS: Lipoprotein particles, especially lower levels of small and large HDL-p identify HIV-infected patients at increased risk of CVD independent of other CVD risk factors.