Canio Martinelli

incidence of Adverse Reactions in Hiv Patients Treated With Protease Inhibitors: A Cohort Study

Objective: To assess the probability that protease inhibitor (PI) therapy might be discontinued because of adverse events (AE) and to evaluate the incidence rate of adverse reactions during PI treatment. Design: A prospective cohort, multicenter study on HIV‐positive patients starting treatment with at least one PI. Setting: Ten departments of infectious diseases in Northern Italy. Patients: A total of 1207 patients who started PI therapy in September 1997 and were consecutively observed up to April 1999. Main Outcome Measures: Adverse reactions following initiation of PI therapy, and time to therapy discontinuation due to AE. Results: During the study period, 35.9% patients presented adverse reactions of any grade, whereas 9.7% presented at least one serious AE. After 12 months of treatment, the percentage of patients who had interrupted treatment was 36% of ritonavir‐treated patients, 14.2% of those treated with indinavir, 13.6% of ritonavir‐saquinavir hard gel capsules (HGC)‐treated patients, and 8.5% and 2.1%, respectively, for those treated with nelfinavir and saquinavir HGC. Women and patients with hepatitis experienced a significantly greater number of adverse events compared with other categories. Gastrointestinal events were more frequently observed in patients treated with either ritonavir alone or in combination with saquinavir HGC, as well as in patients receiving nelfinavir, although in this group serious events were rare. Here again, neurologic, metabolic, and hepatic toxicity occurred more frequently in ritonavir and ritonavirsaquinavir HGC treated patients. Allergic reactions were more often observed in patients receiving nelfinavir. Indinavir‐treated patients presented the highest incidence of renal toxicity. Conclusion: Ritonavir is the drug associated with the largest number of reactions, which appear during the first few months of treatment. Saquinavir HGC and nelfinavir are the best tolerated drugs in a clinical setting.

Is metabolic syndrome associated to HIV infection per se? Results from the HERMES study.

HERMES is a prospective study, including all treatment-naïve patients attending scheduled visits at hospitals in the CISAI group in 2007. The present cross-sectional analysis aims to assess the baseline prevalence and characteristics of Metabolic Syndrome (MS) in a population of HIV-positive treatment-naïve patients. MS was diagnosed using the National Cholesterol Education Program (NCEP) definitions. A total of 292 subjects were enrolled, median age was 37 years, 75% of them were males. The prevalence of MS was 12.3%. The most frequent trio of abnormalities that led to the diagnosis of MS was high blood pressure, triglycerides and HDL. Univariate analysis showed that MS was associated with the following variables: age, education, physical activity, advanced HIV disease (CDC stage C or HIV-RNA >100,000 copies + CD4 <100 cells/mm(3)). Higher educational levels remained protectively associated with MS in multivariate analysis. A higher risk of MS was also associated with advanced HIV disease. Actually, treatment-naïve HIV-positive patients in an advanced stage of the disease have a higher prevalence of abnormal levels of triglycerides, HDL cholesterol and blood glucose than those at a less advanced stage. These findings of the HERMES study suggest, therefore, that HIV infection per se is associated to MS.

An italian approach to postmarketing monitoring : Preliminary results from the SCOLTA (surveillance cohort long-term toxicity antiretrovirals) project on the safety of lopinavir/ritonavir

The SCOLTA project (Surveillance Cohort Long-term Toxicity Antiretrovirals) is a system for online surveying of adverse reactions to recently commercialized antiretroviral drugs and a “sentinel” for unexpected and late adverse reactions arising during any antiretroviral treatment (available at: http://www.cisai.info). To date, 25 Italian departments of infectious diseases have participated at the project. The New Drugs Project is a prospective, multicenter, observational pharmacovigilance study involving 1 cohort of patients for each new drug. All patients who were consecutively started on lopinavir (LPV), tenofovir (TDF), peginterferon (IFN), atazanavir (ATZ), enfuvirtide (T-20), and tipranavir (TPV) were enrolled. All grade III or IV adverse events (according to the AIDS Clinical Trials Group definitions) are reported on the web site. The Unexpected Events Project identifies unexpected adverse reactions during treatment and reports them. This paper presents the preliminary findings for the New Drugs Project. Between October 1, 2002, and March 30, 2004, 1184 patients were enrolled. The lopinavir/ritonavir (LPV/r) cohort comprises 703 patients, the TDF cohort 585, IFN 35, ATZ 95, T-20 10, and TPV 8. So far 100 grades III and IV adverse events have been reported, 73 in the LPV/r group. In this cohort the rate of adverse events per 100 person-years was 14.2 on the basis of all patients treated, 9.8 for treatment-naive patients, and 15 for treatment-experienced patients. These findings, though preliminary, show that this data collection method gives timely real-life information from which to assess the impact of short- and long-term toxicity of new antiretroviral drugs.

Relations between cardiovascular risk estimates and subclinical atherosclerosis in naive HIV patients: results from the HERMES study.

Summary The aim of the study was to evaluate the cardiovascular risk factors associated with subclinical carotid atherosclerosis in antiretroviral therapy-naïve HIV-infected patients. The HERMES (HIV Exposure and Risk of Metabolic Syndrome) study enrolled therapy-naïve patients attending hospitals in the Italian coordination group for the study of allergies and HIV infection (CISAI [Coordinamento Italiano per lo Studio Allergia e Infezione da HIV]) in 2007. It was designed to identify metabolic syndrome (MS) and cardiovascular risk factors. The present analysis is a nested cross-sectional study with a subset of patients examined by carotid ultrasonography. Consecutive antiretroviral therapy-naïve HIV patients attending the facilities involved in the CISAI were included. Their 10-year probability of cardiovascular events was calculated using the Framingham Risk Score (FRS) and three other cardiovascular algorithms (the Global Framingham Risk Score – GFRS, ‘Progetto Cuore’ and ‘SCORE’). Vascular age was estimated using a new model derived from GFRS and was compared with chronological age. The diagnosis of MS was based on the National Cholesterol Education Programme and International Diabetes Federation (IDF) definitions. Subclinical atherosclerosis was determined as ultrasound carotid intima-media thickness >0.9 mm. Out of 140 patients enrolled in the HERMES study by the four centres participating in the nested study, a total of 72 (51.4%) subjects, with no overt cardiovascular disease, were examined using carotid ultrasonography. The median age was 40 years, 79.2% men. The vascular age was 7.6 years higher than the chronological age. The factors associated with subclinical atherosclerosis were age (P < 0.0001), vascular age (P = 0.0002), body mass index (P = 0.003), waist circumference (P = 0.0002), MS (IDF definition, P = 0.004) and all the cardiovascular (CV) models (FRS, P = 0.01, GFRS, P = 0.002, Progetto Cuore, P = 0.018, SCORE, P = 0.03). Independent of other significant factors, waist circumference was significantly associated with pathological results (P = 0.007). The GFRS (area under the receiver-operating characteristic curves, 0.78; P < 0.001) had slightly better predictive accuracy than the other three CV models (FRS, areas under the curve [AUC] = 0.71, P = 0.003; Progetto Cuore, AUC = 0.74, P = 0.0005; SCORE, AUC = 0.77, P < 0.0001); 55% of patients at intermediate risk (6–20%) had subclinical carotid lesions. Subclinical carotid lesions had a highly significant direct association with all the CV risk predictors. The GFRS and vascular age were highly predictive. We recommend a carotid ultrasonographic examination at least among HIV patients with GFRS >6% or with an elevated waist circumference.

Negative influence of HIV infection on day-night blood pressure variability.

Objective: An attenuation of the physiological day-night blood pressure (BP) reduction is an important predictor of cardiovascular (CV) events and death. We compared circadian BP profile in treatment-naive HIV-infected patients and in healthy control subjects. Methods: Fifty-two antiretroviral therapy-naive HIV-infected patients (85% men, age 39 ± 11 years, BP 125/78 ± 11/9 mm Hg) and 156 age- and BP-matched HIV-negative controls (85% men, age 39 ± 10 years, BP 125/78 ± 9/7 mm Hg) underwent 24-hour BP monitoring. Subjects with a nocturnal reduction of systolic BP <10% were defined as “nondippers.” Results: Nighttime BP was higher in HIV-infected subjects (113/69 ± 11/9 vs 109/67 ± 8/6 mm Hg, P = 0.008/0.005). Nocturnal systolic/diastolic BP reduction was 8.8/13.2% in HIV-positive patients and 11.7/17.2% in HIV negative (P = 0.002/0.001). The prevalence of “nondippers” was 35% and 15%, respectively (P = 0.003). In multivariate analysis, nocturnal systolic BP fall was negatively associated to HIV infection (β = −0.22, P = 0.001). HIV viral load, low CD4+ cell count, and AIDS progression risk were all related with a flattened day-night BP profile (P < 0.01). Conclusions: HIV infection per se negatively affects circadian BP rhythm. These findings, obtained in subjects without major CV risk factors and antiretroviral naive, suggest that day-night BP changes may play a role in the HIV-related increase in CV risk.

Raltegravir-based therapy in a cohort of HIV/HCV co-infected individuals

The relationship between hepatic tolerance and hepatitis C virus (HCV) co-infection has not been extensively studied in clinical practice. We assessed the efficacy and safety of raltegravir-based therapy in an Italian cohort of HIV/HCV co-infected patients. One hundred and forty patients with HIV/HCV co-infection initiating raltegravir from SCOLTA project (Surveillance Cohort Long-Term Toxicity Antiretrovirals) were examined. Of them, 43 were women, with mean age of 45.4±6.4years; 65 (46%) had undetectable HIV-RNA<50copies/mL and 75 (54%) HIV-RNA≥50copies/mL. According to CDC classification, 49 (35%) were in stage C. Based on Fib4 score at the time of starting raltegravir, patients were classified in class I in 41 cases, class II in 68 and in class III in 31 cases. Globally, the Fib4 score slightly decreased during 24months follow-up, from 2.2 to a value of 1.8. Hepatic adverse events of any grade were observed in 67 patients, of which only 2 cases (3%) had severe liver toxicity (grade 3-4). Only one patient had to discontinue the therapy because of adverse events. According to univariate analysis, being in CDC stage C represented a risk for the development of liver toxicity, with a hazard ratio (HR) of 2.27 (95% CI 1.06-4.84, P=0.033). None of the other variables considered (age, sex, years since detection of HIV and HCV-RNA detectable, years of previous HIV therapy, concomitant therapy with PI or NRTI, CD4+ cell count, Fib4, and transaminases level at baseline) resulted statistically correlated to the outcome. In conclusion, raltegravir-based regimens can be safely used in HCV infected patients; in this study, the hepatic toxicity has been found to be more frequent in patients with an advanced HIV disease (CDC stage C), independently of HIV-RNA suppression at raltegravir initiation.

Long-term efficacy of boosted and unboosted atazanavir-containing regimens: results from the SCOLTA Project

In this study we evaluated the efficacy of boosted and unboosted ATV in different regimens in a cohort of HIV-1 infected patients.

ADVERSE EFFECTS OF HIV INFECTION ON DAY-NIGHT BLOOD PRESSURE VARIABILITY: PP.14.29

Objective: An attenuation of the physiological day-night blood pressure (BP) reduction is an important predictor of cardiovascular events and death. Human immunodeficiency virus (HIV) infection has been linked with atherosclerotic cardiovascular complications, irrespective of antiretroviral therapy. It is unclear whether patients with HIV infection have an attenuated nocturnal BP reduction. Design: Cross-sectional case-control study, case:control matching ratio 1:3. Methods: Fifty-two antiretroviral therapy-naïve-HIV-infected patients (85% men, age 39 ± 11 years, BP 125/78 ± 11/9 mmHg) and 156 age- and BP-matched healthy controls (85% men, age 39 ± 10 years, BP 125/78 ± 9/7 mmHg) underwent 24-hour BP monitoring. Hypertension, diabetes, cardiovascular and renal disease, obesity, treatment with vasoactive drugs were exclusion criteria. Subjects with a nocturnal reduction of systolic BP <10% were defined as nondippers. Results: Average daytime BP did not differ in HIV and control subjects (124/80 ± 11/9 vs 124/79 ± 9/7 mmHg, p = n.s.). Nighttime BP was higher in HIV-infected subjects (113/69 ± 11/9 vs 109/67 ± 8/6 mmHg, p = 0.008/0.005). As shown in the Figure, nocturnal systolic/diastolic BP reduction was 8.8/13.2% in cases and 11.7/17.2% in controls (p = 0.002/0.001). The prevalence of nondippers was 35% in cases and 15% in controls (p = 0.003). In a multivariate analysis, nocturnal systolic BP fall was predicted by HIV infection (β=-0.22, p = 0.001). HIV viral load, low CD4 + cell count and AIDS progression risk were all related with a flattened day-night BP profile (p < 0.01). Conclusions: HIV infection per se influences negatively circadian BP rhythm. These findings, obtained in subjects without major cardiovascular risk factors and antiretroviral naive, suggest that day-night BP changes may play a role in HIV-related increase in cardiovascular risk. Figure 1. No caption available.