The EuroSIDA study: 25 years of scientific achievements.

The EuroSIDA study was initiated in 1994 and follows adult people living with HIV (PLHIV) in 100 collaborating clinics across 35 countries covering all European regions, Israel and Argentina. The study aims to study the long-term virological, immunological and clinical outcomes of PLHIV and to monitor temporal changes and regional differences in outcomes across Europe. Annually collected data include basic demographic characteristics, information on AIDS- and non-AIDS-related clinical events, and details about antiretroviral therapy (ART), hepatitis C treatment and other medications, in addition to a range of laboratory values. The summer 2016 data set held data from a total of 23 071 individuals contributing 174 481 person-years of follow-up, while EuroSIDA's unique plasma repository held over 160 000 samples. Over the past 25 years, close to 300 articles have been published in peer-reviewed journals (h-index 52), covering a range of scientific focus areas, including monitoring of clinical and virological outcomes, ART uptake, efficacy and adverse events, the influence of hepatitis virus coinfection, variation in the quality of HIV care and management across settings and regions, and biomarker research. Recognizing that there remain unresolved issues in the clinical care and management of PLHIV in Europe, EuroSIDA was one of the cohorts to found The International Cohort Consortium of Infectious Disease (RESPOND) cohort consortium on infectious diseases in 2017. In celebration of the EuroSIDA study's 25th anniversary, this article aims to summarize key scientific findings and outline current and future scientific focus areas.

High rate of hepatitis C virus (HCV) recurrence in HIV-infected individuals with spontaneous HCV RNA clearance.

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.

Rates of cardiovascular disease following smoking cessation in patients with HIV infection: results from the D:A:D study(*).

OBJECTIVES: The aim of the study was to estimate the rates of cardiovascular disease (CVD) events after stopping smoking in patients with HIV infection. METHODS: Patients who reported smoking status and no previous CVD prior to enrolment in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study were included in this study. Smoking status is collected at each visit as current smoker (yes/no) and ever smoker (yes/no). Time since stopping smoking was calculated for persons who had reported current smoking during follow-up and no current smoking subsequently. Endpoints were: myocardial infarction (MI); coronary heart disease (CHD: MI plus invasive coronary artery procedure or death from other CHD); CVD (CHD plus carotid artery endarterectomy or stroke); and all-cause mortality. Event rates were calculated for never, previous and current smokers, and smokers who stopped during follow-up. Incidence rate ratios (IRRs) were determined using Poisson regression adjusted for age, sex, cohort, calendar year, family history of CVD, diabetes, lipids, blood pressure and antiretroviral treatment. RESULTS: A total of 27 136 patients had smoking status reported, with totals of 432, 600, 746 and 1902 MI, CHD, CVD and mortality events, respectively. The adjusted IRR of CVD in patients who stopped smoking during follow-up decreased from 2.32 within the first year of stopping to 1.49 after >3 years compared with those who never smoked. Similar trends were observed for the MI and CHD endpoints. Reductions in risk were less pronounced for all-cause mortality. CONCLUSION: The risk of CVD events in HIV-positive patients decreased with increasing time since stopping smoking. Smoking cessation efforts should be a priority in the management of HIV-positive patients.

A comparison of the long-term durability of nevirapine, efavirenz and lopinavir in routine clinical practice in Europe: a EuroSIDA study.

OBJECTIVES: The durability of combination antiretroviral therapy (cART) regimens can be measured as time to discontinuation because of toxicity or treatment failure, development of clinical disease or serious long-term adverse events. The aim of this analysis was to compare the durability of nevirapine, efavirenz and lopinavir regimens based on these measures. METHODS: Patients starting a nevirapine, efavirenz or lopinavir-based cART regimen for the first time after 1 January 2000 were included in the analysis. Follow-up started ≥ 3 months after initiation of treatment if viral load was <500 HIV-1 RNA copies/mL. Durability was measured as discontinuation rate or development/worsening of clinical markers. RESULTS: A total of 603 patients (21%) started nevirapine-based cART, 1465 (51%) efavirenz, and 818 (28%) lopinavir. After adjustment there was no significant difference in the risk of discontinuation for any reason between the groups on nevirapine and efavirenz (P=0.43) or lopinavir (P=0.13). Compared with the nevirapine group, those on efavirenz had a 48% (P=0.0002) and those on lopinavir a 63% (P<0.0001) lower risk of discontinuation because of treatment failure and a 31% (P=0.01) and 66% (P<.0001) higher risk, respectively, of discontinuation because of toxicities or patient/physician choice. There were no significant differences in the incidence of non-AIDS-related events, worsening anaemia, severe weight loss, increased aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels or increased total cholesterol. Compared with patients on nevirapine, those on lopinavir had an 80% higher incidence of high-density lipoprotein (HDL) cholesterol decreasing below 0.9 mmol/L (P=0.003), but there was no significant difference in this variable between those on nevirapine and those on efavirenz (P=0.39). CONCLUSIONS: The long-term durability of nevirapine-based cART, based on risk of all-cause discontinuation and development of long-term adverse events, was comparable to that of efavirenz or lopinavir, in patients in routine clinical practice across Europe who initially tolerated and virologically responded to their regimen.

Reasons for stopping antiretrovirals used in an initial highly active antiretroviral regimen: increased incidence of stopping due to toxicity or patient/physician choice in patients with hepatitis C coinfection.

Low adherence and toxicities among HIV-positive patients starting highly active antiretroviral therapy (HAART) can lead to discontinuation of therapy and treatment failure. Little is known about hepatitis C (HCV) status and discontinuation of HAART. Poisson regression was used to determine factors related to discontinuation of any part of an initial HAART regimen due to treatment failure (TF) or toxicities and patient/physician choice (TOX), and to investigate the relationship between HCV and discontinuation of a HAART regimen in 1198 patients staring HAART after 1999 from the EuroSIDA study. At 1 year after starting HAART, 70% of patients remained on their original regimen, 24% had changed, and 6% were off all treatment. The most frequent reason for discontinuation was toxicities (30.4%). There was no change over time in the proportion of patients discontinuing after stratification by reason for discontinuation (p = 0.18). Of patients 190 stopped at least one antiretroviral drug used in their initial HAART regimen due to toxicities; the toxicity reported did not vary according to HCV status (p = 0.90). Anti-HCV seropositive patients had a higher incidence of discontinuation due to TOX (IRR 1.46, 95% CI 1.13-1.88, p = 0.0042) compared to patients without HCV. Patients with HCV were more likely to discontinue all or part of their HAART regimens due to toxicity or patient/physician choice. Managing adverse events must remain a key intervention in maintaining HAART. There is a need for further studies to describe the relationship between HCV, specific antiretrovirals, and different treatment strategies.

The dynamics of local tissue damage induced by Bothrops asper snake venom and myotoxin II on the mouse cremaster muscle: an intravital and electron microscopic study.

The acute tissue damaging effects of Bothrops asper snake venom and a myotoxic Lys-49 phospholipase A2 (myotoxin II) on the mouse cremaster muscle were studied by intravital and electron microscopy. Both venom and myotoxin induced local contractions of the muscle fibres within 10-60 sec after exposure, which disappeared after 1-2 min. This observation is consistent with the hypothesis that Bothrops myotoxins act initially at the sarcolemma by affecting its permeability and allowing an influx of calcium. The venom also induced an early but transient vasoconstriction of arterioles. The development of edema was monitored using i.v. FITC-dextran as a marker. Plasma leakage started after about 2 min of exposure to venom or myotoxin, was extensive by 4-5 min, and originated from small venules and their adjoining capillary segments. The venom induced formation of thrombi and emboli in venules, but not in arterioles. Haemorrhage appeared after 4-6 min of exposure, the bleedings always originating from capillaries and small venules. The microbleedings were explosive, appearing as rapid bursts of erythrocytes into the extravascular space, and suggesting a per rhexis type of haemorrhage. This was confirmed by electron microscopy evaluation of the same microvessels observed intravitally, which showed erythrocyte extravasation through gaps in damaged endothelial cells. Other phenomena in the microcirculation included blood-flow disturbances, crenation and sphering of erythrocytes, and stasis with dense packing of cells in capillary networks. Muscle necrosis, caused by either venom or myotoxin, started 3-4 min after application. The first sign of damage in the fibres was the development of a narrow, transverse band with local loss of striation. This was followed by slow retraction of myofibrils until there was a complete transverse rupture of the fibre. This process was often repeated along the same fibre, leaving a row of fragments separated by spaces apparently devoid of myofibrillar material. The results confirm the rapid tissue damaging effects of B. asper venom, implying that potentially useful blocking agents must be administered early and have the ability to diffuse rapidly into the tissues.