Timeliness of antiretroviral therapy initiation in the era before universal treatment.

We assessed the prevalence and factors related to the time to antiretroviral (ART) initiation among persons who entered HIV care and subsequently started ART in Croatia from 2005 to 2014. Included were patients ≥ 18 years, the follow-up ended on Dec/31/2017. 628 patients were included into the study 91.9% were men; median age was 36.1 (Q1-Q3: 29.6-43.8) years. Rapid (within 7 days of diagnosis) ART initiation was observed in 21.8% patients, 49.8% initiated ART within 30 days, 21.7% and 28.5% had intermediate (31 days-1 year) and late initiation (> 1 year), respectively. Of 608 patients that achieved an undetectable viral load, 94% had a plasma HIV-1 RNA < 50 copies/ml at last measurement after a median follow-up of 5.2 years. On quantile regression analysis, calendar year of entry into care, and markers of more advanced HIV disease (higher viral load, lower CD4 cell count and clinical AIDS) were significantly associated with earlier ART initiation. Early ART was not related to a gap in care afterwards at all quantiles. In conclusion, a significant proportion of patients started ART early in Croatia in 2005-2014. Early ART initiation led to durable viral load suppression and was not associated with a subsequent gap in care.

Cardiovascular markers of inflammation and serum lipid levels in HIV-infected patients with undetectable viremia.

Patients successfully treated for HIV infection still have an increased risk for cardiovascular morbidity and mortality, which might be related not only to traditional risks, but also to inflammation and dyslipidemia. We examined the relationship of serum lipid levels with plasma biomarkers of inflammation using a composite inflammatory burden score (IBS) based on individual (>75th percentile) measurements from the following seven markers: CD40L, tPA, MCP-1, IL-8, IL-6, hCRP and P-selectin. IBS was categorized as 0 (none of the biomarkers >75th percentile), 1, 2 and 3 or more scores. Correlations between the IBS and lipid parameters were examined by ordered logistic regression proportional odds models to estimate the odds of more elevated biomarkers. 181 male patients with undetectable HIV-viremia were included into the study. In the multivariate model, a one-unit increase (mmol/L) of total cholesterol and triglycerides was associated with a 1.41-fold (95% CI, 1.13-1.76) and 1.37-fold (95% CI, 1.18-1.60) increased odds of having a greater IBS, respectively. Those with an IBS score ≥1 compared to none had 2.14 (95% CI, 1.43-3.20) higher odds of having a one-unit increased total cholesterol/HDL-cholesterol ratio. In successfully treated HIV-infected persons dyslipidemia was associated with inflammation.

Comparison of four international cardiovascular disease prediction models and the prevalence of eligibility for lipid lowering therapy in HIV infected patients on antiretroviral therapy.

AIM: To compare four cardiovascular disease (CVD) risk models and to assess the prevalence of eligibility for lipid lowering therapy according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, European AIDS Clinical Society Guidelines (EACS), and European Society of Cardiology and the European Atherosclerosis Society (ESC/EAS) guidelines for CVD prevention in HIV infected patients on antiretroviral therapy. METHODS: We performed a cross-sectional analysis of 254 consecutive HIV infected patients aged 40 to 79 years who received antiretroviral therapy for at least 12 months. The patients were examined at the HIV-treatment centers in Belgrade and Zagreb in the period February-April 2011. We compared the following four CVD risk models: the Framingham risk score (FRS), European Systematic Coronary Risk Evaluation Score (SCORE), the Data Collection on Adverse Effects of Anti-HIV Drugs study (DAD), and the Pooled Cohort Atherosclerotic CVD risk (ASCVD) equations. RESULTS: The prevalence of current smoking was 42.9%, hypertension 31.5%, and hypercholesterolemia (>6.2 mmol/L) 35.4%; 33.1% persons were overweight, 11.8% were obese, and 30.3% had metabolic syndrome. A high 5-year DAD CVD risk score (>5%) had substantial agreement with the elevated (≥7.5%) 10-year ASCVD risk equation score (kappa=0.63). 21.3% persons were eligible for statin therapy according to EACS (95% confidence intervals [CI], 16.3% to 27.4%), 25.6% according to ESC/EAS (95% CI, 20.2% to 31.9%), and 37.9% according to ACC/AHA guidelines (95% CI, 31.6 to 44.6%). CONCLUSION: In our sample, agreement between the high DAD CVD risk score and other CVD high risk scores was not very good. The ACC/AHA guidelines would recommend statins more often than ESC/EAS and EACS guidelines. Current recommendations on treatment of dyslipidemia should be applied with caution in the HIV infected population.

Cardiovascular markers of inflammation and serum lipid levels in HIV-infected patients with undetectable viraemia.

INTRODUCTION: Successfully treated HIV-infected patients may still have an increased risk for cardiovascular morbidity and mortality, which might be related not only to traditional risks, but also to inflammation and dyslipidemia induced by HIV and/or antiretroviral therapy [1, 2]. We examined the relationship of serum lipid levels with plasma biomarkers of inflammation using a composite inflammatory burden score (IBS) from the following seven markers of inflammation: CD40L, tPA, MCP-1, IL-8, IL-6, hCRP and P-selectin. MATERIALS AND METHODS: Subjects were selected among consecutive HIV-infected males ≥18 years of age with an undetectable viral load (<50 copies/mL of HIV1-RNA), seen at the University Hospital for Infectious Diseases, Zagreb, Croatia, in the period from January 2012 to March 2013. Plasma inflammatory biomarkers (CD40L, tPA, MCP-1, IL-8, IL-6, hCRP and P-selectin, quantified by bead-based cytometry) >75th percentile were considered elevated and an IBS was constructed as the presence of zero, one, two, or three or more elevated biomarkers. Correlations between the IBS and lipid parameters were examined using Spearman's Rho and by ordered logistic regression proportional odds model to estimate the odds of more elevated (>75th percentile) biomarkers. RESULTS: 181 male patients were included into the study, the median age was 46.7 (Q1-Q3, 39.9-55.0) years and the median current CD4 cell count was 553.0 (Q1-Q3, 389-729) per microliter. The patients were mainly treated with two nucleoside reverse transcriptase inhibitor (NRTI) plus one non-NRTI (NNRTI) (N=100, 60.8%) or two NRTI plus lopinavir (N=50, 27.6%). There was a significant correlation between the IBS and serum cholesterol (Rho=0.23, 95% CI, 0.09-0.37), triglycerides (Rho=0.30, 95% CI, 0.16-0.42) and cholesterol/HDL-cholesterol ratio (Rho=0.25, 95% CI 0.11-0.38). In the multivariable model a one unit increase in cholesterol/HDL-cholesterol ratio was associated with a 1.72-fold (95% CI, 1.27-2.33) increased odds of having a greater IBS. One unit increase (mmol/L) of cholesterol and triglycerides was associated with a 1.41-fold (95% CI, 1.13-1.76) and 1.37-fold (95% CI, 1.18-1.60) increased odds of having a greater IBS, respectively. CONCLUSIONS: Our study suggests that in virologically suppressed patients there is a significant association between markers of inflammation and serum levels of cholesterol and triglycerides as well as the cholesterol/HDL-cholesterol ratio.

Prevalence and concordance of high cardiovascular disease scores in HIV/AIDS patients from Croatia and Serbia with four international algorithms.

INTRODUCTION: We evaluated cardiovascular risks in HIV-infected patients from Croatia and Serbia and the eligibility for statin therapy as recommended by the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, European AIDS Clinical Society (EACS) Guidelines and European Society of Cardiology and the European Atherosclerosis Society (ESC/EAS) guidelines for cardiovascular disease (CVD) prevention [1-3]. MATERIALS AND METHODS: A cross-sectional analysis of consecutive patients between 40 and 79 years old who had received antiretroviral therapy for at least 12 months was performed. RESULTS: Of 254 (132 from Croatia and 122 from Serbia) persons included in the study, 76% were male; median age was 49 years. Up to 51.6% of persons had a high CVD risk. The prevalence of current smoking was 42.9%, hypertension 31.5% and hypercholesterolaemia (>6.2 mmol/L) 35.4%. Statins would be recommended to 21.3% (95% CI, 16.3% to 27.4%) of persons by the EACS, 25.6% (95% CI, 20.2% to 31.9%) by ESC/EAS and 37.9% (95% CI, 31.6 to 44.6%) by the ACC/AHA guidelines. A high 5-year data collection on adverse effects of anti-HIV drugs study risk score (>5%) had a moderate agreement with the high (≥20%) 10-year CVD Framingham risk score (kappa=0.47) and high (≥5%) 10-year European systematic coronary risk evaluation score algorithm (kappa=0.47), and substantial agreement with the elevated (≥7.5%) 10-year Pooled Cohort Atherosclerotic CVD risk equation score (kappa=0.63). CONCLUSION: We found a high prevalence of CVD risks in patients from Croatia and Serbia. The ACC/AHA guideline would recommend statins more often than ESC/EAS and EACS guidelines.

Prevalence of HIV and sexually transmitted infections and patterns of recent HIV testing among men who have sex with men in Zagreb, Croatia.

OBJECTIVE: To determine the prevalence of HIV and other sexually transmitted infections (STIs) among men who have sex with men (MSM) in Zagreb, Croatia, and assess correlates of testing for HIV in the past 12 months. METHODS: The authors carried out a bio-behavioural survey using respondent-driven sampling (RDS) from September 2010 to February 2011. Participants completed a questionnaire and were asked to provide blood, urine, oropharyngeal and rectal swabs for the detection of infections. Data were analysed using RDS Analysis Tool 6.0.1 and STATA V.8.0. RESULTS: A total of 387 MSM were recruited at the University Hospital for Infectious Diseases. The age range of recruited men was 18-57 years. HIV prevalence was 2.8% (95% CI 1.1% to 5.1%) (3.6%, unadjusted), lower than that found in the first RDS survey carried out in 2006 (4.5%, 95% 2.2% to 7.3%) (4.9%, unadjusted). The seroprevalence of herpes virus type 2 was 5.9% (6.9, unadjusted) and that of syphilis measured by Treponema pallidum haemagglutination assay was 7.6% (6.7%, unadjusted). The authors found urethral and/or rectal infections with Chlamydia trachomatis in 7.2% (8.5%, unadjusted) of men and gonoccocal in 2.7% (2.1%, unadjusted). HIV testing in the past 12 months was reported by 32.7% (38.9%, unadjusted). In the multivariate analysis, significant correlates of recent HIV testing were having more than three partners in the past 12 months and the knowledge of HIV status of a regular partner. CONCLUSIONS: The results indicate that there might have not been a progression of an HIV and STI epidemic in the past 5 years among MSM in Croatia. Prevention should expand by providing better uptake of HIV and STI testing services, thus enabling timely treatment.

Frequency of HIV-1 viral load monitoring of patients initially successfully treated with combination antiretroviral therapy.

BACKGROUND: Although considered an essential tool for monitoring the effect of combination antiretroviral treatment (CART), HIV-1 RNA (viral load, VL) testing is greatly influenced by cost and availability of resources. OBJECTIVES: To examine whether HIV infected patients who were initially successfully treated with CART have less frequent monitoring of VL over time and whether CART failure and other HIV-disease and sociodemographic characteristics are associated with less frequent VL testing. METHODS: The study included patients who started CART in the period 1999-2004, were older than 18 years, CART naive, had two consecutive viral load measurements of <400 copies/ml after 5 months of treatment and had continuous CART during the first 15 months. The time between two consecutive visits (days) was the outcome and associated factors were assessed using linear mixed models. RESULTS: We analyzed a total of 128 patients with 1683 visits through December 2009. CART failure was observed in 31 (24%) patients. When adjusted for the follow-up time, the mean interval between two consecutive VL tests taken in patients before CART failure (155.2 days) was almost identical to the interval taken in patients who did not fail CART (155.3 days). On multivariable analysis, we found that the adjusted estimated time between visits was 150.9 days before 2003 and 177.6 in 2008/2009. A longer time between visits was observed in seafarers compared to non-seafarers; the mean difference was 30.7 days (95% CI, 14.0 to 47.4; p<0.001); and in individuals who lived more than 160 kilometers from the HIV treatment center (mean difference, 16 days, p = 0.010). CONCLUSIONS: Less frequent monitoring of VL became common in recent years and was not associated with failure. We identified seafarers as a population with special needs for CART monitoring and delivery.

Prevalence of sexually transmitted infections among men who have sex with men in Zagreb, Croatia.

We used respondent-driven sampling among men who have sex with men (MSM) in Zagreb, Croatia in 2006 to investigate the prevalence of HIV, other sexually transmitted infections and sexual behaviours. We recruited 360 MSM. HIV infection was diagnosed in 4.5%. The seroprevalence of antibodies to viral pathogens was: herpes simplex virus type-2, 9.4%; hepatitis A, 14.2%; hepatitis C, 3.0%. Eighty percent of participants were susceptible to HBV infection (HBs antigen negative, and no antibodies to HBs and HBc antigen). Syphilis seroprevalence was 10.6%. Prevalence of Chlamydia and gonorrhoea was 9.0%, and 13.2%, respectively. Results indicate the need for interventions to diagnose, treat and prevent sexually transmitted infections among this population.

Late presentation to care for HIV infection in Croatia and the effect of interventions during the Croatian Global Fund Project.

There are limited data on how HIV prevention interventions affect individuals presenting to care in settings with a low-level HIV epidemic. We examined whether interventions undertaken during the Croatian Global Fund Project in 2004-2006 had an influence on patients entering care. The number of men who have sex with men (MSM) presenting in 2004-2006 (n = 86) was 59% higher than in 2001-2003 (n = 54); in heterosexual patients the increase was 14% (n = 51 in 2001-2003; n = 58 in 2004-2006). MSM presented at a younger age (median 32 years) in 2004-2006 than in 2001-2003 (median 36 years). Late presentation to care was found in 28% of MSM and in 59% of heterosexual patients in 2004-2006. MSM were less frequently late presenters in 2004-2006 compared with 2001-2003 (odds ratio, 0.48; 95% confidence interval, 0.24 to 0.99; P = 0.046). Additional strategies for earlier initiation of care must be developed for MSM and particularly for heterosexual patients.

Marked improvement in survival among adult Croatian AIDS patients after the introduction of highly active antiretroviral treatment.

We compared the survival of patients following the first AIDS event in Croatia from the period 1986-1996 to the period 1997-2000. A total of 72 (81.8%) out of 88 patients from 1986-1996 and 18 (32.1%) out of 56 from 1997-2000 died. Survival following the first AIDS-defining illness markedly improved in the period 1997-2000 compared to the period 1986-1996 (adjusted Hazard Ratio (HR) for patients surviving more than 6 months: 0.11, 95% confidence interval (95% CI) = 0.04-0.29). A CD4+ cell count of < 100 x 10(6)/L was an independent risk factor for patients surviving up to 2 years (adjusted HR = 1.96, 95% CI = 1.1-3.43, p = 0.02). Patients with tuberculosis or fungal infections had a longer survival when compared to other diagnosis (adjusted HR = 0.53, 95% CI = 0.32-0.90, p = 0.01). However, despite dramatic survival benefit of combination antiretroviral therapy, mortality at six months following the first AIDS event was similar in the two study periods and the one-year probability of death was still substantial (27.2%) in the period 1997-2000.

Immune parameters in hemorrhagic fever with renal syndrome during the incubation and acute disease: case report.

We describe immune parameters in a Croatian soldier who presented with mild flu-like symptoms and interstitial inflammatory infiltrate in the lungs on an X-ray during the incubation phase of hemorrhagic fever with renal syndrome (HFRS). Enzyme-linked immunosorbent assay (ELISA) IgM and polymerase chain reaction (PCR) were negative. Two weeks later, he developed HFRS caused by the Puumala virus. We performed two-color immunofluorescence cytometry with monoclonal antibodies identifying the activation markers on T cells. Serum samples were also examined by enzyme immunoassay (EIA) for the presence of interleukins IL-2 and IL-6 and their soluble receptors (sR). The analysis of early and late activation markers during the period of incubation revealed a small increase in the percentage of helper (CD4+CD25+) T cells and no significant increase in total activated (HLA-DR+TCR+) and cytotoxic (CD8+CD71+) T cells as compared with healthy controls. In the serum, only the concentration of soluble IL-6 receptor was increased. However, when the patient developed HFRS, all activation markers on T cells increased. Concentrations of sIL-2Ralpha and IL-6 remained increased two and six days after HFRS onset, respectively, whereas sIL-6R increased six days after HFRS onset. IL-2 concentration did not change. Our case indicates that rapid, modern diagnostic tools are necessary in the diagnosis of infectious diseases and their differential diagnosis. Immunological tests, which provide information on the patient immune status and especially on early changes in immune parameters, may contribute to the improvement of the diagnosis, prognosis, and therapy of HFRS.

[Hepatitis E in tourists to India]. / Hepatitis E kod putnika u Indiju.

Hepatitis E (HE) is a serious problem in developing countries worldwide, affecting in epidemics or as sporadic cases millions of people. Hepatitis E virus (HEV) is the main cause of enterically transmitted acute viral hepatitis, especially in tropic and subtropic areas. We presented two patients, our citizens who traveled to India, and contracted HE. The source of infection was contaminated drinking water in both of them. The diagnosis of HE was confirmed by the finding of anti-HEV antibodies of class IgG and IgM (ELISA) in acute phase, and by dissappearing of IgM anti-HEV in convalescent period. Thus, these patients are the first documented cases of imported sporadic HE in Croatia.