Incidence of cardiovascular events in HIV-positive patients compared to general population over the last decade: a population-based study from 2000 to 2012.

Cardiovascular diseases are currently a main cause of death among people living with HIV. This population-based study aimed to investigate the incidence of cardiovascular events (CVEs) in HIV-positive people and factors associated with CVEs. We performed a retrospective cohort study of the HIV-infected patients residing in the Local Health Authority of Brescia, northern Italy, from 2000 to 2012. Incidence of CVEs events in HIV-positive patients was compared with that expected in general population living in the same area, computing standardized incidence ratios (SIRs). CVEs-associated risk factors were assessed using Cox regression analysis and competing risk model of death. About 3766 HIV-infected patients were included in the study. Over the 12-year-period, we recorded 134 CVEs: 83 (61.9%) acute myocardial infarctions (CVE type-1), and 51 (38.1%) strokes (CVE type-2). A twofold increased risk (SIR = 2.02) of CVEs was found in HIV-infected patients compared to the general population. Notably, within male patients: for CVE type-1, SIR = 1.89, for CVE type-2 SIR = 2.25; within female patients: for CVE type-1, SIR = 2.91, for CVE type-2 SIR = 2.07. Age >45 years, male gender, diabetes, and total blood cholesterol >200 mg/dl were significantly associated with CVEs incidence (for all, p < .05). These results were confirmed using the competing risk model. Our cohort study confirmed the higher incidence of CVEs in HIV-positive patients, and put emphasis on the importance of traditional cardiovascular risk factors. Overall CVE risk in HIV-positive patients was twice as high as CVE risk in general population. We found a peculiar gender distribution, with a relative risk for CVE type-1 higher in HIV-positive females, and a higher CVE type-2 risk in male patients. More studies are needed in order to support these findings and to further highlight possible gender differences in the risk of developing CVEs in HIV-positive patients.

The burden of chronic diseases and cost-of-care in subjects with HIV infection in a Health District of Northern Italy over a 12-year period compared to that of the general population.

BACKGROUND: The increase in life expectancy of HIV-infected patients has driven increased costs due to life-long HIV treatment and concurrent age-related comorbidities. This population-based study aimed to investigate the burden of chronic diseases and health costs for HIV+ subjects compared to the general population living in Brescia Local health Agency (LHA) over a 12-year period. METHODS: LHA database recorded diagnoses, deaths, drug prescriptions and health resource utilization for all residents during 2003-2014. We estimated HIV prevalence and incidence, HIV-related mortality as well as prevalence of chronic diseases in HIV+ subjects. Observed/expected ratio of chronic diseases was calculated by indirect standardization with the general population as reference. Direct cost of HIV care and determinants were estimates across the period. RESULTS: HIV prevalence increased from 220 to 307 per 100 000 person-years while incidence decreased from 16.1 to 10.8 per 100 000 person-years from 2003 to 2014. Prevalence of most comorbidities increased over time but it reduced significantly (annual mean change - 0.7 %) when adjusting for age and gender. Observed to expected ratio for each chronic disease in HIV+ subjects decreased over time. Cost of HIV+ cures increased (+25 %) mainly due to cost for drugs (+50 %) but it stabilized in recent years. CD4+ cell count at the time of diagnosis was an important predictor of cost for HIV management. CONCLUSIONS: Expenditures for HIV-infection are driven mainly by drugs cost and they have increased overtime. However, our findings suggest that spending on public health for HIV care can improve prognosis of HIV-infected patients, reduce transmission of HIV infection and reduce the global burden of chronic diseases, leading to a reduction of HIV global cost in the medium-long time.

The prognostic role of systemic inflammatory markers on HIV-infected patients with non-Hodgkin lymphoma, a multicenter cohort study.

BACKGROUND: The systemic inflammatory response has been postulated as having prognostic significance in a wide range of different cancer types. We aimed to assess the prognostic role of inflammatory markers on survival in HIV-infected patients with Non-Hodgkin Lymphoma (NHL), and to compute a prognostic score based on inflammatory biomarkers. METHODS: We evaluated data on HIV patients with NLH diagnosis between 1998 and 2012 in a HIV Italian Cohort. Using Cox proportional regression model, we assessed the prognostic role of Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR), Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), Prognostic Index (PI), and Prognostic Nutritional Index (PNI). We also computed a risk score equation, assigning patients to a derivation and a validation sample. The area under the curve (AUC) was use to evaluate the predictive ability of this score. RESULTS: 215 non-Hodgkin lymphoma cases (80.0% males) with a mean age of 43.2 years were included. Deaths were observed in 98 (45.6%) patients during a median follow up of 5 years. GPS, mGPS, PI and PNI were independently associated with risk of death. We also computed a mortality risk score which included PNI and occurrence of an AIDS event within six months from NHL diagnosis. The AUCs were 0.69 (95% CI 0.58 to 0.81) and 0.69 (95% CI 0.57 to 0.81) at 3 and 5 years of the follow-up, respectively. CONCLUSIONS: GPS, mGPS, PI and PNI are independent prognostic factors for survival of HIV patients with NHL.

[A population-based database to study malignancies in HIV-infected patients in the Local Health Unit of Brescia (Northern Italy), period 1999-2009]. / Creazione di un database integrato per lo studio dei tumori maligni nei pazienti con infezione da HIV nell'ASL di Brescia nel periodo 1999-2009.

OBJECTIVE: to complete the database of all patients infected by the human immunodeficiency virus (HIV) who lives in the area belonging to the Local Health Unit (ASL) of Brescia, Northern Italy,with all the cancers diagnosed in the period 1999-2009. DESIGN: diagnoses of cancer between 1999 and 2009 registered in the electronic database in use in the Clinic of Infectious and Tropical Diseases (source A) for the clinic follow-up of HIV-infected patients were checked. Then, the cases were integrated with the data recorded in the ASL database (source B) and in the Cancer Registry of Brescia (source C). SETTING AND PARTICIPANTS: all HIV-infected patients belonging to the ASL of Brescia followed-up in the Clinic of Infectious and Tropical Diseases of Brescia. MAIN OUTCOME MEASURES: in the database were included all HIV-positive patients who had a diagnosis of cancer between 1999 and 2009. The diagnosis of cancer had to be present at least in two of the three sources considered; if it was recorded only in one of them, the source had to be an histological document or confirmed directly by the patient him/herself. RESULTS: from the sourceA, 339 diagnoses of cancer were recorded, then other 82 records from the sources B and C were added, achieving a total of 421 cancers, belonging to 391 different patients. Half of the diagnoses was present in all the three sources considered. Among the AIDS-defining cancers (No. 200; 47.5%), Kaposi's sarcoma and non-Hodgkin lymphoma were the most frequent diagnosed tumours (22.8% and 22.33%, respectively). Among the non-AIDS-defining cancers (No. 221; 52.5%), malignancies of the skin other than melanoma (No. 41; 9.74%), tumours of the liver (No. 34; 8.08%) and Hodgkin lymphoma (No. 31; 7.36%) were the most frequent tumours. CONCLUSIONS: the database of all HIVpositive patients, including the diagnoses of cancer between 1999 and 2009, represents an important instrument, not only for the clinical practice: collecting clinical and sociodemographics characteristics of these patients, it would be possible to perform clinical and epidemiological studies.

Discharge ward during the SARS-CoV-2 pandemic: an effective way to increase patient turnover when human resources are scarce.

During the SARS-CoV-2 pandemic, the province of Brescia (Italy) had a significant number of COVID-19 cases, which led to a subversion of the ordinary structure of the university hospital ASST Spedali Civili, driven by the need to hospitalize as many patients as possible in a narrow period of time. At the peak of the epidemic, a rapid hospitalization discharge area, the Discharge Ward (DW), was set up with the aim of facilitating the rapid turnover of patients in the wards where the most severe patients had to be hospitalized. The organization and activities carried out are described in the results of this reproducible experience during epidemic events.

Prevalence and risk factors for etravirine resistance among patients failing on non-nucleoside reverse transcriptase inhibitors.

BACKGROUND: Prevalence and factors associated with etravirine (EW) resistance mutations among patients failing on first-generation non-nucleoside reverse transcriptase inhibitors (NNRTI) merit investigation. METHODS: The study comprised an analysis of all sequential patients attending the Institute of Infectious Diseases (Brescia, northern Italy) who performed a genotypic resistance testing (GRT) after > or =3 months of a stable NNRTI-based regimen between 2001 and 2006. Multivariable ordinal logistic regression analysis was performed to assess predictors of ETV resistance mutations. RESULTS: Out of 248 strains, 153 (61.7%) harboured > or =1 ETV resistance mutations. In particular, 88 (35.5%), 53 (21.4%) and 12 (4.8%) harboured one, two and three mutations, respectively. The most frequent mutations were G190A (230%), Y181C (23%) and K101E (14.1%). Use of nevirapine (odds ratio [OR] 2.73; 95% confidence level [CI] 1.62-4.62; P<0.001) and a longer time frame between first HIV RNA >500 copies/ml and GRT (per month, OR 1.05; 95% CI 1.01-1.09; P=0.012) were associated with a greater number of ETV resistance mutations. Conversely, higher CD4+ T-cell counts at nadir (per 100 cells/mm3, OR 0.81; 95% CI 0.67-0.98; P=0.029) and use of lamivudine/emtricitabine (OR 0.57; 95% CI 0.37-0.87; P=0.009) were protective. Accumulation of ETV resistance-associated mutations was demonstrated by sequential GRT in 4/35 patients (all treated with nevirapine). CONCLUSIONS: Mutations associated with ETW resistance were common among patients failing on NNRTI, but prevalence of viral strains harbouring three mutations was low. Use of efavirenz and co-administration of lamivudine reduced the risk of ETW resistance. The continued use of the current NNRTI in a failing regimen may select for additional resistant variants.

Analysis of severe hepatic events associated with nevirapine-containing regimens: CD4+ T-cell count and gender in hepatitis C seropositive and seronegative patients.

BACKGROUND: Nevirapine-containing regimens have been associated with a risk of significant elevations of liver transaminase levels. Higher risk in antiretroviral-naive populations has been related to gender and CD4+ T-cell count (women with CD4+ T-cell counts of > or =250/mm(3) or men with CD4+ T-cell counts of > or =400/mm(3), i.e. group at risk). However, recent studies do not confirm this association in HIV populations comprising patients who are antiretroviral-experienced. Moreover, the predictive value of gender and CD4+ T-cell count on the risk of raised transaminase levels has been poorly investigated in populations of patients co-infected with hepatitis C virus (HCV). METHODS: Analysis of HIV-positive patients receiving nevirapine-containing regimens for the first time was conducted. Grade > or =III hepatotoxicity (i.e. > or =5 x upper limit of normal in alanine aminotranferase or aspartate aminotransferase levels) was the primary endpoint. Univariate and multivariable Cox proportional hazard regression models were separately conducted among HCV-antibody (Ab)-positive and HCV-Ab-negative patients. RESULTS: Amongst 905 patients, 49% were HCV-Ab-positive and 79% were antiretroviral-experienced. Grade > or =III liver transaminase elevations developed in 7.1% of patients, accounting for an incidence of 2.47 (95% CI 1.97, 3.09) per 100 patient-years of follow-up. HCV-Ab reactivity was associated with a 3-fold increase in risk of developing relevant liver transaminase elevations (95% CI 1.75, 5.3; p < 0.001), whereas gender and CD4+ T-cell count did not impact significantly. When analysis was performed in HCV-Ab-negative patients, the outcome was independently correlated with the group at risk (hazard ratio [HR] 3.66; 95% CI 1.20, 11.14; p = 0.022). By contrast, in HCV-Ab-positive patients, the group at risk was not significantly associated with the outcome. CONCLUSIONS: Most of the excess rates of relevant raised transaminase levels in patients prescribed nevirapine-containing regimens could be attributed to HCV co-infection. Gender and CD4+ T-cell count appeared to have a statistically significant impact on the risk of relevant transaminase level elevations in HCV-negative, but not in HCV-positive patients, probably due to a diluting effect of HCV. Incidence of hepatic events after nevirapine-containing regimens did not appear to be a major concern in our cohort of patients who were mainly antiretroviral-experienced and negative for HCV-Ab. Preferably, nevirapine should be avoided in HCV co-infected patients and in males with CD4+ T-cell counts of > or =400/mm(3) or females with CD4+ T-cell counts of > or =250/mm(3).

Influence of hepatitis C genotypes on lipid levels in HIV-positive patients during highly active antiretroviral therapy.

BACKGROUND: The independent role of HCV genotype 3 (HCV-3) in dyslipidaemia following highly active antiretroviral therapy (HAART) is still unexplored. METHODS: Analysis of data from a cohort of 307 HIV/HCV-coinfected patients and 415 HIV-monoinfected controls was conducted. Patients with available lipid levels at baseline and minimum 3-month follow-up were ranked into three groups by HCV status (HCV-3, other HCV genotypes or HCV negative). Univariate and multivariate GEE models were performed to assess factors correlated with lipid serum levels as coefficient (Coef., defined as mean difference [mg/dl] across the follow-up). Univariate and multivariate logistic regression analyses were performed for prediction of relevant hypertriglyceridaemia (> or = 500 mg/dl) and relevant hypercholesterolaemia (> or = 240mg/dl) at 3 months of follow-up. RESULTS: HCV-3 correlated with lower triglyceridaemia (Coef.=-38.22; P=0.001), independently from the other considered variables, including age, gender and use of stavudine or lopinavir. Even though HCV infection per se appeared to be protective, HCV-3 in particular was also independently associated with lower cholesterolaemia (Coef.=-46.35; P<0.001). At logistic regression analyses, HCV-3, but not HCV-non-3, was associated with lower risk of relevant hypercholesterolaemia (odds ratio [OR] 0.06; P=0.01) and relevant hypertriglyceridaemia (OR 0.11; P=0.05), independently from other considered variables. CONCLUSIONS: Our data confirm that HCV coinfection per se is associated with lower risk of hypercholesterolaemia after HAART. This effect was particularly attributed to HCV-3, which was the only genotype associated with lower triglyceridaemia during HAART.

Impact of lamivudine on the risk of liver-related death in 2,041 HBsAg- and HIV-positive individuals: results from an inter-cohort analysis.

BACKGROUND: The impact of lamivudine (3TC) as part of combination antiretroviral therapy (cART) on the risk of liver-related death (LRD) in HIV/hepatitis B virus (HBV)-coinfected patients has not been extensively studied. METHODS: We performed an analysis involving HIV/HBV-coinfected patients in 13 cohorts who initiated cART. The end-point was LRD--that is, death with concomitant decompensated liver disease (DLD) or hepatocellular carcinoma--as the main cause. Incidence rates of LRD after initiation of cART were expressed as number of events per 100 person-years of follow-up (PYFU). A Poisson regression model adjusted for cohort, gender, mode of HIV transmission, CD4+ T-cell count at cART initiation, liver disease pre-cART, duration of 3TC before cART, and hepatitis C virus was used to assess the association between use of 3TC and risk of LRD. RESULTS: We analysed 2,041 patients. Follow-up after starting cART was 7,648 PYFU (5,569 spent on 3TC-containing regimens) with a median per person of 48 months (range: 2-91). Of the total, 217 subjects died; 57 deaths were liver-related resulting in a rate of 7.5 per 1,000 PYFU [95% confidence intervals (CI): 5.6-9.7]. The relative risk of LRD per extra year of 3TC use was 0.73 (95% CI: 0.59-0.90, P = 0.004). CONCLUSION: The use of 3TC was associated with a reduced risk of LRD over 4 years of follow-up. This study supports the current view that the use of 3TC as part of cART should be considered in patients who are tested positive for HBsAg.

Expression of interleukin-15 and interleukin-15Rα in monocytes of HIV type 1-infected patients with different courses of disease progression.

Interleukin-15 (IL-15) enhances the effector mechanisms of anti-HIV immune responses and thus is considered a potential adjuvant of HIV-1 vaccine. However, there are a lack of data concerning the relationships between IL-15 expression and regulation in HIV-1-infected patients and the course of disease progression. We found that IL-15, but not IL-15Rα, is expressed at significantly higher levels in the CD14(+) monocytes [stimulated or not with interferon (IFN)-γ] of long-term nonprogressors (LTNP) than in those of HIV-1 progressors or healthy controls. There was no between-group difference in the amounts of soluble IL-15 released from the cells. We also found that like the healthy controls, the LTNP expressed the IL-15 and IL-15Rα genes in a more coordinated manner than the progressors. Our findings show that there are significant differences in IL-15 expression between patients with different courses of HIV infection, and that the coordinated expression of the IL-15 and IL-15Rα genes is dysregulated in patients with progressive disease. They also provide important information concerning the mechanisms of infection and the potential use of IL-15 as a therapeutic agent.

Updated prevalence of genotypic resistance among HIV-1 positive patients naïve to antiretroviral therapy: a single center analysis.

Continuous surveillance of HIV primary resistance mutations is highly important due to their potential clinical impact. All patients naïve to antiretrovirals who had > or =1 genotypic resistance testing at the Institute of Infectious Diseases (Brescia, Northern Italy) between 2001 and 2006 were analyzed. Primary resistance mutations were defined using epidemiological and clinical criteria. Mutations were interpreted using the Stanford University Algorithm. Logistic regression analysis was used to assess possible predictors of primary resistance mutations. Among 569 patients, 11% presented > or =1 mutation. Prevalence of primary resistance mutations to nucleoside reverse-transcriptase inhibitors (NRTI), non-nucleoside reverse-transcriptase inhibitors (NNRTI), and protease inhibitors (PI) was 6.3%, 6%, and 1.6%, respectively. The most frequent mutations to NRTI were substitutions at position 215 (215Y in 3 patients, and 215 revertants in 16), 41L (13), 219Q (12), and 210W (10). Among mutations to NNRTI, 103N was found in 21 patients, while 181C, 188L, and 190A/S in 8, 3, and 4 patients, respectively. Fifty-one patients (9%) had high-to-intermediate resistance to > or =1 antiretroviral drug before starting the treatment. Regarding the new generation drugs, nine patients had intermediate resistance to etravirine, five patients had intermediate resistance to tipranavir, while five, one, and seven patients had low resistance to etravirine, tipranavir, and darunavir. Homosexuals were more likely to harbor a virus with primary resistance mutations (OR:2.68; 95% CI:1.44-5.00; P = 0.002) while non-Italian nationality was protective (OR:0.38; 95% CI:0.17-0.86; P = 0.020). Prevalence of primary resistance mutations suggests that genotypic resistance testing should be performed before starting treatment in naïve patients in Italy, particularly when NNRTI are prescribed.

Exploratory analysis for the evaluation of lopinavir/ritonavir-versus efavirenz-based HAART regimens in antiretroviral-naive HIV-positive patients: results from the Italian MASTER Cohort.

OBJECTIVE: This retrospective longitudinal cohort study compared the virological and immunological responses to highly active antiretroviral therapy containing either efavirenz or lopinavir/ritonavir in previously antiretroviral-naive HIV-infected patients. PATIENTS AND METHODS: A total of 472 patients were selected (348 efavirenz and 124 lopinavir/ritonavir). The primary endpoint of this study was virological success (HIV RNA <50 copies/mL). The immunological response was assessed on the basis of either CD4+ T cell count variations (absolute and percentage) with respect to baseline values or categorical endpoints (defined as either a CD4+ T cell increase of > or =1;50 cells/mm(3) at week 24 or of > or =1;75 cells/mm(3) at week 48). RESULTS: At intention-to-treat (ITT) analysis, the adjusted odds ratio of virological success for patients who started lopinavir/ritonavir, compared with those who started efavirenz, was 0.54 (95% CI: 0.33-0.89, P = 0.016) at week 24 and 0.40 (95% CI: 0.33-0.89, P = 0.002) at week 48. However, patients receiving lopinavir/ritonavir had a more pronounced CD4+ T cell recovery, demonstrating both a mean absolute and percentage increase up to week 48 (MANOVA P < 0.0001). CONCLUSIONS: Although comparisons of drug efficacy in non-randomized studies should be viewed with caution, from a virological point of view efavirenz-containing regimens performed as well (on-treatment analysis) or better (ITT analysis) than those containing lopinavir/ritonavir. In contrast, immunological outcome appeared to favour lopinavir/ritonavir.

A randomized, controlled trial of triple antiviral therapy as initial treatment of chronic hepatitis C in HIV-infected patients.

BACKGROUND/AIMS: Interferon and ribavirin combination therapy for chronic hepatitis C induces a low response rate in human immunodeficiency virus (HIV) infected patients. To assess the impact of intensification of interferon administration and of the addition of amantadine on the efficacy and safety of standard anti-hepatitis C virus (HCV) treatment in HIV-infected patients. METHODS: Multicentre, prospective, open-label, randomized, phase III clinical trial. Eighty co-infected patients were randomized to receive ribavirin 800-1,000 mg/day in combination with, group A: interferon alpha 2a 3MIU thrice weekly; group B: IFN alpha 2a 3MIU daily, plus amantadine 200 mg/day; treatment duration was 24-48 weeks according to HCV genotype. RESULTS: Forty-one patients were randomized in group A and 39 in group B. Intention-to-treat analysis showed a sustained virological response, defined as HCV-RNA negativization, 6 months after stopping treatment in 22% of patients from group A and 13% from group B (P>0.05). The lack of a 2-log drop in HCV-RNA levels after 12 weeks of treatment showed a 100% predictive value of lack of sustained response. CONCLUSIONS: Amantadine addition and interferon intensification do not improve the low efficacy of combination of interferon alfa plus ribavirin in HIV/HCV co-infected patients. Patients with no early virologic response did not have any probability of sustained response.