Maraviroc Intensification Modulates Atherosclerotic Progression in HIV-Suppressed Patients at High Cardiovascular Risk. A Randomized, Crossover Pilot Study

Background Experimental CCR5 antagonism with maraviroc in atherosclerosis-prone mice and preliminary data in humans suggest an anti-atherosclerotic effect of the drug. We assessed the impact of maraviroc treatment in persons living with HIV on subclinical indicators of atherosclerosis. Methods Persons living with HIV on effective antiretroviral therapy (ART) including only protease inhibitors were recruited if they had a Framingham risk score >20% and brachial flow-mediated dilation (bFMD) <4%, as indices of high cardiovascular risk. Maraviroc (300 mg per os for 24 weeks) was administered, in addition to ongoing ART, to all patients using a crossover design. Brachial FMD, carotid-femoral pulse wave velocity (cfPWV), and carotid intima-media thickness (cIMT) were measured as markers of atherosclerosis. Vascular competence—as expressed by the ratio of circulating endothelial microparticles (EMPs) to endothelial progenitor cells (EPCs)—and markers of systemic inflammation and monocyte and platelet activation were assessed. Results Maraviroc treatment significantly improved bFMD, cfPWV, and cIMT by 66%, 11%, and 13%, respectively (P = .002, P = .022, P = .038, respectively). We also found a beneficial effect of maraviroc on the EMP/EPC ratio (P < .001) and platelet/leucocyte aggregates (P = .013). No significant changes in markers of systemic inflammation, monocyte activation, and microbial translocation were observed. Conclusions Maraviroc led to significant improvements in several markers for cardiovascular risk, endothelial dysfunction, arterial stiffness, and early carotid atherosclerosis, which was accompanied by an increase of vascular competence, without seeming to affect systemic inflammation. Our data support the need for larger studies to test for any effects of maraviroc on preventing atherosclerosis-driven pathologies

Discovery of a AHR pelargonidin agonist that counter-regulates Ace2 expression and attenuates ACE2-SARS-CoV-2 interaction

The severe acute respiratory syndrome (SARS)-CoV-2 is the pathogenetic agent of Corona Virus Induced Disease (COVID)19. The virus enters the human cells after binding to the angiotensin converting enzyme (ACE)2 receptor in target tissues. ACE2 expression is induced in response to inflammation. The colon expression of ACE2 is upregulated in patients with inflammatory bowel disease (IBD), highlighting a potential risk of intestinal inflammation in promoting viral entry in the human body. Because mechanisms that regulate ACE2 expression in the intestine are poorly understood and there is a need of anti-SARS-CoV-2 therapies, we have settled to investigate whether natural flavonoids might regulate the expression of Ace2 in intestinal models of inflammation. The results of these studies demonstrated that pelargonidin activates the Aryl hydrocarbon Receptor (AHR) in vitro and reverses intestinal inflammation caused by chronic exposure to high fat diet or to the intestinal braking-barrier agent TNBS in a AhR-dependent manner. In these two models, development of colon inflammation associated with upregulation of Ace2 mRNA expression. Colon levels of Ace2 mRNA were directly correlated with Tnf-α mRNA levels. Molecular docking studies suggested that pelargonidin binds a fatty acid binding pocket on the receptor binding domain of SARS-CoV-2 Spike protein. In vitro studies demonstrated that pelargonidin significantly reduces the binding of SARS-CoV-2 Spike protein to ACE2 and reduces the SARS-CoV-2 replication in a concentration-dependent manner. In summary, we have provided evidence that a natural flavonoid might hold potential in reducing intestinal inflammation and ACE2 induction in the inflamed colon in a AhR-dependent manner

Clusterization of co-morbidities and multi-morbidities among persons living with HIV: a cross-sectional study

Background: Among people living with HIV (PLWH), the prevalence of non-HIV related co-morbidities is increasing. Aim of the present study is to describe co-morbidity and multi-morbidity, their clustering mode and the potential disease-disease interactions in a cohort of Italian HIV patients. Methods: Cross-sectional analysis conducted by the Coordinamento Italiano per lo Studio di Allergia e Infezioni da HIV (CISAI) on adult subjects attending HIV-outpatient facilities. Non-HIV co-morbidities included: cardiovascular disease, diabetes mellitus, hypertension, oncologic diseases, osteoporosis, probable case of chronic obstructive pulmonary disease (COPD), hepatitis C virus (HCV) infection, psychiatric illness, kidney disease. Multi-morbidity was defined as the presence of two or more co-morbidities. Results: One thousand and eighty-seven patients were enrolled in the study (mean age 47.9 \ub1 10.8). One hundred-ninety patients (17.5%) had no co-morbidity, whereas 285 (26.2%) had one condition and 612 (56.3%) were multi-morbid. The most recurrent associations were: 1) dyslipidemia + hypertension (237, 21.8%); 2) dyslipidemia + COPD (188, 17.3%); 3) COPD + HCV-Ab+ (141, 12.9%). Multi-morbidity was associated with older age, higher body mass index, current and former smoking, CDC stage C and longer ART duration. Conclusions: More than 50% of PLHW were multi-morbid and about 30% had three or more concurrent comorbidities. The identification of common patterns of comorbidities address the combined risks of multiple drug and disease-disease interactions

Impact of social determinants on antiretroviral therapy access and outcomes entering the era of universal treatment for people living with HIV in Italy

Background: Social determinants are known to be a driving force of health inequalities, even in high income countries. Aim of our study was to determine if these factors can limit antiretroviral therapy (ART) access, outcome and retention in care of people living with HIV (PLHIV) in Italy. Methods: All ART naïve HIV+ patients (pts) of Italian nationality enrolled in the ICONA Cohort from 2002 to 2016 were included. The association of socio-demographic characteristics (age, sex, risk factor for HIV infection, educational level, occupational status and residency area) with time to: ART initiation (from the first positive anti-HIV test), ART regimen discontinuation, and first HIV-RNA < 50 cp/mL, were evaluated by Cox regression analysis, Kaplan Meier method and log-rank test. Results: A total of 8023 HIV+ pts (82% males, median age at first pos anti-HIV test 36 years, IQR: 29-44) were included: 6214 (77.5%) started ART during the study period. Women, people who inject drugs (PWID) and residents in Southern Italy presented the lowest levels of education and the highest rate of unemployment compared to other groups. Females, pts aged > 50 yrs., unemployed vs employed, and people with lower educational levels presented the lowest CD4 count at ART initiation compared to other groups. The overall median time to ART initiation was 0.6 years (yrs) (IQR 0.1-3.7), with a significant decrease over time [2002-2006 = 3.3 yrs. (0.2-9.4); 2007-2011 = 1.0 yrs. (0.1-3.9); 2012-2016 = 0.2 yrs. (0.1-2.1), p < 0.001]. By multivariate analysis, females (p < 0.01) and PWID (p < 0.001), presented a longer time to ART initiation, while older people (p < 0.001), people with higher educational levels (p < 0.001), unemployed (p = 0.02) and students (p < 0.001) were more likely to initiate ART. Moreover, PWID, unemployed vs stable employed, and pts. with lower educational levels showed a lower 1-year probability of achieving HIV-RNA suppression, while females, older patients, men who have sex with men (MSM), unemployed had higher 1-year risk of first-line ART discontinuation. Conclusions: Despite median time to ART start decreased from 2002 to 2016, socio-demographic factors still contribute to disparities in ART initiation, outcome and durability

What if cancer survival in Britain were the same as in Europe: how many deaths are avoidable?

OBJECTIVE: To estimate the number of deaths among cancer patients diagnosed in Great Britain that would be avoidable within 5 years of diagnosis if the mean (or highest) survival in Europe for patients diagnosed during 1985-1989, 1990-1994 and 1995-1999 were achieved. DESIGN: Five-year relative survival for cancers in Great Britain compared with that from other countries in the EUROCARE-2, -3 and -4 studies. Calculation of excess deaths (those more than expected from mortality in the general population) that would be avoidable among cancer patients in Britain if relative survival were the same as in Europe. SETTING: Great Britain (England, Wales, Scotland) and 13 other European countries. SUBJECTS: 2.8 million adults diagnosed in Britain with 1 of 39 cancers during 1985-1989 (followed up to 1994), 1990-1994 (followed up to 1999) and 1995-1999 (followed up to 2003). MAIN OUTCOME MEASURE: Annual number of avoidable deaths within 5 years of diagnosis. Percentage of the excess (cancer-related) deaths among cancer patients that would be avoidable. RESULTS: Compared with the mean European 5-year relative survival, the largest numbers of avoidable deaths for patients diagnosed during 1985-1989 were for cancers of the breast (about 18% of the excess mortality from this cancer, 7541 deaths), prostate (14%, 4285), colon (9%, 4090), stomach (8%, 3483) and lung (2%, 3548). For 1990-1994, the largest numbers of avoidable deaths were for cancers of the prostate (20%, 7335), breast (15%, 6165), colon (9%, 4376), stomach (9%, 3672), lung (2%, 3735) and kidney (22%, 2644). For 1995-1999, most of the avoidable deaths were for cancers of the prostate (17%, 5758), breast (15%, 5475), lung (3%, 4923), colon (10%, 4295), stomach (9%, 3137) and kidney (21%, 2686).Overall, some 6600-7500 premature deaths would have been avoided each year among cancer patients diagnosed in Britain during 1985-1999 if the mean survival in Europe had been achieved. This represents 6-7% of cancer-related mortality. Compared with the highest European survival, avoidable premature mortality among cancer patients fell from about 12 800 deaths a year (12.2% of cancer-related mortality) to about 11 400 deaths a year (10.6%) over the same period.A large component of the avoidable mortality is due to prostate cancer: excluding this cancer from comparison with the European mean survival reduces the annual number of avoidable deaths by 1000-1500, and the percentage of excess mortality by up to 1%. Compared with the highest survival, the annual number of avoidable deaths would be 1500-2000 fewer, and 1-2% lower as a percentage of excess mortality, but the overall trend in avoidable premature mortality among cancer patients would be similar, falling from 11.4% (1985-1989) to 10.3% (1990-1994) and 9.7% for those diagnosed during 1995-1999.For several cancers, survival in Britain was slightly higher than the mean survival in Europe; this represented some 110-180 premature deaths avoided each year during the period 1985-2003. CONCLUSIONS: Avoidable premature mortality among cancer patients diagnosed in Britain during 1985-1999 has represented 6-7% of cancer-related mortality compared with the mean survival in Europe. Compared with the highest levels of survival in Europe, the reduction from 12.2% to 10.6% of cancer-related mortality reflects small but steady progress over the period 1985-2003

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin