Risk of Cardiovascular Events in People with HIV (PWH) Treated with Integrase Strand-Transfer Inhibitors: The Debate Is Not Over; Results of the SCOLTA Study.

Cardiovascular disease (CVD) is common in people with HIV (PWH), and has great impact in terms of morbidity and mortality. Several intertwined mechanisms are believed to play a role in determining the increased risk of CVD, including the effect of certain antiretrovirals; among these, the role of integrase strand-transfer inhibitors (INSTIs) is yet to be fully elucidated. We conducted a multicenter, observational study comprising 4984 PWH evaluating the antiretroviral therapy (ART)-related nature of CVD in real life settings, both in naïve vs. treatment-experienced people. A comparison was conducted between INSTIs vs. either protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) considering demographic, baseline clinical characteristics, incidence of CVD in both 2-year and complete follow-up periods. Among 2357 PWH exposed to INSTIs, 24 people experienced CVD; the corresponding figure was 12 cases out of 2599 PWH exposed to other ART classes. At univariate and multivariate analysis, a tendency towards an increased risk of CVD was observed in the 2-year follow-up period in PWH exposed to INSTIs in the absence, however, of statistical significance. These findings leave open the hypothesis that INSTIs may play a role, albeit minimal, in determining an increased risk of CVD in PWH.

People with HIV pioneers of injectable cabotegravir and rilpivirine long acting in Italy: who are they?

Injectable cabotegravir and rilpivirine long-acting therapy is a revolutionary new antiretroviral treatment (ART) option for HIV infection in virologically suppressed adults on a stable ART. The aim of this study from SCOLTA multicenter observational prospective database is to describe the first people living with HIV (PWH) who started this regimen in Italy, assessing adherence to eligibility criteria, describing clinical-epidemiological characteristics compared to registration trials-population and describe early treatment-discontinuations.

Real-life safety of Emtricitabine/Tenofovir Alafenamide/Bictegravir.

INTRODUCTION: Integrase strand transfer inhibitors (INSTI) are one of the most prescribed drug classes for the treatment of HIV infection worldwide. Emtricitabine/Tenofovir Alafenamide/ Bictegravir (FTC/TAF/BIC) has been evaluated in randomized clinical trials; few studies have verified tolerability and safety in clinical practice. Our aim was to investigate the metabolic and hepatic safety in a real-life setting of FTC/TAF/BIC. MATERIALS AND METHODS: Consecutive people living with HIV infection (PLWH) enrolled in the SCOLTA project, switching to or initiating their first antiretroviral treatment with FTC/TAF/BIC were included. PLWH with HBV co-infection were excluded. Metabolic and hepatic variables were collected at T0 and T1, were defined as baseline and 6-month follow-up respectively, and their modifications were analysed using the paired t-test and the analysis of variance. RESULTS: Five hundred and thirty-nine PLWH with at least one follow-up visit were included in the analysis. Mean age was 48 years (±12.1), 74% were male, 16.1% were naïve to antiretrovirals (ART). At T1, ART-experienced PLWH showed a significant reduction of total cholesterol (TC) and triglycerides, and a slight increase in blood glucose (BG) and ALT. On the contrary, in ART-naïve PLWH blood lipids significantly increased, although with an unaffected TC/high density lipoprotein (HDL)-c ratio, while alanine aminotransferase (ALT) decreased significantly, mainly in those with altered baseline level. The treatment interruptions were 45 (8.4%) over the whole observation period, 13 (2.4%) due to AEs. The most frequent AEs were related to the central nervous system (6 events of depression, insomnia, headache, agitation) and 3 PLWH discontinued the regimen because of grade 1-2 weight gain. CONCLUSIONS: In ART-experienced PLWH switching to FTC/TAF/BIC a significant improvement of lipid profile occurred but with significant BG and ALT variation without clinical relevance. In ART-naïve PLWH, blood lipids increased even though lipid profile did not worsen, and a trend towards normalization of liver enzymes was suggested. FTC/TAF/BIC is well tolerated in the real life setting.

Lipids and Transaminase in Antiretroviral-Treatment-Experienced People Living with HIV, Switching to a Doravirine-Based vs. a Rilpivirine-Based Regimen: Data from a Real-Life Setting.

Doravirine (DOR) is a newly approved non-nucleoside reverse transcriptase inhibitor (NNRTI). We aimed to investigate, in a real-life setting, how switching to a DOR-based regimen rather than a rilpivirine (RPV)-based regimen impacted metabolic and hepatic safety. The analysis included 551 antiretroviral treatment (ART)-experienced people living with HIV (PLWH), starting RPV-based or DOR-based regimens with viral load < 200 copies/mL, baseline (T0), and at least one control visit (6-month visit, T1). We enrolled 295 PLWH in the RPV and 256 in the DOR cohort. At T1, total cholesterol (TC), low-density lipoprotein-C (LDL-C), and triglycerides significantly decreased in both DOR and RPV cohorts, while high-density lipoprotein-C (HDL-C) only decreased in RPV-treated people. Consistently, the TC/HDL-C ratio declined more markedly in the DOR (-0.36, p < 0.0001) than in the RPV cohort (-0.08, p = 0.25) (comparison p = 0.39). Similar trends were observed when excluding the PLWH on lipid-lowering treatment from the analysis. People with normal alanine aminotransferase (ALT) levels showed a slight ALT increase in both cohorts, and those with baseline ALT > 40 IU/L experienced a significant decline (-14 IU/L, p = 0.008) only in the DOR cohort. Lipid profile improved in both cohorts, and there was a significant reduction in ALT in PLWH with higher-than-normal baseline levels on DOR-based ART.

Lipids and transaminase elevations in ARV-experienced PLWH switching to a doravirine-based regimen from rilpivirine or other regimens.

BACKGROUND: Doravirine (DOR) is a newly approved antiretroviral belonging to the class of non-nucleoside reverse transcriptase inhibitors (NNRTI), well tolerated and leading to an improved lipid profile in antiretroviral experienced people living with HIV (PLWH). We aimed at evaluating if the lipid-lowering effect is linked to the drug class, using real-life data from the SCOLTA cohort. METHODS: We compared the lipid profile modifications in experienced PLWH switching to a DOR-based regimen from rilpivirine or another NNRTI-based regimen or from an integrase strand transferase (INSTI)-based regimen. T0 and T1 were defined as the baseline and 6-month follow-up respectively. Data were collected at baseline and prospectively every six months and changes from baseline were compared using a multivariable linear model. RESULTS: In 107 PLWH, enrolled in the SCOLTA DOR cohort, with undetectable HIV-RNA at baseline, 32.7% switched from RPV-based regimens (DOR1), 29.9% from other NNRTI-including regimens (DOR2) and 37.4% switched from INSTI-including regimens (DOR3). At T1, TC significantly decreased in DOR2 (-15 mg/dL) and DOR3 (-23 mg/dL), and significantly more in DOR3 than in DOR1 (-6 mg/dL) (p = 0.016). HDL-C declined in DOR2 (-2 mg/dL) whereas it increased in DOR1 (+ 3 mg/dL) (p = 0.042) and remained stable in DOR3. LDL-C significantly decreased from baseline in DOR2 (-12 mg/dL) and DOR3 (-22 mg/dL) and was different between DOR1 (-8 mg/dL) and DOR3 (p = 0.022). TC/HDL ratio showed a significant decline in the DOR3 group (-0.45), although similar to DOR1 (-0.23, p = 0.315) and DOR2 (-0.19, p = 0.254). Triglycerides did not noticeably change. ALT significantly decreased in PLWH with a baseline level > 40 UI/mL. CONCLUSIONS: PLWH on doravirine treatment showed different trends in blood lipids according to their previous regimen. In PLWH switching from RPV, minimal modifications were seen, whereas in those switching from other NNRTIs and from INSTI-including regimens, we observed an overall improvement in lipid profile, seemingly independent of the "statin effect" of TDF.

Infective Endocarditis in People Who Inject Drugs: Report from the Italian Registry of Infective Endocarditis.

Intravenous drug use is a predisposing condition for infective endocarditis (IE). We report the clinical features of IE, taken from the Italian Registry of IE, in people who inject drugs (PWIDs). The registry prospectively collected epidemiological, clinical, in-hospital, and follow-up data on patients with IE from 17 Italian centers. A total of 677 patients were enrolled, and 61 (9%) were intravenous drug users (IDUs). Most PWIDs were male (78.6%), and aged between 41 and 50 years old (50%). The most frequent comorbidities were HIV (34.4%) and chronic liver disease (32%). Predisposing factors for IE were present in 6.5% of the patients, and 10% had minor valvular abnormalities. IE had occurred previously in 16.4% of the patients, and 50% of them had undergone heart surgery. Overall mortality was 9.8% in IDUs and 20% in patients with recurrent IE. IE in PWIDs mostly affected the native valves (90%). The echocardiographic diagnosis of IE was based on the detection of vegetation in 91.82% of cases. Staphylococcus aureus was the main microorganism isolated (70%) from blood cultures. Thirty patients (49%) underwent heart surgery: thirteen had aortic valves, eleven had mitral valves, and six had tricuspid valve interventions. IE in PWIDs was relatively common, and patients with native valve right-sided IE had a better prognosis, with a low rate of surgical interventions.

Factors associated with hospital admission for COVID-19 in HIV patients.

: This study reports on hospital admission and outcomes of 69 HIV-infected individuals who were diagnosed with SARS-CoV-2 infection between February and May 2020, in a network of Italian centres. Patients' characteristics and median days between symptoms and diagnosis were similar by hospital admission, whereas admitted patients had lower nadir CD4 cells and current lymphocytes count. These values were also correlated to worse COVID-19 outcome. Antiretroviral drugs did not seem to be associated with disease severity.

Sustained virological response with 16-week glecaprevir/pibrentasvir after failure to sofosbuvir/velpatasvir in post-transplant severe HCV recurrence in HIV.

Direct-acting antivirals (DAAs) demonstrated high efficacy and safety even in the post-liver transplant (LT) setting and in HIV-infected patients, but data are very limited in the early post-LT period with the most recently available DAA. Two HIV/HCV-coinfected LT recipients (both grafts from HIV/HCV-negative donors) experienced early HCV recurrence with severe hepatitis and were treated with sofosbuvir/velpatasvir for 12 weeks. Unfortunately, both patients failed: one (genotype 4d) showed virological breakthrough at week 3 with resistance-associated substitutions (RASs) for both NS5A and NS5B, while the other (genotype 1a) experienced virological relapse without RAS. Both progressed to fibrosing cholestatic hepatitis and were successfully retreated with glecaprevir/pibrentasvir for 16 weeks achieving sustained virological response. The higher prevalence of RAS in experienced genotype 4 patients and the long time to viral suppression observed in subjects with fibrosing cholestatic hepatitis should be taken into account, considering longer treatment duration to increase the chances of achieving sustained virological response.

Outbreak of severe Hepatitis A in Eastern Piedmont, Italy.

Hepatitis A (HA) is caused by a hepatovirus from the family Picornaviridae (Hepatitis A Virus, HAV). Transmission occurs mainly by the orofaecal route through food or water contaminated by faeces. Sexual transmission has also been reported among men who have sex with men (MSM). From February to May 2017, 14 patients with HA were hospitalized at the University Hospital "Maggiore della Carità", Novara (Eastern Piedmont), Italy. One patient was two years old and was therefore admitted to the Paediatric Unit, the remaining 13 to the Infectious Disease Unit. Two of the adults were female and the rest (11) were male. The male patients were MSM, and contracted the infection sexually; three of them were known to be HIV positive, while two had a new diagnosis of syphilis infection. Women contracted the infection from contaminated food.

From soil to blood: first human case of Sphingobacterium hotanense bacteraemia.

This report describes a case of Sphingobacterium hotanense bacteraemia in a patient scratched by a rooster on the right arm. Diagnostic, clinical and therapeutic features are discussed. To the best of our knowledge, this is the first case of Sphingobacterium hotanense bacteremia reported in the medical literature.

Climate, environment and transmission of malaria.

Malaria, the most common parasitic disease in the world, is transmitted to the human host by mosquitoes of the genus Anopheles. The transmission of malaria requires the interaction between the host, the vector and the parasite.The four species of parasites responsible for human malaria are Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae and Plasmodium vivax. Occasionally humans can be infected by several simian species, like Plasmodium knowlesi, recognised as a major cause of human malaria in South-East Asia since 2004. While P. falciparum is responsible for most malaria cases, about 8% of estimated cases globally are caused by P. vivax. The different Plasmodia are not uniformly distributed although there are areas of species overlap. The life cycle of all species of human malaria parasites is characterised by an exogenous sexual phase in which multiplication occurs in several species of Anopheles mosquitoes, and an endogenous asexual phase in the vertebrate host. The time span required for mature oocyst development in the salivary glands is quite variable (7-30 days), characteristic of each species and influenced by ambient temperature. The vector Anopheles includes 465 formally recognised species. Approximately 70 of these species have the capacity to transmit Plasmodium spp. to humans and 41 are considered as dominant vector capable of transmitting malaria. The intensity of transmission is dependent on the vectorial capacity and competence of local mosquitoes. An efficient system for malaria transmission needs strong interaction between humans, the ecosystem and infected vectors. Global warming induced by human activities has increased the risk of vector-borne diseases such as malaria. Recent decades have witnessed changes in the ecosystem and climate without precedent in human history although the emphasis in the role of temperature on the epidemiology of malaria has given way to predisposing conditions such as ecosystem changes, political instability and health policies that have reduced the funds for vector control, combined with the presence of migratory flows from endemic countries.

Intrathecal or intraventricular colistin: a review.

Central Nervous System (CNS) infections related to external ventricular derivation are a major complication of patients undergoing neurosurgical procedures. Antimicrobial treatment of CNS infections should be based not only on the susceptibility of the isolated microorganism, but also on the treatment's pharmacokinetic properties demonstrating the passage of the molecule through the blood-brain barrier. When CNS infections are caused by multi-drug resistant Gram-negative bacteria, intrathecal colistin is considered an effective and safe option. We review the literature of intrathecal/intraventricular use of colistin, comprehensive of both pharmacokinetic data and clinical experiences.

Arthrographis kalrae arthritis: a new case report.

To date, only 11 cases of infection by Arthrographis kalrae have been described. According to the literature, we report a second case of arthritis caused by this mycete after a penetrating wound successfully treated with voriconazole before arthroscopic knee washout for six weeks.

[The mosquito-borne viruses in Europe]. / Virus trasmessi da zanzare in Europa.

Epidemiologic changes of vector-borne diseases in recent years have multiple causes, including climate change. There are about 3500 species of mosquitoes worldwide, three-quarters of which live in tropical and subtropical wetlands. Main viruses transmitted by mosquitoes in Europe belong to the genus Flavivirus; some of them have been recently reported in Italy (Usutu and Japanese encephalitis virus), while others have been circulating for years and autochthonous transmission has been documented (West Nile virus). Mosquito-borne viruses can be classified according to the vector (Aedes or Culex), which, in turn, is associated with different vertebrate host and pathology. The Flavivirus transmitted by Culex have birds as a reservoir and can cause meningoencephalitis, while viruses transmitted by Aedes have primates as reservoir, do not have neurotropism and mainly cause hemorrhagic diseases. Other arbovirus, potentially responsible of epidemics, are the Chikungunya virus (Alphavirus family), introduced for the first time in Europe in 2007, and the virus of Rift Valley fever (Phlebovirus family). The spread in non-endemic areas of vector-born diseases have highlighted the importance of surveillance systems and vector control strategies.

[Vector transmitted diseases and climate changes in Europe]. / Malattie trasmesse da vettorie cambiamenti climatici in Europa.

The increase in temperatures recorded since the mid-nineteenth century is unprecedented in the history of mankind. The consequences of climate changes are numerous and can affect human health through direct (extreme events, natural disasters) or indirect (alteration of the ecosystem) mechanisms. Climate changes have repercussions on ecosystems, agriculture, social conditions, migration, conflicts and the transmission mode of infectious diseases. Vector-borne diseases are infections transmitted by the bite of infected arthropods such as mosquitoes, ticks, triatomines, sand flies and flies. Epidemiological cornerstones of vector-borne diseases are: the ecology and behaviour of the host, the ecology and behaviour of the vector, and the population's degree of immunity. Mosquito vectors related to human diseases mainly belong to the genus Culex, Aedes and Mansonia. Climate changes in Europe have increased the spread of new vectors, such as Aedes albopictus, and in some situations have made it possible to sustain the autochthonous transmission of some diseases (outbreak of Chukungunya virus in northern Italy in 2007, cases of dengue in the South of France and in Croatia). Despite the eradication of malaria from Europe, anopheline carriers are still present, and they may allow the transmission of the disease if the climatic conditions favour the development of the vectors and their contacts with plasmodium carriers. The tick Ixodes ricinus is a vector whose expansion has been documented both in latitude and in altitude in relation to the temperature increase; at the same time the related main viral and bacterial infections have increased. In northern Italy and Germany, the appearance of Leishmaniasis has been associated to climatic conditions that favour the development of the vector Phlebotomus papatasi and the maturation of the parasite within the vector, although the increase of cases of visceral leishmaniasis is also related to host immune factors, particularly immunodepression caused by the human immunodeficiency virus (HIV). Despite the importance of global warming in facilitating the transmission of certain infectious diseases, due consideration must be taken of the role played by other variables, such as the increase in international travel, migration and trade, with the risk of importing parasites and vectors with the goods. In addition, the control of certain infections was possible in the past through improvements in socio-economic conditions of affected populations. However, the reduction in resources allocated to health care has recently led to the re-emergence of diseases that were considered eradicated.

[Parvovirus B19 in adult: report of two cases]. / Infezione da Parvovirus B19 nell'adulto: descrizione di due casi clinici.

Parvovirus B19 infection is asymptomatic in the majority of cases, but the are several well-known clinical manifestation. In adults transient aplastic crisis, chronic anemia, arthropathy, meningitis, encephalitis, myocarditis and acute hepatitis have been described. In this paper the Authors report two cases - arthropathy and acute hepatitis - of Parvovirus B19 infection in adults.

IL28B polymorphism, blood interferon-alpha concentration, and disease stage of HCV mono-infected and HCV-HIV co-infected patients.

Interferon (IFN) preactivation, interleukin-28B (IL28B) alleles, and liver fibrosis act as predictors of response to antiviral therapy against hepatitis C. We aimed to verify if blood IFN concentration, a putative biomarker of interferon preactivation, might depend on carriage of a given IL28B genotype and/or advanced hepatic fibrosis. The study population included 187 hepatitis C patients (75 of whom were HIV coinfected), who were genotyped for the rs12979860 polymorphism and staged non-invasively by transient elastography. Blood IFN, measured by an enzyme immunoassay, was detectable in 68/187 patients (36%). Seventy-three patients (39%) were C/C homozygotes, 25 (13%) were T/T homozygotes, and 89 (48%) were heterozygotes. The fibrosis stage was F0-F1 in 70 patients (37%), F2-F3 in 54 patients (29%), and F4 in 63 patients (34%). IFN levels were higher among patients with HIV coinfection (p=0.044) and patients with better renal function (p=0.041), without association with the IL28B genotype or the hepatitis C stage. From the multivariate analysis, the only independent predictor of higher level of IFN was the age of patients (p=0.019), whereas independent predictors of a fibrosis stage ≥ F2 were age (p=0.007), belonging to the HIV/HCV group (p=0.048) and current alcohol consumption (p=0.008). In conclusion, a sizable proportion of HCV carriers have detectable IFN levels that do not indicate a greater severity of disease or display any relationships to specific rs12979860 variants.

[The pharmacoeconomics of antiretroviral drugs and the role of adherence]. / Farmacoeconomia degli antiretrovirali e ruolo dell'aderenza.

In the past decade health care expenses have increased by 50% in Italy, a country whose population mostly consists of people aged over 50 years old, the main users of health care services. Pharmaceutical expenditure is the main issue: monoclonal antibodies, biological immunosuppressants, antitumorals and antiretrovirals are the most expensive drugs. The cost of HIV/AIDS has remained constant during the last four years. Despite the increase in pharmaceutical costs, which made the infection chronic, hospitalization costs have been reduced. With sustainable economic development as a chiefly long-term target, a clinical governance system is nonetheless needed which also takes account of the adherence to antiretroviral therapy: thus poor adherence leads to a reduction in efficacy and at the same time an increase in welfare and community costs. Recently in SSvD "Prevention and cure of HIV infection and related syndromes" of "Maggiore della Carità" University Hospital, Novara, adherence to antiretroviral therapy in 100 consecutive patients was evaluated. The results show that patients with high adherence to the treatment prescribed have a less expensive drug combination. Moreover, with better infection control and a higher immune recovery, they have less impact on social and health care costs.