Bloodstream infections in patients living with HIV in the modern cART era.

Retrospective multicentre study aiming at analysing the etiology, characteristics and outcome of bloodstream infections (BSI) in people living with HIV (PLWHIV) in an era of modern antiretroviral therapy. Between 2008 and 2015, 79 PLWHIV had at least 1 BSI, for a total of 119 pathogens isolated. Patients were mainly male (72.1%), previous intravenous drug users (55.7%), co-infected with HCV or HBV (58.2%) and in CDC stage C (60.8%). Gram-positive (G+) pathogens caused 44.5% of BSI, followed by Gram-negative (G-), 40.3%, fungi, 10.9%, and mycobacteria, 4.2%. Candida spp. and coagulase-negative staphylococci were the most frequent pathogens found in nosocomial BSI (17% each), while E.coli was prevalent in community-acquired BSI (25%). At the last available follow-up, (mean 3.2 ± 2.7 years) the overall crude mortality was 40.5%. Factors associated with mortality in the final multivariate analysis were older age, (p = 0.02; HR 3.8, 95%CI 1.2-11.7) CDC stage C (p = 0.02; HR 3.3, 95%CI 1.2-9.1), malignancies, (p = 0.004; HR 3.2, 95%CI 1.4-7.0) and end stage liver disease (p = 0.006; HR 3.4, 95%CI 1.4-8.0). In conclusion, the study found high mortality following BSI in PLWHIV. Older age, neoplastic comorbidities, end stage liver disease and advanced HIV stage were the main factors correlated to mortality.

Survival in HIV-infected patients with lymphoma according to the choice of antiretroviral treatment: an observational multicentre study.

OBJECTIVES: Lymphoproliferative disorders are often observed in HIV-positive patients. Combination antiretroviral treatment (cART) during antineoplastic chemotherapy is beneficial, but little is known about the clinical outcome according to different antiretroviral combinations. The aim of the study was to address this gap in current knowledge. METHODS: A retrospective study was conducted in five large Italian centres for the period from 1998 to 2015; HIV-positive patients diagnosed with lymphoma were included and demographic, clinical and therapeutic variables were recorded and associated with clinical outcomes. Bivariate and multivariate analyses were performed, including Cox proportional hazard models for survival. RESULTS: A total of 399 patients were included in the study. The most common types of lymphoma were diffuse large B-cell lymphoma (DLCLB; n = 164), Hodgkin lymphoma (HL; n = 99) and Burkitt lymphoma (BL; n = 57), followed by plasmablastic lymphoma (PBL; n = 38), T-cell lymphoma (TCL; n = 17), indolent lymphoma (n = 10) and other less common types (n = 14). cART was given to 327 (out of 387 evaluable) patients: in 216 subjects it was protease inhibitor (PI)-based, in 73 it was nonnucleoside reverse transcriptase inhibitor (NNRTI)-based and in 18 it was integrase strand transfer inhibitor (INSTI)-based (the remaining 20 individuals received other regimens). The 5-year overall survival was 57.5% (52.8% for DLCLB, 67.8% for HL, 42.3% for BL, 60.6% for PBL and 64.7% for TCL). PI-based ART compared with other compounds was associated with worse survival in non-Hodgkin lymphoma (NHL) and HL patients combined (P ≤ 0.001) and in NHL patients alone (P < 0.001); grade 3-4 haematological toxicities were more commonly observed in PI-treated individuals. Lymphoma diagnosis in recent years, better immunovirological status, lower lymphoma stage and better prognostic indexes were associated with better survival. CONCLUSIONS: PI-based cART while on chemotherapy was associated with worse overall survival and more frequent haematological complications in HIV-positive patients with lymphoma.

Effect of hepatitis B virus on steatosis in hepatitis C virus co-infected subjects: A multi-centre study and systematic review.

It remains unclear whether hepatitis B virus (HBV) infection may modify the severity of viral steatosis in patients coinfected with chronic hepatitis C virus (HCV). We examined the influence of coinfection with HBV on prevalence of steatosis in chronic hepatitis C in a multi-centre cohort of HBV-HCV subjects, and by performing a systematic review and meta-analysis of the literature. We centrally and blindly assessed steatosis prevalence and severity in a cohort of HBV-HCV coinfected subjects compared to HCV and HBV monoinfected controls and we performed a systematic review of studies addressing the prevalence of steatosis in HBV-HCV subjects compared to HCV controls. In the clinical cohort, we included 85 HBV-HCV, 69 HBV and 112 HCV subjects from 16 international centres. There was no significant difference in steatosis prevalence between the HBV-HCV and the HCV groups (33% vs 45%, P = .11). In subgroup analysis, lean HBV-HCV subjects with detectable HBV DNA had less steatosis than lean HCV subjects matched for HCV viremia (15% vs 45%, P = .02). Our literature search identified 5 additional studies included in a systematic review. Overall, prevalence of steatosis > 5% was similar in HBV-HCV infection compared to HCV (pooled odds ratio [OR] 0.91, 95% CI 0.53-1.6) although there was significant heterogeneity (I2 69%, P = .007). In conclusion, although the prevalence of steatosis is similar in HBV-HCV compared to HCV subjects, our analysis suggests that there may be an inhibitory effect of HCV-induced steatogenesis by HBV in certain subgroups of patients.

Randomised clinical trial: sofosbuvir and ledipasvir in patients with transfusion-dependent thalassaemia and HCV genotype 1 or 4 infection.

BACKGROUND: Patients with thalassaemia major depend on blood transfusions. In Italy, up to 80% of thalassaemia patients bear HCV antibodies due to HCV contaminated transfusions before 1990. Thalassaemia patients with HCV infection have high risk of developing HCC. Treatment based on Pegylated-IFN (Peg-IFN) and Ribavirin (RBV) was limited by relevant side effects. AIM: To evaluate the impact of Sofosbuvir/Ledipasvir (SOF/LDV) fixed dose combination for 12 weeks without RBV, in patients with thalassaemia major and HCV Genotype 1 or 4 (GT1/4). METHODS: Open label, historically-controlled, nationwide multicentre study in thalassaemia patients including naïve with cirrhosis and prior treatment failure without cirrhosis. SOF/LDV single pill was administered for 12 weeks to 100 patients of whom 16% had cirrhosis. The control group included 96 patients with comparable baseline characteristics treated with Peg-IFN/RBV. The primary end point was sustained virologic response at follow-up week 12 or 24 after IFN-free or Peg-IFN/RBV, respectively. RESULTS: In the study group, sustained virological response (SVR) was reported in 98% of patients (95% CI 95.3%-100%). Cirrhotic as well as prior treatment failure achieved 100% SVR. In the control group, SVR was 47.9% (95% CI 37.9%-57.9%). Adverse events including fatigue, headache, nausea, decrease in haemoglobin or increase in ferritin levels were rare and significantly less common in the study than in the historical control group. CONCLUSIONS: In conclusion, SOF/LDV for 12 weeks provides simple, highly effective and safe Peg-IFN/RBV-free treatment for HCV GT1/4 thalassaemia patients. EUDRACT number 2015-002401-1.

Effectiveness, safety, durability and immune recovery in a retrospective, multicentre, observational cohort of ART-experienced, HIV-1-infected patients receiving maraviroc.

The aim of this retrospective, multicentre, observational study was to assess the durability, safety, immune recovery and effectiveness on viral suppression of antiretroviral therapy (ART) in a maraviroc (MVC)-based cohort. We collected clinical, demographical, immunological and virological parameters of adult HIV patients who were infected by CCR5-tropic virus and started an ART regimen containing MVC from 2005 to 2012. We created a longitudinal mixed model to assess the change over time of data. We enrolled 126 drug-experienced patients; the median duration of MVC treatment was 25 months. The probability of stopping ART at one year was 13.3%, and at three years was 27.3%. Statistically significant changes were observed for CD4+ cell count increase ( p < 0.001), HIV-RNA decrease ( p < 0.001) and total cholesterol decrease ( p = 0.005). Ninety-four patients (79.7%) had CD4 ≥ 200 cells/mm3 at baseline while nine of them reached this threshold at nine months (7.6%), 17 (13%) after nine months and six (5%) remained below 200 cells/mm3 at the end of the study. Overall, 114 patients (90.5%) achieved an HIV-RNA ≤ 50 cp/ml. A majority of patients maintained CD4 cell counts of ≥ 200 cells/mm3 and achieved an undetectable HIV viral load within three months. MVC-containing regimens are safe and appear to be a feasible therapeutic option for ART.

Quality of life in an Italian cohort of people living with HIV in the era of combined antiretroviral therapy (Evidence from I.A.N.U.A. study-investigation on antiretroviral therapy).

The aims of this study were to assess the Health Related Quality of Life (HRQoL) of People Living with HIV/AIDS (PLWHA) who attend outpatient services in Genoa, Italy, and to evaluate the relationship between HRQoL and clinical factors, primarily: CD4+ cell count, viral load and HIV-Hepatitis C Virus (HCV) coinfection. A cross-sectional study was performed involving a sample of 943 consecutive patients. Firstly the EuroQol-Five Dimensions-Three Level (EQ-5D-3L) self-reported questionnaire was used to evaluate HRQoL, while socio-demographic information was collected using a separate self-administered questionnaire. Descriptive statistical analysis was then used to show the socio-demographic and clinical characteristics of the sample. Having characterized the sample, Pearson's correlation technique was used to assess the relationship between HRQoL and socio-demographic and clinical characteristics. Finally, multivariable linear regression was used to determine factors associated with HRQOL. The median EQ-Visual analogue scale (EQ-VAS) score was 75.4 (SD 18.4). We found statistically significant associations between the EQ-VAS score and age, coinfection with HCV+, education, other drugs taken over cART, hospitalization due to HIV and a CD4+ cell count <200 mm3 compared with CD4+ cell count >500 mm3. Factors independently associated with lower HRQoL were: older age, coinfection with HCV+, other drugs used in addition to cART, hospitalization due to HIV and CD4+ cell count <200 mm3 compared with CD4+ cell count >500 mm3.

Raltegravir Plus Nevirapine as Maintenance Antiretroviral Therapy in HIV-Positive Patients: Safety, Efficacy and Pharmacokinetics.

BACKGROUND: Tolerability, long-term toxicities and selection of resistant variants limit the use and efficacy of antiretroviral drugs in HIV-positive patients. Novel combinations are needed for mantaining long-term control of HIV replication; nevertheless scarse data are available on protease inhibitor-free dual antiretroviral therapies. METHODS: A multi-centric retrospective study was conducted including HIV-1-positive patients on raltegravir/nevirapine dual regimens. Plasma concentrations were measured as therapeutic drug monitoring while a subset of patients underwent intensive 12-hour pharmacokinetic evaluation. RESULTS: A total of 77 patients switching from successful regimens (76.6% male, median age 52 years) was included; 10 patients on raltegravir plus nevirapine once-daily while 67 subjects on twice-daily schedule. After a median follow-up of 32 months 69 patients (89.6%) were still successfully on treatment. Three patients discontinued for side effects (skin rash or hepatoxicity). Virological failure was observed in five patients (6.5%, 3 on once-daily schedule): in 4 patients (80%) resistance-associated mutations were observed (4 reverse transcriptase, 2 integrase). Triglycerides decreased in patients switching with lipid abnormalities (n=52) and estimated creatinine clearance increased in those with less than 60 ml/min (n=13). Median trough raltegravir and nevirapine concentrations were 83 ng/ml (32-227) and 5460 ng/ml (4037-7221); intensive 12-hours pharmacokinetic parameters (n=7) were similar to published data. CONCLUSION: Dual therapy with raltegravir/nevirapine in selected patients was highly effective over a 32-month follow up: virological failure was infrequent (6.5%), most common with once-daily schedule (60%) and often associated with the selection of resistance-associated mutations (80%). Twice-daily raltegravir plus nevirapine deserves further clinical evaluation as an NRTI- and PI-sparing strategy in selected patients.

Could anti-HCV treatment prevent recurrence of hepatocellular carcinoma in HIV-infected patients? Two case reports.

Highly active antiretroviral therapy (HAART) has proven long-term efficacy in human immunodeficiency virus (HIV) infection. Combination therapy with pegylated interferon and ribavirin has become the standard of care in patients with both hepatitis C virus (HCV) chronic hepatitis and HIV/HCV co-infection. Data on the safety and efficacy of combination therapy in chronic hepatitis C patients with hepatocellular carcinoma (HCC) is scarce and even more so in HIV/HCV co-infected subjects. We report the successful administration of both HAART and anti-HCV therapies in two HIV/HCV co-infected patients after HCC eradication. These encouraging results might argue for the feasibility of an aggressive approach in the management of co-infected patients with HCC.

Conserved T cell and natural killer cell function in treatment-experienced adults receiving tenofovir plus didanosine as nucleoside reverse transcription inhibitor backbone.

Anti-retroviral treatment (ART) usually results in efficient control of virus replication and in immune reconstitution. Among potential adverse effects, impairment of immune responses in terms of CD4(+) T cell counts has been attributed to some ART regimens, as with didanosine-tenofovir. We studied the functional integrity of adaptive and innate immunity during didanosine-tenofovir-containing ART. Two groups of extensively pretreated patients completing at least 48 weeks of ART containing either lamivudine-didanosine (n = 21) or tenofovir-didanosine (n = 25) were identified. In addition to standard clinical immune and virological parameters, we performed a flow cytometric analysis of natural killer (NK) cells, of memory and naive CD4(+) T cells and of T cell receptor alphabeta(+) T cells co-expressing inhibitory NK receptors. Functional analysis consisted in specific and total interferon-gamma production by NK cells and of recall antigen proliferation of peripheral blood mononuclear cells. Comparable clinical immunological reconstitution and virological control were confirmed in the two groups of patients in the absence of clinically relevant adverse effects. The proportion of CD4(+)CD45RA(+) T cells and of functionally inhibited killer immunoglobulin-like receptor T cell receptor alphabeta(+) cells, the proliferation to recall antigens as well as NK cell phenotype and function as determined by interferon-gamma production in patients treated with tenofovir-didanosine were comparable to those treated with a different regimen. Thus, no differences in functional innate or adaptive immune reconstitution are detected in drug-experienced human immunodeficiency virus-infected patients on tenofovir-didanosine nucleoside reverse transcription inhibitor regimens.

Gram-positive bacterial resistance. A challenge for the next millennium.

Penicillin G was first used in 1941. Since then, the trend in bacterial infections has changed. New antibiotics have been developed and bacterial resistance has spread as a consequence. The spread of Gram positive resistant bacteria is related to an inappropriate use of antibiotics. Antibacterial agents are abused or overused in various fields: medicine itself, veterinary science and zootechnics. Now, at the beginning of the third millennium we have been forced to limit our therapeutic options in order to combat these insidious enemies. Selective antibiotic pressure on the microbial population, notably on enterococci and staphylococci, made these two pathogens recalcitrant to traditional chemotherapy. It is a matter of concern that today, vancomycin-resistant Enterococcus spp. (VRE) and vancomycin-intermediate and resistant Staphylococcus aureus (VISA and VRSA) are now being observed worldwide among emerging pathogens. Most pharmaceutical companies are today developing antimicrobial drugs that are active against Gram-positive bacteria. Quinupristin/dalfopristin and linezolid are the most promising drugs and are available only for serious infections; future agents being developed for multi-resistant Gram-positive infections include daptomycin and the glycyclines, although these are still in the development phase. Nevertheless, our group has had the opportunity to treat some serious infections with these drugs and the good results achieved are reported in this review.

Linezolid treatment of prosthetic hip Infections due to methicillin-resistant Staphylococcus aureus (MRSA).

Prosthetic joint infection is an infrequent but serious complication of total joint arthroplasty. Complete removal of all foreign material is essential, however when prosthesis removal is not possible or contraindicated, suppressive antibiotic therapy with retention of the functioning hip arthroplasty may be considered. Linezolid, the first approved oxazolidinone, appears to be a promising new agent for the treatment of serious Gram-positive infections. We report two cases of Methicillin-resistant Staphylococcus aureus (MRSA) prosthetic hip infections successfully treated with a long course of linezolid. This observation suggest that linezolid is a promising drug for the treatment of prosthetic joint infections due to MRSA or other Gram-positive pathogens, particularly when other therapeutic approaches are not feasible or a long-term antibiotic therapy is required.

Impact of an antimicrobial formulary and restriction policy in the largest hospital in Italy.

We have analysed the expenditure on antimicrobial drugs in the largest hospital in Italy; over this period, a committee prepared an antibiotic policy document. This formulary lists all antimicrobial drugs available in the hospital. Some drugs were removed from the list and others are only available on special request for a named patient. In the hope of optimising drug utilisation, we included all the reasons for the choice of agent in the document. The introduction of this formulary resulted in an immediate saving and perhaps in the future we shall also observe an improvement in bacterial resistance patterns.