The Clinical Efficacy of Multidose Oritavancin: A Systematic Review

Oritavancin (ORI) is a semisynthetic lipoglycopeptide approved as a single 1200 mg dose intravenous infusion for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by Gram-positive organisms in adults. The pharmacokinetic/pharmacodynamic (PK/PD) linear kinetic profile and long terminal half-life (similar to 393 h) of ORI make it therapeutically attractive for the treatment of other Gram-positive infections for which prolonged therapy is needed. Multidose regimens are adopted in real-world clinical practice with promising results, but aggregated efficacy data are still lacking. A comprehensive search on PubMed/Medline, Scopus, Cochrane and Google Scholar databases was performed to include papers published up to the end of January 2023. All articles on ORI multiple doses usage, including case reports, with quantitative data and relevant clinical information were included. Two reviewers independently assessed papers against the inclusion/exclusion criteria and for methodological quality. Differences in opinion were adjudicated by a third party. From 1751 potentially relevant papers identified by this search, a total of 16 studies met the inclusion criteria and were processed further in the final data analysis. We extracted data concerning clinical response, bacteriologic response, mortality and adverse events (AEs). From the 16 included papers, 301 cases of treatment with multidose ORIs were identified. Multidose regimens comprised an initial ORI dose of 1200 mg followed by 1200 mg or 800 mg subsequent doses with a varying total number and frequency of reinfusions. The most often treated infections and isolates were osteomyelitis (148; 54.4%), ABSSSI (35; 12.9%) and cellulitis (14; 5.1%); and MRSA (121), MSSA (66), CoNS (17), E. faecalis (13) and E. faecium (12), respectively. Clinical cure and improvement by multidose ORI regimens were observed in 85% (231/272) and 8% (22/272) patients, respectively. Multidose ORI was safe and well tolerated; the most frequent AEs were infusion-related reactions and hypoglycemia. A multidose ORI regimen may be beneficial in treating other Gram-positive infections besides ABSSSIs, with a good safety profile. Further studies are warranted to ascertain the superiority of one multidose ORI scheme or posology over the other

Predictors of retention in care for HIV-infected patients: data from San Martino Hospital cohort in Genoa

Background: Retention in care (RC) is a key feature of the cascade of continuum of care that moves from HIV testing to linkage to care, engagement in care and RC. RC play an important role in achieving and maintaining therapeutic success and is crucial for reduction of HIV transmission. The aim of this study was to evaluate the rate of RC in the Infectious Disease unit of San Martino Hospital, in Genoa and to identify predictors associated with failed RC. Methods: All new HIV tested and diagnosed subjects were consecutively enrolled from 01/01/2008 to 01/08/2014. Follow-up period was censored at 01 February 2015. Demographics, immune-virological status, co-infection with HCV and HBV and therapeutic data were collected at baseline and at the time of last observation. Failed RC was defined as lack of laboratory data, clinical visits and drug dispensation for more than 6 months. Causes of failed RC were recorded, if available. Total and partial frequencies were calculated for categorical variables, while media and median were computed for continuous variables .The relationship between the RC and the parameters taken into account was examined with a univariate analysis, using Chi-squared test for dichotomous outcome variables and the Student\u2019s T test for the continuous outcome variables to evaluate the P values. The level of significance was set at P <0.05. Results: we enrolled 209 patients (mean age 45.1 years). Males were 152 (73%), Italian 169 (81%) with mean length of disease of 43.8 months. Co-infection HBV/HIV and HCV/HIV were present in 7 (3%) and 30 (14%) patients respectively. At baseline mean lymphocyte T cell CD4+ was 267/mmc with 46% of subjects with CD4+ <200/mmc of which 42% <50/mmc. HIV-RNA was over 100,000 copies for 38% of patients. Antiretroviral therapy (cART) was prescribed for 194 patients (93%). The rate of RC was 82%. Among patients who failed retaining in care 9 (24%) died and 6 (16%) moved to other medical centers. Differences between patients retained in care and lost at follow up are showed in table 1. Failed RC was associated with foreign origin (p=0.016), HBV/HIV co-infection (p=0.005), CD4+ count <200/mmc and HIV-RNA greater than 50 copies/ml at observation time (p<0.0001 respectively) and being not treated for HIV-infection (p<0.0001). Conclusions: The rate of RC in San Martino cohort is similar than compared to those estimated for US and Italian cohorts (81% and 85%). Foreign origin and lack of prescription of initial cART are the key factors in RC

Predictors of retention in care in HIV-infected patients in a large hospital cohort in Italy

Retention in care is a key feature of the cascade of continuum of care, playing an important role in achieving therapeutic success and being crucial for reduction of HIV transmission. The aim of this study was to evaluate the rate of retention in care in a large referral centre in the North of Italy and to identify predictors associated with failed retention. All new HIV-infected subjects were consecutive enrolled from 1 January 2008 to 31 December 2014. Demographics, immune-virological status, hepatitis co-infection and timing of initiation of combined antiretroviral therapy (cART) data were collected at baseline and at the time of last observation. Failed retention in care was defined as lack of laboratory data, clinical visits and drug dispensation for more than 6 months from the last visit. Cox regression analysis was used. Multivariate analysis of variables with P&lt;0.05 in univariate analysis was performed. We enrolled 269 patients (mean age 46.1 years). Males were 197 (73%), Italian 219 (81%) with mean length of disease of 5.1 years. cART was prescribed for 257 patients (95%). The rate of retention in care was 78.4% and the rate of virological suppression was 75%. Predictors of being loss to follow-up were foreign origin (P = 0.048), CD4+ count &lt;200/mmc (P = 0.001) and not being treated for HIV infection (P = 0.0004). Predictors of cART efficacy were shorter duration of HIV infection and baseline HIV-RNA &lt;100 000 copies/ml. These findings underline the necessity to improve retention in care by identifying groups at increased risk of being loss to follow-up. Retention in care of vulnerable population is crucial to reach 90-90-90 UNAIDS endpoint

Role of HCV-RNA decay and IP-10 levels after 48 hours of standard HCV therapy as predictors of rapid virological response

Background and objectives: Rapid virological response (RVR) is a critical end-point in the era of the new direct-acting antiviral agents (DAA). The aim of this study was to evaluate the predictive value in achieving RVR of HCV-RNA load and IP10 after 48. hours of standard anti HCV therapy. Methods: HCV mono-infected and HIV/HCV co-infected patients naives to interferon were included. Demographic data, immune-virological HIV-related condition and HCV disease status were recorded before starting treatment. HCV-RNA and IP10 concentrations were also measured 48. hours after first interferon dose. Univariate model, logistic regression and ROC curve were performed for statistical analysis. Results: Thirty-two patients were enrolled (mean age 49.2 \ub1 5.6 years): all were treated with pegylated-interferon and ribavirin. Nineteen (59.3%) were HIV/HCV co-infected patients. RVR was reached in 10 patients (31.2%). A decline of more than two log of HCV-RNA after 48. hours of therapy was associated with RVR (P= 0.004). A trend was observed between increased IP10 levels at 48. hours and RVR (P= 0.08). In a multivariable model only HCV-RNA at 48. hours was associated with RVR (P= 0.011). ROC curve analysis for both HCV-RNA at 48. hours and IP-10 at 48. hours showed an area under the curve of 0.87 (95%CI: 0.74-1; P= 0.001) with specificity of 72.2% and sensibility of 90%. Conclusion: In HCV treatment-na\uefve patients HCV-RNA and IP10 determination after 48. hours of interferon and ribavirin may be a worthwhile endpoint to predict RVR and select patients that may not require DAA addition

Increased CD38 expression on T lymphocytes as a marker of HIV dissemination into the central nervous system

Cross-sectional analysis on 20 HIV-1 patients with neurological symptoms admitted to two infectious disease units. Cut-off of HIV-RNA (VL) was 20\u200acopies/ml for plasma and cerebral spinal fluid (CSF). Flow cytometry was used to analyze the phenotype of circulating and CSF T lymphocytes. CD38 mean fluorescence intensity (MFI) was higher on circulating CD4(+)T lymphocytes from patients with VL >20\u200acopies/ml in plasma (P =\u2009 0.001) or CSF (P =\u2009 0.001). The frequency of circulating CD8(+)CD38(+)T cells and CD38 MFI on these cells were higher in patients with VL >20\u200acopies/ml than in those with undetectable plasma VL (P =\u2009 0.030 and P =\u2009 0.023). The frequency of CSF CD4(+)CD38(+)T, as well as their CD38 and CD95 MFI, were increased in patients with detectable than non-detectable plasma VL (P =\u2009 0.01, P =\u2009 0.03, and P =\u2009 0.05). The % CD38(+)CD8(+)T in CSF correlated with time of virological suppression (\u3c1 =\u2009 -\u20090.462, P =\u2009 0.040) and the CNS penetration-effectiveness (CPE) score (\u3c1 =\u2009 -\u20090.467, P\u2009=\u20090.038). In conclusion, (a) the expression of CD38(+) on both CD4(+), CD8(+)T lymphocytes from peripheral blood and CSF discriminated between viremic and non-viremic patients and (b) T cell activation/apoptosis markers inversely correlated with CPE to remark the importance for therapy to restore immunological functions

Pharmacokinetics of Lopinavir Determined with an ELISA Test in Youths with Perinatally Acquired HIV.

To investigate the plasma levels of lopinavir by enzyme-linked immunosorbent assay (ELISA) in a cohort of patients who were vertically infected with human immunodeficiency virus 1 (HIV).Plasma levels of lopinavir (Cmin) were determined by ELISA test in patients treated with lopinavir/ritonavir-based combined antiretroviral therapy who had achieved virological response after 4 wk of therapy. Reference lopinavir concentrations were Cmin 1-8 \u3bcg/mL. Correlation between lopinavir plasma concentration and continuous variables was evaluated by mean of Pearson correlation coefficient. Differences in lopinavir (LPV) concentration for binary categorical variables were assessed by Mann-Whitney test, while for variables with more than two categories Kruskal-Wallis test was used.Thirty-four patients were enrolled; median age was 133 mo (15-265). The median lopinavir dose tested was 383.5 mg/kg (IQR: 266.6-400 mg/kg), with a median plasma concentration of 8.8 \u3bcg/mL (IQR: 5-14 \u3bcg/mL). Lopinavir Cmin was &lt;1 \u3bcg/mL in only one sample (2.9 %), while 14 samples had Cmin between 1 and 8 \u3bcg/mL (41.2 %) and 19 (55.9 %)\u2009&gt;\u20098 \u3bcg/mL. No significant correlations were found between plasma concentrations of lopinavir and the continuous variables considered in the study. A negative but, not completely significant, correlation was found between plasma drug concentration and body mass index (r\u2009=\u2009-0.29; p\u2009=\u20090.09).The use of a simple and relatively cost-effective methodology might render therapeutic drug monitoring (TDM) appeal in the daily clinical practice.Objective: To investigate the plasma levels of lopinavir by enzyme-linked immunosorbent assay (ELISA) in a cohort of patients who were vertically infected with human immunodeficiency virus 1 (HIV). Methods: Plasma levels of lopinavir (Cmin) were determined by ELISA test in patients treated with lopinavir/ritonavir-based combined antiretroviral therapy who had achieved virological response after 4 wk of therapy. Reference lopinavir concentrations were Cmin 1-8 \u3bcg/mL. Correlation between lopinavir plasma concentration and continuous variables was evaluated by mean of Pearson correlation coefficient. Differences in lopinavir (LPV) concentration for binary categorical variables were assessed by Mann-Whitney test, while for variables with more than two categories Kruskal-Wallis test was used. Results: Thirty-four patients were enroled; median age was 133 mo (15-265). The median lopinavir dose tested was 383.5 mg/kg (IQR: 266.6-400 mg/kg), with a median plasma concentration of 8.8 \u3bcg/mL (IQR: 5-14 \u3bcg/mL). Lopinavir Cmin was &lt;1 \u3bcg/mL in only one sample (2.9 %), while 14 samples had C min between 1 and 8 \u3bcg/mL (41.2 %) and 19 (55.9 %)&gt;8 \u3bcg/mL. No significant correlations were found between plasma concentrations of lopinavir and the continuous variables considered in the study. A negative but, not completely significant, correlation was found between plasma drug concentration and body mass index (r=-0.29; p=0.09). Conclusions: The use of a simple and relatively cost-effective methodology might render therapeutic drug monitoring (TDM) appeal in the daily clinical practice. \ua9 2013 Dr. K C Chaudhuri Foundation

Discontinuation of Initial Antiretroviral Therapy in Clinical Practice: Moving Toward Individualized Therapy.

Background: Study aim was to estimate the rate and identify predictors of discontinuation of first combination antiretroviral therapy (cART) in recent years. Methods: Patients who initiated first cART between January 2008 and October 2014 were included. Discontinuation was defined as stop of at least 1 drug of the regimen, regardless of the reason. All causes of discontinuation were evaluated and 3 main endpoints were considered: toxicity, intolerance, and simplification. Predictors of discontinuation were examined separately for all 3 endpoints. Kaplan–Meier analysis was used for the outcome discontinuation of >=1 drug regardless of the reason. Cox regression analysis wasused to identify factors associated with treatment discontinuation because of the 3 reasons considered. Results: A total of 4052 patients were included. Main reason for stopping at least 1 drug were simplification (29%), intolerance (21%), toxicity (19%), other causes (18%), failure (8%), planned discontinuation (4%), and nonadherence (2%). In a multivariable Cox model, predictors of discontinuation for simplification were heterosexual transmission (P = 0.007), being immigrant (P = 0.017), higher nadir lymphocyte T CD4+ cell (P = 0.011), and higher lymphocyte T CD8+ cell count (P = 0.025); for discontinuation due to intolerance: the use of statins (P = 0.029), higher blood glucose levels (P = 0.050). About toxicity: higher blood glucose levels (P = 0.010) and the use of zidovudine/lamivudine as backbone (P = 0.044). Conclusions: In the late cART era, the main reason for stopping the initial regimen is simplification. This scenario reflects the changes in recommendations aimed to enhance adherence and quality of life, and minimize drug toxicity

Safety and therapeutic efficacy of the switch to maraviroc+darunavir/ritonavir in HIV/HCV coinfected patients: initial results from GUSTA study

HIV/HCV coinfection is a risk factor for hepatic injury in patients receiving HAART and previous studies support a favourable effect of antiretroviral regimens including maraviroc (MVC) on the course of coinfection compared with other antiretroviral drugs. There are few observations about MVC use in simplified treatment of coinfected patients