Outcome of Darunavir-Cobicistat-Based Regimens in HIV-Infected People Who Have Experienced Virological Failure.

Objective: To evaluate the virological outcome of darunavir-cobicistat (DRVc)-based regimens in adults living with HIV who had experienced virological failure (VF) on any previous drug combination. Methods: This was a retrospective cohort study (CSLHIV Cohort) of adults living with HIV who started a DRVc-based regimen with HIV-RNA >50 copies/mL after VF on any previous drug combination. Data on demographics, antiretroviral treatment since HIV diagnosis, and immunological and metabolic parameters from baseline (start of DRVc) to 48 weeks were analyzed in order to assess the cumulative proportion of those who achieved virological success (VS), defined as at least one instance of HIV-RNA <50 copies/mL within 12 months from baseline. Follow-up lasted from the start of the DRVc-based regimen (baseline) to the first instance of HIV-RNA <50 copies/mL, last available visit, or loss to follow-up or death, whichever occurred first. Univariate and multivariate Cox proportional-hazard regression models were used to identify baseline factors associated with VS. Results: A total of 176 individuals were included, and 120 (68.2%) achieved <50 HIV-RNA copies/mL within 12 months since baseline. On multivariate analysis, baseline HDL cholesterol was independently associated with the occurrence of VS (adjusted HR 1.021, 95% CI 1.004-1.038; p=0.014). Among the 120 subjects with VS, 27 (22.5%) had had VF during a median follow-up of 20.8 months since the first undetectable HIV-RNA. Resistance testing after VF was available in two cases, which harboured the HIV variant-bearing protease inhibitor-resistance mutations D30N, I50V, and N88D. During a median follow-up of 38.4 months, 65 of 176 (36.9%) individuals discontinued DRVc for any reason (37 of 120, 30.8%) and achieved VS vs. 28 of 56 (50%) without VS (p=0.019). Time to discontinuation was longer in people with VS (41.5 vs. 23.0 months, p=0.0007). No statistically significant changes were observed in immunological or lipid profiles during follow-up. Conclusion: Most individuals in this study achieved VS within 12 months from the beginning of a DRVc-based regimen; therefore, this treatment represent a viable option for people who have experienced VF on other regimens.

Correction to: Patient-Reported Outcomes in an Observational Cohort of HIV-1-Infected Adults on Darunavir/Cobicistat-Based Regimens: Beyond Viral Suppression.

In the original version of this article, in Fig. 2b the formatting on the x-axis of the graph has been published incorrectly.

Patient-Reported Outcomes in an Observational Cohort of HIV-1-Infected Adults on Darunavir/Cobicistat-Based Regimens: Beyond Viral Suppression.

OBJECTIVE: This prospective, multicenter, non-interventional cohort study enrolling human immunodeficiency virus (HIV)-1-infected, virally suppressed adult outpatients in Italy aimed to describe results obtained from patient-reported outcome questionnaires regarding treatment satisfaction and symptom perceptions in HIV-1-positive patients who switched to cobicistat-boosted darunavir antiretroviral regimens, coming from ritonavir-boosted protease inhibitors. METHODS: Patients entered this study between June 2016 and February 2017, once their treating physician had considered them eligible for cobicistat-boosted darunavir-based treatment as per clinical practice. Patients' satisfaction regarding regimen and current symptom burdens were assessed using two previously validated, patient-reported outcome questionnaires: HIV Treatment Satisfaction Questionnaire (HIV-TSQ) and HIV Symptoms Distress Module (HIV-SDM). These questionnaires were administered at prespecified time-points: enrollment (Visit 1), 4-8 weeks later (Visit 2), and 48 ± 6 weeks after study enrollment (Visit 4). Data of patient-reported outcome total scores for both questionnaires are presented as median with 25th-75th percentiles. Questionnaires scores were analyzed overall and stratified by gender when applicable. A p value of less than 0.05 was considered statistically significant. A sensitivity analysis was conducted to evaluate the role of lost to follow-up, using the "last observation carried forward" method. RESULTS: A total of 348 patients were enrolled in this study; 296 patients (208 male and 88 female) provided both evaluable HIV-TSQ and HIV-SDM at enrollment and at 4-8 weeks, while 250 patients (174 male and 76 female) provided questionnaire data at enrollment and at 48 ± 6 weeks. The total scores of HIV-TSQ showed improvements in patient satisfaction in the overall population both at Visit 2 and Visit 4 (p < 0.001, sign test) and also when stratified by gender throughout the study period. In addition, the overall burden of symptoms, as shown by the HIV-SDM scores, decreased. CONCLUSIONS: Switching to a cobicistat-boosted darunavir-based therapy led to overall increased patient satisfaction and reduced symptom burden when compared with previous regimens. The use of patient-reported outcomes in clinical daily practice could provide a useful tool towards achieving guideline goals to achieve "fourth 90", having 90% of virally suppressed patients with a good health-related quality of life.

Effectiveness of Switching to Darunavir/Cobicistat in Virologically Suppressed HIV-Positive Patients Receiving Ritonavir-Boosted Protease Inhibitor-Based Regimen: The "STORE" Study.

OBJECTIVE: This study investigates the effectiveness and tolerability of switching to a darunavir/cobicistat (DRV/c)-based antiretroviral regimen from a ritonavir-boosted protease inhibitor (PI/r)-based regimen in virologically suppressed HIV-positive patients. DRV trough values were also investigated. SETTING: Prospective, multicenter, single-country, noninterventional cohort study. METHODS: This study included patients on a PI/r-based ART for at least 12 months having plasma HIV-1 RNA <50 copies/mL since at least 6 months. The primary endpoint, defined as HIV-1 RNA <50 copies/mL, was measured at 48 ± 6 weeks from baseline. A secondary analysis was performed using the time to loss of virological response algorithm. Biochemical parameters, including DRV trough samples, were collected as per clinical practice and measured using high-performance liquid chromatography. RESULTS: Of 336 patients enrolled, 282 completed the study: 70.8% had plasma HIV-1 RNA <50 copies/mL at 48 weeks; using the time to loss of virological response algorithm, 82.7% maintained virological suppression. Virological failure was observed in 6 patients (1.8%). Adverse event-related discontinuations were 4.5%. After 48 weeks, we found a significant improvement in both triglycerides (median, 130 to 113.5 mg/dL, P = 0.0254) and high-density lipoprotein cholesterol (48 to 49 mg/dL, P < 0.0001) but no change in other biomarkers. DRV trough concentrations in 56 subjects showed a median value of 2862.5 (1469.5-4439) ng/mL, higher in women than in men (4221 vs. 2634 ng/mL, P = 0.046). CONCLUSIONS: In stable HIV-1 positive virologically suppressed patients, the switch to DRV/c-based ART was beneficial in terms of low rates of virological failure and adverse events due to its high tolerability and improvement in triglycerides.

Cost-effectiveness of bedaquiline in MDR and XDR tuberculosis in Italy.

Objective: To evaluate the cost-effectiveness of bedaquiline plus background drug regimens (BR) for multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) in Italy. Methods: A Markov model was adapted to the Italian setting to estimate the incremental cost-effectiveness ratio (ICER) of bedaquiline plus BR (BBR) versus BR in the treatment of MDR-TB and XDR-TB over 10 years, from both the National Health Service (NHS) and societal perspective. Cost-effectiveness was evaluated in terms of life-years gained (LYG). Clinical data were sourced from trials; resource consumption for compared treatments was modelled according to advice from an expert clinicians panel. NHS tariffs for inpatient and outpatient resource consumption were retrieved from published Italian sources. Drug costs were provided by reference centres for disease treatment in Italy. A 3% annual discount was applied to both cost and effectiveness. Deterministic and probabilistic sensitivity analyses were conducted. Results: Over 10 years, BBR vs. BR alone is cost-effective, with ICERs of €16,639/LYG and €4081/LYG for the NHS and society, respectively. The sensitivity analyses confirmed the robustness of the results from both considered perspectives. Conclusion: In Italy, BBR vs. BR alone has proven to be cost-effective in the treatment of MDR-TB and XDR-TB under a range of scenarios.

Cardiovascular disease in women with HIV-1 infection.

Cardiovascular disease is a leading cause of death in women, nevertheless it is often underestimated in female patients without overt risk factors. The chronic infection by Human Immunodeficiency Virus (HIV) is clearly associated, along with the use of certain antiretroviral drugs and traditional risk factors, with an increased risk of cardiovascular diseases. The aim of this manuscript is to review the epidemiology, risk factors, pathogenesis, diagnostic approach, primary and secondary prevention strategies of cardiovascular disease in HIV-negative and HIV-positive female subjects. The ultimate goal is to promote knowledge and development of specific and appropriate clinical interventions and guidelines in this group of high-risk patients, mostly in view of the expected growth of ageing females with HIV.

Emtricitabine/tenofovir in the treatment of HIV infection: current PK/PD evaluation.

INTRODUCTION: Emtricitabine/tenofovir disoproxil fumarate fixed-dose combination (FTC/TDF FDC) is the co-formulation of a nucleoside and a nucleotide, respectively. After oral administration, both drugs exhibit plasma and intracellular half-lives suitable for once-daily dosing. Within the host cells, active metabolites FTC-TP and TFV-DP act as chain terminators to the newly synthesized proviral DNA, showing synergy at enzymatic level (viral reverse transcriptase). When given in HAART combinations, FTC/TDF FDC has a remarkable effectiveness in controlling HIV replication and securing a significant CD4(+) cell recovery. If patients treated with FTC/TDF FDC fail, a lower incidence of TDF-associated K65R resistance mutation seems to develop. Furthermore, cytidine analog-associated M184V is less likely to appear with FTC than with lamivudine when both are given with TDF. FTC and TFV are not metabolized by CYP450 enzymes and are eliminated by the renal route. TFV may accumulate in tubular cells and cause a decrease in GFR and a loss of phosphates. As a onsequence, patients treated with FTC/TDF FCD may experience varied degrees of renal impairment and osteopenia/osteoporosis. AREAS COVERED: This paper has focused on the PK/PD features of FTC and TDF, when given as single agent or when administered as FDC. The interpretation of efficacy/toxicity was guided by PK/PD features. The review of the available literature included also conference presentations and recent guidelines (as of May 2012). EXPERT OPINION: FTC/TDF FDC is a potent and reliable component of most HAART combinations due to its maintained activity across time, as demonstrated in many trials and studies. Toxicity issues (kidney, bone) are still to be entirely elucidated and the drug-induced component well separated from patient- and HIV-related ones. However, the clinical gain associated with the use of FTC/TDF FDC is fully acknowledged by its leading position in most current treatment guidelines.

KIR-HLA genotypes in HIV-infected patients lacking immunological recovery despite effective antiretroviral therapy.

BACKGROUND: In HIV-infected individuals, mechanisms underlying unsatisfactory immune recovery during effective combination antiretroviral therapy (cART) have yet to be fully understood. We investigated whether polymorphism of genes encoding immune-regulating molecules, such as killer immunoglobulin-like receptors (KIR) and their ligands class I human leukocyte antigen (HLA), could influence immunological response to cART. METHODS: KIR and HLA frequencies were analyzed in 154 HIV-infected and cART-treated patients with undetectable viral load divided into two groups: 'immunological non responders' (INR, N = 50, CD4(+) T-cell count <200/mm(3)) and full responders (FR, N = 104, CD4(+) T-cell count >350/mm(3)). Molecular KIR were typed using polymerase chain reaction-based genotyping. Comparisons were adjusted for baseline patient characteristics. RESULTS: The frequency of KIR2DL3 allele was significantly higher in FR than in INR (83.7% vs. 62%, P = 0.005). The functional compound genotype HLA-C1(+)/KIR2DL3(+), even at multivariable analysis, when adjusted for nadir CD4(+) T-cell count, was associated with reduced risk of INR status: odds ratio (95% Confidence Intervals) 0.34 (0.13-0.88), P = 0.03. CONCLUSIONS: Reduced presence of the inhibitory KIR2DL3 genotype detected in INR might provoke an imbalance in NK function, possibly leading to increased immune activation, impaired killing of latently infected cells, and higher proviral burden. These factors would hinder full immune recovery during therapy.

Under representation of the inhibitory KIR3DL1 molecule and the KIR3DL1+/BW4+ complex in HIV exposed seronegative individuals.

The activation of natural killer (NK) cells is modulated by surface molecules. We analyzed NK cells in human immunodeficiency virus (HIV)-exposed seronegative (HESN) individuals by means of molecular typing of HLA B, Cw, and killer cell immunoglobulin-like receptor (KIR) molecules. In HESN individuals, compared with HIV patients, the frequency of the inhibitory KIR3DL1 allele and of the KIR3DL1(+)/Bw4(+) inhibitory complex was reduced, whereas that of the activatory KIR3DS1(+) ligand and the activatory Bw4(+)/3DL1(-)/3DS1(+) complex was increased, resulting in a statistically significant diversion from Hardy-Weinberg equilibrium (KIR3DS1 homozygote) in HESN individuals. The reciprocal equilibrium between inhibitory and activatory NK receptors and their ligands favors NK activation in HESN individuals.

Antiviral hyperactivation-limiting therapeutics as a novel class for the treatment of HIV/AIDS: focus on VS411.

INTRODUCTION: Immune activation plays a central pathogenetic role in both HIV-1 replication and depletion of CD4(+) T cells leading to disease progression and the onset of the AIDS. While current antiretroviral therapies suppress viral replication to undetectable levels, they do not normalize the excessive level of T-cell activation and proliferation. A new class of anti-HIV-1 drugs known as antiviral hyperactivation-limiting therapeutics (AV-HALTs) combines direct antiviral activity with an antiproliferative action to limit the hyperactivation of the immune system now recognized as the key driver of the progressive loss of CD4(+) T cells that occurs over the natural course of the HIV-1 infection. AREAS COVERED: Areas covered include preclinical, Phase I and Phase IIa studies of VS411, the first drug product in a novel class of anti-HIV drugs, AV-HALT agents. EXPERT OPINION: The two drug combination VS411 safely achieved the goals established for the AV-HALT class based on the results of a Phase IIA proof-of-concept study. Additional work is underway to identify and develop new agents that combine the dual attributes of AV-HALTs, direct reduction of both HIV-1 viral load and markers of excessive immune activation, in a single molecule.

Once-a-day (QD) vs. twice-daily (BID) nevirapine as simplification in PI-treated patients after 2 mos. of BID induction.

To assess the efficacy and the tolerability of once-daily (QD) versus twice-daily (BID) nevirapine (NVP)-based highly active antiretroviral therapy (HAART) in virologically suppressed, HIV-positive patients switched from protease inhibitor (PI)-based HAART. Eligible patients were enrolled in the multicenter trial if HIV RNA levels were <50 copies/mL for ³6 months prior. Patients were switched from a PI to NVP 200 mg BID for 2 months, and then randomized to continue with that regimen (group A) or NVP 400 mg QD (group B) for a further 10 months. Virological efficacy (primary endpoint) and tolerability/toxicity were evaluated according to an intention-to-treat analysis. A total of 126 patients (63 per group) were enrolled. Withdrawals from the study (any reason) numbered 15 in group A and 14 in B, virological failures numbered 5 and 2, respectively, and there were 4 cases of adverse events in each group (all p = NS). Mean alanine aminotransaminase (ALT) and gamma-glutamyl transpeptidase (γ-GT) level increases were significant for the whole cohort (33.2±22.9 to 43.3±29.1, p < 0.001; 57.3±72 to 109±131 U/L, p < 0.0002, respectively), but there were no differences between the two groups. Apparently, no significant differences between the QD and BID NVP groups were found, in terms of virological failures or tolerability/toxicity. The switch to NVP may be safely pursued with a QD schedule.

Emerging mutations at virological failure of HAART combinations containing tenofovir and lamivudine or emtricitabine.

OBJECTIVE: To compare the emergence of drug-resistant HIV variants at failure of lamivudine (3TC)/tenofovir (TDF)-containing or emtricitabine (FTC)/TDF-containing HAART as a consequence of the different 3TC and FTC intracellular half-lives. DESIGN: Retrospective evaluation of 859 patients selected from an Italian HIV resistance database (Antiretroviral Resistance Cohort Analysis). METHODS: Patients were selected for analysis if treated with a HAART whose nucleoside/nucleotide reverse transcriptase inhibitor backbone was either 3TC/TDF or FTC/TDF; if they experienced a virological failure after at least 6 months of plasma HIV-RNA undetectability; and if HIV genotypes before treatment and at failure were available. Univariate and multivariate logistic regression analyses were done to detect predictors of resistance mutations emerging at failure. RESULTS: Of 714 patients failing with 3TC/TDF and 145 with FTC/TDF, 35.8 and 21.1% were in Centers for Disease Control and Prevention stage C, and 8.8 and 15.2% were on first-line HAART, respectively. At multivariate analysis, the emergence of K70R (P = 0.002), M184V (P = 0.031), T215F (P = 0.020) and Y181C (P = 0.005) was significantly more common in 3TC-treated than in FTC-treated patients, with an odds ratio of 4, 1.56, 1.89 and 3.84, respectively. CONCLUSION: Despite their close structural similarity, 3TC and FTC are associated with a significantly different rate of drug resistance at treatment failure when combined with TDF in HAART regimens independently of the third drug used.

Nelfinavir+M8 plasma levels determined with an ELISA test in HIV infected patients with or without HCV and/or HBV coinfection: the VIRAKINETICS II study.

Virakinetics II was designed as an observational, multicenter cohort study conducted in HIV-positive patients treated with NFV-based combinations. Trough (pre-dose) concentrations of NFV+M8 in plasma were determined using a novel ELISA test (NFV TDM-ELISA) and analyzed using clinical and laboratory parameters. Drug levels were sorted as below, within or above a given interval (<0.8 microg/mL, 0.8-3.5 microg/mL and >3.5 microg/mL, respectively). Longitudinal analysis was performed in a subset of patients who underwent two or more determinations. Ninety patients on NFV-containing HAART were enrolled and 43 were coinfected with HCV and/or HBV. Among coinfected patients, 10 subjects had a clinical or histological diagnosis of cirrhosis. Compared to the HIV-monoinfected, the coinfected patients were significantly older, more treatment-experienced, with higher frequency of lipodystrophy and altered liver function test values (all p values: <0.05). Coinfected patients were also more likely to be on a reduced dose of NFV than monoinfected (p=0.03). No significant difference was observed between the two groups with regard to NFV+M8 trough values and concentration range distribution. Median NFV+M8 C(trough) concentrations were higher in coinfected patients, but without reaching statistical significance (p=0.2). This new ELISA test proved to be a rapid, convenient and reliable tool for assessing NFV+M8 plasma levels in HIV-positive patients. It could be suitable for use within the framework of routine clinical practice even in peripheral centers without specialized laboratories.

Correlations between atazanavir C(trough )and hyperbilirubinemia: a case report.

INTRODUCTION: Hyperbilirubinemia is a common side effect of the antiretroviral agent atazanavir but is generally reversible upon discontinuation of treatment. We used therapeutic drug monitoring to investigate the occurrence of hyperbilirubinemia in a 49-year-old Hispanic man infected with HIV, following an overdose of ritonavir in ritonavir-boosted atazanavir therapy. CASE PRESENTATION: A 49-year-old Hispanic man with HIV who had received several highly active antiretroviral therapy regimens over a number of years including atazanavir-containing regimens, was diagnosed with hyperbilirubinemia. An inappropriate doubling of ritonavir boosting resulted in a high atazanavir C(trough )and an initial rise in bilirubin plasma levels. Bilirubin levels later decreased, probably as a consequence of enzyme induction, while atazanavir plasma concentrations remained elevated. CONCLUSION: This article describes an occurrence of hyperbilirubinemia in a man infected with HIV and supports the importance of therapeutic drug monitoring in investigations of hyperbilirubinemia among patients receiving antiretroviral agents. That the patient tolerated exceptionally high atazanavir levels further strengthens the tolerability profile of this drug.

Proven intra and interobserver reliability in the echographic assessments of body fat changes related to HIV associated Adipose Redistribution Syndrome (HARS).

OBJECTIVE: To prove intra- and inter-observer's reliability of ultrasound (US) in the assessment of lipoatrophic findings related to the HIV associated Adipose Redistribution Syndrome (HARS). PATIENTS AND METHODS: In two separated sessions, 2 consecutive measurements of subcutaneous fat thickness (SFT) were performed by each observer at the deepest point of Bichat pad, the dorsal face of arm and the mid thigh for the assessment of facial, brachial and crural lipoatrophy, respectively. We enrolled 20 HIV patients, rotating an experienced and untrained sonologist. The assessments were performed avoiding any stand off pads in the skin and excluding artefacts due to the too abundant quantity of gel to obtaining, with minimal transducer pressure, the best resolution of the reference points. RESULTS: Means of facial, brachial and crural SFT showed no significant differences between the workers. Coefficients of variability (SD/mean x100) were similar for facial (ranges: 4.7-5.2% vs 4.9-5.6%, respectively), brachial (ranges: 5.8-8.4% vs 9.7-11.2%) and crural SFTs (ranges: 5.9-6% vs 6.2-8.7%). There was greater consistency in the measurements performed by the experienced vs the untrained worker. Inter-observer agreement, assessed through kappa statistic (k) analysis, confirmed increased measurement's agreement in the facial (k ranged from 0.40 to 0.60), brachial (k: 0.23-0.63) and crural SFT assessments (k: 0.58-0.70) from the 1(st) to 2(nd) session. CONCLUSIONS: US shows low intra observer variability and good inter observer reliability in the assessment of body fat changes related to the HARS. The different degree of consistency by the workers and the improvement of interobserver agreement, suggest to stating a well defined period of training to obtain better US reliability.

Comparability of echographic and tomographic assessments of body fat changes related to the HIV associated adipose redistribution syndrome (HARS) in antiretroviral treated patients.

To assess the comparability of ultrasonographic (US) subcutaneous fat thickness (SFT) measurements in comparison with computed tomography (CT) at reference points (RPs) representative of HIV related adipose redistribution syndrome (HARS) in patients treated with antiretrovirals. US and CT measurements were compared in nine patients with clinical reports of HARS. We obtained the best resolution of facial (at deepest point of Bichat pad), brachial (in the dorsal face of arm) and crural SFT (at mid thigh) by means of minimal transducer pressures avoiding potential biases such as stand off pads pressure on the skin and artefacts due to too abundant quantity of gel. CT scans were obtained in the same RP where US measurements were performed such as identified by means of metallic skin markers. Median US measurement of facial SFT was 8.8 mm (95% CI: 3.1 to 13.4), 3.95 mm (95% CI: 2.62 to 5.84) for brachial SFT and 4 mm (95% CI: 3.4 to 9.4) for crural SFT. Median CT assessments of facial SFT was 8.7 mm (95% CI: 3.5 to 13.5), 4.2 mm (95% CI: 2.6 to 5.88) for brachial SFT and 5 mm (95% CI: 3.9 to 10.3) for crural SFT, with no significant difference at each RP. A linear regression showed good CT/US comparability at each RP, with no significant deviation from linearity (p > 0.10). US shows to be highly comparable with CT, excluding invaliding biases as the transducer pressure on the skin. Given the proven efficacy on the HARS assessments, if well standardized, US could be a reliable method, simpler than CT in the management of body fat changes related to HARS.

Evaluation of Elisa test for therapeutic monitoring of Nelfinavir in HIV-positive patients.

Therapeutic drug monitoring (TDM) is an important tool in the management of antiretroviral (ARV) therapy. The gold standard for measuring drugs plasma levels is High-Performance Liquid Chromatographic Assay (HPLC) however it is technically-demanding and time-consuming. We evaluated a new immunoenzymatic test (TDM-ELISA, Biostrands, Trieste, Italy) for nelfinavir and its active metabolite M8 in comparison with HPLC. A statistically significant difference in Ctrough between the two different tests was demonstrated but this difference was no longer significant when a value of 29% due to M8 aliquot was deleted. This faster TDM-ELISA may have an important role for TDM in HIV patients taking ARVs.

[Amoxicillin in tonsillectomy: preliminary data on the evaluation of serum and tissue concentrations]. / L'amoxicillina nella tonsillectomia: dati preliminari sulla valutazione delle concentrazioni sieriche e tessutali.

Amoxicillin was administered to 50 patients with chronic recurrent tonsillitis waiting for tonsillectomy. Group A (N=16) received 2.2 g of amoxicillin plus clavulanic acid with intravenous injection 10 minutes before tonsillectomy Group B (N=34) was treated with 3 doses of amoxicillin-clavulanic acid administered orally the day before surgery, plus one oral administration 2 hours before tonsillectomy. Antibiotic doses were established on patient's weight using maximum suggested. The measures were, estimated in serum and in tonsils using High Performance Liquid Chromatography, (HPLC). The data show better efficacy of intravenous administration than oral administration.