Disseminated and Relapsing Cryptococcosis: What We Still Have to Learn—a Case Series and Review of Literature

AbstractTwo cases of disseminated cryptococcosis are described. The first was an HIV-infected patient where cryptococcosis was diagnosed as "unmasking immune reconstitution syndrome"; the second was an immunosuppressed patient with multiple myeloma. In both cases, a definitive healing could not be reached despite long therapeutic approaches. This review summarizes both the most recent and relevant studies about disseminated and refractory form of cryptococcal infections and identifies research gaps. Given the limited data, we draw some conclusions with respect to management from literature: not clear and accepted indication are available regarding disseminated cryptococcosis, no specific schemes were identified, and the duration of therapy is usually decided case by case and supported only by case reports. In this perspective, usually standard therapeutic schemes and duration of induction depend on multiple factors (e.g., neurologic deficit, non-HIV/non transplant status, CSF culture positivity at 2 weeks, etc.). We found that there are no empiric and literature data that support a role of cryptococcal serum antigen (CRAG) in guiding the antifungal therapy; with the data collected, we think that although is possible, it is very rare to find disseminated cryptococcosis with negative CRAG. We looked also for the more important risk factor of recurrence. Some possible causes explored are risk of azole resistant strains, pre-existent conditions of patients that play a permissive role and the common situation where flucytosine is unavailable that led to suboptimal induction phase of therapy. Herein, we discuss disseminated cryptococcosis with a particular attention to antifungal therapy, role of cryptococcal antigen, and risk factors for recurrence of disease

Impact of antiretroviral dosing and daily pill burden on viral rebound rates in naive patients receiving a tenofovir-based regimen

Methods A total of 480 ART-naive patients were selected from the GNOMO cohort. Incidence rate of viral rebound (VR = first of two consecutive VL>50 cp/ml) was calculated as number of events over PYFU and expressed at univariate and multivariate analysis as incidence rate ratio (IRR). Number of both pills and doses per day were used to define three different types of regimens: twice-a-day regimens (BID regimens); once-a-day regimens with 3 pills (high-pill QD [hp-QD]). Adjusted rates of viral rebound were estimated by Poisson regression using date of first HIV-RNA <50 c/ml as baseline. Follow-up was censored at the date of VR, death, or loss to follow-up

Long-term data on the efficacy and tolerability of lamivudine plus dolutegravir as a switch strategy in a multi-centre cohort of HIV-1-infected, virologically suppressed patients

BACKGROUND: Results from clinical trials and observational studies suggest that lamivudine plus dolutegravir (3TC+DTG) could be an effective and tolerated option for simplification in human immunodeficiency virus (HIV)-1-positive patients. MATERIALS AND METHODS: This observational study enrolled HIV-1-infected, virologically suppressed patients switching to 3TC+DTG. Kaplan-Meyer survival analysis was performed to evaluate time to virological failure (VF; defined by a single HIV-RNA determination ≥1000 copies/mL or by two consecutive HIV-RNA determinations ≥50 copies/mL) and time to treatment discontinuation (TD; defined as interruption of either 3TC or DTG), Cox regression was performed to assess predictors, and linear mixed model was performed for repeated measures to measure changes in immunological and metabolic parameters. RESULTS: Five hundred and fifty-six patients were eligible for analysis. Their median CD4+ count at baseline was 668 cells/mm3 and median time of virological suppression was 88 months. Estimated probabilities of maintaining virological suppression at 96 and 144 weeks of follow-up were 97.5% [standard deviation (SD) 0.8] and 96.5% (SD 1.0), respectively. Years since HIV diagnosis was the only predictor of VF. In patients with time of virological suppression &lt;88 months, the rate of VF was higher in the presence of the M184V mutation. Estimated probabilities of remaining on 3TC+DTG at 96 and 144 weeks of follow-up were 79.2% (SD 1.9) and 75.2% (SD 2.2), respectively. A significant increase in CD4 cell count (+44 cells/mm3, P=0.015), CD4/CD8 ratio (+0.10, P=0.002) and high-density lipoprotein cholesterol (+5.4 mg/dL, P=0.036) was found at 144 weeks of follow-up; meanwhile, total cholesterol (-9.1 mg/dL, P=0.007) and triglycerides (-2.7, P=0.009) decreased significantly. CONCLUSIONS: These findings confirm the efficacy and tolerability of 3TC+DTG in virologically suppressed patients. Copyright © 2019 Elsevier Ltd. All rights reserved

Switch to maraviroc with darunavir/r, both QD, in patients with suppressed HIV-1 was well tolerated but virologically inferior to standard antiretroviral therapy: 48-Week results of a randomized trial

Objectives Primary study outcome was absence of treatment failure (virological failure, VF, or treatment interruption) per protocol at week 48. Methods Patients on 3-drug ART with stable HIV-1 RNA &lt;50 copies/mL and CCR5-tropic virus were randomized 1:1 to maraviroc with darunavir/ritonavir qd (study arm) or continue current ART (continuation arm).Results In June 2015, 115 patients were evaluable for the primary outcome (56 study, 59 continuation arm). The study was discontinued due to excess of VF in the study arm (7 cases, 12.5%, vs 0 in the continuation arm, p = 0.005). The proportion free of treatment failure was 73.2% in the study and 59.3% in the continuation arm. Two participants in the study and 10 in the continuation arm discontinued therapy due to adverse events (p = 0.030). At VF, no emergent drug resistance was detected. Co-receptor tropism switched to non-R5 in one patient. Patients with VF reported lower adherence and had lower plasma drug levels. Femoral bone mineral density was significantly improved in the study arm. Conclusion Switching to maraviroc with darunavir/ritonavir qd in virologically suppressed patients was associated with improved tolerability but was virologically inferior to 3-drug therap

Edge reductions in cyclically k-connected cubic graphs

AbstractThis paper examines edge reductions in cyclically k-connected cubic graphs, focusing on when they preserve the cyclic k-connectedness. For a cyclically k-connected cubic graph G, we denote by Nk(G) the set of edges whose reduction gives a cubic graph which is not cyclically k-connected. With the exception of three graphs, Nk(G) consists of the edges in independent k-edge cuts. For this reason we examine the properties and interactions between independent k-edge cuts in cyclically k-connected cubic graphs. These results lead to an understanding of the structure of G[Nk]. For every k, we prove that G[Nk] is a forest with at least k trees if G is a cyclically k-connected cubic graph with girth at least k + 1 and Nk ≠ ⊘. Let fk(ν) be the smallest integer such that |Nk(G)| ≤ fk(ν) for all cyclically k-connected cubic graphs G on ν vertices. For all cyclically 3-connected cubic graphs G such that 6 ≤ ν(G) and N3 ≠ ⊘, we prove that G[N3] is a forest with at least three trees. We determine f3 and state a characterization of the extremal graphs. We define a very restricted subset N4b of N4 and prove that if N4g = N4 − N4b ≠ ⊘, then G[N4g] is a forest with at least four trees. We determine f4 and state a characterization of the extremal graphs. There exist cyclically 5-connected cubic graphs such that E(G) = N5(G), for every ν such that 10 ≤ ν and 16 ≠ ν. We characterize these graphs. Let gk(ν) be the smallest integer such that |Nk(G)| ≤ gk(ν) for all cyclically k-connected cubic graphs G with ν vertices and girth at least k + 1. For k ∈ {3, 4, 5}, we determine gk and state a characterization of the extremal graphs

Cohort profile: The Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE)

The Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE) cohort was established in Italy in 2016 to evaluate the overall efficacy and tolerability of dolutegravir (DTG)-based antiretroviral (ARV) regimens in clinical practice

Switch to maraviroc with darunavir/r, both QD, in patients with suppressed HIV-1 was well tolerated but virologically inferior to standard antiretroviral therapy: 48-Week results of a randomized trial

Objectives: Primary study outcome was absence of treatment failure (virological failure, VF, or treatment interruption) per protocol at week 48. Methods: Patients on 3-drug ART with stable HIV-1 RNA &lt;50 copies/mL and CCR5-tropic virus were randomized 1:1 to maraviroc with darunavir/ritonavir qd (study arm) or continue current ART (continuation arm). Results: In June 2015, 115 patients were evaluable for the primary outcome (56 study, 59 continuation arm). The study was discontinued due to excess of VF in the study arm (7 cases, 12.5%, vs 0 in the continuation arm, p = 0.005). The proportion free of treatment failure was 73.2% in the study and 59.3% in the continuation arm. Two participants in the study and 10 in the continuation arm discontinued therapy due to adverse events (p = 0.030). At VF, no emergent drug resistance was detected. Co-receptor tropism switched to non-R5 in one patient. Patients with VF reported lower adherence and had lower plasma drug levels. Femoral bone mineral density was significantly improved in the study arm. Conclusion: Switching to maraviroc with darunavir/ritonavir qd in virologically suppressed patients was associated with improved tolerability but was virologically inferior to 3-drug therapy

Four-drugs regimen containing raltegravir is highly effective in HIV patients starting therapy with >500,000 copies/mL viral load

Introduction: Assessing virological response of four-drugs antiretroviral regimen that include raltegravir (RAL) in naïve patients with high viral load (>500,000 copies/mL) selected from a multicentre Italian database. Methods: Naïve patients with HIV RNA>500,000 copies/mL, who began standard antiretroviral regimens either based on non-nucleoside reverse transcriptase inhibitors (NNRTI) or boosted-PI (PI/r), or a standard regimen plus RAL between 2008 and 2013 were analyzed. Observation was censored at 12 months and the percentage of patients who achieved a viral load below the limit of detection (BLD) was calculated. Virological failure was defined as two consecutive viral loads>40 copies/mL. Results: Overall, 179 patients were included (13% with primary HIV infection (PHI), and 42.5% with AIDS diagnosis). Of them, 156 started standard three-drugs antiretroviral regimen (75.6% PI/r-based, 24.4% NNRTI-based. Among patients with PHI, 23 patients (12.8%), 6 (25%) started a four-drugs antiretroviral regimen containing both RAL and PI/r. Patients’ characteristics were as follows: males 74%, median age 42 years (IQR 35–51), sexually transmission 75.1%, median CD4 count 156 cells/µL (IQR 47–368) and median HIV-RNA 6.1 log10 copies/mL (IQR 5.8–6.4). 91 of 179 patients (50.8%) reached BLD viral load during the twelve months of observation. Three patients (1.7%) who began regimens PI/r-based with three-drugs had virological rebound after reaching BLD viral load. By use of survival analysis, we show that those patients who added RAL to the standard regimen have reached the primary end point faster (mean 8.4 months (95% CI 7.2–9.6) vs 11.4 (95% CI 11.0–11.8) in PI group and 10.3 (95% CI 9.4–11.1) in NNRTI group; p<0.001, Figure 1). In the adjusted analysis, the choice of a standard regimen versus a four-drugs regimen was driven only by higher baseline viral load (OR. 9.05; 95% CI 2.41–37.41; p=0.001). Conclusions: Only half of the naïve patients who began antiretroviral therapy having >500,000 copies/mL HIV-RNA had virological success at 12 months. The success was reached faster using the RAL-containing four-drugs regimen, suggesting that strengthening the initial regimen could be an option in patients with very high viral load to improve virological response

Shall we dance? Extending tango's results to clinical practice

After previous evidence from the ASPIRE trial [1], results from TANGO study [2] definitively proved the efficacy of lamivudine (3TC) plus dolutegravir (DTG) as a maintenance strategy. As trials\u2019 populations often differ from real-practice settings, we aimed to assess whether these results are reproducible in an unselected HIV-population. An observational longitudinal multicenter research study was conducted. HIV-positive patients with viral suppression (at least one HIV-RNA&lt;50 copies/mL) were followed-up from the start of 3TC+DTG. The cohort was divided into two groups based on compliance or not with the inclusion criteria of TANGO study (absence of HBV-coinfection, of previous virological failure (VF), of a M184V-harboring virus and of previous AIDS-event other than cutaneous Kaposi\u2019s sarcoma and nadir CD4 count 64200 mm3). Time to VF (i.e. 2 consecutive HIV-RNA determinations 6550 cps/mL or a single HIV-RNA 651000 cps/mL) and to treatment discontinuation (TD, i.e. the interruption of any of the study drugs) in the 2 groups were compared through Kaplan-Meier with log-rank test and Cox-regression model after adjusting for the main clinical and demographic between-groups differences. Changes in immunological parameters were assessed by linear mixed model for repeated measures. We analyzed 557 patients with a median follow-up time of 22 months: 145 (26.0%) met the TANGO inclusion criteria (TANGO group, TG)