Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders

Despite optimal suppression of HIV replication, restoration of CD4(+) T cells is not always achieved in antiretroviral therapy-treated individuals. Defective CD4 recovery in immunologic nonresponders is possibly associated with TLR-mediated immune activation driven by alterations of gut permeability. Hydroxychloroquine (HCQ) reduces endosomal TLR signaling; thus, we verified whether HCQ could dampen immune activation and be associated with an increase in CD4(+) T cells. To this end, we enrolled in a prospective study 20 HIV-infected immunologic nonresponders (CD4 count < 200 cells/mL or CD4 increase < 5% in the last 12 months) who received 400 mg/day HCQ for 6 months. HCQ had a notable impact on immune activation as shown by significant modifications of the following parameters: (1) reduced plasma lipopolysaccharide; (2) decreased TLR4-expressing CD14(+) cells, TLR4-mediated signal transduction, and mRNA synthesis; (3) reduced percentages of activated CD4(+) (CD4(+)/Ki67(+)) and CD14(+) (CD14(+)/CD69(+)) cells; (4) increased T-regulatory cells (Tregs), naive Tregs, and TLR4-expressing Tregs; (5) augmented plasmacytoid dendritic cells and reduced IFN alpha-secreting plasmacytoid dendritic cells; and (6) reduced IL-6 and TNF alpha production. HCQ-induced immune modulation was associated with increased percentages of circulating CD4(+) T cells and was mostly retained 2 months after therapy interruption. HCQ reduces lipopolysaccharide/TLR-mediated immune activation; this compound could be a useful immunomodulant in HIV-infected patients. This study is registered at EutraCT as 2009-012499-28 with study number HLS01/2009-1-16-03-2009. (Blood. 2011;118(12):3263-3272

Dolutegravir Plus Rilpivirine as a Switch Option in cART-Experienced Patients: 96-Week Data

Background: Data from clinical studies confirm the efficacy of switching to dolutegravir (DTG) plus rilpivirine (RPV) in selected patients. Objective: The primary objective is to report the 96-week virological suppression in our cohort, assessing the durability of this strategy in complicated situations. The secondary objective is to describe the safety and metabolic profile. Methods: All patients who had switched to DTG plus RPV between October 1, 2014, and September 30, 2015, were analyzed using a retrospective-prospective design, approved by ethics committees. Routine metabolic, immunological, and virological data were regularly sent to the coordinating center. Viral control was classified as HIV-1 RNA 6550 copies/mL, 1 to 49 copies/mL, or undetectable (no virus detected [NVD]). Results: We followed 145 patients for a median of 101 weeks. The median age was 52 years; 31.7% were women, and 9.6% non-Caucasian; 50.3% had failed at least 1 antiretroviral regimen; and 15% had 6550 copies/mL at baseline. The reasons for switching were as follows: simplification (51.7%), toxicity (36.5%), drug-drug interactions (6.9%), persistent low-level viremia (3.0%), nonadherence (2.1%), and viral failure (1.4%). By week 96, seven patients dropped out. At week 96, none had 6550 HIV-1 RNA copies/mL, 138 (95.2%) had &lt;50 copies/mL, and 123 (84.8%) had NVD. The low- to high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio decreased significantly (P = 0.04). Of the 287 baseline altered laboratory parameters, 32.7% normalized by week 96. Serum glucose and total- and LDL-cholesterol normalization were statistically significant. Conclusions: Switching to DTG plus RPV improved viral suppression and LDL-C/HDL-C ratio

Fenestrated anaconda™ endograft for juxta/para-renal aortic aneurysms. Preliminary Italian multi-center experience

BACKGROUND: The AnacondaTM Fenestrated endograft (Vascutek, Inchinnan, UK) is a new device that could be used to treat challenging aortic aneurysms (AAA) involving the abdominal visceral vessels. The aim of the present study was to report the preliminary results of the Italian multi-centers experience. METHODS: Patients undergone fenestrated endovascular aneurysm repair (FEVAR) using AnacondaTM Fenestrated endograft, between May 2012 and November 2014, were prospectively enrolled. Clinical, morphological, intra and postoperative data were collected. Indications for FEVARincluded AAAwith proximal neck unsuitable for standard EVAR. Planning was performed on the computed tomography angiography using dedicated software for the advanced vessels analysis. Primary endpoints were technical success (TS) and 30-day clinical success (CS). Secondary endpoints were: adverse events (type I/III endoleaks, target visceral vessels occlusion)/reinterventions FEVAR-related and AAA-related mortality during the follow-up. RESULTS: Twenty-six patients (male, mean age 74±7years, ASAIII/IV:16/10) underwent FEVARusing AnacondaTM Fenestrated endograft in 11 Italian Vascular Surgery Units for 5 short neck AAAand 21 juxta/para-renal AAA. An overall of 67 target visceral vessels were accommodated by using of fenestrations. Fenestrated endograft with 1, 2, 3 and 4 fenestrations were used in 1, 10, 14 and 1 cases, respectively. Abifurcated and tube endograft was planned in 23 and 3 cases, respectively. In 17/26 (65%) cases the endograft was repositioned during the procedure and in 14/26 (54%) cases almost 1 target visceral vessel was cannulated from the brachial access. TSwas achieved in 24/26 (92%) patients (2 type I endoleak). All the target visceral vessels were successfully cannulated and stented. An occlusion of 1 renal artery and 1 type III endoleak (between the aortic endograft and renal artery stent-graft) occurred within the first week. The 30-day mortality was 7.7% (2/26). The 30-day CS was 80%. The mean follow-up was 12 months (range:1-33). No type I/III endoleaks and target visceral vessels occlusion occurred during the follow-up. There were not re-interventions FEVAR-related and AAA-related mortality. CONCLUSIONS: The AnacondaTM Fenestrated endograft can be used to treat challenging AAAinvolving the abdominal visceral vessels. Larger experiences and long-term data are mandatory to confirm this treatment as safe and effective also in the mid and long term follow-up

Proximal aortic neck angle does not affect early and late EVAR outcomes: an AnacondaTM Italian Registry analysis.

AIM: The aim of this paper was to evaluate early and 3-year results of the endovascular repair (EVAR) for abdominal aortic aneurysm (AAA) using the AnacondaTM endograft in patients with severe proximal aortic neck angle. METHODS: A retrospective analysis of the AnacondaTM Italian Registry was carried out. Two groups of patients were identified according to the presence of a severe (Group A, GA: 65 60\ub0) or an absent (Group B, GB: <45\ub0) proximal aortic neck angle. Preoperative, procedural and follow-up data were evaluated. Mortality, proximal type I endoleak, freedom from iliac leg thrombosis and conversion to open repair were analyzed at 30-day and 3-year follow-up. The results of GA and GB were compared. RESULTS: From 2005 to 2012, 1030 patients were enrolled in the Registry. Sixty-five patients (6.3%) were included in GA and 737 (71.5%) in GB. The mean age and AAA diameter were respectively 76.8 years and 62.7 mm in GA and 77.2 years and 56.5 mm in GB (P=NS). The ASA 65 3 was reported in the 95.3% of GA vs. 81% of GB (P=0.005). The endograft main-body was repositioned in 35% of cases in GA and 20.7% in GB (P=0.008); there were no differences in the main-body ballooning and proximal aortic cuff placement. There were no statistical differences in 30-day mortality (GA 1.5% vs. GB 1.3%), proximal type I endoleaks (GA 1.5% vs. GB 0.8%), iliac leg thrombosis (GA 1.5% vs. GB 1.4%) and conversion to open repair (GA 3% vs. GB 0.6%). The 3-year survival was 95.4% in GA and 94.7% in GB (P=NS). Freedom from proximal type I endoleak, iliac leg thrombosis and conversion to open repair were respectively 98.5%, 95.4%, and 95.4% in GA and 97.8%, 96.9%, and 98.5% in GB (P=NS). CONCLUSION: The AnacondaTM Italian Registry reports good results in terms of clinical success at 3-year follow-up. AAA with severe proximal aortic neck can be treated with similar outcomes to AAA with favorable neck anatomy. The endograft repositionability is a benefit in cases with severe neck angl

Antiretroviral genotyping resistance in plasma RNA and whole blood DNA in HIV-1 infected patients failing HAART

The extent to which HIV-1 proviral DNA mutations cause clinically relevant antiretroviral resistance is still controversial. Paired plasma HIV-1 RNA and whole blood DNA were compared in patients failing HAART to investigate if the additional knowledge of archived mutations could improve the selection of potentially active drugs. Seventy-three HIV-1-infected patients with first/second HAART failure were studied before starting a new regimen based on RNA genotyping. Follow-up data after a 12-week therapy were available. DNA genotyping was retrospectively performed on stored whole blood samples and mutational profiles were compared to those from RNA. The mean number of IAS pol mutations was significantly higher in RNA (4.45 +/- 2.76) than in DNA (2.88 +/- 2.47) (P or=1 mutation revealed by DNA genotyping alone, probably affecting therapy success in 2/16. However, neither RNA/DNA discordance nor detection of isolated DNA mutations were statistically associated with outcome. In conclusion, plasma RNA remains the elective choice for HIV genotyping in patients with therapy failure, even if the detection of proviral resistance-associated mutations, not simultaneously found in RNA, is a frequent event. Therefore, in some cases DNA plus RNA genotyping might assist in choosing more accurately subsequent antiretroviral regimen