Loss of Soluble (Pro)renin Receptor Attenuates Angiotensin-II Induced Hypertension and Renal Injury

Rationale: Cleavage of the extra-cellular domain of the (pro)renin receptor (PRR) yields a soluble fragment (sPRR). Although changes in plasma sPRR levels have been reported in hypertension, the causal role of sPRR in blood pressure (BP) regulation is unknown. Objective: Determine the role of sPRR in BP regulation at baseline and following Ang-II induced hypertension. Methods and Results: CRISPR-Cas9 was used to mutate the cleavage site of the PRR such that sPRR is not generated. Because the gene encoding PRR is on the X-chromosome and male mutant sPRR mice are infertile, only male mice were studied. Mutant sPRR mice had virtually undetectable plasma sPRR levels compared to littermate controls. Mutant sPRR mice had normal survival and development and no apparent histological abnormalities in the kidney, heart or aorta despite lower body weight. During normal Na+ intake, no differences in food or water intake, urinary water or Na+ excretion, or acid-base status were observed between control and mutant sPRR mice. Compared to controls, mutant sPRR mice had lower BP at baseline and an attenuated hypertensive response to 2 weeks of Ang-II infusion (400 ng/kg/min) which was partially reversed by infusion of mouse recombinant sPRR. Mutant sPRR mice also had lower albuminuria, renal tubular injury and oxidative stress relative to control mice post Ang-II infusion. Further, mesenteric arteries from mutant sPRR mice displayed reduced Ang-II-induced vasocontraction and greater acetylcholine, but not sodium nitroprusside, evoked vasorelaxation under baseline conditions. Conclusions: Loss of sPRR reduces BP at baseline and decreases Ang-II induced hypertension and renal injury. These effects of sPRR loss are associated with greater endothelium-dependent but not independent vasorelaxation of resistance-sized arteries.

P347 Undetectable levels of adalimumab in clinical practice: Should we say goodbye to the drug?

Background Therapeutic drug monitoring (TDM) is used in inflammatory bowel disease to guide dosing of biologics to individualise drug exposure and optimise outcomes. In case of undetectable levels of Adalimumab (levels <1.6 μg/ml) some authors recommend to discontinue the treatment, although this strategy is not universally accepted. The aim of this study was to describe the evolution (recovery of levels and persistence of treatment) of patients with undetectable levels of ADA and its relationship with the different treatment strategies (dose escalation and/or addition of an immunosuppressant) Methods Since October 13 to August 19, 758 TDM were performed in 260 patients treated with ADA. We selected the patients who had at least a level <1.6 μg / ml. Patients with follow-up fewer than 90 days after level detection and those in whom the drug was withdrawn at that time were excluded Results We identified 46 patients with undetectable levels; 12 were excluded. Thirty-four patients were included, 29 (85.3%) with Crohn’s disease and 5 (14.7%) with ulcerative colitis. Ten (29.4%) patients had combined treatment and 17 (50%) had previously received another anti-TNF. In 24 (70.6%) TDM was performed proactively. After detection of levels <1.6 μg /ml, ADA was intensified in 20 patients (58.8%) either shortening the interval in 18 (90%), increasing the dose in 8 (40%) or with both interventions in 6 (30%). In 5 (14.7%) patients an immunomodulator was added and in 14 (41.2%) the treatment was not modified. At the end of the follow-up (mean 1101 days; SD 510) 61.8% (21/34) of the patients continued with ADA: 75% (15/20) in the intensified group and 42.9% (6/14) in the group of those who did not receive changes in treatment. Fourteen patients (41. 2%) recovered therapeutic levels (>5 μg/ml), 12 (60%) in the intensified-patient group and 2 (14.3%) in the group in whom the treatment was not modified. ADA was withdrawn in 13 patients (32.8%) after a mean time of 358 days (SD 258). The ADA maintenance rate (HR=3.88; 95% CI 1.2–12.4; p = 0.02) and the recovery ratio of ADA levels (HR = 6.75; 95% CI 1.1–39, 8; p = 0.03) was higher in the intensified group. Hypoalbuminemia was associated with an earlier withdrawal of ADA (p = 0.03) Conclusion The intensification of ADA in patients with IBD and undetectable plasma concentrations allows recovery of levels and maintenance of the drug in a high percentage of patients. The decision to withdraw treatment in patients with undetectable levels should be individualised.

Taurine treatment of retinal degeneration and cardiomyopathy in a consanguineous family with SLC6A6 taurine transporter deficiency

In a consanguineous Pakistani family with two affected individuals, a homozygous variant Gly399Val in the eighth transmembrane domain of the taurine transporter SLC6A6 was identified resulting in a hypomorph transporting capacity of ~15% compared with normal. Three-dimensional modeling of this variant has indicated that it likely causes displacement of the Tyr138 (TM3) side chain, important for transport of taurine. The affected individuals presented with rapidly progressive childhood retinal degeneration, cardiomyopathy and almost undetectable plasma taurine levels. Oral taurine supplementation of 100 mg/kg/day resulted in maintenance of normal blood taurine levels. Following approval by the ethics committee, a long-term supplementation treatment was introduced. Remarkably, after 24-months, the cardiomyopathy was corrected in both affected siblings, and in the 6-years-old, the retinal degeneration was arrested, and the vision was clinically improved. Similar therapeutic approaches could be employed in Mendelian phenotypes caused by the dysfunction of the hundreds of other molecular transporters.

Higher rate of long-term serologic response of four double doses vs. standard doses of hepatitis B vaccination in HIV-infected adults: 4-year follow-up of a randomised controlled trial

Background We previously reported that four doses or four double doses of hepatitis B vaccination regimens could not significantly increase a response rate compared with standard doses. However, the antibody levels were higher in the four doses and four double doses groups. This study followed those patients for at least 3 years and aimed to evaluate the immunogenicity of the three vaccination regimens. Methods HIV-infected adults who had CD4+ cell counts > 200 cells/mm3, undetectable plasma HIV-1 RNA, and negative for all hepatitis B virus markers were randomly assigned to receive one of three recombinant vaccines (Hepavax-Gene® Berna, Korea) regimens: 20 μg IM at months 0, 1, and 6 (standard doses group, n = 44), 20 μg IM at months 0, 1, 2, 6 (four doses group, n = 44), or 40 μg IM at months 0, 1, 2, and 6 (four double doses group, n = 44) between February 2011 and May 4, 2012. Of 132 participants, 126 were evaluated from August 2015 to January 2016; 42 in the standard doses, 43 in the four doses, and 41 in the four double doses groups. Results At a median duration of 49.7 months (range 46.7–53.7) after completion of the primary vaccination schedule, the percentages of responders with anti-HBs ≥ 10 mIU/mL were 57.1% (95% CI 41.5–72.8%) in the standard doses group; 76.7% (95% CI 63.6–89.9%) in the four doses group (P = 0.067 vs. the standard doses group); and 80.5% (95% CI 67.8–93.2%) in the four double doses group (P = 0.033 vs. the standard doses group). Factors associated with a responder were the vaccination schedule (either four doses or four double doses groups) and a younger age. Conclusions Despite the highly effectiveness of the standard hepatitis B vaccination regimen at 6 months after completion, the long-term immunogenicity was lower than the four double doses regimen among HIV-infected adults with CD4+ cell counts > 200 cells/mm3 and undetectable plasma HIV-1 RNA. The standard vaccination regimen may not be the best strategy to provide long-term immune response against hepatitis B virus among HIV-infected individuals. Trial registration NCT1289106, NCT02713620

The effectiveness and tolerability of imiquimod suppositories to treat extensive intra-anal high-grade squamous intraepithelial lesions/warts in HIV-infected individuals

Topical imiquimod is a potential treatment for intra-anal condyloma and squamous intraepithelial lesions caused by human papillomavirus (HPV). We aimed to assess the effectiveness and tolerability of imiquimod suppositories for the treatment of anal high-grade intraepithelial lesions (HSIL) and condylomas in HIV-infected patients. We conducted a retrospective analysis in a prospectively followed cohort. High-resolution anoscopy was used for diagnosis and assessment following treatment. Patients’ tolerability was assessed with a self-administered survey. Ninety-five patients (94.7% men) were analyzed. All were on combination antiretroviral therapy. Median CD4 T-cell count was 690 cells/µL, 89% had undetectable plasma viral load. Response to imiquimod was seen in 46.3% (complete: 12.5%, partial: 33.8%) in the intent-to-treat analysis, and in 55.2% (complete: 14.9%, partial: 40.3%) in the on-treatment analysis. Higher response rates were observed for anal condyloma compared with HSIL. A significantly poorer response rate was observed in smokers and in individuals with lower nadir CD4 T-cell counts. Imiquimod tolerability was “good” in 57.1% (n = 36), “acceptable” in 33.3% (n = 21), and “poor” in 9.5% (n = 6). Systemic side effects were reported in 20.7% (n = 13). There was no association between treatment effect and tolerability. In conclusion, imiquimod stands as a well-tolerated option for the treatment of HPV-associated intra-anal pathology in HIV-infected individuals.

Inflammatory flaccid myelitis in a patient with both anti-CRMP-5 IgG and CNS HIV escape

Anticollapsin-responsive mediator protein 5 (CRMP-5) IgG is an antibody generally associated with small-cell lung cancer, which is known to cause paraneoplastic neurological syndromes, including encephalitis, myelitis and neuropathy. HIV escape is a phenomenon in which a patient with low or undetectable levels of HIV RNA in plasma is found to have elevated levels in cerebrospinal fluid (CSF). We present a case of a 58-year-old HIV-positive woman with undetectable plasma viral load who developed a subacute flaccid paraparesis. Over the course of 4 months, she had a broad inflammatory and infectious workup that was unrevealing until repeat imaging showed an inflammatory myelitis. Workup was notable for elevated HIV RNA copies in CSF, as well as anti-CRMP-5 autoantibodies in serum. Despite changing her antiretroviral therapy and multiple modalities of immunomodulation, the patient failed to respond adequately to treatment. This case illustrates a complex clinical picture with a unique presentation of anti-CRMP-5 myelitis.

Comparative Immunovirological and Clinical Responses to Antiretroviral Therapy Between HIV-1 Group O and HIV-1 Group M Infected Patients

BackgroundLittle is known about impact of genetic divergence of human immunodeficiency virus type 1 group O (HIV-1/O) relative to HIV-1 group M (HIV-1/M) on therapeutic outcomes. We aimed to determine if responses to standardized combination antiretroviral therapy (cART) were similar between groups despite strain divergence.MethodsWe performed an open nonrandomized study comparing the immunological, virological, and clinical responses to cART based on 2 nucleoside reverse transcriptase inhibitors plus 1 ritonavir-boosted protease inhibitor, in naive and paired HIV-1/O vs HIV-1/M infected (+) patients (ratio 1:2), matched on several criteria. The primary endpoint was the proportion of patients with undetectable plasma viral load (pVL, threshold 60 copies/mL) at week (W) 48. Secondary endpoints were the proportion of patients with undetectable pVL at W24 and W96 and CD4 evolution between baseline and W24, W48, and W96.ResultsForty-seven HIV-1/O+ and 94 HIV-1/M+ patients were included. Mean pVL at baseline was significantly lower by 1 log for HIV-1/O+ vs HIV-1/M+ patients. At W48, no significant difference was observed between populations with undetectable pVL and differences at W24 and W96 were not significant. A difference in CD4 gain was observed in favor of HIV-1/M at W48 and W96, but this was not significant when adjusted on both matched criteria and pVL at baseline.ConclusionsOur data demonstrate similar immunovirological and clinical response between HIV-1/O+ and HIV-1/M+ patients. They also reveal significantly lower baseline replication for HIV-1/O variants, suggesting specific virological properties and physiopathology that now need to be addressed.Clinical Trials RegistrationNCT00658346.