Inflammatory Markers after Switching to a Dual Drug Regimen in HIV-Infected Subjects: A Two-Year Follow-Up.

Objective: Immunadapt is a study evaluating the impact of combination antiretroviral treatment (cART) simplification on immune activation. We previously showed that switching to dual therapies could be associated six months later with macrophage activation. Followup continued up to 24 months after treatment simplification. Materials and Methods: Immunadapt is a prospective single arm study of successfully treated subjects simplifying cART from triple to dual regimens. Before cART change, at 6 months, and between 18 and 24 months following the switch, we measured IP-10, MCP-1, soluble CD14 (sCD14), soluble CD163 (sCD163), and lipopolysaccharide binding protein. Patients were stratified according to lower or greater likelihood of immune activation (CD4 nadir < 200, previous AIDS-defining event or very-low-level viremia during follow-up). Variables were compared using matched Wilcoxon tests. Results: From April 2019 to September 2021, 14 subjects were included (mean age 60 years, 12 men, 26 years since HIV infection, CD4 nadir 302 cells/mm3, 18 years on cART, 53 months on last cART). Twenty-one months following the switch, all but one subject maintained their viral load < 50 cp/mL. One subject had two viral blips. For the entire population, the sCD163 values increased significantly from baseline (+36%, p = 0.003) and from 6 months after the switch. The other markers did not change. After 6 months, the sCD163 increase was more pronounced in subjects with greater likelihood of immune activation (+53% vs. +19%, p = 0.026) Conclusions: cART simplification to dual therapy was associated with macrophage activation despite successful virological control after almost two years' follow-up. This was more pronounced in those at risk of immune activation.

Emergence of Lyme Disease on the French Riviera, a Retrospective Survey.

Background: The French Riviera has been declared free of Lyme Borreliosis (LB) for years. Many patients are referred for presumed LB, sometimes with atypical clinical signs and/or doubtful serology, calling the diagnosis into question. Methods: Patients were assessed for LB diagnosis, depending on clinical presentation, laboratory findings, and further examination by other medical professionals. Results: Among 255 patients, 45 (18%) were classified as confirmed LB cases [including 28 ongoing LB (10%) and 17 past LB (8%)], and for 210 (82%) a Lyme borreliosis diagnosis was ruled out. Among ongoing LB, 56% had been exposed to or bitten by ticks, exclusively in rural locations of the Alpes-Maritimes. As a result of the diagnostic procedure, 132 (52%) patients had been treated. An alternative diagnosis was established for 134 (52%) patients, covering a wide range of conditions, including mainly psychological (28%) and neurological conditions (25%) or inflammatory and systemic diseases (22%). Conclusions: Our results strongly suggest the endemicity of LB in the Alpes-Maritimes region. Confirmed LB accounted for 18% of patients while 52% were diagnosed with other conditions.

Prevalence and Main Clinical Characteristics of Fully Vaccinated Patients Admitted to Hospital for Delta Variant COVID-19.

Objectives: The Delta variant of the novel beta coronavirus responsible for the current coronavirus pandemic (COVID-19) spread across Europe during the summer of 2021. Little is known of vaccine efficacy on this variant. Our aim was to study the prevalence and clinical characteristics of fully vaccinated subjects admitted to hospital for Delta variant COVID-19. Methods: We identified patients admitted to Cannes hospital for Delta-variant-related Covid-19 infection from July to September 2021. Their main demographic parameters, inflammatory markers, and clinical characteristics were recorded. Differences between fully vaccinated subjects and unvaccinated or incompletely vaccinated individuals were analyzed. Results: We included 126 patients (57% male, mean age 64 years, mean delay since symptoms onset 7.8 days). Among admitted patients, 94 (75%) were not vaccinated, 11 (8%) incompletely so and 21 (17%) were fully vaccinated. Fully vaccinated patients were older (77 vs. 61 vs. 62 years, p = 0.003), with fewer days since symptoms onset (5.9 vs. 8.0 vs. 9.3 days, p = 0.035) than unvaccinated or incompletely vaccinated patients, respectively. Severe pneumonia was less frequent among completely vaccinated subjects (67 vs. 84 vs. 100%, p = 0.038), while rates of transfer to the ICU, mechanical ventilation or death did not differ. Thirteen fully vaccinated patients underwent a thoracic CT scan, revealing involvement of lung parenchyma in four of them. Discussion: Prevalence of hospitalization for Delta-variant COVID-19 in fully vaccinated subjects was low and, despite their age and comorbid conditions, these patients had a high rate of favorable outcome.

Switching to a Dual-Drug Regimen in HIV-Infected Patients Could Be Associated With Macrophage Activation?

Objectives: The aim of this study was to evaluate the effect on immune activation of switching from a triple-drug to a dual-drug regimen in HIV-1 infected patients on successful combination antiretroviral treatment (cART). Immunadapt is a prospective study evaluating the impact of cART simplification on immune activation. Methods: We prospectively collected blood samples in HIV-1 infected patients on stable and successful cART switching from triple to dual regimens as a simplifying strategy. We compared immune activation markers: high sensitivity CRP, IL-1, IL-6, IL-8, IP-10, MCP-1, TNF-alpha, soluble CD14 (sCD14), soluble CD163 (sCD163), lipopolysaccharide binding protein, and D-dimer before cART change and at least 6 months after the switch. Patients were stratified according to low or high risk factors of immune activation (low CD4 nadir, previous AIDS-defining condition or very-low-level viremia during follow-up). Results: From April 2019 to May 2020, 20 subjects were included (mean age 57 years, 25 years since HIV infection, CD4 666 cells/mm3, CD8 766 cells/mm3, CD4/CD8 0.94, CD4 nadir 326 cells/mm3, 15% with AIDS, 18 years on cART, 6 cART regimens received, current cART duration: 56 months). Fourteen patients were prescribed Dolutegravir + Rilpivirine and six received Dolutegravir + Lamivudine. After 6.9 months, a significant sCD163 increase (+ 25.5% vs. + 0.5%, p = 0.02) was observed in subjects with high risk factors, despite maintaining a viral load <50 cp/ml. Conclusion: cART simplification in favor of dual therapy is associated with macrophage activation in patients at risk of immune activation despite sustained virological control. Risk factors should thus be considered before generalizing such strategies.

Detection of emerging tick-borne disease agents in the Alpes-Maritimes region, southeastern France.

Lyme borreliosis is a zoonotic tick-borne infection representing the most frequent vector-borne disease in the northern hemisphere. The Mediterranean rim is generally described as unsuitable for the European vector, Ixodes ricinus. We conducted an epidemiological study to assess whether I. ricinus was present and study its infection status for tick-borne bacteria. Ticks originating from southeastern France were obtained from flagging sampling and removed from animals and tick-bitten patients. Species level identification used morphological keys and MALDI-TOF MS. Quantitative PCR and sequencing assays were used to detect and identify tick-associated bacteria (Borrelia, Rickettsia, Anaplasmataceae, Bartonella, Coxiella burnetii) in each specimen. A total of 1232 ticks were collected in several localities. Among these, 863 were identified as I. ricinus (70%). Bacterial screening allowed identification of Lyme group Borrelia among I. ricinus ticks originating from various regional areas. Other emerging tick-borne pathogens like Borrelia miyamotoi and Rickettsia species were also detected. The Alpes-Maritimes region, part of the French Riviera, harbours I. ricinus ticks infected with Lyme group Borrelia and several other tick-borne bacterial agents. Clinicians and outdoor activity participants should be aware of the local Lyme borreliosis transmission risk.

Perceived HIV-related physical fatigue, sociodemographic characteristics and physical activity: A cross-sectional study.

AIMS AND OBJECTIVES: To get a deeper understanding of correlates of perceived HIV-related fatigue by exploring its associations with sociodemographic characteristics and physical activity level of HIV-infected people. BACKGROUND: Previous studies on HIV-related fatigue have mainly focused on physiological and psychological characteristics, but few have considered its associations with sociodemographic variables. In addition, while physical activity has been found to reduce acute fatigue among HIV-infected people, its links with chronic HIV-related fatigue remain to be explored. DESIGN: The study employed an observational and cross-sectional survey design. The manuscript was organised according to STROBE guidelines. METHOD: A total of 560 people living with HIV in France completed a measure of perceived physical fatigue using the Fatigue Intensity Scale. The predictors targeted sociodemographic characteristics and two measures of individuals' reported level of physical activity. Data were analysed by a stepwise multiple regression model. RESULTS: The results showed that lower age, higher physical activity level and socio-economic status were significantly associated with reduced perceived physical fatigue, explaining 25% of the variance. CONCLUSIONS: The results highlighted the importance of considering sociodemographic and lifestyle characteristics to better characterise HIV-related fatigue, in particular in an era where HIV as a chronic illness challenges questions of quality of life throughout increasingly longer lifespans. RELEVANCE TO CLINICAL PRACTICE: The results of this study have implications for HIV care professionals in terms of improving strategies for managing chronic fatigue or promoting physical activity according to more specific profiles of HIV-infected people.

Exercise stereotypes and fatigue in people living with HIV: does self-efficacy play a mediating or a moderating role?

BACKGROUND: Recent research suggests that exercise stereotypes may influence physical activity through ego depletion and internalization mechanisms. The objective of this study was to better understand exercise stereotypes mechanisms among people living with HIV (PLHIV) by further examining the role of exercise self-efficacy and perceived physical fatigue in the relationship between exercise stereotypes and physical activity. METHODS: Three hundred five people living with HIV were recruited to provide data on their stereotypes related to exercise, exercise self-efficacy, perceived physical fatigue as well as their level of physical activity (PA). RESULTS: From the different models tested, the serial mediation model with exercise self-efficacy and perceived physical fatigue as mediators of the relationship between exercise stereotypes and PA, as well as the moderated mediation model with exercise selfefficacy as a moderator of exercise stereotypes and perceived physical fatigue a mediator, provided good fits to the data. However, the moderated mediation model (with indirect associations between negative exercise stereotypes and PA via perceived physical fatigue being moderated by exercise self-efficacy) explained the most variance in PA (R2 = .27). CONCLUSION: The moderated mediation model suggests that exercise stereotypes might influence PA through ego depletion mechanisms and be tempered by exercise self-efficacy.

Erratum to 'HMGB1/anti-HMGB1 antibodies define a molecular signature of early stages of HIV-Associated Neurocognitive Disorders (HAND)'.

[This corrects the article DOI: 10.1016/j.heliyon.2017.e00245.].

HMGB1/anti-HMGB1 antibodies define a molecular signature of early stages of HIV-Associated Neurocognitive Isorders (HAND).

BACKGROUND: HIV-associated neurocognitive disorders (HAND) persist in the post-HAART era, characterized by asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorders (MND). High mobility group box 1 (HMGB1) is a non-histone chromosomal protein widely expressed in the nucleus of all eukaryotic cells, including brain cells, which acts as a potent proinflammatory cytokine when actively secreted from immune cells. Recent reports suggested that HMGB1 acts on microglial cells to promote neuroinflammation. In this study, our aim was to determine whether HMGB1 is involved in HAND, but also to identify early new markers of neurological impairment in HIV-infected patients. METHODS: CSF and serum were collected from 103 HIV-1-infected patients enrolled in Neuradapt, a prospective study of the prevalence of HAND in HIV-1 infected patients at Nice University Hospital. Stored fluids were assessed for immunological, virological, and brain metabolite parameters. In addition to HIV RNA and DNA measurements, expression of T-cell surface markers of activation (CD38 and HLA-DR) was analyzed on whole blood. Concentration of 27 cytokines and chemokines was measured using multiplex bead assays on serum and CSF. Concentration of HMGB1 and anti-HMGB1 IgG autoantibodies were also measured on the same samples. Changes in cerebral metabolites N-acetyl aspartate (NAA), Choline (Cho) and creatinine (Cr) were assessed by magnetic resonance microscopy (MRS). RESULTS: Clinical, virological and immunological characteristics were comparable between HAND (n = 30) and no HAND (n = 73) patients, except the absolute numbers of CD8+ T cells, which were higher in patients with HAND. Among the 29 molecules tested, only 4 of them were significantly upregulated in the CSF from HAND patients as compared to healthy donors i.e. HMGB1, anti-HMGB1 IgG antibodies, IP-10 and MCP1. CSF HMGB1 levels were positively correlated with HIV-1 DNA in aviremic HAND patients, suggesting a positive impact of HMGB1 on HIV reservoirs. Moreover, in contrast to NAA/Cr and Cho/NAA ratios, circulating anti-HMGB1 IgG antibody levels could discriminate patients with no HAND from patients with no HAND and a single deficit (average ROC-AUC = 0.744, p = 0.03 for viremic patients), thus enabling the identification of a very early stage of neurocognitive impairment. CONCLUSION: We report that brain injury in chronically HIV-infected patients on stable HAART is strongly associated with persistent CNS inflammation, which is correlated with increased levels of HMGB1 and anti-HMGB1 IgG in the CSF. Moreover, we identified circulating anti-HMGB1 IgG as a very early biomarker of neurological impairment in patients without HAND. These results might have important implication for the identification of patients who are at high risk of developing neurological disorders.

COPD in HIV-Infected Patients: CD4 Cell Count Highly Correlated.

BACKGROUND: COPD is a frequent and significant cause of respiratory morbidity in HIV-infected patients despite the control of HIV. We aimed to analyze the factors correlated with COPD in this population to evaluate the existence of specific indicators of vulnerability in this population. METHODS AND FINDINGS: 623 HIV-infected outpatients were enrolled during one year. This population was characterised by a dedicated questionnaire and electronic patient records. COPD screening was performed according to recommended spirometric criteria. The prevalence of COPD was 9.0%. Age and smoking were independently correlated with COPD (OR, 1.61 per 10 years increase, P = 0.007; OR, 1.28 per 10 pack-year increase, P = 0.003, respectively). Body mass index (BMI) and CD4 cell-count were independently and negatively correlated with COPD (OR, 0.78, P < 0.001; 0R, 0.77 per 100 cell/mm3 increase, P < 0.001, respectively). Among COPD patients, 77% did not know their diagnosis. Five COPD-patients never smoked and 44.2% did not have any respiratory symptoms and so were not eligible to perform a spirometry according to the guidelines. CONCLUSIONS: In addition to known risk factors, immune defect through CD4 cell count was independently and strongly correlated with COPD. COPD is largely underdiagnosed and thus unmanaged. However, early management and urgent smoking cessation are essential to improve prognosis. Clinicians' awareness on the particular vulnerability for COPD in HIV-infected patients is crucial. Moreover, indications to perform conventional spirometry to diagnose COPD may include more parameters than tobacco-smoking and respiratory complaints with a particular concern toward patients with a profound CD4 cell count defect.

Exercise stereotypes and health-related outcomes in French people living with HIV: development and validation of an HIV Exercise Stereotypes Scale (HIVESS).

BACKGROUND: The main objective of the current study was to develop and validate a French exercise stereotype scale for people living with HIV (PLHIV) in order to gain visibility to the possible barriers and facilitators for exercise in PLHIV and thus enhance their quality of life. METHODS: A series of four complementary studies was carried out with a total sample of 524 participants to: (a) develop a preliminary version of the HIV Exercise Stereotype Scale (HIVESS) (Stage 1), (b) confirm the factorial structure of the instrument (Stage 2), (c) evaluate the stability of the instrument (Stage 3), and (d) examine the construct and divergent validity of the scale (Stage 4). RESULTS: Results provided support for a 14-item scale with three sub-scales reporting stereotypes related to exercise benefits, exercise risks and lack of capacity for exercise with Cronbach's alphas of .77, .69 and .76 respectively. Results showed good factorial structure, strong reliability and indicators of convergent validity relating to self-efficacy, exercise and quality of life. CONCLUSION: The HIVESS presented satisfactory psychometric properties, constitutes a reliable and valid instrument to measure exercise stereotypes among PLHIV and has applications for future research and clinical practice.

Maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy with tenofovir/emtricitabine/maraviroc/raltegravir in treatment-naive HIV patients.

OBJECTIVE: We assessed the virological efficacy of a 6 month maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy combining tenofovir disoproxil fumarate/emtricitabine with maraviroc/raltegravir. METHODS: HIV-1-infected naive patients were enrolled in an open label, single-arm, Phase 2 trial. All patients received maraviroc 300 mg twice daily, raltegravir 400 mg twice daily and tenofovir/emtricitabine for 24 weeks. Patients with stable HIV-RNA <50 copies/mL stopped tenofovir/emtricitabine at week (W) 24 and pursued maraviroc/raltegravir until W48. The primary endpoint was the virological response defined by HIV-RNA <50 copies/mL at W48. RESULTS: Thirty-three patients were analysed. Patients were mostly male (94%), Caucasians (91%), MSM (82%); their median age was 42 years. At baseline, median CD4 cell count was 453 cells/mm3 and HIV-RNA was 4.3 log copies/mL. All patients had CCR5-tropic viruses by genotropism and phenotropism assays. All but one patient had an HIV-RNA < 50 copies/mL at W24 and entered the simplification phase. Virological success was maintained at W48 in 88% (90% CI 79%-97%) of patients. N155H mutation was detected at failure in one patient. No tropism switch was observed. Raltegravir and maraviroc plasma exposure were satisfactory in 92% and 79% of 41 samples from 21 patients. Five severe adverse events (SAEs) were observed up to W48; none was related to the study drugs. Four patients presented grade 3 AEs; none was related to the study. No grade 4 AE was observed. No patient died. CONCLUSIONS: Maraviroc/raltegravir maintenance therapy following a 6 month induction phase with maraviroc/raltegravir/tenofovir/emtricitabine was well tolerated and maintained virological efficacy in these carefully selected patients.

Telaprevir-based therapy in patients coinfected with chronic hepatitis C virus infection and HIV: INSIGHT study.

OBJECTIVES: INSIGHT (ClinicalTrials.gov NCT01513941) evaluated the efficacy, safety and pharmacokinetics of telaprevir-based therapy and specific antiretroviral agents in hepatitis C virus genotype 1 (HCV-1)/HIV-1-coinfected patients. PATIENTS AND METHODS: Open-label, Phase IIIb, multicentre study of telaprevir with pegylated-IFN (Peg-IFN) α2a and ribavirin in treatment-naive or -experienced HCV-1/HIV-1-coinfected patients on stable HIV HAART comprising efavirenz, atazanavir/ritonavir, darunavir/ritonavir, raltegravir, etravirine or rilpivirine with two nucleos(t)ide analogues. Patients received 750 mg telaprevir (1125 mg, if on efavirenz) every 8 h plus 180 µg/week Peg-IFNα2a and 800 mg/day ribavirin for 12 weeks, followed by Peg-IFNα2a and ribavirin alone for 12 weeks (HCV treatment naive and relapsers without cirrhosis, with extended rapid virological response) or 36 weeks (all others). RESULTS: Overall, 162 patients (median age of 46 years, 78% male, 92% Caucasian and mean CD4 count of 687 cells/mm(3)) were treated; 13% had cirrhosis. One-hundred-and-thirty-two patients (81%) completed telaprevir; 14 (9%) discontinued due to an adverse event (AE). Sustained virological response (SVR) 12 rates (<25 IU/mL HCV RNA 12 weeks after the last planned treatment dose) in treatment-naive patients, relapsers and non-responders were 64% (41 of 64), 62% (18 of 29) and 49% (34 of 69), respectively. SVR12 rates ranged from 51% (33 of 65) (patients receiving efavirenz) to 77% (13 of 17) (patients receiving raltegravir). Most frequently reported AEs during telaprevir treatment were pruritus (43%) and rash (34%) special search categories. Anaemia special search category occurred in 15% of patients; 6% of patients reported a serious AE. CONCLUSIONS: In treatment-naive/-experienced HCV-1/HIV-1 patients there were significantly higher SVR rates with telaprevir-based therapy compared with pre-specified historical controls, and safety comparable to that in HCV-monoinfected patients.

Virological response and resistance mutations to NS3/4A inhibitors in hepatitis C virus-human immunodeficiency virus coinfection.

AIM: To evaluate virological response to telaprevir or boceprevir in combination with pegylated interferon and ribavirin and resistance mutations to NS3/4A inhibitors in hepatitis C virus-human immunodeficiency virus (HCV-HIV) coinfected patients in a real life setting. METHODS: Patients with HCV genotype 1-HIV coinfection followed in Nice University Hospital internal medicine and infectious diseases departments who initiated treatment including pegylated interferon and ribavirin (PegIFN/RBV) + telaprevir or boceprevir, according to standard treatment protocols, between August 2011 and October 2013 entered this observational study. Patient data were extracted from an electronic database (Nadis(®)). Liver fibrosis was measured by elastometry (Fibroscan(®)) with the following cut-off values: F0-F1: < 7.1 kPa, F2: 7.1-9.5 kPa, F3: 9.5-14.5 kPa, F4: ≥ 14.5 kPa. The proportion of patients with sustained virological response (SVR) twelve weeks after completing treatment, frequency and type of adverse events, and NS3/4A protease inhibitor mutations were described. RESULTS: Forty-one patients were included: 13 (31.7%) patients were HCV-treatment naïve, 22 (53.7%) had advanced liver fibrosis or cirrhosis (Fibroscan stage F3 and F4); none had decompensated cirrhosis or hepatocellular carcinoma; all were receiving antiretroviral treatment, consisting for most them (83%) in either a nucleoside reverse-transcriptase inhibitor/protease inhibitor or/integrase inhibitor combination; all patients had undetectable HIV-RNA. One patient was lost to follow-up. SVR was achieved by 52.5% of patients. Five patients experienced virological failure during treatment and four relapsed. Seven discontinued treatment due to adverse events. Main adverse events included severe anemia (88%) and rash (25%). NS3/4A protease mutations were analyzed at baseline and at the time of virological failure in the 9 patients experiencing non-response, breakthrough or relapse. No baseline resistance mutation could predict resistance to HCV protease inhibitor-based treatment. CONCLUSION: Telaprevir and boceprevir retain their place among potential treatment strategies in HIV-HCV coinfected patients including those with advanced compensated liver disease and who failed previous PegIFN/RBV therapy.

Can high central nervous system penetrating antiretroviral regimens protect against the onset of HIV-associated neurocognitive disorders?

OBJECTIVE: To assess changes over time in neuropsychological test results (NPr) and risk factors among a regularly followed HIV-infected patient population. METHODS: Prospective cohort of HIV-infected patients randomly selected to undergo neuropsychological follow-up. Test score was adjusted for age, sex and education. Patients were divided into five groups: normal tests, neuropsychological deficit (one impaired cognitive domain), asymptomatic neurocognitive disorders (ANIs), mild neurocognitive disorders (MNDs) and HIV-associated dementia (HAD). Demographic and background parameters including CSF drug concentration penetration effectiveness (CPE) score 2010 were recorded. Changes in NPr and associated risk factors were analyzed. RESULTS: Two hundred and fifty-six patients underwent neuropsychological tests and 96 accepted follow-up approximately 2 years later. The groups were comparable. Upon neuropsychological retesting, six patients improved, 31 worsened and 59 were stable. The proportion of patients with HIV-associated neurocognitive disorders (HANDs) rose from 26 to 45%, with ANIs and MNDs still mostly represented. Most patients initially diagnosed with HANDs remained stable, five of 25 showed clinical improvement and three of 25 deteriorated. Of 33 patients with normal tests, four deteriorated, whereas 24 of 38 with initial neuropsychological deficit had poorer NPr, and contributed most of the new HAND cases. Patients with clinical deterioration had a lower CPE score both at inclusion (6.9 vs. 8.1; P = 0.005) and at the end of follow-up (7.2 vs. 7.8; P = 0.08) than those with improved or stable performance. This was confirmed by multivariate analysis. CONCLUSION: Patients with higher CPE scores upon inclusion and at the end of follow-up were at lower risk of clinical worsening, suggesting that combination antiretroviral therapy with better CSF penetration could protect against cognitive deterioration.

Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study.

BACKGROUND: The pilot phase IIb VIKING study suggested that dolutegravir (DTG), a human immunodeficiency virus (HIV) integrase inhibitor (INI), would be efficacious in INI-resistant patients at the 50 mg twice daily (BID) dose. METHODS: VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INI-resistant virus received DTG 50 mg BID while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued. The primary efficacy endpoints were the mean change from baseline in plasma HIV-1 RNA at day 8 and the proportion of subjects with HIV-1 RNA <50 c/mL at week 24. RESULTS: Mean change in HIV-1 RNA at day 8 was -1.43 log10 c/mL, and 69% of subjects achieved <50 c/mL at week 24. Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response. Response was most reduced in subjects with Q148 + ≥2 resistance-associated mutations. DTG 50 mg BID had a low (3%) discontinuation rate due to adverse events, similar to INI-naive subjects receiving DTG 50 mg once daily. CONCLUSIONS: DTG 50 mg BID-based therapy was effective in this highly treatment-experienced population with INI-resistant virus. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov (NCT01328041) and http://www.gsk-clinicalstudywww.gsk-clinicalstudyregister.com (112574).

Yeast cells as a tool for analysis of HIV-1 protease susceptibility to protease inhibitors, a comparative study.

HIV develops drug resistance at a high rate under drug selection pressure. Resistance tests are recommended to help physicians optimize antiretroviral drug therapies. For this purpose, genotypic and phenotypic tests have been developed. In order to propose a new phenotypic test that will be less laborious, expensive, and time consuming than the standard ones, a new procedure to measure HIV-1 protease susceptibility to protease inhibitor (PIs) in Saccharomyces cerevisiae yeast cells was developed. This procedure is based on HIV-1 protease expression in yeast. While the viral protein induces yeast cell death, its inhibition by PIs in the culture medium allows the cell to grow in a dose-dependent manner. In a comparative study of standard genotypic analysis vs. yeast cell-based phenotypic tests, performed on HIV-1 protease coding DNA in 17 different plasma samples from infected individuals, a clear match was found between the results obtained using the two technologies. This suggests that the yeast-based procedure is at least as accurate as standard genotypic test in defining susceptibility to protease inhibitors. This encouraging result should be the basis for large-scale validation of the new phenotypic resistance test.

Relevance of lipopolysaccharide levels in HIV-associated neurocognitive impairment: the Neuradapt study.

Contributory factors to HIV-associated neurocognitive disorders (HAND) have been shown to include age, co-morbid infections, medication toxicity, virological, genetic and vascular mechanisms, as well as microbial translocation of lipopolysaccharide (LPS), which is suspected to trigger monocyte activation and increase trafficking of infected cells into the brain. In this study, our aim was to assess the degree of neurocognitive impairment in a group of randomly selected HIV-infected patients and investigate potential risk factors, including LPS plasma levels. Furthermore, we evaluated the relevance of LPS as a potential marker for screening patients with mild neurocognitive impairment. LPS plasma levels were compared among patients with HAND and those with no HAND. As LPS has also been shown to be elevated in hepatitis C co-infection, the analysis was stratified according to the presence or not of hepatitis C virus (HCV) co-infection. Differences between groups were evaluated using chi-square tests and Kruskal-Wallis non-parametric tests. Stepwise logistic regression was performed to identify independent risk factors for HAND in the subgroups of HCV-positive and negative patients. A p value <0.05 was considered significant. Analyses were conducted using SPSS® software. From December 2007 to July 2009, 179 patients were tested (mean age 44, 73 % male, 87 % on treatment, 30 % HCV co-infected, median CD4 504/ml and 67 % with viral load below 40 copies/ml). HAND was identified in 40/179 patients (22 %), the majority displaying asymptomatic neurocognitive impairment or mild neurocognitive disorder. Univariate analysis showed that age, illicit drug use, hepatitis C co-infection, prior AIDS-defining events, CD4/CD8 ratio and LPS plasma levels were significantly associated with HAND. The median LPS level was 98.2 pg/ml in the non-HAND group versus 116.1 pg/ml in the HAND group (p < 0.014). No differences were found in LPS values between subgroups of impairment. There was a clear association between LPS levels and HAND in the HCV-positive group (p = 0.036), while there was none in the HCV-negative group (p = 0.502). No difference in degree of hepatic fibrosis was found between the HAND and non-HAND groups. In conclusion, LPS levels were associated with HAND in the HCV-positive group, while, in the HCV-negative group, age and pro-viral DNA were the only variables independently associated with HAND. There was no difference in degree of liver disease as predicted by score of fibrosis between HAND and non-HAND groups. The role of HCV co-infection and higher LPS levels in the pathogenesis of HAND in patients with viral suppression on treatment requires further investigation.