Economic impact of generic antiretrovirals in France for HIV patients' care: a simulation between 2019 and 2023.

BACKGROUND: In a context where the economic burden of HIV is increasing as HIV patients now have a close to normal lifespan, the availability of generic antiretrovirals commonly prescribed in 2017 and the imminence of patent expiration are expected to provide substantial savings in the coming years. This article aims to assess the economic impact of these generic antiretrovirals in France and specifically over a five-year period. METHODS: An agent-based model was developed to simulate patient trajectories and treatment use over a five-year period. By comparing the results of costs for trajectories simulated under different predefined scenarios, a budget impact model can be created and sensitivity analyses performed on several parameters of importance. RESULTS: The potential economic savings from 2019 to 2023 generated by generic antiretrovirals range from €309 million when the penetration rate of generics is set at 10% to €1.5 billion at 70%. These savings range from €984 million to €993 million as the delay between patent and generic marketing authorisation varies from 10 to 15 years, and from €965 million to €993 million as the Negotiated Price per Unit (NPU) of generics at market-entry varies from 40 to 50% of the NPU for patents. DISCUSSION: This economic savings simulation could help decision makers to anticipate resource allocations for further innovation in antiretrovirals therapies as well as prevention, especially by funding the Pre-Exposure Prophylaxis (PrEP) or HIV screening.

A case of infective endocarditis caused by Arthrobacter woluwensis.

Corynebacteria are rare causative agents of infective endocarditis. This is a reported case of a destructive aorto-mitral infective endocarditis caused by Arthrobacter woluwensis. Microbial identification was achieved by 16S rRNA polymerase chain reaction on valve tissue samples. Outcome was favorable after surgical valve replacement and 4-week antibiotic treatment.

Adoption and Attitudes of eHealth Among People Living With HIV and Their Physicians: Online Multicenter Questionnaire Study.

BACKGROUND: The development of electronic health (eHealth) has offered the opportunity for remote care provision. eHealth addresses issues for patients and professionals favoring autonomy and compliance, respectively, while fostering closer links both between patients and health care professionals and among health care professionals themselves. OBJECTIVE: The aim of this study was to analyze the patterns of use, benefits, and perceived obstacles in eHealth among people living with HIV (PLHIV) and their caring physicians at hospitals. METHODS: An online multicenter observational survey was conducted October 15-19, 2018 in 51 medical units across France by means of self-administered questionnaires to collect sociodemographic and medical data, and perceptions of eHealth. Multiple correspondence analysis followed by mixed unsupervised classification were performed to analyze data of the respondents. RESULTS: A total of 279 PLHIV and 219 physicians responded to all parts of the questionnaire. Three groups of PLHIV were identified based on multivariate analysis. Group 1 comprised "eHealth believers" (121/279, 43.4%), who were more frequently above 60 years old and more likely to be receiving treatments other than antiretrovirals. Group 2, the "technology skeptics" (86/279, 30.8%), comprised more women with at least one child. Group 3, the "internet adopters" (72/279, 25.8%), were more frequently under 49 years of age, men who have sex with men, and more likely to use mobile apps for obtaining wellness/health information and related subjects. Three groups of physicians also emerged. Group 1 comprised those "strongly confident in eHealth" (95/219, 43.4%), who more frequently used mobile apps for wellness/health information and were more likely to accept prescription assistance software. Group 2 comprised physicians "strongly opposed to eHealth" (80/219, 36.5%), frequently asserting that eHealth challenges confidentiality. Group 3 were "open to eHealth" (44/219, 20.1%), comprising a higher proportion of infectious disease specialists, and were more likely to believe that medical apps are useful for patient education and information. No link was found between the groups of PLHIV and physicians. CONCLUSIONS: The literature on eHealth mainly classifies people as enthusiasts and skeptics; however, we identified a third profile among both PLHIV and physicians, albeit without a direct link between them. For PLHIV, this third group is attentive to eHealth for improving their health condition, and for physicians, this group considers eHealth to offer benefits to patients and their own practice.

Epidemiology of autoimmune and inflammatory diseases in a French nationwide HIV cohort.

BACKGROUND: HIV infection and inflammatory and autoimmune diseases (IADs) are both related to immune dysfunction. Epidemiological data on IAD in patients living with HIV (PLHIV) are scarce. The aim of this study was thus to estimate the prevalence of 26 IAD among PLHIV followed in a large French multicenter cohort in the combination antiretroviral therapy (cART) era (from January 2000 to July 2013), and to describe their occurrence according to cART onset, the immuno-virological status of patients and hepatitis C virus (HCV) and/or hepatitis B virus coinfection. METHOD AND RESULTS: During the study period, 33 403 PLHIV were included in the Dat'AIDS cohort; 1381 patients with an IAD were identified. The most prevalent IADs were psoriasis, sarcoidosis, rheumatoid arthritis, ankylosing spondyloarthritis, Grave's disease, autoimmune hemolytic anemia, immune thrombocytopenia and chronic inflammatory bowel disease. In contrast, the prevalence of systemic lupus erythematosus and multiple sclerosis were low. Most patients (59%) developed IAD after HIV infection with a mean delay of 10.6 ±â€Š6.4 years. Compared with the entire cohort, HCV coinfection was significantly more frequent in patients with psoriasis, Grave's disease and immune thrombocytopenia, and chronic hepatitis B in patients was more frequent in those with immune thrombocytopenia and autoimmune hemolytic anemia. Among patients developing IAD after the diagnosis of HIV infection, 572 (70%) were on antiretroviral therapy and 419 of them (73%) had undetectable HIV viral load. CONCLUSION: Our study showed that some IAD are not rare among PLHIV and occur mostly in patients with immuno-virological control under cART. The higher frequency of HCV or hepatitis B virus coinfection for some IAD is also confirmed.

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.

Effectiveness and tolerance of single tablet versus once daily multiple tablet regimens as first-line antiretroviral therapy - Results from a large french multicenter cohort study.

OBJECTIVES: Pill burden during antiretroviral treatment (ART) is associated with worse adherence and impaired virological suppression. We compared the effectiveness, tolerance, and persistence on treatment of single tablet regimens (STRs) with non-STR once-daily regimens in patients receiving first-line ART. METHODS: Retrospective analysis of naïve HIV-1 infected patients prospectively enrolled in the French Dat'AIDS cohort and initiating first-line ART with STRs or once-daily non-STRs from 2004 to 2013. The primary outcome was time to treatment discontinuation defined by any change in the treatment regimen. STR and non-STR groups were compared controlling for baseline risk factors by inverse probability weighted treatment Cox analysis (IPWT) and propensity-score matching (PSM). RESULTS: Overall, 3212 patients (STR 499, non-STR 2713) were included. Median time to treatment discontinuation was shorter in non-STR patients than in STR patients, both in the IPWT (HR = 0.61, p<0.0001) and the PSM cohort (HR = 0.55, p<0.0001). This difference disappeared when censoring ART modification for simplification, both in the IPWT (HR = 0.97, p = 0.65) and the PSM cohort (HR = 0.91, p = 0.33). A lower rate of virological failure was observed with STRs than with non-STRs in both cohorts (HR = 0.23; p = 0.002 and HR = 0.22, p = 0.003, respectively). A lower rate of treatment modification for adverse event was observed with non-STRs in the IPWT cohort (HR = 1.46, p<0.0001), but not in the PSM cohort (HR = 1.22, p = 0.11). CONCLUSION: First-line therapy with STRs was associated with a longer time to treatment discontinuation than with non-STRs. However, when ART modification for simplification was not considered as a failure, STRs and non-STRs were similar.

Failure to achieve immunological recovery in HIV-infected patients with clinical and virological success after 10 years of combined ART: role of treatment course.

OBJECTIVES: We assessed factors, including treatment course, associated with failure to obtain a 10 year immunological response after starting first-generation PI-containing combined ART (cART). PATIENTS AND METHODS: In the prospective COPILOTE cohort of HIV-infected patients started on a first-generation PI-containing regimen in 1997-99, the impact of cART history on the failure to achieve immunological response measured at 10 years was assessed by multivariate logistic regression models in the 399 patients with clinical and virological success of cART. RESULTS: Failure of CD4 response (CD4 >500/mm3) was associated with age ≥40 years at baseline (P < 0.001), CD4 cell counts ≤500/mm3 at month 4 (P = 0.016) or month 12 (P < 0.001) and ≥3 months of cART interruption (P = 0.016). Factors associated with failure to achieve complete immunological response (CD4 >500/mm3 and CD4:CD8 ratio >1) were CD4:CD8 ratio ≤0.8 at month 8 (P < 0.001) or month 12 (P < 0.001), ≥3 months of cumulative cART interruption (P = 0.011), ≥3 antiretroviral regimens (P = 0.009) and ≤4 treatment lines (P = 0.015). Baseline CD4 and CD4:CD8 ratio were not predictors of the 10 year immunological outcomes. CONCLUSIONS: In this therapeutic cohort of patients starting first-generation PI-containing cART in 1997-99, poor initial immunological response had a negative impact on 10 year CD4 and CD4 plus CD4:CD8 ratio response, despite prolonged virological success. Lack of treatment interruption may improve long-term immunological outcome in HIV infection.

CMV+ Serostatus Associates Negatively with CD4:CD8 Ratio Normalization in Controlled HIV-Infected Patients on cART.

Cytomegalovirus (CMV) infection is common among HIV-infected patients but its repercussion on the course of CD4+ and CD8+ T cells after cART initiation remains elusive. The French Dat'AIDS cohort enrolled 5,688 patients on first-line cART, from which we selected patients who achieved HIV suppression for at least 12 months without modification of cART, and for whom CMV serostatus was available. Five hundred and three patients fulfilled the selection criteria (74% male, median age 43 yrs, 15.5% CDC stage C), of whom 444 (88.3%) were seropositive for CMV (CMV+). Multivariate analyses using mixed-linear models adjusted for the time from HIV suppression, sex, age, transmission risk group, duration of HIV follow-up, the interaction between time from HIV suppression and CMV+ serology, and the nadir CD4 count revealed a negative correlation between CMV+ and CD4:CD8 ratio (coeff. = -0.16; p = 0.001). This correlation was also observed among patients displaying optimal CD4 recovery (≥500 cells/mm3 at M12; coeff. = -0.24; p = 0.002). Hence, CMV+ serostatus antagonizes normalization of the CD4:CD8 ratio, although further analyses of the impact of co-morbidities that associate with CMV serostatus, like HCV infection, are needed to elucidate this antagonism formally. However, this might reflect a premature T cell senescence, thus advocating for a close monitoring of T cells in CMV co-infected patients. In addition, our results raise the question of the benefit of treatment for asymptomatic CMV co-infection in HIV-infected patients.

First-line cART regimen impacts the course of CD8+ T-cell counts in HIV-infected patients that achieve sustained undetectable viral load.

The aim of the study was to investigate the impact of first-line combined antiretroviral therapy (cART) regimen on the course of CD8 T-cell counts in human immunodeficiency virus (HIV)-infected patients.A retrospective observational study conducted on the French DAT'AIDS Cohort of HIV-infected patients.We selected 605 patients initiating a first-line cART between 2002 and 2009, and which achieved a sustained undetectable HIV plasma viral load (pVL) for at least 12 months without cART modification. The evolution of CD8 T-cell counts according to cART regimen was assessed.CD8 T-cell counts were assessed in 572 patients treated with 2NRTIs+1PI/r (n= 297), 2NRTIs+1NNRTI (n= 207) and 3NRTIs (n= 68). In multivariate analysis, after 12 months of follow-up, the 3NRTIs regimen was associated with a significantly smaller decrease of CD8 T-cell count compared with NNRTI-containing regimens (-10.2 cells/µL in 3NRTIs vs -105.1 cells/µL; P=0.02) but not compared with PI-containing regimens (10.2 vs -60.9 cells/µL; P=0.21). After 24 months, the 3NRTIs regimen was associated with a smaller decrease of CD8 T-cell count and % compared with PI/r- and NNRTI-containing regimens (0.2 in 3NRTIs vs -9.9 with PI/r-regimens, P=0.001, and vs -11.1 with NNRTI-regimens, p < 0.0001). A focus analysis on 11 patients treated with an INSTI-containing cART regimen during the study period showed after 12 months of follow-up, a median decrease of CD8 T-cell count of -155 [inter quartile range: -302; -22] cells/µL.Our data highlight the fact that cART regimens have differential effects on CD8 pool down regulation.

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.

Perception of antiretroviral generic medicines: one-day survey of HIV-infected patients and their physicians in France.

BACKGROUND: In the interest of cost effectiveness, switching antiretroviral brand name medications to generics is recommended in France since 2013. The study objective was to evaluate the perception of generics per se and antiretroviral generics in HIV-infected patients and their hospital physicians. METHODS AND FINDINGS: 556 out of 703 (79%) adult HIV+ outpatients and 116 physicians in 33 clinics were included in a multicentric cross-sectional survey performed in September 2013. Patients completed a self-questionnaire on their perception and acceptability of generics. Physicians completed a questionnaire on their acceptability of switching antiretroviral to generic. Socio-demographic data, medical history and HIV history were collected. Among the 556 patients with a median HIV duration of 13 years, 77% were France native, 59% in active employment, 100% covered by social insurance, 95% on antiretroviral therapy. Seventy-six percent of the patients accepted generics and 55% trusted them overall. Antiretroviral generics were accepted by 44% of them but only by 17% if the pill burden was going to increase. The factor significantly associated with acceptability of antiretroviral generics was acceptance of generics per se (p<0.001). Among the 116 physicians following a median of 100 HIV-patients/year, 75% would prescribe generics, dropping to 26% if the combo had to be broken. Factors significantly associated with willingness to prescribe antiretroviral generics were the absence of concern regarding the chemical entity (OR = 0.33), being aware that the patient would accept generics for other pathologies (OR = 2.04) and would accept antiretroviral generics (OR = 1.94). No factor related to sociodemographic conditions, HIV status or comorbidities was associated with the acceptability of antiretroviral generics. CONCLUSIONS: Acceptability of antiretroviral generics in this French population was mostly dictated by the patient's and physician's knowledge and use of generics overall. It should be improved with an efficient information of both patients and physicians.

Acceptability and confidence in antiretroviral generics of physicians and HIV-infected patients in France.

INTRODUCTION: Switching brand name medications to generics is recommended in France in the interest of cost effectiveness but patients and physicians are sometimes not convinced that switching is appropriate. Some antiretroviral (ARV) generics (ZDV, 3TC, NVP) have been marketed in France since 2013. MATERIALS AND METHODS: A multicentric cross-sectional survey was performed in September 2013 to evaluate the perception of generics overall and ARV generics in physicians and HIV-infected patients and factors associated to their acceptability. Adult HIV outpatients were asked to complete a self-questionnaire on their perception of generics. Physicians completed a questionnaire on the acceptability of generics and ARV generics. Socio-demographic data, medical history and HIV history were collected. RESULTS: 116 physicians in 33 clinics (68% in University Hospital) included 556 patients (France-native 77%, active employment 59%, covered by social Insurance 100%, homosexual/bisexual contamination 47%, median HIV duration 13 years, hepatitis coinfection 16%, on ARV therapy 95%). Overall, patients accepted and had confidence in generics in 76% and 55% of the cases, respectively. Switching ARVs for generics was accepted by 44% of the patients but only by 17% if the pill burden was going to increase. 75% of the physicians would prescribe generics, but this decreased to only 26% if the combo had to be broken. The main reasons for non-prescription of generics were previous brand name ARV-induced side effects (35%), refusal of generics overall (37%), lack of understanding of generics (26%), risk of non-observance of treatment (44%), anxiety (47%) and depressive symptoms (25%). In multivariate analysis, factors associated with the acceptability of ARV generics in patients were the use of generics overall (p<0.001) and in physicians, the absence of concern regarding the drug efficacy (p<0.001) and being aware that the patient would accept generics overall (p=0.03) and ARV generics (p=0.04). No factors related to sociodemographic conditions, HIV status or comorbidities had a constrictive influence on the use of ARV generics. CONCLUSION: Acceptability of ARV generics in this French population is mostly dictated by the patient's and physician's knowledge and use of generics overall. Switching ARV brand name to a generic would be better accepted if the pill burden remained unchanged.

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.

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.

Bacteremia in patients receiving TNF-alpha antagonists--a prospective multicenter study.

OBJECTIVE: TNF-alpha antagonists have changed the outcome of various chronic inflammatory diseases. Their use has spread widely and many patients receive those treatments for years. Previous reports found that the use of TNF-alpha antagonists may be associated with an increased risk of serious bacterial infections. We report 47 prospective bacteremia cases from the RATIO registry. METHODS: A national prospective study was conducted in France between 2004 and 2007 to collect severe bacterial infections in patients receiving TNF-alpha antagonists. All reported cases of bacteremia were validated by an expert committee. RESULTS: Forty-seven bacteremic episodes were reported. Staphylococcus aureus represented the most frequent causative pathogen (40%) and was mostly associated with bones and/or joints infections (68%) and with a worse outcome compared to that observed with other bacterial pathogens. CONCLUSIONS: Patients receiving TNF-alpha antagonists may develop bacteremia and S. aureus has to be included in the spectrum of the initial empiric antimicrobial therapy.

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.

Randomized placebo-controlled study of the safety, tolerability, antiviral activity, and pharmacokinetics of 10-day monotherapy with BMS-986001, a novel HIV NRTI, in treatment-experienced HIV-1-infected subjects.

OBJECTIVE: To investigate the safety, tolerability, pharmacokinetics, and antiviral activity of BMS-986001 (a nucleoside reverse transcriptase inhibitor) in treatment-experienced, HIV-1-infected subjects not exposed to antiretroviral treatment in the previous 3 months. METHODS: Thirty-two HIV-1-infected subjects were randomized (3:1) to receive BMS-986001 or placebo once daily for 10 days in this double-blind, placebo-controlled, dose-escalating monotherapy phase IIa study. There were 4 treatment groups (100, 200, 300, and 600 mg, all once daily) of 8 subjects each (BMS-986001, n = 6/placebo n = 2). RESULTS: BMS-986001 was generally well tolerated, with no discontinuations due to adverse events and no deaths occurring. Adverse events were experienced by 22 of 24 BMS-986001-treated subjects and did not seem to be dose related. The majority were mild and considered unrelated or unlikely to be related to the study drug. The pharmacokinetics of BMS-986001 were dose proportional. Median decrease in plasma HIV-1 RNA from baseline to day 11 was 0.97, 1.15, 1.28, and 1.15 log10 copies/mL for BMS-986001 at 100, 200, 300, and 600 mg, respectively. Plasma area under the curve correlated with the antiviral activity of BMS-986001, indicating that area under the curves produced by 100-600 mg doses were on the upper end of the exposure-response curve. One subject with a single thymidine analog mutation at baseline responded well to BMS-986001. CONCLUSIONS: Administration of BMS-986001 for 10 days resulted in substantial decreases in plasma HIV-1 RNA levels for all dose groups and was generally well tolerated. These data support continued clinical development of BMS-986001 at a dose of 100 mg, once daily or greater. TRIAL REGISTRATION: EUDRACT Number 2008-004810-29.

Incidence and risk factors of Legionella pneumophila pneumonia during anti-tumor necrosis factor therapy: a prospective French study.

OBJECTIVE: Our objective was to describe the incidence and risk factors of legionellosis associated with tumor necrosis factor (TNF)-α antagonist use. METHODS: From February 1, 2004, to January 31, 2007, we prospectively collected all cases of legionellosis among French patients receiving TNF-α antagonists in the Research Axed on Tolerance of Biotherapies (RATIO) national registry. We conducted an incidence study with the French population as a reference and a case-control analysis with four control subjects receiving TNF-α antagonists per case of legionellosis. RESULTS: Twenty-seven cases of legionellosis were reported. The overall annual incidence rate of legionellosis for patients receiving TNF-α antagonists, adjusted for age and sex, was 46.7 (95% CI, 0.0-125.7) per 100,000 patient-years. The overall standardized incidence ratio (SIR) was 13.1 (95% CI, 9.0-19.1; P < .0001) and was higher for patients receiving infliximab (SIR, 15.3 [95% CI, 8.5-27.6; P < .0001]) or adalimumab (SIR, 37.7 [95% CI, 21.9-64.9; P < .0001]) than etanercept (SIR, 3.0 [95% CI, 1.00-9.2; P = .06]). In the case-control analysis, exposure to adalimumab (OR, 8.7 [95% CI, 2.1-35.1]) or infliximab (OR, 9.2 [95% CI, 1.9-45.4]) vs etanercept was an independent risk factor for legionellosis. CONCLUSIONS: The incidence rate of legionellosis for patients receiving TNF-α antagonists is high, and the risk is higher for patients receiving anti-TNF-α monoclonal antibodies than soluble TNF-receptor therapy. In case of pneumonia occurring during TNF-α antagonist therapy, specific urine antigen detection should be performed and antibiotic therapy should cover legionellosis. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00224562; URL: www.clinicaltrials.gov.

The role of lipopolysaccharide as a marker of immune activation in HIV-1 infected patients: a systematic literature review.

BACKGROUND: Recent observational studies suggest a role for lipopolysaccharide (LPS) as a marker of immune activation in HIV-infected patients, with potential repercussions on the effectiveness of antiretroviral regimens. OBJECT: A systematic review of LPS as a marker of immune activation in HIV-1 infected patients. DATA SOURCES: MEDLINE register of articles and international conference proceedings. REVIEW METHODS: Case-control studies comparing the role of plasma LPS as a marker of immune activation in HIV-infected patients versus HIV negative subjects. DATA SYNTHESIS: Two hundred and six articles were selected using MEDLINE, plus 51 studies presented at international conferences. Plasma LPS is a marker of immune activation in HIV-infected patients, determining the entry of central memory CD4+ T cells into the replication cycle and finally generating cell death. Plasma LPS probably results from immune-mediated alterations of the intestinal barrier, which can occur soon after HIV seroconversion. LPS is a likely marker of disease progression, as it drives chronic monocyte activation, and some studies suggest that hyperexpression of CCR5 receptors, related to LPS plasma levels, could be responsible for monocyte trafficking in the brain compartment and for the appearance of HIV-associated neurocognitive disorders. Long-term combination antiretroviral therapy (cART) generally reduces LPS concentrations, but rarely to the same levels as in the control group. This phenomenon probably depends on ongoing but incomplete repair of the mucosal barrier. Only in patients achieving maximal viral suppression (i.e. viral load < 2.5 cp/ml) are LPS levels comparable to healthy donors. In successfully treated patients who did not restore CD4+ T cells, one hypothesis is that the degree of residual microbial translocation, measured by LPS, alters the turnover of CD4+ T cells. CONCLUSIONS: LPS is a marker of microbial translocation, responsible for chronic immune activation in HIV-infected patients. Even in successfully treated patients, LPS values are rarely normal. Several studies suggest a role for LPS as a negative predictive marker of immune restoration in patients with blunted CD4 T cell gain.