Marco Ripa

Efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate as treatment for primary or recent HIV infection

ical user interface for sequence alignment and phylogenetic tree building. Mol Biol Evol 2010; 27: 221–4. 5 Wirden M, Tubiana R, Fourati S et al. Upgraded Cobas Ampliprep-Cobas Taqman version 2.0 HIV-1 RNA quantification assay versus first version: correction of underestimations. J Clin Microbiol 2011; 49: 2700–2. 6 Mourez T, Delaugerre C, Vray M et al. Comparison of the bioMérieux NucliSENS EasyQ HIV-1 v2.0-HIV-1 RNA quantification assay versus Abbott RealTime HIV-1 and Roche Cobas TaqMan HIV-1 v2.0 on current epidemic HIV-1 variants. J Clin Virol 2015; 71: 76–81.

Beneficial Effects of cART Initiated during Primary and Chronic HIV-1 Infection on Immunoglobulin-Expression of Memory B-Cell Subsets

Introduction During HIV-1 infection the B-cell compartment undergoes profound changes towards terminal differentiation, which are only partially restored by antiretroviral therapy (cART). Materials and Methods To investigate the impact of infection as early as during primary HIV-1 infection (PHI) we assessed distribution of B-cell subsets in 19 PHI and 25 chronic HIV-1-infected (CHI) individuals before and during 48 weeks of cART as compared to healthy controls (n = 23). We also analysed Immunoglobulin-expression of memory B-cell subsets to identify alterations in Immunoglobulin-maturation. Results Determination of B-cell subsets at baseline showed that total and Naive B-cells were decreased whereas Activated Memory (AM), Tissue-like Memory (TLM) B-cells and Plasma cells were increased in both PHI and CHI patients. After 4 weeks of cART total B-cells increased, while AM, TLM B-cells and Plasma cells decreased, although without reaching normal levels in either group of individuals. This trend was maintained until week 48, though only total B-cells normalized in both PHI and CHI. Resting Memory (RM) B-cells were preserved since baseline. This subset remained stable in CHI, while was expanded by an early initiation of cART during PHI. Untreated CHI patients showed IgM-overexpression at the expenses of switched (IgM-IgD-) phenotypes of the memory subsets. Interestingly, in PHI patients a significant alteration of Immunoglobulin-expression was evident at BL in TLM cells, and after 4 weeks, despite treatment, in AM and RM subsets. After 48 weeks of therapy, Immunoglobulin-expression of AM and RM almost normalized, but remained perturbed in TLM cells in both groups. Conclusions In conclusion, aberrant activated and exhausted B-cell phenotypes rose already during PHI, while most of the alterations in Ig-expression seen in CHI appeared later, despite 4 weeks of effective cART. After 48 weeks of cART B-cell subsets distribution improved although without full normalization, while Immunoglobulin-expression normalized among AM and RM, remaining perturbed in TLM B-cells of PHI and CHI.

Viral rebound after switch to maraviroc/raltegravir dual therapy in highly experienced and virologically suppressed patients with HIV-1 infection

+ 800 mg of ribavirin daily + telaprevir (750 mg/ 8 h) she achieved undetectable HCV-RNA at weeks 4 and 12. Treatment was complicated by severe anaemia, requiring pegy-lated interferon and ribavirin dose reduction and blood transfusion. HCV-RNA remained ,15 IU/L, and she continued on pegylated interferon + ribavirin treatment. HIV-RNA remained undetectable at treatment weeks 4, 8 and 12. Darunavir and telaprevir PK data are shown in Table 1. There were decreases in all darunavir PK parameters when administered with telaprevir for both patients, except for unbound trough concentration in Patient 2. These decreases, ranging from 58% to 97%, were even higher than those previously described in healthy volunteers. 2,3 However, darunavir/ritonavir doses were different in both cases (800/100 mg once daily in our patients and 600/ 100 mg twice daily in healthy volunteers). 2 We also observed decreases in unbound darunavir concentrations in both patients (except for the aforementioned increase in unbound C trough in Patient 2), although the free fraction decreased less than total drug (ranging from 46% to 93%). There are scarce data on daru-navir PK in HIV/HCV-coinfected patients: in a Spanish cohort, dar-unavir once-daily concentrations (total and unbound) were higher than those observed in our two patients, even before telaprevir co-administration. 5 We could not evaluate the impact of darunavir on telaprevir concentrations, as antiretroviral therapy was maintained. However, telaprevir concentrations in our patients were much higher than previously reported in healthy volunteers or HCV-monoinfected patients. 2,3,6 These high telaprevir concentrations in our coinfected patients with advanced fibrosis could partially explain the marked reduction in darunavir levels, although an association between telaprevir exposure and extent of drug interaction with antiretrovirals has not been previously described. Despite the impact of telaprevir co-administration on daruna-vir concentrations (total darunavir C trough was below wild-type virus IC 50 in one patient), HIV-RNA remained undetectable during the 12 weeks of telaprevir therapy. Prolonged HIV suppression prior to starting anti-HCV therapy, preserved antiviral potency of the darunavir-based regimen and interferon anti-HIV effect 7 could have played a role in keeping HIV-RNA undetectable. Having only two patients, we must take into account all the potential confounding factors and the inter-and intra-individual variability , which hamper generalization of our results. However, our results are concordant between both patients. Besides, as PK parameters can be modified with hepatic impairment, it is very important to have data on interaction between telaprevir and darunavir/ ritonavir in …

Immunosenescence and hurdles in the clinical management of older HIV-patients

ABSTRACT People living with HIV (PLWH) who are treated with effective highly active antiretroviral therapy (HAART) have a similar life expectancy to the general population. Moreover, an increasing proportion of new HIV diagnoses are made in people older than 50 y. The number of older HIV-infected patients is thus constantly growing and it is expected that by 2030 around 70% of PLWH will be more than 50 y old. On the other hand, HIV infection itself is responsible for accelerated immunosenescence, a progressive decline of immune system function in both the adaptive and the innate arm, which impairs the ability of an individual to respond to infections and to give rise to long-term immunity; furthermore, older patients tend to have a worse immunological response to HAART. In this review we focus on the pathogenesis of HIV-induced immunosenescence and on the clinical management of older HIV-infected patients.

Eosinophils from Physiology to Disease: A Comprehensive Review

Despite being the second least represented granulocyte subpopulation in the circulating blood, eosinophils are receiving a growing interest from the scientific community, due to their complex pathophysiological role in a broad range of local and systemic inflammatory diseases as well as in cancer and thrombosis. Eosinophils are crucial for the control of parasitic infections, but increasing evidence suggests that they are also involved in vital defensive tasks against bacterial and viral pathogens including HIV. On the other side of the coin, eosinophil potential to provide a strong defensive response against invading microbes through the release of a large array of compounds can prove toxic to the host tissues and dysregulate haemostasis. Increasing knowledge of eosinophil biological behaviour is leading to major changes in established paradigms for the classification and diagnosis of several allergic and autoimmune diseases and has paved the way to a “golden age” of eosinophil-targeted agents. In this review, we provide a comprehensive update on the pathophysiological role of eosinophils in host defence, inflammation, and cancer and discuss potential clinical implications in light of recent therapeutic advances.

Maraviroc in addition to cART during primary HIV infection: Results from MAIN randomized clinical trial and 96-weeks follow-up

BACKGROUND Multi-targeted treatment strategies including maraviroc (MVC) during Primary HIV Infection (PHI) may benefit from the immune-modulatory properties of this CCR5-inhibitor. OBJECTIVES We conducted a proof-of-concept clinical trial aimed at assessing whether maraviroc in addition of a combination antiretroviral therapy (cART) initiated during PHI would improve immunological and virological parameters. STUDY DESIGN The MAIN (Maraviroc in HIV Acute INfection) study was a randomized open-label clinical trial (EUDRACT number: 2008-007004-29) which enrolled 29 patients with PHI. Subjects were randomly assigned to receive cART-only (cART), cART+8 weeks of MVC (ST-MVC) or cART+48 weeks of MVC (LT-MVC), regardless of predicted co-receptor usage. After 48 weeks patients in ST-MVC and LT-MVC groups discontinued MVC. Patients were evaluated at week 48 and at week 96 of follow-up to assess differences in CD4 T-cell gain and plasma HIV-RNA. RESULTS Twenty-nine patients were enrolled. Seven patients (24%) had a predicted CXCR4 co-receptor usage. At week 48, 27 patients (93.1%) reached HIV-RNA<50cps/mL. Median CD4 T-cell count increase was 313 cells/μL (p<0.001, Wilcoxon signed-rank test). At multivariate linear regression analysis, LT-MVC arm had the greatest CD4 T-cell increase, while patients in ST-MVC arm had the least gain in CD4 T-cells (p=0.007). At week 96, multivariate analysis showed no associations between former treatment arm and CD4 T-cell gain. CONCLUSIONS The MAIN study showed that MVC for 48 weeks in addition to cART during PHI was able to enhance CD4 T-cell gain, regardless of co-receptor usage. After MVC discontinuation, the difference between treatment arms was lost.

Immunological recovery after 24 weeks of antiretroviral therapy in patients with X4 virus during primary HIV infection.

engagement in HIV care in France: strengths and gaps. Presented at: 20th Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta, GA. 6. Buatois S, Miljkovic D, Manckoundia P, et al. Five times sit to stand test is a predictor of recurrent falls in healthy community-living subjects aged 65 and older. J Am Geriatr Soc. 2008;56:1575–1577. 7. Guralnik JM, Ferrucci L, Simonsick EM, et al. Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability. N Engl J Med. 1995; 332:556–561. 8. Salzman SH. The 6-min walk test: clinical and research role, technique, coding, and reimbursement. Chest. 2009;135:1345–1352. 9. Viccaro LJ, Perera S, Studenski SA. Is timed up and go better than gait speed in predicting health, function, and falls in older adults? J Am Geriatr Soc. 2011;59:887–892. 10. Massy-Westropp NM, Gill TK, Taylor AW, et al. Hand Grip Strength: age and gender stratified normative data in a population-based study. BMC Res Notes. 2011;4:127. 11. Werle S, Goldhahn J, Drerup S, et al. Ageand gender-specific normative data of grip and pinch strength in a healthy adult Swiss population. J Hand Surg Eur Vol. 2009;34:76–84. 12. Innes E. Handgrip strength testing: a review of the literature. Austral Occup Ther J. 1999;46: 120–140. 13. Foldvari M, Clark M, Laviolette LC, et al. Association of muscle power with functional status in community-dwelling elderly women. J Gerontol A Biol Sci Med Sci. 2000;55: M192–M199. 14. Manini TM, Clark BC. Dynapenia and aging: an update. J Gerontol A Biol Sci Med Sci. 2012;67:28–40. 15. Buchner DM, Larson EB, Wagner EH, et al. Evidence for a non-linear relationship between leg strength and gait speed. Age ageing. 1996; 25:386–391.

Influence of empirical double-active combination antimicrobial therapy compared with active monotherapy on mortality in patients with septic shock: a propensity score-adjusted and matched analysis—authors’ response

Objectives To evaluate the influence on mortality of empirical double-active combination antimicrobial therapy (DACT) compared with active monotherapy (AM) in septic shock patients. Methods A retrospective study was performed of monomicrobial septic shock patients admitted to a university centre during 2010-15. A propensity score (PS) was calculated using a logistic regression model taking the assigned therapy as the dependent variable, and used as a covariate in multivariate analysis predicting 7, 15 and 30 day mortality and for matching patients who received DACT or AM. Multivariate models comprising the assigned therapy group and the PS were built for specific patient subgroups. Results Five-hundred and seventy-six patients with monomicrobial septic shock who received active empirical antimicrobial therapy were included. Of these, 340 received AM and 236 DACT. No difference in 7, 15 and 30 day all-cause mortality was found between groups either in the PS-adjusted multivariate logistic regression analysis or in the PS-matched cohorts. However, in patients with neutropenia, DACT was independently associated with a better outcome at 15 (OR 0.29, 95% CI 0.09-0.92) and 30 (OR 0.25, 95% CI 0.08-0.79) days, while in patients with Pseudomonas aeruginosa infection DACT was associated with lower 7 (OR 0.12, 95% CI 0.02-0.7) and 30 day (OR 0.26, 95% CI 0.08-0.92) mortality. Conclusions All-cause mortality at 7, 15 and 30 days was similar in patients with monomicrobial septic shock receiving empirical double-active combination therapy and active monotherapy. However, a beneficial influence of empirical double-active combination on mortality in patients with neutropenia and those with P. aeruginosa infection is worthy of further study.

Soluble endothelial protein C receptor (sEPCR) as an inflammatory biomarker in naive HIV-infected patients during ART

BACKGROUND After the advent of ART, non-AIDS-related comorbidities are the main causes of death in HIV patients. Multiple biomarkers have been studied as markers of disease. We wanted to test soluble endothelial protein C receptor (sEPCR) in an HIV setting. OBJECTIVES The primary objective was to determine whether sEPCR decreases after 48 weeks of ART in naive HIV patients. Secondary objectives were to compare sEPCR levels between patients with chronic HIV infection (CHI) and primary HIV infection (PHI) and to analyse if there is a correlation between sEPCR and both immunovirological parameters and different markers of inflammation. PATIENTS AND METHODS We analysed sEPCR in 33 patients with CHI and 19 patients with PHI naive to ART. sEPCR was compared together with immunovirological parameters (HIV RNA and CD4 cell count) and IL-6 or D-dimer (DD). RESULTS AND CONCLUSIONS After 48 weeks of ART, in CHI, the sEPCR decrease was significant (P = 0.0006) and sEPCR at baseline was correlated with both CD4 cell increase (r = +0.463, P = 0.007) and HIV RNA decrease (r = -0.363, P = 0.038). In PHI, sEPCR was stable (P = 0.35); there was a correlation between 48 week DD change and IL-6 change (r = +0.696, P = 0.0009) and also between 48 week DD change and sEPCR change (r = +0.553, P = 0.014). Despite the small sample size, we hypothesize that sEPCR levels reflect coagulant pathway activation caused by the endothelial damage during chronic infection more than a marker of the cytokine storm that occurs during PHI. Alternatively, in PHI, the link found between sEPCR and DD secondary to IL-6 suggests sEPCR is an indirect marker of inflammation.

Evaluation of ceftazidime/avibactam for serious infections due to multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa

OBJECTIVES The steady progress in resistance of Pseudomonas aeruginosa (PA) has led to difficulties in treating infections due to multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Ceftazidime/avibactam (CAZ/AVI) has in vitro activity against many of these strains, however clinical experience with CAZ/AVI is limited. This study aimed to evaluate the characteristics and outcomes of eight patients with infections due to MDR- or XDR-PA treated with CAZ/AVI, including four strains resistant to ceftolozane/tazobactam. METHODS This was a retrospective descriptive study of patients admitted to a teaching hospital between January 2016 and May 2017 who received CAZ/AVI as initial or continuation therapy for infection due to MDR- and XDR-PA. RESULTS The sources of infection were hospital-acquired lower respiratory tract infection in five patients (62.5%) and osteomyelitis, meningitis and catheter-related bacteraemia in one patient each. Clinical cure was achieved in 4 patients (50.0%). The 30-day and 90-day mortality rates were 12.5% and 37.5%, respectively. One patient (12.5%) developed encephalopathy that improved with discontinuation of the drug. CONCLUSIONS CAZ/AVI may be a valuable option for serious infections due to resistant PA.