Stefania Chiappetta

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.

Levels of soluble endothelial protein C receptor are associated with CD4+ changes in Maraviroc-treated HIV-infected patients.

Background Inflammation is a key feature of HIV infection and is correlated with long-term negative cardiovascular outcomes. Therapy-induced increases in CD4+ cell counts can control inflammation, as shown by decreases of coagulation and inflammation markers during efficacious therapy. Maraviroc, a CCR5-antagonist, has resulted in larger increases in CD4+ counts both in naïve and experienced subjects compared to traditional antiretroviral therapy. Objectives and Methods To examine if a member of the protein C anticoagulant and anti-inflammatory pathway, and marker of coagulation and inflammation, the soluble endothelial protein C receptor, is modified by infection and therapy-related variables in patients treated with Maraviroc. Endothelial protein C receptor, together with other established markers of inflammation and coagulation (CRP, IL-6, D-dimer and soluble thrombomodulin) was studied in 43 patients on traditional antiretroviral therapy and in 45 on Maraviroc during 48 weeks of follow-up. Results Soluble endothelial protein C receptor was the only marker that could discriminate at least partially between patients with a good response to Maraviroc and patients who did not respond with an adequate increase in CD4+ cell counts (more than 500 cells/µL by week 48). Conclusions Elevated levels of soluble endothelial protein C receptor, a sensitive marker of endothelial damage, indicated a low level of inflammation and coagulation activation in Maraviroc treated patients not picked up by other widely used markers. Persistent elevated levels of this marker at 48 weeks from beginning of treatment with Maraviroc were related to a poor increase in CD4+ cells.

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.

The use of circulating cathodic antigen rapid test and serology for diagnosis of active Schistosoma mansoni infection in migrants in Italy, a non-endemic country: a cross sectional study

ABSTRACT Diagnosis of schistosomiasis in migrants coming from endemic areas can be difficult, especially in asymptomatic subjects. Light-intensity disease, in fact, may be missed due to the low sensitivity of the stool microscopy and serologic testing cannot distinguish between a resolved infection and an active infection in patients who have been infected and treated in the past, because specific antibodies can persist despite cure. We describe a cross-sectional study conducted on 82 migrants tested for Schistosoma mansoni on single blood (anti-schistosome antibodies, total IgE) and urine [point-of-care (POC) circulating-cathodic-antigen (CCA) test] samples. A positive POC-CCA test (active infection) resulted in two untreated patients with a positive serology while all patients (n = 66) with a past infection showed a negative POC-CCA test. POC-CCA urine test in combination with serology may be helpful in rapidly differentiate active from past S. mansoni infection in migrants coming from endemic areas.

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.

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.

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

Sir, We thank Ambrosini et al. for their critical reading of our manuscript. We agree with their observation that that the resistance profile among raltegravir, elvitegravir and dolutegravir is different; this is nowadays very well known and in our retrospective study we analyse data collected when elvitegravir/cobicistat/emtricitabine/ tenofovir disoproxil fumarate was the only available integrase strand-transfer inhibitor (InSTI)-based single-tablet regimen. However, we would argue that there are still some potential differences, however defined, between our sets of data and those described by our Spanish colleagues. We have reported accessory mutations to InSTIs according to the Stanford University HIV Drug Resistance Database in one patient with primary HIV infection (PHI) (G163R) and one patient with recent HIV infection (S230N); these data are not in line with those reported by Ambrosioni et al., but rather with our Italian database on patterns of transmitted drug resistance, which supports the choice of an InSTI-based therapy because of the very low prevalence of low-level resistance substitutions and accessory mutations that could be involved in long-term virological failure. Actually, we do not know yet the effect of these accessory mutations on InSTI susceptibility in the setting of naive patients; we consider that there may be an action of accessory mutations (L74I, T97A, E157Q) according to a recent cross-sectional study among patients treated with secondand third-line antiretroviral regimens. The most recent European guidelines recommend the use of a boosted PI in a PHI setting; however, they suggest a combination with InSTI in order to induce rapid viral load suppression. Based on the dolutegravir high genetic barrier data and the possible issue of InSTI mutations in PHI, we agree that there is great clinical interest in having efficacy and safety data on the use of dolutegravir-based regimens in the setting of PHI. We are waiting for the results of studies with adequate sample sizes. We also agree that the evaluation of InSTI polymorphisms and secondary substitutions may help in refining the prescription of an InSTI regimen.

Seminal pharmacokinetics and antiviral efficacy of once-daily maraviroc plus lopinavir/ritonavir in HIV-infected patients

mend a value of .100 for optimal fluconazole exposure when the MIC is tested using EUCAST methodology. Rough estimates of minimum AUC/MIC ratios of fluconazole against C. albicans isolated from bile and/or ascites [expressed as (bile or ascites Cmin.24 h)/MIC for Candida isolate in bile or ascites] were well above this threshold (.600) in our patients. We recognize that the absence of real AUC measurements may be a limitation, since our approach led to gross underestimation of drug exposure. However, the findings confirm the valuable role that fluconazole may have in the treatment of Candida cholangitis and/or peritonitis caused by susceptible strains in LTx patients, and supports the usefulness of TDM for optimizing fluconazole exposure in this setting.