The optimal therapeutic approach for primary HIV infection (PHI) is still debated. We aimed to compare the viroimmunological response to a four- versus a three-drug regimen, both INSTI-based, in patients with PHI. This was a monocentric, prospective, observational study including all patients diagnosed with PHI from December 2014 to April 2018. Antiretroviral therapy (ART) was started, before genotype resistance test results, with tenofovir/emtricitabine and either raltegravir plus boosted darunavir or dolutegravir. Cumulative probability of virological suppression [VS] (HIV-1 RNA< 40 cp/mL), low-level HIV-1 DNA [LL-HIVDNA] (HIV-1 DNA < 200 copies/106PBMC), and CD4/CD8 ratio ≥1 were estimated using Kaplan–Meier curves. Factors associated with the achievement of VS, LL-HIVDNA, and CD4/CD8 ≥ 1 were assessed by a Cox regression model. We enrolled 144 patients (95.8% male, median age 34 years): 110 (76%) started a four-drug-based therapy, and 34 (24%) a three-drug regimen. Both treatment groups showed a comparable high probability of achieving VS and a similar probability of reaching LL-HIVDNA and a CD4/CD8 ratio ≥1 after 48 weeks from ART initiation. Higher baseline HIV-1 RNA and HIV-1 DNA levels lowered the chance of VS, whereas a better preserved immunocompetence increased that chance. Not statistically significant factors associated with LL-HIVDNA achievement were found, whereas a higher baseline CD4/CD8 ratio predicted the achievement of immune recovery. In PHI patients, the rapid initiation of either an intensified four-drug or a standard three-drug INSTI-based regimen showed comparable responses in terms of VS, viral reservoir size, and immunological recovery.

Sofosbuvir plus daclatasvir achieves high rates of sustained virologic response (SVR), with no differences according to HIV serostatus. However, only limited information is available on the pharmacokinetic variability of sofosbuvir and daclatasvir in HIV/HCV-coinfected patients. The aim of this study was to identify patient-, treatment-, and disease-related factors that are significantly associated with sofosbuvir and daclatasvir plasma trough concentrations (Ctrough), including liver and renal function, among HIV/HCV-coinfected persons. In this observational cohort pilot study, HIV/HCV-coinfected patients undergoing sofosbuvir plus daclatasvir treatment were prospectively enrolled. Biochemical and viro-immunological parameters were assessed at baseline, week 4 (W4), end of treatment (EOT), and after EOT. The FIB-4 score and CKD-EPI equation were used to estimate liver disease and glomerular filtration rate (eGFR), respectively. For sofosbuvir, sofosbuvir metabolite (GS-331007), and daclatasvir, Ctrough was measured at W4 and week 8 (W8), and the mean of the values at those two time points (mean-Ctrough) was calculated. The Mann–Whitney test and Spearman’s rank correlation were used to evaluate the correlations between the mean-Ctrough of each direct-acting antiviral (DAA) and the considered variables. Thirty-five patients were included (SVR 94%). An increased GS-331007 mean-Ctrough was significantly correlated with a decreased eGFR at W4 (rho = −0.36; p = 0.037) and EOT (rho = −0.34; p = 0.048). There was a significant correlation between daclatasvir mean-Ctrough and FIB-4 at all time points: baseline (rho = −0.35; p = 0.037), W4 (rho = −0.44; p = 0.008), EOT (rho = −0.40; p = 0.023), and after EOT (rho = −0.39; p = 0.028). In HIV/HCV-coinfected patients in a real-world setting, exposure to a high GS-331007 Ctrough was associated with a slight decrease in renal function, while advanced hepatic impairment was significantly associated with a lower daclatasvir Ctrough. Though the clinical and therapeutic relevance of these findings may be limited, increasing clinicians’ knowledge regarding DAA exposure in difficult-to-treat patients could be relevant in single cases, and further investigations are warranted.

Background: Viral load peak and immune activation occur shortly after exposure during acute or early HIV infection (AEHI). We aimed to define the benefit of early start of antiretroviral treatment (ART) during AEHI in terms of immunological recovery, virological suppression, and treatment discontinuation. Setting: Patients diagnosed with AEHI (Fiebig stages I-V) during 2008-2014 from an analysis of 20 Italian centers. Methods: This was an observational, retrospective, and multicenter study. We investigated the effect of early ART (defined as initiation within 3 months from AEHI diagnosis) on time to virological suppression, optimal immunological recovery (defined as CD4 count ≥500/µL, CD4 ≥30%, and CD4/CD8 ≥1), and first-line ART regimen discontinuation by Cox regression analysis. Results: There were 321 patients with AEHI included in the study (82.9% in Fiebig stage III-V). At diagnosis, the median viral load was 5.67 log10 copies/mL and the median CD4 count was 456 cells/µL. Overall, 70.6% of patients started early ART (median time from HIV diagnosis to ART initiation 12 days, IQR 6-27). Higher baseline viral load and AEHI diagnosis during 2012-2014 were independently associated with early ART. HBV co-infection, baseline CD4/CD8 ≥1, lower baseline HIV-RNA, and AEHI diagnosis in recent years (2012-2014) were independently associated with a shorter time to virological suppression. Early ART emerged as an independent predictor of optimal immunological recovery after adjustment for baseline CD4 (absolute and percentage count) and CD4/CD8 ratio. The only independent predictor of first-line ART discontinuation was an initial ART regimen including > 3 drugs. Conclusions: In a large cohort of well-characterized patients with AEHI, we confirmed the beneficial role of early ART on CD4+ T-cell recovery and on rates of CD4/CD8 ratio normalization. Moreover, we recognized baseline CD4/CD8 ratio as an independent factor influencing time to virological response in the setting of AEHI, thus giving new insights into research of immunological markers associated with virological control.

BackgroundSofosbuvir (SOF) plus daclatasvir (DCV) achieved high rates of sustained virologic response (SVR) with no difference according to HIV serostatus. Only limited information is available on the pharmacokinetics variability of SOF and DCV in HIV/HCV co-infected patients. Aim was to evaluate the association of plasma drug concentrations (Ctrough) of SOF and of DCV with patient-, treatment-, and disease-related factors in the real-world setting of HIV/HCV co-infected persons.MethodsHIV/HCV co-infected patients, undergoing SOF plus DCV treatment, were prospectively enrolled. At baseline, week4 (W4), end of treatment (EOT), and after-EOT, biochemical and viro-immunological parameters were assessed. FIB-4 score and CKD-EPI equation were used for estimation of liver disease and glomerular filtration rate (eGFR), respectively. SOF, SOF metabolite (GS-331007), and DCV Ctrough were measured at W4 and week8 (W8), and the mean value (mean-Ctrough) was calculatedResultsThirty-five patients were included (SVR 94%). Increasing GS-331007 mean-Ctrough significantly correlated with decreasing eGFR at W4 (rho=-0.36; p=0.037) and EOT (rho=-0.34; p=0.048). Between DCV mean-Ctrough and FIB-4, a significant correlation was observed at all time-points: baseline (rho=-0.35; p=0.037), W4 (rho=-0.44; p=0.008), EOT (rho=-0.40; p=0.023), after-EOT (rho=-0.39; p=0.028).ConclusionIn HIV/HCV co-infected patients receiving SOF plus DCV, plasma drug concentrations are associated with renal dysfunction for GS-331007 and with liver impairment for DCV. Though clinical and therapeutically relevance of these findings may apparently be limited, growth of clinicians’ knowledge on DAA exposure in difficult-to-treat patients, as cirrhotic and renal impaired subjects, can be relevant in single cases.

OBJECTIVE:Antiretrovirals with long half-lives, such as tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and efavirenz (EFV), are suitable for reduced frequency dosing, with potential for improved adherence and reduced toxicity and costs. The objective of this study was to investigate the noninferiority of the TDF/FTC/EFV fixed-dose combination on alternate-days versus standard regimen in virologically suppressed patients. DESIGN:A randomized-controlled open-label noninferiority trial enrolling HIV-1-infected patients treated for at least 6 months with TDF/FTC/EFV fixed-dose combination, virologically suppressed (<40 HIV-RNA copies/ml) with EFV plasma concentrations greater than 1000 ng/ml, were randomized to maintain TDF/FTC/EFV standard-of-care regimen (SOC, Arm A) or to switch to TDF/FTC/EFV on AlTernAte Days (ATAD, Arm B). METHODS:Primary end-point was the proportion of patients with less than 40 HIV-RNA copies/ml at week 48. RESULTS:One hundred and ninety-seven patients were randomized (98 in the SOC and 99 in the ATAD arm). One hundred and seventy-nine (90.3%) were men, median age 43.2 years, 133 (67.5%) MSM. CD4+ T-cell count at baseline was 706 cells/μl in SOC and 632 cells/μl in ATAD arm. At week 48, 95 (96.9%) patients in SOC and 93 (93.9%) in ATAD had a virological response (-3.0% overall risk difference, 95% CI: -8.86%/2.86%). Median change from baseline at week 48 in CD4+ T-cell count was 29.4 cells/μl (95% CI: 2.5/56.4) in SOC (P = 0.008) and 61.0 cells/μl (95% CI: 32.1/89.9) in ATAD (P < 0.001). Median change of EFV concentration at week 48 from baseline was -6.5 ng/ml (95% CI: -103/55) in SOC (P = 0.877) and -1124 ng/ml (95% CI: -1375/-928) in ATAD arm (P < 0.001). CONCLUSION:Despite a significant decrease of EFV exposure, TDF/FTC/EFV on ATAD was noninferior to SOC regimen through 48 weeks.

Low vitamin D levels are associated with higher odds of cognitive dysfunction in the older population, and in subjects with mental disorders or with chronic neurologic diseases. With combination antiretroviral therapy (cART), incidence of HIV-associated dementia has reduced, while the prevalence of milder forms of neurocognitive impairment (NCI) persisted stable over time. Hypovitaminosis D is often found in HIV infection but its association with NCI has not been investigated yet. The aim was to explore this association in a clinic-based HIV-positive population. A retrospective, cross-sectional analysis of an existing monocenter dataset obtained from patients undergoing neuropsychological assessment in routine clinical care between January, 2011 and December, 2016 was carried out. NCI was assessed through a standardized battery of 13 tests on 5 different cognitive domains and HIV-associated neurocognitive deficit (HAND) was classified according to Frascati’s criteria. Vitamin D deficiency was defined by 25 hydroxy-vitamin D 25(OH)D levels < 10 ng/mL. Logistic regression was adjusted for main associated covariates and seasonality. 542 patients were included: 96.7% were receiving cART, median CD4 count was 611/mmc (IQR, 421–809), HIV RNA was < 40 cp/mL in 85.8%. Median 25(OH)D was 23.2 ng/mL (IQR, 15.6–29.2), with vitamin D insufficiency 67.7% and deficiency in 9.4%. Overall, NCI was found in 37.1% and HAND in 22.7%. Compared to patients with higher vitamin D levels, subjects with vitamin D deficiency had increased proportions of NCI (52.9% versus 35.4%; p = 0.014) or of HAND (42.9% versus 24.9%; p = 0.012). Median NPZ-8 scores were significantly different based on vitamin D levels (p = 0.021). At multivariable analyses, vitamin D deficiency was the only risk factor of NCI (OR 2.05; 95% CI 1.04–4.05; p = 0.038) or of HAND (OR 2.12; 95% CI 0.99–4.54; p = 0.052). In HIV-positive persons, severe hypovitaminosis D was independently associated with a higher risk of neurocognitive impairment in general, and of HIV-associated neurocognitive disorders in particular. Future studies are needed to elucidate causal relationship and whether vitamin D supplementation may reverse this risk.

Objective We evaluated the characteristics of HIV-1 molecular transmission clusters (MTCs) in 1890 newly diagnosed individuals infected with non-B subtypes between 2005 and 2017 in Italy. Methods Phylogenetic analyses were performed on pol sequences to characterise subtypes/circulating recombinant forms and identify MTCs. MTCs were divided into small (SMTCs, 2–3 sequences), medium (MMTCs, 4–9 sequences) and large (LMTCs, ≥10 sequences). Factors associated with MTCs were evaluated using logistic regression analysis. Results 145 MTCs were identified and involved 666 individuals (35.2%); 319 of them (16.9%) were included in 13 LMTCs, 111 (5.9%) in 20 MMTCs and 236 (12.5%) in 112 SMTCs. Compared with individuals out of MTCs, individuals involved in MTCs were prevalently Italian (72.7% vs 30.9%, p<0.001), male (82.9% vs 62.3%, p<0.001) and men who have sex with men (MSM) (43.5% vs 14.5%, p<0.001). Individuals in MTCs were also younger (median (IQR) years: 41 (35–49) vs 43 (36–51), p<0.001) and had higher CD4 cell count in comparison with individuals out of MTCs (median (IQR): 10 9 /L: 0.4 (0.265–0.587) vs 0.246 (0.082–0.417), p<0.001). The viral load remained stable between the two groups (median (IQR) log 10 copies/mL: 4.8 (4.2–5.5) vs 5.0 (4.3–5.5), p=0.87). Logistic regression confirmed that certain factors such as being MSM, of Italian origin, younger age and higher CD4 cell count were significantly associated with MTCs. Conclusions Our findings show that HIV-1 newly diagnosed individuals infected with non-B subtypes are involved in several MTCs in Italy. These MTCs include mainly Italians and MSM and highlight the complex phenomenon characterising the HIV-1 spread. This is important especially in view of monitoring the HIV epidemic and guiding the public health response.

Myeloid derived suppressor cells (MDSC) is a heterogeneous subset of immature and mature cells of the myeloid lineage, undergoing expansion during pathologic conditions, and able to perform strong immune suppressive functions. It has been shown that cryopreservation selectively impacts the polimorphonuclear (PMN) MDSC viability and recovery, and alters the correct analysis of MDSC subsets. In laboratory practice, cryopreservation is often inevitable, in particular in multicenter studies where samples have to be shipped to a centralized laboratory. Aim of the present work was to set out a new protocol to evaluate the frequency of PMN-MDSC in thawed cells by flow-cytometry. PBMC were isolated from HIV+ patients and healthy donors, and were cryopreserved for at least ten days. After thawing, two different protocols were used: 1. standard protocol (SP) consisting of staining with the antibodies mix and then fixing with formalin 1%; 2. thawed protocol (TP) in which fixation foregoes the staining with the antibodies mix. Results showed that PMN-MDSC frequency in ex vivo PBMC evaluated by means TP was comparable to that analysed by SP, indicating that the protocol did not alter PMN-MDSC quantification in ex vivo cells. We then demonstrated that PMN-MDSC frequency in thawed PBMC tested by TP was almost identical to the frequency obtained in ex vivo cells evaluated by using SP. However, we observed that after three hours of culture post-thawing, PMN-MDSC were not assessable anymore with both SP and TP. In conclusion, we herein demonstrated that fixing PBMC soon after thawing and before antibody staining allows preservation of PMN-MDSC integrity and a reliable cells quantification. Thus, it is possible to phenotipically identify PMN-MDSC in cryopreserved PBMC, consenting adequate test precision and accuracy as well as making multicentre research more feasible.

We read with interest the article by Oldenbuettel et al. [1] on dolutegravir monotherapy as treatment de-escalation in successfully cART-treated HIV-infected individuals. Although these results provided important insights into the safety and feasibility of integrase inhibitor monotherapy in selected patients, it remains unclear whether these effects might impact the persistence of chronic immune dysfunction. In the past few years, antiretroviral therapy with less than 3 drugs (less drug regimen [LDR]), including monotherapy with a ritonavir-boosted protease inhibitor (PImono) have been investigated, due to less toxicity, fewer drug–drug interactions, pill burden and costs [2–5]. However, while increased inflammation and immune activation persist upon virally-suppressive cART and are associated with clinical progression [6–8], few studies have assessed the effect of LDR strategies on immune activation and inflammation [9–12]. We therefore reasoned that assessing inflammation/ immune activation in a PImono might be informative on the effect of LDR strategies on inflammation. Thus, we investigated immune activation/senescence and inflammation, as well as HIV reservoirs, in a subgroup of HIV-positive patients enrolled in the Monotherapy Once a Day with Atazanavir/r (MODAt) study [13,14], for whom we had plasma and peripheral blood mononuclear cells (PBMCs) available at baseline, week 48 (W48) and week 96 (W96). The MODAt study is a prospective, multicentre, open-label, non-inferiority, randomized, 96-week trial (NCT01511809) on patients with atazanavir/ritonavir plus two NRTIs, fully suppressed and without previous virological failure, whose study design and methodology have been previously reported [14]. Patients were randomly assigned 1:1 to continue the ongoing triple-based regimen or to maintain only ritonavir-boosted atazanavir (ATV/r) 300/100 mg daily [14]. In the present sub-study, we included 40 individuals, 22/40 on triple therapy (tATV/r) and 18/40 on mono ATV/r regimen (mATV/r), similar for demographic and clinical features (Table 1). In both arms, we observed stable CD4+ T-cell counts over time (not shown); two mATV/r patients and one mATV/r patient showed detectable HIV RNA (>49 copies/ml) at W48 and at W96, respectively, whereas no HIV viraemia changes were evident in the tATV/r arm. Furthermore, self-reported adherence was similar between the two arms over time, with a not significant decrease in mATV/r between W48 and W96, likely due to the limited sample size. As we previously demonstrated inferior virological efficacy of mATV/r [13], we first investigated HIV reservoir (qPCR, ABIPrism 790 VIR/MET/016; Applied Biosystems, Foster City, CA, USA). In mATV/r, total HIV DNA declined over time, reaching significance at W48 (baseline: 55 copies/10×5 cells [IQR 9–175], W48: 18 copies/10×5 cells [IQR 9–54], P=0.014; W96: 25 copies/10×5 cells [IQR 9–68], P=0.102; Figure 1A). On the contrary, in tATV/r total HIV DNA trended to significant reduction at W96 (16 copies/10×5 cells [9–61], 10 copies/10×5 cells [9–23], P=0.216; 9 copies/10×5 cells [9–16], P=0.054; Figure 1A), resulting in significantly lower levels than mATV/r (P=0.013; Figure 1A). We next investigated T-cell immune phenotypes on cryopreserved PBMCs (fluorochrome-labelled antibodies and FACSVerse cytometer from BD Bioscience, San Jose, CA, USA). Baseline values are listed in Table 1. While the mATV/r group showed a reduction of activated HLA-DR+CD38+CD4+ at W48 (8.4% Letter

BACKGROUND:Possible drug-drug interactions (DDIs) between antiretrovirals (ARVs) and direct-acting antiviral agents (DAAs) are of some concern.OBJECTIVES:To investigate ARV plasma trough concentrations (Ctrough) before and during DAAs in patients treated in the real world.METHODS:Single-centre, prospective, observational study including HIV/HCV coinfected persons undergoing DAA treatment. Self-reported adherence was assessed and ARVs Ctrough measured by HPLC-UV. Blood samples were collected before and after 2 months of DAA treatment.RESULTS:One-hundred and thirty-seven patients were included: 21.2% treated with ombitasvir/paritaprevir/ritonavir ± dasabuvir (2D/3D) and 78.8% with sofosbuvir-based regimens. Suboptimal Ctrough before and during DAA was found, respectively, in 3 (10.3%) and 3 (10.3%) cases treated with 2D/3D, and 16 (14.8%) and 11 (10.2%) with sofosbuvir-based regimens, even if self-reported ARV adherence was always ≥93%. In 2D/3D-treated patients, median darunavir Ctrough during DAAs was significantly lower than observed before DAAs [1125 ng/mL (IQR, 810-1616) versus 1903 ng/mL (IQR 1387-3983), respectively] (n = 5; P = 0.009), with a 40.9% decrease. In the same group, no differences in atazanavir or raltegravir concentrations were found. In patients treated with sofosbuvir-based regimens, Ctrough of all ARVs were similar before and during DAAs.CONCLUSIONS:In the real world of HIV/HCV coinfected patients, ARV plasma concentrations during DAAs were generally not different from those found before anti-HCV treatment. Although assessed in a small number of patients, darunavir concentrations during 2D/3D showed a significant reduction when compared with those found before DAAs. ARV plasma concentrations measurement during anti-HCV treatment may give useful information for managing HIV/HCV coinfected persons receiving treatment for both infections.

Social determinants are known to be a driving force of health inequalities, even in high income countries. Aim of our study was to determine if these factors can limit antiretroviral therapy (ART) access, outcome and retention in care of people living with HIV (PLHIV) in Italy.

Background: The NEAT001/ANRS143 trial demonstrated noninferiority of ritonavir-boosted darunavir combined with either raltegravir (RAL + DRV/r) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC + DRV/r) in HIV-positive, antiretroviral-naive adults. In post hoc analyses, however, RAL + DRV/r showed inferiority in patients with baseline CD4+ <200/mm3 and HIV-1 RNA ≥100,000 copies per milliliter. This preplanned ancillary study was conducted to assess whether differences in adherence might explain efficacy results. Setting: Phase III, open-label, randomized, multicenter study in 15 European countries (ClinicalTrials.gov, NCT01066962). Methods: Seven hundred seventy-four participants self-reported adherence (modified AIDS Clinical Trials Group questionnaire) over 96 weeks [383 RAL + DRV/r (twice daily; 5 pills/day), 391 TDF/FTC + DRV/r (once daily; 4 pills/day)]. Primary endpoint was ≥95% versus <95% adherence to prescribed doses recorded (1) over the last 4 days or (2) on the visual analogue scale over the last 30 days. Results: Characteristics, except age, were similar between arms; 9% had CD4+ <200 cells/mm3 and HIV-1 RNA ≥100,000 copies per milliliter. Adherence ≥95% in the last 4 days (P = 0.029) or at the visual analogue scale (P = 0.0072) was higher with TDF/FTC + DRV/r than with RAL + DRV/r. Adherence ≥95% over the last 4 days was associated with lower probability of virological failure (P = 0.015). Adherence in patients with baseline CD4+ <200 cells/mm3 and HIV-1 RNA ≥100,000 copies per milliliter was similar to the rest of the population, and not significantly associated with efficacy measures, with no significant differences between arms. Conclusion: Adherence was high and slightly better in the TDF/FTC + DRV/r than in the RAL + DRV/r arm. No convincing evidence was found that higher failure rate in the RAL + DRV/r arm in the subgroup with worse baseline viroimmunological status is caused by adherence differences.

HIV-positive patients carry an increased risk of HPV infection and associated cancers. Therefore, prevalence and patterns of HPV infection at different anatomical sites, as well as theoretical protection of nonavalent vaccine should be investigated. Aim was to describe prevalence and predictors of oral HPV detection in HIV-positive men, with attention to nonavalent vaccine-targeted HPV types. Further, co-occurrence of HPV DNA at oral cavity and at anal site was assessed.

The impact of early antiretroviral therapy (ART) during Primary HIV Infection (PHI) on the hematopoietic progenitor cells (HPCs) homeostasis is not available. This study aimed to characterize HPCs and their relationship with cytokines regulating progenitors function in ART-treated patients with PHI. We enrolled HIV infected patients treated with ART during PHI. Circulating HPCs, Lymphoid-HPCs (L-HPCs) frequency and plasmatic concentrations of IL-7, IL-18 and Stem Cell Factor (SCF) were analysed at baseline and after 6 months of therapy. ART introduction during PHI restored the decline of L-HPCs, induced a decrease in the level of pro-inflammatory IL-18 cytokine and a parallel increase of SCF. Moreover, L-HPCs frequency positively correlated with IL-18 at baseline, and with SCF after 6 months of therapy, suggesting that different signals impact L-HPCs expansion and maintenance before and after treatment. Finally, the SCF receptor expression on HPCs decreased after early ART initiation. These insights may open new perspectives for the evaluation of cytokine-driven L-HPCs expansion and their impact on the homeostasis of hematopoietic compartment during HIV infection.

Therapeutic drug monitoring may be crucial in selected clinical conditions for the management of HIV infection. In recent years, new antiretrovirals have been introduced and in particular elvitegravir (EVG) is now recommended for first-line and simplification treatment as well as dolutegravir (DTG) and rilpivirine (RPV). The aim of this study was to develop and validate a high-performance liquid chromatography-ultraviolet (HPLC-UV) method for determining EVG and new antiretrovirals DTG and RPV in human plasma. Solid-phase extraction was applied to a 600 μL plasma sample. Chromatographic separation of the three drugs and internal standard was achieved with a gradient of acetonitrile and phosphate buffer on a C18 reverse-phase analytical column with a 20 min analytical run time. EVG and DTG were detected at 265 nm and RPV at 290 nm. Mean intra- and inter-day precisions were < 10%; the mean accuracy was <15%. Extraction recovery ranged between 105 and 82% for the drugs analyzed. Calibration curves were optimized according to the expected ranges of drug concentrations in patients; the coefficient of determination was >0.997 for all drugs. This method allows for monitoring EVG, DTG and RPV in the plasma of HIV-positive patients using HPLC-UV.

Neurocognitive impairment (NCI) is still a common complication in HIV-infected patients. Aim of this study was to investigate the frequency of NCI in HIV-positive patients successfully treated with fixed-dose EFV/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF). Baseline therapeutic drug monitoring of EFV plasma levels, neuropsychologic examination with the NPZ8 calculation and adherence assessment were performed. 127 HIV-positive patients were analyzed and 25 (19.7%) had neurocognitive impairment: 2 mild NCI, 15 asymptomatic NCI, 8 non-HIV-related impairment. At multivariable logistic regression, NCI was significantly associated with older age (p=0.02) and lower educational level (p<0.001). Considering the 17 patients with HAND, NCI was significantly associated with education only (p=0.03). At multivariable linear regression on the whole population, a better NPZ8 score was significantly associated to higher educational level (p=0.008), while higher EFV plasma levels were significantly associated to a worse performance (p=0.024). Even in the 17 HAND cases, higher EFV plasma levels were significantly associated to a worse performance (p=0.05). In conclusion, we found that, among HIV-infected patients on successful cART with EFV/FTC/TDF, almost 20% had minor forms of NCI, that in two thirds were related to HIV. This finding is noteworthy result because our study population was on stable cART, had a durable control of HIV in plasma and reported high adherence to antivirals. Education was the only factor independently associated with HIV- and non-HIV-related NCI. Higher EFV plasma concentrations correlated to worse neurocognitive performance. Concerns about EFV neurotoxicity are emerging.

Objectives Only a few studies have addressed liver stiffness dynamics after hepatitis C virus ( HCV ) treatment in patients with HIV / HCV coinfection. The aim was to evaluate the variation in liver stiffness and in serum liver fibrosis scores in HIV / HCV ‐coinfected patients before and after treatment with direct‐acting antivirals ( DAA s). Methods Liver stiffness measured using transient elastography as well as serum liver fibrosis scores [fibrosis‐4 ( FIB ‐4) score and the aspartate aminotransferase to platelet ratio index ( APRI )] were evaluated before and at 6–12 months after DAA treatment. Variation in the outcome variables was evaluated using the Wilcoxon nonparametric test. Univariate analysis and multivariate regression models were used. Results A total of 78 HIV / HCV ‐coinfected subjects were included in the study. Median values of hepatic stiffness significantly decreased after DAA treatment compared with baseline [16.8 (interquartile range ( IQR ) 10.2–27.0) kP a at baseline vs . 9.4 ( IQR 6.7–15.0) kP a after DAA treatment; P < 0.01). Further, a decrease in median FIB ‐4 score [2.8 ( IQR 1.5–4.8) vs . 2.0 ( IQR 1.3–3.2), respectively; P < 0.01] and APRI [0.9 ( IQR 0.5–2.2) vs . 0.4 ( IQR 0.2–0.7), respectively; P < 0.01] was found. In univariate analysis, liver stiffness decrease was associated with increasing age, ‘other’ HCV genotype ( vs . G1), the presence of cirrhosis, higher pre‐ DAA liver stiffness, sofosbuvir‐based regimens and longer DAA treatment (all P < 0.05). Multivariate regression confirmed the significance of the association only with higher baseline liver stiffness ( P < 0.01). Greater FIB ‐4 and APRI reductions were associated with higher respective baseline values, while the presence of hepatic steatosis correlated with lower score reduction after DAA. Conclusions A reduction in liver stiffness and an improvement in fibrosis scores were observed in HIV / HCV ‐coinfected patients soon after DAA treatment. The clinical implications of these observations need to be evaluated in larger populations with longer follow‐up.

Adherence to antiretroviral therapy (ART) is critical for successful treatment of Human Immunodeficiency Virus (HIV), but comparisons across settings are difficult because adherence is measured in different ways. We examined utility of different adherence measures for identification of patients at risk of viral failure (VF). Eight cohorts in the ART Cohort Collaboration contributed data from pharmacy refills or self-report questionnaires collected between 1996 and 2013 (N = 11689). For pharmacy data (N = 7156), we examined associations of percentage adherence during the 1st year of ART with VF (>500 copies/mL) at 1 year. For self-report data (N = 4533), we examined 28-day adherence with VF based on closest viral load measure within 6 months after questionnaire date. Since adherence differed markedly by measurement type, we defined different cut-off points for pharmacy (lower <45%, medium 45–99%, higher 100%) and self-report (lower ≤95%, medium 96–99%, higher 100%) data. Adjusted odds ratios (ORs) for VF in lower and medium, compared to higher adherence groups, were 23.04 (95% CI: 18.44–28.78) and 3.84 (3.36–4.39) for pharmacy data. For self-report data, they were 3.19 (2.31–4.40) and 1.08 (0.80–1.46). Both types of measure were strongly associated with VF. Although adherence measurements over longer time-frames are preferable for prediction, they are less useful for intervention.

Background: It has been demonstrated that myeloid-derived suppressor cells (MDSC) are expanded in HIV-1–infected individuals and correlated with disease progression. The phase of HIV infection during which MDSC expansion occurs, and the mechanisms that regulate this expansion remain to be established. In this study, we evaluated the frequency of MDSC in patients during primary HIV infection (PHI) and factors involved in MDSC control. Methods: Patients with PHI and chronic HIV infection (CHI) were enrolled. PHI staging was performed according to Fiebig classification, and circulating MDSC frequency and function were evaluated by flow cytometry. Cytokine levels were evaluated by Luminex technology. Results: We found that granulocytic MDSC (Gr-MDSC) frequency was higher in patients with PHI compared with healthy donors, but lower than that in patients with CHI. Interestingly, Gr-MDSC expansion was observed in the early phases of HIV infection (Fiebig II/III), but it was not associated with HIV viral load and CD4 T-cell count. Interestingly, in PHI, Gr-MDSC frequency was inversely correlated with plasmatic level of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), although a direct correlation was observed in CHI. Furthermore, lower level of Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) was observed in PHI compared with that in CHI. In vitro experiments demonstrated that, differently from CHI, recombinant TRAIL–induced apoptosis of Gr-MDSC from PHI, an effect that can be abrogated by GM-CSF. Conclusion: We found that Gr-MDSC are expanded early during PHI and may be regulated by TRAIL and GM-CSF levels. These findings shed light on the fine mechanisms regulating the immune system during HIV infection and open new perspectives for immune-based strategies.