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Background: Integrase strand transferase inhibitors (INSTI), including raltegravir (RAL), elvitegravir (ELV), and dolutegravir (DTG), have demonstrated better efficacy and tolerability than other combination antiretroviral therapy (cART) classes in clinical trials; however, studies of sustainability of INSTI-containing therapy in the long-term are sparse. The purpose of this study was to provide an epidemiological overview comparing the outcome performance of different INSTI-based regimens longitudinally, including the metrics of efficacy, safety, convenience, and durability among a large, nationally representative cohort of persons living with HIV in Italy. Methods: We selected subjects in the MaSTER cohort (an Italian multicenter, hospital-based cohort established in the mid-1990s that currently has enrolled over 24,000 PLWH) who initiated an INSTI-based regimen either when naïve or following a regimen switch. Cox proportional hazards regression models were fitted to evaluate associations between therapy interruptions and age, sex, nationality, transmission risk group, viral suppression status, CD4 + T-cell count, diagnosis year, cART status (naïve or experienced), and hepatitis coinfection. Results were stratified by cART INSTI type. Results: There were 8173 participants who initiated an INSTI-based cART regimen in the MaSTER cohort between 2009 and 2017. The population was majority male (72.6%), of Italian nationality (88.6%), and cART-experienced (83.0%). Mean age was 49.7 (standard deviation: 13.9) years. In total, interruptions of the 1st INSTI-based treatment were recorded in 34% of cases. The most frequently cited reason for interruption among all three drug types was safety problems. In the survival analysis, past history of cART use was associated with higher hazards of interruption due to poor efficacy for all three drug types when compared to persons who were cART naïve. Non-viral suppression and CD4 + T-cell count < 200/mm3 at baseline were associated with higher hazards of interruption due to efficacy, safety, and durability reasons. Non-Italian nationality was linked to higher hazards of efficacy interruption for RAL and EVG. Age was negatively associated with interruption due to convenience and positively associated with interruption due to safety reasons. People who injects drugs (PWID) were associated with higher hazards of interruption due to convenience problems. Hepatitis coinfection was linked to higher hazards of interruption due to safety concerns for people receiving RAL. Conclusion: One-third of the population experienced an interruption of any drugs included in INSTI therapy in this study. The most frequent reason for interruption was safety concerns which accounted for one-fifth of interruptions among the full study population, mainly switched to DTG. The hazard for interruption was higher for low baseline CD4 + T-cell counts, higher baseline HIV-RNA, non-Italian nationality, older age, PWID and possible co-infections with hepatitis viruses. The risk ratio was higher for past history of cART use compared to persons who were cART naive, use of regimens containing 3 drugs compared to regimens containing 2 drugs. Durability worked in favor of DTG which appeared to perform better in this cohort compared to RAL and EVG, though length of follow-up was significantly shorter for DTG. These observational results need to be confirmed in further perspective studies with longer follow-up. [ABSTRACT FROM AUTHOR]

BACKGROUND: Two-drug regimens antiretroviral therapies are increasingly prescribed to HIV patients, as they are recommended by international guidelines, and they show an excellent efficacy, safety, and tolerability profile. Regimens administered as single tablets (STRs) are usually preferred by patients and they are associated with higher adherence. CASE REPORT: We report two cases of drug-induced hypersensitivity (DIH) that occurred after switching from dolutegravir (DTG) plus rilpivirine (RPV) in separate pills to a fixed dose combination containing the same molecules (DTG/RPV; Juluca®). Following the DIH event, DTG/RPV coformulation was discontinued. At symptomatic resolution, they continued to receive DTG plus RPV in separate pills uneventfully. The component present only in the DTG/RPV coformulation was iron oxide red (E172), contained in the film-coating. Iron oxide red is an approved colorant, used as drug excipient. Patch test with DTG/RV coformulation performed several months after the DIH event was negative. Drug allergy to excipients remains underappreciated and underreported and frequently leads to inappropriate medication discontinuation. CONCLUSION: Our case underscores the role of meticulous medication allergy history in differentiating true medication allergy from excipient allergy. This observation may be useful in the era of antiretroviral simplification to two-drug regimens. [ABSTRACT FROM AUTHOR]

Background: Dolutegravir (DTG) is recommended by international guidelines as a main component of an optimal initial regimen of cART (combination antiretroviral treatment) in people living with HIV (PLWH) and in case of switching for failure or optimization strategies. However, studies on the performance of DTG-containing regimens and indications for switching therapies in the long term are sparse. The purpose of this study was to evaluate prospectively the performance of DTG-based regimens, using the metrics of "efficacy", "safety", "convenience" and ''durability", among a nationally representative cohort of PLWH in Italy. Methods: We selected all PLWH in four centers of the MaSTER cohort who initiated a DTG-based regimen either when naïve or following a regimen switch between 11 July 2018 and 2 July 2021. Participants were followed until the outcomes were recorded or until the end of the study on 4 August 2022, whichever occurred first. Interruption was reported even when a participant switched to another DTG-containing regimen. Survival regression models were fitted to evaluate associations between therapy performance and age, sex, nationality, risk of HIV transmission, HIV RNA suppression status, CD4+ T-cell count, year of HIV diagnosis, cART status (naïve or experienced), cART backbone and viral hepatitis coinfection. Results: There were 371 participants in our cohort who initiated a DTG-based cART regimen in the time frame of the study. The population was predominantly male (75.2%), of Italian nationality (83.3%), with a history of cART use (80.9%), and the majority initiated a DTG-based regimen following a switch strategy in 2019 (80.1%). Median age was 53 years (interquartile range (IQR): 45–58). Prior cART regimen was based mostly on a combination of NRTI drugs plus a PI-boosted drug (34.2%), followed by a combination of NRTIs plus an NNRTI (23.5%). Concerning the NRTI backbone, the majority comprised 3TC plus ABC (34.5%), followed by 3TC alone (28.6%). The most reported transmission risk factor was heterosexual intercourse (44.2%). Total interruptions of the first DTG-based regimen were registered in 58 (15.6%) participants. The most frequent reason for interruption was due to cART simplification strategies, which accounted for 52%. Only 1 death was reported during the study period. The median time of total follow-up was 556 days (IQR: 316.5–722.5). Risk factors for poor performance of DTG-containing-regimens were found to be: a backbone regimen containing tenofovir, being cART naïve, having detectable HIV RNA at baseline, FIB-4 score above 3.25 and having a cancer diagnosis. By contrast, protective factors were found to be: higher CD4+ T-cell counts and higher CD4/CD8 ratio at baseline. Conclusion: DTG-based regimens were used mainly as a switching therapy in our cohort of PLWH who had undetectable HIV RNA and a good immune status. In this type of population, the durability of DTG-based regimens was maintained in 84.4% of participants with a modest incidence of interruptions mostly due to cART simplification strategies. The results of this prospective real-life study confirm the apparent low risk of changing DTG-containing regimens due to virological failure. They may also help physicians to identify people with increased risk of interruption for different reasons, suggesting targeted medical interventions. [ABSTRACT FROM AUTHOR]

Background: Despite the effectiveness of cART, people living with HIV still experience an increased risk of serious non-AIDS events, as compared to the HIV negative population. Whether pre-cART microbial translocation (MT) and systemic inflammation might predict morbidity/mortality during suppressive cART, independently of other known risk factors, is still unclear. Thus, we aimed to investigate the role of pre-cART inflammation and MT as predictors of clinical progression in HIV+ patients enrolled in the Icona Foundation Study Cohort. Methods: We included Icona patients with ≥2 vials of plasma stored within 6 months before cART initiation and at least one CD4 count after therapy available. Circulating biomarker: LPS, sCD14, EndoCab, hs-CRP. Kaplan-Meier curves and Cox regression models were used. We defined the endpoint of clinical progression as the occurrence of a new AIDS-defining condition, severe non-AIDS condition (SNAEs) or death whichever occurred first. Follow-up accrued from the data of starting cART and was censored at the time of last available clinical visit. Biomarkers were evaluated as both binary (above/below median) and continuous variables (logescale). Results: We studied 486 patients with 125 clinical events: 39 (31%) AIDS, 66 (53%) SNAEs and 20 (16%) deaths. Among the analyzed MT and pro-inflammatory markers, hs-CRP seemed to be the only biomarker retaining some association with the endpoint of clinical progression (i.e. AIDS/SNAEs/death) after adjustment for confounders, both when the study population was stratified according to the median of the distribution (1.51 mg/L) and when the study population was stratified according to the 33% percentiles of the distribution (low 0.0–1.1 mg/L; intermediate 1.2–5.3 mg/L; high > 5.3 mg/L). In particular, the higher the hs-CRP values, the higher the risk of clinical progression (p = 0.056 for median-based model; p = 0.002 for 33% percentile-based model). Conclusions: Our data carries evidence for an association between the risk of disease progression after cART initiation and circulating pre-cART hs-CRP levels but not with levels of MT. These results suggest that pre-therapy HIV-driven pro-inflammatory milieu might overweight MT and its downstream immune-activation. [ABSTRACT FROM AUTHOR]

Background: Brescia Province, northern Italy, was one of the worst epicenters of the COVID-19 pandemic. The division of infectious diseases of ASST (Azienda Socio Sanitaria Territoriale) Spedali Civili Hospital of Brescia had to face a great number of inpatients with severe COVID-19 infection and to ensure the continuum of care for almost 4000 outpatients with HIV infection actively followed by us. In a recent manuscript we described the impact of the pandemic on continuum of care in our HIV cohort expressed as number of missed visits, number of new HIV diagnosis, drop in ART (antiretroviral therapy) dispensation and number of hospitalized HIV patients due to SARS-CoV-2 infection. In this short communication, we completed the previous article with data of HIV plasmatic viremia of the same cohort before and during pandemic. Methods: We considered all HIV-patients in stable ART for at least 6 months and with at least 1 available HIV viremia in the time window March 01–November 30, 2019, and another group of HIV patients with the same two requisites but in different time windows of the COVID-19 period (March 01–May 31, 2020, and June 01–November 30, 2020). For patients with positive viremia (PV) during COVID-19 period, we reported also the values of viral load (VL) just before and after PV. Results: the percentage of patients with PV during COVID-19 period was lower than the previous year (2.8% vs 7%). Only 1% of our outpatients surely suffered from pandemic in term of loss of previous viral suppression. Conclusions: Our efforts to limit the impact of pandemic on our HIV outpatients were effective to ensure HIV continuum of care. [ABSTRACT FROM AUTHOR]

Perinatally HIV-infected patients face the consequences of both chronic infection effects per se and long-term combination antiretroviral therapy (cART) on immunosenescence. Aims of our study were to evaluate which factors independently contribute to immunosenescence in HIV-infected young adults with a very different HIV infection duration (perinatally HIV-infected young individuals -pHIVy- and age-matched non perinatally HIV-infected youths –npHIVy), after durable efficient cART. We considered low thymic and bone marrow output, respectively evaluated by quantifying T-cell receptor excision circles (TRECs), K-deleting recombination excision circles (KRECs), and shorter telomeres lenght (TL) as surrogate biomarkers of immunosenescence. Twenty-one pHIVy and 19 npHIVy (with a mean HIV duration of 3–8 years) were included; mean age was 27 years for both groups. Immunosenescence biomarkers were comparable between pHIVy and npHIVy (despite longer HIV-infection, higher frequency of AIDS events, past cART-free periods and concomitant chronic viral infections in pHIVy). At the multivariate analysis, CD4+ was the only variable independently associated with TRECs and TL. Our data suggest that a good level of thymic activity can compensate the deleterious effects of past periods without cART, if HIV replication is suppressed for a sufficient time. [ABSTRACT FROM AUTHOR]

Background: Anemia is frequent during HIV infection and is predictive of mortality. Although cART has demonstrated to reduce its prevalence, several patients still experience unresolved anemia. We aimed to characterize iron homeostasis and inflammation in HIV-infected individuals with mild anemia in relation to cART.Methods: In this retrospective cohort study, HIV-infected patients with mild anemia, CD4+ cells > 200/mm3 at baseline, maintaining virological response for 12 months after cART starting were selected within the Standardized Management of Antiretroviral Therapy Cohort (MASTER) cohort. Several inflammation and immune activation markers and iron homeostasis indexes were measured in stored samples, obtained at cART initiation (T0) and 12 months later (T1). Patients were grouped on the basis of hemoglobin values at T1: group A (> 13 g/dl) and B (< 13 g/dl). Wilcoxon rank sum test was used to compare biomarker values. Pearson correlation coefficients were calculated for all variables.Results: cART improved CD4+ and CD8+ cell counts and their ratio, but this effect was significant only in group A. Only these patients had mild iron deficiency at T0 and showed higher transferrin and lower percentage of transferrin saturation than patients of group B, but differences disappeared with cART. cART decreased inflammation in all patients, but group B had higher levels of all markers than group A, reaching statistical significance only for IL-8 values at T1 (16 vs 2.9 pg/ml; p = 0.017). Hepcidin and IL-6 levels did not show significant differences between groups. Hemoglobin levels both at T0 and T1 did not correlate with any marker.Conclusions: Baseline mild anemia in HIV-infected patients cannot always be resolved with durable efficient cART, possibly due to residual inflammation or immune activation rather than unbalanced iron homeostasis. Further research is needed on cytokine profiling to understand the mechanisms that induce anemia in HIV with suppressive cART. [ABSTRACT FROM AUTHOR]

Background: Country-specific forecasts of the growing non-communicable disease (NCD) burden in ageing HIV-positive patients will be key to guide future HIV policies. We provided the first national forecasts for Italy and the Unites States of America (USA) and quantified direct cost of caring for these increasingly complex patients. Methods and Setting: We adapted an individual-based model of ageing HIV-positive patients to Italy and the USA, which followed patients on HIV-treatment as they aged and developed NCDs (chronic kidney disease, diabetes, dyslipidaemia, hypertension, non-AIDS malignancies, myocardial infarctions and strokes). The models were parameterised using data on 7,469 HIV-positive patients from the Italian Cohort Naïve to Antiretrovirals Foundation Study and 3,748 commercially-insured patients in the USA and extrapolated to national level using national surveillance data. Results: The model predicted that mean age of HIV-positive patients will increase from 46 to 59 in Italy and from 49 to 58 in the USA in 2015–2035. The proportion of patients in Italy and the USA diagnosed with ≥1 NCD is estimated to increase from 64% and 71% in 2015 to 89% and 89% by 2035, respectively, driven by moderate cardiovascular disease (CVD) (hypertension and dyslipidaemia), diabetes and malignancies in both countries. NCD treatment costs as a proportion of total direct HIV costs will increase from 11% to 23% in Italy and from 40% to 56% in the USA in 2015–2035. Conclusions: HIV patient profile in Italy and the USA is shifting to older patients diagnosed with multiple co-morbidity. This will increase NCD treatment costs and require multi-disciplinary patient management. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the association between persistent low-level viraemia, measured as viraemia copy-years (VCY), and all-cause mortality.Methods: We included 3271 HIV-infected patients who initiated their first combined ART (cART) during 1998-2012 enrolled in the multicentre Italian MASTER cohort. VCY was defined as the area under the curve of plasma viral load (pVL) and expressed in log10 copies · years/mL. VCY was evaluated from cART initiation until the end of follow-up [VCY-overall (VCY-o)], and stratified into before [VCY-early (VCY-e)] and after [VCY-late (VCY-l)] the eighth month from starting cART, and as the ratio of VCY-l to follow-up duration (VCY-l/FUD).Results: The risk of death increased of about 40% for higher than the median levels of VCY-o and VCY-e. Compared with subjects with permanently suppressed pVL after the eighth month from starting cART, mortality increased by 70% for those with VCY-l ≥3 log10 copies·years/mL, and by about 20-fold for those with VCY-l/FUD ≥2.3 log10 copies/mL. Patients who maintained low levels of VCY-l (<3 log10 copies · years/mL) or VCY-l/FUD (<2.3 log10 copies/mL) had a risk of death similar to patients with permanently suppressed pVL. CD4 cell count at baseline was predictive of high risk of death only in subjects with VCY-l ≥3 log10 copies · years/mL.Conclusions: The risk of death did not increase in HIV-infected patients with low levels of VCY-l compared with patients with permanent virological suppression. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular risk in HIV-infected patients is related, at least in part, to serum lipid alterations before and after HAART. Lipoprotein-particle subclasses may also have an effect, but comparative data after standard HAART regimens are limited. Methods: This was a substudy of a trial in 91 antiretroviral-naive patients randomized to tenofovir+emtricitabine + atazanavir/ritonavir (ATV/r) or efavirenz (EFV). Over-time trends from baseline to week 48 in total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), HDL particles (HDLp), and TC:HDL-C and TG:HDL-C ratios were analyzed by analysis of covariance (ANCOVA). Furthermore, confidence intervals for differences between the 2 groups at week 48 were calculated. Indications for lipid-lowering interventions and low HDL-C were also studied. Results: ANCOVA showed that, with respect to patients receiving ATV/r, those prescribed efavirenz (EFV) had greater increases reported as mean differences in lipid values at week 48:14 mg/dL (95% CI, 0.2 to 27) for TC, 14 mg/dL (95% CI, 4 to 25) for LDL-C, 5 mg/dL (95% CI, 2 to 9) for HDL-C, and 2.2 mg/dL (95% CI, 0.4 to 4) for large HDLp. Proportions of subjects with indications for lipid-lowering interventions and with HDL-C <40 mg/dL did not differ significantly. Conclusions: Patients prescribed EFV had greater increases in TC, LDL-C, and HDL-C. Although no significant differences were detected between the 2 groups for the TC:HDL ratio and for indications to start lipid-lowering interventions, large HDLp increased more in the EFV group compared to the ATV/r group, suggesting a protective effect associated with EFV use. [ABSTRACT FROM AUTHOR]

Background: Nevirapine-containing regimens have been associated with a risk of significant elevations of liver transaminase levels. Higher risk in antiretroviral-naive populations has been related to gender and CD4+ T-cell count (women with CD4+ T-cell counts of > or =250/mm(3) or men with CD4+ T-cell counts of > or =400/mm(3), i.e. group at risk). However, recent studies do not confirm this association in HIV populations comprising patients who are antiretroviral-experienced. Moreover, the predictive value of gender and CD4+ T-cell count on the risk of raised transaminase levels has been poorly investigated in populations of patients co-infected with hepatitis C virus (HCV).Methods: Analysis of HIV-positive patients receiving nevirapine-containing regimens for the first time was conducted. Grade > or =III hepatotoxicity (i.e. > or =5 x upper limit of normal in alanine aminotranferase or aspartate aminotransferase levels) was the primary endpoint. Univariate and multivariable Cox proportional hazard regression models were separately conducted among HCV-antibody (Ab)-positive and HCV-Ab-negative patients.Results: Amongst 905 patients, 49% were HCV-Ab-positive and 79% were antiretroviral-experienced. Grade > or =III liver transaminase elevations developed in 7.1% of patients, accounting for an incidence of 2.47 (95% CI 1.97, 3.09) per 100 patient-years of follow-up. HCV-Ab reactivity was associated with a 3-fold increase in risk of developing relevant liver transaminase elevations (95% CI 1.75, 5.3; p < 0.001), whereas gender and CD4+ T-cell count did not impact significantly. When analysis was performed in HCV-Ab-negative patients, the outcome was independently correlated with the group at risk (hazard ratio [HR] 3.66; 95% CI 1.20, 11.14; p = 0.022). By contrast, in HCV-Ab-positive patients, the group at risk was not significantly associated with the outcome.Conclusions: Most of the excess rates of relevant raised transaminase levels in patients prescribed nevirapine-containing regimens could be attributed to HCV co-infection. Gender and CD4+ T-cell count appeared to have a statistically significant impact on the risk of relevant transaminase level elevations in HCV-negative, but not in HCV-positive patients, probably due to a diluting effect of HCV. Incidence of hepatic events after nevirapine-containing regimens did not appear to be a major concern in our cohort of patients who were mainly antiretroviral-experienced and negative for HCV-Ab. Preferably, nevirapine should be avoided in HCV co-infected patients and in males with CD4+ T-cell counts of > or =400/mm(3) or females with CD4+ T-cell counts of > or =250/mm(3). [ABSTRACT FROM AUTHOR]

Background: Homocysteinemia (Hcy) increase and risk factors in HIV-positive patients are not clear yet. Methods: HIV-positive patients on stable highly active antiretroviral therapy (HAART) regimens for at least 6 months were enrolled in this cross-sectional study. Among other factors, vitamin B12, folate and length of exposure to protease inhibitors (PIs) were evaluated for their possible correlation with hyper-Hcy (>13 μmol/l in females; >15 μmol/l in males) by logistic regression analysis. Results: Ninety-eight HIV-positive patients were recruited. Twenty-eight (28.6%) had hyper-Hcy. Length of exposure to antiretroviral therapy and PIs did not result to be significantly associated with hyper-Hcy risk. Normal folate level was the only factor associated with the outcome, resulting protective from hyper-Hcy, either at univariate (OR = 0.22; CI 95% = 0.06–0.86; p = 0.029) and multivariable (OR = 0.24; CI 95% = 0.06–0.94; p = 0.04) logistic regression analysis. Folate predictive value of hyper-Hcy risk was driven by levels in the lowest quartiles of the study population (i.e. <10.9 nmol/l). Conclusions: No significant correlations were observed between hyper-Hcy and length of exposure to antiretroviral therapy or PIs. Folate could be a confounding factor in the association between hyper-Hcy and PI exposure found by others. The potential value of folate supplementation, in those who are deficient and in those with hyper-Hcy, merits study. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The risk of hepatotoxicity associated with different highly active antiretroviral therapy (HAART) regimens (containing multiple-protease inhibitors, single-protease inhibitors or non nucleoside reverse transcriptase inhibitors) in HIV-HCV co-infected patients has not been fully assessed. Methods: Retrospective analysis of a prospective cohort of 1,038 HIV-HCV co-infected patients who commenced a new HAART in the Italian MASTER database. Patients were stratified into naïve and experienced to antiretroviral therapy before starting the study regimens. Time to grade ≥III hepatotoxicity (as by ACTG classification) was the primary outcome. Secondary outcome was time to grade IV hepatotoxicity. Results: Incidence of grade ≥III hepatotoxicity was 17.71 per 100 patient-years (p-yr) of follow up in naïve patient group and 8.22 per 100 p-yrs in experienced group (grade IV: 4.13 per 100 p-yrs and 1.08 per 100 p-yrs, respectively). In the latter group, the only independent factors associated with shorter time to the event at proportional hazards regression model were: previous liver transaminase elevations to grade ≥III, higher baseline alanine amino-transferase values, and use of a non nucleoside reverse transcriptase inhibitor based regimen. In the naive group, baseline aspartate transaminase level was associated with the primary outcome. Conclusion: Use of a single or multiple protease inhibitor based regimen was not associated with risk of hepatotoxicity in either naïve or experienced patient groups to a statistically significant extent. A cautious approach with strict monitoring should be applied in HIV-HCV co-infected experienced patients with previous liver transaminase elevations, higher baseline alanine aminotransferase values and who receive regimens containing non nucleoside reverse transcriptase inhibitors. [ABSTRACT FROM AUTHOR]

Reference 1 Merlini E. Inflammation and microbial translocation measured prior to combination antiretroviral therapy (cART) and long-term probability of clinical progression in people living with HIV. B Correction to: BMC Infect Dis 21, 557 (2021) b B https://doi.org/10.1186/s12879-021-06260-y b Following publication of the original article [[1]], the authors identified an error in the author's name of Eugenia Quiros Roldan. [Extracted from the article]

Introduction: During the COVID-19 pandemic, hospitals faced increasing pressure, where people living with HIV risked to either acquire SARS-CoV-2 and to interrupt the HIV continuum of care. Methods: This is a retrospective, observational study. We compared the numbers of medical visits performed, antiretroviral drugs dispensed and the number of new HIV diagnosis and of hospitalizations in a cohort of people living with HIV (PLWH) followed by the Spedali Civili of Brescia between the bimester of the COVID-19 pandemic peak and the bimester of October–November 2019. Data were retrieved from administrative files and from paper and electronic clinical charts. Categorical variables were described using frequencies and percentages, while continuous variables were described using mean, median, and interquartile range (IQR) values. Means for continuous variables were compared using Student's t-tests and the Mann–Whitney test. Proportions for categorical variables were compared using the χ2 test. Results: As of December 31st, 2019, a total of 3875 PLWH were followed in our clinic. Mean age was 51.4 ± 13 years old, where 28% were females and 18.8% non-Italian. Overall, 98.9% were on ART (n = 3834), 93% were viro-suppressed. A total of 1217 and 1162 patients had their visit scheduled at our out-patient HIV clinic during the two bimesters of 2019 and 2020, respectively. Comparing the two periods, we observed a raise of missed visits from 5 to 8% (p < 0.01), a reduction in the number of new HIV diagnosis from 6.4 in 2019 to 2.5 per month in 2020 (p = 0.01), a drop in ART dispensation and an increase of hospitalized HIV patients due to COVID-19. ART regimens including protease inhibitors (PIs) had a smaller average drop than ART not including PIs (16.6 vs 21.6%, p < 0.05). Whether this may be due to the perception of a possible efficacy of PIs on COVID19 is not known. Conclusions: Our experience highlights the importance of a resilient healthcare system and the need to implement new strategies in order to guarantee the continuum of HIV care even in the context of emergency. [ABSTRACT FROM AUTHOR]

Background: Triple-drug regimens are the gold standard for HIV therapy. Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) reducing regimens are used to decrease drugs toxicity, exposure and costs. Aim of our study was to evaluate trends of biochemical and inflammatory indices in patients switching to dual therapy (DT).Methods: We included patients that a) switched to a DT from 2007 to 2015 from a tenofovir/abacavir-based triple regimen b) previously maintained a triple and c) subsequently a dual regimen for 12 months with virological suppression. We retrieved data measured at 5 points (at the switch, 6 and 12 months before and after switch). We used platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR) and CD4/CD8 ratio as inflammatory indices. We assessed temporal trends of viro-immunological, biochemical and inflammatory parameters.Results: Overall, 364 and 65 patients switched from a tenofovir- and an abacavir-triple regimen, respectively. In the tenofovir-reducing group, creatinine clearance and lipids raised after the switch. There was a significant increase in both CD4+ cells and CD4/CD8. CD8+ cells rose after the switch, while opposite trend was found for PLR. In the abacavir-reducing group total lipids showed a decrease during the first 6 months after the switch and then stabilized. An increase of CD4+ and a decrease of CD8+ cells was observed during the study period, although not statistically significant. While CD4/CD8 remained stable after simplification, PLR decreased significantly after 6 months, then returning to baseline. CD8+ cells increased in the tenofovir-reducing group despite a viro-immunological response. Intriguingly, PLR decreased, maintaining this trend for 12 and 6 months after tenofovir and abacavir interruption respectively.Conclusions: Increased PLR has been linked to hypercholesterolemia and metabolic-syndrome, while high CD8+ cells count to increased risk of non-AIDS-related events regardless of CD4 T-cell recovery and to virological failure. Whether these findings may have clinical implications, and which role DT plays on the immune system and on inflammation should be further investigated. [ABSTRACT FROM AUTHOR]

Summary: Background: In the primary analysis of SPRING-2 at week 48, dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for antiretroviral treatment. We present the 96 week results. Methods: SPRING-2 is an ongoing phase 3, randomised, double-blind, active-controlled, non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19, 2010. We present results for the safety cutoff date of Jan 30, 2013. Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more. Patients were randomly assigned (1:1) to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily), plus investigator-selected tenofovir–emtricitabine or abacavir–lamivudine. Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL, CD4 cell count changes from baseline, safety, tolerability, and genotypic or phenotypic resistance. We used an intention-to-treat exposed population (received at least one dose of study drug) for the analyses. Sponsor staff were masked to treatment assignment until primary analysis at week 48; investigators, site staff, and patients were masked until week 96. This study is registered with ClinicalTrials.gov, NCT01227824. Findings: Of 1035 patients screened, 827 were randomly assigned to study group, and 822 received at least one dose of the study drug (411 patients in each group). At week 96, 332 (81%) of 411 patients in the dolutegravir group and 314 (76%) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 4·5%, 95% CI −1·1% to 10·0%) confirming non-inferiority. Secondary analyses of efficacy such as per protocol (HIV RNA <50 copies per mL: 83% for dolutegravir and 80% for raltegravir) and treatment-related discontinuation equals failure (93% without failure for dolutegravir; 91% for raltegravir) supported non-inferiority. Virological non-response occurred less frequently in the dolutegravir group (22 [5%] patients for dolutegravir vs 43 [10%] patients for raltegravir). Median increases in CD4 cell count from baseline were similar between groups (276 cells per μL for dolutegravir and 264 cells per μL for raltegravir). Ten patients (2%) in each group discontinued because of adverse events, with few such events between weeks 48 and 96 (zero in the dolutegravir group and one in the raltegravir group). No study-related serious adverse events occurred between week 48 and week 96. At virological failure, no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir. Interpretation: At week 96, once-daily dolutegravir was non-inferior to twice-daily raltegravir in treatment-naive, patients with HIV-1. Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients. Funding: ViiV Healthcare. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To determine the impact of genotypic inhibitory quotient (GIQ) for lopinavir (LPV) in patients failing HAART with limited antiretroviral exposure. Design: Retrospective analysis of a prospective trial. Methods: Lopinavir GIQ was calculated as the ratio between the mean trough concentration (C trough) and the number of protease mutations using eight different HIV drug resistance mutation lists or algorithms. Early (by week 12) and confirmed (up to week 24) virological response (HIV-RNA<400copies/mL, ECVR) was used as dependent variable in logistic regression model. Results: Seventy-one of 109 (65%) patients achieved ECVR. At multivariable logistic regression analysis, each μg/mL increase of GIQ was correlated with increasing probability of ECVR as far as the following mutations were computed: multi-protease inhibitor (PI) associated mutations listed by IAS (OR=1.17; 95% CI=0.99–1.39; P =0.058), mutations associated with LPV resistance by ANRS algorithm (OR=1.21; 95% CI=1.02–1.44; P =0.03), major mutations associated with LPV resistance by Stanford database (OR=1.16; 95% CI=1–1.35; P =0.05), and the whole set of mutations associated with LPV resistance in the same database (OR=1.22; 95% CI=1.02–1.46; P =0.03). Using ROC curve method, a specific threshold GIQ was assessed, above which this parameter could predict ECVR with the highest sensitivity (74.6% with GIQ obtained through Stanford LPV mutations) or specificity (89.5% with GIQ obtained through ANRS LPV mutations). Conclusions: Our results suggest that increasing GIQ can improve virological outcome even in patients with limited exposure to PIs. Further studies are necessary to understand what HIV protease mutations should be considered and whether such mutations should be weighted differently to improve LPV GIQ predictive value. [Copyright &y& Elsevier]

• In PWH starting a modern ART regimen, estimated probability of becoming 'difficult to treat' due to multiple failures is 6.5% by 6 years. • Difficult to treat PWH had a significantly higher prevalence of AIDS diagnosis, were older and had lower nadir of CD4 compared to the non- difficult to treat PWH. • Difficult to treat PWH showed a higher risk of experiencing virological failure (aHR 2.23, 95% CI: 1.33–3.73), treatment failure (aHR 1.70, 95% CI: 1.03–2.78), and serious non-AIDS events/death (aHR 2.79, 95% CI: 1.18–6.61). Treatment failures to modern antiretroviral therapy (ART) raise concerns, as they could reduce future options. Evaluations of occurrence of multiple failures to modern ART are missing and their significance in the long run is unclear. People with HIV (PWH) in the ICONA cohort who started a modern first-line ART were defined as 'difficult to treat' (DTT) if they experienced ≥1 among: i) ≥2 VF (2 viral loads, VL>200 copies/mL or 1 VL>1000 copies/mL) with or without ART change; ii) ≥2 treatment discontinuations (TD) due to toxicity/intolerance/failure; iii) ≥1 VF followed by ART change plus ≥1 TD due to toxicity/intolerance/failure. A subgroup of the DTT participants were matched to PWH that, after the same time, were non-DTT. Treatment response, analysing VF, TD, treatment failure, AIDS/death, and SNAE (Serious non-AIDS event)/death, were compared. Survival analysis by KM curves and Cox regression models were employed. Among 8061 PWH, 320 (4%) became DTT. Estimates of becoming DTT was 6.5% (95% CI: 5.8–7.4%) by 6 years. DTT PWH were significantly older, with a higher prevalence of AIDS and lower CD4+ at nadir than the non-DTT. In the prospective analysis, DTT demonstrated a higher unadjusted risk for all the outcomes. Once controlled for confounders, significant associations were confirmed for VF (aHR 2.23, 1.33–3.73), treatment failure (aHR 1.70, 1.03–2.78), and SNAE/death (aHR 2.79, 1.18–6.61). A total of 6.5% of PWH satisfied our definition of DTT by 6 years from ART starting. This appears to be a more fragile group who may have higher risk of failure. [ABSTRACT FROM AUTHOR]

Abstract: It is still controversial whether viral hepatitis co-infection can influence antiretroviral plasma drug concentrations and whether drug concentrations are correlated with liver enzyme elevations during highly active antiretroviral therapy. An analysis of data from a cohort of 220 human immunodeficiency virus (HIV)-infected patients was conducted. Univariate and multivariate logistic analyses were performed to identify predictors of plasma drug concentrations. The association of transaminase elevation with higher plasma drug concentrations was explored following stratification of patients into HIV monoinfected and hepatitis C virus (HCV) and/or hepatitis B virus (HBV) co-infected groups. Hepatitis co-infections were independently correlated with drug concentrations above the therapeutic cut-offs at Week 1 (P = 0.06), Week 4 (P = 0.04) and Week 12 (P = 0.005). The apparent effect was independent of the possible impact exerted by other variables such as demographics and medication adherence. The incidence of relevant hypertransaminasaemia was low. Patients with hepatitis co-infections had higher rates of transaminase elevation than monoinfected HIV patients; however, risk of transaminase elevation was not associated with drug concentrations. The presence of HCV and/or HBV co-infections correlated with higher plasma drug concentrations, although it did not appear to influence hepatotoxicity risk. [Copyright &y& Elsevier]

Persistent inflammation, despite anti-retroviral therapy (ART), is an independent predictor of mortality and comorbidities in HIV infection. Multiple factors, including lifestyle and chronic viral coinfections, may contribute. Several of these factors are also associated with a chronic inflammation in the general population. Little is known about the degree to which these factors influence inflammation in HIV infection, particularly within the first year of ART. The purpose of this study was to distinguish the effects of factors (gender, body mass index, cholesterol and triglyceride levels, smoke habit and cytomegalovirus seropositivity), known to contribute to inflammation, on inflammation biomarkers over the first year of ART in HIV-infected patients. Linear mixed model analysis revealed significant biomarker decreases [soluble CD14 (s-CD14), soluble CD163 (s-CD163) and D-dimer (DD)], or increases [C Reactive Protein (CRP) and interleukin-6 (IL-6)] over time in the whole cohort, differences in most categories (genders for IL-6, smoke habit for s-CD14, cytomegalovirus infection for s-CD163 and IL-6) and in some category × time interactions [gender for interleukin-7 (IL-7)], cytomegalovirus infection for s-CD14 and cholesterol levels for s-CD14 and Tumor Necrosis Factor α (TNF-α)]. This explorative longitudinal study suggests further investigations on targeting inflammation pathophysiology in HIV-infected patients on ART. [ABSTRACT FROM AUTHOR]