No need to modify treatment within the first month after rapid start of a tailored antiretroviral therapy: the TWODAY Study.

The aim of the TWODAY Study was to investigate the frequency of early treatment change after rapid start of a tailored ART regimen (a 2-drug regimen - 2DR, when clinically feasible or a 3-drug regimen - 3DR, otherwise). TWODAY was an open-label, prospective, proof-of-concept, single center study. ART-naïve patients started their first-line regimen within a few days from the first laboratory testing with a 2DR of dolutegravir (DTG) and lamivudine (3TC) if CD4+ count >200 cells/mL, HIVRNA <500,000 copies/mL, no transmitted drug resistance to DTG or 3TC and HBsAg undetectable; otherwise, ART was started with a 3DR. The primary endpoint was the proportion of patients who needed to change ART within four week from start, for any reason. Thirty-two patients were enrolled; 19 (59.3%) were deemed eligible for a 2DR. Median time from laboratory testing to ART start was 5 days (5; 5). No regimen modification occurred within one month. In conclusion, no regimen modification was needed within the first month of treatment. Starting a 2DR within a few days after HIV diagnosis was feasible, relying upon complete results of the needed laboratory tests (including resistance testing). A 2DR can be safely proposed provided full laboratory tests are readily available.

Early Diagnosis and Linkage to Care: an Experience over 14 years of Point of Care Rapid HIV Testing.

Point-of-care rapid testing is one of the strategies to increase HIV screening. We present data on over 14 years of the "EASY Test Program", an ongoing cross-sectional collaborative project that provides free and anonymous rapid HIV testing in the metropolitan city of Milan, Italy. Overall, 22,186 HIV tests were performed, with a 0.52% prevalence of HIV infection; 100% of those diagnosed with HIV were linked to care. The "EASY Test Program" is an appropriate test-and-treat strategy, allowing a fast HIV assessment (24 hours). Motivated clinicians, in partnership with community associations, can perform an easy HIV screening out of hospitals in alternative settings, among individuals who in the majority of cases had never tested for HIV, ultimately providing an effective linkage to care.

Early predictors of clinical outcomes of COVID-19 outbreak in Milan, Italy.

BACKGROUND: National health-system hospitals of Lombardy faced a heavy burden of admissions for acute respiratory distress syndromes associated with coronavirus disease (COVID-19). Data on patients of European origin affected by COVID-19 are limited. METHODS: All consecutive patients aged ≥18 years, coming from North-East of Milan's province and admitted at San Raffaele Hospital with COVID-19, between February 25th and March 24th, were reported, all patients were followed for at least one month. Clinical and radiological features at admission and predictors of clinical outcomes were evaluated. RESULTS: Of the 500 patients admitted to the Emergency Unit, 410 patients were hospitalized and analyzed: median age was 65 (IQR 56-75) years, and the majority of patients were males (72.9%). Median (IQR) days from COVID-19 symptoms onset was 8 (5-11) days. At hospital admission, fever (≥ 37.5 °C) was present in 67.5% of patients. Median oxygen saturation (SpO2) was 93% (range 60-99), with median PaO2/FiO2 ratio, 267 (IQR 184-314). Median Radiographic Assessment of Lung Edema (RALE) score was 9 (IQR 4-16). More than half of the patients (56.3%) had comorbidities, with hypertension, coronary heart disease, diabetes and chronic kidney failure being the most common. The probability of overall survival at day 28 was 66%. Multivariable analysis showed older age, coronary artery disease, cancer, low lymphocyte count and high RALE score as factors independently associated with an increased risk of mortality. CONCLUSION: In a large cohort of COVID-19 patients of European origin, main risk factors for mortality were older age, comorbidities, low lymphocyte count and high RALE.

Relapse of Symptomatic Cerebrospinal Fluid HIV Escape.

PURPOSE OF REVIEW: Symptomatic cerebrospinal fluid (CSF) HIV escape defines the presence of neurological disease in combination antiretroviral therapy (cART)-treated persons due to HIV replication in CSF despite systemic suppression or to higher viral replication in CSF than in plasma. The aim was to search for cases of recurrent symptomatic CSF escape and to define their characteristics. RECENT FINDINGS: By review of the literature, we identified symptomatic CSF escape relapses in three patients who had shown clinical remission of a first escape episode following cART optimization. By examination of our cohort of 21 patients with symptomatic CSF escape, we identified five additional patients. In the latter, viral escape relapsed over a median follow-up of 108 months because of low adherence or upon treatment simplification of a previously optimized regimen. cART reoptimization based on resistance profile and potential drug neuropenetration and efficacy led to relapse resolution with no further episodes after a median follow-up of 50 months from relapse. The observation that CSF escape may relapse highlights the importance of long-term neuro-suppressive regimens after a first episode and supports the role of the brain as a reservoir for HIV.

HIV-1 recombinant forms in immigrants regularly residing in Milan, northern Italy.

To assess the HIV -1subtypes distribution in HIV-1 positive migrants living in Milan we studied 77 HIV-1 patients followed at the San Raffaele Hospital of Milan. Twenty subjects were born in Europe, 43 in the Americas, 10 in Africa and 4 in Asia. Unsafe heterosexual activity prevailed in migrants born in Africa and male homosexuality in those born in European, American and Asian countries (p = 0.05). The phylogeny showed that 38/77 (49.3%) subjects carried HIV-B subtype while the remaining strains were classified as not pure HIV-1 B subtypes 13/77 (16.9%) or recombinant forms 26/77 (33.8%). Female gender more frequently showed HIV-1 non-B strains and rarely HIV-1 B subtypes (12/39, 30.8% vs. 3/38, 7.9%, p = 0.02). Transmitted drug resistance was identified in 10/77 (13%) patients predominately with B subtype. Our data underscore a large heterogeneity in HIV-1 subtypes and a large proportion of recombinant forms.

Molecular epidemiology of HIV-1 infection in immigrant population in northern Italy.

Human immunodeficiency virus-1 (HIV-1) is characterised by a vast genetic diversity classified into distinct phylogenetic strains and recombinant forms. We describe the HIV-1 molecular epidemiology and evolution of 129 consecutive HIV-1 positive migrants living in Milan (northern Italy). Polymerase gene sequences of 116 HIV-1 subtype-B positive patients were aligned with HIV-1 reference sequences (https://www.ncbi.nlm.nih.gov/) by using MAFFT alignment and edited by using Bioedit software. A maximum likelihood (ML) phylogenetic tree was performed by MEGA7 and was visualised by using FigTree v1.4.3. Of 129 migrants, 35 were born in Europe (28 in Eastern Europe), 70 in the Americas (67 in South America), 15 in Africa and nine in Asia; 76.4% were men who have sex with men (MSM). The serotype HIV-1-B prevailed (89.9%), followed by -C, -F1, -D and -A. Compared with 116 HIV-B patients, the 13 with HIV-non-B showed lower Nadir of CD4+ cell/mmc (P = 0.043), more frequently had sub Saharan origin (38.5 vs. 1.72%, P = 0.0001) and less frequently were MSM (40 vs. 74.5%, P = 0.02). The ML phylogenetic tree of the 116 HIV-1 subtype-B positive patients showed 13 statistically supported nodes (bootstrap > 70%). Most of the sequences included in these nodes have been isolated from male patients from the Americas and the most common risk factor was MSM. The low number of HIV-1 non-B subtype patients did not allow to perform this analysis. These results suggest a shift of HIV-1 prevention projects' focus and a continuous monitoring of HIV-1 molecular epidemiology among entry populations. Prevention efforts based on HIV molecular epidemiology may improve public health surveillance setting.

Dynamics of HIV-1 POL antibodies after ART in chronic HIV-1 infection.

The aim of this retrospective study was to evaluate Western Blot (WB) antibody response against HIV-1 Pol proteins in people on ≥12 months of Antiretroviral Therapy (ART) and factors associated with a negative HIV-1 Pol response or with its seroreversion from positive to negative. Multivariate logistic regression models were performed to assess factors associated with a negative HIV-1 Pol or with HIV-1 Pol seroreversion. A negative HIV-1 Pol was found in 88 (16.6%) of the 530 individuals evaluated. At multivariate analysis, a negative Pol result was associated with an early ART start [adjusted odds ratio (AOR) per 3-months longer = 0.95, 95% CI=0.90-0.99] and a greater CD4+ recovery since ART start [AOR per 100-cells/µL/year higher=1.11, 95%CI=1.01-1.24]. In a subgroup of 140 patients with WB analysis performed both at HIV-1 diagnosis and after a median of 69 months, Pol seroreverted from positive to negative in 22 (15.7%) patients and was associated with a greater CD4+ recovery [AOR per 100-cells/µL/year higher =2.50 (95%CI=1.28-4.87)]. In conclusion, a negative HIV-1 Pol and a seroreversion from positive to negative were observed in more than 15% of subjects included and were associated with a better immunological profile, suggesting a lower viral exposure to the immune system over time.

SARS-CoV-2 IgG/IgM Rapid Test as a Diagnostic Tool in Hospitalized Patients and Healthcare Workers, at a large Teaching Hospital in northern Italy, during the 2020 COVID-19 Pandemic.

We describe the outcome of a Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) IgG/IgM rapid test, and discuss the potential suitability of antibody testing. Retrospective single cohort study on patients with suspected Coronavirus Disease 2019 (COVID-19) and asymptomatic Healthcare Workers, enrolled from March to April 2020. Subjects had quantitative PCR (qPCR) test for detection of SARS-CoV-2 via nasal swab and serological testing using the COVID-19 IgG/ IgM Rapid Test (PRIMA Lab SA) immunochromatographic assay. Some subjects underwent chemiluminescence immunoassay (CLIA) after rapid test. The aim of the study was to analyse the proportion of those who developed a positive IgM/IgG response for SARS-CoV-2. The correspondence between the results from rapid testing and CLIA, when available, was evaluated. 97 subjects underwent qPCR for SARS-CoV-2 through nasal swab, which resulted positive in 40/43 (93.0%) of symptomatic patients, 2/40 (5%) of asymptomatic HCW, in no subjects with suspected COVID- 19 (clinical and radiological findings) then excluded by repeated nasal swabs and alternative diagnosis (COVID-19-negative patients, CNPs), and in 6/6 (100%) of patients with confirmed diagnosis and negative follow-up nasal swabs (COVID-19-recovered patients, CRPs). IgM resulted positive in 8/43 (18.6%) of symptomatic patients and in 1/6 (16.7%) of CRPs. IgG resulted positive in 36/43 (83.7%) of symptomatic patients, 2/40 (5%) of HCW, and in 1/8 (12.5%) and 6/6 (100%) of CNPs and CRPs, respectively. A comparison between an IgG/IgM Rapid Test and a following CLIA test showed consistency in negative results in 25/28 of HCW and 8/8 of CNPs tested. Our preliminary data support the role of IgG/IgM Rapid Test (PRIMA Lab SA) immunochromatographic assay as a point-of-care test that may complement molecular tests in the screening of SARS-CoV-2 carriers. The test may gain particular relevance in shortening the time needed to refer patients to a COVID or non-COVID Hospital area and to achieve diagnosis in patients with persistently negative nasal swabs.

Analytical treatment interruption in chronic HIV-1 infection: time and magnitude of viral rebound in adults with 10 years of undetectable viral load and low HIV-DNA (APACHE study).

OBJECTIVES: Despite the fact that there are individuals who have chronic HIV infection, few studies have investigated ART interruption in this setting. The aim of this study was to evaluate the ability to spontaneously control viral replication during analytical treatment interruption (ATI) in adults with chronic HIV-1 infection, on ART, with suppressed viraemia for >10 years and with a low reservoir. PATIENTS AND METHODS: This was a prospective, open-label, single-arm, non-randomized, proof-of-concept study (NCT03198325) of subjects with chronic HIV-1 infection, HIV-RNA <50 copies/mL for ≥10 years, without residual viraemia for ≥5 years, CD4+ >500 cells/mm3, HIV-DNA <100 copies/106 PBMCs and without comorbidities or AIDS-defining diseases. Enrolled patients were strictly monitored. The ART regimen in use at ATI was resumed in the case of confirmed viral rebound (CVR, two consecutive HIV-RNA >50 copies/mL). Results are reported as median (IQR). RESULTS: Nine patients underwent ATI. All participants experienced CVR [4.84 (IQR: 3.47-6.47) HIV-RNA log10 copies/mL] after ATI at a median time of 21 days (range 14-56) and restarted ART. After ART resumption, all the subjects achieved HIV-RNA <50 copies/mL in a median of 88 days (range 15-197). No serious adverse event occurred; one subject experienced acute retroviral syndrome. No significant correlation between baseline factors and time to viral rebound was observed, while the magnitude of viral rebound was significantly associated with pre-ART HIV-1 RNA (Spearman r = 0.786, P = 0.036), nadir CD4+ (Spearman r = -0.800, P = 0.010), baseline CD4+ (Spearman r = -0.667, P = 0.049) and years with undetectable viral load (Spearman r = -0.717, P = 0.030). CONCLUSIONS: Despite a long period of HIV viral load suppression and a low viral reservoir, early and consistent viral rebound was observed during ATI in all subjects.

Homeostatic model assessment for insulin resistance index trajectories in HIV-infected patients treated with different first-line antiretroviral regimens.

OBJECTIVE: To describe the trajectories of the homeostatic model assessment for insulin resistance (HOMA-IR) index in a cohort of HIV-1 infected patients during their first-line antiretroviral (ART) regimen. METHODS: Retrospective analysis of naïve patients who started ART from 2007 at the Infectious Diseases Unit of the San Raffaele Hospital, Milan. We included patients treated with two nucleoside reverse transcriptase inhibitors (NRTIs, tenofovir, abacavir, lamivudine or emtricitabine), and one anchor drug (ritonavir-boosted protease inhibitor [PI/r], non-NRTI [NNRTI], or integrase strand transfer inhibitor [InSTI]), and with HOMA-IR assessed both before and after the start of ART. Univariate and multivariate mixed linear models estimated HOMA-IR changes during ART. RESULTS: Among 618 patients included in the study, 218 received InSTI-, 210 PI/r-, and 190 NNRTI-based regimens. Median follow-up was 27.4 (16.3-41.2) months. Adjusted mean change in HOMA-IR index was significantly higher (P = .041) in patients treated with InSTI-based regimens [0.160 (95% CI: 0.003-0.321) units per year] compared with NNRTI-based regimens [-0.005 (95% CI: -0.184-0.074) units per year]; no difference was observed between patients treated with NNRTI- and PI/r-based regimens or between INSTI-based and PI/r-based regimens. CONCLUSION: InSTI-based first-line ARTs were independently associated with greater increases in HOMA-IR index.

Point-of-care testing for hepatitis C virus infection at an Italian dental clinic: portrait of the pilot study population.

The dental clinic is an appropriate place to promote the prevention of hepatitis C virus (HCV) infection and fast access for care of HCV-positive subjects with new-generation anti-HCV drugs. This study aimed to determine the socio-demographic profile of subjects screened for HCV virus in a dental clinic to acquire useful information for future campaigns of prevention. An easy, free-of-charge, screen salivary test was offered to patients referred to the dental clinic of San Raffaele Scientific Research Hospital in Milan, Italy for dental procedures. These patients were also asked to complete an anonymous questionnaire on demographics and risk behaviours. A total of 1388 of 2097 (66.19%) questionnaires were evaluable. The demographics of the population responding to this initiative was primarily Italians citizen (96.47%), homogeneous gender distribution (55.55%), age over 50 (609 subjects; 43.88%), with high-level education and stable professional positions. 905 subjects (65.20%) were never tested for HCV before. The test showed positive reactivity in 22 cases (1.05%); of these, 21 subjects were known to be HCV-positive, and the test confirmed their status. One subject was newly diagnosed as HCV-positive. The percentage of subjects who were never tested for HCV infection appears too high (905 subjects, i.e., 65.20%), especially among subjects with high level of education and professions, and among adults over 40 or young people (18-25). The easy screening test in dental clinic can help raise awareness, promote early diagnosis and prevention, and provide a fast link to care for HCV infection.

Diagnostic and Prognostic Value of JC Virus DNA in Plasma in Progressive Multifocal Leukoencephalopathy.

Background: Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by the polyomavirus JC (John Cunningham; JCV) that affects patients with impaired immune systems. While JCV-DNA detection in cerebrospinal fluid (CSF) is diagnostic of PML, the clinical significance of plasma JCV-DNA is uncertain. Methods: We retrospectively analyzed plasma samples from PML patients that were drawn close to disease onset and from controls without PML. In PML patients, we compared plasma JCV-DNA detection and levels to clinical and laboratory parameters, and patient survival. Results: JCV-DNA was detected in plasma of 49/103 (48%) patients with PML (20/24, 83%, human immunodeficiency virus [HIV] negative; 29/79, 37%, HIV-positive) and of 4/144 (3%) controls without PML (0/95 HIV-negative; 4/49, 8%, HIV-positive), yielding a diagnostic sensitivity and specificity of 48% and 97% (83% and 100% in HIV-negative; 37% and 92% in HIV-positive), respectively. Among 16 PML patients with undetectable CSF JCV-DNA, 4 (25%) had detectable plasma JCV-DNA. Plasma JCV-DNA levels were independently associated with CSF levels (P < .0001) and previous corticosteroid treatment (P = .012). Higher plasma JCV-DNA levels were associated with disease progression in HIV-negative patients (P = .005); in HIV-positive patients, there was an increased risk of progression only in those treated with combination antiretroviral therapy (cART; P < .0001). Conclusions: Testing JCV-DNA in plasma might complement PML diagnosis, especially when CSF is unavailable or JCV-DNA not detectable in CSF. In addition, JCV-DNA plasma levels could be useful as a marker of disease progression in both HIV-negative and cART-treated, HIV-positive PML patients.

Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial.

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are recommended components of initial antiretroviral therapy with two nucleoside reverse transcriptase inhibitors. Bictegravir is a novel, potent INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug-drug interactions. We aimed to assess the efficacy and safety of bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination versus coformulated dolutegravir, abacavir, and lamivudine. METHODS: We did this double-blind, multicentre, active-controlled, randomised controlled non-inferiority trial at 122 outpatient centres in nine countries in Europe, Latin America, and North America. We enrolled HIV-1 infected adults (aged ≥18 years) who were previously untreated (HIV-1 RNA ≥500 copies per mL); HLA-B*5701-negative; had no hepatitis B virus infection; screening genotypes showing sensitivity to emtricitabine, tenofovir, lamivudine, and abacavir; and an estimated glomerular filtration rate of 50 mL/min or more. Participants were randomly assigned (1:1), via a computer-generated allocation sequence (block size of four), to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg, with matching placebo, once daily for 144 weeks. Randomisation was stratified by HIV-1 RNA (≤100 000 copies per mL, >100 000 to ≤400 000 copies per mL, or >400 000 copies per mL), CD4 count (<50 cells per µL, 50-199 cells per µL, or ≥200 cells per µL), and region (USA or ex-USA). Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to group assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48, as defined by the US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. All participants who received one dose of study drug were included in primary efficacy and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02607930. FINDINGS: Between Nov 13, 2015, and July 14, 2016, we randomly assigned 631 participants to receive coformulated bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or coformulated dolutegravir, abacavir, and lamivudine (n=315), of whom 314 and 315 patients, respectively, received at least one dose of study drug. At week 48, HIV-1 RNA less than 50 copies per mL was achieved in 92·4% of patients (n=290 of 314) in the bictegravir, emtricitabine, and tenofovir alafenamide group and 93·0% of patients (n=293 of 315) in the dolutegravir, abacavir, and lamivudine group (difference -0·6%, 95·002% CI -4·8 to 3·6; p=0·78), demonstrating non-inferiority of bictegravir, emtricitabine, and tenofovir alafenamide to dolutegravir, abacavir, and lamivudine. No individual developed treatment-emergent resistance to any study drug. Incidence and severity of adverse events was mostly similar between groups except for nausea, which occurred less frequently in patients given bictegravir, emtricitabine, and tenofovir alafenamide than in those given dolutegravir, abacavir, and lamivudine (10% [n=32] vs 23% [n=72]; p<0·0001). Adverse events related to study drug were less common with bictegravir, emtricitabine, and tenofovir alafenamide than with dolutegravir, abacavir, and lamivudine (26% [n=82] vs 40% [n=127]), the difference being driven by a higher incidence of drug-related nausea in the dolutegravir, abacavir, and lamivudine group (5% [n=17] vs 17% [n=55]; p<0·0001). INTERPRETATION: At 48 weeks, coformulated bictegravir, emtricitabine, and tenofovir alafenamide achieved virological suppression in 92% of previously untreated adults and was non-inferior to coformulated dolutegravir, abacavir, and lamivudine, with no treatment-emergent resistance. Bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated with better gastrointestinal tolerability than dolutegravir, abacavir, and lamivudine. Because coformulated bictegravir, emtricitabine, and tenofovir alafenamide does not require HLA B*5701 testing and provides guideline-recommended treatment for individuals co-infected with HIV and hepatitis B, this regimen might lend itself to rapid or same-day initiation of therapy in the clinical setting. FUNDING: Gilead Sciences.

Long-term efficacy of dolutegravir in treatment-experienced subjects failing therapy with HIV-1 integrase strand inhibitor-resistant virus.

OBJECTIVES: This study evaluated the virological efficacy of dolutegravir 50 mg twice daily in 190 HIV-1 failing antiretroviral-experienced patients with previous exposure to first-generation integrase strand transfer inhibitor (INSTI) over a 5 year follow-up using data from clinical practice. PATIENTS AND METHODS: This analysis included HIV-1-infected patients who were ≥18 years of age, treatment experienced, had HIV-1 RNA >50 copies/mL, with INSTI-resistant virus, who started dolutegravir 50 mg twice daily plus optimized background therapy (OBT), recorded in the national prospective database PRESTIGIO (www.progettoprestigio.it). Follow-up accrued from the start of dolutegravir 50 mg twice daily + OBT until virological failure (VF) or dolutegravir discontinuation for any reason or the last treatment visit on dolutegravir 50 mg twice daily treatment. VF was defined by the lack of achievement of HIV-1 RNA <50 copies/mL by 6 months and thereafter, or the occurrence of two consecutive HIV-1 RNA ≥50 copies/mL after achievement of undetectable viral load. RESULTS: The estimated VF probabilities were 17% (95% CI = 12%-24%), 28% (95% CI = 21%-37%), 33% (95% CI = 25%-43%), 39% (95% CI = 29%-51%) and 52% (95% CI = 39%-67%) at 12, 24, 36, 48 and 60 months since baseline, respectively. A higher risk of VF was independently associated with baseline viral load >100000 copies/mL (adjusted HR = 4.73, 95% CI = 1.33-16.78, P = 0.016) and with ≥1 INSTI mutations plus Q148H/K/R/N and the G140S/A/C as compared with other subjects (adjusted HR = 4.18, 95% CI = 1.32-13.23, P = 0.015). CONCLUSIONS: Our data showed a favourable long-term efficacy of dolutegravir 50 mg twice daily in association with OBT in treatment-experienced failing subjects, with INSTI-resistant virus, in the real world. A close monitoring of adherence is crucial for maintenance of virological response in this fragile subgroup of subjects.

Potential associations between atazanavir exposure and clinical outcome: a pharmacokinetic sub-study from the MODAt randomized trial.

The 96-week results of the Monotherapy Once a Day with Atazanavir/r (MODAt) study [NCT01511809] showed an inferior virological efficacy of atazanavir (ATV)/ritonavir monotherapy versus triple therapy, which was promptly retrieved by the reintroduction of nucleoside/nucleotide inhibitors of reverse transcriptase [N(n)RTIs]. We aimed to identify potential relationships between ATV exposure and clinical outcome in HIV-1 subjects treated with ATV/ritonavir monotherapy [ATV/r 300/100 mg] versus ATV/ritonavir triple therapy [ATV/r 300/100 mg+2NRTIs]. A chromatographic method coupled with tandem mass spectrometry was applied to analyze ATV plasma concentrations in a pharmacokinetic sub-study from the MODAt trial. Mixed linear models were used to examine the ATV plasma concentration trend during follow-up and to assess the association between ATV plasma concentrations trajectories with the study arm or the occurrence of treatment failure or drugrelated adverse events or the grading of baseline total bilirubin (<3 vs ≥3). The analyses were performed using SAS Software, release 9.4 (SAS Institute, Cary, NC, USA). Overall, ATV plasma Ctrough concentration did not vary during follow-up (slope: +0.75 ng/mL/week, 95%CI: -0.97 to 2.47, p=0.387); trajectories did not differ between study arms (p=0.527). The unadjusted model-based means (95%CI) of ATV Ctrough during follow-up were 835 (95%CI: 657-1012) ng/ml in the ATV/r monotherapy arm as compared to 911 (95%CI: 740-1082) ng/mL in the ATV/r triple therapy arm (p=0.621). Mean ATV Ctrough was similar in subjects with or without adverse events (AEs). Subjects treated with ATV/r monotherapy showed significantly higher ATV concentrations as compared to subjects without adverse events or treated with ATV/r triple therapy. ATV concentrations were associated with the grading of baseline total bilirubin and the occurrence of drug-related AEs but not with HCV infection. Our findings showed a lack of association between ATV concentrations and treatment failure both in ATV/r monotherapy and triple therapy. Conversely, these data emphasized that ATV concentrations are associated with the development of side-effects in both subjects treated with ATV/r monotherapy and subjects treated with ATV/r triple therapy.

Evidence-based renewal of the Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons.

The Italian Society for Infectious and Tropical Diseases (SIMIT) in collaboration with the Technical Health Committee (Sections L and M) of the Italian Ministry of Health have supported the renewal of the recommendations for the Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. This publication summarizes the latest updates to the 2017 version of the Italian Guidelines for the management of HIV-1 infected patients and the use of antiretroviral drugs. New recommendations were released framing the clinical questions the use of antiretrovirals according to the Patient Intervention Comparator Outcome (PICO) methodology and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Diagnostic tools for immunological and virological monitoring, when to start, what to start, optimization and therapeutic failure were updated in order to include the recommendation obtained with these newly developed methods. For a complete review of clinical and therapeutic relevant topics we refer the reader to the extended version of the Guidelines.

Managing the long surviving HIV patient: a proposal for a multidimensional first-level diagnostic assessment.

We propose a multidimensional first-level diagnostic assessment easy to use in routine clinical practice to allow infectious disease specialists to have a general and complete overview of persons living with HIV. Following the Delphi method, articles published from January 1, 2011 on controlled trials, clinical reports and observational studies dealing specifically with HIV and its co-morbidities were selected for review by the authors. Participants in the poll were selected among clinicians and infectious diseases specialists, working in 38 different dedicated HIV centres in Italy. The participants were given access to a website dedicated to the project and received a standardized information package containing a synopsis of the study and a description of the Delphi process and the selected literature. A total of 131 Items were divided into 10 first-level survey areas: anamnesis, objective examination, infectious diseases, osteoporosis diagnosis, metabolic pathologies diagnosis, cardiovascular diagnosis, nephrologic diagnosis, hepatological diagnosis, central nervous system diagnosis, evaluation of quality of life (QoL). This simple and concise first level tool identifies a few areas of multi-organ diagnostic assessment beyond the infectivity area. The identification of these areas will allow us to find shared and validated evaluation procedures with the intent to increase the likelihood of early recognition of patients at risk of comorbidity development, in order to facilitate more effective prevention, thereby reducing the overall impact on the quality of life of patients affected by this chronic illness.

Pharmacokinetics of dolutegravir and rilpivirine in combination with simeprevir and sofosbuvir in HIV/hepatitis C virus-coinfected patients with liver cirrhosis.

Objectives: To evaluate the plasma trough concentrations ( C trough ) of dolutegravir and rilpivirine used in combination with simeprevir and sofosbuvir in HIV/hepatitis C virus (HCV)-coinfected patients with liver cirrhosis. Virological efficacy and safety of both ART and anti-HCV therapy were assessed. Patients and methods: A prospective observational study in HIV/HCV-coinfected patients with liver cirrhosis on ART with dolutegravir plus rilpivirine and treated with simeprevir plus sofosbuvir (±ribavirin) was conducted. Dolutegravir, rilpivirine, GS-331007 (sofosbuvir metabolite) and simeprevir C trough were evaluated with a validated HPLC method at anti-HCV treatment baseline and weeks 2 and 4. Geometric means were calculated to summarize C trough values. Results: Twelve patients were evaluated: 75% were males and the median (IQR) age was 53 (53-55) years. All patients were Child-Pugh stage A, except one who was stage B. The geometric mean (95% CI) of C trough of rilpivirine and dolutegravir did not change between baseline and week 4 ( P = 0.654 and P = 0.268, respectively), with corresponding overall values of 135 (102-177) and 1357 (970-1897) ng/mL. The overall geometric mean (95% CI) of GS-331007 and simeprevir C trough was 370 (268-512) and 2537 (1569-4101) ng/mL, respectively, without significant variation between weeks 2 and 4 ( P = 0.643 and P = 0.179, respectively). All patients completed anti-HCV treatment, achieving sustained virological response. All but two patients maintained undetectable HIV-RNA up to post-treatment week 24. Conclusions: Dolutegravir and rilpivirine C trough appeared not to be affected by concomitant treatment with simeprevir plus sofosbuvir in these HIV/HCV-coinfected patients with liver cirrhosis, supporting the use of this antiretroviral regimen in this setting.

Recommendations for the management of pulmonary fungal infections in patients with rheumatoid arthritis.

Often life-threatening pulmonary fungal infections (PFIs) can occur in patients with rheumatoid arthritis (RA) receiving disease-modifying anti-rheumatic drugs (DMARDs). Most of the data concerning PFIs in RA patients come from case reports and retrospective case series. Of the ve most widely described PFIs, Pneumocystis jirovecii pneumonia (PJP) has rarely been seen outside Japan, pulmonary cryptococcosis has been diagnosed in only a small number of patients worldwide, pulmonary coccidioidomycosis has almost only been observed in endemic areas, the limited number of cases of pulmonary histoplasmosis have mainly occurred in the USA, and the rare cases of invasive pulmonary aspergillosis have only been encountered in leukopenic patients. Many aspects of the prophylaxis, diagnosis and treatment of PFIs in RA patients remain to be defined, as does the role of each DMARD in increasing the risk of infection, and the possibility of resuming biological and non-biological DMARD treatment after the infection has been cured. The recommendations for the management of PFIs described in this paper are the product of a consensus procedure promoted by the Italian group for the Study and Management of Infections in Patients with Rheumatic Diseases (the ISMIR group).

NS3 protease resistance-associated substitutions in liver tissue and plasma samples from patients infected by hepatitis C virus genotype 1A or 1B.

The presence of naturally occurring resistance-associated substitutions (RASs) in the HCV-protease domain has been poorly investigated in the liver, the main site of HCV replication. We evaluated the natural resistance of the virus to NS3 protease inhibitors in liver tissue and plasma samples taken from HCV-infected patients. RASs were investigated by means of viral population sequencing in liver tissue samples from 18 HCV-infected patients harbouring genotype 1a or genotype 1b; plasma samples from 12 of these patients were also available for virological investigation. A discordant genotype was found in two of the 12 patients (16.6%) who provided samples from both compartments. Sequence analysis of the NS3 protease domain showed the presence of RASs in four of the 18 liver tissue samples (22.2%), two of which showed cross-resistance to protease inhibitors in clinical use or phase 2-3 trials. The analysis of the 12 paired tissues and plasma samples excluded the presence of RASs in the plasma compartment. The dominance of discordant genotypes in the paired liver and plasma samples of some HCV-infected patients suggests mixed infection possibly leading to the selective advantage of different genotype in the two compartments. The presence of RASs at intra-hepatic level is not uncommon and may lead to the early emergence of cross-resistant strains.