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Despite effective antiretroviral therapies (ARTs), a subset of people living with HIV (PLWH) still experience low-level viremia (LLV, i.e., 50-1,000 copies/mL). The present study compared PLWH experiencing LLV with those maintaining virological suppression (VS) and explored the potential impact of preexisting drug resistance and other factors on LLV. We conducted a retrospective, 1:1 matched case-control study within a cohort of drug-experienced VS subjects from the Italian Antiviral Response Cohort Analysis database, followed in the period 2009-2019. Cases were individuals experiencing LLV, while controls were those who maintained VS. Matching was for calendar year of first ART regimen. Preexisting drug resistance was calculated as cumulative genotypic susceptibility score (GSS) according to regimen administered at the observational period start. To explore the effect of cumulative GSS, treated as a binary variable (& GE;2 and <2) and other factors on LLV, we performed a logistic regression analysis. Within a main population of 3,455 PLWH, 337 cases were selected. Cases were comparable to the controls for both gender and age. However, cases showed that they had experienced a longer time since HIV diagnosis, a higher number of drugs previously administered, lower baseline CD4(+) T cell count and a higher zenith viral load (VL). By multivariate analysis, we found that higher zenith VL [adjusted odds ratio (aOR) (95% confidence interval [CI]) 1.30 (1.14-1.48)], a cumulative usage of both PI [aOR (95% CI): 2.03 (1.19-3.48)] and InSTI [aOR (95% CI): 2.23 (1.47-3.38)] and a cumulative GSS <2 [aOR (95% CI) 0.67 (0.46-0.98)], were associated with a higher risk in developing LLV. In current high-efficacy ART era, in drug-experienced PLWH, the predictors of increased risk of LLV were the presence of preexisting drug resistance, higher zenith VL, and previous PI, and InSTI exposure.

Letter to the Editor: Real-Life Experience of Long-Acting Cabotegravir-Rilpivirine Combination in a Person Living with HIV with Detectable Viremia: A Case Report

Background: Lamivudine + dolutegravir maintenance dual therapy (DT) could be less effective than 3-drug therapy (TT) in the context of resistance-associated mutations to nucleoside reverse transcriptase inhibitors (NRTIs). The ARCA database was queried to test this hypothesis with a trial emulation strategy. Methods: People with HIV taking 2 NRTIs plus a protease inhibitor or a non-NRTI who switched to DT or dolutegravir-based TT were followed up from the first HIV RNA <50 copies/mL (baseline) to virologic failure (VF; ie, 2 consecutive HIV RNA ≥50 copies/mL or 1 HIV RNA ≥200 copies/mL). Those switching to DT within 6 months were assigned to the treatment arm and all other patients to the control arm. Each participant was also cloned, assigned to the opposite strategy, and censored at the time of deviation from that strategy. Using inverse probability of censoring weight Cox regression models, we calculated hazard ratios of VF for DT vs TT stratified for the presence of resistance-associated mutations. Results: Overall 626 people were analyzed: 204 with DT and 422 with TT (73% men; mean age, 44 years). Ten and 31 VFs occurred with DT and TT, respectively, over a median 5.8 years. When compared with a fully active TT, the DT had similar efficacy (adjusted hazard ratio, 0.88; 95% CI, .29-2.61; P = .812) when full susceptibility was confirmed at historical genotype. When previous M184V/I was present in both groups, the risk of VF was higher for DT vs TT but was not statistically significant (adjusted hazard ratio, 3.06; 95% CI, .45-20.84; P = .252). Conclusions: DT was not associated with a significantly higher risk of VF than dolutegravir-based TT.

BackgroundIn May 2022, a new case of Monkeypox Virus (MPX) was reported in a non-endemic area, the United Kingdom, and since then, the number of confirmed cases in Europe has been increasing until WHO, on May 10 2023, declared that MPOX is no longer a public health emergency of international concern. We aimed to describe the clinical and microbiological characteristics of sixteen patients with a confirmed diagnosis of MPX followed by a single Italian clinical centre, the Fondazione Policlinico Universitario Agostino Gemelli, between May 20 and August 30.Materials and methodsA prospective observational study has been conducted, collecting microbiological samples during the time of the infection, as well as epidemiological and clinical data of the patients. All patients provided written informed consent.ResultsDuring clinical practice, 16 individuals presenting with consistent symptoms tested positive for MPX on a polymerase chain reaction. All patients were men having sex with men (MSM). The most frequent clinical presentation was a vesicular erythematous cutaneous rash, mainly distributed on the genital and perianal area, but also regarding limbs, face, neck, chest and back in some of the patients. Systemic symptoms, such as fever or lymphadenopathy, involved eight patients. The symptom most frequently reported by patients was pruritus in the area of the vesicles. Thirteen patients also reported pain. Nine patients were HIV-1 coinfected, but no significant differences have been observed compared to other cohort patients. The median time between the onset of symptoms and the healing was 19.5 days (IQR 14.0-20.3).ConclusionsOur cohort of patients presented a mild manifestation of the disease with no complications and no need for antiviral therapy nor hospitalization. This population seems different from the ones reported in the literature during the previous outbreaks in endemic areas in epidemiological data and clinical manifestations but also from a cohort of patien

Objectives: We aimed to assess the immunologic response to BNT162b2 mRNA COVID-19 vaccine in ART-experienced people living with HIV (PLWH). Methods: In this pilot prospective study, we enrolled 20 PLWH (all on effective ART, 80% with CD4 cells count >500) and 52 immunocompetent health-care workers, as control. All subjects received two doses of vaccine 21 days apart. Serum samples were collected at different time points, immediately before first administration (BL) and 21 days after each dose (T1 and T2) and 45-50 days after second dose (T3). We evaluated the immune response in terms of frequency of responders and antibody titers against SARS-CoV-2 at each timepoint. The viro-immunological parameters of PLWH were also monitored. Results: We found that the participants displayed an immune response after the first dose that increased markedly at T2. At T3 a significantly descending trend of IgG levels was observed in both groups. No difference in humoral immune response assessed in terms of percentage of responders after first and second dose and in terms of IgG titers over time and at each time point was found between groups. Any significant variation in terms of viremia and immunological parameters was observed in PLWH. Conclusions: BNT162b2 mRNA COVID-19 vaccine appears immunogenic in this setting of PLWH eliciting an immune response comparable to that of healthy donors.

Evidence accumulated during past years confirm that people living with HIV (PLWH) still have to deal with comorbidities and chronic complications that can increase physical and psychological issues and can affect daily functioning, quality of life and mental health. Moreover, during the COVID-19 pandemic PLWH proved to be a population at increased risk of psychological distress. We explored the ongoing issues and the characteristics of the mental health interventions for which a cohort of Italian PLWH interacted with a psychologist over the past five years. We analysed a dataset that included 61 PLWH who underwent a psychological intervention between 2018 and 2022. We compared different frequencies in characteristics of mental health interventions according to different demographic and clinical variables, psychopathological symptoms and time of the request for intervention. We showed that psychopathological symptoms most frequently reported by patients were anxiety (55.7%), and depression (49.2%). Furthermore, we reported that most our patients undertook occasional psychological support meetings (31%), sought an intervention after the outbreak of the COVID-19 pandemic (62.3%) and complained about disclosure issues (48.5%). Disclosure issues were mainly reported by younger PLWH (p = 0.002) with a shorter disease (p = 0.031) and treatment history (p = 0.032), and higher interpersonal sensitivity (p = 0.042). It seems fundamental to integrate psychological interventions into the care of PLWH, to give particular attention to PLWH with risky demographic, clinical and mental health factors and to pay special attention to emergency conditions (such as the COVID-19 pandemic) and the most widespread issues to create ad hoc interventions.

Background Blood telomere length (BTL) is a validated biomarker of aging. ART reduces immunosenescence and has benefits in terms of BTL in people living with HIV (PLWH). However, it has also been observed that ART containing NRTIs, such as tenofovir or abacavir, which are potent inhibitors of human telomerase activity in vitro, might negatively affect BTL. Here we investigated the effects on BTL 1 year after switching to a dual therapy (DT) with dolutegravir + lamivudine versus maintaining a standard triple therapy (TT) with a two-NRTI backbone and an anchor drug. Methods This was a longitudinal, prospective, matched, controlled study that included virologically suppressed adults on stable three-drug ART who either switched at baseline (BL) to DT or maintained TT. The DT and TT groups were 1:1 matched for age, sex, years since HIV diagnosis, years on ART and anchor drug. BTL was assessed by a monochrome multiplex qPCR at BL and after 48 weeks (W48). Results We enrolled 120 PLWH, i.e. 60 participants in each group. At BL, the BTL means were comparable between the two groups (P = 0.973). At W48, viro-immunological status was stable and an overall increase in the mean BTL was observed, i.e., +0.161 (95%CI, 0.054-0.268) (P = 0.004). However, the within-group analysis showed a significant mean BTL gain in the DT group (P = 0.003) but not in the TT group (P = 0.656). Conclusions In this setting of virologically suppressed PLWH, simplifying to dolutegravir + lamivudine was associated with a higher gain in BTL than maintaining triple therapy after the 1 year follow-up. These findings suggest that as a simplification strategy dolutegravir + lamivudine might have a positive effect on BTL.

Thanks to the modern ARV regimens and the fact that the morbidity and mortality of metabolic syndrome increases with age, clinicians are continuously researching effective and safe antiretroviral regimens with low impact on the lipid profile. Doravirine (DOR) is the latest non-nucleoside reverse-transcriptase inhibitor (NNRTI) that shows long-term safety and tolerability and a favorable lipid profile. The aim of this study is to assess the impact of DOR-based three-drug regimens on the lipid profile in clinical practice. We retrospectively analyzed a cohort of 38 treatment-experienced, virologically suppressed people living with HIV (PLWH) switching to this regimen, following the eligibility criteria. We carried out comparison analysis of immunological and metabolic parameters between baseline and 48 weeks of follow up. In our cohort of treatment-experienced, virologically suppressed PLWH, three-drug regimens with DOR showed good efficacy and a positive profile on lipid metabolism at 48 weeks of follow up.

Objectives: The aim of this study was to evaluate the impact of resistance mutations on efficacy of dolutegravir-based two-drug regimens (2DR). Methods: Virologically suppressed patients with HIV-1 switching to dolutegravir + lamivudine or rilpivirine or to a dolutegravir-based three-drug regimen (3DR) with pre-baseline genotype were selected. Virological failure (VF) was defined as one HIV-RNA viral load (VL) > 200 cps/mL or two consecutive VL > 50 cps/mL; treatment failure (TF) was defined as VF or treatment discontinuation (TD). Resistance was defined as at least low-level resistance to at least one drug of the current regimen. Propensity score matching was used to conduct adjusted analyses within a competing risks framework. Results: A total of 971 dolutegravir-based regimens were selected: 339 (34.9%) 2DR and 632 (65.1%) 3DR. The adjusted cumulative 48-week incidence of VF was 4.2% (90% CI 3.1%-5.3%) with 2DR and 4.7% (90% CI 3.5%-5.8%) with 3DR. The cumulative 48-week incidence of TF was 15.8% (90% CI 13.9%-17.9%) with 2DR and 24.5% (90% CI 22.2%-27.0%) with 3DR. For VF, the estimated hazard ratio (HR) for 2DR vs. 3DR was 1.02 (90% CI: 0.78-1.34), with evidence of effect modification by low-level resistance (HR 3.96, 90% CI: 2.10-7.46). The estimated HR of TF for 2DR vs. 3DR was 0.54 (90% CI: 0.4 8-0.60). The 4 8-week cumulative incidence of TD was 11.7% (8.7%, 14.6%) in 2DR and 19.6% (16.9%, 22.4%) in 3DR. Conclusions: Dolutegravir-based 2DR showed high virological efficacy and durability; however, past resistance increased the risk of VF, but not of TD or TF. (c) 2022 The Authors. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Purpose: The pandemic diffusion of Coronavirus Disease 2019 (COVID-19) has highlighted significant genderrelated differences in disease severity. Despite several hypotheses being proposed, how the genetic background of COVID-19 patients might impact clinical outcomes remains largely unknown. Methods: We collected blood samples from 192 COVID-19 patients (115 men, 77 women, mean age 67 +/- 19 years) admitted between March and June 2020 at two different hospital centers in Italy, and determined the allelic distribution of nine Single Nucleotide Polymorphisms (SNPs), located at the 3 ' Regulatory Region (3 ' RR)-1 in the immunoglobulin (Ig) heavy chain locus, including *1 and *2 alleles of polymorphic hs1.2 enhancer region. Results: In COVID-19 patients, the genotyped SNPs exhibited strong Linkage Disequilibrium and produced 7 specific haplotypes, associated to different degrees of disease severity, including the occurrence of pneumonia. Additionally, the allele *2, which comprises a DNA binding site for the Estrogen receptor alpha (ER alpha) in the polymorphic enhancer hs1.2 of 3 ' RR-1, was significantly enriched in women with a less severe disease. Conclusions: These findings document genetic variants associated to individual clinical severity of COVID-19 disease. Most specifically, a novel genetic protective factor was identified that might explain the sex-related differences in immune response to Sars-COV-2 infection in humans.

During the COVID-19 pandemic, people living with HIV (PLWH) could have had to face problems with treatment adherence because of the difficulty of accessing services connected with antiretroviral therapy (ART) dispensation, which could have undermined their health. In this article, we described, over the period 2015-2020, both the activities of our home care assistance unit, the "Unita di Trattamento Domiciliare (UTD)", and the characteristics of the comorbid HIV patients followed-up. To determine whether the COVID-19 pandemic affected this service, we compared the number/type of services provided in 2020 with those provided in the preceding 5 years, i.e., 2015-2019. We also compared the proportion of monthly interventions carried out in 2018, 2019 and 2020. We found comparable values with some differences in the types of performances due to the heterogeneity of the population and their medical assistance needs. We also observed a stable viro-immunological status of the patients. All of these data suggest that the UTD was consistently active during the lockdown months and pandemic waves preventing therapy discontinuation, and was able to maintain optimal control of patients' HIV infections.

The care engagement of people living with HIV (PLWH) measured with the patient health engagement (PHE) model and its association with HIV-related internalized stigma are not well established. Indeed, currently there are no data yet about the engagement of PLWH measured with the PHE model. This study aimed to evaluate the effects of HIV-related internalized stigma on care engagement and mental health and to fill the lack of data on PHE model applied to PLWH. We found that the internalized stigma score was significantly higher for PLWH (n=82) in worse care engagement phase and both higher internalized stigma scores and worse engagement were associated to major depression symptoms.In conclusion, our findings describe for the first time the engagement in care of PLWH measured with PHE and highlight the importance of PLWH support to find strategies to cope stigma-related stress and optimize their care engagement.

Despite successful antiretroviral therapy (ART), patients infected with human immunodeficiency virus (HIV) can develop multi-class drug resistance (MDR). This retrospective study aimed to explore the prevalence of HIV-1 drug resistance over the past two decades by focusing on HIV-MDR and its predictors. ART-experienced patients with HIV with results from at least one plasma genotypic resistance test (GRT) from 1998 to 2018, from the Antiviral Response Cohort Analysis database, were included in this study. The temporal trend of resistance to any drug class was evaluated by considering all GRTs. Prevalence and predictors of HIV-MDR were analysed by consideration of cumulative GRTs. Among 15 628 isolates from 6802 patients, resistance to at least one drug class decreased sharply from 1998 to 2010 (1998-2001: 78%; 2008-2010: 59%; P < 0.001) and then remained relatively constant at approximately 50% from 2011 to 2018, with the proportion of isolates with HIV-MDR also stable (approximately 9%).By evaluating factors associated with cumulative HIV-MDR, the following factors were found to be associated with increased risk of HIV-MDR on multi-variate analysis: male gender; sexual and vertical transmission; number of previous protease inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-NRTIs; previous exposure to integrase strand transfer inhibitors, enfuvirtide and maraviroc; and co-infection with hepatitis B virus. In contrast, a nadir CD4 cell count >= 200 cells/mm3, starting first-line ART in 2008 or later and co-infection with hepatitis C virus were associated with lower risk of HIV-MDR. In conclusion, this study revealed that HIV-1 drug resistance has been stable since 2011 despite its dramatic decrease over the past two decades. HIV-MDR is still present, although at a lower rate, suggesting the need for continuous surveillance and accurate management of ART-experienced patients with HIV. (C) 2020 Elsevier Ltd and International Societ

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BACKGROUND: An increase in pretreatment drug resistance (PDR) to first-line antiretroviral therapy (ART) in low-income countries has been recently described. Herein we analyze the prevalence of PDR and risk of virologic failure (VF) over time among migrants to Italy enrolled in ARCA. METHODS: HIV-1 sequences from ART-naïve patients of non-Italian-nationality were retrieved from ARCA database from 1998 to 2017. PDR was defined by at least one mutation from the reference 2009-WHO-surveillance-list. RESULTS: Protease/reverse-transcriptase sequences from 1,155 patients, mainly migrants from Sub-Saharan Africa (SSA) (42%), followed by Latin America (LA) (25%) and Western Countries (WE) (21%), were included. PDR was detected in 8.6% of sequences (13.1% vs 5.8% for B and non-B strains, respectively, p<0.001). 2.1% of patients carried a PDR for protease inhibitors (PIs) (2.1% vs 2.3%, p=0.893), 3.9% for nucleos(t)ide-reverse-transcriptase inhibitors (NRTI) (6.8% vs 2.1%, p<0.001) and 4.3% for non-nucleos(t)ide-reverse-transcriptase inhibitors (NNRTI) (6.3% vs 3.1%, p=0.013). Overall, prevalence of PDR over the years remained stable, while it decreased for PIs in LA (p=0.021), and for NRTI (p=0.020) among migrants from WE. Having more than 1 class of PDR (p=0.015 vs. absence of PDR), higher viral load at diagnosis (p=0.008) and being migrants from SSA (p=0.001 vs. WE) were predictive of VF, while a recent calendar year of diagnosis (p<0.001) was protective for VF. CONCLUSIONS: PDR appeared to be stable over the years in migrants to Italy enrolled in ARCA; however, it still remains an important cause of VF together with VL at diagnosis.

OBJECTIVES: To assess the impact of switching to dolutegravir plus lamivudine maintenance therapy on the HIV cellular reservoir size. PATIENTS AND METHODS: This was a prospective, longitudinal, matched, controlled study. We enrolled virologically suppressed patients on stable three-drug ART who switched at baseline (BL) to dolutegravir/lamivudine (DT group) or maintained triple therapy (TT group); subjects in the TT group were matched 1:1 with those in the DT group according to age, gender, years since HIV diagnosis, years on ART and anchor drug. Total blood-associated HIV DNA levels were assessed by droplet digital PCR at BL and after 48 weeks (T48). Results were expressed as log10 HIV DNA copies/106 leucocytes. RESULTS: We enrolled 40 patients in the DT group and 40 in the TT group; the two groups were homogeneous for all main characteristics except nadir CD4 cell count. At BL, HIV DNA levels were comparable between the DT and TT groups: 2.27 (IQR 1.97-2.47) and 2.26 (IQR 2.05-2.61) log10 HIV DNA copies/106 leucocytes, respectively. Change in HIV DNA load from BL to T48 was -0.105 (IQR -0.384 to 0.121, P = 0.041) in the DT group and -0.132 (IQR -0.362 to 0.046, P = 0.005) in the TT group, with a comparable decline observed between the two groups (P = 0.821). A higher HIV DNA decline was associated with higher BL CD4/CD8 ratio. CONCLUSIONS: Maintenance therapy with dolutegravir/lamivudine had the same impact as the triple regimen on HIV DNA levels after 48 weeks of treatment. These data seem to support the effectiveness of a dolutegravir/lamivudine dual regimen in controlling the magnitude of the cellular reservoir (www.clinicaltrials.gov, number NCT02836782). © The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Editor: Recent data from clinical trials highlight the efficacy of a two-drug strategy with lamivudine (3TC) plus dolutegravir (DTG) as first-line regimen in treatment-naive HIV-infected people living with HIV (PLWH).1 PLWH with transmitted resistance mutations, however, were not included in the two GEMINI trials and thus no data are available on the efficacy of such regimens in PLWH with primary resistances. In a recently published report,2 we described our initial experience in a small cohort of treatment-naive PLWH starting 3TC plus DTG in clinical practice. We would like to further analyze the case of a 23-year-old subject with Y188C and D232N resistance mutations starting 3TC+DTG. The D232N mutation, in particular, is a nonpolymorphic mutation selected in patients previously exposed to raltegravir3 and has been related to potential resistance to first-generation integrase inhibitors (INIs) raltegravir and elvitegravir. The subject was diagnosed with HIV infection in March 2019, with a peak HIV RNA value of 114,866 copies/mL and a nadir CD4+ cell count of 328 cell/mm3. Genotypic test was also performed, showing the mentioned resistance mutations. He subsequently started the two-drug regimen with a rapid decline in HIV RNA, reaching 48 copies/mL after 3 weeks from treatment initiation. His HIV RNA load became undetectable after 8 weeks and as of today, after 24 weeks, it is still undetectable. We also observed a steady improvement in immunological parameters; after 24 weeks his CD4+ cell count was 1,091 cell/mm3. Given the presence of the transmitted resistances, we further investigated the subject's virological status by evaluating total HIV-1 DNA levels, a marker of low-grade inflammation and viral reservoir dynamics.4 In our patient, baseline HIV-1 DNA quantification was 3.00 log10 copies/106 leukocytes. Initial decay was sharp, as HIV DNA levels decreased to 2.69 log10 copies/106 leukocytes after 4 weeks of treatment and to 2.37 log10 copies/106 leukocytes af

The accumulation of drug-resistance mutations on combined antiretroviral regimens (ART) backbone could affect the virological efficacy of the regimen. Our aim was to assess the impact of previous drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) on the probability of virological failure (VF) in patients, under virological control, who switched to dolutegravir (DTG)+2NRTIs regimens. All HIV-1 positive drug-experienced patients who started a regimen composed by DTG+2NRTIs [abacavir/lamivudine or tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)/emtricitabine (FTC)] in the ARCA collaborative group with HIV-RNA <50 cp/mL were included in the analysis. Patients with a previous VF to integrase inhibitors were excluded. The impact of single and combined NRTIs mutations on the probability of VF (defined as 2 consecutive HIV-RNA >50 copies/mL or one HIV-RNA >1000 copies/mL) was assessed by Kaplan Meier curves. A multivariable Cox regression analysis was constructed to assess factors potentially related to VF. Five hundred and eighty-eight patients were included in the analysis with a median time of viral suppression before the switch of 37 months (IQR 12-78), of whom 148 (25.2%) had at least one previous NRTIs resistance mutation. In the multivariable model no association was observed between NRTIs mutations and VF. Conversely, the duration of viral suppression before switch resulted associated with a lower risk of VF (for 1 month increase, adjusted Hazard Ratio 0.98, 95%CI 0.96-0.99; p=0.024). Previous NRTIs mutations appeared to have no impact on the risk of VF in patients switched to DTG+2NRTIs, whereas a longer interval on a controlled viremia decreased significantly the risk of VF.

Background: HIV-induced systemic immune activation and inflammation have been associated with morbidity and mortality in virologically suppressed patients. Objective: To evaluate the impact of treatment switch from a dual regimen with lamivudine (3TC) plus ritonavir-boosted protease inhibitors (PI/r) to 3TC plus dolutegravir (DTG) on the monocyte activation marker soluble CD14 (sCD14) and other inflammatory biomarkers, interleukin-6 (IL-6), C-reactive protein (CRP), intestinal fatty acid-binding protein (I-FABP) and D-dimer. Methods: We performed a retrospective case-crossover study on integrase inhibitors-naïve virologically suppressed patients while on 3TC + PI/r dual maintenance therapy for ≥48 weeks who switched to 3TC + DTG and maintained this regimen for ≥48 weeks. Biomarkers plasma levels were tested by ELISA assays on stored samples at three time points: at switch (BL), 48 weeks before (-48 W) and 48 weeks after switch (+48 W). Results: A total of 67 patients were included. Median sCD14 levels were stable from -48 W to BL (from 6.07 to 6.04 log10 pg/mL, p = 0.235) but showed a statistically significant decrease after switch: from 6.04 (IQR 5.92-6.12) at BL to 5.95 (IQR 5.84-6.07) log10 pg/mL at + W48 (p < 0.001). Concurrently, an improvement in lipid profile was observed, even thought it was not correlated to the change in sCD14. The levels of IL-6, CRP, I-FABP and D-dimer remained stable before and after the switch to 3TC + DTG. Conclusions: In virologically suppressed HIV-infected patients on a 3TC + PI/r dual therapy, switching to 3TC + DTG was associated with a significant decline in sCD14. These data suggest reduced monocyte activation following substitution of boosted PI with DTG, which could have important clinical implications.

Bone toxicity is a well-known side effect of several antiviral agents. In a cohort of virologically suppressed HIV-infected patients, we investigated the effects of a lamivudine/dolutegravir dual therapy on bone mineral density (BMD). We observed a significant improvement in lumbar spine BMD as well as T-score after 12 months of observation with concomitant bisphosphonate therapy independently predicting a greater improvement. These preliminary data show a favorable effect of this 2-drug regimen on bone health.

Background: The influence of HIV-1 co-receptor usage on the course of therapy in subjects fully responding to ART has been poorly investigated. Objectives: To explore the relationship between co-receptor tropism and cellular reservoir size, residual viremia and subsequent virological outcome in ART-treated patients with HIV-1 RNA stable <50 copies/mL. Study design: Viral co-receptor usage was predicted by viral env DNA sequencing with geno2pheno interpretation (FPR20%) and classified as R5 and non-R5. Total blood-associated HIV-1 DNA levels (log10 copies/106 leukocytes) were measured by qRT-PCR (5′LTR). Residual plasma viremia was categorized as detectable (1–49 cps/mL) or undetectable (<1 copy/mL). Virological rebounds (any HIV-1 RNA >50 copies/mL) were evaluated over 96 weeks. Results: The study included 116 subjects. Patients with R5 virus (n = 59) and non-R5 virus (n = 57) were homogeneous for the main characteristics except for the lower nadir CD4 cell count in the non-R5 group. Patients with non-R5 variants showed higher levels of HIV-1 DNA as compared to patients with R5 virus: mean 2.47 (95% CI 2.37–2.56) vs 2.17 (2.08–2.26) (p < 0.001). Moreover, a higher proportion of patients in the non-R5 group displayed detectable residual viremia with respect to the R5-group (54.4% vs 32.2%, p =.016). Detectable residual viremia was found to be significantly associated with viral rebounds. Conclusion: The presence of non-R5 viral DNA variants is related to a higher probability of residual viremia and to a larger size of the cellular viral reservoir in this setting. These data highlight a potential role of viral tropism in the monitoring of HIV-1 infection in virologically controlled subject.

Objectives: To investigate the long-term safety and efficacy of a treatment switch to dual ART with atazanavir/ritonavir + lamivudine versus continuing a standard regimen with atazanavir/ritonavir + 2NRTI in virologically suppressed patients. Methods: ATLAS-M is a 96 week open-label, randomized, non-inferiority (margin -12%) trial enrolling HIV-infected adults on atazanavir/ritonavir + 2NRTI, with stable HIV-RNA <50 copies/mL and CD4 counts >200 cells/mm3. At baseline, patients were randomized 1:1 to switch to atazanavir/ritonavir + lamivudine or to continue the previous regimen. Here, we report the 96 week efficacy and safety data. The study was registered with ClinicalTrials.gov, number NCT01599364. Results: Overall, 266 subjects were enrolled (133 in each arm). At 96 weeks, in the ITT population, patients free of treatment failure totalled 103 (77.4%) with atazanavir/ritonavir + lamivudine and 87 (65.4%) with triple therapy (difference +12.0%, 95% CI +1.2/+22.8, P = 0.030), demonstrating the superiority of dual therapy. Two (1.5%) and 9 (6.8%) virological failures occurred in the dual-therapy arm and the triple-therapy arm, respectively, without development of resistance to any study drug. Clinical adverse events occurred at similar rates in both arms. A higher frequency of grade 3-4 hyperbilirubinemia (66.9% versus 50.4%, P = 0.006) and hypertriglyceridaemia (6.8% versus 1.5%, P = 0.031) occurred with dual therapy, although this never led to treatment discontinuation. A significant improvement in renal function and lumbar spine bone mineral density occurred in the dual-therapy arm. The evolution of CD4, HIV-DNA levels and neurocognitive performance was similar in both arms. Conclusions: In this randomized study, a treatment switch to atazanavir/ritonavir + lamivudine was superior over the continuation of atazanavir/ritonavir + 2NRTI in virologically suppressed patients, with a sustained benefit in terms of improved renal function and bone mineral density.

Background Biomarkers of systemic inflammation predict non-AIDS events and overall mortality in virologically suppressed HIV-1-infected patients. Objectives To determine whether switching to a dual antiretroviral maintenance therapy was associated with modification of biomarkers of systemic inflammation as compared with continuation of successful standard triple therapy. Methods In this substudy of the randomized ATLAS-M trial, we compared in virologically suppressed patients the impact at 1 year of simplification to a dual therapy with atazanavir/ritonavir plus lamivudine versus maintaining atazanavir/ritonavir plus two NRTI triple therapy on markers of systemic inflammation. Plasma levels of interleukin-6, C-reactive protein (CRP), soluble CD14 (sCD14) and D-dimer were quantified by ELISA at baseline and at 48 weeks. Results A subset of 139 of 266 randomized patients with available samples was analysed: 69 in the triple therapy arm and 70 in the dual therapy arm. The baseline biomarker levels were comparable between randomization arms. No significant differences in changes from baseline to week 48 were observed between arms (dual therapy versus triple therapy): IL-6, −0.030 versus −0.016 log10 pg/L; CRP, +0.022 versus +0.027 log10 pg/mL; sCD14, −0.016 versus +0.019 log10 pg/mL; and D-dimer, −0.031 versus +0.004 log10 pg/mL. A history of cancer was associated with higher baseline levels of IL-6 (P = 0.002) and CRP (P = 0.049). No relationship was observed between baseline biomarker level and persistent residual viraemia, HIV-1 DNA load, plasma lipids and other potential explanatory variables. Conclusions Simplification with atazanavir/ritonavir plus lamivudine does not affect plasma markers of systemic inflammation in virologically suppressed patients. The association between these findings and clinical outcomes requires further evaluation

OBJECTIVES: The AtLaS-M randomized trial showed that in patients with HIV-1 RNA <50 copies/mL on atazanavir/ritonavir + two NRTIs, switching to a dual therapy with atazanavir/ritonavir+lamivudine had superior efficacy as compared with continuing the previous triple therapy. This substudy was designed to evaluate at 48 weeks the impact of the dual therapy versus the three-drug atazanavir/ritonavir-based therapy on the HIV-1 cellular reservoir as reflected by the quantification of blood-associated HIV-1 DNA levels. METHODS: In a representative subset of 201 of 266 randomized patients (104 in the dual-therapy arm and 97 in the triple-therapy arm) total HIV-1 DNA levels in whole blood at baseline and after 48 weeks and factors associated with the HIV-1 DNA levels were evaluated. RESULTS: The mean baseline HIV-1 DNA levels (2.47 log 10 copies/10 6 leucocytes) were comparable between arms. A significant mean decrease between baseline and week 48 was observed: -0.069 log 10 copies/10 6 leucocytes in the dual-therapy arm ( P = 0.046) and -0.078 in the triple-therapy arm ( P = 0.011); the mean difference between arms was -0.009 ( P = 0.842). Nadir CD4 count was inversely correlated with baseline HIV-1 DNA ( P = 0.009); longer duration of ART and lower nadir CD4 correlated with a less prominent HIV-1 DNA decrease (both P < 0.005). Higher baseline HIV-1 DNA was associated with residual viraemia at week 48 ( P = 0.031). CONCLUSIONS: When compared with continuing three-drug therapy, atazanavir/ritonavir+lamivudine dual therapy resulted in a similar decline in HIV-1 DNA levels in patients with sustained virological suppression. These data support the safety of this simplified treatment strategy in terms of its effect on the cellular HIV-1 reservoir

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Nearly all persons newly infected with HIV-1 harbor exclusively CCR5-using virus. CXCR4-using variants eventually arise in up to 50% of patients infected with subtypes B or D. This transition to efficient CXCR4 utilization is often co-incident with progression to AIDS. The basis for HIV-1's initial dependence on CCR5, the selective force(s) that drive CXCR4-utilization, and the evolutionary pathways by which it occurs are incompletely understood. Greater knowledge of these processes will inform interventions at all stages, from vaccination to cure. The determinants of co-receptor use map primarily, though not exclusively, to the V3 loop of gp120. In this study, we describe five clonal variants with identical V3 loops but divergent CXCR4 use. Mutagenesis revealed two residues controlling this phenotypic switch: a rare polymorphism in C1 and a highly conserved N-glycan in C2. To our knowledge, this is the first description of co-receptor usage regulated by the Nglycan at position 262.

Context: Mandibuloacral dysplasia type A ( MADA; OMIM 248370) is a rare progeroid syndrome characterized by dysmorphic craniofacial and skeletal features, lipodystrophy, and metabolic complications. Most Italian patients carry the same homozygous missense mutation ( p. R527H) in the C- terminal tail domain of the LMNA gene, which encodes lamin A/ C, an intermediate filament component of the nuclear envelope.Objective: The objective of the study was to identify novel LMNA mutations in individuals with clinical characteristics ( bird- like facies, mandibular and clavicular hypoplasia, acroosteolysis, lipodystrophy, alopecia) observed in other well- known patients.Design: The LMNA gene was sequenced. Functional properties of the mutant alleles were investigated. Patient: We report a 27- yr- old Italian woman showing a MADA- like phenotype. Features include a hypoplastic mandible, acroosteolysis, pointed nose, partial loss of sc fat, and a progeric appearance. Due to the absence of clavicular dysplasia and normal metabolic profiles, generally associated with muscle hyposthenia and generalized hypotonia, this phenotype can be considered an atypical laminopathy.Results: We identified a patient compound heterozygote for the p. R527H and p. V440M alleles. The patient's cells showed nuclear shape abnormalities, accumulation of pre- lamin A, and irregular lamina thickness. Lamins A and C showed normal expression and localization. The electron microscopy detected heterochromatin defects with a pattern similar to those observed in other laminopathies. However, chromatin analysis showed a normal distribution pattern of the major heterochromatin proteins: heterochromatin protein- 1 beta and histone H3 methylated at lysine 9.Conclusions: The clinical and cellular features of this patient show overlapping laminopathy phenotypes that could be due to the combination of p. R527H and p. V440M alleles.