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Background: Mortality among people with human immunodeficiency virus (HIV) declined with the introduction of combination antiretroviral therapy. We investigated trends in mortality in people with HIV from 1999 through 2020., Methods: Data were collected from the Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) cohort between January 1999 through January 2015 and the International Cohort Consortium of Infectious Disease (RESPOND) from October 2017 through December 2020. Age-standardized all-cause and cause-specific mortality rates, classified using Coding Causes of Death in HIV, were calculated. Poisson models were used to assess mortality over time., Results: Among 55 716 participants followed for median 6 years (interquartile range, 3-11), 5263 died (mortality rate [MR], 13.7/1000 person-years of follow-up [PYFU]; 95% confidence interval [CI], 13.4-14.1). Changing mortality was observed: AIDS mortality was most common between 1999-2009 (n = 952; MR, 4.2/1000 PYFU; 95% CI, 4.0-4.5) and non-AIDS-defining malignancy (NADM) between 2010-2020 (n = 444; MR, 2.8/1000 PYFU; 95% CI, 2.5-3.1). In multivariable analysis, all-cause mortality declined (adjusted mortality rate ratio [aMRR], 0.97 per year; 95% CI, .96-.98), mostly 1999-2010 (aMRR, 0.96 per year; 95% CI, .95-.97) but was stable 2011-2020 (aMRR, 1.00 per year; 95% CI, .96-1.05). Mortality due to all known causes except NADM also declined., Conclusions: Mortality among people with HIV in the D:A:D and/or RESPOND cohorts declined between 1999-2009 and was stable over the period 2010-2020. This decline in mortality was not fully explained by improvements in immunologic-virologic status or other risk factors., Competing Interests: Potential conflicts of interest . A. M. reports consulting fees from Eiland and Bonnin. H. F. G. reports honoraria for data and safety monitoring board or advisory board membership from Merck, Gilead Sciences, ViiV Healthcare, GSK, Janssen, Johnson & Johnson, and Novartis; a travel grant from Gilead Sciences; unrestricted research grants from Gilead Sciences; grants or contracts paid to institution from the Swiss National Science Foundation, Swiss HIV Cohort Study, National Institute of Health; and an unrestricted research grant from Gilead Sciences, Yvonne Jacob Foundation. J. J. V. reports personal fees from Merck Sharp & Dohme, Gilead, Pfizer, Astellas Pharma, Basilea, German Centre for Infection Research (DZIF), University Hospital Freiburg/ Congress and Communication, Academy for Infectious Medicine, University Manchester, German Society for Infectious Diseases (DGI), Ärztekammer Nordrhein, University Hospital Aachen, Back Bay Strategies, German Society for Internal Medicine (DGIM), Shionogi, Molecular Health, Netzwerk Universitätsmedizin, Janssen, NordForsk, Biontech, and APOGEPHA and grants from Merck Sharp & Dohme, Gilead, Pfizer, Astellas Pharma, Basilea, German Centre for Infection Research (DZIF), German Federal Ministry of Education and Research (BMBF), Deutsches Zetrum für Luft- und Raumfahrt (DLR), University of Bristol, Rigshospitalet Copenhagen, and Network University Medicine. F. W. reports personal fees for attending advisory boards from ViiV Healthcare. A. d’A. M. reports fees for lectures sponsored by ViiV, Gilead, and Pfizer and projects sponsored (to institution) by ViiV, Gilead, and Merck Sharpe & Dohme. V. S. reports CME education fees from Gilead Sciences, Merck Sharp & Dohme, and ViiV Healthcare. C. C. reports an unrestricted Nordic Fellowship Grant from Gilead Sciences Nordic; honoraria from GSK and ViiV, Gilead Sciences, and Merck Sharp & Dohme (paid to institution), and has participated on an advisory board for GSK, ViiV and Gilead Sciences (paid to institution). P. S. reports honoraria and/or speaking fees from Gilead, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, and ViiV Healthcare and a research grant from ViiV Healthcare, all outside of the submitted work. A. C. reports consulting fees from Gilead Sciences, Merck Sharp & Dohme, and ViiV Healthcare; honoraria for presentations from Gilead Sciences and ViiV Healthcare; support for travel to advisory board and to study investigator meetings from Merck Sharp & Dohme; and receipt of study medication and supplies from Merck Sharp & Dohme. K. P. reports unrestricted research funding made to institution by Gilead Australia and ViiV Healthcare Australia. F. Bonnet reports grants from Gilead and ViiV Healthcare and honoraria from Gilead, ViiV Healthcare, and Merck Sharp & Dohme. S. D. W. reports payments from the D:A:D and RESPOND studies paid to institution. J. G. is an employee of Gilead Sciences. V. V. is an employee of ViiV Healthcare. L. Y. is an employee of Merck Sharp & Dohme. C. S. reports honoraria for preparation of educational materials from Gilead Sciences and honoraria for speaking and preparation of educational materials from ViiV Healthcare. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Due to a limited range of effective treatment options, highly treatment-experienced (HTE) people with HIV (PWH) still struggle to maintain virological suppression and obtain an adequate immunological recovery. To increase the likelihood of virologic success, HTE PWH require an individualized treatment regimen based on cumulative genotypic resistance testing (GRT) data, potential drug-drug interactions, and adherence. From the PRESTIGIO Registry, we present a case of a 28-year-old man with vertically transmitted HIV-1 infection, on therapy with an ibalizumab-including regimen and desiring a treatment simplification. In January 2024, the patient was started on a lenacapavir-containing regimen along with optimized background therapy in an attempt to maintain sustained virological suppression, simplify antiretroviral regimen, and potentially increase CD4+ T-cell count. At six months follow-up evaluation, virological suppression was confirmed, and an increase in CD4+ T-cell count of 60 cells/μL was observed. Close follow-up of this patient is ongoing.

Retrospective, cohort analysis including people with HIV and 4-class drug resistance (4DR). The 8-year probability of malignancy after first evidence of 4DR was 12%, with an incidence of 1.6/100 person years of follow-up. Cancer risk tended to increase with higher precancer viremia copy-years adjusted for time [per 1 - log10 copies/ml higher: adjusted hazard ratio (aHR) = 1.35; 95% confidence interval (95% CI) = 0.98-1.85] and male sex-assigned-at-birth (aHR = 2.50; 95% CI = 0.86-7.27). Efforts to achieve long-term undetectability, risk factor control, prevention, and more aggressive cancer screening are needed in this fragile population., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To clarify whether next-generation sequencing (NGS) can be useful for resistance assessment in virologically suppressed highly treatment-experienced (HTE) individuals with MDR HIV., Methods: Ninety-one participants from the PRESTIGIO Registry were included. NGS was performed on HIV-DNA at 1%, 5% and 20% cut-offs; major drug resistance mutations (DRMs) were evaluated and compared with those detected in historical plasma genotypic resistance testing (h-GRT). APOBEC editing was also characterized., Results: Participants had a complex and long treatment history [median 23 (IQR 21-25) years of ART exposure) and had been virologically suppressed since a median of 3 (IQR 2-5) years. Among all major DRMs detected by HIV-DNA NGS and/or h-GRT, 30% were exclusively found through NGS. The highest detection rate of historical major DRMs was reached with NGS set at 1%, but unusual substitutions and extensive APOBEC hypermutations suggest technical issues and poor clinical relevance in the 1%-5% interval. At NGS set at 5%, 67.2% of historical major DRMs were detected. The number of major DRMs detected exclusively by DNA-NGS as minority variants (frequency 5%-20%) was significantly higher in individuals who later experienced virological rebound compared with those who maintained virological control [median 2 (IQR 1-3) versus 1 (0-2), P = 0.030] and positively correlated with viraemia levels at rebound (rho = 0.474, P = 0.030)., Conclusions: In non-viraemic people with an MDR virus, HIV-1 DNA NGS set at 5% is an acceptable technical cut-off that might help to reveal mutations with a potential clinical relevance. Moreover, the number of minority resistance mutations additionally detected by NGS might be associated with loss of virological control., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: The course of HIV infection has changed radically with the introduction of antiretroviral therapy (ART), which has significantly reduced mortality and improved quality of life. However, antiretroviral drugs can cause adverse effects, including cardiometabolic complications and diseases, which are among the most common. Compared to the adult population, there are fewer studies in the pediatric population on treatment-related complications. The purpose of this review is to provide an update on the literature regarding cardiometabolic complications and diseases in children and adolescents with HIV., Areas Covered: A comprehensive literature review was conducted using PubMed and related bibliographies to provide an overview of the current knowledge of metabolic complications (dyslipidemia, insulin resistance, lipodystrophy, weight gain and liver complications) and diseases (prediabetes/diabetes and cardiovascular diseases) associated with ART in children and adolescents with HIV., Expert Opinion: Metabolic complications are conditions that need to be closely monitored in children and adolescents with HIV, as they increase the risk of early development of non-communicable diseases, such as cardiovascular disease. Key areas for improvement include ensuring access to treatment, reducing side effects and improving diagnostic capabilities. Overcoming existing challenges will require collaborative efforts across disciplines, advances in technology, and targeted interventions to address socioeconomic disparities.

Objectives: Heavily treatment-experienced (HTE) people living with HIV (PLWH) pose unique challenges due to limited antiretroviral treatment (ART) options. Our study aimed to investigate the prevalence and features of HTE individuals followed up in the Italian Cohort Naïve Antiretrovirals (ICONA) cohort as of December 31, 2021., Methods: HTE were defined based on meeting specific conditions concerning their current ART and their ART history up to December 31, 2021. Descriptive statistics were performed by HTE status. Regression analyses explored factors associated with becoming HTE based on pre-ART patients' characteristics. Cluster dendrogram analysis provided insights into subgroups with inadequate responses based on clusters of differentiation (CD4) counts and viral load (VL) trajectories., Results: Among the 8758 PLWH actively followed in our cohort, 163 individuals (1.9%), mainly female, younger, Italian, and infected through heterosexual contact, met the HTE criteria. A lower CD4 count at ART initiation (odds ratio [OR] 1.60 per 100 cells/mmc lower CD4, 95% confidence interval [CI] 1.06-2.41, P = 0.03) and hepatitis C virus antibody positivity (OR 1.90, 95% CI 1.16-3.11, P = 0.01) were associated with higher HTE risk. Thirty PLWH exhibited ongoing immune-virological failure (18% of the HTE subgroup and 0.003% of the total population). Thirty PLWH exhibited ongoing immune-virological failure (i.e., with a current CD4 count <200 cells/mmc or VL>200 copies/mL). A cluster analysis identified 13 (43%) with a current CD4 count <200 cells/mmc. Also, notably, 19/30 (63%) had major acquired resistance-associated mutations to at least one antiretroviral drug class., Conclusions: HTE is rare in our cohort and tends to co-exist with major resistance mutations. A focused investigation into treatment history and immuno-virological response is warranted, particularly given the availability of new antiretroviral drugs., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Management of virological failure in heavily treatment-experienced people with multidrug-resistant (MDR) HIV infection is a serious clinical challenge. New drugs with novel mechanisms of action have recently been approved, and their use has improved the outcome of subjects with limited treatment options (LTO). In this setting, the choice of antiretroviral therapy (ART) should be tailored based on the pattern of resistance, treatment history and patients' individual characteristics. While genotypic resistance testing is the reference method for analysing residual drug susceptibility, phenotypic resistance testing can provide additional support when facing LTO. Herein, we present the case of a patient with MDR HIV-1 infection on virological failure enrolled in the PRESTIGIO Registry. The salvage ART regimen, which included drugs with novel mechanisms of action (MoA), was tailored to the patient's clinical characteristics and on the resistance pattern explored with genotypic and phenotypic investigation, allowing the achievement of viro-immunological success. The use of recently approved drugs with novel MoA, combined with an optimized background regimen, may also achieve virological suppression in people with LTO.

Objectives: People with HIV and extensive antiretroviral exposure may have limited/exhausted treatment options (LExTO) due to resistance, comorbidities, or antiretroviral-related toxicity. Predictors of LExTO were investigated in the RESPOND cohort., Methods: Participants on ART for at least 5 years were defined as having LExTO when switched to at least two anchor agents and one third antiretroviral (any class), a two-drug regimen of two anchor agents (excluding rilpivirine with dolutegravir/cabotegravir), or at least three nucleoside reverse transcriptase inhibitors. Baseline was the latest of January 1, 2012, cohort enrolment or 5 years after starting antiretrovirals. Poisson regression modeled LExTO rates and clinical events (all-cause mortality, non-AIDS malignancy, cardiovascular disease [CVD], and chronic kidney disease [CKD])., Results: Of 23 827 participants, 2164 progressed to LExTO (9.1%) during 130 061 person-years follow-up (PYFU); incidence 1.66/100 PYFU (95% CI 1.59-1.73). Predictors of LExTO were HIV duration more than 15 years (vs. 7.5-15; adjusted incidence rate ratio [aIRR] 1.32; 95% CI 1.19-1.46), development of CKD (1.84; 1.59-2.13), CVD (1.64; 1.38-1.94), AIDS (1.18; 1.07-1.30), and current CD4 + cell count of 350 cells/μl or less (vs. 351-500 cells/μl, 1.51; 1.32-1.74). Those followed between 2018 and 2021 had lower rates of LExTO (vs. 2015-2017; 0.52; 0.47-0.59), as did those with baseline viral load of 200 cp/ml or less (0.46; 0.40-0.53) and individuals under 40. Development of LExTO was not significantly associated with clinical events after adjustment for age and current CD4, except CKD (1.74; 1.48-2.05)., Conclusion: Despite an aging and increasingly comorbid population, we found declining LExTO rates by 2018-2021, reflecting recent developments in contemporary ART options and clinical management. Reassuringly, LExTO was not associated with a significantly increased incidence of serious clinical events apart from CKD., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The PRESTIGIO Registry was established in 2017 to collect clinical, virological and immunological monitoring data from people living with HIV (PLWH) with documented four-class drug resistance (4DR). Key research purposes include the evaluation of residual susceptibility to specific antiretrovirals and the validation of treatment and monitoring strategies in this population., Participants: The PRESTIGIO Registry collects annual plasma and peripheral blood mononuclear cell samples and demographic, clinical, virological, treatment and laboratory data from PLWH followed at 39 Italian clinical centres and characterised by intermediate-to-high genotypic resistance to ≥1 nucleoside reverse transcriptase inhibitors, ≥1 non-nucleoside reverse transcriptase inhibitors, ≥1 protease inhibitors, plus either intermediate-to-high genotypic resistance to ≥1 integrase strand transfer inhibitors (INSTIs) or history of virological failure to an INSTI-containing regimen. To date, 229 people have been recorded in the cohort. Most of the data are collected from the date of the first evidence of 4DR (baseline), with some prebaseline information obtained retrospectively. Samples are collected from the date of enrollment in the registry., Findings to Date: The open-ended cohort has been used to assess (1) prognosis in terms of survival or development of AIDS-related or non-AIDS-related clinical events; (2) long-term efficacy and safety of different antiretroviral regimens and (3) virological and immunological factors predictive of clinical outcome and treatment efficacy, especially through analysis of plasma and cell samples., Future Plans: The registry can provide new knowledge on how to implement an integrated approach to study PLWH with documented resistance to the four main antiretroviral classes, a population with a limited number of individuals characterised by a high degree of frailty and complexity in therapeutic management. Given the scheduled annual updates of PLWH data, the researchers who collaborate in the registry can send study proposals at any time to the steering committee of the registry, which evaluates every 3 months whether the research studies can be conducted on data and biosamples from the registry and whether they are aimed at a better understanding of a specific health condition, the emergence of comorbidities or the effect of potential treatments or experimental drugs that may have an impact on disease progression and quality of life. Finally, the research studies should aim to be inclusive, innovative and in touch with the communities and society as a whole., Trial Registration Number: NCT04098315., Competing Interests: Competing interests: RG reports payments to her institution from Gilead Sciences; personal fees for speaker panels and educational material from ViiV Healthcare, Merck Sharp and Dohme and Gilead Sciences and advisory boards from Theratechnologies, Janssen-Cilag and Gilead Sciences. FL reports personal fees for speaker panels from ViiV Healthcare, Janssen-Cilag and Merck Sharp and Dohme; travel grants from Gilead Sciences, ViiV Healthcare and Janssen-Cilag and advisory boards from ViiV Healthcare and Janssen-Cilag. EF reports personal fees for consultancy from Merck Sharp and Dohme, ViiV Healthcare, Gilead Sciences and Swedish Orphan Biovitrum; speaker panels and educational material from ViiV Healthcare and Gilead Sciences and advisory boards from ViiV Healthcare, Gilead Sciences and Merck Sharp and Dohme. ADB reports personal fees for speaker panels and educational material from ViiV Healthcare and Gilead Sciences and travel grants from ViiV Healthcare. AdCe reports personal fees for speaker panels from ViiV Healthcare. FM reports personal fees for consultancy and advisory boards from Merck Sharp and Dohme, ViiV Healthcare and Gilead Sciences. GM reports personal fees for speaker panels and educational material from Gilead Sciences; travel grants from Janssen-Cilag, Gilead Sciences and ViiV Healthcare and advisory boards from Gilead Sciences, ViiV Healthcare and Angelini Pharma. GC reports personal fees for speaker panels and educational material from Gilead Sciences, ViiV Healthcare and AbbVie and travel grants from Gilead Sciences. SR reports payments to his institution from Gilead Sciences, Janssen-Cilag and ViiV Healthcare; personal fees for travel grants from Gilead Sciences, Janssen-Cilag and ViiV Healthcare and advisory boards from Gilead Sciences, Janssen-Cilag, ViiV Healthcare and Merck Sharp and Dohme. MZ reports personal fees for consultancy and speaker panels and educational material from Gilead Sciences, ViiV Healthcare and Merck Sharp and Dohme. MMS reports personal fees for speaker panels and educational material from ViiV Healthcare, Merck Sharp and Dohme and Janssen-Cilag and advisory boards from ViiV Healthcare and Theratechnlogies. VS reports grants from Gilead Sciences and personal fees for speaker panels from Gilead Sciences, ViiV Healthcare and Merck Sharp & Dohme. AnCa reports personal fees for advisory boards, speaker panels and educational materials from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, Merck Sharp & Dohme and Theratechnlogies. PRESTIGIO Registry received funding from Gilead Sciences, ViiV Healthcare, Merck Sharp & Dohme, and Theratechnologies.All other authors: no potential conflicts., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

People aging with 4 antiretroviral class resistant HIV are a very challenging population. It is difficult to build up a fully suppressive regimen, and the high prevalence of comorbidities and polypharmacy may cause drug-drug interactions and put adherence at risk. We herein present the case of an 80-year-old man, participating in the PRESTIGIO registry, asking for a reduction in his antiretroviral burden while on polypharmacy for his comorbidities.

Objectives: 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., Methods: 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., Results: 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)., Conclusion: 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., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Analysis of bictegravir/emtricitabine/tenofovir alafenamide (BFTAF) efficacy and safety in virologically suppressed people living with HIV (PLWH) in clinical practice., Patients and Methods: The retrospective cohort study, which included adult treatment-experienced and virologically suppressed PLWH, switched to BFTAF from June 2019 to June 2021. Efficacy and safety were evaluated as virological failure (VF=2 consecutive HIV-RNA>50 copies/mL or a single HIV-RNA>400 copies/mL) and treatment failure (TF=VF or discontinuation for any reason) until data freezing (August 2022)., Results: Of the 1040 PLWH included, 67.8% switched from elvitegravir/cobicistat/FTAF. VF occurred in 4.2% (n=44), with incidence rate of 1.63 per 1000 person-months of follow-up (PMFU) and probability at 24-30 months of 3.8%-4.0%, respectively. Out of the 44 VF, in 75% virological re-suppression was achieved while maintaining BFTAF. Discontinuation occurred in 15% after a median time of 13.5 months of follow-up, with an incidence rate of 5.67 per 1000 PMFU, and a probability at 24-30 months of 11.9%-15.3%, respectively. Main discontinuation reasons were simplification (51.3%) and toxicity (21.8%, involving CNS in half of cases). TF occurred in 18.6% with an incidence rate of 7.01 per 1000 PMFU after a median time of 13.6 observation months; probability at 24-30 months was 14.8%-18.4%, respectively., Conclusion: BFTAF has proven effective and well tolerated in clinical practice., Competing Interests: DC has received research grants from Gilead Sciences and GlaxoSmithKline and received payment for educational events and support for attending meetings from Merck Sharp & Dohme and ViiV Healthcare. SN received fee for Advisory Boards and consultations from Gilead Sciences. VS reports grants and/or personal fees from GILEAD SCIENCES, ViiV Healthcare, and MSD, outside the submitted work. AC has received personal fees for advisory boards, speaker panels, and educational materials from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, Merck Sharp & Dohme, and Theratechnologies. NG has been an advisor for Gilead Sciences, Janssen-Cilag, ViiV Healthcare, and Merck Sharp & Dohme and has received speakers’ honoraria from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, and Merck Sharp & Dohme. All other authors declare no competing interests in this work., (© 2023 Canetti et al.)

Retrospective, cohort analysis including people with four-class drug-resistant HIV. Bacterial sexually transmitted infections (STIs) had an incidence of 1.3/100-person-years-of-follow-up (PYFU) in men (3.5/100-PYFU in MSM) whereas no STIs were diagnosed in women. The occurrence of STIs in this fragile population might be related to the achievement of good HIV infection control; however, given the remaining risk of virological failure and possible transmission of a multidrug-resistant virus, STI prevention counselling and HIV viremia monitoring should be prioritized., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Few data on management of two-drug regimen (2DR) failure in people living with HIV (PLWH) are available., Methods: Retrospective study of treatment-experienced PLWH on a 2DR who experienced virological failure (VF) [two consecutive viral loads (VLs) ≥50 copies/mL, single VL ≥1000 copies/mL, or antiretroviral therapy (ART) switch after single VL ≥50 copies/mL with previous blips] or discontinuation for toxicity (baseline). Integrase strand transfer inhibitor (INSTI)-based [one INSTI plus one nucleoside reverse transcriptase inhibitor (NRTI) (n = 78) or one non-NRTI (n = 20)] or boosted protease inhibitor (PI/b)-based [one PI/b plus one NRTI (n = 116) or one INSTI (n = 12)] 2DRs were included. Probabilities of treatment success (TS), VF and discontinuation for any other cause of rescue regimens were estimated by Kaplan-Meier curves. A stepwise Cox model was performed to assess predictors of TS., Results: Overall, 226 PLWH were evaluated: at baseline, 144 individuals discontinued 2DR for toxicity and 82 had VF [median viraemia 81 (63-212) copies/mL]; 171 switched therapy (49.7% to triple regimen, 40.9% to different 2DR), while 55 (exclusively with VF) maintained failing regimens. Probabilities of 12- and 24-month TS were 75.6% and 64.7%, respectively. Higher TS probabilities were observed in individuals who switched ART at 2DR failure (P = 0.003) and PLWH who discontinued 2DR for toxicity (P = 0.008). Therapy switch was the only predictor of TS (P = 0.002)., Conclusions: Overall probability of rescue regimens' TS introduced after 2DR failure is good. Prompt ART switch after 2DR failure is advisable., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Background: We assessed the vaccination effectiveness (VE) of multicomponent meningococcal serogroup B (4CMenB) vaccine against gonorrhea among people living with HIV (PLWH) with a previous diagnosis of sexually transmitted infection., Methods: Unmatched case-control study on men who have sex with men living with HIV, in care at San Raffaele Scientific Institute, Milan, Italy, with gonorrhea, syphilis, chlamydia, or anal human papillomavirus between July 2016 (beginning of 4CMenB vaccination) and February 2021 (date of freezing). For the analysis, cases were people with ≥1 gonorrhea infection since July 2016, and controls were people with ≥1 syphilis, chlamydia, or anal human papillomavirus infection since July 2016. Logistic regression was used to provide the estimate of 4CMenB VE against gonorrhea., Results: Included people living with HIV were 1051 (103 cases, 948 controls); 349 of 1051 (33%) received 2 doses of 4CMenB vaccination. The median follow-up was 3.8 years (2.1-4.3 years). The unadjusted estimate for VE against gonorrhea was 42% (95% confidence interval, 6%-64%; P = 0.027). Logistic regression showed that VE against gonorrhea remained significant (44%; 95% confidence interval, 9%-65%; P = 0.020) after adjusting for some factors that might have a potential influence on VE or those with significant unbalanced distributions between cases and controls at univariable analysis., Conclusions: 4CMenB vaccination is associated with a lower risk of gonorrhea in the setting of men who have sex with men living with HIV with a previous sexually transmitted infection., Competing Interests: Conflict of Interest and Sources of Funding: None declared., (Copyright © 2023 American Sexually Transmitted Diseases Association. All rights reserved.)

Management of heavily treatment experienced (HTE) people with HIV remains a challenge. Tailored antiretroviral therapy (ART) is needed in this fragile population who almost invariably harbor viral quasispecies with resistance-associated mutations (RAMs). The reference method for HIV genotypic resistance testing (GRT) has long been Sanger sequencing (SS), but next-generation sequencing (NGS), following recent progress in workflow and cost-effectiveness, is replacing SS because of higher sensitivity. From the PRESTIGIO Registry, we present a case of a 59-year-old HTE woman who failed darunavir/ritonavir plus raltegravir at low-viremia levels due mainly to high pill burden and poor adherence. NGS-GRT was performed on HIV-RNA at failure and the results were compared to all past SS-GRT data available (historical genotype). In this case, NGS-GRT did not detect any minority drug-resistant variants. After discussing several therapeutic options, the treatment was changed to dolutegravir 50 mg twice daily plus doravirine 100 mg once a day, based on clinical history, adherence issues, and pill burden, as well as the historical SS-GRT and the latest NGS-GRT results. At six months follow-up visit, the patient had HIV-RNA below 30 copies/ml and CD4+ T cell count increased from 673 cells/ mm3 to 688 cells/ mm3. Close follow-up of this patient is ongoing.

Objectives: Four-class drug-resistant (4DR) people living with HIV (PLWH) are a fragile population with a high burden of disease. No data on their inflammation and T-cell exhaustion markers are currently available., Methods: Inflammation, immune activation and microbial translocation biomarkers were measured through ELISA in 30 4DR-PLWH with HIV-1 RNA ≥ 50 copies/mL, 30 non-viremic 4DR-PLWH and 20 non-viremic non-4DR-PLWH. Groups were matched by age, gender and smoking habit. T-cell activation and exhaustion markers were assessed by flow cytometry in 4DR-PLWH. An inflammation burden score (IBS) was calculated from soluble marker levels and associated factors were estimated through multivariate regression., Results: The highest plasma biomarker concentrations were observed in viremic 4DR-PLWH, the lowest ones in non-4DR-PLWH. Endotoxin core immunoglobulin G showed an opposite trend. Among 4DR-PLWH, CD38/HLA-DR and PD-1 were more expressed on CD4 + (p = 0.019 and 0.034, respectively) and CD8 + (p = 0.002 and 0.032, respectively) cells of viremic compared to non-viremic subjects. An increased IBS was significantly associated with 4DR condition, higher values of viral load and a previous cancer diagnosis., Conclusions: Multidrug-resistant HIV infection is associated with a higher IBS, even when viremia is undetectable. Therapeutic approaches aimed to reduce inflammation and T-cell exhaustion in 4DR-PLWH need to be investigated., Competing Interests: Declaration of interest None., (Copyright © 2023 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: To explore different sexual behaviours as risk factors for STI among men who have sex with men (MSM) living with HIV., Methods: This is a cross-sectional study on MSM living with HIV followed at the Infectious Diseases Unit of San Raffaele Hospital, Milan, with at least one diagnosis of gonorrhoea, syphilis, chlamydia or anal human papilloma virus (HPV), between July 2016 and February 2021. We conducted a survey on high-risk sexual behaviours with regard to (1) mean number of partners per month, (2) estimated percentage of condom use and (3) most frequent type of sexual intercourse during 2016-2021. Data on these variables were grouped as follows: (1a) ≤5 vs >5, (1b) >10 vs ≤ 10, (2a) 0% vs >0%, (2b) ≤50% vs >50%, (2c) 100% vs <100%, (3a) ≥50% vs <50% receptive, (3b) 100% vs <100% insertive, and (3c) 100% vs <100% receptive. A high-risk group was defined as >5 partners, <100% use of condom and ≥50% receptive intercourse. Univariate logistic regressions were applied to assess the association between sexual behaviours and the risk of each STI., Results: Out of 1051 MSM with at least one STI diagnosis, 580 (55%) answered the survey. The risk of chlamydia was lower among individuals with ≤5 partners (≤5 partners vs >5 partners: OR=0.43, 95% CI 0.28 to 0.66, p=0.001) and among those using condoms more frequently (≤50% use of condom vs >50% use of condom: OR=1.55, 95% CI 1.06 to 2.27, p=0.025; 100% vs <100%: OR=0.35, 95% CI 0.20 to 0.59, p=0.001). Individuals using condoms more frequently also had lower risk of gonorrhoea (100% use of condom vs <100% use of condom: OR=0.37, 95% CI 0.17 to 0.79, p=0.011). The risks of chlamydia (OR=3.07, 95% CI 1.92 to 4.90, p<0.001) and gonorrhoea (OR=2.05, 95% CI 1.12 to 3.75, p=0.020) were higher among individuals belonging to the high-risk group., Conclusions: Chlamydia and gonorrhoea are more likely associated with high-risk sexual behaviours than syphilis and anal HPV among MSM living with HIV., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Doravirine shows a rather distinct resistance profile within the nonnucleoside reverse transcriptase inhibitor (NNRTI) class. This study aimed to evaluate the phenotypic susceptibility to doravirine, rilpivirine and etravirine in a panel of multidrug-resistant (MDR) HIV-1 isolates collected from people living with HIV (PLWH) enrolled in the PRESTIGIO Registry., Methods: Recombinant viruses expressing PLWH-derived protease, reverse transcriptase coding regions were generated from plasma samples at virological failure with documented resistance to protease inhibitors, nucleoside reverse transcriptase inhibitors, NNRTIs and integrase strand transfer inhibitors. In vitro susceptibility was assessed through a phenotypic assay measuring fold-change values with respect to the reference NL4-3 virus. Genotypic susceptibility was computed by the Stanford HIVdb algorithm 8.9-1., Results: Plasma samples were collected from 22 PLWH: 20 (91%) were male, median age 55 years (IQR 50-58), time since HIV-1 diagnosis 27 years (23-31) and time on antiretroviral treatment 23 years (22-26). Median doravirine, etravirine and rilpivirine fold-change values were 9.8 (2.9-40.4), 42.9 (3.1-100.0) and 100.0 (17.9-100.0), respectively. According to the fold-change cut-offs, full susceptibility was observed in five (23%), four (18%) and one (5%) cases with doravirine, etravirine and rilpivirine, respectively. Irrespective of the presence of specific doravirine mutations, higher numbers of NNRTI mutations correlated with higher fold-change values for doravirine. By comparing the distribution of fold-change values with the Stanford HIVdb predicted susceptibility, a significant correlation was detected for doravirine and rilpivirine but not etravirine., Conclusion: Despite extensive cross-resistance among NNRTIs, doravirine can be a valid option in a proportion of PLWH with MDR HIV-1. Doravirine activity appeared to be inferred with fair accuracy by the HIVdb algorithm., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Weight gain following the initiation or the switch of antiretroviral therapy (ART) is well documented and mainly associated with some of the most recent drugs, such as integrase strand transfer inhibitors and tenofovir alafenamide. However, limited data have been published on weight trends in ART-experienced people living with HIV (PLWH) with a long exposure to HIV infection and antiretroviral drugs. In our study, we assessed changes in weight after switching ART among PLWH who reported weight gain under a previous regimen.

Background: Aims of this study are assessing prevalence of anal human papillomavirus (HPV) genotypes in male who have sex with men (MSM) living with HIV over a period of 5 years and determining risk factors for anal infection from high-risk (HR) HPV genotypes or included in vaccine Gardasil 9., Setting: Time-trend, monocentric study on MSM living with HIV who underwent HPV test at anal site from 2015 to 2019., Methods: Anal swabs were processed by multiplex real-time polymerase chain reaction to detect HPV genotypes. The Cochran-Armitage test was used to assess linear trend in HPV prevalence over time and logistic regression models to estimate risk factors., Results: Of the 1352 MSM living with HIV, 168 (12%) were not infected by any HPV genotypes and only 6 were infected with a maximum of 6 genotypes; prevalence of HR-HPV genotypes or those included in the 9-valent vaccine remained stable over time. At multivariable analysis, the risk of carrying at least 1 genotype classified as HR or included in Gardasil 9 was associated with younger age [adjusted odds ratio (aOR) for younger than 30 years vs older than 45 years (95% confidence interval) 2.714 (1.484 to 4.961), P = 0.001, and 1.868 (1.141 to 3.060), P < 0.013, respectively] and a history of gonorrhea [aOR 2.118 (1.100 to 4.078), P = 0.025, and 1.785 (1.056 to 3.018), P = 0.031, respectively]., Conclusion: Our findings suggest that prevalence remained stable over time and that all MSM with HIV would benefit from Gardasil 9 immunization, particularly the youngest and those with a prior gonococcal infection., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To compare the incidence of hypertension in people living with HIV receiving integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) versus non-nucleoside reverse transcriptase inhibitors (NNRTIs) or boosted protease inhibitors (PIs) in the RESPOND consortium of HIV cohorts., Methods: Eligible people with HIV were aged ≥18 years who initiated a new three-drug ART regimen for the first time (baseline), did not have hypertension, and had at least two follow-up blood pressure (BP) measurements. Hypertension was defined as two consecutive systolic BP measurements ≥140 mmHg and/or diastolic BP ≥90 mmHg or initiation of antihypertensives. Multivariable Poisson regression was used to determine adjusted incidence rate ratios (aIRRs) of hypertension, overall and in those who were ART naïve or experienced at baseline., Results: Overall, 4606 people living with HIV were eligible (INSTIs 3164, NNRTIs 807, PIs 635). The median baseline systolic BP, diastolic BP, and age were 120 (interquartile range [IQR] 113-130) mmHg, 78 (70-82) mmHg, and 43 (34-50) years, respectively. Over 8380.4 person-years (median follow-up 1.5 [IQR 1.0-2.7] years), 1058 (23.0%) participants developed hypertension (incidence rate 126.2/1000 person-years, 95% confidence interval [CI] 118.9-134.1). Participants receiving INSTIs had a higher incidence of hypertension than those receiving NNRTIs (aIRR 1.76; 95% CI 1.47-2.11), whereas the incidence was no different in those receiving PIs (aIRR 1.07; 95% CI 0.89-1.29). The results were similar when the analysis was stratified by ART status at baseline., Conclusion: Although unmeasured confounding and channelling bias cannot be excluded, INSTIs were associated with a higher incidence of hypertension than were NNRTIs, but rates were similar to those of PIs overall, in ART-naïve and ART-experienced participants within RESPOND., (© 2022 The Authors. HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: The primary objective of this study was to estimate the proportion of people living with HIV (PLWH) who switched from a non-protease inhibitor (PI)-based regimen [integrase strand transfer inhibitor (InSTI)-based or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen] to darunavir, cobicistat, emtricitabine, tenofovir alafenamide (D/C/F/TAF)., Methods: This was a retrospective study on PLWH treated with a non-PI regimen in January 2017, who switched to D/C/F/TAF or to another antiretroviral therapy (ART) within November 2019. Follow-up was from the start date of D/C/F/TAF until the last available visit or discontinuation for any reason of this regimen. Virological failure (VF) was defined as 2 consecutive HIV-RNA values >50 copies/mL. Characteristics were reported as median (interquartile range) or frequency (%). A univariate Poisson regression model was used to measure the incidence rate of switch to D/C/F/TAF. Changes in laboratory parameters during D/C/F/TAF were assessed by univariate mixed linear models., Results: Overall, 3076 PLWH were included; 83% were male, median age at ART switch was 50 (42-56) years and median time on ART was 5.2 (0.3-13.0) years. PLWH had a median follow-up of 4.76 (3.70-6.38) years; during 17,099 person-years of follow-up (PYFU), 423/3076 (14%) participants discontinued the non-PI-based regimen and 106/423 (25%) switched to D/C/F/TAF, with an overall incidence rate of switch to D/C/F/TAF of 6.2 per 1000-PYFU (95% CI: 5.0-7.4). Among PLWH who switched to D/C/F/TAF, the ongoing regimen was based on NNRTIs in 37 (35%) and on InSTIs in 69 (65%). Main reasons leading to switch to D/C/F/TAF included neuropsychiatric adverse events (37%), VF (26%) and Kaposi sarcoma progression (5%)., Conclusion: In the last years, a non-negligible proportion of patients on an NNRTI- or an InSTI-based regimen switched to D/C/F/TAF., Competing Interests: Dr Nicola Gianotti reports grants from Janssen-Cilag, during the conduct of the study. Dr Vincenzo Spagnuolo reports grants and/or personal fees from Gilead Sciences, ViiV Healthcare, outside the submitted work. Dr Daniela Mancusi is an employee of Janssen-Cilag SpA. Dr Roberta Termini was an employee of Janssen Cilag SpA during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2022 Ranzenigo et al.)

Background: HLA-B27 and -B57 were found in people with low levels of HIV-1 DNA, suggesting that HLA class I molecules may influence the size of HIV-1 reservoir. Aim of the study was to explore the association between HLA class I molecules and HIV-1 DNA in people with chronic HIV-1 infection., Methods: Post-hoc analysis of the APACHE trial, on adults with chronic HIV-1 infection, prolonged suppressive antiretroviral therapy and good immunological profile. HIV-1 DNA was quantified in peripheral blood mononuclear cells (PBMCs); HLA-A, -B and -C were tested on genomic DNA. Crude odds ratios (OR) with their respective 95% Wald confidence intervals (95% CIs) were estimated by univariable logistic regression for HLAs with a p-value <0.10., Results: We found 78 and 18 patients with HIV-1 DNA ≥100 copies/106PBMCs and with HIV-1 DNA <100 copies/106PBMCs, respectively. HLA-A24 was present in 21 (29.6%) participants among subjects with HIV-1 DNA ≥100 copies/106PBMCs and 1 (5.9%) among those with HIV-1 DNA <100 copies/106PBMCs (OR = 5.67, 95%CI = 0.79-46.03; p = 0.105); HLA-B39 was present in 1 (1.4%) with HIV-1 DNA ≥100 copies/106PBMCs and in 3 (17.6%) with HIV-1 DNA <100 copies/106PBMCs (OR = 13.71, 95%CI = 1.33-141.77; p = 0.028) and HLA-B55 in 3 (4.2%) and 3 (17.6%), respectively (OR = 4.43, 95%CI = 0.81-24.29; p = 0.087). All the three patients with HLA-B39 and HIV-1 DNA <100 copies/106PBMCs did not have HLA-A24., Conclusions: In patients with HIV-1 infection who maintained a good virological and immunological profile, HLA-B39 and -B55 may be associated with lower levels of HIV-1 DNA., Competing Interests: The authors have declared that no competing interests exist.

Background: HIV-1 pan-resistance refers to a reduced susceptibility to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and integrase strand tranfer inhibitors. Although still anecdotal, its management remains a concern both for affected people living with HIV (PLWH) and for public health., Methods: We described genotypic resistance testing (GRT) of three PLWH with a documented poor virological response to previous antiretroviral therapies, who started ibalizumab, an anti-CD4 monoclonal antibody, combined with an optimized background therapy. Both historical and most recent GRT on plasma RNA and peripheral blood mononuclear cell DNA were interpreted according to the Stanford HIVDb version 9.0 (last updated on 22 February, 2021). After the switch to a regimen including the monoclonal antibody, HIV-1 RNA has been quantified biweekly (PCR Cobas® HIV-1 test 6800 Systems, Roche Diagnostics). Follow-up was censored at data freezing (16 January, 2021)., Findings: We report findings from heavily treatment-experienced PLWH with a pan-resistant HIV-1 infection, who achieved virological control once introduced injections of ibalizumab, that is free from cross-resistance with all the antiretroviral drugs available and ensures patient adherence due to a close monitoring attributable to the route of administration, combined with recycled enfuvirtide and an optimized background regimen, selected on the basis of an accurate evaluation of resistance mutations., Interpretation: In these cases, this new approach has revealed to be a turning point in achieving virological control., Funding: None, this research was supported by internal funding., Competing Interests: Declaration of interests DC, CM, LG, AP and MF declare no competing interests. VS has received grants from a Gilead Sciences fellowship program, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and support for attending meetings and/or travel from Gilead Sciences and ViiV Healthcare. NG has received consulting fees from Janssen-Cilag and ViiV Healthcare, support for attending meetings and/or travel from ViiV Healthcare and participated on a Data Safety Monitoring Board or Advisory Board for ViiV Healthcare. AC has received consulting fees, honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, support for attending meetings and/or travel from Merck Sharp & Dohme, Gilead Sciences, Janssen-Cilag, ViiV Healthcare, and Theratecnologies., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Heavily-treatment-experienced people living with human immunodeficiency virus (HTE-PLWH) represent a population with limited therapeutic options and at high-risk of clinical progression, morbidity, and mortality. The development of new drugs and new drug classes for the treatment of HIV-1 infection in HTE-PLWH is critical to successfully suppress HIV-1 replication, restore the immune system, and improve quality of life. Fostemsavir is the first attachment inhibitor approved by Food and Drug Administration and European Medicines Agency for the treatment of HIV-1 infection. It is approved in combination with other antiretrovirals, for HTE-PLWH with multi-drug resistant HIV-1 after failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. In this review, we present and discuss the mechanism of action, the pharmacodynamic and pharmacokinetic properties, and the efficacy and safety of fostemsavir as an antiretroviral agent for the treatment of HIV-1 infection., Competing Interests: V.S. received speaking fees by Gilead Sciences, ViiV Healthcare, Merck Sharp and Dohme, Janssen-Cilag. A.C. received speaking fees by Gilead Sciences, ViiV Healthcare, Merck Sharp and Dohme, Janssen-Cilag, and Theratechnologies. The authors report no other conflicts of interest in this work., (© 2022 Muccini et al.)

Background: Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus., Methods: Antiretroviral treatment-experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012-1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression., Results: Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years [interquartile range, 46.7-59.0] vs 47.7 [39.7-54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%). There were 619 events during 27 159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU; 95% confidence interval [CI]: 20.7-24.5) on 3DRs and 79 (30.9/1000 PYFU; 95% CI: 24.8-38.5) on 2DRs. The most common events were death (7.5/1000 PYFU; 95% CI: 6.5-8.6) and non-AIDS cancer (5.8/1000 PYFU; 95% CI: 4.9-6.8). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio, 0.92; 95% CI: .72-1.19; P = .53)., Conclusions: This is the first large, international cohort to assess clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes. Further research on resistance barriers and long-term durability of 2DRs is needed., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objectives: Few studies have investigated chronically infected individuals after antiretroviral therapy (ART) interruption (ATI, analytical therapy interruption); thus, we investigated the association between some HIV-specific antibodies and viral control., Design: All enrolled patients were previously described in the APACHE study. Briefly, the study was conducted on HIV-1 chronically infected patients, with HIV-RNA less than 50 copies/ml for at least 10 years, CD4+ cell count greater than 500 cells/μl and HIV-DNA less than 100 copies/106 PBMC. The ART regimen in use at the time of ATI was resumed at confirmed viral rebound (CVR, defined as two consecutive HIV-RNA >50 copies/ml)., Methods: Collection of sera and analysis of both binding antibodies (BAbs) and neutralizing antibodies (NAbs) was performed at three different time points: ATI, CVR and time of viral re-suppression after ART resumption., Results: IgG subclasses (IgG1, IgG2, IgG3 and IgG4) from the four patients with highest levels of neutralization were found to block viral infection. All patients had CVR after ATI at a median time of 21 days (14-56). After ART resumption, all the enrolled patients achieved HIV-RNA less than 50 copies/ml in 42 days (21-98). We observed a strong increase of either BAbs and NAbs titers from ATI to viral re-suppression in one patient, who showed the longest period of virus undetectability during ATI. In this patient, BAbs and NAbs specifically belonged to both IgG1 and IgG4 subclasses, directed to env antigen., Conclusion: env-specific NAbs and BAbs belonging to IgG1, IgG4 subclasses could be helpful to monitor long-term responses able to control virus replication and eradicate HIV infection., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

In this randomized, single-centre, open-label, 96-week, superiority, controlled trial of 50 HIV-infected patients with HIV-RNA less than 50 copies/ml on a two-drug regimen based on dolutegravir as well as one reverse transcriptase inhibitor (RTI), switching to a single-tablet regimen of cobicistat, elvitregravir, emtricitabine along with tenofovir alafenamide did not appear to mitigate the burden of residual viremia, both at week 48 and at week 96. The immunological changes observed during follow-up and the safety of the two regimens were similar., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Coronary artery disease (CAD) is one of the leading causes of death among people living with HIV (PLWH). We evaluated ECG stress testing (EST) for detecting CAD in PLWH with multiple cardiovascular risk factors., Methods: CORDIS was a cross-sectional study conducted in PLWH. Inclusion criteria were men at least 50 years or postmenopausal women, HIV-1 RNA less than 50 copies/ml and at least one of the following cardiovascular risk factor: familial history of CAD, smoking, hypertension, hypercholesterolemia or diabetes. Patients with a previous diagnosis of CAD or with cardiac symptoms were excluded. EST was performed concomitantly with bilateral carotid color-Doppler ultrasonography (CDU) and evaluated by a cardiologist. Results were described by median (interquartile range) or frequency (%). Logistic regression was applied to evaluate predictive factors of inducible myocardial ischemia (IMI)., Results: EST and CDU were performed in 309 individuals; IMI prevalence was 7.4% [95% confidence interval (CI): 5.0-11.0%]. Among patients with a normal CDU, no cases of IMI were observed. In people with abnormal CDU, IMI prevalence increased accordingly with the atherosclerotic cardiovascular disease (ASCVD) risk score: 10.2%, 16.9%, 19.7%, 27.8% and 30.4% among individuals with ASCVD score 7.5% or less, more than 7.5%, more than 10%, more than 15% and more than 20%, respectively (P for trend: 0.02). At multivariate analysis, ASCVD risk score was associated with EST suggestive of IMI (adjusted odds ratio for 1% increase = 1.08; 95% CI: 1.02-1.13, P = 0.005) and with confirmed IMI (adjusted odds ratio for 1% increase = 1.11; 95% CI: 1.04-1.19, P = 0.003)., Conclusion: Prevalence of IMI was 7.4% in the CORDIS study. We suggest EST as first-line screening for CAD in PLWH without cardiac symptoms, with an abnormal CDU and a high ASCVD risk score., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction : Oral pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) represent the cornerstones of HIV infection prevention and treatment. However, despite their high efficacy, the need to take daily oral pill(s) negatively impacts long-term patient adherence. In some cases, it can also be associated with drug-drug interactions and adverse gastrointestinal effects, as well as being a constant reminder to individuals of their HIV status. The availability of long-acting non-orally administered antiretroviral drugs could, therefore, be extremely useful. Cabotegravir (CAB) is a second-generation integrase strand transfer inhibitor, characterized by a relatively high genetic barrier and good antiretroviral potency, which is administrable as a long-acting injectable suspension (LAI CAB). Areas covered : The authors present and discuss the efficacy and available safety data of LAI CAB, either when co-administered with rilpivirine (RPV; LAI CAB + RPV) for the treatment of HIV infection, or when used as single agent for PrEP. Expert opinion : Cabotegravir has the potential to play a primary role in the treatment and prevention of HIV infection. The future availability of LAI CAB + RPV and LAI CAB may mark the beginning of an era of LAI ART and PrEP, respectively.

Background: HIV-DNA is a marker of HIV reservoirs. Objectives of the study were to determine prevalence of HIV-DNA < 100 copies/106 PBMCs in blood and to identify factors associated with this in a cohort of HIV-1-infected subjects treated with ART and with undetectable viral load (VL)., Methods: This was a cross-sectional study on chronic HIV-1-infected people living with HIV (PLWH) followed up at the Department of Infectious Diseases of San Raffaele Scientific Institute on current ART without change for 12 months, with available pre-ART HIV-RNA and with undetectable VL for ≥12 months. HIV-DNA was amplified and quantified by real-time PCR (ABI Prism 7900); limit of detectability was 100 copies/106 PBMCs. Logistic regression was used to identify predictive factors for HIV-DNA < 100 copies/106 PBMCs., Results: Four hundred and sixty-eight PLWH were considered in the analyses, 119 (25%) with HIV-DNA < 100 copies/106 PBMCs. At multivariate analysis, we found that PLWH with lower zenith HIV-RNA, higher nadir CD4 and a shorter time between HIV diagnosis and ART start were more likely to have HIV-DNA < 100 copies/106 PBMCs, after adjustment for age, gender, calendar year of ART start, type of current ART regimen, percentage time spent with undetectable VL since ART start, current CD4 and CD4/CD8 ratio., Conclusions: In our chronic PLWH on virological suppression for 4 years, the prevalence of HIV-DNA < 100  copies/106 PBMCs was found to be 25%. Lower zenith HIV-RNA, shorter time between HIV diagnosis and starting ART and higher CD4 nadir were independently associated with low HIV-DNA., (© 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.)

Background: Despite increased integrase strand transfer inhibitor (INSTI) use, limited large-scale, real-life data exists on INSTI uptake and discontinuation., Setting: International multicohort collaboration., Methods: RESPOND participants starting dolutegravir (DTG), elvitegravir (EVG), or raltegravir (RAL) after January 1, 2012 were included. Predictors of INSTI used were assessed using multinomial logistic regression. Kaplan-Meier and Cox proportional hazards models describe time to and factors associated with discontinuation., Results: Overall, 9702 persons were included; 5051 (52.1%) starting DTG, 1933 (19.9%) EVG, and 2718 (28.0%) RAL. The likelihood of starting RAL or EVG vs DTG decreased over time and was higher in Eastern and Southern Europe compared with Western Europe. At 6 months after initiation, 8.9% (95% confidence interval: 8.3% to 9.5%) had discontinued the INSTI (6.4% DTG, 7.4% EVG, and 14.0% RAL). The main reason for discontinuation was toxicity (44.2% DTG, 42.5% EVG, 17.3% RAL). Nervous system toxicity accounted for a higher proportion of toxicity discontinuations on DTG (31.8% DTG, 23.4% EVG, 6.6% RAL). Overall, treatment simplification was highest on RAL (2.7% DTG, 1.6% EVG, and 19.8% RAL). Factors associated with a higher discontinuation risk included increasing year of INSTI initiation, female gender, hepatitis C coinfection, and previous non-AIDS-defining malignancies. Individuals in Southern and Eastern Europe were less likely to discontinue. Similar results were seen for discontinuations after 6 months., Conclusions: Uptake of DTG vs EVG or RAL increased over time. Discontinuation within 6 months was mainly due to toxicity; nervous system toxicity was highest on DTG. Discontinuation was highest on RAL, mainly because of treatment simplification.

We compared invasive cervical cancer (ICC) incidence rates in Europe, South Africa, Latin and North America among women living with HIV who initiated antiretroviral therapy (ART) between 1996 and 2014. We analyzed cohort data from the International Epidemiology Databases to Evaluate AIDS (IeDEA) and the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. We used flexible parametric survival models to determine regional ICC rates and risk factors for incident ICC. We included 64,231 women from 45 countries. During 320,141 person-years (pys), 356 incident ICC cases were diagnosed (Europe 164, South Africa 156, North America 19 and Latin America 17). Raw ICC incidence rates per 100,000 pys were 447 in South Africa (95% confidence interval [CI]: 382-523), 136 in Latin America (95% CI: 85-219), 76 in North America (95% CI: 48-119) and 66 in Europe (95% CI: 57-77). Compared to European women ICC rates at 5 years after ART initiation were more than double in Latin America (adjusted hazard ratio [aHR]: 2.43, 95% CI: 1.27-4.68) and 11 times higher in South Africa (aHR: 10.66, 95% CI: 6.73-16.88), but similar in North America (aHR: 0.79, 95% CI: 0.37-1.71). Overall, ICC rates increased with age (>50 years vs. 16-30 years, aHR: 1.57, 95% CI: 1.03-2.40) and lower CD4 cell counts at ART initiation (per 100 cell/μl decrease, aHR: 1.25, 95% CI: 1.15-1.36). Improving access to early ART initiation and effective cervical cancer screening in women living with HIV should be key parts of global efforts to reduce cancer-related health inequities., (© 2019 UICC.)

Background: The aim of the study was to evaluate whether negative HIV-1 pol on Western blot (WB) was associated with low HIV-DNA in adults with chronic HIV-1 infection and suppressive antiretroviral therapy., Methods: Cross-sectional parent study of the APACHE trial, conducted in subjects with chronic infection, HIV-1 RNA <50 copies/mL for ≥10 years, no residual viremia for ≥5 years and CD4 >500 cells/µL screened for HIV-1 DNA. HIV-1 DNA was quantified in peripheral blood mononuclear cells (PBMCs) by real-time polymerase chain reaction and HIV-1 serostatus was tested by HIV Blot 2.2 WB assay. Multivariate logistic regression was used to determine factors associated with low HIV-1 DNA., Results: We evaluated 96 patients: 78 (81%) and 18 (19%) subjects with HIV-1 DNA ≥100 copies/10 PBMCs and with HIV-1 DNA <100 copies/10 PBMCs, respectively. Median age was 32.5 (25.3-38.9), and 61 (64%) were men; moreover, we reported that nadir CD4 was 253 (167-339) cells/µL and HIV-RNA <50 copies/mL for 11.7 (10.6-14.0) years. At multivariate analysis, higher nadir CD4 [adjusted odds ratio (AOR) [95% confidence interval (CI) 1.35 (95% CI: 1.03 to 1.76), P = 0.029], longer years of HIV-1 RNA <50 copies/mL [AOR (95% CI) 2.98 (95% CI: 1.25 to 7.10), P = 0.014], a R5-tropic virus [AOR (R5 vs. non-R5) 0.20 (95% CI: 0.04 to 0.96), P = 0.044], and negative HIV-1 pol [AOR 6.59 (95% CI: 1.47 to 29.54), P = 0.014] were associated with low HIV-1 DNA., Conclusions: In patients with chronic HIV-1 infection and suppressive antiretroviral therapy, negative HIV-1 pol on WB was associated with low HIV-1 DNA as well as higher nadir CD4, longer years of HIV-1 RNA <50 copies/mL, and a R5-tropic virus.

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., (© 2019 Wiley Periodicals, Inc.)

Introduction: In the last two decades, an increasing number of people living with HIV (PLWH) have undergone solid-organ and hematopoietic cell transplantation as a treatment of end-stage organ and hematological diseases, respectively. Although transplant outcomes are more than satisfactory, transplantation in PLWH is still challenging for clinicians because of concerns regarding potentially higher rates of infective complications, higher risks of allograft rejection, and drug-drug interactions between antiretroviral drugs and immunosuppressive agents., Areas Covered: This review provides an overview of transplantation in PLWH, with focus on the management of combination antiretroviral therapy in this population., Expert Opinion: Solid-organ and hematopoietic cell transplantations should be proposed without any reservation to all PLWH who may benefit from them. Particular attention should be paid to possible drug-drug interactions between antiretrovirals and immunosuppressive agents; moreover, when feasible, integrase strand transfer inhibitor-based antiretroviral regimens should be preferred to protease and non-nucleoside reverse transcriptase inhibitors. Considering the worse prognosis in HIV/hepatitis C virus (HCV) transplant recipients, treatment of HCV with new direct-acting antivirals (DAAs) represents a key issue in the management of this population. However, the timing of treatment (before or early after transplant) should be individualized by considering short-term prognosis, access to transplant, and comorbidities.

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., (© The Author(s) 2019. 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.)

Competing Interests: Disclosure AC, AL, SN, and NG have received consultancy payments and speaking fee from Bristol–Myers Squibb, Gilead, ViiV Healthcare, Merck Sharp Dohme, Janssen. VS has received consultancy payments and speaking fee from Gilead, ViiV Healthcare and Janssen-Cilag. The authors report no other conflicts of interest in this work.

Background: The pilot Phase IIb VIKING study suggested that dolutegravir (DTG), an HIV integrase inhibitor (INI), is efficacious in INI-resistant patients at the 50 mg twice-daily dose. However, DTG response was most reduced in subjects carrying resistance-associated mutations at position G140 and Q148. These mutations can cause a 10-20-fold reduced susceptibility to DTG as well as a 96% lower odds of achieving HIV-1 RNA <50 copies/ml at week 24 if compared with those with no mutations at these positions., Methods: Five multi-experienced patients harbouring the mutation complex G140-Q148, resistant to at least three drug classes, and previously exposed to DTG 50 mg twice daily, were treated with an increased dose of DTG (100 mg twice daily) in association with an optimized background regimen (OBR) based on their individual viral genotyping assays. The blood concentration of DTG was measured in order to determine whether a solubility issue is related with this high dosage., Results: Four out of five patients attained an HIV-1 RNA <50 copies/ml at week 48 and no relevant adverse events were detected. The measured DTG blood concentration was that expected for the administered dosage, ruling out any solubility concerns., Conclusions: For the first time 100 mg twice daily of DTG was administered to five multi-experienced patients harbouring the mutation complex G140-Q148. Although a small number of patients were tested, the results show a potential for a high-dose regimen of DTG as a rescue therapy in patients harbouring integrase strand transfer inhibitor resistant viruses.

Objective: To investigate the association between total, direct, and indirect bilirubin and the presence of carotid lesions in a large sample of HIV-1-infected patients on virological suppression., Design: Retrospective study on adult HIV-1-infected patients, with a carotid ultrasound (CUS) examination performed between January 2008 and August 2016, with HIV-RNA <50 copies per milliliter at CUS and without previous cardiovascular events., Methods: Intima media thickness was measured in 4 segments: carotid common artery and bifurcation on the left and right sides. Carotid lesion was defined as an intima media thickness ≥1.5 mm in ≥1 region at CUS. Patients were classified as: normal if all bilirubin values before CUS were below the upper normal limit and with hyperbilirubinemia if ≥1 bilirubin value above upper normal limit before CUS was recorded. Multivariate logistic regression was used to determine whether hyperbilirubinemia showed association with the presence of ≥1 carotid lesion, after adjusting for confounding factors., Results: Overall, 903 patients were evaluated, 511 with ≥1 and 392 without carotid lesions. At multivariate analysis, total [adjusted odds ratio (95% confidence interval) 0.57 (0.36 to 0.90), P = 0.016] and indirect hyperbilirubinemia before CUS [adjusted odds ratio (95% confidence interval) 0.62 (0.40 to 0.97), P = 0.036] were associated with a lower risk of carotid lesions in addition to younger age, negative hepatitis C virus antibodies, higher nadir CD4, lower low-density lipoprotein cholesterol, higher high-density lipoprotein cholesterol, lower triglycerides, and no use of statin; no effect of atazanavir treatment on carotid lesions was detected., Conclusions: In HIV-1-treated patients, total or indirect hyperbilirubinemia was likely associated with the absence of carotid lesions.

Purpose: To investigate if the regimen used when starting antiretroviral therapy (ART) affects the time spent with residual viraemia (RV) after achieving <50 HIV-RNA copies/mL., Methods: Retrospective cohort study on patients infected with human immunodeficiency virus (HIV), followed prospectively, who started ART with a boosted protease inhibitor (PI/r)-, a non-nucleoside reverse transcriptase inhibitor (NNRTI)- or an integrase inhibitor (InSTI)-based triple regimen, or a regimen with more than three drugs. RV was defined as any detectable polymerase chain reaction (PCR) signal <50 HIV-RNA copies/mL, as assessed by kinetic PCR or Abbott real-time PCR. The percentage of time spent with RV (%RV) was calculated as the cumulative follow-up time spent with RV on the observed follow-up, and was estimated using a generalized linear model., Results: Seven hundred and seventy-one patients (33%, 32%, 30% and 5% receiving PI/r-, NNRTI-, InSTI-based triple regimens, or a regimen with more than three drugs, respectively) were included in the analysis. After a median of 2.16 (interquartile range 1.27-3.16) years of follow-up, adjusted means of %RV were 37.9% [95% confidence interval (CI) 30.3-45.4%], 23.9% (95% CI 16-31.8%), 25.3% (95% CI 17.8-32.7%) and 45.5% (95% CI 34.6-56.4%) in the PI/r, NNRTI, InSTI and more than three drugs groups, respectively; %RV was significantly higher in patients who started ART with a regimen with more than three drugs (P=0.030), and was significantly lower in patients who started ART with an NNRTI-based regimen (P<0.0001) or an InSTI-based regimen (P=0.030) than in those who started ART with a PI/r-based regimen. %RV was independently associated with pre-ART HIV-RNA (P<0.0001), time to HIV-RNA <50 copies/mL (P<0.0001), NRTI backbone (P=0.037) and baseline HIV-RNA (P<0.0001)., Conclusion: First-line regimens based on PIs/r or on more than three drugs are associated with a greater percentage of time spent with RV after achieving virological suppression., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose of Review: In this review, we will highlight and discuss the recent efficacy and safety data of bictegravir (BIC), a novel second-generation integrase strand transfer inhibitor (INSTI) that has been recently approved, in coformulation with emtricitabine and tenofovir alafenamide (B/F/TAF), for the treatment of HIV-1 infection in antiretroviral naïve subjects and in those with suppressed viremia., Recent Findings: Preclinical data showed that BIC has a genetic barrier that is higher than that of raltegravir and elvitegravir but is similar to that of dolutegravir (DTG), with retained activity in vitro against isolates containing substitutions associated with resistance against other INSTIs. Its pharmacokinetic interaction risks appear to be low. Results of the phase 3 GS-US-380-1489 and GS-US-380-1490 clinical trials showed that the coformulation B/F/TAF is not inferior to the recommended DTG-containing regimens in naïve subjects. Moreover, B/F/TAF exhibited excellent tolerability, and no treatment-emergent resistance to any component of the coformulation was observed. In addition, preliminary data support switching from DTG and emtricitabine/tenofovir alafenamide or boosted protease inhibitor-containing regimens to B/F/TAF in subjects with undetectable viremia., Summary: The coformulation bictegravir/emtricitabine/tenofovir alafenamide is set to become a new option in the management of patients who are antiretroviral naïve and in those with suppressed viremia.