BACKGROUND/OBJECTIVES:Among the antiretroviral therapies (ARTs) recently introduced for people living with HIV (PLWH), the fixed-dose combination of bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) became reimbursable in Italy in June 2019. METHODS:This study evaluated drug utilization, healthcare resource consumption and direct costs among ART-naïve adults initiating B/F/TAF or other non-bictegravir-based regimens, identified from June 2019 to September 2022 within administrative databases of healthcare entities covering approximately nine million citizens. Baseline clinical characteristics at first ART prescription were compared across B/F/TAF-treated patients, those receiving other ART regimens, and non-HIV controls, while treatment outcomes during follow-up were evaluated among PLWH receiving B/F/TAF or other ARTs; healthcare consumption and costs were assessed after propensity score matching within the PLWH cohorts only. RESULTS:Overall, 374 individuals initiated B/F/TAF and 5576 other ARTs. Patients treated with B/F/TAF showed greater adherence and persistence, with multivariate analyses confirming a lower risk of discontinuation or switching (HR = 0.66, 95% CI 0.57-0.76, p < 0.001) and a higher likelihood of adherence (HR = 2.40, 95% CI 1.58-3.64, p < 0.001). After matching, the B/F/TAF group exhibited lower 12-month consumption of non-HIV medications, fewer non-HIV hospitalizations, and reduced total healthcare costs, particularly for non-HIV drug prescriptions compared to other ART users. CONCLUSIONS:Overall, B/F/TAF was associated with better treatment continuity and meaningful cost savings.

Background:The risk of developing low-level viral rebound (LLVR) after achieving human immunodeficiency virus HIV-1 (HIV) RNA suppression with 2-drug regimens (2DR) compared to 3-drug regimens (3DR) remains uncertain. Methods:We conducted a matched 1:3 case-control study nested within the ICONA cohort including persons with HIV (PWH) who achieved virological suppression (≥2 consecutive HIV-RNA ≤50 copies/mL over 6 months) after 11 November 2014 (baseline [BL]). Cases were defined as PWH experiencing a single HIV-RNA of 51-199 copies/mL after BL (index date); controls were defined as those who maintained HIV-RNA ≤50 copies/mL up to the index date and were matched for history of care gaps and number of drugs failed. The cumulative incidence of LLVR after virological suppression was estimated using Kaplan-Meier methods, and conditional logistic regression models were used to evaluate the association between the current antiretroviral therapy regimen (2DR [dolutegravir/lamivudine, dolutegravir/rilpivirine, dolutegravir/doravirine, or cabotegravir/rilpivirine] vs 3DR [dolutegravir, bictegravir, rilpivirine, doravirine, boosted darunavir, or boosted atazanavir-based with a backbone of tenofovir and lamivudine or emtricitabine]) and LLVR risk. In sensitivity analyses cases were defined as PWH experiencing 2 consecutive HIV-RNA of 51-199 copies/mL. Results:Among 1033 PWH (261 cases, 772 matched controls), 21% were female, median age was 43 (interquartile range [IQR], 34-51) years, and BL CD4 count was 601 (IQR, 379-826) cells/μL; 2DR use was 25% in cases versus 29% in controls (P = .23). Two years after viral suppression, cumulative LLVR incidence was 2.7% (95% CI, 2.3%-3.1%) when considering single LLVR events and 1.8% (95% CI, 1.4%-2.1%) when limited to 2 consecutive values. After adjusting for confounding, evidence for an association with current regimen was inconclusive (adjusted odds ratio, 0.86 [95% CI, .57-1.29]). Conclusions:Despite the wide range of plausibility, we can exclude a risk of LLVR higher than 29% when using 2DR versus 3DR regimens.

Modern ART is evolving, allowing the use of new drug formulations and alternative routes of administration to oral therapy. Long-acting (LA) cabotegravir and rilpivirine, the first fully injectable antiretroviral regimen approved for clinical use, is a test case for this new route of administration, and an innovation with implications for the quality of life of people with HIV (PWH). However, its use requires a reorganization of outpatient clinics and outpatient services, and a number of issues remain to be defined regarding the management of PWH on LA drugs, including the correct selection of people who can be treated with LA cabotegravir and rilpivirine. There is also ongoing debate about the best way to monitor both efficacy and tolerability of LA treatment and whether the management of virological failures and blips should be different from that reserved for oral regimens. The present article reviews the data on the use and management of LA cabotegravir and rilpivirine in different settings, with a review of clinical trial data and also the first available real-life experiences. The article focuses on the following: the reasons for the use of LA drugs; the implementation of their use in clinical practice; and the monitoring of treated people over time.

OBJECTIVES:This study evaluated the impact of pre-existing resistance-associated mutations (RAMs) to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) on treatment outcomes in people living with HIV (PWH) receiving bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in a real-world setting. METHODS:We conducted a single-centre, retrospective review of treatment-experienced adult PWH switched to B/F/TAF, comparing those with and without NRTI RAMs. The primary endpoint was virological success at week 96 (<50 HIV RNA copies/mL). Secondary endpoints were changes in absolute CD4+ counts and CD4+/CD8+ ratio. Continuous variables were analysed using the Wilcoxon rank sum test and categorical variables with the Chi-square or Fisher's exact test. Longitudinal changes in absolute CD4+ counts and CD4+/CD8+ ratio were assessed using linear mixed-effects models, accounting for repeated measurements over time. RESULTS:A total of 257 PWH were included, of whom 21 were viraemic at the time of switch; 41 had pre-existing NRTI RAMs, while no RAMs were documented in the remaining 216 participants. At week 96, virological suppression was achieved in 100% of individuals with RAMs and 97.2% of those without NRTI RAMs, respectively (P = ns). Absolute CD4+ counts increased in 44.4% of participants, with no significant impact of NRTI RAMs. The CD4+/CD8+ ratio showed an apparent increase of more than 50% in 73.2% and 62.0% of participants with and without NRTI RAMs, respectively. However, longitudinal trend analysis revealed a significant negative rate of change in both groups, which was less pronounced among participants with RAMs. CONCLUSIONS:B/F/TAF is an effective treatment option for PWH with NRTI RAMs.

In this study, we explored the link between gut impairment and severe COVID-19 in people with HIV (PWH). We compared PWH with COVID-19 to HIV-uninfected individuals hospitalized for the same condition. Despite more severe clinical symptoms in PWH, we did not observe significant differences in gut barrier dysfunction markers between the two groups. Our findings suggest a link between SARS-CoV-2 pneumonia and gut damage, independent of HIV status, warranting further investigation into its role in COVID-19 severity.

Introduction: Few data are available on the forgiveness of 2-drug (2DR) or low-barrier 3-drug antiretroviral regimens. The aim of this study is to evaluate the real-life forgiveness of lamivudine/dolutegravir (3TC/DTG) and emtricitabine/tenofovir alafenamide/rilpivirine (FTC/TAF/RPV). Methods: A 2-center retrospective observational study enrolled all people with HIV treated with 3TC/DTG or FTC/TAF/RPV. Adherence was measured as the proportion of days covered (PDC) by drug supply. Binary logistic regression was used to test the impact of baseline variables and adherence on the achievement of virological suppression. Results: In total, 1258 adult people with HIV were enrolled, 368 in 3TC/DTG and 890 in FTC/TAF/RPV. Most were men (71%), with a median age of 51 years (IQR 43-58 years) and a median CD4 nadir of 305 cells/mcL (IQR 132-485). Median cohort follow-up was 4558 persons/year. Median adherence, as calculated from PDC, was of 0.98 (IQR 0.93-1). Regardless of the treatment group, a PDC of 0.8 was sufficient to achieve HIV-RNA levels below 200 copies/mL in almost all study participants. With the same level of adherence, >90% of study participants achieved HIV-RNA below 50 copies/mL. PDC (P < 0.0001), Italian origin (P < 0.0001), and male sex (P = 0.038) were significantly correlated with achieving <200 copies/mL. Conclusions: In this study, we found a similar and high level of forgiveness with the INSTI-based 2-drug regimen 3TC/DTG and the NNRTI-based 3-drug regimen FTC/TAF/RPV.

Objectives: Treatment failures to modern antiretroviral therapy (ART) raise concerns, as they could re-duce 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 > 10 0 0 copies/mL) with or without ART change; ii) >= 2 treatment discontinuations (TD) due to toxic-ity/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. Treat-ment 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.(c) 2023 The Author(s). Published by Elsevier Ltd.

: Background : ART forgiveness is the ability of a regimen to maintain HIV-RNA suppression despite a documented imperfect adherence. We explored forgiveness of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). : Methods : In this retrospective cohort study pharmacy drug refills were used to calculate the proportion of days covered (PDC) as a proxy of adherence. Forgiveness was defined as the possibility to achieve a selected HIV-RNA threshold by a given level of imperfect adherence. A logistic model was applied to verify the impact of baseline variables and adherence on the virologic outcomes. : Results : We enrolled 420 adults. From them, 787 one-year time-periods were derived for a median cohort follow-up of 873 person/years. Most of them were males (73.1%); the most frequent risk factor for HIV infection was heterosexual contacts (49.5% of cases), followed by 22.5% MSM and 22.5% intravenous drug users. The median age of enrolled persons with HIV was 51 years (IQR 45-57 years); the median duration of HIV infection was 7.9 years (IQR 4-18 years) and the median nadir of CD4 cells was 277 cells/mcL (IQR 100-513 cells/mcL). Adherence showed a median of 0.97 (IQR 0.91-1.00), consequently only 17 time-periods (2.2%) in 17 different individuals (4.0%) showed HIV-RNA blood levels above 200 copies/ml. A PDC of 0.75 was sufficient to obtain in > 90% of cases the virologic outcome for both 200 copies/ml or 50 copies/ml. An adherence value of 0.85 obtained a positive response in virtually all subjects either for a cut-off of 50 or 200 copies/ml. : Conclusions : Long-term success of ART needs effective, well tolerated, friendly regimens. Adherence remains a crucial determinant of long-term success, but suboptimal adherence levels are relatively common. Given this, an elevated forgiveness plays a relevant role to further improve long-term outcomes and should be considered a fundamental characteristic of any antiretroviral regimen. B/F/TAF has been proved to have all of these characteristics.

Objective: To evaluate the efficacy and safety of 96 weeks of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) treatment in participants switching from dolutegravir (DTG)-based therapy. Design: Studies 1489 (NCT02607930) and 1490 (NCT02607956) were phase 3 randomized, double-blind, active-controlled, first-line therapy trials in people with HIV-1. After 144 weeks of DTG-based or B/F/TAF treatment, participants could enter a 96-week open-label extension (OLE) of B/F/TAF. Methods: A pooled analysis evaluated viral suppression (HIV-1 RNA <50 copies/ml) and changes in CD4(+) cell count at OLE Weeks 48 and 96, treatment-emergent resistance, safety, and tolerability after switch from a DTG-based regimen to B/F/TAF. Outcomes by prior treatment were summarized using descriptive statistics and compared by two-sided Wilcoxon rank sum test. Results: At OLE Week 96, participants who switched to B/F/TAF (N = 519) maintained high levels of virologic suppression (99.5 and 99.1% in those switching from DTG/abacavir/lamivudine and DTG+F/TAF, respectively) and CD4(+) cell count, with no treatment-emergent resistance to B/F/TAF. Twenty-one participants experienced drug-related adverse events after switching, with diarrhea, weight gain, and headache occurring most commonly. There were no cases of proximal renal tubulopathy, drug-related Grade 4 adverse events, or serious adverse events. Two participants discontinued B/F/TAF due to treatment-related adverse events. Participants who switched from DTG/abacavir/lamivudine experienced statistically significant greater weight gain than those who switched from DTG+F/TAF; however, median weight change from the blinded phase baseline to OLE Week 96 was numerically similar across treatment groups. Conclusion: This medium-term analysis demonstrates the safety and efficacy of switching to B/F/TAF from a DTG-containing regimen in people with HIV-1.

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.

Definitive data on the long-term success of the latest antiretroviral therapy (ART) strategies are still lacking. A panel of infectious diseases specialists was convened to develop a consensus on how to tailor and follow ART over time. Panelists used a Delphi technique to develop a list of statements describing preferred management approaches for ART and patient monitoring and quality of life evaluation. Ninety infectious diseases specialists from several Infectious Diseases Centers in Italy participated in the consensus process. A consensus was reached on virological and immunological parameters to use to monitor long-term efficacy of antiretroviral treatment, while there was no consensus on the use of specific inflammation and immune-activation markers in clinical routine. The panel agreed on the need for an antiretroviral treatment with the lowest impact on bone, kidney and cardiovascular toxicity and on the utility of quality-of-life monitoring during the standard follow up of people living with HIV. The consensus statements developed by a panel of infectious diseases specialists may provide guidance to practitioners for a person-centered approach aimed at obtaining long-term virological and clinical success for people living with HIV.

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.

Background: Meeting the challenge of antiretroviral therapy (ART) whose efficacy can last a lifetime requires continuous updating of the virological, pharmacological, and quality of life outcomes to be pursued and a continuous review of literature data on the efficacy and tolerability of new drugs and therapeutic strategies. Methods: With the aim of identifying open questions and answers about the current controversies in modern ART, we adapted the Design Thinking methodology to the needs of the design phase of a scientific article, involving a team of experts in HIV care. Results: Five main pillars of treatment success were discussed: sustained virologic suppression over time; immunological recovery; pharmacological attributes; long-term tolerability and safety of ART; and people’s satisfaction and quality of life. The definition of the outcomes to be achieved in each thematic area and the tools to achieve them were reviewed and discussed. Conclusions: Long-term treatment success should be intended as a combination of HIV-RNA suppression, immune recovery, and high quality of life. To achieve this, the regimen should be well-tolerated, with high potency, genetic barrier, and forgiveness, and should be tailored by a person-centered perspective, based on individual needs, preferences, and therapeutic history.

Background Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single-tablet regimen recommended for HIV-1 treatment. The safety and efficacy of B/F/TAF as initial therapy was established in two Phase 3 studies: 1489 (vs dolutegravir [DTG]/abacavir/lamivudine) and 1490 (vs DTG + F/TAF). After 144 weeks of randomized follow-up, an open-label extension evaluated B/F/TAF to 240 weeks. Methods Of 634 participants randomized to B/F/TAF, 519 completed the double-blinded treatment, and 506/634 (80%) chose the 96-week open-label B/F/TAF extension, which was completed by 444/506 (88%) participants. Efficacy was based on the secondary outcome of the proportion of participants with HIV-1 RNA <50 copies/mL at Week 240 by missing = excluded and missing = failure methods. All 634 participants who were randomized to B/ F/TAF and received at least one dose of B/F/TAF were included in efficacy and safety analyses. (Study 1489: ClinicalTrials.gov NCT02607930; EudraCT 2015-004024-54. Study 1490: ClinicalTrials.gov NCT02607956; EudraCT 2015-003988-10). Findings Of those with available virologic data, 98.6% (95% CI [97.0%-99.5%], 426/432) maintained HIV-1 RNA <50 copies/mL at Week 240 (missing = excluded); when missing virologic data were considered as failure, 67.2% (95% CI [63.4%-70.8%], 426/634) maintained HIV-1 RNA <50 copies/mL. Mean (SD) change in CD4+ count from baseline was +338 (236.2) cells/& mu;L. No treatment-emergent resistance to B/F/TAF was detected. Adverse events led to drug discontinuation in 1.6% (n = 10/634) of participants (n = 5 with events considered drug-related). No discontinuations were due to renal adverse events. Median (IQR) total cholesterol increased 21 (1,42) mg/dL from baseline; the change in total cholesterol:HDL was 0.1 (-0.5,0.6). Median (IQR) weight change from baseline was +6.1 kg (2.0, 11.7) at Week 240. In Study 1489, hip and spine bone mineral density mean percent changes from baseline were & LE;0.6%. Interpretation Through 5 years of follow-up, B/F/TAF maintained high rates of virologic suppression with no treatment-emergent resistance and rare drug discontinuations due to adverse events. These results demonstrate the durability and safety of B/F/TAF in people with HIV.