The future of long-acting cabotegravir plus rilpivirine therapy: deeds and misconceptions

HIV infection is currently managed as a chronic disease because of improvements in antiretroviral therapy (ART). Switching to a new regimen is a natural event during long-term therapy to avoid problems related to toxicity, adherence, failure, and potential selection of drug resistance. The development of co-formulations of multiple agents in one pill, and novel drug classes and drugs with a high genetic barrier to resistance have been important in this context. The approval of the long-acting, once-monthly or bimonthly injectable combination of the second-generation strand transfer integrase inhibitor (InSTI), cabotegravir (CAB) together with the non-nucleoside reverse transcriptase inhibitor (NNRTI), rilpivirine (RPV) represents the most recent achievement in the search for potent and convenient ART. Several pivotal trials (such as LATTE-2, ATLAS, FLAIR, and ATLAS-2M) showed the high efficacy and safety of this long-acting formulation used as an induction-maintenance strategy. Few confirmed virological failures (CVF) have been observed. The combination of at least two of the following baseline factors, HIV-1 subtype A6/A1, a body mass index (BMI) ≥30 kg/m2, and RPV resistance-associated mutations, was associated with an increased risk of CVF at week 48. The data indicate that this long-acting therapeutic strategy is attractive and potent; therefore, defining the most appropriate patient for this treatment and how to handle practical issues is warranted

Is HAART based on newest active antiretroviral drugs influenced by GSS

Methods Major enrollment criterion was the administration of maraviroc, enfuvirtide, raltegravir, etravirine, darunavir/r or tipranavir/r, alone or in combination, in the latest antiretroviral regimen, decided upon the last genotypic RNA resistance test. This allowed us to assess the genotypic sensitivity score (GSS) at the same time. We also recorded previous presence of specific mutations in all available genotypic resistance tests, their persistence in time and their correlation to the last GSS

Positron emission tomography response and minimal residual disease impact on progression-free survival in patients with follicular lymphoma. A subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi

The aim of the present study was to analyze the prognostic role of combined PET and BCL2/IGH analysis, performed at the EOT, in a subset study of the phase III trial FOLL05 (NCT00774826), in which patients with FL were randomized to R-CVP (rituximab plus cyclophosphamide, vincristine and prednisone), R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) or R-FM (rituximab plus fludarabine and mitoxantrone).6 This study was conducted in compliance with the Declaration of Helsinki, was approved by the appropriate research ethics committee, and required each patient to provide written informed consent

Reduced probability of improving viro-immunological state in subjects with vertical transmission of HIV reaching adult age: A multicenter retrospective cohort study

Introduction: Young adults with vertical transmission (VT) of human immunodeficiency virus (HIV) represent a fragile population. This study evaluates factors associated with viro-immunological outcome of these patients. Methods: We performed a multicenter study including HIV-infected subjects with VT ≥ 18 years old from six Italian clinics. Subjects were observed from birth to death, lost to follow-up, or last visit until December 31, 2019. Condition of "optimal viro-immunological status" (OS) was defined as the simultaneous presence of HIV ribonucleic acid (RNA) < 50 copies/mL, CD4+ > 500 cells/mm3 , and CD4+/CD8+ ratio ≥ 1. Results: A total of 126 subjects were enrolled. At 18 years of age, 52/126 (44.4%) had HIV-RNA > 50 copies/mL, 47/126 (38.2%) had CD4+ < 500/mm3 , and 78/126 (67.2%) had CD4+/CD8+ < 1; 28 subjects (23.7%) presented in the condition of OS. Having a CD4+/CD8+ ratio ≥ 1 at 18 years of age was related with an increased probability of shift from suboptimal viro-immunological status (SOS) to OS (HR: 7.7, 95% confidence interval [CI]: 4.23-14.04), and a reduced risk of shift from the OS to the SOS (HR: 0.49, 95% CI: 0.26-0.92). Acquired immunodeficiency syndrome (AIDS) diagnosis significantly reduced the probability of shift from a viro-immunological SOS to OS (HR: 0.09, 95% CI: 0.03-0.30). Subjects who had not achieved an OS at 18 years of age had an increased risk of discontinuation of combination antiretroviral therapy (cART, p = .019). Conclusions: Only a small proportion of subjects with VT of HIV reached the adult age with "OS". Transition to the adult care with a compromised viro-immunological condition represents a negative driver for future optimal infection control, with a higher risk of discontinuation of cART and a reduced probability to improve the immunological status later in the years

Atazanavir/ritonavir monotherapy as maintenance strategy in HIV-1 treated subjects with viral suppression: 96-week analysis results of the MODAT study

The 48-week interim analysis of the MODAT study showed that confirmed virologic failure (CVF) was more frequent in patients simplifying to ATV/r monotherapy compared to maintaining ATV/r-based triple therapy. The DSMB recommended stopping study enrollment but continuing follow-up of enrolled patients. We present the 96-week efficacy analysis

Simulating the development and progression of Chronic Kidney Disease and osteoporosis in people living with HIV

The "chronicization" of HIV infection brings about a growing necessity to attentively evaluate current and potential complications when prescribing the individual therapeutic regimen. Starting from this need, we developed two HIV-comorbidity simulators that, basing on the evidence available in medical literature and starting from the current clinical and demographic features of the individual patient, project and compare the risks of developing and worsening of nephropathy and osteopathy associated with possible ARV regimens. These simulators are embedded in a desktop, user-friendly software thought to be used by the treating physician during prescription discussion with his/her patients, in order to highlight expected clinical outcomes and healthcare resource consumption that may differ according to the therapeutic strategy selected. In this article we present the sources and methods used in developing the mathematical models, alongside a set of examples and the results of cohort-level validation runs

Evaluation of plan complexity and dosimetric plan quality of total marrow and lymphoid irradiation using volumetric modulated arc therapy

PurposeTo assess the impact of the planner's experience and optimization algorithm on the plan quality and complexity of total marrow and lymphoid irradiation (TMLI) delivered by means of volumetric modulated arc therapy (VMAT) over 2010-2022 at our institute. MethodsEighty-two consecutive TMLI plans were considered. Three complexity indices were computed to characterize the plans in terms of leaf gap size, irregularity of beam apertures, and modulation complexity. Dosimetric points of the target volume (D2%) and organs at risk (OAR) (Dmean) were automatically extracted to combine them with plan complexity and obtain a global quality score (GQS). The analysis was stratified based on the different optimization algorithms used over the years, including a knowledge-based (KB) model. Patient-specific quality assurance (QA) using Portal Dosimetry was performed retrospectively, and the gamma agreement index (GAI) was investigated in conjunction with plan complexity. ResultsPlan complexity significantly reduced over the years (r = -0.50, p < 0.01). Significant differences in plan complexity and plan dosimetric quality among the different algorithms were observed. Moreover, the KB model allowed to achieve significantly better dosimetric results to the OARs. The plan quality remained similar or even improved during the years and when moving to a newer algorithm, with GQS increasing from 0.019 +/- 0.002 to 0.025 +/- 0.003 (p < 0.01). The significant correlation between GQS and time (r = 0.33, p = 0.01) indicated that the planner's experience was relevant to improve the plan quality of TMLI plans. Significant correlations between the GAI and the complexity metrics (r = -0.71, p < 0.01) were also found. ConclusionBoth the planner's experience and algorithm version are crucial to achieve an optimal plan quality in TMLI plans. Thus, the impact of the optimization algorithm should be carefully evaluated when a new algorithm is introduced and in system upgrades. Knowledge-based strategies can be useful to increase standardization and improve plan quality of TMLI treatments

Automatic planning of the lower extremities for total marrow irradiation using volumetric modulated arc therapy

Purpose Total marrow (and lymphoid) irradiation (TMI-TMLI) is limited by the couch travel range of modern linacs, which forces the treatment delivery to be split into two plans with opposite orientations: a head-first supine upper-body plan, and a feet-first supine lower extremities plan. A specific field junction is thus needed to obtain adequate target coverage in the overlap region of the two plans. In this study, an automatic procedure was developed for field junction creation and lower extremities plan optimization. Methods Ten patients treated with TMI-TMLI at our institution were selected retrospectively. The planning of the lower extremities was performed automatically. Target volume parameters (CTV_J-V-98% > 98%) at the junction region and several dose statistics (D-98%, D-mean, and D-2%) were compared between automatic and manual plans. The modulation complexity score (MCS) was used to assess plan complexity. Results The automatic procedure required 60-90 min, depending on the case. All automatic plans achieved clinically acceptable dosimetric results (CTV_J-V-98% > 98%), with significant differences found at the junction region, where D-mean and D-2% increased on average by 2.4% (p < 0.03) and 3.0% (p < 0.02), respectively. Similar plan complexity was observed (median MCS = 0.12). Since March 2022, the automatic procedure has been introduced in our clinic, reducing the TMI-TMLI simulation-to-delivery schedule by 2 days. Conclusion The developed procedure allowed treatment planning of TMI-TMLI to be streamlined, increasing efficiency and standardization, preventing human errors, while maintaining the dosimetric plan quality and complexity of manual plans. Automated strategies can simplify the future adoption and clinical implementation of TMI-TMLI treatments in new centers

Switch to maraviroc with darunavir/r, both QD, in patients with suppressed HIV-1 was well tolerated but virologically inferior to standard antiretroviral therapy: 48-Week results of a randomized trial

Objectives Primary study outcome was absence of treatment failure (virological failure, VF, or treatment interruption) per protocol at week 48. Methods Patients on 3-drug ART with stable HIV-1 RNA <50 copies/mL and CCR5-tropic virus were randomized 1:1 to maraviroc with darunavir/ritonavir qd (study arm) or continue current ART (continuation arm).Results In June 2015, 115 patients were evaluable for the primary outcome (56 study, 59 continuation arm). The study was discontinued due to excess of VF in the study arm (7 cases, 12.5%, vs 0 in the continuation arm, p = 0.005). The proportion free of treatment failure was 73.2% in the study and 59.3% in the continuation arm. Two participants in the study and 10 in the continuation arm discontinued therapy due to adverse events (p = 0.030). At VF, no emergent drug resistance was detected. Co-receptor tropism switched to non-R5 in one patient. Patients with VF reported lower adherence and had lower plasma drug levels. Femoral bone mineral density was significantly improved in the study arm. Conclusion Switching to maraviroc with darunavir/ritonavir qd in virologically suppressed patients was associated with improved tolerability but was virologically inferior to 3-drug therap