Cabotegravir plus rilpivirine long-acting (CAB + RPV-LA) injectable therapy marks a major milestone in HIV care, offering an efficacious, well-tolerated alternative to daily oral antiretroviral treatment. This article reviews data from pivotal trials and observational studies of CAB + RPV-LA, addressing emerging questions and highlighting key research priorities. We examine factors influencing virological outcomes, including issues related to HIV subtype, archived drug resistance, body mass index, and pharmacokinetics, and discuss challenges related to hepatitis B virus immunity and infection, pregnancy, and adherence. We outline strategies to address barriers to implementation, advocating for a tailored approach to maximize the potential of CAB + RPV-LA in improving outcomes across diverse populations with HIV.

KIR3DS1 is an activating natural killer (NK) cell receptor gene– present in 10-40% of humans– and is associated with extended AIDS-free survival. Although its ligand HLA-F has been identified, the underlying protective mechanism in HIV-1 is not yet understood. We sought to uncover the role of the KIR3DS1/HLA-F axis through investigating HLA-F surface and transcriptional changes during acute and chronic HIV-1 infection. HLA-F+ CD4 T cells were detected in people living with HIV (PLHIV) without antiretroviral treatment (N=102) and frequencies correlated with viremia but not with CD4 T cell count. Single-cell transcriptome analyses of PLHIV following acute HIV-1 acquisition revealed increased HLA-F mRNA levels in CD4 T cells associated with innate signaling signatures. In vitro, HLA-F mRNA was upregulated in both HIV-1–infected and bystander CD4 T cells. Functional studies demonstrated that bystander-activated CD4 T cells were reduced in the presence of NK cells during HIV-1 infection, and depleting NK cells increased the frequency of HLA-F+ CD4 T cells. Genotyping of our cohort revealed that KIR3DS1+ PLHIV exhibited significantly lower frequencies of HLA-F+ CD4 T cells. Taken together, these results establish HLA-F as a novel marker of innate T cell activation that is linked to HIV-1 viremia and suggest an immunoregulatory role of NK cells in controlling HIV-1-mediated inflammation by killing activated bystander CD4 T cells.

Background Virologic failure (VF) is still a major concern in the use of cabotegravir (CAB) and rilpivirine (RPV) long-acting (LA) for many healthcare professionals (HCP). While many results from clinical trials have been published, there is suspicion that they might underestimate the risk under less-controlled real-life conditions. This study aimed to estimate the probability of VF (primary objective) as well as discontinuation for any reason (secondary objective) among people with HIV (PWH) on CAB and RPV LA every two months (Q2M) in real life using Bayesian methodology.  Methods Bayesian estimation of VF based on prior knowledge about VF and discontinuation on CAB and RPV Q2M from randomized controlled trials (ATLAS-2M, SOLAR) and real-world data from CAB and RPV LA from a large single-center cohort. Results Among 175 PWH, two (1.1%) met the criteria of VF through week 48 (W48), resulting in an estimated risk of VF at W48 of 1.2% [0.6%; 1.9%] using Bayesian estimation. In one of the PWH, two-class resistance was observed at the time of VF, most likely being therapy emerging.  The probability of discontinuation for any reason by W48 was 21.4%, leading to a Bayesian risk estimate of 8.9% [7.3%; 10.5%]. The main reasons for discontinuation were injection-site reactions (n=10). Conclusions Risk of VF on CAB and RPV LA under real-life conditions seems to be comparable to results in clinical trials. This finding can be reassuring for both PWH and HCPs considering CAB and RPV LA as an alternative to oral antiretroviral treatment, particularly when considering the risk factors for VF that have been identified from the cases of VF in the clinical trials for patient selection. At the same time, rates of discontinuation may be considerably higher. However, this does not seem to be an indicator of a worse safety profile outside clinical trials, but probably could be the result of making CAB and RPV LA available to a wider population of PWH.

BackgroundDrug-sparing antiretroviral treatment (ART) regimens are gaining interest in the treatment of HIV-1. Dolutegravir (DTG), a second-generation integrase inhibitor, has been pivotal in this development, allowing treatment with fewer drugs while maintaining virologic control. This study aimed to analyze and compare treatment persistence in people with HIV (PWH) on DTG-based two-drug regimens (2DRs) and three-drug regimens (3DRs) at an HIV center in Munich, Germany.MethodsRetrospective, observational, longitudinal analysis using electronic patient records at MVZ München am Goetheplatz. All people with HIV-1 receiving DTG-containing ART regimens-combined with rilpivirine (RPV) or lamivudine (3TC) for 2DRs, or with tenofovir (TAF or TDF) and emtricitabine (FTC), or abacavir (ABC) and FTC for 3DRs-were included. Exclusion criteria included HIV-2 infection or concomitant use of other antiretroviral drugs. The primary endpoint was the comparison of time-to-discontinuation between 2DRs and 3DRs. Secondary endpoints included an analysis of reasons for discontinuation. Kaplan-Meier estimates, log-rank tests, and accelerated failure time (AFT) models were used for statistical analysis.ResultsOverall, 854 individuals were included in the study, with 462 (54.1%) on a 2DR. For the primary endpoint, 141 events occurred. In the unadjusted analysis, treatment persistence was significantly longer in the 2DR group compared to the 3DR group (p = .005, log-rank test). Median persistence was not reached in either group. In AFT models, being on a 2DR was associated with a 74.9% (23.0%-126.8%), 85.7% (30.5%-140.8%), and 98.0% (36.7%-159.0%) longer time-to-discontinuation in the unadjusted, partially adjusted (sex, age, route of transmission), and fully adjusted models (additionally adjusted for CD4 nadir and baseline resistance) after multiple imputation, respectively. For the secondary endpoint, 196 events occurred. Persistence on 2DRs and 3DRs was found to be comparable (p = .190). Reasons for discontinuation included cardiovascular risk, unspecified side effects, gastrointestinal side effects, impaired kidney function, weight gain, convenience (switch to a single-tablet regimen), and other factors. Weight gain (p = .018), impaired renal function (p = .008), cardiovascular risk (p = .004), unspecified side effects (p = .003), gastrointestinal side effects (p = .003), and switching to a single-tablet regimen (p < .001) remained significant after adjusting for multiple testing.ConclusionsThis study found significant associations between the type of antiretroviral treatment regimen (2DR or 3DR) and time-to-discontinuation. DTG-based 2DRs were associated with significantly longer treatment persistence compared to 3DRs, as confirmed in parametric and non-parametric time-to-event analyses and after adjusting for baseline differences. Virologic efficacy was comparable between the two regimens, aligning with previous studies. The main drivers of higher discontinuation rates in 3DRs were side effects, supporting the hypothesis that drug-sparing regimens might contribute to better tolerability and lower toxicity. These findings suggest that drug-sparing regimens could lead to improved long-term treatment adherence. However, the study's retrospective nature and center-specific characteristics may limit generalizability. More real-world data are warranted to confirm these results.

Cabotegravir (CAB) and rilpivirine (RPV) constitute the first complete non-oral ART regimen for HIV-1 treatment. Due to virologic failure (VF) with resistance in clinical trials, concerns persist regarding broader use in clinical practice. In particular, the role of trough drug concentrations in relation to viremia and VF remains unclear. This study explored the association between CAB and RPV trough concentrations in a retrospective, single-center study. We retrospectively analyzed data from the HIV research and clinical care center MVZ München am Goetheplatz, Germany. Inclusion criteria were CAB and RPV long-acting therapy every 8 weeks without additional ART and availability of drug concentrations within 7 days before the next administration. A modified Wilcoxon test assessed differences in concentrations between samples with HIV-1 RNA < 20 vs. ≥20 copies/mL. Odds ratios (ORs) were estimated using generalized estimation equation (GEE) models, and ROC analysis identified potential alternative drug concentration thresholds. A total of 737 samples from 185 individuals were included. Median CAB concentrations were 1,480 µg/L (IQR: 1,097–1,955) vs. 1,180 µg/L (879–1,570) for samples with HIV-1 RNA levels < 20 copies/mL vs. ≥ 20 copies/mL, respectively (p = 0.001); for RPV, 77 µg/L (53–107) vs. 63 µg/L (47–87) (p = 0.001). Using ROC-derived thresholds, low concentrations of CAB (< 1,240 µg/L) or RPV (< 76 µg/L) were found in 11.5

OBJECTIVES:This post-hoc evaluation of the DUALIS study aimed to examine cardiovascular risk and the achievement of low-density lipoprotein cholesterol (LDL-C) targets in a virologically suppressed cohort of people living with HIV in Germany. METHODS:Baseline cardiovascular risk was assessed using the European Society of Cardiology (ESC)-Systematic COronary Risk Evaluation 2 (SCORE2)/SCORE2-Older Persons (OP) and the current ESC guideline-recommended LDL-C targets among participants aged ≥40 years in the DUALIS study. Risk categorization was based on the ESC-SCORE2/SCORE2-OP results and the presence of specific comorbidities indicative of high risk and very high risk of CVD. Participants were enrolled between July 2015 and June 2017. RESULTS:The use of lipid-lowering therapy (LLT) was low in the DUALIS study, with 12 out of 188 participants (6%) receiving the treatment. The median ESC-SCORE2/SCORE2-OP was 5.0%. Overall, 92 participants (49%) had low-to-moderate CVD risk, 77 (41%) high risk, and 19 (10%) very high risk. Only one participant in the high-risk group and none in the very high-risk group met the guideline-recommended LDL-C targets. Even when using the less stringent LDL-C targets valid at the time of data collection (2016 ESC guideline), only 19.7% of the high-risk and none of the very high-risk participants met these targets. In addition, a strong correlation regarding the estimated CVD risk was observed between the D:A:D (R) and ESC SCORE2/SCORE2-OP scores (r = 0.95). CONCLUSIONS:The achievement of guideline-recommended LDL-C targets was low in the high- and very high-CVD-risk groups in the DUALIS study, reflecting low utilization of LLT in clinical practice.

Currently available antiretroviral 2-drug regimen (2DR) fixed dose combinations may not be suitable for specific situations including the presence of resistance associated mutations (RAM) or drug − drug interactions (DDI). The data on the use of the non-nucleoside reverse transcriptase inhibitor doravirine (DOR) and the integrase inhibitor dolutegravir (DTG) as an alternative 2DR remain scarce. People living with HIV with DOR + DTG as a 2DR are being followed in a prospective observational study. This analysis describes 85 participants with a median age of 57 years. Median CD4-nadir was 173/µl and a majority (66

Eine hohe Anzahl von Menschen, die mit HIV leben, werden erst in einem fortgeschrittenen Stadium der Infektion diagnostiziert, was mit einer erhöhten Morbidität, Mortalität sowie erhöhten Kosten einhergeht. Ziel der FindHIV Studie ist die Entwicklung eines Scoring-Instrumentes zur Beförderung einer frühzeitigen Diagnose von HIV Infektionen. Bundesweit wurden Daten von Menschen mit neuer HIV Diagnose in den letzten 6 Monaten zu Symptomen und Erkrankungen erhoben, die als verpasste Chancen einer früheren HIV Diagnosestellung gewertet werden können. Basierend auf den Ergebnissen wurde ein Scoring-Instrument zur Beförderung einer frühzeitigen HIV Diagnosestellung entwickelt, welches in Fokusgruppen diskutiert und daraufhin angepasst wurde. Die am häufigsten angegebenen Symptome/Erkrankungen mit verpassten Chancen einer Diagnose der HIV Infektion wurden in das Scoring-Instrument aufgenommen. Dazu zählten ungeklärter Gewichtsverlust, ungeklärtes Fieber oder Nachtschweiß, allgemeine Leistungsminderung, Hautausschlag, chronische Durchfälle ohne nachgewiesene Erreger, akuter hochfieberhafter Infekt, Lymphadenopathie, sexuell übertragbare Erkrankungen, Indikator-/HIV-assoziierte Erkrankungen sowie AIDS-definierende Erkrankungen. Zusätzlich zum Scoring-Instrument wurden Handlungsempfehlungen erstellt. Das entwickelte Scoring-Instrument hat das Potential, Aufmerksamkeit für die HIV-Infektion zu schaffen und bei Anwendung eine frühzeitige Diagnosestellung zu befördern.

Delayed HIV diagnosis at advanced stages of disease remains common (33%-64%). This analysis of the multi-center FindHIV study including newly diagnosed HIV-infected adults in Germany, focused on the potential role of socio-demographic and psychological factors on late diagnosis (formerly "late presentation", AIDS diagnosis or CD4 cells <350/mu L). These data were collected from patient profiles, physician-patient interviews and questionnaires. Participating centers (n = 40) represented the diverse health care settings in HIV care and geographic regions. Of 706 newly diagnosed adults (92% male, median age 39 years) between 2019 and 2020, 55% (388/706) were diagnosed late with a median CD4 cell count of 147/mu L; 20% (142/706) presented with AIDS. From the physicians' perspective, earlier diagnosis would have been possible in 45% of participants (late versus non-late presentation 58% versus 29%). The most common physician-perceived reason was an underestimated risk for HIV infection by the patient (37%). In multivariable logistic regression analysis, older age, sexual contacts with both sexes as possible route of HIV transmission, being married, and a poor level of knowledge about HIV treatment were found to be associated with a significantly elevated risk for late presentation. Education, employment status, sexual relations, migration background and personality traits were not.

The DUALIS study demonstrated efficacy and safety of switching to dolutegravir plus ritonavir-boosted darunavir (DRV/r) (2DR) as compared to standard-of-care-therapy with two nucleoside reverse transcriptase inhibitors + DRV/r (3DR) in pretreated people living with HIV (PLWH), 48 weeks after switching. This DUALIS sub-study investigates health-related-quality-of-life (HrQoL) in this study-population. The Hospital Anxiety and Depression Scale (HADS) and the Medical Outcome Survey-HIV (MOS-HIV) were used assessing anxiety and depression symptoms, respectively HrQoL. Data were collected at baseline, 4, 24, and 48 weeks after randomization. Outcome scores were dichotomized and used as criteria in longitudinal models identifying differential developments. Odds ratios (ORs) with 95% confidence intervals (CIs) were computed as main measures of effects. ORs<1 indicate better results for HADS, and worse for MOS-HIV scores in the 2DR compared to 3DR group. In total, 263 subjects were randomized and treated (2DR n=131, 3DR n=132; median age 48 years). Significant different progressions could only be found for HADS-Depression scores (OR=.87, 95% CI: .78, .98, p=.02). While HADS-Depression scores decreased in the 2DR group, they increased in 3DR group. This sub-study showed no disadvantages regarding HrQoL in PLWH after switching to DTG+DRV/r. Considering lifelong requirements for antiretroviral medication, close attention to HrQL is required.

NK cells play a pivotal role in viral immunity, utilizing a large array of activating and inhibitory receptors to identify and eliminate virus-infected cells. Killer-cell immunoglobulin-like receptors (KIRs) represent a highly polymorphic receptor family, regulating NK cell activity and determining the ability to recognize target cells. Human leukocyte antigen (HLA) class I molecules serve as the primary ligand for KIRs. Herein, HLA-C stands out as being the dominant ligand for the majority of KIRs. Accumulating evidence indicated that interactions between HLA-C and its inhibitory KIR2DL receptors (KIR2DL1/L2/L3) can drive HIV-1-mediated immune evasion and thus may contribute to the intrinsic control of HIV-1 infection. Of particular interest in this context is the recent observation that HIV-1 is able to adapt to host HLA-C genotypes through Vpu-mediated downmodulation of HLA-C. However, our understanding of the complex interplay between KIR/HLA immunogenetics, NK cell-mediated immune pressure and HIV-1 immune escape is still limited. Therefore, we investigated the impact of specific KIR/HLA-C combinations on the NK cell receptor repertoire and HIV-1 Vpu protein sequence variations of 122 viremic, untreated HIV-1+ individuals. Compared to 60 HIV-1- controls, HIV-1 infection was associated with significant changes within the NK cell receptor repertoire, including reduced percentages of NK cells expressing NKG2A, CD8, and KIR2DS4. In contrast, the NKG2C+ and KIR3DL2+ NK cell sub-populations from HIV-1+ individuals was enlarged compared to HIV-1- controls. Stratification along KIR/HLA-C genotypes revealed a genotype-dependent expansion of KIR2DL1+ NK cells that was ultimately associated with increased binding affinities between KIR2DL1 and HLA-C allotypes. Lastly, our data hinted to a preferential selection of Vpu sequence variants that were associated with HLA-C downmodulation in individuals with high KIR2DL/HLA-C binding affinities. Altogether, our study provides evidence that HIV-1-associated changes in the KIR repertoire of NK cells are to some extent predetermined by host KIR2DL/HLA-C genotypes. Furthermore, analysis of Vpu sequence polymorphisms indicates that differential KIR2DL/HLA-C binding affinities may serve as an additional mechanism how host genetics impact immune evasion by HIV-1.