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Latency reversal agents (LRAs) have proven to induce HIV-1 transcription in vivo but are ineffective at decreasing the size of the latent reservoir in antiretroviral treated patients. The capacity of the LRAs to perturb the viral reservoir present in distinct subpopulations of cells is currently unknown. Here, using a new RNA FISH/flow ex vivo viral reactivation assay, we performed a comprehensive assessment of the viral reactivation capacity of different families of LRAs, and their combinations, in different CD4+ T cell subsets. We observed that a median of 16.28% of the whole HIV-reservoir induced HIV-1 transcripts after viral reactivation, but only 10.10% of these HIV-1 RNA+ cells produced the viral protein p24. Moreover, none of the LRAs were powerful enough to reactivate HIV-1 transcription in all CD4+ T cell subpopulations. For instance, the combination of Romidepsin and Ingenol was identified as the best combination of drugs at increasing the proportion of HIV-1 RNA+ cells, in most, but not all, CD4+ T cell subsets. Importantly, memory stem cells were identified as highly resistant to HIV-1 reactivation, and only the combination of Panobinostat and Bryostatin-1 significantly increased the number of cells transcribing HIV within this subset. Overall, our results validate the use of the RNA FISH/flow technique to assess the potency of LRAs among different CD4+ T cell subsets, manifest the intrinsic differences between cells that encompass the latent HIV reservoir, and highlight the difficulty to significantly impact the latent infection with the currently available drugs. Thus, our results have important implications for the rational design of therapies aimed at reversing HIV latency from diverse cellular reservoirs.

Background. It is unknown if tenofovir disoproxil fumarate (TDF), which is often coformulated with the lipid-neutral emtricitabine (FTC), has a lipid-lowering effect. Methods. We performed a randomized, crossover, double-blind, placebo-controlled clinical trial on human immunodeficiency virus type 1 (HIV-1)–infected subjects with HIV-1 RNA < 50 copies/mL during ≥6 months on stable darunavir/ritonavir (800/100 mg once daily) or lopinavir/ritonavir (400/100 mg twice daily) monotherapy, fasting total cholesterol (TC) ≥200 mg/dL or low-density lipoprotein cholesterol (LDL-c) ≥130 mg/dL, and no lipid-lowering drugs. In arm 1, TDF/FTC was added for 12 weeks, followed by 12 weeks of placebo (washout) and 12 additional weeks of placebo (placebo period). Subjects in arm 2 added placebo for 12 weeks (placebo period) followed by TDF/FTC for 12 weeks and placebo for 12 additional weeks (washout). The primary endpoint was change in median fasting TC levels. Results. Of 46 subjects enrolled, 56% received darunavir/ritonavir and 44% lopinavir/ritonavir. Exposure to TDF/FTC reduced TC from 234 to 205 mg/dL (P < .001), LDL-c from 155 to 128 mg/dL (P < .001), and high-density lipoprotein cholesterol (HDL-c) from 50.3 to 44.5 mg/dL (P < .001). It also decreased the proportion of subjects with fasting TC ≥200 mg/dL from 86.7% to 56.8% (P = .001), and LDL-c ≥130 mg/dL from 87.8% to 43.9% (P < .001). After 12 weeks, TDF/FTC exposure was associated with lower TC and LDL-c levels than placebo (P = .001 and P = .002, respectively). The TC/HDL-c ratio and triglyceride levels did not change with TDF/FTC exposure. Conclusions. Coformulated TDF/FTC has an intrinsic lipid-lowering effect, likely attributable to TDF. Clinical Trials Registration. NCT01458977.

Elite controllers (ECs), a unique group of people with HIV (PWH), exhibit remarkable control of viral replication in the absence of antiretroviral therapy. In this study, we comprehensively characterized the NK cell repertoire in ECs after long-term viral control. Phenotypic profiling of NK cells revealed profound differences compared with other PWH, but marked similarities to uninfected individuals, with a distinctive prevalence of NKG2C+CD57+ memory-like NK cells. Functional analyses indicated that ECs had limited production of functional molecules upon NK stimulation and consequently reduced natural cytotoxicity against non-HIV target cells. Importantly, ECs showed an exceptional ability to kill primary HIV-infected cells by the antibody-dependent cell cytotoxicity adaptive mechanism, which was achieved by a specific memory-like NK population expressing CD16, NKG2A, NKG2C, CD57, and CXCR3. In-depth single-cell RNA-seq unveiled a unique transcriptional signature in these NK cells linked to increased cell metabolism, migration, chemotaxis, effector functions, cytokine secretion, and antiviral response. Our findings underscore a pivotal role of NK cells in the immune control of HIV and identify specific NK cells as emerging targets for immunotherapies.

IntroductionThe objective was to characterize real-world outcomes of drug–drug interactions (DDIs) between antiretrovirals (ARVs) and other drugs, including over-the-counter medications (OTC), and treatment outcomes in clinical practice.Methodswww.clinicalcasesDDIs.com is an open-access website for healthcare providers to consult and briefly describe real-world clinical cases on DDI with ARVs. We reviewed all the clinical cases reported to the website between March 2019 and May 2023.ResultsA total of 139 cases were reported, mostly involving ritonavir or cobicistat (boosters; 74 cases), unboosted integrase inhibitors (InSTI; 29 cases), and non-nucleoside reverse transcriptase inhibitors (NNRTI; 23 cases). Central nervous system drugs (29 cases) and cardiovascular drugs (19 cases) were the most frequently described co-medications. Notably, OTC medications were implicated in 27 cases, including mineral supplements (11 cases), herbals (8 cases), weight loss drugs (4 cases), anabolic steroids (3 cases), and recreational drugs (1 case). OTC acted as the perpetrator drug in 21 cases, leading to loss of ARV efficacy in 17 instances (mineral supplements in 10 cases, weight loss drugs in 4 cases, herbals in 3 cases). Additionally, toxicity was reported in 4 out of 6 cases where OTC was considered the victim drug of the DDI (anabolic steroids in 3 cases, MDMA in 1 case).ConclusionsFrequent unwanted outcomes resulting from DDIs between ARVs and OTC medications underscore the importance of integrating non-prescription drugs into medication reconciliation. The real-world data available through www.clinicalcasesDDIs.com serves as a valuable resource for assessing the clinical relevance of DDIs.

Background Randomized, placebo-controlled clinical trials (RCTs) that include analytical treatment interruptions (ATI) are conducted to test the efficacy of HIV cure strategies. Two independent RCTs, AELIX-002 and AELIX-003, evaluated the HTI immunogen-based vaccines alone or combined with the TLR7 agonist vesatolimod in early-treated people with HIV (etPWH). These studies individually demonstrated that higher levels of vaccine-induced HTI-specific T-cell responses were associated with extended time off antiretroviral therapy (ART) during a 24-week ATI. Methods We conducted a pooled analysis of both RCTs including the individual data of a total of 88 participants. The association between clinical, immunogenicity and viral data and rebound outcomes during the ATI was evaluated using logistic regression and receiver operating characteristic (ROC) analyses. Results We identify an HTI-specific threshold of 835 spot-forming cells/10 6 peripheral blood mononuclear cells as a predictor of delayed and slower viral rebound during ATI. This threshold distinguishes participants who remain off ART for >12 weeks, with 58% sensitivity, 85% specificity, 75% positive and 73% negative predictive value. Conclusions These findings confirm that HTI-specific T-cell magnitude at ATI initiation is the strongest predictor of ATI outcomes observed in AELIX002/003 studies and that a threshold of vaccine-induced HTI-specific T-cell responses can be used as futility criteria before ATI and/or guide participant selection in future HTI-based HIV cure trials aimed at achieving therapy-free remission. Plain language summary People with HIV have a weakened immune system and so cannot respond well to other infections. Current treatment usually requires people to take antiretroviral therapy (ART) for life. Vaccination could potentially help the body’s immune system control the virus without daily treatment. To test how well vaccinations work, people with HIV were asked stop taking ART. In this study, we combined the results from two clinical trials that tested different combinations of HIV vaccines that were given alone or with another drug that stimulated the immune system. We found that participants who developed higher levels of immune responses to the vaccines were more likely to keep the virus under control for longer periods of time after stopping ART. Importantly, we found an amount of vaccine response that could predict which participants could remain withoutART for at least 12 weeks. This information could be useful in future HIV treatment studies to recommend which study participants can or cannot stop ART, which is helpful to reduce the risks associated to ART interruption. Bailón, Alarcón-Soto et al. perform a pooled analysis of individual data from two randomized clinical trials evaluating HTI-based therapeutic HIV vaccines with or without a TLR7 agonist in early-treated people with HIV. They identify an vaccine-immune response threshold that predicts virological outcomes after treatment interruption.

Purpose Our aim was to describe non-AIDS-defining cancer (NADC) mortality among people living with HIV (PLWH), to compare it with that of the general population, and to assess potential risk factors. Methods We included antiretroviral-naive PLWH from the multicentre CoRIS cohort (2004–2021). We estimated mortality rates and standardised mortality ratios (SMRs). We used cause-specific Cox models to identify risk factors. Results Among 17,978 PLWH, NADC caused 21% of all deaths observed during the follow-up. Mortality rate due to NADC was 1.58 (95%CI 1.36, 1.83) × 1000 person-years and lung and liver were the most frequent cancer-related causes of death. PLWH had 79% excess NADC mortality risk compared to the general population with the highest SMR found for Hodgkin lymphoma, anal and liver cancers. The SMRs decreased with age and were the highest in age groups under 50 years. The most important prognostic factor was low CD4 count, followed by smoking, viral hepatitis and HIV transmission through heterosexual contact or injection drug use. Conclusion Non-AIDS cancers are an important cause of death among PLWH. The excess mortality related to certain malignancies and the association with immunodeficiency, smoking, and coinfections highlights the need for early detection and treatment of cancer in this population.

To date, clinical trials have been underpowered to assess which antiretrovirals perform best in people with advanced HIV disease. We aimed to investigate the efficacy and safety of an integrase inhibitor-containing versus a boosted protease inhibitor-containing regimen for this population. In this open-label, multicentre, non-inferiority trial in seven European countries (Spain, France, Italy, Germany, Belgium, Ireland, and the UK), therapy-naive adults with advanced HIV disease were randomly allocated (1:1) to receive either bictegravir, emtricitabine, and tenofovir alafenamide (integrase inhibitor group) or darunavir, cobicistat, emtricitabine, and tenofovir alafenamide (boosted protease inhibitor group) for 48 weeks. Randomisation was computer generated in permuted blocks within strata with block sizes of four and stratified by country and baseline CD4 cell count. The primary composite outcome (time to first occurrence of specified virological or clinical events) and its components were evaluated by Kaplan–Meier and Cox regression analyses in both modified intention-to-treat (mITT) and per-protocol populations. The mITT population included all randomly allocated participants who received at least one dose of the study drug, whereas the per-protocol population excluded those who received incorrect treatment. Non-inferiority of the integrase inhibitor-based regimen versus the boosted protease inhibitor-containing regimen was declared if the upper limit of the 95% CI of the hazard ratio (HR) for the primary composite endpoint was less than 1·606, corresponding to a 12% difference in the cumulative probability of the composite primary endpoint. Adverse events, a secondary endpoint, were recorded at eight visits in all participants. This trial is registered with ClinicalTrials.gov, NCT03696160, and is completed. Between May 13, 2019, and June 26, 2023, 222 people were randomly assigned to the integrase inhibitor group and 225 to the boosted protease inhibitor group. Of these 447 recruited participants, 442 (99%) participants with a median CD4 count of 41 cells per μL (IQR 17–79) received at least one dose. 358 (81%) of the 442 treated participants self-reported as male and 84 (19%) female, and 276 (62%) were of White ethnicity, 83 (19%) Black, and 83 (19%) other. In the mITT analysis, the 48-week composite primary outcome event occurred in 49 (22%) of 220 participants in the integrase inhibitor group versus 70 (32%) of 222 participants in the boosted protease inhibitor group (adjusted HR 0·70 [95% CI 0·48–1·00]; non-inferiority shown). The per-protocol analysis gave a similar estimated adjusted HR of 0·69 (0·48–1·00; non-inferiority shown). By mITT, drug-related adverse events (grade ≥2) occurred in 16 (7%) of 220 participants in the integrase inhibitor group versus 32 (14%) of 222 in the boosted protease inhibitor group (p=0·043). The rates of serious adverse events or adverse events leading to study discontinuation did not differ between groups. 12 deaths occurred during the study (nine in the integrase inhibitor group and three in the boosted protease inhibitor group), not related to the study drugs. In people with advanced HIV disease, bictegravir, emtricitabine, and tenofovir alafenamide was shown to be non-inferior to darunavir, cobicistat, emtricitabine, and tenofovir alafenamide and resulted in fewer adverse events, supporting its use as a preferred first-line antiretroviral regimen in this vulnerable population. Gilead Sciences and Janssen Pharmaceuticals.

Introduction Anterior Cervical Discectomy and Fusion (ACDF) is the gold standard treatment for symptomatic cervical spondylosis refractory to analgesic medical management. Currently, there are numerous approaches and devices used; however, there is no single implant that is preferred for this procedure. The aim of this study is to evaluate the radiological outcomes of ACDF procedures performed in the regional spinal surgery centre in Northern Ireland. The results of this study will aid surgical decision-making, specifically with regard to the choice of implant. The implants that will be assessed in this study are the stand-alone polyetheretherketone (PEEK) cage (Cage) and the Zero-profile augmented screw implant (Z-P). Methods A total of 420 ACDF cases were reviewed retrospectively. Following exclusion and inclusion criteria, 233 cases were reviewed. In the Z-P group, there were 117 patients, with 116 in the Cage group. Radiographic assessment was carried out at the pre-operative stage, day one post-operation, and follow-up (> three months). Measured parameters included segmental disc height, segmental Cobb angle, and spondylolisthesis displacement distance. Results Patient characteristic features showed no significant difference between the two groups (p>0.05) and no significant difference in mean follow-up time (p=0.146). The Z-P implant was superior in increasing and maintaining disc height post-operatively (+0.4±0.94mm, 5.20±0.66mm) compared to the Cage (+0.1±1.00mm, 4.40±0.95mm) (p<0.001). Z-P was also more successful in restoring and maintaining cervical lordosis in comparison to the Cage group, as it had a significantly smaller kyphosis incidence (0.85% vs. 34.5%) at follow-up (p<0.001). Conclusions Results of this study show a more advantageous outcome in the Zero-profile group as it restores and maintains both disc height and cervical lordosis; it is also more successful in treating spondylolisthesis. This study advocates cautious endorsement of the use of the Zero-profile implant in ACDF procedures for symptomatic cervical disc disease.

Evaluation of: Decloedt E, McIlleron H, Smith P, Merry C, Orrell C, Maartens G. Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin with adjusted doses of lopinavir-ritonavir tablets. Antimicrob. Agents Chemother. 55(7), 3195-3200 (2011). HIV and TB coinfection is a widespread problem, especially in resource-limited settings. Interactions between drugs metabolized through cytochrome P450 enzymes and p-glycoprotein efflux pump, such as rifampin and HIV protease inhibitors, complicate the management of both pathologies when they coexist. The article by Decloedt et al. elegantly assesses the pharmacokinetics of three twice-daily escalating doses of lopinavir/ritonavir (400/100 mg, 600/150 mg and 800/200 mg), together with 600 mg daily of rifampin in 21 black African HIV-infected patients without TB. The article also reports safety, tolerability and virological outcomes after 3 weeks. Doubling lopinavir/ritonavir dose overcomes rifampin induction effect with good tolerability. However, concerns arise regarding the real interactions, tolerability and virological efficacy in HIV-TB-coinfected patients, which may differ from healthy volunteers or HIV-infected patients without TB.

We aimed to study the prevalence, characteristics and risk factors of asymptomatic sexually transmitted infections (STIs) in HIV-infected men who have sex with men (MSM). We conducted a prospective cross-sectional study, including asymptomatic HIV-infected MSM attending regular visits between December 2014 and December 2017. Of the 301 patients included, 60 patients (19.9%) presented at least one STI. The most common STI was syphilis (33 of 69 STIs), followed by chlamydia (19 of 69), gonorrhoea (10 of 69), hepatitis C virus (4 of 69) and lymphogranuloma venereum (3 of 69). Illicit drug use during sex was the only variable significantly associated with the presence of an STI on multivariate analysis (OR 2.13; 95% CI 1.17–3.89). We were unable to identify a subgroup of patients where we could potentially avoid STI screening. Our findings support current guidelines that recommend routine screening for all HIV-infected MSM regardless of their self-reported sexual history.