Prophylaxis and treatment of HIV infection in pregnancy, Swedish guidelines 2024.

In May 2024, the Swedish Reference Group on Antiviral Therapy updated the guidelines on management of HIV infection in pregnancy. The most important recommendations and revisions were: (i) ART during pregnancy should be started as early as possible and continue after delivery; (ii) Suppressive ART should normally not be modified; (iii) The treatment target of HIV RNA <20 copies/ml remains; (iv) Dolutegravir/emtricitabine/tenofovir DF is the first-line drug combination also in pregnant women and women planning pregnancy; (v) There is no evidence of an increased risk of neural tube defects associated with dolutegravir; (vi) Mode of delivery for women with effective ART and HIV RNA <200 copies/ml should follow standard obstetric procedures; (vii) Caesarean section is recommended if HIV RNA ≥200 copies/ml; (viii) Scalp electrode, foetal blood sampling and/or vacuum delivery should be used on strict indications, but does not necessitate intensified infant prophylaxis; (ix) Management and mode of delivery in case of premature or full-term rupture of membranes should follow standard obstetric procedures; (x) Recommended infant antiretroviral prophylaxis has been updated; (xi) The duration of infant antiretroviral prophylaxis (gestational age ≥35 weeks and mother on effective ART and HIV RNA <200 copies/ml) has been changed from 4 to 2 weeks; (xii) Infants born to women with HIV RNA ≥200 copies/ml should receive 4 weeks of combination prophylaxis; (xiii) Fertility evaluation and assisted reproduction should be offered to women on suppressive ART according to the same principles as for other women; (xiv) Women living with HIV should still be advised against breastfeeding; (xv) Women who nevertheless opt to breastfeed should be offered intensified support and follow-up.

Incorporating temporal dynamics of mutations to enhance the prediction capability of antiretroviral therapy's outcome for HIV-1.

MOTIVATION: In predicting HIV therapy outcomes, a critical clinical question is whether using historical information can enhance predictive capabilities compared with current or latest available data analysis. This study analyses whether historical knowledge, which includes viral mutations detected in all genotypic tests before therapy, their temporal occurrence, and concomitant viral load measurements, can bring improvements. We introduce a method to weigh mutations, considering the previously enumerated factors and the reference mutation-drug Stanford resistance tables. We compare a model encompassing history (H) with one not using this information (NH). RESULTS: The H-model demonstrates superior discriminative ability, with a higher ROC-AUC score (76.34%) than the NH-model (74.98%). Wilcoxon test results confirm significant improvement of predictive accuracy for treatment outcomes through incorporating historical information. The increased performance of the H-model might be attributed to its consideration of latent HIV reservoirs, probably obtained when leveraging historical information. The findings emphasize the importance of temporal dynamics in acquiring mutations. However, our result also shows that prediction accuracy remains relatively high even when no historical information is available. SUPPLEMENTARY INFORMATION: Supplementary material is available.

In-hospital mortality during the wild-type, alpha, delta, and omicron SARS-CoV-2 waves: a multinational cohort study in the EuCARE project.

Background: Investigating outcomes of hospitalised COVID-19 patients throughout the pandemic is crucial to understand the impact of different SARS-CoV-2 variants. We compared 28-day in-hospital mortality of Wild-type, Alpha, Delta, and Omicron variant infections. Whether the difference in risk by variant varied by age was also evaluated. Methods: We conducted a cohort study including patients ≥18 years, hospitalised between 2020 and 02-01 and 2022-10-15 with a SARS-CoV-2 positive test, from nine countries. Variant was classified based on sequenced viruses or from national public metadata. Mortality was compared using the cumulative incidence function and subdistribution hazard ratios (SHR) adjusted for age, sex, calendar time, and comorbidities. Results were shown age-stratified due to effect measure modification (P < 0.0001 for interaction between age and variant). Findings: We included 38,585 participants: 19,763 Wild-type, 6387 Alpha, 3640 Delta, and 8795 Omicron. The cumulative incidence of mortality decreased throughout the study period. Among participants ≥70 years, the adjusted SHR (95% confidence interval) for Delta vs. Omicron was 1.66 (1.29-2.13). This estimate was 1.66 (1.17-2.36) for Alpha vs. Omicron, and 1.34 (0.92-1.95) for Wild-type vs. Omicron. These were 1.21 (0.81-1.82), 1.21 (0.68-2.17), and 0.98 (0.53-1.82) among unvaccinated participants. When comparing Omicron sublineages, the aSHR for BA.1 was 1.92 (1.43-2.58) compared to BA.2 and 1.52 (1.11-2.08) compared to BA.5. Interpretation: The herein observed decrease in in-hospital mortality seems to reflect a combined effect of immunity from vaccinations and previous infections, although differences in virulence between SARS-CoV-2 variants may also have contributed. Funding: European Union's Horizon Europe Research and Innovation Programme.

Heavy antiretroviral exposure and exhausted/limited antiretroviral options: predictors and clinical outcomes.

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.

The molecular epidemiology of HIV-1 in Sweden 1996 to 2022, and the influence of migration from Ukraine.

BackgroundThe global distribution of HIV-1 subtypes is evolving, which is reflected in the Swedish HIV cohort. The subtype HIV-1A6, which may be prone to developing resistance to cabotegravir, is the most common subtype in Ukraine.AimWe aimed to examine trends in HIV-1 subtype distribution in Sweden, with a special focus on HIV-1A6, and to describe the virology, demography and treatment of Ukrainian people living with HIV (PLWH) who migrated to Sweden in 2022.MethodsData about PLWH in Sweden are included in a national database (InfCareHIV). We used the online tool COMET to establish HIV-1 subtypes and the Stanford database to define drug resistance mutations. We investigated the relation between virological characteristics and demographic data.ResultsThe early epidemic was predominated by HIV-1 subtype B infections in people born in Sweden. After 1990, the majority of new PLWH in Sweden were PLWH migrating to Sweden, resulting in an increasingly diverse epidemic. In 2022, HIV-1A6 had become the sixth most common subtype in Sweden and 98 of the 431 new PLWH that were registered in Sweden came from Ukraine. We detected HIV RNA in plasma of 32 Ukrainian patients (34%), of whom 17 were previously undiagnosed, 10 had interrupted therapy and five were previously diagnosed but not treated. We found HIV-1A6 in 23 of 24 sequenced patients.ConclusionThe molecular HIV epidemiology in Sweden continues to diversify and PLWH unaware of their HIV status and predominance of HIV-1A6 should be considered when arranging care directed at PLWH from Ukraine.

Anakinra or tocilizumab in patients admitted to hospital with severe covid-19 at high risk of deterioration (IMMCoVA): A randomized, controlled, open-label trial.

BACKGROUND: Anakinra and tocilizumab are used for severe Covid-19, but only one previous randomized controlled trial (RCT) has studied both. We performed a multi-center RCT comparing anakinra or tocilizumab versus usual care (UC) for adults at high risk of deterioration. METHODS: The study was conducted June 2020 to March 2021. Eligibility required ≥ 5 liters/minute of Oxygen to maintain peripheral oxygen saturation at ≥ 93%, CRP > 70 mg/L, ferritin > 500 µg/L and at least two points where one point was awarded for lymphocytes < 1x 109/L; D-dimer ≥ 0.5 mg/L and; lactate dehydrogenase ≥ 8 microkatal/L. Patients were randomly assigned 1:1:1 to receive either a single dose of tocilizumab (8 mg/kg) or anakinra 100 mg IV QID for seven days or UC alone. The primary outcome was time to recovery. RESULTS: Recruitment was ended prematurely when tocilizumab became part of usual care. Out of a planned 195 patients, 77 had been randomized, 27 to UC, 28 to anakinra and 22 to tocilizumab. Median time to recovery was 15, 15 and 11 days. Rate ratio for recovery for UC vs anakinra was 0.91, 0.47 to 1.78, 95% [CI], p = 0.8 and for UC vs tocilizumab 1.13, 0.55 to 2.30; p = 0.7. There were non-significant trends favoring tocilizumab (and to limited degree anakinra) vs UC for some secondary outcomes. Safety profiles did not differ significantly. CONCLUSION: Premature closure of trial precludes firm conclusions. Anakinra or tocilizumab did not significantly shorten time to clinical recovery compared to usual care. (IMMCoVA, NCT04412291, EudraCT: 2020-00174824).

Impact of the gut microbiome on immunological responses to COVID-19 vaccination in healthy controls and people living with HIV.

Although mRNA SARS-CoV-2 vaccines are generally safe and effective, in certain immunocompromised individuals they can elicit poor immunogenic responses. Among these individuals, people living with HIV (PLWH) have poor immunogenicity to several oral and parenteral vaccines. As the gut microbiome is known to affect vaccine immunogenicity, we investigated whether baseline gut microbiota predicts immune responses to the BNT162b2 mRNA SARS-CoV-2 vaccine in healthy controls and PLWH after two doses of BNT162b2. Individuals with high spike IgG titers and high spike-specific CD4+ T-cell responses against SARS-CoV-2 showed low α-diversity in the gut. Here, we investigated and presented initial evidence that the gut microbial composition influences the response to BNT162b2 in PLWH. From our predictive models, Bifidobacterium and Faecalibacterium appeared to be microbial markers of individuals with higher spike IgG titers, while Cloacibacillus was associated with low spike IgG titers. We therefore propose that microbiome modulation could optimize immunogenicity of SARS-CoV-2 mRNA vaccines.

EuCARE-hospitalised study protocol: a cohort study of patients hospitalised with COVID-19 in the EuCARE project.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), can lead to hospitalisation, particularly in elderly, immunocompromised, and non-vaccinated or partially vaccinated individuals. Although vaccination provides protection, the duration of this protection wanes over time. Additional doses can restore immunity, but the influence of viral variants, specific sequences, and vaccine-induced immune responses on disease severity remains unclear. Moreover, the efficacy of therapeutic interventions during hospitalisation requires further investigation. The study aims to analyse the clinical course of COVID-19 in hospitalised patients, taking into account SARS-CoV-2 variants, viral sequences, and the impact of different vaccines. The primary outcome is all-cause in-hospital mortality, while secondary outcomes include admission to intensive care unit and length of stay, duration of hospitalisation, and the level of respiratory support required. METHODS: This ongoing multicentre study observes hospitalised adult patients with confirmed SARS-CoV-2 infection, utilising a combination of retrospective and prospective data collection. It aims to gather clinical and laboratory variables from around 35,000 patients, with potential for a larger sample size. Data analysis will involve biostatistical and machine-learning techniques. Selected patients will provide biological material. The study started on October 14, 2021 and is scheduled to end on October 13, 2026. DISCUSSION: The analysis of a large sample of retrospective and prospective data about the acute phase of SARS CoV-2 infection in hospitalised patients, viral variants and vaccination in several European and non-European countries will help us to better understand risk factors for disease severity and the interplay between SARS CoV-2 variants, immune responses and vaccine efficacy. The main strengths of this study are the large sample size, the long study duration covering different waves of COVID-19 and the collection of biological samples that allows future research. TRIAL REGISTRATION: The trial has been registered on ClinicalTrials.gov. The unique identifier assigned to this trial is NCT05463380.

Generating synthetic clinical data that capture class imbalanced distributions with generative adversarial networks: Example using antiretroviral therapy for HIV.

OBJECTIVE: Clinical data's confidential nature often limits the development of machine learning models in healthcare. Generative adversarial networks (GANs) can synthesise realistic datasets, but suffer from mode collapse, resulting in low diversity and bias towards majority demographics and common clinical practices. This work proposes an extension to the classic GAN framework that includes a variational autoencoder (VAE) and an external memory mechanism to overcome these limitations and generate synthetic data accurately describing imbalanced class distributions commonly found in clinical variables. METHODS: The proposed method generated a synthetic dataset related to antiretroviral therapy for human immunodeficiency virus (ART for HIV). We evaluated it based on five metrics: (1) accurately representing imbalanced class distribution; (2) the realism of the individual variables; (3) the realism among variables; (4) patient disclosure risk; and (5) the utility of the generated dataset for developing downstream machine learning models. RESULTS: The proposed method overcomes the issue of mode collapse and generates a synthetic dataset that accurately describes imbalanced class distributions commonly found in clinical variables. The generated data has a patient disclosure risk of 0.095%, lower than the 9% threshold stated by Health Canada and the European Medicines Agency, making it suitable for distribution to the research community with high security. The generated data also has high utility, indicating the potential of the proposed method to enable the development of downstream machine learning algorithms for healthcare applications using synthetic data. CONCLUSION: Our proposed extension to the classic GAN framework, which includes a VAE and an external memory mechanism, represents a promising approach towards generating synthetic data that accurately describe imbalanced class distributions commonly found in clinical variables. This method overcomes the limitations of GANs and creates more realistic datasets with higher patient cohort diversity, facilitating the development of downstream machine learning algorithms for healthcare applications.

Cohort Profile: A European Multidisciplinary Network for the Fight against HIV Drug Resistance (EuResist Network).

The EuResist cohort was established in 2006 with the purpose of developing a clinical decision-support tool predicting the most effective antiretroviral therapy (ART) for persons living with HIV (PLWH), based on their clinical and virological data. Further to continuous extensive data collection from several European countries, the EuResist cohort later widened its activity to the more general area of antiretroviral treatment resistance with a focus on virus evolution. The EuResist cohort has retrospectively enrolled PLWH, both treatment-naïve and treatment-experienced, under clinical follow-up from 1998, in nine national cohorts across Europe and beyond, and this article is an overview of its achievement. A clinically oriented treatment-response prediction system was released and made available online in 2008. Clinical and virological data have been collected from more than one hundred thousand PLWH, allowing for a number of studies on the response to treatment, selection and spread of resistance-associated mutations and the circulation of viral subtypes. Drawing from its interdisciplinary vocation, EuResist will continue to investigate clinical response to antiretroviral treatment against HIV and monitor the development and circulation of HIV drug resistance in clinical settings, along with the development of novel drugs and the introduction of new treatment strategies. The support of artificial intelligence in these activities is essential.

Plasma Human Immunodeficiency Virus 1 RNA and CD4+ T-Cell Counts Are Determinants of Virological Nonsuppression Outcomes With Initial Integrase Inhibitor-Based Regimens: A Prospective RESPOND Cohort Study.

BACKGROUND: There are conflicting data regarding baseline determinants of virological nonsuppression outcomes in persons with human immunodeficiency virus (HIV) starting antiretroviral treatment (ART). We evaluated the impact of different baseline variables in the RESPOND cohort. METHODS: We included treatment-naive participants aged ≥18 who initiated 3-drug ART, in 2014-2020. We assessed the odds of virological suppression (VS) at weeks 48 and 96 using logistic regression. Viral blips, low-level viremia (LLV), residual viremia (RV), and virological failure (VF) rates were assessed using Cox regression. RESULTS: Of 4310 eligible participants, 72% started integrase strand transfer inhibitor (INSTI)-based regimens. At 48 and 96 weeks, 91.0% and 93.3% achieved VS, respectively. At 48 weeks, Kaplan-Meier estimates of rates were 9.6% for viral blips, 2.1% for LLV, 22.2% for RV, and 2.1% for VF. Baseline HIV-1 RNA levels >100 000 copies/mL and CD4+ T-cell counts ≤200/µL were negatively associated with VS at weeks 48 (adjusted odds ratio, 0.51 [95% confidence interval, .39-.68] and .40 [.27-.58], respectively) and 96 and with significantly higher rates of blips, LLV, and RV. CD4+ T-cell counts ≤200/µL were associated with higher risk of VF (adjusted hazard ratio, 3.12 [95% confidence interval, 2.02-4.83]). Results were consistent in those starting INSTIs versus other regimens and those starting dolutegravir versus other INSTIs. CONCLUSIONS: Initial high HIV-1 RNA and low CD4+ T-cell counts are associated with lower rates of VS at 48 and 96 weeks and higher rates of viral blips, LLV, and RV. Low baseline CD4+ T-cell counts are associated with higher VF rates. These associations remain with INSTI-based and specifically with dolutegravir-based regimens. These findings suggest that the impact of these baseline determinants is independent of the ART regimen initiated.

Synergistic antiviral activity against drug-resistant HIV-1 by naturally occurring dipeptide and A single-stranded oligonucleotide.

The novel dipeptide WG-am and single-stranded oligonucleotide combination (WG-am:ssON) showed synergistic antiviral activity against HIV-1 integrase-, protease- or reverse transcriptase drug resistant isolates, with over 95% reduction. The highest selectivity indexes were for integrase resistant isolates. WG-am:ssON can be a future option for treatment of HIV drug-resistant strains.

Naturally occurring dipeptide from elite controllers with dual anti-HIV-1 mechanism.

BACKGROUND: Enhanced levels of a dipeptide, WG-am, have been reported among elite controllers - patients who spontaneously control their HIV-1 infection. This study aimed to evaluate anti-HIV-1 activity and mechanism of action of WG-am. METHODS: Drug sensitivity assays in TZM.bl cells, PBMCs and ACH-2 cells using WT and mutated HIV-1 strainswere performed to evaluate the antiviral mechanism of WG-am. Mass spectrometry-based proteomics and Real-time PCR analysis of reverse transcription steps were performed to unravel the second anti-HIV-1 mechanism of WG-am. RESULTS: The data suggest that WG-am binds to the CD4 binding pocket of HIV-1 gp120 and blocks its binding to the host cell receptors. Additionally, the time course assay showed that WG-am also inhibited HIV-1 at 4-6 hours post-infection, suggesting a second antiviral mechanism. Drug sensitivity assays under acidic wash conditions confirmed the ability of WG-am to internalise into the host cell in an HIV independent manner. Proteomic studies showed a clustering of all samples treated with WG-am independent of the number of doses or presence or absence of HIV-1. Differentially expressed proteins due to the WG-am treatment indicated an effect on HIV-1 reverse transcription, which was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR). CONCLUSION: Naturally occurring in HIV-1 elite controllers, WG-am stands out as a new kind of antiviral compound with two independent inhibitory mechanisms of action on HIV-1 replication. WG-am halts HIV-1 entry to the host cell by binding to HIV-1 gp120, thereby blocking the binding of HIV-1 to the host cell. WG-am also exerts a post-entry but pre-integration antiviral effect related to RT-activity.

Cohort profile: InfCareHIV, a prospective registry-based cohort study of people with diagnosed HIV in Sweden.

PURPOSE: The Swedish InfCareHIV cohort was established in 2003 to ensure equal and effective care of people living with HIV (PLHIV) and enable long-term follow-up. InfCareHIV functions equally as a decision support system as a quality registry, ensuring up-to-date data reported in real time. PARTICIPANTS: InfCareHIV includes data on >99% of all people with diagnosed HIV in Sweden and up to now 13 029 have been included in the cohort. InfCareHIV includes data on HIV-related biomarkers and antiretroviral therapies (ART) and also on demographics, patient-reported outcome measures and patient-reported experience measures. FINDINGS TO DATE: Sweden was in 2015 the first country to reach the UNAIDS (United Nations Programme on HIV/AIDS)/WHO's 90-90-90 goals. Late diagnosis of HIV infection was identified as a key problem in the Swedish HIV-epidemic, and low-level HIV viraemia while on ART associated with all-cause mortality. Increased HIV RNA load in the cerebrospinal fluid (CSF) despite suppression of the plasma viral load was found in 5% of PLHIV, a phenomenon referred to as 'CSF viral escape'. Dolutegravir-based treatment in PLHIV with pre-existing nucleoside reverse transcriptase inhibitor-mutations was non-inferior to protease inhibitor-based regimens. An increase of transmitted drug resistance was observed in the InfCareHIV cohort. Lower efficacy for protease inhibitors was not due to lower adherence to treatment. Incidence of type 2 diabetes and insulin resistance was high in the ageing HIV population. Despite ART, the risk of infection-related cancer as well as lung cancer was increased in PLHIV compared with HIV-negative. PLHIV were less likely successfully treated for cervical precancer and more likely to have human papillomavirus types not included in current HPV vaccines. Self-reported sexual satisfaction in PLHIV is improving and is higher in women than men. FUTURE PLANS: InfCareHIV provides a unique base to study and further improve long-term treatment outcomes, comorbidity management and health-related quality of life in people with HIV in Sweden.

Role of myeloid cells in system-level immunometabolic dysregulation during prolonged successful HIV-1 treatment.

OBJECTIVE: Why people with HIV-1 on ART (PWH ART ) display convoluted metabolism and immune cell functions during prolonged suppressive therapy is not well evaluated. In this study, we aimed to address this question using multiomics methodologies to investigate immunological and metabolic differences between PWH ART and HIV-1 negative individuals (HC). DESIGN: Cross-sectional study. METHODS: Untargeted and targeted metabolomics was performed using gas and liquid chromatography/mass spectrometry, and targeted proteomics using Olink inflammation panel on plasma samples. The cellular metabolic state was further investigated using flow cytometry and intracellular metabolic measurement in single-cell populations isolated by EasySep cell isolation. Finally, flow cytometry was performed for deep-immunophenotyping of mononuclear phagocytes. RESULTS: We detected increased levels of glutamate, lactate, and pyruvate by plasma metabolomics and increased inflammatory markers (e.g. CCL20 and CCL7) in PWH ART compared to HC. The metabolite transporter detection by flow cytometry in T cells and monocytes indicated an increased expression of glucose transporter 1 (Glut1) and monocarboxylate transporter 1 (MCT-1) in PWH ART . Single cell-type metabolite measurement identified decreased glucose, glutamate, and lactate in monocytic cell populations in PWH ART . Deep-immunophenotyping of myeloid cell lineages subpopulations showed no difference in cell frequency, but expression levels of CCR5 were increased on classical monocytes and some dendritic cells. CONCLUSIONS: Our data thus suggest that the myeloid cell populations potentially contribute significantly to the modulated metabolic environment during suppressive HIV-1 infection.

Analysis of mutational history of multidrug-resistant genotypes with a mutagenetic tree model.

Human immunodeficiency virus (HIV) can develop resistance to all antiretroviral drugs. Multidrug resistance, however, is a rare event in modern HIV treatment, but can be life-threatening, particular in patients with very long therapy histories and in areas with limited access to novel drugs. To understand the evolution of multidrug resistance, we analyzed the EuResist database to uncover the accumulation of mutations over time. We hypothesize that the accumulation of resistance mutations is not acquired simultaneously and randomly across viral genotypes but rather tends to follow a predetermined order. The knowledge of this order might help to elucidate potential mechanisms of multidrug resistance. Our evolutionary model shows an almost monotonic increase of resistance with each acquired mutation, including less well-known nucleoside reverse transcriptase (RT) inhibitor-related mutations like K223Q, L228H, and Q242H. Mutations within the integrase (IN) (T97A, E138A/K G140S, Q148H, N155H) indicate high probability of multidrug resistance. Hence, these IN mutations also tend to be observed together with mutations in the protease (PR) and RT. We followed up with an analysis of the mutation-specific error rates of our model given the data. We identified several mutations with unusual rates (PR: M41L, L33F, IN: G140S). This could imply the existence of previously unknown virus variants in the viral quasispecies. In conclusion, our bioinformatics model supports the analysis and understanding of multidrug resistance.

Longitudinal decline of plasma neurofilament light levels after antiretroviral initiation in people living with HIV.

BACKGROUND: This retrospective follow-up study aims to investigate the dynamic longitudinal change of plasma neurofilament light (NfL) levels after antiretroviral therapy (ART) initiation in a cohort of people living with human immunodeficiency virus (HIV) (PWH). METHODS: We tested a convenience sample of 116 patients from the NORTHIV study. Plasma NfL levels-measured using Single molecule array (Simoa) technology-as well as other laboratory parameters were collected at baseline, weeks 4, 48, 96, and 144. Linear mixed-effects models were estimated to evaluate longitudinal change over time. Baseline CD4+ T-cell levels, CDC classification, and HIV RNA levels were considered. Models were adjusted by age, sex, treatment regimen, and baseline serum creatinine levels. RESULTS: Plasma NfL levels were higher at baseline and also declined faster during the follow-up for participants with CD4+ count <100 cells/µl compared with >100 cells/µl. No significant difference was found between the CD4+ strata 100-199 and 200-499/µl. Participants with CDC classification stages B and C had higher levels of plasma NfL at baseline, as well as faster decline compared with participants with stage A. No significant main effects or change over time was found in baseline HIV RNA levels, treatment regimen, or sex. CONCLUSION: Plasma NfL is a sensitive biomarker to assess ongoing central nervous system injury in PWH. Plasma NfL concentrations decline relatively fast following ART initiation and then stabilize after 48 weeks. Plasma NfL concentrations are associated with CD4+ count and stage of HIV disease. No correlations were seen with different ART regimens.

Recent abacavir use and incident cardiovascular disease in contemporary-treated people with HIV.

OBJECTIVE: Assessing whether the previously reported association between abacavir (ABC) and cardiovascular disease (CVD) remained amongst contemporarily treated people with HIV. DESIGN: Multinational cohort collaboration. METHODS: RESPOND participants were followed from the latest of 1 January 2012 or cohort enrolment until the first of a CVD event (myocardial infarction, stroke, invasive cardiovascular procedure), last follow-up or 31 December 2019. Logistic regression examined the odds of starting ABC by 5-year CVD or chronic kidney disease (CKD) D:A:D risk score. We assessed associations between recent ABC use (use within the past 6 months) and risk of CVD with negative binomial regression models, adjusted for potential confounders. RESULTS: Of 29 340 individuals, 34% recently used ABC. Compared with those at low estimated CVD and CKD risks, the odds of starting ABC were significantly higher among individuals at high CKD risk [odds ratio 1.12 (95% confidence interval = 1.04-1.21)] and significantly lower for individuals at moderate, high or very high CVD risk [0.80 (0.72-0.88), 0.75 (0.64-0.87), 0.71 (0.56-0.90), respectively]. During 6.2 years of median follow-up (interquartile range; 3.87-7.52), there were 748 CVD events (incidence rate 4.7 of 1000 persons-years of follow up (4.3-5.0)]. The adjusted CVD incidence rate ratio was higher for individuals with recent ABC use [1.40 (1.20-1.64)] compared with individuals without, consistent across sensitivity analyses. The association did not differ according to estimated CVD (interaction P  = 0.56) or CKD ( P  = 0.98) risk strata. CONCLUSION: Within RESPOND's contemporarily treated population, a significant association between CVD incidence and recent ABC use was confirmed and not explained by preferential ABC use in individuals at increased CVD or CKD risk.

Virologic Failure Following Low-level Viremia and Viral Blips During Antiretroviral Therapy: Results From a European Multicenter Cohort.

BACKGROUND: It is unclear whether low-level viremia (LLV), defined as repeatedly detectable viral load (VL) of <200 copies/mL, and/or transient viremic episodes (blips) during antiretroviral therapy (ART), predict future virologic failure. We investigated the association between LLV, blips, and virologic failure (VF) in a multicenter European cohort. METHODS: People with HIV-1 who started ART in 2005 or later were identified from the EuResist Integrated Database. We analyzed the incidence of VF (≥200 copies/mL) depending on viremia exposure, starting 12 months after ART initiation (grouped as suppression [≤50 copies/mL], blips [isolated VL of 51-999 copies/mL], and LLV [repeated VLs of 51-199 copies/mL]) using Cox proportional hazard models adjusted for age, sex, injecting drug use, pre-ART VL, CD4 count, HIV-1 subtype, type of ART, and treatment experience. We queried the database for drug-resistance mutations (DRM) related to episodes of LLV and VF and compared those with baseline resistance data. RESULTS: During 81 837 person-years of follow-up, we observed 1424 events of VF in 22 523 participants. Both blips (adjusted subhazard ratio [aHR], 1.7; 95% confidence interval [CI], 1.3-2.2) and LLV (aHR, 2.2; 95% CI, 1.6-3.0) were associated with VF, compared with virologic suppression. These associations remained statistically significant in subanalyses restricted to people with VL <200 copies/mL and those starting ART 2014 or later. Among people with LLV and genotype data available within 90 days following LLV, 49/140 (35%) had at least 1 DRM. CONCLUSIONS: Both blips and LLV during ART are associated with increased risk of subsequent VF.

Natural killer cells induce HIV-1 latency reversal after treatment with pan-caspase inhibitors.

The establishment of a latency reservoir is the major obstacle for a cure of HIV-1. The shock-and-kill strategy aims to reactivate HIV-1 replication in HIV -1 latently infected cells, exposing the HIV-1-infected cells to cytotoxic lymphocytes. However, none of the latency reversal agents (LRAs) tested so far have shown the desired effect in people living with HIV-1. We observed that NK cells stimulated with a pan-caspase inhibitor induced latency reversal in co-cultures with HIV-1 latently infected cells. Synergy in HIV-1 reactivation was observed with LRAs prostratin and JQ1. The supernatants of the pan-caspase inhibitor-treated NK cells activated the HIV-1 LTR promoter, indicating that a secreted factor by NK cells was responsible for the HIV-1 reactivation. Assessing changes in the secreted cytokine profile of pan-caspase inhibitor-treated NK cells revealed increased levels of the HIV-1 suppressor chemokines MIP1α (CCL3), MIP1ß (CCL4) and RANTES (CCL5). However, these cytokines individually or together did not induce LTR promoter activation, suggesting that CCL3-5 were not responsible for the observed HIV-1 reactivation. The cytokine profile did indicate that pan-caspase inhibitors induce NK cell activation. Altogether, our approach might be-in combination with other shock-and-kill strategies or LRAs-a strategy for reducing viral latency reservoirs and a step forward towards eradication of functionally active HIV-1 in infected individuals.