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Article ; Online: Non-suppressible viraemia during HIV-1 therapy: a challenge for clinicians.

Esteban-Cantos, Andrés / Montejano, Rocío / Pinto-Martínez, Adriana / Rodríguez-Centeno, Javier / Pulido, Federico / Arribas, José R

The lancet. HIV

2024 Volume 11, Issue 5, Page(s) e333–e340

Abstract: In individuals receiving antiretroviral therapy (ART), persistent low-level viraemia not attributed to suboptimal ART adherence, detrimental pharmacological interactions, or drug resistance is referred to as non-suppressible viraemia (NSV). This Review ... ...

Abstract	In individuals receiving antiretroviral therapy (ART), persistent low-level viraemia not attributed to suboptimal ART adherence, detrimental pharmacological interactions, or drug resistance is referred to as non-suppressible viraemia (NSV). This Review presents recent findings in the virological characterisation of NSV, revealing that it consists of one or a few identical populations of plasma viruses without signs of evolution. This finding suggests that NSV originates from virus production by expanded HIV-infected cell clones, reflecting the persistence of the HIV reservoir despite ART. We discuss knowledge gaps regarding the management and the clinical consequences of NSV. The prevalence of NSV remains to be precisely determined and there is very little understanding of its effects on virological failure, HIV transmission, secondary inflammation, morbidity, and mortality. This issue, along with the absence of specific recommendations for the management of NSV in HIV clinical guidelines, underscores the complexities involved in treating individuals with NSV.
MeSH term(s)	Humans ; HIV Infections/drug therapy ; HIV Infections/virology ; Viremia/drug therapy ; HIV-1/drug effects ; HIV-1/physiology ; Anti-HIV Agents/therapeutic use ; Viral Load/drug effects ; Antiretroviral Therapy, Highly Active
Chemical Substances	Anti-HIV Agents
Language	English
Publishing date	2024-04-08
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2352-3018
ISSN (online)	2352-3018
DOI	10.1016/S2352-3018(24)00063-8
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Article ; Online: Ageing with HIV: Challenges and biomarkers.

Rodés, Berta / Cadiñanos, Julen / Esteban-Cantos, Andrés / Rodríguez-Centeno, Javier / Arribas, José Ramón

EBioMedicine

2022 Volume 77, Page(s) 103896

Abstract: The antiretroviral treatment (ART) developed to control HIV infection led to a revolution in the prognosis of people living with HIV (PLWH). PLWH underwent from suffering severe disease and often fatal complications at young ages to having a chronic ... ...

Abstract	The antiretroviral treatment (ART) developed to control HIV infection led to a revolution in the prognosis of people living with HIV (PLWH). PLWH underwent from suffering severe disease and often fatal complications at young ages to having a chronic condition and a life expectancy close to the general population. Nevertheless, chronic age-related diseases increase as PLWH age. The harmful effect of HIV infection on the individual's immune system adds to its deterioration during ageing, exacerbating comorbidities. In addition, PLWH are more exposed to risk factors affecting ageing, such as coinfections or harmful lifestyles. The ART initiation reverses the biological ageing process but only partially, and additionally can have some toxicities that influence ageing. Observational studies suggest premature ageing in PLWH. Therefore, there is considerable interest in the early prediction of unhealthy ageing through validated biomarkers, easy to implement in HIV-clinical settings. The most promising biomarkers are second-generation epigenetic clocks and integrative algorithms.
MeSH term(s)	Aging ; Anti-Retroviral Agents/therapeutic use ; Biomarkers ; Coinfection ; HIV Infections/complications ; HIV Infections/drug therapy ; HIV Infections/epidemiology ; Humans
Chemical Substances	Anti-Retroviral Agents ; Biomarkers
Language	English
Publishing date	2022-02-25
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2022.103896
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Article: Monocyte Activation and Ageing Biomarkers in the Development of Cardiovascular Ischaemic Events or Diabetes in People with HIV.

Bernardino, Jose I / Alejos, Belen / Rodriguez-Centeno, Javier / Esteban-Cantos, Andrés / Mora-Rojas, Beatriz / Montejano, Rocío / De Miguel, Rosa / Montero-Alonso, Marta / Ayerdi, Oskar / Hernández-Gutierrez, Cristina / Curran, Adriá / Arribas, Jose R / Rodés, Berta

Microorganisms

2023 Volume 11, Issue 7

Abstract: We investigated whether blood telomere length (TL), epigenetic age acceleration (EAA), and soluble inflammatory monocyte cytokines are associated with cardiovascular events or diabetes (DM) in people living with HIV (PLHIV). This was a case-control study ...

Abstract	We investigated whether blood telomere length (TL), epigenetic age acceleration (EAA), and soluble inflammatory monocyte cytokines are associated with cardiovascular events or diabetes (DM) in people living with HIV (PLHIV). This was a case-control study nested in the Spanish HIV/AIDS Cohort (CoRIS). Cases with myocardial infarction, stroke, sudden death, or diabetes after starting antiretroviral therapy were included with the available samples and controls matched for sex, age, tobacco use, pre-ART CD4 cell count, viral load, and sample time-point. TL (T/S ratio) was analysed by quantitative PCR and EAA with DNA methylation changes by next-generation sequencing using the Weidner formula. Conditional logistic regression was used to explore the association with cardiometabolic events. In total, 180 participants (94 cases (22 myocardial infarction/sudden death, 12 strokes, and 60 DM) and 94 controls) were included. Of these, 84% were male, median (IQR) age 46 years (40-56), 53% were current smokers, and 22% had CD4 count ≤ 200 cells/mm
Language	English
Publishing date	2023-07-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720891-6
ISSN	2076-2607
ISSN	2076-2607
DOI	10.3390/microorganisms11071818
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Article ; Online: Epigenetic ageing accelerates before antiretroviral therapy and decelerates after viral suppression in people with HIV in Switzerland: a longitudinal study over 17 years.

The lancet. Healthy longevity

2023 Volume 4, Issue 5, Page(s) e211–e218

Abstract: Background: Accelerated epigenetic ageing can occur in untreated HIV infection and is partially reversible with effective antiretroviral therapy (ART). We aimed to make a long-term comparison of epigenetic ageing dynamics in people with HIV during ... ...

Abstract	Background: Accelerated epigenetic ageing can occur in untreated HIV infection and is partially reversible with effective antiretroviral therapy (ART). We aimed to make a long-term comparison of epigenetic ageing dynamics in people with HIV during untreated HIV infection and during suppressive ART. Methods: In this longitudinal study, conducted over 17 years in HIV outpatient clinics in Switzerland, we applied 5 established epigenetic age estimators (epigenetic clocks) in peripheral blood mononuclear cells (PBMCs) in Swiss HIV Cohort Study participants before or during suppressive ART. All participants had a longitudinal set of PBMC samples available at four timepoints (T1-T4). T1 and T2 had to be 3 years or longer apart, as did T3 and T4. We assessed epigenetic age acceleration (EAA) and a novel rate of epigenetic ageing. Findings: Between March 13, 1990, and Jan 18, 2018, we recruited 81 people with HIV from the Swiss HIV Cohort Study. We excluded one participant because a sample did not meet quality checks (transmission error). 52 (65%) of 80 patients were men, 76 (95%) were white, and the median patient age was 43 (IQR 37·5-47) years. Per year of untreated HIV infection (median observation 8·08 years, IQR 4·83-11·09), mean EAA was 0·47 years (95% CI 0·37 to 0·57) for Horvath's clock, 0·43 years (0·3 to 0·57) for Hannum's clock, 0·36 years (0·27 to 0·44) for SkinBlood clock, and 0·69 years (0·51 to 0·86) for PhenoAge. Per year of suppressive ART (median observation 9·8 years, IQR 7·2-11), mean EAA was -0·35 years (95% CI -0·44 to -0·27) for Horvath's clock, -0·39 years (-0·50 to -0·27) for Hannum's clock, -0·26 years (-0·33 to -0·18) for SkinBlood clock, and -0·49 years (-0·64 to -0·35) for PhenoAge. Our findings indicate that people with HIV epigenetically aged by a mean of 1·47 years for Horvath's clock, 1·43 years for Hannum's clock, 1·36 years for SkinBlood clock, and 1·69 years for PhenoAge per year of untreated HIV infection; and 0·65 years for Horvath's clock, 0·61 years for Hannum's clock, 0·74 years for SkinBlood clock, and 0·51 years for PhenoAge, per year of suppressive ART. GrimAge showed some change in the mean EAA during untreated HIV infection (0·10 years, 0·02 to 0·19) and suppressive ART (-0·05 years, -0·12 to 0·02). We obtained very similar results using the rate of epigenetic ageing. Contribution of multiple HIV-related, antiretroviral, and immunological variables, and of a DNA methylation-associated polygenic risk score to EAA was small. Interpretation: In a longitudinal study over more than 17 years, epigenetic ageing accelerated during untreated HIV infection and decelerated during suppressive ART, highlighting the importance of limiting the duration of untreated HIV infection. Funding: Swiss HIV Cohort Study, Swiss National Science Foundation, and Gilead Sciences.
MeSH term(s)	Male ; Humans ; Aged ; Female ; Longitudinal Studies ; Cohort Studies ; Switzerland/epidemiology ; Leukocytes, Mononuclear ; HIV Infections/drug therapy ; HIV Infections/epidemiology ; HIV Infections/genetics ; Aging/genetics ; Epigenesis, Genetic
Language	English
Publishing date	2023-05-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-7568
ISSN (online)	2666-7568
DOI	10.1016/S2666-7568(23)00037-5
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Article ; Online: Effect of HIV infection and antiretroviral therapy initiation on genome-wide DNA methylation patterns.

EBioMedicine

2023 Volume 88, Page(s) 104434

Abstract: Background: Previous epigenome-wide association studies have shown that HIV infection can disrupt the host DNA methylation landscape. However, it remains unclear how antiretroviral therapy (ART) affects the HIV-induced epigenetic modifications.: ... ...

Abstract	Background: Previous epigenome-wide association studies have shown that HIV infection can disrupt the host DNA methylation landscape. However, it remains unclear how antiretroviral therapy (ART) affects the HIV-induced epigenetic modifications. Methods: 184 individuals with HIV from the NEAT001/ANRS143 clinical trial (with pre-ART and post-ART samples [96 weeks of follow-up]) and 44 age-and-sex matched individuals without HIV were included. We compared genome-wide DNA methylation profiles in whole blood between groups adjusting for age, sex, batch effects, and DNA methylation-based estimates of leucocyte composition. Findings: We identified 430 differentially methylated positions (DMPs) between HIV+ pre-ART individuals and HIV-uninfected controls. In participants with HIV, ART initiation modified the DNA methylation levels at 845 CpG positions and restored 49.3% of the changes found between HIV+ pre-ART and HIV-uninfected individuals. We only found 15 DMPs when comparing DNA methylation profiles between HIV+ post-ART individuals and participants without HIV. The Gene Ontology enrichment analysis of DMPs associated with untreated HIV infection revealed an enrichment in biological processes regulating the immune system and antiviral responses. In participants with untreated HIV infection, DNA methylation levels at top HIV-related DMPs were associated with CD4/CD8 ratios and viral loads. Changes in DNA methylation levels after ART initiation were weakly correlated with changes in CD4+ cell counts and the CD4/CD8 ratio. Interpretation: Control of HIV viraemia after 96 weeks of ART initiation partly restores the host DNA methylation changes that occurred before antiretroviral treatment of HIV infection. Funding: NEAT-ID Foundation and Instituto de Salud Carlos III, co-funded by European Union.
MeSH term(s)	Humans ; DNA Methylation ; HIV Infections/drug therapy ; HIV Infections/genetics ; Epigenesis, Genetic ; CD4 Lymphocyte Count ; CD4-CD8 Ratio ; DNA ; Anti-Retroviral Agents/therapeutic use
Chemical Substances	DNA (9007-49-2) ; Anti-Retroviral Agents
Language	English
Publishing date	2023-01-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2022.104434
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Article ; Online: Corrigendum to "Dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a non-randomized, pilot clinical trial (ART-PRO)".

De Miguel, Rosa / Rial-Crestelo, David / Dominguez-Dominguez, Lourdes / Montejano, Rocío / Esteban-Cantos, Andrés / Aranguren-Rivas, Paula / Stella-Ascariz, Natalia / Bisbal, Otilia / Bermejo-Plaza, Laura / Garcia-Alvarez, Mónica / Alejos, Belén / Hernando, Asunción / Santacreu-Guerrero, Mireia / Cadiñanos, Julen / Mayoral, Mario / Castro, Juan Miguel / Moreno, Victoria / Martin-Carbonero, Luz / Delgado, Rafael /

Rubio, Rafael / Pulido, Federico / Arribas, José Ramón

EBioMedicine

2023 Volume 89, Page(s) 104486

Language	English
Publishing date	2023-02-18
Publishing country	Netherlands
Document type	Published Erratum
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2023.104486
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Article ; Online: Effects of tenofovir on telomeres, telomerase and T cell maturational subset distribution in long-term aviraemic HIV-infected adults.

Rodríguez-Centeno, Javier / Esteban-Cantos, Andrés / Montejano, Rocío / Stella-Ascariz, Natalia / De Miguel, Rosa / Mena-Garay, Beatriz / Saiz-Medrano, Gabriel / Alejos, Belén / Jiménez-González, María / Bernardino, Jose I / Cadiñanos, Julen / Castro-Alvarez, Juan M / Rodés, Berta / Arribas, Jose R

The Journal of antimicrobial chemotherapy

2022 Volume 77, Issue 4, Page(s) 1125–1132

Abstract: Objectives: To evaluate whether the negative impact of tenofovir on telomere length (TL) is due to immune reconstitution interference or inhibition of telomerase.: Methods: One hundred and twenty-eight long-term aviraemic HIV adults treated with ... ...

Abstract	Objectives: To evaluate whether the negative impact of tenofovir on telomere length (TL) is due to immune reconstitution interference or inhibition of telomerase. Methods: One hundred and twenty-eight long-term aviraemic HIV adults treated with tenofovir-containing (n = 79) or tenofovir-sparing regimens (n = 49) were recruited to compare the following: TL in whole blood, PBMCs, CD4+ T cells and CD8+ T cells by quantitative PCR (qPCR); telomerase activity in PBMCs, CD4+ cells and CD8+ T cells using the TRAPeze RT Telomerase Detection Kit; and T cell maturational subset distribution by flow cytometry. Results: In an adjusted analysis, participants treated with tenofovir for at least 4 years had shorter TL in CD8+ T cells (P = 0.04) and lower telomerase activity in CD4+ (P = 0.012) and CD8+ T cells (P = 0.023). Tenofovir treatment was also associated with lower proportions of recent thymic emigrant (RTE) CD4+ cells (P = 0.031) and PD1 marker expression (P = 0.013). Conclusions: In long-term aviraemic HIV adults, the inhibition of telomerase by tenofovir could explain telomere shortening in CD8+ T cells. There is no telomere shortening in the CD4+ compartment and the decrease in telomerase activity could be explained both by the inhibition by tenofovir and by the lower proportion of RTE CD4+cells.
MeSH term(s)	Adult ; CD4-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes ; HIV Infections ; Humans ; Telomerase/metabolism ; Telomere/metabolism ; Tenofovir/therapeutic use
Chemical Substances	Tenofovir (99YXE507IL) ; Telomerase (EC 2.7.7.49)
Language	English
Publishing date	2022-01-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkab492
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Article ; Online: Longitudinal Changes in Epigenetic Age Acceleration in Aviremic Human Immunodeficiency Virus-Infected Recipients of Long-term Antiretroviral Treatment.

Esteban-Cantos, Andrés / Montejano, Rocio / Rodríguez-Centeno, Javier / Saiz-Medrano, Gabriel / De Miguel, Rosa / Barruz, Pilar / Bernardino, Jose I / Mena-Garay, Beatriz / Cadiñanos, Julen / Jiménez-González, María / Nevado, Julián / Valencia, Eulalia / Mayoral-Muñoz, Mario / Arribas, Jose R / Rodés, Berta

The Journal of infectious diseases

2021 Volume 225, Issue 2, Page(s) 287–294

Abstract: Background: Human immunodeficiency virus (HIV) infection induces epigenetic age acceleration (EAA), but it remains unclear whether epigenetic aging continues to accelerate during successful antiretroviral therapy (ART) and prolonged virological ... ...

Abstract	Background: Human immunodeficiency virus (HIV) infection induces epigenetic age acceleration (EAA), but it remains unclear whether epigenetic aging continues to accelerate during successful antiretroviral therapy (ART) and prolonged virological suppression. Methods: We longitudinally analyzed 63 long-term aviremic HIV-infected adults. Using blood DNA methylation patterns, we calculated EAA measures based on 3 epigenetic clocks (Horvath's clock, PhenoAge, and GrimAge). We recorded the emergence of serious AIDS-related and non-AIDS-related events throughout the study to assess its association with EAA. Results: All participants were on stable ART and were virologically suppressed. After 4 years of follow-up, PhenoAge-EAA and GrimAge-EAA showed no differences, whereas Horvath-EAA slightly decreased (median difference, -0.53 years; P = .015). Longitudinal changes in EAA measures were independent of changes in CD4 cell counts, the ART regimen, or other HIV-related factors. Nineteen percent of participants experienced a serious clinical event during the study. Horvath-EAA was significantly higher at baseline in participants with clinical events (P = .027). After adjusting for confounders, we found a trend toward an association of higher levels of all EAA measures at baseline with serious clinical events. Conclusions: Epigenetic aging did not accelerate in long-term aviremic HIV-infected adults after 4 years of successful ART. EAA measures deserve further study as potential tools for predicting clinical events.
Language	English
Publishing date	2021-06-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiab338
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Article: Long-term Evaluation of Residual Viremia in a Clinical Trial of Dolutegravir Plus Lamivudine as Maintenance Treatment for Participants With and Without Prior Lamivudine Resistance.

Open forum infectious diseases

2022 Volume 9, Issue 11, Page(s) ofac610

Abstract: In this pilot clinical trial, we evaluated rates of residual replication in persons without lamivudine resistance-associated mutations in proviral DNA population sequencing who switched to dolutegravir plus lamivudine. After 144 weeks, there was no ... ...

Abstract	In this pilot clinical trial, we evaluated rates of residual replication in persons without lamivudine resistance-associated mutations in proviral DNA population sequencing who switched to dolutegravir plus lamivudine. After 144 weeks, there was no signal of changes in residual viremia based on qualitative detection methods, irrespective of past lamivudine resistance.
Language	English
Publishing date	2022-11-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2757767-3
ISSN	2328-8957
ISSN	2328-8957
DOI	10.1093/ofid/ofac610
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Article ; Online: Detection of archived lamivudine-associated resistance mutations in virologically suppressed, lamivudine-experienced HIV-infected adults by different genotyping techniques (GEN-PRO study).

Montejano, Rocio / Dominguez-Dominguez, Lourdes / de Miguel, Rosa / Rial-Crestelo, David / Esteban-Cantos, Andrés / Aranguren-Rivas, Paula / García-Álvarez, Mónica / Alejos, Belén / Bisbal, Otilia / Santacreu-Guerrero, Mireia / Hernando, Asunción / Bermejo-Plaza, Laura / Cadiñanos, Julen / Mayoral, Mario / Castro, Juan Miguel / Moreno, Victoria / Martin-Carbonero, Luz / Rodés, Berta / Delgado, Rafael /

Rubio, Rafael / Pulido, Federico / Arribas, José Ramón

The Journal of antimicrobial chemotherapy

2021 Volume 76, Issue 12, Page(s) 3263–3271

Abstract: Background: Previously selected lamivudine resistance-associated mutations (RAMs) may remain archived within the proviral HIV-DNA.: Objectives: To evaluate the ability of proviral DNA genotyping to detect lamivudine RAMs in HIV-1 virologically ... ...

Abstract	Background: Previously selected lamivudine resistance-associated mutations (RAMs) may remain archived within the proviral HIV-DNA. Objectives: To evaluate the ability of proviral DNA genotyping to detect lamivudine RAMs in HIV-1 virologically suppressed participants; the correlation between Sanger and next generation sequencing (NGS); and predictive factors for detection of lamivudine RAMs in proviral DNA. Methods: Cross-sectional study of participants on stable antiretroviral therapy and suppressed for ≥1 year. Analysis of proviral DNA was performed by Sanger sequencing in whole blood and by NGS in PBMCs. Results: We analysed samples from 102 subjects (52 with and 50 without lamivudine RAMs in historical plasma RNA-genotypes). Among participants with previous lamivudine resistance, Sanger sequencing detected RAMs in 26.9%. Detection rates significantly increased using NGS: 47.9%, 64.6%, 75% and 87.5% with the 20%, 10%, 5% and 1% thresholds, respectively. As for participants without historical lamivudine resistance, Sanger detected the RAMs in 1/49 (2%), and NGS (5% threshold) in 8/45 (17.8%). Multivariate models fitted to the whole population revealed that having a history of lamivudine resistance was a risk factor for detection of lamivudine RAMs by NGS. Among participants with historical lamivudine resistance, multivariate analysis showed that a longer time since HIV diagnosis was associated with persistence of archived mutations by NGS at thresholds of >10% [OR 1.10 (95% CI: 1.00-1.24)] and >5% [OR 1.16 (95% CI: 1.02-1.32)]. Conclusions: Proviral DNA Sanger sequencing does not detect the majority of historical lamivudine RAMs. NGS increases the sensitivity of detection at lower thresholds, although the relevance of these minority populations with lamivudine RAMs needs further evaluation.
MeSH term(s)	Anti-HIV Agents/therapeutic use ; Cross-Sectional Studies ; Drug Resistance, Viral ; Genotype ; Genotyping Techniques ; HIV Infections/drug therapy ; Humans ; Lamivudine/therapeutic use ; Mutation ; Viral Load
Chemical Substances	Anti-HIV Agents ; Lamivudine (2T8Q726O95)
Language	English
Publishing date	2021-08-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkab323
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