Levels of intracellular HIV-DNA in patients with suppressive antiretroviral therapy

Cuzin, Lise; Puglièse, Pascal; Sandres-Sauné, Karine; Allavena, Clotilde; Ghosn, Jade; Cottalorda, J.; Rodallec, Audrey; Chaix, Marie Laure; Fafi‐Kremer, Samira; Soulié, Cathia; Ouka, M.; Charpentier, Charlotte; Bocket, Laurence; Mirand, Audrey; Guiguet, Marguerite

doi:10.1097/qad.0000000000000723

Cited by 46 publications

(38 citation statements)

References 36 publications

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“…We did not observe any sex‐related difference in long‐term levels of total HIV DNA under ART, contrary to two cross‐sectional studies that reported lower levels in women [14,15]. Most of participants of these studies were chronic initiators, whereas ART initiated during AHI is a major determinant of viral reservoir reduction [16,56‐58].…”

Section: Discussioncontrasting

confidence: 89%

“…Finally, recent reviews have highlighted the lack of data on sex‐related differences in the establishment and size of the viral reservoir [6,12]. Previous studies have described lower total HIV DNA in women than in men in the first months after infection [13] and under long‐term suppressive ART [14‐16] but no study has assessed it longitudinally.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced immunovirological response in women compared to men after antiretroviral therapy initiation during acute and early HIV‐1 infection: results from a longitudinal study in the French ANRS Primo cohort

et al. 2020

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Introduction: Previous studies have reported better immunovirological characteristics in women compared with men after HIV seroconversion. We investigated whether differences persisted under long-term antiretroviral therapy (ART) in individuals treated since acute and early HIV-1 infection (AHI). Methods: Data were obtained for 262 women and 1783 men enrolled between 1996 and 2017 in the French multicentre ANRS PRIMO cohort. We modelled the viral response, long-term immune recovery and HIV DNA decay in the 143 women and 1126 men who initiated ART within the first three months of infection. Results: The participants were mostly white. The mean age was 37 years at AHI diagnosis. Pre-ART viral loads were lower in women than men, 5.2 and 5.6 log 10 copies/mL (p = 0.001). After ART initiation, women more rapidly achieved viral suppression than men (adjusted hazard ratio: 1.33, 95% confidence interval 1.09 to 1.69). They also experienced a faster increase in CD4 + T-cell count and CD4:CD8 ratio during the first months of treatment. Sex-related differences in CD4 + T-cell counts were more pronounced with increasing age. This led to a sustained mean difference of 99 to 168 CD4 + T-cells/µL depending on age between women and men at 150 months of ART. Moreover, CD4:CD8 ratio of women was higher than that of men by 0.31, at 150 months of ART. There was no statistically significant difference between sexes for the levels of HIV DNA over time (mean estimate at the last modelling point: 1.9 log 10 copies/10 6 PBMCs after 70 months of ART for both sexes). Conclusions: The high level of immune recovery and decrease in total HIV DNA levels achieved after ART initiation during AHI reinforce the importance of early diagnosis of HIV infection and immediate ART initiation. The immunological benefit of being female increased throughout prolonged ART duration, which may give women additional protection from adverse clinical events and premature ageing.

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Section: Discussioncontrasting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Enhanced immunovirological response in women compared to men after antiretroviral therapy initiation during acute and early HIV‐1 infection: results from a longitudinal study in the French ANRS Primo cohort

et al. 2020

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“…Likewise, Ananworanich et al showed that total blood HIV DNA at cART initiation predicted the HIV reservoir size at week 24 of treatment that was started during PHI (P Ͻ 0.001) (78). The plasma HIV RNA zenith and the CD4 cell nadir were predictive of HIV DNA load during cART in patients whose plasma HIV RNA remained below the detection limit for more than 3 years; HIV DNA load during cART correlated positively with pretherapeutic HIV RNA load and negatively with the CD4 cell nadir (189,190,191,192). Total HIV DNA load, measured 6 weeks after cART initiation, was the strongest independent predictor of the pretherapeutic HIV RNA level (193).…”

Section: Total Hiv Dna Load During Cart Is Informative Of Patient Prementioning

confidence: 99%

“…HIV DNA load during cART was independently associated with cumulative HIV RNA viremia over the previous 5 years ( 93,192). HIV DNA load could therefore reflect therapeutic adherence over time.…”

Section: Total Hiv Dna Load During Cart Is Informative Of Patient Prementioning

confidence: 99%

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

et al. 2016

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SUMMARYHIV-1 DNA persists in infected cells despite combined antiretroviral therapy (cART), forming viral reservoirs. Recent trials of strategies targeting latent HIV reservoirs have rekindled hopes of curing HIV infection, and reliable markers are thus needed to evaluate viral reservoirs. Total HIV DNA quantification is simple, standardized, sensitive, and reproducible. Total HIV DNA load influences the course of the infection and is therefore clinically relevant. In particular, it is predictive of progression to AIDS and death, independently of HIV RNA load and the CD4 cell count. Baseline total HIV DNA load is predictive of the response to cART. It declines during cART but remains quantifiable, at a level that reflects both the history of infection (HIV RNA zenith, CD4 cell count nadir) and treatment efficacy (residual viremia, cumulative viremia, immune restoration, immune cell activation). Total HIV DNA load in blood is also predictive of the presence and severity of some HIV-1-associated end-organ disorders. It can be useful to guide individual treatment, notably, therapeutic de-escalation. Although it does not distinguish between replication-competent and -defective latent viruses, the total HIV DNA load in blood, tissues, and cells provides insights into HIV pathogenesis, probably because all viral forms participate in host cell activation and HIV pathogenesis. Total HIV DNA is thus a biomarker of HIV reservoirs, which can be defined as all infected cells and tissues containing all forms of HIV persistence that participate in pathogenesis. This participation may occur through the production of new virions, creating new cycles of infection and disseminating infected cells; maintenance or amplification of reservoirs by homeostatic cell proliferation; and viral transcription and synthesis of viral proteins without new virion production. These proteins can induce immune activation, thus participating in the vicious circle of HIV pathogenesis.

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“…Individuals on ART continue to have detectable HIV-1 DNA in circulating CD4+ T cells and many also have measurable HIV-1 RNA in cells and plasma using sensitive detection methods[8]. Given the intense interest in reducing HIV-1 reservoirs to achieve ART-free remission or cure, determining the factors that impact the size and transcriptional activity of the infected cell population is critically important[9]; these determinants, however, are incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation

et al. 2017

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Antiretroviral therapy (ART) reduces levels of HIV-1 and immune activation but both can persist despite clinically effective ART. The relationships among pre-ART and on-ART levels of HIV-1 and activation are incompletely understood, in part because prior studies have been small or cross-sectional. To address these limitations, we evaluated measures of HIV-1 persistence, inflammation, T cell activation and T cell cycling in a longitudinal cohort of 101 participants who initiated ART and had well-documented sustained suppression of plasma viremia for a median of 7 years. During the first 4 years following ART initiation, HIV-1 DNA declined by 15-fold (93%) whereas cell-associated HIV-1 RNA (CA-RNA) fell 525-fold (>99%). Thereafter, HIV-1 DNA levels continued to decline slowly (5% per year) with a half-life of 13 years. Participants who had higher HIV-1 DNA and CA-RNA before starting treatment had higher levels while on ART, despite suppression of plasma viremia for many years. Markers of inflammation and T cell activation were associated with plasma HIV-1 RNA levels before ART was initiated but there were no consistent associations between these markers and HIV-1 DNA or CA-RNA during long-term ART, suggesting that HIV-1 persistence is not driving or driven by inflammation or activation. Higher levels of inflammation, T cell activation and cycling before ART were associated with higher levels during ART, indicating that immunologic events that occurred well before ART initiation had long-lasting effects despite sustained virologic suppression. These findings should stimulate studies of viral and host factors that affect virologic, inflammatory and immunologic set points prior to ART initiation and should inform the design of strategies to reduce HIV-1 reservoirs and dampen immune activation that persists despite ART.

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Levels of intracellular HIV-DNA in patients with suppressive antiretroviral therapy

Abstract: Chronically HIV-infected patients with long-term suppressive ART can achieve low total HIV-DNA but one over six still presented HIV-DNA above 1000 copies/10 PBMCs despite long-term viral suppression.

Cited by 46 publications

References 36 publications

Enhanced immunovirological response in women compared to men after antiretroviral therapy initiation during acute and early HIV‐1 infection: results from a longitudinal study in the French ANRS Primo cohort

Enhanced immunovirological response in women compared to men after antiretroviral therapy initiation during acute and early HIV‐1 infection: results from a longitudinal study in the French ANRS Primo cohort

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation

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