HIV-1 DNA Levels in Peripheral Blood Mononuclear Cells and Cannabis Use are Associated With Intermittent HIV Shedding in Semen of Men Who Have Sex With Men on Successful Antiretroviral Regimens

Ghosn, Jade; Leruez‐Ville, Marianne; Blanche, Jérôme; Delobelle, Aurore; Beaudoux, Céline; Mascard, L.; Lécuyer, Hervé; Canestri, Ana; Landman, Roland; Zucman, David; Ponscarme, Diane; Rami, Agathe; Viard, Jean‐Paul; Spire, Bruno; Rouzioux, Christine; Costagliola, Dominique; Suzan‐Monti, Marie

doi:10.1093/cid/ciu187

Cited by 42 publications

(39 citation statements)

References 32 publications

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“…Actually, it was not shown in our study that the measured spVLs were produced locally; therefore, these viruses can also reflect a residual replication somewhere in the body, particularly in another compartment with perhaps insufficient drug levels. In the same way, Ghosn et al have reported that the size of the blood HIV-1 reservoir was highly associated with spVL detection (28).…”

Section: Discussionmentioning

confidence: 75%

“…The Evarist-ANRS EP 49 study's main objective was to evaluate the proportion of men having an undetectable blood HIV RNA BP VL (Ͻ50 copies · ml Ϫ1 ) and a concomitant detectable viral load in semen (28). Men older than 18 years having sex with men, infected by HIV-1, receiving the same antiretroviral treatment for at least 3 months, and having an undetectable BP viral load (Ͻ50 copies · ml Ϫ1 ) for at least 6 months were eligible.…”

Section: Methodsmentioning

confidence: 99%

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Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients

Valade

Bouazza

Lui

et al. 2017

Antimicrob Agents Chemother

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The aims of this study were to describe the blood plasma (BP) and seminal plasma (SP) pharmacokinetics of tenofovir (TFV) in HIV-1-infected men, to assess the role of genetic polymorphism in the variability of TFV transfer into the male genital tract, and to evaluate the impact of TFV SP exposure on seminal plasma HIV load (spVL). Men from the Evarist-ANRS EP 49 study treated with TFV as part of their antiretroviral therapy were included in the study. A total of 248 and 217 TFV BP and SP concentrations from 129 men were available for the analysis. For pharmacogenetic assessment, a total of 121 single nucleotide polymorphisms (SNP) were genotyped. Data were analyzed using a nonlinear mixed-effects modeling approach. TFV pharmacokinetics were best described by a two-compartment model for BP and by an effect compartment with different input and output constants for SP. TFV exposures (area under the concentration-time curve from 0 to 24 h [AUC 0 -24 ]) were higher in SP than in BP (median AUC 0 -24 , 7.01 versus 2.97 mg · liter Ϫ1 · h, respectively). The median (range) SP-to-BP AUC 0 -24 ratio was 2.24 (0.53 to 34.13). After correction for multiple testing, none of the SNPs were significantly associated with the TFV transfer rate constant. The impact of the TFV SP AUC 0 -24 or TFV SP-to-BP AUC 0 -24 ratio on spVL was not significant (P ϭ 0.808 and 0.768, respectively). This is the first population model describing TFV pharmacokinetics in the male genital tract. TFV SP concentrations were higher than BP concentrations. Despite TFV SP exposures being higher than BP exposures, an spVL was detectable for 12.2% of the men.

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Section: Discussionmentioning

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients

Valade

Bouazza

Lui

et al. 2017

Antimicrob Agents Chemother

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“…High HIV DNA load in PBMC is associated with intermittent HIV shedding in the semen of men who have sex with men and who have been on successful antiretroviral therapy for Ͼ6 months: after multivariable adjustments, total HIV DNA (OR of 2.6 and 95% confidence interval [CI] of 1.2 to 6.0 for Ͼ2.5 log 10 copies/10 6 PBMC; P ϭ 0.02) and cannabis use accompanying sexual intercourse (OR of 2.8, CI of 1.2 to 6.7; P ϭ 0.02) were the two factors significantly associated with HIV RNA detection in seminal plasma (199).…”

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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“…This persistent virus release in semen occurs despite an undetectable blood HIV RNA load and an absence of detectable sexually transmitted infections (STIs), the latter being a well-identified factor favoring HIV shedding in semen irrespective of HAART (9)(10)(11). HIV RNA has been evidenced in the semen of 3% to 48% of chronically infected men under suppressive HAART for over 6 months with no detected STIs (6,(12)(13)(14)(15)(16)(17)(18)(19)) (see additional references in reference 20). Levels of HIV RNA detected during HAART are often low; nevertheless, high levels of shedding (i.e., Ͼ1,000 RNA copies/ml) have been described in a substantial subset of individuals (6,14,15,(17)(18)(19).…”

mentioning

confidence: 99%

Detection of Simian Immunodeficiency Virus in Semen, Urethra, and Male Reproductive Organs during Efficient Highly Active Antiretroviral Therapy

Matusali

Dereuddre-Bosquet

Tortorec

et al. 2015

J Virol

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A number of men receiving prolonged suppressive highly active antiretroviral therapy (HAART) still shed human immunodeficiency virus (HIV) in semen. To investigate whether this seminal shedding may be due to poor drug penetration and/or viral production by long-lived cells within male genital tissues, we analyzed semen and reproductive tissues from macaques chronically infected with simian immunodeficiency virus mac251 (SIVmac251) who were treated for 4 months with HAART, which was intensified over the last 7 weeks with an integrase inhibitor. We showed that a subset of treated animals continued shedding SIV in semen despite efficient HAART. This shedding was not associated with low antiretroviral drug concentrations in semen or in testis, epididymis, seminal vesicles, and prostate. HAART had no significant impact on SIV RNA in the urethra, whereas it drastically reduced SIV RNA levels in the prostate and vas deferens and to a lesser extent in the epididymis and seminal vesicle. The only detectable SIV RNA-positive cells within the male genital tract after HAART were urethral macrophages. SIV DNA levels in genital tissues were not decreased by HAART, suggesting the presence throughout the male genital tract of nonproductively infected cells. In conclusion, our results demonstrate that 4 months of HAART induced variable and limited control of viral infection in the male reproductive organs, particularly in the urethra, and suggest that infected long-lived cells in the male genital tract may be involved in persistent seminal shedding during HAART. These results pave the way for further investigations of male genital organ infection in long-term-treated infected individuals. IMPORTANCEA substantial subset of men receiving prolonged HAART suppressing viral loads in the blood still harbor HIV in semen, and cases of sexual transmission have been reported. To understand the origin of this persistence, we analyzed the semen and male reproductive tissues from SIV-infected macaques treated with HAART. We demonstrated that persistent seminal shedding was not linked to poor drug penetration in semen or semen-producing prostate, seminal vesicle, epididymis, and testis. We revealed that HAART decreased SIV RNA to various extents in all male genital organs, with the exception of the urethra, in which SIV RNA ؉ macrophages were observed despite HAART. Importantly, HAART did not impact SIV DNA levels in the male genital organs. These results suggest that infection of male genital organs, and particularly the urethra, could be involved in the release of virus in semen during HAART.A pproximately 35.3 million people worldwide are living with human immunodeficiency virus (HIV)/AIDS, and 2.3 million new infections occur annually (1). Over 80% of these new infections are caused by unprotected sexual intercourse. The risk of sexual transmission of HIV is strongly correlated with HIV RNA levels in genital secretions (2). Because semen is the most common vector of HIV dissemination worldwide (3-5), preventing HIV transmission by...

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HIV-1 DNA Levels in Peripheral Blood Mononuclear Cells and Cannabis Use are Associated With Intermittent HIV Shedding in Semen of Men Who Have Sex With Men on Successful Antiretroviral Regimens

Cited by 42 publications

References 32 publications

Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients

Population Pharmacokinetic Modeling of Tenofovir in the Genital Tract of Male HIV-Infected Patients

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

Detection of Simian Immunodeficiency Virus in Semen, Urethra, and Male Reproductive Organs during Efficient Highly Active Antiretroviral Therapy

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