Antiretroviral drug concentrations in the male and female genital tract: implications for the sexual transmission of HIV

Taylor, Stephen; Davies, Sophia

doi:10.1097/coh.0b013e32833a0b69

Cited by 42 publications

(42 citation statements)

References 63 publications

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“…This discordance between BP HIV RNA level and SP HIV RNA was close to the mean percentage previously reported (10%) (7). TFV penetration in the male genital tract was variable, and TFV SP AUC 0 -24 values were lower than TFV BP AUC 0 -24 values in 12.9% of the men.…”

Section: Discussionsupporting

confidence: 49%

“…However, other studies have described a discordance between HIV BP viral load and SP HIV RNA load (spVL) (4)(5)(6). Thus, despite suppression of HIV replication in BP reflected by undetectable HIV RNA levels, spVL was detectable for some patients receiving cART (7). This discordance suggests a compartmentalization of HIV replication in the male genital tract, where the distribution of antiretroviral drugs could be a determinant of HIV shedding (7).…”

mentioning

confidence: 87%

“…A poor drug distribution in this compartment could lead to suboptimal concentrations, allowing HIV replication. The distribution of antiretroviral drugs in the genital tract has been reported to be drug specific and highly variable among individuals even for the same drug (7)(8)(9). For some protease inhibitors, SP concentrations have been reported to be lower than BP concentrations, whereas indinavir SP concentrations have been reported to be much higher (9).…”

mentioning

confidence: 99%

“…Thus, despite suppression of HIV replication in BP reflected by undetectable HIV RNA levels, spVL was detectable for some patients receiving cART (7). This discordance suggests a compartmentalization of HIV replication in the male genital tract, where the distribution of antiretroviral drugs could be a determinant of HIV shedding (7). A poor drug distribution in this compartment could lead to suboptimal concentrations, allowing HIV replication.…”

mentioning

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: Discussionsupporting

confidence: 49%

mentioning

confidence: 87%

mentioning

confidence: 99%

mentioning

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 proportion of patients with undetectable bpVL but detectable HIV-RNA levels in seminal plasma (SP) ranged from 3 to 48% (8)(9)(10)(11). The mean proportion of patients with this discordance was estimated at 10% (12,13). A longitudinal study in HIV-1-infected men who have sex with men (MSM) has reported a 7.6% discordance (14).…”

mentioning

confidence: 99%

Emtricitabine Seminal Plasma and Blood Plasma Population Pharmacokinetics in HIV-Infected Men in the EVARIST ANRS-EP 49 Study

Valade

Tréluyer

Illamola

et al. 2015

Antimicrob Agents Chemother

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Mechanisms of HIV persistence in HIV reservoirs

Mzingwane

Tiemessen

2017

Reviews in Medical Virology

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The establishment and maintenance of HIV reservoirs that lead to persistent viremia in patients on antiretroviral drugs remains the greatest challenge of the highly active antiretroviral therapy era. Cellular reservoirs include resting memory CD4+ T lymphocytes, implicated as the major HIV reservoir, having a half-life of approximately 44 months while this is less than 6 hours for HIV in plasma. In some individuals, persistent viremia consists of invariant HIV clones not detected in circulating resting CD4+ T lymphocytes suggesting other possible sources of residual viremia. Some anatomical reservoirs that may harbor such cells include the brain and the central nervous system, the gastrointestinal tract and the gut-associated lymphoid tissue and other lymphoid organs, and the genital tract. The presence of immune cells and other HIV susceptible cells, occurring in differing compositions in anatomical reservoirs, coupled with variable and poor drug penetration that results in suboptimal drug concentrations in some sites, are all likely factors that fuel the continued low-level replication and persistent viremia during treatment. Latently, HIV-infected CD4+ T cells harboring replication-competent virus, HIV cell-to-cell spread, and HIV-infected T cell homeostatic proliferation due to chronic immune activation represent further drivers of this persistent HIV viremia during highly active antiretroviral therapy.

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Antiretroviral drug concentrations in the male and female genital tract: implications for the sexual transmission of HIV

Cited by 42 publications

References 63 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

Emtricitabine Seminal Plasma and Blood Plasma Population Pharmacokinetics in HIV-Infected Men in the EVARIST ANRS-EP 49 Study

Mechanisms of HIV persistence in HIV reservoirs

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