Genital Tract, Cord Blood, and Amniotic Fluid Exposures of Seven Antiretroviral Drugs during and after Pregnancy in Human Immunodeficiency Virus Type 1-Infected Women

Yeh, Rosa F.; Rezk, Naser L.; Kashuba, Angela D. M.; Dumond, Julie B.; Tappouni, Hiba L.; Tien, Hsiao Chuan; Chen, Ya Chi; Vourvahis, Manoli; Horton, Amanda; Fiscus, Susan A.; Patterson, Kristine B.

doi:10.1128/aac.01523-08

Cited by 54 publications

(51 citation statements)

References 51 publications

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“…Thus, data from this model provide the first information on the protective TFV-DP levels and point to TFV-DP concentrations in vaginal lymphocytes that are above the in vitro IC 95 as predictors of high protection by TFV gels. Although we have not measured the TFV-DP concentrations in vaginal lymphocytes after oral TDF dosing in macaques, recent data for humans are consistent with our macaque data and have demonstrated much higher TFV-DP exposures in vaginal tissues after TFV gel compared to oral TDF dosing, implying that oral TDF may not confer the same level of protection as topical TFV gel against vaginal infection (3,27,39). An interim analysis of two human clinical trials has recently shown conflicting efficacy results.…”

Section: Discussionsupporting

confidence: 67%

Durable Protection from Vaginal Simian-Human Immunodeficiency Virus Infection in Macaques by Tenofovir Gel and Its Relationship to Drug Levels in Tissue

Dobard

Sharma

Martin

et al. 2012

J Virol

100

117

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A vaginal gel containing 1% tenofovir (TFV) was found to be safe and effective in reducing HIV infection in women when used pericoitally. Because of the long intracellular half-life of TFV and high drug exposure in vaginal tissues, we hypothesized that a vaginal gel containing TFV may provide long-lasting protection. Here, we performed delayed-challenge experiments and showed that vaginal 1% TFV gel protected 4/6 macaques against vaginal simian-human immunodeficiency virus (SHIV) exposures occurring 3 days after gel application, demonstrating long-lasting protection. Despite continued gel dosing postinfection, neither breakthrough infection had evidence of drug resistance by ultrasensitive testing of SHIV in plasma and vaginal lavage. Analysis of the active intracellular tenofovir diphosphate (TFV-DP) in vaginal lymphocytes collected 4 h to 3 days after gel dosing persistently showed high TFV-DP levels (median, 1,810 fmol/10 6 cells) between 4 and 24 h that exceed the 95% inhibitory concentration (IC 95 ), reflecting rapid accumulation and long persistence. In contrast to those in peripheral blood mononuclear cells (PBMCs) following oral dosing, TFV-DP levels in vaginal lymphocytes decreased approximately 7-fold by 3 days, exhibiting a much higher rate of decay. We observed a strong correlation between intracellular TFV-DP in vaginal lymphocytes, in vitro antiviral activity, and in vivo protection, suggesting that TFV-DP above the in vitro IC 95 in vaginal lymphocytes is a good predictor of high efficacy. Data from this model reveal an extended window of protection by TFV gel that supports coitus-independent use. The identification of protective TFV-DP concentrations in vaginal lymphocytes may facilitate the evaluation of improved delivery methods of topical TFV and inform clinical studies. Human immunodeficiency virus (HIV) continues to spread primarily through heterosexual routes, with women being disproportionately infected in many parts of the world (30, 35). While condoms have been shown to be one of the most reliable methods for preventing HIV transmission, such interventions are often limited by adherence and the ability of women to negotiate their use (24, 37). In the absence of an effective HIV vaccine, increasing efforts have been made toward developing vaginal gels formulated with antiretroviral (ARV) drugs, as a femalecontrolled option for women to protect themselves against HIV acquisition (10,21,33,37).Topical gels containing tenofovir (TFV), a nucleotide analogue reverse transcriptase inhibitor, have recently shown great promise against vaginal HIV transmission. Results of the CAPRISA 004 trial demonstrated for the first time that women who used a vaginal gel containing 1% TFV were 39% less likely overall to contract HIV than those who used a placebo gel (1). The trial evaluated a coitus-dependent before-and-after (BAT) modality, with one gel application administered up to 12 h before sex followed by a second gel application up to 12 h after sex. Importantly, effectiveness was found to be dependen...

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Section: Discussionsupporting

confidence: 67%

Durable Protection from Vaginal Simian-Human Immunodeficiency Virus Infection in Macaques by Tenofovir Gel and Its Relationship to Drug Levels in Tissue

Dobard

Sharma

Martin

et al. 2012

J Virol

100

117

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“…However, this ratio is mostly dependent on delivery time, and maternal and fetal samples are rarely taken simultaneously. The values reported previously varied from Ͻ1% to 57% (8,(19)(20)(21)(22). In the present study, the estimated ratio was 11.6%, confirming that LPV placental transfer is low.…”

Section: Discussionsupporting

confidence: 70%

“…Placental transfer was estimated based on the exposure ratio between fetal and maternal LPV/r AUCs for 12 h. The placental transfer was estimated to be 11.6% (1.2% to 48.9%). This value is slightly lower than those suggested for the fetal-to-maternal concentration ratio at delivery (14 to 20%) (8,(19)(20)(21)(22)(23).…”

Section: Resultscontrasting

confidence: 42%

“…The LPV placental transfer is low and variable at 20% (coefficient of variation [CV], ϳ65%) (8,(19)(20)(21)(22)(23), but this transfer has only been reported as a ratio of concentrations, whatever the delay between drug administration and delivery. The LPV placental transfer variability can be explained by the differences of delays and may also be explained by the genetic polymorphisms of the placental transporters.…”

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confidence: 99%

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Population Approach To Analyze the Pharmacokinetics of Free and Total Lopinavir in HIV-Infected Pregnant Women and Consequences for Dose Adjustment

Fauchet

Tréluyer

Illamola

et al. 2015

Antimicrob Agents Chemother

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The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy. N ew recommendations were published by the World Health Organization (WHO) in 2013 for use of antiretroviral drugs for treating and preventing HIV infection (1). These recommendations suggested simplification and harmonization of the firstline therapy in order to improve health outcomes and facilitate adherence and drug procurement (1). A new combination regimen has been suggested for all HIV-infected adults, including pregnant and breastfeeding women. Two nucleoside reverse transcriptase inhibitors (NRTIs) and one nonnucleoside reverse transcriptase inhibitor are recommended as a first-line regimen to treat infected pregnant women or to prevent mother-to-child transmission (MTCT). However, the use of NRTIs during pregnancy has been recently debated. Indeed, NRTIs cross the placenta with an affinity for both mitochondrial and nuclear human DNA (2, 3). The use of NRTIs in large cohorts of neonates and children has been associated with toxicities (including mitochondrial dysfunction and neurological disease) (4, 5). Moreover, genotoxic biomarkers were identified in neonates exposed to zidovudine (ZDV) alone or in combination with lamivudine (3TC) (6, 7). The long-term toxicities of NRTIs remain unknown, but they raise concern about use of these drugs during pregnancy.Considering the possible NRTI toxicities during pregnancy, the ANRS 135 PRIMEVA study compared a triple-therapy regimen containing NRTIs versus LPV monotherapy. The study also compared the effi...

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“…Indeed, TFV has shown high rates of penetration in semen, male and female genital tracts, rectal tissue, and amniotic fluid in pregnant women (22). A recent work has shown, however, very poor diffusion of TFV in breast milk, whereas FTC diffused relatively well, reaching concentrations above the virus IC 50 (2).…”

mentioning

confidence: 99%

Concentrations of Tenofovir and Emtricitabine in Saliva: Implications for Preexposure Prophylaxis of Oral HIV Acquisition

Lastours

Fonsart

Burlacu

et al. 2011

Antimicrob Agents Chemother

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To prevent acquisition of HIV through oral sex, drugs used for preexposure prophylaxis (Prep) need to diffuse in saliva. We measured tenofovir (TFV) and emtricitabine (FTC) concentrations simultaneously in the plasma and saliva of 41 HIV-infected patients under stable antiretroviral treatment. Mean ratios of saliva/ plasma concentration were 3% (؎4%) and 86.9% (؎124%) for TFV and FTC, respectively. Tenofovir disoproxil fumarate (TDF) should be used in combination with FTC to prevent oral acquisition of HIV.Thirty years into the HIV pandemic, a high incidence of new HIV infections persists, particularly in the subgroup of men having sex with men (MSM), where HIV transmission is sustained (16). Innovative approaches to prevent HIV transmission include the use of antiretrovirals as preventive tools, known as preexposure prophylaxis (Prep), either as oral pills or topical microbicides containing an active antiviral agent (13). Recent studies have shown a partial reduction in HIV acquisition in women using a vaginal tenofovir gel (1) and in MSM taking a daily oral tenofovir disoproxil fumarate (TDF)-emtricitabine (FTC) combination pill (11), the favored combination for Prep.While it is agreed that oral sex carries a much lower HIV infection risk than vaginal and anal sex, studies have convincingly demonstrated that both insertive and receptive oral sex are independent risk factors for transmission of HIV (6,19,20). The risk increases with frequency of activity, the presence of oral ulcers, oropharyngeal inflammation, or sexually transmitted infections in the oropharynx. This route of transmission should not be underestimated, in particular in MSM, where oral sex is rarely protected (8). In order for Prep to prevent HIV transmission through oral sex also, antiviral drugs should be taken orally, and their saliva concentrations should be sufficient to inhibit viral replication. Yet, no data are available on the penetration of tenofovir (TFV) and FTC in saliva. The aim of this work is to measure TFV and FTC saliva concentrations and saliva-to-plasma ratios in HIV-infected patients receiving either a TDF-or a TDF-FTC-based treatment.HIV-infected patients regularly followed in our HIV clinic were included if they were receiving a stable antiretroviral regimen, including 245 mg TDF daily and/or 200 mg FTC daily for at least 3 months, and gave informed consent. The study was approved by the Paris Saint-Louis Institutional Review Board. Blood and saliva samples were collected simultaneously during a routine follow-up evaluation of their HIV infection. Saliva samples were obtained by having participants spit 10 ml saliva in a sterile pot. To confirm that saliva had been sampled, samples were tested by validated colorimetric assays for total proteins (Biuret test) and saliva ␣-amylase (S type, enzymatic method) levels, using a Roche Modular analyzer (Roche Diagnostics France, Meylan, France). Both plasma and saliva TFV and FTC levels were measured by a validated high-performance liquid chromatography with tandem mass spectromet...

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Genital Tract, Cord Blood, and Amniotic Fluid Exposures of Seven Antiretroviral Drugs during and after Pregnancy in Human Immunodeficiency Virus Type 1-Infected Women

Cited by 54 publications

References 51 publications

Durable Protection from Vaginal Simian-Human Immunodeficiency Virus Infection in Macaques by Tenofovir Gel and Its Relationship to Drug Levels in Tissue

Durable Protection from Vaginal Simian-Human Immunodeficiency Virus Infection in Macaques by Tenofovir Gel and Its Relationship to Drug Levels in Tissue

Population Approach To Analyze the Pharmacokinetics of Free and Total Lopinavir in HIV-Infected Pregnant Women and Consequences for Dose Adjustment

Concentrations of Tenofovir and Emtricitabine in Saliva: Implications for Preexposure Prophylaxis of Oral HIV Acquisition

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