Detection of multiple drug-resistance-associated pol mutations in cervicovaginal secretions from women largely treated with antiretroviral agents

Stefano, Mariantonietta Di; Fiore, Josè Ramon; Monno, Laura; Lepera, Achiropita; Pastore, G; Angarano, Gioacchino

doi:10.1097/00002030-199905280-00018

Cited by 7 publications

(3 citation statements)

References 9 publications

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“…The female genital tract has been demonstrated to express heterogeneous HIV-1 populations, as well as ART resistance [61][62][63]. Differences between the genotype and phenotype of viral populations in plasma and the genital tract have been observed, including different patterns of ART resistance [44,54,64,65].…”

Section: Discussionmentioning

confidence: 99%

Cell‐Associated Genital Tract Virus and Vertical Transmission of Human Immunodeficiency Virus Type 1 in Antiretroviral‐Experienced Women

Tuomala¹,

O’Driscoll

Bremer

et al. 2003

J INFECT DIS

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Section: Discussionmentioning

confidence: 99%

Cell‐Associated Genital Tract Virus and Vertical Transmission of Human Immunodeficiency Virus Type 1 in Antiretroviral‐Experienced Women

Tuomala¹,

O’Driscoll

Bremer

et al. 2003

J INFECT DIS

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“…The main sanctuary sites are the central nervous system, genital tract, and lymphoid tissue. The viral loads and resistance profiles in these compartments have been described to be discordant from those in plasma (1,4,14,27,29).…”

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confidence: 99%

Discrepancies between Protease Inhibitor Concentrations and Viral Load in Reservoirs and Sanctuary Sites in Human Immunodeficiency Virus-Infected Patients

Solas

Lafeuillade

Halfon

et al. 2003

Antimicrob Agents Chemother

154

139

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The variable penetration of antiretroviral drugs into sanctuary sites may contribute to the differential evolution of human immunodeficiency virus (HIV) and the emergence of drug resistance. We evaluated the penetration of indinavir, nelfinavir, and lopinavir-ritonavir (lopinavir/r) in the central nervous system, genital tract, and lymphoid tissue and assessed the correlation with residual viral replication. Plasma, cerebrospinal fluid (CSF), semen, and lymph node biopsy samples were collected from 41 HIV-infected patients on stable highly active antiretroviral therapy regimens to determine drug concentrations and HIV RNA levels. When HIV RNA was detectable, sequencing of the reverse transcriptase and protease genes was performed. Ratios of the concentration in semen/concentration in plasma were 1.9 for indinavir, 0.08 for nelfinavir, and 0.07 for lopinavir. Only indinavir was detectable in CSF, with a concentration in CSF/concentration in plasma ratio of 0.17. Differential penetration into lymphoid tissue was observed, with concentration in lymph node tissue/ concentration in plasma ratios of 2.07, 0.58, and 0.21 for indinavir, nelfinavir, and lopinavir, respectively. HIV RNA levels were <50 copies/ml in all CSF samples of patients in whom HIV RNA was not detectable in plasma. HIV RNA was detectable in the semen of three patients (two patients receiving nelfinavir and one patient receiving lopinavir/r), and its detection was associated with multiple resistance mutations, while the viral load in plasma was undetectable. HIV RNA was detectable in all lymph node tissue samples. Differential drug penetration was observed among the three protease inhibitors in the sanctuary sites, but there was no correlation between drug levels and HIV RNA levels, suggesting that multiple factors are involved in the persistence of viral reservoirs. Further studies are required to clarify the role and clinical relevance of drug penetration in sanctuaries in terms of long-term efficacy and drug resistance.

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“…Lopinavir and indinavir were detectable in 29 and 93% of CVS samples, respectively, a finding that may be ascribed to these drugs' differences in protein binding and pK a . The relationship between lopinavir and indinavir pharmacodynamics and viral evolution in the female genital tract should be assessed over time.Differential viral load suppression and rate of emergence of drug resistance-associated viral mutations have been observed between blood and genital compartments, a fact which has possibly been related to inadequate penetration of antiretroviral drugs into sanctuaries (3,4,9,11,12,14,15). Numerous studies have evaluated the penetration of antiretrovirals into the male genital tract (7,8,16,17).…”

mentioning

confidence: 99%

Differential Diffusions of Indinavir and Lopinavir in Genital Secretions of Human Immunodeficiency Virus-Infected Women

Launay¹,

Tod

Louchahi

et al. 2004

Antimicrob Agents Chemother

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Plasma and cervicovaginal secretion (CVS) samples were collected from 19 human immunodeficiency virus type 1-infected women on lopinavir-or indinavir-containing regimens. Lopinavir and indinavir were detectable in 29 and 93% of CVS samples, respectively, a finding that may be ascribed to these drugs' differences in protein binding and pK a . The relationship between lopinavir and indinavir pharmacodynamics and viral evolution in the female genital tract should be assessed over time.Differential viral load suppression and rate of emergence of drug resistance-associated viral mutations have been observed between blood and genital compartments, a fact which has possibly been related to inadequate penetration of antiretroviral drugs into sanctuaries (3,4,9,11,12,14,15). Numerous studies have evaluated the penetration of antiretrovirals into the male genital tract (7,8,16,17). In contrast, data on the diffusion of antiretrovirals in the female genital tract are scarce, but preliminary results evidenced major differences between drugs in terms of detection in cervicovaginal secretions (CVS) (8,14). Protease inhibitors (PIs) exhibit variable protein binding capacities and physicochemical properties, which might influence PI diffusion into the female genital tract. We thus decided to compare the pharmacokinetics of indinavir alone or combined with ritonavir and that of lopinavir-ritonavir in the plasma and genital secretions of human immunodeficiency virus type 1 (HIV-1)-infected women.HIV-1-infected women who were on a lopinavir-or indinavir-containing regimen for a minimum of 4 weeks were recruited between October 2001 and July 2002. They had no symptoms of genital infection and no genital bleeding during the 5 days preceding the visit and were asked to avoid sexual intercourse and intravaginal medications within 2 days before sample processing. To assess whether the patients were adherent to their treatment, they were asked to fill out a simple self-administered questionnaire regarding their drug intake during the 4 days preceding the study visit. After the introduction of a speculum, genital secretions were collected by a lavage performed with 3 ml of phosphate-buffered saline, pH 7.2, containing a 10 mM concentration of lithium chloride. Within 15 min after collection of the genital secretion, a blood sample was taken for the measurement of plasma lopinavir or indinavir concentration. None of the women had taken drugs susceptible to interaction with the metabolism of either indinavir or lopinavir. For each woman, samples were precisely collected just before and 3 to 4 h after intake of the last drug for measurements of 12-h trough and peak plasma concentrations simultaneously with that of drug levels in genital secretions. Both peak and trough concentrations were measured at two different visits separated by 1 to 3 months. The study protocol was approved by the Ethics Committee of the Pitié-Salpêtrière Hospital, Paris, France, and signed informed consent was obtained from all women. Measurements of antiretroviral d...

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Detection of multiple drug-resistance-associated pol mutations in cervicovaginal secretions from women largely treated with antiretroviral agents

Cited by 7 publications

References 9 publications

Cell‐Associated Genital Tract Virus and Vertical Transmission of Human Immunodeficiency Virus Type 1 in Antiretroviral‐Experienced Women

Cell‐Associated Genital Tract Virus and Vertical Transmission of Human Immunodeficiency Virus Type 1 in Antiretroviral‐Experienced Women

Discrepancies between Protease Inhibitor Concentrations and Viral Load in Reservoirs and Sanctuary Sites in Human Immunodeficiency Virus-Infected Patients

Differential Diffusions of Indinavir and Lopinavir in Genital Secretions of Human Immunodeficiency Virus-Infected Women

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