HIV resides within anatomical ‘sanctuary sites’, where local drug exposure and viral dynamics may differ significantly from the systemic compartment. Suboptimal anti-retroviral concentrations in the genital tract may result in compartmentalized viral replication, selection of resistant mutations and possible re-entry of wild-type/resistant virus into the systemic circulation. Therefore, achieving adequate antiretroviral exposure in the genital tract has implications for the prevention of sexual and vertical transmission of HIV.
Penetration of antiretrovirals in the genital tract is expressed by accumulation ratios derived from the measurement of drug concentrations in time-matched seminal plasma/cervicovaginal fluid and plasma samples. Penetration varies by gender and may be drug (as opposed to class) specific with high interindividual variability. Concentrations in seminal plasma are highest for nucleoside analogues and lowest for protease inhibitors and efavirenz. Seminal accumulation of newer agents, raltegravir and maraviroc, is moderate (rank order of accumulation is nucleoside/nucleotide reverse transcriptase inhibitors [lamivudine/zidovudine/tenofovir/didanosine > stavudine/abacavir] > raltegravir > indinavir/maraviroc/nevirapine >> efavirenz/protease inhibitors [amprenavir/atazanavir/darunavir > lopinavir/ritonavir > saquinavir] > enfuvirtide). In the female genital tract, the nucleoside analogues exhibit high accumulation ratios, whereas protease inhibitors have limited penetration; however, substantial variability exists between individuals and study centres. Second generation non-nucleoside reverse transcriptase inhibitor etravirine, and maraviroc and raltegravir, demonstrate effective accumulation in cervicovaginal secretions (rank order of accumulation is nucleoside/nucleotide reverse transcriptase inhibitor [zidovudine/lamivudine/didanosine > emtricitabine/tenofovir] > indinavir > maraviroc/raltegravir/darunavir/etravirine > nevirapine/abacavir > protease inhibitors [amprenavir/atazanavir/ritonavir] > lopinavir/stavudine/efavirenz > saquinavir).
References
1.
PalellaF.J.Jr., BakerR.K., MoormanA.C.Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr2006; 43: 27–34.
2.
BenzieA.A., BansiL.K., SabinC.A.Increased duration of viral suppression is associated with lower viral rebound rates in patients with previous treatment failures. AIDS2007; 21: 1423–1430.
3.
BurgerD.M., HoetelmansR.M., HugenP.W.Low plasma concentrations of indinavir are related to virological treatment failure in HIV-1-infected patients on indinavir-containing triple therapy. Antivir Ther1998; 3: 215–220.
4.
de Vries-SluijsT.E., DielemanJ.P., ArtsD.Low nevirapine plasma concentrations predict virological failure in an unselected HIV-1-infected population. Clin Pharmacokinet2003; 42: 599–605.
5.
MasquelierB., BreilhD., NeauD.Human immunodeficiency virus type 1 genotypic and pharmacokinetic determinants of the virological response to lopinavir-ritonavir-containing therapy in protease inhibitor-experienced patients. Antimicrob Agents Chemother2002; 46: 2926–2932.
6.
DuvalX., MentreF., LamotteC.Indinavir plasma concentration and adherence score are codeterminant of early virologic response in HIV-infected patients of the APROCO cohort. Ther Drug Monit2005; 27: 63–70.
7.
ChunT.W., CarruthL., FinziD.Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature1997; 387: 183–188.
8.
ChunT.W., StuyverL., MizellS.B.Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A1997; 94: 13193–13197.
9.
EronJ.J., VernazzaP.L., JohnstonD.M.Resistance of HIV-1 to antiretroviral agents in blood and seminal plasma: implications for transmission. AIDS1998; 12: F181–F189.
10.
HoetelmansR.M.Sanctuary sites in HIV-1 infection. Antivir Ther1998; 3Suppl 4: 13–17.
11.
MayerK.H., BoswellS., GoldsteinR.Persistence of human immunodeficiency virus in semen after adding indinavir to combination antiretroviral therapy. Clin Infect Dis1999; 28: 1252–1259.
12.
GünthardH.F., HavlirD.V., FiscusS.Residual human immunodeficiency virus (HIV) type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years. J Infect Dis2001; 183: 1318–1327.
13.
SwindellsS., DiRienzoA.G., WilkinT.Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy after sustained virologic suppression. JAMA2006; 296: 806–814.
14.
VernazzaP., DaneelS., SchifferV.The role of compartment penetration in PI-monotherapy: the Atazanavir-Ritonavir Monomaintenance (ATARITMO) Trial. AIDS2007; 21: 1309–1315.
15.
DelfraissyJ.F., FlandreP., DelaugerreC.Lopinavir/ ritonavir monotherapy or plus zidovudine and lamivudine in antiretroviral-naive HIV-infected patients. AIDS2008; 22: 385–393.
16.
KotlerD.P., ShimadaT., SnowG.Effect of combination antiretroviral therapy upon rectal mucosal HIV RNA burden and mononuclear cell apoptosis. AIDS1998; 12: 597–604.
17.
PereiraA.S., KashubaA.D., FiscusS.A.Nucleoside analogues achieve high concentrations in seminal plasma: relationship between drug concentration and virus burden. J Infect Dis1999; 180: 2039–2043.
18.
Cu-UvinS., CaliendoA.M., ReinertS.Effect of highly active antiretroviral therapy on cervicovaginal HIV-1 RNA. AIDS2000; 14: 415–421.
19.
VernazzaP.L., TroianiL., FleppM.J.Potent antiretroviral treatment of HIV-infection results in suppression of the seminal shedding of HIV. The Swiss HIV Cohort Study. AIDS2000; 14: 117–121.
20.
GhosnJ., ViardJ.P., KatlamaC.Evidence of genotypic resistance diversity of archived and circulating viral strains in blood and semen of pre-treated HIV-infected men. AIDS2004; 18: 447–457.
21.
DiemK., NickleD.C., MotoshigeA.Male genital tract compartmentalization of human immunodeficiency virus type 1 (HIV). AIDS Res Hum Retroviruses2008; 24: 561–571.
22.
LiuzziG., ChirianniA., ZaccarelliM.Differences between semen and plasma of nucleoside reverse transcriptase resistance mutations in HIV-infected patients, using a rapid assay. In Vivo2004; 18: 509–512.
23.
EllerbrockT.V., LennoxJ.L., ClancyK.A.Cellular replication of human immunodeficiency virus type 1 occurs in vaginal secretions. J Infect Dis2001; 184: 28–36.
24.
TiradoG., JoveG., KumarR.Differential virus evolution in blood and genital tract of HIV-infected females: evidence for the involvement of drug and non-drug resistance-associated mutations. Virology2004; 324: 577–586.
25.
PasquierC., SauneK., RaymondS.Determining seminal plasma human immunodeficiency virus type 1 load in the context of efficient highly active antiretroviral therapy. J Clin Microbiol2009; 47: 2883–2887.
26.
ShethP.M., KovacsC., KemalK.S.Persistent HIV RNA shedding in semen despite effective antiretroviral therapy. AIDS2009; 23: 2050–2054.
27.
MarcelinA.G., TubianaR., Lambert-NiclotS.Detection of HIV-1 RNA in seminal plasma samples from treated patients with undetectable HIV-1 RNA in blood plasma. AIDS2008; 22: 1677–1679.
28.
GrahamS.M., HolteS.E., PeshuN.M.Initiation of antiretroviral therapy leads to a rapid decline in cervical and vaginal HIV-1 shedding. AIDS2007; 21: 501–507.
29.
NeelyM.N., BenningL., XuJ.Cervical shedding of HIV-1 RNA among women with low levels of viremia while receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr2007; 44: 38–42.
30.
TaylorS., DaviesS.Antiretroviral drug concentrations in the male and female genital tract: implications for the sexual transmission of HIV. Curr Opin HIV AIDS2010; 5: 335–343.
31.
CohenM.S., GayC., KashubaA.D., BlowerS., PaxtonL.Narrative review: antiretroviral therapy to prevent the sexual transmission of HIV-1. Ann Intern Med2007; 146: 591–601.
32.
MalmborgA.S.Antimicrobial drugs in human seminal plasma. J Antimicrob Chemother1978; 4: 483–485.
33.
KashubaA.D., DyerJ.R., KramerL.M., RaaschR.H., EronJ.J., CohenM.S.Antiretroviral-drug concentrations in semen: implications for sexual transmission of human immunodeficiency virus type 1. Antimicrob Agents Chemother1999; 43: 1817–1826.
34.
NdoviT.T., ParsonsT., ChoiL., CaffoB., RohdeC., HendrixC.W.A new method to estimate quantitatively seminal vesicle and prostate gland contributions to ejaculate. Br J Clin Pharmacol2007; 63: 404–420.
35.
TaylorS., BackD.J., WorkmanJ.Poor penetration of the male genital tract by HIV-1 protease inhibitors. AIDS1999; 13: 859–860.
36.
AndersonP.L., NoormohamedS.E., HenryK., BrundageR.C., BalfourH.H.Jr., FletcherC.V.Semen and serum pharmacokinetics of zidovudine and zidovudine-glucuronide in men with HIV-1 infection. Pharmacotherapy2000; 20: 917–922.
37.
TaylorS., van HeeswijkR.P., HoetelmansR.M.Concentrations of nevirapine, lamivudine and stavudine in semen of HIV-1-infected men. AIDS2000; 14: 1979–1984.
38.
van PraagR.M., ReppingS., de VriesJ.W., LangeJ.M., HoetelmansR.M., PrinsJ.M.Pharmacokinetic profiles of nevirapine and indinavir in various fractions of seminal plasma. Antimicrob Agents Chemother2001; 45: 2902–2907.
39.
ReddyY.S., GotzkowskyS.K., EronJ.J.Pharmacokinetic and pharmacodynamic investigation of efavirenz in the semen and blood of human immunodeficiency virus type 1-infected men. J Infect Dis2002; 186: 1339–1343.
40.
CaoY.J., HendrixC.W.Male genital tract pharmacology: developments in quantitative methods to better understand a complex peripheral compartment. Clin Pharmacol Ther2008; 83: 401–412.
41.
CaoY.J., NdoviT.T., ParsonsT.L., GuidosA.M., CaffoB., HendrixC.W.Effect of semen sampling frequency on seminal antiretroviral drug concentration. Clin Pharmacol Ther2008; 83: 848–856.
42.
SolasC., LafeuilladeA., HalfonP., ChadapaudS., HittingerG., LacarelleB.Discrepancies between protease inhibitor concentrations and viral load in reservoirs and sanctuary sites in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother2003; 47: 238–243.
43.
LafeuilladeA., SolasC., ChadapaudS., HittingerG., PoggiC., LacarelleB.HIV-1 RNA levels, resistance, and drug diffusion in semen versus blood in patients receiving a lopinavir-containing regimen. J Acquir Immune Defic Syndr2003; 32: 462–464.
44.
ChaudryN.I., EronJ.J., NadererO.J.Effects of formulation and dosing strategy on amprenavir concentrations in the seminal plasma of human immunodeficiency virus type 1-infected men. Clin Infect Dis2002; 35: 760–762.
45.
IsaacA., TaylorS., CaneP.Lopinavir/ritonavir combined with twice-daily 400 mg indinavir: pharmacokinetics and pharmacodynamics in blood, CSF and semen. J Antimicrob Chemother2004; 54: 498–502.
46.
VergaraT.R., EstrelaR.C., Suarez-KurtzG., SchechterM., Cerbino-NetoJ., BarrosoP.F.Limited penetration of lopinavir and ritonavir in the genital tract of men infected with HIV-1 in Brazil. Ther Drug Monit2006; 28: 175–179.
47.
van LeeuwenE., Ter HeineR., van der VeenF., ReppingS., BeijnenJ.H., PrinsJ.M.Penetration of atazanavir in seminal plasma of men infected with human immunodeficiency virus type 1. Antimicrob Agents Chemother2007; 51: 335–337.
48.
VourvahisM., TappouniH.L., PattersonK.B.The pharmacokinetics and viral activity of tenofovir in the male genital tract. J Acquir Immune Defic Syndr2008; 47: 329–333.
49.
PereiraA.S., KenneyK.B., CohenM.S.Simultaneous determination of lamivudine and zidovudine concentrations in human seminal plasma using high-performance liquid chromatography and tandem mass spectrometry. J Chromatogr B Biomed Sci Appl2000; 742: 173–183.
50.
PereiraA.S., KenneyK.B., CohenM.S., EronJ.J., TidwellR.R., DunnJ.A.Determination of amprenavir, a HIV-1 protease inhibitor, in human seminal plasma using high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci2002; 766: 307–317.
51.
HuangY., ZurlindenE., LinE.Liquid chromatographictandem mass spectrometric assay for the simultaneous determination of didanosine and stavudine in human plasma, bronchoalveolar lavage fluid, alveolar cells, peripheral blood mononuclear cells, seminal plasma, cerebrospinal fluid and tonsil tissue. J Chromatogr B Analyt Technol Biomed Life Sci2004; 799: 51–61.
52.
DumondJ.B., ReddyY.S., TroianiL.Differential extracellular and intracellular concentrations of zidovudine and lamivudine in semen and plasma of HIV-1-infected men. J Acquir Immune Defic Syndr2008; 48: 156–162.
53.
EstrelaR.C., RibeiroF.S., SeixasB.V., Suarez-KurtzG.Determination of lopinavir and ritonavir in blood plasma, seminal plasma, saliva and plasma ultra-filtrate by liquid chromatography/tandem mass spectrometry detection. Rapid Commun Mass Spectrom2008; 22: 657–664.
54.
AveryL.B., ParsonsT.L., MeyersD.J., HubbardW.C.A highly sensitive ultra performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) technique for quantitation of protein free and bound efavirenz (EFV) in human seminal and blood plasma. J Chromatogr B Analyt Technol Biomed Life Sci2010; 878: 3217–3224.
55.
HenryK., ChinnockB.J., QuinnR.P., FletcherC.V., de MirandaP., BalfourH.H.Jr.. Concurrent zidovudine levels in semen and serum determined by radioimmunoassay in patients with AIDS or AIDS-related complex. JAMA1988; 259: 3023–3026.
56.
PereiraA.S., SmeatonL.M., GerberJ.G.The pharmacokinetics of amprenavir, zidovudine, and lamivudine in the genital tracts of men infected with human immunodeficiency virus type 1 (AIDS clinical trials group study 850). J Infect Dis2002; 186: 198–204.
57.
GhosnJ., ChaixM.L., PeytavinG.Penetration of enfuvirtide, tenofovir, efavirenz, and protease inhibitors in the genital tract of HIV-1-infected men. AIDS2004; 18: 1958–1961.
58.
van PraagR.M., van HeeswijkR.P., JurriaansS., LangeJ.M., HoetelmansR.M., PrinsJ.M.Penetration of the nucleoside analogue abacavir into the genital tract of men infected with human immunodeficiency virus type 1. Clin Infect Dis2001; 33: e91–e92.
TaylorS., PhillayD., VeldkampA.Abacavir and lamivudine reach high concentrations in the semen of HIV-1-infected men.6th International Congress on Drug Therapy in HIV-Infection. 17–21 November 2002, Glasgow, UK. Abstract P168.
61.
FletcherC.V., KawleS.P., KakudaT.N.Zidovudine triphosphate and lamivudine triphosphate concentration-response relationships in HIV-infected persons. AIDS2000; 14: 2137–2144.
62.
BarryM.G., KhooS.H., VealG.J.The effect of zidovudine dose on the formation of intracellular phosphorylated metabolites. AIDS1996; 10: 1361–1367.
63.
GaoW.Y., AgbariaR., DriscollJ.S., MitsuyaH.Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2′,3′-dideoxynucleoside analogs in resting and activated human cells. J Biol Chem1994; 269: 12633–12638.
64.
SteinD.S., MooreK.H.Phosphorylation of nucleoside analog antiretrovirals: a review for clinicians. Pharmacotherapy2001; 21: 11–34.
65.
RobbinsB.L., WilcoxC.K., FridlandA., RodmanJ.H.Metabolism of tenofovir and didanosine in quiescent or stimulated human peripheral blood mononuclear cells. Pharmacotherapy2003; 23: 695–701.
66.
RobbinsB.L., SrinivasR.V., KimC., BischofbergerN., FridlandA.Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA. Antimicrob Agents Chemother1998; 42: 612–617.
67.
la PorteC.J.L., BackD.J., BlaschkeT.Updated guideline to perform therapeutic drug monitoring for antiretroviral agents. Reviews in Antiviral Therapy2006; 3: 4–14.
68.
ChanD.J., RayJ.E., McNallyL., BatterhamM., SmithD.E.Correlation between HIV-1 RNA load in blood and seminal plasma depending on antiretroviral treatment status, regimen and penetration of semen by antiretroviral drugs. Curr HIV Res2008; 6: 477–484.
69.
TaylorS., ReynoldsH., SabinC.A.Penetration of efavirenz into the male genital tract: drug concentrations and antiviral activity in semen and blood of HIV-1-infected men. AIDS2001; 15: 2051–2053.
70.
MarzoliniC., TelentiA., DecosterdL.A., GreubG., BiollazJ., BuclinT.Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS2001; 15: 71–75.
71.
van PraagR.M., WeverlingG.J., PortegiesP.Enhanced penetration of indinavir in cerebrospinal fluid and semen after the addition of low-dose ritonavir. AIDS2000; 14: 1187–1194.
72.
TaylorS., BackD.J., DrakeS.M.Antiretroviral drug concentrations in semen of HIV-infected men: differential penetration of indinavir, ritonavir and saquinavir. J Antimicrob Chemother2001; 48: 351–354.
73.
GhosnJ., ChaixM.L., PeytavinG.Absence of HIV-1 shedding in male genital tract after 1 year of first-line lopinavir/ritonavir alone or in combination with zidovudine/lamivudine. J Antimicrob Chemother2008; 61: 1344–1347.
74.
LoweS.H., WensingA.M., DrosteJ.A.No virological failure in semen during properly suppressive antiretroviral therapy despite subtherapeutic local drug concentrations. HIV Clin Trials2006; 7: 285–290.
75.
TaylorS., BoffitoM., VernazzaP.L.Antiretroviral therapy to reduce the sexual transmission of HIV. J HIV Ther2003; 8: 55–66.
76.
de Cassia EstrelaR., RibeiroF.S., BarrosoP.F.ABCB1 polymorphisms and the concentrations of lopinavir and ritonavir in blood, semen and saliva of HIV-infected men under antiretroviral therapy. Pharmacogenomics2009; 10: 311–318.
77.
SankatsingS.U., DrosteJ., BurgerD.Limited penetration of lopinavir into seminal plasma of HIV-1-infected men. AIDS2002; 16: 1698–1700.
78.
TaylorS., JayasuriyaA.N., BerryA.Darunavir concentrations exceed the protein-corrected EC for wild-type HIV in the semen of HIV-1-infected men. AIDS2010; 24: 2583–2587.
79.
Lambert-NiclotS., PeytavinG., DuvivierC.Low frequency of intermittent HIV-1 semen excretion in patients treated with darunavir-ritonavir at 600/100 milligrams twice a day plus two nucleoside reverse transcriptase inhibitors or monotherapy. Antimicrob Agents Chemother2010; 54: 4910–4913.
80.
BarauC., DelaugerreC., BraunJ.High concentration of raltegravir in semen of HIV-infected men: results from a substudy of the EASIER-ANRS 138 trial. Antimicrob Agents Chemother2010; 54: 937–939.
81.
CalcagnoA., BonoraS., D'AvolioA.Raltegravir penetration in seminal plasma of healthy volunteers. Antimicrob Agents Chemother2010; 54: 2744–2745.
82.
IwamotoM., WenningL.A., PetryA.S.Safety, tolerability, and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects. Clin Pharmacol Ther2008; 83: 293–299.
83.
ChakrabortyH., SenP.K., HelmsR.W.Viral burden in genital secretions determines male-to-female sexual transmission of HIV-1: a probabilistic empiric model. AIDS2001; 15: 621–627.
84.
BrownK., PattersonK.B., MaloneS.Antiretrovirals for prevention: maraviroc exposure in the semen and rectal tissue of healthy male volunteers after single and multiple dosing.17th Conference on Retroviruses and Opportunistic Infections. 16–19 February 2010, San Francisco, CA, USA. Abstract 611.
85.
TiraboschiJ.M., CurtoJ., PodzamczerD.Maraviroc levels in cerebrospinal fluid (CSF) and seminal plasma from HIV-infected pateints.17th Conference on Retroviruses and Opportunistic Infections. 16–19 February 2010, San Francisco, CA, USA. Abstract 114.
86.
DorrP., WestbyM., DobbsS.Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother2005; 49: 4721–4732.
87.
ClinicalTrials.gov.Phase IV, open label study in healthy male subjects to investigate the extent of darunavir/ritonavir and etravirine exposure in blood, seminal fluid, and rectal mucosal tissue following single and multiple dosing of darunavir/ritonavir and etravirine. (Updated 11 May 2011. Accessed 28 Sept 2010.) Available from http://clinicaltrials.gov/ct2/show/NCT00855088.
88.
ClinicalTrials.gov.Antiretroviral activity and tolerability of once daily etravirine in treatment-naive adults with HIV-1 infection (Updated 2 June 2011. Accessed 28 Sept 2010.) Available from http://clinicaltrials.gov/show/NCT00959894.
89.
ClinicalTrials.gov.PrEP TMC278LA: safety, tolerability and pharmacokinetics of TMC278LA in HIV negative volunteers. (Updated 27 January 2011. Accessed 28 Sept 2010.) Available from http://clinicaltrials.gov/ct2/show/NCT01275443.
TuomalaR.E., O'DriscollP.T., BremerJ.W.Cell-associated genital tract virus and vertical transmission of human immunodeficiency virus type 1 in antiretroviral-experienced women. J Infect Dis2003; 187: 375–384.
92.
TownsendC.L., Cortina-BorjaM., PeckhamC.S., de RuiterA., LyallH., TookeyP.A.Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS2008; 22: 973–981.
93.
CastillaJ., Del RomeroJ., HernandoV., MarincovichB., GarciaS., RodriguezC.Effectiveness of highly active antiretroviral therapy in reducing heterosexual transmission of HIV. J Acquir Immune Defic Syndr2005; 40: 96–101.
94.
MeloM.G., SantosB.R., De Cassia LiraR.Sexual transmission of HIV-1 among serodiscordant couples in Porto Alegre, southern Brazil. Sex Transm Dis2008; 35: 912–915.
95.
VernazzaP., HirschelB., BernasconiE., FleppM.HIV transmission under highly active antiretroviral therapy. Lancet2008; 372: 1806–1807.
96.
YehR.F., RezkN.L., KashubaA.D.Genital tract, cord blood, and amniotic fluid exposures of seven antiretroviral drugs during and after pregnancy in human immunodeficiency virus type 1-infected women. Antimicrob Agents Chemother2009; 53: 2367–2374.
97.
PattersonK., JenningsS., FalconR., MrusJ.M., KashubaA.Darunavir, ritonavir and etravirine pharmacokinetics in the cervicovaginal fluid and blood plasma of HIV-infected women. Antimicrob Agents Chemother2011; 55: 1120–1122.
98.
KwaraA., DelongA., RezkN.Antiretroviral drug concentrations and HIV RNA in the genital tract of HIV-infected women receiving long-term highly active antiretroviral therapy. Clin Infect Dis2008; 46: 719–725.
99.
DumondJ.B., YehR.F., PattersonK.B.Antiretroviral drug exposure in the female genital tract: implications for oral pre-and post-exposure prophylaxis. AIDS2007; 21: 1899–1907.
100.
MinS.S., CorbettA.H., RezkN.Protease inhibitor and nonnucleoside reverse transcriptase inhibitor concentrations in the genital tract of HIV-1-infected women. J Acquir Immune Defic Syndr2004; 37: 1577–1580.
101.
JonesA., TalamehJ., PattersonK.First-dose and steady-state pharmacokinetics (PK) of raltegravir (RAL) in the genital tract (GT) of HIV uninfected women.10th International Workshop on Clinical Pharmacology of HIV Therapy. 15–17 April 2009, Amsterdam, the Netherlands. Abstract O_06.
102.
DumondJ.B., PattersonK.B., PechaA.L.Maraviroc concentrates in the cervicovaginal fluid and vaginal tissue of HIV-negative women. J Acquir Immune Defic Syndr2009; 51: 546–553.
FletcherC.V., AndersonP.L., KakudaT.N.Concentration-controlled compared with conventional antiretroviral therapy for HIV infection. AIDS2002; 16: 551–560.
105.
Cu-UvinS., SnyderB., HarwellJ.I.Association between paired plasma and cervicovaginal lavage fluid HIV-1 RNA levels during 36 months. J Acquir Immune Defic Syndr2006; 42: 584–587.
106.
Si-MohamedA., KazatchkineM.D., HeardI.Selection of drug-resistant variants in the female genital tract of human immunodeficiency virus type 1-infected women receiving antiretroviral therapy. J Infect Dis2000; 182: 112–122.
107.
LaunayO., TodM., LouchahiK.Differential diffusions of indinavir and lopinavir in genital secretions of human immunodeficiency virus-infected women. Antimicrob Agents Chemother2004; 48: 632–634.
108.
BouleyM., BriereC., PadoinC., PetitjeanO., TodM.Sensitive and rapid method for the simultaneous quantification of the HIV-protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir in human plasma by reversed-phase liquid chromatography. Ther Drug Monit2001; 23: 56–60.
109.
ElseL.J., LyonsF., O'SheaS.Total and unbound lopinavir concentrations in the female genital tract of HIV-1 infected women during pregnancy. AIDS2011; 25: 722–725.
110.
IvanovicJ., BellagambaR., NicastriE.Use of darunavir/ ritonavir once daily in treatment-naive pregnant woman: pharmacokinetics, compartmental exposure, efficacy and safety. AIDS2010; 24: 1083–1084.
111.
ClavelC., MandelbrotL., MarcelinA.G.Raltegravir concentrations in the cervicovaginal compartment exceed the median inhibitory concentration in HIV-1 infected women treated with a raltegravir-containing regimen: DIVA 01 Study.17th Conference on Retroviruses and Opportunistic Infections. 16–19 February 2010, San Francisco, CA, USA. Abstract 608.
112.
TalamehJ.A., RezkN.L., KashubaA.D.Quantifying the HIV-1 integrase inhibitor raltegravir in female genital tract secretions using high-performance liquid chromatography with ultraviolet detection. J Chromatogr B Analyt Technol Biomed Life Sci2010; 878: 92–96.
113.
HartC.E., LennoxJ.L., Pratt-PalmoreM.Correlation of human immunodeficiency virus type 1 RNA levels in blood and the female genital tract. J Infect Dis1999; 179: 871–882.
114.
KovacsA., WassermanS.S., BurnsD.Determinants of HIV-1 shedding in the genital tract of women. Lancet2001; 358: 1593–1601.
115.
McClellandR.S., WangC.C., OverbaughJ.Association between cervical shedding of herpes simplex virus and HIV-1. AIDS2002; 16: 2425–2430.
116.
PattersonK., PrinceH., KraftM.Exposure of extracellular and intracellular tenofovir and emtricitabine in mucosal tissues after a single fixed dose of TDF/FTC: implications for pre-exposure HIV prophylaxis (PrEP).XVII International Aids Conference. 18–23 July 2010, Vienna, Austria. Abstract THB50305.
117.
OwenD.H., KatzD.F.A review of the physical and chemical properties of human semen and the formulation of a semen simulant. J Androl2005; 26: 459–469.
118.
PfauA., PerlbergS., ShapiraA.The pH of the prostatic fluid in health and disease: implications of treatment in chronic bacterial prostatitis. J Urol1978; 119: 384–387.
119.
BoffitoM., BackD.J., BlaschkeT.F.Protein binding in antiretroviral therapies. AIDS Res Hum Retroviruses2003; 19: 825–835.
120.
NicolM.R., KashubaA.D.Pharmacologic opportunities for HIV prevention. Clin Pharmacol Ther2010; 88: 598–609.
121.
Salas HerreraI.G., PearsonR.M., TurnerP.Quantitation of albumin and alpha-1-acid glycoprotein in human cervical mucus. Hum Exp Toxicol1991; 10: 137–139.
122.
LizanaJ., BladE.Immunonephelometry of specific proteins in human seminal plasma. Clin Chem1983; 29: 618–623.
123.
PanidisD., RoussoD., PanidouE., AsseoP.Orosomucoid levels in the seminal plasma or fertile and infertile men. Arch Androl1993; 30: 161–164.
124.
CaoY.P.T., BakshiR.P., FuchsE.J.A novel method demonstrating protein unbound indinavir concentration in seminal plasma. Clin Pharmacol Ther2007; 81: S99.
125.
AveryL.B., BakshiR.P., CaoY., HendrixC.W.The male genital tract is not a pharmacological sanctuary from efavirenz. Clin Pharmacol Ther2011; 90: 151–156.
126.
ThiebautF., TsuruoT., HamadaH., GottesmanM.M., PastanI., WillinghamM.C.Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A1987; 84: 7735–7738.
127.
Corden-CardoC., O'BrienJ.P., CasalsD.Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci U S A1989; 86: 695–698.
128.
HolashJ.A., HarikS.I., PerryG., StewartP.A.Barrier properties of testis microvessels. Proc Natl Acad Sci U S A1993; 90: 11069–11073.
129.
FinstadC.L., SaigoP.E., RubinS.C.Immunohistochemical localization of P-glycoprotein in adult human ovary and female genital tract of patients with benign gynecological conditions. J Histochem Cytochem1990; 38: 1677–1681.
130.
StewartP.A., BeliveauR., RogersK.A.Cellular localization of P-glycoprotein in brain versus gonadal capillaries. J Histochem Cytochem1996; 44: 679–685.
131.
BartJ., HollemaH., GroenH.J.The distribution of drug-efflux pumps, P-gp, BCRP, MRP1 and MRP2, in the normal blood-testis barrier and in primary testicular tumours. Eur J Cancer2004; 40: 2064–2070.
132.
ChooE.F., LeakeB., WandelC.Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos2000; 28: 655–660.
133.
KawaiK., SakuraiM., SakaiT.Demonstration of MDR1 P-glycoprotein isoform expression in benign and malignant human prostate cells by isoform-specific monoclonal antibodies. Cancer Lett2000; 150: 147–153.
134.
SchummerB., SiegsmundM., SteidlerA., ToktomambetovaL., KohrmannK.U., AlkenP.Expression of the gene for the multidrug resistance-associated protein in human prostate tissue. Urol Res1999; 27: 164–168.
135.
CondraJ.H., PetropoulosC.J., ZiermannR., SchleifW.A., ShivaprakashM., EminiE.A.Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy. J Infect Dis2000; 182: 758–765.
