Limited penetration of lopinavir into seminal plasma of HIV-1-infected men
Sankatsing, Sanjay U. C.a,b; Droste, Jackied; Burger, Davidd; van Praag, Rieneke M. E.a,b; Jurriaans, Suzannec; Lange, Joep M. A.a,b,c; Prins, Jan M.a
aDepartment of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, bInternational Antiviral Therapy Evaluation Center (IATEC), and cDepartment of Human Retrovirology, Academic Medical Center, University of Amsterdam, the Netherlands; and dDepartment of Clinical Pharmacy, University Medical Center, Nijmegen, the Netherlands.
Sponsorship: This study was financially supported by a foundation that does not wish to be named.
Part of this study was presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle, USA, February 2002.
Received: 8 February 2002;
revised: 7 March 2002; accepted: 25 March 2002.
Antiretroviral therapy can decrease the amount of HIV-1 RNA in blood plasma and in semen . However, the decline of the HIV-1-RNA concentration and the evolution of virus in semen during therapy can show discordance with blood plasma, indicating viral compartmentalization [2,3]. Poor penetration into the male genital tract by some antiretroviral drugs can contribute to the different viral dynamics in this compartment . Data available on drug concentrations in semen show that the penetration of the protease inhibitors (PI) nelfinavir, ritonavir and saquinavir is poor . The nucleoside analogues zidovudine, stavudine, lamivudine and abacavir, the non-nucleoside reverse transcriptase inhibitors nevirapine and efavirenz, and the PI indinavir and amprenavir penetrate well into the male genital tract [3,6–12]. There are no data on the penetration of the PI lopinavir into the male genital tract.
HIV-1-infected men who were on a lopinavir-containing regimen for a minimum of 4 weeks were recruited from our HIV outpatient clinic. The patients had to have no signs or symptoms of a genital infection. Semen samples were obtained by masturbation, centrifuged between 2 and 4 h after collection at 1200 g for 10 min to obtain seminal plasma and stored at −70°C until analysis. Within 2 h after semen collection, a blood sample was taken for the measurement of the blood plasma lopinavir and HIV-1-RNA concentrations. The local Medical Ethics Committee approved the study, and written informed consent was obtained from all patients.
HIV-1 RNA in ethylenediamine tetraacetic acid plasma was measured using the quantiplex bDNA assay (Bayer Corporation, Diagnostics Division, Emeryville, CA, USA), with a lower limit of quantification of 50 copies/ml. HIV-1 RNA in seminal plasma was measured using the ultra Nuclisens HIV-1 QT assay (Organon Teknika, Boxtel, the Netherlands), with a lower limit of quantification of 50 copies/ml. Lopinavir concentrations in heparinized blood plasma and in seminal plasma were measured using a high-performance liquid chromatographic procedure . The intra- and interday variation of this assay was less than 5%.
Fourteen patients on a lopinavir-containing regimen for a median of 16 weeks (range 4–41 weeks) were included in this study. Lopinavir was started in nine of the patients because of virological failure on their previous antiretroviral regimen and in five because of side-effects of their previous regimen. The five patients who switched therapy because of side-effects had an undetectable HIV-1-RNA level in blood plasma at the moment of switching therapy. At the time the study samples were taken all five patients still had an undetectable HIV-1-RNA level in blood plasma and an undetectable HIV-1-RNA level in seminal plasma. Of the nine patients starting lopinavir because of virological failure, four had a detectable HIV-1-RNA level in blood plasma at the time the study samples were taken. These patients were not yet in a steady state, and during follow-up their blood plasma HIV-1-RNA levels decreased further. Only one of these four patients had an undetectable HIV-1-RNA level in seminal plasma. The other five patients starting lopinavir because of virological failure had an undetectable blood plasma HIV-1-RNA level. One of these patients had a detectable HIV-1-RNA level in seminal plasma.
In five of the 14 patients the blood plasma concentration of lopinavir was below the desired concentration of 5.0 mg/l (Abbott product information). The other nine patients had a plasma concentration greater than 5.0 mg/l (Fig. 1a).
The lopinavir concentration in seminal plasma ranged between 0.046 and 3.9 mg/l [median 0.23 mg/l, interquartile range (IQR) 0.15–0.33]. No relationship was found between the lopinavir concentration in seminal plasma and the time since medication intake (ρ = 0.22, P = 0.45; Spearman's rank) (Fig. 1b). There was a weak relationship between the blood plasma and the seminal plasma concentration (ρ = 0.51, P = 0.07; Spearman's rank). The median ratio of the concentrations of lopinavir in seminal plasma and in blood plasma was only 0.034 (IQR 0.021–0.070) (Fig. 1c). There was no relationship between the lopinavir concentration in blood plasma or seminal plasma and HIV-1-RNA level in blood plasma or in seminal plasma (ρ = 0.11, P = 0.73; Spearman's rank) (Fig. 1a and b) and no relationship between the lopinavir concentration in seminal plasma and HIV-1-RNA level in seminal plasma (ρ = 0.46, P = 0.11; Spearman's rank).
We demonstrated that lopinavir has a poor penetration into the seminal plasma, with a median concentration of only 0.23 mg/l (range 0.046–3.9 mg/l), assuming the same percentage protein binding in seminal plasma as in blood plasma (98–99%; Abbott product information). Because of this poor penetration one would expect a poor suppression of the viral replication in semen. However, only four out of the 14 patients had a detectable HIV-1-RNA level in seminal plasma, of which three patients were not yet in a steady state. An explanation for this could be that all patients were on a regimen containing at least one other antiretroviral drug with a good penetration into the seminal plasma (data not shown). It is, however, conceivable that the replication of HIV-1 in the genital tracts of our patients is only partly suppressed by the other drugs of the regimen, usually two nucleoside analolgues. Although most of the patients had an undetectable HIV-1-RNA level in seminal plasma, the median time on lopinavir was only 16 weeks, and it is possible that in time there will be a selection of HIV-1 strains resistant for the other drugs used. There are indications that the selection of resistant HIV-1 strains in the male genital tract can differ from that in blood plasma . If resistant HIV strains migrate to other compartments a patient is at risk of systemic virological failure. Resistant strains in seminal plasma may also lead to the infection of other individuals with resistant strains. A longer follow-up of HIV-1-RNA levels in seminal plasma is necessary to be confident that the selection of resistance mutations is not a risk of regimens with only partial penetration into the male genital tract.
Sanjay U. C. Sankatsinga,b
Rieneke M. E. van Praaga,b
Joep M. A. Langea,b,c
Jan M. Prinsa
1. Vernazza PL, Troiani L, Flepp MJ. et al. Potent antiretroviral treatment of HIV-infection results in suppression of the seminal shedding of HIV. The Swiss HIV Cohort Study. AIDS 2000, 14: 117–121.
2. Eron JJ, Vernazza PL, Johnston DM. et al. Resistance of HIV-1 to antiretroviral agents in blood and seminal plasma: implications for transmission. AIDS 1998, 12: F181–F189.
3. Eron JJ, Smeaton LM, Fiscus SA. et al. The effects of protease inhibitor therapy on human immunodeficiency virus type 1 levels in semen (AIDS clinical trials group protocol 850). J Infect Dis 2000, 181: 1622–1628.
4. Kashuba AD, Dyer JR, Kramer LM, Raasch RH, Eron JJ, Cohen MS. Antiretroviral-drug concentrations in semen: implications for sexual transmission of hu human immunodeficiency virus type 1. Antimicrob Agents Chemother 1999, 43: 1817–1826.
5. Taylor S, Back DJ, Workman J. et al. Poor penetration of the male genital tract by HIV-1 protease inhibitors. AIDS 1999, 13: 859–860.
6. van Praag RM, Repping S, de Vries JW, Lange JM, Hoetelmans RM, Prins JM. Pharmacokinetic profiles of nevirapine and indinavir in various fractions of seminal plasma. Antimicrob Agents Chemother 2001, 45: 2902–2907.
7. Taylor S, Reynolds H, Sabin CA. et al. Penetration of efavirenz into the male genital tract: drug concentrations and antiviral activity in semen and blood of HIV-1-infected men. AIDS 2001, 15: 2051–2053.
8. van Praag RM, van Heeswijk RP, Jurriaans S, Lange JM, Hoetelmans RM, Prins JM. Penetration of the nucleoside analogue abacavir into the genital tract of men infected with human immunodeficiency virus type 1. Clin Infect Dis 2001, 33: E91–E92.
9. Henry K, Chinnock BJ, Quinn RP, Fletcher CV, de Miranda P, Balfour HHJ. Concurrent zidovudine levels in semen and serum determined by radioimmunoassay in patients with AIDS or AIDS-related complex. JAMA 1988, 259: 3023–3026.
10. Pereira AS, Kashuba AD, Fiscus SA. et al. Nucleoside analogues achieve high concentrations in seminal plasma: relationship between drug concentration and virus burden. J Infect Dis 1999, 180: 2039–2043.
11. Taylor S, van Heeswijk RP, Hoetelmans RM. et al. Concentrations of nevirapine, lamivudine and stavudine in semen of HIV-1-infected men. AIDS 2000, 14: 1979–1984.
12. van Praag RM, Weverling GJ, Portegies P. et al. Enhanced penetration of indinavir in cerebrospinal fluid and semen after the addition of low-dose ritonavir. AIDS 2000, 14: 1187–1194.
13. Hugen PW, Verweij-van Wissen CP, Burger DM, Wuis EW, Koopmans PP, Hekster YA. Simultaneous determination of the HIV-protease inhibitors indinavir, nelfinavir, saquinavir and ritonavir in human plasma by reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1999, 727: 139–149.
14. Eyre RC, Zheng G, Kiessling AA. Multiple drug resistance mutations in human immunodeficiency virus in semen but not blood of a man on antiretroviral therapy. Urology 2000, 55: 591.591.
© 2002 Lippincott Williams & Wilkins, Inc.