Pharmacokinetic/pharmacodynamic investigation of raltegravir with or without lamivudine in the context of HIV-1 pre-exposure prophylaxis (PrEP)

Carolina Herrera, Julianne Lwanga, Ming Lee, Suna Mantori, Alieu Amara, Laura Else, Sujan Dilly Penchala, Deirdre Egan, Elizabeth Challenger, Laura Dickinson, Marta Boffito, Robin Shattock, Saye Khoo, Julie Fox, Carolina Herrera, Julianne Lwanga, Ming Lee, Suna Mantori, Alieu Amara, Laura Else, Sujan Dilly Penchala, Deirdre Egan, Elizabeth Challenger, Laura Dickinson, Marta Boffito, Robin Shattock, Saye Khoo, Julie Fox

Abstract

Background: To characterize their potential use in pre-exposure prophylaxis (PrEP) we compared the pharmacokinetics of raltegravir and lamivudine in genital tissue against ex vivo tissue infection with HIV-1.

Methods: Open-label trial of 36 HIV-negative females and males randomized to 7 days raltegravir 400 mg twice daily and 7 days raltegravir 400 mg+lamivudine 150 mg twice daily (after washout), or vice versa. Blood, saliva, rectal fluid, rectal tissue, vaginal fluid and vaginal tissue were sampled at baseline and on and off PrEP during a total of 12 days, for pharmacokinetics and antiviral activity via ex vivo HIV-1BaL challenge. Ex vivo infectivity was compared with baseline. The trial has been registered in https://ichgcp.net/clinical-trials-registry/NCT03205566" title="See in ClinicalTrials.gov">NCT03205566.

Results: Steady state for both drugs was reached by day 4. Dosing with raltegravir alone provided modest ex vivo HIV protection with higher drug levels in rectal tissue and vaginal tissue than in plasma on and off PrEP. Off PrEP, plasma and vaginal concentrations declined rapidly, while persisting in the rectum. On PrEP, the highest lamivudine concentrations were in the rectum, followed by vaginal tissue then plasma. Lamivudine washout was rapid in plasma, while persisting in the rectum and vagina. Raltegravir/lamivudine increased ex vivo protection on and off PrEP compared with raltegravir alone, reaching maximum protection at day 2 in rectal tissue and at day 8 in vaginal tissue.

Conclusions: Raltegravir 400 mg+lamivudine 150 mg showed high levels of ex vivo HIV protection, associated with high drug concentrations persisting after discontinuation in vaginal and rectal compartments, supporting further investigation of these agents for PrEP.

© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.
Figure 1.
Study design. Two PrEP regimens were investigated and all 36 individuals (18 men and 18 women) received both regimens separated by a 1 month washout. Arm A started with 14 days of raltegravir 400 mg twice daily and arm B started with 14 days of raltegravir 400 mg+lamivudine 150 mg twice daily to remove sequential selection bias. Participants were randomized according to gender to one of six arms with three men and three women per block (A1, A2, A3, B1, B2 and B3). bd, twice daily; 3TC, lamivudine.
Figure 2.
Figure 2.
Longitudinal PK analysis. Raltegravir (a and b) and lamivudine (c) levels were measured in vaginal fluid, rectal fluid, vaginal tissue, rectal tissue, plasma and saliva at each sampling point during and after PrEP dosing with raltegravir 400 mg (a) and raltegravir 400 mg+lamivudine 150 mg (b and c). Data are mean ± SEM. The dotted line indicates the timepoint when PrEP dosing stopped. RAL, raltegravir; 3TC, lamivudine; VF, vaginal fluid; RF, rectal fluid; VT, vaginal tissue; RT; rectal tissue.
Figure 3.
Figure 3.
Longitudinal analysis of protection level. Ex vivo protection of rectal and vaginal explants was defined as day 15 p24 level >60% lower compared with day 15 p24 of baseline explants following challenge with HIV-1BaL at a high titre (104 TCID50/mL) (a and b) or a low titre (102 TCID50/mL) (c and d). Data are the percentage of samples considered protected under this criterion at each timepoint on and off PrEP with raltegravir 400 mg (a and c) and raltegravir 400 mg+lamivudine 150 mg (b and d). The dotted line indicates the timepoint when PrEP dosing stopped. RAL, raltegravir; 3TC, lamivudine.
Figure 4.
Figure 4.
Correlations of drug concentrations with p24 levels in culture supernatants. Log-transformed p24 levels in day 15 culture supernatants of rectal (a, b, c, d, e, f, m, n, o, p, q and r) and vaginal (g, h, i, j, k, l, s, t, u, v, w and x) explants challenged ex vivo with HIV-1BaL at a high titre (104 TCID50/mL) or a low titre (102 TCID50/mL) were correlated with log-transformed raltegravir and lamivudine concentrations in plasma and mucosal tissue (rectal tissue or vaginal tissue) by Pearson correlation. P < 0.05 was considered statistically significant. RAL, raltegravir; 3TC, lamivudine; RT, rectal tissue; VT, vaginal tissue.

References

    1. Baeten JM, Donnell D, Ndase P. et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012; 367: 399–410.
    1. Grant RM, Lama JR, Anderson PL. et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363: 2587–99.
    1. Thigpen MC, Kebaabetswe PM, Paxton LA. et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012; 367: 423–34.
    1. Van Damme L, Corneli A, Ahmed K. et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med 2012; 367: 411–22.
    1. Molina JM, Capitant C, Spire B. et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med 2015; 373: 2237–46.
    1. Mulligan K, Glidden DV, Anderson PL. et al. Effects of emtricitabine/tenofovir on bone mineral density in HIV-negative persons in a randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2015; 61: 572–80.
    1. Clement ME, Kofron R, Landovitz RJ.. Long-acting injectable cabotegravir for the prevention of HIV infection. Curr Opin HIV AIDS 2020; 15: 19–26.
    1. Adams JL, Greener BN, Kashuba AD.. Pharmacology of HIV integrase inhibitors. Curr Opin HIV AIDS 2012; 7: 390–400.
    1. Neff CP, Ndolo T, Tandon A. et al. Oral pre-exposure prophylaxis by anti-retrovirals raltegravir and maraviroc protects against HIV-1 vaginal transmission in a humanized mouse model. PLoS One 2010; 5: e15257.
    1. Veselinovic M, Yang KH, Sykes C. et al. Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: implications for HIV pre-exposure prophylaxis. Virology 2016; 489: 173–8.
    1. Else LJ, Taylor S, Back DJ. et al. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the male and female genital tract. Antivir Ther 2011; 16: 1149–67.
    1. Trezza CR, Kashuba AD.. Pharmacokinetics of antiretrovirals in genital secretions and anatomic sites of HIV transmission: implications for HIV prevention. Clin Pharmacokinet 2014; 53: 611–24.
    1. Patterson KB, Prince HA, Stevens T. et al. Differential penetration of raltegravir throughout gastrointestinal tissue: implications for eradication and cure. AIDS 2013; 27: 1413–9.
    1. Lee SA, Telwatte S, Hatano H. et al. Antiretroviral therapy concentrations differ in gut vs. lymph node tissues and are associated with HIV viral transcription by a novel RT-ddPCR assay. J Acquir Immune Defic Syndr 2020; 83: 530–7.
    1. Herrera C, Cranage M, McGowan I. et al. Reverse transcriptase inhibitors as potential colorectal microbicides. Antimicrob Agents Chemother 2009; 53: 1797–807.
    1. Herrera C, Cranage M, McGowan I. et al. Colorectal microbicide design: triple combinations of reverse transcriptase inhibitors are optimal against HIV-1 in tissue explants. AIDS 2011; 25: 1971–9.
    1. Herrera C, Shattock RJ.. Candidate microbicides and their mechanisms of action. Curr Top Microbiol Immunol 2014; 383: 1–25.
    1. Shaw GM, Hunter E.. HIV transmission. Cold Spring Harb Perspect Med 2012; 2: a006965.
    1. Cranage M, Sharpe S, Herrera C. et al. Prevention of SIV rectal transmission and priming of T cell responses in macaques after local pre-exposure application of tenofovir gel. PLoS Med 2008; 5: e157.
    1. Dereuddre-Bosquet N, Morellato-Castillo L, Brouwers J. et al. MiniCD4 microbicide prevents HIV infection of human mucosal explants and vaginal transmission of SHIV162P3 in cynomolgus macaques. PLoS Pathog 2012; 8: e1003071.
    1. Wallace GS, Cheng-Mayer C, Schito ML. et al. Human immunodeficiency virus type 1 nucleocapsid inhibitors impede trans infection in cellular and explant models and protect nonhuman primates from infection. J Virol 2009; 83: 9175–82.
    1. Anton PA, Cranston RD, Kashuba A. et al. RMP-02/MTN-006: a phase 1 rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of tenofovir 1% gel compared with oral tenofovir disoproxil fumarate. AIDS Res Hum Retroviruses 2012; 28: 1412–21.
    1. Fox J, Tiraboschi JM, Herrera C. et al. Brief Report: pharmacokinetic/pharmacodynamic investigation of single-dose oral maraviroc in the context of HIV-1 pre-exposure prophylaxis. J Acquir Immune Defic Syndr 2016; 73: 252–7.
    1. McGowan I, Cranston RD, Duffill K. et al. A phase 1 randomized, open label, rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of three formulations of tenofovir 1% gel (the CHARM-01 study). PLoS One 2015; 10: e0125363.
    1. McGowan I, Wilkin T, Landovitz RJ. et al. The pharmacokinetics, pharmacodynamics, and mucosal responses to maraviroc-containing pre-exposure prophylaxis regimens in MSM. AIDS 2019; 33: 237–46.
    1. Richardson-Harman N, Hendrix CW, Bumpus NN. et al. Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study. PLoS One 2014; 9: e111507.
    1. Richardson-Harman N, Mauck C, McGowan I. et al. Dose-response relationship between tissue concentrations of UC781 and explant infectibility with HIV type 1 in the RMP-01 rectal safety study. AIDS Res Hum Retroviruses 2012; 28: 1422–33.
    1. Richardson-Harman N, Lackman-Smith C, Fletcher PS. et al. Multisite comparison of anti-human immunodeficiency virus microbicide activity in explant assays using a novel endpoint analysis. J Clin Microbiol 2009; 47: 3530–9.
    1. Else L, Watson V, Tjia J. et al. Validation of a rapid and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay for the simultaneous determination of existing and new antiretroviral compounds. J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878: 1455–65.
    1. U.S. Department of Health and Human Services, FDA, Center for Drug Evaluation and Research, Center for Veterinary Medicine. Bioanalytical Method Validation Guidance for Industry. 2018. .
    1. Hu Q, Frank I, Williams V. et al. Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue. J Exp Med 2004; 199: 1065–75.
    1. Gartner S, Markovits P, Markovitz DM. et al. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 1986; 233: 215–9.
    1. Drogan D, Rauch P, Hoffmann D. et al. The antiretroviral potency of emtricitabine is approximately 3-fold higher compared to lamivudine in dual human immunodeficiency virus type 1 infection/competition experiments in vitro. Antiviral Res 2010; 86: 312–5.
    1. Massud I, Martin A, Dinh C. et al. Pharmacokinetic profile of raltegravir, elvitegravir and dolutegravir in plasma and mucosal secretions in rhesus macaques. J Antimicrob Chemother 2015; 70: 1473–81.
    1. Vishwanathan SA, Guenthner PC, Lin CY. et al. High susceptibility to repeated, low-dose, vaginal SHIV exposure late in the luteal phase of the menstrual cycle of pigtail macaques. J Acquir Immune Defic Syndr 2011; 57: 261–4.
    1. Poles MA, Elliott J, Taing P. et al. A preponderance of CCR5+ CXCR4+ mononuclear cells enhances gastrointestinal mucosal susceptibility to human immunodeficiency virus type 1 infection. J Virol 2001; 75: 8390–9.

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