Pharmacodynamics of efavirenz 400 mg in treatment-naïve Chinese HIV-infected patients in a prospective cohort study

Ling Xu, Wenxiu Peng, Xiaojing Song, Yanling Li, Yang Han, Ting Zhu, Qiang Fu, Xiaoli Du, Wei Cao, Taisheng Li, Ling Xu, Wenxiu Peng, Xiaojing Song, Yanling Li, Yang Han, Ting Zhu, Qiang Fu, Xiaoli Du, Wei Cao, Taisheng Li

Abstract

Background: The plasma concentration of patients treated with efavirenz (EFV) 600 mg was found to exceed the upper limit of the proposed therapeutic window in most Chinese HIV-infected individuals; thus, dosage reduction of EFV to 400 mg daily warranted consideration. This study aimed to assess the pharmacodynamics of EFV 400 mg for HIV-1-infected patients in China.

Method: Twenty cART-naïve individuals were enrolled in this study. EFV 400 mg combined with tenofovir (TDF) and lamivudine (3TC) as an initial antiretroviral regimen was administered for 48 weeks. EFV concentration and T cell subsets as well as HIV RNA load were evaluated at baseline and at 4, 12, 24, and 48 weeks. Moreover, neuropsychiatric adverse effects were also assessed by the Hamilton depression (HAMD) scale and Pittsburgh sleep quality index (PSQI).

Results: Eighteen males and two females whose median age was 26 (interquartile range [IQR]: 23-32) years completed 48 weeks of follow-up. The median EFV concentrations were 1.88 (IQR: 1.54-2.42), 1.74 (IQR: 1.36-1.93), 1.93 (IQR: 1.66-2.22), and 1.85 (IQR: 1.54-2.14) mg/L at weeks 4, 12, 24, and 48, respectively. The viral load was 4.59 (IQR: 4.10-5.19) log10 copies/mL at baseline, and it decreased by 4.6 (IQR: 3.98-5.18) log10 copies/mL from baseline to week 48. Three of 20 (15%), 10 of 20 (50.0%), 17 of 20 (85%), and 18 of 19 (95%) participants had a plasma viral load less than 50 copies/mL at weeks 4, 12, 24, and 48, respectively. The median CD4 cell count was 330 (IQR: 237-410) cells/μL at baseline, and it increased to 473 (IQR: 344-574) cells/μL at 48 weeks. The HAMD score was 5 (IQR: 3-9.8) and 3 (IQR: 2.25-4) at baseline and 48 weeks, respectively. The PSQI score was 4 (IQR: 2-5.8) and 3 (IQR: 2-4) at baseline and 48 weeks, respectively. Dizziness was the most common event, occurring in 70% of patients within the first 2 weeks of treatment.

Conclusion: Patients prescribed with EFV 400 mg-containing agents demonstrated favourable virological and immunological responses. And the plasma EFV concentration was within the recommended therapeutic range, with fewer adverse reactions than with EFV 600 mg. EFV 400 mg was effective and safe in Chinese HIV-infected patients.

Trial registration: NCT04596488 ; Registered 21 October, 2020; Retrospectively registered.

Keywords: EFV 400 mg; HAMD; HIV RNA load; PSQI; Plasma EFV concentration.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow of patients through the screening process
Fig. 2
Fig. 2
Dynamic changes to the plasma EFV concentration during cART treatment. The plasma EFV concentration in 79 samples a and patients stratified by body weight b and the correlation between weight and EFV concentration c were shown
Fig. 3
Fig. 3
Virological responses in HIV-infected individuals commenced on EFV 400 mg. The decrease of HIV RNA load a and proportion of patients who achieved virological suppression at different time-points b were recorded
Fig. 4
Fig. 4
Immunological responses in HIV-infected patients. The graphs demonstrated the increase of CD4 cell counts a and CD4/D8 ratio during follow-up period b
Fig. 5
Fig. 5
The changes of safety parameters. The trajectory of score on HAMD and PSQI a and the occurrence of adverse events b were displayed in details
Fig. 6
Fig. 6
The dynamics of biochemical or haematological parameters. No significant change was observed in terms of WBC counts a, PLT counts b, transaminase c, Creatinine d, Glucose e and blood lipid levels f during follow-up period

References

    1. UNAIDS.
    1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. USA: Department of Health and Human Services; 2019. Available at . . Accessed 19 Jun 2020.
    1. EACS Guidelines version 9.1, October 2018. 2018. . org/files/2018_guidelines-9.1-english.pdf. .
    1. Long-Term Virological Suppression Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord. Long-term virological suppression on first-line efavirenz + tenofovir + emtricitabine/lamivudine for HIV-1. AIDS. 2019;33(4):745–751. doi: 10.1097/QAD.0000000000002126.
    1. WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. Geneva: World Health Organization. June, 2013.
    1. Rockstroh JK, DeJesus E, Lennox JL, Yazdanpanah Y, Saag MS, Wan H, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1- infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr. 2013;63(1):77–85. doi: 10.1097/QAI.0b013e31828ace69.
    1. Walmsley SL, Antela A, Clumeck N, Duiculescu D, Eberhard A, Gutiérrez F, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807–1818. doi: 10.1056/NEJMoa1215541.
    1. Scourfield A, Zheng J, Chinthapalli S, Waters L, Martin T, Mandalia S, et al. Discontinuation of Atripla as first-line therapy in HIV-1 infected individuals. AIDS. 2012;26(11):1399–1401. doi: 10.1097/QAD.0b013e328353b047.
    1. Gutiérrez F, Navarro A, Chinthapalli S, Waters L, Martin T, Mandalia S, et al. Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin Infect Dis. 2005;41(11):1648–1653. doi: 10.1086/497835.
    1. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1- infected patients. AIDS. 2001;15(1):71–75. doi: 10.1097/00002030-200101050-00011.
    1. Guo F, Cheng X, Hsieh E, Du X, Fu Q, Peng W, et al. Prospective plasma efavirenz concentration assessment in Chinese HIV-infected adults enrolled in a large multicentre study. HIV Med. 2018. 10.1111/hiv.12607.
    1. van Luin M, Gras L, Richter C, van der Ende ME, Prins JM, de Wolf F, et al. Efavirenz dose reduction is safe in patients with high plasma concentrations and may prevent efavirenz discontinuations. J Acquir Immune Defic Syndr. 2009;52(2):240–245. doi: 10.1097/QAI.0b013e3181b061e6.
    1. ENCORE1 Study Group Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet. 2014;383(9927):1474–1482. doi: 10.1016/S0140-6736(13)62187-X.
    1. Wyen C, Hendra H, Vogel M, Hoffmann C, Knechten H, Brockmeyer NH, et al. Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients. J Antimicrob Chemother. 2008;61(4):914–918. doi: 10.1093/jac/dkn029.
    1. Cohen CJ, Andrade-Villanueva J, Clotet B, Fourie J, Johnson MA, Ruxrungtham K, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011;378(9787):229–237. doi: 10.1016/S0140-6736(11)60983-5.
    1. Nyakutira C, Röshammar D, Chigutsa E, Chonzi P, Ashton M, Nhachi C, et al. High prevalence of the CYP2B6 516G-->T(*6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe. Eur J Clin Pharmacol. 2008;64(4):357–365. doi: 10.1007/s00228-007-0412-3.
    1. To KW. Liu ST, Cheung SW, Chan DP, Chan RC, Lee SS. Pharmacokinetics of plasma efavirenz and CYP2B6 polymorphism in southern Chinese. Ther Drug Monit. 2009;31(4):527–530. doi: 10.1097/FTD.0b013e3181ad74a4.
    1. Dickinson L, Amin J, Else L, Boffito M, Egan D, Owen A, et al. Comprehensive pharmacokinetic, Pharmacodynamic and Pharmacogenetic evaluation of once-daily Efavirenz 400 and 600 mg in treatment-Na ¨ıve HIV-infected patients at 96 weeks: results of the ENCORE1 study. Clin Pharmacokinet. 2016;55(7):861–873. doi: 10.1007/s40262-015-0360-5.
    1. Luetkemeyer AF, Rosenkranz SL, Lu D, Marzan F, Ive P, Hogg E. Relationship between weight, Efavirenz exposure, and Virologic suppression in HIV-infected patients on rifampin-based tuberculosis treatment in the AIDS Clinical Trials Group A5221 STRIDE study. Clin Infect Dis. 2013;57(4):586–593. doi: 10.1093/cid/cit246.
    1. Bellagamba R, Giancola ML, Tommasi C, Piselli P, Tempestilli M, Angeletti C, et al. Randomized clinical trial on efficacy of fixed-dose efavirenz/tenofovir/emtricitabine on alternate days versus continuous treatment. AIDS. 2019;33(3):493–502. doi: 10.1097/QAD.0000000000002067.
    1. Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis. 2007;44(3):441–446. doi: 10.1086/510746.
    1. Mutoh Y, Nishijima T, Inaba Y, Tanaka N, Kikuchi Y, Gatanaga H, et al. Incomplete recovery of CD4 cell count, CD4 percentage, and CD4/CD8 ratio in patients with human immunodeficiency virus infection and suppressed Viremia during long-term antiretroviral therapy. Clin Infect Dis. 2018;67(6):927–933. doi: 10.1093/cid/ciy176.
    1. Kenedi CA, Goforth HW. A systematic review of the psychiatric side-effects of efavirenz. AIDS Behav. 2011;15(8):1803–1818. doi: 10.1007/s10461-011-9939-5.
    1. Ford N, Shubber Z, Pozniak A, Vitoria M, Doherty M, Kirby C, et al. Comparative safety and neuropsychiatric adverse events associated with Efavirenz use in first-line antiretroviral therapy: a systematic review and meta-analysis of randomized trials. J Acquir Immune Defic Syndr. 2015;69(4):422–429. doi: 10.1097/QAI.0000000000000606.
    1. Sun J, Chen J, Yao Y, Zhang R, Zheng Y, Liu L, et al. Minimum effective plasma. Concentration of efavirenz in treatment-naive Chinese HIV-infected patients. Int J STD AIDS. 2010;21(12):810–813. doi: 10.1258/ijsa.2010.010114.
    1. Fumaz CR, Muñoz-Moreno JA, Moltó J, Negredo E, Ferrer MJ, Sirera G, et al. Long-term neuropsychiatric disorders on efavirenz-based approaches: quality of life, psychologic issues, and adherence. J Acquir Immune Defic Syndr. 2005;38(5):560–565. doi: 10.1097/01.qai.0000147523.41993.47.
    1. Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh. Sleep quality index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193–213. doi: 10.1016/0165-1781(89)90047-4.
    1. Mowla A, Dastgheib SA, Razeghian JL. Comparing the effects of. Sertraline with duloxetine for depression severity and symptoms: a double-blind, randomized controlled trial. Clin Drug Investig. 2016;36(7):539–543. doi: 10.1007/s40261-016-0399-6.
    1. Hidese S, Ota M, Wakabayashi C, Noda T, Ozawa H, Okubo T, et al. Effects of. Chronic l-theanine administration in patients with major depressive disorder: an open-label study. Acta Neuropsychiatr. 2017;29(2):72–79. doi: 10.1017/neu.2016.33.
    1. Huang X, Meyers K, Liu X, Li X, Zhang T, Xia W, et al. The double burdens of. Mental Health Among AIDS Patients With Fully Successful Immune Restoration: A Cross-Sectional Study of Anxiety and Depression in China. Front Psychiatry. 2018;9:384. doi: 10.3389/fpsyt.2018.00384.
    1. Wang J, Sönnerborg A, Rane A, Josephson F, Lundgren S, Ståhle L, et al. Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz. Pharmacogenet Genomics. 2006;16(3):191–198.
    1. Jamshidi Y, Moreton M, McKeown DA, Andrews S, Nithiyananthan T, Tinworth L, et al. Tribal ethnicity and CYP2B6 genetics in Ugandan and Zimbabwean populations in the UK: implications for efavirenz dosing in HIV infection. J Antimicrob Chemother. 2010;65(12):2614–2619. doi: 10.1093/jac/dkq369.
    1. Ribaudo HJ, Liu H, Schwab M, Schaeffeler E, Eichelbaum M, Motsinger-Reif AA, et al. Effect of CYP2B6, ABCB1, and CYP3A5 polymorphisms on efavirenz pharmacokinetics and treatment response: an AIDS Clinical Trials Group study. J Infect Dis. 2011;202(5):717–722. doi: 10.1086/655470.
    1. Sarfo FS, Zhang Y, Egan D, Tetteh LA, Phillips R, Bedu-Addo G, et al. Pharmacogenetic associations with plasma efavirenz concentrations and clinical correlates in a retrospective cohort of Ghanaian HIV-infected patients. J Antimicrob Chemother. 2014;69(2):491–499. doi: 10.1093/jac/dkt372.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться