Skip to main content
Log in

Lamivudine/Tenofovir Disoproxil Fumarate is an Appropriate PrEP Regimen

  • Current Opinion
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Oral pre-exposure prophylaxis (PrEP) containing tenofovir disoproxil fumarate (TDF) co-formulated with emtricitabine (FTC) or lamivudine (3TC) is recommended as an additional prevention option for persons at substantial risk of HIV infection by both the World Health Organization (WHO) and the US President’s Emergency Plan for AIDS Relief (PEPFAR). The WHO and PEPFAR consider 3TC clinically interchangeable with FTC for PrEP given comparable pharmacologic equivalence, resistance and toxicity patterns, and indirect clinical trial evidence from TDF-containing studies. Globally, FTC/TDF has been widely used in clinical trials, open-label extension studies and demonstration projects. Thus, most PrEP efficacy and safety data are based on FTC/TDF use in heterosexual women and men, men who have sex with men, and people who inject drugs. However, generic 3TC/TDF is less expensive than FTC/TDF, is already available in supply chains for HIV drugs, and has 60–70% of the global adult market share, making it particularly appealing in settings with limited availability or affordability of FTC/TDF. Compelling indirect evidence suggests that scaling up use of 3TC/TDF is potentially cost saving for HIV programs in settings where restricting drug choice to FTC/TDF would delay PrEP implementation. Guideline committees and public health decision-makers in countries should encourage flexibility in PrEP drug selection, support off-label use of 3TC/TDF, and approve use of generic formulations to decrease the cost of PrEP medications and accelerate PrEP delivery through the public and private sectors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Joint United Nations Programme on HIV/AIDS (2019). UNAIDS Data 2019. Available from: https://www.unaids.org/sites/default/files/media_asset/2019-UNAIDS-data_en.pdf. Accessed 20 Feb 2020.

  2. Joint United Nations Programme on HIV/AIDS (2018). Miles to go—closing gaps, breaking barriers, righting injustices. Available from: http://www.unaids.org/sites/default/files/media_asset/miles-to-go_en.pdf. Accessed 20 Feb 2020

  3. MMWR Morbidity and mortality weekly report. Centers for Disease Control and Prevention (CDC). Interim guidance: preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. 2011;60(3):65–8.

    Google Scholar 

  4. MMWR Morbidity and mortality weekly report. Centers for Disease Control and Prevention (CDC). Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. 2012;61(31):586–9.

  5. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587–99. https://doi.org/10.1056/NEJMoa1011205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Baeten JMDD, Wangisi J, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399–410. https://doi.org/10.1056/NEJMoa1108524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Thigpen MC, Kebaabetswe PM, Paxton LA, Smith DK, Rose CE, Segolodi TM, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367(5):423–34. https://doi.org/10.1056/NEJMoa1110711.

    Article  CAS  PubMed  Google Scholar 

  8. Molina JM, Capitant C, Spire B, Pialoux G, Cotte L, Charreau I, et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med. 2015;373(23):2237–46. https://doi.org/10.1056/NEJMoa1506273.

    Article  CAS  PubMed  Google Scholar 

  9. McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet. 2016;387(10013):53–60. https://doi.org/10.1016/s0140-6736(15)00056-2.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fonner VA, Dalglish SL, Kennedy CE, Baggaley R, O'Reilly KR, Koechlin FM, et al. Effectiveness and safety of oral HIV preexposure prophylaxis for all populations. AIDS. 2016;30(12):1973–83. https://doi.org/10.1097/qad.0000000000001145.

    Article  PubMed  PubMed Central  Google Scholar 

  11. US Food and Drug Administration (2014). Truvada for PrEP fact sheet: Ensuring safe and proper use. Available from: https://www.fda.gov/media/83586/download. Accessed 20 Feb 2020.

  12. World Health Organization (2015). Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. Available from: http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/. Accessed 9 Nov 2019.

  13. AVAC (2018). PrEPWatch. Country Updates. Available from: https://www.prepwatch.org/in-practice/country-updates/. Accessed 9 Nov 2019.

  14. World Health Organization (2017). Technical Update on Appropriate Medicines Options for Pre-Exposure Prophylaxis. Available from: https://apps.who.int/iris/bitstream/handle/10665/273934/WHO-CDS-HIV-18.22-eng.pdf?ua=1. Accessed 9 Nov 2019.

  15. European Medicines Agency (2016). Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP). Available from: https://www.ema.europa.eu/news/first-medicine-hiv-pre-exposure-prophylaxis-recommended-approval-eu. Accessed 20 Feb 2020.

  16. World Health Organization (2018). WHO essential medicines and health products: annual report 2017: towards access 2030 (No. WHO/EMP/2018.01). Available from: https://apps.who.int/iris/handle/10665/272972. Accessed 20 Feb 2020.

  17. Ford N, Vitoria M, Doherty M, Gray A. Candidates for inclusion in a universal antiretroviral regimen: are lamivudine and emtricitabine interchangeable? Curr Opin HIV AIDS. 2017;12(4):334–8. https://doi.org/10.1097/coh.0000000000000377.

    Article  CAS  PubMed  Google Scholar 

  18. Else LJ, Jackson A, Puls R, Hill A, Fahey P, Lin E, et al. Pharmacokinetics of lamivudine and lamivudine-triphosphate after administration of 300 milligrams and 150 milligrams once daily to healthy volunteers: results of the ENCORE 2 study. Antimicrob Agents Chemother. 2012;56(3):1427–33. https://doi.org/10.1128/aac.05599-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang LH, Begley J, St Claire RL, 3rd, Harris J, Wakeford C, Rousseau FS. Pharmacokinetic and pharmacodynamic characteristics of emtricitabine support its once daily dosing for the treatment of HIV infection. AIDS Res Human Retrovir. 2004;20(11):1173–82. https://doi.org/10.1089/aid.2004.20.1173.

  20. Yuen GJ, Lou Y, Bumgarner NF, Bishop JP, Smith GA, Otto VR, et al. Equivalent steady-state pharmacokinetics of lamivudine in plasma and lamivudine triphosphate within cells following administration of lamivudine at 300 milligrams once daily and 150 milligrams twice daily. Antimicrob Agents Chemother. 2004;48(1):176–82. https://doi.org/10.1128/aac.48.1.176-182.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rower JE, Meditz A, Gardner EM, Lichtenstein K, Predhomme J, Bushman LR, et al. Effect of HIV-1 infection and sex on the cellular pharmacology of the antiretroviral drugs zidovudine and lamivudine. Antimicrob Agents Chemother. 2012;56(6):3011–9. https://doi.org/10.1128/aac.06337-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Seifert SM, Glidden DV, Meditz AL, Castillo-Mancilla JR, Gardner EM, Predhomme JA, et al. Dose response for starting and stopping HIV preexposure prophylaxis for men who have sex with men. Clin Infect Dis. 2015;60(5):804–10. https://doi.org/10.1093/cid/ciu916.

    Article  CAS  PubMed  Google Scholar 

  23. Rodriguez JF, Rodriguez JL, Santana J, García H, Rosario O. Simultaneous quantitation of intracellular zidovudine and lamivudine triphosphates in human immunodeficiency virus-infected individuals. Antimicrob Agents Chemother. 2000;44(11):3097–100. https://doi.org/10.1128/aac.44.11.3097-3100.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Moore KH, Barrett JE, Shaw S, Pakes GE, Churchus R, Kapoor A, et al. The pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells from patients infected with HIV-1. Aids. 1999;13(16):2239–50. https://doi.org/10.1097/00002030-199911120-00006.

    Article  CAS  PubMed  Google Scholar 

  25. Bazzoli C, Bénech H, Rey E, Retout S, Salmon D, Duval X, et al. Joint population pharmacokinetic analysis of zidovudine, lamivudine, and their active intracellular metabolites in HIV patients. Antimicrob Agents Chemother. 2011;55(7):3423–31. https://doi.org/10.1128/aac.01487-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dickinson L, Yapa HM, Jackson A, Moyle G, Else L, Amara A, et al. Plasma tenofovir, emtricitabine, and rilpivirine and intracellular tenofovir diphosphate and emtricitabine triphosphate pharmacokinetics following drug intake cessation. Antimicrob Agents Chemother. 2015;59(10):6080–6. https://doi.org/10.1128/aac.01441-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Anderson PL, Kakuda TN, Kawle S, Fletcher CV. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. Aids. 2003;17(15):2159–68. https://doi.org/10.1097/00002030-200310170-00003.

    Article  CAS  PubMed  Google Scholar 

  28. Bruno R, Regazzi MB, Ciappina V, Villani P, Sacchi P, Montagna M, et al. Comparison of the plasma pharmacokinetics of lamivudine during twice and once daily administration in patients with HIV. Clin Pharmacokinet. 2001;40(9):695–700.

    Article  CAS  Google Scholar 

  29. Schinazi RF. Assessment of the relative potency of emtricitabine and lamivudine. J Acquir Immune Defic Syndr. 2003;34(2):243–5 (author reply 5–6).

  30. Bushman LR, Kiser JJ, Rower JE, Klein B, Zheng JH, Ray ML, et al. Determination of nucleoside analog mono-, di-, and tri-phosphates in cellular matrix by solid phase extraction and ultra-sensitive LC-MS/MS detection. J Pharm Biomed Anal. 2011;56(2):390–401. https://doi.org/10.1016/j.jpba.2011.05.039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Maserati R. Differentiating emtricitabine (FTC) from lamivudine (3TC): what a “fine-tuning” of antiretroviral therapy might entail. Available from: http://win.mnlpublimed.com/public/HA10-A04.pdf. Accessed 11 Sept 2020.

  32. Dumond JB, Yeh RF, Patterson KB, Corbett AH, Jung BH, Rezk NL, et al. Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis. Aids. 2007;21(14):1899–907. https://doi.org/10.1097/QAD.0b013e328270385a.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dumond JB, Reddy YS, Troiani L, Rodriguez JF, Bridges AS, Fiscus SA, et al. Differential extracellular and intracellular concentrations of zidovudine and lamivudine in semen and plasma of HIV-1-infected men. J Acquir Immune Defic Syndr. 2008;48(2):156–62. https://doi.org/10.1097/QAI.0b013e31816de21e.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hendrix CW, Andrade A, Bumpus NN, Kashuba AD, Marzinke MA, Moore A, et al. Dose frequency ranging pharmacokinetic study of tenofovir-emtricitabine after directly observed dosing in healthy volunteers to establish adherence benchmarks (HPTN 066). AIDS Res Hum Retroviruses. 2016;32(1):32–433. https://doi.org/10.1089/aid.2015.0182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Valade E, Tréluyer JM, Illamola SM, Bouazza N, Foissac F, De Sousa MM, et al. Emtricitabine seminal plasma and blood plasma population pharmacokinetics in HIV-infected men in the EVARIST ANRS-EP 49 study. Antimicrob Agents Chemother. 2015;59(11):6800–6. https://doi.org/10.1128/aac.01517-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Seifert SM, Chen X, Meditz AL, Castillo-Mancilla JR, Gardner EM, Predhomme JA, et al. Intracellular tenofovir and emtricitabine anabolites in genital, rectal, and blood compartments from first dose to steady state. AIDS Res Hum Retrovir. 2016;32(10–11):981–91. https://doi.org/10.1089/aid.2016.0008.

    Article  CAS  PubMed  Google Scholar 

  37. Patterson KB, Prince HA, Kraft E, Jenkins AJ, Shaheen NJ, Rooney JF et al. Penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of HIV-1 transmission. Sci Transl Med. 2011;3(112):112re4. https://doi.org/10.1126/scitranslmed.3003174.

  38. Zemlicka J. Enantioselectivity of the antiviral effects of nucleoside analogues. Pharmacol Ther. 2000;85(3):251–66.

    Article  CAS  Google Scholar 

  39. Liou JY, Dutschman GE, Lam W, Jiang Z, Cheng YC. Characterization of human UMP/CMP kinase and its phosphorylation of d- and l-form deoxycytidine analogue monophosphates. Cancer Res. 2002;62(6):1624–31.

    CAS  PubMed  Google Scholar 

  40. World Health Organization (2012). Technical update on treatment optimization: pharmacological equivalence and clinical interchangeability of lamivudine and emtricitabine: a review of current literature. Available from: https://apps.who.int/iris/handle/10665/70936. Accessed 20 Feb 2020.

  41. Rousseau FS, Wakeford C, Mommeja-Marin H, Sanne I, Moxham C, Harris J, et al. Prospective randomized trial of emtricitabine versus lamivudine short-term monotherapy in human immunodeficiency virus-infected patients. J Infect Dis. 2003;188(11):1652–8. https://doi.org/10.1086/379667.

    Article  CAS  PubMed  Google Scholar 

  42. Ford N, Shubber Z, Hill A, Vitoria M, Doherty M, Mills EJ, et al. Comparative efficacy of Lamivudine and emtricitabine: a systematic review and meta-analysis of randomized trials. PLoS ONE. 2013;8(11):e79981. https://doi.org/10.1371/journal.pone.0079981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. World Health Organization (2002). Scaling up antiretroviral therapy in resource-limited settings: guidelines for a public health approach: executive summary. Available from: https://apps.who.int/iris/bitstream/handle/10665/42514/9241545674.pdf. Accessed 20 Feb 2020.

  44. World Health Organization (2016). Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. Available from: https://apps.who.int/iris/bitstream/handle/10665/208825/9789241549684_eng.pdf. Accessed 20 Feb 2020.

  45. Derdelinckx I, Wainberg MA, Lange JM, Hill A, Halima Y, Boucher CA. Criteria for drugs used in pre-exposure prophylaxis trials against HIV infection. PLoS Med. 2006;3(11):e454.

    Article  Google Scholar 

  46. Boucher CA, Cammack N, Schipper P, Schuurman R, Rouse P, Wainberg MA, et al. High-level resistance to (−) enantiomeric 2'-deoxy-3'-thiacytidine in vitro is due to one amino acid substitution in the catalytic site of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 1993;37(10):2231–4.

    Article  CAS  Google Scholar 

  47. Diallo K, Gotte M, Wainberg MA. Molecular impact of the M184V mutation in human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 2003;47(11):3377–83.

    Article  CAS  Google Scholar 

  48. Turner D, Brenner B, Wainberg MA. Multiple effects of the M184V resistance mutation in the reverse transcriptase of human immunodeficiency virus type 1. Clin Diagn Lab Immunol. 2003;10(6):979–81.

    Article  CAS  Google Scholar 

  49. Quercia R, Perno CF, Koteff J, Moore K, McCoig C, St Clair M, et al. Twenty-five years of lamivudine: current and future use for the treatment of HIV-1 infection. J Acquir Immune Defic Syndr. 2018;78(2):125–35. https://doi.org/10.1097/qai.0000000000001660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wolf K, Walter H, Beerenwinkel N, Keulen W, Kaiser R, Hoffmann D, et al. Tenofovir resistance and resensitization. Antimicrob Agents Chemother. 2003;47(11):3478–84.

    Article  CAS  Google Scholar 

  51. Larder BA, Kemp SD, Harrigan PR. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science. 1995;269(5224):696–9.

    Article  CAS  Google Scholar 

  52. Pillay D, Albert J, Bertagnolio S, Boucher C, Brun-Vezinet F, Clotet B, et al. Implications of HIV drug resistance on first- and second-line therapies in resource-limited settings: report from a workshop organized by the Collaborative HIV and Anti-HIV Drug Resistance Network. Antiviral Therapy. 2013;18(6):831–6. https://doi.org/10.3851/imp2650.

    Article  CAS  PubMed  Google Scholar 

  53. World Health Organization (2017). Global Price Reporting Mechanism for HIV, tuberculosis and malaria. Available from: http://www.who.int/hiv/amds/gprm/en/. Accessed 20 Feb 2020.

  54. Massud I, Sykes C, Cong ME, Ellis S, Kelly K, Heneine W et al. Pharmacokinetic profile of lamivudine (3TC) in macaques and relative drug exposure in rectal and vaginal tissues. abstracts of the HIV research for prevention meeting, HIVR4P, 17–20 October, 2016, Chicago, USA. AIDS Res Human Retrovir. 2016;32(S1):1–409. https://doi.org/10.1089/aid.2016.5000.abstracts.

  55. Vyankandondera J, Luchters S, Hassink E, Pakker N, Mmiro F, Okong P et al., editors. Reducing risk of HIV-1 transmission from mother to infant through breastfeeding using antiretroviral prophylaxis in infants (SIMBA-study). In: 2nd IAS Conference on HIV Pathogenesis and Treatment. Paris; 2003.

  56. Kilewo C, Karlsson K, Massawe A, Lyamuya E, Swai A, Mhalu F, et al. Prevention of mother-to-child transmission of HIV-1 through breast-feeding by treating infants prophylactically with lamivudine in Dar es Salaam, Tanzania: the Mitra Study. J Acquir Immune Defic Syndr. 2008;48(3):315–23. https://doi.org/10.1097/QAI.0b013e31816e395c.

    Article  CAS  PubMed  Google Scholar 

  57. de Vincenzi I. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infect Dis. 2011;11(3):171–80. https://doi.org/10.1016/s1473-3099(10)70288-7.

    Article  PubMed  Google Scholar 

  58. Nagot N, Kankasa C, Tumwine JK, Meda N, Hofmeyr GJ, Vallo R, et al. Extended pre-exposure prophylaxis with lopinavir-ritonavir versus lamivudine to prevent HIV-1 transmission through breastfeeding up to 50 weeks in infants in Africa (ANRS 12174): a randomised controlled trial. Lancet. 2016;387(10018):566–73. https://doi.org/10.1016/s0140-6736(15)00984-8.

    Article  CAS  PubMed  Google Scholar 

  59. Mancuzo AV, Carvalho LV, Carvalho GC et al. Evaluation of the acceptability, feasibility, safety and adherence to pre-exposure prophylaxis (PrEP) for HIV prevention in men who have sex with men (MSM): Phase 1 study (submitted abstract) [cited in https://apps.who.int/iris/bitstream/handle/10665/273934/WHO-CDS-HIV-18.22-eng.pdf?ua=1].

  60. Hodges-Mameletzis I. TDF/3TC for PrEP: the rationale and the evidence. Geneva: World Health Organization; 2019.

    Google Scholar 

  61. Baeten JM, Donnell D, Mugo NR, Ndase P, Thomas KK, Campbell JD, et al. Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial. Lancet Infect Dis. 2014;14(11):1055–64. https://doi.org/10.1016/s1473-3099(14)70937-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. PEPFAR. Recommendations on the Use of PrEP for All Populations. PEPFAR Scientific Advisory Board (SAB). 2015.

  63. European AIDS Clinical Society Guidelines (Version 9.0, October 2017). Available from: https://www.eacsociety.org/files/guidelines_9.0-english.pdf. Accessed 20 Feb 2020.

  64. Hodges-Mameletzis I, Dalal S, Msimanga-Radebe B, Rodolph M, Baggaley R. Going global: the adoption of the World Health Organization's enabling recommendation on oral pre-exposure prophylaxis for HIV. Sexual health. 2018;15(6):489–500. https://doi.org/10.1071/sh18125.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andrew Mujugira.

Ethics declarations

Funding

This work was supported through research grants from National Institutes of Health (research grant number K43 TW010695 (AM) and K24 mentor award MH114732 (JEH)). This paper represents the opinions of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of Interest

JMB served as an advisor for Gilead Sciences, Janssen, and Merck. JEH is a consultant for Merck. AM received donated FTC/TDF from Gilead Sciences for an investigator-sponsored study.

Ethics Approval

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Materials

Not applicable.

Code Availability

Not applicable.

Author Contributions

AM, JMB, and JEH conceptualized the paper. AM wrote the first draft along with JEH. IHM, JMB, JEH, and AM reviewed drafts and provided substantial edits. All authors read and approved the final manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mujugira, A., Baeten, J.M., Hodges-Mameletzis, I. et al. Lamivudine/Tenofovir Disoproxil Fumarate is an Appropriate PrEP Regimen. Drugs 80, 1881–1888 (2020). https://doi.org/10.1007/s40265-020-01419-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-020-01419-4

Navigation