Drugs

Tenofovir-Based Microbicides

Other Names: GS-1278, PMPA gel, TFV gel, tenofovir 1% gel, tenofovir gel Drug Class: Microbicides
Molecular Formula: C9 H14 N5 O4 P
Registry Number: 147127-20-6 (CAS) Chemical Name: [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methylphosphonic acid Chemical Class: Purine Nucleotides Organization: Centre for the AIDS Programme of Research in South Africa, Gilead Sciences, Inc. Phase of Development: Tenofovir vaginal gel has been studied in a Phase 3 trial. Tenofovir rectal gel has been studied in a Phase 2 trial. Intravaginal rings containing tenofovir are currently being studied in a Phase 2a trial. Other tenofovir-based microbicides are in earlier phases of study.

Chemical Image:

(Click to enlarge)
tenofovir

tenofovir

Molecular Weight: 287.2146

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and ClinicalTrials.gov3-12)

Pharmacology


Mechanism of Action: Microbicide; nucleoside reverse transcriptase inhibitor. HIV-specific topical microbicides formulated with ARV drugs, such as tenofovir, are being developed as a pre-exposure prophylaxis (PrEP) strategy to prevent the sexual transmission of HIV. ARV-based topical microbicides are designed to inhibit the infection process at the vaginal or rectal mucosa and directly interfere with the HIV replication cycle.13-16

Tenofovir, an adenosine nucleoside monophosphate (nucleotide) analog, is intracellularly phosphorylated to the active metabolite tenofovir diphosphate (TFV-DP). TFV-DP competitively inhibits the activity of HIV reverse transcriptase and causes DNA chain termination.15,17 Tenofovir, formulated as a microbicide, has primarily been studied for preventing sexually transmitted HIV; secondarily, it has been studied for its potential impact on preventing other sexually transmitted infections, such as HSV-2.3

Several different tenofovir-based microbicide products have been or will be studied in clinical trials, including vaginal dosage forms (gel, film, tablet, ring, and insert), as well as rectal dosage forms (gel, douche, and insert).3-7,9-12 The tenofovir vaginal gel is the furthest along in development, with a completed Phase 3 efficacy study (FACTS 001; NCT01386294). Results from this trial found that the gel did not protect women from acquiring HIV and that product adherence was an important factor in the overall results of the trial.3,18 A Phase 2 study on tenofovir rectal gel has been completed (MTN-017; NCT01687218).A Phase 2a study of an intravaginal ring (IVR) delivering both tenofovir and levonorgestrel and an IVR delivering tenofovir only is currently underway.8

Half-life (T½): When given as a single oral dose of tenofovir DF, tenofovir has a plasma elimination half-life of approximately 17 hours and an intracellular half-life that is greater than 60 hours.15

In a study of tenofovir vaginal gel in macaques, the estimated intracellular half-life of tenofovir in vaginal lymphocytes was 25 hours. In comparison, with orally dosed tenofovir DF in macaques, the tenofovir intracellular half-life in PBMCs was 49 hours.19

In a study that compared rectally applied tenofovir gel to oral tenofovir DF, the tenofovir plasma half-life was at least 5 hours shorter with single and multiple rectal dosing than with single oral dosing.20

Metabolism/Elimination: Tenofovir is not a CYP substrate. Approximately 70% to 80% of an intravenously administered dose of tenofovir is recovered in the urine as unchanged drug.15

Of note, in a study assessing the impact of vaginal bacteria on tenofovir gel efficacy in women participating in the CAPRISA 004 trial, researchers found that tenofovir gel was substantially less effective in women who had non-Lactobacillus bacteria than in women who had Lactobacillus-dominant bacteria. Gardnerella vaginalis and other anaerobes rapidly metabolized and depleted tenofovir before the drug could be changed to its active form in target cells.21

Resistance: In the CAPRISA 004 trial (NCT00441298), which evaluated tenofovir 1% vaginal gel, no resistance mutations related to tenofovir, thymidine analog mutations (TAMs), or mutations conferring multi-NRTI resistance were detected among HIV seroconverters.22

In the VOICE trial (NCT00705679), which assessed the effectiveness of a topical HIV prevention method (tenofovir 1% vaginal gel) and two different oral HIV prevention methods (tenofovir DF and emtricitabine/tenofovir DF [Truvada]), one participant in the Truvada group who underwent HIV-1 seroconversion 11 months after enrollment developed the M184V HIV resistance mutation.23


Select Clinical Trials


Tenofovir-based microbicides for rectal use

Rectal gel
Study Identifiers
: MTN-017; NCT01687218
Sponsor: CONRAD
Phase: 2
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety and acceptability of reduced-glycerin tenofovir 1% gel applied rectally versus oral Truvada.
Study Population: Participants were men and transgender women without HIV.4
Selected Study Results:

Additional clinical trials of tenofovir 1% rectal gel have been completed. One example is the Phase 1 MTN-007 study (NCT01232803), which tested the safety and acceptability of reduced glycerin tenofovir 1% gel for rectal use. Other examples include the Phase 1 CHARM-01 and CHARM-02 studies (NCT01575405 and NCT01575418), which evaluated the safety, acceptability, and pharmacokinetics of three gel formulations used rectally: a vaginal formulation, a reduced glycerin vaginal formulation, and a rectal-specific formulation.24-26 

Other rectal dosage forms
A tenofovir rectal douche is being studied in two Phase 1 trials: DREAM-02 (NCT04195776) and DREAM-03 (NCT04016233). See the ClinicalTrials.gov record for the DREAM-02 study's status. The DREAM-03 study is currently recruiting participants.9,10

A tenofovir alafenamide/elvitegravir insert for rectal administration is also in Phase 1 study (MTN-039; NCT04047420). This study is currently recruiting participants.12

Tenofovir-based vaginal microbicides

Vaginal gel
Study Identifiers: FACTS 001; NCT01386294
Sponsor: CONRAD
Phase: 3
Status: This study has been completed.
Study Purpose: The purpose of this study was to assess the safety and effectiveness of tenofovir 1% vaginal gel for preventing HIV infection and HSV-2 infection in women.
Study Population: Participants were sexually active women without HIV in South Africa.3
Selected Study Results:

Additional clinical trials evaluating tenofovir vaginal gel have also been completed. These include the Phase 2b CAPRISA 004 trial (NCT00441298) and the Phase 2b VOICE trial (MTN-003; NCT00705679).27,28

Intravaginal rings
Study Identifiers: Protocol B17-144; NCT03762382 
Sponsor: CONRAD
Phase: 2a
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety, pharmacokinetics, tolerability, and acceptance of an IVR delivering both tenofovir and levonorgestrel and an IVR delivering tenofovir only, compared to a placebo IVR, in women.
Study Population: Participants are healthy, non-pregnant women without HIV, assessed to be at lower risk for acquiring HIV, in Western Kenya.8

A Phase 1 trial (NCT03255915) is evaluating the safety and pharmacokinetics of an IVR delivering both tenofovir DF and emtricitabine. This study is currently recruiting participants.29

Other vaginal dosage forms
Additional tenofovir-based vaginal microbicide studies have been completed. These include a Phase 1 trial (NCT01694407) that evaluated tenofovir-containing vaginal tablets and a Phase 1 trial (FAME-04; NCT01989663) that assessed tenofovir vaginal gel and film formulations.5,6 A vaginal insert containing tenofovir alafenamide and elvitegravir has also been evaluated in a Phase 1 study (NCT03762772).11


Adverse Events


MTN-017 (NCT01687218):

In this Phase 2 study, which compared rectally applied reduced glycerin tenofovir 1% gel with oral Truvada, the gel was reported to be safe, with the majority of adverse events (AEs) being minor. Grade 2 or higher AE rates in the gel groups were similar to the rates in the oral Truvada group.4,30,31 

FACTS 001 (NCT01386294):
In this Phase 3 study, which compared tenofovir 1% vaginal gel with a placebo gel, a higher incidence of Grade 2 AEs was observed among participants in the tenofovir group than in the placebo group. The most common Grade 2 or higher product-related AEs were hypophosphataemia, genital symptoms, or elevated transaminases. No product-related serious AEs occurred during the trial. There were no notable differences in product-related AEs, Grade 3 AEs, or Grade 4 AEs between treatment groups.32


Drug Interactions


A Phase 1 pharmacokinetic study evaluated the effect of oral contraceptive (levonorgestrel/ethinyl estradiol) or depot medroxyprogesterone acetate use in women using tenofovir vaginal gel. Results demonstrated that contraceptive hormone use caused a significant decrease in concentrations of tenofovir in cervicovaginal aspirate. However, investigators determined that tenofovir concentrations still remained at sufficiently high levels to maintain mucosal anti-HIV efficacy.33,34


References


  1. United States National Library of Medicine. ChemIDplus Advanced: Tenofovir. https://chem.nlm.nih.gov/chemidplus/rn/147127-20-6. Accessed February 17, 2020
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed February 17, 2020
  3. CONRAD. A Phase III, multi-centre, randomized controlled trial to assess the safety and effectiveness of the vaginal microbicide 1% tenofovir gel in the prevention of human immunodeficiency virus type 1 infection in women, and to examine effects of the microbicide on the incidence of herpes simplex virus type 2 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 28, 2011. NLM Identifier: NCT01386294. https://www.clinicaltrials.gov/ct2/show/NCT01386294. Accessed February 17, 2020
  4. CONRAD. A Phase 2 randomized sequence open label expanded safety and acceptability study of oral emtricitabine/tenofovir disoproxil fumarate tablet and rectally-applied tenofovir reduced-glycerin 1% gel. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 27, 2012. NLM Identifier: NCT01687218. https://www.clinicaltrials.gov/ct2/show/NCT01687218. Accessed February 17, 2020
  5. CONRAD. A Phase I trial to assess the safety of tenofovir gel and film formulations: FAME 04. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 5, 2013. NLM Identifier: NCT01989663. https://www.clinicaltrials.gov/ct2/show/NCT01989663. Accessed February 17, 2020
  6. CONRAD. A Phase I clinical trial assessing the safety, pharmacokinetics, pharmacodynamics, and disintegration time of vaginal tablets containing tenofovir and/or emtricitabine. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 17, 2012. NLM Identifier: NCT01694407. https://www.clinicaltrials.gov/ct2/show/NCT01694407. Accessed February 17, 2020
  7. CONRAD. Phase I, 90-Day safety, pharmacokinetic, and pharmacodynamic study of intravaginal rings releasing tenofovir and levonorgestrel. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 23, 2017. NLM Identifier: NCT03279120. https://www.clinicaltrials.gov/ct2/show/NCT03279120. Accessed February 17, 2020
  8. CONRAD. Phase IIa, 90-day safety, adherence, and acceptability study of intravaginal rings releasing tenofovir with and without levonorgestrel among women in Western Kenya. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 16, 2018. NLM Identifier: NCT03762382. https://clinicaltrials.gov/ct2/show/study/NCT03762382. Accessed February 17, 2020
  9. Johns Hopkins University. A Phase 1 open label study evaluating the distribution of a tenofovir douche in combination with tap water douching and simulated receptive anal intercourse (DREAM-02). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 10, 2019. NLM Identifier: NCT04195776. https://clinicaltrials.gov/ct2/show/NCT04195776. Accessed February 17, 2020
  10. Johns Hopkins University. A Phase I, open-label multiple dose safety, pharmacokinetic, pharmacodynamic, and acceptability study of tenofovir rectal douche. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 9, 2019. NLM Identifier: NCT04016233. https://clinicaltrials.gov/ct2/show/NCT04016233. Accessed February 17, 2020
  11. CONRAD. A Phase I study to assess safety, pharmacokinetics, and pharmacodynamics of a vaginal insert containing tenofovir alafenamide and elvitegravir. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 16, 2018. NLM Identifier: NCT03762772. https://clinicaltrials.gov/ct2/show/NCT03762772. Accessed February 17, 2020
  12. National Institute of Allergy and Infectious Diseases (NIAID). A Phase 1 open label safety and pharmacokinetic study of rectal administration of a tenofovir alafenamide/elvitegravir insert at two dose levels. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 5, 2019. NLM Identifier: NCT04047420. https://clinicaltrials.gov/ct2/show/NCT04047420. Accessed February 17, 2020
  13. Shattock RJ, Rosenberg Z. Microbicides: topical prevention against HIV. Cold Spring Harb Perspect Med. 2012;2(2):a007385.
  14. National Institute of Allergy and Infectious Diseases (NIAID). Microbicides to block transmission of HIV. https://www.niaid.nih.gov/diseases-conditions/microbicides. Accessed February 17, 2020
  15. Gengiah TN, Baxter C, Mansoor LE, Kharsany AB, Abdool Karim SS. A drug evaluation of 1% tenofovir gel and tenofovir disoproxil fumarate tablets for the prevention of HIV infection. Expert Opin Investig Drugs. 2012;21(5):695-715. doi:10.1517/13543784.2012.667072
  16. Balzarini J, Van Damme L. Intravaginal and intrarectal microbicides to prevent HIV infection. CMAJ. 2005;172(4):461-464. doi:10.1503/cmaj.1041462
  17. Verma NA, Lee AC, Herold BC, Keller MJ. Topical prophylaxis for HIV prevention in women: becoming a reality. Curr HIV/AIDS Rep. 2011;8(2):104-113. doi:10.1007/s11904-011-0075-7
  18. Rees H, Delany-Moretlwe SA, Lombard C, et al. FACTS 001 Phase III trial of pericoital tenofovir 1% gel for HIV prevention in women. Abstract presented at: 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, Washington. Abstract 26LB. http://www.croiconference.org/sessions/facts-001-phase-iii-trial-pericoital-tenofovir-1-gel-hiv-prevention-women. Accessed February 17, 2020
  19. Dobard C, Sharma S, Martin A, et al. Durable protection from vaginal simian-human immunodeficiency virus infection in macaques by tenofovir gel and its relationship to drug levels in tissue. J Virol. 2012;86(2):718-725. doi:10.1128/JVI.05842-11
  20. Yang KH, Hendrix C, Bumpus N, et al. A multi-compartment single and multiple dose pharmacokinetic comparison of rectally applied tenofovir 1% gel and oral tenofovir disoproxil fumarate. PLoS ONE. 2014;9(10):e106196. doi:10.1371/journal.pone.0106196
  21. Klatt NR, Cheu R, Birse K, et al. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science. 2017;356(6341):938-945. doi:10.1126/science.aai9383
  22. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010;329(5996):1168-1174. doi:10.1126/science.1193748
  23. Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372(6):509-518.
  24. CONRAD. A Phase 1 randomized, double-blinded, placebo-controlled rectal safety and acceptability study of tenofovir 1% gel. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 1, 2010. NLM Identifier: NCT01232803. https://www.clinicaltrials.gov/ct2/show/NCT01232803. Accessed February 17, 2020
  25. Ian McGowan. A randomized, double blind Phase 1 safety, acceptability, and pharmacokinetic study comparing three formulations of tenofovir 1% gel administered rectally to HIV-1 seronegative adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 29, 2012. NLM Identifier: NCT01575405. https://clinicaltrials.gov/ct2/show/NCT01575405. Accessed February 17, 2020
  26. Ian McGowan. An exploratory, double-blinded, randomized, pharmacokinetic and safety study of three rectally-applied tenofovir 1% microbicide gel formulations. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 1, 2012. NLM Identifier: NCT01575418. https://clinicaltrials.gov/ct2/show/NCT01575418. Accessed February 17, 2020
  27. Centre for the AIDS Programme of Research in South Africa. Phase IIb trial to assess the safety and effectiveness of the vaginal microbicide 1% tenofovir gel for the prevention of HIV infection in women in South Africa. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 27, 2007. NLM Identifier: NCT00441298. https://www.clinicaltrials.gov/ct2/show/NCT00441298. Accessed February 17, 2020
  28. National Institute of Allergy and Infectious Diseases (NIAID). Phase 2B safety and effectiveness study of tenofovir 1% gel, tenofovir disproxil fumarate tablet and emtricitabine/tenofovir disoproxil fumarate tablet for the prevention of HIV infection in women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 24, 2008. NLM Identifier: NCT00705679. https://www.clinicaltrials.gov/ct2/show/NCT00705679. Accessed February 17, 2020
  29. Oak Crest Institute of Science. Randomized order, controlled, double blind, crossover early Phase 1 pilot study to assess safety and pharmacokinetics of a tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) releasing IVR over 28 days compared to placebo. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 26, 2017. NLM Identifier: NCT03255915. https://clinicaltrials.gov/ct2/show/NCT03255915. Accessed February 17, 2020
  30. Cranston R, Lama J, Richardson BA, et al. MTN-017: rectal Phase 2 extended safety and acceptability study of 1% tenofovir gel. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 22-25, 2016; Boston, MA. Abstract 108LB. http://www.croiconference.org/sessions/mtn-017-rectal-phase-2-extended-safety-and-acceptability-study-1-tenofovir-gel. Accessed February 17, 2020
  31. Microbicide Trials Network. News Release, dated February 24, 2016. International study finds rectal microbicide gel safe when used daily and with sex. https://mtnstopshiv.org/news/international-study-finds-rectal-microbicide-gel-safe-when-used-daily-and-sex. Accessed February 17, 2020
  32. Delany-Moretlwe S, Lombard C, Baron D, et al. Tenofovir 1% vaginal gel for prevention of HIV-1 infection in women in South Africa (FACTS-001): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018;18(11):1241-1250. doi:10.1016/S1473-3099(18)30428-6
  33. CONRAD. Assessing the effect of contraception and the menstrual cycle on pharmacokinetics, pharmacodynamics, and vaginal safety in tenofovir vaginal gel users. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 9, 2011. NLM Identifier: NCT01421368. https://clinicaltrials.gov/ct2/show/study/NCT01421368. Accessed February 17, 2020
  34. Thurman AR, Schwartz JL, Brache V, et al. Effect of hormonal contraception on pharmacokinetics of vaginal tenofovir in healthy women: increased tenofovir diphosphate in injectable depot medroxyprogesterone acetate users. J Acquir Immune Defic Syndr. 2019;80(1):79-88. doi:10.1097/QAI.0000000000001864


Last Reviewed: February 17, 2020