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: CONRAD, Gilead Sciences, Inc. Phase of Development: Tenofovir vaginal gel has been studied in a Phase III trial. Tenofovir rectal gel has been studied in a Phase II trial. Intravaginal rings containing tenofovir are currently being studied in a Phase IIa 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.gov3-9)

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.10-13

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.12,14 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 studied in clinical trials, including a vaginal gel, film, tablet, and ring, as well as a rectal gel and enema.3-8 The tenofovir vaginal gel is the furthest along in development, with a completed Phase III 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.3,15 A Phase II study on tenofovir rectal gel has been completed (MTN-017; NCT01687218).A Phase IIa study of an intravaginal ring (IVR) delivering both tenofovir and levonorgestrel and an IVR delivering tenofovir only is currently underway.9

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.12

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.16

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.17

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.12

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.18

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.19

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.20


Select Clinical Trials


Tenofovir-based microbicides for rectal use

Study Identifiers: MTN-017; NCT01687218
Sponsor: CONRAD
Phase: II
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 I MTN-007 study (NCT01232803), which tested the safety and acceptability of reduced glycerin tenofovir 1% gel for rectal use. Other examples include the Phase I 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.21-23 A rectal enema is in early stages of development.8

Tenofovir-based vaginal microbicides

Vaginal gel

Study Identifiers: (1) CAPRISA 004; NCT00441298 (2) CAPRISA 008; NCT01691768 and (3) CAPRISA 009; NCT01387022
Sponsor: Centre for the AIDS Programme of Research in South Africa
Phase: CAPRISA 004 was a Phase IIb trial.
Status: These studies have been completed.
Study Purpose: The purpose of CAPRISA 004 was to assess the safety and effectiveness of tenofovir 1% vaginal gel for preventing HIV infection in women. CAPRISA 008 was an open-label follow-on study that provided previous CAPRISA 004 participants with tenofovir gel. CAPRISA 009 was an open-label follow-on study designed to evaluate if the use of tenofovir gel impacted the efficacy of tenofovir-containing ART in women who acquired HIV during CAPRISA 004 or CAPIRSA 008.
Study Population: Participants in CAPRISA 004 were sexually active women without HIV in South Africa.24-26
Selected Study Results:


Study Identifiers: MTN-003; VOICE; NCT00705679
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: IIb
Status: This study has been completed.
Study Purpose: The purpose of this study was to assess the safety and effectiveness of oral tenofovir DF (Viread), oral Truvada, and tenofovir 1% vaginal gel for the prevention of HIV infection in women.
Study Population: Participants were sexually active women without HIV in South Africa, Uganda, and Zimbabwe.27
Selected Study Results:


Study Identifiers: FACTS 001; NCT01386294
Sponsor: CONRAD
Phase: III
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:

Intravaginal rings

Study Identifiers: Protocol B17-144; NCT03762382 
Sponsor: CONRAD
Phase: IIa
Status: This study has been enrolling by invitation.
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.9

The tenofovir IVR will also be studied in a Phase I trial (MTN-038; NCT03670355). This study is currently recruiting participants.28

Additional tenofovir-based vaginal microbicide studies have been completed. These include a Phase I trial (NCT01694407) that evaluated tenofovir-containing vaginal tablets and a Phase I trial (FAME-04; NCT01989663) that assessed tenofovir vaginal gel and film formulations.5,6


Adverse Events


MTN -017 (NCT01687218):

In this Phase II 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.4,29,30


CAPRISA 004 (NCT00441298):

In this Phase IIb study, tenofovir 1% vaginal gel that was used over a 30-month period by women demonstrated no evidence of increased renal, hepatic, pregnancy-related, or genital AEs when compared with placebo. Mild and self-limiting diarrhea was reported more frequently in the tenofovir gel group than in the placebo group.19,24


VOICE (NCT00705679):

In this Phase IIb study, elevations in serum creatinine levels (all mild, except one) occurred more frequently among participants in the oral Truvada group than among participants in the oral placebo group. No other significant differences in safety concerns were noted in the study.20,27,31

FACTS 001 (NCT01386294):
In this Phase III 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 I 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 May 1, 2019
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed May 1, 2019
  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 May 1, 2019
  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 May 1, 2019
  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 May 1, 2019
  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 May 1, 2019
  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 May 1, 2019
  8. Johns Hopkins University. DREAM-01: optimization of a tenofovir enema for HIV prevention. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 11, 2016. NLM Identifier: NCT02750540. https://clinicaltrials.gov/ct2/show/NCT02750540. Accessed May 1, 2019
  9. 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/record/NCT03762382. Accessed May 1, 2019
  10. Shattock RJ, Rosenberg Z. Microbicides: topical prevention against HIV. Cold Spring Harb Perspect Med. 2012;2(2):a007385
  11. National Institute of Allergy and Infectious Diseases (NIAID). Microbicides to block transmission of HIV. https://www.niaid.nih.gov/diseases-conditions/microbicides. Accessed May 1, 2019
  12. 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
  13. Balzarini J, Van Damme L. Intravaginal and intrarectal microbicides to prevent HIV infection. CMAJ. 2005;172(4):461-464. doi:10.1503/cmaj.1041462
  14. 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
  15. 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 May 1, 2019
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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 May 1, 2019
  22. 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 May 1, 2019
  23. 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 May 1, 2019
  24. 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 May 1, 2019
  25. Centre for the AIDS Programme of Research in South Africa. Open-label randomized controlled trial to assess the implementation effectiveness and safety of 1% tenofovir gel provision through family planning services in KwaZulu-Natal, South Africa. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 5, 2012. NLM Identifier: NCT01691768. https://www.clinicaltrials.gov/ct2/show/NCT01691768. Accessed May 1, 2019
  26. Centre for the AIDS Programme of Research in South Africa. Open label randomized controlled trial to assess the impact of prophylactic exposure to tenofovir gel on the efficacy of subsequent tenofovir-containing antiretroviral therapy on viral suppression. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 21, 2011. NLM Identifier: NCT01387022. https://www.clinicaltrials.gov/ct2/show/study/NCT01387022. Accessed May 1, 2019
  27. 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 May 1, 2019
  28. National Institute of Allergy and Infectious Diseases (NIAID). A Phase 1, randomized pharmacokinetic and safety study of a 90 Day intravaginal ring containing tenofovir. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 12, 2018. NLM Identifier: NCT03670355. https://clinicaltrials.gov/ct2/show/record/NCT03670355. Accessed May 1, 2019
  29. 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 May 1, 2019
  30. 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 May 1, 2019
  31. Marrazzo J, Rabe L, Kelly C, et al. Association of tenofovir (TFV) detection with reduced risk of herpes simplex virus type-2 (HSV-2) acquisition in the VOICE (MTN 003) study. Abstract presented at: HIV Research for Prevention 2014: AIDS Vaccine, Microbicide and ARV-based Prevention Science (HIVR4P); October 28-31, 2014; Cape Town, South Africa. Abstract OA10.06 LB. https://www.liebertpub.com/doi/pdf/10.1089/aid.2014.5047a.abstract. Accessed May 1, 2019
  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/record/NCT01421368. Accessed May 1, 2019
  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: May 1, 2019