Drugs

Dapivirine

Other Names: DAP, DPV, DVR, DVR-004, Ring-004, TMC-120, dapivirine IVR, dapivirine intravaginal ring Drug Class: Microbicides
Molecular Formula: C20 H19 N5
Registry Number: 244767-67-7 (CAS) Chemical Name: 4-[[4-(2,4,6-trimethylanilino)pyrimidin-2-yl]amino]benzonitrile Chemical Class: Pyrimidines Organization: Janssen Sciences Ireland UC; International Partnership for Microbicides (IPM) Phase of Development: The monthly dapivirine intravaginal ring has completed Phase IIIb testing, and is currently being reviewed by the European Medicines Agency (EMA). The drug sponsor plans to seek approval for the dapivirine ring from the U.S. Food and Drug Administration and the South African Health Products Regulatory Authority in 2019. Other dapivirine-based microbicide products are in earlier phases of study.

Chemical Image:

(Click to enlarge)
dapivirine

dapivirine

Molecular Weight: 329.405

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 International Partnership for Microbicides [IPM] publication,3 and IPM website4)

Pharmacology


Mechanism of Action: Microbicide; non-nucleoside reverse transcriptase inhibitor (NNRTI). HIV-specific topical microbicides formulated with antiretroviral (ARV) drugs, such as dapivirine, 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 infection at the vaginal or rectal mucosa and directly interfere with the HIV replication cycle.4–7

Dapivirine, a substituted diarylpyrimidine derivative, irreversibly binds to and inhibits HIV reverse transcriptase, preventing the conversion of viral RNA to proviral DNA. Because of dapivirine’s tight binding and lipophilic characteristics, it may be active against both cell-free and cell-associated HIV.8,9

Several different dapivirine-based microbicide products have been studied in clinical trials. The monthly dapivirine intravaginal ring (IVR) is the furthest along in development and has completed Phase IIIb trials.3,4

Half-life (T½): In a study of two formulations of dapivirine vaginal gel (0.05%) used once daily over 11 days, the dapivirine terminal half-life was 72 to 73 hours in plasma and 15 to 17 hours in vaginal fluids.10 In a study of dapivirine matrix and reservoir IVRs, dapivirine half-life was measured in women after IVR removal following 28 consecutive days of use. The estimated terminal half-life for dapivirine was 64 hours in plasma and 15 to 16 hours in vaginal fluids with the matrix IVR, and it was 83 hours in plasma and 15 to 16 hours in vaginal fluids with the reservoir IVR.11

Metabolism/Elimination: CYP and UGT enzymes have been found to be locally expressed in vaginal and colorectal tissues and may have a role in the metabolism of dapivirine in these tissue compartments.12

Resistance: Results from two Phase III clinical trials (Ring study; NCT01539226 and ASPIRE study; NCT01617096) found that use of the dapivirine IVR did not appear to increase ARV-resistant HIV among participants who acquired HIV.13–15 However, among participants who acquired HIV in the Ring study, the E138A substitution (an HIV-1 subtype C polymorphism) was noted to occur more frequently in dapivirine participants than in placebo participants.16 In the ASPIRE trial, this mutation was found to occur at a similar frequency in both study groups and was determined to be unlikely to cause a reduction in IVR efficacy. In addition, follow-up from ASPIRE found that the effectiveness of standard recommended NNRTI-containing ART regimens in participants who had acquired HIV during the study was not impacted by dapivirine IVR use.17,18


Select Clinical Trials


Dapivirine-Based IVR

Study Identifiers: (1) Ring Study; IPM 027; NCT01539226 and (2) DREAM Study; IPM 032; NCT02862171
Sponsor: International Partnership for Microbicides, Inc.
Phase: The Ring study was a Phase III trial, and the DREAM study was a follow-on Phase IIIb trial.
Status: The Ring and DREAM studies have both been completed. 
Study Purpose: The Ring study was designed to evaluate the safety and efficacy of a monthly dapivirine silicone elastomer matrix IVR (Ring-004) for the prevention of HIV infection in women. The DREAM study was an open-label follow-on study that continued to evaluate dapivirine safety and participant adherence in women who were enrolled in the Ring study.
Study Population:

  • Participants in the Ring study were HIV-negative, sexually active women 18 to 45 years of age from South Africa and Uganda.
  • Participants in the DREAM study were HIV-negative women who previously participated in the Ring study.3,15,17,19,20

Selected Study Results:


Study Identifiers: (1) ASPIRE Study; MTN-020; NCT01617096 and (2) HOPE Study; MTN-025; NCT02858037
Sponsor: International Partnership for Microbicides, Inc.
Phase: ASPIRE was a Phase III trial, and HOPE was a Phase IIIb follow-on trial.
Status: The ASPIRE and HOPE studies have both been completed. 
Study Purpose: The ASPIRE study was designed to evaluate the safety and effectiveness of a dapivirine silicone elastomer matrix IVR (Ring-004) for the prevention of HIV infection in women. HOPE was an open-label follow-on study that continued to evaluate dapivirine safety and participant adherence in women who were enrolled in ASPIRE.
Study Population:
  • Participants in the ASPIRE study were HIV-negative, sexually active women 18 to 45 years of age from Malawi, South Africa, Uganda, and Zimbabwe.
  • Participants in the HOPE study were HIV-negative women who previously participated in ASPIRE.16,21
Selected Study Results:

Additional dapivirine-based IVR studies have also been completed or are ongoing or planned.22 These include the following trials:

  • MTN-036/IPM 047 (NCT03234400): A completed Phase I pharmacokinetic and safety study that compared three IVRs containing different doses of dapivirine.23
  • MTN-044/IPM 053/CCN019 (NCT03467347): A Phase I pharmacokinetic and safety study assessing a combination IVR containing dapivirine and levonorgestrel. Participants will use the IVR either continuously for 90 days or cyclically (worn for 28 days and removed for 2 days) for 90 days. This study is currently recruiting participants.24
  • REACH; MTN-034 (NCT03593655): A Phase IIa study evaluating the safety of and adherence to the monthly dapivirine IVR and oral emtricitabine/tenofovir DF in adolescent and young adult female participants. This study is currently recruiting participants.25,26

Other Dapivirine-Based Microbicide Formulations

Other dapivirine-based microbicide formulations are also in clinical development, including a vaginal film (Phase I) and gel administered rectally (Phase I) or vaginally (Phase II). A combination vaginal gel containing dapivirine and darunavir has also been studied in a Phase I trial.4,27,28


Adverse Events


Ring study (NCT01539226); DREAM study (NCT02862171):

In the Phase III Ring study, dapivirine IVR use in women was reported to be safe, with a similar rate of adverse events (AEs) in both the active drug and placebo arms.14,17 No dapivirine-related serious adverse events (SAEs) or Grade 3 or 4 AEs occurred. AEs related to dapivirine IVR included metrorrhagia, pelvic discomfort/pain, suprapubic pain, and application site pain, all of which were mild in severity.

In interim results from the open-label follow-on DREAM study, of the 900 enrolled participants, 461 (51.3%) reported having an AE. However, only three participants (0.3%), experienced an AE that was considered to be related to the study product. These dapivirine-related AEs included suprapubic pain (Grade 1), vulvovaginitis (Grade 2), and vulvovaginal pain (Grade 1), each occurring in one participant. SAEs occurred in 11 participants, although all were unrelated to dapivirine.29

ASPIRE study (NCT01617096):

Similarly, in the Phase III ASPIRE study, dapivirine IVR use in women was also reported to be safe, with a similar rate of AEs in both the active drug and placebo arms.14,17,30 Again, no dapivirine-related SAEs or Grade 3 or 4 AEs occurred. Dapivirine-related AEs included moderate cervivitis, urinary tract infection, headache, urinary incontinence, cervix erythema and oedema, dyspareunia, and pelvic pain.31


Drug Interactions


A drug-drug interaction study between dapivirine IVR (Ring-004) and miconazole nitrate (1200-mg vaginal capsule) found that concomitant use caused local and systemic changes to levels of both drugs; however, such changes are not likely to alter the effectiveness of either drug.32

In the ASPIRE trial (NCT01617096), investigators evaluated whether the dapivirine IVR would alter the effectiveness of hormonal contraception. Among women who were receiving various forms of hormonal contraception during the study, no difference in pregnancy incidence between the dapivirine group and the placebo group was seen.33


References


  1. United States National Library of Medicine. ChemIDplus advanced: Dapivirine. https://chem.nlm.nih.gov/chemidplus/rn/244767-67-7. 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. International Partnership for Microbicides (IPM). A long-acting ring to help protect women against HIV. https://www.ipmglobal.org/sites/default/files/media_block_files/ring_backgrounder_-_feb_2019.pdf. Accessed May 1, 2019.
  4. International Partnership for Microbicides (IPM) website. Our products. https://www.ipmglobal.org/our-work/product-pipeline. Accessed May 1, 2019.
  5. 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.
  6. Shattock RJ, Rosenberg Z. Microbicides: topical prevention against HIV. Cold Spring Harb Perspect Med. 2012;2(2):a007385.
  7. Balzarini J, Van Damme L. Intravaginal and intrarectal microbicides to prevent HIV infection. CMAJ. 2005;172(4):461-464. doi:10.1503/cmaj.1041462
  8. Adams JL, Kashuba AD. Formulation, pharmacokinetics and pharmacodynamics of topical microbicides. Best Pract Res Clin Obstet Gynaecol. 2012;26(4):451-462. doi:10.1016/j.bpobgyn.2012.01.004
  9. Garg AB, Nuttall J, Romano J. The future of HIV microbicides: challenges and opportunities. Antivir Chem Chemother. 2009;19(4):143-150. doi:10.1177/095632020901900401
  10. Nuttall JP, Thake DC, Lewis MG, Ferkany JW, Romano JW, Mitchnick MA. Concentrations of dapivirine in the rhesus macaque and rabbit following once daily intravaginal administration of a gel formulation of [14C] dapivirine for 7 days. Antimicrob Agents Chemother. 2008;52(3):909-914. doi:10.1128/AAC.00330-07
  11. Nel AM, Smythe SC, Habibi S, Kaptur PE, Romano JW. Pharmacokinetics of 2 dapivirine vaginal microbicide gels and their safety vs. hydroxyethyl cellulose-based universal placebo gel. J Acquir Immune Defic Syndr. 2010;55(2):161-169. doi:10.1097/QAI.0b013e3181e3293a
  12. Nel A, Smythe S, Young K, et al. Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women. J Acquir Immune Defic Syndr. 2009;51(4):416-423.
  13. Schader SM, Oliveira M, Ibanescu R-I, Moisi D, Colby-Germinario SP, Wainberg MA. In vitro resistance profile of the candidate HIV-1 microbicide drug dapivirine. Antimicrob Agents Chemother. 2012;56(2):751-756. doi:10.1128/AAC.05821-11
  14. International Partnership for Microbicides (IPM): Press Release, dated February 22, 2016. Two large studies show IPM’s monthly vaginal ring helps protect women against HIV. https://www.ipmglobal.org/publications/two-large-studies-show-ipm%E2%80%99s-monthly-vaginal-ring-helps-protect-women-against-hiv. Accessed May 1, 2019.
  15. International Partnership for Microbicides, Inc. A multi-centre, randomised, double-blind, placebo-controlled safety and efficacy trial of a dapivirine vaginal matrix ring in healthy HIV-negative women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 21, 2012. NLM Identifier: NCT01539226. https://clinicaltrials.gov/ct2/show/NCT01539226. Accessed May 1, 2019.
  16. International Partnership for Microbicides, Inc. A multi-center, randomized, double-blind, placebo-controlled Phase 3 safety and effectiveness trial of a vaginal matrix ring containing dapivirine for the prevention of HIV-1 infection in women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 8, 2012. NLM Identifier: NCT01617096. https://clinicaltrials.gov/ct2/show/NCT01617096. Accessed May 1, 2019.
  17. Nel A, van Niekerk N, Kapiga S, et al. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N Engl J Med. 2016;375(22):2133-2143. doi:10.1056/NEJMoa1602046
  18. Penrose K, Goetz BJ, Gordon KC, et al. Does the E138A mutation in ASPIRE seroconverters affect susceptibility to dapivirine? Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, WA. Abstract 951. http://www.croiconference.org/sessions/does-e138a-mutation-aspire-seroconverters-affect-susceptibility-dapivirine. Accessed May 1, 2019.
  19. Rosenberg Z. Dapivirine ring: the roadmap to licensure. Slides presented at: MTN Regional Meeting; October 4-8, 2015; Cape Town, South Africa. http://www.mtnstopshiv.org/sites/default/files/attachments/ROSENBERG2015-10-MTN-regional-mtg-Zeda_draftSept29.pdf. Accessed May 1, 2019.
  20. International Partnership for Microbicides, Inc. A follow-on, open-label trial to assess continued safety of and adherence to the dapivirine (25 mg) vaginal Ring-004 in healthy, HIV-negative women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 25, 2016. NLM Identifier: NCT02862171. https://clinicaltrials.gov/ct2/show/NCT02862171. Accessed May 1, 2019.
  21. International Partnership for Microbicides, Inc. A Phase 3B open-label follow-on trial to assess the continued safety of and adherence to a vaginal ring containing dapivirine in women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 18, 2016. NLM Identifier: NCT02858037. https://clinicaltrials.gov/ct2/show/NCT02858037. Accessed May 1, 2019.
  22. International Partnership for Microbicides (IPM) website. Clinical trials. https://www.ipmglobal.org/our-work/research/clinical-trial. Accessed May 1, 2019.
  23. International Partnership for Microbicides, Inc. A Phase 1, randomized pharmacokinetics and safety study of extended duration dapivirine vaginal rings. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 25, 2017. NLM Identifier: NCT03234400. https://clinicaltrials.gov/ct2/show/NCT03234400. Accessed May 1, 2019.
  24. International Partnership for Microbicides, Inc. A randomized, Phase 1, open-label study in healthy HIV-negative women to evaluate the pharmacokinetics, safety and bleeding patterns associated with 90-day use of matrix vaginal rings containing 200 mg dapivirine and 320 mg levonorgestrel. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 9, 2018. NLM Identifier: NCT03467347. https://clinicaltrials.gov/ct2/show/NCT03467347. Accessed May 1, 2019.
  25. National Institute of Allergy and Infectious Diseases (NIAID). A Phase 2a crossover trial evaluating the safety of and adherence to a vaginal matrix ring containing dapivirine and oral emtricitabine/tenofovir disoproxil fumarate in an adolescent and young adult female population. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 10, 2018. NLM Identifier: NCT03593655. https://clinicaltrials.gov/ct2/show/NCT03593655. Accessed May 1, 2019.
  26. Microbicide Trials Network (MTN): Press Release, dated February 7, 2019. About the REACH Study (MTN-034). https://mtnstopshiv.org/news/about-reach-study-mtn-034. Accessed May 1, 2019.
  27. International Partnership for Microbicides (IPM) website. Darunavir. https://www.ipmglobal.org/our-work/arvs-in-the-pipeline/darunavir. Accessed May 1, 2019.
  28. National Institute of Allergy and Infectious Diseases (NIAID). An Open Label Randomized Phase 1 Pharmacokinetic Study of Dapivirine Gel Administered Rectally to HIV-1 Seronegative Adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 2, 2018. NLM Identifier: NCT03393468. https://clinicaltrials.gov/ct2/show/NCT03393468. Accessed May 1, 2019.
  29. Rosenberg ZF. HIV Incidence and adherence in DREAM - an open-label trial of dapivirine vaginal ring. Presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 4-7, 2018; Boston, MA. http://www.croiwebcasts.org/console/player/37319?mediaType=slideVideo&&crd_fl=0&ssmsrq=1525645233234&ctms=5000&csmsrq=5001. Accessed May 1, 2019.
  30. Baeten JM, Palanee-Phillips T, Brown ER, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med. 2016;375(22):2121-2132. doi:10.1056/NEJMoa1506110
  31. Baeten J. High uptake and reduced HIV-1 incidence in an open-label trial of the dapivirine ring. Presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 4-7, 2018; Boston, MA. http://www.croiwebcasts.org/console/player/37318?mediaType=slideVideo&&crd_fl=1&ssmsrq=1521029770826&ctms=5000&csmsrq=780. Accessed May 1, 2019.
  32. Nel A, Haazen W, Russell M, Nuttall J, Van Niekerk N, Treijtel N. Drug-drug Interactions between the Dapivirine Vaginal Ring (Ring-004) and Miconazole Nitrate Vaginal Capsule (Gyno-Daktarin®). AIDS Research and Human Retroviruses. 2014;30(S1):A144-A144. doi:10.1089/aid.2014.5291.abstract
  33. Balkus J, Palanee-Phillips T, Siva S, et al. Dapivirine ring use does not diminish the effectiveness of hormonal contraception. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13–16, 2017; Seattle, WA. Abstract 88. http://www.croiconference.org/sessions/dapivirine-ring-use-does-not-diminish-effectiveness-hormonal-contraception. Accessed May 1, 2019.


Last Reviewed: May 1, 2019