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AIDSinfo Drug Database

AIDSinfo Drug Database

Drugs by class

FDA-approved

Investigational

Dapivirine  Audio icon

Other Names: DAP, 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
Company: Janssen Research and Development, LLC; International Partnership for Microbicides (IPM)
Phase of Development: Phase III (Dapivirine intravaginal ring [IVR] is in Phase III testing. Other dapivirine-based microbicide products are in earlier phases of study.)
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Chemical Image:
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dapivirine
dapivirine
Molecular Weight: 329.405

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

What is an investigational drug?

An investigational drug is one that is under study and is not approved by the U.S. Food and Drug Administration (FDA) for sale in the United States. Medical research studies are conducted to evaluate the safety and effectiveness of an investigational drug. These research studies are also called clinical trials. Once an investigational drug has been proven safe and effective in clinical trials, FDA may approve the drug for sale in the United States.

To learn more about investigational drugs, read the AIDSinfo What is an Investigational HIV Drug? fact sheet.

What is dapivirine?

Dapivirine is an investigational drug that is being studied to prevent sexual transmission of HIV. It is a type of drug product called a topical microbicide. Topical microbicides are products that are applied to the vagina or rectum (such as gels, films, or creams) or inserted into the vagina (such as vaginal rings) to prevent getting sexually transmitted infections, such as HIV infection.5,6

Dapivirine belongs to a class (group) of HIV drugs called non-nucleoside reverse transcriptase inhibitors (NNRTIs).6 NNRTIs attach to and block an HIV enzyme called reverse transcriptase. (An enzyme is a protein that starts or increases the speed of a chemical reaction.) By blocking reverse transcriptase, NNRTIs prevent HIV from multiplying and from spreading to other cells.

Several different forms of dapivirine-based microbicide products are being studied, including vaginal rings (also known as intravaginal rings or IVRs), vaginal gels, and a vaginal film.4,7-10 The dapivirine vaginal ring is furthest along in development.8,9,11 It provides long-term delivery of dapivirine over a month-long period.11

How do topical microbicides work?

retroviral microbicides can also be referred to as topical pre-exposure prophylaxis (PrEP) products.5,6 PrEP means using a medicine before possible exposure to a virus or bacteria to reduce the risk of becoming infected with the virus or bacteria. For more information on PrEP, see the AIDSinfo Pre-Exposure Prophylaxis (PrEP) fact sheet.

Topical microbicides to prevent HIV infection are designed to work close to where they are applied and near to where HIV might enter the body (through the vagina or rectum).6,12

Early development of microbicides focused on products that used non-antiretroviral (ARV) medicines. These products worked in various ways, such as by inactivating pathogens, strengthening the body’s natural defenses, or blocking virus from getting into healthy cells.13-15

Current microbicide research is mainly focused on testing products that contain ARV medicines. ARV-based microbicides work at a particular step in the HIV life cycle and act almost exclusively against HIV. They may contain more than one ARV medicine to help make the product more effective. ARV-based microbicides might:

  • prevent HIV entry into healthy cells;
  • prevent HIV from converting its RNA into DNA, which stops HIV from replicating;
  • prevent HIV from inserting its genetic material into the DNA of host cells, which stops HIV from replicating;
  • prevent HIV from becoming a mature virus that can infect healthy cells.13,16,17

Dapivirine works by preventing HIV from converting its RNA into DNA, which helps to stop HIV from replicating.6

How are clinical trials of investigational drugs conducted?

Clinical trials are conducted in phases. Each phase has a different purpose and helps researchers answer different questions.18

  • Phase I trials: Researchers test an investigational drug in a small group of people (20–80) for the first time. The purpose is to evaluate its safety and identify side effects.
  • Phase II trials: The investigational drug is administered to a larger group of people (100–300) to determine its effectiveness and to further evaluate its safety.
  • Phase III trials: The investigational drug is administered to large groups of people (1,000–3,000) to confirm its effectiveness, monitor side effects, compare it with standard or equivalent treatments, and collect information that will allow the investigational drug to be used safely.18

In most cases, an investigational drug must be proven effective and must show continued safety in a Phase III clinical trial to be considered for approval by FDA for sale in the United States. Some drugs go through FDA’s accelerated approval process and are approved before a Phase III clinical trial is complete. After a drug is approved by FDA and made available to the public, researchers track its safety in Phase IV trials to seek more information about the drug’s risks, benefits, and optimal use.18

In what phase of testing is dapivirine?

The dapivirine vaginal ring is currently being studied in Phase III clinical trials.2,4

Other dapivirine-based microbicides are in Phase I and II studies. These include the following: 1) a combination ARV vaginal ring containing dapivirine and the FDA-approved HIV medicine maraviroc (brand name: Selzentry); 2) a dapivirine vaginal gel; 3) a combination vaginal gel containing dapivirine and the FDA-approved HIV medicine darunavir (brand name: Prezista); and 4) a dapivirine vaginal film.4,19-21

What are some studies on dapivirine?


Study Name: IPM 027 (The Ring Study); NCT01539226
Phase: III
Location: South Africa and Uganda
Participants: HIV-uninfected, sexually active women who were 18 to 45 years of age
Purpose: The purpose of this study was to evaluate whether a dapivirine vaginal ring is safe and effective in protecting women against sexually acquired HIV.
Study Design: Participants were randomly assigned to use either a monthly dapivirine vaginal ring or a monthly placebo ring for 2 years. (A placebo is an inactive drug that is identical in appearance to the active drug being studied.) Participants were instructed on how to insert one new vaginal ring after removing the used ring each month.
Results:

  • The study enrolled 1,959 HIV-uninfected women. Overall, results from The Ring Study showed that the dapivirine vaginal ring, when compared to placebo, reduced the risk of HIV infection by 31%.
  • When looking at a subset of participants who were older than 21, the effectiveness of the dapivirine ring at reducing HIV infection increased to 37%.
  • In contrast, when looking at a subset of participants who were younger (ages 18 to 21), the effectiveness of the ring dropped to 15%.
  • Women with better adherence or more consistent ring use appeared to have increased protection against HIV infection.
  • The dapivirine ring was considered safe to use, with no difference in safety concerns between the dapivirine ring group and the placebo group. Also, among participants who became infected with HIV, use of the dapivirine ring did not increase the presence of ARV-resistant HIV.8,11,22,23
* An extension study called DREAM is planned to take place. DREAM will provide the dapivirine ring to eligible Ring Study participants and will help to answer critical questions about the product.22



Study Name: MTN-020 (ASPIRE); NCT01617096
Phase: III
Location: Malawi, South Africa, Uganda, and Zimbabwe
Participants: HIV-uninfected, sexually active women who were 18 to 45 years of age
Purpose: The purpose of this study was to evaluate whether a dapivirine vaginal ring is safe and effective in protecting women against sexually acquired HIV.
Study Design: Participants were randomly assigned to use either a monthly dapivirine vaginal ring or a monthly placebo ring for at least 1 year. Participants were instructed on how to insert a new vaginal ring after removing the used ring each month.
Results:
  • The study enrolled 2,629 HIV-uninfected women. Overall, results from ASPIRE showed that the dapivirine vaginal ring, when compared to placebo, reduced the risk of HIV infection by 27%. When researchers excluded data from two study sites where it was clear that women were not returning for visits or not using the ring consistently, the ring reduced the risk of HIV infection by 37%.
  • Participants older than 21 had better adherence or more consistent ring use, and this was associated with increased protection against HIV infection. Among participants older than 21, the dapivirine ring reduced the risk of HIV infection by 56%, and among women older than 25, the ring reduced the risk of HIV infection by 61%.
  • In contrast, when looking at a subset of younger participants (ages 18 to 21), the dapivirine ring provided no protection.
  • In terms of safety, there was no difference in safety concerns between the dapivirine ring group and the placebo group. Among participants who became infected with HIV, use of the dapivirine ring did not increase the presence of ARV-resistant HIV.9,11,22,24-26

* An extension study called HOPE is planned to take place. HOPE will provide the dapivirine ring to eligible ASPIRE study participants and will gather additional safety and adherence data.27

On the basis of results from The Ring Study and ASPIRE, as well as from other dapivirine ring studies, the ring’s developers have reported that they plan to seek regulatory approval of the dapivirine vaginal ring in 2017, with possible commercial availability in some countries in 2018.22

Other dapivirine vaginal ring studies have been completed or are ongoing or planned, including studies in post-menopausal women and in adolescent females.28-30

What side effects might dapivirine cause?

In both Phase III studies (The Ring Study and ASPIRE) discussed under the previous question, the dapivirine ring was reported to be safe, with no difference in safety concerns between the dapivirine ring group and the placebo group.22 In the Ring Study, some side effects related to the dapivirine ring included abnormal uterine bleeding, pelvic discomfort or pain, lower abdominal (suprapubic) pain, and pain where the ring was located.23

Because the dapivirine vaginal ring is still being studied, information on possible side effects of the drug product is not complete. As testing of the dapivirine vaginal ring continues, additional information on possible side effects will be gathered.

Where can I get more information about clinical trials studying dapivirine?

More information about dapivirine-related research studies is available from the AIDSinfo database of ClinicalTrials.gov study summaries. Click on the title of any trial in the list to see the ClinicalTrials.gov trial summary and more information about the study.

I am interested in participating in a clinical trial of dapivirine. How can I find more information about participating in a clinical trial?

Participating in a clinical trial can provide benefits. For example, a volunteer participant can benefit from new research treatments before they are widely available. Participants also receive regular and careful medical attention from a research team that includes doctors and other health professionals. However, clinical trials may also involve risks of varying degrees, such as unpleasant, serious, or even life-threatening side effects from the treatment being studied.18

Your health care provider can help you decide whether participating in a clinical trial is right for you. For more information, visit NIH Clinical Research Trials and You.

References

  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/244767-67-7. Last accessed on March 10, 2016.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on March 10, 2016.
  3. International Partnership for Microbicides (IPM): Press Release, dated May 8, 2014. IPM Receives Worldwide Rights to HIV Prevention Medicine. Available at: http://ipmglobal.org/publications/ipm-receives-worldwide-rights-hiv-prevention-medicine. Last accessed on March 10, 2016.
  4. International Partnership for Microbicides (IPM) website. Our Products. Available at: http://www.ipmglobal.org/our-work/our-products. Last accessed on March 10, 2016.
  5. National Institute of Allergy and Infectious Diseases (NIAID). NIAID Research on Microbicides. Available at: http://www.niaid.nih.gov/topics/hivaids/research/prevention/pages/topicalmicrobicides.aspx. Last accessed on March 10, 2016.
  6. Shattock RJ, Rosenberg Z. Microbicides: Topical Prevention against HIV. Cold Spring Harb Perspect Med. 2012 Feb; 2(2): a007385. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281595/. Last accessed on March 10, 2016.
  7. Adams JL, Kashuba AD. Formulation, pharmacokinetics and pharmacodynamics of topical microbicides. Best Pract Res Clin Obstet Gynaecol. 2012 Aug; 26(4): 451-62. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662244/. Last accessed on March 10, 2016.
  8. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01539226. Last accessed on March 10, 2016.
  9. 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01617096. Last accessed on March 10, 2016.
  10. International Partnership for Microbicides, Inc. Comparison of the Pharmacokinetics and Pharmacodynamics of Single Dose Dapivirine Vaginal Gel and Film Formulation. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 13, 2013. NLM Identifier: NCT01924091. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01924091. Last accessed on March 10, 2016.
  11. 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. Available at: http://www.ipmglobal.org/publications/two-large-studies-show-ipm%E2%80%99s-monthly-vaginal-ring-helps-protect-women-against-hiv. Last accessed on March 10, 2016.
  12. Cranage M, Sharpe S, Herrera C, et al. Prevention of SIV Rectal Transmission and Priming of T Cell Responses in Macaques after Local Pre-exposure Application of Tenofovir Gel. PLoS Med. 2008 Aug 5; 5(8): e157; discussion e157. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2494562/. Last accessed on April 18, 2016.
  13. Global Campaign for Microbicides website. About Microbicides—How do they work? Available at: http://www.global-campaign.org/the_science.htm#work. Last accessed on March 10, 2016.
  14. CONRAD website. Microbicide Development. Available at: http://www.conrad.org/microbicides.html. Last accessed on March 13, 2016.
  15. CONRAD website. Microbicide Mechanisms of Action. Available at: http://www.conrad.org/microbicides-research-mechanisms.html. Last accessed on March 13, 2016.
  16. Global Campaign for Microbicides. Antiretroviral (ARV)-Based Microbicides: The Promise and the Puzzle; 2010. Available at: http://www.global-campaign.org/clientfiles/FS-ARV-BasedMicrobicides[E].pdf. Last accessed on March 13, 2016.
  17. International Partnership for Microbicides (IPM) website. How ARV-based Microbicides Work. Available at: http://www.ipmglobal.org/why-microbicides/how-arv-based-microbicides-work. Last accessed on March 13, 2016.
  18. National Institutes of Health (NIH). NIH Clinical Research Trials and You. Available at: http://www.nih.gov/health-information/nih-clinical-research-trials-you. Last accessed on March 10, 2016.
  19. Chen BA, Panther L, Marzinke MA, et al. Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: A Double-Blind Randomized Trial. J Acquir Immune Defic Syndr. 2015 Nov 1; 70(3): 242-9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26034880. Last accessed on March 10, 2016.
  20. Bunge KE, Dezzutti CS, Rohan LC, et al. A Phase 1 trial to assess the safety, acceptability, pharmacokinetics and pharmacodynamics of a novel dapivirine vaginal film. J Acquir Immune Defic Syndr. 2015 Nov 11. [Epub ahead of print]. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26565716. Last accessed on March 10, 2016.
  21. Nel AM, Coplan P, van de Wijgert JH, et al. Safety, tolerability, and systemic absorption of dapivirine vaginal microbicide gel in healthy, HIV-negative women. AIDS. 2009 Jul 31; 23(12): 1531-8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19550287. Last accessed on March 10, 2016.
  22. International Partnership for Microbicides website. Phase III Results: Frequently Asked Questions. Available at: http://ipmglobal.org/our-work/our-products/dapivirine-ring/phase-iii-results/frequently-asked-questions. Last accessed on March 10, 2016.
  23. Nel A, Kapiga S, Bekker LG, Devlin B, Borremans M, Rosenberg Z. Safety and Efficacy of Dapivirine Vaginal Ring for HIV-1 Prevention in African Women. Abstract presented at: 23rd Conference on Retroviruses and Opportunistic Infections (CROI); February 22 – 25, 2016; Boston, MA. Abstract 110LB. Available at: http://www.croiconference.org/sessions/safety-and-efficacy-dapivirine-vaginal-ring-hiv-1-prevention-african-women. Last accessed on March 10, 2016.
  24. 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. February 22, 2016; DOI: 10.1056/NEJMoa1506110. Available at: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1506110. Last accessed on March 10, 2016.
  25. National Institute of Allergy and Infectious Diseases (NIAID): News Release, dated February 22, 2016. Vaginal Ring Provides Partial Protection from HIV in Large Multinational Trial. Available at: http://www.niaid.nih.gov/news/newsreleases/2016/Pages/ASPIRE.aspx. Last accessed on March 10, 2016.
  26. Microbicide Trials Network (MTN): Press Release, dated February 22, 2016. Dapivirine vaginal ring helped protect women against HIV in ASPIRE Phase III trial. Available at: http://www.mtnstopshiv.org/node/7229. Last accessed on March 10, 2016.
  27. National Institute of Allergy and Infectious Diseases (NIAID): News Release, dated March 13, 2016. NIAID to Fund Further Study of Dapivirine Vaginal Ring for HIV Prevention. Available at: http://www.niaid.nih.gov/news/newsreleases/2016/Pages/HOPE-trial.aspx. Last accessed on March 14, 2016.
  28. International Partnership for Microbicides, Inc. Phase 2a Safety Study of a Vaginal Matrix Ring Containing Dapivirine in a Postmenopausal Femal Population. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 14, 2013. NLM Identifier: NCT02010593. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02010593. Last accessed on March 10, 2016.
  29. Chen BA, Hoesley C, Salata RA, et al. Safety and Pharmacokinetics of Dapivirine Vaginal Rings in Postmenopausal US Women. Abstract presented at: 23rd Conference on Retroviruses and Opportunistic Infections (CROI); February 22 – 25, 2016; Boston, MA. Abstract 872. Available at: http://www.croiconference.org/sessions/safety-and-pharmacokinetics-dapivirine-vaginal-rings-postmenopausal-us-women. Last accessed on March 10, 2016.
  30. International Partnership for Microbicides, Inc. Phae 2A Study of a Vaginal Ring Containing Dapivirine in Adolescent Females. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 2, 2014. NLM Identifier: NCT02028338. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02028338. Last accessed on March 10, 2016.


Last Reviewed: March 13, 2016

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