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Drugs

Dapivirine

Dapivirine

Other Names: DAP, DPV, 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 Research and Development, LLC; International Partnership for Microbicides (IPM) Phase of Development: The dapivirine intravaginal ring is in Phase IIIb testing. Other dapivirine-based microbicide products are in earlier phases of study.

(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?

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?

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 gels, vaginal rings (also known as intravaginal rings or IVRs), and a vaginal film. The dapivirine vaginal ring is furthest along in development. It provides long-term delivery of dapivirine over a month-long period.4,7

How do topical microbicides work?

How do topical microbicides work?

Topical 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).6,8

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.9-11

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 1 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.9,12,13

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?

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.14

  • 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.14

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.14 (Some clinical trials are categorized as “a” or “b,” such as “Phase Ia” or “Phase IIb.” These different subphases typically mean that a study is researching certain types of information or using a certain type of participant population.)

In what phase of testing is dapivirine?

In what phase of testing is dapivirine?

The dapivirine vaginal ring is currently being studied in Phase IIIb 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.4,15

What are some studies on dapivirine?

What are some studies on dapivirine?

Study Names: (1) Ring Study; IPM 027; NCT01539226 and (2) DREAM Study; IPM 032; NCT0282171
Sponsor: International Partnership for Microbicides, Inc.
Phase: The Ring study was a Phase III trial, and the DREAM study is a Phase IIIb trial.
Location: South Africa and Uganda
Participants:

  • Participants in the Ring study were sexually active women who were 18 to 45 years of age and were not infected with HIV.
  • Participants in the ongoing DREAM study are women who participated in the Ring study and who are not infected with HIV.

Purpose: The purpose of the Ring study was to evaluate whether a dapivirine vaginal ring was safe and effective in protecting women against sexually acquired HIV. The DREAM study is an ongoing study that continues to evaluate the safety of the dapivirine vaginal ring. The DREAM study also looks at how well participants follow the study instructions for using the vaginal ring.16-19



Study Names: (1) ASPIRE Study; MTN-020; NCT01617096 and (2) HOPE Study; MTN-025; NCT02858037
Sponsor: International Partnership for Microbicides, Inc.
Phase: The ASPIRE study was a Phase III trial, and the HOPE study is a Phase IIIb trial.
Location: Malawi, South Africa, Uganda, and Zimbabwe
Participants:

  • Participants in the ASPIRE study were sexually active women who were 18 to 45 years of age and were not infected with HIV.
  • Participants in the ongoing HOPE study are women who participated in the ASPIRE study and who are not infected with HIV.

Purpose: The purpose of the ASPIRE study was to evaluate whether a dapivirine vaginal ring was safe and effective in protecting women against sexually acquired HIV. The HOPE study is an ongoing study that continues to evaluate the safety of the dapivirine vaginal ring. The HOPE study also looks at how well participants follow the study instructions for using the vaginal ring.20,21

For more details on the studies listed above, see the Health Professional version.

Additional dapivirine vaginal ring studies have been completed or are ongoing or planned, including:

  • REACH (NCT03074786), a Phase IIa study in women 16 to 21 years of age
  • MTN-030/IPM 041 (NCT02855346), a Phase I study on a vaginal ring containing dapivirine and the hormone-based medicine levonorgestrel
  • MTN-013/IPM 026 (NCT01363037), a Phase I study on a vaginal ring containing dapivirine and the HIV medicine maraviroc.22-25
 

What side effects might dapivirine cause?

What side effects might dapivirine cause?

In both Phase III studies—the Ring study (NCT01539226) and ASPIRE study (NCT01617096)—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.26,27 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. All of these side effects were mild in severity. In the ASPIRE study, side effects related to the dapivirine ring included the following: inflammation, reddening, or swelling of the cervix; urinary tract infection; loss of bladder control; headache; pain during sex; and pelvic pain.27-29

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?

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.

How can I find more information about participating in a clinical trial?

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.14

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

References

  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: https://chem.sis.nlm.nih.gov/chemidplus/rn/244767-67-7. Last accessed on April 28, 2017.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on April 28, 2017.
  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 April 28, 2017.
  4. International Partnership for Microbicides (IPM) website. Product pipeline. Available at: http://www.ipmglobal.org/our-work/product-pipeline. Last accessed on April 28, 2017.
  5. National Institute of Allergy and Infectious Diseases (NIAID). Microbicides to block transmission of HIV. Available at: https://www.niaid.nih.gov/diseases-conditions/microbicides. Last accessed on April 28, 2017.
  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 April 28, 2017.
  7. 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 April 28, 2017.
  8. 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 28, 2017.
  9. 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 April 28, 2017.
  10. CONRAD website. Microbicide Development. Available at: http://www.conrad.org/microbicides.html. Last accessed on April 28, 2017.
  11. CONRAD website. Microbicide Mechanisms of Action. Available at: http://www.conrad.org/microbicides-research-mechanisms.html. Last accessed on April 28, 2017.
  12. 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 April 28, 2017.
  13. 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 April 28, 2017.
  14. 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 April 28, 2017.
  15. International Partnership for Microbicides (IPM) website. Darunavir. Available at: http://www.ipmglobal.org/our-work/arvs-in-the-pipeline/darunavir. Last accessed on April 28, 2017.
  16. 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 April 28, 2017.
  17. 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. Available at: https://clinicaltrials.gov/ct2/show/NCT02862171. Last accessed on April 28, 2017.
  18. Rosenberg Z. Dapivirine ring: the roadmap to licensure. Slides presented at: MTN Regional Meeting; October 4-8, 2015; Cape Town, South Africa. Available at:  http://www.mtnstopshiv.org/sites/default/files/attachments/ROSENBERG2015-10-MTN-regional-mtg-Zeda_draftSept29.pdf. Last accessed on April 28, 2017.
  19. International Partnership for Microbicides (IPM) website. IPM 032. Available at: http://www.ipmglobal.org/content/ipm-032. Last accessed on April 28, 2017.
  20. 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 April 28, 2017.
  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. Available at: https://clinicaltrials.gov/ct2/show/NCT02858037. Last accessed on April 28, 2017.
  22. International Partnership for Microbicides, Inc. 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 February 10, 2017. NLM Identifier: NCT03074786. Available at: https://clinicaltrials.gov/ct2/show/NCT03074786. Last accessed on April 28, 2017.
  23. International Partnership for Microbicides, Inc. A Phase 1, randomized, double-blind pharmacokinetic and safety study of dapivirine/levonorgestrel vaginal rings. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 21, 2016. NLM Identifier: NCT02855346. Available at:  https://clinicaltrials.gov/ct2/show/NCT02855346. Last accessed on April 28, 2017.
  24. International Partnership for Microbicides, Inc. Phase 1 safety and pharmacokinetics of dapivirine/maraviroc vaginal ring. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 27, 2011. NLM Identifier: NCT01363037. Available at: https://clinicaltrials.gov/ct2/show/NCT01363037. Last accessed on April 28, 2017.
  25. International Partnership for Microbicides (IPM) website. Clinical trials. Available at: https://www.ipmglobal.org/our-work/research/clinical-trial. Last accessed on April 28, 2017.
  26. 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 April 28, 2017.
  27. Nel A, van Niekerk N, Kapiqa S, et al. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N Engl J Med. 2016 Dec 1;375(22):2133-2143. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1602046#t=article. Last accessed on April 28, 2017.
  28. 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 April 28, 2017.
  29. 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 April 28, 2017.
 

Last Reviewed: April 28, 2017