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.
The topical microbicide form of tenofovir is an investigational drug that is being studied to prevent sexual transmission of HIV and herpes simplex virus type 2 (HSV-2). 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.4 (There are other forms of tenofovir-containing products, such as oral tenofovir disoproxil fumarate [brand name: Viread], that are different from the topical microbicide form. Oral tenofovir disoproxil fumarate is FDA approved for treating HIV infection and is taken by mouth.)
Topical microbicides can also be referred to as topical pre-exposure prophylaxis (PrEP) products.3,4 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. 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).3,5 They may prevent HIV transmission in a number of ways. For example, HIV topical microbicides might:
Tenofovir microbicide works by preventing HIV infection from spreading to other cells. It belongs to a class (group) of HIV drugs called nucleoside reverse transcriptase inhibitors (NRTIs).3 NRTIs 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, NRTIs prevent HIV from multiplying and from spreading to other cells.
Tenofovir microbicide is currently in a gel form. The gel is being studied for vaginal and rectal use.6,7 (Tenofovir gel for rectal use contains a reduced amount of glycerin, an inactive ingredient, and it may be referred to as reduced glycerin tenofovir gel.)6
Clinical trials are conducted in phases. Each phase has a different purpose and helps researchers answer different questions.8
In most cases, an investigational drug must be proven safe and effective 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. 8
In a Phase IIb study (known as CAPRISA 004), tenofovir vaginal gel was compared to placebo in HIV-uninfected South African women for 30 months. (A placebo is an inactive drug that is identical in appearance to the active drug being studied.) The participants in this study were instructed to insert one dose of tenofovir gel intravaginally within 12 hours before sex and a second dose of tenofovir gel as soon as possible within 12 hours after sex. No more than two doses of gel were to be used within a 24-hour period.9
In the CAPRISA 004 study, tenofovir vaginal gel, when compared to placebo, was shown to reduce sexually transmitted HIV infection by 39%. Study investigators noted that a high number of study participants did not use the gel exactly as prescribed. When looking at a subset of study participants who consistently used the gel as prescribed, the effectiveness of tenofovir vaginal gel at reducing HIV infection increased to 54%. This study showed that tenofovir vaginal gel may potentially work as an effective strategy for preventing HIV infection in women.9 In addition, the CAPRISA 004 study also demonstrated that tenofovir vaginal gel may help protect women from acquiring sexually transmitted HSV-2.10
In a separate Phase IIb study (known as MTN-003 or the VOICE study), two HIV prevention strategies were tested in HIV-uninfected women: a vaginal microbicide (tenofovir vaginal gel) and oral tablets. One group of participants was instructed to use one dose of tenofovir vaginal gel once daily. The time of gel use was not dependent on time of sexual activity. The other group of participants received either the FDA-approved oral NRTI tenofovir disoproxil fumarate (brand name: Viread) or the FDA-approved oral combination medicine emtricitabine/tenofovir disoproxil fumarate (brand name: Truvada). All three prevention medicines were tested against a placebo control group.11,12,13
In the VOICE study, both tenofovir vaginal gel and the two oral tablets failed to show efficacy in preventing transmission of HIV in a study population of mostly young and unmarried African women. One of the reasons noted for the VOICE study failures was poor medicine adherence among the majority of the study population. (Adherence means using a medicine exactly as prescribed.)12,13 (Note: Truvada, along with safer sex practices, is FDA approved for oral PrEP to reduce the risk of sexually acquired HIV infection in high risk adult populations.)14
A Phase III study (known as FACTS 001) of tenofovir vaginal gel is underway. This study will continue to evaluate how well tenofovir vaginal gel works in protecting women against sexual transmission of HIV and HSV-2.7
Reduced glycerin tenofovir gel used rectally is also being studied. In a Phase I clinical trial (known as MTN-007), men and women used reduced glycerin tenofovir gel rectally on a daily basis for 7 days. This study showed that reduced glycerin tenofovir gel used rectally was safe and acceptable (meaning study participants reported that they were likely to use the product in the future).15 A Phase II study (known as MTN-017) will continue to investigate the safety and acceptability of rectally applied reduced glycerin tenofovir gel in men and transgender women.6
In the Phase IIb CAPRISA 004 study, tenofovir vaginal gel did not cause more side effects than placebo in terms of kidney, liver, genital, or pregnancy-related side effects. More cases of mild diarrhea were reported in the tenofovir vaginal gel group than in the placebo group.9
In the Phase I MTN-007 study, side effects associated with rectally applied tenofovir gel were mild to moderate. The most common side effects were gastrointestinal symptoms, including abdominal pain, sudden urge to have a bowel movement, diarrhea, and flatulence (gas).15
Because tenofovir gel is still being studied, information on possible side effects of the drug is not complete. As testing of tenofovir gel continues, additional information on possible side effects will be gathered.
More information about tenofovir gel-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.
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.8
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.
5. 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. Last accessed on January 5, 2014.
6. 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. Last accessed on January 5, 2014.
7. 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. Last accessed on January 5, 2014.
9. 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 Sep 3;329(5996):1168-74. Last accessed on January 5, 2014.
10. 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 May;21(5):695-715. Last accessed on January 5, 2014.
11. Friend DR, Kiser PF. Assessment of topical microbicides to prevent HIV-1 transmission: concepts, testing, lessons learned. Antiviral Res. 2013 Sep;99(3):391-400. Last accessed on January 5, 2014.
12. National Institute of Allergy and Infectious Diseases (NIAID): News Releases, dated March 4, 2013. Daily-Use HIV Prevention Approaches Prove Ineffective Among Women in NIH Study. Last accessed on January 5, 2014.
13. 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. Last accessed on January 5, 2014.
15. McGowan I, Hoesley C, Cranston RD, et al. A Phase 1 Randomized, Double Blind, Placebo Controlled Rectal Safety and Acceptability Study of Tenofovir 1% Gel (MTN-007). 2013;8(4):e60147. Last accessed on January 5, 2014.
Last Reviewed: January 5, 2014
Last Updated: January 5, 2014