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.
What is tenofovir microbicide?
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.4,5 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).5,6 They may prevent HIV transmission in a number of ways. For example, HIV topical microbicides might:
- inactivate HIV or other pathogens (also called disease-causing microorganisms);
- strengthen the body’s normal defenses;
- block HIV from attaching to healthy cells susceptible to infection;
- prevent HIV infection from spreading to other cells that are healthy.4
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).5 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.
Several different forms of tenofovir-based microbicide products are being studied, including a vaginal gel, a rectal gel, a vaginal ring (also known as an intravaginal ring or IVR), a vaginal tablet, and a vaginal film. The vaginal gel is furthest along in development.7-13 (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.)7
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
In what phase of testing is tenofovir microbicide?
Tenofovir vaginal gel is currently being studied in Phase III clinical trials. Reduced glycerin tenofovir gel for rectal use is currently in Phase II clinical trials.2,3,7,9
(Other forms of tenofovir-based microbicides, including an intravaginal ring, vaginal tablet, and vaginal film, are in Phase I studies.)10-13
What are some studies on tenofovir microbicide?
Tenofovir Vaginal Gel
CAPRISA 004 Study: In a Phase IIb study (known as CAPRISA 004), investigators looked at the safety and effectiveness of tenofovir vaginal gel to prevent HIV infection in women. 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.15,16
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.15 In addition, the CAPRISA 004 study also demonstrated that tenofovir vaginal gel may help protect women from acquiring sexually transmitted HSV-2.17
MTN-003 (VOICE) Study: In a separate Phase IIb study (known as MTN-003 or the VOICE study), three HIV prevention strategies were tested in HIV-uninfected women: a vaginal microbicide (tenofovir vaginal gel) and two different 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 two groups 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); the participants also received placebo tablets so that all participants assigned to an oral medicine group received similar looking tablets and the same number of tablets daily. All three prevention medicines were tested against either a placebo gel control group or a placebo oral tablet control group.18-20
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.)19,21 In an analysis of participants who had used tenofovir vaginal gel regularly versus those who had not, investigators noted that women who regularly used tenofovir vaginal gel significantly reduced their risk of acquiring HSV-2 infection.22,23 (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.)24
FACTS 001 Study: In a Phase III study (known as FACTS 001) involving over 2000 participants, investigators continued to evaluate how well tenofovir vaginal gel works in protecting women against sexual transmission of HIV and HSV-2. Participants were primarily young, unmarried South Africa women. In this study, HIV-uninfected women were assigned to use either tenofovir vaginal gel or placebo gel. Both groups of participants were instructed to insert one dose of gel intravaginally within 12 hours before sex and a second dose of gel as soon as possible within 12 hours after sex, and to use no more than two doses of gel within a 24-hour period.8,25
In the FACTS 001 study, tenofovir vaginal gel did not prove effective overall in preventing the study population from acquiring HIV. On the basis of returned gel applicators and self-reporting, participants in the study used the gel in about half of their sex acts. Only 13% of participants used the gel during more than 80% of sex acts. An analysis of a subset of participants in the tenofovir gel group showed that detection of tenofovir in vaginal fluid samples was associated with a significant reduction in HIV acquisition by 52%, while women who had no drug detected in vaginal fluid samples were more likely to become infected. Investigators concluded that even though tenofovir gel was effective in protecting those women who used the gel consistently as instructed, overall, when looking at the entire study population, gel adherence was too low to prove the effectiveness of tenofovir gel. Investigators will also be analyzing HSV-2 data from this study to determine if tenofovir gel can be useful in preventing genital herpes.25,26
Tenofovir Rectal Gel
MTN-007 Study: In a Phase I clinical trial (known as MTN-007) in HIV-uninfected men and women, reduced glycerin tenofovir gel was compared in terms of safety and acceptability to a nonoxynol-9 gel, a placebo gel, and no treatment. After clinic staff applied the initial gel dose, participants self-applied their assigned gel rectally and once daily 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).27,28
MTN-017 Study: 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. This study will compare the effects of the following three study regimens:
- Reduced glycerin tenofovir gel applied rectally and once daily.
- Reduced glycerin tenofovir gel applied rectally within 12 before sex and a second dose used as soon as possible within 12 hours after sex, and no more than two doses used in a 24-hour period.
- Emtricitabine/tenofovir disoproxil fumarate combination tablet (brand name: Truvada) taken orally and once daily.
All study participants will follow each of the regimens for 8 weeks, with a 1-week period between regimens during which no study product will be used.7,29
What side effects might tenofovir microbicide cause?
In the CAPRISA 004 study discussed under the previous question, 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.15
In the MTN-003 (VOICE) study, no significant differences in safety outcomes among the study groups were noted, except for elevated creatinine blood levels (mostly mild) in participants taking oral emtricitabine/tenofovir disoproxil fumarate combination tablets (brand name: Truvada) when compared to participants taking oral placebo.21
In the 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).28
Because both tenofovir vaginal and rectal gel are still being studied, information on possible side effects of the drug products is not complete. As testing of tenofovir gel continues, additional information on possible side effects will be gathered.
Where can I get more information about clinical trials studying tenofovir microbicide?
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.
I am interested in participating in a clinical trial of tenofovir microbicide. 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.
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- 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 8, 2015.
- AIDS Vaccine Advocacy Coalition (AVAC). Microbicides by the Numbers: Science, products, money and more. Available at: http://www.avac.org/sites/default/files/resource-files/Microbicides_by_the_Numbers_Oct%202014.pdf. Last accessed on March 8, 2015.
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- 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 March 8, 2015.
- 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01687218. Last accessed on March 8, 2015.
- 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01386294. Last accessed on March 8, 2015.
- 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01691768. Last accessed on March 8, 2015.
- Albert Einstein College of Medicine of Yeshiva University. Phase 1 Safety and Pharmacokinetic Study of Polyurethane Tenofovir Disoproxil Fumarate Vaginal Ring. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 19, 2013. NLM Identifier: NCT02006264. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02006264. Last accessed on March 8, 2015.
- CONRAD. Phase I One-Month Safety, Pharmacokinetic, Pharmacodynamic, and Acceptability Study of Intravaginal Rings Releasing Tenofovir and Levonorgestrel or Tenofovir Alone. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November July 14, 2014. NLM Identifier: NCT02235662. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02235662. Last accessed on March 8, 2015.
- 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01694407. Last accessed on March 8, 2015.
- 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01989663. Last accessed on March 8, 2015.
- 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 8, 2015.
- 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001187/. Last accessed on March 8, 2015.
- 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. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00441298. Last accessed on March 8, 2015.
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- Microbicide Trials Network (MTN): Press Release, dated October 28, 2014. New results from VOICE associates tenofovir gel use with lower HSV-2 risk in women. Available at: http://www.mtnstopshiv.org/node/6216. Last accessed on March 8, 2015.
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Last Reviewed: March 8, 2015