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 disulfiram?
Disulfiram is a drug that has been approved by FDA for helping in the management of alcoholism. It has also been studied to see if it could be effective as part of a strategy to cure HIV infection.4-8
Currently, there is no cure for HIV infection. One of the main obstacles to curing HIV infection is that the virus can remain hidden and inactive (latent) inside certain cells of the immune system (such as resting CD4 T cells) for many months or even years. While HIV is in this latent state, the immune system cannot recognize the virus, and antiretroviral therapy (ART) has no effect on it. (ART is the recommended treatment for HIV infection and involves using a combination of different antiretroviral [ARV] drugs to prevent HIV from replicating.)9,10
Disulfiram belongs to a general class (group) of HIV drugs called latency-reversing agents.2 Latency-reversing agents reactivate (turn back on) latent HIV within resting CD4 T cells.10,11 There are different types of latency-reversing agents. Disulfiram is a type of latency-reversing agent called a phosphatase and tensin homolog (PTEN) inhibitor.11,12
How do latency-reversing agents work?
Latency-reversing agents reactivate (turn back on) latent HIV within resting CD4 T cells. When latent HIV is reactivated, it is once again able to produce new virus and multiply (replicate). It is hoped that after latent HIV is reactivated, the CD4 T cells in which the virus was hiding are more likely to die off on their own or be recognized and killed by the body’s immune system.10,11
In addition, any new virus that is produced during reactivation can then be prevented from infecting other cells with the use of ongoing ART.10,11 Recent research has shown that additional therapies, together with latency-reversing agents, may be needed to fully eliminate latent HIV from the body.11
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.13
- 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.13
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.13
In what phase of testing is disulfiram?
Disulfiram has been studied in Phase I/II clinical trials.4
What are some studies on disulfiram?
Study Name: NCT01286259
Phase: Not available
Location: United States
Participants: HIV-infected adults who had taken HIV medicines before starting the study (called treatment-experienced) and whose HIV infection was being controlled with ART. Participants also had:
- been on ART for at least 18 months
- a viral load level (the amount of HIV in a blood sample) that was suppressed to less than 50 copies/mL for the past 12 months
- a CD4 count that was greater than 200 cells/mm3 for the 24 weeks before starting the study
(A CD4 count is a laboratory test that measures the number of CD4 cells in a sample of blood and is an important indicator of immune function. The CD4 count of a healthy person ranges from 500 to 1,600 cells/mm3.)
The purpose of this study was to look at the safety of disulfiram and to see whether disulfiram added to ART could reactivate and then reduce the amount of latent HIV.6,7
For more details on this study, see the Health Professional version
Study Name: NCT01944371
United States and Australia
- HIV-infected, treatment-experienced adults whose HIV infection was being controlled with ART. The participants’ ART included either the HIV medicine efavirenz (brand name: Sustiva) or the HIV medicine ritonavir (brand name: Norvir).
- Participants had viral load levels that were less than 50 copies/mL for at least 3 years and CD4 counts greater than 350 cells/mm3 during the 6 months before being screened for the study.
The purpose of this study was to look at the safety and effects of different doses of disulfiram on reactivating latent HIV.4,5
For more details on this study, see the Health Professional version
What side effects might disulfiram cause?
In the study NCT01286259 discussed under the previous question, one participant withdrew from the study after 12 days of taking disulfiram. Side effects that occurred during the study were reported as being either mild or moderate in severity.6,7
In the Phase I/II study (NCT01944371), side effects that were likely or definitely caused by disulfiram included dry mouth/impaired taste, headache, nausea, drowsiness, and light headedness, all of which were reported as mild in severity. Seven participants had an electrolyte imbalance in which the level of phosphate in the blood was too low (called hypophosphatemia).4,14
Other side effects associated with disulfiram are described in the FDA-approved Antabuse Full Prescribing Information.8
Information on possible side effects of disulfiram use in HIV-infected people is not complete. As testing of disulfiram continues, additional information on possible side effects will be gathered.
Where can I get more information about clinical trials studying disulfiram?
More information about disulfiram-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 disulfiram. 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.13
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.
- United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/97-77-8. Last accessed on June 13, 2016.
- Treatment Action Group website. Research Toward a Cure Trials. Available at: http://www.treatmentactiongroup.org/cure/trials. Last accessed on June 13, 2016.
- Kulkarni RA, Stanford SM, Vellore NA, et al. Thiuram Disulfides as Pseudo-irreversible Inhibitors of the Lymphoid Tyrosine Phosphatase. ChemMedChem. 2013 Sep; 8(9): 1561-8. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863632/. Last accessed on June 13, 2016.
- University of California, San Francisco. Short-term Disulfiram Administration to Reverse Latent HIV Infection: a Dose Escalation Study. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 12, 2013. NLM Identifier: NCT01944371. Available at: https://clinicaltrials.gov/ct2/show/NCT01944371. Last accessed on June 13, 2016.
- Lee SA, Elliott JH, McMahon J, et al. Disulfiram Reactivates Latent HIV Infection in a Dose-Dependent Manner. Abstract presented at: 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy; May 26-28, 2015; Washington, DC. Abstract 11. Available at: http://regist2.virology-education.com/abstractbook/2015_4.pdf. Last accessed on June 13, 2016.
- University of California, San Francisco. Short-term Disulfiram Administration to Accelerate the Decay of the HIV Reservoir in Antiretroviral-treated HIV Infected Individuals. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 27, 2011. NLM Identifier: NCT01286259. Available at: https://clinicaltrials.gov/ct2/show/NCT01286259. Last accessed on June 13, 2016.
- Spivak AM, Andrade A, Eisele E, et al. A Pilot Study Assessing the Safety and Latency-Reversing Activity of Disulfiram in HIV-1–Infected Adults on Antiretroviral Therapy. Clin Infect Dis. 2014 Mar 15; 58(6): 883–890. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935499/. Last accessed on June 13, 2016.
- Teva Women's Health, Inc. ANTABUSE- disulfiram tablet: Full Prescribing Information, May 23, 2016. DailyMed. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f0ca0e1f-9641-48d5-9367-e5d1069e8680. Last accessed on June 13, 2016.
- National Institute of Allergy and Infectious Diseases (NIAID): Bulletin, dated June 16, 2009. NIAID Invites Applications to Conduct Basic Research on HIV Persistence: Studies Key to Search for a Cure. Available at: http://www.niaid.nih.gov/news/newsreleases/Archive/2009/Pages/HIV_persistence.aspx. Last accessed on June 13, 2016.
- Siliciano RF, Greene WC. HIV Latency. Cold Spring Harb Perspect Med. 2011 Sep; 1(1): a007096. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234450/. Last accessed on June 13, 2016.
- Rasmussen TA, Tolstrup M, Winckelmann A, Ostergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies. Hum Vaccin Immunother. 2013 Apr 1; 9(4) :790-799. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903897/. Last accessed on June 13, 2016.
- Archin NM, Sung JM, Garrido C, Soriano-Sarabia N, Margolis DM. Eradicating HIV-1 infection: seeking to clear a persistent pathogen. Nat Rev Microbiol. 2014 Nov; 12(11): 750–764. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383747/. Last accessed on June 13, 2016.
- 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 June 13, 2016.
- Elliott JH, McMahon JH, Hartogensis, et al. Short-term Disulfiram to Reverse Latent HIV Infection: a Dose Escalation Study. Poster presented at: 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, WA. Poster 428LB. Available at: http://www.croiconference.org/sites/default/files/posters-2015/428LB.pdf. Last accessed on June 13, 2016.
Last Reviewed: June 13, 2016