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 hydroxychloroquine?
Hydroxychloroquine is a drug that has been approved by FDA for the treatment of malaria, lupus, and rheumatoid arthritis.7 It has also been studied as an investigational drug for HIV infection. As an HIV therapy, hydroxychloroquine is categorized as an immune modulator.2 Immune modulators (also called immunomodulators) are substances that modify (activate, enhance, or suppress) the functioning of the immune system.
HIV infection can make a person’s immune system not work properly over the course of the viral infection. When this happens:
- CD4 counts can drop and HIV infection can worsen.
(A CD4 count is a laboratory test that measures the number of CD4 cells — a type of immune cell — in a sample of blood and is an important indicator of immune function.)
- Other immune system cells or proteins may not be produced in normal amounts and may not work normally.
- A person may not respond well to antiretroviral therapy (ART).
(ART is the recommended treatment for HIV infection and involves using a combination of different antiretroviral [ARV] drugs to prevent HIV from multiplying.)
- Latent HIV reservoirs can form and persist in the body.
(Latent HIV reservoirs are “resting” CD4 cells or other cells that are infected with HIV but not actively producing HIV in the body. Because ART does not work against HIV that’s hidden in latent reservoirs, these reservoirs are one of the main obstacles to curing HIV infection.)8-13
Hydroxychloroquine may be able to suppress or calm an overactive immune system.8,9 However, some results from clinical trials evaluating the effectiveness of hydroxychloroquine in patients with HIV have been mixed.2,8,9 A more recent study has looked at the use of hydroxychloroquine, along with other drugs, to help clear the body of latent HIV reservoirs that cannot be removed with ART alone.5
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 hydroxychloroquine?
Hydroxychloroquine has been studied in Phase II clinical trials.5,6
What are some studies on hydroxychloroquine?
Study Names: SEARCH 019; NCT02475915
Sponsor: South East Asia Research Collaboration with Hawaii
- The study involved HIV-infected adults who had previously taken HIV medicines (also called treatment-experienced) and who began their ART during acute HIV infection, which is an early stage of HIV infection that extends about 1 to 4 weeks from the initial infection.
- Participants had viral load levels (the amount of HIV in a blood sample) of less than 50 copies/mL for more than 48 weeks. Participants also had CD4 counts of at least 450 cells/mm3.
This study examined how safely and effectively a combination of ART, vorinostat
, hydroxychloroquine, and maraviroc controlled participants’ viral loads during a treatment interruption that followed. (A treatment interruption is a planned break from HIV medicines to evaluate how well an investigational drug can maintain control of a participant's viral load during a clinical trial.) The researchers compared this combination to ART alone.5,17,18
A central nervous system (CNS) sub-study (SEARCH 026; NCT02470351
) was also completed.15,19
Medical Research Council
- The study involved HIV-infected adults who were either treatment-experienced or had never taken HIV medicines before entering the study (also called treatment-naive).
- Participants had stopped their ART for at least 12 months before the study.
- Participants had no symptoms of HIV, viral load levels greater than 1000 copies/mL, and CD4 counts greater than 400 cells/mm3.
The purpose of this study was to determine whether hydroxychloroquine could reduce immune system activity and slow the decline of CD4 counts in participants who were not receiving ART.6,8
- The study involved HIV-infected, treatment-experienced adults who were receiving ART.
- Participants had suppressed viral load levels of less than 37 copies/mL and CD4 counts of less than 200 cells/mm3 during the past 12 months.
The purpose of this study was to determine whether hydroxychloroquine could reduce immune system activity and increase CD4 cell counts in people whose CD4 counts didn’t improve on ART even when their viral loads were suppressed.2
Other HIV-related studies evaluating hydroxychloroquine have been completed or are ongoing. One ongoing study (NCT02079077
) is looking at whether aspirin or hydroxycholoroquine can reduce immune system activity in women who are not infected with HIV.16
For more details on the studies listed above, see the Health Professional version
What side effects might hydroxychloroquine cause?
In the SEARCH 019 study (NCT02475915) discussed under the previous question, 2 out of 10 people receiving the combination of ART, vorinostat, hydroxychloroquine, and maraviroc experienced serious side effects. One of these participants dropped out of the study due to kidney problems and low levels of platelets (a type of blood cell) caused by the treatment. The other participant had diarrhea, which may have been caused by food poisoning. All of the study participants experienced non-serious side effects, but only people receiving the combination of ART, vorinostat, hydroxychloroquine, and maraviroc had low platelet counts and elevated creatinine levels (which are sometimes a sign of kidney problems).5,17 No long-term side effects were reported for participants taking the combination treatment in the CNS sub-study (NCT02470351).15,19
In the HCQ-01study (NCT01067417), there were no reported serious side effects related to hydroxychloroquine. Most of the side effects that occurred during the study were mild in severity. Flu-like illness and upper respiratory tract infections occured more commonly in participants who received hydroxychloroquine than in participants who received placebo. (A placebo is an inactive drug that is identical in appearance to the active drug being studied.)6,8
In the EutraCT (2009-012499-28) study, hydroxychloroquine was reported as “well tolerated” in all participants, except for one participant who experienced skin rash.2
Because hydroxychloroquine is still being studied, information on possible side effects of the drug is not complete. As testing of hydroxychloroquine continues, additional information on possible side effects will be gathered.
Where can I get more information about clinical trials studying hydroxychloroquine?
More information about hydroxychloroquine-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?
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.
- United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/118-42-3. Last accessed on September 13, 2016.
- Piconi S, Parisotto S, Rizzardini G, et al. Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders. Blood. 2011 Sep 22; 118(12): 3263-72. Available at: http://www.bloodjournal.org/content/bloodjournal/118/12/3263.full.pdf. Last accessed on September 13, 2016.
- Clayden P, Collins S, Frick M, et al. HIV i-BASE/Treatment Action Group. 2015 Pipeline Report. Benzacar A, ed. July 2015. Available at:http://www.pipelinereport.org/sites/default/files/201509/2015%20Pipeline%20Report%20Full.pdf. Last accessed on September 13, 2016.
- Delves M, Plouffe D, Scheurer C, et al. The Activities of Current Antimalarial Drugs on the Life Cycle Stages of Plasmodium: A Comparative Study with Human and Rodent Parasites. PLoS Med. 2012 Feb; 9(2): e1001169. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283556/. Last accessed on September 13, 2016.
- South East Asia Research Collaboration with Hawaii. A Randomized Study to Compare the Efficacy of Vorinostat/Hydroxychloroquine/Maraviroc (VHM) in Controlling HIV After Treatment Interruption in Subjects Who Initiated ART During Acute HIV Infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 3, 2015. NLM Identifier: NCT02475915. Available at: https://clinicaltrials.gov/ct2/show/NCT02475915. Last accessed on September 13, 2016.
- Medical Research Council. Evaluation of the Efficacy of Hydroxychloroquine in Decreasing Immune Activation in Asymptomatic HIV-infected Patients. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 10, 2010. NLM Identifier: NCT01067417. Available at: https://clinicaltrials.gov/ct2/show/NCT01067417. Last accessed on September 13, 2016.
- Concordia Pharmaceuticals Inc. PLAQUENIL- hydroxychloroquine sulfate tablet: Full Prescribing Information, August 30, 2015. DailyMed. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34496b43-05a2-45fb-a769-52b12e099341. Last accessed on September 13, 2016.
- Paton NI, Goodall RL, Dunn DT, et al. Effects of Hydroxychloroquine on Immune Activation and Disease Progression Among HIV-Infected Patients Not Receiving Antiretroviral Therapy A Randomized Controlled Trial. JAMA. 2012 Jul 25; 308(4): 353-61. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821003/. Last accessed on September 13, 2016.
- Savarino A, Shytaj IL. Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS. Retrovirology. 2015; 12: 51. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472405/. Last accessed on September 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 September 13, 2016.
- Barouch DH, Deeks SG. Immunologic Strategies for HIV-1 Remission and Eradication. Science. 2014 Jul 11; 345(6193): 169–174. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096716/. Last accessed on September 14, 2016.
- Lederman MM, Rodriguez B, Sieg S. Immunopathogenesis of HIV Infection. In: Coffey S and Volberding P, eds. HIV InSite Knowledge Base. University of California San Francisco; 2004. Available at: http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-02-01-04. Last accessed on September 14, 2016.
- Kedzierska K, Crowe SM. Cytokines and HIV-1: interactions and clinical implications. Antivir Chem Chemother. 2001 May; 12(3): 133-50. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12959322. Last accessed on September 14, 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 September 13, 2016.
- South East Asia Research Collaboration with Hawaii. Study SEARCH 026 Assessment of the HIV CNS Reservoir, Neurological and Neuro-cognitive Effects, and Source of Rebound HIV in CNS in Subjects Participating in Study SEARCH 019. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 2, 2015. NLM Identifier: NCT02470351. Available at: https://clinicaltrials.gov/ct2/show/NCT02470351. Last accessed on September 13, 2016.
- University of Manitoba. Limiting HIV Target Cells by Inducing Immune Quiescence in the Female Genital Tract. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 3, 2014. NLM Identifier: NCT02079077. Available at: https://clinicaltrials.gov/ct2/show/NCT02079077. Last accessed on September 13, 2016.
- Kroon E, Ananworanich J, Eubanks K, et al. Effect of vorinostat, hydroxychloroquine and maraviroc combination therapy on viremia following treatment interruption in individuals treated during acute HIV infection. 21st International AIDS Conference (AIDS 2016); July 18-22, 2016; Durban, South Africa. Mascolini: Vorinostat, HCQ, Maraviroc Do Not Delay Time to Rebound After Interruption. Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2016. Available at: http://www.natap.org/2016/IAC/IAC_07.htm. Last accessed on September 13, 2016.
- Kroon E, Ananworanich J, Eubanks K, et al. Effect of vorinostat, hydroxychloroquine and maraviroc combination therapy on viremia following treatment interruption in individuals initiating ART during acute HIV infection. Abstract presented at: 21st International AIDS Conference (AIDS 2016); July 18-22, 2016; Durban, South Africa. Abstract TUAX0101LB. Available at: http://programme.aids2016.org/Abstract/Abstract/10535. Last accessed on September 13, 2016.
- Kroon E, Ananworanich J, Le LT, et al. Central nervous system impact of vorinostat, hydroxychloroquine and maraviroc combination therapy followed by treatment interruption in individuals treated during acute HIV infection (SEARCH 026). Poster presented at: 21st International AIDS Conference (AIDS 2016); July 18-22, 2016; Durban, South Africa. Poster LBPE005. Available at: http://programme.aids2016.org/PAGMaterial/eposters/0_10588.pdf. Last accessed on September 13, 2016.
Last Reviewed: September 13, 2016