Drug Database: Lefitolimod

What is lefitolimod?What is lefitolimod?

What is lefitolimod?

Lefitolimod is an investigational drug that is being studied as part of a strategy to cure HIV. Lefitolimod belongs to a group of HIV drugs called latency-reversing agents.²

To learn about how investigational drugs are tested during clinical trials, read the HIVinfo What is an Investigational HIV Drug? and HIV and AIDS Clinical Trials fact sheets.

How do latency-reversing agents work?How do latency-reversing agents work?

How do latency-reversing agents work?

Currently, there is no cure for HIV. One of the main obstacles to curing HIV is that the virus can remain hidden and inactive (latent) inside certain cells of the immune system (such as resting CD4 cells) for many months or even years. The cells where latent HIV hides are known as the latent HIV reservoir. Because HIV in this latent state is inactive, the immune system cannot detect the virus, and the antiretroviral (ARV) drugs that are used to treat HIV have no effect on it.^5-7

Latency-reversing agents work by drawing HIV out of its latent state within resting CD4 cells. Once the latent HIV is reactivated, the CD4 cells that harbor the virus may be more likely to be recognized and killed by the body’s immune system or may be killed by certain HIV therapies, such as those that can enhance the body’s immune response to HIV. Researchers hope that the combined use of lefitolimod and other HIV-fighting strategies, including ongoing antiretroviral therapy (ART), may fully eliminate HIV from the body.^5-7 To learn more, see the HIVinfo What is a Latent HIV Reservoir? fact sheet.

Select clinical trials of lefitolimodSelect clinical trials of lefitolimod

Select clinical trials of lefitolimod

Study Names: TEACH study; NCT02443935

Phase: 1b/2a
Status: This study has been completed.
Location: Denmark
Purpose: The purpose of this study was to see whether lefitolimod could reactivate latent HIV and improve immune responses in participants. Researchers also looked at whether lefitolimod could reduce the size of the latent HIV reservoir and delay the time it takes for HIV to rebound after participants temporarily stopped ART (analytical treatment interruption).^2,8
Selected Study Results: Results were published in Clin Infect Dis (2017) and AIDS (2019) and showed that lefitolimod improved immune responses against HIV and worked to reactivate latent HIV. However, lefitolimod treatment did not work to reduce the size of the latent HIV reservoir and did not delay the time it took for HIV to rebound after participants stopped ART.^2,9
Additional Published Material:

• Mucosal Immunol article, 2018: The TLR9 agonist MGN1703 triggers a potent type 1 interferon response in the sigmoid colon
• EBioMedicine, 2019: TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes

Study Name: NCT04357821

Phase: 1/2
Status: This study is ongoing, but not recruiting participants.
Location: United States
Purpose: The purpose of this study is to see whether using a combination regimen can control viral load levels in participants undergoing an analytical treatment interruption of ART. The combination regimen includes (1) therapeutic HIV vaccines, (2) the broadly neutralizing antibodies (bNAbs) VRC07-523LS and 10-1074, and (3) lefitolimod.¹⁰
Selected Study Results: Results were presented at the Conference on Retroviruses and Opportunistic Infections (CROI) 2023 and published in Nature (2026) and showed that most of the participants who received combination therapy had at least partial control of viral load levels after stopping ART.^11,12
Additional Published Material:

• CROI, 2026: Evidence of immune activation during bNAb-mediated HIV suppression following ATI

Study Names: TITAN; NCT03837756

Phase: 2a
Status: This study has been completed.
Location: United States, Australia, Denmark, and Norway
Purpose: The purpose of this study was to see whether lefitolimod given with the bNAbs 3BNC117 and 10-1074 is safe and whether this combination regimen could delay the time it takes for HIV to rebound after participants temporarily stopped ART.⁴
Selected Study Results: Results were published in Nat Med (2023) and presented at CROI 2023. Researchers found that the time it took for HIV to rebound after participants stopped ART was much longer in participants who received bNAbs than in participants who did not receive bNAbs. Adding lefitolimod to bNAb treatment did not help with viral control compared to using bNAb treatment by itself.^13,14

For more details on the studies listed above, see the Health Professional version of this drug summary.

What side effects might lefitolimod cause?What side effects might lefitolimod cause?

What side effects might lefitolimod cause?

One goal of HIV research is to identify safe new drugs that have fewer side effects. The following side effects were observed in some of the studies of lefitolimod listed above.

TEACH study (NCT02443935)

In the first part of the TEACH study, the most common side effect related to lefitolimod was temporary redness (erythema) around the injection site. All drug-related side effects that occurred during the study were mild, except for four cases of low white blood cell counts (neutropenia). All side effects, including the cases of neutropenia, went away on their own.^2,8

The types of side effects that occurred during the second part of the TEACH study were reported to be similar to previously reported side effects for lefitolimod.¹⁵

NCT04357821

In this Phase 1/2 study, 10 participants received a combination regimen consisting of therapeutic HIV vaccines, the bNAbs VRC07-523LS and 10-1074, and lefitolimod. Two participants had higher than normal levels of liver enzymes in their blood. In both participants, liver enzyme levels returned to normal, and there were no long-term problems. Even though the most likely cause of the abnormal liver enzyme levels was unrelated to the study drugs, researchers could not completely rule out the study drugs as a cause.¹²

TITAN (NCT03837756)

In this Phase 2a trial, participants received either placebo/placebo, lefitolimod/placebo, placebo/bNAbs, or lefitolimod/bNAbs. Eighty-one cases of side effects, most of which were mild, were considered related to lefitolimod. The most common side effects related to lefitolimod were injection site reactions and fatigue.¹³

Because lefitolimod is still being studied, information on possible side effects of the drug is not complete. As testing of lefitolimod continues, additional information on possible side effects will be gathered.

Where can I get more information about clinical trials studying lefitolimod?Where can I get more information about clinical trials studying lefitolimod?

Where can I get more information about clinical trials studying lefitolimod?

More information about lefitolimod-related research studies is available from ClinicalTrials.gov. (The ClinicalTrials.gov search can be modified so that you can get results that better match your interests.)

Some clinical trials may be looking for volunteer participants. 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.

ReferencesReferences

References

1. National Center for Biotechnology Information. PubChem Substance Record for SID 472407762, Lefitolimod, Source: FDA Global Substance Registration System agonist (GSRS). Accessed June 19, 2026
2. Vibholm L, Schleimann MH, Højen JF, et al. Short-course toll-like receptor 9 treatment impacts innate immunity and plasma viremia in individuals with human immunodeficiency virus infection. Clin Infect Dis. 2017;64(12):1686-1695. doi:10.1093/cid/cix201. Accessed June 19, 2026
3. National Cancer Institute (NCI). NCI Drug Dictionary: TLR9 agonist MGN1703. Accessed June 19, 2026
4. University of Aarhus. Combining a TLR9 agonist with broadly neutralizing antibodies for reservoir reduction and immunological control of HIV infection: an investigator-initiated randomized, placebo-controlled, Phase IIa trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 7, 2019. NLM Identifier: NCT03837756. Accessed June 19, 2026
5. Siliciano RF, Greene WC. HIV latency. Cold Spring Harb Perspect Med. 2011;1(1):a007096. Accessed June 19, 2026
6. Rasmussen TA, Tolstrup M, Winckelmann A, Østergaard L, Søgaard OS. Eliminating the latent HIV reservoir by reactivation strategies. Hum Vaccin Immunother. 2013;9(4):790-799. Accessed June 19, 2026
7. National Institute of Allergy and Infectious Diseases (NIAID). HIV viral eradication. Accessed July 22, 2025
8. University of Aarhus. Toll-like receptor 9 enhancement of antiviral immunity in chronic HIV-1 infection: a Phase 1b/2a trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 30, 2015. NLM Identifier: NCT02443935. Accessed June 19, 2026
9. Vibholm LK, Konrad CV, Schleimann MH, et al. Effects of 24-week toll-like receptor 9 agonist treatment in HIV type 1+ individuals. AIDS. 2019;33(8):1315-1325. doi:10.1097/QAD.0000000000002213. Accessed June 19, 2026
10. University of California, San Francisco. Combinatorial therapy with a therapeutic conserved element DNA vaccine, MVA vaccine boost, TLR9 agonist and broadly neutralizing antibodies: a proof-of-concept study aimed at inducing an HIV remission. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 18, 2020. NLM Identifier: NCT04357821. Accessed June 19, 2026
11. Peluso M, Deitchman A, Magombedze G, et al. Rebound dynamics following immunotherapy with an HIV vaccine, TLR-9 agonist, and broadly neutralizing antibodies. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 19-22, 2023; Seattle, WA. Poster 435. Accessed June 19, 2026
12. Peluso MJ, Sandel DA, Deitchman AN, et al. Correlates of HIV-1 control after combination immunotherapy. Nature. 2026;650(8100):187-195. doi:10.1038/s41586-025-09929-5. Accessed June 19, 2026
13. Gunst JD, Højen JF, Pahus MH, et al. Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial. Nat Med. 2023;29(10):2547-2558. doi:10.1038/s41591-023-02547-6. Accessed June 19, 2026
14. Gunst JD, Reikvam DH, McMahon JH, et al. The impact of 3BNC117, 10-1074, and lefitolimod on HIV-1 persistence: the TITAN trial. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 19-22, 2023; Seattle, WA. Abstract 136. Accessed June 19, 2026
15. Vibholm LK, Frattari G, Schleimann MH, et al. Effect of 24 weeks TLR9 agonist therapy on CTL responses and viral rebound during ATI. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI): March 4-7, 2018; Boston, MA. Poster 357. Accessed June 19, 2026