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 infection. 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 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 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 investigate whether lefitolimod could reactivate latent HIV, improve immune responses in participants with HIV, reduce the size of the latent HIV reservoir, and delay the time to viral rebound after an analytical treatment interruption of ART. The study also assessed the safety of lefitolimod.^2,8
Selected Study Results: Results published in Clinical Infectious Diseases (2017) and AIDS (2019) showed that lefitolimod enhanced antiviral immune responses and acted as a latency-reversing agent by increasing HIV transcription in a subset of participants. However, lefitolimod treatment had no significant impact on latent HIV reservoir size and did not delay the time to viral rebound after analytical treatment interruption of 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 evaluate 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) broadly neutralizing antibodies (bNAbs) VRC07-523LS and 10-1074, and (3) lefitolimod.¹⁰
Selected Study Results: Results presented at CROI 2023 indicated that most of the participants (seven out of 10) who received combination therapy had at least partial virologic control after ART interruption. The average time to viral rebound following ART interruption was 15 weeks.¹¹
Additional Published Material:

• CROI, 2024: Post-intervention HIV control linked to early in vivo CD8+ T-cell proliferative response to rebound
• CROI, 2024: Effect of broadly neutralizing antibody exposure on HIV rebound following combination immunotherapy

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 evaluate the safety of lefitolimod administered with the bNAbs 3BNC117 and 10-1074 and to evaluate whether this combination regimen could delay the time to viral rebound during an analytical treatment interruption of ART.⁴
Selected Study Results: Results published in Nature Medicine (2023) and presented at CROI 2023 showed that the groups receiving dual bNAb treatment had a significant delay in time to viral rebound during an analytical treatment interruption of ART, as compared to groups receiving placebos only or lefitolimod plus placebo. The addition of lefitolimod to dual bNAb treatment did not confer any additional effect on viral control compared to dual bNAb treatment alone.^12,13

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 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.¹⁴

TITAN (NCT03837756)

In this Phase 2a trial, participants were randomly assigned to receive 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 lefitolimod-related side effects 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 August 5, 2024
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 August 5, 2024
3. National Cancer Institute (NCI). NCI Drug Dictionary: TLR9 agonist MGN1703. Accessed August 5, 2024
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 August 5, 2024
5. Siliciano RF, Greene WC. HIV latency. Cold Spring Harb Perspect Med. 2011;1(1):a007096. Accessed August 5, 2024
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 August 5, 2024
7. National Institute of Allergy and Infectious Diseases (NIAID). HIV viral eradication. Accessed August 5, 2024
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 August 5, 2024
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 August 5, 2024
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 August 5, 2024
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 August 5, 2024
12. 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 August 5, 2024
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 August 5, 2024
14. 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 August 5, 2024