What is the DART (Directly Acting Antiviral Regimen) regimen?

DART Regimen in HIV Treatment

DART (Dual-Affinity Re-Targeting) is not a standard antiretroviral therapy regimen for HIV treatment but rather an experimental immunotherapeutic approach that uses bispecific antibody-based molecules to target and eliminate HIV-infected cells by redirecting T cells to kill them. 1, 2

What DART Actually Is

DART molecules are bispecific, antibody-based proteins designed with:

1. One arm that binds to HIV envelope proteins on infected cells
2. Another arm that engages CD3 on cytotoxic T lymphocytes (CTLs)

This dual binding allows DARTs to redirect polyclonal T cells to specifically engage with and kill HIV-infected cells that express envelope proteins, without requiring HIV-specific immunity 1.

Mechanism of Action

• HIVxCD3 DARTs connect T cells to HIV-infected cells by simultaneously binding to:
  • HIV envelope proteins on infected cells
  • CD3 receptors on T cells
• This connection triggers T cell-mediated killing of the HIV-infected cells
• The approach can potentially target latently infected cells after viral reactivation 2

Current Status and Evidence

DARTs are still experimental and not part of standard HIV treatment guidelines. Research studies have shown:

• DARTs derived from antibodies like PGT121, PGT145, A32, and 7B2 demonstrated potent CTL-dependent killing of HIV-infected CD4+ T cells 2
• In laboratory studies, DARTs mediated CD8+ T cell clearance of CD4+ T cells infected with different HIV-1 subtypes 1
• When combined with HIV latency reversing agents, DARTs showed potential to clear latent HIV-1 reservoirs in ex vivo studies 1

Distinction from Standard HIV Treatment

It's important to understand that DART is not one of the standard antiretroviral therapy (ART) regimens recommended by major guidelines. Current recommended HIV treatment regimens typically include:

1. Integrase strand transfer inhibitors (InSTIs) plus two nucleoside reverse transcriptase inhibitors (NRTIs):

   • Bictegravir/TAF/emtricitabine
   • Dolutegravir/abacavir/lamivudine
   • Dolutegravir plus TAF/emtricitabine 3, 4

2. Alternative regimens when preferred options aren't suitable:

   • Darunavir/cobicistat plus TAF (or TDF)/emtricitabine
   • Efavirenz/TDF/emtricitabine
   • Raltegravir plus TAF (or TDF)/emtricitabine 3

Potential Future Applications

DART molecules represent a potential future immunotherapeutic approach that might be used alongside standard ART to:

• Target and eliminate latent HIV reservoirs
• Potentially contribute to HIV cure strategies
• Address chronic immune dysfunction despite effective ART 2

Conclusion

DART is not a standard HIV treatment regimen but an experimental immunotherapeutic approach using bispecific antibodies to redirect T cells to kill HIV-infected cells. Current HIV treatment guidelines continue to recommend InSTI-based regimens as first-line therapy for most people with HIV.