# Next-Generation HIV-1 Therapeutics in Co-Endemic Settings

## TL;DR

This paper discusses how new HIV treatments can be more effective if they account for co-infections like dengue and Zika in regions like South America.

## Contribution

The paper introduces a 'co-infection-aware' approach to HIV-1 therapeutic development and clinical trial design in co-endemic regions.

## Key findings

- Co-infections like dengue and Zika disrupt HIV treatment efficacy through immune activation and altered drug metabolism.
- New HIV treatments like lenacapavir and cabotegravir need to be evaluated in the context of co-endemic viral challenges.
- Incorporating co-infection endpoints into clinical trials can improve the durability and global effectiveness of HIV interventions.

## Abstract

The development of next-generation HIV-1 therapeutics, including ultralong-acting antivirals, novel mechanistic classes, and curative immunotherapies, promises to overcome the limitations of lifelong, daily antiretroviral therapy (ART). However, the real-world efficacy of these treatments depends on the complex epidemiological landscapes in which they are used. In South America, HIV-1 epidemics intersect hyperendemic arboviruses, including dengue, Zika, chikungunya, and yellow fever, and regionally isolated pathogens, such as mammarenaviruses. These co-infections cause profound episodic immune activation and organ dysfunction that alter drug pharmacokinetics, disrupting healthcare access and adherence. These factors can compromise ART efficacy, promote resistance, and influence latent reservoir dynamics. This review synthesizes clinical and translational evidence of this intersection. We evaluate how emergent agents, such as capsid inhibitors (lenacapavir), long-acting injectables (cabotegravir/rilpivirine), maturation inhibitors (GSK3640254), and broadly neutralizing antibodies (bNAbs), perform in the context of co-endemic viral challenges. Specifically, we argue that therapeutic development must become “co-infection-aware” to progress toward a cure and achieve durable HIV-1 control. We provide a translational roadmap that explicitly incorporates co-infection endpoints into clinical trials, develops preclinical models that better reflect real-world viral exposures, and prioritizes implementation strategies that remain effective in the case of recurrent outbreaks. Integrating regional viral ecology into HIV-1 therapeutic research is therefore a necessary step toward developing interventions that are durable and effective on a global scale.