Clinical trials aimed at HIV cure or remission: new pathways and lessons learned

ABSTRACT

Introduction

The main barrier to finding a cure against HIV is the latent HIV reservoir, which persists in people living with HIV (PLWH) despite antiretroviral treatment (ART). Here, we discuss recent findings from interventional studies using mono- and combination therapies aimed at enhancing immune-mediated killing of the virus with or without activating HIV from latency.

Areas covered

We discuss latency reversal agents (LRAs), broadly neutralizing antibodies, immunomodulatory therapies, and studies aimed at inducing apoptosis.

Expert opinion

The landscape of clinical trials for HIV cure and remission has evolved considerably over the past 10 years. Several novel interventions such as immune checkpoint inhibitors, therapeutic vaccines, and broadly neutralizing antibodies have been tested either alone or in combination with LRAs but studies have so far not shown a meaningful impact on the frequency of latently infected cells. Immunomodulatory therapies could work differently in the setting of antigen expression, that is, during active viremia, and timing of interventions could therefore, be key to future therapeutic success. Lessons learned from clinical trials aimed at HIV cure indicate that while we are still far from reaching a complete eradication cure of HIV, clinical interventions capable of inducing enhanced control of HIV replication in the absence of ART might be a more feasible goal.

KEYWORDS:

• Broadly neutralizing antibodies
• elite and posttreatment controllers
• HIV cure studies
• immune checkpoint blockade
• interferon and interleukin therapy
• latency-reversing agents

Article highlights

• Clinical trials of latency-reversing agents in people living with HIV (PLWH) on ART has demonstrated their ability to activate latent HIV, but despite increased viral transcription-infected cells are not effectively eliminated.

• Combination clinical trials including both a latency-reversing and an immunotherapeutic agent have also not demonstrated any consistent impact on the latent HIV reservoir or enhanced control during ART interruption.

• Multiple immunotherapies including therapeutic vaccines, broadly neutralizing antibodies, immune checkpoint inhibitors, and interferon/cytokine therapy are under active investigation for their ability to boost anti-HIV immunity and enhance control of HIV replication in the absence of ART.

• Improved immunological control and delayed time to viral rebound were observed in a clinical trial where bNAbs were administered at ART initiation suggesting that timing of intervention could impact the course of HIV infection.

• Pharmaceutical agents aimed at enhancing the function of immune effector cells or sensitizing latently infected cells to undergo apoptosis could be important adjuvant therapies in future HIV cure strategies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

The authors Maya Dyveke Schou (MDS), Ole Schmeltz Søgaard (OSS) and Thomas Aagaard Rasmussen (TAR) confirm contribution to the paper as follows: study conception and design: MDS, OSS, TAR; data collection: MDS, TAR; analysis and interpretation of results: MDS, OSS, TAR; draft manuscript preparation: MDS, TAR. All authors reviewed the results and approved the final version of the manuscript.

Additional information

Funding

This paper was not funded.