# Recent Developments in HIV Antivirals: The Prospect of Prophylactic Drugs to Change the Pandemic

## TL;DR

This paper reviews the development of HIV antiviral drugs, focusing on how prophylactic treatments could change the course of the HIV pandemic.

## Contribution

The paper highlights the transition from daily oral drugs to long-acting injectable antivirals for HIV prevention.

## Key findings

- Injectable antiviral drugs like cabotegravir and lenacapavir show promise in preventing HIV infections.
- Long-acting injectables reduce the need for daily medication, improving adherence in high-risk groups.
- Clinical trials indicate these injectables are effective in preventing HIV among men and women at high risk.

## Abstract

The human immunodeficiency‐1 virus was identified in 1983 as the etiological agent of AIDS. Four years later, the first HIV‐1 antiviral drug was approved: the nucleoside analog zidovudine inhibiting the viral reverse transcriptase (RT). Subsequently, non‐nucleoside inhibitors of RT, viral protease, viral integrase, and viral entry inhibitors were approved as antiviral drugs. Combining these drugs into a highly active antiretroviral therapy (HAART) decreased the viral load in chronically infected patients and suppressed AIDS defining symptoms. HAART became a medical success story, but the chronic HIV infection cannot be cured by antiviral drugs. Therefore, substantial efforts were undertaken to use antiviral drugs prophylactically to prevent HIV infections in high‐risk groups. PreExposure Prophylaxis (PrEP) with oral combined antiretroviral therapy (cART) showed some success in preventing infections in infants born to HIV‐infected mothers, decreased the rate of HIV infection in men having sex with men, in women having sex with men, in couples discordant for HIV status and in intravenous drug users. However, the daily burden of pill swallowing compromised seriously the adherence of people to antiviral drugs. The development of injectable long‐acting antiviral drugs based on the integrase inhibitor cabotegravir, which needs an injection every 2 months, or the viral capsid inhibitor lenacapavir, injected every half year, showed impressive results in prevention trials with men and women at high risk of infection. The present article describes aspects of HIV antiviral drug development, the outcome of pertinent clinical trials, and discusses economic and political hurdles for injected long‐acting antivirals to become a gamechanger for the HIV pandemic.

Replication cycle of HIV‐1. The scheme provides an overview from virus entry over reverse transcription of viral RNA into viral DNA, provirus DNA integration into the host genome, genome expression by transcription and translation, proteolytic processing of the viral polyproteins, viral maturation to viral release from the cell. The various targets for antivirals mentioned in the main text are indicated by red arrows and marked as entry inhibitors, nucleoside reverse transcriptase inhibitors (NRTI) or non‐nucleoside reverse transcriptase inhibitors (NNRTI), integrase inhibitors (INI), protease inhibitors (PRI), and capsid assembly inhibitors (CAI). Figure credit: scheme from T. Splettstoesser, displayed in Wikipedia.