Long-Acting Antiretroviral Therapy for HIV

Introduction

In the past two decades, antiretroviral therapies (ART) for HIV treatment and prevention have dramatically improved the survival and quality of life for people living with HIV. In 2021, although 650 000 people died of AIDS and 1.5 million were newly infected, this was a 68% decline compared with the average figures in 2004.1

However, major treatment challenges including adherence to daily oral ARTs, drug-to-drug interactions, and ART-associated stigma persist. Also, the clinical management of heavily treatment-experienced (HTE) patients, who account for 1% to 2% of adults living with HIV, remains a concern, especially in resource-limited settings.2 HTE patients develop resistance or intolerance to their regimens and are generally unable to remain virologically suppressed. Additionally, the recent COVID-19 pandemic has illuminated how vulnerable drug supply chains are and the difficulties that can arise for patients on daily medications.

This review summarizes advances in the development of long-acting antiretrovirals (LA ARTs), a potential solution to the highlighted challenges.

Approved Long-acting ARTs

Cabotegravir and Rilpivirine

In January 2021, a 2-monthly combination of the long-acting injectable [LAI] cabotegravir and rilpivirine was approved in the United States of America. It had already been approved in the European Union, United Kingdom, and Canada in 2020. The approvals were based on the results of the ATLAS, ATLAS 2M, and FLAIR studies, which were large phase 3 clinical trials. It is the first LAI combination to be approved for treating adults with HIV-1 who are virologically suppressed and have no history of treatment failure or resistance to either drug.3,4

Cabotegravir, an integrase strand transfer inhibitor [INSTI], inhibits HIV replication by preventing the viral integrase enzyme from inserting its DNA into host T-cells. Rilpivirine, a non-nucleoside reverse transcriptase inhibitor [NNRTI], interferes with the enzyme reverse transcriptase, which stops the virus from multiplying.

An average biological half-life of 12 weeks for both injectable drugs makes the 2-monthly drug schedule suitable. A 4-week “lead-in” oral dose for both drugs is recommended to establish safety before starting injectables. Cabotegravir is given at 600 mg and rilpivirine at 900 mg on the last day of the patient’s current antiretroviral therapy or after the oral “lead-in” for 2 consecutive months and then every 2 months thereafter. Both drugs are delivered intramuscularly and have a high barrier to resistance.5  

The ATLAS 2M trial data showed that 2-monthly cabotegravir was non-inferior to a 1-monthly regimen. The primary endpoint was participants with more than 50 HIV-1 RNA copies per mL at week 48. At week 48, 1.7% of participants in the twice-monthly arm and 1.0% of participants in the once-monthly arm were not virologically suppressed (adjusted difference, 0.8%; 95% CI, -0.6% to 2.2%). The twice-monthly group had 8 participants with virological failure and the once-monthly group had 2 participants with virological failure. Notably, 5 out of the 8 participants (63%) with virological failure in the twice-monthly group had NNRTI-associated mutations to rilpivirine at baseline.6

The safety profiles for both groups were similar. Therefore, both the efficacy and safety data from the ATLAS 2M trial support the use of combined cabotegravir and rilpivirine twice monthly for treating people living with HIV-1.6