Injectable HIV drugs are superior to oral ones for patients who frequently miss doses

When a person is diagnosed with HIV, they are put on lifelong HIV treatment called antiretroviral therapy to control virus. However, for many people, taking daily medications can be difficult for a variety of reasons, leading to missed doses and poor health.

To address this problem, Jose Castillo-Mansilla, MD, a volunteer associate clinical professor in the Division of Infectious Diseases at the University of Colorado, co-led a national clinical trial with Aadya Rana, MD, a professor at the University of Alabama, in 2014. Called Long-Acting Therapy to Improve Treatment Success in Daily Life (LATITUDE), the study examined whether monthly injectable anti-HIV medications were a better treatment option than taking daily pills.

Nearly a decade later, interim data from a clinical trial showed what Castillo-Mansilla had long suspected: Long-acting antiretroviral therapy was superior to suppressing HIV replication compared with daily pills. In fact, its superiority was so significant that the National Institutes of Health recommended that all study participants take long-acting medications.

“To learn that the results of our study confirmed our hopes and that we were able to prove that this treatment strategy could help these patients was incredible,” says Castillo-Mansilla. "I confess that I have shed many tears of joy."

The need for this research Castillo-Mansilla has been interested in helping people with HIV since the late 1990s, when he conducted research at the National Cancer Institute in Mexico and saw very sick patients with advanced HIV.

For HIV patients, achieving viral suppression, also known as "undetectability," is important, he says. This means that the patient controls HIV and cannot transmit it to others.

"HIV control is important to prevent the disease from progressing from HIV to AIDS," he says. "Being undetectable is also important to prevent the development of drug resistance and other complications such as cardiovascular disease."

To achieve this, however, it is important to take medication regularly, which can be a problem for some. Up to 25% of people prescribed traditional antiretroviral therapy stop taking the medications for a period of time, the NIH said in 2019.

“Sticking to lifelong therapy is a very difficult task, even for the most dedicated patients,” says Castillo-Mansilla. "Many of our patients face competing priorities that make it difficult to take their daily pills. These include barriers such as employment, child care, transportation, stigma, active mental illness or substance use, and others."

Designing a study that focused on a population of patients who have difficulty taking daily medications was important because traditionally such patients have not been included in clinical trials, despite the fact that they represent a vulnerable group for whom available treatment options do not work..

"Given the fact that a third of people living with HIV in the US have trouble maintaining viral suppression," he says. "Identifying new successful strategies to help these patients could be critical in our efforts to end the HIV epidemic."

Creating LATITUDE Castillo-Mansilla worked with Rana on the concept of the LATITUDE trial in 2014, when long-acting HIV therapies were still being developed. They wanted to find out whether two injectable forms of long-acting antiretroviral therapy—specifically the drugs rilpivirine and cabotegravir, given every four weeks—would help people with HIV who have difficulty taking their daily medications become and remain undetectable.

Together with their research team, Castillo-Mansilla and Rana wrote proposals that were submitted to Advancing Clinical Therapeutics Globally (ACTG), formerly known as AIDS Clinical Trials Group. They were able to create a study protocol and partnership with ViiV Healthcare, which provided the study drug.

Through extensive work and collaboration, an open-label clinical trial began at 31 sites across the country, including Puerto Rico, and enrolled approximately 350 volunteers. Castillo-Mansilla co-chaired the study with Rana until he joined ViiV Healthcare in 2023.

How Interim Data Changed the Study The LATITUDE study was broken into several phases. Initially, as part of Phase 2, participants were to continue taking their standard oral HIV drugs or switch to long-acting drugs.

However, interim data from the randomized trial showed that long-acting antiretroviral therapy was superior in suppressing HIV replication compared with daily pills.

Based on these interim data, in February of this year, the National Institutes of Health recommended stopping randomization and offering all eligible study participants long-acting drugs. The NIH accepted this recommendation, meaning Phase 2 of the study was stopped and participants were no longer randomized; instead, all eligible participants are offered long-term therapy.

"The fact that Phase 2 was stopped doesn't mean the study was stopped. It just means that every participant in the study is now offered long-term therapy," says Castillo-Mancilla. "The study actually has a Phase 3, which is 48 weeks long, to evaluate the durability of the treatment strategy."

Once Phase 3 is complete and their participation in the study is over, participants can decide with their healthcare provider whether they want to continue receiving the long-acting injectable therapy or not.

"If they decide to continue this therapy, they can receive it through their regular clinical care, not as study participants," he says.

Looking Ahead Given the positive results of the clinical trial, the research team now aims to complete the study and disseminate the results to the medical community so that patients can benefit, Castillo-Mancilla says.

"The main message to the medical community is that we have new treatment strategies for our patients who are facing barriers to adherence and are unable to take their daily medications," he says.

He wants HIV patients to know that this is a new option that can help them achieve viral suppression, that is, a state of "undetectableness," so they can live longer, healthier lives. It's what he hoped for nearly a decade ago when the study was conceived.

"This clinical trial has been my life for the last 10 years. It has allowed me to meet and work with incredible colleagues and friends like Dr. Rana and my colleagues at ACTG and ViiV Healthcare," says Castillo-Mancilla. "Most importantly, it has allowed us to contribute to the fight to end the HIV epidemic."

The results of the work are detailed in a paper published in Clinicaltrials.