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When Injection Succeeds Where the Pill Fails: Reframing Adherence Through Long-Acting ART

Released: August 10, 2026

Monica Gandhi
Monica Gandhi, MD, MPH
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For decades, HIV healthcare professionals (HCPs) have been taught that treatment failure is primarily a problem to be solved with increasingly potent regimens. Yet, in practice, for many people living with HIV who struggle with achieving or maintaining virologic suppression, the problem is not the potency of modern antiretroviral therapy (ART). Instead, they are struggling because daily oral therapy is incompatible with the realities of their lives. The emergence of long-acting injectable ART over the past 5 years has challenged us to reconsider inadequate adherence not as a personal deficit but as a modifiable treatment barrier.

Adherence, Not Potency
A particularly instructive phenotype is the individual whose virus repeatedly fails to achieve suppression on oral ART despite access to highly active regimens, but subsequently attains durable suppression after transition to long-acting injectable therapy. This experience has become increasingly familiar in contemporary HIV practice and echoes observations from real-world programs and recent clinical trials of long-acting therapy.

The cases presented by the UCSF/Ward 86 group illustrate the complexity of modern HIV management. Several people had extensive treatment histories, periods of disengagement from care, resistance mutations, drug intolerance, and significant comorbidities. These people were unable to achieve virologic suppression on oral therapy but could do so on long-acting ART. Collectively, they underscore a central lesson: Virologic outcomes are often determined less by theoretical regimen potency than by the ability to consistently receive therapy.

Historically, HCPs were reluctant to consider long-acting cabotegravir plus rilpivirine outside the original population for whom the drugs were approved: people with current viral suppression on oral therapy. However, experience from Ward 86 in San Francisco demonstrated that people with ongoing viremia related to adherence challenges could achieve virologic suppression after initiation of long-acting injectable ART when accompanied by intensive clinical support. Investigators reported high rates of virologic suppression among individuals who entered treatment with detectable viremia, many of whom had struggled for years with oral adherence.

The strongest evidence for the use of long-acting ART with adherence challenges to oral ART now comes from the ACTG A5359 LATITUDE trial. In this landmark study, individuals with a history of poor adherence, virologic failure, or loss to follow-up were first supported to achieve suppression on oral therapy and then randomized to continue oral ART or switch to monthly long-acting cabotegravir plus rilpivirine injections. The study was stopped early because long-acting therapy demonstrated superiority over standard oral treatment for key outcomes, providing the first randomized trial evidence that injectable ART can improve treatment outcomes in populations historically underserved by conventional adherence strategies.

Drivers of Treatment Failure and Success
Consider a representative person living with HIV: an individual with years of intermittent adherence, detectable HIV-1 RNA despite experience with multiple oral regimens, and repeated cycles of engagement and disengagement from care. Such a person may be labeled “nonadherent,” but this description obscures the true drivers of treatment failure, such as housing instability, mental health conditions, substance use disorders, pill fatigue, stigma, adverse effects, and competing life priorities. These often make daily medication-taking extraordinarily difficult. When therapy is transformed from a daily responsibility into a monthly or bimonthly clinic-administered intervention, the adherence burden shifts from the person to the healthcare system. For some individuals, that shift is transformative. 

Of importance, successful use of long-acting ART in these settings should not be viewed as a rescue via medication alone. The Ward 86 SPLASH program and related implementation efforts highlight that outcomes depend on robust multidisciplinary care involving physicians, pharmacists, nurses, outreach workers, and navigation teams. Long-acting therapy works best when embedded within systems designed to proactively prevent missed injections and to rapidly reengage people who fall out of care.

Surpassing Viral Suppression
A further lesson from these experiences is that virologic suppression should not be viewed as the sole outcome of interest. People who transition successfully to long-acting therapy frequently report reduced treatment stigma, decreased anxiety related to missed doses, and greater treatment satisfaction. Although these outcomes may be difficult to quantify, they are often the scaffolds to sustained viral suppression and engagement in HIV care.

As we enter the next phase of HIV therapeutics, with emerging long-acting and ultra–long-acting strategies, including lenacapavir-based treatment combinations, HIV care has surpassed the question of whether injectable therapy works. The more relevant questions are who should be receiving long-acting therapy, and how do we reach them? 

To me, the person who cannot achieve suppression on oral ART but becomes virologically suppressed on long-acting injectable therapy, represents one of the most compelling success stories in contemporary HIV medicine. These cases remind us that the most effective regimen is not necessarily the one with the highest genetic barrier or the fewest resistance concerns. It is the regimen that the person can reliably receive. For a subset of people living with HIV, long-acting injectable ART transforms adherence from the central obstacle to sustained viral suppression into a manageable component of care, redefining what treatment success can look like in real-world practice.

Your Thoughts
Long-acting ART can help people living with HIV and adherence challenges to oral ART achieve virologic suppression, but what concerns do you have for adherence to injection appointments with long-acting ART? Leave a comment to join the discussion!

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