Overcoming HIV Treatment Barriers: The LATITUDE Trial and Long-Acting Injectable Therapy

Why 4 in 10 People Struggle With Daily HIV Medication

Modern antiretroviral therapy can suppress HIV to undetectable levels, effectively preventing disease progression and transmission. But that suppression depends on something deceptively simple: taking a pill every single day for the rest of your life. For millions of people living with HIV, this daily requirement becomes the point of failure.

In the LATITUDE trial published in the New England Journal of Medicine, 41.2% of participants assigned to continue daily oral antiretroviral therapy experienced regimen failure within 48 weeks. That number reflects the reality for people who face overlapping barriers to daily medication adherence.

These barriers fall into two broad categories: structural and behavioral.

Key insight: Adherence failure is rarely about forgetting a single dose. It results from the accumulated weight of systemic obstacles and psychological burden that compound over months and years of daily treatment.

Structural Barriers

Structural barriers are external forces that make accessing and maintaining treatment difficult regardless of motivation. According to NIH clinical guidelines on ART adherence, these include transportation difficulties, limited clinic hours, housing instability, healthcare system fragmentation, and poverty. People experiencing homelessness face particular challenges with medication storage, maintaining routines, and privacy for pill-taking.

HIV-related stigma operates as both a structural and psychological barrier. Research published in AIDS and Behavior found that people concerned about HIV stigma were 3.3 times more likely to be non-adherent compared to those reporting less stigma concern.

Behavioral Barriers

Behavioral barriers stem from mental health, substance use, and the psychological weight of chronic illness management. In the LATITUDE cohort, 57% of participants had a psychiatric diagnosis and 41% reported current or prior substance use.

Treatment fatigue goes beyond simple forgetfulness. A qualitative study in Health Psychology and Behavioral Medicine described how patients feel "worn out" by the daily confrontation with their HIV status that each pill represents. Managing depression alongside HIV treatment presents particular challenges, as the cognitive symptoms of depression directly impair the ability to manage daily mental health and maintain medication routines.

Barrier Type	Examples	Impact on Adherence
Transportation	No reliable transit to pharmacy or clinic	Missed refills, lapsed prescriptions
Housing instability	Homelessness, frequent relocation	No safe medication storage, disrupted routines
Stigma	Fear of disclosure, discrimination	3.3x higher non-adherence risk
Mental health	Depression, anxiety, PTSD	Cognitive impairment reduces daily compliance
Substance use	Alcohol, recreational drugs	Disrupted routines, impaired decision-making
Treatment fatigue	Emotional exhaustion from daily pills	Pill holidays, gradual disengagement

Inside the LATITUDE Trial: A New Approach to an Old Problem

Previous studies of long-acting injectable antiretroviral therapy enrolled people who were already virologically suppressed and adherent to oral medication. Those trials answered an important question: can injectables maintain suppression as well as pills? The answer was yes.

But they left a critical gap. The people most likely to benefit from injectable therapy were never studied. The LATITUDE trial (ACTG A5359), conducted across 31 sites in the United States and Puerto Rico, specifically recruited people with documented adherence challenges or who had disengaged from HIV care.

Trial Design

LATITUDE used a two-step design. In Step 1, all 453 enrolled participants received guideline-recommended daily oral ART with adherence support, including conditional economic incentives, to achieve viral suppression (HIV-1 RNA at or below 200 copies/mL). In Step 2, the 306 participants who achieved suppression were randomized 1:1 to either long-acting injectable cabotegravir plus rilpivirine every four weeks or continued daily oral therapy.

Characteristic	LATITUDE Participants (n=453)
Median age	40 years
Black/African American	63%
Female	29%
Hispanic	17%
Psychiatric diagnosis	57%
Current or prior substance use	41%
Prior injection drug use	14%

The primary endpoint was the cumulative probability of regimen failure, a composite of virologic failure or permanent treatment discontinuation for any reason, by week 48. This composite was deliberately chosen to capture real-world treatment outcomes beyond laboratory markers alone.

How Long-Acting Injectables Replace the Daily Pill

Cabenuva (cabotegravir plus rilpivirine) is the first complete long-acting injectable regimen for HIV treatment. Approved by the FDA in January 2021 for monthly dosing and February 2022 for every-two-month dosing, it converts daily self-administered oral therapy into clinician-administered intramuscular gluteal injections.

The pharmacokinetic design is conceptually similar to advances in other therapeutic areas, such as long-acting GLP-1 receptor agonist formulations, where extended-release drug delivery reduces dosing frequency and shifts adherence patterns.

How it works: Two intramuscular injections (cabotegravir 400mg + rilpivirine 600mg for monthly dosing, or 600mg + 900mg for bimonthly dosing) are administered into the gluteal muscle by a healthcare provider. The drugs form a depot at the injection site and release slowly over weeks.

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The shift from daily pills to periodic injections does more than reduce dosing frequency. It fundamentally changes who bears the responsibility for adherence. Instead of relying on individuals dealing with unstable housing, active substance use, or untreated depression to remember and choose to take medication every day, the healthcare system schedules and administers treatment. Regular injection visits also create structured touchpoints for mental health screening, substance use support, and social services referrals.

What Long-Acting Injectables Address

• Pill fatigue: Eliminates the daily reminder of HIV status
• Stigma: No pill bottles to hide or explain
• Routine disruption: Treatment no longer depends on daily routine stability
• Forgetfulness: Clinic-administered dosing removes self-management burden
• Mental health barriers: Reduced cognitive demand for people with depression or other psychiatric conditions

LATITUDE Results: Injectable Therapy Cut Treatment Failure in Half

The 48-week results, published in the New England Journal of Medicine in February 2026, demonstrated that long-acting injectable therapy was not merely noninferior to oral treatment. It was superior.

Outcome (48 Weeks)	Long-Acting Injectable	Daily Oral ART	Difference
Regimen failure (primary endpoint)	22.8%	41.2%	-18.4 percentage points
Virologic failure	6.8%	28.2%	-21.4 percentage points
Treatment-related failure	8.9%	28.1%	-19.2 percentage points
Permanent discontinuation	19.8%	28.2%	-8.4 percentage points

The difference in virologic failure, 6.8% versus 28.2%, was particularly striking. When adherence-challenged individuals received injectable therapy, their probability of achieving and maintaining viral suppression improved dramatically compared to continuing with daily pills.

Trial halted early: In February 2024, the independent Data and Safety Monitoring Board recommended stopping randomization and offering all eligible participants long-acting injectable therapy based on interim efficacy data demonstrating clear superiority.

The safety profile was comparable between arms, with 43.5% of injectable recipients and 42.4% of oral recipients experiencing adverse events. Injection site reactions occurred in approximately 60% of participants receiving injectables, but these were predominantly mild and only two participants discontinued treatment due to injection site pain. Four confirmed virologic failures across both arms developed new resistance-associated mutations, two per arm.

The Clinical Evidence Trail: From ATLAS to FLAIR to LATITUDE

The LATITUDE findings build on a progression of clinical trials that methodically established the evidence base for long-acting injectable antiretroviral therapy. Understanding this sequence, and how clinical trial methodology evolves to answer increasingly targeted questions, helps clarify why LATITUDE represents a turning point.

FLAIR (First Long-Acting Injectable Regimen)

Published in 2020, FLAIR enrolled treatment-naive adults who achieved suppression on dolutegravir-abacavir-lamivudine, then randomized them to monthly injectable or continued oral therapy. At 48 weeks, HIV-1 RNA at or above 50 copies/mL occurred in 2.1% of the injectable arm versus 2.5% of the oral arm, establishing noninferiority. Ninety-one percent of injectable recipients preferred injections over pills.

ATLAS (Antiretroviral Therapy as Long-Acting Suppression)

Also published in 2020, ATLAS enrolled treatment-experienced, virologically suppressed adults on various oral regimens. At 48 weeks, 1.6% of the injectable arm versus 1.0% of the oral arm had virologic non-suppression, confirming noninferiority. Eighty-six percent preferred injectables.

ATLAS-2M (Every Two Months)

ATLAS-2M demonstrated that dosing every eight weeks was noninferior to every four weeks, with virologic non-suppression rates of 2% versus 1%. This result was maintained through 152 weeks of follow-up, establishing bimonthly dosing as a viable option that further reduces clinic visits.

How the Trials Compare

Trial	Population	Injectable Failure	Oral Failure	Result	Preference
FLAIR (2020)	Treatment-naive, suppressed	2.1%	2.5%	Noninferior	91%
ATLAS (2020)	Treatment-experienced, suppressed	1.6%	1.0%	Noninferior	86%
ATLAS-2M (2020)	Suppressed, Q8W vs Q4W	2.0% (Q8W)	1.0% (Q4W)	Noninferior	N/A
LATITUDE (2026)	Adherence-challenged	22.8%*	41.2%*	Superior	N/A

*Regimen failure (composite of virologic failure + discontinuation), not virologic failure alone

The pattern is clear: in already-adherent populations, injectables match oral therapy. In adherence-challenged populations, injectables dramatically outperform it. A pooled analysis of ATLAS and FLAIR data found that 98% of participants who received injectable therapy preferred it over their previous oral regimen, among the highest treatment preference rates reported in HIV medicine.

What Stands Between Patients and Long-Acting Treatment

Despite the clinical evidence, scaling long-acting injectable therapy faces real-world obstacles that healthcare systems are still working to address.

Infrastructure and Logistics

Rilpivirine must be stored at 2-8°C and used within six hours of removal from refrigeration. Clinics need dedicated refrigeration space, temperature monitoring, and private examination rooms for gluteal injections. Each visit requires scheduling two separate intramuscular injections administered by a trained healthcare provider. These implementation requirements demand workflow redesign from clinics accustomed to sending patients home with a bottle of pills.

The Visit Frequency Paradox

Stable patients on oral ART typically visit their clinic every three to six months. Injectable therapy requires visits every one to two months. For adherence-challenged populations, this increased contact is a feature, providing regular engagement with the healthcare system and opportunities for supportive services. But it creates capacity strain on already-stretched clinics, particularly those serving high volumes of patients with complex needs.

Cost and Access

Cabenuva's wholesale acquisition cost runs approximately $3,960 per month for maintenance doses, with additional costs for clinic visits and administration. While this is comparable to branded oral regimens like Biktarvy, the gap widens significantly when compared to generic alternatives available internationally.

Access through AIDS Drug Assistance Programs remains inconsistent. Multiple states have not added cabotegravir-rilpivirine to their formulary, and others require prior authorization, creating an equity gap where the populations most likely to benefit are least likely to have coverage. ViiV Healthcare offers a patient assistance program that can reduce out-of-pocket costs to zero for eligible patients.

A comprehensive approach to HIV care also benefits from attention to nutritional support for immune health, as adequate nutrition plays a supporting role in treatment outcomes for people living with HIV.

The Next Frontier: Twice-Yearly and Once-Yearly HIV Injections

The trajectory of HIV treatment is moving toward progressively longer intervals between doses. If monthly and bimonthly injections can dramatically improve outcomes for adherence-challenged populations, what could twice-yearly or once-yearly dosing achieve?

Lenacapavir: Six Months Between Doses

Lenacapavir is a first-in-class capsid inhibitor approved by the FDA in December 2022 for treatment of multidrug-resistant HIV, and in June 2025 as the first twice-yearly injectable for HIV prevention. The World Health Organization recommended injectable lenacapavir for HIV prevention in July 2025.

For treatment, clinical development is advancing toward a complete twice-yearly regimen. A Phase II study combining lenacapavir with two broadly neutralizing antibodies, administered as long-acting injections every six months, showed 96% of 80 participants maintained viral suppression at week 26. The FDA granted Breakthrough Therapy Designation in 2025.

Once-Yearly Formulations on the Horizon

Phase I data on intramuscular lenacapavir formulations demonstrated drug levels above the effective threshold for at least 56 weeks after a single injection, with peak concentrations 3.5 to 5 times higher than the twice-yearly subcutaneous formulation. Gilead Sciences has announced plans for Phase III trials, potentially bypassing Phase II based on these favorable results.

The Dosing Evolution

Era	Regimen	Dosing Frequency	Status
Standard of care	Oral ART (various)	Daily	Current standard
First-generation LAI	Cabenuva (CAB+RPV)	Monthly	FDA approved (2021)
Extended LAI	Cabenuva (CAB+RPV)	Every 2 months	FDA approved (2022)
Next-generation	Lenacapavir + oral agents	Every 6 months	FDA approved for MDR (2022)
Complete long-acting	Lenacapavir + bNAbs	Every 6 months	Phase II (Breakthrough designation)
Ultra-long-acting	IM lenacapavir	Once yearly	Phase I complete

Home-based administration of long-acting injectables is also being studied through protocols like INVITE-HOME, which could eliminate the clinic visit requirement entirely and further reduce barriers to treatment access.

Frequently Asked Questions

What is the LATITUDE trial and why does it matter?

LATITUDE (Long-Acting Therapy to Improve Treatment SUccess in Daily lifE) is a Phase III clinical trial that tested long-acting injectable cabotegravir-rilpivirine against daily oral antiretroviral therapy in people with documented adherence challenges. It is the first trial to demonstrate that injectable therapy is superior, not just equivalent, to daily pills in the population that struggles most with oral medication. The trial was published in the New England Journal of Medicine in February 2026.

How often do you need injections with Cabenuva?

Cabenuva is administered as two intramuscular gluteal injections either every month or every two months, depending on the prescribed dosing schedule. Both regimens require administration by a healthcare provider in a clinical setting. The bimonthly option was established through the ATLAS-2M trial.

Can anyone with HIV switch to injectable therapy?

Currently, Cabenuva is approved for virologically suppressed adults with HIV-1 RNA below 50 copies/mL on a stable antiretroviral regimen, with no history of treatment failure and no known resistance to cabotegravir or rilpivirine. Your healthcare provider can assess whether you meet these criteria and discuss the potential benefits based on your individual situation.

What are the most common side effects of long-acting injectable ART?

Injection site reactions are the most common side effect, occurring in approximately 60% of recipients. These reactions are predominantly mild and typically resolve within three days. In the LATITUDE trial, only two out of 152 participants receiving injectables discontinued due to injection site reactions. Overall adverse event rates were similar between injectable and oral therapy groups.

Is there a once-yearly HIV treatment available?

Not yet. Phase I data on intramuscular lenacapavir formulations showed effective drug levels lasting at least 56 weeks after a single injection, and Phase III trials are planned. A complete twice-yearly injectable regimen combining lenacapavir with broadly neutralizing antibodies is further along in development, with Phase II data showing 96% viral suppression at 26 weeks.

Sources Used in This Guide

• Cabotegravir plus Rilpivirine for Persons with HIV and Adherence Challenges — New England Journal of Medicine, 2026
• Long-Acting Intramuscular Cabotegravir and Rilpivirine in Adults with HIV-1 Infection (FLAIR) — New England Journal of Medicine, 2020
• Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection (ATLAS) — New England Journal of Medicine, 2020
• Pooled Efficacy and Safety of ATLAS and FLAIR at 48 Weeks — Antiviral Therapy, 2020
• Cabotegravir and Rilpivirine Every 2 Months (ATLAS-2M) — The Lancet, 2020
• NIH Clinical Guidelines: Adherence to the Continuum of Care — U.S. Department of Health and Human Services
• Qualitative Analysis of ART Treatment Fatigue — Health Psychology and Behavioral Medicine, 2022
• HIV-Related Stigma and Treatment Adherence — AIDS and Behavior, 2014
• Long-Acting ART Suppresses HIV Among People with Unstable Housing, Mental Illnesses, Substance Use Disorders — National Institutes of Health
• Long-Acting Injectable ART to Advance Health Equity — Implementation Science, 2024
• Patient-Reported Outcomes in ATLAS and FLAIR — AIDS and Behavior, 2020
• Lenacapavir Plus Broadly Neutralizing Antibodies as Twice-Yearly HIV Treatment — aidsmap, 2025
• WHO Recommends Injectable Lenacapavir for HIV Prevention — World Health Organization, 2025
• Adherence to ART in Adults with Mental and Substance Abuse Disorders — Journal of the International Association of Providers of AIDS Care, 2017

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