UAB-Led LATITUDE Study in NEJM: Long-Acting Injectables Revolutionize HIV Treatment Adherence

The LATITUDE Study: A Game-Changer for HIV Management

In a landmark publication in the New England Journal of Medicine, researchers from the University of Alabama at Birmingham (UAB) and the AIDS Clinical Trials Group (ACTG) unveiled results from the LATITUDE study, demonstrating that long-acting injectable antiretrovirals outperform daily oral therapies for people living with HIV (PLWH) who struggle with adherence. 59 58 This phase 3 trial, known formally as ACTG A5359, addresses a critical gap in HIV care: ensuring consistent viral suppression in high-risk populations facing barriers like substance use, mental health issues, and unstable housing.

The study enrolled 453 participants across 33 U.S. sites, with UAB playing a pivotal role as one of the top enrollers. Participants, predominantly Black (63%) and including 29% assigned female at birth, had documented non-adherence—either poor virologic control or loss to follow-up. After an induction phase with adherence support and incentives achieving viral suppression in 67%, 306 were randomized to monthly injections of cabotegravir (400 mg) and rilpivirine (600 mg)—marketed as Cabenuva—or standard oral antiretroviral therapy (ART).

Study Design and Participant Profile

The LATITUDE trial featured a rigorous, multi-step design. Step 1 provided up to 24 weeks of optimized oral ART, including financial incentives up to $675, counseling, and standard care to suppress HIV-1 RNA to ≤200 copies/mL. Those succeeding entered Step 2 randomization: cabotegravir–rilpivirine injections (with optional 4-week oral lead-in) versus continued oral ART. The trial halted early after a median 48-week follow-up due to clear superiority of the injectable regimen. 59

Demographics reflected real-world challenges: median age 40, 65% with poor virologic response history, 21% lost to follow-up. This diverse cohort—17% with injection drug use history—mirrors U.S. disparities, particularly in the Southeast where HIV incidence remains high and suppression lags. 58

• Key Inclusion: Age ≥18, ART-exposed ≥6 months, non-adherence evidence (VL >200 copies/mL twice or lapses).
• Exclusions: Active hepatitis B, prior cabotegravir exposure, resistance mutations.
• Primary Outcome: Regimen failure (confirmed virologic failure >200 copies/mL or discontinuation).

Breakthrough Results: Superior Viral Suppression

The headline result: cumulative regimen failure at week 48 was 22.8% in the injectable group versus 41.2% in oral ART (difference -18.4%; 98.4% CI -32.4 to -4.3; P=0.002). Virologic failure alone dropped dramatically: 3.9% versus 22.1% (difference -21.4%). Only 6 injectable failures occurred, mostly after week 24, linked to higher BMI (>30) and shorter needles; all but one resuppressed on oral ART. 59 46

In the oral group, 34 virologic failures emerged, with 46% reporting missed doses. Resistance mutations appeared in 40% of injectable failures versus 9% oral, underscoring injectables' protective edge. These findings validate long-acting therapy as a durable option, reducing transmission risk via sustained suppression (U=U: undetectable = untransmittable).

Safety Profile: Manageable and Comparable

Adverse events were balanced: 43.5% injectable versus 42.4% oral. Injection-site reactions (ISRs) affected 60% receiving injections—pain (39%), nodules (22%), swelling (4%)—mostly mild, resolving in days; only 1.4% discontinued due to ISRs. Serious events (19.3% vs. 14.5%) and grade 3/4 (30% vs. 23%) showed no significant differences. Two unrelated deaths occurred in the injectable arm. 59

This tolerability supports scalability, though BMI considerations (longer needles recommended) are key for optimization.

UAB's Pivotal Role in HIV Research Leadership

UAB's Division of Infectious Diseases spearheaded LATITUDE, leveraging its expertise in HIV trials amid Alabama's stagnant new infections—linked to 40% non-suppressed PLWH nationally.Explore research positions at UAB. Lead investigator Aadia Rana, MD, emphasized: “This is exactly the population we need to target... in the Southeast, most disproportionately impacted.” UAB's contributions advance the university's mission in addressing regional epidemics. 58

As part of NIH-funded ACTG, UAB exemplifies higher education's translational impact, training fellows and producing evidence for policy shifts.

HIV Adherence Challenges in the U.S.: A Persistent Crisis

Nationally, ~1.2 million PLWH face adherence hurdles; only 67% achieve suppression on oral ART, with 40% not fully benefiting—exacerbated by stigma, poverty, and comorbidities. 58 Southeast hotspots like Alabama see higher incidence despite advances. LATITUDE's real-world cohort (unstable housing, substance use) highlights injectables' potential to close gaps, aligning with Ending the HIV Epidemic goals.CDC EHE Initiative

• 63% Black participants reflect disparities.
• 14% injection drug use history.
• Urban/rural sites ensure generalizability.

Real-World Context: Cabenuva's Evolution Since FDA Approval

FDA-approved in 2021 for virally suppressed adults, Cabenuva (every 1-2 months) built on phase 3 trials excluding non-adherent groups. LATITUDE fills this void, providing RCT evidence for switches post-suppression. Real-world data reinforce: 80%+ adherence despite prior issues. 37 ViiV's CROWN study explores unsuppressed starters.

Career advice for HIV researchers.

Implications for Clinical Practice and Policy

LATITUDE shifts paradigms: injectables as first-line for non-adherent PLWH post-induction, potentially halving failures. Multidisciplinary rollout—training nurses, addressing logistics (cold chain, BMI dosing)—is essential. Cost-effectiveness, equity in access (Ryan White programs), and integration with PrEP scale-up loom large. 46

• Benefits: Provider-observed dosing, stigma reduction, travel flexibility.
• Risks: ISRs, virologic rebound if missed (though rare).
• Comparisons: Superior to oral in challenging cohorts; complements lenacapavir (twice-yearly).

Stakeholder Perspectives and Expert Opinions

Aadia Rana (UAB): “40% not benefiting... Southeast lags.” Kimberly Smith (ViiV): “Validates long-acting for this group... significant difference.” ACTG's real-world focus lauded for inclusivity. Community advocates hail reduced pills' burden; challenges include equity for underserved.

Future Outlook: Long-Acting HIV Therapies on Horizon

LATITUDE paves for broader LAI adoption, trials in viremic PLWH (CROWN), and combos like VH-184 (every 6 months). Gene editing (lenacapavir) promises biannual dosing. Higher ed's role: UAB-like hubs training via clinical research jobs. Ending U.S. epidemic demands implementation science.

Actionable Insights for Researchers and Clinicians

• Screen non-adherent PLWH for LAI eligibility post-suppression.
• Prioritize BMI assessments, longer needles.
• Advocate policy for reimbursement, training.
• Monitor resistance, durability beyond 48 weeks.

LATITUDE exemplifies university-led innovation transforming lives.