New England Journal of Medicine October 15, 2026

Long-Acting HIV Therapy in African Adults with Adherence Challenges

Fiona V. Cresswell et al.

Bottom Line

In an African population of adults with HIV facing adherence challenges, long-acting injectable cabotegravir and rilpivirine administered every 8 weeks was noninferior to daily oral therapy for maintaining viral suppression at 48 weeks.

Key Findings

1. At 48 weeks, 91.0% of participants receiving long-acting injectable cabotegravir and rilpivirine maintained a viral load of <50 copies/mL, compared to 89.2% of those receiving daily oral dolutegravir-based therapy, meeting the prespecified noninferiority margin of -10 percentage points.

2. Confirmed virologic failure occurred in 5 participants in the long-acting injectable group versus 0 participants in the standard oral therapy group, which also met noninferiority criteria.

3. Injection-site reactions were reported by 37.3% of participants in the long-acting therapy arm; all were grade 1 or 2, and none resulted in treatment discontinuation.

4. Excluding injection-site reactions, adverse events were observed in 84.1% of the long-acting therapy group and 76.6% of the oral therapy group.

5. Despite the requirement for injections and associated local reactions, 93.6% of participants who received the long-acting injectable therapy preferred it over their prior daily oral regimen.

Study Design

Design

RCT

Open-Label

Sample

540

Patients

Duration

48 wk

Median

Setting

Multicenter, Africa

Population African adults with HIV experiencing challenges with adherence to oral antiretroviral therapy (median age 40 years; 60% women; 99.6% Black).

Intervention Long-acting injectable cabotegravir and rilpivirine administered every 8 weeks.

Comparator Standard of care daily oral single-tablet regimen of tenofovir, lamivudine, and dolutegravir.

Outcome Proportion of participants maintaining an HIV-1 RNA viral load of less than 50 copies/mL at week 48 (assessed with a -10 percentage point noninferiority margin).

Study Limitations

• The open-label design of the trial inherently introduces a risk of bias, particularly concerning subjective endpoints such as patient-reported treatment preference.

• The highly structured clinical trial environment, featuring rigorous follow-up and clinical support, may overestimate actual adherence and patient engagement compared to real-world routine care in African public health systems.

• Long-acting cabotegravir/rilpivirine is currently not approved or commercially available in many low- and middle-income countries, presenting a significant barrier to broad implementation.

• Routine use in public health settings in Africa may be complicated by a scarcity of background resistance testing and infrequent viral load monitoring compared to the trial setting.

Clinical Significance

This trial demonstrates that long-acting injectable antiretroviral therapy is a highly effective, noninferior alternative to daily oral regimens for African patients who struggle with adherence. By addressing "pill fatigue" and disengagement from care—which are primary drivers of advanced HIV disease and viral transmission—this approach could serve as a vital public health tool in high-burden settings, provided that barriers to drug access and infrastructure can be overcome.

Historical Context

While highly effective daily oral antiretroviral therapy (ART) has transformed HIV into a manageable chronic condition, inconsistent adherence continues to drive treatment failure, mortality, and viral transmission. Earlier milestone trials (such as FLAIR and ATLAS) established the efficacy of long-acting injectable cabotegravir and rilpivirine in virologically suppressed patients, and the LATITUDE trial demonstrated its superiority over oral therapy in North American patients with adherence challenges. However, data on long-acting injectables for populations explicitly struggling with adherence in sub-Saharan Africa were lacking, as previous regional trials (like CARES) largely focused on stable patients. The 2026 IMPALA trial was designed to address this critical gap, evaluating whether the benefits of infrequent, directly administered injectable therapy could translate to resource-limited African settings where advanced HIV disease is increasingly a consequence of care disengagement.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Cabotegravir and rilpivirine represent two distinct classes of antiretroviral therapy. What are the specific mechanisms of action of these two drugs, and why is combining an integrase inhibitor with a non-nucleoside reverse transcriptase inhibitor (NNRTI) effective for maintaining viral suppression?

Key Response

Cabotegravir blocks HIV integrase, preventing the insertion of viral DNA into the host genome. Rilpivirine binds allosterically to reverse transcriptase, halting viral DNA synthesis. Combining classes targets different stages of the viral life cycle and requires the virus to develop multiple independent mutations to survive, which is essential for durable viral suppression and preventing resistance.

Resident

A patient receiving every-8-week long-acting cabotegravir/rilpivirine misses their scheduled injection by 3 weeks. According to clinical management principles for long-acting antiretrovirals, what is the next best step, and what are the major virologic risks of delayed dosing with this specific regimen?

Key Response

The major risk of delayed injections is the 'pharmacokinetic tail' of these drugs, where subtherapeutic levels persist in the body for months, creating selective pressure for NNRTI and INSTI resistance mutations. Management typically involves dispensing an oral bridge therapy (like daily oral CAB/RPV or another suppressive regimen) if a delay is anticipated, or rapidly re-evaluating viral load and potentially re-loading the injectable regimen.

Fellow

Given the high prevalence of baseline NNRTI resistance and non-B HIV-1 subtypes (e.g., Subtypes A, C, A6) in many African cohorts, how do these virologic factors uniquely impact the efficacy and barrier to resistance of the cabotegravir/rilpivirine regimen compared to standard dolutegravir-based oral regimens?

Key Response

Rilpivirine has a lower barrier to resistance compared to second-generation integrase inhibitors. In regions with prevalent non-B subtypes (which naturally harbor polymorphisms affecting drug binding) or archived NNRTI mutations from prior NNRTI-based rollouts, the risk of virologic failure on CAB/RPV is heightened. Fellows must understand the importance of proviral DNA genotyping or assessing population-level resistance patterns before switching.

Attending

Historically, clinical trials for long-acting injectable ART restricted enrollment to patients with proven, excellent adherence and stable viral suppression on oral regimens. How does this study's inclusion of patients with 'adherence challenges' shift our clinical paradigm regarding the allocation of long-acting therapies?

Key Response

This study challenges the traditional dogma that injectables are a 'reward' for good adherence. It provides evidence that long-acting ART can actually serve as a rescue strategy or adherence intervention for vulnerable patients failing oral therapy due to psychosocial or structural barriers, fundamentally changing resource allocation to prioritize those with the highest need.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

In designing a non-inferiority trial for a population explicitly defined by 'adherence challenges,' how does the anticipated higher rate of loss to follow-up or virologic failure in the control arm (daily oral therapy) complicate the selection of the non-inferiority margin and the interpretation of intention-to-treat (ITT) versus per-protocol analyses?

Key Response

High failure rates in the active control arm can artificially make the experimental arm appear non-inferior (biasing the result towards the null). Researchers must carefully select a stringent, narrow non-inferiority margin and balance ITT (which is conservative for superiority but can falsely favor non-inferiority) with per-protocol analyses (which is preferred in non-inferiority trials to ensure the intervention truly works when taken as directed).

Journal Editor

As a peer reviewer evaluating this manuscript, what are the primary threats to validity regarding how the investigators operationalized 'adherence challenges' at baseline, and why might a 48-week primary endpoint be insufficient to capture the true incidence of emergent resistance in this specific cohort?

Key Response

'Adherence challenges' can be highly subjective, heterogeneous, and prone to selection bias depending on how the inclusion criteria were defined. Furthermore, due to the extremely long pharmacokinetic tail of long-acting CAB/RPV, virologic failure and complex dual-class resistance might emerge well past the 48-week mark, making longer-term follow-up (96 or 144 weeks) essential before declaring definitive durability and safety.

Guideline Committee

Current DHHS and WHO guidelines primarily recommend long-acting cabotegravir/rilpivirine only for individuals who are currently virologically suppressed on a stable regimen with no history of treatment failure. Based on this trial's findings in non-adherent populations, how should guidelines be updated regarding the prerequisites for initiating injectable ART in resource-limited settings?

Key Response

This study provides high-quality evidence that strict prior virologic suppression and flawless adherence are not absolute prerequisites for success with long-acting ART. Guidelines should be updated to cautiously recommend LA CAB/RPV as a therapeutic option for viremic patients struggling with adherence, provided baseline NNRTI resistance can be reasonably excluded or managed, thereby removing a major barrier to access for the most vulnerable patients.

Clinical Landscape

Noteworthy Related Trials

2020

FLAIR Trial

n = 566 · NEJM

Tested

Long-acting cabotegravir and rilpivirine

Population

Treatment-naive adults with HIV-1

Comparator

Oral dolutegravir-abacavir-lamivudine

Endpoint

HIV-1 RNA >= 50 copies/mL at 48 weeks

Key result: Long-acting injectable therapy was non-inferior to daily oral therapy in maintaining viral suppression after an induction phase.

2020

ATLAS Trial

n = 616 · NEJM

Tested

Monthly long-acting cabotegravir and rilpivirine

Population

Virologically suppressed adults with HIV-1

Comparator

Continuation of daily oral ART

Endpoint

HIV-1 RNA >= 50 copies/mL at 48 weeks

Key result: Transitioning to monthly injections was non-inferior to continuing daily oral regimens for maintaining HIV suppression.

2020

HPTN 084 Trial

n = 3,224 · Lancet

Tested

Long-acting cabotegravir every 8 weeks

Population

Cisgender women in sub-Saharan Africa at risk for HIV

Comparator

Daily oral TDF/FTC

Endpoint

Incident HIV infections

Key result: Long-acting cabotegravir was superior to daily oral pills for HIV prevention, significantly reducing infection rates.

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