HIV Clinical Trials Africa: IMPALA Trial Validates CAB/RPV LA Efficacy

Key Takeaways

• The FDA approved CABENUVA (cabotegravir plus rilpivirine) in January 2021 based on the ATLAS and FLAIR phase 3 trials, which showed noninferior viral suppression compared with daily oral therapy. FDA label
• The IMPALA study (NCT05546242) is a phase 3b open-label trial enrolling 540 virologically suppressed adults with histories of suboptimal adherence in Kenya, Uganda, and South Africa. ClinicalTrials.gov
• Long-acting injectable HIV therapy could address adherence barriers that affect viral suppression rates, particularly in settings where daily medication poses challenges.
• SAHPRA approved Apretude (cabotegravir alone for HIV prevention) in August 2024, but the combination for HIV treatment remains unregistered in South Africa.
• Primary completion of IMPALA is expected in April 2025, with full study completion scheduled for March 2026.

What is CAB/RPV LA?

CAB/RPV LA combines two antiretroviral drugs: cabotegravir, an integrase strand transfer inhibitor (InSTI), and rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI). The fixed-dose combination comes as separate extended-release injectable suspensions for intramuscular gluteal injection.

The dosing schedule begins with an optional one-month oral lead-in to assess tolerability. Patients then receive 600 mg cabotegravir plus 900 mg rilpivirine at month 1, followed by maintenance doses of 400 mg cabotegravir plus 600 mg rilpivirine every two months.

This regimen differs from standard first-line therapy in Sub-Saharan Africa, which typically uses daily oral dolutegravir combined with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) or emtricitabine (FTC). By reducing dosing frequency from daily to bimonthly, the long-acting approach targets a key barrier to treatment success.

What Evidence Supports Long-Acting Injectables?

The ATLAS phase 3 trial randomly assigned 616 adults with suppressed HIV-1 RNA to continue oral therapy or switch to monthly injections. At week 48, HIV-1 RNA of 50 copies per milliliter or higher occurred in 1.6% of the long-acting group versus 1.0% of the oral group. The adjusted difference was 0.6 percentage points (95% CI, −1.2 to 2.5), establishing noninferiority against the 6-percentage-point margin.

The FLAIR trial extended these findings by enrolling individuals who had not previously taken HIV treatment. After 20 weeks of oral induction with dolutegravir-based therapy, 566 participants with suppression were randomized to continue oral therapy or switch to monthly injections. At week 48, 2.1% of the long-acting group versus 2.5% of the oral group had HIV-1 RNA ≥50 copies per milliliter, again demonstrating noninferiority.

In 2022, the FDA expanded approval to allow every-two-month dosing based on additional pharmacokinetic and efficacy data showing sustained drug concentrations with the extended interval.

Trial	Phase	Participants	Design	Key Finding
ATLAS	3	616	Switch from oral to monthly injections	Noninferior suppression at week 48
FLAIR	3	566	Induction then switch vs continuation	Noninferior suppression at week 48
IMPALA	3b	540	Switch vs continuation in adherence-challenged patients	Results pending (primary completion April 2025)

What is the IMPALA Trial?

The IMPALA study addresses a specific gap in the evidence base: how long-acting injectables perform in populations with documented adherence difficulties. Most phase 3 efficacy trials enroll participants who can reliably attend visits and take medication. IMPALA specifically targets adults with histories of suboptimal engagement with care.

The trial randomly assigns 540 virologically suppressed adults (HIV-1 RNA below 200 copies per milliliter) to either continue first-line oral therapy with dolutegravir plus two nucleoside reverse transcriptase inhibitors or switch to bimonthly cabotegravir and rilpivirine injections. Study sites operate in Kenya, Uganda, and South Africa.

Participants may choose between an oral lead-in phase or direct-to-injection initiation. The total study duration is 24 months. Follow-up continues through March 2026.

Why does this research matter for Africa?

Sub-Saharan Africa carries the highest HIV burden globally. South Africa alone accounts for nearly 20% of worldwide infections. Daily oral therapy suppresses virus effectively, but adherence challenges—driven by stigma, transportation barriers, and competing priorities—lead to treatment failure in some patients.

Long-acting injectables could reduce clinic visit frequency while ensuring medication exposure between appointments. For patients who struggle with pill-taking, injections eliminate the daily reminder of HIV status and the risk of missed doses.

The IMPALA trial tests whether this approach works specifically in African populations with adherence barriers. If successful, it would provide evidence for regional treatment guidelines to include long-acting options for selected patients.

What is the regulatory status in South Africa?

SAHPRA registered Apretude (cabotegravir long-acting injectable suspension for pre-exposure prophylaxis) in August 2024. This approval covers HIV prevention, not treatment. Apretude targets HIV-negative individuals at risk of infection.

CABENUVA, the combination of cabotegravir and rilpivirine for treating existing HIV infection, is not currently registered with SAHPRA. Registration would require submission of clinical data, quality documentation, and proposed labeling for regulatory review.

IMPALA trial data could inform any future SAHPRA submission for the combination product. The study enrolled participants in South Africa specifically, generating locally relevant evidence.

Frequently Asked Questions

Primary Sources

1. U.S. Food and Drug Administration. CABENUVA (cabotegravir and rilpivirine) prescribing information. January 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212888s000lbl.pdf
2. ClinicalTrials.gov. Improving HIV-1 Control in Africa with Long Acting Antiretrovirals (IMPALA). NCT05546242. December 2022. https://clinicaltrials.gov/study/NCT05546242
3. Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection. N Engl J Med. 2020;382(12):1124-1135. doi:10.1056/NEJMoa1909512
4. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression. N Engl J Med. 2020;382(12):1112-1123. doi:10.1056/NEJMoa1904398
5. ViiV Healthcare. Significant milestone for HIV prevention in Sub-Saharan Africa as South Africa grants regulatory approval for Apretude. August 2024. https://viivhealthcare.com/hiv-news-and-media/news/company-statements/significant-milestone-for-hiv-prevention/