Long-acting CAB/RPV in people with suboptimal adherence: IMPALA study results at 48 weeks

17 July 2025. Related: Early access, Conference reports, Antiretrovirals, Drug resistance, IAS 13th Kigali 2025.

Simon Collins, HIV i-Base

The greatest potential for long-acting injectable ART has always been to support people who have difficulty with adherence to oral treatment.

This population is often excluded however as CAB/RPV-LA was only approved as a switch option for people who have durable suppression in oral treatment. Studies in a broader population are therefore of high interest and importance.

IAS 2025 included 48-week results from the phase 3b IMPALA study in people who in the previous two years had either a viral load >1000 copies/mL on current ART, people who had disconnected from care for >4 weeks; or people who had disconnected from care for more than three months since HIV diagnosis. However, entry criteria still included having viral load <200 copies/mL at baseline. [1]

This open-label non-inferiority trial randomised (1:1) 540 participants in seven sites in Uganda, Kenya and South Africa to either switch to injectable ART every two months or continue oral treatment. Results were presented by Fiona Cresswell from the UK Medical Research Council (MRC).

The primary endpoint was the proportion with VL <50 copies/mL at 48 weeks (ITT analysis using a –10% non-inferiority margin).

Baseline characteristics include 60% women, median age 40 years (IQR: 33 to 48), 99% Black African, 31% were HBV eAb+ and 22% had BMI >30. Median CD4 count was 629 (IQR: 453 to 873) with median ART duration of 7.5 years (IQR: 4.6 to 10.8). CD4 nadir was not given but 26% had a previous AIDS-defining illness. Although 78% had previous NNRTI experience, DNA testing for archived resistance was only performed retrospectively and is still ongoing.

At week 48, the primary endpoint was reported at 91% (245/268) vs 89% (240/269) in injectable vs oral ART arms respectively. The risk difference (RD) was +2.3% (95%CI: –2.7% to 7.2%), showing non-inferiority.

Injectable ART was also non-inferior on two secondary endpoints (using –4% margin). However, all five cases of confirmed viral failure were reported with injectable ART in 1.9% (5/268) vs 0/269 with oral ART; +1.9% (95%CI: 0.3% to 3.5%); and viral non-response was 6.3% (17/268) vs 7.8% (21/269) respectively; –1.5 (–5.8 to +2.8).

There were also significantly fewer reports of any viral load >1000 copies/mL with injectable ART (7/268 vs 18/269); –4.1%, (95%CI: –7.7% to –0.6%), showing superiority for CAB/RPV-LA.

Details for the five cases of viral failure are also important and are shown in Table 1.

Only two participants had identifiable baseline risk factors; one with BMI >38 and one with high-level RPV resistance. All 5/5 resuppressed on oral ART including 4/5 using INSTI-based TLD, despite intermediate resistance predicted to dolutegravir.

However, although viral load at failure was generally very low in 4/5 cases with lower confirmation results, one participant with no baseline predictive risks had viral load of 36,000 at failure that had increased to 96,000 when confirmed.

Table 1: Case details for confirmed viral failure on CAB/RPV-LA

n/k – not known or ongoing.

Serious adverse effects were numerically higher with injectable ART but the differences were not statistically significant. There were two drug-related discontinuations in each arm but none due to injection site reactions.

There were 6 vs 4 pregnancies (with 4 vs 2 elected terminations) and 2 live births in each arm, all RNA/DNA negative.

Quality of life increased in both arms but was significantly higher with injectable ART (p=0.0001). A high percentage of participants on injectable ART (93%) preferred this to their previous oral treatment (related to privacy and reduced stigma). Qualitative results in a subset of 40 participants were also presented in a poster. [2]

The study concluded that the results showed injectable ART to be non-inferior to oral ART in African countries in people who have difficulties with oral medicine, even without baseline resistance testing – and that access to injectable ART should be made a priority.

comments

These positive results are welcomed and the emphasis on ensuring access to injectable ART in African countries is essential.

The comment that CAB/RPV-LA implies lower risk of HIV transmission due to fewer participants having viral rebound to >1000 copies/mL (7 vs 18) should perhaps be challenged, given higher and more significant levels of viral load occurred with injectable ART.

Although WHO defines viral load >1000 copies/mL as a risk for sexual transmission, this risk is likely to remain low if viral load continues just above this level (Quinn et al, NEJM 2000).

In contrast, viral load with confirmed viral failure rebounded to significantly higher levels, including to 36,000 in one participant, and subsequently reached >96,000 with the confirmatory test.

This suggests the importance of using a lower threshold to define viral failure, which could obviate the need for a confirmatory test.

References

1. Cresswell FV et al.  Long-acting cabotegravir and rilpivirine in adults with suboptimal HIV control in sub-Saharan Africa: the IMPALA trial 48-week results. IAS 2025, 13-16 July 2025, Kigali, Rwanda. Oral late-breaker abstract OAS0105LBP.
   https://programme.ias2025.org/Abstract/Abstract/?abstractid=6781
2. Bukenya AD et al. The acceptability of long-acting injectable antiretroviral therapy in Uganda and South Africa: a qualitative methods sub-study of the IMPALA trial. IAS 2025, 13-16 July 2025, Kigali, Rwanda. Electronic poster EP0539.
   https://programme.ias2025.org/Abstract/Abstract/?abstractid=1911