Switching to long-acting injectable ART with detectable viral load in people struggling with oral ART

6 August 2025. Related: Antiretrovirals, Treatment strategies, Drug resistance.

Simon Collins, HIV i-Base

Two studies just published in CID review the limitations of the current indication to only prescribe injectable CAB/RPV-LA to people who have undetectable viral load on oral ART. [1, 2]

The first is a retrospective review of people with complex HIV histories at a single centre in the US has reported high response rates from injectable ART, despite switching when viral load was still detectable >50 copies/mL. The second is a modelling study that provocatively challenges the the current recommendations as a denial of access and reports significant benefits from broader access.

These results are timely as two studies at IAS 2025 presented results on similar off-label prescribing of CAB/RPV-LA. [3, 4]

The first paper, from Jonathan Colasanti from Ponce De Leon Center in Atlanta and colleagues, includes results from 81 people managed at an urban US public HIV clinic in Atlanta who had received injectable CAB/RPV-LA at least three times. Participant characteristics included median age 38 (IQR: 30 to 49), 93% were Black, 36% were cis women and 4% (n=3) were trans women. Median annual income was $25K (IQR: 20 to 33) with 51% and 36% having food and housing insecurity, respectively.

Median time since HIV diagnosis was 15 years (IQR: 8 to 20), 11% had perinatal transmission and just under half had a previous OI. Median viral load when starting injectable ART was 4.0 log copies/mL (IQR: 2.9 to 4.8), with 13% (n=11) starting above 100,000 c/mL. Median CD4 count was 186 cells/mm3 (IQR: 62 to 420).

Four different injectable combinations were used: CAB/RPV (n=56), CAB±RPV+lenacapavir (n=22) and CAB±RPV+lenacapavir+ibalizumab (n=3). Lenacapavir was included if there were concerns about INSTI and/or NNRTI resistance and ibalizumab was included based on individualised concerns about achieving an optimal combination. Adherence support was also individualised. CAB/RPV-LA was given every 4 weeks and only switched to every 8 weeks after three consecutive undetectable viral load results. Management also included HBV vaccination when needed.

Two people were lost to follow-up. Both had extensive treatment experience, very high viral load (5.6 and 7.0 log), CD4 counts <50 cells/mm3, and didn’t respond to intensive attempts to reconnect them to care.

Of the remaining 79 cases, 73/79 (92%) achieved viral suppression after a median of one injection. Viral suppression was maintained in all 73 participants who became undetectable over a median follow-up of 263 days (IQR: 179 to 344).

Injection adherence was very high with 98% of CAB/RPV-LA and 100% of other injections in the permitted window.

The median CD4 count during follow-up increased to 353 (IQR: 187 to 501).

Of the six participants who remained >50 copies/mL, two had low-level viraemia 50-200 copies/mL; two were >200 copies/mL but without resistance and two rebounded to >200 copies/mL with significant dual class resistance. Both these last cases started with very high viral load and only used CAB/RPV-LA. One reduced viral load from 400,000 to 1500 by week 36 and the second reduced from 1 million to about 800 copies/mL by week 32. Both continued to have detectable viral load after returning to oral ART.

The paper also described the service delivery that was developed to support this population as having many challenges, including many social determinants of poorer health. Importantly though, the authors concluded that their results show that long-acting injectable ART can lead to impressive virologic and immunologic outcomes in people with significant viral load and late stage HIV.

The second study, from Pamela Pel at Massachusetts General Hospital in Boston and colleagues, modelled the clinical outcomes from four alternative access situations to CAB/RPV-LA, and report the impact on both viral suppression and mortality. [2]

This group compared three different implementation approaches with different projected uptakes to current standard of care, all of which included intensive adherence support that is appropriate for people who have difficulties with oral ART.

Modelling the current access (about 1% uptake) projected 35,810 patient years of viral suppression (VSPY) and 17,640 deaths by 5 years. By comparison, in the most effective scenario of implementing immediate complete access to CAB/RPV-LA, predicted increasing VSPY by an additional 26,830 person years and averted 3,980 deaths.

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These studies are especially important for the details on the potential role of long-acting ART in people with complex social histories and who are struggling to adhere to oral ART. 

Understanding both the risk and the benefits in the short and longer term also depends on comparison with a similar control group, which is unlikely to be included in prospective studies.

It is good that ViiV are currently recruiting for the randomised phase 3b CROWN study, currently only in Spain and the US. This open-label study will enrol adolescents and adults with viral load >1000 to <100,000 copies/mL and documented adherence difficulties with oral ART. [5]

Hopefully additional implementation studies will also continue until the results are available from CROWN.

In the same week, Lancet HIV published results of an international consensus review to define virological failure and discontinuation for injectable CAB/RPV-LA that should help in management and future research. [6]

References

1. Colasanti JA et al. Long-acting cabotegravir/rilpivirine, lenacapavir, and ibalizumab use among persons with HIV-1 viremia at a Ryan White-funded clinic in the urban US South. Clinical Infectious Diseases, 2025; ciaf425. (5 August 2025).
   https://doi.org/10.1093/cid/ciaf425
2. Pei PP et al. Clinical consequences of delaying implementation of long-acting antiretroviral therapy for people with HIV and persistent viremia in the US, Clinical Infectious Diseases, 2025;, ciaf428,
   https://doi.org/10.1093/cid/ciaf428
3. IAS 2025: Long-acting CAB/RPV in people with suboptimal adherence: IMPALA study results at 48 weeks. HTB July 2025.
   https://i-base.info/htb/51876
4. Switching to injectable CAB/RPV-LA with detectable viral load: results from the OPERA cohort, HTB 28 July 2025.
   https://i-base.info/htb/52049
5. Clinicaltrials.gov. A Study to Evaluate the Effectiveness of Long-acting (LA) Cabotegravir CAB) + Rilpivirine (RPV) LA When Given to Participants With Detectable HIV-1.
   https://clinicaltrials.gov/study/NCT06694805
6. Orkin C et al. Establishing shared definitions of virological failure and discontinuation for long-acting injectable cabotegravir and rilpivirine therapy (the CONSENSUS-LAI Study): an international survey and Delphi process. The Lancet HIV. (4 August 2025).
   https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(25)00131-6/fulltext