Low levels of RPV-LA might explain failure with injectable ART despite perfect adherence

Kirk Taylor, HIV i-Base

BHIVA guidelines caution that long-acting (LA) CAB/RPV regimens have virologic failure rates of 1 in 70 at 12 months, rising to 1 in 60 at 24 months. Inter-person variability in PK parameters, especially of RPV-LA could be one explanation. [1]

Early data from a sub-study of the Swiss HIV Cohort Study (SHCS) reports high inter-person variability in Cmin ­levels for CAB and RPV. Whilst Cmin values were above their respective IC90 levels, some readings were close to this threshold prompting concerns about safety and efficacy. [2]

Therapeutic dose monitoring (TDM) can help to identify real-world variations in PK parameters to inform dosing and monitoring intervals.

The ATLAS-2M and FLAIR studies showed that LA-CAB/RPV can effectively manage HIV but real-world PK data is also required outside of stringent clinical studies. This prospective observational sub-study of the SHCS reports LA-CAB/RPV PK data in people living with HIV.

Most PK samples (84%) were collected prior to Q8W dosing when participants were expected to be close to Cmin levels. Blood samples were collected at routine visits (n=61) or during the oral lead-in period (n=30). In line with Swiss treatment guidelines, two participants who were on Q4W schedules transitioned to Q8W regimens.

Inter-participant variability of Cmin was reported as 101% and 94% for CAB and RPV, respectively. Intra-participant variability was significantly lower at 50% for CAB (p=0.002) and 27% for RPV (p<0.0001). The range of Cmin values for CAB and RPV was approximately 250 to 1,100 ng/mL and 18 to 300 ng/mL, respectively.

All reported PK values exceeded the IC90 values for CAB (166 ng/mL) and RPV (12 ng/mL). However, RPV levels were close to the IC90 for some participants, raising concerns of efficacy and safety.

Data collected up to July 2022 (n=46) were from participants who were female (17%), with median age of 45 years (range: 28 to 62), Caucasian (63%), Black (13%), Hispanic (7%) or Asian (7%). HIV viral load was below 200 copies/mL for all participants and <50 copies/mL (94%). Median CD4 count was 667 cells/mm3 (range: 191 to 1192).

BHIVA guidelines indicate that obesity can be a risk factor for virologic failure on LA-CAB/RPV regimens. Median BMI was 26 kg/m2 (range: 19 to 37) with 15% and 54% classified as obese and overweight, respectively.

Low grade adverse events, such as injection site reactions, were reported by 30% of participants. No virologic failures were reported.


Currently, based on the current BHIVA guidelines, a large proportion of people are contraindicated from using CAB-LA/RPC/LA due to obesity.

Although the risk of viral failure was lower with monthly dosing, the added inconvenience of more frequent injections make this an unlikely choice, even if it was recommended in guidelines.

The study aims to enrol 200-300 people over the next two years.


  1. Waters L et al. Interim BHIVA guidance on long-acting cabotegravir/rilpivirine (LA-CAB/RPV) for antiretroviral therapy. (07 Feb 2022).
  2. Thoueille P et al. Real-life therapeutic concentration monitoring of long-acting cabotegravir and rilpivirine: preliminary results of an ongoing prospective observational study in Switzerland. Pharmaceutics 14(8). (29 July 2022).  

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