Cabotegravir levels can be detected several years: PK tail to be covered by oral PrEP
Simon Collins, HIV i-Base
The properties of long-acting PrEP drugs that reduce the need for daily dosing also presents a new set of challenges if and when people decide to stop.
When LA drugs are used for treatment, this is less of a problem, as HIV positive people will usually be switching to an alternative drug combination.
However, when these drugs are used for PrEP, there will be months – or in some cases years – where there are different concerns from the long time they take to leave the body. In the phase 2 ECLAIR study, 17% of men had detectable cabotegravir levels a year after their final injection of 800 mg IM given on a 12-week schedule.
One presentation at R4P2018 included the most detailed results so far on the variability in the time taken for cabotegravir LA to leave the body during the long tail phase.
Final PK results from an earlier HPTN 077 study, using either 600 mg IM Q8W or 800 mg Q12W dosing. Results were presented from the 135/177 participants (33 placebo) who had follow up 76-weeks after the final injection. Results were combined from both arms as no differences were seen on the tail PK. Overall, 60% of participants were women.
Individual PK results were presented with reference to protein adjusted IC90 levels and expected levels of protection.
At 60-weeks after the final injection, 23% men and 63% women had detectable cabotegravir levels above the lower limit of quantification (25 ng/mL, LLOQ) which dropped to 13% and 42% at week 76, see Table 1. It was emphasised that at these levels cabotegravir was modelled to still provide >74-80% protection.
In multivariate analysis, factors associated with longer PK tail were female sex at birth [1.45 (95%CI: 1.17 to 1.81), p=0.001] and higher BMI per unit increase [1.02 (95%CI 1.01 to 1.04), p<0.003]. However, only 17% of the variation was explained by these two parameters.
The median estimated time to LLOQ was 42 weeks (range 20 to 134) for men and 66 weeks (range 17 to 182) for women, but the upper ranges were 2.5 years and 3.5 years for men and women respectively, noted by the session chair to be “rather a long time”.
Phase 3 studies are recommending using oral PrEP for 48 weeks after the last injection although this threshold for risk of developing drug resistance is not yet known. In practice though, people who chose long-acting injections might be those who either cannot or do not want to use oral PrEP.
Table 1: Cabotegravir drug levels after final injection
|Week 60||Week 76|
|LLOQ to <1xPA-IC90||15%||40%||13%||31%|
|1x to 4 x PA-IC90||8%||23%||0||11%|
Key: LLOQ: lower limited of quantifications (<25 ng/mL), PA-IC90 protein adjusted 90% inhibitory concentration.
Landovitz R. Tail-phase Safety, Tolerability and Pharmacokinetics of Long-acting Injectable Cabotegravir in HIV-uninfected Individuals: HPTN 077 Final Results. Oral late-breaker abstract OA15.06LB.