Long-Acting Cabotegravir as PrEP Protects Macaques Against IV Exposure but Will Need Two-Monthly Injections in Human Studies
March 4, 2016
Slow release, long-acting formulations have the potential to overcome difficulties with adherence to oral PrEP, even with reduced event-driven dosing.
A long-acting (LA) injection of cabotegravir (an analogue of dolutegravir) is being developed as HIV treatment and also being studied for PrEP.
Cabotegravir LA has a very long half life (approximately 50 days), with therapeutic drug levels sustained for at least three months and detectable drug from a single dose recoverable a year later. Animal studies have already reported high protection in models that mimic sexual transmission.
Two oral presentations on the use of cabotegravir LA (CAB) for PrEP were included at CROI 2016.
In the first, Chastity Andrew from Aaron Diamond Centre reported remarkable results against IV challenge -- a much higher risk than sexual transmission and closer to that from blood transfusion or shared injecting drug use -- in several macaque studies. The first of these reported results from 13 animals (5 were placebo controls) who were give a single dose of cabotegravir (50 mg/kg, equivalent to human 800 mg dose) at baseline and week 4, followed by a single intravenous (IV) challenge with SHIV at a dose high enough to expect infection.
While all placebo animals became infected within one week of exposure, only one of the animals receiving CAB became infected -- with 7/8 being protected out to 24 weeks. Plasma concentrations in the single infection were above the 4 x protein adjusted (PA) IC90 target.
When this study was repeated using only a single 50 mg/kg CAB injection, all 5 control animals became infected, but this time all 8/8 animals receiving CAB were protected (p=0.0008), showing that the second dose was not required for protection. However, drug levels fell below the 4 x PA IC90 earlier at 5 weeks compared to 9 weeks in the single vs two injection dose.
A third study used a lower (25 mg/kg) dose injection, with IV challenge at week 2, and a second standard dose (50 mg/kg) injection at week 4. This schedule resulted in all 5/5 controls being infected compared to only 2/8 animals receiving active drug, both of whom has the lowest PK drug levels.
This showed that a second injection is not needed for protection against single challenge, but is likely to be needed to sustain drug levels and protection over two rather than one month. Two of the three infected animals were with wild-type virus and one had novel mutation, previously not associated with catotegravir resistance.
The second study was a phase 2a safety and pharmacokinetic (PK) study of a three 800 mg doses (each with two intramuscular injections) using both catotegravir long acting injection in HIV negative men.2
The study randomised HIV negative men aged 18 to 65 years (median age 30 years; range 20-61) who were at high risk of HIV to either active (n=105) or placebo control (n=21). Recent PrEP use and chronic liver disease were exclusion criteria.
The study had a four week oral induction phase followed by 12-weekly 800 mg IM injections at weeks 5, 17 and 29. Results presented at CROI were for 12 weeks after the last injection, and continued follow-up will continue out to 52 weeks. Participants in the control arm used oral placebo and saline injections.
Data was presented for 87/94 (82%) and 20/21 (95%) who completed the oral and all injections, with four people discontinuing due to intolerance to injections.
There were two seroconversions, one in each of the placebo groups that occurred before the third injection and at 24 weeks after the last injection in the placebo vs active groups respectively.
In the PK analysis, plasma concentrations of cabotegravir were lower than observed in the previous HIV positive LATTE study where cabotegravir was used as treatment. Of concern, mean drug levels dropped below the target 4 x PA IC90 levels before 12 weeks with and dropped below the PA IC90 for some participants. This meant 15-31% of trough concentrations were below the PA IC90 and only 30-37% were above the 4 x PA IC90 therapeutic target.
Although few people discontinued, side effects occurred significantly more often in the active vs placebo arms, in both the oral and IM phases. Most related to injection site reactions and were grade 2 or lower, but 10% of events (27/272 events) were grade 3, all in the active arm. Overall patient satisfaction was reported as high for both formulations, although four people discontinued the study (after the third injection) due to injection reactions. These surveys scored higher for the injection over the oral phase.
The PK results have resulted in changing the future dosing to use injections every 8 rather than 12 weeks.
Two posters from this study reported injections to be broadly acceptable to most participants but that tolerability concerns are real and might not be acceptable for all people. As with PrEP itself, the options of oral pills and injections will be individualised based on personal preference.3,4
Clinical data from the long-acting dual formulation of cabotegravir plus rilpivirine as treatment in HIV positive people in the Latte-2 study were presented as a late-breaker abstract.5
Unless stated otherwise, all references are to the Programme and Abstracts of the Conference on Retroviruses and Opportunistic Infections, 22-25 February 2016, Boston, USA.
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