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Injected Long-Acting Cabotegravir Protects Macaques From Injected SIV
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Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston
Mark Mascolini
Twenty-one of 24 macaques (87.5%) receiving various doses of long-acting injected cabotegravir remained free of SIV injected 2 weeks after cabotegravir [1]. The findings suggest that injectable cabotegravir should be evaluated as HIV PrEP in people who inject drugs.
Long-acting cabotegravir, formulated as a 200-mg/mL nanosuspension, is being tested for preexposure prophylaxis (PrEP) of sexually transmitted HIV [2] and as maintenance therapy in combination with rilpivirine [3]. Plasma concentrations of cabotegravir in macaques are comparable to those attained in humans [4], and cabotegravir prevents intrarectal and intravaginal simian HIV (SHIV) transmission in macaques [4].
The new study aimed to determine whether injected cabotegravir protects macaques from intravenous challenge with SIVmac251. Aaron Diamond AIDS Research Center investigators and colleagues tested three dosing patterns in three groups of 8 macaques each: (1) 50 mg/kg on week 0 and 4 with SIV challenge at week 2, (2) 50 mg/kg on week 0 with SIV challenge at week 2, and (3) 25 mg/kg on week 0 and 50 mg/kg on week 4 with SIV challenge at week 2. Cabotegravir concentrations should be optimal 2 weeks after injection. The SIVmac251 exposure was planned to simulate a per-act probability of infection comparable to blood transfusions.
Five macaques who did not receive cabotegravir all became infected 1 week after SIV challenge. Of the 8 macaques who received two doses of cabotegravir, 7 remained free of SIV through week 24 (P = 0.0047 versus untreated animals). At the time of SIV challenge, cabotegravir plasma concentrations in all 8 macaques, including the 1 who got infected, exceeded the target concentration of 4 times the protein binding-adjusted 90% inhibitory concentration (IC90).
Among the 8 macaques who received a single 50-mg/kg dose of cabotegravir, all 8 remained free of SIV infection for 20 weeks (P = 0.0008 versus untreated animals). Among the 8 macaques who received a 25 mg/kg dose at week 0 and 50 mg/kg at week 4, 6 of 8 remained free of SIV through week 24 (P = 0.021 versus untreated animals); the second 50-mg/kg dose at week 4 did not appear to affect the outcome.
Plasma cabotegravir averaged 2.58 ug/mL (range 1.00 to 5.56) in the 21 macaques who resisted infection and 1.17 ug/mL (range 0.67 to 1.93) in the 3 macaques who became infected (P = 0.0524). The researchers suggested that cabotegravir concentrations at the time of viral challenge may be more important than sustained concentrations after that challenge.
The investigators believe their results "support the evaluation of cabotegravir long-acting as PrEP in people who inject drugs."
References
1. Andrews CD, St. Bernard L, Poon A, et al. Cabotegravir long-acting injection protects macaques against intravenous challenge. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 105.
2. Markowitz M, Frank I, Grant R, et al. ECLAIR: Phase 2A safety and PK study of cabotegravir LA in HIV-uninfected men. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 106.
3. ViiV Healthcare. A phase IIb study evaluating a long-acting intramuscular regimen of GSK1265744 plus TMC278 for the maintenance of virologic suppression following an induction of virologic suppression on an oral regimen of GSK1265744 plus abacavir/lamivudine in HIV-1 infected, antiretroviral therapy-naive adult subjects. NLM Identifier NCT02120352. http://www.clinicaltrials.gov/ct2/show/NCT02120352
4. Andrews CD, Spreen WR, Mohri H, et al. Long-acting integrase inhibitor protects macaques from intrarectal simian/human immunodeficiency virus. Science. 2014;343:1151-1154. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4308974/
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