One injection of long-acting cabotegravir (CAB LA) protected 21 of 24 macaques from intravenous challenge with simian immunodeficiency virus (SIV). The researchers believe their results "support the clinical investigation of CAB long acting as PrEP in people who inject drugs."
Cabotegravir is an analogue of dolutegravir (Tivicay, DTG), an integrase inhibitor licensed for treatment of HIV infection. CAB LA is being developed for every-eight-week pre-exposure prophylaxis (PrEP) and for monthly maintenance therapy (with long-acting rilpivirine [Edurant]) in people who gain viral control with oral regimens. CAB LA provided complete protection against repeated intrarectal or intravaginal challenge with simian HIV (SHIV) in macaques. Daily oral tenofovir/emtricitabine (Truvada) lowered HIV acquisition risk in injection drug users. Researchers at the Aaron Diamond AIDS Research Center and other institutions conducted the macaque study to test CAB LA against intravenous challenge.
The study involved three macaque groups, each including eight animals. On weeks zero and four, group 1 received a 50-mg/kg intramuscular injection of CAB LA, the same dosing regimen used in previous studies of mucosal SHIV transmission. Group 2 received only a 50-mg/kg injection of CAB LA on week 0 to see whether the second dose is needed for protection. Group 3 received a 25-mg/kg dose on week 0 and a 50-mg/kg dose on week four. Five control macaques remained untreated. All macaques were intravenously challenged with an infectious dose of SIVmac251 on week two. Researchers used real-time PCR to check macaques for plasma SIV RNA every week for 20 weeks after the last CAB LA injection (study week 24).
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In all five untreated macaques, both SIV RNA in plasma and proviral DNA in peripheral blood mononuclear cells (PBMCs) could be detected in the first week after SIV challenge, and anti-SIV antibodies could be detected in three to four weeks. Seven of eight group 1 macaques remained free of SIV RNA in plasma through study week 24 (P = .0047 versus controls). The seven aviremic animals did not have detectable SIV DNA in PBMCs or detectable anti-SIV antibodies. SIV remained undetectable in plasma and PBMCs through 24 weeks in all eight group 2 animals (P = .0008 versus controls). Among the 15 of 16 macaques receiving an initial 50-mg/kg dose, CAB concentration in plasma averaged 2.97 µg/mL, compared with 1.93 µg/mL in the one animal that became infected. But the infected macaque did not have the lowest CAB plasma concentration at the time of challenge after the 50 mg/kg dose.
Six of the eight group 3 animals remained free of SIV in plasma through 24 weeks (P = .021 versus controls). The two animals that became infected after an initial 25-mg/kg dose had CAB plasma concentrations of 0.67 and 0.91 µg/mL at the time of challenge, the lowest levels recorded in the study. Proviral DNA and anti-SIV antibodies could be detected in the two infected macaques but not in the six macaques that remained uninfected.
Altogether, 21 of 24 animals (87.5%) receiving CAB LA remained free of SIV. Fifteen of 16 macaques (94%) that received the 50-mg/kg dose resisted intravenous challenge with SIV. The one infected macaque that received the 50-mg/kg dose appeared to have adequate CAB levels in plasma. With this exception, the researchers propose that CAB plasma concentrations at the time of SIV challenge "appear to correlate with protective efficacy." But protection appeared not to require a second 50-mg/kg dose of CAB LA two weeks after challenge in this model of intravenous viral exposure. The investigators propose that their findings, coupled with previous work, show "complete or high protective efficacy [with CAB LA] in both mucosal and parenteral transmission in macaques [and demonstrate] its potential utility to reduce infections through multiple routes of infection."
Mark Mascolini writes about HIV infection.