A long-acting integrase inhibitor protects female macaques from repeated high-dose intravaginal SHIV challenge

Abstract

GSK1265744 long-acting (GSK744 LA) is a strand-transfer inhibitor of HIV/SIV integrase and was shown to be an effective pre-exposure prophylaxis agent in a low-dose intrarectal SHIV rhesus macaque challenge model. Here, we examined the pharmacokinetics and efficacy of GSK744 LA as PrEP against repeat high-dose intravaginal SHIV challenge in female rhesus macaques treated with Depo-Provera which promotes viral transmission vaginally. When Depo-Provera-treated female rhesus macaques were dosed with 50 mg/kg of GSK744 LA monthly, systemic and tissue drug concentrations were lower than previously observed in male rhesus macaques. GSK744 concentrations were 5-fold lower on average in cervical tissues than rectal tissues. Eight female rhesus macaques were treated with GSK744 LA at week 0, and four female rhesus macaques served as controls. All animals received a high dose challenge of SHIV162P3 at week 1. No infection was detected in GSK744 LA-treated rhesus macaques, whereas viremia was detected 1 to 2 weeks after SHIV challenge in all control animals. The GSK744 LA-treated rhesus macaques were given a second administration of drug at week 4 and further challenged at weeks 5 and 7. GSK744 LA treatment protected 6 of 8 female rhesus macaques against three high-dose SHIV challenges, whereas all control animals became infected after the first challenge (P = 0.0003, log-rank test). These results support further clinical development of GSK744 LA for pre-exposure prophylaxis.

A Shot in the Arm for HIV Prevention? Recent Successes and Critical Thresholds

“…However, when systemic levels of the drug dipped below therapeutic levels, systemic infection emerged in one of the animals months after the last viral challenge. 39 A second study of a sustained released formulation of rilpivirine in humanized mice showed a similar result. In some cases the virus that emerged had remained hidden for up to 4 months before emerging as systemic infection.…”

“…Two recently published studies highlight this potential problem. 33,39 In one, rhesus macaques appeared to be protected from multiple vaginal high dose viral challenge by an injectable nanoformulation of cabotegravir. However, when systemic levels of the drug dipped below therapeutic levels, systemic infection emerged in one of the animals months after the last viral challenge.…”

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

“…Macaque models of rectal and vaginal transmission of SIV and SHIV have provided data that support the use of topical gels with reverse transcriptase (RT) inhibitors such as tenofovir (TFV) and MIV150 (3)(4)(5) and integrase inhibitors such as L-870812, an analogue of RAL (6), toward reductions of viral transmission rates. A long-acting form of a new INSTI, cabotegravir (also known as S/GSK-1265744), which is a DTG analogue, was shown to protect macaques against repeated vaginal and rectal challenges using SHIV (7,8). Prolonged TFV monotherapy of macaques infected with SIV or SHIV resulted in the emergence of viral mutants with the K65R substitution in RT, the same mutation that is associated with TFV treatment failure (9,10).…”

Long-acting rilpivirine for HIV prevention

“…In a human volunteer study, intramuscular injections 3-monthly maintained plasma concentrations well above the IC90 and trough concentrations achieved with effective oral administration [18]. Nonhuman primate studies have suggested that this agent provides effective protection at vaginal and rectal mucosa against viral challenge [19,20]. Thus, combination of two agents for HIV prevention may be considered in the future, potentially providing synergistic efficacy and protection against the development of resistance.…”