Sexually transmitted infections and depot medroxyprogesterone acetate do not impact protection from simian HIV acquisition by long-acting cabotegravir in macaques

Abstract

Objective: We had previously shown that long-acting cabotegravir (CAB-LA) injections fully protected macaques from vaginal simian HIV (SHIV) infection. Here, we reassessed CAB-LA efficacy in the presence of depot medroxyprogesterone acetate and multiple sexually transmitted infections (STIs) that are known to increase HIV susceptibility in women. Design: Two macaque models of increasing vaginal STI severity were used for efficacy assessment. Methods: The first study ( n = 11) used a double STI model that had repeated exposures to two vaginal STI, Chlamydia trachomatis and Trichomonas vaginalis . Six animals were CAB-LA treated and five were controls. The second study ( n = 9) included a triple STI model with repeated exposures to C. trachomatis , T. vaginalis and syphilis, and the contraceptive, depot medroxyprogesterone acetate (DMPA). Six animals were CAB-LA treated and three were controls. All animals received up to 14 vaginal SHIV challenges. A survival analysis was performed to compare the number of SHIV challenges to infection in the drug-treated group compared with untreated controls over time. Results: All six CAB-LA treated animals in both models, the double STI or the triple STI-DMPA model, remained protected after 14 SHIV vaginal challenges, while the untreated animals became SHIV-infected after a median of two challenges (log-rank P < 0.001) or one challenge (log-rank P = 0.002), respectively. Both models recapitulated human STI disease, with vaginal discharge, ulcers, and seroconversion. Conclusion: In these high and sustained susceptibility models spanning more than 3 months, CAB-LA maintained complete efficacy, demonstrating robustness of the CAB-LA dose used in clinical trials, and suggesting its insensitivity to multiple STIs and DMPA.

Broadly neutralizing antibody-mediated protection against simian-HIV infection among macaques with vaginal sexually transmitted infections

“…vaginalis/T. pallidum ) co-infection/DMPA model, which was utilized in the current study [8]. Taken together, these earlier studies evaluating antiretroviral drug-based PrEP regimens demonstrate the variable impact that STIs may have on protective efficacy against vaginal SHIV infection and highlight differences between PrEP regimens with regard to their delivery route, potency, and vulnerability to inflammation or ulceration.…”

“…vaginalis/T. pallidum ) STI co-infection model, in addition to the effects of C. trachomatis and T. vaginalis , cervicovaginal ulceration is also present, which persists up to 12 weeks following initial T. pallidum inoculation and recurs following subsequent T. pallidum re-exposure (Supplemental Fig 1, http://links.lww.com/QAD/C783) [8]. These clinical and immunologic features resemble those seen in women with these STIs.…”

“…This model has been utilized to evaluate the protection of PrEP with oral tenofovir disoproxil fumarate (TDF)/ emtricitabine (FTC), vaginal tenofovir (TFV) gel, or intramuscular long-acting cabotegravir (CAB-LA) PrEP regimens [4,[6][7][8]. Additionally, ulcerative vaginal syphilis infection with Treponema pallidum has been combined with C. trachomatis and T. vaginalis vaginal co-infection to generate a triple-STI model, wherein syphilitic vaginal lesions appear 1-2 weeks following T. pallidum inoculation, persist for up to 12 weeks, and recur following reexposure to T. pallidum [8]. This model was used to assess the efficacy of CAB-LA against vaginal SHIV infection in pigtail macaques [8].…”

“…Among these, 10-1074, which targets the base of the third variable loop and surrounding glycans on the HIV envelope, has been shown to be efficient and well tolerated in HIV-infected and uninfected individuals, and has been evaluated preclinically, by others and us, in macaque models of vaginal, rectal, penile, or intravenous SHIV acquisition wherein high levels of protective efficacy have been characterized [10,[12][13][14]. To assess the impact of vaginal STIs on the efficacy of bNAb-mediated PrEP, we evaluated the protection that a single dose of 10-1074 provided against repeated vaginal challenges with SHIV SF162P3 among pigtail macaques using a triple-STI (C. trachomatis, T. vaginalis, T. pallidum) model that ensures high and sustained inflammation and ulceration during SHIV challenges because of repeated STI inoculations [8]. Using this model, we determined a correlate of 10-1074-mediated protection against vaginal SHIV infection and compared it with that from contemporaneous and historical controls without STIs.…”

Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection

“…Five of the animals received two 1 mL injections (total of 1000 mg CAB) and one animal (RH-1080) received injection volumes of 1 and 0.5 mL (total of 750 mg CAB). CAB levels were measured weekly in plasma for up to 11 months and in tissues at weeks 4, 8, and 12 using a validated LC-MS method as previously described 55 . Rectal and vaginal biopsies were collected from macaques RH-42012, RA-1048, and RA-1080 at weeks 4, 8, and 12.…”