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Sexually transmitted infections and depot medroxyprogesterone acetate do not impact protection from simian HIV acquisition by long-acting cabotegravir in macaques
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AIDS Feb 2022 Vishwanathan, Sundaram Ajaya; Zhao, Chunxiaa; Luthra, Roopab; Khalil, George K.a; Morris, Monica M.c; Dinh, Chuonga; Gary, Michelle J.d; Mitchell, Jamesa; Spreen, William R.e; Pereira, Lara E.c; Heneine, Walida; García-Lerma, J. Gerardoa; McNicholl, Janet M.a
We show that CAB-LA maintained full protection reflecting high robustness of the CAB-LA dose and its insensitivity to STI/DMPA mediated inflammation, ulceration or vaginal thinning.....In summary, we demonstrate in two macaque models robustness of the CAB-LA clinical dose and its insensitivity to multiple STIs and DMPA supporting the implementation of CAB-LA for HIV prevention in women. Our STI-DMPA models provide an additional preclinical tool to confirm efficacy and dose selection of novel PrEP modalities.
Various reports have shown that nonulcerative STIs such as C. trachomatis and T. vaginalis can result in a two to fivefold increase in HIV acquisition risk in women [9], as can ulcerative STI such as T. pallidum[7]. The mechanisms by which these STI increase HIV risk vary, but all likely cause elevated cytokine concentrations, an influx of activated immune cells to the vaginal milieu providing more target cells for HIV, and a compromised mucosal barrier [10]. STIs alter immune responses and, in the case of T. pallidum, also cause mucosal ulceration thus enabling easier HIV access to internal vasculature and immune cells [9,11]. The impact of STI on PrEP efficacy can be evaluated in animal models that recapitulate human STIs. This is difficult to evaluate in clinical trials as participants are carefully followed and treated for STIs.
We have developed vaginal NHP models of STI, including C. trachomatis, T. vaginalis, and T. pallidum[12,13]. The double STI model with C. trachomatis and T. vaginalis increased vaginal susceptibility to SHIV [13], likely because of prolonged inflammation in the female genital tract (FGT).
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.
In agreement with the clinical findings, we have previously demonstrated that a clinical CAB-LA fully protected against vaginal SHIV infection in macaques [5]. Using a similar SHIV challenge strategy and CAB-LA dose, we have assessed in this study CAB-LA efficacy in two STI models of increased severity. We show that CAB-LA maintained full protection reflecting high robustness of the CAB-LA dose and its insensitivity to STI/DMPA mediated inflammation, ulceration or vaginal thinning. The findings are reassuring and support the current clinical CAB-LA dose. The study has benefited from the use of STI models that recapitulate clinical infections, combine ulcerative and nonulcerative STIs, and are augmented by DMPA that facilitates SHIV acquisition in macaques. The models were designed to sustain STI manifestations over 3 months by repeat STI exposures which overlapped repetitive physiologic SHIV challenges.
The findings observed with CAB-LA do not parallel those we observed when TDF/FTC efficacy was tested in the double C. trachomatis /T. vaginalis STI model [22]. Although TDF/FTC maintained significant protection, two out of six macaques became SHIV-infected compared with zero out of six in the absence of STI. It is unclear why CAB-LA efficacy was not similarly impacted. It is possible that the CAB-LA dose used is very potent and able to overcome any STI-mediated increase in SHIV infection and spread. In fact, previous work in the macaque model defined the correlate of protection by showing plasma CAB concentrations more than 3x PA-IC90 conferred 100% protection, whereas concentrations at least 1x PA-IC90 conferred nearly 97% protection [4]. Thus, the demonstration of plasma CAB concentrations persisting above 4x PA-IC90 in all animals supports the idea of a highly potent PrEP dose. Also, the detection of CAB in the vaginal secretions from the STI-infected animals, although lower than plasma levels, is also important because it suggests mucosal antiviral activity that may have contributed to protection. It is also possible that the drug class and its mechanism of action maybe differently affected by the mucosal environment. Unlike CAB, which is an integrase inhibitor, both tenofovir and FTC are nucleotide analogs of dATP and dCTP, respectively, and maybe sensitive to competition by higher intracellular natural substrates that are commonly increased in activated target cells during inflammation. Indeed, our prior studies in the double STI model showed elevated dATP and dCTP concentrations in vaginal tissues [22], suggesting a possible reduction in local antiviral activity.
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.
Discussion
On the basis of its high clinical efficacy and safety, it is anticipated that CAB-LA will be approved soon for HIV prevention in men and women. In agreement with the clinical findings, we have previously demonstrated that a clinical CAB-LA fully protected against vaginal SHIV infection in macaques [5]. Using a similar SHIV challenge strategy and CAB-LA dose, we have assessed in this study CAB-LA efficacy in two STI models of increased severity. We show that CAB-LA maintained full protection reflecting high robustness of the CAB-LA dose and its insensitivity to STI/DMPA mediated inflammation, ulceration or vaginal thinning. The findings are reassuring and support the current clinical CAB-LA dose. The study has benefited from the use of STI models that recapitulate clinical infections, combine ulcerative and nonulcerative STIs, and are augmented by DMPA that facilitates SHIV acquisition in macaques. The models were designed to sustain STI manifestations over 3 months by repeat STI exposures which overlapped repetitive physiologic SHIV challenges.
The findings observed with CAB-LA do not parallel those we observed when TDF/FTC efficacy was tested in the double C. trachomatis /T. vaginalis STI model [22]. Although TDF/FTC maintained significant protection, two out of six macaques became SHIV-infected compared with zero out of six in the absence of STI. It is unclear why CAB-LA efficacy was not similarly impacted. It is possible that the CAB-LA dose used is very potent and able to overcome any STI-mediated increase in SHIV infection and spread. In fact, previous work in the macaque model defined the correlate of protection by showing plasma CAB concentrations more than 3x PA-IC90 conferred 100% protection, whereas concentrations at least 1x PA-IC90 conferred nearly 97% protection [4]. Thus, the demonstration of plasma CAB concentrations persisting above 4x PA-IC90 in all animals supports the idea of a highly potent PrEP dose. Also, the detection of CAB in the vaginal secretions from the STI-infected animals, although lower than plasma levels, is also important because it suggests mucosal antiviral activity that may have contributed to protection. It is also possible that the drug class and its mechanism of action maybe differently affected by the mucosal environment. Unlike CAB, which is an integrase inhibitor, both tenofovir and FTC are nucleotide analogs of dATP and dCTP, respectively, and maybe sensitive to competition by higher intracellular natural substrates that are commonly increased in activated target cells during inflammation. Indeed, our prior studies in the double STI model showed elevated dATP and dCTP concentrations in vaginal tissues [22], suggesting a possible reduction in local antiviral activity. One limitation of this study is the lack of consistent T. vaginalis infections, especially in the presence of DMPA, which may have resulted in lower than expected levels of vaginal inflammation. The impact of inconsistent T. vaginalis infection may, however, be limited in the presence of consistent infection with C. trachomatis, T. pallidum, and a DMPA effect. We have not evaluated the combination of syphilitic manifestation or DMPA singly with CT-TV coinfection, and therefore cannot determine the individual contributions of syphilis and DMPA.
In a prior study of DMPA-treated rhesus macaques, lower systemic concentrations of CAB were observed than in non-DMPA treated macaques [21]. One mechanism proposed was increased metabolism of CAB due to upregulation of components of the hepatic glucuronidation pathway by progesterone. However, these studies also compared male and female macaques, raising the possibility of sex differences in CAB metabolism, and used a high DMPA dose (30 mg per macaque or approximately 3 mg/kg). In our experiment, we were able to directly compare CAB concentrations in the same female macaques before and after DMPA administration. We used lower doses of DMPA (1.5 mg/kg) which our prior work [15] suggests is a more physiologic dose that suppresses ovulation and causes significant thinning of vaginal epithelium. We show no impact by DMPA on plasma CAB concentrations obviating the need for dose modification.
In summary, we demonstrate in two macaque models robustness of the CAB-LA clinical dose and its insensitivity to multiple STIs and DMPA supporting the implementation of CAB-LA for HIV prevention in women. Our STI-DMPA models provide an additional preclinical tool to confirm efficacy and dose selection of novel PrEP modalities.
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