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Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251

Andrews, Chasity D.; Bernard, Leslie St.; Poon, Amanda Yee; Mohri, Hiroshi; Gettie, Natanya; Spreen, William R.; Gettie, Agegnehu; Russell-Lodrigue, Kasi; Blanchard, James; Hong, Zhi; Ho, David D.; Markowitz, Martin

doi: 10.1097/QAD.0000000000001343
Basic Science

Objective: We evaluated the effectiveness of cabotegravir (CAB; GSK1265744 or GSK744) long acting as preexposure prophylaxis (PrEP) against intravenous simian immunodeficiency virus (SIV) challenge in a model that mimics blood transfusions based on the per-act probability of infection.

Design: CAB long acting is an integrase strand transfer inhibitor formulated as a 200 mg/ml injectable nanoparticle suspension that is an effective PrEP agent against rectal and vaginal simian/human immunodeficiency virus transmission in macaques.

Methods: Three groups of rhesus macaques (n = 8 per group) were injected intramuscularly with CAB long acting and challenged intravenously with 17 animal infectious dose 50% SIVmac251 on week 2. Group 1 was injected with 50 mg/kg on week 0 and 4 to evaluate the protective efficacy of the CAB long-acting dose used in macaque studies mimicking sexual transmission. Group 2 was injected with 50 mg/kg on week 0 to evaluate the necessity of the second injection of CAB long acting for protection against intravenous challenge. Group 3 was injected with 25 mg/kg on week 0 and 50 mg/kg on week 4 to correlate CAB plasma concentrations at the time of challenge with protection. Five additional macaques remained untreated as controls.

Results: CAB long acting was highly protective with 21 of the 24 CAB long-acting-treated macaques remaining aviremic, resulting in 88% protection. The plasma CAB concentration at the time of virus challenge appeared to be more important for protection than sustaining therapeutic plasma concentrations with the second CAB long acting injection.

Conclusion: These results support the clinical investigation of CAB long acting as PrEP in people who inject drugs.

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aAaron Diamond AIDS Research Center, The Rockefeller University, New York City, New York

bViiV Healthcare, Research Triangle Park, North Carolina

cTulane National Primate Research Center, Covington, Louisiana

dGlaxoSmithKline, Research Triangle Park, North Carolina, USA.

Correspondence to Martin Markowitz, MD, Aaron Diamond AIDS Research Center, The Rockefeller University, New York City, NY 10016, USA. Tel: +1 212 448 5020; e-mail: mmarkowitz@adarc.org

Received 11 July, 2016

Revised 26 October, 2016

Accepted 4 November, 2016

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

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Introduction

It is estimated that 1.7 million (13.1%) of the 12.1 million people who inject drugs worldwide are infected with HIV-1 [1]. Preexposure prophylaxis (PrEP) with antiretroviral drugs is a promising biomedical intervention to prevent HIV-1 transmission. A once daily oral tenofovir disoproxil fumarate (TDF) or TDF–emtricitabine (FTC) regimen as PrEP reduced HIV-1 infections via sexual transmission by 44–75% in randomized clinical trials [2–4]. In the Bangkok Tenofovir Study [5], daily oral TDF reduced HIV-1 transmission by 49% in injection drug users, with the protective efficacy further increased to 74% when restricted to participants with detectable levels of tenofovir. All clinical trials to date, including those that failed to demonstrate TDF or TDF/FTC-based PrEP efficacy [6,7] have reported a direct correlation between the effectiveness of an agent and adherence to the prescribed regimen. These studies suggest the need for additional methods to improve PrEP adherence, and long-acting PrEP agents are one such possibility.

Cabotegravir (CAB), an analogue of dolutegravir, is an integrase strand transfer inhibitor with physiochemical properties that permit its formulation as an injectable 200 mg/ml nanosuspension. CAB long acting is undergoing clinical development for both HIV-1 treatment and prevention [8–11]. Recent data from a phase 2b clinical trial indicated that CAB long acting in conjunction with rilpivirine long acting is sufficient to maintain virologic suppression in HIV-1-infected adults when administered every 4 or 8 weeks [12]. In healthy individuals, a phase 2 clinical study suggested that CAB long acting is safe and well tolerated, but intramuscular dosing every 12 weeks failed to result in plasma CAB trough concentrations above levels that were highly protective in preclinical studies of sexual transmission in nonhuman primates [13]. In both studies, participants indicated a preference for the injectable formulation compared with an oral regimen [12,13]

The utility of CAB long acting as PrEP has previously been evaluated extensively in macaque models mimicking HIV-1 sexual transmission [14–16]. In low-dose challenge models designed to more closely mimic HIV-1 transmission in humans, macaques administered CAB long acting as PrEP were completely protected from repeated intrarectal [14] or intravaginal [15] SHIV162P3 challenges. Additionally, in a female rhesus macaque model utilizing Depo-Provera to thin the cervicovaginal epithelium to increase the probability of infection, CAB long acting protected six of eight female macaques from repeated high-dose intravaginal challenges [16]. Interestingly, in this study, a late breakthrough infection was observed in one animal with virus detected 7 weeks after the last challenge suggesting the importance of maintaining levels of CAB not only at challenge but also for weeks thereafter. However, the importance of drug levels at the time of and after challenge may differ between mucosal challenge and infection by intravenous exposure. In the current study, we evaluated the protective efficacy of CAB long acting administered as PrEP against intravenous challenge in a macaque model mimicking parenteral transmission. In addition, we modified the CAB long acting treatment regimen to assess the relative importance of plasma CAB levels at the time of and the contribution of maintaining CAB concentrations subsequent to intravenous challenge.

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Methods

Animals

The intravenous challenge study was a four-arm study that included 24 female Indian rhesus macaques. Six of the macaques were recycled from earlier intravaginal challenge studies [16] after confirmation of lack of SHIV162P3 infection. Five of the macaques utilized in the 25 mg/kg; 50 mg/kg study were recycled into the single 50 mg/kg study 40 weeks after the challenge and confirmation of lack of infection. Assuming that 100% of control macaques would become infected following one challenge, each study had 89% power to detect 75% PrEP effectiveness using a log-rank test with a P value of 0.05. The Institutional Animal Care and Use Committee of Tulane National Primate Research Center (TNPRC) approved all studies. TNPRC is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC # 000594). TNPRC's OLAW animal welfare assurance number is A4499–01 and USDA registration number is 72-R-0002.

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SIVmac251 viral stock

The SIVmac251 viral stock was kindly provided by Dr Ron Desrosiers. The viral stock was previously titrated in rhesus macaques via intravenous inoculation. The SIVmac251 challenge stock also had an end point titer of 5 × 103 50% tissue culture infectious dose (TCID50)/ml on CEM × 174 cells by the method of Reed and Muench [17].

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Efficacy of cabotegravir long acting in preventing simian immunodeficiency virus intravenous transmission

The efficacy of CAB long acting against intravenous simian immunodeficiency virus (SIV) transmission was evaluated in three groups of Indian rhesus macaques (Macaca mulatta; n = 8 per group) injected intramuscularly with CAB long acting and challenged intravenously with 17 animal infectious dose 50% (AID50) SIVmac251 on week 2. Group 1 was injected with 50 mg/kg CAB long acting on week 0 and 4, the same dosing regimen used in previous studies assessing CAB long-acting prevention efficacy against mucosal transmission [14,16]. Group 2 was injected with 50 mg/kg of CAB long acting on week 0 to understand the relative importance of CAB concentrations at the time of challenge and negating the potential benefit of a second injection that would prevent infection distal to the time of challenge as had been seen in the high-dose challenge experiments in female rhesus macaques [16]. Group 3 was injected with 25 mg/kg CAB long acting on week 0 and 50 mg/kg CAB long acting on week 4 to determine the importance of CAB concentration at the time of challenge while maintaining the second injection thereby modifying a single variable, peak drug concentrations at the time of intravenous challenge. CAB long acting is a 200 mg/ml nanosuspension that was administered based on body weights measured at the time of dosing (5.4–11.3 kg) with the dose split into four injections, two per quadriceps. Five additional macaques remained untreated as controls. Systemic infection was monitored weekly for 20 weeks after the last CAB long acting administration by detection of SIV RNA in plasma using real-time reverse transcription polymerase chain reaction assay with a sensitivity of 40 SIV RNA copies/ml as previously described [14]. Peripheral blood mononuclear cell (PBMC) proviral DNA amplification was performed as previously described [16]. Serology was performed utilizing SIVmac251 gp120-coated plates (ImmuneTech, New York, New York, USA). CAB plasma concentration analyses were performed as previously described [14]. Integrase sequence analyses from bulk plasma virus was performed as previously described [14,16].

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Construction of single-cycle simian immunodeficiency virus recombinant virus and determination for susceptibility to cabotegravir

Mutant viruses were constructed and their susceptibility to CAB was evaluated as previously described [16].

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Statistical methods

Fisher's exact test was used to compare CAB long-acting-treated and untreated macaques for number of infections. An unpaired two-tailed t-test or one-way analysis of variance followed by Tukey's multiple comparison post hoc test was performed to assess CAB concentration differences. All statistical analyses were performed using GraphPad Prism software (version 6.0; GraphPad, Inc., La Jolla, California, USA).

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Results

Preexposure prophylaxis efficacy of cabotegravir long acting using doses previously evaluated in macaques

We previously evaluated the pharmacokinetic profile of CAB long acting in male rhesus macaques and established that dosing every 4 weeks with 50 mg/kg maintained plasma concentrations similar to those achieved in a phase 1 study of healthy human volunteers administered 800 mg of CAB long acting intramuscularly every 3 months [14]. This dosing regimen provided drug concentrations that were completely protective against repeated low-dose rectal [14] and vaginal [15] challenge. In this study, we wanted to determine if the same dosing regimen of CAB long acting that protected macaques from mucosal simian/human immunodeficiency virus (SHIV) transmission, 50 mg/kg CAB long acting administered on weeks 0 and 4, could protect macaques from intravenous challenge. Eight macaques were administered 50 mg/kg CAB long acting on weeks 0 and 4, with five macaques remaining untreated as controls. All macaques were challenged by intravenous inoculation with 17 AID50 SIVmac251 at week 2 (Fig. 1a). Plasma viral RNA (vRNA) was detected in all five untreated macaques 1 week after challenge (Fig. 1b and c). Proviral DNA was also detected in PBMCs 1 week after challenge and anti-SIV antibodies were detected 3–4 weeks after challenge (data not shown). Seven of the eight CAB long-acting-treated macaques remained aviremic through week 24 (P = 0.0047; Fisher's exact test). Plasma vRNA was detected in one CAB long-acting-treated macaque, IB13, 2 weeks after challenge (Fig. 1b and c). Because this macaque was administered a second dose of CAB long acting at week 4, the viral loads were subsequently suppressed and were detectable again at week 9 (Fig. 1c). Proviral DNA was detected in PBMCs from IB13 concurrently with plasma vRNA and anti-SIV antibodies were detected 7 weeks after challenge (data not shown). The seven aviremic macaques did not have detectable proviral DNA or anti-SIV antibodies. IB13 did not have the lowest CAB plasma concentration at the time of challenge. The plasma CAB concentration for IB13 at the time of challenge was 1.93 μg/ml compared with the mean plasma CAB concentration of 2.58 (range: 1.63–3.51) μg/ml for the seven aviremic macaques (Fig. 1d). The integrase gene from plasma virus from IB13 collected between weeks 9 and 16 was sequenced, and one mutation, I191M, was identified, compared with the original SIVmac251 inoculum (Table S1, http://links.lww.com/QAD/B19). This mutant virus demonstrated susceptibility to CAB similar to wild-type virus with an half maximal inhibitory concentration (IC50) in TZM-bl cells of 3.2 nmol/l and 3.1 nmol/l, respectively.

Fig. 1

Fig. 1

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Preexposure prophylaxis efficacy of single 50 mg/kg cabotegravir long acting dose

Next, we wanted to determine if the second CAB long acting injection was required to maintain protective efficacy against intravenous challenge. In this study, eight macaques were given one 50 mg/kg CAB long acting injection on week 0 and challenged intravenously with 17 AID50 of the same stock of SIVmac251 on week 2 (Fig. 2a). All eight macaques given a single 50 mg/kg CAB long acting dose remained aviremic (P = 0.0008; Fisher's exact test; Fig. 2b), proviral DNA negative, and seronegative through week 20. As expected, individual plasma CAB concentrations from macaques administered a single 50 mg/kg dose on week 0 fell below 4× protein-adjusted IC90 (PAIC90) between weeks 4 and 6 (Fig. 2c), compared with weeks 8 and 10 for macaques administered 50 mg/kg CAB long acting on weeks 0 and 4 (Fig. 1d). The mean plasma CAB concentration at the time of challenge was comparable between the two groups administered 50 mg/kg of CAB long acting on week 0 irrespective of receiving a second 50 mg/kg CAB long acting injection at week 4, 3.31 (range: 2.03–5.56) and 2.50 (range: 1.63–3.51) μg/ml, respectively (Fig. S1, http://links.lww.com/QAD/B19). Of the 16 macaques that were dosed with 50 mg/kg of CAB long acting prior to challenge, the mean plasma CAB concentration of the macaques that remained aviremic following challenge was 2.97 μg/ml (n = 15) compared with 1.93 μg/ml for IB13, the macaque that became infected.

Fig. 2

Fig. 2

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Influence of plasma cabotegravir concentration at time of challenge on preexposure prophylaxis efficacy

From the previous experiment (Fig. 2), it appeared that CAB concentrations at the time of challenge were critical in providing protection against intravenous challenge. We then went on to challenge animals after dosing with a lower initial dose of CAB to confirm that lower plasma CAB concentrations at the time of challenge could affect protective efficacy. For this experiment, eight macaques were administered 25 mg/kg CAB long acting on week 0, challenged intravenously with 17 AID50 SIVmac251 on week 2, and administered 50 mg/kg CAB long acting on week 4 (Fig. 3a). The second injection of CAB long acting at week 4 was performed as per the first challenge experiment to avoid changing two variables simultaneously, which could be potentially confounding in interpreting the results of the experiment. We posited that in the absence of the second injection plasma CAB concentrations could decrease below protective levels earlier simply because of lower initial dosing, thereby not allowing us to assess the impact of plasma CAB concentration at time of challenge on protective efficacy. Based on the repeated high-dose vaginal challenge experiment where one macaque had detectable viremia 7 weeks after the last challenge [16], it was expected that plasma concentrations must to be maintained above the protective threshold for a given time to prevent infection. The single 50 mg/kg CAB dose indicates that one 50 mg/kg CAB long acting dose provides sufficient CAB concentrations over a given time to protect the macaques. In this experiment, if the animals were only given a single 25 mg/kg CAB long acting injection, the concentration at challenge would have decreased as well as the protective duration. Therefore, to only evaluate CAB concentration at the time of challenge, the animals were given 50 mg/kg CAB long acting at week 4 to maintain the protective duration. Six of the eight macaques given a 25 mg/kg dose followed by a 50 mg/kg dose of CAB long acting remained aviremic through week 24 (P = 0.021; Fisher's exact test; Fig. 3b). Two CAB long-acting-treated macaques, EL75 and FB90, became infected with plasma virus detected 1 or 2 weeks after challenge, respectively (Fig. 3c). EL75 and FB90 had the lowest plasma CAB concentrations at the time of challenge, 0.67 and 0.91 μg/ml, respectively (Fig. S1, http://links.lww.com/QAD/B19), and vRNA was first detected when plasma CAB concentrations were 0.77 and 0.28 μg/ml, respectively (Fig. 3d). Proviral DNA was detected 2 weeks after challenge for both infected animals, whereas the aviremic animals remained proviral DNA negative (data not shown). Both infected animals had anti-SIV antibodies detected 7–8 weeks after challenge, whereas all aviremic animals remained seronegative (data not shown).

Fig. 3

Fig. 3

The integrase-coding region was sequenced from plasma virus collected from EL75 at weeks 7 and 8 revealing that EL75 was infected with SIVmac251 containing the V110I mutation (Table S1, http://links.lww.com/QAD/B19), which is a polymorphic site in the integrase protein. In previous rectal [14] and vaginal [16] challenge studies, the SHIV162P3 viral stock contained an Ile at the 110 position, indicating the susceptibility of this mutation to CAB. EL75 exhibited a unique plasma CAB pharmacokinetic profile (Fig. 3d) as demonstrated by the extremely slow decay of CAB from the plasma. Plasma CAB concentrations decreased below 4× PAIC90 at week 9 and it took until week 20 for the plasma concentrations to decrease below 1× PAIC90 (Fig. 3d). During this time, two additional mutations (D232N and A248T) accumulated in the integrase protein; however, these mutations are not known to be resistance-conferring mutations (Table S1, http://links.lww.com/QAD/B19). Owing to the low viral loads observed in FB90, the first time point postinfection that was successfully amplified was week 15, which corresponded to wild-type SIVmac251 (Table S1, http://links.lww.com/QAD/B19). I210V was identified at week 16, but this mutation was transient (Table S1, http://links.lww.com/QAD/B19).

Overall, CAB long acting protected 88% (21/24) of macaques from intravenous SIVmac251 challenge (Fig. S2A, http://links.lww.com/QAD/B19). The mean plasma pharmacokinetics from each group are as expected based on the dosing regimen (Fig. S2B, http://links.lww.com/QAD/B19). The mean plasma CAB concentration at the time of challenge in the macaques remaining aviremic was 2.58 (range 1.00–5.56; n = 21) μg/ml, compared with 1.17 (range 0.67–1.93; n = 3) μg/ml for the animals that became infected (P = 0.0524; t-test; Fig. 4), and while not significantly different, the number of animals infected was small.

Fig. 4

Fig. 4

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Discussion

People who inject drugs are at high risk for HIV-1 infection and account for an estimated 30% of new HIV-1 infections outside of sub-Saharan Africa [18]. Long-acting formulations offer an alternative to daily oral PrEP regimens that may be preferred by some and offer the potential to increase adherence. Here, we demonstrated that CAB long acting at concentrations achievable in humans affords protection against intravenous SIV challenge in rhesus macaques. Plasma CAB concentrations at the time of challenge appear to correlate with protective efficacy; however, maintaining therapeutic plasma CAB concentrations after challenge by a second administration of 50 mg/kg CAB long acting at week 4 are not required for protection.

Macaque models have been valuable tools in demonstrating the protective efficacy of tenofovir-based PrEP agents prior to clinical evaluation. Early studies demonstrated that PMPA (tenofovir) protected macaques when administered as PrEP 48 h prior to intravenous challenge with SIVmne [19]. In our study, macaques were challenged with 17 AID50 SIVmac251, a dose determined by in-vivo titration in rhesus macaques via intravenous inoculation. As expected, all control macaques (100%) were infected following one challenge. Based on the estimated per-act HIV-1 transmission risk by exposure, our macaque model more closely mimics blood transfusions where an estimated 9250 transmissions occur during every 10 000 exposures to contaminated blood products, which is significantly higher than 63 transmissions during every 10 000 exposures to contaminated needles during injection drug use (92.5 and 0.63%, respectively) [20].

Overall, 15 of 16 macaques administered 50 mg/kg CAB long acting, which provides plasma concentrations similar to those achieved in humans, were protected from intravenous challenge. No correlation could be made between the plasma CAB concentration of IB13 at the time of challenge and the outcome. This animal is a clear outlier and we are hard pressed to explain this outcome. Viral infection even in the face of drug may be stochastic, or the possibility also exists that systemic virus traveled to a compartment with low CAB concentrations relative to plasma where infection and replication occurred. Although the plasma CAB concentrations at the time of challenge were the lowest in the study for the two animals administered 25 mg/kg CAB long acting that became infected (0.67 and 0.91 μg/ml), the plasma CAB concentrations were higher than 3× PAIC90 (0.498 μg/ml), the plasma concentration which correlated with 100% protective efficacy in a low-dose rectal challenge experiment [14]. In these experiments, macaques were challenged at week 2, after peak plasma CAB concentrations waned; however, the mean plasma concentration of the protected animals at the time of challenge was 2.58 μg/ml. The seemingly higher plasma CAB concentrations required for protection in this study is likely because of the large inoculum used in this macaque challenge model where 100% of controls become infected with one challenge.

In conclusion, CAB long acting afforded a high level of protective efficacy in this stringent macaque model demonstrating CAB activity and supporting the clinical investigation of CAB long acting as PrEP in people who inject drugs not only to determine efficacy but also to understand tolerability and acceptability of long-acting injections in this high-risk group. Preclinical studies with CAB long acting have demonstrated complete or high protective efficacy in both mucosal and parenteral transmission in macaques demonstrating its potential utility to reduce infections through multiple routes of infection.

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Acknowledgements

We thank Dr Ronald Desrosiers for providing tittered challenge viral stock; Mar Boente-Carrera and Mili R. Gajjar for technical assistance and Yun Lan Yueh for DMPK support. C.D.A., W.R.S., Z.H., D.D.H., and M.M. designed experiments. A.G., K.R.L. and J.B. executed the macaque studies. C.D.A., L.S., A.Y.P., and N.G. performed sample analyses. H.M. designed assays and evaluated drug susceptibility of mutant viruses. C.D.A. and H.M. performed statistical analyses. C.D.A. and M.M. wrote the manuscript. This work was supported by NIH grants R01-AI100724 and the Tulane National Primate Research Center grant 2P51-OD11104-52.

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Conflicts of interest

W.R.S. is a full time employee of, and holds shares in ViiV Healthcare; Z.H. is a full-time employee of, and holds shares in GlaxoSmithKline and serves on the ViiV Healthcare Board. D.D.H. is a paid consultant to GlaxoSmithKline and M.M. receives grants from GlaxoSmithKline.

Data presented previously at Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, MA on February 22–26, 2016.

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Keywords:

cabotegravir; GSK1265744; long acting; macaque; preexposure prophylaxis

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