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Cabotegravir (GSK744) long-acting for HIV-1 prevention...... Long-acting rilpivirine for HIV prevention (2 review articles)
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Current Opinion in HIV & AIDS: July 2015
"Plasma concentrations correlating with protection in macaques can be achieved in humans dosed with 800 mg of cabotegravir long-acting every 3 months.......data from all macaque studies to date demonstrate high efficacy of cabotegravir long-acting against vaginal infection and support the selection of an 800 mg dose administered every 3 months for PrEP in women......
.......long-acting ARV drug formulations are being advanced to improve adherence because they are not dependent on daily dosing and only require user compliance for infrequent medical visits. Interest in long-acting PrEP products has recently focused on the development of intravaginal rings and injectable long-acting ARV formulations that provide sustained drug exposures over many weeks [14,15,16,17]. Two long-acting injectable ARVs, currently under evaluation for both HIV-1 treatment and prevention, include the HIV-1 reverse transcriptase inhibitor TMC278 (rilpivirine) and the integrase inhibitor cabotegravir, also known as GSK1265744 or GSK744 [15,17,18]. This article reviews data on the development of injectable long-acting ARVs for HIV-1 prevention and focuses on cabotegravir long-acting, while a companion article will focus on TMC278 (below as well following Cabotegravir article)"
CROI: GSK744 and Rilpivirine as Two Drug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results - (03/05/14)
new PrEP for women........CROI: GSK1265744 Long-Acting Protects Macaques against Repeated High-Dose Intravaginal Challenges & Depo Provera-treated - (03/14/14)
PrEP for MSM.....CROI: Long-Acting Integrase Inhibitor GSK744 for PrEP (Once Monthly or maybe longer) - (03/05/14)......."GSK744 LA has afforded high---level protection against repeated intrarectal SHIV challenges in rhesus macaques......plasma concentrations >3X PAIC90 result in 100% protection.....plasma levels corresponding to protection can be readily achieved in man with quarterly 800mg intramuscular injections.......These data support moving GSK744 LA into clinical evaluation as PrEP in high-risk men who have sex with men - Phase 2 safety and tolerability studies commence in Spring 2014
CROI/2013 (Andrews): PrEP GSK744 Integrase Administered Monthly Perhaps Quarterly Prevents HIV-Infection in Monkeys - (03/07/13)......"Long-Acting Parenteral Formulation of GSK1265744 Protects Macques against Repeated Intrarectal Challenges with SHIV"
CROI/2014 (Andrews): Long-Acting Integrase Inhibitor GSK744 for PrEP (Once Monthly or maybe longer) - (03/05/14)....." Correlating GSK1265744 Plasma Levels To Prevention of Rectal SHIV Transmission in Macaques"
CROI/2014 - Monthly GSK744 long-acting injections protect macaques against repeated vaginal SHIV exposures.......http://www.natap.org/2014/CROI/croi_91.htm
Cabotegravir long-acting for HIV-1 prevention
Current Opinion in HIV & AIDS: July 2015
Andrews, Chasity D.a; Heneine, Walidb
aAaron Diamond AIDS Research Center, The Rockefeller University, New York, New York
bLaboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD, and Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
Purpose of review:
Preexposure prophylaxis (PrEP) with daily Truvada has demonstrated clinical efficacy against HIV-1 acquisition that correlates with high adherence. Long-acting antiretroviral drugs offer an alternative to daily regimens and may improve PrEP adherence. This review summarizes the preclinical nonhuman primate studies for evaluating the efficacy of cabotegravir long-acting as PrEP and the ongoing phase 2a studies assessing safety, tolerability, and acceptability of cabotegravir long-acting.
Recent findings: Cabotegravir is an HIV-1 integrase strand transfer inhibitor with intrinsic properties that permit its formulation as a long-acting injectable suspension. In clinical evaluation, cabotegravir long-acting has a half-life that permits infrequent dosing, possibly once every 3 months. In validated macaque models, cabotegravir long-acting demonstrated high protection against both rectal and vaginal transmission at clinically achievable drug concentrations.
Summary: PrEP, after approval of Truvada, continues to evolve to address adherence limitations of daily dosing. As a long-acting injectable antiretroviral drug, cabotegravir long-acting permits quarterly dosing and demonstrated high efficacy in macaque models supporting dose selection and clinical development. Clinical studies have confirmed dose selection in phase 2a trials with cabotegravir long-acting to ultimately lead to phase 2b/3 PrEP efficacy trials.
Two decades ago Tsai et al.[1] demonstrated that subcutaneous tenofovir could protect macaques from intravenous simian immunodeficiency virus (SIV) infection, providing the first proof-of-concept of the efficacy of antiretroviral (ARV) prophylaxis as a strategy for HIV-1 prevention. Subsequent animal modeling with clinically relevant regimens and doses showed that the marketed oral formulation of tenofovir, tenofovir disoproxil fumarate (TDF), in combination with oral emtricitabine (Truvada, Gilead Sciences), protected macaques from rectal and vaginal infection providing further support for clinical trials of preexposure prophylaxis (PrEP) for sexual HIV-1 prevention [2-4]. In the United States, the results of these oral PrEP studies led to Truvada being licensed in 2012 for HIV-1 prevention [5]. Because an effective HIV-1 vaccine remains elusive, the licensure of Truvada for PrEP ushered in the promise of a new biomedical intervention to address the global spread of HIV-1, estimated to 2.1 million new infections in 2013 acquired primarily through sex [6]. Women bear the greatest burden of infections in sub-Saharan Africa, whereas HIV-1 spread among MSM dominates in resource-rich countries [6,7].
Although clinical PrEP trials with daily TDF or Truvada reduce the risk of HIV-1 infection by 44-75%, they also highlight the difficulty of participants to adhere to the daily oral regimen as only approximately 50-80% had consistently detectable tenofovir, a marker of compliance [8-10]. Better adherence to the PrEP regimen increased efficacy estimates to approximately 74-92% as the risk of HIV-1 acquisition was found to be substantially lower among participants with detectable drugs than those with undetectable drug [8-10]. Very low adherence (<30%) was also the likely reason why two clinical trials among young African women (VOICE and FEM-PrEP) failed to show any efficacy of either daily TDF or Truvada [11,12]. Recent data from an open-label study with daily Truvada also noted inconsistent adherence among participants who were made aware of the safety and efficacy of the PrEP regimen [13].
Although many factors contribute to poor PrEP adherence, long-acting ARV drug formulations are being advanced to improve adherence because they are not dependent on daily dosing and only require user compliance for infrequent medical visits. Interest in long-acting PrEP products has recently focused on the development of intravaginal rings and injectable long-acting ARV formulations that provide sustained drug exposures over many weeks [14,15,16,17]. Two long-acting injectable ARVs, currently under evaluation for both HIV-1 treatment and prevention, include the HIV-1 reverse transcriptase inhibitor TMC278 (rilpivirine) and the integrase inhibitor cabotegravir, also known as GSK1265744 or GSK744 [15,17,18]. This article reviews data on the development of injectable long-acting ARVs for HIV-1 prevention and focuses on cabotegravir long-acting, while a companion article will focus on TMC278. Cabotegravir is an analogue of the marketed integrase inhibitor, dolutegravir, formulated as a long-acting nanosuspension for parenteral administration (cabotegravir long-acting). Cabotegravir is very potent and has a 50% inhibitory concentration (IC50) of around 0.22 nmol/l [17] with activity against various clades of HIV-1 [19]. Cabotegravir is also highly protein-bound and has a higher IC50 of around 100 nmol/l in the presence of human serum [17]. Cabotegravir dosed orally at 5 or 30 mg/day reduced HIV-1 RNA in plasma by 2.2-2.3 log10 copies per milliliter during a 10-day monotherapy trial in HIV-1-infected persons [20]. The high potency of cabotegravir, low water solubility, low metabolic clearance, and other pharmaceutical properties enabled cabotegravir to be formulated in a 200-mg/ml suspension as a long-acting injectable. Two phase 1 studies in humans demonstrated that cabotegravir long-acting is well tolerated, and that monthly or quarterly intramuscular injection maintains plasma drug levels that exceed four times the protein-adjusted 90% inhibitory concentration (PAIC90) for cabotegravir [17,18,21]. A study of repeated cabotegravir long-acting injections demonstrated that these injections were generally well tolerated and no grade 3 or 4 adverse events were reported [18]. Two phase 2a studies (ViiV Healthcare sponsored protocol 201120 and HPTN 077) are underway to assess safety, tolerability, and acceptability of cabotegravir long-acting for PrEP in HIV-1 uninfected men and women.
Animal models are invaluable preclinical tools to provide proof-of-concept data on efficacy and inform dose selection. The pharmacokinetic profile of cabotegravir long-acting was evaluated in macaques to determine a cabotegravir long-acting dosing regimen that provides similar plasma concentrations to those achieved in humans. Pharmacokinetic studies were performed in male Indian rhesus macaques (Macaca mulatta) comparing plasma concentrations from macaques dosed with 10, 30, or 50 mg/kg of cabotegravir long-acting [22]. On a weight basis, 10 mg/kg cabotegravir long-acting is similar to an 800-mg dose in an approximately 70 kg human; however, this dose provided lower plasma concentrations in macaques than observed in humans [22]. Although 30 mg/kg of cabotegravir long-acting provided comparable peak concentrations as observed in humans, the trough concentrations were significantly lower than in humans [22]. The lower plasma concentrations observed when macaques were dosed with 10 or 30 mg/kg of cabotegravir long-acting were not unexpected, as smaller mammals often eliminate drug more rapidly than humans [23]. A dose of 50 mg/kg of cabotegravir long-acting administered every 4 weeks maintained plasma concentrations similar to those observed in humans dosed with 800 mg cabotegravir long-acting every 12 weeks [22]. Similar plasma pharmacokinetic results were observed when administering 50 mg/kg of cabotegravir long-acting to female pigtail macaques (Macaca nemestrina) [24] and slightly lower trough concentrations were observed in female rhesus macaques pretreated with Depo-Provera [25]. The average terminal elimination half-life of cabotegravir long-acting was much shorter in macaques, 8.4-9.6 days [22,24,25], compared with 21-50 days observed humans [17], requiring more frequent dosing in the macaque to sustain clinical drug exposures.
Penetration of ARVs to mucosal tissues and secretions is a property that is considered important for PrEP agents utilized against sexual HIV-1 transmission; however, mucosal distribution differs widely among ARVs [26]. Penetration of cabotegravir to the mucosal site of virus entry was evaluated following various dosing regimens at various time points in nonhuman primates and was compared with the limited data available from humans (Table 1). A linear correlation between plasma and tissue concentration was observed in humans and nonhuman primates; however, rectal, vaginal, and cervical tissue:plasma ratios were generally low in all studies [21,22,24,25]. The low tissue penetration of cabotegravir may be related to its high protein binding similar to what has been observed with dolutegravir in human studies [27,28]. Despite the lower cabotegravir concentrations in mucosal tissues, levels remained above the PAIC90 in vaginal secretions from pigtail macaques during dosing cycles with the clinically relevant 50 mg/kg regimen [24]. Overall, the similarities in the distribution of cabotegravir in plasma and mucosal tissues between macaques and humans provide further support for using these macaque models to test efficacy under pharmacologically relevant conditions and inform dose selection for human trials.
The efficacy of cabotegravir long-acting was first evaluated in a repeat low-dose intrarectal challenge macaque model that was developed to more closely mimic HIV-1 transmission in humans [2,3,29-31]. Repeated challenge with SHIV162p3 containing an R5-tropic subtype B HIV-1 envelope (SF162) at a lower and more physiologically relevant inoculum is performed to evaluate protection against multiple transmission events [2,3,29-31]. To evaluate the efficacy of cabotegravir long-acting as PrEP in this model, eight male rhesus macaques were administered 50 mg/kg of cabotegravir long-acting on weeks 0 and 4, and an additional eight male rhesus macaques remained untreated as controls [22]. All macaques were challenged intrarectally beginning on week 1 with 50 TCID50 SHIV162p3 weekly for up to eight challenges or until infection was detected [22]. All control macaques became infected after a median of 2 (range 1-7) challenges, whereas all cabotegravir long-acting-treated macaques remained aviremic and seronegative during the challenge and drug washout phase of the study [22].
An additional study was conducted using the same model to determine plasma cabotegravir concentrations that correlate with protection from SHIV infection. In this study, 12 male rhesus macaques were administered a single dose of 50 mg/kg of cabotegravir long-acting 1 week prior to beginning repeated weekly SHIV challenges until infection was detected [22]. A single dose of cabotegravir long-acting delayed infection by five to 10 challenges compared with control macaques [22]. When plasma concentrations were more than three times PAIC90, viremia was not detected during 59 collective challenges confirming results of the initial challenge study that showed complete protection at high (>3x PAIC90) plasma concentrations [22]. However, as plasma cabotegravir concentrations waned, one macaque became viremic at plasma concentrations between one to three times PAIC90, whereas the remaining 11 macaques became viremic at plasma concentrations less than one times PAIC90[22]. Overall, these studies demonstrated that cabotegravir long-acting is an effective PrEP agent against intrarectal SHIV challenge. Plasma concentrations correlating with protection in macaques can be achieved in humans dosed with 800 mg of cabotegravir long-acting every 3 months.
Because of the physiological and pharmacological differences between vaginal and rectal tissues, the efficacy of cabotegravir long-acting against vaginal transmission cannot be predicted from rectal prevention data. The efficacy of cabotegravir long-acting against vaginal transmission was evaluated in both rhesus and pigtail macaques. Female rhesus and pigtail macaques exhibit different susceptibilities to SIV/SHIV infection [32], which influence the challenge design in each species. The barriers to infection are more substantial in the vagina compared with the rectum. Although untreated rhesus macaques can be infected vaginally with large challenge doses of SIV, pretreatment with progesterone thins the vaginal epithelium increasing susceptibility of the macaque to vaginal infection [33]. This rhesus macaque model utilizes a progestin-based contraceptive, Depo-Provera (depot medroxyprogesterone acetate, Pfizer), and has been employed to assess the efficacy of vaccines, neutralizing antibodies, ARVs, and vaginal microbicides against SIV/SHIV infection [34-44]. This model is limited by the use of a challenge dose exceeding physiological relevance and excessive thinning of the vaginal epithelium by a high dose of Depo-Provera, both of which can potentially underestimate the efficacy [45]. A vaginal efficacy study was recently reported using this rhesus macaque model [25]. Depo-Provera pretreated rhesus macaques were administered 50 mg/kg of cabotegravir long-acting on weeks 0 and 4, and macaques were challenged intravaginally with 300 TCID50 SHIV162p3 on weeks 1, 5, and 7 [25]. As expected in this model, all control macaques became infected with viremia detected 1-2 weeks after the challenge, whereas viremia was detected in two of the cabotegravir long-acting-treated macaques at weeks 10 and 14 [25]. In the cabotegravir long-acting-treated infected macaques, sequencing analysis indicated that infection was established by virus encoding wild-type integrase [25]. Six of eight cabotegravir long-acting-treated macaques remained protected from three intravaginal challenges during the challenge phase and drug washout phase [25]. Although there are some limitations with model that may underestimate the protective efficacy of an agent against intravaginal transmission, cabotegravir long-acting was at least 90% protective in this model.
Vaginal efficacy was also evaluated in the repeat-low dose model in pigtail macaques [24]. This well established model has several advantages, including the use of pigtail macaques, which have a menstrual cycle similar to women, a low SHIV162p3 inoculum dose (50 TCID50) similar to the physiologic HIV-1 RNA range found in semen, and twice-weekly virus challenges to mimic high-risk human exposure [4]. In previous studies, this model has accurately predicted the efficacy of oral Truvada PrEP in women [4,9,10]. This study reported complete protection in cycling animals treated with 50 mg/kg of cabotegravir long-acting every 4 weeks that recapitulates the quarterly 800 mg dose in humans [24]. Protected animals remained uninfected despite receiving 22 SHIV challenges over three cabotegravir long-acting cycles compared with a median of four SHIV challenges required to infect controls reflecting the robustness and durability of the protection [24].
Additional studies in rhesus macaques challenged longitudinally with intravaginal high-dose SIVmac251 (1000 TCID50) also provided important information on the correlation of plasma cabotegravir concentrations and efficacy [46]. In this study, cabotegravir long-acting was given at three dose levels (10, 30, and 50 mg/kg; n = 9) at days -7 and -1 prior to initiation of weekly intravaginal challenges. Significant protection from virus acquisition was noted in macaques dosed with 30 and 50 mg/kg cabotegravir long-acting, whereas no protection was observed at the 10 mg/kg dose [46]. Analysis of plasma cabotegravir concentrations suggested that targeting four times PAIC90 may be sufficient to protect against vaginal SIV transmission [46]. Therefore, data from all macaque studies to date demonstrate high efficacy of cabotegravir long-acting against vaginal infection and support the selection of an 800 mg dose administered every 3 months for PrEP in women.
Preclinical studies (Table 2) have supported the advancement of cabotegravir long-acting into clinical trials for HIV-1 prevention. Two phase 2a studies, a ViiV Healthcare-sponsored study (ƒCLAIR; NCT02076178) and a Division of AIDS, United States National Institute of Allergy and Infections Diseases sponsored study (HPTN 077; NCT02178800) will assess the safety, tolerability, and acceptability of cabotegravir long-acting in HIV-1-uninfected adults. The ƒCLAIR study has enrolled HIV-1-uninfected men in 10 United States-based sites [47], whereas HPTN 077 has begun to enroll both HIV-1-uninfected men and women in Brazil, sub-Saharan Africa, and the USA [48]. Both studies are double-blind, placebo-controlled trials [47,49]. Both studies were designed with a lead-in phase of 30 mg daily oral cabotegravir for 4 weeks with a 1-week washout phase to assess safety prior to initiating intramuscular administration of 800 mg cabotegravir long-acting every 12 weeks for three doses [47,49]. Demonstration of safety, tolerability, and acceptability of cabotegravir long-acting in phase 2a studies will lead to large phase 2b/3 efficacy studies to evaluate cabotegravir long-acting as an HIV-1 prevention agent.
As PrEP with daily Truvada is now a proven prevention strategy against HIV-1 acquisition, next-generation PrEP agents are being developed to provide sustained drug delivery to alleviate poor adherence associated with daily regimens. Such products include novel intravaginal rings for women and long-acting injectable drugs such as cabotegravir long-acting. Preclinical data in macaque models that have previously predicted Truvada efficacy in humans show that cabotegravir long-acting was highly protective against both rectal and vaginal SHIV transmission. Efficacy was seen at cabotegravir plasma concentrations achievable clinically by quarterly dosing of 800 mg of cabotegravir long-acting supporting clinical evaluation of this regimen as PrEP. Although long-acting ARVs provides hope for improving PrEP adherence, the clinical experience, gained once phase 2a trials are completed, will better address the safety, tolerability, and acceptability of cabotegravir long-acting for repeated dosing. Ultimately the efficacy of cabotegravir long-acting must be addressed in phase 2b/3 clinical trials to understand the full potential of this agent.
Long-acting rilpivirine for HIV prevention
Current Opinion in HIV & AIDS: July 2015
Jackson, Akila; McGowan, Ianb
aDepartment of HIV/Genito-Urinary Medicine, St. Stephen's Centre, Chelsea and Westminster Hospital, London, UK
bMagee-Womens Research Institute, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Purpose of review:
Long-acting injectable antiretroviral (ARV) formulations are being developed for the treatment and prevention of HIV infection. The purpose of this review is to summarize recent preclinical and clinical data on TMC278 (rilpivirine), a nonnucleoside reverse transcriptase inhibitor (NNRTI), that is being developed for both a treatment and prevention indication.
Recent findings: Long-acting rilpivirine has demonstrated efficacy in preventing HIV acquisition in a humanized mouse model and has been found to be well tolerated and acceptable in several Phase I clinical trials. Pharmacokinetic data from Phase I studies suggest that 1200 mg of long-acting rilpivirine administered every 8 weeks would be associated with plasma and tissue levels of rilpivirine anticipated to be necessary for preventing HIV infection. This regimen is being evaluated in the HPTN-076 Phase II expanded safety study that will enroll women in South Africa, Zimbabwe, and the USA. The HPTN-076 study requires a 4-week run in with oral rilpivirine (25 mg capsules) before receiving 1200 mg of rilpivirine. It is not yet certain whether oral dosing will remain a prerequisite in future trials or post licensure.
Summary: Long-acting rilpivirine shows promise as a candidate agent for HIV prevention. Preclinical efficacy has been demonstrated in a murine model. Phase I studies have shown good safety and efficacy, but breakthrough infection and resistance have been documented with lower doses of long-acting rilpivirine. Phase II development for a prevention indication is ongoing.
Despite advances in the diagnosis and treatment of HIV infection, new cases continue to occur on a daily basis in both the developed and developing world. In the USA, the licensure of tenofovir/emtricitabine for HIV prevention provides a new option for individuals at risk for HIV infection. However, it is clear that daily oral preexposure prophylaxis (PrEP) is not suited for all at-risk populations. This is perhaps exemplified in the VOICE study in which over 5000 women in sub-Saharan Africa were randomized to receive oral or topical tenofovir as PrEP. The study failed to demonstrate the efficacy of either product. Tenofovir was only detected in the plasma of 30% or less of the participants suggesting very low levels of product adherence. To make matters worse, the participants least likely to take the study product were young unmarried women who were at the greatest risk for HIV infection [1]. This same population routinely uses intermittent injectable progestins such as depot-medroxyprogesterone acetate (DMPA) for contraceptive purposes [2] and might be anticipated to favor an injectable form of PrEP. Recent qualitative surveys support this hypothesis and extend the potential interest in injectable PrEP to include other groups such as men who have sex with men (MSM) [3,4]. An ideal long-acting antiretroviral (ARV) PrEP agent will need to have most, if not all, of the following characteristics to be successful; ideally the product should be given as a single intramuscular injection every 2-3 months, the volume of injection should less than 3 mL, and injection site discomfort should be minimal. In addition, implementation of the intervention, especially in the developing world, will be facilitated by the absence of a cold chain storage requirement and low unit cost. As will be seen below, long-acting rilpivirine meets some but not all of these requirements.
Rilpivirine is an nonnucleoside reverse transcriptase inhibitor (NNRTI) that is currently licensed for the treatment of chronic HIV infection [5]. NNRTI act early in the cycle of viral replication, are potent ARV agents, and unlike tenofovir do not require metabolism to be active against HIV. Several NNRTI drugs have been evaluated as PrEP agents. Nevirapine is an important agent for the prevention of mother-to-child transmission of HIV infection [6]. UC781, MIV-150, and dapivirine have all been evaluated in gel or intravaginal ring formulations [7-9]. Initial studies in rats and dogs established an optimal 200 nm nanosuspension formulation with 300 mg of TMC278 per milliliter of the final formulation [10,11]. Currently, the long-acting rilpivirine formulation does require storage between 2 and 8°C, which has implications for PrEP implementation.
In a study conducted using immunodeficient mice reconstituted with human thymus, liver fragments and donor-matched human hematopoietic stem cells [12], Snyder et al. were able to show that mice given long-acting rilpivirine intramuscularly were protected from HIV infection when challenged with HIV-1CHO40[13].
Four Phase I clinical trials of long-acting rilpivirine have been completed and one trial is ongoing. During this process, several different formulations and injection sites have been used and details of these studies are provided below.
The C146 study
Sixty healthy participants were enrolled in the C146 clinical trial of the F004 formulation (100 mg/ml nanosuspension) of long-acting rilpivirine containing poloxamer 338. The pharmacokinetics (PK) and safety of long-acting rilpivirine were evaluated for at least 12 weeks following a single subcutaneous (SQ) or intramuscular injection of 200, 400, or 600 mg in six panels of healthy volunteers. In healthy participants, similar pharmacokinetic profiles were obtained after SQ (umbilicus region) and intramuscular (gluteal muscles) injections of long-acting rilpivirine. Following a rapid initial absorption, reaching its maximum at Day 4 (median), plasma concentrations of rilpivirine slowly declined, with plasma concentrations sustained above 10 ng/ml for up to 20 weeks after a single 600-mg dose. At this dose level, maximum plasma concentrations were approximately110 ng/ml (median). The pharmacokinetics were demonstrated to be dose proportional for the range from 200 to 600 mg, both for SQ and intramuscular dosing, except for the Cmax, which increased less than proportional to the dose between 400 and 600 mg injections after intramuscular dosing. The C146 trial showed favorable safety and tolerability and no serious adverse events (SAE), grade 3 or grade 4 adverse events, or rash were reported. Injections were well tolerated, particularly when administered intramuscularly in the gluteus. Placebo injections were better tolerated than injections with long-acting rilpivirine; injections of 600 mg intramuscularly in the gluteus were better tolerated than 600 mg SQ and better than 400 mg intramuscularly in the deltoid. Indurations at the injection site were more frequent after SQ than after intramuscular injections. Injection site reactions (pain, erythema, edema, and site induration) were also more pronounced and long-lasting after SQ than after intramuscular administration. Administration of 400 mg intramuscularly in the deltoid muscle was also well tolerated with injection site pain noted predominantly during the first week post dosing.
C150 study
A single-dose intramuscular Phase I study of the F006 formulation (300 mg/ml nanosuspension) of long-acting rilpivirine, containing polysorbate 80 as excipient, was completed. The formulation was associated with poor PK exposure and is no longer in development.
C158 study
This study in healthy volunteers examined the safety, tolerability and PK of the G001 formulation (300 mg/mL nanosuspension) of long-acting rilpivirine, which contains poloxamer 338. The C158 study had an adaptive design; participants in the open-label Part 1 received either a single intramuscular dose of 300 mg (Panel 1, n = 6) or 600 mg (Panel 2, n = 5) in the gluteus. After data review of interim pharmacokinetic and local safety/tolerability data of all participants in both panels, it was decided to continue in Part 2 with monthly intramuscular injections in the gluteus of respectively 1200 mg (loading dose), 600 mg, and 600 mg in Panel 3 (six participants on long-acting rilpivirine, two participants on vehicle). The Cmax following a single intramuscular dose of long-acting rilpivirine1200 mg was 139.5 ng/ml. The plasma concentrations of rilpivirine, after single 300, 600, 1200 mg intramuscular doses of long-acting rilpivirine (G001 formulation) were well below the concentrations associated with QTc prolongation in humans. During this study, no SAEs were noted. Adverse events were generally mild and transient. Overall, laboratory findings were normal and besides some mild, transient, and expected increases in few inflammatory parameters (i.e., fibrinogen and C-reactive protein levels), there was no evidence of systemic adverse reaction to treatment. There were no effects on vital signs, on body temperature, or on electrocardiograph profile including the absence of any effect on QTc.
The SSAT040 study
This study was an exploratory dose-ranging study, conducted at a single center in UK, which aimed to determine the initial feasibility of long-acting rilpivirine for PrEP use by measuring plasma exposure over 84 days after a single intramuscular dose given to 60 female HIV-negative volunteers [14]. This allowed comparison with paired samples of collected vaginal fluid, as a proxy for tissue drug exposure, and a more limited number (2 per participant) of vaginal tissue biopsies, at assorted intervals spanning 7-56 days post dose. At the time the study was performed, in the absence of any data to guide the target drug concentrations required to inhibit HIV-1 infection from tissue models, a plasma rilpivirine concentration of 50 ng/ml was used for comparison; this being the upper limit of the lowest quartile of plasma concentrations found to be effective in the oral rilpivirine Phase 3 treatment studies. The protocol used a phased adaptive design, from starting doses of 300 and 600 mg, the plasma concentrations over 28 days were compared with this target and a decision made to use a higher dose of 1200 mg in subsequent phases, rather than using the option to reduce the administered dose to 150 mg. Additionally, a small sub-study of six male volunteers all received a 600-mg dose and followed a similar protocol with rectal fluid and tissue sampling.
All doses administered were well tolerated and resulted in a rapid onset of detectable drug in plasma and tissue within the first 24 h, reaching maximum concentrations from 6-8 days and showing prolonged persistence with detectable rilpivirine in all samples through to day 84 (Fig. 1). The ratio of drug detectable in vaginal fluid to that in plasma remained at or above 0.8 throughout the study with higher maximum concentrations at peak (days 5-8); this was consistent with vaginal tissue concentrations measured at days 7, 14, 28, and 56. This gave a good indication that plasma concentrations could be measured as a proxy for tissue exposure in any later efficacy studies. Dose proportionality was confirmed between stratified doses and by day 28, volunteers in the 600-mg dose had dropped plasma concentrations from 82 ng/ml at maximum to just below the 50 ng/ml target, whereas those receiving1200 mg peaked at 160 ng/ml, declining to 83 and 45 ng/ml at days 28 and 56, respectively. An indication of an effect on viral inhibition was demonstrated using an ex-vivo assay [15], with cervicovaginal lavage fluid from volunteers receiving 1200 mg, but not 300 mg, when compared with fluid collected before the dose.
Male volunteers appeared to experience higher peak plasma concentrations compared with females receiving 600 mg, though this effect was limited to the early postdose period and was no longer observed in concentrations after day 28. Rilpivirine concentrations in collected rectal fluid appeared to be significantly lower than in plasma; however, tissue concentrations were more closely matched. This is likely because of technical issues when measuring rectal fluid concentrations with assay interference and sample contamination. There were no adverse events of a serious nature, nor of moderate severity or greater and serial electrocardiographs showed no prolongation of QT interval over the course of the study.
A significant consideration with the use of an antiretroviral drug with prolonged action for PrEP is that persistence of drug at levels lower than that required to prevent infection may form a selective pressure for new resistance mutations in cases where infection has occurred. Just such a breakthrough infection occurred in one female participant in SSAT040 illustrating the reality of this concern [16]. This volunteer had received the 300-mg dose and became infected during a single episode of vaginal intercourse with a new male sexual partner, without protocol-specified use of barrier contraception. The partner had previously tested negative within 8 weeks prior to the infectious exposure and on subsequent testing was found to be newly HIV-seropositive. The infection event occurred at day 40 postdose and retrospective viral load testing confirmed no detectable plasma HIV RNA until first detectable on day 56 at 370 copies/ml, and subsequently on day 84 where seroconversion was first picked up by a fourth generation combined antibody/antigen test, with a viral load of 175 060 copies/ml. Protocol scheduled samples taken within a couple of days after presumed exposure, measured plasma, and cervicovaginal fluid rilpivirine concentrations at 6.8 and 11.2 ng/mL, respectively, significantly lower than the therapeutic target concentration of 50 ng/ml. At Day 115, antiretroviral therapy with a combination of tenofovir, emtricitabine, darunavir with ritonavir was initiated as soon as infection had been confirmed. At this time, the viral load peaked at 644 925 copies/ml. Importantly, in this participant, rilpivirine remained detectable above assay limits up to 9 months after the single 300-mg dose. Taken together, these results indicate that the 300-mg dose would not provide protection against infection and where infection occurred could readily select for NNRTI resistance. In the case of the infection event not being recognized, this selection pressure would be exerted for a considerable time, potentially allowing the accumulation of further resistance.
The MWRI-01 study
Healthy HIV-1 seronegative participants were enrolled into three cohorts. Twelve women and six men received an intramuscular dose of either 1200 (Cohort 1; N = 18) or 600 mg (Cohort 2: N = 18) of long-acting rilpivirine. A third cohort will enroll 12 participants (8 women and 4 men) who will receive 1200 mg of long-acting rilpivirine every 8 weeks for 16 weeks. Plasma and tissue (rectal, cervical, and vaginal) are collected before and after exposure to long-acting rilpivirine. Participants are followed for up to 4 months after receiving long-acting rilpivirine. Safety, acceptability, multicompartmental PK, and pharmacodynamics (colorectal and genital ex-vivo explant challenge with HIV-1BaL) are characterized throughout the study. Enrollment and follow-up are completed for the first two single-dose cohorts and enrollment is ongoing for the multiple dose cohort.
The HPTN-076 study
This Phase II expanded safety study of long-acting rilpivirine is currently enrolling HIV-negative women in the USA, South Africa, and Zimbabwe. Following enrollment, approximately 132 participants will be randomized (2 : 1) to receive either daily oral rilpivirine (25 mg) or placebo for 4 weeks. In the absence of any safety signals, they will then progress to receive 1200 mg of long-acting rilpivirine or placebo every 8 weeks for a total of six injections. The primary objective of the study is to characterize the safety of multiple injections of long-acting rilpivirine. However, 96/132 of the participants will be enrolled in Africa and so the study may generate some preliminary efficacy data. As with the SSAT040 and MWRI-01 studies, the 1200 mg dose of long-acting rilpivirine is administered as a 2 ml intramuscular injection in both gluteal muscles.
Another long-acting nanoparticle suspension, the integrase strand-transfer inhibitor GSK1265744 (Cabotegravir), has been studied with long-acting rilpivirine for potential use in treatment [17]. 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.
Long-acting rilpivirine given intramuscularly is tolerated well at single and multiple doses and favorable pharmacokinetics allied to evidence of protection at tissues vulnerable to HIV infection supports its further development for PrEP. This strategy may also circumvent the negative impact of nonadherence to daily oral PrEP. Concerns remain about the potential for breakthrough HIV infection and the development of NNRTI resistance. In addition, the use of a long-acting injectable PrEP agent brings a number of implementation challenges, which differ significantly from those associated with the use of oral PrEP.

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