Methods for achieving HIV remission using long-acting antiretroviral agents

Abstract

1. A method for achieving viral remission in a patient in need thereof, comprising administering early antiretroviral therapy (eART) of therapeutically effective amounts of cabotegravir and rilpivirine long-acting antiretrovirals after exposure of the patient to the HIV virus, and discontinuing the early antiretroviral therapy after eART suppression of the virus.

Description

【Technical Field】 【0001】 Statement regarding federally funded research This invention was made with government support under Project No. 1845 and Cooperative Agreement No. D-588-16 by the Centers for Disease Control and Prevention (CDC), National Center for HIV / AIDS, Viral Hepatitis, STD, and TB Prevention, Division of HIV / AIDS Prevention. The government has certain rights in this invention. 【0002】 This invention relates to the prevention or treatment of human immunodeficiency virus (HIV) infection. In particular, the invention relates to a process for achieving partial or complete remission of HIV infection, where treatment is initiated early with a combination regimen that includes long-acting antiretroviral drugs, with or without a latent infection reactivator. 【Background Art】 【0003】 Among viruses, the human immunodeficiency virus (HIV), a type of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). Potent combination antiretroviral therapy (cART) has revolutionized the treatment of patients with HIV infection. A cure of HIV infection (such that cART is no longer required) has been difficult to achieve because of the persistence of both a low level of viral load in the blood and a long-lived reservoir of latently infected cells that are mostly memory CD4+ T cells that can be activated to produce infectious virus. Hong FF., AIDS Rev. 2015;17(2):71-82. 【0004】 In asymptomatic patients with CD4+ counts exceeding a certain threshold, it was common practice to delay the initiation of antiretroviral therapy. De Cock KM.,N Engl J Med 2013;368:886-889. The effect of the timing of antiretroviral therapy initiation on clinical and microbiological outcomes has been controversial, as has the assessment of the benefits of therapy, as well as the associated short- and long-term complications and costs. For many years, antiretroviral therapy was delayed until patients' CD4+ counts fell to less than 200 cells per cubic millimeter, which led to a high incidence of opportunistic infections. Severe P.,N Engl J Med.2010 Jul 15;363(3):257-65. A retrospective analysis of patients with HIV-1 infection treated in developed countries suggests the benefits of early antiretroviral therapy (eART). Cohen MS., N Engl J Med. 2011;365(6):493-505. These data, along with observational studies, provide strong evidence for initiating antiretroviral therapy in patients with more CD4+ cells per cubic millimeter. Lundgren J., N Engl J Med. 2016;374(4):394. 【0005】 It is desirable to achieve combination antiretroviral therapy administered at an early time point in antiretroviral therapy to reduce low levels of circulating viral load and reservoirs of latent infected cells. However, no combination antiretroviral therapy composition has yet been found that achieves the above criteria, ultimately allowing the patient to discontinue antiretroviral therapy due to either remission or cure. 【0006】 Therefore, in this field, there is a need for antiretroviral therapy that effectively treats HIV by further reducing low levels of viral load in the blood and the potential reservoir of CD4+ cells that can reintroduce infectious viruses into the host. [Overview of the project] 【0007】 A method for achieving virological remission (also referred to as functional remission) in primate hosts infected with immunodeficiency viruses without requiring continuous antiviral treatment is disclosed. Remission is demonstrated by the absence of viral rebound in plasma after discontinuation of suppressive antiretroviral therapy. Remission is achieved when treatment is initiated within days or weeks after acute exposure with a combination regimen including a long-acting antiretroviral (ARV) drug. In this specification, the inventors demonstrate virological remission with a combination regimen including a pharmacologically effective dose of the long-acting integrase inhibitor cabotegravir (CAB-LA) and a pharmacologically effective dose of the long-acting non-nucleoside reverse transcriptase inhibitor rilpivirine (RPV-LA). Treatment is effective when initiated within days or weeks after acute exposure. In certain descriptions, viral remission is achieved when treatment is discontinued after a period of sustained viral suppression. This finding signals a new biomedical approach to achieving virological functional remission and potential remission of HIV. 【0008】 Early antiretroviral therapy, or eART, improves clinical outcomes by reducing the size and diversity of the viral reservoir, limiting immune impairment, and delaying viral rebound after treatment discontinuation. Latent infection reactivators (or LRAs) activate the viral reservoir. Viralally suppressed individuals have been treated with LRAs in attempts to eliminate latent viruses for a "shock and kill" strategy, but this has not been clinically successful to date. The use of LRAs during acute infection has not been evaluated. Here, we show that the clinical outcomes of eART can be improved with the use of long-acting antiretroviral drugs. These formulations have a long-lasting drug tail that can further delay viral rebound, which may result in a chemovagal effect. Secondly, we show that adding LRAs to an eART regimen can reduce viral reservoir formation by eliminating viral reservoir formation during the initial infection and stimulating a stronger immune response. 【0009】 According to one embodiment, a method is provided for achieving HIV viral remission in a patient in need thereof, comprising the steps of administering early antiretroviral therapy (eART) of a therapeutically effective dose of cabotegravir and rilpivirine long-acting antiretroviral agents after the patient has been infected with HIV, and discontinuing the early antiretroviral therapy after the eART has suppressed the virus. 【0010】 According to one embodiment, the early antiretroviral therapy is initiated a predetermined time after the patient's HIV infection. According to another embodiment, the early antiretroviral therapy is initiated while the patient's CD4+ cells / ml are >500. 【0011】 According to another embodiment, early antiretroviral therapy further comprises the administration of at least one additional antiretroviral agent. The one or more additional antiretroviral agents may include emtricitabine (FTC) and / or tenofovir or their prodrugs. 【0012】 According to another embodiment, the method for achieving HIV virus remission further comprises administering a latent infection reactivator. In one embodiment, the latent infection reactivator is a TLR7 agonist. An exemplary TLR7 agonist is besatrimod. 【0013】 According to one embodiment, a long-acting antiretroviral agent, cabotegravir and rilpivirine, is provided for use as early antiretroviral therapy (eART) to achieve HIV viral remission in patients who require it. [Brief explanation of the drawing] 【0014】 [Figure 1]Figure 1 is a graph showing the experimental design. Rhesus macaques (=10) were rectally infected with a single high-dose pathogenic RT-SHIV isolate containing a T-to-C substitution at position 8 of the SIV tRNA primer binding site, which enhances viral replication and increases pathogenicity. Group I (n=4) rhesus macaques were inoculated with the virus and confirmed to be infected by detection of RT-SHIV RNA in plasma, and treatment with CAB-LA / RPV-LA / FTC / tenofovir alafenamide (TAF) was initiated on days 5 / 6. Treatment with CAB-LA / RPV-LA / FTC / TAF was continued for 6 months, followed by a simplified regimen with CAB LA / RPV LA for another 6 months. All treatments were discontinued at 12 months. In group II (n=4), rhesus monkeys were treated with CAB-LA / RPV-LA / FTC / TAF on days 6 and 8 after infection, followed by weekly VES treatment from days 8 to 11. VES treatment was discontinued after 3 months, and CAB-LA / RPV-LA / FTC / TAF was discontinued after 4 months. In group III (n=2), rhesus monkeys were untreated controls. [Figure 2] Figure 2 is a graph showing the dynamics of viral replication during the first 50 days after infection, represented by log10 RNA copies of SHIV RNA in plasma. The horizontal dotted line indicates the limit of quantification (lower limit) of the SHIV RNA assay (12.5 copies / ml (plasma)). Plasma SHIV RNA levels during early acute infection were significantly reduced in groups I and II compared to the untreated control in group III. Peak blood viral loads were similar in groups I and II (3.4 [range = 2.7~4.3] and 4.2 [3.7~4.4] log10 RNA copies / ml, p = 0.111) and lower than the untreated control (6.8~7.0 log10 RNA copies / ml). Viral replication from the start of treatment to viral suppression was also similar in animals of group I and group II (AUC viral load = 42.6 [31.6~59.7] and 45.0 [38.4~51.07] RNA copies / ml / day, p=0.886), but replication was suppressed earlier in animals of group II (18 [14~22] and 13 [11~13] dpi, p=0.029). [Figure 3]Figure 3 is a graph showing the dynamics of viral replication throughout the entire treatment period and after discontinuation of treatment. All animals from Group I were virus-free in plasma during the 12-month treatment period and remained nonviral (including transient depletion of CD8-positive cells from blood) after discontinuation of treatment and during the 22-month (months 12-34) follow-up period. Similarly, all animals from Group II were virus-free during the 4-month treatment period and remained nonviral (including transient depletion of CD8-positive cells from blood) after discontinuation of treatment and during the 16-month (months 4-20) follow-up period. [Figure 4] Figure 4 is a graph showing plasma CAB and RPV concentrations throughout the entire treatment period and after discontinuation of treatment. After the final dose, CAB and RPV concentrations decreased to undetectable levels over a period of 4–7 months. No viral rebound was observed during this drug tail and for the following 4–5 months. [Figure 5] Figures 5 and 6 are graphs showing antibody responses to p66, gp130, gp41, nef, gp36, g p140, and p27. In the untreated control, serological responses were observed for all panels tested. In contrast, responses in groups I (Figure 5) and II (Figure 6) were mainly limited to gp140, although the rate of expression differed (14 [14-17] days and 36.5 [33-40] days post-infection, respectively, p=0.029). [Figure 6] Figures 5 and 6 are graphs showing antibody responses to p66, gp130, gp41, nef, gp36, g p140, and p27. In the untreated control, serological responses were observed for all panels tested. In contrast, responses in groups I (Figure 5) and II (Figure 6) were mainly limited to gp140, although the rate of expression differed (14 [14-17] days and 36.5 [33-40] days post-infection, respectively, p=0.029). [Modes for carrying out the invention] 【0015】 definition As used herein, “pharmaceutical composition (singular)” or “pharmaceutical composition (plural)” refers to the combinations described herein and at least one pharmacovigilant carrier or adjuvant. The term “pharmacovigilant carrier or adjuvant” refers to a carrier or adjuvant that can be administered to a patient together with the combinations of the present invention, and which does not destroy its pharmacological activity and is non-toxic when administered in a dose sufficient to deliver a therapeutic dose of the antiviral agent. 【0016】 Examples of pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, oral, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and intravitreal) administration. The compositions may, for convenience, be provided in unit dosage forms and may be prepared by any method well known in the art of pharmaceuticals. Such methods represent a further feature of the present invention and include the step of compounding the active ingredient with the carrier (which constitutes one or more incidental components). Generally, the compositions are prepared by uniformly and closely compounding the active ingredient with a liquid carrier, a pulverized solid carrier, or both, and then, if necessary, shaping the product. The present invention further comprises the pharmaceutical compositions defined above, wherein the compounds of the present invention or pharmaceutically acceptable derivatives thereof and other therapeutic agents are provided separately from each other as kits of components. 【0017】 In one particular embodiment, the exemplary pharmaceutical composition is suitable for parenteral administration and comprises an aqueous or non-aqueous isotonic sterile injection solution (which may contain antioxidants, buffers, bacteriostatic agents, and solutes to make the pharmaceutical composition isotonic with the blood of the recipient to whom it is intended); an aqueous or non-aqueous sterile suspension (which may contain suspending agents and thickeners); and liposomes or other microparticle systems (which are designed to target the compound to blood components or one or more organs). The pharmaceutical composition may be supplied in single-dose or multi-dose sealed containers, e.g., ampoules and vials, and may be stored in a lyophilized state, requiring only the addition of the sterile liquid carrier (e.g., water for injection) immediately before use. Injection solutions and suspensions prepared on the spot may be prepared from the sterile powders, granules, and tablets of the types already described. Unit dose pharmaceutical formulations contain, as described above, a daily dose or a divided daily dose of the active ingredient, or appropriately divided portions thereof. 【0018】 As used herein, “patient” or “subject” means mammal, including human and non-human mammals. 【0019】 As used herein, “treating” a disease in a patient or “treatment” a disease means 1) preventing the onset of the disease in a patient who is susceptible to the disease or who has not yet exhibited symptoms of the disease; 2) suppressing the disease or preventing its development; or 3) improving or regressing the disease. 【0020】 Accordingly, in one embodiment, a method is provided for treating HIV infection in a subject, comprising administering the combination described herein, or a pharmaceutically acceptable salt thereof, to the subject. In another embodiment, a combination for use in the treatment of HIV infection is also provided. In yet another embodiment, the use of the combination in the manufacture of therapeutic agents for treating HIV infection is also provided. 【0021】 Thus, in one aspect, provided is a method for preventing HIV infection in a subject, comprising administering to the subject a combination described herein, or a pharmaceutically acceptable salt thereof. Also, in another aspect, provided is a combination for use in preventing HIV infection. Also, in another aspect, provided is the use of the combination in the manufacture of a therapeutic agent for preventing HIV infection. 【0022】 As used herein, "latency" refers to 1) a dormant state of viral activity within a cell population (where viral production, viral packaging, and host cell lysis do not occur or occur very infrequently), or 2) a concept for representing downregulation or absence of gene expression within infected cells. As used herein, "reactivating HIV latent infection" refers to a treatment that upregulates the expression of the integrated HIV genome within latently infected cells (e.g., as a non-limiting example, a compound that can activate the non-canonical NF-κB pathway, which renders the infected cells sensitive to virus-induced cell death or immune clearance). As used herein, "eliminating HIV latent infection" refers to the elimination of HIV latently infected cells that can occur as a result of reactivation of HIV latency by an agent such as a drug that activates the non-canonical NF-κB pathway. 【0023】 Thus, in one aspect, the present invention provides a method for eliminating HIV latently infected cells, comprising administering to the subject a combination described herein, or a pharmaceutically acceptable salt thereof. Also, in another aspect, provided is a combination for use in eliminating HIV latently infected cells. Also, in another aspect, provided is the use of the combination in the manufacture of a therapeutic agent for treating HIV infection. 【0024】 As used herein, "virological remission" or "functional cure" refers to the eradication, suspension, cessation or termination of the human immunodeficiency virus or symptoms, or the progression of said symptoms or virus, over a predetermined period. By way of example, in one embodiment, "virological remission" or "functional cure" refers to a therapeutic combination of administration that, alone or in combination with one or more other compounds, induces sustained viral control of the human immunodeficiency virus (e.g., a level of viral load in plasma that is undetectable (collectively, "undetectable") by polymerase chain reaction (PCR) testing, branched DNA (bDNA) testing or nucleic acid sequence based amplification (NASBA) testing) and maintains it for at least 3 months without any other therapeutic intervention. The above PCR, bDNA and NASBA tests are well known and commonly used techniques by those skilled in the art. As another example, in one embodiment, "virological remission" or "functional cure" refers to a therapeutic combination of administration that, alone or in combination with one or more other compounds, induces and maintains sustained viral control (defined as maintaining less than 50 copies / ml of HIV viral RNA determined by appropriate testing and maintaining it for at least 3 months without any other therapeutic intervention). 【0025】 In another embodiment, the virus is undetectable for at least 6 months without any other therapeutic intervention. Alternatively, in another embodiment, the virus is undetectable for 12 or 18 months without any other therapeutic intervention. In another embodiment, the virus is undetectable for a period up to 2 years without any other therapeutic intervention. 【0026】 In another embodiment, the viral load is maintained at less than 50 copies / ml for at least 6 months without any other therapeutic intervention. Alternatively, in another embodiment, the viral load is maintained at less than 50 copies / ml for at least 12 or 18 months without any other therapeutic intervention. In yet another embodiment, the viral load is maintained at less than 50 copies / ml for a period of up to 2 years without any other therapeutic intervention. 【0027】 As used herein, “cure” or “curing” a disease in a patient is used to mean the eradication, cessation, suspension, or termination of human immunodeficiency virus or symptoms, or the progression of symptoms or the virus, over a specified period of time. For example, in one embodiment, “cure” or “curing” refers to a therapeutic combination of administrations, either alone or in combination with one or more other compounds, that induces and maintains sustained control of human immunodeficiency virus (e.g., a plasma viral load undetectable by polymerase chain reaction (PCR) testing, bDNA (branched-strand DNA) testing, or NASBA (nucleic acid sequence-based amplification) testing) for at least two years without any other therapeutic intervention. The PCR, bDNA, and NASBA tests described above are performed using techniques well known and commonly used by those skilled in the art. For example, the eradication, cessation, suspension, or termination of human immunodeficiency virus or symptoms, or the progression of symptoms or the virus, may last for at least two years. 【0028】 Accordingly, in one embodiment, the present invention provides a method for curing HIV infection in a subject, comprising administering the combination described herein to the subject. In another embodiment, the combination for use in curing HIV infection is also provided. In yet another embodiment, the use of the combination in the manufacture of therapeutic agents for curing HIV infection is also provided. 【0029】 Early antiretroviral therapy, or eART, is a method of improving clinical outcomes by initiating antiretroviral therapy early enough after HIV infection to reduce the opportunity for the virus to establish the size and diversity of the viral reservoir. Established benefits of eART also include limited immune system impairment and a delay in the time to viral rebound. The viral reservoir contains latent infected cells and viruses within immune-privileged tissue sites that are highly resistant (if not completely) to clearance by concomitant antiretroviral therapy (cART) or any innate immune mechanisms (Okoye et al., Nat Med. 2018 September;24(9):1430-1440). According to one embodiment, eART is characterized by the number of CD4 cells per cubic millimeter (ml) of the individual remaining immediately before the initiation of ART. According to another embodiment, eART is simply characterized by the delay time between HIV exposure and the initiation of ART. 【0030】 "Antiretroviral therapy" or "ART" is a treatment for HIV infection that involves administering at least one antiretroviral agent (e.g., one, two, three, or four antiretroviral agents) to an HIV-infected (or HIV-exposed) individual during the course of treatment. 【0031】 Early antiretroviral therapy (eART) In some embodiments, one or more antiretroviral agents are administered to or co-administered to a subject within a specific time point, for example, 12 hours, 24 hours, 48 ​​hours, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. 【0032】 In some embodiments, one or more antiretroviral agents are administered or co-administered to the subject before CD4+ cell depletion. For example, eART may be initiated when the subject's CD4+ cell / ml is >500. eART may be initiated when the subject's CD4+ cell / ml is >350. eART may be initiated when the subject's CD4+ cell / ml is >200. 【0033】 In one embodiment, eART includes a combination regimen of cabotegravir and rilpivirine. The patient may be administered according to the current clinical regimen specified for the use of the ART agent. For example, the patient may be administered 30 mg of oral cabotegravir and 25 mg of rilpivirine once daily during the induction period (e.g., the first four weeks). Alternatively, initially, or after the induction period, the patient may receive an initial dose of 600 mg of cabotegravir and 900 mg of rilpivirine (3 ml injection of each drug) by IM injection, and then every four or eight weeks until ART treatment is discontinued, 400 mg of cabotegravir and 600 mg of rilpivirine (2 ml injection of each drug) by injection. Naturally, the cabotegravir and rilpivirine ART regimen may be adjusted by body weight or otherwise reasonably adjusted to be clinically appropriate. 【0034】 In another embodiment, the cabotegravir and rilpivirine eART identified above is administered in combination with one or more additional antiretroviral agents. The purpose of the one or more additional antiretroviral agents is to ensure complete initial suppression of the HIV virus immediately after initiating eART treatment. Appropriate additional agents may include NRTIs and / or NtRTIs. 【0035】 In order to be incorporated into viral DNA, nucleoside analog reverse transcriptase inhibitors (NRTIs) must be activated within the cell by the addition of a phosphate group to the deoxyribose moiety, forming the NRTI triphosphate. This phosphorylation process is carried out by cell kinase enzymes. Examples of NRTIs include zidovudine, didanosine, zalcitabine, stabudine, lamivudine, abacavir, and emtricitabine (also known as FTC). 【0036】 Nucleotide analog reverse transcriptase inhibitors (NtRTIs), also known as NTARTs and NtRTIs, are nucleotide analogs of cytidine, guanosine, thymidine, and adenosine that are useful in treating HIV infection. For example, tenofovir (including the prodrugs TDF and TAF) is an NtRTI adenosine analog. 【0037】 According to one embodiment, eART includes treatment with cabotegravir and rilpivirine in combination with FTC and TAF. According to another embodiment, eART includes treatment with cabotegravir and rilpivirine in combination with FTC and TAF, which are administered as 200 mg / day of FTC and 10 mg / day of TAF during the period of eART. 【0038】 TLR modulator A "TLR modulator" is a drug that functionally interacts with TLRs expressed in mammalian cells (e.g., human cells). In some embodiments, the modulator is a TLR agonist. In some embodiments, the modulator is a TLR antagonist. In some embodiments, the modulator is a drug selective for TLR7. In some embodiments, the modulator is a drug selective for TLR7 and one or more TLRs (e.g., TLR8). 【0039】 TLR Agonist The term "TLR agonist" refers to a drug that binds to and activates TLRs expressed in mammalian cells (e.g., human cells). In some embodiments, TLR agonists bind to and activate TLR7. Non-limiting examples of TLR agonists include Bhardwaj et al., Cancer J.16(4):382-391, 2010; Meyer et al., Exp. Opin. Investig. Drugs 17(7):1051-1065, 2008; Adams, Immunotherapy 1(6):949-964, 2009; Hennessy et al., Nat. Rev. Drugs Discov.9:293-307,2010; and US Patent No. 7,498,409; US Patent No. 9,421,254; US Patent No. 8,409,813; US Patent No. 8,361,98 No. 6; No. 8,795,678; No. 8,728,486; No. 8,636,979; No. 8,999,946; No. 9,359,360; No. 9,050,37 This is described in No. 6; and Nos. 9,556,167; US2014 / 0322271; US2016 / 0206690; US2009 / 0253622; US2011 / 0135669; US2011 / 0250175; US2014 / 0220074; and US2012 / 0219615 (each of which is incorporated herein in whole). In some embodiments, the TLR agonist is a peptide or a fusion protein (Huleatt et al., Vaccine 25:763-775, 2007). 【0040】 In some embodiments, TLR agonists are administered in combination with other compositions (Dowling et al., Clin. Transl. Immunol. 5:e85, 2016). In some embodiments, TLR agonists are endogenous molecules released from dead cells (e.g., heat shock proteins (HSPs) and mobility group box 1 (HMGB1); Asea et al., J. Biol. Chem. 277:15028-15034, 2002; Kepp et al., Cancer Metastasis 30:61-69, 2011). 【0041】 TLR7 Agonist In some embodiments, the TLR agonist is besatrimod (formerly known as GS-9620). In some embodiments, the TLR agonist is ANA975 (isotorabine) (Anadys / Novartis) or ANA773 (Anadys / Novartis). In some embodiments, the TLR7 agonist is imidazoquinoline or its variant (e.g., imiquimod (Aldara® trademark); Kaspari et al., British J. Dermatology 147:757-759, 2002; Smorlesi et al., Gene Therapy 12:1324-133, 2005; Prins et al., J. Immunol. 176:157-164, 2006; Shackleton et al., Cancer These include Immun. 4:9, 2004; Green et al., Br. J. Dermatol. 156(2):337-345, 2007; Geisse et al., Am. Acad. Dermatol. 50(5):722-733, 2004; Wolf et al., Arch. Dermatol. 139(3):273-276, 2003, and resikimod (R848; Hemmi et al., Nat. Immunol. 3:196-200, 2002; Jurk et al., Nat. Immunol. 3:49, 2002; Rook et al., Blood 126(12):1452-1461, 2015; Dovedi et al., Blood 121:251-259, 2013). In some embodiments, the TLR agonist is a synthetic imidazoquinoline or a variant thereof that mimics viral single-stranded RNA (ssRNA) (852A) (Dudek et al., Clin. Cancer Res. 13(23):7119-7125, 2007; Dummer et al., Clin. Cancer Res. 14(3):856-864, 2008; Weigel et al., Am. J. Hematol. 87(10):953-956, 2012; Geller et al., Cancer Immunol. Immunother. 59(12):1877-1884, 2010; Inglefield et al., J. Interferon Cytokine Res. 28(4):253-263, 2008). In some embodiments, the TLR agonist is a small molecule.In some embodiments, the small molecule mimics viral ssRNA (e.g., motolimod (VTX-2337)) or a variant thereof (Dietsch et al., Clin. Cancer Res. 21(24):5445-5452, 2015; Northfelt et al., Clin. Cancer Res. 20(14):3683-3691, 2014; Lu et al., Clin. Cancer Res. 18(2):499-509, 2012). In some embodiments, the small molecule is GS-9620 or a variant thereof (Bam et al., Antimicrob Agents Chemother. 61(1):e01369, 2016; Rebbapragada et al., PLoS One 11(1):e0146835, 2016; Gane et al., J. Hepatol. 63(2):320-328, 2015; Fosdick et al., J. Med. Chem. 56(18):7324-7333, 2013). In some embodiments, the small molecule is SC1 (Wiedemann et al., Oncoimmunology 5(7):e1189051, 2016; Hamm et al., J. Immunol. 6(4):257-265, 2009).In some embodiments, the small molecule is gardikimod (Ma et al., Cell.Mol.Immunol.7:381-388, 2010; Hjelm et al., Hum.Vaccin.Immunother.10(2):410-416, 2014; Buitendijk et al., AIDS Res.Hum.Retroviruses 29(6):907-918, 2013), CL075 (Philbin et al., J.Allergy Clin.Immunol.130:195-204, 2012; Dowling et al., PLoS One) 8(3):e58164,2013), CL097 (Gorden et al., J.Immunol.174:1259-1268,2005; Gorski et al., Int.Immunol.18:1115,2006; Levy et al., Blood 108:1284-1289,2006; Wille-Reece et al., J.Exp.Med.203:1249-1258,2006), loxoribine (Pope et al., Cell Immunol.162:333,1995; Heil et al., Eur.J.Immunol.33:2987-2997,2003; Lee et al., PNAS 100:6646-6651,2003), or VTX-294 (Dowling et al., PLoS One) 8(3):e58164,2013). In some embodiments, the TLR7 agonist is IMO-9200. In some embodiments, the TLR7 agonist is IPH-32XX (Innate Pharma). 【0042】 According to another embodiment, a method for achieving HIV virus remission further comprises the administration of a latent infection reactivator. In one embodiment, the latent infection reactivator is a TLR7 agonist. An exemplary TLR7 agonist is besatrimod. [Examples] 【0043】 The inventors investigated the dynamics of viral suppression after early initiation of treatment with combinations of CAB-LA, RPV-LA, FTC, and TAF, with or without the immunomodulatory agent VES, in eight rhesus monkeys, and determined the dynamics of viral rebound after discontinuation of treatment. The inventors demonstrated that there was no permanent viral rebound in all eight monkeys. Previous studies in similar rhesus monkey models of early treatment with suppressive antiretroviral regimens, including daily administration of drugs such as tenofovir, emtricitabine, and dolutegravir, have resulted in little to no remission (Okoye et al., Nat Med 2018; Whitney et al., Nature 2014; Whitney et al., Nat Comm 2018; Namazi et al., J Infec Dis 2018). Therefore, the regimens and methods described herein, including long-acting ARVs, have superior remission-inducing ability. This potent regimen includes long-acting ARV drugs that provide prolonged antiviral activity and may be able to induce a chemovagal effect after treatment discontinuation. 【0044】 Example 1 Antiretroviral drug administration CAB LA at 50 mg / kg and RPV at 200 mg / kg were administered intramuscularly once a month. As a result of these administrations, plasma CAB and RPV concentrations were well above the respective protein regulatory concentrations required for 90% viral inhibition (0.166 μg / ml and 12 ng / ml), and within the concentration range observed in humans (Andrews et al., Science 2014; Melody et al., AAC 2015). TAF (1.5 mg / kg) and FTC (20 mg / kg) were administered once daily with feed, except for subcutaneous administration on the day of sample collection or if the animals did not eat the total oral dose. As a result of FTC and TAF administration, plasma and intracellular drug concentrations were within the concentration range achieved in humans (Massud et al., J Infect Dis 2016). 【0045】 Example 2 Viral vaccination and treatment regimens Rhesus monkeys were infected with a chimeric RT-SHIV isolate containing the reverse transcriptase of HIV-1 clone HXBc2 in a SIVmac239 background. RT-SHIV contained a T-to-C substitution at position 8 of the SIV tRNA primer binding site that increased pathogenicity (Soderberg et al., 2002) and was obtained from the National Institutes of Health (NIH) AIDS Research and Reference Reagent Program. Rhesus monkeys received a single intrarectal dose of RT-SHIV (10 3.3 The animals were infected with TCID50). Blood samples were collected over an extended period to monitor infection status and drug concentrations. Figure 1 shows the study design and the treatments evaluated in each group of animals. Rhesus monkeys in Group I (n=4) were treated with CAB-LA / RPV-LA / FTC / TAF on post-infection days 5 / 6. Treatment with CAB-LA / RPV-LA / FTC / TAF continued for 6 months, followed by a simplified regimen of CAB LA / RPV LA for another 6 months. All treatments were discontinued at 12 months. Rhesus monkeys in Group II (n=4) were treated with CAB-LA / RPV-LA / FTC / TAF on post-infection days 6 / 8, and then weekly VES treatment was started on days 8-11. VES treatment was discontinued at 3 months, and CAB-LA / RPV-LA / FTC / TAF was discontinued at 4 months. Group III (n=2) rhesus monkeys were untreated controls. SHIV RNA in plasma was monitored by RT-PCR assay with a limit of 12.5 RNA copies / ml (plasma). 【0046】 Example 3 Dynamics of acute SHIV infection Figure 2 shows that in all eight animals in the treatment group, plasma SHIV RNA rapidly became undetectable within 20–25 days of infection. Peak SHIV RNA concentrations were similar in animals in groups I and II (3.4 [range = 2.7–4.3] and 4.2 [3.7–4.4] log10 RNA copies / ml, p = 0.111), and were lower than those in the untreated control group (6.8–7.0 log10 RNA copies / ml). Viral replication from the start of treatment to viral suppression, as indicated by the area under the curve (AUC), was also similar in animals in group 1 and group 2 (AUC = 42.6 [31.6~59.7] and 45.0 [38.4~51.07] RNA copies / ml / day, p = 0.886), but replication was suppressed more rapidly in animals in group II (18 [14~22] vs. 13 [11~13] dpi, p = 0.029). Therefore, regimens including CAB-LA / RPV-LA / FTC / TAF, with or without VES, were able to rapidly suppress viral replication within 3-4 weeks of treatment. 【0047】 Example 4 Infection outcomes during long-term treatment and after treatment discontinuation Plasma SHIV RNA concentrations were monitored weekly or bi-weekly throughout all treatment phases of the study, and remained below the detection limit of the assay in all eight treated animals from groups I and II at all time points tested (Figure 3). Plasma samples were also collected 24 hours after weekly VES administration during the 3-month VES treatment of animals in group II, but no viral peaks were detected in any rhesus monkey at any time point tested. 【0048】 Treatment with CAB-LA / RPV-LA / FTC / TAF was discontinued at 12 months in animals in Group I. Figure 3 shows that plasma SHIV RNA levels remained undetectable in all four animals 22 months after treatment discontinuation, despite transient depletion of CD8-positive cells from the blood. Treatment with VES was discontinued at 3 months in animals in Group II, and treatment with CAB-LA / RPV-LA / FTC / TAF was discontinued 1 month later. Figure 3 shows that plasma SHIV RNA levels remained undetectable in all four animals 16 months after the end of treatment, with the exception of one animal which showed a transient peak at 5 months. Transient depletion of CD8-positive cells in these animals did not lead to a sustained viral rebound. 【0049】 Example 5 Concentrations of CAB and RPV in plasma Plasma concentrations of CAB and RPV were measured using LC-MS with a limit of quantification (lower limit) of 10 ng / ml. Figure 5 shows the plasma concentrations of CAB and RPV throughout the entire treatment period and after the final dose. CAB and RPV concentrations were still detectable in plasma 4–7 months after the final dose, clearly indicating that these two antiviral agents persist for several months after treatment discontinuation. Therefore, the long-term persistence of CAB and RPV in plasma after treatment discontinuation was associated with viral remission and chemovagal efficacy. 【0050】 Example 6 Virus-specific antibody response Antibody responses to p66, gp130, gp41, nef, gp36, gp140, and p27 were measured using the SIV / HIV Bio-Plex assay. In untreated controls from Group III onward, serological responses were observed for all panels tested. In contrast, in Groups I and II, responses were limited to gp140, although the rate of expression differed (14 [14–17] days and 36.5 [33–40] days post-infection, respectively, p=0.029) (Figures 5 and 6). 【0051】 Summary of Examples Background: Early antiretroviral therapy (eART) protects immune function and limits viral diversification, but is not curative in humans due to rapid viral reservoir establishment. We modeled the effects of potent eART regimens [emtricitabine and long-acting cabotegravir / rilpivirine (CAB-LA / RPV-LA)] with and without the TLR7 agonist besatrimod (VES) in rhesus monkeys. 【0052】 Methods: Eight rhesus macaques infected rectally with RT-SHIV were treated with human equivalent doses of oral FTC / TAF (20 and 1.5 mg / kg, once daily) and intramuscular CAB-LA / RPV-LA (50 and 200 mg / kg, once monthly) at 6 days post-infection (dpi) (range = 5-8 days). Group I (n=4) was treated for 12 months. Group II (n=4) was treated for 4 months and also received VES (0.15 mg / kg) once weekly. Two untreated animals were used as controls. Plasma viral load was monitored by RT-PCR (limit of quantification = 50 copies). Antibody responses to p66, gp130, gp41, nef, gp36, gp140, and p27 were measured using the SIV / HIV Bio-Plex assay. The Wilcoxon rank-sum test was used to compare medians. 【0053】 Results: Peak serum viral loads were similar in the eART-only group and the eART+VES group (3.4 [range = 2.7~4.3] and 4.2 [3.7~4.4] log10 RNA copies / ml, p = 0.111), and lower than in the untreated control (6.8~7.0 log10 RNA copies / ml). Viral replication from the start of treatment to viral suppression was similar in eART-only animals and eART+VES animals (AUC = 42.6 [31.6~59.7] and 45.0 [38.4~51.07] RNA copies / ml / day, p = 0.886), but eART+VES suppressed replication more quickly (18 [14~22] and 13 [11~13] dpi, p = 0.029). Viral loads in the blood of all rhesus monkeys from the eART-alone group were undetectable during treatment and remained nonviral 10 months after treatment discontinuation. In the untreated controls, a serological response was observed in all panels tested. In contrast, in the eART and eART+VES groups, the response was limited to gp140, although the rate of expression differed (14[14-17] and 36.5[33-40] post-infection, respectively, p=0.029). The eART-VES animals have currently had treatment discontinued. 【0054】 Conclusion: Using a suitable rhesus monkey model of mucosal infection, we demonstrate that potent early ART leads to long-lasting viral control after treatment discontinuation. Serological responses (limited to gp140) are consistent with effective viral control. The combination of eART and VES rapidly suppresses blood viral load and also delays the serological response. Further characterization of immune function and viral dynamics would shed light on the immunomodulatory effects of VES during acute infection. The present invention encompasses the following embodiments. [1] A method for achieving HIV virus remission in a patient in need thereof, comprising the steps of administering to the patient early antiretroviral therapy (eART) of a therapeutically effective dose of cabotegravir and rilpivirine long-acting antiretroviral agents after the patient's exposure to the HIV virus, and discontinuing the early antiretroviral therapy after the suppression of the HIV virus by eART. [2] The method according to [1], wherein the early antiretroviral therapy is initiated within two weeks after the patient's exposure to the HIV virus. [3] The method according to [1], wherein the early antiretroviral therapy is initiated while the patient's CD4+ cells / ml is >500. [4] The method according to [1], further comprising administering one or more additional antiretroviral agents as early antiretroviral therapy. [5] The method according to which the one or more antiretroviral agents comprises emtricitabine (FTC) and / or tenofovir or a prodrug thereof. [6] The method according to [4], further comprising administering an early antiretroviral therapy to the patient. [7] The method according to [6], wherein the latent infection reactivator is a TLR7 agonist. [8] The method according to [7], wherein the TLR7 agonist is besatrimod. [9] Cabotegravir and rilpivirine long-acting antiretroviral agents for use as early antiretroviral therapy (eART) to achieve HIV virus remission in patients who require it.

[10] The method according to [1], wherein the early antiretroviral therapy is initiated while the patient's CD4+ cells / ml are >350.

[11] The method according to [1], wherein the early antiretroviral therapy is initiated while the patient's CD4+ cells / ml are >200.

Claims

[Claim 1] A pharmaceutical composition for use in a method to achieve HIV remission in patients who require it, The aforementioned pharmaceutical composition comprises a therapeutically effective amount of cabotegravir and rilpivirine, a long-acting antiretroviral agent. The method comprises the steps of administering to the patient early antiretroviral therapy (eART) of a therapeutically effective dose of cabotegravir and rilpivirine, a long-acting antiretroviral agent, after the patient's exposure to the HIV virus, and The procedure includes discontinuing the early antiretroviral therapy after the suppression of the HIV virus by eART. The aforementioned early antiretroviral therapy is initiated within two weeks of the patient's exposure to the HIV virus. Pharmaceutical composition. [Claim 2] A pharmaceutical composition for use in a method to achieve HIV remission in patients who require it, The aforementioned pharmaceutical composition comprises a therapeutically effective amount of cabotegravir and rilpivirine, a long-acting antiretroviral agent. The method comprises the steps of administering to the patient early antiretroviral therapy (eART) of a therapeutically effective dose of cabotegravir and rilpivirine, a long-acting antiretroviral agent, after the patient's exposure to the HIV virus, and The procedure includes discontinuing the early antiretroviral therapy after the suppression of the HIV virus by eART. The aforementioned early antiretroviral therapy is initiated while the patient's CD4+ cells / ml are >500. Pharmaceutical composition. [Claim 3] The pharmaceutical composition according to claim 1 or 2, further comprising administering one or more additional antiretroviral agents as early antiretroviral therapy. [Claim 4] The pharmaceutical composition according to claim 3, wherein the one or more antiretroviral agents include emtricitabine (FTC) and / or tenofovir, tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF). [Claim 5] The pharmaceutical composition according to claim 3, further comprising administering a TLR7 agonist to the patient as early antiretroviral therapy. [Claim 6] The pharmaceutical composition according to claim 5, wherein the TLR7 agonist is besatrimod.

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