Regimens for treating HIV infections and aids

Abstract

To provide a combination for treating a virologically suppressed human immunodeficiency virus (HIV)-infected adult subject.SOLUTION: The invention provides a combination for treating a human immunodeficiency virus (HIV) infected adult subject who adhered to an at least 3-drug (3-drug+) AntiRetroviral Therapy (ART) regimen and is virologically suppressed, comprising a therapeutic dose of each of only 2 ARV drugs, the two ARV drugs being (1) dolutegravir (DTG) or a pharmaceutically acceptable salt thereof and (2) lamivudine (3TC) or a pharmaceutically acceptable salt thereof, where the combination is administered at a certain dosing interval.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] A method of treating human immunodeficiency virus (HIV) or AIDS in a human subject. [Background technology]

[0002] Human immunodeficiency virus ("HIV") infection and related diseases are a major global public health problem. Human immunodeficiency virus type 1 ("HIV-1") is a retrovirus that encodes three enzymes necessary for viral replication: reverse transcriptase, protease, and integrase. Drugs that target reverse transcriptase and protease are widely used and have shown efficacy, but their usefulness is limited by toxicity and the development of resistant strains, especially when used in combination (Palella et al., 1998 N. Engl. J. Med. 338:853-860; Richman, 2001 Nature 410:995-1001).

[0003] Antiretroviral therapy (ART) aims to maximally suppress HIV in HIV-infected individuals and halt the progression of HIV disease. Numerous clinical data sets have shown that HIV viral load (RNA levels) decreases after initiation of ART, and that reductions in HIV viral load are associated with a reduced risk of AIDS progression and / or AIDS-related death (Murray et al., "The use of plasma HIV RNA as a study endpoint in efficacy trials of antiretroviral drugs," 1999 AIDS 13(7):797-804; Marschner et al., "Use of changes in plasma levels of human immunodeficiency virus type 1 RNA to assess the clinical benefit of antiretroviral therapy," 1998 J Infect Dis. 177(1):40-47; Thiebaut et al., "Clinical progression of HIV-1 infection according to the viral response during the first year of antiretroviral treatment," 2000 AIDS 14(8):971-978). In light of these findings, HIV viral load testing is an established technique for determining treatment response, and in particular, a reduced HIV viral load is a recognized marker of positive treatment response (HIV Surrogate Marker Collaborative Group, Human immunodeficiency virus type 1 RNA level and CD4 count as prognostic markers and surrogate end points: a meta-analysis, 2000 AIDS Res Hum Retroviruses 16(12):1123-1133). A statistically significant change in viral load is a 3-fold change and a 0.5 log 10This is equivalent to a change in the number of copies / mL. Depending on the study or assay used, overall viral suppression is defined as a viral load below the level of detection, which is 20 to 75 copies of HIV RNA per milliliter (c / mL). Viral suppression may also be defined as an HIV RNA copy number of less than 50 copies per milliliter (<50 c / mL) (Damond et al., Human immunodeficiency virus type 1 (HIV-1) plasma load discrepancies between the Roche COBAS AMPLICOR HIV-1 MONITOR Version 1.5 and the Roche COBAS AmpliPrep / COBAS TaqMan HIV-1 assays, 2007 J Clin Microbiol. 45(10):3436-3438).

[0004] Treatment guidelines published by the U.S. Department of Health and Human Services stipulate that ART is recommended for all HIV-infected individuals (regardless of CD4 cell count) and that achieving viral suppression requires the use of combination therapy (two or more drugs from at least two drug classes) (PANEL ON ANTIRETROVIRAL GUIDELINES FOR ADULTS AND ADOLESCENTS: GUIDELINES FOR THE USE OF ANTIRETROVIRAL AGENTS IN HIV-1-INFECTED ADULTS AND ADOLESCENTS. Department of Health and Human Services. Section available at http: / / aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf. Accessed April 19, 2017). Indeed, the standard course of care for patients infected with HIV or diagnosed with AIDS is treatment with a combination of three or more antiretroviral (ARV) drugs ("combination antiretroviral therapy" (cART)). Often, this treatment utilizes two different antiretroviral agents (the "backbone"), each targeting HIV reverse transcriptase, and at least one additional antiretroviral agent (the "anchor") that is active against an HIV protease inhibitor, a non-nucleoside or non-nucleotide HIV inhibitor of reverse transcriptase, a nucleoside or nucleotide HIV inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, or a combination thereof.

[0005] Although ART substantially increases the life expectancy and quality of life of HIV-infected individuals, HIV infection requires lifelong treatment. This means that in order for HIV-infected individuals to achieve a life expectancy approaching that of those without HIV, they also begin to receive treatment for common non-HIV conditions, such as diabetes, cardiovascular disease, arthritis, osteoporosis, or other age-related conditions and diseases (Zhou et al., Total Daily Pill Burden in HIV-Infected Patients in the Southern United States, 2014 AIDS PATIENT CARE and STDs 28(6):311-317). This increased drug burden (for HIV patients who are also currently receiving medication for indications unrelated to HIV) increases the risk of drug-drug interactions and overlapping toxicities, not to mention increasing patient healthcare costs and medication burden (Zhou et al., AIDS PATIENT CARE and STDs 28(6):311-317). Furthermore, the increased complexity of drug therapy can affect treatment adherence and virologic suppression (Zhou et al., AIDS PATIENT CARE and STDs 28(6):311-317).

[0006] Various combinations of antiretroviral drugs have been developed for the treatment of HIV, including dual (two-ARV) combination therapy. However, previously developed dual-drug therapies rapidly led to HIV treatment failure due to the emergence of resistance-associated mutations and insufficient HIV suppression (Vella et al., The History of Antiretroviral Therapy and its Implementation in Resource-Limited Areas of the World, 2012 AIDS 26:1231-1241; Lolekha et al., Resistance to Dual Nucleoside Reverse-Transcriptase Inhibitors in Children Infected with HIV Class A / E, 2005 Clin. Infect. Dis 40(2):309-312). Indeed, two-drug HIV treatment regimens have been, and remain unpopular, at least in the field, because they are thought to pose a "higher risk of resistance" (Gilead HIV Drug Tops GSK Combo, But Rivalry 'Intense' With GSK Doublet, INVESTOR'S BUSINESS DAILY, February 14, 2017). However, it is generally accepted that, in terms of long-term toxicity, two-drug therapies are better than those containing three or more drugs. Summary of the Invention [Problem to be solved by the invention]

[0007] For at least the above reasons, there remains an unmet medical need to reduce the drug burden of patients infected with HIV or diagnosed with AIDS, particularly to treat patients infected with HIV or diagnosed with AIDS with fewer antiretroviral agents, for example, only two ARVs. Additionally, there remains an unmet medical need for effective two-ARV drug HIV treatment regimens. [Means for solving the problem]

[0008] The present invention provides methods and compositions for treating subjects infected with human immunodeficiency virus using only two ARVs.

[0009] The present invention provides a method of treating a virologically suppressed adult subject infected with human immunodeficiency virus (HIV) who is compliant with at least a triple (triple+) antiretroviral therapy (ART) regimen, comprising administering to the subject therapeutic doses of only two ARV drugs, each at a dosing interval, wherein the two ARV drugs are (1) dolutegravir (DTG) or a pharmaceutically acceptable salt thereof, and (2) lamivudine (3TC) or a pharmaceutically acceptable salt thereof.

[0010] The present invention provides a method of treating a virologically suppressed human immunodeficiency virus (HIV)-infected subject who is adhering to a triple-drug antiretroviral therapy (ART) regimen, comprising administering to the subject dolutegravir (DTG) or a pharmaceutically acceptable salt thereof, and lamivudine (3TC) or a pharmaceutically acceptable salt thereof, at a dosing interval that results in (i) a total daily dose of DTG or a pharmaceutically acceptable salt thereof between about 40 mg and about 60 mg, and (ii) a total daily dose of 3TC or a pharmaceutically acceptable salt thereof between about 200 mg and about 400 mg.

[0011] The present invention provides a method of treating human immunodeficiency virus (HIV) infection with only two ARV drugs, comprising administering a total daily dose of between about 40 mg and about 60 mg of dolutegravir (DTG) or a pharmaceutically acceptable salt thereof, and a total daily dose of between about 200 mg and about 400 mg of lamivudine (3TC) or a pharmaceutically acceptable salt thereof to an HIV-infected subject who is selected because (1) he / she is compliant with a two-drug regimen of DTG and 3TC, (2) he / she is virologically suppressed, or (3) he / she was virologically suppressed prior to (1) he / she was compliant with a three-drug plus antiretroviral therapy (ART) regimen.

[0012] The present invention provides a method for reducing the drug burden of a human immunodeficiency virus (HIV)-infected subject who is virologically suppressed on a triple-drug plus antiretroviral therapy (ART) regimen, comprising the step of administering to the subject multiple doses of a two-drug pharmaceutical composition with an interval between doses of between about 24 and about 48 hours, wherein the two-drug pharmaceutical composition comprises a therapeutic dose of dolutegravir (DTG) or a pharmaceutically acceptable salt thereof, and a therapeutic dose of lamivudine (3TC) or a pharmaceutically acceptable salt thereof.

[0013] The present invention provides a method of treating virologically suppressed human immunodeficiency virus (HIV)-infected subjects who are compliant with a triple-drug antiretroviral therapy (ART) regimen, comprising the steps of: (a) administering to the subjects once daily therapeutic doses of only two ARV drugs, wherein the two ARV drugs are (1) dolutegravir (DTG) or a pharmaceutically acceptable salt thereof, and (2) lamivudine (3TC) or a pharmaceutically acceptable salt thereof; (b) obtaining the number of HIV RNA copies per milliliter in a plasma sample taken from each of the subjects 21 to 27, 49 to 55, 77 to 83, 161 to 167, 245 to 251, 329 to 335, or 358 to 362 days after (a); and (c) administering another therapeutic dose of each of the two ARV drugs to subjects selected for having less than 50 HIV RNA copies per milliliter in a plasma sample.

[0014] In one embodiment, only two ARV drugs, each at a therapeutic dose, are administered to an infected subject with a dosing interval. In a further embodiment, the subject is an adult subject, e.g., an adult subject. In one embodiment of the present invention, the subject is virologically suppressed before the two ARV drugs are administered. In one embodiment of the present invention, the subject has adhered to at least a triple (triple+) antiretroviral therapy (ART) regimen before the administration of the two ARV drug composition of the present invention. In one embodiment, the subject has adhered to a triple+ART regimen for at least about 4 years, about 6 months, or about 3 months before the administration of the two ARV drugs of the present invention. In one embodiment, the subject is selected to not have chronic hepatitis B virus infection.

[0015] In one embodiment of the present invention, the triple-drug + ART regimen was a tenofovir alafenamide (TAF)-based (TAF3D+) regimen. The present invention provides that the TAF3D+ regimen included the administration of bictegravir or a pharmaceutically acceptable salt thereof, emtricitabine or a pharmaceutically acceptable salt thereof, and TAF or a pharmaceutically acceptable salt thereof. In one embodiment of the present invention, the triple-drug + ART regimen was a bictegravir-based regimen. In another embodiment, the triple-drug + ART regimen was a combination of a DTG regimen, an FTC regimen, and a TDF regimen.

[0016] In one embodiment, the two ARV drugs are (1) dolutegravir (DTG) or a pharmaceutically acceptable salt thereof, and (2) lamivudine (3TC) or a pharmaceutically acceptable salt thereof. The present invention provides that, prior to administration, the HIV is not partially or completely resistant to (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii). In one embodiment of the present invention, the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is between about 40 mg and about 60 mg. In a further embodiment, the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is about 50 mg. In one embodiment of the present invention, the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is between about 200 mg and about 400 mg. In a further embodiment, the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is about 300 mg. In one embodiment of the present invention, the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is between about 40 mg and about 60 mg, and the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is between about 200 mg and about 400 mg. In one embodiment of the present invention, the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is about 50 mg, and the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is about 300 mg. In one embodiment of the present invention, the administration interval results in (i) a total daily dose of DTG or a pharmaceutically acceptable salt thereof of about 50 mg, and (ii) a total daily dose of 3TC or a pharmaceutically acceptable salt thereof of about 300 mg. The present invention provides that the administration interval between therapeutic doses or total daily doses is between about 24 and about 48 hours. The present invention provides that DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof are administered once about every 24 hours. In one embodiment of the present invention, the administration interval is about 24 hours.

[0017] In one embodiment of the present invention, (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii) are administered orally or by injection. In one embodiment of the present invention, (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii) are in the form of a tablet or liquid formulation.

[0018] In one embodiment of the present invention, DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof are co-administered. In one embodiment of the present invention, one or more non-ARV drugs are co-administered. In one embodiment, one or more non-ARV drugs are co-administered.

[0019] In one embodiment of the invention, DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof are administered simultaneously with food intake, in some embodiments, the food has at least a moderate fat content.

[0020] In one embodiment of the present invention, DTG or a pharmaceutically acceptable salt thereof and / or 3TC or a pharmaceutically acceptable salt thereof are in a pharmaceutical composition. In one embodiment, DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof are both in a two-drug pharmaceutical composition. The two-drug pharmaceutical composition of the present invention may be in the form of a fixed-dose composition and / or a tablet or liquid formulation. The two-drug pharmaceutical composition of the present invention may be administered orally or by injection. The two-drug pharmaceutical composition of the present invention may further comprise one or more non-ARV drugs.

[0021] In one embodiment of the invention, after administration, HIV does not exhibit partial or complete resistance to (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii).

[0022] The present invention provides that after administration, the subject is virologically suppressed. In one embodiment, virological suppression consists of the subject having less than 50 copies of HIV RNA per milliliter of plasma (<50 c / mL).

[0023] In one embodiment of the invention, the subject is infected with human immunodeficiency virus type 1 (HIV-1).

[0024] The present invention provides a method for administering at least a 22nd therapeutic dose of a dual pharmaceutical composition to a subject infected with HIV, wherein the subject is virologically suppressed after administration of the 21st dose; administering at least a 50th therapeutic dose of a dual pharmaceutical composition to a subject infected with HIV, wherein the subject is virologically suppressed after administration of the 49th dose; administering at least a 78th therapeutic dose of a dual pharmaceutical composition to a subject infected with HIV-1, wherein the subject is virologically suppressed after administration of the 77th dose; and administering at least a 162nd therapeutic dose of a dual pharmaceutical composition to a subject infected with HIV. administering at least a 246th therapeutic dose of the dual pharmaceutical composition to the HIV-infected subject, wherein the subject is virologically suppressed after administration of the 245th dose; administering at least a 330th therapeutic dose of the dual pharmaceutical composition to the HIV-infected subject, wherein the subject is virologically suppressed after administration of the 329th dose; and administering at least a 358th therapeutic dose of the dual pharmaceutical composition to the HIV-infected subject, wherein the subject is virologically suppressed after administration of the 357th dose.

[0025] The present invention provides a two-drug pharmaceutical composition for use in treating human immunodeficiency virus (HIV) infection.

[0026] The present invention provides a two-drug pharmaceutical composition for use in treating a virologically suppressed human immunodeficiency virus (HIV) infected subject who is complying with a triple drug plus antiretroviral therapy (ART) regimen. The present invention provides a two-drug pharmaceutical composition for use in treating a virologically suppressed human immunodeficiency virus (HIV) infected subject who is complying with a triple drug plus antiretroviral therapy (ART) regimen.

[0027] The present invention provides a two-drug pharmaceutical composition for use in reducing the drug burden in a subject infected with human immunodeficiency virus (HIV) who is virologically suppressed on a triple-drug plus antiretroviral therapy (ART) regimen.

[0028] The present invention provides the use of a two-drug pharmaceutical composition for the treatment of human immunodeficiency virus (HIV) infection.

[0029] The present invention provides for the use of a two-drug pharmaceutical composition for treating a virologically suppressed human immunodeficiency virus (HIV) infected subject who is adhering to a triple-drug plus antiretroviral therapy (ART) regimen. The present invention provides for the use of a two-drug pharmaceutical composition in the treatment of a virologically suppressed human immunodeficiency virus (HIV) infected subject who is adhering to a triple-drug plus antiretroviral therapy (ART) regimen.

[0030] The present invention provides for the use of a two-drug pharmaceutical composition to reduce the drug burden of a human immunodeficiency virus (HIV) infected subject who is virologically suppressed on a triple-drug plus antiretroviral therapy (ART) regimen. [Brief explanation of the drawings]

[0031] [Figure 1] Non-inferior efficacy of dolutegravir (DTG) plus lamivudine (3TC) versus DTG plus tenofovir disoproxil fumarate / emtricitabine (TDF / FTC) fixed-dose combination in antiretroviral therapy - Treatment-naive HIV-1-infected adults - 48-week results DETAILED DESCRIPTION OF THE INVENTION

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, a limited number of exemplary methods and materials are described herein.

[0033] As used in this disclosure and the claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. That is, "a" means "one or more" unless otherwise indicated.

[0034] The term "and / or" as used in a phrase, e.g., "A and / or B," is intended to include "A and B," "A or B," "A," and "B." Similarly, the term "and / or" as used in a phrase, e.g., "A, B, and / or C," is intended to encompass each of the following specific expressions: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0035] Unless otherwise specified, all of the designations "A% to B%, "A to B%, "A% to B%, "A to B%, "A% to B%, "A% to B", "A% to B", and "A% to B" are given their ordinary and customary meaning. In some embodiments, these designations are synonymous.

[0036] The term "comprising" encompasses "including" and "consisting of," e.g., a composition "comprising" X may consist exclusively of X or may include additional items, e.g., X+Y. The terms "comprising" and "having," when used as transitional phrases herein, are open-ended, whereas the term "consisting of," when used as a transitional phrase herein, is closed (i.e., limited to what is listed, and does not include others).

[0037] Unless otherwise specified, methods that include mixing two or more components do not require any particular order of mixing. Thus, the components can be mixed in any order. If there are three components, two components can be combined with each other, and then the combination can be combined with a third component, etc. Similarly, method steps may be numbered (e.g., (1), (2), (3), etc., or (i), (ii), (iii)), but the numbering of the steps does not imply that the steps must be performed in that order (i.e., step 1, then step 2, then step 3, etc.). The word "then" may be used to specify the order of method steps.

[0038] "For example," "an example," "such as," and "eg" can be used interchangeably and are meant to refer to or relate to non-exhaustive examples.

[0039] "HIV" or "human immunodeficiency virus" means HIV-1 or HIV-2, respectively, or any mutant, group, clinical isolate, subtype, or clade thereof.

[0040] As used herein, "adult" means at least 18 years of age. Thus, the term "adult" can be used to refer to a subject who is at least 18 years of age.

[0041] As used herein, "subject(s)" or "human" or "human subject(s)" or "person(s)" is used to refer to Homo sapiens.

[0042] As used herein, "adhered" means to have complied with or previously complied with. For example, as used herein, "adhered to a therapeutic regimen" means that a subject complied with or complied with the therapeutic regimen (i.e., the subject received the prescribed doses at the prescribed dosing intervals). As used herein, a subject who is "adherent" to an ART regimen (e.g., a "triple-drug plus ART regimen" or a "triple-drug plus ARV regimen") and is "virologically suppressed" means that the subject is virologically suppressed as a result of complying with the prior ART regimen (e.g., virologically suppressed as a result of the triple-drug plus ARV regimen).

[0043] "ART experienced" or "antiretroviral therapy experienced" means in reference to a person who has been currently or recently treated with one or more antiretroviral agents used to treat HIV or AIDS.

[0044] As used herein, "antiretroviral drug" or "ARV drug" refers to a molecule or compound classified as an inhibitor of reverse transcriptase, protease, and / or integrase. The ARV drug of the present invention may be one or more types of reverse transcriptase, protease, and / or integrase inhibitor. For example, tenofovir alafenamide fumarate (TAF) is an "ARV drug" as used herein and has been evaluated for the treatment of both HIV infection and hepatitis B infection. Similarly, boceprevir is an "ARV drug" as used herein and has been evaluated for the treatment of hepatitis C. Similarly, atazanavir is an "ARV drug" as used herein and has been evaluated for the treatment of HIV. As used herein, ARV drugs include, for example, dolutegravir, lamivudine, bictegravir, emtricitabine, tenofovir alafenamide, rilpivirine, enofovir disoproxil fumarate, atazanavir, ritonavir, darunavir, efavirenz, etravirine, lopinavir, fosamprenavir, tenofovir, tipranavir, boceprevir, elvitegravir, raltegravir, abacavir, or pharmaceutically acceptable salts, hydrates, or solvates thereof. One embodiment of the present invention includes a first antiviral regimen comprising an integrase inhibitor, e.g., bictegravir, dolutegravir, elvitegravir, raltegravir; a composition comprising dolutegravir, abacavir, and 3TC (e.g., TRIUMEQ), or a composition comprising bictegravir, emtricitabine, and tenofovir alafenamide (“TAF”) (e.g., bictegravir (50 mg), emtricitabine (200 mg), and TAF (25 mg)).

[0045] As used herein, "non-ARV drug" or "non-ARV agent" refers to a biologically active or inactive component that is not an antiretroviral (ARV). In some embodiments of the present invention, the non-ARV agent is selected from the group consisting of a pharmacokinetic enhancer, an excipient, a multivitamin, clarithromycin, erythromycin, telithromycin, an antacid, a calcium supplement, an iron supplement, an H2 receptor antagonist, metformin, methadone, rifabutin, daclatasvir, ethinyl estradiol, midazolam, norelgestromin, carbamazepine, daclatasvir, ferrous fumarate, omeprazole, rednison, rifampin, or a combination thereof. In some embodiments, the antacid is an aluminum-containing antacid, a magnesium hydroxide-containing antacid, or a calcium carbonate-containing antacid. In some embodiments, the H2 receptor antagonist is famotidine, cimetidine, nizatidine, or ranitidine.

[0046] As used herein, an "at least triple antiretroviral therapy" regimen or a "triple plus ARV" regimen or a "triple plus ART" regimen refers to a regimen that includes the administration of at least three antiretroviral (ARV) drugs. In one embodiment of the present invention, the triple plus ART regimen includes the administration of at least three ARV drugs selected from the group consisting of dolutegravir, lamivudine, bictegravir, emtricitabine, tenofovir alafenamide, tenofovir disoproxil fumarate, rilpivirine, enofovir disoproxil fumarate, atazanavir, ritonavir, darunavir, efavirenz, etravirine, lopinavir, fosamprenavir, tenofovir, tipranavir, boceprevir, elvitegravir, raltegravir, abacavir, and pharmaceutically acceptable salts, hydrates, or solvates thereof. In one embodiment of the present invention, the triple-drug plus ART regimen comprises administering at least bictegravir, emtricitabine, and TAF. In one embodiment of the present invention, the triple-drug plus ART regimen comprises administering at least 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of TAF. In another embodiment of the present invention, the triple-drug plus ART regimen comprises administering at least 50 mg of dolutegravir, 300 mg of tenofovir disoproxil fumarate or 25 mg of tenofovir alafenamide, and 200 mg of emtricitabine.

[0047] One embodiment of the present invention is provided, which comprises switching from using an antiretroviral regimen comprising two NRTIs and one or more antiretroviral agents selected from the group consisting of an INI, an NNRTI, or a PI to using a two-ARV drug antiretroviral regimen. anti-HIV agents, HIV protease inhibitors, non-nucleoside or non-nucleotide HIV inhibitors of reverse transcriptase, nucleoside or nucleotide HIV inhibitors of reverse transcriptase, HIV integrase inhibitors, MK8591 (EFdA), bictegravir, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) or CD4 attachment inhibitors (e.g., combinectins), CXCR4 inhibitors, gp120 inhibitors, G6PD or NADH oxidase inhibitors, HIV vaccines, latent infection reactivators (e.g., histone deacetylase inhibitors, proteasome inhibitors, protein kinase C (PKC) activators, or BRD4 inhibitors), compounds targeting the HIV capsid ("capsid inhibitors", e.g., capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors, HIV p24 capsid protein inhibitors), pharmacokinetic enhancers, immune-based therapies (e.g., Pd-1 modulators, Pd-L1 modulators, CTLA4 modulators, ICOS modulators, OX40 modulators, etc.), toll-like receptor modulators, IL-15 agonists, anti-HIV antibodies, bispecific antibodies or "antibody-like" therapeutic proteins (e.g., DART, DUOBODY, BITE, XmAb, TandAb, Fab derivatives), including those targeting HIV gp120 or gp41, HIV combination drugs, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIVvif gene regulators, vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef regulators, Hck tyrosine kinase regulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, retrorocyclin regulators, CDK-9 inhibitors, dendritic ICAM-3-binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, HIV gene therapy, PI3K inhibitors, WO2013 / 006738 (Gilead Sciences), US2013 / 0165489 (University of Pennsylvania), WO2013 / 091096A1 (Boehringer Ingelheim), WO2009 / 062285 (Boehringer Ingelheim), US20140221380 (Japan Tobacco Inc.), US20140221378 (Japan Tobacco Inc.), WO2010 / 130034 (Boehringer Ingelheim), WO2013 / 159064 (Gilead Sciences), WO2012 / 145728 (Gilead Sciences), WO2012 / 003497 (Gilead Sciences), WO2014 / 100323 (Gilead Sciences), WO2012 / 145728 (Gilead Sciences), WO2013 / 159064 (Gilead Sciences), WO2012 / 003498 (Gilead Sciences), and WO2013 / 006792 (PharmaceuticalIn one embodiment of the present invention, the method comprises switching from using a combination comprising at least three antiviral compounds selected from the group consisting of compounds such as those disclosed in (R.I., "Antiviral Drugs"), ... and other drugs for treating HIV, to using a 2-ARV drug composition.

[0048] As used herein, "+" means "more than." For example, as used herein, a "3-drug plus ARV regimen" refers to an antiretroviral (ARV) regimen that utilizes three or more (+) different ARV drugs; thus, a "3-drug plus ARV regimen" encompasses regimens that utilize four, five, six, seven, eight, nine, ten, etc. different ARV drugs.

[0049] As used herein, a "dual pharmaceutical composition" refers to a pharmaceutical composition consisting of only two drugs. Similarly, as used herein, a "dual-ARV drug" composition refers to a composition consisting of only two antiretroviral (ARV) drugs, and does not include, for example, a composition consisting of one, three, four, five, six, seven, eight, nine, or ten (or any higher integer) ARV drugs. However, a dual-ARV drug composition may also contain one or more non-ARV drugs. For example, a "dual pharmaceutical composition" of the present invention "comprising a therapeutic dose of dolutegravir or a pharmaceutically acceptable salt thereof and a therapeutic dose of lamivudine or a pharmaceutically acceptable salt thereof" comprises (1) a therapeutic dose of dolutegravir or a pharmaceutically acceptable salt thereof, (2) a therapeutic dose of lamivudine or a pharmaceutically acceptable salt thereof, and, optionally, (3) one or more components that are not ARV drugs (which may be, for example, an excipient).

[0050] As used herein, "viral load" refers to the amount of virus in a referenced bodily fluid, usually expressed as a measure of viral particles (e.g., RNA copy number) per milliliter (mL). A statistically significant change in viral load is greater than 0.5 log 10 A change of 3 fold equates to a change in copies / mL.

[0051] As used herein, "virologically suppressed" or "viral suppression" means that the number of HIV ribonucleic acid (RNA) copies per milliliter (mL) (i.e., viral load) is below a given threshold. Viral suppression may be defined as a viral load below the level of detection, e.g., an HIV RNA copy number of less than 20-75 copies per milliliter (c / mL). The threshold may be defined, for example, as between 0-200 copies per mL, 20 copies per mL, 50 copies per mL, 100 copies per mL, or 200 copies per mL. In certain embodiments, the threshold may be defined as 50 copies per mL. Thus, viral suppression may be defined as an HIV RNA copy number per mL that is between 0-200 copies per mL, less than 20 copies per mL, 50 copies per mL, 100 copies per mL, or 200 copies per mL. In certain embodiments, viral suppression may be defined as an HIV RNA copy number per mL that is less than 50 copies per milliliter (<50 copies / mL). The HIV RNA copy number per mL can be determined using known techniques, including TaqMan 2.0 (Roche Diagnostics, Indianapolis, IN, USA) or ABBOTT REALTIME HIV-1 VIRAL LOAD (Abbott Molecular Inc, Des Plaines, IL, USA). In one embodiment, being virologically suppressed is defined as having an HIV copy number between 0 and 200 copies per mL, 20 copies per mL, 50 copies per mL, 100 copies per mL, or less than 200 copies per mL. As an embodiment of any copy number of the present invention, each integer copy number between each endpoint of the copy number range is also provided. For example, a copy number range of 20 copies per mL to 50 copies per mL may also include 21, 22, 23, and up to 49 copies per mL.

[0052] As used herein, "therapeutic dose" refers to a dose that, when administered according to a dosing interval, is effective in reducing viral load below a given threshold. In some embodiments, for example, a therapeutic dose of dolutegravir (DTG) is defined as about 40 milligrams (mg) to about 45 mg, about 40 mg to about 50 mg, about 40 mg to about 55 mg, about 40 mg to about 60 mg, about 45 mg to about 50 mg, about 45 mg to about 55 mg, about 45 mg to about 60 mg, about 50 mg to about 55 mg, about 50 mg to about 60 mg, or about 55 mg to about 60 mg. In certain embodiments, a therapeutic dose of the present invention is defined as about 50 mg. For example, about 50 mg of dolutegravir (DTG). In some embodiments, for example, a therapeutic dose of dolutegravir (DTG) is defined as between 40 milligrams (mg) and 45 mg (40-45 mg), between 40 mg and 50 mg (40-50 mg), between 40 mg and 55 mg (40-55 mg), between 40 mg and 60 mg (40-60 mg), between 45 mg and 50 mg (45-50 mg), between 45 mg and 55 mg (45-55 mg), between 45 mg and 60 mg (45-60 mg), between 50 mg and 55 mg (50-55 mg), between 50 mg and 60 mg (50-60 mg), or between 55 mg and 60 mg (55-60 mg). In certain embodiments, a therapeutic dose of the present invention is defined as 50 mg. For example, 50 mg of dolutegravir (DTG). Other therapeutic doses of dolutegravir can be determined or optimized using known pharmaceutical or clinical practice.

[0053] In some embodiments, for example, a therapeutic dose of lamivudine (3TC) is defined as about 200 mg to about 250 mg, about 200 mg to about 300 mg, about 200 mg to about 350 mg, about 200 mg to about 400 mg, about 250 mg to about 300 mg, about 250 mg to about 350 mg, about 250 mg to about 400 mg, about 300 mg to about 350 mg, about 300 mg to about 400 mg, or about 350 mg to about 400 mg. In certain embodiments, a therapeutic dose of the present invention is defined as about 300 mg. For example, about 300 mg of lamivudine (3TC). In some embodiments, for example, a therapeutic dose of lamivudine (3TC) is defined as between 200 mg and 250 mg (200-250 mg), between 200 mg and 300 mg (200-300 mg), between 200 mg and 350 mg (200-350 mg), between 200 mg and 400 mg (200-40 mg), between 250 mg and 300 mg (250-300 mg), between 250 mg and 350 mg (250-350 mg), between 250 mg and 400 mg (250-400 mg), between 300 mg and 350 mg (300-350 mg), between 300 mg and 400 mg (300-400 mg), or between 350 mg and 400 mg (350-400 mg). In certain embodiments, a therapeutic dose of the present invention is defined as 300 mg. For example, 300 mg of lamivudine (3TC). Unless otherwise stated, the term "between" herein includes the starting point and the endpoint. For example, "therapeutic dose between 40 mg and 60 mg" includes the therapeutic doses of 40 mg and 60 mg. "Exclusive" can be used to exclude the starting point and the endpoint. For example, "therapeutic dose between 40 mg and 60 mg (exclusive)" does not include the starting point of 40 mg or the endpoint of 60 mg. Other therapeutic doses of lamivudine can be determined or optimized using known pharmaceutical or clinical practice.

[0054] [Table 1]

[0055] [Table 2] TIFF2025128082000004.tif140165

[0056] The present invention provides for administering to subjects once daily therapeutic doses of only two ARV drugs; (b) obtaining the number of HIV RNA copies per milliliter in plasma samples taken from each of the subjects 21 to 27, 49 to 55, 77 to 83, 161 to 167, 245 to 251, 329 to 335, or 358 to 362 days after (a); and then (c) administering another therapeutic dose of each of the two ARV drugs to subjects selected for having less than 50 HIV RNA copies per milliliter in plasma samples. In one embodiment of the present invention, a plasma sample taken 21 days after the first administration means that a plasma sample may be taken on day 22 (a sample taken on the first day of the fourth week of treatment); thus, samples taken between 21 and 27 days after (a) are taken during the fourth week of treatment. In one embodiment of the present invention, a plasma sample collected 49 days after the first dose means that the plasma sample may be collected on day 50 (sample collected on the first day of week 8 of treatment), and therefore a sample collected between 49 and 55 days after (a) is collected during week 8 of treatment. In one embodiment of the present invention, a plasma sample collected 77 days after the first dose means that the plasma sample may be collected on day 78 (sample collected on the first day of week 12 of treatment), and therefore a sample collected between 77 and 83 days after (a) is collected during week 12 of treatment. In one embodiment of the present invention, a plasma sample collected 161 days after the first dose means that the plasma sample may be collected on day 162 (sample collected on the first day of week 24 of treatment), and therefore a sample collected between 161 and 167 days after (a) is collected during week 24 of treatment. In one embodiment of the invention, a plasma sample collected 245 days after the first dose means that the plasma sample may be collected on day 246 (sample collected on the first day of the 36th week of treatment), and therefore a sample collected between 245 and 251 days after (a) has been collected during the 36th week of treatment.In one embodiment of the invention, a plasma sample collected 329 days after the first dose means that the plasma sample may be collected on day 330 (sample collected on the first day of week 48 of treatment), and therefore a sample collected between 329 and 335 days after (a) has been collected during week 48 of treatment. In one embodiment of the invention, a plasma sample collected 358 days after the first dose means that the plasma sample may be collected on day 359 (sample collected on the first day of week 52 of treatment), and therefore a sample collected between 358 and 362 days after (a) has been collected during week 52 of treatment.

[0057] The invention provides for viral load to be assessed on day 22 of a once-daily treatment regimen (i.e., assessing viral load after administration of the 21st dose), optionally further providing for administering a 22nd therapeutic dose on day 22. The invention provides for viral load to be assessed on day 50 of a once-daily treatment regimen (i.e., assessing viral load after administration of the 49th dose), optionally further providing for administering a 50th therapeutic dose on day 50. The invention provides for viral load to be assessed on day 78 of a once-daily treatment regimen (i.e., assessing viral load after administration of the 77th dose), optionally further providing for administering a 78th therapeutic dose on day 78. The invention provides for viral load to be assessed on day 162 of a once-daily treatment regimen (i.e., assessing viral load after administration of the 161st dose), optionally further providing for administering a 162nd therapeutic dose on day 162. The invention provides that viral load is assessed on day 246 of the once-daily treatment regimen (i.e., assessing viral load after administration of dose 245), optionally further providing for administering a 246th therapeutic dose on day 246. The invention provides that viral load is assessed on day 330 of the once-daily treatment regimen (i.e., assessing viral load after administration of dose 329), optionally further providing for administering a 330th therapeutic dose on day 330. The invention provides that viral load is assessed on day 358 of the once-daily treatment regimen (i.e., assessing viral load after administration of dose 357), optionally further providing for administering a 358th therapeutic dose on day 358.

[0058] An "effective amount," e.g., a "therapeutically effective amount of an ARV drug," means an amount sufficient to produce a referenced effect or result. An "effective amount" can be determined empirically and routinely using known techniques relevant to the above purpose.

[0059] As used herein, a "fixed dose combination" or "fixed dose composition" means a combination of at least two active agents in a single dosage form and is defined according to its usage in the art: U.S. Food and Drug Administration, Industry Guidance Document entitled Fixed Dose Combination and Co-Packaged Drug Products for Treatment of HIV (May 2004); and Gautam and Saha (Fixed dose drug combinations (FDCs): rational or irrational: a view point, 2008 Br. J. Clin. Pharmacol. 65(5):795-796).

[0060] As used herein, "dosing interval" refers to the time between dose administrations (e.g., every 2 hours) or the frequency of dose administration over a particular period of time (e.g., twice daily). A "dosing interval" includes the first dose administration and therefore does not require at least two dose administrations to be performed. An interval of "0," e.g., a "dosing interval of 0 hours," can be used to clarify that the first dose administration is included. In one embodiment of the invention, the dosing interval is once every 6, 12, 18, 24, 30, 36, 42, or 48 hours. In one embodiment of the invention, the dosing interval is once every 24 hours. In one embodiment of the invention, the dosing interval is once every 48 hours. In one embodiment of the invention, the dosing interval is once every 24 to 48 hours.

[0061] As used herein, "co-administered" means that two or more referenced molecules, compounds, drugs, agents, etc. are administered at the same time, but not necessarily together in one composition. For example, in one embodiment of the present invention, two ARV drugs are administered at the same time (i.e., "co-administered"), but each is in a separate (distinct) pharmaceutical composition (i.e., not together). In one embodiment of the present invention, "co-administration" is defined as a time interval of 0 minutes.

[0062] "Concurrently" is used herein to indicate that the two activities can have different durations (i.e., one longer than the other) and that the two actions occur during overlapping periods. For example, a 2-ARV drug composition administered "concurrently with food intake" is administered to a subject at any time between the start of food intake or after the start of food intake and the end of food intake or before the end of food intake (i.e., the drug is administered during a meal).

[0063] As used herein, "sequential administration" or "adjacent administration" means that at least two of the two or more referenced molecules, compounds, drugs, agents, etc. are not administered simultaneously but are administered sequentially (one after the other). In one embodiment of the present invention, at least two of the two or more drugs or agents are administered sequentially within 12, 11.5, 11, 10.5, 10, 9.5, 9, 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5 hours of each other. In certain embodiments of the present invention, two ARV drugs are administered sequentially within one hour. In certain embodiments of the present invention, two ARV drugs are administered sequentially within 0.5 hours (i.e., 30 minutes). As used herein, "within" means, for example, that "within one hour" includes one hour and less than one hour.

[0064] As used herein, "dosing regimen" or "regimen" refers to the dose and dosing interval (i.e., the amount of a drug administered and the frequency of dosing, respectively). In some embodiments, "dosing regimen" can also refer to the formulation, route of administration, and / or duration of treatment.

[0065] As used herein, "multiple doses" is meant to encompass at least two doses, and thus, for example, 3, 4, 5, 6, 7, 8, 9, 10 (and any higher integer) doses.

[0066] As used herein, "total daily dose" refers to the total amount (e.g., in milligrams (mg)) of a referenced molecule, compound, drug, combination, or composition administered to a subject in one day (i.e., in a 24-hour period). "Total daily dose" encompasses any number of administrations. Thus, for example, a total daily dose of 50 mg of dolutegravir (DTG) administered at 24-hour dosing intervals encompasses both a single administration of 50 mg of DTG every 24 hours and two administrations of 25 mg each of DTG (total of 50 mg) within a 24-hour period, unless otherwise specified.

[0067] As used herein, "pharmaceutically acceptable" means capable of being administered to a subject without undesired physiological effects. For example, "pharmaceutically acceptable salts thereof" includes solvates, polymorphs, and / or salts of the referenced compound.

[0068] "About" or "approximately" means within the error range of the field, skill, or subject matter to which the reference is made. When the term "about" or "approximately" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values ​​set forth. For example, "between about 0.005 and 0.006 μM" means that the boundaries of the numerical range extend below 0.005 and above 0.006, such that the particular value in question achieves the same functional result as one within the range of 0.005 to 0.006 μM. For example, "about" and "approximately," as practiced in the art, can mean within 1 or more than 1 standard deviation. Alternatively, "about" and "approximately" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably up to 1% of a given value.

[0069] As used herein, "year" means a period of 365 days. As used herein, "leap year" means a period of 366 days. As used herein, "month" means a period of 30 days. As used herein, "calendar month" means one of January, February, March, April, May, June, July, August, September, October, November, and December (i.e., a "calendar month" is not limited by a period of 28, 29, 30, or 31 days). As used herein, "calendar year" means all of January, February, March, April, May, June, July, August, September, October, November, and December (i.e., 12 calendar months). As used herein, "week" means a period of 7 days. As used herein, "day" means a period of 24 hours. As used herein, "hour" means a period of 60 minutes.

[0070] "Biologic fluid" or "biological specimen" or "sample" is used herein broadly to refer to biological material from a subject, and includes, for example, blood (e.g., a blood sample), urine (e.g., a urine sample), blood plasma, cerebrospinal fluid, semen, synovial fluid, saliva, mucus, vaginal lubrication, amniotic fluid, tears, interstitial fluid, serum, breast milk, lymph, human stool, stomach acid, bile, pus, sputum, and earwax. As used herein, "plasma" refers to blood plasma.

[0071] As used herein, "moderate fat content" in a food comprising at least a "moderate fat content" means that about 30% of the food's total calories are from fat. As used herein, a "moderate fat diet" is a diet of about 600 kilocalories (kcal) with about 30% of calories from fat. As used herein, a "high fat content" in a food comprising at least a "high fat content" means that about 53% of the food's total calories are from fat. As used herein, a "high fat diet" is a diet of about 870 kilocalories (kcal) with about 53% of calories from fat. As used herein, a "low fat content" in a food comprising at least a "low fat content" means that about 7% of the food's total calories are from fat. As used herein, a "low-fat diet" is a diet of about 300 kilocalories (kcal) that contains about 7% of calories from fat (Song et al., Effect of Food on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir, 2012 Antimicrob. Agents Chemother. 56(3):1627-1629).

[0072] Also provided in one embodiment is a regimen of the invention or a composition of the invention administered to or used to treat an ART-experienced subject. Certain embodiments also provide that the subject is virologically suppressed.

[0073] The regimen of the invention or the composition of the invention is used to treat a subject infected with wild-type or mutant HIV, or a virus containing an HIV integrase homolog.

[0074] One embodiment of the present invention provides a composition of the invention administered to a subject infected with wild-type HIV-1 or HIV-2, HIV M clade (subtype) A, B, C, D, E, F, G, or H, or HIV group O virus.

[0075] Optionally, the subject is tested to assess the extent of renal dysfunction or skin or tissue damage. Optionally, the subject is selected to be free of chronic hepatitis B virus infection prior to administration of the 2-ARV drug pharmaceutical composition to the subject.

[0076] One embodiment of the present invention provides that (1) subjects co-infected with hepatitis C or hepatitis B and HIV are observed and determined to have a higher incidence of liver chemistry elevation (one stage) compared to (2) subjects not co-infected with either hepatitis virus, and that methods of treatment are provided by testing performed to determine HIV infection and hepatitis C and / or hepatitis B infection either before or during the regimen of the present invention.

[0077] A further embodiment provides for discontinuing use of the composition of the present invention if the subject develops a rash, atopic dermatitis, or diarrhea after administration of the composition of the present invention.

[0078] Resistant strains As used herein, a "partially resistant" strain is an HIV strain that contains one or more polynucleotide variants (e.g., mutations) that result in the reverse transcriptase, protease, and / or integrase of the HIV strain being only partially inhibited by the referenced ARV drug (i.e., the referenced ARV drug only partially inhibits the reverse transcriptase, protease, and / or integrase of the HIV strain). As used herein, a "fully resistant" strain is an HIV strain that contains one or more polynucleotide variants (e.g., mutations) that result in the reverse transcriptase, protease, and / or integrase of the HIV strain not being inhibited by the referenced ARV drug (i.e., the referenced ARV drug does not inhibit the reverse transcriptase, protease, and / or integrase of the HIV strain). Resistance can be determined using known techniques, including, for example, Sanger sequencing (Sanger et al., DNA Sequencing with Chain-terminating Inhibitors, 1977 PNAS 74(12):5463-5467).

[0079] In one embodiment, the human immunodeficiency virus comprises an integrase that is not resistant to either antiretroviral component of the two-ARV drug composition of the invention, or that is partially resistant to one or both of the antiretroviral component(s), or that is resistant to an integrase inhibitor, e.g., elvitegravir or raltegravir.

[0080] One embodiment of the present invention is directed to a mutant HIV, e.g., an HIV-1 mutant or an HIV-2 mutant; an HIV-1 or HIV-2 mutant comprising an NNRTI-resistant amino acid substitution, an NRTI-resistant amino acid substitution, a PI-resistant amino acid substitution, or an integrase inhibitor-resistant amino acid substitution, a raltegravir-resistant amino acid substitution, an elvitegravir-resistant amino acid substitution, or a G118R, S153A / F / Y, R263K, T97A, E138K, M154I, N155H, E157E / K / Q / P, L74I / M, Q95K / L / R, G140A / C / S, V151I / L / A, T66A / I / K, E92Q / V / G, Y143C / H / R, Q148H / K / R, E138A / D / K / T / G / R / Q, G163E / K / Q / R / S, G193E / R, M50I, K101E / P, V179L, Y18 1C / I / V, Y188L, H221Y, F227C, M230I / L, L100I / K103N, E92Q / N155H, Q148R / N155H, T66K / L74M, E92Q / N155H, G 140C / Q148R, G140S / Q148H / R / K, T97A / G140S / Q148, E138 / G140 / Q148, A153G / N155H / S163G, E92Q / T97A / N155 The present invention includes a 2-ARV drug composition for use in treating patients infected with HIV that contain one or more integrase amino acid substitution(s) selected from the group consisting of H / S163D, E138K / Q148K, G140S / Q148R, E92Q / N155H, S147G, H51Y, L68I / V, V72A / N / T, F121C / Y, A128T, P145S, Q146I / K / L / P / R, and E170A.

[0081] One embodiment of the regimen of the present invention provides for administering a 2-ARV drug composition to a human infected with certain mutant HIV viruses that exhibit reduced antiviral activity of reverse transcriptase inhibitors, for example, viruses containing one or more of the following mutations: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, M230L, or L100I+K103N.

[0082] formulation One embodiment of the present invention provides a 2-ARV drug pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. See "Non-ARV Drugs" above. Pharmaceutically acceptable excipients for a variety of different dosage forms are well known in the art and include carriers, diluents, fillers, binders, lubricants, disintegrants, glidants, colorants, pigments, taste-masking agents, sweeteners, flavoring agents, plasticizers, and any acceptable auxiliary substances, such as absorption enhancers, penetration enhancers, surfactants, co-surfactants, and specialized oils. The appropriate excipient(s) are selected, in part, based on the dosage form, intended mode of administration, intended release rate, and manufacturing reliability. Examples of common types of excipients include various polymers, waxes, calcium phosphate, and sugars, among others.

[0083] Other embodiments include pharmaceutical compositions formulated in various dosage forms, for example, solutions or suspensions, or tablets, capsules, granules, pellets, or sachets for oral administration. Particularly preferred pharmaceutical compositions are in the form of oral solid dosage forms, preferably tablets. The tablets are preferably swallowable tablets. Optionally, they can be coated with a film coat comprising essentially any suitable inert coating material known in the art. The above list of excipients and forms is not exhaustive.

[0084] The pharmaceutical composition of the present invention can be prepared according to standard methods known in the art. Granules according to the present invention can be obtained by dry compression or wet granulation. These granules can then be mixed with suitable disintegrants, glidants, and lubricants, for example, and the mixture can be compressed into tablets or filled into sachets or capsules of suitable size.

[0085] Tablets can also be obtained by direct compression of suitable powder mixtures, ie without any prior granulation of excipients.

[0086] Suitable powder or granular mixtures according to the present invention can also be obtained by spray drying, freeze drying, melt extrusion, pellet layering, coating with active pharmaceutical ingredients, or any other suitable method. The powder or granules thus obtained can be mixed with one or more suitable ingredients, and the resulting mixture can be compressed to form tablets or filled into sachets or capsules. The aforementioned methods, known in the art, also include milling and sieving techniques that can adjust the particle size distribution to the desired level.

[0087] In a further embodiment, the compositions of the present invention are adapted for parenteral administration, e.g., by intravenous administration of one or both of the DTG-containing composition and / or the 3TC-containing composition. Also provided are embodiments that include solid (e.g., nanoparticulate compositions), solution, or liquid formulations for parenteral administration. Parenteral administration can be carried out using any suitable device, some of which are known.

[0088] The composition according to the invention may be used as a medicament or used to manufacture a medicament. The composition of the invention may be supplied in a pack or kit.

[0089] The symbol "↓" means a lower dosage or less frequent dosage.

[0090] The symbol "↑" means an increase in dosage or frequency of dosage.

[0091] The symbol "<->" means that the dosage or frequency of administration remains the same.

[0092] Dolutegravir (DTG) "Dolutegravir" or DTG inhibits HIV integrase by binding to the integrase active site and blocking the strand-transfer step of retroviral deoxyribonucleic acid ("DNA") integration, which is essential for the HIV replication cycle. DTG is an integrase strand-transfer inhibitor (INSTI). A strand-transfer biochemical assay using purified HIV-1 integrase and pretreated substrate DNA demonstrated an IC of 2.7 nM. 50 (50% inhibitory concentration) values ​​are obtained (Kalama and Murphy, Dolutegravir for the Treatment of HIV, 2012 Exp. Op. Invest. Drugs 21(4):523-530).

[0093] The chemical name of dolutegravir is (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,12,12a-tetrahydro-2H-pyrido[5,6]pyrazino[2,6-b][1,3]oxazine-9-carboxamide (CAS Registry Number 1051375-16-6). Certain regimens and compositions of the invention include a pharmaceutically acceptable form of dolutegravir, such as a pharmaceutically acceptable salt, hydrate, and / or solvate thereof. An exemplary pharmaceutically acceptable salt of dolutegravir is dolutegravir sodium (marketed as "TIVICAY"). The sodium salt of dolutegravir, and certain crystalline forms of this sodium salt, or hydrates thereof, are disclosed in U.S. Patent No. 8,624,023. Amorphous dolutegravir sodium is described, for example, in U.S. Patent No. 9,206,197. Polymorphs, isomers, prodrugs, and esters of dolutegravir are also contemplated for the present invention. In one embodiment of the present invention, it may be specified that dolutegravir is used in its free form (not as a salt), or that dolutegravir exists in a non-solvated / non-hydrated form. Unless otherwise specified, the weight (mg) of dolutegravir is based on the weight of dolutegravir in its free form.

[0094] Dolutegravir has the following structural formula: Formula I:

[0095] [ka]

[0096] Methods for making dolutegravir are described, for example, in U.S. Patent No. 9,573,965. See also U.S. Patent No. 8,217,034 and U.S. Pregrant Publication No. 2016 / 0184332.

[0097] Dolutegravir is metabolized primarily by glucuronidation. Dolutegravir is thought to be a substrate for CYP3A4, but only to a small extent, approximately 15%. Furthermore, dolutegravir exhibits induction or inhibition of cytochrome P450 (CYP) isoenzymes in vitro. See U.S. Pregrant Publication No. 2016 / 0184332.

[0098] As used herein, a "dolutegravir-based regimen" or a "DTG-based regimen" or a "dolutegravir-containing regimen" or a "DTG-containing regimen" means a regimen that includes administration of dolutegravir or a pharmaceutically acceptable salt thereof (e.g., administration of a pharmaceutical composition that includes dolutegravir or a pharmaceutically acceptable salt thereof).

[0099] Lamivudine (3TC) "Lamivudine" or 3TC is a synthetic nucleoside analog whose active 5'-triphosphate metabolite (lamivudine triphosphate (3TC-TP)) inhibits at least HIV reverse transcriptase by DNA chain termination following incorporation of the nucleoside analog. 3TC is a nucleoside reverse transcriptase inhibitor (NRTI). The antiviral activity of lamivudine against HIV-1 has been evaluated using standard susceptibility assays in several cell lines (including monocytes and novel human peripheral blood lymphocytes) and EC 50Values ​​(50% effective concentration) ranged from 0.003 to 15 μM (1 μM = 0.23 mcg / mL) (see Section 12.4, 2013 Highlights of the Literature, Prescribing Information, for EPIVIR (lamivudine) Tablets and Oral Solution, available on the World Wide Web at (www).viivhealthcare.com / media / 32160 / us_epivir.pdf).

[0100] The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (CAS Registry Number 134678-17-4). Certain regimens and compositions of the present invention comprise pharmaceutically acceptable forms of lamivudine, such as pharmaceutically acceptable salts, hydrates, and / or solvates thereof. Polymorphs, isomers, prodrugs, and esters of lamivudine are also contemplated in accordance with the present invention. Lamivudine has the following structural formula: Formula II:

[0101] [ka]

[0102] Methods for making lamivudine are described, for example, in US Pat. Nos. 5,905,082, 8,481,554, and 8,158,607.

[0103] As used herein, a "lamivudine-based regimen" or a "3TC-based regimen" or a "lamivudine-containing regimen" or a "3TC-containing regimen" means a regimen that includes the administration of lamivudine or a pharmaceutically acceptable salt thereof (e.g., the administration of a pharmaceutical composition that includes lamivudine or a pharmaceutically acceptable salt thereof).

[0104] Tenofovir alafenamide fumarate (TAF) "Tenofovir alafenamide fumarate" (TAF) (formerly known as "GS-7340") is the fumarate form of "tenofovir alafenamide," a prodrug of tenofovir (TVF). Activated TAF is a nucleoside analog that inhibits at least HIV reverse transcriptase by DNA chain termination following incorporation of the nucleoside analog. TAF is a nucleoside reverse transcriptase inhibitor (NRTI). TAF antiretroviral activity in CD4+ T cells isolated from 13 HIV-infected individuals was measured with a mean EC2 of 11.0 nM. 50 (median EC of 10.2 nM 50 ) and monocyte-derived macrophage (MDM) activity was observed with a mean EC 50 (median EC 50 10.3 nM) (Bam et al., Metabolism and Antiretrovial Activity of Tenofovir Alafenamide in CD4+ T-cells and Macrophages from Demographically Diverse Donors, 2014 Antiviral Ther. 19:669-677).

[0105] The chemical name of tenofovir alafenamide fumarate (TAF) is L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1) (CAS Registry Number 379270-37-8) (see 2016 Prescribing Information Highlights of Literature for GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) Tablets for Oral Use, page 24, available at www.accessdata.fda.gov / drugsatfda_docs / label / 2016 / 207561s003lbl.pdf). Certain regimens and compositions of the present invention comprise a pharmaceutically acceptable form of tenofovir, such as a pharmaceutically acceptable salt, hydrate, and / or solvate thereof. Certain regimens and compositions of the present invention comprise a pharmaceutically acceptable form of tenofovir alafenamide, such as a pharmaceutically acceptable salt thereof. Certain regimens and compositions of the present invention comprise a pharmaceutically acceptable form of tenofovir alafenamide fumarate, such as a pharmaceutically acceptable salt thereof, such as tenofovir alafenamide hemifumarate. Polymorphs, isomers, prodrugs, and esters of tenofovir (TVF) and / or tenofovir alafenamide and / or tenofovir alafenamide fumarate are contemplated for the present invention. An alternative fumarate prodrug of tenofovir is, for example, tenofovir disoproxil fumarate (TDF) (see Ray et al., Tenofovir Alafenamide: A Novel Prodrug of Tenofovir for the Treatment of Human Immunodeficiency Virus, 2016 Antiviral Res. 125:63-70). Tenofovir alafenamide fumarate has the following structural formula: Formula III:

[0106] [ka]

[0107] Methods for making tenofovir alafenamide and tenofovir alafenamide fumarate are described, for example, in US Pat. No. 9,487,546.

[0108] As used herein, "tenofovir-based regimen" or "TFV-based regimen" or "tenofovir-containing regimen" or "TFV-containing regimen" refers to a regimen comprising administration of tenofovir or a pharmaceutically acceptable salt thereof (e.g., administration of a pharmaceutical composition comprising tenofovir or a pharmaceutically acceptable salt thereof). For example, a regimen comprising administration of emtricitabine and tenofovir disoproxil fumarate (e.g., that marketed as TRUVADA). For example, a regimen comprising administration of tenofovir alafenamide fumarate (e.g., that marketed as VEMLIDY). For example, a regimen comprising administration of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (e.g., that marketed as GENVOYA). For example, a regimen comprising administration of emtricitabine and tenofovir alafenamide (e.g., that marketed as DESCOVY).

[0109] As used herein, a "tenofovir alafenamide-based regimen" or a "tenofovir alafenamide-containing regimen" means a regimen that includes the administration of tenofovir alafenamide or a pharmaceutically acceptable salt thereof (e.g., the administration of a pharmaceutical composition that includes tenofovir alafenamide or a pharmaceutically acceptable salt thereof).

[0110] As used herein, "tenofovir alafenamide fumarate-based regimen" or "TAF-based regimen" or "tenofovir alafenamide fumarate-containing regimen" or "TAF-containing regimen" refers to a regimen that includes administration of tenofovir alafenamide fumarate or a pharmaceutically acceptable salt thereof (e.g., administration of a pharmaceutical composition that includes tenofovir alafenamide fumarate or a pharmaceutically acceptable salt thereof). For example, a regimen that includes administration of tenofovir alafenamide fumarate (e.g., that marketed as VEMLIDY), a regimen that includes administration of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (e.g., that marketed as GENVOYA), or a regimen that includes administration of emtricitabine and tenofovir alafenamide (e.g., that marketed as DESCOVY).

[0111] As used herein, "TAF3D+" means an antiretroviral (ARV) therapy regimen that includes the administration of at least three ARV drugs, where at least one of the three ARV drugs is a TAF.

[0112] Bictegravir "Bictegravir" inhibits HIV integrase by binding to the integrase active site and blocking the strand-transfer step of retroviral deoxyribonucleic acid ("DNA") integration, which is essential to the HIV replication cycle. Bictegravir is an integrase strand-transfer inhibitor (INSTI). It has an IC50 of 7.5 nM in a strand-transfer biochemical assay using purified HIV integrase and pretreated substrate DNA. 50 (Tsiang, M. et al., Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile, Antimicrobial Agents and Chemotherapy, Vol. 60:12, 2016).

[0113] The chemical name of bictegravir is (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide (CAS Registry Number 1611493-60-7). Certain regimens and compositions of the invention include pharmaceutically acceptable forms of bictegravir, such as pharmaceutically acceptable salts, hydrates, and / or solvates thereof. Bictegravir has the following structural formula: Formula IV:

[0114] [ka]

[0115] Methods for making bictegravir are described in US Pat. No. 9,216,996.

[0116] Bictegravir is metabolically eliminated through the actions of CYP3A4 and UGT1A1. In vitro studies have demonstrated that bictegravir is a substrate of UGT1A3, UGT1A9, BCRP, and P-gp. Therefore, certain drug-drug interactions may occur (Gallant, J. et al., Antiviral Activity, Safety, and Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults, 2017 Clinical Science 75(1):61-66).

[0117] As used herein, a "bictegravir-based regimen" or a "bictegravir-containing regimen" means a regimen that includes the administration of bictegravir or a pharmaceutically acceptable salt thereof (e.g., the administration of a pharmaceutical composition that includes bictegravir or a pharmaceutically acceptable salt thereof).

[0118] Emtricitabine (FTC) "Emtricitabine" or FTC is a synthetic nucleoside analog of cytidine that, in its phosphorylated active form, emtricitabine 5'-triphosphate, inhibits at least HIV reverse transcriptase by incorporating into nascent viral DNA, resulting in DNA chain termination. FTC is a nucleoside reverse transcriptase inhibitor (NRTI). The antiviral activity of emtricitabine against HIV-1 has been evaluated in several cell lines, including lymphoblastoid cell lines, MAGI-CCR5 cell lines, and peripheral blood mononuclear cells, and the EC 50 Values ​​(50% effective concentration values) ranged from 0.0013 to 0.64 μM (0.003 to 0.158 μg / mL) (see Section 12.4, 2012 Highlights of the Literature, Prescribing Information, for EMTRIVA (emtricitabine) Capsules and Oral Solution, available at www.accessdata.fda.gov / drugsatfda_docs / label / 2012 / 021500s019lbl.pdf).

[0119] The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3 oxathiolan-5-yl]cytosine (CAS Registry Number 143491-57-0). Certain regimens and compositions of the present invention include pharmaceutically acceptable forms of emtricitabine, such as pharmaceutically acceptable salts, hydrates, and / or solvates thereof. Polymorphs, isomers, prodrugs, and esters of emtricitabine are also contemplated for the present invention. Emtricitabine has the following structural formula: Formula V:

[0120] [ka]

[0121] Methods of making emtricitabine are described, for example, in U.S. Patent Nos. 7,939,660 and 7,534,885. See also U.S. Pregrant Publication No. 2016 / 0184332.

[0122] As used herein, "emtricitabine-based regimen" or "FTC-based regimen" or "emtricitabine-containing regimen" or "FTC-containing regimen" means a regimen that includes administration of emtricitabine or a pharmaceutically acceptable salt thereof (e.g., administration of a pharmaceutical composition that includes emtricitabine or a pharmaceutically acceptable salt thereof).

[0123] Under certain circumstances, any information provided herein or derived therefrom regarding the regimens or compositions of the invention may be included in the product labeling. Such circumstances may include, for example, regulatory agency requirements, results or data from clinical studies, or decisions of manufacturers or other companies.

[0124] All referenced patents and applications are incorporated herein by reference in their entirety.

Claims

1. A method for treating a virologically suppressed adult subject infected with human immunodeficiency virus (HIV) who is compliant with at least a three-drug (3+) antiretroviral therapy (ART) regimen, comprising administering to the subject therapeutic doses of only two ARV drugs, each at a dosing interval, wherein the two ARV drugs are (1) dolutegravir (DTG) or a pharmaceutically acceptable salt thereof, and (2) lamivudine (3TC) or a pharmaceutically acceptable salt thereof.

2. 2. The method of claim 1, wherein the 3-drug + ART regimen was a tenofovir alafenamide (TAF)-based (TAF3D+) regimen.

3. 10. The method of claim 1, wherein the triple-drug plus ART regimen was a bictegravir-based regimen.

4. 3. The method of claim 2, wherein the TAF3D+ regimen comprised administration of bictegravir or a pharmaceutically acceptable salt thereof, emtricitabine or a pharmaceutically acceptable salt thereof, and TAF or a pharmaceutically acceptable salt thereof.

5. 10. The method of claim 1, wherein the subject has adhered to the triple drug plus ART regimen for at least about 4 years, about 6 months, or about 3 months prior to the administering step.

6. 2. The method of claim 1, wherein prior to administration, the HIV is not partially or completely resistant to (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii).

7. 10. The method of claim 1, wherein being virologically suppressed comprises having less than 50 copies of HIV RNA per milliliter of plasma (<50 c / mL) in the subject.

8. 2. The method of claim 1, wherein (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii) are administered orally or by injection.

9. 9. The method of claim 8, wherein (i), (ii), or (iii) is administered orally.

10. 2. The method of claim 1, wherein (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii) are in the form of a tablet or liquid formulation.

11. 11. The method of claim 10, wherein (i), (ii), or (iii) is in the form of a tablet formulation.

12. 12. The method of claim 11, wherein (iii) is in the form of a tablet formulation.

13. 10. The method of claim 1, wherein DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof are administered simultaneously.

14. 10. The method of claim 1, further comprising administration of one or more non-ARV drugs.

15. 15. The method of claim 14, wherein (1), (2), and one or more non-ARV agents are administered simultaneously.

16. 2. The method of claim 1, wherein DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof are administered simultaneously with food intake.

17. 17. The method of claim 16, wherein the food has at least a moderate fat content.

18. 10. The method of claim 1, wherein the DTG or a pharmaceutically acceptable salt thereof is in a pharmaceutical composition.

19. 10. The method of claim 1, wherein the 3TC or a pharmaceutically acceptable salt thereof is in a pharmaceutical composition.

20. 14. The method of claim 13, wherein DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof are both in a two-drug pharmaceutical composition.

21. 21. The method of claim 20, wherein the two-drug pharmaceutical composition is a fixed-dose composition.

22. 22. The method of claim 21, wherein the two-drug pharmaceutical composition is in the form of a tablet or liquid formulation.

23. 23. The method of claim 22, wherein the two-drug pharmaceutical composition is in the form of a tablet formulation.

24. 21. The method of claim 20, wherein the two-drug pharmaceutical composition is administered orally or by injection.

25. 25. The method of claim 24, wherein the two-drug pharmaceutical composition is administered orally.

26. 21. The method of claim 20, wherein the two-drug pharmaceutical composition further comprises one or more non-ARV drugs.

27. 10. The method of claim 1, wherein the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is between about 40 mg and about 60 mg.

28. 28. The method of claim 27, wherein the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is about 50 mg.

29. 10. The method of claim 1, wherein the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is between about 200 mg and about 400 mg.

30. 30. The method of claim 29, wherein the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is about 300 mg.

31. 2. The method of claim 1, wherein the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is between about 40 mg and about 60 mg, and the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is between about 200 mg and about 400 mg.

32. 32. The method of claim 31, wherein the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is about 50 mg and the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is about 300 mg.

33. 10. The method of claim 1, wherein the administration interval is between about 24 and about 48 hours.

34. 33. The method of claim 32, wherein the administration interval is between about 24 and about 48 hours.

35. 2. The method of claim 1, wherein after administration, HIV does not exhibit partial or complete resistance to (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii).

36. 10. The method of claim 1, wherein after administration, the subject is virologically suppressed.

37. 37. The method of claim 36, wherein being virologically suppressed comprises the subject having less than 50 copies of HIV RNA per milliliter of plasma (<50 c / mL).

38. 10. The method of claim 1, wherein the adult subject is infected with human immunodeficiency virus type 1 (HIV-1).

39. 1. A method of treating a human immunodeficiency virus (HIV) infected subject who is virologically suppressed and adheres to a triple-drug antiretroviral therapy (ART) regimen, comprising administering dolutegravir (DTG) or a pharmaceutically acceptable salt thereof, and lamivudine (3TC) or a pharmaceutically acceptable salt thereof, (i) a total daily dose of between about 40 mg and about 60 mg of DTG or a pharmaceutically acceptable salt thereof, and (ii) a total daily dose of 3TC or a pharmaceutically acceptable salt thereof between about 200 mg and about 400 mg; to a subject at a dosing interval that results in

40. 40. The method of claim 39, wherein the 3-drug + ART regimen was a tenofovir alafenamide (TAF)-based (TAF3D+) regimen.

41. 40. The method of claim 39, wherein the triple-drug plus ART regimen was a bictegravir-based regimen.

42. 42. The method of claim 41, wherein the TAF3D+ regimen comprised administration of bictegravir or a pharmaceutically acceptable salt thereof, emtricitabine or a pharmaceutically acceptable salt thereof, and TAF or a pharmaceutically acceptable salt thereof.

43. 40. The method of claim 39, wherein the subject has been adherent to the triple drug plus ART regimen for at least about 4 years, about 6 months, or about 3 months prior to the administering step.

44. 40. The method of claim 39, wherein prior to administration, the HIV is not partially or completely resistant to (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii).

45. 40. The method of claim 39, wherein being virologically suppressed comprises the subject having less than 50 copies of HIV RNA per milliliter of plasma (<50 c / mL).

46. 40. The method of claim 39, wherein (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii) are administered orally or by injection.

47. 47. The method of claim 46, wherein (i), (ii), or (iii) is administered orally.

48. 40. The method of claim 39, wherein (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii) are in the form of a tablet or liquid formulation.

49. 49. The method of claim 48, wherein (i), (ii), or (iii) is in the form of a tablet formulation.

50. 50. The method of claim 49, wherein (iii) is in the form of a tablet formulation.

51. 40. The method of claim 39, wherein DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof are administered simultaneously.

52. 40. The method of claim 39, further comprising administration of one or more non-ARV drugs.

53. 53. The method of claim 52, wherein (1), (2), and one or more non-ARV agents are administered simultaneously.

54. 40. The method of claim 39, wherein DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof are administered simultaneously with food intake.

55. 55. The method of claim 54, wherein the food has at least a moderate fat content.

56. 40. The method of claim 39, wherein the DTG or a pharmaceutically acceptable salt thereof is in a pharmaceutical composition.

57. 40. The method of claim 39, wherein the 3TC or a pharmaceutically acceptable salt thereof is in a pharmaceutical composition.

58. 52. The method of claim 51, wherein DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof are both in a two-drug pharmaceutical composition.

59. 59. The method of claim 58, wherein the two-drug pharmaceutical composition is a fixed-dose composition.

60. 60. The method of claim 59, wherein the two-drug pharmaceutical composition is in the form of a tablet or a liquid formulation.

61. 61. The method of claim 60, wherein the two-drug pharmaceutical composition is in the form of a tablet formulation.

62. 59. The method of claim 58, wherein the two-drug pharmaceutical composition is administered orally or by injection.

63. 63. The method of claim 62, wherein the two-drug pharmaceutical composition is administered orally.

64. 59. The method of claim 58, wherein the two-drug pharmaceutical composition further comprises one or more non-ARV drugs.

65. 40. The method of claim 39, wherein the dosing interval results in (i) a total daily dose of about 50 mg of DTG or a pharmaceutically acceptable salt thereof, and (ii) a total daily dose of about 300 mg of 3TC or a pharmaceutically acceptable salt thereof.

66. 66. The method of claim 65, wherein the administration interval is between about 24 and about 48 hours.

67. 40. The method of claim 39, wherein the adult subject is infected with human immunodeficiency virus type 1 (HIV-1).

68. A method of treating human immunodeficiency virus (HIV) infection with only two ARV drugs, comprising administering a total daily dose of between about 40 mg and about 60 mg of dolutegravir (DTG) or a pharmaceutically acceptable salt thereof, and a total daily dose of between about 200 mg and about 400 mg of lamivudine (3TC) or a pharmaceutically acceptable salt thereof to an HIV-infected subject who is selected because (1) he / she is adhering to a two-drug regimen of DTG and 3TC, (2) he / she is virologically suppressed, or (3) he / she was adhering to a three-drug plus antiretroviral therapy (ART) regimen prior to (1) he / she is virologically suppressed.

69. 69. The method of claim 68, comprising administering about 50 mg of DTG or a pharmaceutically acceptable salt thereof and about 300 mg of 3TC or a pharmaceutically acceptable salt thereof.

70. 69. The method of claim 68, comprising administering DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof about once every 24 hours.

71. 69. The method of claim 68, comprising the step of simultaneously administering DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof.

72. 72. The method of claim 71, wherein the co-administration step is simultaneous with food intake.

73. 73. The method of claim 72, wherein the food has at least a moderate fat content.

74. 69. The method of claim 68, further comprising administration of one or more non-ARV agents.

75. 75. The method of claim 74, comprising co-administering DTG or a pharmaceutically acceptable salt thereof, 3TC or a pharmaceutically acceptable salt thereof, and one or more non-ARV agents.

76. 69. The method of claim 68, wherein (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii) are in a two-drug pharmaceutical composition.

77. 77. The method of claim 76, wherein the two-drug pharmaceutical composition is a fixed-dose composition.

78. 69. The method of claim 68, wherein (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii) are in the form of a tablet or liquid formulation.

79. 79. The method of claim 78, wherein (i), (ii), or (iii) is in the form of a tablet formulation.

80. 80. The method of claim 79, wherein (iii) is in the form of a tablet formulation.

81. 69. The method of claim 68, wherein (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii) are administered orally or by injection.

82. 82. The method of claim 81, wherein (i), (ii), or (iii) is administered orally.

83. 69. The method of claim 68, wherein being virologically suppressed comprises the subject having less than 50 copies of HIV RNA per milliliter of plasma (<50 c / mL).

84. 65. The method of claim 64, wherein the 3-drug + ART regimen was a tenofovir alafenamide (TAF)-based (TAF3D+) regimen.

85. 69. The method of claim 68, wherein the 3-drug plus ART regimen was a bictegravir-based regimen.

86. 69. The method of claim 68, wherein the three-drug plus ART regimen comprised administration of bictegravir or a pharmaceutically acceptable salt thereof, emtricitabine or a pharmaceutically acceptable salt thereof, and tenofovir alafenamide or a pharmaceutically acceptable salt thereof.

87. 69. The method of claim 68, wherein the subject (3) has adhered to a triple drug plus ART regimen for at least about 4 years, about 6 months, or about 3 months prior to (1).

88. 69. The method of claim 68, wherein the subject is further selected because (4) the HIV is not partially or completely resistant to (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii).

89. 69. The method of claim 68, wherein the adult subject is infected with human immunodeficiency virus type 1 (HIV-1).

90. 1. A method of reducing drug burden in a human immunodeficiency virus (HIV) infected subject who is virologically suppressed on a triple-drug plus antiretroviral therapy (ART) regimen, comprising:

1. A method comprising administering to a subject multiple doses of a two-drug pharmaceutical composition with a dosing interval of between about 24 and about 48 hours, wherein the two-drug pharmaceutical composition comprises a therapeutic dose of dolutegravir (DTG) or a pharmaceutically acceptable salt thereof, and a therapeutic dose of lamivudine (3TC) or a pharmaceutically acceptable salt thereof.

91. 74. The method of claim 73, wherein the 3-drug + ART regimen was a tenofovir alafenamide (TAF)-based (TAF3D+) regimen.

92. 91. The method of claim 90, wherein the 3-drug plus ART regimen was a bictegravir-based regimen.

93. 91. The method of claim 90, wherein the TAF3D+ regimen comprised administration of bictegravir or a pharmaceutically acceptable salt thereof, emtricitabine or a pharmaceutically acceptable salt thereof, and TAF or a pharmaceutically acceptable salt thereof.

94. 91. The method of claim 90, wherein the subject has been adherent to the triple drug plus ART regimen for at least about 4 years, about 6 months, or about 3 months prior to the administering step.

95. 91. The method of claim 90, wherein prior to administration, the HIV is not partially or completely resistant to (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii).

96. 85. The method of claim 84, wherein being virologically suppressed comprises the subject having less than 50 copies of HIV RNA per milliliter of plasma (<50 c / mL).

97. 91. The method of claim 90, wherein the two-drug pharmaceutical composition is a fixed-dose composition.

98. 91. The method of claim 90, wherein the two-drug pharmaceutical composition is in the form of a tablet or a liquid formulation.

99. 99. The method of claim 98, wherein the two-drug pharmaceutical composition is in the form of a tablet formulation.

100. 91. The method of claim 90, wherein the two-drug pharmaceutical composition is administered orally or by injection.

101. 101. The method of claim 100, wherein the two-drug pharmaceutical composition is administered orally.

102. 91. The method of claim 90, further comprising administration of one or more non-ARV agents.

103. 103. The method of claim 102, wherein the two-drug pharmaceutical composition and the one or more non-ARV drugs are administered simultaneously.

104. 104. The method of claim 103, wherein the two-drug pharmaceutical composition comprises one or more non-ARV drugs.

105. 91. The method of claim 90, wherein the two-drug pharmaceutical composition is administered simultaneously with food intake.

106. 106. The method of claim 105, wherein the food has at least a moderate fat content.

107. 91. The method of claim 90, wherein the administration interval is about 24 hours.

108. 108. The method of claim 107, comprising administering at least a 22nd therapeutic dose of the two-drug pharmaceutical composition to a subject infected with HIV, wherein the subject is virologically suppressed after administration of the 21st dose.

109. 108. The method of claim 107, comprising administering at least a fiftieth therapeutic dose of the two-drug pharmaceutical composition to a subject infected with HIV, wherein the subject is virologically suppressed after administration of the forty-ninth dose.

110. 108. The method of claim 107, comprising administering at least a 78th therapeutic dose of the two-drug pharmaceutical composition to a subject infected with HIV-1, wherein the subject is virologically suppressed after administration of the 77th dose.

111. 108. The method of claim 107, comprising administering at least a 162nd therapeutic dose of the two-drug pharmaceutical composition to a subject infected with HIV, wherein the subject is virologically suppressed after administration of the 161st dose.

112. 108. The method of claim 107, comprising administering at least a 246th therapeutic dose of the two-drug pharmaceutical composition to a subject infected with HIV, wherein the subject is virologically suppressed after administration of the 245th dose.

113. 108. The method of claim 107, comprising administering at least a 330th therapeutic dose of the two-drug pharmaceutical composition to a subject infected with HIV, wherein the subject is virologically suppressed after administration of a 329th dose.

114. 108. The method of claim 107, comprising administering at least a 358th therapeutic dose of the two-drug pharmaceutical composition to a subject infected with HIV, wherein the subject is virologically suppressed after administration of the 357th dose.

115. 91. The method of claim 90, wherein the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is between about 40 mg and about 60 mg.

116. 116. The method of claim 115, wherein the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is about 50 mg.

117. 91. The method of claim 90, wherein the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is between about 200 mg and about 400 mg.

118. 118. The method of claim 117, wherein the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is about 300 mg.

119. 91. The method of claim 90, wherein the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is between about 40 mg and about 60 mg, and the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is between about 200 mg and about 400 mg.

120. 85. The method of claim 84, wherein after administration of multiple doses, HIV-1 does not exhibit partial or complete resistance to (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii).

121. 91. The method of claim 90, wherein the adult subject is infected with human immunodeficiency virus type 1 (HIV-1).

122. 1. A method of treating a virologically suppressed human immunodeficiency virus (HIV) infected subject who is compliant with a triple-drug plus antiretroviral therapy (ART) regimen, comprising: (a) administering to a subject once daily therapeutic doses of only two ARV drugs, the two ARV drugs being (1) dolutegravir (DTG) or a pharmaceutically acceptable salt thereof, and (2) lamivudine (3TC) or a pharmaceutically acceptable salt thereof; (b) obtaining the number of copies of HIV RNA per milliliter of plasma sample taken from each of the subjects 21-27, 49-55, 77-83, 161-167, 245-251, 329-335, or 358-362 days after (a); (c) administering another therapeutic dose of each of two ARV drugs to subjects selected for having less than 50 copies of HIV RNA per milliliter of plasma sample; A method comprising:

123. The method of claim 122, wherein the 3-drug + ART regimen was a tenofovir alafenamide (TAF)-based (TAF3D+) regimen.

124. 123. The method of claim 122, wherein the triple-drug plus ART regimen was a bictegravir-based regimen.

125. 125. The method of claim 124, wherein the TAF3D+ regimen comprised administration of bictegravir or a pharmaceutically acceptable salt thereof, emtricitabine or a pharmaceutically acceptable salt thereof, and TAF or a pharmaceutically acceptable salt thereof.

126. 123. The method of claim 122, wherein the subject has been adherent to the triple drug plus ART regimen for at least about 4 years, about 6 months, or about 3 months prior to the administering step.

127. 123. The method of claim 122, wherein the HIV is not partially or completely resistant to (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii).

128. 123. The method of claim 122, wherein being virologically suppressed comprises the subject having less than 50 copies of HIV RNA per milliliter of plasma (<50 c / mL).

129. 123. The method of claim 122, wherein (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii) are administered orally or by injection.

130. 130. The method of claim 129, wherein (i), (ii), or (iii) is administered orally.

131. 123. The method of claim 122, wherein (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii) are in the form of a tablet or liquid formulation.

132. 132. The method of claim 131, wherein (i), (ii), or (iii) is in the form of a tablet formulation.

133. 133. The method of claim 132, wherein (iii) is in the form of a tablet formulation.

134. 123. The method of claim 122, wherein DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof are administered simultaneously.

135. 123. The method of claim 122, further comprising administration of one or more non-ARV agents.

136. 136. The method of claim 135, wherein DTG or a pharmaceutically acceptable salt thereof, 3TC or a pharmaceutically acceptable salt thereof, and one or more non-ARV agents are administered simultaneously.

137. 123. The method of claim 122, wherein DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof are administered simultaneously with food intake.

138. 138. The method of claim 137, wherein the food has at least a moderate fat content.

139. 123. The method of claim 122, wherein the DTG or a pharmaceutically acceptable salt thereof is in a pharmaceutical composition.

140. 123. The method of claim 122, wherein the 3TC or a pharmaceutically acceptable salt thereof is in a pharmaceutical composition.

141. 123. The method of claim 122, wherein DTG or a pharmaceutically acceptable salt thereof and 3TC or a pharmaceutically acceptable salt thereof are both in a two-drug pharmaceutical composition.

142. 142. The method of claim 141, wherein the two-drug pharmaceutical composition is a fixed-dose composition.

143. 142. The method of claim 141, wherein the two-drug pharmaceutical composition is in the form of a tablet or liquid formulation.

144. 144. The method of claim 143, wherein the two-drug pharmaceutical composition is in the form of a tablet formulation.

145. 142. The method of claim 141, wherein the two-drug pharmaceutical composition is administered orally or by injection.

146. 146. The method of claim 145, wherein the two-drug pharmaceutical composition is administered orally.

147. 142. The method of claim 141, wherein the two-drug pharmaceutical composition further comprises one or more non-ARV drugs.

148. 123. The method of claim 122, wherein the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is between about 40 mg and about 60 mg.

149. 149. The method of claim 148, wherein the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is about 50 mg.

150. 123. The method of claim 122, wherein the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is between about 200 mg and about 400 mg.

151. 151. The method of claim 150, wherein the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is about 300 mg.

152. 123. The method of claim 122, wherein the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is between about 40 mg and about 60 mg, and the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is between about 200 mg and about 400 mg.

153. 153. The method of claim 152, wherein the therapeutic dose of DTG or a pharmaceutically acceptable salt thereof is about 50 mg and the therapeutic dose of 3TC or a pharmaceutically acceptable salt thereof is about 300 mg.

154. 123. The method of claim 122, wherein the HIV is not partially or completely resistant to (i) DTG or a pharmaceutically acceptable salt thereof, (ii) 3TC or a pharmaceutically acceptable salt thereof, or (iii) both (i) and (ii).

155. 123. The method of claim 122, wherein the adult subject is infected with human immunodeficiency virus type 1 (HIV-1).

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