WO2016196471A1 - Procédés et compositions pour le traitement d'une infection par le vih - Google Patents

Procédés et compositions pour le traitement d'une infection par le vih Download PDF

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WO2016196471A1
WO2016196471A1 PCT/US2016/035027 US2016035027W WO2016196471A1 WO 2016196471 A1 WO2016196471 A1 WO 2016196471A1 US 2016035027 W US2016035027 W US 2016035027W WO 2016196471 A1 WO2016196471 A1 WO 2016196471A1
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hiv
treatment
cells
inhibitors
administered
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Kenneth G. COOPER
Mark S. DE SOUZA
Keith EUBANKS
David H. Starr
John D. KAPSON
Hua Yang
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Cooper Human Systems Llc
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
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    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
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    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/15—Depsipeptides; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the invention is in the general field of treatment of HIV infections and particularly in the field of treatment of latent HIV infections to maintain reduced viral load following cessation of drug treatment.
  • HIV Human immunodeficiency virus
  • CD4 cells human immunodeficiency virus
  • T cells Human immunodeficiency virus
  • HIV can destroy so many of these cells that the body cannot fight off infections and disease. HIV disease has a well-documented progression. Untreated, HIV is almost universally fatal because it eventually overwhelms the immune system— resulting in acquired immunodeficiency syndrome (AIDS). HIV treatment helps people at all stages of the disease, and treatment can slow or prevent progression from one stage to the next.
  • AIDS acquired immunodeficiency syndrome
  • Acute infection Within 2 to 4 weeks after infection with HIV, acute retroviral syndrome (ARS) or primary HIV infection, results in large amounts of HIV being produced in your body.
  • ARS acute retroviral syndrome
  • the virus uses CD4 cells to make copies of itself and destroys these cells in the process. The amount of virus in the blood is very high during this stage. Eventually, the immune response will reduce the amount of virus to a stable level, and the CD4 count will begin to increase, but typically does not return to pre-infection levels.
  • Clinical latency (inactivity or dormancy): This period is sometimes called asymptomatic HIV infection or chronic HIV infection. During this phase, HIV is still active, but reproduces at very low levels, and the individual may not have any symptoms or get sick during this time. People who are on antiretroviral therapy (ART) may live with clinical latency for several decades. For people who are not on ART, this period can last up to a decade, but some may progress through this phase faster. Toward the middle and end of this period, the viral load begins to rise and the CD4 cell count continues to drop. This correlates with development of symptoms of HIV infection as the immune system becomes too weak to protect against other diseases and cancer.
  • ART antiretroviral therapy
  • AIDS immunodeficiency syndrome
  • opportunistic infections This is the stage of infection that occurs when one becomes vulnerable to a range of bacterial, viral and fungal pathogens termed opportunistic infections. AIDS is defined as when the number of CD4 cells falls below 200 cells/mm 3 blood. AIDS may also be diagnosed upon development of one or more opportunistic infections, regardless of the CD4 count. Without treatment, people who are diagnosed with AIDS typically survive about three years.
  • the HIV reservoir is established during primary infection.
  • lymphocytes in lymphoid tissue Hufert et al, AIDS 199 '; 11: 849-57; Stellbrink et al, AIDS 1997; 11: 1 103-10.
  • most proviral HIV is found in central memory and transitional memory T cells, which maintain the reservoir because of their intrinsic capacity to persist through homoeostatic proliferation and renewal (Chomont et al., Nat. Med. 2009; 15: 893-900).
  • Other cellular reservoirs that might exist include naive CD4 T cells, monocytes and macrophages, astrocytes, microglial cells (Deeks et al., Nat. Rev. Immunol. 2012; 12: 607-14) and T stem cell memory cells (Buzon et al. Nat Med.
  • a prerequisite for the establishment of HIV latency is the integration of viral DNA into the host chromatin and epigenetic silencing of active viral transcription.
  • the molecular mechanisms contributing to the silencing of latent HIV are complex (Karn and Stoltzfus, Cold Spring Harb. Per pect. Med. 2012; 2: a006916).
  • Infected cells with replication-competent provirus are transcriptionally silenced by co-repressor complexes that include histone deacetylases. histone methyltransferases, and heterochromatin proteins. Active methylation of the long terminal repeat might also play a part (Van Duyne et al., J. Mol. Biol.
  • Epigenetic silencing of a provirus can be reversed by agents that mobilize chromatin remodeling complexes to replace repressive complexes poised at the viral long terminal repeat (Hakre et al.. FEMS Microbiol. Rev. 2012; 36: 706-16).
  • Signals delivered through the T cell receptor (TCR-CD3) complex and CD28 co-stimulation can drive productive transcription, suggesting that physiological activation of memory CD4 T cells can lead to virus production in vivo (Rong and Perelson, PLoS Comput. Biol. 2009; 5: el000533).
  • Activated CD4 T cells are the most permissive target for HIV infection. How recently infected activated cells become long-lived latently infected resting memory cells is not fully understood. Many regulatory pathways designed to blunt the effect of cell activation are turned on during T cell activation, including the upregulation of negative regulators of T cell activation— for example, PD-1, CTLA-4, TRIM-3, LAG3. CD160, and 2B4 cell surface receptors. Cells expressing these receptors could be preferential reservoirs of HIV. In a cross-sectional study of long-term treated individuals. PD-1- expressing cells were enriched with latent HIV (Chomont et al., Nat Med 2009; 15 : 893).
  • ART is one of the major medical successes in the era of AIDS. ART can provide indefinite viral suppression, restored immune function, improved quality of life, the near normalization of expected lifespan, and reduced viral transmission. However, ART does not eliminate viral reservoirs, and needs to be used indefinitely to keep AIDS at bay. ART is also expensive with potential short-term and long-term toxic effects. Despite virus control. HIV- associated complications persist, including a higher than normal risk of cardiovascular disease, cancer, osteoporosis, and other end-organ diseases. This increased risk might be due to the toxic effects of treatment or the consequences of persistent inflammation and immune dysfunction associated with HIV. Treatment approaches that eliminate persistent virus and do not need lifelong adherence to expensive and potentially toxic antiretroviral drugs are needed.
  • a functional cure is defined as an intervention that renders patients with progressive disease able to permanently control viral replication, thereby preventing clinical immunodeficiency and transmission (adapted from: Eisele E, Siliciano RF. Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity. 2012 Sep 21 ;37(3):377-88).
  • a functional cure suppresses viral replication for a pre-defined period of time in the absence of drug therapy, restores and stabilizes effective immune function, and decreases both HIV-induced inflammation (which could increase the risk of AIDS or non-AIDS morbidity) and, in those individuals that maintain stable low-level plasma viral loads, reduces the risk of virus transmission to others.
  • ART first-line antiretroviral therapy
  • NRTIs nucleoside reverse transcriptase inhibitors
  • NRTI non-nucleoside reverse-transcriptase inhibitor
  • TDF + 3TC (or FTC) + EFV as a fixed-dose combination is recommended as the preferred option to initiate ART (strong recommendation, moderate-quality evidence).
  • TDF + 3TC (or FTC) + EFV is contraindicated or not available, one of the following options is recommended: AZT + 3TC + EFV; AZT + 3TC + NVP; or TDF + 3TC (or FTC) + NVP (strong recommendation, moderate-quality evidence).
  • Integrase inhibitors have been adopted as part of current antiretroviral regimens. However, integrase inhibitors combined with protease inhibitors do not result in a significant better virological outcome.
  • HIV-cure-related trials raise many complex issues, given potentially toxic interventions to patients doing very well on ART, and needs careful assessment.
  • Rasmussen et al. Human Vaccines & Immunotherapeutics 9:4, 790- 799 (April 2013), review all of the strategies proposed to eradicate HIV infection.
  • Prolonged combination antiretroviral treatment (cART) has not led to eradication of HIV infection.
  • Current research is focused on characterizing latent HIV reservoirs and understanding the intricate mechanisms that establish HIV latency and enable the virus to persist for decades evading host immune responses and potent cART.
  • proviral latency referring to the presence of replication competent but transcriptionally silent provirus within resting cells
  • residual viremia referring to the continuous existence of trace levels of extracellular HIV- RNA in plasma during suppressive cART.
  • HDAC histone deacetylase
  • HDAC HDAC inhibitors
  • HDACs are particularly important to maintaining latency.
  • HDAC3 inhibition was found to be essential for reactivating viral expression.
  • Class I HDACs are ubiquitously expressed and deacetylation of lysine residues on histones is a key function of class I HDACs. However, they may deacetylate more than 1750 nonhistone proteins. To which degree, if any, the non-histone effects of HDACi contribute to the desired circumvention of HIV latency is largely unknown.
  • HDACi acting on HDAC metalloenzymes may be categorized according to their chemical structure into short chain fatty acids, hydroxamic acids and cyclic tetrapeptides, and are further characterized as selective or pan-inhibitors according to their spectrum of action. Consistent with the role histone deacetylases play in repressing transcription, HDAC inhibitors have been shown to disrupt HIV-latency and induce virus HIV-1 expression in latently infected cell lines, latently infected primary T-cells, resting CD4+ T- cells isolated from HIV-infected donors and, recently, in vivo.
  • Valproic acid (VP A), a known anticonvulsant that also exerts weak HDAC inhibition, was the first HDACi to be tested in a clinical study with the objective of depleting the latent reservoir of HIV- 1 infection. Whereas a substantial decline was seen in the frequency of replication competent HIV in circulating resting CD4 T cells in the initial study, additional studies failed to demonstrate any effect of VP A, even in the setting of intensified cART.
  • Vorinostat is a hydroxamic acid containing pan-HDACi with activity against class I, II, and IV HDACs. It is the most extensively investigated HDACi in HIV, having consistently shown the ability to reactivate HIV-1 expression at therapeutic concentrations in latently infected cell lines, latently infected primary cells, and resting CD4+ T-cells from HIV infected patients on suppressive HAART.
  • a recent study investigating the HDACi vorinostat, VPA and oxamflatin found that the levels of HIV production by HDAC inhibitor stimulated resting CD4+ T-cells from aviremic donors were not significantly different from those of cells treated with media alone, based on measurement of virion-associated (extracellular) HIV-RNA rather than cell-associated HIV-RNA.
  • HDACi induced immune suppression via Tregs may impact the course of HIV infection since the virus induces excess inflammation that drives disease progression in untreated HIV infection and causes premature immunosenescence and morbidity in persons on HAART.
  • HDACi induced Treg expansion and/or function could be either beneficial, by suppressing generalized T-cell activation, or detrimental, by weakening HIV- specific immune responses, thereby hindering immune-mediated clearance of latently infected reactivated CD4 T cells.
  • predicting the effects in vivo of different HDACi on immune responses to HIV may prove challenging since even structurally related compounds have been shown to have opposing actions.
  • interleukin (IL)-2 therapy might impact on the frequency of resting cells harboring replication competent virus, but rebound viremia occurred rapidly upon interruption of cART. Additional studies could not establish an effect of IL-2 on the pool of latently infected CD4 T cells or HIV production, and when IL-2 was used in combination with anti-CD3 antibody OKT3 this led to detrimental T cell activation and irreversible CD4 T cell depletion.
  • IL-7 induces virus outgrowth ex vivo in the resting CD4 T cells of HIV infected patients on cART (Wang et al., J. Clin. Invest. , 115: 128-137 (2005);
  • TLR toll-like receptor
  • CpG ODNs synthetic CpG oligodeoxynucleotides that stimulate immune cells via TLR9 induced HIV reactivation in vitro.
  • combination ART has transformed HIV from a deadly to a chronic disease, but HIV infected patients are still burdened with excess morbidity and mortality, acquisition of viral resistance to drug regimens, regimen-adherence issues, long-term toxicities from cART, stigmatization and, finally, insufficient access to cART worldwide.
  • a cure for HIV would have a substantial impact on society as well as the individual and continues to be a high research priority.
  • HIV infection immunodeficiency virus (HIV) infections have been developed which dampen immune activation with a bias more on the CD4 T cells relative to the CD8 T cell response, inhibit HIV replication, reactivate latent HIV, and inhibit infection of cells by HIV. It has been discovered that pushing latent HIV into active infections with inhibition of cell infection by the reactivated HIV can substantially reduce the number of cells infected with HIV and the viral load of HIV, which is not achieved using just the combination of ART and compounds which activate latent HIV.
  • HIV immunodeficiency virus
  • the methods involve administering three or more compounds to an HIV-infected subject collectively dampening immune activation with a bias more on the CD4 T cell relative to the CD8 T cell response, inhibiting HIV replication, reactivating latent HIV, and inhibiting infection of CD4 T cells by HIV, wherein the compounds are provided in dosages substantially reducing the number of cells infected with HIV or the viral load of HIV, relative to which is achieved using just the combination of ART and compounds which activate latent HIV.
  • NRTIs nucleoside reverse transcriptase inhibitors
  • NRTIs nucleoside reverse transcriptase inhibitors
  • tenofovir emtricitabine, zidovudine (AZT), lamivudine (3TC), abacavir, and tenofovir alafenamide fumarate
  • NRTIs non-nucleotide reverse transcriptase inhibitors
  • rilpivirine, and etravirine integrase inhibitors such as raltegravir, dolutegravir and elvitegravir
  • protease inhibitors such as ritonavir, darunavir, atazanavir and lopinavir.
  • Representative compounds dampening immune activation include anti-inflammatories such as hydroxychloroquine, chloroquine, cyclo-oxygenase-2 inhibitors (such as celecoxib, parecoxib, valdecoxib and etoricoxib), peroxisome proliferator-activated receptor-c (PPAR-c) agonists (such as pioglitazone), leflunomide, methotrexate, and mesalazine, and anti-fibrotic agents such as angiotensin-converting enzyme (ACE) inhibitors.
  • anti-inflammatories such as hydroxychloroquine, chloroquine, cyclo-oxygenase-2 inhibitors (such as celecoxib, parecoxib, valdecoxib and etoricoxib), peroxisome proliferator-activated receptor-c (PPAR-c) agonists (such as pioglitazone), leflunomide, methotrexate, and mesalazin
  • Representative inhibitors of HIV infection of CD4 T cells include C-C chemokine receptor type 5 (CCR5) inhibitors, C-X-X chemokine receptor type 4 (CXCR4) inhibitors, CD4 inhibitors, gpl20 inhibitors, and gp41 inhibitors.
  • the stimulator of CD8 T cell response to HIV can be a direct stimulator of CD8 T cell response to HIV or a differential stimulator of CD8 T cell response to HIV.
  • Representative compounds include IL-2. IL-12, IL-15. or a combination thereof, or a composition that stimulates production in the subject of IL-2, IL- 12, IL-15, or a combination thereof.
  • Representative compounds that stimulate reactivation of latent HIV include HDACi such as vorinostat, romidepsin, panobinostat, givinostat, belinostat, valproic acid, entinostat, mocentinostat, CI-994, BML-210, M344 and NVP-LAQ824; NF-KB-inducing agents such as anti-CD3/CD28 antibodies, tumor necrosis factor alpha (TNFa), prostratin. ionomycin.
  • HDACi such as vorinostat, romidepsin, panobinostat, givinostat, belinostat, valproic acid, entinostat, mocentinostat, CI-994, BML-210, M344 and NVP-LAQ824
  • NF-KB-inducing agents such as anti-CD3/CD28 antibodies, tumor necrosis factor alpha (TNFa), prostratin. ionomycin.
  • HMT histone methyltransferase
  • pro-apoptotic and cell differentiating molecules such as JQ1, nutlin3, disulfiram, aphidicolin, hexamethylene bisacetamide (HMBA), dactinomycin, aclarubicin, cytarabine, Wnt small molecule inhibitors, and Notch inhibitors
  • immune modulators such as anti-PD-1 antibodies, anti-CTLA-4 antibodies, anti- TRIM-3 antibodies, and BMS-936558
  • toll-like receptor 7 agonists such as GS-9620 (Gilead)
  • CD4 T cell vaccines such as anti-PD-1 antibodies, anti-CTLA-4 antibodies, anti- TRIM-3 antibodies, and BMS-936558
  • CD4 T cell vaccines such as GS-9620 (Gilead)
  • these are administered with a combination of nucleos(t)ide and non-nucleos(t)ide retroviral inhibitors
  • the inhibitor is a CCR5 inhibitor such as Maraviroc at a dosage of 300 to 1200 mg of Maraviroc per day
  • the compound dampening immune activation is a chloroquine compound such as hydroxychloroquine at a dosage of 150 to 400 mg administered per day
  • the stimulator of reactivation of latent HIV is a histone deacetylase inhibitor such as Vorinostat at a dosage of 150 to 400 mg administered per day.
  • a clinical study is proposed having the following treatment:
  • Vorinostat at 400mg orally every 24 hours for 3 cycles of 14 days with an interim rest-period of 14 days between cycles;
  • HAART in the form of t o-nucleos(t)ide reverse-transcriptase inhibitors such as emtricitabine (FTC) and tenofovir (TDF) and one non- nucleoside reverse transcriptase inhibitor such as efavirenz (EFV) or a protease or integrase inhibitor in subjects who are intolerant to EFV for the duration of the treatment at a dosage equivalent to FTC, 200mg lX/day; TDF, 300mg ⁇ /day and EFV, 600mg ⁇ /day or a protease-inhibitor or integrase-inhibitor.
  • FTC emtricitabine
  • TDF tenofovir
  • EMV efavirenz
  • a protease or integrase inhibitor in subjects who are intolerant to EFV for the duration of the treatment at a dosage equivalent to FTC, 200mg lX/day; TDF, 300
  • the administration of the inhibitors and reactivation stimulator can be a course of treatment including a plurality of administrations of the inhibitors and reactivation stimulator over a period of time.
  • the inhibitors and reactivation stimulator can be administered daily.
  • the period of time can be, for example, from 10 weeks to 40 weeks. In particular embodiments, the period of time can end after the earlier of 40 weeks or 2 weeks after HIV infected cells or HIV viral load becomes undetectable.
  • the subject has not been administered any anti-HIV treatment for at least two weeks prior to administration of the inhibitors and reactivation stimulator. In some embodiments, the subject has not been administered any anti-HIV treatment for at least 10 weeks prior to administration of the inhibitors and reactivation stimulator.
  • the method includes administering to the subject a highly active antiretroviral therapy (HAART), a direct stimulator of CD8 T cell response to HIV and a differential stimulator of CD8 T cell response to HIV.
  • HAART highly active antiretroviral therapy
  • the drugs are preferably administered together, over one or more periods of time.
  • the second period of time can completely overlap with the first period of time, can partially overlap with the first period of time, or can follow the first period of time. In some embodiments, no part of the second period of time precedes the first period of time.
  • the second period of time overlaps the last two weeks of the first period of time.
  • the methods and compositions can result in a CD4 T cell count, HIV viral load and/or HIV infected cell count at or below a threshold level for four weeks, 8 weeks, more preferably 3 months, more preferably 6 months, and most preferably 12 months following the end of a course of treatment.
  • the CD4 T cell count can remain at or above 350 per cubic millimeter, preferably 500 per cubic millimeter; HIV viral load can remain at or below 1000 copies per milliliter of blood, preferably 100 copies per milliliter of blood, most preferably undetectable; and/or HIV infected cell count can remain at or below 1% of peripheral blood mononuclear cells, preferably below 0.1% of peripheral blood mononuclear cells, most preferably below 0.01 % of peripheral blood mononuclear cells, for 8 weeks, preferably 3 months, more preferably 6 months, and most preferably 12 months following the end of a course of treatment.
  • Figures lA- lH are graphs of the actual results as well as computer modeled simulated results for clinical trials described in the prior art.
  • Figure 2 is a graph of HIV virus load (loglO RNA copies/ml) versus time (weeks) in an immune system simulation of baseline (untreated) HIV infection (upper line at week 52) and treatment holding new infections in check (as with a CCR5 inhibitor), reactivating HIV in latently infected cells (as with a histone deacetylase inhibitor), and stimulation of CD8 T cell response (as with IL-15) (lower line at week 52). The treatment was started at week 26 and continued to week 40.
  • Figure 3 is a graph of CD4 T cell count (cells/ ⁇ ) versus time (weeks) in an immune system simulation of baseline (untreated) HIV infection (lower line at week 52) and treatment holding new infections in check (as with a CCR5 inhibitor), reactivating HIV in latently infected cells (as with a histone deacetylase inhibitor), and stimulation of CD8 T cell response (as with IL- 15) (upper line at week 52). The treatment was started at week 26 and continued to week 40.
  • Figure 4 is a graph of HIV virus load (loglO RNA copies/ml) versus time (weeks) in an immune system simulation of baseline (untreated) HIV infection (upper line at week 55) and treatment holding new infections in check (as with a CCR5 inhibitor) and reactivating HIV in latently infected cells (as with a histone deacetylase inhibitor) (lower line at week 55). The treatment was started at week 26 and continued to week 80.
  • Figure 5 is a graph of CD4 T cell count (cells/ ⁇ ) versus time (weeks) in an immune system simulation of baseline (untreated) HIV infection (lower line at week 55) and treatment holding new infections in check (as with a CCR5 inhibitor) and reactivating HIV in latently infected cells (as with a histone deacetylase inhibitor) (upper line at week 55). The treatment was started at week 26 and continued to week 80.
  • Figure 6 is a graph of HIV virus load (loglO RNA copies/ml) versus time (weeks) in an immune system simulation of baseline (untreated) HIV infection (upper line at week 55) and treatment starting at week 26 and ending at week 36 holding new infections in check (as with a CCR5 inhibitor) and reactivating HIV in latently infected cells (as with a histone deacetylase inhibitor), followed by a standard HAART protocol starting at week 34 and ending at week 46 (lower line at week 55).
  • Figure 7 is a graph of CD4 T cell count (cells/ ⁇ ) versus time (weeks) in an immune system simulation of baseline (untreated) HIV infection (lower line at week 55) and treatment starting at week 26 and ending at week 36 holding new infections in check (as with a CCR5 inhibitor) and reactivating HIV in latently infected cells (as with a histone deacetylase inhibitor), followed by a standard HAART protocol starting at week 34 and ending at week 46 (upper line at week 55).
  • Figure 8 is a graph of HIV infected cells (log cells) versus time (weeks) in an immune system simulation of treatment inhibiting new infections with Maraviroc and reactivating HIV in latently infected cells with Vorinostat.
  • the treatment was started at week 26 and continued to week 78.
  • Figure 9 is a graph of HIV infected cells (log cells) versus time (weeks) in an immune system simulation of treatment inhibiting new infections with Maraviroc and hydroxychloroquine and reactivating HIV in latently infected cells with Vorinostat in various combinations.
  • the no treatment base is the only line at 20 weeks, full treatment using effective amounts of all three drugs (VMC) is the lowest line at week 41. and treatment with both Vorinostat and Maraviroc (VM) is the second lowest line at week 41.
  • the other lines at week 104 are treatment with both Vorinostat and Maraviroc (VM), treatment with both hydroxychloroquine alone (C), treatment with both hydroxychloroquine and Maraviroc (MC) and treatment with Maraviron alone (M) (lines overlap), no treatment base, and treatment with both Vorinostat and hydroxychloroquine (VC) and treatment with Vorinostat alone (V) (lines overlap).
  • VM Vorinostat and Maraviroc
  • C hydroxychloroquine alone
  • MC hydroxychloroquine and Maraviroc
  • M Maraviron alone
  • no treatment base and treatment with both Vorinostat and hydroxychloroquine (VC) and treatment with Vorinostat alone (V) (lines overlap).
  • the treatment was started at week 26 and continued through week 42.
  • Figure 10 is a graph of HIV infected cells (log cells) versus time (weeks) in an immune system simulation of treatment inhibiting new infections with Maraviroc and hydroxychloroquine and reactivating HIV in latently infected cells with Vorinostat using varying amounts of Vorinostat.
  • the lines at week 40 are the no treatment base, treatment with hydroxychloroquine, Maraviroc, and Vorinostat at 0.5 (V0.5MC) , treatment with hydroxychloroquine, Maraviroc, and Vorinostat at 1 (VIMC), treatment with hydroxychloroquine, Maraviroc, and Vorinostat at 2 (V2MC), treatment with hydroxychloroquine, Maraviroc. and Vorinostat at 4 or 5 (V4MC and V5MC) (lines overlap), and treatment with
  • VMC hydroxychloroquine, Maraviroc, and Vorinostat at 3
  • Figure 1 1 is a graph of HIV infected cells (log cells) versus time (weeks) in an immune system simulation of treatment inhibiting new infections with Maraviroc and hydroxychloroquine and reactivating HIV in latently infected cells with Vorinostat using varying amounts of Maraviroc.
  • the lines at week 30, in order from top to bottom, are the no treatment base, treatment with hydroxychloroquine, Vorinostat, and Maraviroc at -0.1 (VM0.1C) , treatment with hydroxychloroquine, Vorinostat, and Maraviroc at -0.5 (VM0.5C), treatment with hydroxychloroquine, Vorinostat, and Maraviroc at -1.5 (VM1 5C), treatment with hydroxychloroquine,
  • Vorinostat, and Maraviroc at -2 (VM2C; the full treatment), treatment with hydroxychloroquine, Vorinostat, and Maraviroc at -2.5 (VM2.5C), and treatment with hydroxychloroquine, Vorinostat, and Maraviroc at -3 (VM3C).
  • the treatment was started at week 26 and continued through week 42.
  • Figure 12 is a graph of HIV infected cells (log cells) versus time (weeks) in an immune system simulation of treatment inhibiting new infections with Maraviroc and hydroxychloroquine and reactivating HIV in latently infected cells with Vorinostat using varying amounts of
  • the lines at week 35 are the no treatment base, treatment with Maraviroc, Vorinostat, and
  • VMC0.01 hydroxychloroquine at -0.01
  • VMC0.05 treatment with Maraviroc, Vorinostat, and hydroxychloroquine at -0.05
  • VMC0.2 the full treatment
  • VMC0.4 hydroxychloroquine at -0.4
  • VMC0.6 treatment with Maraviroc, Vorinostat, and hydroxychloroquine at -0.6
  • HIV infection immunodeficiency virus (HIV) infections have been developed. Efforts to cure individuals of HIV infection have been stymied by a remaining reservoir of latently infected T cells. Front line anti-HIV treatments generally target only active HIV infections and cannot reach cells that are latently infected. If anti-HIV treatment is paused or stopped, reactivation of latent HIV can generate newly infected cells and resurgent viral loads. Lifelong treatment with anti-HIV therapy has been the only answer to this problem.
  • Latent HIV infection must be attacked to produce more robust and longer lasting reduction in infected cell counts and viral load.
  • the approach disclosed herein involves reactivation of latent HIV and inhibiting infection of cells by HIV. in combination with inhibitors of viral replication.
  • a combination of driving HIV out of latency with inhibition of cell infection and subsequent viral replication in newly infected cells substantially reduces the number of cells infected with HIV and the viral load of HIV.
  • HIV targets the immune system the state of the immune system can affect reactivation of latent HIV, cell infection by HIV, and HIV replication. Having a more active immune response can increase the effectiveness of the methods. It is believed that a more active cellular cytotoxic response leads to more effective hindrance of cell infection by HIV.
  • anti-HIV therapy such as standard HAART
  • anti-HIV therapy may result in a waning of the measurable CD8 T cell immune response
  • the method uses inhibitors of HIV infection that have different effects or targets of action.
  • Hydroxychloroquine has been shown in HIV treatment trials to have less of an impact on CD8 T cell function relative to its impact on CD4 T cell function (Piconi et al , Blood, 118(12):3263-72 (2011)).
  • the method can be made more effective by using one or more different inhibitors of HIV infection, preferably having different effects or targets of action, and/or by using one or more stimulators of reactivation of latent HIV, preferably having different effects or targets of action.
  • HAART is included to inhibit HIV replication and hinder new target cell infection by HIV, thus helping to reduce the viral load and HIV infected cell count.
  • the CD8 T cell response to HIV can be stimulated and/or differentially regulated relative to CD4 T cell responses in blood in the method.
  • the immune system ' s attack on HIV infected cells can thus help to decrease the viral load and HIV infected cell count once or as latent HIV is reactivated by the method.
  • active infection and “active viral infection” refer to a viral infection where viral replication and production is ongoing.
  • HIV Production of virus refers to production of copies of viral genomes and production of viral particles. Unless noted othenvise, all references herein to "HIV" refer to HIV-1 and all genomic subtypes within HIV-1.
  • a “plurality of administrations” refers to multiple administrations made at different times, different routes, and/or different forms. In the context of a plurality of administrations over a period of time, the plurality of administrations at least refers to multiple administrations made at different times during the period of time.
  • anti-HIV therapy refers to a treatment or therapy that has the purpose of reducing the number of cells infected with HIV, reducing HIV viral load, or both.
  • anti-HIV therapy holiday refers to a break or pause in administration of anti-HIV therapies to a subject.
  • a subject that "has not been administered any anti-HIV treatment” refers to subjects that are naive to anti-HIV therapy or that are on an anti-HIV therapy holiday. The latter is generally used in the context of a subject that has not been administered any anti-HIV treatment for a specified period of time.
  • interruption in the context of treatment, therapy, or administration, refers to a break or pause in treatment, therapy, or administration of a compound to a subject.
  • An interruption can be of, for example, a course of treatment, a cycle of administration, or individual administrations.
  • An interruption can be of, for example, one. more, or all compounds administered in a course of treatment, a cycle of administration, or individual administrations.
  • Cessation in the context of treatment, therapy, or administration, refers to a stop in treatment, therapy, or administration of a compound to a subject for an indefinite period of time (that is, with no fixed plan to resume the treatment, therapy, or administration). Cessation can be of, for example, a course of treatment, a cycle of administration, or individual administrations. Cessation can be of. for example, one, more, or all compounds administered in a course of treatment, a cycle of
  • cell count refers to the number of cells having a specified characteristic.
  • an HIV infected cell count refers to the number of cells infected with HIV.
  • a CD4 T cell count refers to the number of CD4 T cells.
  • Cell count is generally based on or expressed relative to a volume or amount of sample tested. Thus, for example, a direct or derived measurement of 10 HIV infected cells in a 5 ⁇ sample of blood can be expressed as a cell count of 2/ ⁇ 1 of blood, 2,000/ml, or some other equivalent.
  • expressions such as "HIV infected cells are no longer detected” and "HIV infected cells are undetectable” refer to HIV infected cell counts that are undetectable under the assay conditions used.
  • course of treatment refers to a plurality of administrations to a subject that follow a plan or schedule of treatment.
  • a "cycle" of administration refers to a plurality of administrations of a given compound or combination of compounds to a subject over part of a course of treatment followed by a change or interruption of the administrations.
  • a course of administration having cycles of administration generally includes two or more cycles of administration.
  • ⁇ ел ⁇ ество As used herein, "effective amount" of a compound or composition refers therapeutically effective amount of the compound to provide the desired result.
  • fixed-dose combination refers to a composition, such as a pill or capsule, which includes two or more compounds in fixed proportions in the same formulation.
  • co-packaging refers to packaging of packaging of different drugs, compositions, or drug units together in the same package compartment or area of the packaging.
  • unit-of-use packaging refers to co-packaging of two or more different drugs, compositions, or drug units to be taken together.
  • multi-unit packaging refers to packaging of multiple drugs, compositions, drug units, fixed dose combinations, or units- of-use in the same package, such as in the same blister pack, tray, or box.
  • following refers to an event or act that takes place after a period of time, existence of a condition, or a prior act or event has ended or no longer exists.
  • administering HAART following a course of treatment with a stimulator of reactivation of latent HIV means that the HAART is administered after the course of treatment with the stimulator has ended.
  • control of HIV infection and disease progression refers to HIV-infected subjects in which CD4 T cell count remains greater than or equal to 500 cells/mm 3 and viral load remains less than or equal to 10,000 copies/ml blood.
  • elite control of HIV infection and disease progression refers to HIV-infected subjects in which CD4 T cell count remains greater than or equal to 500 cells/mm 3 and viral load remains less than or equal to 500 copies/ml blood.
  • Control and elite control of HIV infection and disease progression can be defined or specified in terms of a period of time, such as one year, five years, etc.
  • long-term nonprogressor refers to an HIV-infected subject that maintains a CD4 T cell count greater than or equal to 500 cells/ ⁇ , that maintains a viral load less than or equal to 10.000 copies/ml blood, and that does not develop symptoms of AIDS over a long period of time, at least longer than a year and generally for at least a few years.
  • Long- term nonporgressors can be defined or specified in terms of a period of time, such as one year, five years, etc.
  • controller in the context of HIV, refers to an HIV- infected subject that maintains a CD4 T cell count greater than or equal to 500 cells/mm 3 , that maintains a viral load less than or equal to 500 copies/ml blood over a long period of time, at least longer than a year and generally for at least a few years. Controllers can be defined or specified in terms of a period of time, such as one year, five years, etc.
  • “functional cure” refers to long-term control of HIV infection and disease progression in the absence of ART over a long period of time, at least longer than a year and generally for at least a few years. Functional cures can be defined or specified in terms of a period of time, such as one year, five years, etc. Generally, a subjects said herein to be functionally cured are HIV-infected subjects that were treated with ART and then meet the definition of functional cure after cessation of ART. In contrast, long-term nonprogressors and controllers generally meet their respective definition without having been treated with ART.
  • precedes refers to an event or act that takes place before a period of time, existence of a condition, or a prior act or event has begun or no exists.
  • administration of a stimulator of reactivation of latent HIV preceding HAART means that the stimulator is administered before the HAART treatment.
  • virus infection of a cell refers to entry of virus into a cell and the beginning of an active infection of the cell. Unless the context indicates otherwise, this is meant to refer to the event of the virus beginning infection of a cell.
  • Ongoing HIV infections can be referred to as active HIV infections. Active HIV infections generate new events of HIV infection of T cells.
  • viral production refers to the intracellular process of viral production, including replication, packaging, and release from infected cells.
  • inhibiting refers to reduction or decrease in activity or expression.
  • inhibiting HIV infection of T cells refers to a reduction or decrease in entry of HIV into T cells and the beginning of an active infection of the T cells compared to a control or standard level. This can be a complete inhibition or activity or expression, or a partial inhibition. Inhibition can be compared to a control or to a standard level.
  • inhibitor of cell infection by virus refers to a compound or composition that inhibits virus infection of a cell.
  • inhibitor of cell infection by HIV refers to a compound or composition that inhibits HIV infection of a cell.
  • inhibitor of viral production refers to a compound or composition that inhibits production of virus.
  • inhibitor of HIV production or replication refers to a compound or composition that inhibits production of HIV.
  • latent viral infection refers to a viral infection where the viral genome is incorporated into a chromosome (as a provirus) and is dormant and there is not an active infection.
  • Latent viral infection can refer to a subject as a whole or, more commonly, to cells. Thus, for example, a cell of a subject can be latently infected while other cells in the subject can be actively infected.
  • Latent HIV infection refers to an HIV infection where the HIV genome is incorporated into a chromosome (as a provirus) and is dormant and there is not an active infection.
  • overlapping with refers to an event or act that takes place during a specified period of time, during the existence of a condition, or while an act or event is ongoing or exists.
  • a first period of time can be overlapping with a second period of time.
  • a course of treatment of HAART administered during a first period of time overlaps with a course of treatment with a stimulator of reactivation of latent HIV during a second period of time when the first and second periods of time overlap.
  • a course of treatment of HAART overlaps with a course of treatment with a stimulator of reactivation of latent HIV when any administrations in the course of HAART treatment are at the same time as or interspersed with administrations of the course of stimulator treatment.
  • completely overlaps with refers to an event or act that takes place completely and only during a specified period of time, during the existence of a condition, or while an act or event is ongoing or exists. That is, no part of the event or act takes place outside of, before, or after the specified period of time, the existence of the condition, or the other act or event.
  • a first period of time completely overlaps w ith a second period of time when no part of the first period of time is outside of the second period of time.
  • partially overlaps with refers to an event or act that takes place partially during a specified period of time, during the existence of a condition, or while an act or event is ongoing or exists and partially outside of, before, or after the specified period of time, the existence of the condition, or the other act or event.
  • a first period of time partially overlaps with a second period of time when part of the first period of time overlaps w ith the second period of time and part of the first period of time is outside of the second period of time.
  • a first period of time partially overlaps and follows a second period of time when part of the first period of time overlaps with the second period of time and part of the first period of time is after the second period of time.
  • a first period of time partially overlaps and precedes a second period of time when part of the first period of time overlaps with the second period of time and part of the first period of time is before the second period of time.
  • period of time refers to a specified continuous interval of time.
  • no part of a period of time refers to a period of time, event, or act that does not overlap with the specified period of time.
  • sequential time periods refers to periods of time that follow one another. Unless otherwise noted, the sequential time periods do not overlap. There may or may not be gaps in time between the sequential time periods.
  • pharmaceutically acceptable refers to a material that is not biologically or otherwise undesirable; that is, the material can be administered to a subject along with the selected compound without causing undesirable biological effects or interacting in a deleterious manner with the other components of the pharmaceutical composition in which it is contained.
  • activation refers to a shift of a provirus from latency or dormancy into active infection.
  • reducing HIV viral load refers to a reduction or decrease in the amount of HIV in an involved body fluid. Reduction generally can be compared to an initial of starting number, amount, or level, but can also be compared to a control or to a standard number, amount, or level.
  • selective affects refers to a compound, composition, treatment, condition, etc. that has a greater effect on one component or condition as compared to another component or condition. For example, in the context of immune responses, a composition can be said to selectively affect, for example. CD4 T cell-based immune response as compared to CD8 T cell-based immune response.
  • an antiinflammatory compound can selectively affect CD4 T cells compared to CD8 T cells, meaning, for example, that the CD4 T cell immune response is dampened or inhibited while the CD8 T cell immune response is not inhibited or is less inhibited than the CD4 T cell immune response.
  • separate administration refers to an administration that is of a separate composition, at a different time, by a different route, and/or in a different manner than another administration.
  • separate composition refers to a composition that is physically separate from another composition.
  • different pills that are not bound or attached to each other are separate compositions.
  • two liquid solutions that are mixed together are not separate compositions once they are mixed together.
  • single composition refers to a combination of components in one composition rather than in separate compositions.
  • a first inhibitor of HIV infection of CD4 T cells a second inhibitor of HIV infection of CD4 T cells, and a stimulator of reactivation of latent HIV formulated in a single pill are in a single composition.
  • stimulator of reactivation of the latent virus refers to a compound or composition that stimulates or promotes a shift of a provirus from latency or dormancy into active infection.
  • stimulator of reactivation of the latent HIV refers to a compound or composition that stimulates a shift of an HIV provirus from latency or dormancy into active HIV infection.
  • damaged of immune activation refers to reduction of activation of an immune response or immune responses in general.
  • a compound that dampens immune activation is a compound or compounds that reduces activation of an immune response or immune responses in general. Such a compound can be referred to as a "dampener of immune activation.”
  • Immune activation and dampening of immune activation can affect, for example, CD4 T cell response, CD8 T cell responses, or both.
  • “Dampening of immune activation with a bias more on the CD4 T cell response relative to the CD8 T cell response” refers to dampening of immune activation that reduces the CD4 T cell response more than it affects CD 8 T cell response.
  • stimulation of CD8 T cell response to HIV refers to a compound or composition that stimulates, increases, or promotes a CD8 T cell response to HIV.
  • Such stimulation can be relative to a prior or baseline CD8 T cell response to HIV (this can be referred to as direct stimulation of CD8 T cell response to HIV) and/or such stimulation can be relative to CD4+ activation (this can be referred to as differential stimulation of CD8 T cell response to HIV).
  • a stimulator of CD8 T cell response to HIV can increase CD8 T cell response to HIV relative to the prior existing CD8 T cell response to HIV, can decrease CD4 T cell activation with no or a lesser decrease of the prior existing CD8 T cell response to HIV, or can both increase CD8 T cell response to HIV relative to the prior existing CD8 T cell response to HIV and decrease CD4 T cell activation.
  • a "direct stimulator” of CD8 T cell response to HIV supports direct stimulation of CD8 T cell response to HIV.
  • a “differential stimulator” of CD8 T cell response to HIV supports direct stimulation of CD8 T cell response to HIV.
  • an increase of CD8 T cell response to HIV relative to the prior existing CD8 T cell response to HIV can be
  • a decrease of CD4 T cell activation with no or a lesser decrease of the prior existing CD8 T cell response to HIV can be accomplished with a differential stimulator of CD8 T cell response to HIV.
  • a combination of an increase of CD8 T cell response to HIV relative to the prior existing CD8 T cell response to HIV and a decrease of CD4 T cell activation can be accomplished with a direct stimulator and a differential stimulator of CD8 T cell response to HIV.
  • subject refers to a human.
  • substantially in connection with reducing, increasing, inhibiting, stimulating, etc., of an amount or level refers to a change of the amount or level in the indicated direction of at least 20%. A preferred substantial change is at least 50%. A most preferred substantial change is at least 90%. As used herein, “substantially” in connection with removal or elimination of all or most of something, refers to measurable diminution or elimination of detectable amounts.
  • viral load refers to the amount of virus in an involved body fluid.
  • viral load can be given in viral copies per milliliter of blood plasma.
  • HIV viral load refers to the amount of HIV in an involved body fluid.
  • Viral load is a measure of the severity of a viral infection. Tracking viral load is used to monitor therapy during chronic viral infections.
  • HIV viral load becomes undetectable refers to the condition where no virus is detected in the sample being tested by standard commercial quantitative viral load assays. Because of limits of assay methods, HIV can be undetectable in an assay when virus is still present in the sample, albeit at a very low level. HIV is considered to be functionally absent when HIV viral load is undetectable.
  • Compounds that inhibit HIV infection of CD4 T cells include, for example, entry inhibitors, such as C-C chemokine receptor type 5 (CCR5) inhibitors, C-X-X chemokine receptor type 4 (CXCR4) inhibitors, CD4 inhibitors, gpl20 inhibitors, and gp41 inhibitors (such as enfuvirtide); and PD-1 inhibitors.
  • entry inhibitors such as C-C chemokine receptor type 5 (CCR5) inhibitors, C-X-X chemokine receptor type 4 (CXCR4) inhibitors, CD4 inhibitors, gpl20 inhibitors, and gp41 inhibitors (such as enfuvirtide); and PD-1 inhibitors.
  • CCR5 inhibitors include maraviroc, aplaviroc, and vicriviroc.
  • Maraviroc is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection. Maraviroc is a virus entry inhibitor. It also appears to reduce graft-versus-host disease in patients treated with allogeneic bone marrow transplantation for leukemia.
  • Maraviroc is a negative allosteric modulator of the CCR5 receptor.
  • the drug binds to CCR5, thereby blocking the HIV protein gpl20 from associating with the receptor. HIV is then unable to enter human macrophages and T-cells. Because HIV can also use other co-receptors, such as CXCR4, an HIV tropism test such as a Trofile assay should be performed to determine if the drug will be effective.
  • Maraviroc is administered twice daily, at a dosage of 600mg daily when co-administered with certain antiretroviral medicals, 300 mg daily when administered with CYP3A inhibitors such as a protease inhibitors other than tipranavir, or 1200 mg daily when administered with a CYP3A inducer such as efavirenz or etravirine.
  • CYP3A inhibitors such as a protease inhibitors other than tipranavir
  • a CYP3A inducer such as efavirenz or etravirine.
  • Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria. Chloroquine was discovered in 1934 and clinical trials for antimalarial drug development during World War II showed that chloroquine has a significant therapeutic value as an antimalarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria. Chloroquine inhibits thiamine uptake. It acts specifically on the transporter SLC19A3. As an antiviral agent, chloroquine impedes the completion of the viral life cycle by inhibiting some processes that occur within intracellular organelles and that require a low pH. As for HIV-1, chloroquine inhibits the glycosylation of the viral envelope glycoprotein gpl20, which occurs within the Golgi apparatus.
  • AMD070 (Genzyme) is an entry inhibitor specific for CXCR4.
  • AMD-070 is a selective, reversible, small molecule CXCR4 chemokine coreceptor antagonist. AMD-070 prevents CXCR4-mediated viral entry of T- cell tropic synctium-inducing HIV (associated with advanced stages of HIV - 1 infection) by binding to transmembrane regions of the coreceptor, blocking the interaction of the CD4-gpl20 complex with the ECL2 domain of the CXCR4 coreceptor. AMD-070 is administered orally and twice daily in 200mg doses. In healthy participants, the median estimated terminal half-life ranged from 7.6 to 12.6 hours (single-dose cohorts, 50 to 400 mg) and from 11.2 to 15.9 hours (multiple-dose cohorts, 100 to 400 mg twice daily).
  • Aplaviroc (INN, GW873140) (GlaxoSmithKline) is a CCR5 entry inhibitor developed for the treatment of HIV infection. Aplaviroc is administered orally at 100 mg twice daily, 200 mg twice daily or 400 mg once daily.
  • BMS-488043 (Bristol Meyers-Squibb) is a unique oral small- molecule inhibitor of the attachment of human immunodeficiency virus type 1 (HIV-1) to CD4 + lymphocytes. BMS-488043 is administered orally at 800 mg or 1,800 mg twice daily.
  • BMS-663068 (Bristol Meyers-Squibb) is a HIV-1 entry inhibitor.
  • BMS-663068 is a methyl phosphate prodrug of the small molecule inhibitor BMS-626529.
  • BMS-626529 prevents viral entry by binding to the viral envelope gpl20 and interfering with virus attachment to the host CD4 receptor.
  • BMS-663068 is administered orally in various doses and dosing schedules with total daily BMS-663068 doses ranging from 1200 mg to 2400 mg. For example, 400 or 800 mg twice daily; or 600 or 1200 mg once daily.
  • Cenicriviroc is a small-molecule CCR5 coreceptor antagonist that prevents viral entry by binding to a domain of CCR5 and subsequently inhibiting the interaction between HIV-1 gpl20 and CCR5.
  • Cenicriviroc is also a CCR2 antagonist.
  • Cenicriviroc is administered once daily and orally. Cenicriviroc doses range from 25 mg to 150 mg.
  • Enfuvirtide (T20) (Roche) is a fusion inhibitor (interferes with gp41 fusion to the cell membrane). Enfuvirtide is administered subcutaneously at 90 mg twice daily.
  • Epigallocatechin gallate also known as epigallocatechin-3- gallate, is the ester of epigallocatechin and gallic acid, and is a type of catechin.
  • EGCG is the most abundant catechin in tea and is a potent antioxidant that may have therapeutic applications in the treatment of many disorders (e.g. cancer). It is found in green tea, but not black tea. EGCG is administered orally once daily at 800 mg.
  • Ibalizumab Human5A8, TMB-355, TNX-355) (TaiMed Biologies) is an entry inhibitor specific for CCR5/CXCR4. Ibalizumab allows binding to CD4 but interferes with co-receptor binding. Ibalizumab, a humanized monoclonal antibody (mAb), binds to extracellular domain 2 of the CD4 receptor. The ibalizumab binding epitope is located at the interface betw een domains 1 and 2, opposite from the binding site for major histocompatibility complex class II molecules and gpl20 attachment. Ibalizumab's post-binding conformational effects prevent viral entry and fusion. Ibalizumab can be administered via IV infusion at a dose of 10 mg/kg weekly, 15 mg/kg biweekly, 800 mg every 2 weeks, or 2000 mg every 4 weeks.
  • INCB-9471 (INCB009471) (Incyte) is a HIV-1 entry inhibitor.
  • INCB-9471 is a selective, reversible, small-molecule CCR5 coreceptor antagonist that binds to a CCR5 binding pocket that is different from what Maraviroc binds to. INCB-9471 prevents viral entry by inhibiting the interaction between HIV-1 gpl20 and CCR5. INCB-9471 prevents CCR5- mediated viral entry via allosteric noncompetitive mechanisms. INCB-9471 does not inhibit CXCR4-tropic or dual -tropic viruses. INCB-9471 is administered once daily in a dose of 100 mg or 200 mg of an immediate- release formulation or 300 mg of a slow-release formulation.
  • Plerixafor (AMD3100) (Genzyme) is an entry inhibitor specific for CXCR4. It is administered in a dosage of 0.16 to 0.24 mg/kg for cancer therapy.
  • PRO 140 (PA14) (CytoDyn Inc) is a HIV-1 entry inhibitor.
  • PRO- 140 a humanized IgG4 monoclonal antibody (mAb) binds to hydrophilic extracellular domains on CCR5, and via competitive mechanisms it inhibits CCR5-mediated HIV-1 viral entry, without preventing CC-chemokine signaling at antiviral concentrations.
  • PRO- 140 does not inhibit CXCR4- using viruses.
  • PRO-140 can be administered via SC or IV infusion at a dose of 5 mg/kg or 10 mg/kg.
  • Sifuvirtide is a fusion inhibitor (interferes with gp41 fusion to the cell membrane).
  • Vicriviroc is an entry inhibitor specific for CCR5. It is administered in a dosage of 20-30mg/day. Caseiro, et al. J Infect. 2012 Oct;65(4):326-35.
  • Useful dosages of compounds that inhibit HIV infection of CD4 T cells can be dosages equivalent to Maraviroc, 300 to 1200 mg lX/day.
  • NRTIs nucleoside reverse transcriptase inhibitors
  • NRTIs nucleoside reverse transcriptase inhibitors
  • ZT zidovudine
  • 3TC lamivudine
  • abacavir tenofovir alafenamide fumarate
  • N RTIs non-nucleotide reverse transcriptase inhibitors
  • efavirenz efavirenz
  • rilpivirine rilpivirine
  • etravirine etravirine
  • integrase inhibitors such as raltegravir , dolutegravir and elvitegravir
  • protease inhibitors such as ritonavir, darunavir, atazanavir and lopinavir.
  • HAART is used to reduce the likelihood of the virus developing resistance.
  • the WHO has recently recommended that HAART be initiated when the CD4 T cell count declines to ⁇ 500/ ⁇ 1 (IAS Conference. Kuala Lumpur, Malaysia, 2013). Data suggest that these recommendations mean a substantial increase in the number of patients who will require treatment and need early HIV testing.
  • Six classes of US FDA approved antiretro viral agents currently exist, as follows: nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (Pis), integrase inhibitors (lis), fusion inhibitors (FIs), and chemokine receptor antagonists (CRAs).
  • Each class targets a different step in the viral life cycle as the virus infects a CD4 + T lymphocyte or other target cell.
  • the use of these agents in clinical practice is largely dictated by their ease or complexity of use, side- effect profile, efficacy based on clinical evidence, practice guidelines, and clinician preference. Resistance, adverse effects, pregnancy, and coinfection with hepatitis B virus, or hepatitis C virus present important challenges to clinicians when selecting and maintaining therapy.
  • HAART Compounds for HAART are well known and include, for example, a combination of two or more nucleoside reverse transcriptase inhibitors (NRTIs), such as tenofovir, emtricitabine, zidovudine (AZT), lamivudine (3TC), abacavir, and tenofovir alafenamide fumarate; and one or more non- nucleotide reverse transcriptase inhibitors (NNRTIs), such as efavirenz, rilpivirine, and etravirine; integrase inhibitors, such as raltegravir and elvitegravin and/or protease inhibitors, such as ritonavir, darunavir, atazanavir, and lopinavir.
  • NRTIs nucleoside reverse transcriptase inhibitors
  • NRTIs non- nucleotide reverse transcriptase inhibitors
  • integrase inhibitors such as
  • HAART medicines that are most often used to treat HIV infection include nucleoside/nucleotide reverse transcriptase inhibitors, such as tenofovir, emtricitabine, and abacavir; and non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as efavirenz, nevirapine. or etravirine; protease inhibitors (Pis), such as atazanavir, ritonavir, or darunavir; fusion and entry inhibitors, such as enfuvirtide and maraviroc; and integrase inhibitors, such as raltegravir and dolutegravir.
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • Pro protease inhibitors
  • Pro protease inhibitors
  • fusion and entry inhibitors such as enfuvirtide and maraviroc
  • integrase inhibitors such as raltegravir and dolutegravir
  • Abacavir (ZIAGEN) is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5 '-triphosphate (dGTP). CBV-TP inhibits the activity of HIV- 1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3'-OH group in the incorporated nucleotide analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated.
  • CBV-TP carbovir triphosphate
  • dGTP deoxyguanosine-5 '-triphosphate
  • RT reverse transcriptase
  • CBV-TP is a weak inhibitor of cellular DNA polymerases ⁇ , ⁇ , and ⁇ .
  • the recommended oral dose of abacavir (ZIAGEN) for adults is 600 mg daily, administered as either 300 mg twice daily or 600 mg once daily, in combination with other antiretroviral agents.
  • ATRIPLA is a combination of Efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg.
  • COMBIVIR (GlaxoSmithKline) is a combination of zidovudine 300mg + lamivudine 150mg. COMBIVIR is administered orally twice daily.
  • COMPLERA (Gilead) is a combination of emtricitabine 200 mg + rilpivirine 25 mg + tenofovir 300 mg. COMPLERA is administered orally daily.
  • Darunavir is a second-generation protease inhibitor (PI).
  • PI protease inhibitor
  • Didanosine (VIDEX, Didex) (Bristol-Myers Squibb) is a nucleoside reverse transcriptase inhibitor.
  • Didanosine given orally Patient weight ⁇ 60 kg: (Tablets): 125 mg orally twice daily or 250mg once daily or 167 mg (Buffered powder) twice daily. Patient weight > 60kg: (Tablets): 200mg orally twice daily or 400mg orally once daily. (Buffered Powder): 250mg orally twice daily.
  • DCM205 is a small molecule based on L-chicoric acid, an integrase inhibitor. DCM205 is an entry inhibitor specific for CCR5 and CXCR4.
  • Dolutegravir prevents viral DNA integration into the host genome.
  • Dolutegravir tablets are administered orally and without regard to food at a dose of 50 mg once or twice daily.
  • Emtricitabine a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5 '-triphosphate.
  • Emtricitabine 5 '-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxy cytidine 5'- triphosphate and by being incorporated into nascent viral DNA which results in chain termination.
  • Emtricitabine 5 '-triphosphate is a weak inhibitor of mammalian DNA polymerase ⁇ , ⁇ , ⁇ , and mitochondrial DNA polymerase T. The dose for adults is 200 mg orally once daily.
  • Epzicom is a combination of abacavir 600 mg + lamivudine 300 mg. Epzicom is administered orally once daily.
  • Lamivudine (3TC) is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. CBV-TP and 3TC-TP are weak inhibitors of cellular DNA polymerases ⁇ , ⁇ , and ⁇ . The adult dose is one tablet (abacavir 600 mg and lamivudine 300 mg) once daily.
  • Etravirine is a non-nucleoside reverse transcriptase inhibitor.
  • Etravirine is administered orally twice daily at 200 mg.
  • Stavudine (ZERIT) is given at a dose of 40mg orally twice daily to patients weighing more than 60 kg; at a dose of 30mg orally twice daily for patients weighing less than 60 kg.
  • Tenofovir (VIREAD) is given at a dose of 300 mg orally once daily with a meal.
  • TRIZAVIR is a combination of Abacavir 300 mg, lamivudine 150 mg. and zidovudine 300 mg.
  • TRUVADA is a combination of emtricitabine 200 mg and tenofovir 300 mg.
  • Zalcitabine (HIVID) is administered as 0.75 mg orally three times daily.
  • Zidovudine (RETROVIR) is given orally at a dose of 300 mg twice daily or 200 mg 3 times/day.
  • Atazanavir (Reyataz) (Bristol Myers-Squibb) is a protease inhibitor.
  • Atazanavir is administered orally at 300 mg or 400 mg once daily.
  • Cobicistat (GS-9350) (Gilead) is a booster of protease inhibitors that inhibits cytochrome P450. Cobicistat is administered daily orally at 150 mg.
  • Efavirenz (SUSTIVA) (Bristol-Myers Squibb) is a non-nucleoside reverse transcriptase inhibitor. Efavirenz is administered orally at 300 or 600 mg once daily.
  • Elvitegravir (EVG, GS-9137, JTK-303) (Japan Tobacco Inc.; Gilead Sciences; GlaxoSmithKline) is a HIV-1 integrase strand transfer inhibitor. Elvitegravir prevents viral DNA integration into the host genome.
  • Elvitegravir is administered orally and once daily in combination with a boosting agent (CYP3A inhibitor) and with food at a dose at 85 mg or 150 mg.
  • a boosting agent CYP3A inhibitor
  • S/GSK1265744 (GSK-1265744, GSK1265744, S-265744) (ViiV Healthcare) is a HIV-1 integrase strand transfer inhibitor. S/GSK1265744 prevents viral DNA integration into the host genome.
  • S/GSK1265744 LAP can be administered via IM or SC injection; 800-mg loading dose given at Month 1, followed by monthly maintenance doses (200 mg or 400 mg). S/GSK1265744 can be administered once daily and orally at a dose at 10, 30, or 60 mg.
  • COMBIVIR zidovudine and lamivudine
  • TRIZIVIR abacavir, zidovudine and lamivudine
  • KALETRA lopinavir and ritonavir
  • EPZICOM abacavir and lamivudine
  • TRUVADA tenofovir and emtricitabine
  • ATRIPLA efavirenz, tenofovir and emtricitabine
  • COMPLERA rilpivirine, tenofovir, and emtricitabine
  • STRIBILD elvitegravir, cobicistat, tenofovir and emtricitabine.
  • tenofovir/emtricitabine (a combination of two NRTIs) and efavirenz (a NNRTI); tenofovir/emtricitabine and raltegravir (an integrase inhibitor); tenofovir/emtricitabine, ritonavir, and darunavir (both latter are protease inhibitors); tenofovir/emtricitabine, ritonavir, and atazanavir (both latter are protease inhibitors).
  • Most current HAART regimens consist of three drugs: 2 NRTIs + a PI/NNRTI/II. Initial regimens use "first-line" drugs with a high efficacy and low side-effect profile.
  • Useful dosages for inhibitors of HIV production can be a
  • HDAC histone deacetylase
  • HMT methyltransferase
  • pro- apoptotic and cell differentiating molecules such as JQl, nutlin3, disulfiram, aphidicolin, hexamethylene bisacetamide (HMBA), dactinomycin, aclarubicin, cytarabine, Wnt small molecule inhibitors, and Notch inhibitors
  • immune modulators such as anti-PD- 1 antibodies, anti-CTLA-4 antibodies, anti-TRIM-3 antibodies, and BMS-936558
  • toll-like receptor 7 agonists such as GS-9620 (Gilead)
  • CD4 T cell vaccines Combinations of such stimulators can also be used. The effects of some stimulators on reactivation of HIV can also be enhanced by combination with other compounds.
  • Histone deacetylase inhibitors are a class of compounds that interfere with the function of histone deacetylase. HDAC inhibitors have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they have been investigated as treatments for cancers and inflammatory diseases. To carry out gene expression, a cell must control the coiling and uncoiling of DNA around histones.
  • HAT histone acetylases
  • histone deacetylases which remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin.
  • Reversible modification of the terminal tails of core histones constitutes the major epigenetic mechanism for remodeling higher- order chromatin structure and controlling gene expression.
  • HDAC inhibitors block this action and can result in hyperacetylation of histones, thereby affecting gene expression. It is this effect that allows HDAC inhibitors to reactivate dormant proviruses.
  • the "classical" HDAC inhibitors act on Class I, Class II, and Class
  • HDACs by binding to the zinc-containing catalytic domain of the HDACs.
  • HDAC inhibitors fall into several groupings, in order of decreasing potency:
  • hydroxamic acids such as trichostatin A
  • cyclic tetrapeptides such as trapoxin B
  • depsipeptides such as benzamides, such as entinostat
  • aliphatic acid compounds such as phenylbutyrate and valproic acid.
  • HDAC inhibitors include the hydroxamic acids vorinostat (SAHA), belinostat (PXD101), LAQ824, and panobinostat
  • NAD+ NAD+ and are, therefore, inhibited by nicotinamide, as well derivatives of
  • NAD dihydrocoumarin
  • naphthopyranone 2-hydroxynaphaldehydes
  • Vorinostat or suberoylanilide hydroxamic acid is a member of a larger class of compounds that inhibit histone deacetylases (HDAC).
  • Histone deacetylase inhibitors HDAC inhibitors
  • Vorinostat has been shown to bind to the active site of histone deacetylases and act as a chelator for Zinc ions also found in the active site of histone deacetylases, Vorinostat's inhibition of histone deacetylases results in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the expression of genes needed to induce cell differentiation.
  • Panobinostat (LBH-589) (Novartis) is a HDACi developed by
  • panobinostat inhibits multiple histone deacetylase enzymes, a mechanism leading to apoptosis of malignant cells via multiple pathways.
  • a phase I/II HIV treatment trial using panobinostat at a dosage of 20 mg/day on days 1 ,3, 5 every other week for a period of 8 weeks has recently been completed (NCTO 1680094) and reported (Rasmussen et al., The Lancet HIV l(l):el3 - e21).
  • Romidepsin is a histone deacetylase inhibitor approved in the United States for the treatment of T-cell lymphomas.
  • RMD Romidepsin
  • RMD romidepsin
  • Belinostat (PXD101) is a histone deacetylase inhibitor for the treatment of hematological malignancies and solid tumors. Belinostat is a HDAC inhibitor affecting class I and II HDACs. Belinostat is administered orally and IV. Belinostat is administered orally at 500 mg/m 2 or 1000 mg/m 2 once or twice daily, and IV at 400 mg/m 2 per day.
  • Aclarubicin (INN) or Aclacinomycin A is an anthracycline drug that is used in the treatment of cancer. Soil bacteria Streptomyces galilaeus can produce aclarubicin.
  • the IV dosage initially is 175-300 mg/m 2 , divided over 3-7 consecutive days, with a maintenance dose of 25-100 mg/m 2 3-4 weekly.
  • Antibody bl2 is a HIV-1 gpl20 monoclonal antibody obtained as a Fab fragment by selection against IIIB gpl20 from an antibody phage display library prepared from bone marrow of a long term asymptomatic HIV-1 seropositive donor. Antibody bl2 is administered IV weekly at 1 mg/kg.
  • Aphidicolin is defined as a tetracyclic diterpene antibiotic with antiviral and antimitotical properties.
  • Aphidicolin is a reversible inhibitor of eukaryotic nuclear DNA replication. It blocks the cell cycle at early S phase. It is a specific inhibitor of DNA polymerase A,D in eukaryotic cells and in some viruses and an apoptosis inducer in HeLa cells.
  • Natural aphidicolin is a secondary metabolite of the fungus Nigrospora oryzae.
  • Apicidin is a HDAC inhibitor affecting class I HDACs. Apicidin is administered orally daily at 10 mg/kg.
  • BIX-01294 a diazepin-quinazolinamine derivative, is a histone- lysine methyltransf erase (HMTase) inhibitor that modulates the epigenetic status of chromatin.
  • HMTase histone- lysine methyltransf erase
  • BIX-01294 inhibits the G9aHMTase dependent levels of histone-3 lysine (9) methylation (H3K9me).
  • BMS-936558 is an antibody against PD-1, a protein involved in repressing the immune system. Blocking PD-1 with an antibody activates the immune system and enables it to fight tumors. BMS-936558 is administered IV at 3 mg/kg or 10 mg/kg at two or three week intervals.
  • Bryostatin-1 is a macrocyclic lactone isolated from the bryozoan Bugula neritina with antineoplastic activity. Bryostatin-1 binds to and inhibits the cell-signaling enzyme protein kinase C, resulting in the inhibition of tumor cell proliferation, the promotion of tumor cell differentiation, and the induction of tumor cell apoptosis. This agent may act synergistically with other chemotherapeutic agents. Bryostatin-1 is administered IV at 25 ⁇ g/m 2 or 40 ⁇ g/m 2 per day.
  • CG05/CG06 is a HDAC inhibitor. CG05/CG06 is administered at 0.15 ⁇ ⁇ ⁇ .3 ⁇ .
  • CI-994 (Tacedinaline, PD-123654, GOE-5549, Acetyldinaline) is an orally active compound with a wide spectrum of antitumor activity in preclinical models, in vitro and in vivo.
  • CI-994 is an inhibitor of Class I and II HDACs.
  • CI-994 is administered orally daily at 500 mg/kg or 600 mg/kg.
  • Cytarabine is a nucleoside analog that interferes with nucleic acid replication. Cytarabine is administered IV or subcutaneously at 100 mg/m 2 per day.
  • Dactinomycin (actinomycin D, Cosmegen, Act-D) is the most significant member of actinomycines. which are a class of polypeptide antibiotics isolated from soil bacteria of the genus Streptomyces .
  • Dactinomycin is administered IV daily at 15 ⁇ g/kg per day or 400 ⁇ g/m 2 per day.
  • Dihydrocoumarin is a compound found in Melilotus officinalis (sweet clover) that is commonly added to food and cosmetics. Dihydrocoumarin is an HDAC inhibitor that disrupts heterochromatic silencing.
  • Dihydrocoumarin is administered orally.
  • Disulfiram (Antabuse) is administered orally at 250 mg or 500 mg daily.
  • Givinostat (ITF2357) is a pan HDAC inhibitor. Givinostat is administered orally once or twice daily at 50 mg or 100 mg (Rowinsky, et al. JCO December 1986 4 (12): 1835-1844).
  • GS-9620 (Gilead) is a toll-like receptor 7 agonist that activates HIV from latent reservoir (Sloan et al., 22 nd Conference on Retroviruses and Opportunistic Infections, February 23-26, 2015, Poster 417).
  • Hexamethylene bisacetamide (HMBA) at a dose from 4.8 to 33.6 g/m 2 /day.
  • Oxamflatin is a HDAC inhibitor affecting class I HDACs.
  • Romidepsin (Celgene) is a HDAC inhibitor that affects class I HDACs.
  • Scriptaid is a pan HDAC inhibitor.
  • Sodium butyrate is a HDAC inhibitor affecting class I and Ila HDACs.
  • Trichostatin A is a pan HDAC inhibitor.
  • Valproic acid is a pan HDAC inhibitor.
  • Useful dosages of compounds that stimulate reactivation of latent HIV can be equivalent to Vorinostat, up to 400mg lX/day.
  • immune activation can be dampened by inhibiting or reducing activation of the T cell response.
  • Compounds that dampen immune activation include, for example, antiinflammatories such as hydroxychloroquine, chloroquine, cyclo-oxygenase-2 inhibitors (such as celecoxib, parecoxib, valdecoxib, and etoricoxib), peroxisome proliferator-activated receptor-c (PPAR-c) agonists (such as pioglitazone), leflunomide, methotrexate, and mesalazine, and anti-fibrotic agents such as angiotensin-converting enzyme (ACE) inhibitors.
  • antiinflammatories such as hydroxychloroquine, chloroquine, cyclo-oxygenase-2 inhibitors (such as celecoxib, parecoxib, valdecoxib, and etoricoxib), peroxisome proliferator-activated receptor-c (PPAR-c) agonists (such as pioglitazone), leflunomide, methotrexate, and me
  • Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria. Chloroquine is known for its anti-inflammatory effects (Salmeron and Lipsky, Am. J. Med. 75: 19-24 (1983); Ornstein et al, Arthritis Rheum. 39: 157-161 (1996)).
  • Hydroxychloroquine is also an antimalarial drug and is used to reduce inflammation in the treatment of rheumatoid arthritis and lupus. Hydroxychloroquine differs from chloroquine by the presence of a hydroxyl group at the end of the side chain: The N-ethyl substituent is beta- hydroxylated. It is available for oral administration as hydroxychloroquine sulfate (PLAQUENIL) of which 200 mg contains 155 mg base.
  • PDAQUENIL hydroxychloroquine sulfate
  • Hydroxy chloroquine has similar pharmacokinetics to chloroquine, with quick gastrointestinal absorption and is eliminated by the kidney.
  • Cytochrome P450 enzymes converts N- desethylated hydroxychloroquine to N-desethylhydroxy chloroquine.
  • Hydroxychloroquine is used to treat systemic lupus erythematosus, rheumatic disorders like rheumatoid arthritis and Sjogren's Syndrome, and porphyria cutanea tarda. Hydroxychloroquine increases lysosomal pH in antigen presenting cells. In inflammatory conditions, it blocks TLR on plasmacytoid dendritic cells (pDCs). TLR 9, which recognizes DNA- containing immune complexes, leads to the production of interferon and causes the dendritic cells to mature and present antigen to T cells.
  • pDCs plasmacytoid dendritic cells
  • Hydroxychloroquine by decreasing TLR signaling, reduces the activation of dendritic cells and the inflammatory process.
  • Hydroxychloroquine and its quinoline analogue chloroquine have been used in HIV- 1 therapeutic trials since 1995 (Sperber et al , Clin. Ther. 1995 Jul-Aug;17(4):622-36.). Both drugs are similar in structure with identical biological mechanisms. The free base form of the drugs accumulates in lysosomes, increasing the pH to levels that inhibit lysosomal proteases, thereby diminishing intracellular processing, glycosylation, and secretion of cellular proteins. These drugs interfere with a number of steps in the T-cell activation pathway including antigen-presentation (Ziegler and Unanue, Proc. Natl. Acad. Sci. U.S.A.
  • hydroxychloroquine and chloroquine have antiviral properties resulting in inhibition of viral protein glycosylation (Savarino et al. , J. Acquir. Immune Deflc. Syndr. , 2004 Mar l ;35(3):223-32).
  • hydroxychloroquine and chloroquine have been either singly or in combination with anti-retroviral therapy (Paton et al. , JAMA., 2012 Jul 25;308(4):353-61 ; Piconi et al , Blood, 201 1 Sep 22;118(12):3263-72).
  • the effect of hydroxychloroquine appears to be more significant on CD4+ compared to CD8 T cells in terms of dampening immune activation, with a significant effect on the former, but minimal impact on the latter (Piconi et al. , Blood, 2011).
  • Such selective effect on CD4+ and CD8 T cells is useful because a reduction in activation of CD4 T cell-based immune response aids in inhibiting HIV infection of CD4 T cells while CD8 T cell-based immune response aids in clearing HIV infected cells.
  • the anti-inflammatory compound selectively affects CD4 T cells versus CD8 T cells.
  • Celecoxib was the first specific COX-2 inhibitor (coxib) approved to treat patients with rheumatism and osteoarthritis. A study showed that the absorption rate, when given orally, is moderate, and peak plasma concentration occurs after about 2-4 hours. However, the extent
  • Celecoxib has the affinity to bind extensively to plasma proteins, especially to plasma albumin. It has an apparent volume of distribution (VD) of 455 +/- 166 L in humans and the area under the plasma concentration-time curve (AUC) increases proportionally to increased oral doses, between 100 and 800 mg.
  • VD apparent volume of distribution
  • AUC area under the plasma concentration-time curve
  • Celecoxib is metabolized primarily by CYP2C9 isoenzyme to carboxylic acid and also by non-CYP-dependent glucuronidation to glucuronide metabolites. The metabolites are excreted in urine and feces, with a small proportion of unchanged drug (2%) in the urine.
  • Parecoxib sodium is a water-soluble inactive ester
  • amide prodrug of valdecoxib a novel second-generation COX-2-specific inhibitor and the first such agent to be developed for injectable use. It is rapidly converted by hepatic enzymatic hydrolysis to the active form valdecoxib. The compound then undergoes another conversion, which involves both cytochrome P450-mediated pathway (CYP2C9, CYP3A4) and non-cytochrome P450-mediated pathway, to hydroxylated metabolite and glucuronide metabolite. The hydroxylated metabolite, that also has weak COX-2-specific inhibitory properties, is then further metabolized by non- cytochrome P450 pathway to a glucuronide metabolite.
  • cytochrome P450-mediated pathway CYP2C9, CYP3A4
  • non-cytochrome P450-mediated pathway hydroxylated metabolite and glucuronide metabolite.
  • the hydroxylated metabolite that also has weak COX-2
  • Parecoxib plasma concentration of Valdecoxib declines slowly because of a longer half-life (Karim et al, J Clin Pharmacol 41(10): 1 111-1119 (2001)).
  • Valdecoxib is taken orally it is absorbed rapidly (1- 2 hours), but presence of food can delay peak serum concentration. It then undergoes the same metabolism that is described above for Parecoxib. It is extensively protein-bound (98%), and the plasma half-life is about 7-8 hours. Note that the half-life can be significantly prolonged in the elderly or those with hepatic impairment, and can lead to drug accumulation (Burke et al., Ch.26: Analgesic-antipyretic agents; pharmacotherapy of gout.
  • Valdecoxib or about 1/10 of the plasma levels of Valdecoxib (Karim et al., J Clin Pharmacol 41(10): 11 11-1119 (2001)).
  • Etoricoxib typically used for patients with chronic arthropathies and musculoskeletal and dental pain, is absorbed moderately when given orally.
  • a study on its pharmacokinetics showed that the plasma peak concentration of etoricoxib occurs after approximately 1 hour. It has shown to be extensively bound to plasma albumin (about 90%), and has an apparent volume of distribution (V D ) of 120 L in humans.
  • the area under the plasma concentration-time curve (AUC) increases in proportion to increased dosage (5-120 mg).
  • the elimination half-life is about 20 hours in healthy individuals, and such long half-life enables the choice to have once-daily dosage.
  • Etoricoxib like the other coxibs, is excreted in urine and feces and also metabolized in likewise manner.
  • CYP3A4 is mostly responsible for biotransformation of etoricoxib to carboxylic acid metabolite, but a non CYP450 metabolism pathway to glucuronide metabolite is also at hand. A very small portion of etoricoxib ( ⁇ 1%) is eliminated unchanged in the urine. Patients with chronic renal insufficiency do not appear to have different plasma concentration curve (AUC) compared to healthy individuals. It has though been reported that patients with moderate hepatic impairment have increased plasma concentration curve (AUC) by approximately 40%.
  • Pioglitazone is used for the treatment of diabetes mellitus type 2 either alone or in combination with a sulfonylurea, metformin, or insulin.
  • DHODH dehydrogenase
  • Teriflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with their cell cycle progression while nonlymphoid cells are able to use another pathway to make their
  • ribonucleotides by use of the salvage pyrimidine pathway, and so are less dependent on de novo synthesis.
  • Teriflunomide also has antiviral effects against numerous viruses including CMV, HS V 1 and the BK virus, which it achieves by interfering with nucleocapsid tegumentation and hence virion assembly.
  • Mesalazine also known as mesalamine or 5-aminosalicylic acid (5- ASA)
  • mesalamine or 5-aminosalicylic acid is an anti -inflammatory drug used to treat inflammatory bowel disease, such as ulcerative colitis and mild-to-moderate Crohn's
  • Mesalazine is a bowel-specific aminosalicylate drug that acts locally in the gut, thereby having few systemic side effects. As a derivative of salicylic acid, mesalazine is also thought to be an antioxidant that traps free radicals, which are potentially damaging byproducts of metabolism.
  • Mesalazine is the active moiety of sulfasalazine, which is metabolized to sulfapyridine and mesalazine.
  • Mesalazine is the active component of the prodrug balsalazide along with the inert carrier molecule 4- aminobenzoyl-beta-alanine.
  • Methotrexate is used in the treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate can be taken orally or administered by injection (intramuscular, intravenous,
  • Useful oral doses of compounds that dampen immune activation range from, 5mg/week to continuous therapy equivalent to
  • Stimulation of an effective response by naive T cells requires three signals: TCR engagement, costimulation/IL-2, and a third signal that can be provided by IL-12.
  • IL-2 contributes to both primary and secondary expansion in memory CD8+ T-cell differentiation. IL-2 is responsible for optimal expansion and generation of effector functions following primary antigenic challenge. As the magnitude of T-cell expansion determines the numbers of memory CD8 T cells surviving after pathogen elimination, these events influence memory cell generation. Moreover, during the contraction phase of an immune response w here most antigen-specific CD8 T cells disappear by apoptosis, IL-2 signals are able to rescue CD8 T cells from cell death and provide a durable increase in memory CD8+ T-cell counts. At the memory stage.
  • CD8+ T-cell frequencies can be boosted by administration of exogenous IL-2.
  • CD8 T cells that have received IL-2 signals during initial priming are able to mediate efficient secondary expansion following renewed antigenic challenge.
  • IL-2 signals during different phases of an immune response are important in optimizing CD8+ T-cell functions, thereby affecting both primary and secondary responses of these T cells.
  • IL-12 family members are an important link between innate and adaptive immunity. IL-12 drives Thl responses by augmenting IFN-gamma production, which is generally important for clearance of intracellular pathogens.
  • IL-12 is the major cytokine influencing the level of IFN-gamma production by CD8 T cells. IL-12 promotes longer duration conjugation events between CD8 T cells and DC. IL-12 augments naive CD8 T cell activation by facilitating chemokine production, thus promoting more stable cognate interactions during priming. In addition to being required for acquisition of cytolytic function, IL-12 is required for optimal IL-2- dependent proliferation and clonal expansion.
  • IL-12 stimulates expression of the IL-2R-chain (CD25) to much higher levels than are reached in response to just TCR and costimulation and/or IL-2.
  • high CD25 expression is substantially prolonged in the presence of IL-12.
  • the cells proliferate more effectively in response to low levels of IL-2.
  • IL-2 and IL-12 both act to increase expression of both CD25 and the IL-12R, thus providing positive cross-regulation of receptor expression.
  • IL-15 in HIV-infected individuals can enhance the function, survival, and expansion of HIV-specific CD8 T cells.
  • IL-15 is crucial for the development of naive and memory CD8 T cells and is delivered through a mechanism called transpresentation.
  • memory CD8 T cells grow more dependent on IL-15 transpresentation by dendritic cells.
  • IL-15 promotes activation and maintenance of natural killer (NK) and CD8 T effector memory (T(EM)) cells, making it a potential immunotherapeutic agent for the treatment of cancer and immunodeficiency states.
  • IL-15 at a dose of 20 ⁇ g/kg/d administered by continuous intravenous infusion for 10 days resulted in a massive (100-fold) expansion of CD8 T(EM) cells in the peripheral blood.
  • the administration of 20-40 ⁇ g/kg/d of IL-15 by subcutaneous injection resulted in a more modest (10-fold) expansion of CD8 T(EM) cells.
  • NK expansion was similar in both the continuous intravenous and daily subcutaneous treatment groups.
  • IL-15 administered by intravenous infusion is able to induce markedly greater expansions of CD8 T(EM) cells than the same dose administered by other routes.
  • HIV can be from 0.3 to 20 ⁇ g/kg/day by intravenous infusion.
  • HIV Antigens
  • HIV antigens for use with the disclosed compositions and in the disclosed methods can be any suitable HIV antigens. Many HIV antigens have been derived from HIV proteins and many others can be derived.
  • HIV antigens form such vaccines can be used with the disclosed methods to improve the effect of the methods. It is expected that HIV antigens, including those that did not result in a successful standalone vaccine, can improve the overall effect of the disclosed methods by, for example, improving the immune response to virus produced from reactivated latent HIV. Thus, any suitable HIV antigen can be used in the disclosed compositions and method.
  • HIV antigens are known and can be used in the disclosed compositions and methods. Generally, the most useful HIV antigens are derived from the gag, pol, or env proteins. Combinations of these and other HIV proteins are also considered useful.
  • a preferred antigen is HIVconsv, a single chimeric protein from the 14 most invariable segments of the HIV-1 proteome, each 27-128 amino acids in length, and alternating individual regions among the four major clades (A, B, C, and D) (Rosario et al, Eur. J. Immunol. 40: 1973-1984 (2010). Examples of HIV antigens are described in Kok et al., Clinical & Translational Immunology 3, e24 (2014).
  • HIV-1 Due to the great variability in the HIV genome, which results from mutation, recombination, insertion and/or deletion, HIV has been classified in groups, subgroups, types, subtypes and genotypes. There are two major HIV groups (HIV-1 and HIV-2) and many subgroups because the HIV genome mutates constantly. The major difference between the groups and subgroups is associated with the viral envelope. HIV-1 is classified into a main subgroup (M), said subgroup M being divided into nine subtypes (clades or subtypes) designed A through J (Hu et al, JAMA 275:210-216, 1996; Korber et al., Science 280: 1868-1871, 1998), and a 10th outlier subgroup (0).
  • M main subgroup
  • the HIV virus is HIV-1 or HIV-2, including all known and so far unknown clades thereof. Yet preferably, it is HIV-1.
  • HIV antigen is from HIV origin and can be related to one or more specific HIV group, subgroup, type, subtype or to a combination of several subtypes.
  • HIV antigen is a HIV-1 or HIV-2 antigen.
  • the HIV antigen(s) can be independently derived from one or more of the following proteins: gag (p24gag, p55gag), pol, env (gpl60, gpl40, gpl20, gp41), tax, tat, rex, rev, nef, vif, vpu, or vpr.
  • the HIV antigen(s) can be HIV Env polypeptides, such as gpl60, gpl40 or gpl20.
  • the Env polypeptides can be monomers or oligomers, for example a gpl20 monomer, or homo- or hetero-oligomers of gpl40 and gpl60.
  • the HIV antigen can be derived from HIV (e.g., HIV-1) Env protein (including, e.g., gpl20, gpl40, and gpl60).
  • HIV-1 HIV-1 Env protein
  • Env protein including, e.g., gpl20, gpl40, and gpl60.
  • Env protein (gp l60 precursors) from HIV-1 Bru, HIV-1 MN, HIV-1 ELI, HIV-1 RF, HIV-1 SF2C and HIV-1 SC, are disclosed as SEQ ID NOS; 1-6 in U.S. Pat. No. 6,284,248. It is well-known that Env is synthesized first as a g l60 polyprotein precursor in the endoplasmic reticulum, which is cleaved to form gpl20 and gp41, or truncated to form gpl40.
  • gpl20 corresponds to the N-terminal end of the gpl 60 without the oligomerization domain or transmembrane domain
  • gpl40 corresponds to the N-terminal end of the gpl60 without the transmembrane domain, but retains the oligomerization domain. See, Morikawa et al., J. Virol, 67:3601-3604 (1993); Richmond et al., J. Virol, 72:9092-9100 ( 1998); Earl et al. J. Virol., 75:645-653 (2001).
  • the gpl60 polyprotein precursor is cleaved, at a major cleavage site and/or minor cleavage site, to form gpl20. If desired one or both cleavage sites can be mutated to prevent processing of gpl60 into gpl20.
  • suitable mutations are well known in the art and are described, for example, in U.S. Pat. No. 6,284,248, and U.S. Patent Application Publication No. 2010/0316698.
  • compositions disclosed herein can be formulated in any useful way. Generally, the nature of the compound and the route of administration will influence the choice of formulation.
  • the inhibitors of HIV infection of CD4 T cells and stimulator of reactivation of latent HIV can be administered together in a single composition.
  • the inhibitors and reactivation stimulator are administered in separate compositions.
  • the first and second inhibitors of HIV infection of CD4 T cells are administered together in a single composition while the reactivation stimulator is administered in a separate composition.
  • the first inhibitor of HIV infection of CD4 T cells and the reactivation stimulator are administered together in a single composition while the second inhibitor of HIV infection of CD4 T cells is administered in a separate composition.
  • the second inhibitor of HIV infection of CD4 T cells and the reactivation stimulator are administered together in a single composition while the first inhibitor of HIV infection of CD4 T cells is administered in a separate composition.
  • the dosage can be adjusted by the individual physician based on the clinical condition of the subject involved. The dose, schedule of doses and route of administration can be varied.
  • the efficacy of administration of a particular dose of the compounds or compositions according to the methods described herein can be determined by evaluating the particular aspects of the medical history, signs, symptoms, and objective laboratory tests that are known to be useful in evaluating the status of a subject in need of treatment of HIV infection or other diseases and/or conditions. These signs, symptoms, and objective laboratory tests will vary, depending upon the particular disease or condition being treated or prevented, as will be known to any clinician who treats such patients or a researcher conducting experimentation in this field.
  • a subject's physical condition is shown to be improved (e.g., a tumor has partially or fully regressed)
  • the progression of the disease or condition is shown to be stabilized, or slowed, or reversed, or (3) the need for other medications for treating the disease or condition is lessened or obviated, then a particular treatment regimen will be considered efficacious.
  • any of the compounds disclosed herein can be used therapeutically in combination with a pharmaceutically acceptable carrier.
  • the compounds described herein can be conveniently formulated into pharmaceutical compositions composed of one or more of the compounds in association with a pharmaceutically acceptable carrier. See, e.g., Remington's Pharmaceutical Sciences, latest edition, by E.W. Martin Mack Pub. Co.. Easton, PA, which discloses typical carriers and conventional methods of preparing
  • compositions that can be used in conjunction with the preparation of formulations of the compounds described herein. These most typically would be standard carriers for administration of compositions to humans. Other compounds can be administered according to standard procedures used by those skilled in the art.
  • the pharmaceutical compositions described herein can include, but are not limited to, carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice. Generally, oral administration is preferred and is generally available for the compounds and compositions disclosed herein.
  • Parenteral administration if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Parenteral administration can use a slow release or sustained release system such that a constant dosage is maintained.
  • the disclosed compounds and compositions containing the compounds can be packaged in any suitable manner.
  • Packaging
  • containers for holding the disclosed compounds and compositions can include, but are not limited to. bottles, blisters, trays, syringes, capsules, blow fill seal, vials, ampoules, or container closure systems made of metal, polymer (e.g., plastic, elastomer), glass, or the like.
  • the different compounds and compositions can be packaged separately, together, individually, or in combination.
  • the compounds and compositions to be administered as separate compositions but as part of the same course of treatment can be packaged together (co-packaged), such as in unit-of-use packaging.
  • Co-packaged compounds and compositions can be referred to as a kit.
  • separate pills or capsules of different compounds can be co-packaged in unit-of-use packaging.
  • unit-of-use packaging can be, for example, a blister pack with each blister containing a combination of capsules or pills to be taken at the same time.
  • Many variations of co- packaging and unit-of-use packaging can be used.
  • Preferred co-packaging uses unit-of-use packaging of each combination of capsules or pills to be taken at the same time in multi-packs that package multiple units-of-use combinations by time, day, and date of all or a part of a course of treatment.
  • the combination of compounds can be provided in packaging that provides the drugs in an appropriate dosage form on a per administration basis, designated by day of administration.
  • Kits can typically include instructions for coordinating the administration of the different compounds and compositions of the combination therapies.
  • the compounds and compositions can be administered at certain times during the day in order to reduce side effects.
  • the instructions and/or packaging can indicate which dose(s) should be administered and when the dose(s) should be administered. For example, a first dose on day one, a second higher dose on day two, a third higher dose on day three, and so on, until a maintenance dose is reached.
  • the dose unit pack can contain multiple compounds and compositions to provide different drug combinations to be taken together and/or taken at different times, e.g. on different days or different times of the day.
  • co-packaged and unit-of-use packaged compounds include co-packaging or unit-of-use packaging of three or more compounds to an HIV-infected subject collectively dampening immune activation with a bias more on the CD4 T cell relative to the CD8 T cell response, inhibiting HIV replication, reactivating latent HIV, and inhibiting infection of CD4 T cells by HIV.
  • co-packaging or unit-of-use packaging of three or more compounds to an HIV-infected subject collectively dampening immune activation with a bias more on the CD4 T cell relative to the CD8 T cell response, inhibiting HIV replication, reactivating latent HIV, and inhibiting infection of CD4 T cells by HIV.
  • Maraviroc, hydroxychloroquine, Vorinostat, and a HAART drug combination can be co-packaged, preferable in unit-of-use packaging.
  • the disclosed compounds and compositions can be administered in any manner or route suitable to the compound or composition and the formulation of the compound or composition. Such techniques are well-known and can be applied to the methods and compositions disclosed herein. Courses of Treatment
  • compositions can be used in courses of treatment in order to achieve clinical or other goals.
  • the compositions can be administered over periods of time measured in weeks and months.
  • Viral infections such as HIV are generally affected by treatments over similar time periods.
  • Reactivation of latent virus and subsequent clearing of infected cells generally requires weeks to months of treatment.
  • reactivation and clearance of the small number of infected cells remaining after the beginning and middle of treatment requires time.
  • Reactivation of latent virus and clearance of infected cells can be conceptualized as occurring via half- life kinetics based on a rate constant.
  • a course of treatment generally should last long enough to reduce remaining latently and/or actively infected cells to below a threshold level.
  • Such clinical factors and their assessment are well known and are discussed elsewhere herein.
  • the schedule of treatment during a course of treatment generally can be a schedule of treatment that will keep the compounds or compositions at or above an effective, therapeutic level in the subject.
  • reactivation of latent virus and clearance of infected cells generally does not require constant levels of the compounds or compositions. Rather, the levels need only be sufficient to reduce the half-life of latent virus and/or infected cells and to reduce the possibility of new cell infection and provirus integration.
  • administrations are preferred to irregular schedules and frequent administrations.
  • the half-life of therapeutic compounds and compositions in subjects generally determine the frequency of administration.
  • the schedule of administration generally will be one or more administrations per day of the compositions.
  • the disclosed compositions can be administered from 10 to 80 weeks, preferably from 10 to 40 weeks, more preferably from 10 to 30 weeks, and most preferably from 20 to 40 weeks.
  • the period of time can end after the earlier of 40 weeks or 4 weeks after HIV infected cells are no longer detected, preferably 3 weeks after HIV infected cells are no longer detected, most preferably 2 weeks after HIV infected cells are no longer detected.
  • the period of time can end after the earlier of 40 weeks or 4 weeks after the HIV viral load becomes undetectable, preferably 3 weeks after the HIV viral load becomes undetectable, most preferably 2 weeks after the HIV viral load becomes undetectable.
  • the inhibitors of HIV infection of CD4 T cells can be administered one to four times daily, preferably one to three times daily, more preferably one or two times daily, most preferably one time daily.
  • the inhibitors of HIV infection of CD4 T cells can be administered one to four times daily, preferably one to three times daily, more preferably one or two times daily, most preferably one time daily.
  • the stimulator of reactivation of latent HIV can be administered one to four times daily, preferably one to three times daily, more preferably one or two times daily, most preferably one time daily.
  • the highly active antiretroviral therapy can be administered one to four times daily, preferably one to three times daily, more preferably one or two times daily, most preferably one time daily.
  • HAART can be administered one to four times daily, preferably one to three times daily, more preferably one or two times daily, most preferably one time daily.
  • the stimulator of CD8 T cell response to HIV can be administered one to four times daily, preferably one to three times daily, more preferably one or two times daily, most preferably one time daily.
  • Different compounds and compositions can be administered following the same schedule, a similar schedule, or different schedules.
  • courses of treatment of different compounds and compositions can be overlapping, completely overlapping, partially overlapping, or sequential.
  • the highly active antiretroviral therapy (HAART), stimulator of CD8 T cell response to HIV, or both can be administered simultaneous with, overlapping with, or following the administration of the inhibitors of HIV infection of CD4 T cells and the stimulator of reactivation of latent HIV.
  • the methods and compositions can be used with any virally infected subject.
  • the subject has CD4 T cell count of 500 per cubic millimeter or greater.
  • the subject is receiving anti-HIV therapy.
  • the subject is naive of anti-HIV therapy or on an anti-HIV therapy holiday.
  • the subject began and continued anti-HIV therapy up to some period of time before beginning a course of treatment, up to and overlapping with a course of treatment, up to the beginning a course of treatment, up to and throughout a course of treatment, or up to, throughout, and beyond the end of a course of treatment.
  • the subject began anti-HIV therapy during acute HIV infection.
  • the subject began anti-HIV therapy during acute HIV infection and continued with anti-HIV therapy up to some period of time before beginning a course of treatment, up to and overlapping with a course of treatment, up to the beginning a course of treatment, up to and throughout a course of treatment, or up to, throughout, and beyond the end of a course of treatment.
  • the subject has not been administered any anti-HIV treatment for at least 2 weeks prior to beginning a course of treatment of the methods or compositions disclosed herein, preferably for at least 3 weeks, more preferably for at least 4 weeks, most preferably for at least 5 weeks, and in some embodiments, for at least 10 weeks prior to administration of the inhibitors and reactivation stimulator.
  • the subject is not administered HAART for at least the first 10 weeks of the start of a course of treatment disclosed herein, preferably for at least the first 15 weeks, more preferably for at least the first 20 weeks, most preferably for at least the first 30 weeks.
  • the subject begins or continues anti-HIV therapy following the end of a course of treatment for a period of time, such as 1 day to 8 weeks, 7 days to 4 weeks, or 2 weeks following the end of a course of treatment.
  • anti-HIV therapy ends at the end of a course of treatment.
  • the inhibitors of HIV infection of CD4 T cells and stimulator of reactivation of latent HIV are administered in the same course of treatment. In some embodiments, the inhibitors and reactivation stimulator are administered in different courses of treatment. In some embodiments, the first and second inhibitors of HIV infection of CD4 T cells are administered in the same course of treatment while the reactivation stimulator is administered in a different course of treatment. In some embodiments, the first inhibitor of HIV infection of CD4 T cells and the reactivation stimulator are administered in the same course of treatment while the second inhibitor of HIV infection of CD4 T cells is administered in a different course of treatment. In some embodiments, the second inhibitor of HIV infection of CD4 T cells and the reactivation stimulator are
  • the inhibitors and reactivation stimulator can be administered in different course of treatment from the highly active antiretroviral therapy (HAART), the stimulator of CD8 T cell response to HIV. or both.
  • HAART highly active antiretroviral therapy
  • Preferred courses of treatment include multiple cycles of
  • a cycle of administration can involve administration of daily dosage regimes of a set of compounds for a set number of days, followed by an interruption of, or change in, the administration of the compounds.
  • Preferred courses of treatment will include two or more such cycles of administration separated by gaps of a set number of days or weeks between (interrupting) the cycles of administration.
  • a course of treatment can involve three cycles of administration each lasting 14 days and each interrupted by a break or pause in administration lasting 14 days.
  • the number of cycles, the number of days of administration in a cycle, and the number of days or weeks interrupting the cycles can vary in different embodiments.
  • cycles of administration are used for only one or some of the compounds, the remaining compounds can be administered throughout the course of administration (with no cycles and no interruptions). Different compounds and different administrations can also follow different cycles that are overlapping or non-overlapping, or that are interspersed.
  • Courses of treatment can also include interspersed cycles of administration of one, more, or all of the compounds used in the course of treatment with dosages staying the same or changing in the interspersed cycles for one. more, or all of the compounds used in the course of treatment.
  • Cycles that are interspersed are non-overlapping consecutive cycles. For example, a cycle of one type or schedule of administration that, once interrupted, is replaced by a cycle of a different type or schedule of administration, usually with the compounds, dosages, or both, differing in the interspersed cycles.
  • the course of treatment can include three or more cycles of administration of at least three compounds collectively having the following activities: (i) dampening of immune activation with a bias more on the CD4 T cell response relative to the CD8 T cell response, (ii) inhibition of HIV replication, (iii) stimulation of reactivation of latent HIV, and (iv) inhibition of infection of CD4 T cells by HIV.
  • Each cycle can last 7 to 21 days and be interrupted for 7 to 21 days.
  • Interspersed between (during the interruption of) these cycles can be cycles of administration of at least three compounds collectively having the following activities: (i) dampening of immune activation with a bias more on the CD4 T cell response relative to the CD8 T cell response, (ii) inhibition of HIV replication, and (iii) inhibition of infection of CD4 T cells by HIV.
  • the interspersed cycles would last for the period of interruption of the main cycles: 7 to 21 days.
  • the course of treatment can end after the same number of main and interspersed cycles, ending on an interspersed cycle, or, preferably, the course of treatment can end after the last main cycle, with one fewer interspersed cycle than the number of main cycles.
  • the number of cycles, the length of cycles, the length of interruptions of the cycles, or a combination thereof can be varied during the course of treatment.
  • the variations can be set at the beginning or the course of treatment or, preferably, can be adjusted during the course of treatment based on assessment of the effectiveness of the treatment.
  • cycles can be added until one or more clinical endpoints, one or more clinical factors, or a combination thereof, have reached a threshold level.
  • the length of cycles can be increased in later cycles if, for example, one or more clinical endpoints, one or more clinical factors, or a combination thereof, have not yet reached a threshold level.
  • cycles can be dropped if one or more clinical endpoints, one or more clinical factors, or a combination thereof, have reached a threshold level; and the length of cycles can be decreased in later cycles if, for example, one or more clinical endpoints, one or more clinical factors, or a combination thereof, have reached a threshold level.
  • cycles can be added until CD4 T cell count has increased to or above a threshold level, HIV viral load has decreased to or below a threshold level, HIV infected cell count has decreased to or below a threshold level, or a combination thereof.
  • cycles can be added until: CD4 T cell count has increased to or above 350 per cubic millimeter, preferably 500 per cubic millimeter; until HIV viral load has decreased to or below 1000 copies per milliliter of blood, preferably 100 copies per milliliter of blood, most preferably undetectable; until HIV infected cell count has decreased to or below 1% of peripheral blood mononuclear cells, preferably below 0.1% of peripheral blood mononuclear cells, most preferably below 0.01 % of peripheral blood mononuclear cells; or a combination thereof.
  • cycles can be added until: CD4 T cell count has increased to or above 350 per cubic millimeter, preferably 500 per cubic millimeter; until HIV viral load remains at or below 1000 copies per milliliter of blood, preferably 100 copies per milliliter of blood, most preferably undetectable at 1 week, preferably 2 weeks, most preferably 3 weeks after the course of treatment; until HIV infected cell count has decreased to or below 1 % of peripheral blood mononuclear cells, preferably below 0.1% of peripheral blood mononuclear cells, most preferably below 0.01 % of peripheral blood mononuclear cells; or a combination thereof.
  • the length of cycles can be increased until CD4 T cell count has increased to or above a threshold level, HIV viral load has decreased to or below a threshold level, HIV infected cell count has decreased to or below a threshold level, or a combination thereof.
  • the length of cycles can be increased until: CD4 T cell count has increased to or above 350 per cubic millimeter, preferably 500 per cubic millimeter; until HIV viral load has decreased to or below 1000 copies per milliliter of blood, preferably 100 copies per milliliter of blood, most preferably undetectable; until HIV infected cell count has decreased to or below 1 % of peripheral blood mononuclear cells, preferably below 0.1% of peripheral blood mononuclear cells, most preferably below 0.01 % of peripheral blood mononuclear cells; or a combination thereof.
  • courses of treatment can also be used.
  • the same or a different course of treatment can be administered if, for example, one or more clinical endpoints, one or more clinical factors, or a combination thereof, moves to or beyond a threshold level.
  • a new course of treatment can be administered if CD4 T cell count has decreased to or above 1000 per cubic millimeter, preferably 500 per cubic millimeter, most preferably 350 per cubic millimeter; until HIV viral load increases to or above 100 copies per milliliter of blood, preferably 500 copies per milliliter of blood, most preferably 1000 copies per milliliter of blood; until HIV infected cell count has increased to or above 0.1 % of peripheral blood mononuclear cells, preferably above 1 % of peripheral blood mononuclear cells, most preferably above 2% of peripheral blood mononuclear cells; or a combination thereof.
  • the effectiveness of the methods and compositions can be assessed in any suitable manner.
  • the effect of the methods and compositions on subjects in which they are used is a preferred approach.
  • the methods and courses of treatment can be assessed by testing one or more clinical factors.
  • assessments can include, for example, CD4 T cell count, HIV viral load, and HIV infected cell count. Any other assessment of the state of HIV infection can also be used.
  • the methods and courses of treatment can also be assessed and adjusted based on assessments of the state of viral infection. For example, methods and courses of treatment in the methods can be continued for one or more clinical endpoints and/or until one or more clinical factors have reached a threshold level. For example, a course of treatment can be continued until CD4 T cell count has increased to or above a threshold level, HIV viral load has decreased to or below a threshold level, and/or HIV infected cell count has decreased to or below a threshold level.
  • a course of treatment can be continued until: CD4 T cell count has increased to or above 350 per cubic millimeter, preferably 500 per cubic millimeter; until HIV viral load has decreased to or below 1000 copies per milliliter of blood, preferably 100 copies per milliliter of blood, most preferably undetectable; and/or until HIV infected cell count has decreased to or below 1% of peripheral blood mononuclear cells, preferably below 0.1% of peripheral blood mononuclear cells, most preferably below 0.01% of peripheral blood mononuclear cells.
  • the methods and compositions can result in an improved state of viral infection.
  • the methods and compositions can result in an improved state of viral infection for a period of time following the end of a course of treatment.
  • CD4 T cell count can remain at or above a threshold level
  • HIV viral load can remain at or below a threshold level
  • HIV infected cell count can remain at or below a threshold level for and/or at 8 weeks, preferably 3 months, more preferably 6 months, and most preferably 12 months following the end of a course of treatment. In particular embodiments.
  • CD4 T cell count can remain at or above 350 per cubic millimeter, preferably 500 per cubic millimeter; HIV viral load can remain at or below 1000 copies per milliliter of blood, preferably 100 copies per milliliter of blood, most preferably undetectable; and/or HIV infected cell count can remain at or below 1% of peripheral blood mononuclear cells, preferably below 0.1% of peripheral blood mononuclear cells, most preferably below 0.01% of peripheral blood mononuclear cells for and/or at 8 weeks, preferably 3 months, more preferably 6 months, and most preferably 12 months following the end of a course of treatment.
  • Clinical factors of HIV infection generally can be assessed in blood or blood components. However, in some embodiments, clinical factors can be assessed in other types of samples, such as semen, vaginal secretions, gut- associated lymphoid tissue (GALT), bone marrow, saliva, lymphatic fluid, lymph tissue, and cerebrospinal fluid.
  • GALT gut-associated lymphoid tissue
  • administering means that the viral load of the patient remains suppressed following discontinuation of treatment for at least two weeks, one month, two months, or longer. This can be determined using any of the foregoing methods, but typically is performed by measuring the amount of virus in the blood.
  • the disclosed methods can result in treated subjects in which, for example, CD4 T cell count remains greater than or equal to 500 cells/mm 3 and viral load remains less than or equal to 10,000 copies/ml blood for at least 1 year after cessation of treatment, preferably 2 years after cessation of treatment, and more preferably 3 years after cessation of treatment.
  • the disclosed methods can result in treated subjects in which, for example, CD4 T cell count remains greater than or equal to 500 cells/mm 3 and viral load remains less than or equal to 500 copies/ml blood for at least 1 year after cessation of treatment, preferably 2 years after cessation of treatment, and more preferably 3 years after cessation of treatment.
  • the disclosed methods can result in treated subjects being long-term nonprogressors, controllers, or functionally cured for at least 1 year after cessation of treatment, preferably 2 years after cessation of treatment, and more preferably 3 years after cessation of treatment.
  • the disclosed methods can result in treated subjects in which, for example, CD4 T cell count remains greater than or equal to 500 cells/mnr and viral load remains less than or equal to 10,000 copies/ml blood for at least 1 year after cessation of anti-viral therapy, preferably 2 years after cessation of anti-viral therapy, and more preferably 3 years after cessation of anti-viral therapy.
  • the disclosed methods can result in treated subjects in which, for example.
  • CD4 T cell count remains greater than or equal to 500 cells/mm 3 and viral load remains less than or equal to 500 copies/ml blood for at least 1 year after cessation of anti-viral therapy, preferably 2 years after cessation of anti-viral therapy, and more preferably 3 years after cessation of anti-viral therapy.
  • the disclosed methods can result in treated subjects being long-term nonprogressors, controllers, or functionally cured for at least 1 year after cessation of anti-viral therapy, preferably 2 years after cessation of anti-viral therapy, and more preferably 3 years after cessation of anti-viral therapy.
  • any subject in need of the disclosed methods and compositions can be treated.
  • suitable subjects are infected with HIV or have been exposed to HIV.
  • Subjects can be, for example, newly infected, infected long- term, anti-HIV therapy experienced, or naive to anti-HIV therapy.
  • Anti-HIV therapy in naive subjects may be more receptive to the method and make one or more of the compounds used more effective.
  • Subjects generally should be selected for such appropriate characteristics. Such selection and
  • the selected subject has CD4 T cell count of 500 per cubic millimeter or greater. In some embodiments, the selected subject is receiving anti-HIV therapy. In some embodiments, the subject is naive of anti-HIV therapy or on an anti-HIV therapy holiday. In some embodiments, the selected subject began and continued anti-HIV therapy up to some period of time before beginning a course of treatment, up to and overlapping with a course of treatment, up to the beginning a course of treatment, up to and throughout a course of treatment, or up to, throughout, and beyond the end of a course of treatment. In some embodiments, the selected subject began anti-HIV therapy during acute HIV infection.
  • the selected subject began anti-HIV therapy during acute HIV infection and continued with anti-HIV therapy up to some period of time before beginning a course of treatment, up to and overlapping with a course of treatment, up to the beginning a course of treatment, up to and throughout a course of treatment, or up to, throughout, and beyond the end of a course of treatment.
  • HIV can use CXCR4 as the co-receptor rather than CCR5
  • subjects should be selected based on their co-receptor tropism if, for example, maraviroc (a CCR5 receptor antagonist) is used.
  • Examples 2-4 demonstrate combination therapies that should be effective in maintaining low viral load after cessation of drug therapy as defined above, as well as combinations that are not effective.
  • Example 1 Simulation of HIV infection Treatment Outcome and Correlation with Multiple Clinical Trials
  • a computer model of the human immune system has been developed which can accurately simulate the effect on the immune system and clinical factors of HIV infection and clinical treatments of HIV infection.
  • the model has been validated by inputting the drugs, dosages, and dosing regimens as well as patients to be treated, for drugs in which the clinical outcomes have been described in the literature.
  • the results obtained with the computer model which is not based on input of the clinical trial results to be validated, demonstrate that the treatments using reverse transcriptase inhibitors do not result in elimination of HIV reservoirs, as shown by a rapid rise in blood viral load following cessation of drug treatment.
  • AZT a "classic" HIV drug, inhibits HIV replication in target cells by inhibiting reverse transcription of the virus.
  • the treatment used 250mg AZT, 4 times daily, for 6 months. CD4 T cell count was monitored.
  • the simulation is an extremely accurate predictor of the median impact observed in Concorde trial— both the quantum and the timing, fallin within the range of impact observed at 3 months into treatment using 300 mg AZT 2 times daily for 13 days (trial stopped).
  • AZT zidovudine
  • the Ruane trial monitored (a) viral load in bloodstream, as reduced by treatment, and (b) the viral load rebound after treatment ended.
  • the simulation exhibits the same time pattern and the same magnitude of impact on the viral load as was observed during and after the treatment.
  • the simulation shows return to untreated viral set point within 2 weeks of ending treatment, just as was observed in the trial results.
  • Gallant et al. (N Engl. J .Med. 2006 Jan 19; 354(3):251 -60) reported on an open-label, noninferiority study involving 517 patients with HIV infection who had not previously received anti-retroviral therapy and who were randomly assigned to receive either a regimen of tenofovir disoproxil fumarate (DF). emtricitabine. and efavirenz once daily (tenofovir- emtricitabine group) or a regimen of fixed-dose zidovudine and lamivudine twice daily plus efavirenz once daily (zidovudine-lamivudine group).
  • DF tenofovir disoproxil fumarate
  • HAART combines two nucleoside/nucleotide reverse-transcription inhibitors (NRTIs) and one non-nucleoside reverse-transcription inhibitor (NNRTI), thus reducing viral integration in the target cell.
  • NRTIs nucleoside/nucleotide reverse-transcription inhibitors
  • NRTI non-nucleoside reverse-transcription inhibitor
  • SQV/r treatment was noninferior in virologic suppression at 48 weeks to LPV/r treatment and offered a better triglyceride profile.
  • Example 2 Simulated Treatment to hinder CD4 T cell infection; force latently infected cells to produce and present HIV; and push a stronger CD8 T cell response to HIV.
  • Treatment simulation was performed to target three points at the same time to hinder CD4 T cell infection; force latently infected cells to produce and present HIV; and push a stronger CD8 T cell response to HIV.
  • new infections are held in check directly (as with a CCR5 inhibitor), latent cells are pushed out via activation (such as with a histone deacetylase inhibitors), and the CD8 T cell response is magnified (as IL-15 might accomplish), for example, by administering Maraviroc. vorinostat and IL-15 using standard dosing: Maraviroc at 600mg /2x/daily, Vomisotat at 400mg daily.
  • Figures 2 and 3 show the results of a simulated treatment protocol being initiated at week 26 and continuing to week 40.
  • Figure 2 tracks the HIV viral load and shows that the HIV viral load in the blood approaches zero around week 36.
  • Figure 3 tracks CD4 T cell count and shows that CD4 T cell count increases during the course of treatment (for the duration of the simulation shown).
  • Example 3 Simulation of combination treatment to reduce HIV infection of CD4+T cells, drives HIV and associated antigen presentation from latently infected cells, and prevents viral replication.
  • This example describes simulations using the model of a treatment strategy that uses two targets (“levers") concurrently, then adds a third, HAART, to clear the rest of the HIV.
  • the initial targets are to reduce HIV infection of CD4+T cells and to drive HIV and associated antigen presentation from latently infected cells.
  • the first effect can be accomplished with, for example, a CCR5 inhibitor such as Maraviroc.
  • the second effect can be accomplished with, for example, a histone deacetylase inhibitors such as Vorinostat. All simulations using Vorinostat assume 400 mg, once daily and Maraviroc at 600mg/2x/daily.
  • Variations on this protocol can drive simulated viral load to zero and completely eliminate the simulated virus.
  • a protocol termed "multiple levers and HAART” the two-lever protocol can be applied from the start of week 26 through the start of week 36 and a standard HAART protocol (two non-nucleoside reverse transcriptase inhibitors and one protease inhibitor) can be added from the start of week 34 through week 46.
  • Figures 6 and 7 show the results of this protocol.
  • viral load does not return following the termination of treatment ( Figure 6).
  • CD4 T cell counts increase during the course of treatment and continue increasing following the termination of treatment ( Figure 7).
  • the model of the human immune system can show the dependency of the results of treatment protocols on the effectiveness of the levers that are used.
  • This example shows the dependency' of HIV infected cell count on the use of three drugs, two for reduction HIV infection and one for reactivating latent HIV, in a treatment protocol.
  • the two drugs for reduction of HIV infection are a CCR5 inhibitor such as Maraviroc, and anti-inflammatory, such as hydroxy chloquine.
  • Reactivating latent HIV uses a histone deacetylase inhibitor such as Vorinostat in this example treatment protocol.
  • Table 1 Reduction of HIV infection with a CCR5 inhibitor; an antiinflammatory; and a histone deacetylase inhibitor
  • the quantity of absorbed and available drug is translated into an effect on HIV infectivity, CD4 T cell activation or reactivation of latent HIV.
  • the infection rate was calculated as a product of the concentration of viral particles with the concentration of target cells and a rate constant.
  • the effectiveness of Maraviroc is applied via the rate constant.
  • the priming and activation of CD4 T cells was calculated as a product of the concentration of mature antigen presenting dendritic cells, the concentration of HIV specific naive and central memory CD4 T cells and a rate constant.
  • the effectiveness of hydroxychloroquine is applied via the rate constant.
  • the reactivation of latent HIV was calculated as a product of a concentration of latently infected CD4 T cells and a rate constant.
  • the effectiveness of Vorinostat is applied via the rate constant.
  • Figure 9 displays the output from a series of simulations that include a no treatment base (only line at 20 weeks), a full treatment using effective amounts of all three drugs (VMC; lowest line at week 41), and treatments leaving one or two of the drugs out.
  • the results show the full treatment (VMC) clears HIV infected cells by week 41. Only the treatment with both Vorinostat and Maraviroc (VM) shows clearance (second lowest line at week 41). All other treatments with only one or two of the drugs fail to clear HIV infected cells (all lines over 7.5 at week 104). In fact, all of these other treatments are essentially no better than the no treatment base.
  • hydroxychloroquine is not essential for clearance of HIV infected cells, the full treatment includes it to speed and increase the reliability of clearance.
  • Figure 10 displays the output from a series of simulations that include a no treatment base (only line at 25 weeks), a full treatment using effective amounts of all three drugs (VMC; lowest line at week 41), and treatments where the effectiveness of Vorinostat is varied from the base amount. All treatments were begun at week 26 and ended after week 42. Table 2 shows the drugs used in the different treatments, with an "x" indicating use of the effective amount of the drug for that row. The number shown for Vorinostat is the rate constant used in the simulation expressed as the fold effectiveness of Vorinostat.
  • VMC full treatment
  • Figure 11 displays the output from a series of simulations that include a no treatment base (only line at 25 weeks), a full treatment using effective amounts of all three drugs (VMC; line that goes to zero at week 41), and treatments where the effectiveness of Maraviroc is varied from the base amount. All treatments were begun at week 26 and ended after week 42. Table 3 shows the drugs used in the different treatments, with an " x" indicating use of the effective amount of the drug for that row. The number shown for Maraviroc is the rate constant used in the simulation expressed as the fold effectiveness of Maraviroc.
  • VMC full treatment
  • VM2.5C lines that go to zero at weeks 34 and 36, respectively
  • VMC full treatment
  • Figure 12 displays the output from a series of simulations that include a no treatment base (only line at 25 weeks), a full treatment using effective amounts of all three drugs (VMC; line that goes to zero at week 41), and treatments where the effectiveness of hydroxychloroquine is varied from the base amount. All treatments were begun at week 26 and ended after week 42. Table 4 shows the drugs used in the different treatments, with an "x " indicating use of the effective amount of the drug for that row. The number shown for hydroxychloroquine is the rate constant used in the simulation expressed as the fold effectiveness of hydroxychloroquine.
  • VHM vorinostat/hydroxv chloroquine /maraviroc
  • VHM vorinostat/hydroxychloroquine/maraviroc
  • TRC-ARC This is a single-center proof-of-concept study in which enrolment was completed April 1, 2015 and follow-up of volunteers is ongoing at the TRC-ARC.
  • the TRC-ARC has extensive experience in executing clinical HIV treatment studies with intensive specimen collections, processing, storage, international shipments and complex laboratory assays.
  • the TRC- ARC is associated with two intemationally-accredited (College of American Pathologists) clinical laboratory facilities.
  • Subj ects were recruited from RV254/SEARCH 010.
  • RV254/SEARCH 010 is an acute HIV infection cohort funded by the US Military HIV Research Program and conducted by the TRC-ARC in Bangkok, Thailand. Subjects were co-enrolled in RV254/SEARCH 010 but do not have any blood drawn for RV254/SEARCH 010 during the period of co-enrollment, so the total blood draw in this treatment interruption study represents the only blood samples that will be taken from these patients.
  • Vorinostat is administered at 400mg orally every 24h for 3 cycles, each of 14 days with an interim rest-period of 14 days between cycles.
  • HCQ is administered at a dose of 200mg 2X/daily during the course of vorinostat administration (10 weeks).
  • Maraviroc is administered at 600 mg 2X/daily on the same schedule as HCQ. This dose of maraviroc is based on its concomitant use with efavirenz. Maraviroc dosing is adjusted as appropriate should the subject be on an integrase or a protease inhibitor instead of efavirenz due to intolerance to the drug or primary NNRTI resistance.
  • NRTI nucleos(t)ide reverse- transcriptase inhibitors
  • FTC emtricitabine
  • TDF tenofovir
  • EVF non-nucleoside reverse transcriptase inhibitor
  • NNRTI In subjects on NNRTI -based therapy, the NNRTI is interrupted at week 8 and the rest of the regimens are interrupted at week 10.
  • protease inhibitor replacement therapy with darunavir 900 mg ⁇ /day with ritonavir 100 mg I X/day is given between weeks 8 and 10 and maraviroc reduced from 1200 mg/day to 300mg/day; TDF, 300mg ⁇ /day, and EFV, 600mg lX/day. Studv Duration

Abstract

L'invention concerne des procédés et des compositions destinés au traitement d'infections par le virus de l'immunodéficience humaine (VIH), lesdits procédés et compositions atténuant l'activation immunitaire avec un biais avantageant les cellules T CD4 par rapport à la réponse des cellules T CD8, inhibant la réplication du VIH, réactivant le VIH latent et inhibant l'infection de cellules par le VIH. Induire le VIH latent à susciter des infections actives en faisant obstacle à l'infection des cellules par le VIH réactivé peut réduire de façon substantielle le nombre de cellules infectées par le VIH et la charge virale de VIH, ce qui ne se produit pas si l'on utilise que la combinaison d'une TAR et de composés qui activent le VIH latent. Les procédés impliquent l'administration à un sujet infecté par le VIH de trois composés ou plus qui atténuent collectivement l'activation immunitaire avec un biais avantageant les cellules T CD4 par rapport à la réponse des cellules T CD8, inhibant la réplication du VIH, réactivant le VIH latent et inhibant l'infection de cellules T CD4 par le VIH.
PCT/US2016/035027 2015-06-02 2016-05-31 Procédés et compositions pour le traitement d'une infection par le vih WO2016196471A1 (fr)

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US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
CN110101705A (zh) * 2019-05-07 2019-08-09 河南农业大学 Bet家族蛋白抑制剂的抗病毒用途
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
WO2021146272A1 (fr) * 2020-01-13 2021-07-22 The Regents Of The University Of California Procédés de traitement d'infections virales
WO2021231797A1 (fr) * 2020-05-13 2021-11-18 Rapa Therapeutics, Llc Traitement ou prévention de maladies ou d'états pro-inflammatoires à l'aide de lymphocytes t régulateurs induits (itreg)
WO2022003598A1 (fr) * 2020-07-02 2022-01-06 Viiv Healthcare Company Procédé d'obtention d'une rémission virale du vih à l'aide d'agents antirétroviraux à action prolongée

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CN110101705B (zh) * 2019-05-07 2022-01-14 河南农业大学 Bet家族蛋白抑制剂的抗病毒用途
WO2021146272A1 (fr) * 2020-01-13 2021-07-22 The Regents Of The University Of California Procédés de traitement d'infections virales
WO2021231797A1 (fr) * 2020-05-13 2021-11-18 Rapa Therapeutics, Llc Traitement ou prévention de maladies ou d'états pro-inflammatoires à l'aide de lymphocytes t régulateurs induits (itreg)
WO2022003598A1 (fr) * 2020-07-02 2022-01-06 Viiv Healthcare Company Procédé d'obtention d'une rémission virale du vih à l'aide d'agents antirétroviraux à action prolongée

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