Abstract:
The present invention provides a method of treating HIV-1 infection in a subject. The method comprises administering to the subject a combination of anti-HIV-1 agents wherein the combination comprises an effective dose of Apricitabine and an effective dose of Atazanavir.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to a combination of anti-viral agents to treat human immunodeficiency virus type 1 (HIV-1) infection. The combination includes Apricitabine and Atazanavir. 
       BACKGROUND OF THE INVENTION 
       [0002]    Since its discovery HIV-1 has been the subject of intense study to understand the virus and the pathogenesis associated with infection. These studies have lead to the development of a number of anti-HIV-1 agents which target different points in the HIV-1 replication cycle and in the manner in which the virus infects cells. These agents fall into the following groups: (i) nucleoside and nucleotide reverse transcriptase inhibitors (NRTI); (ii) nonnucleoside reverse transcriptase inhibitors (NNRTI); (iii) protease inhibitors (PI); (iv) integrase inhibitors (INSTI); and (v) binding and entry inhibitors. Examples of these agents and the target of their activity are set out in Table 1. 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Anti-HIV-1 Agents 
               
             
          
           
               
                 Compound type and generic 
                 Common 
                   
               
               
                 name 
                 abbreviation 
                 Target 
               
               
                   
               
               
                 NRTIs 
                   
                   
               
               
                 Azidothymidine 
                 AZT 
                 HIV-1 reverse transcriptase 
               
               
                 Zalcitabine 
                 ddC 
               
               
                 Didanosine 
                 ddI 
               
               
                 Lamivudine 
                 3TC 
               
               
                 Stavudine 
                 D4T 
               
               
                 Abacavir 
                 ABC 
               
               
                 Emtricitabine 
                 FTC 
               
               
                 Tenofovir 
                 TDF 
               
               
                 Apricitabine 
                 ATC 
               
               
                 NNRTIs 
               
               
                 Nevirapine 
                 NVP 
                 HIV-1 reverse transcriptase 
               
               
                 Delaviridine 
                 DLV 
               
               
                 Efavirenz 
                 EFV 
               
               
                 Etravirine 
                 ETV 
               
               
                 Rilpivarine 
                 RPV 
               
               
                 PIs 
               
               
                 Amprenavir 
                 APV 
                 HIV-1 protease 
               
               
                 Indinavir 
                 IDV 
               
               
                 Nelfinavir 
                 NFV 
               
               
                 Atazanavir 
                 ATV 
               
               
                 Lopinavir 
                 LPV 
               
               
                 Saquinavir 
                 SQV 
               
               
                 Darunavir 
                 DRV 
               
               
                 Fosamprenavir 
                 FPV 
               
               
                 Ritonavir 
                 RTV 
               
               
                 Tipranavir 
                 TPV 
               
               
                 INSTI 
               
               
                 Raltegravir 
                 RAL 
                 HIV-1 integrase 
               
               
                 Binding and entry inhibitors 
               
               
                 Maraviroc 
                 MVC 
                 CCR5 in its role as an HIV- 
               
               
                   
                   
                 coreceptor 
               
               
                 Enfuvirtide 
                 T-20 
                 gp-41-mediated fusion 
               
               
                   
               
             
          
         
       
     
         [0003]    It has long been recognized mono-therapy for HIV-1 infection is only transiently effective. This has lead to the development of combination therapies for HIV-1 (HAART). The principle driving force behind the development of these therapies was the emergence of drug resistance following the therapeutic use of single antiretroviral drugs such as AZT. 
         [0004]    Apricitabine (4-amino-1-[(2R,4R)-2-(hydroxymethyl)-1,3-oxathiolan-4-yl]pyrimidin-2(1H)-one((ATC) is a nucleoside reverse transcriptase inhibitor (NRTI) active against HIV. It is structurally related to Lamivudine and Emtricitabine, and, like these, is an analogue of cytidine. 
         [0000]    
       
                 
         
             
             
         
       
     
       Apricitabine 
       [0005]    Atazanavir (methyl N-[(1S)-1-{[(2S,3S)-3-hydroxy-4-[(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethyl-N′-{[4-(pyridin-2-yl)phenyl]methyl}butanehydrazido]-1-phenylbutan-2-yl]carbamoyl}-2,2-dimethylpropyl]carbamate) (ATV), marketed under the trade name Reyataz by Bristol Myers, is an antiretroviral drug of the protease inhibitor (PI) class. Atazanavir is distinguished from other PIs in that it can be given once-daily (rather than requiring multiple doses per day) and has lesser effects on the patient&#39;s lipid profile. Like other protease inhibitors, it is used only in combination with other HIV medications. 
         [0000]    
       
                 
         
             
             
         
       
     
       Atazanavir 
     SUMMARY OF THE INVENTION 
       [0006]    The present inventors have found that a combination of Apricitabine and Atazanavir is more efficacious than a combination of Lamivudine and Atanazavir. 
         [0007]    Accordingly, a first aspect the present invention provides a method of treating HIV-1 infection in a subject comprising administering to the subject a combination of anti-HIV-1 agents wherein the combination comprises an effective dose of Apricitabine and an effective dose of Atanazavir. 
         [0008]    In a second aspect the present invention provides a combination of anti-HIV-1 agents wherein the combination comprises an effective dose of Apricitabine and an effective dose of Atanazavir for treating HIV-1 infection. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0009]    The present invention relates to combination therapies for HIV-1 infection. As mentioned above the present inventors have found that a combination of ATC and ATV is more useful in reducing viral load than a combination of 3TC and ATV. Accordingly the present invention relates to combination therapy where the combination comprises ATC and ATV. 
         [0010]    The combination comprises an effective dose of both ATC and ATV. As used herein an “effective dose” is a dose which results in a reduction of viral load. Typically an effective dose of ATC is 400 to 1200 mg b.i.d and an effective dose of ATV is 400 mg QD or 300 mg QD with 100 mg Ritonavir QD. 
         [0011]    It is preferred that the combination includes one or more other anti-HIV-1 agents. Preferably the combination includes NRTIs such as Azidothymidine, Didanosine, Lamivudine, Stavudine, Abacavir; NNRTIs such as Nevirapine, Delaviridine, Efavirenz Rilpivirine and Etravirine; the NtRTI Tenofovir: PI&#39;s such as Amprenavir, Indinavir, Nelfinavir, Lopinavir, Saquinavir, Darunavir, Fosamprenavir, Tipranavir and Ritonavir; INSTIs such as Raltegravir and the Binding and entry inhibitors such as Maraviroc and Enfuvirtide. 
         [0012]    Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. 
         [0013]    All publications mentioned in this specification are herein incorporated by reference. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia or elsewhere before the priority date of each claim of this application. 
         [0014]    As used in the subject specification, the singular forms “a”, “an” and “the” include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to “a” includes a single as well as two or more; reference to “an” includes a single as well as two or more; reference to “the” includes a single as well as two or more and so forth. 
         [0015]    Having generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended as limiting. 
       EXAMPLES OF THE INVENTION 
       [0016]    Groups of HIV-1 positive patients were treated (as part of an optimized regimen) with ATC+either LPV or ATV, and compared to patients treated with 3TC+either LPV or ATV. Samples were taken after therapy to determine the number of patients who achieved an undetectable plasma HIV-1 RNA level (&lt;50 copies/mL). The results are set out in Table 2. 
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                 TABLE 2 
               
             
             
               
                   
                   
               
               
                   
                 Patients achieving &lt;50 copies/mL 
                   
               
             
          
           
               
                   
                 800 mg BID ATC 
                   
                 150 mg BID 3TC 
                   
               
             
          
           
               
                   
                 Drug 
                 n/N 
                 % 
                 n/N 
                 % 
               
               
                   
                   
               
             
          
           
               
                   
                 LPV 
                 18/30 
                 60 
                 18/29 
                 62 
               
               
                   
                 ATV 
                  8/12 
                 66.7 
                  6/14 
                 42.9 
               
               
                   
                   
               
             
          
         
       
     
         [0017]    A surprisingly greater number of patients receiving ATC+ATV responded compared to those receiving 3TC+ATV.