BACKGROUND OF THE INVENTION 3'-Azido-3'-deoxythymidine (Retrovir, zidovudine) is now well established as an important and useful chemotherapeutic agent for the treatment and/or prophylaxis of HIV-infections including related clinical conditions such as AIDS, AIDS-related complex (ARC), AIDS dementia complex (ADC) and also for the treatment of patients who have an asymptomatic HIV infection or who are anti-HIV antibody-positive. Treatment with zidovudine prolongs the disease-free interval in asymptomatic patients infected with HIV and delays death in symptomatic patients.

The success of modern multiple-drug treatments for HIV often requires strict compliance with a complex treatment regimen that can require the administration of many different drugs per day, administered at precisely timed intervals with careful attention to diet. Patient non-compliance is a well known problem accompanying such complex treatment regimens. Patient non-compliance is a critical problem in the treatment of HIV because such non-compliance may lead to the emergence of multiple-drug resistant strains of HIV.

From a patient lifestyle standpoint, the methods of the present invention would also be more convenient than a multiple daily dosing regimen. Patients would be subjected less frequently to the inconvenience of having to take the drug multiple times per day, particularly in light of the fact that management of

HIV infections involves multiple drug treatments with varying dosing schedules and food requirements, for example, fasting or administration with food. The methods of the present invention are likely to have the advantage of promoting better patient compliance, which in turn can translate into better therapeutic efficacy and reduced risk of emergence of drug-resistant HIV strains.

The present invention addresses the issue of non-compliance by methods of treatment of HIV infections involving alternative dosing regimens.

BRIEF DESCRIPTION OF THE INVENTION The present invention features methods for the treatment of an HIV infection comprising administration of a pharmaceutically effective amount of 3'-azido-3'- deoxythymidine once daily.

DETAILED DESCRIPTION OF THE INVENTION Retrovirus (zidovudine), also known as 3'-azido-3'-deoxythymidine, is approved for the treatment of HIV infections in combination with other antiretroviral agents. It is also indicated for the prevention of maternal-fetal HIV transmission as part of a regiment that includes oral zidovudine beginning between 14 and 34 weeks of gestation, intravenous zidovudine during labor, and administration of zidovudine syrup to the neonate after birth.

Therapy with Retrovirus has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV disease and to delay disease progression in asymptomatic HIV-infected patients.

The recommended oral dose of Retrovirs is 600 mg per day in divided doses in combination with other antiretroviral agents. The recommended dose in

pediatric patients 6 weeks to 12 years of age is 160 mg/m2 every 8 hours in combination with other antiretroviral agents.

Zidovudine is rapidly absorbed and distributed, with peak serum concentrations occurring within 0.5 and 1.5 hours. Elimination is rapid with terminal half-life of approximately 1.5-2 hours. It is renally eliminated by hepatic metabolism. It was originally thought that the intracellular half-life of the active metabolite, zidovudine triphosphate, would not be adequate to provide sufficient levels of the drug to achieve a therapeutic effect upon administration of the drug in a once daily regimen compared with 300 mg twice daily administration. However, we have recently discovered that, surprisingly, administration of zidovudine once daily is sufficient to provide a therapeutic effect. The results of an open-label, pharmacodynamic trial in antiretroviral therapy-naive subjects with 600 mg of zidovudine administered as a single dose once a day for 14 days indicated clear virologic activity (Example 1). The slope of viral load decline from Day 1 to Day 14 was-0.045. At day 14,10 of the 14 subjects had at least a 0.5 logic decrease in HIV-1 RNA.

The present invention features methods for the treatment of an HIV infection in a host, for example, a mammal, for example, a human, comprising administering to said host a therapeutically effective amount of 3'-azido-3'- deoxythymidine, or a pharmaceutically acceptable derivative thereof, once daily.

As used herein, the term"pharmaceutically acceptable derivative"includes any physiologically acceptable salt, ether, ester, salt of such ester of zidovudine, or solvates of any thereof and their physiologically functional derivatives; or any other compound which upon administration to the recipient, is capable of providing (directly or indirectly) such a compound or an antivirally active metabolite or residue thereof.

Preferred esters in accordance with the invention are independently selected from the following group: (1) carboxylic acid esters in which the non-carbonyl

moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n- butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, Cl_4 alkyl, or Cl 4 alkoxy), or amino; (2) sulphonate esters, such as alkyl-or aralkylsulphonyl (for example, methanesulphonyl); (3) amino acid esters (for example, L-valyl or L- isoleucyl) ; and (4) phosphonate esters. In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group. Any reference to any of the above compounds also includes a reference to a physiologically acceptable salt thereof.

Advantageous pharmaceutically acceptable derivatives of zidovudine are the mono-, di-, and tri-phosphate esters of zidovudine or any other compound which upon administration to a human subject is capable of providing (directly or indirectly) said mono-, di-, or triphosphate esters or their pharmaceutically acceptable base salts, for example, alkali metal, alkaline earth or ammonium salt.

The phrase"therapeutically effective amount, "as used herein, means a sufficient amount of a drug, compound, composition, product or pharmaceutical agent to abate or reverse or treat a malady in a human or other mammal without severely harming the tissues of the mammal to which the drug or pharmaceutical agent is administered.

It will be appreciated by those skilled in the art that reference herein to "treatment"extends to both the prophylaxis and the treatment of an established malady, infection or its symptoms.

It will be appreciated that zidovudine may exist in the keto or enol tautomeric form and the use of such a tautomeric form is within the scope of this invention.

Zidovudine can be prepared, for example, as described in U. S. Patent 4,724, 232, incorporated herein by reference hereto. Zidovudine can also be obtained from Aldrich Chemical Co. , Milwaukee, WI 53233, USA.

Zidovudine or its pharmaceutically acceptable derivatives may be employed in combination with other therapeutic agents for the treatment of HIV infection or conditions associated with HIV infection or AIDS. Such combination therapies according to the present invention comprise the administration of zidovudine or a pharmaceutically acceptable derivative thereof with at least one other pharmaceutically active ingredient. The active ingredient (s) and pharmaceutically active agents may be administered simultaneously in either the <BR> <BR> same or different pharmaceutical compositions or sequentially in any order. The amounts of the active ingredient (s) and pharmaceutically active agent (s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Preferably the combination therapy involves the administration of zidovudine and another therapeutic agent selected from [ [ [2- <BR> <BR> (6-amino-9H-purin-9-yl) ethoxy] methyl] phosphinylidene] bis (oxymethylene) -2, 2- dimethylpropanoic acid (bis-POM PMEA, adefovir dipivoxil), [ [ (1R)-2- (6- amino-9H-purin-9-yl)-1-methylethoxy] methyl] phosphonic acid (tenofovir), and (R)- [ [2- (6-Amino-9H-purin-9-yl)-1-methylethoxy] methyl] phosphonic acid bis- (isopropoxycarbonyloxymethyl) ester (bis-POC-PMPA), hydroxyurea, 2', 3'- dideoxycytidine (ddC, zalcitabine), 2', 3'-dideoxyadenosine, 2', 3'-dideoxyinosine (ddI, didanosine), 2', 3'-didehydrothymidine (d4T, stavudine), (-) -beta-D-2, 6- diaminopurine dioxolane (DAPD), (-)-cis-1- (2-hydroxymethyl)-1, 3-oxathiolane <BR> <BR> 5-yl) -cytosine (lamivudine), cis-1-(2-(hydroxymethyl)-1, 3-oxathiolan-5-yl)-5- fluorocytosine (FTC), (-)-cis-4- [2-amino-6- (cyclopropylamino)-9H-purin-9-yl]- 2-cyclopentene-1-methanol (abacavir), protease inhibitors, for example indinavir, ritonavir, nelfinavir, amprenavir, saquinavir, (R)-N-tert-butyl-3- [ (2S, 3S) -2-

hydroxy-3-N-[(R)-2-N-(isoquinolin-5-yloxyacetyl) amino-3- methylthiopropanoyl] amino-4-phenylbutanoyl]-5, 5-dimethyl-1, 3-thiazolidine-4- carboxamide (KNI-272), 4R- (4alpha, 5alpha, 6beta)]-1, 3-bis [ (3- aminophenyl) methyl] hexahydro-5,6-dihydroxy-4, 7-bis (phenylmethyl)-2H-1, 3- diazepin-2-one dimethanesulfonate (mozenavir), 3- [1- [3- [2- (5- trifluoromethylpyridinyl)-sulfonylamino] phenyl] propyl]-4- hydroxy-6alpha- <BR> <BR> phenethyl-6beta-propyl-5,6-dihydro-2-pyranone (tipranavir), N'- [2 (S) -Hydroxy- 3 (S)-[N-(methoxycarbonyl)-l-tert-leucylamino]-4-phenylbutyl-N alpha_ (methoxycarbonyl)-N'- [4- (2-pyridyl) benzyl]-L- tert-leucylhydrazide (BMS- <BR> <BR> 232632, atazanavir), 3- (2 (S) -Hydroxy-3 (S)- (3-hydroxy-2-methylbenzamido)-4-<BR> phenylbutanoyl) -5, 5-dimethyl-N- (2-methylbenzyl) thiazolidine-4 (R) -<BR> carboxamide (AG-1776), N- (2 (R)-hydroxy-1 (S) -indanyl) -2 (R)-phenyl-methyl- 4 (S)-hydroxy-5- (l- (1- (4-benzo [b] furanylmethyl)-2 (S)-N'- (tert- butylcarboxamido) piperazinyl) pentanamide (MK-944A), and (3S)- tetrahydrofuran-3-yl (IS, 2R)- [ [ (4-aminophenyl) sulphonyl)] (isobutyl) amino]-1- benzyl-2- (phosphonooxy) propylcarbamate monocalcium salt (fosamprenavir, GW 433908), non-nucleoside reverse transcriptase inhibitors (NNRTIs), for <BR> <BR> example nevirapine (BI-RG-587), alpha- ( (2-acetyl-5-methylphenyl) amino) -2,6- dichloro-benzeneacetamide (loviride), 1- [3- (isopropylamino)-2-pyridyl]-4- [5- (methanesulfonamido)-1H-indol-2-ylcarbonyl] piperazine monomethanesulfonate (delavirdine), (4S)-6-Chloro-4- [lE)-cyclopropylethenyl)-3, 4- dihydro-4- (trifluoromethyl) -2 (lH)-quinazolinone (DPC-083), (S) -6-chloro-4-<BR> (cyclopropylethynyl) -1, 4-dihydro-4-(trifluoromethyl)-2H-3, 1-benzoxazin-2-one (efavirenz, DMP 266), 1- (ethoxymethyl)-5- (1-rnethylethyl)-6- (phenylmetliyl)- 2,4 (1H, 3H)-pyrimidinedione (MKC-442), and 5- (3, 5-dichlorophenyl) thio-4- isopropyl-1- (4-pyridyl) methyl-1 H-imidazol-2-ylmethyl carbamate (capravirine), cytokine antagonists, for example reticulose (Product-R), 1, 1'-azobis-formamide (ADA), S-1360 and 1, 11- (1, 4-phenylenebis (methylene)) bis-1, 4,8, 11- tetraazacyclotetradecane octahydrochloride (AMD-3100), or fusion inhibitors, for example T-20 and T-1249.

Advantageously, the therapeutic agent to be combined with zidovudine for once daily administration is selected from (-)-cis-1- (2-hydroxymethyl)-1, 3- oxathiolane 5-yl)-cytosine (lamivudine), (-)-cis-4- [2-amino-6- (cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (abacavir), 2', 3'- dideoxyinosine (ddI, didanosine), efavirenz (DMP 266), nevirapine, and tenofovir.

The present invention further features a method for the prevention or treatment of an HIV infection in host, for example, a mammal, for example, a human, comprising once daily administration of zidovudine and another therapeutic agent selected from (-)-cis-1- (2-hydroxymethyl)-1, 3-oxathiolane 5- yl) -cytosine (lamivudine), or a pharmaceutically acceptable derivative of lamivudine, and (-)-cis-4- [2-amino-6- (cyclopropylamino)-9H-purin-9-yl]-2- cyclopentene-1-methanol (abacavir), or a pharmaceutically acceptable derivative of abacavir. Particularly suitable are methods according to the present invention comprising once daily administration of zidovudine and lamivudine. Other suitable methods according to the present invention comprise once daily administration of zidovudine, lamivudine and abacavir.

The phrase"pharmaceutically acceptable derivative of abacavir"as used herein, means any pharmaceutically acceptable salt, solvate, ester, or salt of such ester, of abacavir, or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) abacavir or any antivirally active metabolite or residue thereof.

The phrase"pharmaceutically acceptable derivative of lamivudine"as used herein, means any pharmaceutically acceptable salt, solvate, ester, or salt of such ester, of lamivudine, or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) lamivudine or any antivirally active metabolite or residue thereof.

Preferably, lamivudine is provided substantially free of the corresponding (+)- <BR> <BR> enantiomer. "Substantially free"as used herein, means that there is less than<BR> about 10% w/w of the (+) -enantiomer present compared with the amount of lamivudine. Preferably there is less than about 5% w/w of the (+)-enantiomer present compared with the amount of lamivudine.

Abacavir (also known as (1S, 4R)-cis-4- [2-amino-6- (cyclopropylamino)-9H- purin-9-yl]-2-cyclopentene-1-methanol, 1592U89, Ziagen@) and its antiviral use, particularly against HIV infections may be prepared by methods described in European Patent Specification Number 0434450 or W095/21161, incorporated herein by reference. The succinate salt of (1S, 4R)-cis-4-[2-amino-6- (cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol is described in W096/06844. The hemisulfate salt of (1S, 4R)-cis-4- [2-amino-6- (cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol is described in W098/52949. Preferred salts of abacavir include the succinate salt and the hemisulfate salt.

Lamivudine (also known as EPIVIO, 3TC@, (2R, cis)-4-amino-1- (2- hydroxymethyl-1, 3-oxathiolan-5-yl)-(lH)-pyrimidin-2-one, (-)-cis-1-[2- (hydroxymethyl)-1, 3-oxathiolan-5-yl] cytosine) has proven antiviral activity against human immunodeficiency virus (HIV) and other viruses such as hepatitis B. Lamivudine and its use against HIV are described in EP 0382526 and W091/17159. Crystalline forms of lamivudine are described in WO 92/21676.

Methods for the preparation of lamivudine are described in, inter alia, WO 92/20669 and WO 95/29174.

The antiviral regimens of the present invention include once daily administration of 600 mg zidovudine and 300 mg lamivudine, administered either as two 300 mg tablets and two 150 mg tablets, respectively, or as two combination tablets. The present invention also features once daily administration of 600 mg zidovudine, 300 mg lamivudine, and 600 mg abacavir,

administered either as two 300 mg tablets, two 150 mg tablets, and two 600 mg tablets, respectively, or as two combination tablets.

The present invention also features a method for treating, reversing, reducing or inhibiting retroviral infections in particular HIV infections, in a mammal, in particular a human, which method comprises administering to said mammal a safe and effective amount of a composition comprising zidovudine administered once daily. The compositions of the present invention may optionally employ a safe and effective amount of a diluent, a safe and effective amount of a disintegrant, and a safe and effective amount of a lubricant or any other safe and effective amounts of excipients commonly used in the art.

The invention is preferably presented as a pharmaceutical formulation suitable for oral administration. Such formulations may conveniently be presented as discrete units such as tablets, caplets, capsules, or any other form suitable for oral administration and compatible with the compositions of the present invention, each containing a predetermined amount of the active ingredients. A particularly suitable formulation may be prepared from direct compression or granulation processes. Such formulations may contain safe and effective amounts of conventional excipients such as binding agents, fillers, lubricants, or disintegrants. The tablets may also be coated according to any method known to persons skilled in the art that would not interfere with the tablets'release properties, or the other physical or chemical characteristics of the present Invention. Tablet coating is further described and delineated by Remington, The Science & Practice of Pharmacy 19th ed. 1995 incorporated herein by reference.

When desired, the above formulations may also be modified by any method known to persons skilled in the art to achieve sustained release of active ingredients. The formulations may also include a safe and effective amount of other active ingredients, such as antimicrobial agents or preservatives.

It will be appreciated by those skilled in the art that the amount of active ingredients required for use in treatment will vary according to a variety of

factors, including the nature of the condition being treated and the age and condition of the patient, and will ultimately be at the discretion of the attending physician, veterinarian or health care practitioner.

The current recommended oral dose of zidovudine is 600 mg per day in divided doses, preferably 300 mg twice daily in combination with other antiretroviral agents. The recommended dose in pediatric patients 6 weeks to 12 years of age is 160 mg/m2 every 8 hours (480 mg/m2/day up to a maximum of 200 mg every 8 hours) in combination with other antiretroviral agents. In general, a suitable dose of zidovudine may be in the range of 1 to 500 mg per kilogram body weight of recipient per day, preferably in the range of 7.5 to 250 mg per kilogram body weight per day and most preferably in the range of 1 to 100 mg per kilogram body weight per day. The regimens of the present invention provide for administration of 50 to 1200 mg of zidovudine once daily.

The current recommended dose of abacavir is 300 mg twice daily in combination with other antiretroviral agents. The recommended oral dose of abacavir for adolescents and pediatric patients 3 months to up to 16 years of age is 8 mg/kg twice daily (up to a maximum of 300 mg twice daily) in combination with other antiretroviral agents. In general, a suitable dose of abacavir for administration to a human for treatment of an HIV injection may be in the range of 0.1 to 120 mg per kilogram body weight of the recipient per day, preferably in the range of 3 to 90 mg per kilogram body weight per day and most preferably in the range 3 to 60 mg per kilogram body weight per day.

The current recommended oral dose of lamivudine for adults and adolescents is 300 mg daily, administered as 150 mg twice daily or 300 mg once daily, in combination with other antiretroviral agents. The recommended oral dose of lamivudine for HIV-infected pediatric patients 3 months up to 16 years of age is 4 mg/kg twice daily (up to a maximum of 150 mg twice a day) administered in combination with other antiretorviral agents.

The regimens of the present invention enable patients greater freedom from multiple dosage medication regimens and ease the needed diligence required in remembering complex daily dosing times and schedules.

The methods of the present invention conveniently allow administration of two or more drugs in unit dosage form containing, for example, from about 10 to 700 mg zidovudine and from about 15 to about 1000 mg of lamivudine. Other regimens of the present invention allow administration of three or more separate compounds in unit dosage form containing, for example, from about 10 to about 700 mg zidovudine, from about 15 to about 1200 mg of abacavir, and from about 15 to about 1000 mg of lamivudine. The methods of the present invention provide for administration of zidovudine and lamivudine either as a fixed dose combination administered once daily or as separate tablets adminstered simultaneously or sequentially. The methods of the present invention provide for administration of zidovudine, lamivudine, and abacavir either as a fixed dose combination administered once daily or as separate tablets administered simultaneously or sequentially.

The present invention also features methods for the treatment of an HIV infection in a host comprising administration of zidovudine, lamivudine, and efavirenz once daily. Efavirenz may be made according to U. S. patent nos. 5,519, 021; 5,663, 169 ; and 5,811, 423. The methods of the present invention conveniently allow once daily administration of zidovudine, lamivudine, and efavirenz in unit dosage form containing, for example, from about 10 to 700 mg zidovudine, from about 15 to about 1000 mg of lamivudine, from about 10 to 1000 mg efavirenz. Other regimens of the present invention allow administration of zidovudine, lamivudine, abacavir and efavirenz in unit dosage form containing, for example, from about 10 to about 700 mg zidovudine, from about 15 to about 1200 mg of abacavir, from about 15 to about 1000 mg of lamivudine and from about 10 to 1000 mg efavirenz. The methods of the present invention provide for administration of zidovudine, lamivudine, and efavirenz either as a

fixed dose combination administered once daily or as separate tablets administered simultaneously or sequentially. The methods of the present invention provide for administration of zidovudine, lamivudine, abacavir, and efavirenz either as a fixed dose combination administered once daily or as separate tablets administered simultaneously or sequentially.

EXAMPLES The following examples further describe and demonstrate particular embodiments within the scope of the present Invention. The examples are given solely for illustration and are not to be construed as limitations as many variations are possible without departing from spirit and scope of the invention.

Example 1 A clinical study of zidovudine 600 mg once daily versus zidovudine 300 mg twice daily in therapy-naive HIV-infected patients Antiretroviral-naive subjects (t18 years, HIV RNA >7, 500 c/ml, CD4 >300 cells/mm3, no thymidine analog mutations) were randomized to open-label monotherapy with zidovudine 600mg Q24H ( 3 hours) or 300mg Q12H ( 3 hours). HIV-1 RNA (VL) was measured daily and 1 dose of zidovudine was observed each day. The sample size of 16 subjects/arm provided at least 80% power to detect a 0.036 difference in the slope of VL decline between groups over 14 days (approximately a 0.5 loglo difference at Day 14). VL was log transformed prior to analysis.

All 32 subjects (94% male, median age 34 years) completed the 14-day study.

Mean baseline (BL) VL was 4.33 and 4.40 logic c/mL in the QD and BID arms, respectively. The slope of VL decline from Days 1-14 was-0.045 for QD and- 0.065 for BID (difference=-0. 020 logic c/mL/day (p=0.065)). In additional

analyses, the differences in slope of VL decline from Days 3-14, Days 1-10, and Days 3-10 were-0.009 (p=0.355),-0. 036 (p=0.006),-0. 024 (p=0. 042), respectively, in favor of the BID arm. The mean change from BL (95% CI) in VL at Day 14 was-0. 585 (-0.728,-0. 442) and-0. 849 (-1.067,-0. 630) loglo c/mL in the QD and BID arms, respectively (p=0.056). A faster initial decline in VL was observed in the BID arm compared to the QD arm; both arms achieved a mean reduction in VL of >0. 5 loglo c/mL. Both dosing regimens were well tolerated and safety profiles were comparable. No serious adverse events (SAE) or Grade 3/4 AEs were reported.

This study provides evidence that zidovudine administered QD has antiviral activity as monotherapy.

Q24H = one dose per 24 hours Q12H = one dose per 12 hours VL = viral load BL = baseline QD = once daily administration BID = twice daily administration