Combination of sirna agent and reverse transcriptase inhibitor and use thereof in treating hepatitis b

Abstract

The present application provides a combination of an siRNA agent and a reverse transcriptase inhibitor and a use thereof in treating hepatitis B. The present application specifically relates to a drug combination of an siRNA agent and tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof, a drug combination of an siRNA agent and entecavir or a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutical use thereof.

Description

Combination of siRNA agent and reverse transcriptase inhibitor and use thereof for treating hepatitis B TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry, and relates to the combination of siRNA agent and reverse transcriptase inhibitor and the use thereof for treating hepatitis B. Specifically, it relates to the pharmaceutical combination of siRNA agent and tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof, the pharmaceutical combination of siRNA agent and entecavir or a pharmaceutically acceptable salt thereof or a solvate thereof, and the medical use thereof. BACKGROUND

[0002] Chronic hepatitis B is a serious public health problem worldwide, with about 296 million people infected globally, and about 1.5 million new infections each year. If chronic hepatitis B patients are not effectively treated, the risk of developing fatal diseases, including liver failure, cirrhosis and liver cancer, will be greatly increased.

[0003] Currently, drugs for treating chronic hepatitis B include nucleos(t)ide compounds and interferon. Nucleos(t)ide compounds inhibit viral replication by inhibiting reverse transcriptase, cannot directly eliminate cccDNA, cannot continuously inhibit the production of viral proteins, and with the increase of continuous treatment time, hepatitis B virus (HBV) virus is prone to develop drug resistance. Interferon has a low recurrence rate after treatment, but only a small number of patients can obtain a good response, and the drug has serious side effects. Therefore, there is a need to improve the treatment of chronic hepatitis B in the art to overcome the shortcomings of existing treatments. SUMMARY

[0004] In one aspect, the present application provides the use of a siRNA agent in the preparation of a medicament for treating or preventing hepatitis B.

[0005] In another aspect, the present application provides the use of a siRNA agent in the treatment or prevention of hepatitis B.

[0006] In another aspect, the present application provides a method for treating or preventing hepatitis B, comprising administering to a subject in need thereof an effective amount of a siRNA agent of the present application.

[0007] In yet another aspect, the present application provides a siRNA agent of the present application for use in the treatment or prevention of hepatitis B.

[0008] In another aspect, the present application provides a kit comprising a siRNA agent and instructions for using the siRNA agent for treating or preventing hepatitis B.

[0009] In one aspect, the present application provides the use of a siRNA agent in the preparation of a medicament for treating or preventing hepatitis B, wherein the treatment or prevention further comprises other therapeutic drugs.

[0010] In one aspect, the application provides use of an siRNA agent in the manufacture of a medicament for treating or preventing hepatitis B, in combination with another therapeutic agent.

[0011] In some embodiments, the other therapeutic agent is selected from reverse transcriptase inhibitors.

[0012] In another aspect, the application provides a pharmaceutical combination comprising an siRNA agent and a reverse transcriptase inhibitor.

[0013] In some embodiments, the pharmaceutical combination is a fixed combination.

[0014] In some embodiments, the siRNA agent and the reverse transcriptase inhibitor in the fixed combination are present in the same pharmaceutical composition.

[0015] In some embodiments, the pharmaceutical combination is a non-fixed combination.

[0016] In some embodiments, the siRNA agent and the reverse transcriptase inhibitor in the non-fixed combination are each in the form of a pharmaceutical composition.

[0017] In some embodiments, the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination are each packaged in separate kits, the separate kits further comprising instructions for the siRNA agent and the reverse transcriptase inhibitor to be used in combination to treat or prevent hepatitis B.

[0018] In another aspect, the application provides a kit comprising an siRNA agent, and instructions for the siRNA agent and a reverse transcriptase inhibitor to be used in combination to treat or prevent hepatitis B.

[0019] In another aspect, the application provides a kit comprising an siRNA agent, a reverse transcriptase inhibitor, and instructions for the siRNA agent and the reverse transcriptase inhibitor to be used in combination to treat or prevent hepatitis B.

[0020] In yet another aspect, the application provides use of a pharmaceutical combination or a kit of the application in the manufacture of a medicament for treating or preventing hepatitis B. The application provides a method of treating or preventing hepatitis B, comprising administering to a subject in need thereof an effective amount of a pharmaceutical combination or a kit of the application. The application provides use of a pharmaceutical combination or a kit of the application in the treatment or prevention of hepatitis B. The application provides a pharmaceutical combination or a kit of the application for use in the treatment or prevention of hepatitis B.

[0021] In another aspect, the present application provides uses of the siRNA agent of the present application and a reverse transcriptase inhibitor in the manufacture of a medicament for treating or preventing hepatitis B. The present application provides methods of treating or preventing hepatitis B, comprising administering to a subject in need thereof an effective amount of the siRNA agent of the present application and a reverse transcriptase inhibitor. The present application provides uses of the siRNA agent of the present application and a reverse transcriptase inhibitor in the treatment or prevention of chronic hepatitis B. The present application provides the siRNA agent of the present application and a reverse transcriptase inhibitor for use in treating or preventing hepatitis B. The present application provides uses of the siRNA agent of the present application in the manufacture of a medicament for treating or preventing hepatitis B in combination with a reverse transcriptase inhibitor.

[0022] In some embodiments, the hepatitis B is selected from acute hepatitis B or chronic hepatitis B. In some embodiments, the hepatitis B is selected from chronic hepatitis B.

[0023] In some embodiments, the reverse transcriptase inhibitor is selected from tenofovir, or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof, or entecavir, or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0024] In some embodiments, the reverse transcriptase inhibitor is selected from tenofovir, or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the reverse transcriptase inhibitor is selected from entecavir, or a pharmaceutically acceptable salt thereof or a solvate thereof.

[0026] siRNA agent or a pharmaceutical composition thereof

[0027] In some embodiments, the siRNA agent comprises a sense strand containing at least 15 consecutive nucleotides of a nucleotide sequence as set forth in SEQ ID NO: 1 and the sense strand has a length of no more than 21 nucleotides, and an antisense strand containing at least 15 consecutive nucleotides of a nucleotide sequence as set forth in SEQ ID NO: 2 and the antisense strand has a length of no more than 23 nucleotides; one or more nucleosides in the sense strand or the antisense strand are replaced with r, r is:

[0028] SEQ ID NO: 1: 5'-GUGUGCACUUCGCUUCACA-3',

[0029] SEQ ID NO: 2: 5'-UGUGAAGCGAAGUGCACACUU-3';

[0030] each of the nucleotides and r in the siRNA agent is independently modified or unmodified;

[0031] The siRNA agent optionally comprises a conjugate group.

[0032] In some embodiments, the siRNA agent comprises a sense strand having a nucleotide sequence as set forth in SEQ ID NO: 1 and a length of no more than 21 nucleotides, and an antisense strand having a nucleotide sequence as set forth in SEQ ID NO: 2 and a length of no more than 23 nucleotides; one or more nucleosides in the sense strand or the antisense strand are replaced with r, r being:

[0033] SEQ ID NO: 1: 5'-GUGUGCACUUCGCUUCACA-3',

[0034] SEQ ID NO: 2: 5'-UGUGAAGCGAAGUGCACACUU-3';

[0035] Each of the nucleotides in the siRNA agent and r is independently modified or unmodified;

[0036] The siRNA agent optionally comprises a conjugate group.

[0037] In some embodiments, the siRNA agent comprises a sense strand having a nucleotide sequence as set forth in SEQ ID NO: 1 and an antisense strand having a nucleotide sequence as set forth in SEQ ID NO: 2; one or more nucleosides in the sense strand or the antisense strand are replaced with r, r being:

[0038] SEQ ID NO: 1: 5'-GUGUGCACUUCGCUUCACA-3',

[0039] SEQ ID NO: 2: 5'-UGUGAAGCGAAGUGCACACUU-3';

[0040] Each of the nucleotides in the siRNA agent and r is independently modified or unmodified;

[0041] The siRNA agent optionally comprises a conjugate group.

[0042] In some embodiments, one or more of the nucleotides in the siRNA agent and r are modified, while the other nucleotides and r are unmodified. The modifications include, for example, methoxy modification, fluoro modification, phosphorothioate linkage, or replacement of nucleotides with (S)-glycerol nucleic acid or (E)-vinyl phosphate modification, etc. The modifications include, for example, methoxy modification, fluoro modification, phosphorothioate linkage, or replacement of nucleotides with (S)-glycerol nucleic acid, etc.

[0043] In some embodiments, substantially all of the nucleotides and r in the siRNA agent are modified. In some embodiments, all of the nucleotides and r in the siRNA agent are modified. In some embodiments, all of the nucleotides and r in the sense strand and the antisense strand of the siRNA agent are modified.

[0044] In some embodiments, 70%, 75%, 80%, 85%, 90%, or more than 95% of the nucleotides and r in the siRNA agent are modified.

[0045] In some embodiments, the SEQ ID NO: 1 or SEQ ID NO: 2 optionally includes overhangs at the 5' end and / or the 3' end. In some embodiments, the SEQ ID NO: 1 or SEQ ID NO: 2 includes 0, 1, or 2 nucleotide overhangs at the 5' end and / or the 3' end.

[0046] In some embodiments, where the SEQ ID NO: 2 includes 2 nucleotide overhangs at the 5' end and / or the 3' end, there are optionally 2 phosphorothioate linkages between the 3 nucleotides at the end, where 2 of the 3 nucleotides are overhangs and the other nucleotide is a paired nucleotide adjacent to the overhangs. In some embodiments, the overhangs are preferably selected from modified or unmodified UU. In some embodiments, the overhangs are preferably selected from uu. In some embodiments, there are 2 phosphorothioate linkages between the overhangs uu and the 1 paired nucleotide adjacent thereto.

[0047] In some embodiments, the SEQ ID NO: 2 includes an overhang at the 3' end, which is preferably selected from modified or unmodified UU. In some embodiments, the SEQ ID NO: 2 includes an overhang at the 3' end, which is preferably selected from uu. In some embodiments, the SEQ ID NO: 2 includes an overhang at the 3' end, which is uu with 2 phosphorothioate linkages between the overhang uu and the 1 paired nucleotide adjacent thereto (e.g., c·u·u).

[0048] In some embodiments, the sense strand of the siRNA agent comprises a sequence in which one or more nucleosides in the sequence set forth as SEQ ID NO: 1 are replaced with r. For example, the sense strand comprises a sequence in which one nucleoside in the sequence set forth as SEQ ID NO: 1 is replaced with r.

[0049] In some embodiments, the sense strand in the siRNA agent comprises a sequence in which one or more nucleosides in the sequence set forth as SEQ ID NO: 1 are replaced with r. For example, the sense strand comprises a sequence in which one, two, three, four, or five nucleosides in the sequence set forth as SEQ ID NO: 1 are replaced with r.

[0050] In some embodiments, the sense strand in the siRNA agent comprises a sequence in which one or more nucleosides in the sequence set forth as SEQ ID NO: 1 are replaced with r, the r replacement occurring at any position in SEQ ID NO: 1. Preferably, the r replacement occurs at positions 1-19 at the 5’ end of SEQ ID NO: 1. For example, the r replacement occurs at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 at the 5’ end of SEQ ID NO: 1. Preferably, the r replacement occurs at positions 2, 3, 7, 12, 15, 17, or 19 at the 5’ end of SEQ ID NO: 1. Preferably, the r replacement occurs at positions 2 and / or 15 at the 5’ end of SEQ ID NO: 1. Preferably, the r replacement occurs at position 2 at the 5’ end of SEQ ID NO: 1.

[0051] In some embodiments, the antisense strand in the siRNA agent comprises a sequence in which one or more nucleosides in the sequence set forth as SEQ ID NO: 2 are replaced with r. For example, the antisense strand comprises a sequence in which one nucleoside in the sequence set forth as SEQ ID NO: 2 is replaced with r.

[0052] In some embodiments, the antisense strand in the siRNA agent comprises a sequence in which one or more nucleosides in the sequence set forth as SEQ ID NO: 2 are replaced with r. For example, the antisense strand comprises a sequence in which one, two, three, four, or five nucleosides in the sequence set forth as SEQ ID NO: 2 are replaced with r.

[0053] In some embodiments, the antisense strand in the siRNA agent comprises a sequence in which one or more nucleosides in the sequence set forth as SEQ ID NO: 2 are replaced with r, the r-replacement occurring at any position of SEQ ID NO: 2. Preferably, the r-replacement occurs at positions 1-21 or 1-19 of the 5’ end of SEQ ID NO: 2. For example, the r-replacement occurs at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 of the 5’ end of SEQ ID NO: 2. Preferably, the r-replacement occurs at position 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 16, or 18 of the 5’ end of SEQ ID NO: 2. Preferably, the r-replacement occurs at position 7 of the 5’ end of SEQ ID NO: 2.

[0054] In some specific embodiments, the sense strand and the antisense strand in the siRNA agent comprise a sequence in which one or more nucleosides in the sequence are replaced with r, for example, the sense strand in the siRNA agent comprises a sequence in which one nucleoside in the sequence set forth as SEQ ID NO: 1 is replaced with r, the r-replacement occurring at position 2 of the 5’ end, and the antisense strand comprises a sequence in which one nucleoside in the sequence set forth as SEQ ID NO: 2 is replaced with r, the r-replacement occurring at position 7 of the 5’ end of SEQ ID NO: 2.

[0055] In some embodiments, the sense strand in the siRNA agent comprises or consists of the sequence set forth as SEQ ID NO: 3 or SEQ ID NO: 5. In some embodiments, the sequence includes further nucleotide modifications, such as methoxy modifications, fluoro modifications, phosphorothioate linkages, or replacement of nucleotides with (S)-glycerol nucleic acids, etc.

[0056] In some embodiments, the sense strand in the siRNA agent comprises or consists of the sequence set forth as SEQ ID NO: 7 or SEQ ID NO: 9.

[0057] In some embodiments, the antisense strand in the siRNA agent comprises or consists of the sequence set forth as SEQ ID NO: 4 or SEQ ID NO: 6. In some embodiments, the sequence includes further nucleotide modifications, such as methoxy modifications, fluoro modifications, phosphorothioate linkages, or replacement of nucleotides with (S)-glycerol nucleic acids, etc.

[0058] In some embodiments, the antisense strand in the siRNA agent comprises or consists of the sequence set forth as SEQ ID NO: 8 or SEQ ID NO: 10.

[0059] In some embodiments, the sense strand and the antisense strand of the siRNA agent are selected from any one of AD01 to AD05:

[0060] AD01: the sense strand is SEQ ID NO: 3 and the antisense strand is SEQ ID NO: 4;

[0061] AD02: the sense strand is SEQ ID NO: 5 and the antisense strand is SEQ ID NO: 6;

[0062] AD03: the sense strand is SEQ ID NO: 7 and the antisense strand is SEQ ID NO: 8;

[0063] AD04: the sense strand is SEQ ID NO: 9 and the antisense strand is SEQ ID NO: 8;

[0064] AD05: the sense strand is SEQ ID NO: 7 and the antisense strand is SEQ ID NO: 10.

[0065] In some embodiments, the siRNA agent is selected from Table 1:

[0066] Table 1

[0067] In some embodiments, the siRNA agent comprises a conjugate group.

[0068] In some embodiments, the conjugate group contains 1 to 5 GalNAc (N-acetylgalactosamine) groups. Preferably, the conjugate group contains 1, 2, 3, 4, or 5 GalNAc groups. More preferably, the conjugate group contains 3 or 4 GalNAc groups.

[0069] In some embodiments, the conjugate group comprises compound group D or L96:

[0070] In some embodiments, the conjugate group is attached to the 3’ end of the sense strand of the siRNA agent.

[0071] In some embodiments, the phosphorothioate moiety of the siRNA agent comprises (R)- and (S)-enantiomers, diastereomers, and / or racemic mixtures thereof.

[0072] In some embodiments, the siRNA agent is selected from Table 2:

[0073] Table 2

[0074] The D is as previously shown.

[0075] In some embodiments, the siRNA agent can be in the form of a pharmaceutically acceptable salt.

[0076] In some embodiments, the salt as described above is selected from the group consisting of base addition salts, acid addition salts, and combinations thereof.

[0077] In some embodiments, the base addition salt is selected from the group consisting of sodium, potassium, calcium, ammonium, organic amine, magnesium salts, and combinations thereof, and the acid addition salt is selected from the group consisting of inorganic acid salts, organic acid salts, and combinations thereof. In some embodiments, the base addition salt is selected from the group consisting of alkali metal salts (e.g., lithium, sodium, or potassium, etc.). In some embodiments, the base addition salt is selected from the group consisting of sodium salts.

[0078] In some embodiments, the inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and combinations thereof, and the organic acid is selected from the group consisting of acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzene sulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and combinations thereof.

[0079] In some embodiments, the siRNA agent has a sense strand of g·r·guGcACUucgcuucacaD (SEQ ID NO: 11) and an antisense strand of u·G·ugaArCGaaguGcAcac·u·u (SEQ ID NO: 12).

[0080] In some embodiments, the siRNA agent has a sense strand of g·r·guGcACUucgcurcacaD (SEQ ID NO: 13) and an antisense strand of u·G·ugaArCGaaguGcAcac·u·u (SEQ ID NO: 12).

[0081] In some embodiments, the siRNA agent is selected from the group consisting of a sense strand of g·r·guGcACUucgcuucacaD (SEQ ID NO: 11) and an antisense strand of VPu·G·ugaArCGaaguGcAcac·u·u (SEQ ID NO: 14).

[0082] In some embodiments, the siRNA agent is in the form of a pharmaceutical composition; preferably, the pharmaceutical composition is selected from the group consisting of liquid pharmaceutical compositions, more preferably from injections.

[0083] In some embodiments, the siRNA agent is in the form of a pharmaceutical composition, and a single dose of the pharmaceutical composition is selected from the group consisting of 1 mg to 2000 mg, 50 mg to 1000 mg, 50 mg to 800 mg, or 100 mg to 600 mg, preferably from 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or a range formed by any of the foregoing. In some embodiments, the siRNA agent is in the form of a pharmaceutical composition, and a single dose of the pharmaceutical composition is selected from the group consisting of 100 mg to 600 mg, 100 mg to 400 mg, or 100 mg to 200 mg. In some embodiments, the siRNA agent is in the form of a pharmaceutical composition, and a single dose of the pharmaceutical composition is selected from the group consisting of 200 mg to 400 mg. In some embodiments, a single dose of the pharmaceutical composition of the siRNA agent is selected from the group consisting of 600 mg. In some embodiments, a single dose of the pharmaceutical composition of the siRNA agent is selected from the group consisting of 400 mg. In some embodiments, a single dose of the pharmaceutical composition of the siRNA agent is selected from the group consisting of 200 mg. In some embodiments, a single dose of the pharmaceutical composition of the siRNA agent is selected from the group consisting of 100 mg.

[0084] In some aspects, the siRNA agent is in the form of a pharmaceutical composition, and the strength of the pharmaceutical composition is selected from the group consisting of 50 to 1200 mg / vial.

[0085] In some aspects, the siRNA agent is in the form of a pharmaceutical composition, and the strength of the pharmaceutical composition is selected from the group consisting of 50 mg / vial, 100 mg / vial, 150 mg / vial, 200 mg / vial, 300 mg / vial, 400 mg / vial, 500 mg / vial, 600 mg / vial, 700 mg / vial, 800 mg / vial, 900 mg / vial, 1000 mg / vial, 1100 mg / vial, or 1200 mg / vial.

[0086] In some aspects, the siRNA agent is in the form of a pharmaceutical composition, and the strength of the pharmaceutical composition is selected from the group consisting of 100 to 600 mg / vial, 100 to 400 mg / vial, or 100 to 200 mg / vial. In some aspects, the siRNA agent is in the form of a pharmaceutical composition, and the strength of the pharmaceutical composition is selected from the group consisting of 600 mg / vial. In some aspects, the siRNA agent is in the form of a pharmaceutical composition, and the strength of the pharmaceutical composition is selected from the group consisting of 400 mg / vial. In some aspects, the siRNA agent is in the form of a pharmaceutical composition, and the strength of the pharmaceutical composition is selected from the group consisting of 200 mg / vial. In some aspects, the siRNA agent is in the form of a pharmaceutical composition, and the strength of the pharmaceutical composition is selected from the group consisting of 100 mg / vial.

[0087] A reverse transcriptase inhibitor, or a pharmaceutical composition thereof

[0088] In some embodiments, the reverse transcriptase inhibitor is in the form of a pharmaceutical composition; preferably, the pharmaceutical composition is selected from a solid pharmaceutical composition, more preferably from a tablet or a capsule.

[0089] In some embodiments, the reverse transcriptase inhibitor is in the form of a pharmaceutical composition, wherein a single dose of the pharmaceutical composition is selected from 0.01 mg to 500 mg, preferably 0.01 mg, 0.02 mg, 0.05 mg, 0.08 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, or 1.4 mg. g, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8m g, 2.9mg, 3mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7mg, 7. 1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, 7.9mg, 8mg, 8.1mg, 8.2mg, 8.3mg, 8.4mg, 8. 5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9mg, 9.1mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg, 9.6mg, 9.7mg, 9.8mg, 9.9 mg, 10 mg, 15 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 140 mg, 150 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 180 mg, 190 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 220 mg, 230 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, or a range formed by any of the above values. In some embodiments, the reverse transcriptase inhibitor is in the form of a pharmaceutical composition having a single dose of 0.01 mg to 5 mg, 0.05 mg to 2.5 mg, 0.1 mg to 1.5 mg, or 0.5 mg to 1 mg. In some embodiments, the reverse transcriptase inhibitor is in the form of a pharmaceutical composition having a single dose of 10 to 50 mg, 15 to 40 mg, or 20 to 30 mg. In some embodiments, the reverse transcriptase inhibitor is in the form of a pharmaceutical composition having a single dose of 80 mg to 500 mg, 100 mg to 400 mg, or 150 mg to 300 mg.

[0090] In some embodiments, the reverse transcriptase inhibitor is in the form of a pharmaceutical composition having a single dose selected from 0.5 mg or 1 mg.

[0091] In some embodiments, the reverse transcriptase inhibitor is selected from entecavir, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0092] As used herein, the entecavir chemical name is 2-amino-9-[(1S,3R,4S)-4-hydroxy-3- hydroxymethyl-2-methylene cyclopentyl]-1,9-dihydro-6H-purin-6-one, which has the following structural formula:

[0093] In some embodiments, the pharmaceutically acceptable salt of entecavir is selected from the group consisting of a maleate salt. In some embodiments, the pharmaceutically acceptable salt of entecavir is selected from the group consisting of a mono-maleate salt.

[0094] In some embodiments, the solvate of entecavir is selected from the group consisting of entecavir hydrate. In some embodiments, the entecavir hydrate is selected from the group consisting of entecavir 0.5-2 hydrate. In some embodiments, the entecavir hydrate is selected from the group consisting of entecavir monohydrate.

[0095] In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof or a solvate thereof is selected from the group consisting of entecavir mono-maleate, entecavir monohydrate, or entecavir mono-maleate monohydrate. In some embodiments, the reverse transcriptase inhibitor (or the entecavir or a pharmaceutically acceptable salt thereof or a solvate thereof) is selected from the group consisting of entecavir monohydrate.

[0096] As used herein, the entecavir or a pharmaceutically acceptable salt thereof or a solvate thereof, or a pharmaceutical composition thereof can be selected from a commercially available product.

[0097] In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof or a solvate thereof is in the form of a pharmaceutical composition; preferably, the pharmaceutical composition is selected from the group consisting of a solid pharmaceutical composition, more preferably a tablet or a capsule.

[0098] In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof or solvate thereof is in the form of a pharmaceutical composition having a single dose selected from the group consisting of 0.01 mg to 10 mg, preferably 0.01 mg, 0.02 mg, 0.05 mg, 0.08 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7 mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, 8 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, 10 mg, or a range formed by any of the above values. In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof or solvate thereof is in the form of a pharmaceutical composition having a single dose selected from the group consisting of 0.01 mg to 5 mg, 0.05 mg to 2.5 mg, 0.1 mg to 1.5 mg, or 0.5 mg to 1 mg. In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof or solvate thereof is in the form of a pharmaceutical composition having a single dose selected from the group consisting of 0.5 mg or 1 mg.

[0099] In some embodiments, the reverse transcriptase inhibitor (or the entecavir or a pharmaceutically acceptable salt thereof or solvate thereof) is entecavir monohydrate in the form of a pharmaceutical composition having a single dose selected from the group consisting of 0.5 mg or 1 mg.

[0100] In some embodiments, the single dose of entecavir monohydrate is selected from 0.5 mg or 1 mg.

[0101] In some embodiments, the reverse transcriptase inhibitor is selected from tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, is in the form of a pharmaceutical composition; preferably, the pharmaceutical composition is selected from a solid pharmaceutical composition, more preferably from a tablet or a capsule.

[0103] In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, and the single dose of the pharmaceutical composition is selected from the group consisting of 10 mg to 500 mg. In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, and the single dose of the pharmaceutical composition is selected from the group consisting of 10 mg, 15 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 140 mg, 150 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 180 mg, 190 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 220 mg, 230 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, or a range formed by any of the foregoing. In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, and the single dose of the pharmaceutical composition is selected from the group consisting of 10 mg to 50 mg or 80 mg to 500 mg. In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, and the single dose of the pharmaceutical composition is selected from the group consisting of 15 mg to 40 mg or 100 mg to 300 mg. In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, and the single dose of the pharmaceutical composition is selected from the group consisting of 20 mg to 30 mg or 150 mg to 300 mg. In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, and the single dose of the pharmaceutical composition is selected from the group consisting of 25 mg to 40 mg or 120 mg to 300 mg.In some embodiments, the tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, and the single dose of the pharmaceutical composition is selected from 25 mg, 30 mg, 33 mg, 40 mg, 123 mg, 150 mg, 163 mg, 200 mg, 204 mg, 245 mg, 250 mg, 291 mg, or 300 mg.

[0104] In some embodiments, the reverse transcriptase inhibitor (or the tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof) is in the form of a pharmaceutical composition, and the single dose of the pharmaceutical composition is selected from 20 mg - 30 mg (e.g., 25 mg) or 120 mg - 300 mg (e.g., 300 mg).

[0105] As used herein, the tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can be selected from a commercially available product.

[0106] In some embodiments, the pharmaceutically acceptable prodrug of the tenofovir is selected from prodrug tenofovir alafenamide or emtricitabine.

[0107] In some embodiments, the pharmaceutically acceptable salt of the tenofovir or a pharmaceutically acceptable prodrug thereof is selected from a phosphate salt, a fumarate salt, a succinate salt, an orotate salt, a disulfonate salt, or an aspartate salt, preferably a fumarate salt.

[0108] In some embodiments, the tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof is selected from tenofovir, tenofovir alafenamide, emtricitabine, tenofovir alafenamide fumarate, or emtricitabine fumarate.

[0109] In some embodiments, the tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof is selected from tenofovir alafenamide or a pharmaceutically acceptable salt thereof. In some embodiments, the reverse transcriptase inhibitor (or the tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof) is selected from tenofovir alafenamide fumarate.

[0110] In some embodiments, the tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof is selected from the following structure:

[0111] In some embodiments, the reverse transcriptase inhibitor (or tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof, or the tenofovir alafenamide or a pharmaceutically acceptable salt thereof) is selected from tenofovir alafenamide fumarate (TAF), which has the following structure:

[0112] In some embodiments, the tenofovir alafenamide or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition having a single dose selected from the group consisting of 10 mg, 15 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or a range formed by any of the foregoing. In some embodiments, the tenofovir alafenamide or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition having a single dose selected from the group consisting of 10 mg-50 mg, 15 mg-40 mg, or 20 mg-30 mg. In some embodiments, the tenofovir alafenamide or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition having a single dose selected from the group consisting of 20 mg-30 mg (e.g., 25 mg).

[0113] In some embodiments, the reverse transcriptase inhibitor (or the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof) is selected from the group consisting of tenofovir alafenamide fumarate, in the form of a pharmaceutical composition having a single dose selected from the group consisting of 20-30 mg (e.g., 25 mg).

[0114] In some embodiments, the single dose of tenofovir alafenamide fumarate is selected from the group consisting of 25 mg.

[0115] In some embodiments, the pharmaceutically acceptable prodrug of tenofovir is selected from the group consisting of tenofovir disoproxil or emtricitabine.

[0116] In some embodiments, the pharmaceutically acceptable salt of tenofovir or pharmaceutically acceptable prodrug thereof is selected from the group consisting of a phosphate salt, a fumarate salt, a succinate salt, an ascorbate salt, a disulfonate salt, or an aspartate salt, preferably a fumarate salt.

[0117] In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is selected from the group consisting of tenofovir, tenofovir disoproxil, emtricitabine, tenofovir disoproxil phosphate, tenofovir disoproxil fumarate, tenofovir disoproxil succinate, tenofovir disoproxil ascorbate, tenofovir disoproxil hemi-disulfonate, tenofovir disoproxil aspartate, or emtricitabine fumarate.

[0118] In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is selected from the group consisting of tenofovir disoproxil or a pharmaceutically acceptable salt thereof. In some embodiments, the reverse transcriptase inhibitor (or the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof) is selected from the group consisting of tenofovir disoproxil fumarate.

[0119] In some embodiments, the reverse transcriptase inhibitor (or the tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof) is selected from the following structures:

[0120] In some embodiments, the reverse transcriptase inhibitor (or the tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof, or tenofovir disoproxil or a pharmaceutically acceptable salt thereof) is selected from tenofovir disoproxil fumarate (TDF), which has the following structure:

[0121] In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition having a single dose selected from the group consisting of 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 140 mg, 150 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 180 mg, 190 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 220 mg, 230 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, or a range formed by any of the foregoing. In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition having a single dose selected from the group consisting of 80 mg - 500 mg. In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition having a single dose selected from the group consisting of 100 mg - 300 mg (e.g., 300 mg). In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition having a single dose selected from the group consisting of 120 mg - 300 mg (e.g., 300 mg). In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition having a single dose selected from the group consisting of 30 mg, 33 mg, 40 mg, 123 mg, 150 mg, 163 mg, 200 mg, 204 mg, 245 mg, 250 mg, 291 mg, or 300 mg.

[0122] In some embodiments, the reverse transcriptase inhibitor (or the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof) is selected from the group consisting of tenofovir disoproxil fumarate in the form of a pharmaceutical composition having a single dose selected from the group consisting of 120 mg - 300 mg (e.g., 300 mg).

[0123] In some embodiments, the single dose of the tenofovir disoproxil fumarate salt is selected from the group consisting of 300 mg.

[0124] Drug combination

[0125] In some embodiments, the drug combination comprises: 1) a siRNA agent described herein in a single dose of 1 mg to 2000 mg; and 2) a reverse transcriptase inhibitor described herein in a single dose of 0.01 mg to 500 mg.

[0126] In some embodiments, the reverse transcriptase inhibitor is selected from the group consisting of a tenofovir described herein, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the reverse transcriptase inhibitor is selected from the group consisting of entecavir described herein, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0127] In some embodiments, the drug combination comprises: 1) a siRNA agent described herein in a single dose of 1 mg to 2000 mg; and 2) a tenofovir described herein, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in a single dose of 10 mg to 500 mg. In some embodiments, the drug combination comprises: 1) a siRNA agent described herein in a single dose of 1 mg to 2000 mg; and 2) entecavir described herein, or a pharmaceutically acceptable salt thereof, or a solvate thereof, in a single dose of 0.01 mg to 5 mg.

[0128] In some embodiments, in the drug combination, the ratio of single doses of the siRNA agent and the reverse transcriptase inhibitor is selected from 2000: 1 to 0.1 : 1. In some embodiments, in the drug combination, the ratio of single doses of the siRNA agent and the reverse transcriptase inhibitor is selected from 2000: 1 to 1 : 1. In some embodiments, in the drug combination, the ratio of single doses of the siRNA agent and the reverse transcriptase inhibitor is selected from 2000: 1, 1900: 1, 1800: 1, 1700: 1, 1600: 1, 1500: 1, 1400: 1, 1300: 1, 1200: 1, 1100: 1, 1000: 1, 900: 1, 800: 1, 700: 1, 600: 1, 500: 1, 400: 1, 300: 1, 200: 1, 100: 1, 90: 1, 80: 1, 70: 1, 60: 1, 50: 1, 40: 1, 30: 1, 29: 1, 28: 1, 27: 1, 26: 1, 25: 1, 24: 1, 23: 1, 22: 1, 21: 1, 20: 1, 19: 1, 18: 1, 17: 1, 16: 1, 15: 1, 14: 1, 13: 1, 12: 1, 11: 1, 10.5: 1, 10: 1, 9.5: 1, 9: 1, 8.5: 1, 8: 1, 7.5: 1, 7: 1, 6.5: 1, 6: 1, 5.5: 1, 5: 1, 4.9: 1, 4.8: 1, 4.7: 1, 4.6: 1, 4.5: 1, 4.4: 1, 4.3: 1, 4.2: 1, 4.1: 1, 4: 1, 3.9: 1, 3.8: 1, 3.7: 1, 3.6: 1, 3.5: 1, 3.4: 1, 3.3: 1, 3.2: 1, 3.1: 1, 3: 1, 2.9: 1, 2.8: 1, 2.7: 1, 2.6: 1, 2.5: 1, 2.4: 1, 2.3: 1, 2.2: 1, 2.1: 1, 2: 1, 1.9: 1, 1.8: 1, 1.7: 1, 1.6: 1, 1.5: 1, 1.4: 1, 1.3: 1, 1.2: 1, 1.1: 1, 1: 1, 0.9: 1, 0.8: 1, 0.7: 1, 0.6: 1, 0.5: 1, 0.4: 1, 0.3: 1, 0.2: 1, 0.1: 1, or a range formed by any of the aforementioned values. In some embodiments, in the drug combination, the ratio of single doses of the siRNA agent and the reverse transcriptase inhibitor is selected from 1500: 1 to 100: 1, 50: 1 to 1: 1, or 10: 1 to 0.1 : 1. In some embodiments, in the drug combination, the ratio of single doses of the siRNA agent and the reverse transcriptase inhibitor is selected from 1200: 1 to 0.1 : 1. In some embodiments, in the drug combination, the ratio of single doses of the siRNA agent and the reverse transcriptase inhibitor is selected from 1500: 1 to 400: 1, 50: 1 to 10: 1, or 10: 1 to 1: 1.In some embodiments, in the drug combination, the ratio of single doses of the siRNA agent and the reverse transcriptase inhibitor is selected from 1200: 1 to 2: 1. In some embodiments, in the drug combination, the ratio of single doses of the siRNA agent and the reverse transcriptase inhibitor is selected from 1200: 1, 600: 1, 24: 1, 4: 1, 3: 1, 2.4: 1, or 2: 1. In some embodiments, in the drug combination, the ratio of single doses of the siRNA agent and the reverse transcriptase inhibitor is selected from 800: 1, 400: 1, 200: 1, 100: 1, 16: 1, 8: 1, 1.33: 1, 0.67: 1, or 0.33: 1.

[0129] In some embodiments, the ratio of the periodic doses of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from 1 : (0.001-500). In some embodiments, the ratio of the periodic doses of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from 1 : (0.001-1), 1 : (0.005-1), 1 : (0.01-1), 1 : (0.01-0.5), or 1 : (0.02-0.2). In some embodiments, the ratio of the periodic doses of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from 1 : 0.001, 1 : 0.005, 1 : 0.01, 1 : 0.015, 1 : 0.0175, 1 : 0.02, 1 : 0.025, 1 : 0.03, 1 : 0.035, 1 : 0.04, 1 : 0.045, 1 : 0.05, 1 : 0.055, 1 : 0.06, 1 : 0.065, 1 : 0.07, 1 : 0.075, 1 : 0.08, 1 : 0.085, 1 : 0.09, 1 : 0.095, 1 : 0.1, 1 : 0.14, 1 : 0.15, 1 : 0.2, 1 : 0.25, 1 : 0.28, 1 : 0.3, 1 : 0.35, 1 : 0.36, 1 : 0.4, 1 : 0.45, 1 : 0.48, 1 : 0.5, 1 : 0.55, 1 : 0.56, 1 : 0.6, 1 : 0.65, 1 : 0.7, 1 : 0.75, 1 : 0.8, 1 : 0.85, 1 : 0.9, 1 : 0.95, 1 : 1, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of the periodic doses of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from 1 : 0.0175, 1 : 0.035, 1 : 0.07, 1 : 0.14, 1 : 0.28, 1 : 0.56, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of the periodic doses of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from 1 : (0.1-50), 1 : (0.5-50), 1 : (1-20), 1 : (1-15), 1 : (1.5-10), or 1 : (1.5-5).In some embodiments, the ratio of the periodic doses of the siRNA agent and the reverse transcriptase inhibitor in the drug combination is selected from 1 :0.1, 1 :0.5, 1 :0.875, 1 :1, 1 :1.1, 1 :1.15, 1 :1.2, 1 :1.25, 1 :1.3, 1 :1.35, 1 :1.4, 1 :1.45, 1 :1.5, 1 :1.55, 1 :1.6, 1 :1.65, 1 :1.7, 1 :1.75, 1 :1.8, 1 :1.85, 1 :1.9, 1 :1.95, 1 :2, 1 :2.5, 1 :3, 1 :3.5, 1 :4, 1 :4.5, 1 :5, 1 :5.5, 1 :6, 1 :6.5, 1 :7, 1 :7.5, 1 :8, 1 :8.5, 1 :9, 1 :9.5, 1 :10, 1 :14, 1 :20, 1 :30, 1 :40, 1 :50, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of the periodic doses of the siRNA agent and the reverse transcriptase inhibitor in the drug combination is selected from 1 :0.875, 1 :1.75, 1 :3.5, 1 :7, 1 :14, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of the periodic doses of the siRNA agent and the reverse transcriptase inhibitor in the drug combination is selected from 1 :(1-500), 1 :(2-200), 1 :(4-200), 1 :(6-150), 1 :(15-100), or 1 :(15-80). In some embodiments, the ratio of the periodic doses of the siRNA agent and the reverse transcriptase inhibitor in the drug combination is selected from 1 :1, 1 :5, 1 :5.25, 1 :7, 1 :8.75, 1 :10, 1 :10.5, 1 :12, 1 :14, 1 :16, 1 :17, 1 :17.5, 1 :18, 1 :19, 1 :20, 1 :21, 1 :22, 1 :23, 1 :24, 1 :26, 1 :28, 1 :30, 1 :32, 1 :34, 1 :35, 1 :36, 1 :38, 1 :39, 1 :40, 1 :41, 1 :42, 1 :43, 1 :44, 1 :46, 1 :48, 1 :50, 1 :52, 1 :54, 1 :56, 1 :58, 1 :60, 1 :62, 1 :64, 1 :66, 1 :68, 1 :69, 1 :70, 1 :72, 1 :74, 1 :76, 1 :78, 1 :80, 1 :82, 1 :84, 1 :86, 1 :88, 1 :90, 1 :100, 1 :112, 1 :120, 1 :140, 1 :160, 1 :168, 1 :180, 1 :200, 1 :300, 1 :400, 1 :500, or optionally a range formed by the aforementioned values.In some embodiments, in the drug combination, the ratio of the periodic dose of the siRNA agent and the periodic dose of the reverse transcriptase inhibitor is selected from 1 :5.25, 1 :7, 1 :8.75, 1 :10.5, 1 :14, 1 :17.5, 1 :21, 1 :28, 1 :35, 1 :42, 1 :56, 1 :70, 1 :84, 1 :112, 1 :140, 1 :168, or optionally a range formed by the aforementioned values.

[0130] In some embodiments, the ratio of each dose of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from the group consisting of 1 : (0.0001-100). In some embodiments, the ratio of each dose of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from the group consisting of 1 : (0.1-0.0.5), 1 : (0.001-0.05), or 1 : (0.00125-0.01). In some embodiments, the ratio of each dose of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from the group consisting of 1 :0.0001, 1 :0.0005, 1 :0.001, 1 :0.00125, 1 :0.0015, 1 :0.002, 1 :0.0025, 1 :0.003, 1 :0.0035, 1 :0.004, 1 :0.0045, 1 :0.005, 1 :0.006, 1 :0.007, 1 :0.008, 1 :0.009, 1 :0.01, 1 :0.02, 1 :0.03, 1 :0.04, 1 :0.05, 1 :0.06, 1 :0.07, 1 :0.08, 1 :0.09, 1 :0.1, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of each dose of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from the group consisting of 1 :0.00125, 1 :0.0025, 1 :0.005, 1 :0.01, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of each dose of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from the group consisting of 1 : (0.01-1), 1 : (0.05-0.5), or 1 : (0.0625-0.25). In some embodiments, the ratio of each dose of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from the group consisting of 1 :0.01, 1 :0.02, 1 :0.03, 1 :0.04, 1 :0.05, 1 :0.06, 1 :0.0625, 1 :0.07, 1 :0.08, 1 :0.09, 1 :0.1, 1 :0.125, 1 :0.2, 1 :0.25, 1 :0.3, 1 :0.4, 1 :0.5, 1 :0.6, 1 :0.7, 1 :0.8, 1 :0.9, 1 :1, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of each dose of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from the group consisting of 1 :0.0625, 1 :0.125, 1 :0.25, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of each dose of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from the group consisting of 1 : (0.005-20), 1 : (0.01-10), 1 : (0.3-5), 1 : (0.375-3).In some embodiments, the ratio of each dose of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from 1 :0.005, 1 :0.01, 1 :0.015, 1 :0.02, 1 :0.025, 1 :0.03, 1 :0.035, 1 :0.04, 1 :0.045, 1 :0.05, 1 :0.065, 1 :0.07, 1 :0.075, 1 :0.08, 1 :0.085, 1 :0.09, 1 :0.095, 1 :0.1, 1 :0.2, 1 :0.3, 1 :0.375, 1 :0.4, 1 :0.5, 1 :0.6, 1 :0.625, 1 :0.7, 1 :0.75, 1 :0.8, 1 :0.9, 1 :1, 1 :1.2, 1 :1.25, 1 :1.4, 1 :1.5, 1 :1.6, 1 :1.8, 1 :2, 1 :2.2, 1 :2.4, 1 :2.5, 1 :2.6, 1 :2.8, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :12, 1 :14, 1 :16, 1 :18, 1 :20, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of each dose of the siRNA agent and the reverse transcriptase inhibitor in the pharmaceutical combination is selected from 1 :0.375, 1 :0.5, 1 :0.625, 1 :0.75, 1 :1, 1 :1.25, 1 :1.5, 1 :2, 1 :2.5, 1 :3, or optionally a range formed by the aforementioned values.

[0131] In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof is selected from 100: 1 to 0.1: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof is selected from 100: 1 to 1: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof is selected from 100: 1, 90: 1, 80: 1, 70: 1, 60: 1, 50: 1, 40: 1, 30: 1, 29: 1, 28: 1, 27: 1, 26: 1, 25: 1, 24: 1, 23: 1, 22: 1, 21: 1, 20: 1, 19: 1, 18: 1, 17: 1, 16: 1, 15: 1, 14: 1, 13: 1, 12: 1, 11: 1, 10.5: 1, 10: 1, 9.5: 1, 9: 1, 8.5: 1, 8: 1, 7.5: 1, 7: 1, 6.5: 1, 6: 1, 5.5: 1, 5: 1, 4.9: 1, 4.8: 1, 4.7: 1, 4.6: 1, 4.5: 1, 4.4: 1, 4.3: 1, 4.2: 1, 4.1: 1, 4: 1, 3.9: 1, 3.8: 1, 3.7: 1, 3.6: 1, 3.5: 1, 3.4: 1, 3.3: 1, 3.2: 1, 3.1: 1, 3: 1, 2.9: 1, 2.8: 1, 2.7: 1, 2.6: 1, 2.5: 1, 2.4: 1, 2.3: 1, 2.2: 1, 2.1: 1, 2: 1, 1.9: 1, 1.8: 1, 1.7: 1, 1.6: 1, 1.5: 1, 1.4: 1, 1.3: 1, 1.2: 1, 1.1: 1, 1: 1, 0.9: 1, 0.8: 1, 0.7: 1, 0.6: 1, 0.5: 1, 0.4: 1, 0.3: 1, 0.2: 1, 0.1: 1, or a range formed by any of the aforementioned values. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof is selected from 50: 1 to 0.1: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof is selected from 50: 1 to 1: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof is selected from 50: 1 to 10: 1 or 10: 1 to 1: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof is selected from 50: 1 to 10: 1 or 5: 1 to 1: 1.In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, is selected from 24:1, 4:1, 3:1, 2.4:1, or 2:1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, is selected from 16:1 or 1.33:1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, is selected from 50:1 to 1:1 or 5:1 to 0.1:1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, is selected from 24:1, 16:1, 8:1, 4:1, 3:1, 2.4:1, 2:1, 1.33:1, 0.67:1, or 0.33:1.

[0132] In some embodiments, the ratio of the periodic dosages of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from the group consisting of 1:(0.1-500). In some embodiments, the ratio of the periodic dosages of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from 1:0.1, 1:0.5, 1:0.875, 1:1, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5, 1:1.55, 1:1.6, 1:1.65, 1:1.7, 1:1.75, 1:1.8, 1:1.85, 1:1.9, 1:1.95, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:5.25, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:8.75, 1:9, 1:9.5, 1:10, 1:10.5, 1:12, 1:14, 1:16, 1:17, 1:17.5, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:26, 1:28, 1:30, 1:32, 1:34, 1:35, 1:36, 1:38, 1:39, 1:40, 1:41, 1:42, 1:43, 1:44, 1:46, 1:48, 1:50, 1:52, 1:54, 1:56, 1:58, 1:60, 1:62, 1:64, 1:66, 1:68, 1:69, 1:70, 1:72, 1:74, 1:76, 1:78, 1:80, 1:82, 1:84, 1:86, 1:88, 1:90, 1:100, 1:112, 1:120, 1:140, 1:160, 1:168, 1:180, 1:200, 1:300, 1:400, 1:500, or optionally a range formed by the aforementioned values.

[0133] In some embodiments, the ratio of the periodic dosages of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from 1 : (0.1-50), 1 : (0.5-50), 1 : (1-20), 1 : (1-15), 1 : (1.5-10), or 1 : (1.5-5). In some embodiments, the ratio of the periodic dosages of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from 1 :0.1, 1 :0.5, 1 :0.875, 1 :1, 1 :1.1, 1 :1.15, 1 :1.2, 1 :1.25, 1 :1.3, 1 :1.35, 1 :1.4, 1 :1.45, 1 :1.5, 1 :1.55, 1 :1.6, 1 :1.65, 1 :1.7, 1 :1.75, 1 :1.8, 1 :1.85, 1 :1.9, 1 :1.95, 1 :2, 1 :2.5, 1 :3, 1 :3.5, 1 :4, 1 :4.5, 1 :5, 1 :5.5, 1 :6, 1 :6.5, 1 :7, 1 :7.5, 1 :8, 1 :8.5, 1 :9, 1 :9.5, 1 :10, 1 :14, 1 :20, 1 :30, 1 :40, 1 :50, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of the periodic dosages of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from 1 :0.875, 1 :1.75, 1 :3.5, 1 :7, 1 :14, or optionally a range formed by the aforementioned values.

[0134] In some embodiments, the ratio of the periodic dosages of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from 1 : (1-500), 1 : (2-200), 1 : (4-200), 1 : (6-150), 1 : (15-100), or 1 : (15-80). In some embodiments, the ratio of the periodic dosages of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from 1 : 1, 1 : 5, 1 : 5.25, 1 : 7, 1 : 8.75, 1 : 10, 1 : 10.5, 1 : 12, 1 : 14, 1 : 16, 1 : 17, 1 : 17.5, 1 : 18, 1 : 19, 1 : 20, 1 : 21, 1 : 22, 1 : 23, 1 : 24, 1 : 26, 1 : 28, 1 : 30, 1 : 32, 1 : 34, 1 : 35, 1 : 36, 1 : 38, 1 : 39, 1 : 40, 1 : 41, 1 : 42, 1 : 43, 1 : 44, 1 : 46, 1 : 48, 1 : 50, 1 : 52, 1 : 54, 1 : 56, 1 : 58, 1 : 60, 1 : 62, 1 : 64, 1 : 66, 1 : 68, 1 : 69, 1 : 70, 1 : 72, 1 : 74, 1 : 76, 1 : 78, 1 : 80, 1 : 82, 1 : 84, 1 : 86, 1 : 88, 1 : 90, 1 : 100, 1 : 112, 1 : 120, 1 : 140, 1 : 160, 1 : 168, 1 : 180, 1 : 200, 1 : 300, 1 : 400, 1 : 500, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of the periodic dosages of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from 1 : 5.25, 1 : 7, 1 : 8.75, 1 : 10.5, 1 : 14, 1 : 17.5, 1 : 21, 1 : 28, 1 : 35, 1 : 42, 1 : 56, 1 : 70, 1 : 84, 1 : 112, 1 : 140, 1 : 168, or optionally a range formed by the aforementioned values.

[0135] In some embodiments, the ratio of each dose of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from the group consisting of 1 : (0.01-100). In some embodiments, the ratio of each dose of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from 1 :0.005, 1 :0.01, 1 :0.015, 1 :0.02, 1 :0.025, 1 :0.03, 1 :0.035, 1 :0.04, 1 :0.045, 1 :0.05, 1 :0.06, 1 :0.0625, 1 :0.065, 1 :0.07, 1 :0.075, 1 :0.08, 1 :0.085, 1 :0.09, 1 :0.095, 1 :0.1, 1 :0.125, 1 :0.2, 1 :0.25, 1 :0.3, 1 :0.375, 1 :0.4, 1 :0.5, 1 :0.6, 1 :0.625, 1 :0.7, 1 :0.75, 1 :0.8, 1 :0.9, 1 :1, 1 :1.2, 1 :1.25, 1 :1.4, 1 :1.5, 1 :1.6, 1 :1.8, 1 :2, 1 :2.2, 1 :2.4, 1 :2.5, 1 :2.6, 1 :2.8, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :12, 1 :14, 1 :16, 1 :18, 1 :20, or optionally a range formed by the aforementioned values.

[0136] In some embodiments, the ratio of each dose of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from the group consisting of 1 : (0.01-1), 1 : (0.05-0.5), or 1 : (0.0625-0.25). In some embodiments, the ratio of each dose of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from 1 :0.01, 1 :0.02, 1 :0.03, 1 :0.04, 1 :0.05, 1 :0.06, 1 :0.0625, 1 :0.07, 1 :0.08, 1 :0.09, 1 :0.1, 1 :0.125, 1 :0.2, 1 :0.25, 1 :0.3, 1 :0.4, 1 :0.5, 1 :0.6, 1 :0.7, 1 :0.8, 1 :0.9, 1 :1, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of each dose of the siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from 1 :0.0625, 1 :0.125, 1 :0.25, or optionally a range formed by the aforementioned values.

[0137] In some embodiments, the ratio of each dose of the siRNA agent and the tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from the group consisting of 1 : (0.005-20), 1 : (0.01-10), 1 : (0.3-5), 1 : (0.375-3). In some embodiments, the ratio of each dose of the siRNA agent and the tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from the group consisting of 1 :0.005, 1 :0.01, 1 :0.015, 1 :0.02, 1 :0.025, 1 :0.03, 1 :0.035, 1 :0.04, 1 :0.045, 1 :0.05, 1 :0.065, 1 :0.07, 1 :0.075, 1 :0.08, 1 :0.085, 1 :0.09, 1 :0.095, 1 :0.1, 1 :0.2, 1 :0.3, 1 :0.375, 1 :0.4, 1 :0.5, 1 :0.6, 1 :0.625, 1 :0.7, 1 :0.75, 1 :0.8, 1 :0.9, 1 :1, 1 :1.2, 1 :1.25, 1 :1.4, 1 :1.5, 1 :1.6, 1 :1.8, 1 :2, 1 :2.2, 1 :2.4, 1 :2.5, 1 :2.6, 1 :2.8, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :12, 1 :14, 1 :16, 1 :18, 1 :20, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of each dose of the siRNA agent and the tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from the group consisting of 1 :0.375, 1 :0.5, 1 :0.625, 1 :0.75, 1 :1, 1 :1.25, 1 :1.5, 1 :2, 1 :2.5, 1 :3, or optionally a range formed by the aforementioned values.

[0138] In some embodiments, in the pharmaceutical combination, the ratio of the single dose of the siRNA agent and the single dose of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 100: 1 to 10: 1. In some embodiments, in the pharmaceutical combination, the ratio of the single dose of the siRNA agent and the single dose of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 100: 1, 90: 1, 80: 1, 70: 1, 60: 1, 50: 1, 40: 1, 30: 1, 29: 1, 28: 1, 27: 1, 26: 1, 25: 1, 24: 1, 23: 1, 22: 1, 21: 1, 20: 1, 19: 1, 18: 1, 17: 1, 16: 1, 15: 1, 14: 1, 13: 1, 12: 1, 11: 1, 10.5: 1, 10: 1, or a range formed by any of the aforementioned values. In some embodiments, in the pharmaceutical combination, the ratio of the single dose of the siRNA agent and the single dose of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 50: 1 to 10: 1. In some embodiments, in the pharmaceutical combination, the ratio of the single dose of the siRNA agent and the single dose of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 30: 1 to 20: 1. In some embodiments, in the pharmaceutical combination, the ratio of the single dose of the siRNA agent and the single dose of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 30: 1 to 1: 1, 20: 1 to 1: 1, or 10: 1 to 1: 1. In some embodiments, in the pharmaceutical combination, the ratio of the single dose of the siRNA agent and the single dose of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 24: 1. In some embodiments, in the pharmaceutical combination, the ratio of the single dose of the siRNA agent and the single dose of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 16: 1. In some embodiments, in the pharmaceutical combination, the ratio of the single dose of the siRNA agent and the single dose of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 8: 1. In some embodiments, in the pharmaceutical combination, the ratio of the single dose of the siRNA agent and the single dose of tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 4: 1.

[0139] In some embodiments, the drug combination, the ratio of the periodic dose of the siRNA agent and the tenofovir alafenamide or a pharmaceutically acceptable salt thereof is selected from 1 : (0.1-50), 1 : (0.5-50), 1 : (1-20), 1 : (1-15), 1 : (1.5-10), or 1 : (1.5-5). In some embodiments, the drug combination, the ratio of the periodic dose of the siRNA agent and the tenofovir alafenamide or a pharmaceutically acceptable salt thereof is selected from 1 :0.1, 1 :0.5, 1 :0.875, 1 :1, 1 :1.1, 1 :1.15, 1 :1.2, 1 :1.25, 1 :1.3, 1 :1.35, 1 :1.4, 1 :1.45, 1 :1.5, 1 :1.55, 1 :1.6, 1 :1.65, 1 :1.7, 1 :1.75, 1 :1.8, 1 :1.85, 1 :1.9, 1 :1.95, 1 :2, 1 :2.5, 1 :3, 1 :3.5, 1 :4, 1 :4.5, 1 :5, 1 :5.5, 1 :6, 1 :6.5, 1 :7, 1 :7.5, 1 :8, 1 :8.5, 1 :9, 1 :9.5, 1 :10, 1 :14, 1 :20, 1 :30, 1 :40, 1 :50, or optionally a range formed by the above values. In some embodiments, the drug combination, the ratio of the periodic dose of the siRNA agent and the tenofovir alafenamide or a pharmaceutically acceptable salt thereof is selected from 1 :0.875, 1 :1.75, 1 :3.5, 1 :7, 1 :14, or optionally a range formed by the above values.

[0140] In some embodiments, the drug combination, the ratio of each dose of the siRNA agent and the tenofovir alafenamide or a pharmaceutically acceptable salt thereof is selected from 1 : (0.01-1), 1 : (0.05-0.5), or 1 : (0.0625-0.25). In some embodiments, the drug combination, the ratio of each dose of the siRNA agent and the tenofovir alafenamide or a pharmaceutically acceptable salt thereof is selected from 1 :0.01, 1 :0.02, 1 :0.03, 1 :0.04, 1 :0.05, 1 :0.06, 1 :0.0625, 1 :0.07, 1 :0.08, 1 :0.09, 1 :0.1, 1 :0.125, 1 :0.2, 1 :0.25, 1 :0.3, 1 :0.4, 1 :0.5, 1 :0.6, 1 :0.7, 1 :0.8, 1 :0.9, 1 :1, or optionally a range formed by the above values. In some embodiments, the drug combination, the ratio of each dose of the siRNA agent and the tenofovir alafenamide or a pharmaceutically acceptable salt thereof is selected from 1 :0.0625, 1 :0.125, 1 :0.25, or optionally a range formed by the above values.

[0141] In some embodiments, the drug combination, the drug combination, comprises an siRNA agent and tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the drug combination includes a siRNA agent and tenofovir alafenamide fumarate.

[0143] In some embodiments, the drug combination includes a siRNA agent and tenofovir alafenamide fumarate.

[0144] In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 10: 1 to 0.1: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 10: 1 to 1: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 10: 1, 9.5: 1, 9: 1, 8.5: 1, 8: 1, 7.5: 1, 7: 1, 6.5: 1, 6: 1, 5.5: 1, 5: 1, 4.9: 1, 4.8: 1, 4.7: 1, 4.6: 1, 4.5: 1, 4.4: 1, 4.3: 1, 4.2: 1, 4.1: 1, 4: 1, 3.9: 1, 3.8: 1, 3.7: 1, 3.6: 1, 3.5: 1, 3.4: 1, 3.3: 1, 3.2: 1, 3.1: 1, 3: 1, 2.9: 1, 2.8: 1, 2.7: 1, 2.6: 1, 2.5: 1, 2.4: 1, 2.3: 1, 2.2: 1, 2.1: 1, 2: 1, 1.9: 1, 1.8: 1, 1.7: 1, 1.6: 1, 1.5: 1, 1.4: 1, 1.3: 1, 1.2: 1, 1.1: 1, 1: 1, 0.9: 1, 0.8: 1, 0.7: 1, 0.6: 1, 0.5: 1, 0.4: 1, 0.3: 1, 0.2: 1, 0.1: 1, or a range formed by any of the aforementioned values. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 5: 1 to 1: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 4: 1 to 2: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 4: 1, 3: 1, 2.4: 1, or 2: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 5: 1 to 0.1: 1, 4: 1 to 0.1: 1, or 2: 1 to 0.2: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and tenofovir alafenamide, or a pharmaceutically acceptable salt thereof, is selected from 2: 1, 1.33: 1, 0.67: 1, or 0.33: 1.

[0145] In some embodiments, the ratio of the periodic dosages of the siRNA agent and the tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from 1 : (1-500), 1 : (2-200), 1 : (4-200), 1 : (6-150), 1 : (15-100), or 1 : (15-80). In some embodiments, the ratio of the periodic dosages of the siRNA agent and the tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from 1 : 1, 1 : 5, 1 : 5.25, 1 : 7, 1 : 8.75, 1 : 10, 1 : 10.5, 1 : 12, 1 : 14, 1 : 16, 1 : 17, 1 : 17.5, 1 : 18, 1 : 19, 1 : 20, 1 : 21, 1 : 22, 1 : 23, 1 : 24, 1 : 26, 1 : 28, 1 : 30, 1 : 32, 1 : 34, 1 : 35, 1 : 36, 1 : 38, 1 : 39, 1 : 40, 1 : 41, 1 : 42, 1 : 43, 1 : 44, 1 : 46, 1 : 48, 1 : 50, 1 : 52, 1 : 54, 1 : 56, 1 : 58, 1 : 60, 1 : 62, 1 : 64, 1 : 66, 1 : 68, 1 : 69, 1 : 70, 1 : 72, 1 : 74, 1 : 76, 1 : 78, 1 : 80, 1 : 82, 1 : 84, 1 : 86, 1 : 88, 1 : 90, 1 : 100, 1 : 112, 1 : 120, 1 : 140, 1 : 160, 1 : 168, 1 : 180, 1 : 200, 1 : 300, 1 : 400, 1 : 500, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of the periodic dosages of the siRNA agent and the tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt thereof, in the pharmaceutical combination is selected from 1 : 5.25, 1 : 7, 1 : 8.75, 1 : 10.5, 1 : 14, 1 : 17.5, 1 : 21, 1 : 28, 1 : 35, 1 : 42, 1 : 56, 1 : 70, 1 : 84, 1 : 112, 1 : 140, 1 : 168, or optionally a range formed by the aforementioned values.

[0146] In some embodiments, the ratio of each dose of the siRNA agent and the tenofovir disoproxil fumarate or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is selected from the group consisting of 1 : (0.005-20), 1 : (0.01-10), 1 : (0.3-5), 1 : (0.375-3). In some embodiments, the ratio of each dose of the siRNA agent and the tenofovir disoproxil fumarate or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is selected from the group consisting of 1 :0.005, 1 :0.01, 1 :0.015, 1 :0.02, 1 :0.025, 1 :0.03, 1 :0.035, 1 :0.04, 1 :0.045, 1 :0.05, 1 :0.065, 1 :0.07, 1 :0.075, 1 :0.08, 1 :0.085, 1 :0.09, 1 :0.095, 1 :0.1, 1 :0.2, 1 :0.3, 1 :0.375, 1 :0.4, 1 :0.5, 1 :0.6, 1 :0.625, 1 :0.7, 1 :0.75, 1 :0.8, 1 :0.9, 1 :1, 1 :1.2, 1 :1.25, 1 :1.4, 1 :1.5, 1 :1.6, 1 :1.8, 1 :2, 1 :2.2, 1 :2.4, 1 :2.5, 1 :2.6, 1 :2.8, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :12, 1 :14, 1 :16, 1 :18, 1 :20, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of each dose of the siRNA agent and the tenofovir disoproxil fumarate or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is selected from the group consisting of 1 :0.375, 1 :0.5, 1 :0.625, 1 :0.75, 1 :1, 1 :1.25, 1 :1.5, 1 :2, 1 :2.5, 1 :3, or optionally a range formed by the aforementioned values.

[0147] In some embodiments, the pharmaceutical combination comprises an siRNA agent and tenofovir disoproxil fumarate.

[0148] In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and entecavir, or a pharmaceutically acceptable salt thereof, or solvate thereof, is selected from 2000: 1 to 1 : 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and entecavir, or a pharmaceutically acceptable salt thereof, or solvate thereof, is selected from 2000: 1, 1900: 1, 1800: 1, 1700: 1, 1600: 1, 1500: 1, 1400: 1, 1300: 1, 1200: 1, 1100: 1, 1000: 1, 900: 1, 800: 1, 700: 1, 600: 1, 500: 1, 400: 1, 300: 1, 200: 1, 100: 1, or a range formed by any of the aforementioned values. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and entecavir, or a pharmaceutically acceptable salt thereof, or solvate thereof, is selected from 1500: 1 to 400: 1 or 1200: 1 to 600: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and entecavir, or a pharmaceutically acceptable salt thereof, or solvate thereof, is selected from 1200: 1, or 600: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and entecavir, or a pharmaceutically acceptable salt thereof, or solvate thereof, is selected from 1500: 1 to 100: 1, 1200: 1 to 100: 1, or 1200: 1 to 200: 1. In some embodiments, in the pharmaceutical combination, the ratio of single doses of the siRNA agent and entecavir, or a pharmaceutically acceptable salt thereof, or solvate thereof, is selected from 1200: 1, 800: 1, 600: 1, 400: 1, or 200: 1.

[0149] In some embodiments, the ratio of the periodic doses of the siRNA agent and entecavir, or a pharmaceutically acceptable salt thereof, or solvate thereof, in the pharmaceutical combination is selected from 1 : (0.001-1), 1 : (0.005-1), 1 : (0.01-1), 1 : (0.01-0.5), or 1 : (0.02-0.2). In some embodiments, the ratio of the periodic doses of the siRNA agent and entecavir, or a pharmaceutically acceptable salt thereof, or solvate thereof, in the pharmaceutical combination is selected from 1 :0.001, 1 :0.005, 1 :0.01, 1 :0.015, 1 :0.0175, 1 :0.02, 1 :0.025, 1 :0.03, 1 :0.035, 1 :0.04, 1 :0.045, 1 :0.05, 1 :0.055, 1 :0.06, 1 :0.065, 1 :0.07, 1 :0.075, 1 :0.08, 1 :0.085, 1 :0.09, 1 :0.095, 1 :0.1, 1 :0.14, 1 :0.15, 1 :0.2, 1 :0.25, 1 :0.28, 1 :0.3, 1 :0.35, 1 :0.36, 1 :0.4, 1 :0.45, 1 :0.48, 1 :0.5, 1 :0.55, 1 :0.56, 1 :0.6, 1 :0.65, 1 :0.7, 1 :0.75, 1 :0.8, 1 :0.85, 1 :0.9, 1 :0.95, 1 :1, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of the periodic doses of the siRNA agent and entecavir, or a pharmaceutically acceptable salt thereof, or solvate thereof, in the pharmaceutical combination is selected from 1 :0.0175, 1 :0.035, 1 :0.07, 1 :0.14, 1 :0.28, 1 :0.56, or optionally a range formed by the aforementioned values.

[0150] In some embodiments, the ratio of each dose of the siRNA agent and entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, in the pharmaceutical combination is selected from 1 : (0.1-0.0.5), 1 : (0.001-0.05), or 1 : (0.00125-0.01). In some embodiments, the ratio of each dose of the siRNA agent and entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, in the pharmaceutical combination is selected from 1 :0.0001, 1 :0.0005, 1 :0.001, 1 :0.00125, 1 :0.0015, 1 :0.002, 1 :0.0025, 1 :0.003, 1 :0.0035, 1 :0.004, 1 :0.0045, 1 :0.005, 1 :0.006, 1 :0.007, 1 :0.008, 1 :0.009, 1 :0.01, 1 :0.02, 1 :0.03, 1 :0.04, 1 :0.05, 1 :0.06, 1 :0.07, 1 :0.08, 1 :0.09, 1 :0.1, or optionally a range formed by the aforementioned values. In some embodiments, the ratio of each dose of the siRNA agent and entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, in the pharmaceutical combination is selected from 1 :0.00125, 1 :0.0025, 1 :0.005, 1 :0.01, or optionally a range formed by the aforementioned values.

[0151] In some embodiments, the pharmaceutical combination includes an siRNA agent and entecavir monomaleate, entecavir monohydrate, or entecavir entecavir monomaleate monohydrate. In some embodiments, the pharmaceutical combination includes an siRNA agent and entecavir monohydrate.

[0152] In some embodiments, the ratio of the doses of the siRNA agent and the reverse transcriptase inhibitor (e.g., entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof) in the pharmaceutical combination is a single dose, a ratio of doses per treatment cycle, or a ratio of doses per administration.

[0153] In some embodiments, each treatment cycle is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or more. In some embodiments, each treatment cycle is 2 weeks to 27 weeks. In some embodiments, each treatment cycle is 2 weeks, 4 weeks, 6 weeks, 8 weeks, or 10 weeks. In some embodiments, each treatment cycle is 2 weeks, 4 weeks, or 8 weeks. In some embodiments, each treatment cycle is 4 weeks.

[0154] Dosing / treatment or prophylaxis regimen of the pharmaceutical combination

[0155] The present application provides a method of treating or preventing hepatitis B comprising administering to an individual in need thereof an effective amount of a siRNA agent of the present application and a reverse transcriptase inhibitor (e.g., tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, e.g., entecavir or a pharmaceutically acceptable salt thereof, or a solvate thereof).

[0156] The present application provides the use of a siRNA agent of the present application and a reverse transcriptase inhibitor (e.g., tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, e.g., entecavir or a pharmaceutically acceptable salt thereof, or a solvate thereof) for the treatment or prevention of hepatitis B.

[0157] The present application provides the use of a siRNA agent of the present application and a reverse transcriptase inhibitor (e.g., tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, e.g., entecavir or a pharmaceutically acceptable salt thereof, or a solvate thereof) for the treatment or prevention of hepatitis B.

[0158] The present application provides the use of a siRNA agent of the present application for the preparation of a medicament for use in combination with a reverse transcriptase inhibitor (e.g., tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, e.g., entecavir or a pharmaceutically acceptable salt thereof, or a solvate thereof) for the treatment or prevention of hepatitis B.

[0159] In some embodiments, an effective amount of the siRNA agent and a reverse transcriptase inhibitor (e.g., tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, e.g., entecavir or a pharmaceutically acceptable salt thereof, or a solvate thereof) can be administered simultaneously, sequentially or at intervals to an individual in need thereof.

[0160] In some embodiments, an effective amount of the siRNA agent and a reverse transcriptase inhibitor (e.g., tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, e.g., entecavir or a pharmaceutically acceptable salt thereof, or a solvate thereof) can be administered to an individual in need thereof according to the same or different dosing regimen.

[0161] In some embodiments, the siRNA agent is administered once every 1 day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, or once every 10 weeks. In some embodiments, the siRNA agent is administered once every 1 week, once every 2 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks. In some embodiments, the siRNA agent is administered once every 2 weeks, once every 4 weeks, or once every 8 weeks. In some embodiments, the siRNA agent is administered once every 2 weeks or once every 4 weeks. In some embodiments, the siRNA agent is administered once every 4 weeks.

[0162] In some embodiments, the siRNA agent is administered once each on day 1, or / and day 15, and / or day 29, and / or day 57. In some embodiments, the siRNA agent repeats the last dosing cycle.

[0163] In some embodiments, the siRNA agent is administered subcutaneously.

[0164] In some embodiments, the siRNA agent is administered at approximately the same time each administration.

[0165] In some embodiments, the siRNA agent is administered at a dose as previously described.

[0166] In some embodiments, the siRNA agent is administered at a dose of 1 mg - 1200 mg, 1 mg - 1000 mg, 10 mg - 1000 mg, 50 mg - 1000 mg, 50 mg - 800 mg, or 80 mg - 800 mg per administration. In some embodiments, the siRNA agent is administered at a dose of 1200 mg, 1100 mg, 1000 mg, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 500 mg, 480 mg, 460 mg, 450 mg, 440 mg, 420 mg, 400 mg, 380 mg, 360 mg, 350 mg, 340 mg, 320 mg, 300 mg, 280 mg, 260 mg, 250 mg, 240 mg, 220 mg, 200 mg, 180 mg, 160 mg, 150 mg, 140 mg, 120 mg, 100 mg, 80 mg, 50 mg, 10 mg, or a range formed by any of the foregoing values per administration. In some embodiments, the siRNA agent is administered at a dose of 400 mg, 200 mg, 100 mg, or a range formed by any of the foregoing values per administration. In some embodiments, the siRNA agent is administered at a dose of 400 mg, 200 mg, 100 mg, or a range formed by any of the foregoing values per administration. In some embodiments, the siRNA agent is administered at a dose of 400 mg, 200 mg, or a range formed by any of the foregoing values per administration.

[0167] In some embodiments, the siRNA agent is administered once every 2 weeks, once every 4 weeks, or once every 8 weeks at a dose of 1 mg to 1200 mg, 1 mg to 1000 mg, 10 mg to 1000 mg, 50 mg to 1000 mg, 50 mg to 800 mg, or 80 mg to 800 mg per administration. In some embodiments, the siRNA agent is administered once every 2 weeks, once every 4 weeks, or once every 8 weeks at a dose of 1200 mg, 1100 mg, 1000 mg, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 500 mg, 480 mg, 460 mg, 450 mg, 440 mg, 420 mg, 400 mg, 380 mg, 360 mg, 350 mg, 340 mg, 320 mg, 300 mg, 280 mg, 260 mg, 250 mg, 240 mg, 220 mg, 200 mg, 180 mg, 160 mg, 150 mg, 140 mg, 120 mg, 100 mg, 80 mg, 50 mg, 10 mg, or a range formed by any of the above values. In some embodiments, the siRNA agent is administered once every 2 weeks, once every 4 weeks, or once every 8 weeks at a dose of 100 mg to 400 mg, or 100 mg to 200 mg per administration. In some embodiments, the siRNA agent is administered once every 2 weeks, once every 4 weeks, or once every 8 weeks at a dose of 400 mg, 200 mg, 100 mg, or a range formed by any of the above values. In some embodiments, the siRNA agent is administered once every 2 weeks or once every 4 weeks at a dose of 400 mg, 200 mg, 100 mg, or a range formed by any of the above values. In some embodiments, the siRNA agent is administered once every 4 weeks at a dose of 100 mg to 400 mg per administration. In some embodiments, the siRNA agent is administered once every 4 weeks at a dose of 400 mg, 200 mg, 100 mg, or a range formed by any of the above values. In some embodiments, the siRNA agent is administered once every 4 weeks at a dose of 100 mg to 200 mg per administration. In some embodiments, the siRNA agent is administered once every 4 weeks at a dose of 200 mg, 100 mg, or a range formed by any of the above values. In some embodiments, the siRNA agent is administered once every 4 weeks at a dose of 400 mg, 200 mg, or a range formed by any of the above values.

[0168] In some embodiments, the reverse transcriptase inhibitor is administered once a day, twice a day, or once every 2 days.

[0169] In some embodiments, the reverse transcriptase inhibitor is administered at a dose of 0.01 mg to 500 mg per administration, preferably 0.01 mg, 0.02 mg, 0.05 mg, 0.08 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7 mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 7.6 mg, 7.7 mg, 7.8 mg, 7.9 mg, 8 mg, 8.1 mg, 8.2 mg, 8.3 mg, 8.4 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9 mg, 9.1 mg, 9.2 mg, 9.3 mg, 9.4 mg, 9.5 mg, 9.6 mg, 9.7 mg, 9.8 mg, 9.9 mg, 10 mg, 10.1 mg, 10.2 mg, 10.3 mg, 10.4 mg, 10.5 mg, 10.6 mg, 10.7 mg, 10.8 mg, 10.9 mg, 11 mg, 11.1 mg, 11.2 mg, 11.3 mg, 11.4 mg, 11.5 mg, 11.6 mg, 11.7 mg, 11.8 mg, 11.9 mg, 12 mg, 12.1 mg, 12.2 mg, 12.3 mg, 12.4 mg, 12.5 mg, 12.6 mg, 12.7 mg, 12.8 mg, 12.9 mg, 13 mg, 13.1 mg, 13.2 mg, 13.3 mg, 13.4 mg, 13.5 mg, 13.6 mg, 13.7 mg, 13.8 mg, 13.9 mg, 14 mg, 14.1 mg, 14.2 mg, 14.3 mg, 14.4 mg, 14.5 mg, 14.6 mg, 14.7 mg, 14.8 mg, 14.9 mg, 15 mg, 15.1 mg, 15.2 mg, 15.3 mg, 15.4 mg, 15.5 mg, 15.6 mg, 15.7 mg, 15.8 mg, 15.9 mg, 16 mg, 16.1 mg, 16.2 mg, 16.3 mg, 16.4 mg, 16.5 mg, 16.6 mg, 16.7 mg, 16.8 mg, 16.9 mg, 17 mg, 17.1 mg, 17.2 mg, 17.3 mg, 17.4 mg, 17.5 mg, 17.6 mg, 17.7 mg, 17.8 mg, 17.9 mg, 18 mg, 18.1 mg, 18.2 mg, 18.3 mg, 18.4 mg, 18.5 mg, 18.6 mg, 18.7 mg, 18.8 mg, 18.9 mg, 19 mg, 19.1 mg, 19.2 mg, 19.3 mg, 19.4 mg, 19.5 mg, 19.6 mg, 19.7 mg, 19.8 mg, 19.9 mg, 20 mg, 20.1 mg, 20.2 mg, 20.3 mg, 20.4 mg, 20.5 mg, 20.6 mg, 20.7 mg, 20.8 mg, 20.9 mg, 21 mg, 21.1 mg, 21.2 mg, 21.3 mg, 21.4 mg, 21.5 mg, 21.6 mg, 21.7 mg, 21.8 mg, 21.9 mg, 22 mg, 22.1 mg, 22.2 mg, 22.3 mg, 22.4 mg, 22.5 mg, 22.6 mg, 22.7 mg, 22.8 mg, 22.9 mg, 23 mg, 23.1 mg, 23.2 mg, 23.3 mg, 23.4 mg, 23.5 mg, 23.6 mg, 23.7 mg, 23.8 mg, 23.9 mg, 24 mg, 24.1 mg, 24.2 mg, 24.3 mg, 24.4 mg, 24.5 mg, 24.6 mg, 24.7 mg, 24.8 mg, 24.9 mg, 25 mg, 25.1 mg, 25.2 mg, 25.3 mg, 25.4 mg, 25.5 mg, 25.6 mg, 25.7 mg, 25.8 mg, 25.9 mg, 26 mg, 26.1 mg, 26.2 mg, 26.3 mg, 26.4 mg, 26.5 mg, 26.6 mg, 26.7 mg, 26.8 mg, 26.9 mg, 27 mg, 27.1 mg, 27.2 mg, 27.3 mg, 27.4 mg, 27.5 mg, 27.6 mg, 27.7 mg, 27.8 mg, 27.9 mg, 28 mg, 28.1 mg, 28.2 mg, 28.3 mg, 28.4 mg, 28.5 mg, 28.6 mg, 28.7 mg, 28.8 mg, 28.9 mg, 29 mg, 29.1 mg, 29.2 mg, 29.3 mg, 29.4 mg, 29.5 mg, 29.6 mg, 29.7 mg, 29.8 mg, 29.9 mg, 30 mg, 30.1 mg, 30.2 mg, 30.3 mg, 30.4 mg, 30.5 mg, 30.6 mg, 30.7 mg, 30.8 mg, 30.9 mg, 31 mg, 31.1 mg, 31.2 mg, 31.3 mg, 31.4 mg, 31.5 mg, 31.6 mg, 31.7 mg, 31.8 mg, 31.9 mg, 32 mg, 32.1 mg, 32.2 mg, 32.3 mg, 32.4 mg, 32.5 mg, 32.6 mg, 32.7 mg, 32.8 mg, 32.9 mg, 33 mg, 33.1 mg, 33.2 mg, 33.3 mg, 33.4 mg, 33.5 mg, 33.6 mg, 33.7 mg, 33.8 mg, 33.9 mg, 34 mg, 34.1 mg, 34.2 mg, 34.3 mg, 34.4 mg,9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 140 mg, 150 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 180 mg, 190 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 220 mg, 230 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, or a range of values formed by any of the foregoing. In some embodiments, the reverse transcriptase inhibitor is administered at a dose of 0.01 mg to 5 mg, 0.1 mg to 2.0 mg, 0.25 mg to 2 mg, 0.5 mg to 1 mg, 0.1 mg to 1 mg, or 0.2 mg to 0.5 mg per administration. In some embodiments, the reverse transcriptase inhibitor is administered at a dose of 5 mg to 50 mg, 10 mg to 40 mg, or 10 mg to 25 mg per administration. In some embodiments, the reverse transcriptase inhibitor is administered at a dose of 80 mg to 500 mg, 100 mg to 400 mg, or 150 mg to 300 mg per administration.

[0170] In some embodiments, the reverse transcriptase inhibitor is administered once a day at a dose of 0.01 mg - 5 mg, 0.1 mg - 2.0 mg, 0.25 mg - 2 mg, 0.5 mg - 1 mg, 0.1 mg - 1 mg, or 0.2 mg - 0.5 mg per administration. In some embodiments, the reverse transcriptase inhibitor is administered once a day at a dose of 5 mg - 50 mg, 10 mg - 40 mg, or 10 mg - 25 mg per administration. In some embodiments, the reverse transcriptase inhibitor is administered once a day at a dose of 80 mg - 500 mg, 100 mg - 400 mg, or 150 mg - 300 mg per administration.

[0171] In some embodiments, the reverse transcriptase inhibitor is as described herein.

[0172] In some embodiments, the reverse transcriptase inhibitor is selected from the group consisting of tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, is administered once a day, twice a day, or once every two days. In some embodiments, the tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, is administered once a day.

[0174] In some embodiments, the tenofovir, or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof, is administered at a dose as previously described.

[0175] In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 500 mg per administration, preferably 10 mg, 15 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 140 mg, 150 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 180 mg, 190 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 220 mg, 230 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, or a range formed by any of these values. In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is administered at a dose of 15 mg to 40 mg or 100 mg to 300 mg per administration. In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is administered at a dose of 25 mg to 40 mg or 120 mg to 300 mg per administration. In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is administered at a dose of 25 mg, 30 mg, 33 mg, 40 mg, 123 mg, 150 mg, 163 mg, 200 mg, 204 mg, 245 mg, 250 mg, 291 mg, or 300 mg per administration.

[0176] In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is administered once a day at a dose of 15 mg - 40 mg or 100 mg - 300 mg per administration. In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is administered once a day at a dose of 25 mg - 40 mg or 120 mg - 300 mg per administration. In some embodiments, the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is administered once a day at a dose of 25 mg, 30 mg, 33 mg, 40 mg, 123 mg, 150 mg, 163 mg, 200 mg, 204 mg, 245 mg, 250 mg, 291 mg, or 300 mg per administration.

[0177] In some embodiments, the siRNA agent is administered at a dose of 1 mg - 1200 mg, 1 mg - 1000 mg, 10 mg - 1000 mg, 50 mg - 1000 mg, 50 mg - 800 mg, or 80 mg - 800 mg per administration; and the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is administered once a day at a dose of 15 mg - 40 mg or 100 mg - 300 mg per administration.

[0178] In some embodiments, the siRNA agent is administered at a dose of 1 mg - 1200 mg, 1 mg - 1000 mg, 10 mg - 1000 mg, 50 mg - 1000 mg, 50 mg - 800 mg, or 80 mg - 800 mg per administration; and the tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof is administered once a day at a dose of 15 mg - 40 mg or 100 mg - 300 mg per administration.

[0179] In some embodiments, the reverse transcriptase inhibitor (or tenofovir or pharmaceutically acceptable prodrug thereof or pharmaceutically acceptable salt thereof) is selected from tenofovir alafenamide or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the tenofovir alafenamide or pharmaceutically acceptable salt thereof is administered once a day, twice a day, or once every two days. In some embodiments, the tenofovir alafenamide or pharmaceutically acceptable salt thereof is administered once a day.

[0181] In some embodiments, the tenofovir alafenamide or pharmaceutically acceptable salt thereof is administered at a dose as previously described.

[0182] In some embodiments, the propagermanium tenofovir or pharmaceutically acceptable salt thereof is administered at a dose of 10 mg - 50 mg per administration, preferably 10 mg, 15 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or a range formed by any of the aforementioned values. In some embodiments, the propagermanium tenofovir or pharmaceutically acceptable salt thereof is administered at a dose of 15 mg - 40 mg per administration. In some embodiments, the propagermanium tenofovir or pharmaceutically acceptable salt thereof is administered at a dose of 25 mg - 40 mg per administration. In some embodiments, the propagermanium tenofovir or pharmaceutically acceptable salt thereof is administered at a dose of 25 mg per administration.

[0183] In some embodiments, the propagermanium tenofovir or pharmaceutically acceptable salt thereof is administered at a dose of 10 mg - 50 mg per administration, preferably 10 mg, 15 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or a range formed by any of the aforementioned values. In some embodiments, the propagermanium tenofovir or pharmaceutically acceptable salt thereof is administered at a dose of 15 mg - 40 mg per administration. In some embodiments, the propagermanium tenofovir or pharmaceutically acceptable salt thereof is administered at a dose of 25 mg - 40 mg per administration. In some embodiments, the propagermanium tenofovir or pharmaceutically acceptable salt thereof is administered at a dose of 25 mg per administration.

[0184] In some embodiments, the siRNA agent is administered at a dose of 1 mg - 1200 mg, 1 mg - 1000 mg, 10 mg - 1000 mg, 50 mg - 1000 mg, 50 mg - 800 mg, or 80 mg - 800 mg per administration; and the propagermanium tenofovir or pharmaceutically acceptable salt thereof is administered at a dose of 15 mg - 40 mg per administration.

[0185] In some embodiments, the siRNA agent is administered at a dose of 1 mg - 1200 mg, 1 mg - 1000 mg, 10 mg - 1000 mg, 50 mg - 1000 mg, 50 mg - 800 mg, or 80 mg - 800 mg per administration; and the propagermanium tenofovir or pharmaceutically acceptable salt thereof is administered at a dose of 15 mg - 40 mg per administration.

[0186] In some embodiments, the siRNA agent is administered at a dose of 1 mg - 1200 mg, 1 mg - 1000 mg, 10 mg - 1000 mg, 50 mg - 1000 mg, 50 mg - 800 mg, or 80 mg - 800 mg per administration; and the propagermanium tenofovir or pharmaceutically acceptable salt thereof is administered at a dose of 15 mg - 40 mg per administration.

[0187] In some embodiments, the siRNA agent is administered once every four weeks at a dose of 100 mg - 400 mg per administration; the prodrug of tenofovir or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 25 mg - 40 mg per administration.

[0188] In some embodiments, the siRNA agent is administered once every four weeks at a dose of 200 mg - 400 mg per administration; the prodrug of tenofovir or a pharmaceutically acceptable salt thereof is administered once a day at a dose of 25 mg per administration.

[0189] In some embodiments, the reverse transcriptase inhibitor (or tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof) is selected from tenofovir disoproxil or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, the tenofovir disoproxil or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or once every two days. In some embodiments, the tenofovir disoproxil or a pharmaceutically acceptable salt thereof is administered once a day.

[0191] In some embodiments, the tenofovir disoproxil or a pharmaceutically acceptable salt thereof is administered at a dose as previously described.

[0192] In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is administered in a dose of 50 mg - 500 mg per administration, preferably 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 140 mg, 150 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 180 mg, 190 mg, 200 mg, 201 mg, 202 mg, 203 mg, 204 mg, 205 mg, 206 mg, 207 mg, 208 mg, 209 mg, 210 mg, 220 mg, 230 mg, 240 mg, 241 mg, 242 mg, 243 mg, 244 mg, 245 mg, 246 mg, 247 mg, 248 mg, 249 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, or a range of values formed by any of the foregoing. In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is administered in a dose of 80 mg - 500 mg per administration. In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is administered in a dose of 100 mg - 300 mg per administration. In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is administered in a dose of 120 mg - 300 mg per administration. In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is administered in a dose of 30 mg, 33 mg, 40 mg, 123 mg, 150 mg, 163 mg, 200 mg, 204 mg, 245 mg, 250 mg, 291 mg, or 300 mg per administration.

[0193] In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is administered once a day at a dose of 80 mg - 500 mg per administration. In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is administered once a day at a dose of 100 mg - 300 mg per administration. In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is administered once a day at a dose of 120 mg - 300 mg per administration. In some embodiments, the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is administered once a day at a dose of 30 mg, 33 mg, 40 mg, 123 mg, 150 mg, 163 mg, 200 mg, 204 mg, 245 mg, 250 mg, 291 mg, or 300 mg per administration.

[0194] In some embodiments, the siRNA agent is administered once every two weeks, once every four weeks, or once every eight weeks at a dose of 1 mg - 1200 mg, 1 mg - 1000 mg, 10 mg - 1000 mg, 50 mg - 1000 mg, 50 mg - 800 mg, or 80 mg - 800 mg per administration; and the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is administered once a day at a dose of 120 mg - 300 mg per administration.

[0195] In some embodiments, the siRNA agent is administered once every two weeks, once every four weeks, or once every eight weeks at a dose of 1 mg - 1200 mg, 1 mg - 1000 mg, 10 mg - 1000 mg, 50 mg - 1000 mg, 50 mg - 800 mg, or 80 mg - 800 mg per administration; and the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is administered once a day at a dose of 120 mg - 300 mg per administration.

[0196] In some embodiments, the siRNA agent is administered once every four weeks at a dose of 100 mg - 400 mg per administration; and the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is administered once a day at a dose of 120 mg - 300 mg per administration.

[0197] In some embodiments, the siRNA agent is administered once every four weeks at a dose of 200 mg - 400 mg per administration; and the tenofovir disoproxil fumarate or pharmaceutically acceptable salt thereof is administered once a day at a dose of 300 mg per administration.

[0198] In some embodiments, the reverse transcriptase inhibitor is selected from entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof.

[0199] In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered once a day, twice a day, or once every two days. In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered once a day.

[0200] In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered at a dose as previously described.

[0201] In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered at a dose of 0.01 mg to 5 mg per administration, preferably 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5 mg, or a range formed by any of the foregoing values. In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered at a dose of 0.01 mg to 5 mg, 0.1 mg to 2 mg, 0.25 mg to 2 mg, 0.5 mg to 1 mg, 0.1 mg to 1 mg, or 0.2 mg to 0.5 mg per administration.

[0202] In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered once a day at a dose of 0.01 mg to 5 mg, 0.1 mg to 2 mg, 0.25 mg to 2 mg, 0.5 mg to 1 mg, 0.1 mg to 1 mg, or 0.2 mg to 0.5 mg per administration. In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered once a day at a dose of 0.2 mg to 0.5 mg per administration. In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered once a day at a dose of 0.5 mg or 1 mg per administration.

[0203] In some embodiments, the siRNA agent is administered at a dose of 1 mg - 1200 mg, 1 mg - 1000 mg, 10 mg - 1000 mg, 50 mg - 1000 mg, 50 mg - 800 mg, or 80 mg - 800 mg per administration; the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered once a day at a dose of 0.01 mg - 5 mg, 0.1 mg - 2.0 mg, 0.25 mg - 2 mg, 0.5 mg - 1 mg, 0.1 mg - 1 mg, or 0.2 mg - 0.5 mg per administration.

[0204] In some embodiments, the siRNA agent is administered once every two weeks, once every four weeks, or once every eight weeks at a dose of 1 mg - 1200 mg, 1 mg - 1000 mg, 10 mg - 1000 mg, 50 mg - 1000 mg, 50 mg - 800 mg, or 80 mg - 800 mg per administration; the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered once a day at a dose of 0.01 mg - 5 mg, 0.1 mg - 2.0 mg, 0.25 mg - 2 mg, 0.5 mg - 1 mg, 0.1 mg - 1 mg, or 0.2 mg - 0.5 mg per administration.

[0205] In some embodiments, the siRNA agent is administered once every two weeks, once every four weeks, or once every eight weeks at a dose of 1 mg - 1200 mg, 1 mg - 1000 mg, 10 mg - 1000 mg, 50 mg - 1000 mg, 50 mg - 800 mg, or 80 mg - 800 mg per administration; the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered once a day at a dose of 0.1 mg - 1 mg per administration.

[0206] In some embodiments, the siRNA agent is administered once every four weeks at a dose of 100 mg - 400 mg per administration; the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered once a day at a dose of 0.1 mg - 1 mg per administration.

[0207] In some embodiments, the siRNA agent is administered once every four weeks at a dose of 100 mg - 400 mg per administration; the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered once a day at a dose of 0.2 mg - 0.5 mg per administration.

[0208] In some embodiments, the siRNA agent is administered once every four weeks at a dose of 200 mg - 400 mg per administration; the entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is administered once a day at a dose of 0.5 mg per administration.

[0209] In some embodiments, the tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of tenofovir alafenamide fumarate.

[0210] In some embodiments, the tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of tenofovir disoproxil fumarate.

[0211] In some embodiments, the entecavir or a pharmaceutically acceptable salt thereof or a solvate thereof is selected from the group consisting of entecavir monohydrate.

[0212] Chronic hepatitis B, a subject in need thereof

[0213] In some embodiments, the subject in need thereof has serum HBsAg positive for more than 6 months.

[0214] In some embodiments, the subject in need thereof has serum HBsAg positive for more than 6 months, 100 IU / mL≤ HBsAg quantitation≤ 5000 IU / mL.

[0215] In some embodiments, the subject in need thereof has serum HBsAg positive for more than 6 months, 100 IU / mL≤ HBsAg quantitation≤ 3000 IU / mL.

[0216] In some embodiments, the subject in need thereof is selected from the group consisting of a naive or a treated subject.

[0217] In some embodiments, the subject in need thereof is selected from a treated subject. In some embodiments, the treated refers to prior receipt of chronic hepatitis B antiviral treatment (e.g., nucleos(t)ide analogs and interferon). In some embodiments, the treated refers to receipt of nucleos(t)ide analog treatment for≥ 6 months and stable treatment regimen for≥ 3 months. In some embodiments, the subject in need thereof is selected from a naive subject. In some embodiments, the naive refers to never having received chronic hepatitis B antiviral treatment (e.g., nucleos(t)ide analogs and interferon) or having received irregular chronic hepatitis B antiviral treatment but has discontinued treatment for≥ 3 months.

[0218] In some embodiments, the treated subject refers to one or more of the following:

[0219] 1) having received nucleos(t)ide analog treatment for≥ 6 months and stable treatment regimen for≥ 3 months; and / or,

[0220] 2) Have documented history of HBV DNA < lower limit of normal (LLOQ) at 6 months or more prior to treatment, and HBV DNA < 20 IU / mL (Roche COBAS Taqman assay) at screening; and / or,

[0221] 3) ALT < 2 ULN; and / or,

[0222] 4) FibroScan < 9.7 kPa within 6 months prior to screening.

[0223] In some embodiments, the untreated individual refers to one who meets one or more of the following conditions:

[0224] 1) The individual has never received antiviral treatment for chronic hepatitis B (e.g. oral nucleos(t)ide and interferon), or has had irregular antiviral treatment in the past, but has not received any antiviral treatment for chronic hepatitis B for 3 months prior to enrollment; and / or,

[0225] 2) HBV DNA > 2000 IU / mL (Roche COBAS Taqman assay); and / or,

[0226] 3) ALT < 5 x ULN; and / or,

[0227] 4) FibroScan < 12.4 kPa within 6 months prior to screening.

[0228] Definitions and Descriptions

[0229] The following terms as used in this application have the following meanings, unless a different meaning is stated. A particular term should not be construed as indefinite or unclear if not specifically defined, but should be understood in accordance with the ordinary meaning in the art.

[0230] When a trade name appears in the present disclosure, it is intended to refer to its corresponding commercial product or its active ingredient.

[0231] In this application, unless otherwise stated, the terms "comprise", "comprises" and "comprising" or equivalents thereof are open-ended, meaning that, in addition to the listed elements, components, and steps, other unspecified elements, components, and steps can also be present.

[0232] Unless specifically stated otherwise, singular terms shall encompass the plural where the context allows for such. Unless specifically stated otherwise, the term "or" means "and / or". Unless specifically stated otherwise, the term "one" means "at least one".

[0233] For purposes of description and disclosure, all patents, patent applications, and other publications identified herein are expressly incorporated herein by reference. Such publications are provided solely for their disclosure prior to the filing date of the present application. All statements as to the date or dates of these documents are based on available information and are believed to be accurate, but are not admitted as evidence as to their correctness. Furthermore, all references cited are incorporated by reference in their entirety and for all purposes to the extent possible under 37 C.F.R. § 1.84.

[0234] As used herein, unless otherwise indicated, the reverse transcriptase inhibitor includes the free base of the compound, a pharmaceutically acceptable prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. The reverse transcriptase inhibitor includes nucleotide-based compounds.

[0235] As used herein, unless otherwise indicated, the mass, the single dose, the cycle dose, the dose per time of the siRNA agent or the reverse transcriptase inhibitor is calculated based on the strength of the pharmaceutical composition of the siRNA agent or the reverse transcriptase inhibitor, which can refer to the free base, the salt, or the solvate according to different pharmaceutical compositions. For example, the strength of the pharmaceutical composition of the tenofovir alafenamide fumarate tablet under the trade name of Vemlidy is calculated based on tenofovir alafenamide free base; the strength of the pharmaceutical composition of the tenofovir disoproxil fumarate tablet under the trade name of Viread is calculated based on tenofovir disoproxil fumarate or tenofovir disoproxil; the strength of the pharmaceutical composition of the entecavir under the trade name of Baraclude is calculated based on entecavir free base. The free base refers to non-salt and non-solvate (non-water).

[0236] The term "pharmaceutical combination" as used herein means a combination of two or more active ingredients (administered in the form of the respective active ingredient per se, or in the form of pharmaceutically acceptable salts or esters or other derivatives, prodrugs or compositions thereof) administered to the individual simultaneously or sequentially with each other. In the present context, the terms "pharmaceutical combination" and "pharmaceutical combination" are used interchangeably.

[0237] As used herein, "in combination" or "in conjunction" means that two or more active agents can be administered to an individual simultaneously in a single entity or dosage form, or separately in respective entities or dosage forms, either simultaneously, concurrently, or sequentially in any order, therapeutically.

[0238] The term "treatment" generally means obtaining a desired pharmacologic and / or physiologic effect. The effect can be therapeutic in whole or in part, stabilizing or curing a disease and / or adverse effect resulting from the disease. As used herein, "treatment" covers any treatment of a patient, including: (a) inhibiting the disease, i.e., arresting its development; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or symptoms.

[0239] The term "prevention" generally means (a) preventing a disease from occurring in a subject that is predisposed or does not yet experience symptoms of the disease or (b) delaying the onset of a disease or symptoms of the disease.

[0240] The term "effective amount" means the amount of a compound of the application that will elicit the biological or medical response of a particular disease, condition, or disorder as described herein. The amount of an active material that constitutes an "effective amount" will vary depending on the subject's state of disease, age, gender, and weight, and the ability of the therapeutic or therapeutic combination to elicit a desired response in the subject. An effective amount is also routinely determined by one of skill in the art, based on his own knowledge and the disclosure herein.

[0241] The term "administering" or "administration" means physically introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0242] The terms "day," "daily," and the like, in connection with dosing schedules, refer to a period of time within a calendar day, beginning at midnight and ending at the next midnight.

[0243] The term "pharmaceutically acceptable" or "pharmacologically acceptable" in reference to compounds, materials, compositions, and / or dosage forms is intended to mean those that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0244] The term "pharmaceutically acceptable salt" includes salts of a compound containing an alkali metal ion with a free acid or a salt of a compound containing an acid ion with a free base.

[0245] The term "prodrug" means a compound which is transformed in vivo (e.g. by hydrolysis in blood or in target cells) to yield the parent compound. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[0246] The term "pharmaceutical composition" means a mixture of one or more active ingredients or a pharmaceutical combination thereof, with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the application or a pharmaceutical combination thereof to a subject.

[0247] The term "pharmaceutically acceptable excipient" means an excipient that is not biologically or otherwise undesirable, i.e., the excipient can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The suitable excipient is well known to a person skilled in the art, such as carbohydrates, waxes, water-soluble and / or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0248] The pharmaceutical composition of the application can be prepared by combining a compound of the application with a suitable pharmaceutically acceptable excipient, for example, it can be formulated into solid preparations (e.g., granules, tablets, pills, capsules, etc.), or into liquid preparations (e.g., injection solutions).

[0249] The pharmaceutical composition of the application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying or lyophilizing processes.

[0250] Solid oral compositions can be prepared by conventional mixing or compaction methods, e.g., using a tableting machine. Commonly used excipients include binding agents, diluents, fillers, lubricants, disintegrants, wetting agents, and the like. Examples of excipients include, but are not limited to, starch, calcium carbonate, sodium carbonate, calcium phosphate, confectioner's sugar, microcrystalline cellulose, sucrose, lactose, talc, magnesium stearate, stearic acid, sodium stearyl fumarate, sodium starch glycolate, acacia, corn starch, gelatin, glucose, lactose, sucrose, magnesium stearate, sodium stearates, sodium stearyl fumarate, sodium chloride, and the like.

[0251] In the present application, the terms "subject" or "patient" or "individual" are used interchangeably. In some embodiments, the term "subject" or "patient" or "individual" is a mammal. In some embodiments, the subject or patient or individual is a mouse. In some embodiments, the subject or patient or individual is a human.

[0252] The term "single dose pharmaceutical composition" refers to the smallest unit of packaging containing a certain amount of a drug product, for example, a box of medicine has seven capsules, each capsule is a single dose pharmaceutical composition; or each bottle of injection is a single dose pharmaceutical composition. In the present application, the terms "single dose pharmaceutical composition" and "unit dose pharmaceutical composition" have the same meaning and can be used interchangeably.

[0253] The term "multiple dose pharmaceutical composition" consists of multiple single dose pharmaceutical compositions.

[0254] The term "single dose" refers to the content of the active ingredient in a single dose pharmaceutical composition. In the present application, the terms "single dose" and "unit dose" have the same meaning and can be used interchangeably. For example, a single dose of 600 mg of siRNA agent pharmaceutical composition refers to a single dose pharmaceutical composition containing 600 mg of siRNA agent as the active ingredient.

[0255] The term "daily dose" refers to the dose administered to a patient in a day.

[0256] The term "fixed combination" refers to the administration of active ingredients (e.g., siRNA agent or reverse transcriptase inhibitor) to an individual as a fixed dose or in a fixed ratio of doses, or in a single entity, pharmaceutical composition or formulation. In some embodiments, for example, in the same tablet or the same capsule or the same injection or the same drug bag.

[0257] The term "non-fixed combination" refers to the administration of two or more active ingredients to an individual as separate entities (e.g., pharmaceutical compositions, drug formulations) either simultaneously, concurrently or sequentially with no specific time limits, wherein the amounts of the active ingredients administered have the intended effects. An example of a non-fixed combination is a cocktail, for example, administration of two, three or more active ingredients. In a non-fixed combination, the individual active ingredients can be packaged, sold or administered independently of one another.

[0258] As used herein, the siRNA agent or the reverse transcriptase inhibitor can be administered by any suitable route, including, but not limited to, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal, and intrathecal. In some embodiments, the siRNA agent is administered by a parenteral route. In some embodiments, the siRNA agent is administered intravenously, intramuscularly, subcutaneously, or intraperitoneally. In some embodiments, the reverse transcriptase inhibition is administered orally. A therapeutically effective amount of the siRNA agent or the reverse transcriptase inhibitor includes, but is not limited to, from 0.0001 to 20 mg / kg weight / day, for example, from 0.001 to 10 mg / kg weight / day. The frequency of the dose of the siRNA agent or the reverse transcriptase inhibitor is determined by the needs of the individual patient, including severity, response to the disease, any treatment-related toxicity, age, and health status of the patient. The administration can be intermittent, for example, where the subject receives the siRNA agent or the reverse transcriptase inhibitor for a period of several days, followed by a period of several days or more where the patient does not receive the siRNA agent or the reverse transcriptase inhibitor.

[0259] The reverse transcriptase inhibitor (e.g., tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof) can be administered by a variety of routes, including, but not limited to, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal, and intrathecal. In some particular embodiments, the reverse transcriptase inhibitor (e.g., tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof) is administered orally. The amount of the reverse transcriptase inhibitor (e.g., tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof) administered can be determined according to the severity of the disease, the response to the disease, any treatment-related toxicity, age, and health status of the patient. For example, the daily dose of the reverse transcriptase inhibitor (e.g., tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof) can be from 0.05 mg to 500 mg. The reverse transcriptase inhibitor (e.g., tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof) can be administered once or more than once per day. In some embodiments, the reverse transcriptase inhibitor (e.g., tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof) is administered once a day in an oral solid formulation.

[0260] In this application, the HBV gene refers to the DNA sequence as shown in Genbank Accession No. NC_003977.1. The gene as shown in Genbank Accession No. NC_003977.1 is the complete genome of HBV.

[0261] As used herein, unless otherwise indicated, the siRNA agent includes a double-stranded siRNA analogue, or a conjugate of a double-stranded siRNA analogue, or a pharmaceutically acceptable salt thereof. The preparation method and chemical properties of the siRNA agent described in the present application can refer to WO2021249352.

[0262] In some embodiments, the double-stranded siRNA analogue can target the X opening reading frame (XORF) of HBV.

[0263] In the present application, the double-stranded siRNA analogue refers to a complex of ribonucleic acid molecules, which has a double-stranded structure, including two anti-parallel and substantially complementary nucleic acid chains, which have "sense" and "antisense" orientations relative to the target RNA. In the present disclosure, "complementary" has the meaning well known to those skilled in the art, i.e., in a double-stranded nucleic acid molecule, the bases of one strand are paired with the bases on the other strand in a complementary manner. The purine base adenine (A) is always paired with the pyrimidine base uracil (U); the purine base guanine (C) is always paired with the pyrimidine base cytosine (G). Each base pair includes one purine and one pyrimidine. When adenine on one strand is always paired with uracil on the other strand, and guanine is always paired with cytosine, the two strands are considered to be complementary to each other, and the sequence of the chain can be inferred from the sequence of its complementary chain.

[0264] In the present application, unless otherwise specified, capital letters C, G, U, A represent the base composition of nucleotides. Lowercase letters c, g, u, a respectively represent the 2'-methoxy-modified nucleotides represented by their corresponding capital letters; the underlined represents the 2'-fluoro-modified nucleotides represented by the capital letters; the dash "·" represents a phosphorothioate linkage between the two nucleotide residues adjacent to the left and right of the dash "·"; VP represents that the nucleotide to the right of the letter VP is an (E)-vinyl phosphate-modified nucleotide. For example, "a·g" represents a phosphorothioate linkage between a and g residues.

[0265] In the present application, the "modification" of the nucleotide includes but is not limited to methoxy modification, fluoro modification, (E)-vinyl phosphate modification, phosphorothioate linkage, or replacement of nucleotides with (S)-glycerol nucleic acid, etc. The sequences described in the present application can include those listed in "further modified sequences" in Table 1.

[0266] In the present application, the fluoro-modified nucleotide refers to a nucleotide in which the hydroxyl group at the 2' position of the ribosyl group is replaced by fluorine, and the methoxy-modified nucleotide refers to a nucleotide in which the 2'-hydroxyl group of the ribosyl group is replaced by methoxy.

[0267] In the present application, the (E)-vinylphosphonate modified nucleotide means the following structural unit:

[0268] wherein E is selected from

[0269] X is selected from OCH3and F.

[0270] In the present application, the (S)-glycol nucleic acid (Agn) means the following structural unit:

[0271] (Agn) and other nucleotide residues are connected to each other by phosphonate or thiophosphonate, such as "a·(Agn)" means that a and (Agn) residues are connected by thiophosphonate group, "a(Agn)" means that a and (Agn) residues are connected by phosphonate group.

[0272] In some embodiments, the double-stranded siRNA analog comprises a sense strand or a r' embedded sense strand and a r' embedded antisense strand. The sense strand, the r' embedded sense strand and the r' embedded antisense strand all contain nucleotide groups as the basic structural unit. It is well known to those skilled in the art that the nucleotide group contains a phosphate group, a ribose group and a base, which will not be repeated here.

[0273] In the present application, the r' embedded sequence means that there is at least one nucleotide residue connected with r in the sequence, including the sequence in which one nucleotide is replaced by r in the sequence (such as SEQ ID NO: 2). In the present application, the r' embedded sequence includes but is not limited to: r' embedded double-stranded siRNA, r' embedded sense strand and r' embedded antisense strand. For example, 5'-aGUrrA·C-3', 5'-rGgAAC-3' and 5'-AG·UrAAcCuCr-3' all belong to the r' embedded case.

[0274] In the present application, the r' embedded double-stranded siRNA means that there is at least one nucleotide residue connected with r in the sequence of the double-stranded siRNA, including the double-stranded siRNA in which one nucleotide is replaced by r in the sequence of the double-stranded siRNA. In the present application, the r' embedded sense strand means that there is at least one nucleotide residue connected with r in the sense strand, including the case in which one or more nucleotides in the sense strand are replaced by r. In the present application, the r' embedded antisense strand means that there is at least one nucleotide residue connected with r in the antisense strand, including the case in which one or more nucleotides in the antisense strand are replaced by r.

[0275] In the present application, the r' is (wherein X is selected from SH and OH), is an analog of a natural nucleotide base, different from any published natural nucleotide base, which introduces unpredictable activity into the nucleic acid sequence.

[0276] In the present application, the r represents the following structural unit:

[0277] r and other nucleotide residues are connected to each other by phosphates or phosphorothioates, such as "a r" represents that a and r residues are connected by a phosphorothioate group, and "ar" represents that a and r residues are connected by a phosphate group.

[0278] In the present application, the "multiple" refers to an integer greater than or equal to 2, including but not limited to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, up to the theoretical upper limit of the double-stranded siRNA analog.

[0279] In the present application, the sense strand or the antisense strand of the double-stranded siRNA analog can also include "overhangs", such as unpaired overhanging nucleotides that do not directly participate in the RNA double helix structure, wherein the RNA double helix structure is usually formed by the "sense strand" and the "antisense strand" pair defined herein. Such overhangs can include one or more modified or unmodified U, T and A. For example, the SEQ ID NO: 2 can include modified or unmodified UU overhangs at the 5' and / or 3' end.

[0280] In the present application, the conjugate of the double-stranded siRNA analog is a compound formed by the connection of the double-stranded siRNA analog and the pharmaceutically acceptable conjugate group (ligand), and the double-stranded siRNA analog and the pharmaceutically acceptable conjugate group are covalently connected.

[0281] In the present application, the pharmaceutically acceptable conjugate group can be connected to the 3' end of the sense strand or the r' embedded sense strand of the double-stranded siRNA analog.

[0282] Generally, the pharmaceutically acceptable conjugate group comprises a pharmaceutically acceptable targeting molecule and an optional linker. The types of exemplary conjugate groups, linkers, targeting molecules can be found in the disclosure of WO2015006740A2. Exemplary conjugate groups include but are not limited to L96 or compound group D.

[0283] In the context of the present application, unless otherwise specified, "conjugation" refers to the connection of two or more chemical moieties each having a specific function to each other in a covalent connection; accordingly, "conjugate" refers to a compound formed by the covalent connection between the respective chemical moieties.

[0284] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including (R)- and (S)-enantiomers, diastereomers, as well as the racemic mixtures and other mixtures of those, for example, atropisomers, all in any proportion. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure.

[0285] The term "enantiomers" or "optical isomers" means stereoisomers that are mirror images of one another unless otherwise specified.

[0286] The term "diastereomers" means stereoisomers that are not mirror images of one another unless otherwise specified.

[0287] Unless otherwise indicated, the term "wedge" means a solid line bond and the term "wedge" means a dashed line bond The term "straight" means a solid line bond and the term "straight" means a dashed line bond The term "wavy" means a wavy line The term "wedge" means a solid line bond or the term "wedge" means a dashed line bond or the term "wavy" means a wavy line The term "straight" means a solid line bond and / or the term "straight" means a dashed line bond

[0288] The term "enantiomers" or "optical isomers" means stereoisomers that are mirror images of one another unless otherwise specified.

[0289] The term "enantiomers" or "optical isomers" means stereoisomers that are mirror images of one another unless otherwise specified.

[0290] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound disclosed herein, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide a pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates). The compounds of this disclosure may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure.

[0291] The term "salt" refers to salts of the compounds of the present disclosure, which are prepared from compounds of the present disclosure having acidic or basic groups with relatively non-toxic acids or bases. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds in either a pure solution or a suitable inert solvent with a sufficient amount of the base of interest. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or similar salts. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds in either a pure solution or a suitable inert solvent with a sufficient amount of the acid of interest. Examples of pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, hydrogensulfuric, hydriodic, phosphorous, and the like; and organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, ethanesulfonic, and the like; also salts of amino acids such as arginate, gluconate, and the like; and salts of organic acids like glucuronic, and the like. Certain specific compounds of the present disclosure contain both basic and acidic functionalities and as such can be converted into either base or acid addition salts.

[0292] The salts in the present application can be synthesized from the parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, such salts are prepared either by reacting the free base or acid forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two; or by treating a solution of the free base or acid forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.

[0293] The compounds in the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining the other chemical synthetic methods well known in the art, and equivalent alternatives thereof well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

[0294] The solvents used in the present application can be commercially available.

[0295] The solvent ratios used in the column chromatography and preparative thin layer silica gel chromatography of the present disclosure are all volume ratios, unless otherwise specified.

[0296] All patents, patent applications, and other publications identified are expressly incorporated herein by reference for the purposes of describing and disclosing the publications in question that are prior art and to provide support for treating the publication's teaching as prior art. The citation of any reference is not an admission that it is prior art with respect to a presently claimed application, nor is it an admission that it is prior art with respect to any patent applied for by Applicant or its affiliated or related companies. Further, the dates of publication provided can be off by a significant number of days (usually a few days to a few weeks). Therefore, any references should be generally construed as being dated as of the date of their actual publication or as of the date on which they appear to have been filed in the U.S. Patent Office, or as of the date on which they were received by the Federal Science and Technology Information computer database.

[0297] Technical effects

[0298] The drug combination of the present application has high safety in naive / treated patients with chronic hepatitis B, for example, low incidence and severity of adverse events (AEs) and serious adverse events (SAEs). The drug combination of the present application has low immunogenicity in naive / treated patients with chronic hepatitis B, for example, low incidence of anti-drug antibodies (ADA) and titers thereof, and low incidence of neutralizing antibodies (Nab) in subjects. The drug combination of the present application has better clinical benefits in naive / treated patients with chronic hepatitis B, for example, high proportion of subjects with HBsAg clearance and / or seroconversion, high proportion of subjects with HBeAg clearance and / or seroconversion (limited to HBeAg-positive subjects), high proportion of patients with HBV DNA turning negative, high proportion of subjects with HBsAg <100 IU / ml and HBV DNA negative, high proportion of subjects with HBsAg negative and HBV DNA negative; significant changes in serum HbsAg, HBV DNA, and HBeAg compared to baseline at different treatment cycles, for example, at the end of week 16 or 24.

[0299] The drug combination of the present application can significantly inhibit HBV DNA, HBsAg, and HBeAg or alleviate other HBV indicators (e.g., HBsAb, HBeAb, HBV RNA, HBcrAg). And compared with single drug, the drug combination of the present application shows synergistic effect. And the incidence and severity of adverse events (AEs) and serious adverse events (SAEs) are low. The pharmacokinetic parameters show advantages, for example, peak time (Tmax), peak concentration (Cmax), area under the plasma concentration-time curve (AUC), apparent volume of distribution (Vd / F), plasma clearance (CL / F), plasma elimination half-life (t1 / 2), etc. It shows that the drug combination of the present application has good pharmaceutical value.

[0300] Clinical studies show that the siRNA agent of the present application combined with TAF, TDF or ETV administration 2 times (siRNA agent administration dose 100 mg-400 mg), HBsAg gradually decreased, about 16 weeks to the lowest point, an average of 1.6-2.0 logIU / mL, almost all subjects HBsAg decreased to <100 IU / mL.

[0301] Abbreviations: ETV means Entecavir monohydrate; TDF means Tenofovir disoproxil fumarate; TAF means Propanedisoproxil tenofovir fumarate; Q2W means once every two weeks; Q4W means once every four weeks; Q8W means once every eight weeks. DETAILED DESCRIPTION

[0302] For the sake of clarity, the present application is further illustrated by examples, but the examples are not intended to limit the scope of the present application. All reagents used in the present application are commercially available and used without further purification.

[0303] Example 1A Combination therapy for patients with chronic hepatitis B

[0304] 1. Test drug

[0305] siRNA agent (for example, conjugate of double-stranded siRNA analogs in Table 2, serial numbers AD03L, AD04L and AD05L): prepared into 600 mg / bottle, 400 mg / bottle, 200 mg / bottle or 100 mg / bottle for standby.

[0306] Propanedisoproxil tenofovir fumarate: commercially available propanedisoproxil tenofovir fumarate tablets, specification 25 mg / tablet, including but not limited to Propanedisoproxil tenofovir fumarate tablets

[0307] Tenofovir disoproxil fumarate: commercially available tenofovir disoproxil fumarate tablets, specification 300 mg / tablet, including but not limited to Tenofovir disoproxil fumarate tablets

[0308] Entecavir: commercially available entecavir monohydrate tablets, specification 0.5 mg / tablet. Commercially available entecavir tablets include but are not limited to Entecavir dispersible tablets

[0309] 2. Enrolled subjects

[0310] Diagnosed as chronic hepatitis B: serum HBsAg positive and more than 6 months. HBsAg quantification 100 IU / ml≤ HBsAg quantification≤ 5000 IU / ml at the screening period.

[0311] Treated patients need to meet the following conditions:

[0312] 1) Subjects must have received oral nucleos(t)ide therapy for > 6 months prior to screening and be on a stable treatment regimen for > 3 months prior to the screening period;

[0313] 2) Have documented HBV DNA < lower limit of normal (LLN) for 6 months prior to enrollment and HBV DNA < 20 IU / mL (Roche COBAS Taqman assay) at screening;

[0314] 3) ALT < 2 ULN;

[0315] 4) FibroScan < 9.7 kPa within 6 months prior to screening.

[0316] Naive patients need to meet the following conditions:

[0317] 1) Subjects have never received antiviral therapy for chronic hepatitis B (oral nucleos(t)ide and interferon) at the time of screening, or have had irregular antiviral therapy in the past but have not received any antiviral therapy for chronic hepatitis B for 3 months prior to enrollment;

[0318] 2) HBV DNA > 2000 IU / mL (Roche COBAS Taqman assay);

[0319] 3) ALT < 5 x ULN;

[0320] 4) FibroScan < 12.4 kPa within 6 months prior to screening.

[0321] 3. Dosage and administration

[0322] siRNA agent (e.g., conjugates of double-stranded siRNA analogs of SEQ ID NOs: AD03L, AD04L, and AD05L in Table 2): administered by injection, with multiple dose levels selected from the range of 50-800 mg (or 100-400 mg) doses studied in treated / naive CHB patients; administered subcutaneously once on Days 1 and 15 or 29 or 57; or administered subcutaneously once every 2 weeks, every 4 weeks, or every 8 weeks.

[0323] Exemplary dosing regimens include, but are not limited to, the following, e.g., 2 doses administered over a 16-week treatment cycle:

[0324] 1) 2 doses administered over a treatment cycle, 100 mg each, Q4W (once on Day 1 and Week 4);

[0325] 2) 2 doses administered over a treatment cycle, 200 mg each, Q4W (once on Day 1 and Week 4);

[0326] 3) 2 doses administered over a treatment cycle, 200 mg each, Q2W (once on Day 1 and Week 2);

[0327] 4) 2 doses of 400 mg co-administered during the treatment cycle, Q8W (once on Day 1 and once on Week 8);

[0328] 5) 2 doses of 400 mg co-administered during the treatment cycle, Q4W (once on Day 1 and once on Week 4);

[0329] 4) 2 doses of 300 mg co-administered during the treatment cycle, Q8W (once on Day 1 and once on Week 8);

[0330] 5) 2 doses of 300 mg co-administered during the treatment cycle, Q4W (once on Day 1 and once on Week 4).

[0331] Peginterferon alfa-2a: 150 μg / week, subcutaneously, once a week.

[0332] Tenofovir disoproxil fumarate: 300 mg / once, orally, once a day.

[0333] Entecavir monohydrate tablets: 0.5 mg / once, orally, once a day.

[0334] 4. Efficacy endpoints

[0335] Virology-related endpoints, such as HBsAg, HBsAb, HBeAg, HBeAb, HBV DNA, HBV RNA, HBcrAg, etc.

[0336] Example 1B Combination therapy for patients with chronic hepatitis B

[0337] 1. Test drug

[0338] siRNA agent (e.g., conjugates of double-stranded siRNA analogs of SEQ ID NOs: AD03L, AD04L, and AD05L in Table 2): prepared into 600 mg / vial, 400 mg / vial, 200 mg / vial, or 100 mg / vial for use.

[0339] Peginterferon alfa-2a: commercially available peginterferon alfa-2a tablets, 150 μg / tablet, including but not limited to Pegasys® tablets

[0340] Tenofovir disoproxil fumarate: commercially available tenofovir disoproxil fumarate tablets, 300 mg / tablet, including but not limited to Viread® tablets

[0341] Entecavir: commercially available entecavir monohydrate tablets, 0.5 mg / tablet. Commercially available entecavir tablets include but are not limited to Baraclude® tablets

[0342] 2. Enrolled subjects

[0343] 1) Diagnosed as chronic hepatitis B: serum HBsAg positive for more than 6 months. 100 IU / mL≤ HBsAg quantification≤ 3000 IU / mL or 5000 IU / mL at the screening period; if there is no evidence of HBsAg positive for 6 months, the patient is judged as chronic infection according to the results of the initial diagnosis, the clinical manifestations of the patient and the family history of hepatitis B, etc.

[0344] 2) The subject must have received oral nucleos(t)ide treatment for more than 12 months before screening and the stable treatment regimen for more than 3 months before the screening period;

[0345] 3) There is a record of HBV DNA < lower limit of normal detection in the medical history for more than 6 months before enrollment, and HBV DNA < 20 IU / mL (Roche COBAS Taqman detection) at the screening period;

[0346] 4) ALT≤2ULN;

[0347] 5) FibroScan < 9.7 kPa within 6 months before screening.

[0348] 3. Dosage and administration

[0349] siRNA agent (for example, conjugates of double-stranded siRNA analogs in Table 2, serial numbers AD03L, AD04L and AD05L): injection administration, multiple dose levels are selected from the dose range of 50-800 mg (or 100-400 mg) to study in treated / naive CHB patients; administration once every 4 weeks.

[0350] Exemplary administration regimens include, but are not limited to, the following, for example, a total of 6 times of administration (i.e., administration once every 4 weeks) in a treatment cycle of 24 weeks:

[0351] 1) 100 mg each time, Q4W;

[0352] 2) 200 mg each time, Q4W.

[0353] 3) 300 mg each time, Q4W.

[0354] 4) 400 mg each time, Q4W.

[0355] 5) 500 mg each time, Q4W.

[0356] 6) 600 mg each time, Q4W.

[0357] Propenofyloxalate tenofovir fumarate salt: oral, 25 mg / time, once a day.

[0358] Tenofovir disoproxil fumarate: oral, 300 mg per time, once a day.

[0359] Entecavir monohydrate tablets: oral, 0.5 mg per time, once a day.

[0360] 4. Effectiveness indicators

[0361] Virology-related indicators, such as HBsAg, HBsAb, HBeAg, HBeAb, HBV DNA, HBV RNA, HBcrAg, etc.

[0362] Example 2 Anti-hepatitis B virus (HBV) activity

[0363] HepG2.2.15 cells were cultured in MEM complete medium (Gibco, Cat. No. 11095-080) containing 10% fetal bovine serum (Gibco, Cat. No. 10099-141), 380 μg / mL G418 (Gibco, Cat. No. 10131-027) at 37°C in a 5% CO2 incubator. When the cells grew to near confluence, the cells were released from the culture flask using trypsin treatment, and the HepG2.2.15 cells were seeded at 2 x 10 4 The cells were seeded in 96-well plates at 2 x 10 cells per well and cultured overnight, and when the cell density reached 70-80%, the drug was administered. The siRNA agent (e.g., the conjugate of the double-stranded siRNA analogs of SEQ ID NOs: AD03L, AD04L, and AD05L in Table 2) was orthogonally combined with TAF, ETV, or TDF at different concentrations, and the siRNA was transfected using Lipofectamine RNAiMAX transfection reagent (Invitrogen, Cat. No. 13778150) for administration. The initial concentration was 10 nM, and 3-fold dilution was performed for a total of 9 concentrations. TAF, ETV, or TDF was first diluted with DMSO and then further diluted with culture medium. The initial concentration was 1 μM, and 3-fold dilution was performed for a total of 9 concentrations. The cells were cultured for 6 days, and the medium was changed every 3 days. The supernatant was collected for detection. On the 6th day, CCK-8 (Tongren Chemical, Cat. No. CK04) was used to detect cell viability.

[0364] The DNA in the supernatant was lysed and released according to the instructions of the Hepatitis B Virus Nucleic Acid Assay Kit (Shengxiang Biotech, Item No. 101604042), and quantitative PCR was performed to detect the expression level of HBV DNA in the cell supernatant; the expression level of HBsAg in the cell supernatant was detected according to the instructions of the Hepatitis B Virus Surface Antigen (HBsAg) Assay Kit (Beijing Komabiotech Co., Ltd., Item No. 1010803042); the expression level of HBeAg in the cell supernatant was detected according to the instructions of the Hepatitis B Virus e Antigen (HBeAg) Assay Kit (Beijing Komabiotech Co., Ltd., Item No. 1010801042); the inhibition rate was calculated, and the Compusyn software was used to calculate and confirm whether there was a synergistic effect. The CI value was fitted according to the Compusyn software, wherein CI < 1, = 1 and > 1 represent synergistic effect, additive effect and antagonistic effect, respectively.

[0365] Data statistical processing method

[0366] The data was processed by EXCEL, and the mean ± standard deviation (Mean ± SD) was used to represent the data. When processing the data, more than or equal to 1 was retained to three significant digits, and less than 1 was retained to two digits after the decimal point. Due to the retention of significant digits, there are small calculation differences in some data, which do not affect the final result judgment.

[0367] HBV DNA inhibition rate = (1 - compound group concentration (IU / mL) / control group concentration (IU / mL)) x 100.

[0368] HBsAg inhibition rate (%) = (1 - compound group concentration (ng / mL) / control group concentration (ng / mL)) x 100

[0369] HBeAg inhibition rate (%) = (1 - compound group concentration (NCU / mL) / control group concentration (NCU / mL)) x 100.

[0370] The test results (see Table 3) show that the siRNA agent (for example, the conjugate of the double-stranded siRNA analogs of SEQ ID NOs: AD03L, AD04L and AD05L in Table 2) has a synergistic effect with the reverse transcriptase inhibitor (for example, TAF, ETV or TDF).

[0371] Table 3. Synergistic effect of siRNA agent and reverse transcriptase inhibitor (for example, TAF, ETV or TDF) Note: Fa is the inhibition efficiency simulated by the software.

[0372] Example 3A AAV-HBV mouse test

[0373] 3.1 Test method and grouping

[0374] AAV-HBV model, rAAV8-1.3HBV, D type (ayw), was purchased from Wuhan KeyGene Biotech Co., Ltd., 1.00 x 1011v.g / mL, batch number Ayw1-p4-220928. rAAV8-1.3HBV was prepared into a 1 x 1011v.g / mL solution with sterile PBS before injection. 6-8 week old male Ces1c-KO mice (Shanghai SLAC Laboratory Animal Co., Ltd.) were injected with 200 μL via the tail vein, i.e., each mouse was injected with 2 x 1011v.g. 12 viral genome (v.g) / mL, batch number Ayw1-p4-220928. rAAV8-1.3HBV was prepared into a 1 x 1011v.g / mL solution with sterile PBS before injection. 6-8 week old male Ces1c-KO mice (Shanghai SLAC Laboratory Animal Co., Ltd.) were injected with 200 μL via the tail vein, i.e., each mouse was injected with 2 x 1011v.g. 11 viral genome (v.g) / mL, batch number Ayw1-p4-220928. rAAV8-1.3HBV was prepared into a 1 x 1011v.g / mL solution with sterile PBS before injection. 6-8 week old male Ces1c-KO mice (Shanghai SLAC Laboratory Animal Co., Ltd.) were injected with 200 μL via the tail vein, i.e., each mouse was injected with 2 x 1011v.g. 10 v.g. On day 28 after virus injection, all mice were taken blood from the eye orbit for serum collection to detect HBV DNA.

[0375] After the success of animal modeling, the mice were randomly divided into groups according to the serum HBV DNA content (6 mice per group), and the following groups were set up: a vehicle control group (DMSO + PBS), a siRNA agent (e.g., a conjugate of the double-stranded siRNA analogs with serial numbers AD03L, AD04L, and AD05L in Table 2, 3 mg / kg) group, a TAF (2 mg / kg) group, a siRNA agent (e.g., a conjugate of the double-stranded siRNA analogs with serial numbers AD03L, AD04L, and AD05L in Table 2, 3 mg / kg) + TAF (2 mg / kg) group, with a drug volume of 5 mL / kg. The siRNA agent (e.g., a conjugate of the double-stranded siRNA analogs with serial numbers AD03L, AD04L, and AD05L in Table 2, 3 mg / kg) was administered by single subcutaneous (S.C.) injection on the back; the TAF (2 mg / kg) was administered once a day for 28 consecutive days by gavage; the vehicle control group was injected with PBS solution subcutaneously and 2% DMSO + 98% PBS solution by gavage. The first day of administration was designated as day 0 of the experiment. Blood was taken from the eye orbit before administration and on days 7, 14, 21, 28, 42, 56, 70, and 84 after administration, and the serum was separated for detection of the HBV DNA content at each time point. The administration schedule is shown in Table 4A. The experimental results are shown in Table 5A.

[0376] Table 4A. Administration schedule

[0377] After the animal modeling is successful, the serum HBV DNA content is randomly grouped (6 animals per group), and a solvent control group (DMSO+PBS), a siRNA agent (for example, a conjugate of double-stranded siRNA analogs in Table 2, serial numbers AD03L, AD04L, and AD05L, 3 mg / kg) group, a TDF (1 mg / kg) group, a siRNA agent (for example, a conjugate of double-stranded siRNA analogs in Table 2, serial numbers AD03L, AD04L, and AD05L, 3 mg / kg)+TDF (1 mg / kg) group, with a dose of 5 mL / kg. The siRNA agent (for example, a conjugate of double-stranded siRNA analogs in Table 2, serial numbers AD03L, AD04L, and AD05L, 3 mg / kg) is administered by single subcutaneous (S.C.) injection on the back; the TDF (1 mg / kg) is administered once a day for 28 consecutive days by gavage; the solvent control group is injected subcutaneously with a PBS solution and gavaged with a 2% DMSO+98% PBS solution. The first day of administration is set as the 0th day of the experiment. Before administration and on the 7th, 14th, 21st, 28th, 42nd, 56th, 70th, and 84th days after administration, the blood is collected from the orbit, the serum is separated, and the HBV DNA content in the serum is detected at each time point. The administration scheme is shown in Table 4B. The experimental results are shown in Table 5B.

[0378] Table 4B. Administration scheme

[0379] 3.2 Data statistical processing method

[0380] The data is processed by EXCEL, and the mean ± standard deviation (Mean ± SD) is used to represent the comparison between groups, and p<0.05 is considered statistically significant. When processing data, numbers greater than or equal to 1 are kept to three significant digits, and numbers less than 1 are kept to two decimal places. Some data or due to the reasons for retaining effective digits, there are small calculation differences, which do not affect the final result judgment.

[0381] The HBV DNA inhibition rate is calculated according to the following equation:

[0382] The HBV DNA expression level = (post-administration HBV DNA content / pre-administration HBV DNA content) x 100%.

[0383] The HBV DNA inhibition rate = (1-post-administration HBV DNA content / pre-administration HBV DNA content) x 100%.

[0384] Wherein, the HBV DNA content is expressed as the number of equivalent (IU) HBV DNA per milliliter (ml) of serum.

[0385] The results (see Tables 5A and 5B) show that the combination of the siRNA agent (conjugate of double-stranded siRNA analogs of SEQ ID NOs: AD03L, AD04L and AD05L in Table 2) and the reverse transcriptase inhibitor (e.g. TAF or TDF) significantly reduces the content of HBV DNA in the serum of mice, improves the therapeutic effect, and has a synergistic effect, compared with the administration of the siRNA agent or the reverse transcriptase inhibitor alone.

[0386] Table 5A. HBV DNA (log IU / mL) in the serum of mice after administration of AD03L + TAF 10 Table 5A. HBV DNA (log IU / mL) in the serum of mice after administration of AD03L + TAF Note: *P < 0.05, **P < 0.01, ***P < 0.001 compared with i. group; P < 0.05, □ P < 0.05, □□ P < 0.01, □□□ P < 0.001 compared with ii. group; P < 0.05, △ P < 0.05, △△ P < 0.01, △△△ P < 0.001.

[0387] Table 5B. HBV DNA (log IU / mL) in the serum of mice after administration of AD03L + TDF 10 Table 5B. HBV DNA (log IU / mL) in the serum of mice after administration of AD03L + TDF Note: *P < 0.05, **P < 0.01, ***P < 0.001 compared with i. group; P < 0.05, □ P < 0.05, □□ P < 0.01, □□□ P < 0.001 compared with ii. group; P < 0.05, △ P < 0.05, △△ P < 0.01, △△△ P < 0.001.

[0388] Example 4 Anti-HBV efficacy in AAV / HBV mouse model

[0389] Male C57BL / 6 mice were injected with a dose of 1 x 10 10vg(viral genome) / mouse of rAAV8-1.3HBV virus (type D, ayw). 42 mice were screened and randomly divided into 7 groups, 6 mice in each group. The mice were administered according to the group from the 28th day after virus injection (i.e. the 0th day after administration). The 1st group was subcutaneously injected (SC) with PBS twice on the 0th and 28th days; the 2nd group was orally administered (PO) with 0.001 mg / kg entecavir (ETV) once a day from the 0th to 41st day; the 3rd group was subcutaneously injected with AD03L once on the 0th day at a dose of 1 mg / kg; the 4th group was subcutaneously injected with AD03L twice on the 0th and 28th days at a dose of 3 mg / kg; the 5th group was subcutaneously injected with AD03L twice on the 0th and 28th days at a dose of 15 mg / kg; the 6th group was administered in combination, subcutaneously injected with 15 mg / kg AD03L on the 0th and 28th days, and orally administered with 0.001 mg / kg ETV once a day from the 0th to 41st day. The mice were collected for plasma samples by submandibular vein on the 0th, 7th, 14th, 21st, 28th, 35th and 42nd day after administration, and for liver samples on the 42nd day. The HBV DNA level in the plasma at a specific time point after administration was quantitatively detected.

[0390] Quantitative PCR detection of HBV DNA content in mouse plasma: DNA was extracted from plasma, and the experimental procedures were referred to the QIAamp 96 DNA Blood Kit instructions. The DNA was quantified by Nanodrop (Thermo), and then the content of HBV DNA was detected by qPCR. The PCR reaction conditions were as follows: 95°C for 10 minutes, 95°C for 15 seconds, 60°C for 1 minute; and the program of 95°C for 15 seconds and 60°C for 1 minute was repeated for 40 cycles.

[0391] The mean value ± standard error of each group of mouse samples was represented, and the statistical analysis was performed by Student’s t-test, and p<0.05 was considered to have significant difference.

[0392] Table 6. Administration scheme

[0393] The mice showed good tolerance to all treatments, with stable weight gain and good condition during the administration period.

[0394] The results of HBV DNA in plasma are shown in Table 7. Compared with PBS, 1 mg / kg AD03L, 3 mg / kg AD03L and 15 mg / kg AD03L can significantly reduce the level of HBV DNA in the plasma of mice, and show obvious dose dependence. 15 mg / kg AD03L can continuously maintain the level of HBV DNA to the LLOQ level. Compared with PBS, the combination of AD03L and ETV can significantly reduce the level of HBV DNA in the plasma of mice, and continuously maintain the level of HBV DNA to the LLOQ level.

[0395] In addition, the content of HBV DNA in the plasma of mice in the combination of AD03L and ETV is significantly lower than that in the ETV group from the 7th day to the 42nd day after the first administration.

[0396] Table 7. Specific detection results of HBV DNA in the plasma of mice Note: " / " represents not tested; LLOQ = 2.08 log 10 copy / μL of plasma, and the values below LLOQ are expressed as 2.08 log 10 copy / μL; "a*" and "a**" respectively represent p<0.05 and p<0.01 compared with the PBS group (group 1); "b*" and "b**" respectively represent p<0.05 and p<0.01 compared with the ETV group (group 2).

[0397] The test results show that the siRNA agent of the present application has a synergistic effect with the reverse transcriptase inhibitor (such as ETV).

Claims

1. A pharmaceutical combination comprising an siRNA agent and a reverse transcriptase inhibitor.

2. The pharmaceutical combination of claim 1, wherein the siRNA agent comprises a sense strand comprising at least 15 consecutive nucleotides of the nucleotide sequence set forth as SEQ ID NO: 1 and the sense strand is no more than 21 nucleotides in length, and an antisense strand comprising at least 15 consecutive nucleotides of the nucleotide sequence set forth as SEQ ID NO: 2 and the antisense strand is no more than 23 nucleotides in length; one or more nucleotides in the sense strand or the antisense strand are replaced with r, r is: SEQ ID NO: 1: 5'-GUGUGCACUUCGCUUCACA-3', SEQ ID NO: 2: 5'-UGUGAAGCGAAGUGCACACUU-3'; each of the nucleotides in the sense strand and the antisense strand and r in the siRNA agent is independently modified or unmodified. i.

3. The pharmaceutical combination of claim 1 or 2, wherein all of the nucleotides in the sense strand and the antisense strand and r in the siRNA agent are modified.

4. The pharmaceutical combination of any one of claims 1 to 3, wherein the modification comprises a methoxy modification, a fluoro modification, an (E)-vinylphosphonate modification, a phosphorothioate linkage, a replacement of a nucleotide with (S)-glycerol nucleic acid.

5. The pharmaceutical combination of any one of claims 1 to 4, wherein the sense strand comprises a sequence in which one, two, three, four, or five nucleotides are replaced with r in the sequence set forth as SEQ ID NO: 1; optionally, the sense strand comprises a sequence in which one nucleotide is replaced with r in the sequence set forth as SEQ ID NO:

1.

3. The pharmaceutical combination of claim 2, wherein, 6. The pharmaceutical combination of any one of claims 1 to 5, wherein the antisense strand comprises a sequence in which one, two, three, four, or five nucleotides are replaced with r in the sequence set forth as SEQ ID NO: 2; optionally, the antisense strand comprises a sequence in which one nucleotide is replaced with r in the sequence set forth as SEQ ID NO:

2.

4. The pharmaceutical association according to claim 2 or 3, wherein, 7. The pharmaceutical combination of any one of claims 1 to 6, wherein the sense strand comprises or consists of the sequence set forth as SEQ ID NO: 3 or SEQ ID NO: 5; or the sense strand comprises or consists of the sequence set forth as SEQ ID NO: 7 or SEQ ID NO:

9.

5. The pharmaceutical association according to any one of claims 2-4, wherein, 8. The pharmaceutical combination of any one of claims 1 to 7, wherein the antisense strand comprises or consists of the sequence set forth as SEQ ID NO: 4 or SEQ ID NO: 6; or the antisense strand comprises or consists of the sequence set forth as SEQ ID NO: 8 or SEQ ID NO:

10.

6. The pharmaceutical association according to any one of claims 2-5, wherein, 9. The pharmaceutical combination of any one of claims 1 to 8, wherein the sense strand and the antisense strand of the siRNA agent are selected from any one of AD01 to AD05: AD01: the sense strand is SEQ ID NO: 3 and the antisense strand is SEQ ID NO: 4; AD02: the sense strand is SEQ ID NO: 5 and the antisense strand is SEQ ID NO: 6; AD03: the sense strand is SEQ ID NO: 7 and the antisense strand is SEQ ID NO: 8; AD04: the sense strand is SEQ ID NO: 9 and the antisense strand is SEQ ID NO: 8; AD05: the sense strand is SEQ ID NO: 7 and the antisense strand is SEQ ID NO:

10.

7. The pharmaceutical association according to any one of claims 2-6, wherein, ​ 8. The pharmaceutical association according to any one of claims 2-7, wherein, ​ 9. The pharmaceutical association according to any one of claims 1-8, wherein, ​ ​ ​ ​ ​ ​ 10. The pharmaceutical association according to any one of claims 1-9, wherein, The siRNA agent optionally comprises a conjugate group comprising a GalNAc group; optionally, the conjugate group comprises 1 to 5 GalNAc groups.

11. The pharmaceutical combination of claim 10, wherein, The conjugating group comprises a compound group D or L96:

12. The pharmaceutical association according to claim 10 or 11, wherein, The conjugate group is linked to the 3' end of the sense strand.

13. The pharmaceutical association according to any one of claims 1-12, wherein, The sense strand and the antisense strand of the siRNA agent are selected from any one of AD03L to AD05L: AD03L: the sense strand is SEQ ID NO: 11 and the antisense strand is SEQ ID NO: 12; AD04L: the sense strand is SEQ ID NO: 13 and the antisense strand is SEQ ID NO: 12; AD05L: the sense strand is SEQ ID NO: 11 and the antisense strand is SEQ ID NO:

14.

14. The pharmaceutical association according to any one of claims 1-13, wherein, The drug combination comprises: 1) the siRNA agent in a single dose of 1 mg - 2000 mg; and 2) a reverse transcriptase inhibitor in a single dose of 0.01 mg to 500 mg.

15. The pharmaceutical association according to any one of claims 1-14, wherein, The ratio of the single dose of the siRNA agent and the reverse transcriptase inhibitor is selected from 2000:1 to 0.1:

1.

16. The pharmaceutical association according to any one of claims 1-15, wherein, The ratio of the cycle dose of the siRNA agent and the reverse transcriptase inhibitor is selected from 1:(0.001-500).

17. The pharmaceutical association according to any one of claims 1-16, wherein, The ratio of each dose of the siRNA agent and the reverse transcriptase inhibitor is selected from 1:(0.0001-100).

18. The pharmaceutical association according to any one of claims 1-17, wherein, The siRNA agent is in the form of a pharmaceutical composition, the single dose of which is selected from 1 mg - 2000 mg, 50 mg - 1000 mg, 50 mg - 800 mg, 100 mg - 600 mg, or 100 mg - 400 mg.

19. The pharmaceutical association according to any one of claims 1-18, wherein, The reverse transcriptase inhibitor is in the form of a pharmaceutical composition, the single dose of which is selected from 0.01 mg - 500 mg.

20. The pharmaceutical association according to any one of claims 1-19, wherein, The reverse transcriptase inhibitor is selected from tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof, or entecavir or a pharmaceutically acceptable salt thereof or a solvate thereof.

21. The pharmaceutical association according to any one of claims 1-20, wherein, The drug combination comprises: 1) the siRNA agent in a single dose of 1 mg - 2000 mg; and 2) tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof in a single dose of 10 mg - 500 mg.

22. The pharmaceutical association according to any one of claims 1-21, wherein, The ratio of the single dose of the siRNA agent and tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof is selected from 100:1 to 0.1:

1.

23. The pharmaceutical association according to any one of claims 1-22, wherein, The ratio of the cycle dose of the siRNA agent and tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof is selected from 1:(0.1-500).

24. The pharmaceutical association according to any one of claims 1-23, wherein, The ratio of each dose of the siRNA agent and tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof is selected from 1:(0.01-100).

25. The pharmaceutical association according to any one of claims 1-24, wherein, Tenofovir or a pharmaceutically acceptable prodrug thereof or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, the single dose of which is selected from 10 mg - 500 mg.

26. The pharmaceutical association according to any one of claims 1-25, wherein, The siRNA agent is administered once every 1 week, once every 2 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks.

27. The pharmaceutical association according to any one of claims 1-26, wherein, The siRNA agent is administered at a dose of 1 mg - 1200 mg, 1 mg - 1000 mg, 10 mg - 1000 mg, 50 mg - 1000 mg, 50 mg - 800 mg, or 80 mg - 800 mg per administration.

28. The pharmaceutical association according to any one of claims 1-27, wherein, The reverse transcriptase inhibitor is administered once a day, twice a day, or once every 2 days; or, once a day.

29. The pharmaceutical association according to any one of claims 1-28, wherein, The reverse transcriptase inhibitor, or tenofovir or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg - 500 mg per administration.

30. The pharmaceutical combination according to any one of claims 1-29, wherein the reverse transcriptase inhibitor, or tenofovir or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof is selected from tenofovir alafenamide or emtricitabine tenofovir; optionally, the pharmaceutically acceptable salt of the tenofovir or a pharmaceutically acceptable prodrug thereof is selected from a phosphate salt, a fumarate salt, a succinate salt, an oxalate salt, a disulfonate salt, or an aspartate salt; or, is selected from tenofovir, tenofovir alafenamide, emtricitabine tenofovir, tenofovir alafenamide fumarate, or emtricitabine tenofovir fumarate; or the pharmaceutically acceptable salt of the tenofovir or a pharmaceutically acceptable prodrug thereof is selected from tenofovir alafenamide fumarate.

31. The pharmaceutical combination according to any one of claims 1-29, wherein the reverse transcriptase inhibitor, or tenofovir or a pharmaceutically acceptable prodrug thereof, or a pharmaceutically acceptable salt thereof is selected from tenofovir disoproxil or emtricitabine tenofovir; optionally, the pharmaceutically acceptable salt of the tenofovir or a pharmaceutically acceptable prodrug thereof is selected from a phosphate salt, a fumarate salt, a succinate salt, an oxalate salt, a disulfonate salt, or an aspartate salt; or, is selected from tenofovir, tenofovir disoproxil, emtricitabine tenofovir, tenofovir disoproxil phosphate, tenofovir disoproxil fumarate, tenofovir disoproxil succinate, tenofovir disoproxil oxalate, tenofovir disoproxil hemi-disulfonate, tenofovir disoproxil aspartate, or emtricitabine tenofovir fumarate; or the pharmaceutically acceptable salt of the tenofovir or a pharmaceutically acceptable prodrug thereof is selected from tenofovir disoproxil fumarate.

32. The pharmaceutical association according to any one of claims 1-20, wherein, The pharmaceutical combination comprises: 1) the siRNA agent at a single dose of 1 mg - 2000 mg; and 2) entecavir or a pharmaceutically acceptable salt thereof, or a solvate thereof, at a single dose of 0.01 mg - 5 mg.

33. The pharmaceutical association according to any one of claims 1-20 or 32, wherein, The ratio of the single dose of the siRNA agent and entecavir or a pharmaceutically acceptable salt thereof, or a solvate thereof, is selected from 2000: 1 to 1:

1.

34. The pharmaceutical combination of any one of claims 1-20 or 32-33, wherein, The ratio of the cycle dose of the siRNA agent and entecavir or a pharmaceutically acceptable salt thereof, or a solvate thereof, is selected from 1: (0.001 - 1).

35. The pharmaceutical combination according to any one of claims 1-20 or 32-34, wherein, The ratio of the per dose of the siRNA agent and entecavir or a pharmaceutically acceptable salt thereof, or a solvate thereof, is selected from 1: (0.1 - 0.0.5).

36. The pharmaceutical combination according to any one of claims 1-20 or 32-35, wherein, The entecavir or a pharmaceutically acceptable salt thereof, or a solvate thereof, is in the form of a pharmaceutical composition, the single dose of which is selected from 0.01 mg - 5.0 mg.

37. The pharmaceutical combination according to any one of claims 1-20 or 32-36, wherein, The dose of the reverse transcriptase inhibitor or entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, per administration is 0.01 mg to 5.0 mg.

38. The pharmaceutical association according to any one of claims 1 to 20 or 32 to 36, wherein the reverse transcriptase inhibitor, entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is selected from the group consisting of entecavir monomaleate, entecavir monohydrate, or entecavir monomaleate monohydrate.

39. The pharmaceutical association according to any one of claims 1 to 38, wherein the siRNA agent and the reverse transcriptase inhibitor are each in the form of a pharmaceutical composition.

40. A kit comprising the pharmaceutical association according to any one of claims 1 to 38, and instructions for the combined treatment or prophylaxis of hepatitis B with the siRNA agent and the reverse transcriptase inhibitor.

41. Use of the pharmaceutical association according to any one of claims 1 to 38 or of the kit according to claim 40 for the manufacture of a medicament for the treatment or prophylaxis of hepatitis B.

42. The use according to claim 41, characterized in that The hepatitis B is selected from the group consisting of chronic hepatitis B; optionally, the patient with chronic hepatitis B is selected from the group consisting of naive or treated individuals. The dose of the reverse transcriptase inhibitor or entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, per administration is 0.01 mg to 5.0 mg.

38. The pharmaceutical association according to any one of claims 1 to 20 or 32 to 36, wherein the reverse transcriptase inhibitor, entecavir or a pharmaceutically acceptable salt thereof, or solvate thereof, is selected from the group consisting of entecavir monomaleate, entecavir monohydrate, or entecavir monomaleate monohydrate.

39. The pharmaceutical association according to any one of claims 1 to 38, wherein the siRNA agent and the reverse transcriptase inhibitor are each in the form of a pharmaceutical composition.

40. A kit comprising the pharmaceutical association according to any one of claims 1 to 38, and instructions for the combined treatment or prophylaxis of hepatitis B with the siRNA agent and the reverse transcriptase inhibitor.

41. Use of the pharmaceutical association according to any one of claims 1 to 38 or of the kit according to claim 40 for the manufacture of a medicament for the treatment or prophylaxis of hepatitis B. The hepatitis B is selected from the group consisting of chronic hepatitis B; optionally, the patient with chronic hepatitis B is selected from the group consisting of naive or treated individuals.

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