Application of anti-HIV (human immunodeficiency virus) pharmaceutical composition in immune improvement

Abstract

The invention provides an application of an anti-HIV (human immunodeficiency virus) pharmaceutical composition in immune improvement, in particular to an application of the HIV pharmaceutical composition in preparation of a medicine for immune regulation, the medicine for immune regulation is a medicine for carrying out immune regulation on HIV-1 infected people inhibited by viruses, and the anti-HIV pharmaceutical composition comprises an HIV fusion inhibitor and an HIV integrase inhibitor, the infected person is the infected person treated by an ART scheme. Experiments show that the pharmaceutical composition has a good antiviral effect and safety, and has a very good effect on immune reconstruction of patients.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of AIDS treatment, and in particular, the present application provides a use of an anti-HIV pharmaceutical composition in immune improvement, specifically, a technical scheme of using an HIV fusion inhibitor and an HIV integrase inhibitor to prepare a medicine for immune regulation of an HIV-1 infected person with viral inhibition. BACKGROUND

[0002] Acquired immunodeficiency syndrome (AIDS), i.e., AIDS, is an infectious disease caused by human immunodeficiency virus (HIV) and has become an important public health problem for human health. Since the first antiretroviral therapy (ART) drug, Zidovudine (AZT), was introduced in 1987, it has taken the first step in the treatment of AIDS in humans. By using nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors, and CCR5 type antagonists in combination, HIV replication can be inhibited at different stages. Currently, ART has formed a stable and effective combination therapy regimen and can achieve and maintain HIV viral suppression in most HIV infected persons.

[0003] However, the ART regimen has many restrictive conditions. Patients must take antiretroviral drugs every day for life, and missed or missed doses will increase the risk of drug resistance. Long-term medication has a certain impact on the quality of life of patients and also brings potential risks of long-term drug side effects and drug resistance. Further improving the current HAART medication mode and reducing the number of medications are the wishes of many HIV-1 infected patients. For example, the treatment regimen of 3TC (Lamivudine) + DTG is not recommended for use in combination with HBV infection, and the viral resistance of 3TC is high. With the extension of the treatment time, the incidence of viral drug resistance mutation is high. The presence of NRTI drug resistance will increase the risk of DTG drug resistance after treatment failure.

[0004] HIV mainly attacks the immune system of the human body, and CD4 + T lymphocytes are the main target cells of HIV infection, mainly manifested as a continuous decrease in the number of CD4 + T lymphocytes, which eventually leads to defects in the cellular immune function of the human body and causes various opportunistic infections and the occurrence of tumors.

[0005] After HIV enters the human body, viral components can be detected in the peripheral blood about 5-10 days, followed by viremia, leading to acute infection, and CD4 +The number of T lymphocytes is rapidly and transiently reduced in the short term. After anti-retroviral therapy (ART) in most HIV / AIDS patients, the immune abnormalities caused by HIV can be restored to normal or near normal levels, including CD4 + The recovery of T lymphocyte numbers, i.e. immune reconstitution. However, 10-30% of HIV / AIDS patients cannot achieve complete immune reconstitution even if they can maintain long-term viral suppression, and the most important clinical feature is long-term peripheral blood CD4 + The incidence of low T lymphocyte counts and poor clinical outcomes is generally higher than that of good immune reconstitution. Studies have shown that after starting ART, CD4 + The risk of opportunistic infections is reduced by 39-68% for every 50 / μL increase in T lymphocyte counts from baseline. Studies have also shown that the mortality rate of patients with incomplete immune reconstitution is significantly higher than that of HIV-infected patients with normal immune reconstitution. CD4 + The all-cause mortality rate of patients with CD4 + The mortality rate of patients with incomplete immune reconstitution with T lymphocyte counts of 350-500 / μL is 2.17 times that of the baseline, 200-350 / μL is 3.19 times, 50-200 / μL is 13.38 times, and <50 / μL is 37.26 times. Therefore, immune reconstitution and reducing abnormal immune activation are one of the goals of HIV treatment.

[0006] So far, there is no drug or intervention approved to improve immune reconstitution worldwide. There is a huge unmet clinical need to achieve the goal of immune reconstitution for HIV / AIDS patients with incomplete immune reconstitution.

[0007] Therefore, a long-acting injection formulation with equivalent antiviral effect, which can effectively regulate the immune clinical needs of HIV patients, has fewer dosing frequencies and is simple in dosage, can be used as the preferred ART regimen for such populations. In summary, there is a need in the art to develop a better HIV two-drug regimen, especially one that can regulate the immune function of patients. SUMMARY

[0008] The purpose of the present application is to provide a two-drug regimen for HIV, specifically a two-drug regimen using an HIV fusion inhibitor and an HIV integrase inhibitor.

[0009] In a first aspect, the present application provides a use of an anti-HIV pharmaceutical composition in the manufacture of a medicament for immune modulation of a viral-suppressed HIV-1 infected subject, wherein the pharmaceutical composition comprises an HIV fusion inhibitor and an HIV integrase inhibitor; the HIV fusion inhibitor can be a GP41 membrane fusion inhibitor or a GP120 membrane fusion inhibitor, wherein the GP41 membrane fusion inhibitor is selected from the group consisting of albuvirtide (ABT), enfuvirtide (T-20), LP-98 and LP-80; the HIV integrase inhibitor is selected from the group consisting of dolutegravir (DTG).

[0010] In another preferred embodiment, the pharmaceutical composition is selected from the group consisting of albuvirtide and dolutegravir.

[0011] Preferably, the infected subject is a protocol-treated subject; more preferably, the infected subject is a subject who has been treated for 12-120 months since the initial ART protocol.

[0012] In another preferred embodiment, the infected subject is a subject who has been treated with an ART protocol, in particular a protocol comprising an HIV integrase inhibitor; preferably, the ART protocol is a protocol comprising DTG, which is selected from the group consisting of DTG / 3TC, DTG+3TC+TDF.

[0013] In another preferred embodiment, the immune modulation comprises an increase in the CD4 + T cell count in the subject after administration of the pharmaceutical composition compared to before administration of the pharmaceutical composition; and / or

[0014] The immune modulation comprises an increase in the CD4 / CD8 cell ratio in the subject after administration of the pharmaceutical composition compared to before administration of the pharmaceutical composition.

[0015] In another preferred embodiment, the viral-suppressed HIV-1 infected subject has a serum baseline HIV-RNA of less than 50 copies / mL.

[0016] In another preferred embodiment, the viral-suppressed HIV-1 infected subject has a serum baseline CD4 + of less than 500 / μL, preferably less than 400 / μL, more preferably less than 350 / μL.

[0017] In another preferred embodiment, the viral-suppressed HIV-1 infected subject is a subject who is co-infected with another infectious agent.

[0018] In another preferred embodiment, the infectious source is selected from the group consisting of viral hepatitis (e.g., hepatitis B, hepatitis C), syphilis, opportunistic infection (e.g., bacterial infection or fungal infection), or a combination thereof.

[0019] In another preferred embodiment, the pharmaceutical composition comprises a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is selected from the group consisting of ABT, T-20, LP-98, and LP83; and the second therapeutic agent is selected from the group consisting of DTG.

[0020] Preferably, the first therapeutic agent comprises ABT; and the second therapeutic agent comprises DTG; and

[0021] The first therapeutic agent is an injection; and the second therapeutic agent is an oral preparation or an injection.

[0022] Further preferably, the first therapeutic agent comprises ABT; and the second therapeutic agent comprises DTG; and

[0023] The first therapeutic agent is an injection; and the second therapeutic agent is an oral preparation.

[0024] In another preferred embodiment, the first therapeutic agent is an intravenous drip.

[0025] In another preferred embodiment, the first therapeutic agent comprises 600-700 mg of ABT; and the second therapeutic agent comprises 40-60 mg of DTG.

[0026] In another preferred embodiment, the immunomodulatory pharmaceutical further comprises instructions for use, the instructions for use comprising the following:

[0027] (i) using a first therapeutic agent every 4 weeks;

[0028] (ii) using a second therapeutic agent, which is DTG, once a day.

[0029] In another preferred embodiment, the instructions for use further comprise the following: administering the drug continuously for 20-50 weeks, preferably 20-40 weeks, and more preferably 20-30 weeks.

[0030] In another aspect of the present application, there is provided a method for immunomodulating an HIV-1 infected subject with viral suppression using ABT and DTG, the anti-HIV pharmaceutical composition comprising an HIV fusion inhibitor and an HIV integrase inhibitor, the method comprising: administering to the infected subject in need thereof a first therapeutic agent comprising an HIV fusion inhibitor and a second therapeutic agent comprising an HIV fusion inhibitor;

[0031] The HIV fusion inhibitor can be a GP41 membrane fusion inhibitor or a GP120 membrane fusion inhibitor, wherein the GP41 membrane fusion inhibitor is selected from the group consisting of albuvirtide (ABT), enfuvirtide (T-20), LP-98 and LP83; the HIV integrase inhibitor is selected from the group consisting of dolutegravir (DTG).

[0032] In another preferred embodiment, the pharmaceutical composition is selected from the group consisting of albuvirtide, dolutegravir.

[0033] Preferably, the infected subject is an infected subject treated by an ART regimen; more preferably, the infected subject is an infected subject treated by an initial ART regimen for 12-120 months.

[0034] In another preferred embodiment, the first therapeutic agent and the second therapeutic agent are administered simultaneously, sequentially or in any order to the infected subject in need thereof.

[0035] In another preferred embodiment, the ART regimen is an ART regimen comprising DTG; preferably, the ART regimen comprising DTG is selected from the group consisting of DTG / 3TC, DTG+3TC+TDF.

[0036] In another preferred embodiment, the immune modulation comprises an increase in CD4 + T cell count in the patient after administration of the pharmaceutical composition compared to before administration of the pharmaceutical composition; and / or

[0037] The immune modulation comprises an increase in CD4 / CD8 cell ratio in the patient after administration of the pharmaceutical composition compared to before administration of the pharmaceutical composition.

[0038] In another preferred embodiment, the virus-suppressed HIV-1 infected subject has a serum baseline HIV-RNA lower than 50 copies / mL.

[0039] In another preferred embodiment, the virus-suppressed HIV-1 infected subject has a serum baseline CD4 + < 500 / μL, preferably < 400 / μL, more preferably < 350 / μL.

[0040] In another preferred embodiment, the virus-suppressed HIV-1 infected subject is an infected subject co-infected with other infectious agents.

[0041] In another preferred embodiment, the infectious agents are selected from the group consisting of viral hepatitis (such as hepatitis B, hepatitis C), syphilis, opportunistic infections (such as bacterial infections or fungal infections), or a combination thereof.

[0042] In another preferred embodiment, the first therapeutic agent is an injection.

[0043] In another preferred embodiment, the second therapeutic agent is an oral preparation or an injection preparation.

[0044] In another preferred embodiment, the first therapeutic agent is an intravenous drip.

[0045] In another preferred embodiment, the first therapeutic agent contains 600-700 mg of active ingredient ABT; and the second pharmaceutical composition contains 40-60 mg of active ingredient DTG.

[0046] In another preferred embodiment, the method comprises the following steps (i) and (ii):

[0047] (i) using a dose of the first therapeutic agent every 4 weeks;

[0048] (ii) using a dose of the second therapeutic agent, which is DTG, once a day.

[0049] In another preferred embodiment, the method further comprises: during the treatment, continuously using the drugs for 20-30 weeks.

[0050] In another preferred embodiment, during the treatment, the dose adjustment of the ART scheme is not allowed.

[0051] It should be understood that, within the scope of the present application, the above technical features of the present application and the technical features specifically described in the following (such as the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0052] Figure 1 CD4 + T cell count of the subject during the treatment;

[0053] Figure 2 CD4 / CD8 ratio of the subject during the treatment;

[0054] Figure 3 Intravenous drip of elvitegravir and tenofovir. DETAILED DESCRIPTION

[0055] The present inventors have developed a two-scheme combination of HIV fusion inhibitors and HIV integrase inhibitors through long-term and in-depth research, and specifically a combination of elvitegravir and dolutegravir for treating AIDS infection, which can effectively improve the immune function of patients after ART treatment, and this improvement is not related to viral suppression, and thus is expected to be used as a supplementary treatment scheme for HIV patients. Based on the above findings, the present inventors have completed the present application.

[0056] HIV fusion inhibitors and their application in the treatment of AIDS

[0057] Common HIV fusion inhibitors can be GP41 membrane fusion inhibitors or GP120 membrane fusion inhibitors. GP41 membrane fusion inhibitors include epovitamide, enfuvirtide (T-20), LP-98, and LP80, all of which target the gp41 viral membrane protein to inhibit the fusion of the viral envelope with the human CD4+ cell membrane. GP120 membrane fusion protein inhibitors can be 3BC117.

[0058] Albuvirtide (ABT) is my country's first independently developed long-acting fusion inhibitor for HIV. It was approved for marketing by the China National Medical Products Administration in 2018 and is a drug recommended for antiretroviral therapy in adult and adolescent patients in the "Chinese Guidelines for the Diagnosis and Treatment of HIV / AIDS (2021 Edition)". Abovetine is a polypeptide composed of 34 amino acids, with an ε-amino group linked to an N-{2-[2-(N-(3-cis-butenylimidepropionyl)amino)ethoxy]ethoxy}acetyl group at position 13 of the lysine residue. Its chemical name is: Acetyl-chromo-gluten-gluten-chromo-tranquil-gluten-isoleucine-tranquilamine-tranquilamine-tyrosine-threo-(N-{2-[2-(N-(3-cis-butenylimidepropionyl)amino)ethoxy]ethoxy}acetyl)lysine-leucine-isoleucine-hit-glutenine-isoleucine-glutenine-glutenine-serine-glutamine-tranquilamine-tranquilamine-glutamine-glutenine-lysine-tranquilamine-glutenine-leucine-tranquilamine, and its molecular formula is: C 204 H 306 N 54 O 72 With a molecular weight of 4666.93, it has the following chemical structure:

[0059]

[0060] After entering the body, ABT forms a stable 1:1 molecular ratio conjugate with albumin, with a half-life of 10-13 days. In vitro experiments have confirmed that ABT has a strong inhibitory effect on globally prevalent HIV-1 subtypes A, B, and C, as well as the currently prevalent subtypes B′, CRF07_BC, and CRF01_AE in China. It is also effective against some HIV-1 variants resistant to entrefovir (T20). In vitro resistance induction assays showed that the virus developed resistance to ABT by the 9th generation, demonstrating that ABT has a high resistance barrier.

[0061] Clinical phase I-III trials have shown good safety and effectiveness. Phase I clinical single-drug single-dose and multiple-dose trials have shown that ABT is safe and has clear anti-HIV-1 viral activity. The results of the phase II clinical trial of ABT, which for the first time uses a protease inhibitor and an entry inhibitor as a brand-new two-drug combination to treat HIV-infected patients, show that the combination of ABT and LPV / r has good tolerability and safety, and clear anti-HIV-1 viral activity, with a decrease in HIV-1 RNA of 2.20 ± 0.33 log10 copies / mL after 47 days of treatment. The confirmatory phase III clinical trial shows that the combination of ABT (320 mg / time / week) and LPV / r for the treatment of HIV-1-infected patients who have failed first-line treatment for 24-48 weeks has good safety, no injection site reactions, and can effectively avoid the renal function damage caused by tenofovir (TDF). The primary and secondary efficacy indicators all meet the pre-set non-inferiority test. The WHO standard three-drug formula in the control group is comparable or superior to the test group, and the percentage of subjects with HIV-1 RNA < 50 copies / mL in the FAS set of the test group and the control group after 48 weeks of treatment was 80.4% and 66.0%, respectively, and the non-inferiority test was qualified; the PPS set was 94.9% and 74.4%, respectively, and the difference between the two groups was statistically significant (P < 0.05), indicating that the test group was superior to the control group in terms of efficacy.

[0062] The present application attempts to use DTG combined with ABT as a two-drug simplified regimen for the clinical use of virological suppression in the switch treatment of HIV-infected patients, and the results show that it has good antiviral effect and safety, and has the function of improving immune regulation of patients, which has far-reaching significance in the field of HIV treatment.

[0063] HIV integrase inhibitors and their use in the treatment of AIDS

[0064] Common HIV integrase inhibitors include dolutegravir (DTG), which is an antiretroviral drug that inhibits the integrase activity of HIV virus, preventing the virus from integrating its genome into the DNA of host cells, and thus inhibiting the replication and spread of HIV virus.

[0065] Dolutegravir (commonly used in the form of sodium salt, i.e. dolutegravir sodium) is an antiretroviral drug belonging to the integrase inhibitor class, which is an HIV-1 virus integrase inhibitor widely used for the treatment of patients with HIV-1 infection in adults and children (body weight at least 30 kg). Its structural formula is as follows:

[0066]

[0067] The DTG-based two-drug regimen has been suggested to have good antiviral effect and safety in prior art research.

[0068] So far, there are few research data on the development of resistance to HIV integrase inhibitors such as dolutegravir, and the two-drug regimen (i.e., using different combinations of antiviral drugs) is a common means to improve the resistance of antiviral drugs, however, a certain degree of drug resistance is still observed in the two-drug regimen of DTG.

[0069] The application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the application and not to limit the scope of the application. The experimental methods in the following examples are not specified, which are usually carried out according to the conventional conditions, or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0070] Unless otherwise specified, the patients in the following examples have signed the informed consent form.

[0071] Example Study on the treatment regimen of abelvitae combined with dolutegravir

[0072] This study is an open-label, prospective, single-center, single-arm study. The main purpose is to evaluate the effectiveness, pharmacokinetics and safety of ABT 640 mg every 4 weeks combined with DTG treatment regimen for 24 weeks in virologically suppressed HIV-1 infected persons. It is planned to enroll 10 subjects who have received ART regimen treatment and obtained virological suppression, and the subjects will enter the 24-week treatment after screening.

[0073] Dosing regimen: DTG combined with ABT for 24 weeks:

[0074] ABT: 640 mg / time, once every 4 weeks, intravenous infusion;

[0075] DTG: 50 mg / time, once a day, oral, for 24 weeks of treatment.

[0076] During the entire treatment, dose adjustment of the ART regimen is not allowed.

[0077] 1. Subject selection:

[0078] The subject needs to meet all the following inclusion criteria:

[0079] ① Age ≥ 18 years old;

[0080] ② Both male and female;

[0081] ③ Positive for HIV-1 antibody confirmation test;

[0082] IV. Stable on current antiretroviral regimen (not including ABT) for more than 3 months, and previous regimen or drug switch was not due to virologic failure;

[0083] - Switches between the following single antiretroviral drugs are not considered a switch in ART regimen:

[0084] a. Protease inhibitor (PI) / ritonavir to the same protease inhibitor in combination with cobicistat (and vice versa)

[0085] b. Lamivudine (3TC) to Emtricitabine (and vice versa)

[0086] c. Tenofovir disoproxil fumarate (TDF) to Tenofovir alafenamide fumarate (and vice versa)

[0087] V. Plasma HIV-1 RNA measurement less than 50 copies / mL within 12 months prior to screening, and if the date of the measurement reporting is within 6 months prior to the screening period, then the measurement prior to that must also be less than 50 copies / mL;

[0088] VI. Plasma HIV-1 RNA < 50 copies / mL at screening;

[0089] VII. Understands and signs the informed consent form prior to any study-related procedures being performed and complies with the requirements of the study.

[0090] Final enrolled patient information is as follows:

[0091]

[0092] 2. Analysis data set

[0093] FAS Full Analysis Set, is the set of eligible cases and dropouts, excluding those who were excluded, 10 cases in the trial group.

[0094] PPS set is the per-protocol set, cases that meet the trial protocol, good compliance, and complete the CRF specified content, 10 cases in the trial group.

[0095] SS set is the safety data set, cases that have at least one treatment and have safety index records, 10 cases in the trial group.

[0096] 3. Demographic and baseline characteristics

[0097] 3.1 Demographics

[0098] Among the 10 subjects, the average age was (44.60 ± 9.34) years old, the male to female ratio was 7:3, the Han and minority ethnic composition ratio was 9:1, and the average body mass index was (22.52 ± 2.61) kg / m2 Detailed information is shown in Table 1 below.

[0099] Table 1: Demographic data

[0100]

[0101]

[0102] 3.2 Analysis of co-morbidities and infections

[0103] Among the 10 subjects, 1 (10%) had viral hepatitis (type C), 1 (10%) had syphilis, 2 (20%) had one opportunistic infection, and 1 (10%) had more than two opportunistic infections. Detailed information is shown in Table 2 below.

[0104] Table 2: Co-morbidities and infections

[0105]

[0106]

[0107] 3.3 Analysis of antiviral treatment regimen before enrollment

[0108] The regimen before enrollment was mainly TDF + 3TC + EFV (600 mg / 400 mg) (4 / 10). Detailed regimen is shown in Table 3 below.

[0109] Table 3: Antiviral treatment regimen before enrollment

[0110]

[0111] Note: NRTIs are nucleoside reverse transcriptase inhibitors; NNRTIs are non-nucleoside reverse transcriptase inhibitors; INSTIs are integrase inhibitors; PIs are enhanced protease inhibitors; INSTIs are integrase inhibitors.

[0112] 3.4 Analysis of baseline viral load and immune function indicators

[0113] The baseline HIV-RNA of the 10 subjects was lower than the detection lower limit (defined as 50 copies / mL). The baseline CD4 + T cell count of all subjects was more than 200 / μL, and the average CD4 + T cell count was 461.80 ± 219.76 / μL. The average CD4 / CD8 ratio was 0.54 ± 0.19, and the ratio of 1 subject was greater than 0.8. Detailed information is shown in Table 4 below.

[0114] Table 4: Baseline HIV-RNA, CD4+ T cell count, CD4 / CD8 ratio

[0115]

[0116] 4. Endpoint analysis

[0117] 4.1 Failure rate of viral suppression at 12 weeks, 24 weeks

[0118] At 12 weeks of treatment, the failure rate of viral suppression was 0%.

[0119] At 24 weeks of treatment, 10 subjects had HIV-RNA test results below the detection limit (HIV-1 RNA < 50 copies / mL), and the failure rate of viral suppression was 0%.

[0120] 4.2 CD4 + T cell count

[0121] The average CD4 + T cell count at 4 weeks, 12 weeks, and 24 weeks of treatment was 501.50 ± 179.20 cells / μL, 490.60 ± 310.02 cells / μL, and 572.70 ± 317.47 cells / μL, respectively, with an average increase of 39.70 ± 105.72, 28.80 ± 130.71, and 110.90 ± 211.98 cells / μL compared to baseline (Table 6). Using a mixed effects model to test for a time trend: the CD4+ T cell count at 24 weeks was significantly higher than at baseline, with statistical significance (F = 4.37, P = 0.0462). Figure 1

[0122] Table 5: CD4 + T cell count during treatment

[0123]

[0124] Table 6: Change in CD4 at 4 weeks, 12 weeks, and 24 weeks compared to baseline

[0125]

[0126]

[0127] The results show that during the course of treatment, the average CD4 + ​Horizontal CD4+T lymphocyte levels increased. CD4+T lymphocytes are a key cell type in the immune system, playing a central role in the body's immune defense mechanisms. The number and functional status of CD4 cells are important indicators of the immune health of HIV-infected individuals, and an increase in their number generally reflects the recovery of the immune system. Therefore, the increase in the CD4+level of the patient indicates that the patient's immune network has been rebuilt.

[0128] Notably, the patients of the present application are all patients who have received long-term ART treatment and have low viral load, and thus are difficult to benefit from conventional ART treatment (because the patient's viral replication level is not high per se), but in the present application, the patient's CD4+level is still observed to increase, indicating that the ABT+DTG treatment method improves the patient's immunity independently of viral suppression, and is independent of the viral suppression process.

[0129] 4.3 CD4 / CD8 ratio

[0130] The average CD4 / CD8 ratio at 4 weeks, 12 weeks, and 24 weeks of treatment was 0.56±0.18, 0.57±0.23, and 0.60±0.18, respectively (Table 7, Figure 2 ), an average increase of 0.02±0.07, 0.02±0.14, 0.05±0.06 from baseline (Table 8). Using a mixed effects model to test for a time trend: F=3.22, P=0.0780, i.e., there was no statistically significant time trend in the CD4 / CD8 level.

[0131] Table 7: CD4 / CD8 ratio during treatment

[0132]

[0133]

[0134] As can be seen from the above results, the average CD4 / CD8 ratio of the patients showed an increasing trend as the treatment time progressed, which is consistent with the treatment expectations, indicating that the ABT+DTG regimen effectively improved the patient's immune function.

[0135] Table 8: Change from baseline at 4 weeks, 12 weeks, and 24 weeks (CD4 / CD8)

[0136]

[0137] Table 9: CD4 + T cell levels of enrolled subjects over time

[0138]

[0139]

[0140] The results show that the CD4+ level of each patient is improved to some extent.

[0141] 4.4 Incidence of disease progression within 24 weeks

[0142] According to the 2014 CDC adult HIV infection classification system in the United States, no subject had HIV disease progression within 24 weeks.

[0143] 4.5 Pharmacokinetic index analysis

[0144] The pharmacokinetic results after ABT administration are shown in Tables 10, 11 and Figure 3 The results show that the blood concentration of Elbasvir in the patients can be maintained within the therapeutic effective concentration during the administration of Elbasvir, indicating that the regimen of 640 mg intravenous infusion can maintain the therapeutic effect.

[0145] Table 10: Summary of Elbasvir concentration (μg / mL) in subjects after 640 mg intravenous infusion (PKCS)

[0146]

[0147] Table 11: Summary of pharmacokinetic parameters in subjects after 640 mg intravenous infusion (PKPS)

[0148]

[0149]

[0150] 4.6 Safety index analysis

[0151] During the 24-week follow-up, a total of 16 adverse events occurred in 8 subjects, 4 cases of hypertriglyceridemia, 4 cases of hypercholesterolemia, 3 cases of increased blood creatinine, 2 cases of upper respiratory tract infection, 1 case of elevated blood glucose, 1 case of hyperuricemia, and 1 case of proteinuria. The severity of the adverse event was 1 case (proteinuria) judged as severe (grade 3), accounting for 6.25% of the total adverse events; 2 cases (upper respiratory tract infection) were judged as moderate (grade 2), accounting for 12.50% of the total adverse events, and the rest were judged as mild (grade 1), accounting for 81.25% of the total adverse events. The subject reporting grade 3 adverse event of proteinuria had a history of kidney damage, and the investigator judged that the AE was not related to the study drug; the subject reporting grade 2 adverse event of upper respiratory tract infection did not stop using the study drug, and the symptoms disappeared after symptomatic treatment, which was judged by the investigator to be unrelated to the study drug. (Refer to CTCAE version 5.0)

[0152] Table 12: Abnormal laboratory index and adverse event report during the study

[0153]

[0154] 5. Conclusion

[0155] The antiretroviral regimen of albuvirtide 640 mg every 4 weeks intravenous administration combined with oral doravirine achieved good immunological and virological responses in HIV infected patients with stable virological suppression and also showed good safety.

[0156] In the present application, the combination of HIV fusion inhibitor and HIV integrase inhibitor is used, specifically, the combination of DTG and ABT as a dual simplified regimen for the treatment of HIV infected patients with virological suppression, and the results show that it has good antiviral effect and safety, and has very good effect on the immune reconstruction of patients. In the conventional ART regimen for HIV treatment, the viral load of the initial treatment patients is high, and the CD4 + level is low, which will recover slowly after treatment. However, for non-initial treatment patients, the viral load has already reached a low level, so it is usually difficult to further improve the CD4 + level by conventional treatment methods. In the present application, the combination of ABT and DTG can still observe a large degree of immune reconstruction effect for patients who have experienced ART regimen treatment, and does not need to change the original treatment regimen of the patients, which indicates that the treatment regimen is helpful for the immune function reconstruction of HIV patients, and can overcome the problem of drug resistance in the ART regimen of the prior art, and has far-reaching significance in the field of HIV treatment.

[0157] All the documents mentioned in the present application are cited as references in the present application, as if each document is cited as a reference individually. In addition, it should be understood that various modifications or changes can be made to the present application by those skilled in the art after reading the above teaching of the present application, and these equivalent forms also fall within the scope defined by the claims attached to the present application.

Claims

1. The use of an anti-HIV pharmaceutical composition in the preparation of a medicament for immunomodulation, wherein the immunomodulatory medicament is a medicament for immunomodulating HIV-1 infected individuals with viral suppression, the pharmaceutical composition comprising an HIV fusion inhibitor and an HIV integrase inhibitor; the HIV fusion inhibitor may be a GP41 membrane fusion inhibitor or a GP120 membrane fusion inhibitor, wherein... The GP41 membrane fusion inhibitor is selected from Abivita (ABT), Enfviride (T-20), LP-98, and LP-80; the HIV integrase inhibitor is selected from the following group: Dolutegravir (DTG).

2. The application according to claim 1, characterized in that, The infected person is an infected person who has undergone ART treatment; more preferably, the infected person is an infected person who has been receiving ART treatment for 12-120 months, and the ART treatment regimen may be a treatment regimen that includes HIV integrase inhibitors; even more preferably, the ART treatment regimen is a DTG treatment regimen, which is selected from the following group: DTG / 3TC, DTG+3TC+TDF.

3. The application as described in any one of claims 1 to 2, characterized in that, The immune modulation includes: after administration of the pharmaceutical composition, the patient's CD4... + T cell count increased compared to pre-treatment levels of the pharmaceutical composition; and / or The immune modulation includes: an increase in the CD4 / CD8 cell ratio in the patient after administration of the drug composition compared to before administration of the drug composition.

4. The application as described in any one of claims 1 to 3, characterized in that, The baseline serum HIV-RNA in the HIV-1 infected individuals with viral suppression is less than 50 copies / mL; and / or The baseline serum CD4 of the virus-suppressed HIV-1 infected individuals + The value is <500 cells / μL, preferably <400 cells / μL, and even more preferably <350 cells / μL.

5. The application as described in any one of claims 1 to 4, characterized in that, The HIV-1 infected individuals with viral suppression mentioned above are those infected with other sources of infection. Preferably, the source of infection is selected from the group consisting of: viral hepatitis (such as hepatitis B, hepatitis C), syphilis, opportunistic infections (such as bacterial or fungal infections), or combinations thereof.

6. The application as described in any one of claims 1 to 5, characterized in that, The pharmaceutical composition comprises a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is selected from the group consisting of: Abovirtide (ABT), entfuvirtide (T-20), LP-98, and LP-80; and the second therapeutic agent is selected from dolutegravir (DTG). The first pharmaceutical composition is an injection, preferably an intravenous infusion; the second pharmaceutical composition is an oral preparation or an injection. More preferably, the first therapeutic agent is ABT; the second therapeutic agent is DTG; and The first pharmaceutical composition is an injection; the second pharmaceutical composition is an oral preparation. More preferably, the first therapeutic agent contains 600-700 mg of the active ingredient ABT; and the second therapeutic agent contains 40-60 mg of the active ingredient DTG.

7. The application as described in claim 6, characterized in that, The immunomodulatory drug also includes an instruction manual, which contains the following information: (i) Administer one dose of the first treatment every 4 weeks; (ii) Use one dose of the second treatment agent once daily, when the second treatment agent is DTG.

8. A method for immunomodulation of a virally suppressed HIV-1 infected person using an anti-HIV drug composition, said anti-HIV drug composition comprising an HIV fusion inhibitor and an HIV integrase inhibitor, the method comprising: For infected individuals in need, a first treatment agent comprising an HIV fusion inhibitor and a second treatment agent comprising an HIV fusion inhibitor are administered; the HIV fusion inhibitor is selected from the group consisting of: ibevite (ABT), entfuvirtide (T-20), LP-98, and LP83; the HIV integrase inhibitor is selected from dolutegravir (DTG).

9. The method according to claim 8, characterized in that, The infected individuals are those who have undergone ART treatment; more preferably, the infected individuals are those whose initial ART treatment was 12-120 months prior; and the first and second therapeutic agents are administered sequentially or sequentially to the infected individuals in need, wherein the ART treatment is a treatment regimen including DTG, selected from the following group: DTG / 3TC, DTG+3TC+TDF; Preferably, the immune modulation includes: after administration of the pharmaceutical composition, the patient's CD4... + T cell count increased compared to pre-treatment levels of the pharmaceutical composition; and / or The immune modulation includes: an increase in the CD4 / CD8 cell ratio in the patient after administration of the drug composition compared to before administration of the drug composition; More preferably, the baseline serum HIV-RNA in the virus-suppressed HIV-1 infected individuals is less than 50 copies / mL; More preferably, the baseline CD4 count in the serum of the viral-suppressed HIV-1 infected individual is... + The concentration is <500 cells / μL, more preferably <400 cells / μL, and even more preferably <350 cells / μL; More preferably, the HIV-1 infected person with viral suppression is an infected person who is co-infected with other sources of infection; More preferably, the source of infection is selected from the group consisting of: viral hepatitis (such as hepatitis B, hepatitis C), syphilis, opportunistic infections (such as bacterial or fungal infections), or combinations thereof.

10. The method according to any one of claims 8 to 9, characterized in that, The first therapeutic agent is an injection, preferably an intravenous drip; the second therapeutic agent is an oral or injectable preparation; preferably, the first therapeutic agent contains 600-700 mg of the active ingredient ABT; the second pharmaceutical composition contains 40-60 mg of the active ingredient DTG. More preferably, the method includes steps (i) and (ii): (i) Administer one dose of the first treatment every 4 weeks; (ii) Use one dose of the second treatment agent, which is DTG, once daily; More preferably, the method further includes: continuous medication for 20-30 weeks during the treatment process; Preferably, the dosage of the ART regimen is not allowed to be adjusted during the treatment process.

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