RU2751164C1 - Dynamic antiretroviral hiv-infection therapy - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to a method of treating HIV infection. The method consists in the fact that when HIV infection is detected in a patient treatment is started by administering three antiretroviral drugs, namely a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor, or an integrase inhibitor such as dolutegravir, in combination with two nucleoside reverse transcriptase inhibitors, one of which is tenofovir, for at least 6 months, and then after the level of HIV RNA in the blood reaches less than 50 copies/ml and the level of CD4 T-lymphocytes is at least 450 cells/mcl in at least two measurements at an interval of 1 month, lifelong administering of dolutegravir at a dosage of 50 mg and emtricitabine at a dosage of 200 mg is started.

EFFECT: proposed method can be used for effective treatment of patients with HIV infection in order to minimize risks of developing adverse events in conducted therapy.

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Description

The technical field to which the invention relates

The invention relates to medicine, namely to methods of treating infectious diseases, in terms of HIV infection, and can be used to effectively treat patients with HIV infection in order to minimize the risks of developing adverse events during therapy.

State of the art

Currently, HIV infection is classified as a chronic infectious disease with the possibility of therapeutic control. It is impossible to completely recover from this disease, and therefore patients receive drugs for life. The need for many years of taking drugs leads to a high risk of developing adverse events.

The mainstay of treatment for HIV infection is therapy with three antiviral drugs. Tritotherapy of HIV infection involves the appointment of one drug from the group of integrase inhibitors (protease, non-nucleoside reverse transcriptase inhibitor) and two drugs from the group of nucleoside reverse transcriptase inhibitors [Hammer SM et al. A controlled trial of two nucleoside analogs plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team New Engl J Med. 1997 Sep 11; 337 (11): 725-33]. This form of therapy makes it possible to achieve an undetectable level of HIV viral load in human blood, which is undetectable by modern methods, which limits the mutation of the virus, stops the progression of HIV infection, makes it possible to restore the immune system, ensures the absence of clinical manifestations of HIV infection, work capacity and a high quality of life.

The starting standard treatment regimen is an antiretroviral therapy regimen consisting of a drug from the group of non-nucleoside reverse transcriptase inhibitors (usually efavirenz) and two drugs from the group of nucleoside reverse transcriptase inhibitors. The effectiveness of this scheme according to literature sources is 50-60% [Bednasz CJ et al. Efavirenz Therapeutic Range in HIV-1 Treatment-Naive Participants. Ther. Drug Monit. 2017 Dec; 39 (6): 596-603].

In 2017, the European AIDS Clinical Society updated guidelines for the treatment of HIV and related diseases. All HIV-infected patients, regardless of CD4 count, are advised to start antiretroviral therapy and use start-up regimens that include two drugs in the nucleoside reverse transcriptase inhibitor (NRTI) class and one drug in the class of integrase inhibitors (II) [EACS Guidelines Version 9.0 October 2017. http: //www.eacsociety.org/files/guidelines_9.0-russian.pdf].

In recent years, data have appeared on the possibility of simplifying the regimens in stable patients: if an undetectable viral load is reached (the level of HIV RNA in the blood is less than 50 copies / ml), it is possible to switch from a standard regimen consisting of three antiretroviral drugs: two drugs from the group of nucleoside reverse inhibitors. transcriptase (nucleoside base) and one drug from any other group, on a scheme that includes two drugs: an integrase inhibitor and one drug from the group of nucleoside reverse transcriptase inhibitors or non-nucleoside reverse transcriptase inhibitors. The largest amount of data has been accumulated on switching to the dolutegravir / rilpivirine regimen. There are also clinical studies on starting therapy with dolutegravir / lamivudine, which have not yet been completed, but it has already been shown that preexisting mutations to lamivudine can occur or appear. Bitotherapy regimens are characterized by a lower suppression power, which, when starting treatment with bitotherapy, may be reflected in an increased level of CD8 + T-lymphocytes associated with insufficient infection control, although viral load is not determined [Mussini C. et al. Access Switching to dual / monotherapy determines an increase in CD8 + in HIV-infected individuals: an observational cohort BMC Medicine (2018) 16:79 https://doi.org/10.1186/s12916-018-1046-2].

Closest to the claimed is a method of treating HIV infection with a combination of drugs of the NRTI class tenofovir and emtricitabine with efavirenz [Gallant JE et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006 Jan 19; 354 (3): 251-60-12; Margot NA et al. Development of HIV-1 drug resistance through 144 weeks in antiretroviral-naïve subjects on emtricitabine, tenofovir disoproxil fumarate, and efavirenz compared with lamivudine / zidovudine and efavirenz in study GS-01-934. J Acquir Immune Defic Syndr. 2009 Oct 1; 52 (2): 209-21; Albrecht H Abacavir / 3TC vs. tenofovir / FTC: interim results from ACTG 5202. AIDS Clin Care. 2008 Apr; 20 (4): 28; Sax PE et al, Abacavir / lamivudine versus tenofovir DF / emtricitabine as part of combination regimens for initial treatment of HIV: final results. J. Infect Dis. 2011 Oct 15; 204 (8): 1191-201]. However, this method has a drawback. Antiretroviral therapy in HIV-infected patients is currently carried out for life, while with prolonged use of tenofovir, a number of potential adverse events may develop, which mainly accumulate gradually

(3-5 years of use). These include a decrease in the level of glomerular filtration, an increase in creatinine, proteinuria, osteoporosis. In this regard, careful monitoring and even drug withdrawal is required. The development of side effects reduces the effectiveness of the treatment, and can lead to discontinuation of antiretroviral therapy. At the same time, as the studies have shown, the appointment of the drug tenofovir for a period of six months to a year does not entail undesirable effects and does not lead to the above undesirable consequences [Joshi K et al. Changes in renal function with long-term exposure to antiretroviral therapy in HIV-infected adults in Asia. Pharmacoepidemiol Drug Saf. 2018 Nov; 27 (11): 1209-1216. doi: 10.1002 / pds.4657].

Thus, there is a need to develop methods of therapy that allow maintaining a high efficiency of treatment of HIV-infected patients: persistently undetectable viral load in the blood (HIV RNA level less than 50 copies / ml) with a CD4 T-lymphocyte level of at least 450 cells / μl, with the absence of the development of undesirable phenomena leading to interruption of treatment and separation of patients from therapy.

Disclosure of invention

The technical result achieved by the claimed invention is a high efficiency of treatment: undetectable viral load (the level of HIV RNA in the blood is less than 50 copies / ml), the level of CD4 T-lymphocytes in the blood is not less than 450 cells / μl, the safety of lifelong therapy for HIV infection: indicators calcium metabolism, the level of glomerular filtration, lipid profile indicators are at levels that do not increase the risk of developing the corresponding diseases.

The technical result is achieved by a method for treating HIV infection, which consists in the fact that patients are treated according to the principle of dynamic antiretroviral therapy, namely, they begin antiretroviral therapy according to various schemes, where non-nucleoside reverse transcriptase inhibitors of the first generation or protease inhibitors are used as the third component, and after the viral load is below the detection threshold, however, undesirable effects are noted in the form of hypercholesterolemia, dyslipidemia, a decrease in the glomerular filtration rate, an increase in hepatic transaminases or any other undesirable phenomena, then they switch to biterapy with dolutegravir and emtricitabine at a dose of 50 mg and 200 mg, respectively, at the same time, the effectiveness of treatment does not decrease, tolerance is radically improved, namely, there is no decrease in the glomerular filtration rate in the long term, while the cost of treatment is reduced. Dolutegravir and emtricitabine are taken together once daily without any connection with food intake at the same time.

As an initiation of antiretroviral therapy, it is preferable to use the regimen (tritotherapy) - dolutegravir, tenofovir, emtricitabine at a dose of 50 mg, 300 mg and 200 mg, respectively, and receive it for at least 6 months, and then those patients who achieve an undetectable viral load (at least than in two measurements with an interval of 1 month) and CD4 + T-lymphocytes are restored (to a level of at least 450 cells / μl).

The method consists in the fact that at the start of treatment, maximum efficacy is achieved, including through the use of insufficiently safe drugs, and then upon reaching maximum efficiency, including through the formation of an own immune response to HIV, unsafe drugs are removed from the scheme and treatment continues with optimal a selected combination of dolutegravir and emtricitabine in standard dosages, the drugs are taken simultaneously, the frequency and time of administration correspond to the instructions for use of the drug.

An essential point is the choice of a critical switching point, necessary and sufficient for the formation of one's own immune response to HIV, which ensures the safety and efficiency of switching. The critical switching point is assigned no earlier than 6 months after the start of therapy and assumes a doubly undetectable level of viral load (the level of HIV RNA in the blood is less than 50 copies / ml) and a CD4 T-lymphocyte level of at least 450 cells / μL in the last measurement, while unwanted the phenomena of the drug tenofovir do not have time to develop or do not fully develop, and the withdrawal of the drug during the transition to bitotherapy leads to a complete restoration of the altered biochemical parameters.

Brief Description of Drawings

The invention is illustrated by the following drawings.

FIG. 1 shows the general formula of the proposed method.

Implementation of the invention

The essence of the proposed method lies in the fact that patients are treated according to the principle of dynamic antiretroviral therapy, namely, start ART on a triple scheme - dolutegravir, tenofovir, emtricitabine or any other standard antiretroviral therapy regimen, which includes a drug from the group of non-nucleic first-generation reverse transcriptase inhibitors or protease inhibitors, and then those patients who achieve an undetectable viral load (HIV RNA level in the blood is less than 50 copies / ml) and CD4 + T-lymphocytes are restored (to a level of at least 450 cells / μl), they switch to dual therapy with dolutegravir and emtricitabine, while the effectiveness of treatment does not decrease: an undetectable viral load remains, the level of CD4 T-lymphocytes is at least 450 cells / μL, treatment tolerance is radically improved due to the withdrawal of tenofovir: undesirable reactions from the urinary and bone systems.

It is assumed that in these patients, due to undetectable viral load and the restored level of CD 4+ T-lymphocytes, the formation of an effective own immune response to HIV begins, which makes it possible to use a lightweight therapy regimen, namely biterapy.

Performance criteria

• During the observation period, the patient had an undetectable viral load, no viral load blips were observed, and no resistance formation occurred;

• There was no decrease in the level of CD4 + T-lymphocytes;

• There were no adverse events associated with therapy

The present invention is illustrated by specific examples of implementation, which are not the only possible, but clearly demonstrates the possibility of achieving the required technical result.

Clinical example 1. Patient SKB, 39 years old (if identified). Among the vulnerable group of the population are men who practice same-sex sex. HIV infection was detected in 2016, the route of infection is sexual. He was regularly tested for HIV infection, as he was aware of his risks. When detected, the viral load is 180 thousand copies / ml, the level of CD 4 T-lymphocytes is 560 copies / μl. The creatinine level is 89.5 μmol / l, the glomerular filtration rate is 97 ml / min / 1.73m ² , the parathyroid hormone level (the indicator reflects the effect of the drug on calcium metabolism) is 36.9 pg / ml. Therapy was started immediately after detection according to the scheme dolutegravir 50 mg, tenofovir 300 mg, emtricitabine 200 mg, taking the drugs together once a day without any connection with food intake at the same time.

After 6 months, minor changes in biochemical indices: creatinine level of 88.4 mmol / l, glomerular filtration rate 98 ml / min / 1,73m ^2, PTH level 40.3 pg / ml. The viral load is not determined in two measurements with an interval of 1 month, the level of CD 4 T-lymphocytes is 780 cells / μl. In order to prevent adverse events and ensure lifelong metabolically beneficial therapy, in accordance with the claimed method, a switch was made to biterapy with dolutegravir 50 mg, emtricitabine 200 mg, taking drugs together once a day without any connection with food intake at the same time.

12 months after switching to biotherapy, he receives treatment according to the same scheme, the viral load is not determined, the level of CD 4 T-lymphocytes is 1210 cells / μl. Biochemical parameters are within normal limits, there are no adverse effects of therapy, adherence is high. The creatinine level is 86 μmol / l, the glomerular filtration rate is 97 ml / min / 1.73 m2, the parathyroid hormone level is 34.8 pg / ml.

Thus, against the background of 6 months of treatment with an ART regimen, which included tenofovir, there was no adverse effect on metabolic parameters. During the next 6 months of treatment after the withdrawal of tenofovir, there was no negative effect on the above metabolic parameters either. Initial treatment with an ART regimen consisting of three drugs dolutegravir, emtricitabine, tenofovir was effective; it did not have a negative effect on metabolic parameters of tenofovir during a short course. Switching to bitotherapy according to the dolutegravir regimen, emtricitabine did not affect the effectiveness of therapy, but prevented the long-term undesirable consequences of long-term use of tenofovir.

Clinical example 2. Patient MSE, 63 years old (if identified). The route of infection is heterosexual intercourse. He was examined for HIV due to weight loss (by 15 kg), repeated pneumonia. When detected, the viral load is 320 thousand copies / ml, the level of CD 4 T-lymphocytes is 290 copies / μl. Therapy was started immediately after detection according to the scheme dolutegravir 50 mg, tenofovir 300 mg, emtricitabine 200 mg, taking the drugs together once a day without any connection with food intake at the same time. Creatinine level of 78.3 mmol / l, glomerular filtration rate 91 ml / min / 1,73m ^2, PTH level 45.8 pg / ml.

After 6 months, the viral load is not determined, the level of CD 4 T-lymphocytes is 390 cells / μl.

After 1 year, the patient achieved the level of CD4 T-lymphocytes in repeated measurements of 510 cells / μl and 560 cells / μl, the viral load is still not determined. Creatinine 84.6 .mu.mol / l, glomerular filtration rate 84 ml / min / 1,73m ^2, respectively, the level of parathyroid hormone (figure reflects the effects of the drug on calcium metabolism) 70.5 pg / ml, respectively. Thus, a decrease in renal function was noted.

Dolutegravir 50 mg bitotherapy and 200 mg emtricitabine were switched to bitotherapy, taking drugs together once a day without any connection with food intake at the same time.

12 months after switching to biotherapy, he receives treatment according to this scheme, the viral load is not determined, the level of CD 4 T-lymphocytes is 690 cells / μl. The creatinine level is 74 μmol / l, the glomerular filtration rate is 91 ml / min, the parathyroid hormone level is 43.6 pg / ml.

Thus, against the background of 12 months of treatment with an ART regimen, which included tenofovir, there was a change in indicators associated with calcium metabolism. Initial treatment with an ART regimen of three drugs, dolutegravir, emtricitabine, and tenofovir, allowed an undetectable viral load to be achieved, but there was a negative effect of tenofovir on the kidneys and calcium metabolism. On biterapy according to the dolutegravir and emtricitabine scheme, the immunological efficacy increased, and the metabolic parameters improved.

Clinical example 3. Patient VDE, 56 years old, HIV infection was detected at the age of 52 years 4 years ago during examination before planned surgery (removal of the gallbladder). The route of infection is sexual. At the time of detection of HIV infection, the level of CD4 T-lymphocytes was 340 cells / μl, VL 42,000 copies / ml. For 3.5 years he has been receiving therapy according to the scheme of efavirenz 600 mg, tenofovir 300 mg, lamivudine 150 mg. On treatment, the viral load was undetectable, the level of CD4 T-lymphocytes was 510 cells / μL, however, there were changes in the biochemical blood test: a persistent increase in the level of creatinine to 80.3 μmol / L and a decrease in the glomerular filtration rate to 71 ml / min / 1.73m ² , the level of parathyroid hormone 121.7 pg / ml.

Taking into account the revealed biochemical changes, the patient was transferred to biotherapy with dolutegravir 50 mg, emtricitabine 200 mg. After a year of treatment with this regimen, the CD4 T-lymphocyte level was 695 cells / μL, the viral load was undetectable, the creatinine level decreased to 68.9 μmol / L, the glomerular filtration rate increased to 85 ml / min / 1.73 m², the level of parathyroid hormone is 68.9 pg / ml. Thus, against the background of the use of a metabolically favorable regimen of dolutegravir, emtricitabine, the normalization of biochemical parameters was noted with a high efficiency of the conducted bitotherapy.

Claims (4)

1. A method of treating HIV infection, which consists in the fact that when HIV infection is detected in a patient, treatment is started with taking three antiretroviral drugs, namely a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor, or an integrase inhibitor, such as dolutegravir, in combination with two nucleoside reverse transcriptase inhibitors, one of which is tenofovir, for at least 6 months, and then when the level of HIV RNA in the blood reaches less than 50 copies / ml and the level of CD4 T-lymphocytes is at least 450 cells / μl in at least two dimensions with an interval of 1 month, they switch to lifelong administration of dolutegravir at a dosage of 50 mg and emtricitabine at a dosage of 200 mg. 2. The method according to claim 1, characterized in that the starting antiretroviral therapy consists in taking drugs dolutegravir, tenofovir and emtricitabine. 3. The method according to claim 2, characterized in that dolutegravir is taken in a dose of 50 mg, tenofovir 300 mg and emtricitabine 200 mg. 4. The method according to claim 1, characterized in that the intake of dolutegravir and emtricitabine is carried out together once daily without any connection with food intake at the same time.

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