A method of treating HIV in pediatric patients using rilpivirine.

Abstract

This provides a method for treating children infected with the HIV virus. [Solution] A method comprising administering to a child infected with the HIV virus 25 mg or less of a rilpivirine non-nucleoside reverse transcriptase inhibitor or an equivalent amount of a pharmaceutically acceptable salt of rilpivirine once daily.

Description

[Technical Field]

[0001] This disclosure relates to rilpivirine or its salts for the treatment of HIV infection in children. It is intended for use. [Background technology]

[0002] Those infected with HIV are treated with nucleoside / nucleotide reverse transcriptase inhibitors (N[t]R TI), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, pharmacokinetics A combination of multiple drugs including PK boosters, integrase inhibitors, and fusion inhibitors. It is treated regularly with a combination therapy (highly active antiretroviral (ARV) therapy). This treatment is, In a significant proportion of subjects, HIV-1 ribonucleic acid (RNA) was reduced to undetectable levels. This reduces the risk of virus resistance developing. [Overview of the project]

[0003] Rilpivirine (RPV, formerly known as TMC278[R27]), a diarylpyrimidine derivative.

[8474] ) is used against wild-type (WT) HIV1 and NNRTI-resistant HIV1 variants. It is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI) with in vitro activity. The medical need for developing age / weight-appropriate therapies in adolescents and children remains. exist.

[0004] This disclosure pertains to a method for treating children infected with the HIV virus. The patient weighs over 11 kg, has previously received treatment, and has discontinued their first antiretroviral therapy. The patient is being treated with an illus regimen. The method involves rilpivirine at a dose of 25 mg or less once daily. A certain non-nucleoside reverse transcriptase inhibitor (or a pharmaceutically acceptable salt of an equivalent amount of rilpivirine) This includes administering ) to the subject for at least 24 weeks. According to the method described, the subject will receive ril for at least 24 weeks. After once-daily administration of a pharmaceutically acceptable salt of pibirine or an equivalent amount of rilpivirine, plasma 1m³ This indicates the viral load of HIV virus particles, specifically 50 copies or less per liter (≤50 c / mL).

[0005] This disclosure shall be interpreted in relation to the following detailed description which forms part of this disclosure. This can be more easily understood by referring to the following. This disclosure is described herein. and / or limited to the specific apparatus, method, use, conditions or parameters indicated. There is no specific definition, and the terms used herein are merely for illustrative purposes to illustrate certain embodiments. It is understood that this is not intended to limit the claimed disclosure. stomach.

[0006] When used herein, including in the attached claims, the singular form "one (a)" "One (an)" and "that" encompass plural forms, and referencing a specific number is clear from the context. Unless otherwise specified, include at least that particular value.

[0007] If a range of values ​​is expressed, another embodiment may be from one specific value and / or other specific values. It includes up to a certain value. All ranges are comprehensive and combinable. Furthermore, within the range The references to values ​​listed include all values ​​within that range. When expressed as an approximation, it is understood that a particular value may form a different embodiment. It will be done. When referring to measurable values ​​such as quantity or length of time, the term used herein is... When used, the term "about" encompasses a reasonable variation of that value, such as ±10% from the specified value. For example, the expression "about 50%" can include ±10% of 50, that is, 45 % to 55%.

[0008] For clarity, it should be understood that the specific features of the present disclosure described herein in connection with individual embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, the various features of the present disclosure described in connection with a single embodiment may be provided individually or in any sub-combination.

[0009] The present invention can be understood by reference to the following detailed description that forms a part of the present disclosure. The present invention is not limited to the specific methods, conditions or parameters described and / or shown herein, and the technical terms used herein are for the purpose of merely describing specific embodiments by way of example and are not intended to limit the claimed invention.

[0010] Scientific and technical terms used in connection with this application shall have the meanings commonly understood by those skilled in the art, unless otherwise defined herein.

[0011] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure that are pharmaceutically acceptable and retain the pharmacological activity of the desired parent compound. In particular, such salts can be non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, examples of such salts include: (1) hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like and the following: (1) hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like ​​​​​​​​It is formed by inorganic acids such as acetic acid, propionic acid, hexanoic acid, cyclo Pentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, apple Acids, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzo Iol-benzoic acid, tartaric acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- Ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-hydroxyethanesulfonic acid Lolobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor α-sulfonic acid, 4-methylbicyclo[2.2.2]-octa-2-en-1-carbone Acids, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid , lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoate, salicylic acid, ste (2) Acid addition salts formed by organic acids such as aric acid, muconic acid, and the like; or (2) Acid protons present in the parent compound can be metal ions, such as alkali metal ions, alkalis. Substituted with earth metal ions or aluminum ions, or ethanolamine Diethanolamine, triethanolamine, N-methylglucamine and similar substances Salts formed when coordinating with organic bases such as sodium. Potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc. Furthermore, if the compound contains basic functionalities, hydrochloride, hydrobromide, tartrate, mesylate, Further examples include salts of non-toxic organic or inorganic acids such as acetates, maleates, and oxalates. .

[0012] Rilpivirine, administered once daily at a dose of 25 mg, is used in the United States, Canada, Japan, and the European Union. In several countries, including, as a single 25 mg tablet (EDURANT) or as a compound Standard dose combinations (i.e., the integrase inhibitor dolutegravir [DTG], tenofo) Vildisoproxil fumarate / emtricitabine [TDF / FTC] and tenofovir As part of rafenamid / FTC [TAF / FTC], anti-retero It is approved for the treatment of HIV-1 infected adults who are vulnerable to the treatment of other viruses (ARVs). The trademark for products containing lupivirine is COMPLERA (emtricitabine / rilpivirine). (Tenofovir disoproxil fumarate), ODEFSEY and JULUCA (Dolte Gravir (rilpivirine) is one example.

[0013] This disclosure relates to a method for treating children infected with the HIV virus or to a method for treating children infected with the HIV virus. This invention relates to methods for treating infected children. In a preferred embodiment, the children are HIV- 1. Infected with the virus. The target age group for children is under 18 years old, preferably ≥2 to <12 years old. In other embodiments, the target children are ≥6 years to <12 years old. In some embodiments, the target children The elephants are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 1 They are 6 or 17 years old.

[0014] According to this disclosure, the children treated using the described method weigh 11 kg or more. In some embodiments, the pediatric subject treated using the described method is 11 kg ~25kg, for example 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 2 The body weight is 1, 22, 23, 24, or 25 kg. In other embodiments, the method described is used. The children treated are those weighing over 25 kg, for example, 26, 27, 28, 29, 30, 31, 3 2, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 ,46,47,48,49,50,51,52,53,54,55,56,57,58, Body weight of 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or 70 kg It is heavy.

[0015] According to this disclosure, the pediatric subjects are “having experienced treatment,” that is, the subjects are antiretrotherapy. The patient has been previously administered antiviral drugs. Similarly, according to this disclosure, the pediatric subject may have one or more antiviral drugs. A first (e.g., prior) antiretroviral regimen consisting of retroviral drugs was administered in the past. Given, the first antiretroviral regimen is any of the methods disclosed herein. It is interrupted before it can be started. In some embodiments, the first antiretroviral regime The operation is interrupted at least 12 hours before commencing any of the methods disclosed herein.

[0016] According to the method described, for children (preferably ≥2 years to <12 years), approximately 25 mg or less Below, preferably 25 mg or less of a rilpivirine non-nucleoside reverse transcriptase inhibitor is administered. It is administered. Preferably, in the method disclosed herein, the only non-nucleate administered to pediatric subjects. Oside reverse transcriptase inhibitors are rilpivirine or its salts. In some embodiments, children The subjects (preferably ≥2 years to <12 years) should take a pharmaceutically acceptable salt of rilpivirine, 25 It is administered in an equivalent amount to rilpivirine in mg or less. Examples of rilpivirine salts include ri Lupivine hydrochloride is one example.

[0017] In some embodiments, the child subject weighs between 11 kg and 25 kg. In some cases, the pediatric dose is 15 mg of rilpivirine (or an equivalent dose of rilpivirine). The patient is given a salt (tolerable for the patient) once a day.

[0018] In some embodiments, the child subject weighs more than 25 kg. For children, the dosage is 25 mg of rilpivirine (or an equivalent amount of rilpivirine, pharmaceutically acceptable). The salt (which is used) is administered once a day. In some embodiments, pediatric subjects are naive to treatment. In some cases, pediatric subjects have experienced treatment.

[0019] In some embodiments, the dosage for children is 2.5 mg to approximately 25 mg, for example, 2.5 mg, 5 mg, or 7 mg. 5, 10, 12.5, 15, 17.5, 20, 22.5 or 25 mg of rilpivirine (or The patient is administered an equal dose of a pharmaceutically acceptable salt of rilpivirine once daily.

[0020] In some embodiments, the amount of rilpivirine or a pharmaceutically acceptable salt thereof is used in a single dose. It is administered in a daily dose form, namely, rilpivirine or a pharmaceutically acceptable salt thereof. The entire amount is administered as a single dose in the form of a tablet or capsule. For example, 1 The entire daily dose consists of 25 mg tablets or capsules or 15 mg tablets or capsules. It is administered as follows.

[0021] In some embodiments, the amount of rilpivirine or a pharmaceutically acceptable salt thereof is multiple It is administered as a single dosage form, that is, rilpivirine or one of its pharmaceutically acceptable salts. The entire daily dose is administered in several units. For example, 15 mg of rilpi per day. The dose of biline is administered as six tablets or capsules, each tablet or capsule containing 2.5mg of milk. It contains g of rilpivirine. In another example, the daily dose of rilpivirine is 17.5 mg. It is administered as individual tablets or capsules, each tablet or capsule containing 2.5 mg of rilpivil It contains . In another example, a daily dose of 7.5 mg of rilpivirine is 3 tablets or caps. It is administered as a cell, with each tablet or capsule containing 2.5 mg of rilpivirine.

[0022] In some aspects of this disclosure, the administration of rilpivirine (or the pharmaceutically appropriate administration of an equivalent amount of rilpivirine) The administration of salts (tolerable in the subject) is when the subject is in a state of dietary intake. In some cases, rilpivirine is administered (or an equivalent amount of rilpivirine is administered in a pharmaceutically acceptable manner). Salt administration is used when the subject is in a fasting state.

[0023] According to the method described, children should take rilpivirine (or rilpivirine) for at least 24 weeks. After once-daily administration of bivirine salt, HIV virus particles of 50 copies or less per 1 mL of plasma were observed. This indicates the viral load of a child (e.g., an HIV-1 virus particle).

[0024] In some aspects of this disclosure, pediatric subjects are given rilpivirine for at least 48 weeks (or After once-daily administration of rilpivirine salt, HIV viruses with fewer than 50 copies per 1 mL of plasma were detected. This indicates the viral load of a particle (e.g., an HIV-1 virus particle).

[0025] In some aspects of this disclosure, the pediatric subjects are 24 to 48 weeks old (e.g., 24, 25, 26 , 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, Rilpivirine (or) for 40, 41, 42, 43, 44, 45, 46, 47 or 48 weeks After once-daily administration of rilpivirine salt, HIV viruses with fewer than 50 copies per 1 mL of plasma were detected. This indicates the viral load of a particle (e.g., an HIV-1 virus particle).

[0026] In some embodiments, in addition to the administration of rilpivirine or rilpivirine salt, pediatric subjects may also be given the following treatment: Antiretroviral (AR) anti V) A background regimen is administered. The ARV background regimen is, for example... For example, this technology is used to treat individuals infected with HIV viruses such as the HIV-1 virus. It may contain one or more active drug components (APIs) used in the field. Useful APIs for treating infected subjects include nucleoside reverse transcriptase inhibitors and nucleosides. Examples include ostide reverse transcriptase inhibitors. In some embodiments, ARV background rate Dimen is a nucleoside reverse transcriptase inhibitor and / or nucleotide reverse transcriptase inhibitor. Includes transcriptase inhibitors. Examples of APIs for use in ARV background regimes. For example, azidothymidine (AZT), abacavir (ABC), lamivudine (3T) C) Dolutegravir, tenofovir, pharmaceutically acceptable salts of tenofovir, tenofovir Lodrugs (e.g., tenofovir disoproxil, tenofovir alafenamide), tenofo pharmaceutically acceptable salts of virprodrugs (e.g., tenofovir disoproxil fumarate) Examples include salt, emtricitabine, and combinations thereof.

[0027] In some aspects of this disclosure, the subject matter is rilpivirine or rilpivirine pharmaceutically The virus is suppressed before administration of the acceptable salt. For example, in pediatric subjects, rilpivirine or Before the once-daily administration of a pharmaceutically acceptable salt of rilpivirine, 50 units per 1 mL of plasma should be used. This indicates the viral load of HIV virus particles smaller than P (e.g., HIV-1 virus particles). Obtain. In some embodiments, pediatric subjects may use rilpivirine or rilpivirine pharmaceutically acceptable The patient has been under viral suppression for at least 12 months prior to administering the salt once daily. In this embodiment, children are given rilpivirine or a pharmaceutically acceptable salt of rilpivirine once a day. The virus has been suppressed for 2 to 12 months prior to the first dose. In some embodiments, the pediatric subjects are Before the once-daily administration of rilpivirine or a pharmaceutically acceptable salt of rilpivirine, take 1, 2, or 3 The virus has been suppressed for 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0028] In some aspects of this disclosure, methods for treating pediatric subjects include adolescent development, for example, Tanner It does not have a significant effect on adolescent development assessed at each stage. In other aspects of this disclosure, Treatment methods used for children do not have a significant impact on adolescent development.

[0029] In some aspects of this disclosure, the results of the method are grade 3 or higher compared to conventional treatment methods. This reduces the incidence of four drug side effects (ADRs). Examples of ADRs include headaches and stomach upset. Symptoms include heart problems, insomnia, dizziness, abnormal dreams, rash, abdominal pain, depression, fatigue, and vomiting.

[0030] In some aspects of this disclosure, the results of the method are compared to conventional treatment methods with Grade 2 The incidence of ADR decreases. Examples of ADR include depression, headaches, insomnia, and transgressions. Symptoms include increased minase levels, rash, and abdominal pain.

[0031] In some aspects of this disclosure, the results of the method, compared to conventional treatment methods, are virological The failure rate decreases. In some aspects of this disclosure, the method results in a difference from conventional treatment methods. In comparison, the incidence of treatment resistance decreases. In some aspects of this disclosure, as a result of the method, Compared to conventional treatment methods, the incidence of drug-drug interactions is reduced. In this embodiment, the results of the method, compared to conventional treatment methods, show improved redistribution of body fat and / or accumulation of body fat. For example, central obesity, cervical and dorsal fat hypertrophy (buffalo hump), peripheral emaciation, facial emaciation, and mammary gland hypertrophy. The incidence of "Cushing-like appearance" is reduced. In some aspects of this disclosure, the method As a result, compared to conventional treatments, immune reconstitution inflammatory syndrome (e.g., asymptomatic or symptomatic) Wami infections (Mycobacterium avium complex, cytomegalovirus, pneumocystis) Pneumocystis jiroveci (pneumonia and tuberculosis, etc.) The incidence of inflammatory responses (to the virus) decreases.

[0032] The following examples are illustrative of the present invention and are not intended to limit it. [Examples]

[0033] This refers to HIV-1 infected participants (males and children) aged ≥2 to <12 years old and weighing at least 11 kg. In girls, once-daily RPV in combination with ARV selected by other researchers. Phase 2 open-label single-agent study to evaluate the PK, safety, tolerability, and efficacy of switching to [the new drug]. This is a multicenter intervention study.

[0034] All participants will undergo a screening phase that will be completed within six weeks. The phase may be extended by up to two weeks if unpredictable circumstances arise. All participants During the research intervention phase, participants will receive 48 weeks of open-label treatment. Screening and research intervention The total study period for each participant, including the phases, was approximately 54 weeks. (Independent Data Monitoring Committee) The organization () was appointed to this research.

[0035] Intervention group and duration Rilpivirine (25 mg or a dose based on body weight or an equivalent amount of rilpivirine salt) is N (t)RTIs and other ARVs and integrase inhibitors selected by researchers It is administered orally once daily in combination with the background regimen. However, P Protease inhibitors and ARVs requiring K boosters are permitted from baseline onward. It will not be done.

[0036] All participants must complete a total treatment period of 48 weeks (or discontinue treatment before that). Continue the research intervention and ARV background regime (data evaluation where appropriate). (Throughout the period). Where appropriate, dose adjustments of RPV due to weight changes are permitted.

[0037] Evaluation of effectiveness Important efficacy assessments include determining the plasma HIV-1 RNA viral load and using a CD4+ cell count. One example is the measurement of numbers.

[0038] Pharmacokinetic evaluation Pharmacokinetics Based on individual plasma concentration-time data, the actual dose taken and the PK sample used Using the time interval, derive the following PK parameter for RPV: C 0h , C min , C ma x , C ss,av t max AUC 24h CL / F, Vss / F and FI.

[0039] Population pharmacokinetics Based on individual plasma concentration-time data, the actual dose taken and the PK sample used Using time intervals, population PK modeling is used to derive the PK parameters and exposure information of the RPV. To release.

[0040] Pharmacokinetic / pharmacodynamic evaluation Pharmacokinetic / PD assessments are conducted to study the relationship between PK and safety / efficacy variables. .

[0041] Safety evaluation Important safety assessments include monitoring for (S)AEs and HIV-related events (HIV infection). AIDS-defining diseases and stage 3-defining opportunistic diseases [according to the criteria since 2014] The cutoff age for stage 3 disease is 6 years old (including clinical laboratory tests (≥6 years)). (Including endocrine assessment in 12-year-old participants), monitoring of cardiovascular safety (vital signs and This includes a 12-lead electrocardiogram and physical examinations (including growth). In addition, this group As part of the local standard treatment, questionnaires or other means (available on-site) are used. A depression assessment will be conducted.

[0042] Other reviews Other assessments and procedures include HIV-1 genotyping and retrospective evaluation of RAM in PBMCs. These include tolerance testing based on valency, documentation of RPV intake by completing a diary, and adherence to treatment. It is possible.

[0043] statistical methods The initial analysis (using formal database locking) showed that all participants reached week 24. is completed (or interrupted earlier). The final analysis (using the formal database lock ) is completed (or interrupted earlier) when all participants reach week 48. A detailed statistical analysis plan (SAP) for each analysis is described and signed off before the database lock.

[0044] Efficacy analysis Efficacy analysis Plasma viral load Outcome analysis (i.e., the proportion of participants with plasma viral load < 50 and < 400 HIV-1 RNA copies / m L) is performed using a snapshot approach. The snapshot analysis is based on the plasma viral load data last observed within the visit window (i.e., weeks 24 and 48). The proportion of participants with virologic failure per snapshot approach (i.e., HIV-1 RNA ≥ 50 and ≥ 400 copies / mL) is provided. Participants who switched ARV due to intolerance not permitted by the protocol are considered virologic failures for this snapshot approach. The proportion is presented as the percentage of the Clopper Pearson 95% confidence interval (CI) at each time point.

[0045] Time-to-event data (i.e., time to loss of virologic response) is illustrated by a Kaplan-Meier curve.

[0046] CD4 + cell count analysis is based on the observed values and imputed values using NC = F, i.e., participants who had their study terminated early had their CD4 + cell counts at baseline substituted after the interruption ( (resulting in a change of 0), and having a substitution where the last observation for intermediate missing values ​​is carried over. ru.

[0047] Actual data and changes from the baseline are shown descriptively and graphically.

[0048] Safety analysis Adverse events / HIV-related events Regarding AE / HIV-related events that occurred during each treatment, at least one occurrence of a given event The percentage of participants who experienced life will be tallied for each research stage (i.e., the screening stage, Intervention stage and follow-up). Individual summaries will be compiled as needed, based on severity and research intervention. It is done on a case-by-case basis.

[0049] Death, discontinuation of the study intervention due to adverse events (AEs), or grade 3 / 4 AEs, particularly of interest. Summary, listing, dataset, or participant information of participants who have experienced deep AE or SAE. Discourse may be provided as appropriate.

[0050] Clinical laboratory testing Laboratory data is summarized by type of laboratory test. Descriptive statistics are provided for each planned test. At the time of the observation, the observed values ​​for each laboratory analyte at baseline and This is calculated based on the change from the baseline. Descriptive statistics include the number of observations (n), mean, and standard deviation. Includes standard deviation (SD), median, minimum, and maximum values.

[0051] The frequency of change from baseline is aggregated using a pre-intervention vs. post-intervention crosstabulation (below the mean range). (Including classifications within the mean range and above the mean range). Regarding available tests, please refer to the laboratory. Abnormalities are determined using the AIDS Treatment and Research (DAIDS) grading table. After baseline. A frequency summary of the worst abnormal grades is generated. Grade 3 / 4 laboratory abnormalities are generated as needed. Frequency summaries and lists are provided for participants who exhibited the behavioral pattern.

[0052] electro-cardiogram Descriptive statistics for ECG values ​​and changes from baseline are summarized at their respective scheduled time points. Descriptive statistics include the number of observations (n), mean, standard deviation (SD), median, minimum, and maximum. A regular frequency count is performed.

[0053] Vital signs Pulse rate and blood pressure (systolic and diastolic) (supine and standing) values, and baseline Descriptive statistics of the changes are summarized at each scheduled point in time. Descriptive statistics are based on the number of observations (n Includes mean, SD, median, minimum, and maximum values. Values ​​exceeding clinically significant limits. The percentage of participants with a value is summarized at each point in time.

[0054] Physical examination Physical examination findings for each body tissue are summarized at their respective scheduled times. Any abnormalities found during the inspection will be listed.

[0055] Growth is tracked regularly and continuously evaluated using standardized growth curves. Height, year-to-year Descriptive statistics for age-to-height ratio, weight, age-to-weight ratio, body mass index (BMI), and age-to-BMI ratio are as follows: The baseline and the observed values ​​and their changes from the baseline are as follows: The calculation is performed at the given time. Descriptive statistics include the number of observations (n), mean, standard deviation (SD), median, and minimum. and includes the maximum value.

[0056] The Tanner stages (for pubic hair and genitals / chest) are compared to the baseline for each age group. Loss is tallied. In addition, in girls, the occurrence of first menstruation during treatment is also compared to baseline. The data is then cross-tabulated, and the dates of menarche are listed.

[0057] Pharmacokinetic analysis Same size (n), arithmetic mean, standard deviation, coefficient of variation (percentage) ([%]CV), geometric mean, Descriptive statistics, including median, minimum, and maximum values, are derived from the PK parameters of the RPV. It is calculated for each individual.

[0058] Efficacy and safety parameters are used for PK / PD analysis. Various efficacy and safety parameters The data is linked to the PK of the RPV, and graphical tools and, where possible, statistical models. Apply this.

[0059] Other analyses Frequency summaries and lists are generated.

[0060] endpoint Primary endpoints The region under the plasma concentration-time curve from the time of administration to 24 hours after RPV administration. Grade 3 / 4 AE, SAE, HIV-related event (Acquired immunodeficiency in HIV infection) Syndrome (including AIDS-defining diseases and stage 3-defining opportunistic diseases) and 24-week study The incidence of adverse events (AEs) that lead to the discontinuation of research interventions through treatment.

[0061] Secondary endpoints Incidence and severity of AE / HIV-related events during 24 and 48 weeks of study treatment, and The relevance of these RPVs. Toxicity grade / abnormality vs. clinical laboratory parameters, E, throughout 24 and 48 weeks of study treatment. Time course from baseline in CG parameters, vital signs, and physical examination criteria. Typical changes and transitions. Through 24 and 48-week study treatments, the U.S. Food and Drug Administration (FDA) snapshots Percentage of participants with HIV-1 RNA <50 and ≥50 copies / mL using the approach. . CD4 through 24 and 48 weeks of research treatment + Cell count (absolute and total lymphocytes) Immunological changes measured by a percentage. Pharmacokinetic parameters of RPV (excluding the region below the plasma concentration-time curve (AUC)). RPV derived from population PK modeling through 24 and 48-week study treatments Pharmacokinetic parameters. Viral genotypes at the time of virological failure during 24 and 48 weeks of research treatment. Pediatric European Network for the Treat Comment of AIDS (PENTA) Compliance Questionnaire and 24- and 48-week study treatments Adherence to treatment assessed through reporting obligations for research interventions. Retrospective peripheral blood mononuclear cells (PBMCs) or plasma-based bioavailability through 24 and 48 weeks of study treatment. Mutations in HIV-1 DNA or HIV-1 RNA, as assessed by spectroscopy.

[0062] Research Design This refers to HIV-1 infected participants (boys) aged ≥2 to <12 years old and weighing at least 11 kg. In girls, once-daily RPV in combination with ARV selected by other researchers. Phase 2 open-label single-agent study to evaluate the PK, safety, tolerability, and efficacy of switching to [the new drug]. This is a multicenter intervention study.

[0063] To comply with overall regulatory requirements, approximately 40 participants (with a baseline weight of <25kg) Approximately 12 participants (including g) will be enrolled in this study. Approximately 25-30 target participants. They will be enrolled in this study. The actual number of participants in this study will vary depending on the number of enrolled participants. Participants weighing <25kg and ≥25kg will be registered concurrently.

[0064] Each participant had been on a stable ARV regimen for at least 6 months at the time of screening. It needs to be suppressed HIV-wise (i.e., HIV-1 RNA < 50 copies / mL) Furthermore, participants must have no history of virological failures. In addition, participants should, if available, The results of that historical HIV-1 genotyping test prove that any RPV resistance Sex-related mutations (RAM) should also be absent. However, participants ≥2 years to <6 years old This refers to the historical HIV- available at the time of screening, provided to the clinical trial sponsor. 1. The results of a genotype determination should be available. Historical HIV-1 genotype determination. The results and availability of subtypes must be recorded in the CRF. Participants ≥6 to <12 years old. In this case, the availability of historical HIV-1 genotyping results should be recorded in the CRF. It should.

[0065] Rilpivirine (25 mg or a dose based on body weight or an equivalent amount of rilpivirine salt) is N (t)RTIs and other ARVs and integrase inhibitors selected by researchers It is administered orally once daily in combination with the background regimen. However, P Protease inhibitors and ARVs requiring K boosters are permitted from baseline onward. It will not be done.

[0066] All participants will continue treatment until they reach a total treatment period of 48 weeks (or discontinue treatment before that). Continue the research intervention and ARV background regime (data evaluation period if appropriate). (Throughout the period). Where appropriate, dose adjustments of RPV due to weight changes are permitted.

[0067] All participants will have a screening phase that is intended to be completed within six weeks. However, the screening phase may be extended for up to two weeks if unpredictable circumstances arise. It may be extended. All participants will receive 48 weeks of open-label treatment during the study intervention phase. At the completion of the study, participants who were still experiencing clinical benefits from RPV treatment were considered to have completed the study. The opportunity to continue treatment will be given. Total for each participant, including the screening and research intervention phases. The research period was approximately 54 weeks.

[0068] Important safety assessments include monitoring for (S)AEs and HIV-related events (HIV infection). AIDS-defining diseases and stage 3-defining opportunistic diseases [according to the criteria since 2014] The cutoff age for stage 3 disease is 6 years old (including clinical laboratory tests (≥6 years)). (Including endocrine assessment in 12-year-old participants), monitoring of cardiovascular safety (vital signs and This includes a 12-lead electrocardiogram and physical examinations (including growth). In addition, this group As part of the local standard treatment, questionnaires or other means (available on-site) are used. A depression assessment will be conducted.

[0069] Important efficacy assessments include determining the plasma HIV-1 RNA viral load and CD4 + cell meter One example is the measurement of numbers.

[0070] Other assessments and procedures include HIV-1 genotyping and retrospective evaluation of RAM in PBMCs. Tolerance testing based on valency, documentation of RPV intake by completing a diary, and adherence to treatment are among the measures taken. It can be listed.

[0071] The initial analysis (using formal database locking) showed that all participants reached week 24. It is completed when (or interrupted before) and then the final analysis (formal database) (Using locks) is completed when all participants reach week 48 (or earlier) (It was interrupted earlier.)

[0072] research group The medical importance of developing novel potent ARVs and age / weight-appropriate formulations for children. Children (boys and girls) aged ≥2 to <12 years who are infected with HIV-1 are registered due to necessity. It will be done.

[0073] Children with HIV infection may exhibit stunted growth and low birth weight compared to healthy children. It is known that this is often the case, especially when there are further risk factors for growth disorders. To ensure that representative fractions of HIV-1-infected child populations can be studied. A child weighing 11 kg (i.e., 10 percent of the weight growth curve for a healthy 2-year-old girl) Those with a certain level of interest are permitted to participate in the study.

[0074] In clinical studies, approximately 5% of adult and pediatric participants who received abacavir (ABC) experienced hypersensitivity. Sexual reactions have been reported. The risk of such reactions occurring is related to human leukocyte antigen (HLA). -Because it is associated with the presence of the B*5701 allele, it limits the risk of hypersensitivity reactions. Therefore, participants without previously documented HLA-B*5701 negative results (for these participants) (Researchers consider ABC in the background regimen) H at screening The LA-B*5701 test should show a negative result. ABC-containing background residue If a switch to men is planned during the study, the eligibility to initiate ABC treatment will be determined. Therefore, an HLA-B*5701 test must be performed (based on past documented negative results). (Unless the fruit is available.)

[0075] Research intervention administration The combined use of multiple ARVs in HIV-1 infected participants is associated with a uniquely high H This is currently recommended due to the IV mutation rate. Therefore, all participants must, in addition to RPV, Patients are administered a background regimen selected by the researcher. ART treatment guidelines According to the instructions, susceptibility to selected ARVs is determined by historical HIV-1 genotype analysis. This is established at the time of screening using the results. Participants ≥6 years to <12 years old will be subject to this age The group participants, particularly in developing countries, have historical HIV-1 genotyping results. Because the possibility is limited and the disappearance of the HIV-1 mutation is expected, screening is performed. It is not required to have an available historical HIV-1 genotype test result.

[0076] Research assessment PK assessment will be performed at least 4 weeks after the study treatment. The blood sample collection scheme is as follows: Designed to accurately and completely describe the PK of RPV with the minimum number of blood samples recovered. Ta.

[0077] If a virological response is lost, RAM accumulation will be avoided, allowing for timely termination of the research. To achieve this, in addition to real-time plasma-based virus resistance testing, frequent plasma viral load testing is performed. Monitoring will be carried out. CD4 +The sample used to determine cell count is the plasma viral load sample. In addition, it will be taken.

[0078] Nonclinical studies showed changes in adrenal hormones. As a precautionary measure, clinical laboratory assessments were R To verify whether any clinically relevant adrenal or gonadal effects of PV are observed. This also includes endocrine assessments in participants aged ≥6 to <12 years.

[0079] In participants who received approved NNRTIs, a history of mental illness or substance abuse was observed, primarily among those with a history of mental illness or substance abuse. Delusions and inappropriate behavior were reported in participants with the condition. To assess the risk of depression in this population, as part of the local standard of care... An assessment will be conducted using a questionnaire or other means (available on-site). This will determine who is most skilled. Determine whether a complete mental health assessment by a mental health professional is necessary. Any clinically relevant changes that occur are reported as adverse events (AEs).

[0080] Medication adherence is essential for the success of all treatment regimens. Furthermore, in this study, R Suboptimal compliance with PV has an impact on the PK assessment of RPV. Furthermore, RPV Maintaining the status (i.e., essentially monotherapy) against background ARV regimens If compliance is insufficient, not only will the suppression of viral replication be incomplete, leading to treatment failure. This could potentially lead to the emergence of drug-resistant viruses. This is a concern in children. This is evidence that the problem occurs frequently. In a randomized controlled treatment study, caregivers were 30 children. % reported missing one or more doses of ARV in the past three days. The observations demonstrate the difficulty of maintaining a high level of compliance, and that cooperation with families is needed for compliance assessments and education. This study emphasizes the need to address the issue and supports essential elements of care. Medication adherence for background ARVs is assessed using the PENTA compliance questionnaire. Adherence to medication for RPV is also assessed by the number of tablets taken (reporting obligation for research interventions). If a participant's intake of RPV or background ARV is not in accordance with the protocol, The researchers will take the necessary steps to ensure compliance with the protocol in the future. take.

[0081] [Table 1]

[0082] [Table 2]

[0083] [Table 3]

[0084] [Table 4]

[0085] [Table 5]

[0086] background regimen N(t)RTI (for example, AZT, ABC, TAF in combination with FTC or 3TC) While TDF is one example, the ARV selected by the researcher is not limited to these, and may be specific. In that country, is it approved and sold for children ≥2 to <12 years old, or is it considered standard treatment in that country? Whichever of the above is done, joint production will be carried out in accordance with local availability and use within the country. It is administered as a drug or as individual components (for example, Combivir® or 3TC / AZT, Epzicom® / Kivexa®, or ABC / 3TC, Truvada®, or FTC / TDF). Integrase inhibitors. (For example, DTG or raltegravir) may also be administered in combination with RPV as needed. The two-part combination of DTG and RPV is currently the only approved drug for adults. However, protease inhibitors and ARVs that require PK boosters are base-level It is not permitted from the "n" onwards.

[0087] The selected background ARV is specified in the individual prescribing information or by age. It is used in doses for which sufficient background data on its use in the group is available. Applicable procedures and guidance based on this should be respected (e.g., administering a dose). (If this fails). Background ARV intake should be determined according to the local applicable procedures and accompanying instructions. As per the instructions, it is preferable to administer the RPV simultaneously with the ARV in a once-daily regimen. For ARV in a twice-daily regimen, one of the doses is preferably taken together with RPV. One dose is taken, and the other dose is taken according to the package insert. All ARVs are taken on the same day (sun It should start on day 1. Regarding the storage conditions for background ARVs, Please refer to the corresponding attached document.

[0088] Temporary discontinuation of all ARVs during the research intervention phase is permitted only if toxicity is suspected. .

[0089] For participants who cannot tolerate the selected background ARV, several predetermined toxins In contrast to the nature of the trademark, alternative ARVs (modified trademarks [i.e., provisionally approved by the US FDA]) [Generic drugs that are approved and / or have undergone pre-qualification review by the WHO] or that cannot be used In other cases, with the approval of the clinical trial sponsor, approval may be obtained from the local health authority or from the United Nations. Switching to generic drugs manufactured by international organizations is permitted.

[0090] Effectiveness assessment Blood to determine plasma HIV-1 RNA viral load for assessing antiviral activity Liquid sample and CD4 + To determine the cell count (percentage of absolute and total lymphocytes) Take a sample.

[0091] Plasma viral load levels were measured in the central laboratory using a standardized HIV-1 viral load assay. It is measured as the concentration of HIV-1 RNA in plasma. CD4 + Cell counting is performed in the central laboratory. It is measured by flow cytometry. The specimen preparation procedure is described in the laboratory manual. It is defined.

[0092] Plasma viral load or CD4 + Change from baseline in cell count (increase or decrease) (Either of the above) is not reported as (S)AE.

[0093] Safety assessment Safety and tolerability were evaluated throughout the entire study, from the signing of the ICF to the final research-related activity. It is worth.

[0094] Adverse events are reported and investigated by the researchers. Adverse events of interest are targeted to the group. These compatibility within the group, these known associations with other ARVs and / or RPVs This is based on the potential importance of these data demonstrated by nonclinical and clinical data. This includes endocrine events of interest, events that prolong the latent QTc interval of interest, and interest Examples include liver events of interest, neuropsychiatric events of interest, and skin events of interest.

[0095] Any clinically relevant changes that occur during the study should be recorded in the AE section of the CRF. Any clinically significant abnormalities remaining at the time of the final research visit will be addressed until they are resolved. This will be pursued by researchers until it reaches a clinically stable state.

[0096] Approximately 1 mL of venous blood sample is collected to measure the plasma concentration of RPV at a predetermined time. .

[0097] Analysis Procedure Plasma PK samples are prepared by the sponsor or the clinical trial sponsor to determine the concentration of RPV. Under the supervision of [name / organization], effective, specific, and highly accurate liquid chromatography (quality) The analysis is performed using quantitative analysis (mass spectrometry).

[0098] If necessary, use standard diagnostic methods to record the presence of blood metabolites by taking several blood samples. A serum sample can be analyzed.

[0099] Pharmacokinetic parameters and evaluation Based on individual plasma concentration-time data, the actual dose taken and the PK sample used Using the time interval, derive the following PK parameter for RPV: C 0h , C min , C ma x , C ss,av t max AUC24h CL / F, V ss / F and FI.

[0100] If necessary, other PK parameters may be inferred for data analysis.

[0101] For PK parameters, the definition and calculation method are as follows:

[0102] [Table 6]

[0103] Efficacy analysis Plasma viral load Outcome analysis (i.e., serum viral load <50 and <400 HIV-1 RNA copies / mL) The percentage of participants who meet certain criteria will be determined using a snapshot approach. The analysis was performed using plasma samples last observed within the visit window (i.e., weeks 24 and 48). Based on viral load data. Virological loss per snapshot approach. The proportion of participants with remission (i.e., HIV-1 RNA ≥ 50 and ≥ 400 copies / mL) Provided. Participants who switched ARVs due to tolerance issues not permitted by the protocol. This is considered a virological failure for this snapshot approach. The sum is expressed as a percentage of the Clopper-Pearson 95% CI at each point in time. ru.

[0104] Time-versus-event data (i.e., time to loss of virological response) is based on Kaplan-Meyer's research. —This is illustrated by a curve.

[0105] CD4 + cell counting The analysis is based on observed values ​​and attributed values ​​using NC=F, i.e., early in the study. The participants who discontinued their CD4s had their baseline values ​​substituted after the interruption. + Having cell counting ( (resulting in a change of 0), and having a substitution where the last observation for intermediate missing values ​​is carried over. ru.

[0106] Actual data and changes from the baseline are shown descriptively and graphically.

[0107] Safety analysis Adverse events / HIV-related events The verbatim term used by researchers in the CRF to identify AEs is Me dical Dictionary for Regulatory Activiti Encoded using es. Treatment-induced AEs (including HIV-related events) are administered via An AE that begins during admission or is a result of a pre-existing condition that has worsened from baseline. All reported adverse events (AEs) are included in the analysis. AEs / HIV-related events that occurred during each treatment are included. Regarding the event, the percentage of participants who experienced at least one occurrence of a given event is being studied. Aggregate data for each stage (i.e., screening stage, intervention stage, and follow-up). The data will be compiled separately for each severity level and the relationship with the research intervention, as needed.

[0108] Death, discontinuation of the study intervention due to adverse events (AEs), or grade 3 / 4 AEs, particularly of interest. Summary, listing, dataset, or participant information of participants who have experienced deep AE or SAE. Discourse may be provided as appropriate.

[0109] Clinical laboratory testing Laboratory data is summarized by type of laboratory test. Descriptive statistics are provided for each planned test. At the time of the observation, the observed values ​​for each laboratory analyte at baseline and This is calculated based on the change from the baseline. Descriptive statistics include the number of observations (n), mean, and standard deviation. Includes standard deviation (SD), median, minimum, and maximum values.

[0110] The frequency of change from baseline is aggregated using a pre-intervention vs. post-intervention crosstabulation (below the mean range). (Including classifications within the mean range and above the mean range). Regarding available tests, please refer to the laboratory. Anomalies are determined using the DAIDS grading table. The worst anomaly grade after baseline is Frequency summaries are generated. If necessary, for participants who experienced Grade 3 / 4 laboratory abnormalities. Frequency aggregation and listing are provided.

[0111] Endocrine assessment (cortisol, follicle-stimulating hormone [FSH], luteinizing hormone [LH]) androstenedione, testosterone and dehydroepiandrosterone sulfate Descriptive statistics are generated for the effective value and change from baseline of [DHEAS].

[0112] Endocrine assessment 60 minutes after ACTH stimulation (cortisol and 17-hydroxyprogesin) Descriptive statistics of the effective value and change from baseline of teron are shown. In addition, ACTH Cortisol levels before stimulation and 60 minutes after ACTH stimulation were <500 nmol / L (18. The percentage of participants with a 1 μg / dL level will be tallied.

[0113] electro-cardiogram Descriptive statistics for ECG values ​​and changes from baseline are summarized at their respective scheduled time points. The ECG parameters analyzed are heart rate, PR interval, QRS interval, RR interval, and Q The T interval, QTcB, and QTcF are used. Descriptive statistics include the number of observations (n), mean, standard deviation (SD), and median. This includes the minimum and maximum values. Anomaly frequency summaries are performed.

[0114] Vital signs Pulse rate and blood pressure (systolic and diastolic) (supine and standing) values, and baseline Descriptive statistics of the changes are summarized at each scheduled point in time. Descriptive statistics are based on the number of observations (n Includes mean, SD, median, minimum, and maximum values. Values ​​exceeding clinically significant limits. The percentage of participants with a value is summarized at each point in time.

[0115] Physical examination Physical examination findings for each body tissue are summarized at their respective scheduled times. Any abnormalities found during the inspection will be listed.

[0116] Growth is tracked regularly and continuously evaluated using standardized growth curves. Height, year-to-year Descriptive statistics for age-to-height ratio, weight, age-to-weight ratio, body mass index (BMI), and age-to-BMI ratio are as follows: The baseline and the observed values ​​and their changes from the baseline are as follows: The calculation is performed at the given time. Descriptive statistics include the number of observations (n), mean, standard deviation (SD), median, and minimum. and includes the maximum value.

[0117] The Tanner stages (for pubic hair and genitals / chest) are compared to the baseline for each age group. Loss is tallied. In addition, in girls, the occurrence of first menstruation during treatment is also compared to baseline. The data is then cross-tabulated, and the dates of menarche are listed.

Claims

1. A method for treating a child infected with the HIV virus, wherein the subject A non-nucleoside reverse transcriptase inhibitor, rilpivirine, administered once daily at a dose of 25 mg or less. pharmaceutically acceptable salts of an equal amount of rilpivirine This includes administering, The subjects mentioned above are those weighing 11 kg or more, who have experienced treatment, and whose first antibiotic treatment has been discontinued. He is being treated with a retroviral regimen. The subject is a drug that provides at least 24 weeks of rilpivirine or an equivalent amount of rilpivirine. After the aforementioned once-daily administration of a scientifically acceptable salt, the number of copies per 1 mL of plasma should be 50 or less (≤50). A method for indicating the viral load of HIV virus particles at c / mL.

2. The subject is administered a pharmaceutically acceptable salt of rilpivirine, as described in claim 1. Law.

3. Claim 1: The pharmaceutically acceptable salt of rilpivirine is rilpivirine hydrochloride. Or the method described in 2.

4. For the aforementioned pediatric subjects, dolutegravir, tenofovir, tenofovir disoproxil fumarate, Administer tenofovir alafenamide, emtricitabine, or a combination thereof. The method according to any one of claims 1 to 3.

5. The method according to any one of claims 1 to 4, wherein the pediatric subject is ≥2 to <12 years old.

6. The aforementioned child subject is a person having a weight of <25 kg as described in any one of claims 1 to 5. Law.

7. The aforementioned child subject is a person who has a weight of ≤70 kg as described in any one of claims 1 to 6. Law.

8. The aforementioned pediatric subjects are pharmaceutically acceptable to rilpivirine or an equivalent amount of rilpivirine. Before the once-daily administration of the salt, H₂O₃₀ The method according to any one of claims 1 to 7, which indicates the amount of virus in IV virus particles.

9. The method according to any one of claims 1 to 8, wherein the HIV virus is HIV-1. 。

10. The aforementioned non-nucleoside reverse transcriptase inhibitors, such as rilpivirine, in doses of 25 mg or less, or the aforementioned etc. The amount of the pharmaceutically acceptable salt of rilpivirine is administered as a single-dose dosage form, claim The method described in any one of items 1 to 9.

11. The aforementioned non-nucleoside reverse transcriptase inhibitors, such as rilpivirine, in doses of 25 mg or less, or the aforementioned etc. The amount of the pharmaceutically acceptable salt of rilpivirine is administered in multiple single-dose dosage forms. The method according to any one of claims 1 to 9.

12. The subject is the rilpivirine or the rilpivirine pharmaceutically After once-daily administration of an acceptable salt, the number of copies per mL of plasma should be less than 50 (≤50 c / mL). The viral load of HIV-1 virus particles as described in any one of claims 1 to 11. The method.

13. Rilpivirine or It is a pharmaceutically acceptable salt of rilpivirine, a non-nucleoside reverse transcriptase inhibitor. The method described above applies to the target, The non-nucleoside reverse transcriptase inhibitor, rilpivirine, administered once daily at a dose of 25 mg or less. or an equivalent amount of a pharmaceutically acceptable salt of rilpivirine. This includes administering, The subjects mentioned above are those weighing 11 kg or more, who have experienced treatment, and whose first antibiotic treatment has been discontinued. He is being treated with a retroviral regimen. The subject is a drug that provides at least 24 weeks of rilpivirine or an equivalent amount of rilpivirine. After the aforementioned once-daily administration of a scientifically acceptable salt, the number of copies per 1 mL of plasma should be 50 or less (≤50). The viral load of HIV virus particles (c / mL) is shown by a non-nucleoside reverse transcriptase inhibitor. 。

14. The subject is administered a pharmaceutically acceptable salt of rilpivirine, as described in claim 13. Rilpivirine or pharmaceutically acceptable salts of rilpivirine for use, non-nucleosy Reverse transcriptase inhibitor.

15. Claim 1: The pharmaceutically acceptable salt of rilpivirine is rilpivirine hydrochloride. Rilpivirine or pharmaceutically acceptable salts of rilpivirine for use as described in 3 or 14. It is a non-nucleoside reverse transcriptase inhibitor.

16. The above method involves administering dolutegravir, tenofovir, and tenofovir disoproxy to the pediatric subjects. Rufumarate, tenofovir alafenamide, emtricitabine, or a combination thereof The use of rilpi according to any one of claims 13 to 15, further comprising administering Non-nucleoside reverse transcriptase inhibitors that are pharmaceutically acceptable salts of biline or rilpivirine. 。

17. The aforementioned child subject is ≥2 to <12 years old, and the use according to any one of claims 13 to 16. Rilpivirine or pharmaceutically acceptable salts of rilpivirine, non-nucleosides, for use. Reverse transcriptase inhibitor.

18. The aforementioned child subject has a weight of <25 kg, as described in any one of claims 13 to 17. Rilpivirine or a pharmaceutically acceptable salt of rilpivirine for use as a non-nucleo Sid reverse transcriptase inhibitor.

19. The aforementioned child subject has a weight of ≤70 kg, as described in any one of claims 13 to 18. Rilpivirine or a pharmaceutically acceptable salt of rilpivirine for use as a non-nucleo Sid reverse transcriptase inhibitor.

20. The aforementioned pediatric subjects are pharmaceutically acceptable to rilpivirine or an equivalent amount of rilpivirine. Before the once-daily administration of the salt, H₂O₃₀ The use according to any one of claims 13 to 19, which indicates the viral load of IV virus particles. Non-nucleoside inversion, which is rilpivirine or a pharmaceutically acceptable salt of rilpivirine. Enzyme inhibitor.

21. The HIV virus is HIV-1, as described in any one of claims 13 to 20. Rilpivirine or pharmaceutically acceptable salts of rilpivirine for use, non-nucleosy Reverse transcriptase inhibitor.

22. The aforementioned non-nucleoside reverse transcriptase inhibitor or pre- The equivalent amount of a pharmaceutically acceptable salt of rilpivirine is administered as a single-dose dosage form. Rilpivirine or rilpivirine for use according to any one of claims 13 to 21 A pharmaceutically acceptable salt of a non-nucleoside reverse transcriptase inhibitor.

23. The aforementioned non-nucleoside reverse transcriptase inhibitors, such as rilpivirine, in doses of 25 mg or less, or the aforementioned etc. The amount of the pharmaceutically acceptable salt of rilpivirine is administered in multiple single-dose dosage forms. or rilpivirine or rilpivirine for use according to any one of claims 13 to 21 A pharmaceutically acceptable salt of non-nucleoside reverse transcriptase inhibitor.

24. The subject is the rilpivirine or the rilpivirine pharmaceutically After once-daily administration of an acceptable salt, the number of copies per mL of plasma should be less than 50 (≤50 c / mL). The viral load of HIV-1 virus particles as described in any one of claims 13 to 23. Rilpivirine or a pharmaceutically acceptable salt of rilpivirine for use as described above is a non-nucleate. Oside reverse transcriptase inhibitor.

25. Dolutegravir for use in treating children infected with the HIV virus. Tenofovir, Tenofovir disoproxil fumarate, Tenofovir alafenamide, M Tricitabine or a combination thereof, wherein the method applies to the subject, The aforementioned dolutegravir, tenofovir, tenofovir disoproxil fumarate, tenofovir Rafenamid, emtricitabine, or a combination thereof, A non-nucleoside reverse transcriptase inhibitor, rilpivirine, administered once daily at a dose of 25 mg or less. Equivalent amounts of pharmaceutically acceptable salts of rilpivirine and This includes administering, The subjects mentioned above are those weighing 11 kg or more, who have experienced treatment, and whose first antibiotic treatment has been discontinued. He is being treated with a retroviral regimen. The subject is a drug that provides at least 24 weeks of rilpivirine or an equivalent amount of rilpivirine. After the aforementioned once-daily administration of a scientifically acceptable salt, the number of copies per 1 mL of plasma should be 50 or less (≤50). The viral load of HIV virus particles (c / mL) is shown for dolutegravir, tenofovir, and te Nofovir disoproxil fumarate, tenofovir alafenamide, emtricitabine or These combinations.

26. A claim further comprising the features described in any one or more of claims 14, 15, or 17-24. Dolutegravir, tenofovir, tenofovir disoproxil fuma for use as described in 25 Alofovir salt, tenofovir alafenamide, emtricitabine, or a combination thereof.

27. Rilpiviri for the manufacture of drugs to treat children infected with the HIV virus The use of non-nucleoside reverse transcriptase inhibitors, which are pharmaceutically acceptable salts of rilpivirine or rilpivirine. For use, the drug is used on the subject, The non-nucleoside reverse transcriptase inhibitor, rilpivirine, administered once daily at a dose of 25 mg or less. or an equivalent amount of a pharmaceutically acceptable salt of rilpivirine. Prepared for administration, The subjects mentioned above are those weighing 11 kg or more, who have experienced treatment, and whose first antibiotic treatment has been discontinued. He is being treated with a retroviral regimen. The subjects in question received the drug once daily for at least 24 weeks, and then 5 per 1 mL of plasma. This indicates the viral load of HIV virus particles with 0 copies or less (≤50 c / mL).

28. Dolutegra for the manufacture of drugs to treat children infected with the HIV virus. Tenofovir, Tenofovir disoproxil fumarate, Tenofovir alafenamide, The use of emtricitabine or a combination thereof, wherein the drug is used on the subject, A non-nucleoside reverse transcriptase inhibitor, rilpivirine, administered once daily at a dose of 25 mg or less. pharmaceutically acceptable salts of an equal amount of rilpivirine Prepared for administration, The subjects mentioned above are those weighing 11 kg or more, who have experienced treatment, and whose first antibiotic treatment has been discontinued. He is being treated with a retroviral regimen. The subject is a drug that provides at least 24 weeks of rilpivirine or an equivalent amount of rilpivirine. After the aforementioned once-daily administration of a scientifically acceptable salt, the number of copies per 1 mL of plasma should be 50 or less (≤50). This indicates the viral load of HIV virus particles (c / mL) and is used for reference.

29. A claim further comprising the features described in any one or more of claims 14, 15, or 17-24. Use as described in 27 or 28.

30. Simultaneous, individual, or sequential use in the treatment of children infected with the HIV virus. As a combination preparation for that purpose, Non-nucleoside reverse transcriptases that are rilpivirine or pharmaceutically acceptable salts of rilpivirine. Inhibitors, Dolutegravir, Tenofovir, Tenofovir disoproxil fumarate, Tenofovir alaf Enamide, emtricitabine, or a combination thereof A product containing the above-mentioned treatment, and the above-mentioned treatment is performed on the above-mentioned subject, The non-nucleoside reverse transcriptase inhibitor, rilpivirine, administered once daily at a dose of 25 mg or less. or an equivalent amount of a pharmaceutically acceptable salt of rilpivirine. This includes administering, The subjects mentioned above are those weighing 11 kg or more, who have experienced treatment, and whose first antibiotic treatment has been discontinued. He is being treated with a retroviral regimen. The subject is a drug that provides at least 24 weeks of rilpivirine or an equivalent amount of rilpivirine. After the aforementioned once-daily administration of a scientifically acceptable salt, the number of copies per 1 mL of plasma should be 50 or less (≤50). A product indicating the viral load of HIV virus particles (c / mL).

31. A claim further comprising the features described in any one or more of claims 14, 15, or 17-24. The product described in item 30.

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