The role of pharmacogenetics in Efficacy and safety of protease inhibitor based therapy in human immunodeficiency virus type (HIV) infection.

Antiretroviral therapy has markedly reduced morbidity and mortality for persons living with human immunodeficiency virus (HIV). HIV can now be classified as a chronic disease; until a cure is found, patients are likely to require life-long therapy. However, despite these undoubted advances, there are many issues that need to be resolved, including the problems associated with long-term efficacy and toxicity. Moreover, pharmacotherapy of patients infected with HIV is challenging because a great number of comorbidities increase polypharmacy and the risk for drug-drug interactions. There is considerable interindividual variability in patient outcomes in terms of drug disposition, drug efficacy and adverse events. The basis of these differences is multifactorial, but host genetics are believed to play a significant part. HIV-infected population consists of ethnically diverse individuals on complex and potentially toxic antiretroviral regimens on a long-term basis. These individuals would benefit greatly from predictive tests that identify the most durable regimens. Pharmacogenetics holds that promise. Thus, detailed understanding of the metabolism and transport of antiretrovirals and the influence of genetics on these pathways is important. To this end, this review provides an up-to-date overview of the metabolism of antiHIV therapeutics of the protease inhibitors Lopinavir and Ritonavir and the impact of genetic variation in drug metabolism and transport on the treatment of HIV

Comorbid disease in children and adolescents with perinatal HIV infection: A pilot study

Background. With the increased use of combination antiretroviral therapy, the mortality of people living with HIV has decreased significantly, which has led to an increase of comorbidity and secondary HIV-related pathology in both adults and also in children and adolescents living with HIV infection. The incidence of children and adolescents with HIV infection and those in the general population varies significantly.The aim. To assess the frequency and range of chronic comorbidities in children and adolescents with perinatal HIV infection Methods. We carried out an observational study. Data on the incidence of 161 children with perinatal HIV infection registered in the Irkutsk Regional AIDS Center were copied.Results. Overall incidence of tuberculosis (18633.5 per 100 000 children), diseases of the digestive system (24844.7 per 100 000 children), diseases of the eye and adnexa (28571.4 per 100 000 children), diseases of the nervous system (18012.4 per 100 000 children), mental and behavioral disorders (13,664.6 per 100 000 children) in children with perinatal HIV infection is the higher than in children of comparable age. The overall incidence values of the endocrine system diseases, eating and metabolic disorders, diseases of the ear and mastoid process, diseases of the circulatory system, diseases of the genitourinary system, as well as congenital disorders and chromosomal disorders in children and adolescents with and without perinatal HIV infection are comparable.Conclusion. The prevalence of diseases of the circulatory, respiratory and genitourinary systems in children with perinatal HIV infection is comparable to that in the corresponding population. Prevalence of tuberculosis, anemia, diseases of the gastrointestinal tract, diseases of the eye and adnexa, diseases of the nervous system, mental and behavioral disorders is higher compared to children not exposed to HIV

Some pharmacogenetic aspects of the <i>ABCB1</i> gene in lopinavir / ritonavir concentration variability in children with HIV infection: A pilot study

Polymorphic variants of the multidrug resistance gene (ABCB1 or MDR1) are associated with changes in the absorption and transport of drugs in the body. One of the substrates of the ABCB1 transporter is an antiretroviral drug from the class of protease inhibitors, lopinavir.   The aim. To research the effect of polymorphic variants C1236T and C3435T in the ABCB1 gene on the plasma concentration of lopinavir / ritonavir in children and adolescents living with HIV infection.   Methods. The genotypes of polymorphic variants of the ABCB1 gene were identified in 136 HIV infected children and adolescents; median age – 10 [7–12] years. The plasma concentration of lopinavir / ritonavir was measured from blood taken during the next scheduled appointment as part of dispensary observation at the Irkutsk Regional AIDS Centre using high performance liquid chromatography.   Results. The average duration of lopinavir/ritonavir use as part of an antiretroviral therapy was 55 months. Median viral load in patients was 1 [1–2.03] log 10  copies/ mL; the number of CD4 +  T cells – 38.36 %. The frequency of occurrence of the 3435T and 1236T alleles of the ABCB1 gene was ~50 %. In carriers of the 3435TT genotype, the median lopinavir concentrations 2 and 12 hours after drug intake were 5050.8 [3615.8–5847.7] and 2665.5 [216–4896.3] ng/mL, respectively. In carriers of the 1236TT genotype, median lopinavir concentrations 2 and 12 hours after drug intake were 4913.5 [3355.1–5733.7] and 3290.6 [159.1–4972.5] ng/mL, respectively.   Conclusions. The study did not reveal a significant relationship between the carriage of the C3435T and C1236T genotypes of the ABCB1 gene and the concentrations of lopinavir and ritonavir 2 and 12 hours after drug intake

Вирусологическая неэффективность антиретровирусной терапии и связанные с ней социальные и клинические факторы у детей и подростков, живущих с ВИЧ-инфекцией

   According to the World Health Organization, sustained virological suppression of 90 % should be achieved among children and adolescents living with HIV / AIDS, which makes it important to assess the prevalence of virological failure of antiretroviral therapy.   The aim of this study was to determine the prevalence of virological failure and the clinical factors associated with it, as well as therapeutic drug monitoring in groups divided by the viral load level among children and adolescents with HIV.   Materials and Methods: A retrospective analysis of the medical records of 184 children and adolescents receiving antiretroviral therapy and registered at the Irkutsk Regional Center for the Prevention and Control of AIDS and Infectious Diseases, Irkutsk, was carried out. The study included 172 children aged 1-18 years with perinatal HIV infection. Patients were divided into groups depending on the level of viral load: group 1 – 21 patients with viral load &gt; 1000 copies/ml of plasma, group 2 – 42 patients with viral load 50– 1000 copies/ml of plasma, group 3 – 109 patients with undetectable viral load (&lt; 50 copies/ml). All patients underwent standard tests in accordance with clinical guidelines for the treatment of HIV infection in children, as well as therapeutic drug monitoring.   Results. Against the background of ongoing antiretroviral therapy, a significant number of patients 21 / 172 (12,2 %) experienced virological failure. The proportion of children and adolescents with incomplete suppression of HIV replication is 42 / 172 (24,4 %). Statistically significant differences were obtained by changing the ART regimen (p = 0,031). In the first group, the proportion of patients who changed the therapy regimen is 7 / 21 (33,3 %), which is two times less than in the group with a zero viral load of 70 / 109 (64,2 %). There are differences in the proportion of children and adolescents with zero concentrations of ritonavir and lopinavir (p = 0,020 and p = 0,012) in the three compared groups. The distribution of patients with zero concentrations was as follows: for ritonavir in the first group 3 / 17 (17,6 %), in the second – 8/37 (21,6 %), in the third group – 4/80 (5 %); for lopinavir – 4/17 (23,5 %), 6/36 (16,7 %), 3/80 (3,8 %), respectively.   Conclusion. This study demonstrates that the prevalence of virological failure among children and adolescents receiving ART remains high. To achieve sustained virological suppression in children and adolescents taking a protease inhibitor regimen, adherence to therapy must be increased. As one of the methods for assessing adherence, therapeutic drug monitoring can be used.   Согласно целям Всемирной организации здравоохранения, среди детей и подростков, живущих с ВИЧ / СПИДом, необходимо достичь 90 % устойчивого вирусологического подавления, что определяет важность оценки распространенности вирусологической неэффективности антиретровирусной терапии.   Цель: определение распространенности вирусологической неэффективности и оценка социальных и клинических факторов, определяющих ее. Среди детей и подростков с разным уровнем вирусной нагрузки ВИЧ провести и оценить терапевтический лекарственный мониторинг.   Материалы и методы: проведен ретроспективный анализ медицинских карт 172 детей и подростков с перинатальной ВИЧ-инфекцией в возрасте от 1 до 18 лет, получающих антиретровирусную терапию и находящихся на диспансерном учете в Иркутском областном центре по профилактике и борьбе со СПИД и инфекционными заболеваниями г. Иркутска. Пациенты разделены на группы в зависимости от уровня вирусной нагрузки: 1 группа – 21 пациент с вирусной нагрузкой (&gt; 1000 копий/мл плазмы); 2 группа – 42 пациента с вирусной нагрузкой (≤ 50 ≥ 1000 копий/мл плазмы); 3 группа – 109 пациентов с неопределяемым уровнем вирусной нагрузки (&lt; 50 копий / мл). Всем пациентам проводились стандартные исследования согласно клиническим рекомендациям по лечению ВИЧ-инфекции у детей, а также терапевтический лекарственный мониторинг.   Результаты: на фоне проводимой антиретровирусной терапии у 63,4 %(109 / 172) детей и подростков вирусная нагрузка ВИЧ имела неопределяемые значения в плазме крови. Вместе с тем, у значительного количества пациентов (36,6 %) наблюдалась вирусологическая неэффективность, причем у 21 / 172 (12,2 %) вирусная нагрузка ВИЧ была выше 1000 копий на мл плазмы крови. Статически значимые различия получены между пациентами, у которых в анамнезе были изменения схем терапии, и теми, у кого схема АРТ не изменялась (p = 0,031). В первой группе пациентов, не достигших вирусологической эффективности, доля детей и подростков, имевших в анамнезе изменение схемы терапии, составляет 7 / 21 (33,3 %), что в 2 раза меньше, чем в группе пациентов с неопределяемой вирусной нагрузкой 70 / 109 (64,2 %). Выявлены статистически значимые различия среди детей и подростков с нулевыми концентрациями ритонавира и лопинавира (p = 0,020 и p = 0,012) в 3 сравниваемых группах. Распределение пациентов с нулевыми концентрациями было следующим: по ритонавиру в 1 группе – 3 / 17 (17,6 %), во 2 группе – 8 / 37 (21,6 %), в 3 группе – 4 / 80 (5 %); по лопинавиру – 4 / 17 (23,5 %), 6 / 36 (16,7 %), 3 / 80 (3,8 %) соответственно.   Заключение. Проведенное исследование демонстрирует, что распространенность вирусологической неэффективности среди детей и подростков, получающих антиретровирусную терапию, остается высокой. Для достижения устойчивого вирусологического подавления у детей и подростков, принимающих схему на основе ингибиторов протеазы, необходимо повышать приверженность к терапии. Как один из объективных методов оценки приверженности можно использовать терапевтический лекарственный мониторинг