Natella Rakhmanina

Efavirenz in the therapy of HIV infection.

Importance of the field: The use of the first generation non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) as a component of first-line antiretroviral therapy has been accepted worldwide. EFV is the only antiretroviral agent currently on the market that has been combined with emtricitabine and tenofovir disoproxil fumarate in a single tablet and administered once daily. Areas covered in this review: This article reviews efficacy and safety data on EFV and the role of pharmacogenetics in EFV exposure. Published articles and conference presentations on EFV are reviewed. What the reader will gain: CYP2B6 genetic polymorphisms influence the metabolism of EFV. The CYP2B6 G to T polymorphism at position 516 is shown to be associated with elevated plasma concentrations and an increase in neurotoxicity of EFV, while the wild-type genotype has been associated with sub-therapeutic concentrations of EFV, potentially leading to the development of viral resistance. This polymorphism is significantly higher in sub-Saharan Africans and African Americans as compared to Hispanic, European and Asian populations. Take home message: The significance of CYP2B6 polymorphism in EFV exposure indicates the need for prospective clinical studies to evaluate the utility of genotype-driven dose adjustments in populations of diverse descent.

Therapeutic drug monitoring in children with HIV/AIDS.

In this paper we present an overview on the use of TDM in the treatment of HIV-1-infected children. The processes of growth and development have a significant impact on drug metabolism. The use of TDM makes it possible to optimize plasma drug concentrations of antiretroviral drugs. This is important when one considers that the levels of viral suppression and drug toxicity in adults and children are associated with the plasma concentration of PIs and NNRTIs. Indeed, in clinical practice the use of TDM in the treatment of HIV-1-infected children has favorable results. However, there is a serious shortage of population reference values of antiretroviral medication in children. Targeting plasma drug levels in children to adult reference values may be insufficient because of the unique features of HIV infection in children. Apart from its primary function for dose optimization, TDM can also be used as a tool to assess adherence to antiviral medication. One should, however, be cautious to base assumptions on plasma levels alone because aberrant plasma levels may also be the result of other factors such as changes in nutritional habits, drug-drug interactions, or changing gastric motility. We conclude that TDM is a useful tool in the treatment of HIV-1-infected children. Additional data are needed to establish child-specific reference values and to assess the optimal method of TDM.

Evaluating Adherence to Medication in Children and Adolescents with HIV

Objective: The study was aimed to evaluate the relationship between pharmacy supply, self-reported treatment adherence and HIV viral load in HIV-infected children. Methods: A retrospective (52 weeks) cohort study was conducted through the review of the existing databases. Pharmacy supply was classified as “home delivery” when the medications were delivered home and as “in pharmacy pick-up” when they were picked up at the pharmacy. Adherence was assessed through retrospective (3 days recall) self-report. Fisher’s exact model, univariate and multivariate logistic regression analyses were used. Settings: The study collected data on 140 HIV-infected children (<18 years). Adherence, pharmacy supply information and HIV viral loads were obtained from clinical and research databases. Patients: The data from 127 HIV-infected children (60 boys and 67 girls; mean age 9.9 years) were collected. Main Outcome Measures: Complete adherence (100%) was reported in only 24% of patients. With 40% of patients being rarely or never completely adherent, 64% of children achieved undetectable viral loads during the study period. Results: No association between pharmacy supply and self-reported adherence was found (p = 0.605). Self-reported adherence (p = 0.0328) and age (p = 0.025) were the significant predictors of reaching undetectable viral loads. Adolescents (>13 years) were significantly less likely to reach undetectable viral loads than children under 13 years (odds ratio 0.38; 95% CI 0.16 to 0.89). Conclusion: In our study, pharmacy supply was not associated with self-reported adherence. Most importantly, adherence and age were significant predictors of reaching undetectable viral loads.

Pharmacokinetics of Lopinavir/Ritonavir Crushed versus Whole Tablets in Children

ObjectiveLopinavir/ritonavir (Kaletra) is first-line therapy for pediatric HIV infection. In clinical practice, Kaletra tablets are occasionally crushed for pediatric administration. This study compared lopinavir/ritonavir exposure between whole and crushed tablets in HIV-infected children. DesignThis was a randomized, open-label, cross-over study of pediatric patients taking lopinavir/ritonavir as part of their antiretroviral regimen. Each subject had 2 separate (within 30 days) steady-state 12-hour pharmacokinetic (PK) studies with crushed and whole 200/50 mg lopinavir/ritonavir tablets. MethodsPK blood samples were drawn at 0 (predose), 1, 2, 4, 6, 8, and 12 hours postdose. Lopinavir and ritonavir plasma concentrations measured by high-performance liquid chromatography were used to calculate non-compartmental area under the concentration versus time curve (AUC) and clearance. Wilcoxon signed-rank tests compared PK values between crushed and whole tablets. ResultsTwelve children, median age of 13 years (10–16 years), took 550/138 mg·m−2 per day lopinavir/ritonavir divided every 12 hours. The median lopinavir AUC after crushed and whole tablets were 92 mg·hr·L−1 and 144 mg·hr·L−1, respectively, with an AUC ratio of 0.55 (P = 0.003). Median ritonavir AUC of crushed and whole tablets were 7 mg·hr·L−1 and 13.3 mg·hr·L−1, respectively, with an AUC ratio of 0.53 (P = 0.006). ConclusionsAdministration of crushed 200/50 mg lopinavir/ritonavir tablets to children significantly reduced lopinavir and ritonavir exposure with a decrease in AUC by 45% and 47%, respectively. The administration of crushed tablets would require higher doses and therapeutic drug monitoring to ensure adequate lopinavir exposure in patients requiring this practice. The use of crushed lopinavir/ritonavir tablets should be avoided, if possible.

Pharmacokinetic Optimization of Antiretroviral Therapy in Children and Adolescents

There are over 2.1 million HIV-infected children worldwide, who are increasingly exposed to antiretroviral therapy. Given the enormous physiological changes associated with maturation, the role of individualized therapy and optimal dosing in children and adolescents is likely different than in adults. This review summarizes the pharmacodynamics, pharmacokinetics and pharmacogenomics of antiretroviral therapy in children and adolescents, and it discusses the roles of these in the optimization of therapy through the practice of therapeutic drug monitoring/management. Within the pharmacodynamics section are tables and discussion about what is known of the relationships between drug concentrations, inhibitory quotients and effects — both desired and toxic. The pharmacokinetics section summarizes all reported antiretroviral pharmacokinetic data in children, divided into data from population and non-population analytic approaches. Measures of interindividual pharmacokinetic variability are reported. Sampling strategies for the measurement and the interpretation of plasma antiretroviral drug concentrations are suggested, as well as dosing with degrees of renal or hepatic failure. Relevant pharmacogenomic polymorphisms are summarized, and the role for pharmacogenomics testing is discussed. Incorporation of dose adjustment on the basis of measured serum drug concentrations is reviewed, including all such paediatric experience reported in the literature. Discussion of the influences of malnutrition and herbal remedies is also included. Finally, consideration is given to future work in this field.

Age-dependent Pharmacokinetics of Lamivudine in HIV-infected Children

The recommended dose of lamivudine in children is higher when compared with adults: 4 mg/kg vs ~2 mg/kg (150 mg) and administered twice a day. Limited data are available to demonstrate that this increased dose results in adequate exposure to lamivudine in children with human immunodeficiency virus (HIV) infection. Data were selected from children who were using lamivudine for at least 2 weeks before a full pharmacokinetic (PK) study was conducted. Lamivudine PK parameters were significantly related to age. The age of 6 years appeared to be a cutoff for a change in PK parameters of lamivudine, with children <6 years of age (n=17) having a median area under the curve 43% lower and a median peak plasma concentration 47% lower (both P<0.001) than older children (n=34). In conclusion, further investigation of the relationship between decreased lamivudine exposure and treatment outcome and long‐term resistance development in younger children with HIV infection is warranted.

Population Pharmacokinetics of Lopinavir Predict Suboptimal Therapeutic Concentrations in Treatment-Experienced Human Immunodeficiency Virus-Infected Children

ABSTRACT In adult protease inhibitor (PI)-experienced patients, a lopinavir (LPV) phenotypic inhibitory quotient (PIQ) of >15 has been associated with a higher likelihood of viral suppression. The aims of this study were to develop a population pharmacokinetic (PK) model of LPV in children and to estimate the probability of achieving a PIQ of >15. HIV-infected, PI-experienced children receiving LPV were intensively sampled for 12 h to measure plasma LPV. The data were fitted to candidate PK models (using MM-USCPACK software), and the final model was used to simulate 1,000 children to determine the probability of achieving an LPV PIQ of >15. In 50 patients (4 to 18 years old), the median LPV plasma 12-hour-postdose concentration was 5.9 mg/liter (range, 0.03 to 16.2 mg/liter) lower than that reported in adults. After a delay, LPV was absorbed linearly into a central compartment whose size was dependent on the weight and age of the patient. Elimination was dependent on weight. The regression line of observed versus predicted LPV had an R2 of 0.99 and a slope of 1.0. Visual predictive checks against all available measured concentrations showed good predictive ability of the model. The probability of achieving an LPV PIQ of >15 was >90% for wild-type virus but <10% for even moderately resistant virus. The currently recommended dose of LPV/ritonavir appears to be adequate for children infected with wild-type virus but is unlikely to provide adequate inhibitory concentrations for even moderately resistant human immunodeficiency virus (HIV). PI-experienced HIV-infected children will likely benefit from longitudinal, repeated LPV measurement in plasma to ensure that drug exposure is most often near the maximal end of the observed safe range.

Disparities in achieving and sustaining viral suppression among a large cohort of HIV-infected persons in care – Washington, DC*

ABSTRACT One goal of the HIV care continuum is achieving viral suppression (VS), yet disparities in suppression exist among subpopulations of HIV-infected persons. We sought to identify disparities in both the ability to achieve and sustain VS among an urban cohort of HIV-infected persons in care. Data from HIV-infected persons enrolled at the 13 DC Cohort study clinical sites between January 2011 and June 2014 were analyzed. Univariate and multivariate logistic regression were conducted to identify factors associated with achieving VS (viral load < 200 copies/ml) at least once, and Kaplan–Meier (KM) curves and Cox proportional hazards models were used to identify factors associated with sustaining VS and time to virologic failure (VL ≥ 200 copies/ml after achievement of VS). Among the 4311 participants, 95.4% were either virally suppressed at study enrollment or able to achieve VS during the follow-up period. In multivariate analyses, achieving VS was significantly associated with age (aOR: 1.04; 95%CI: 1.03–1.06 per five-year increase) and having a higher CD4 (aOR: 1.05, 95% CI 1.04–1.06 per 100 cells/mm3). Patients infected through perinatal transmission were less likely to achieve VS compared to MSM patients (aOR: 0.63, 95% CI 0.51–0.79). Once achieved, most participants (74.4%) sustained VS during follow-up. Blacks and perinatally infected persons were less likely to have sustained VS in KM survival analysis (log rank chi-square p ≤ .001 for both) compared to other races and risk groups. Earlier time to failure was observed among females, Blacks, publically insured, perinatally infected, those with longer standing HIV infection, and those with diagnoses of mental health issues or depression. Among this HIV-infected cohort, most people achieved and maintained VS; however, disparities exist with regard to patient age, race, HIV transmission risk, and co-morbid conditions. Identifying populations with disparate outcomes allows for appropriate targeting of resources to improve outcomes along the care continuum.

A urinary biomarker profile for children with HIV-associated renal diseases.

Human immunodeficiency virus (HIV)-infected children are at risk of developing several types of renal diseases, including HIV-associated nephropathy (HIVAN), which is usually seen during late stages of infection in children with a high viral load. This disease is defined by the presence of proteinuria associated with mesangial hyperplasia and/or global-focal segmental glomerulosclerosis combined with microcystic transformation of the renal tubules. Because HIVAN can have an insidious clinical onset, renal biopsy is the only definitive way of establishing a diagnosis. Given the risk of performing this procedure in HIV-infected children with other AIDS-defining illness, we sought to identify informative biomarkers such as growth factors in the urine of 55 HIV-infected children that might be predictive of the extent and activity of the renal lesions characteristic of HIVAN. We found that the levels of epidermal growth factor were lower in the urine of children with renal disease, whereas levels of fibroblast growth factor-2 and metalloproteinase-2 were higher as compared with those levels in infected children without renal disease. Similar changes were observed in HIV-Tg26 mice correlating with the progression of renal disease in this model of HIVAN. Our findings suggest that this urinary growth factor profile may be useful in facilitating the diagnosis of HIV-infected children at risk of developing HIVAN when interpreted in the appropriate clinical setting.

Nevirapine concentration in nonstimulated saliva: an alternative to plasma sampling in children with human immunodeficiency virus infection.

Background: The monitoring of nevirapine (NVP) concentrations in pediatric patients has gained interest since the introduction of NVP as part of the preferred first-line antiretroviral regimen for human immunodeficiency virus (HIV)-infected children in resource-limited settings. Adequate trough concentrations of NVP predict successful therapy, whereas subtherapeutic levels are correlated with virologic failure and development of resistance. The aim of this study was to determine the extent of agreement between total and free plasma NVP concentrations and nonstimulated saliva NVP concentrations and to evaluate the feasibility of saliva sampling as an alternative tool for therapeutic drug monitoring of NVP in children. Design and Methods: The study was designed as an observational cohort analysis. NVP concentrations were obtained in paired plasma and saliva samples of pediatric patients receiving antiretroviral therapy, including NVP. NVP plasma and saliva concentrations were determined by a tandem-mass spectrometric method. The intraclass correlation coefficient and Bland-Altman analysis were used to evaluate agreement and to assess pattern in any discrepancies between measurements. Results: For the random paired plasma and saliva NVP sampling, 19 African-American children (8 boys, 11 girls) with a median age of 8.0 years were enrolled. Two male subjects were recruited for the 12 hour NVP plasma and saliva pharmacokinetics study. The intraclass correlations between saliva and serum measurements of NVP concentrations indicated >90% agreement between these two modes of measurement. The saliva concentrations reflected the free concentrations very closely but were on average 34% higher. The Bland-Altman plots indicated that the discrepancy between saliva and plasma measures is consistent across the range of average NVP concentrations. Conclusions: Our study results strongly indicate agreement between saliva and plasma NVP concentrations in pediatric patients with HIV infection, on the basis of Bland-Altman analysis. Nonstimulated NVP saliva concentrations can be used as an alternative noninvasive, reliable, cost-effective method for direct measurement of adherence and application of therapeutic drug monitoring in NVP therapy.