No abstract

The primary objective of this study was to measure atazanavir-ritonavir and tenofovir pharmacokinetics when the drugs were used in combination in young adults with human immunodeficiency virus (HIV). HIV-infected subjects >18 to <25 years old receiving (>28 days) 300/100 mg atazanavir-ritonavir plus 300 mg tenofovir disoproxil fumarate (TDF) plus one or more other nucleoside analogs underwent intensive 24-h pharmacokinetic studies following a light meal. Peripheral blood mononuclear cells were obtained at 1, 4, and 24 h postdose for quantification of intracellular tenofovir diphosphate (TFV-DP) concentrations. Twenty-two subjects were eligible for analyses. The geometric mean (95% confidence interval [CI]) atazanavir area under the concentration-time curve from 0 to 24 h (AUC 0-24 ), maximum concentration of drug in serum (C max ), concentration at 24 h postdose (C 24 ), and total apparent oral clearance (CL/F) values were 35,971 ng ⅐ hr/ml (30,853 to 41,898), 3,504 ng/ml (2,978 to 4,105), 578 ng/ml (474 to 704), and 8.3 liter/hr (7.2 to 9.7), respectively. The geometric mean (95% CI) tenofovir AUC 0-24 , C max , C 24 , and CL/F values were 2,762 ng ⅐ hr/ml (2,392 to 3,041), 254 ng/ml (221 to 292), 60 ng/ml (52 to 68), and 49.2 liter/hr (43.8 to 55.3), respectively. Body weight was significantly predictive of CL/F for all three drugs. For every 10-kg increase in weight, there was a 10%, 14.8%, and 6.8% increase in the atazanavir, ritonavir, and tenofovir CL/F, respectively (P < 0.01). Renal function was predictive of tenofovir CL/F. For every 10 ml/min increase in creatinine clearance, there was a 4.6% increase in tenofovir CL/F (P < 0.0001). The geometric mean (95% CI) TFV-DP concentrations at 1, 4, and 24 h postdose were 96.4 (71.5 to 130), 93.3 (68 to 130), and 92.7 (70 to 123) fmol/million cells. There was an association between renal function, tenofovir AUC, and tenofovir C max and intracellular TFV-DP concentrations, although none of these associations reached statistical significance. In these HIV-infected young adults treated with atazanavir-ritonavir plus TDF, the atazanavir AUC was similar to those of older adults treated with the combination. Based on data for healthy volunteers, a higher tenofovir AUC may have been expected, but was not seen in these subjects. This might be due to faster tenofovir CL/F because of higher creatinine clearance in this age group. Additional studies of the exposure-response relationships of this regimen in children, adolescents, and adults would advance our knowledge of its pharmacodynamic properties.

Purpose Youth living with HIV account for over one-third of new HIV infections and are at high risk of adverse psychosocial, everyday living, and health outcomes. HIV-associated neurocognitive disorders (HAND) are known to affect health outcomes of HIV-infected adults even in the era of combination antiretroviral therapy (cART). Thus, the current study aimed to characterize the prevalence and clinical correlates of HAND in youth living with HIV. Here we report baseline neurocognitive data for behaviorally HIV-infected youth enrolled in a prospective study evaluating strategies of antiretroviral treatment initiation and use. Methods Two hundred twenty participants, age 18-24, naïve to treatment (except for prevention of mother to child HIV transmission; n=3), completed a comprehensive neurocognitive, substance use, and behavioral health assessment battery. Results 64.7% of youth met criteria for HAND (96.4% asymptomatic, 3.5% syndromic), with deficits in episodic memory and fine-motor skills emerging as the most commonly affected ability areas. Multivariable models showed that lower CD4 count, longer time since HIV diagnosis, and high risk alcohol use were uniquely associated with neurocognitive deficits. Conclusions Over two-thirds of youth with behaviorally acquired HIV evidence neurocognitive deficits, which have modest associations with more advanced HIV disease as well as other factors. Research is needed to determine the impact of such neuropsychiatric morbidity on mental health and HIV disease treatment outcomes (e.g., non-adherence) and transition to independent living responsibilities in HIV-infected youth, as well as its long-term trajectory and possible responsiveness to cognitive rehabilitation and pharmacotherapy.

Although youth living with behaviorally acquired HIV (YLWH) are at risk for cognitive impairments, the relationship of impairments to HIV and potential to improve with antiretroviral therapy (ART) are unclear. This prospective observational study was designed to examine the impact of initiation and timing of ART on neurocognitive functioning in YLWH in the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Treatment naïve YLWH age 18–24 completed baseline and four additional assessments of attention/working memory, complex executive, and motor functioning over 3 years. Group 1 co-enrolled in an early ART initiation study and initiated ART at enrollment CD4 >350 (n=56); group 2 had CD4 >350 and were not initiating ART (n=66); group 3 initiated ART with CD4 <350 (n=59) per standard of care treatment guidelines at the time. Treatment was de-intensified to boosted protease inhibitor monotherapy at 48 weeks for those in group 1 with suppressed viral load. Covariates included demographic, behavioral, and medical history variables. Analyses used hierarchical linear modeling. All groups showed improved performance with peak at 96 weeks in all three functional domains. Trajectories of change were not significantly associated with treatment, timing of treatment initiation, or ART de-intensification. Demographic variables and comorbidities were associated with baseline functioning but did not directly interact with change over time. In conclusion, YLWH showed improvement in neurocognitive functioning over time that may be related to practice effects and nonspecific impact of study participation. Neither improvement nor decline in functioning was associated with timing of ART initiation or therapy de-intensification.

Adolescents, in general, are among the most challenging groups to engage in care. Caring for HIV-infected adolescents is a complex process that is further complicated by the wide range of adolescents' psychosocial needs. In addition, understanding the developmental stages and tasks for these adolescents is imperative. Multiple disciplines must collaborate in order to provide optimal and comprehensive health care to this subpopulation of adolescents.