No abstract

Background Voriconazole pharmacokinetic (PK) and pharmacodynamic (PD) data are lacking in children. Methods Records at the Childrens Hospital Los Angeles were reviewed for children with ≥1 serum voriconazole concentration obtained between May 1, 2006 and June 1, 2007. Demographics, dosing histories, serum concentrations, toxicity/survival data and outcomes were obtained. Analysis was with R 2.9.1 and the non-parametric modeling and simulation MM-USCPACK software. Results There were 207 voriconazole concentrations obtained from 46 patients (0.8 – 20.5 years). A 2-compartment Michaelis-Menten PK model fit the data best, but only explained 80% of the observed variability. Crude mortality was 13 (28%), and each trough serum voriconazole concentration <1,000 ng/mL was associated with a 2.6-fold increased odds of death (95% CI 1.6 – 4.8, P=0.002). Serum voriconazole concentrations were not associated with hepatotoxicity. Simulations predicted an intravenous dose of 7 mg/kg or oral dose of 200 mg twice daily would achieve a trough >1,000 ng/mL in the majority of patients, but with a very wide range of possible concentrations. Conclusions We found a PD association between a voriconazole trough >1,000 ng/mL and survival, and marked PK variability, particularly after enteral dosing, justifying measurement of serum concentrations.

World-wide, hepatitis C virus (HCV) accounts for approximately 130 million chronic infections, with an overall 3% prevalence. Four to 5 million persons are co-infected with HIV. It is well established that HIV has a negative impact on the natural history of HCV, including a higher rate of viral persistence, increased viral load, and more rapid progression to fibrosis, end-stage liver disease, and death. Whether HCV has a negative impact on HIV disease progression continues to be debated. However, following the introduction of effective combination antiretroviral therapy, the survival of coinfected individuals has significantly improved and HCV-associated diseases have emerged as the most important co-morbidities. In this review, we summarize the newest studies regarding the pathogenesis of HIV/HCV coinfection, including effects of coinfection on HIV disease progression, HCV-associated liver disease, the immune system, kidney and cardiovascular disease, and neurologic status; and effectiveness of current anti-HIV and HCV therapies and proposed new treatment strategies.

Worldwide, 90% of HIV-1 infections are transmitted heterosexually. Because the genital mucosa are the sites of initial contact with HIV-1 for most exposed individuals, study of the virus from the genital tract is critical for the development of vaccines and therapeutics. Previous analyses of HIV-1 in various tissues have documented compartmentalization of viral genomes. Whether compartmentalization was associated with viral phenotypic differences or immune status, however, was not well understood. We compared HIV-1 gp120 env sequences from the genital tract and plasma of 12 women. Eight women displayed compartmentalized HIV-1 RNA genomes, with viral sequences from each site that were clearly discrete, yet phylogenetically related. The remaining four exhibited env sequences that were intermingled between the two sites. Women with compartmentalized HIV-1 genomes had higher CD4 ؉ cell counts than those displaying intermingled strains (P ‫؍‬ 0.02). Intrapatient HIV-1 recombinants comprising sequences that were characteristic of both sites were identified. We next compared viral phenotypes in each compartment. HIV-1 coreceptor usage was often compartmentalized (P < 0.01). The number of N-linked glycosylation sites, associated with neutralization resistance, also differed between compartments (P < 0.01). Furthermore, disparities between the density of gp120 glycosylations in each compartment correlated with higher CD4 ؉ counts (P ‫؍‬ 0.03). These data demonstrate that the genital tract and plasma can harbor populations of replicating HIV-1 with different phenotypes. The association of higher CD4 ؉ cell counts with compartmentalization of viral genomes and density of gp120 glycosylations suggests that the immune response influences the development of viral genotypes in each compartment. These findings are relevant to the prevention and control of HIV-1 infection.