Sociodemographic factors predict early discontinuation of HIV non-nucleoside reverse transcriptase inhibitors and protease inhibitors.

BACKGROUND/OBJECTIVE: HIV infection has a devastating impact on individual and public health, and affects populations disproportionately. Treatment with antiretroviral therapy (ART) saves lives, but long-term adherence to ART is critical to its success. We performed an observational cohort study to determine the influence of race, sex and other sociodemographic factors on early ART discontinuations among HIV-infected persons. METHODS: TennCare-enrolled adults of black or white non-Hispanic race beginning ART with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) between 1996-2003 (N=3654) were assessed for early discontinuation. A subgroup of discontinuations was validated using the primary medical record. RESULTS: Blacks were more likely than whites to discontinue NNRTIs (37 vs. 28%; P=0.003) and PIs (36 vs. 25%; P < or = 0.001). In multivariable models adjusting for race, sex, age, early HIV-related medical encounter, urban residence and TennCare enrollment category, black race, female sex and younger age were independent predictors of discontinuation among those starting PIs. Among persons starting NNRTIs, black race, younger age and a disability-based enrollment category predicted early drug discontinuation, but female sex did not. CONCLUSIONS: Our results suggest that sociodemographic factors were associated with early NNRTI and PI discontinuation in this population, and some factors were ART class specific.

Constitutively active K-cyclin/cdk6 kinase in Kaposi sarcoma-associated herpesvirus-infected cells.

BACKGROUND: Kaposi sarcoma-associated human herpesvirus (KSHV) encodes K-cyclin, a homologue of D-type cellular cyclins, which binds cyclin-dependent kinases to phosphorylate various substrates. K-cyclin/cdk phosphorylates a subset of substrates normally targeted by cyclins D, E, and A. We used cells naturally infected with KSHV to further characterize the biochemical features of K-cyclin. METHODS: We used immunoprecipitation with K-cyclin antibodies to examine the association of K-cyclin with cdk2, cdk6, p21Cip1, and p27Kip1 proteins in BC3 cells. We separated populations of BC3 cells enriched in cells in G1, S, or G2/M phases by elutriation and measured K-cyclin protein and the kinase activity of K-cyclin/cdk6 complexes. The half-life of K-cyclin and cyclin D2 proteins was determined by blocking protein synthesis with cycloheximide and measuring proteins in cell lysates by western blot analysis. We fused the entire K-cyclin sequence to the carboxyl-terminal sequence of cellular cyclin D that contains the PEST degradation sequence to produce K-cyclin/D2 and transfected K-cyclin/D2 into K-cyclin-negative cells to investigate the effect of the PEST sequence on K-cyclin's stability. RESULTS: Viral K-cyclin interacted with cyclin-dependent kinases cdk2, cdk4, and cdk6 and with the cyclin/cdk inhibitory proteins p21Cip1 and p27Kip1 in BC3 cell lysates. Unlike D-type cyclins, whose expression is cell cycle dependent, the level of K-cyclin was stable throughout the cell cycle, and the kinase associated with the K-cyclin/cdk6 complex was constitutively active. The half-life of K-cyclin (6.9 hours) was much longer than that of cellular cyclin D2 (0.6 hour) and that of K-cyclin/D2 (0.5 hour), probably because K-cyclin lacks the PEST degradation sequence present in D-type cyclins. CONCLUSION: The constitutive activation of K-cyclin/cdk complexes in KSHV-infected cells appears to result from the extended half-life of K-cyclin and may explain its role in Kaposi sarcoma.