A phase II study of sequential decitabine and rapamycin in acute myelogenous leukemia.

A phase II study was conducted to ascertain whether sequential exposure to decitabine followed by rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor would result in better responses than decitabine alone. Newly diagnosed acute myelogenous leukemia (AML) patients who were >65 years old and not eligible for intensive induction regimens or patients with relapsed or refractory AML received 10 days of decitabine followed by 12 days of rapamycin in cycle 1 and 5 days of decitabine followed by 17 days of rapamycin in subsequent cycles. The composite complete remission rate (CR) was 33 % (CR plus CR with incomplete count recovery). Median overall survival was 7.7 months in newly diagnosed elderly AML patients and 6.6 months in relapsed/refractory AML patients. Twenty-four evaluable patients were enrolled, and the study did not meet its primary endpoint of demonstrating a significant improvement in composite CR rate with the combination as compared to an established historical CR rate of 25 % with decitabine alone. Despite that, the survival rates in relapsed/refractory cases appear comparable to what is reported with other salvage regimens, and no significant patterns of non-hematologic toxicity were noted. 50 % of subjects in the de novo group achieved a composite CR which is significantly higher (p = 0.02) than the rate of 25 % with decitabine alone. This trial is registered at clinical trials.gov as NCT02109744.

HIV economic burden of illness in the Veterans Health Administration population.

The objective was to assess the human immunodeficiency virus (HIV) economic burden of illness in the Veterans Health Administration (VHA) population. Adults (aged 18-64 years) with a HIV diagnosis (International Classification of Diseases 9th Revision, Clinical Modification [ICD-9-CM] code 042.x, V08) from 1 June 2007 to 31 May 2012 were selected from VHA Medical SAS(®) data-sets. Continuous VHA insurance coverage 12-month pre- and postindex date, with no antiretroviral therapy (ART) prescriptions within 180 days pre-index date, was required for treatment-naive (TN) HIV-infected patients. One baseline CD4 count or HIV viral load measured within three months after HIV diagnosis or one ART anchor drug claim postindex date was required for group comparison. All-cause health-care costs and utilizations were evaluated and stratified by CD4 cell count, viral load, nonnucleoside reverse transcriptase inhibitor (NNRTI) anchor drugs (efavirenz/non-efavirenz), and ART (NNRTI/PI/INSTI/CCR-5 Antagonist-based) regimen cohorts. The overall economic burden was compared between HIV-infected vs. non-HIV-infected patients. CD4 count, viral load, and treatment patterns and the associated costs were compared among TN patients. A 1:1 propensity score matching (PSM) was used to adjust for baseline differences. A total of 25,648 HIV-infected patients were identified (mean age 51; 96.4% male; 49.7% non-Hispanic black) of which 11,371 were TN. HIV-infected patients incurred higher PSM-adjusted total costs than non-HIV-infected patients ($25,232 vs. $10,206, p < 0.0001). Total costs for TN with CD4 cell counts ≤50 cells/mm(3) were higher than all other CD4 cell strata (p < 0.001). Total costs for TN with viral loads >100,000 copies/mL were higher than all other viral load categories (p < 0.001). Efavirenz-treated patients incurred higher ART-related ($8663 vs. $2846, p = 0.0266), but lower non-ART-related ($2339 vs. $6628, p = 0.0042) pharmacy costs than non-efavirenz patients. NNRTI-based cohort incurred lower total costs than protease inhibitor-based ($32,829 vs. $39,073, p = 0.0005) but no significant differences compared to integrase strand transfer inhibitor cohorts. This study offers new health-care costs and resource utilization estimates associated with the burden of HIV in the VHA population.

Burden of nonnucleoside reverse transcriptase inhibitor resistance in HIV-1-infected patients: a systematic review and meta-analysis.

The prevalence of HIV drug resistance varies with geographic location, year, and treatment exposure. This study generated yearly estimates of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in treatment-naive (TN) and treatment-experienced (TE) patients in the United States (US), Europe (EU), and Canada. Studies reporting NNRTI resistance identified in electronic databases and 11 conferences were analyzed in three groups: (1) TN patients in one of four geographic regions [US, Canada, EU countries with larger surveillance networks ("EU1"), and EU countries with fewer data ("EU2")]; (2) TE patients from any region; and (3) TN patients failing NNRTI-based treatments in clinical trials. Analysis data included 158 unique studies from 22 countries representing 84 cohorts of TN patients, 21 cohorts of TE patients, and 8 trials reporting resistance at failure. From 1995 to 2000, resistance prevalence in TN patients increased in US and EU1 from 3.1% to 7.5% and 0.8% to 3.6%, respectively. Resistance in both regions stabilized in 2006 onward. Little resistance was identified in EU2 before 2000, and increased from 2006 (5.0%) to 2010 (13.7%). One TN Canadian study was identified and reported resistance of 8.1% in 2006. Half of TN clinical trial patients had resistance after treatment failure at weeks 48-144. Resistance in TE patients increased from 1998 (10.1%) to 2001 (44.0%), then decreased after 2004. Trends in NNRTI resistance among TN patients show an increased burden in the US and some EU countries compared to others. These findings signify a need for alternate first-line treatments in some regions.

Cost of treatment in a US commercially insured, HIV-1-infected population.

OBJECTIVE: Recent treatment patterns and cost data associated with HIV in the United States are limited. This study assessed first-line persistence and healthcare costs of HIV-1 in patients by treatment line and CD4 cell count. METHODS: MarketScan Commercial Claims and Encounters Database (2007-2011) and Lab Database (2007-2010) were used to construct two HIV-1 cohorts: 1) newly treated HIV-1-infected patients with ≥6 months' continuous enrollment prior to first third-agent drug claim (Newly Treated Cohort) and 2) CD4 cell count test results (CD4 Measurements Cohort). All patients were ≥18 years old and without hepatitis co-infection. The Kaplan-Meier method was used to measure treatment switch rates. Generalized linear models (gamma distribution, log link) were used to compare healthcare costs by treatment line and CD4 cell count controlling for potential confounders. RESULTS: Newly treated patients (n = 8,617) had mean age of 41, 82% were male, and 20% had experienced AIDS-defining events at baseline. Over 20% of newly treated patients switched initial treatment regimen within 2 years. Average unadjusted (and covariate-adjusted) total healthcare cost/year was $33,674 ($28,861) for first-line, $39,191 ($35,805) for second-line, and $39,882 ($40,804) for third-line treatment. Covariate-adjusted costs of care on second- and third-line treatments were significantly more expensive than first-line treatment (24% [p<0.001] and 41% [p = 0.006] higher, respectively). The CD4 Measurements Cohort included 803 CD4 measurements (mean age 49, 76% male, 8% experienced an AIDS-defining event). Costs associated with CD4 measurements <100 cells/µL were 92% higher than those with >350 cells/µL (p<0.001). For higher CD4 cell counts, the majority of expenditures were for antiretrovirals (64% of total for CD4 >350 cells/µL). CONCLUSIONS: Despite modern advances in antiretroviral therapy and medical care, direct medical costs of HIV-1-infected patients increase after treatment switch and with lower CD4 counts, consistent with previous costing studies.

The prevalence of transmitted resistance to first-generation non-nucleoside reverse transcriptase inhibitors and its potential economic impact in HIV-infected patients.

Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based highly active antiretroviral therapy (HAART) including efavirenz is recommended as a 1(st)-line treatment choice in international HIV guidelines, and it is one of the most common components of initial therapy. Resistance to 1(st)-generation NNRTIs is found among treated and untreated HIV-infected individuals creating a subpopulation of HIV-infected individuals in whom efavirenz is not fully effective. This analysis reviewed published articles and conference abstracts to examine the prevalence of 1(st)-generation NNRTI resistance in Europe, the United States (US), and Canada and to identify published evidence of the economic consequences of resistance. The reported prevalence of NNRTI resistance was generally higher in US/Canada than in Europe and increased in both regions from their introduction in the late 1990s until the early 2000s. The most recent time-based trends suggest that NNRTI-resistance prevalence may be stable or decreasing. These estimates of resistance may be understated as resistance estimates using ultra-sensitive genotypic testing methods, which identify low-frequency mutations undetected by standard testing methods, showed increased prevalence of resistance by more than two-fold. No studies were identified that explicitly investigated the costs of drug resistance. Rather, most studies reported costs of treatment change, failure, or disease progression. Among those studies, annual HIV medical costs of those infected with HIV increased 1) as CD4 cells decreased, driven in part by hospitalization at lower CD4 cell counts; 2) for treatment changes, and 3) for each virologic failure. The possible erosion of efficacy or of therapy choices through resistance transmission or selection, even when present with low frequency, may become a barrier to the use of 1(st)-generation NNRTIs and the increased costs associated with regimen failure and disease progression underlie the importance of identification of treatment resistance to ensure optimal initial therapy choice and regimen succession.

Continuous nucleocytoplasmic shuttling underlies transcriptional activation of PPARgamma by FABP4.

FABP4 delivers specific ligands from the cytosol to the nuclear receptor PPARgamma in the nucleus, thereby facilitating the ligation and enhancing the transcriptional activity of the receptor. Here, we delineate the structural features that underlie the nucleocytoplasmic transport of FABP4. The primary sequence of FABP4 does not harbor a readily identifiable nuclear localization signal (NLS). However, such a signal could be found in the three-dimensional structure of the protein and was mapped to three basic residues that form a functional NLS stabilized by the FABP4/PPARgamma ligand troglitazone. We show that FABP4 is also subject to active nuclear export. Similarly to the NLS, the nuclear export signal (NES) is not apparent in the primary sequence, but assembles in the tertiary structure from three nonadjacent leucine residues to form a motif reminiscent of established NES. The data demonstrate that both nuclear export and nuclear import are critical for enabling FABP4 to enhance the transcriptional activity of PPARgamma. Additionally, the observations provide insight into the fundamental question of how proteins are activated by ligands. Such an activation may be understood by the "induced-fit" model, which states that ligand-induced conformational changes precede activation of a protein. Alternatively, the "pre-existing equilibrium" hypothesis postulates that activated conformations exist within the repertoire of apoproteins, and that ligands do not induce these but merely stabilize them. Studies of the subcellular localization of FABP4 support the validity of the "pre-existing equilibrium" model for the ligand-controlled activation of the nuclear import of FABP4.