A transgenic mouse model demonstrating the oncogenic role of mutations in the polycomb-group gene EZH2 in lymphomagenesis.

The histone methyltransferase EZH2 is frequently mutated in germinal center-derived diffuse large B-cell lymphoma and follicular lymphoma. To further characterize these EZH2 mutations in lymphomagenesis, we generated a mouse line where EZH2(Y641F) is expressed from a lymphocyte-specific promoter. Spleen cells isolated from the transgenic mice displayed a global increase in trimethylated H3K27, but the mice did not show an increased tendency to develop lymphoma. As EZH2 mutations often coincide with other mutations in lymphoma, we combined the expression of EZH2(Y641F) by crossing these transgenic mice with Eµ-Myc transgenic mice. We observed a dramatic acceleration of lymphoma development in this combination model of Myc and EZH2(Y641F). The lymphomas show histologic features of high-grade disease with a shift toward a more mature B-cell phenotype, increased cycling and gene expression, and epigenetic changes involving important pathways in B-cell regulation and function. Furthermore, they initiate disease in secondary recipients. In summary, EZH2(Y641F) can collaborate with Myc to accelerate lymphomagenesis demonstrating a cooperative role of EZH2 mutations in oncogenesis. This murine lymphoma model provides a new tool to study global changes in the epigenome caused by this frequent mutation and a promising model system for testing novel treatments.

Medicare and Medicaid enrollment and outside hospitalizations among HIV-infected and uninfected veterans engaged in VA care: a retrospective cohort study.

BACKGROUND: Many veterans engaged in care with the Veterans Administration (VA) health system are also enrolled in Medicare and/or Medicaid and may receive care both inside and outside of the VA. Use of dual health systems has been associated with worse outcomes. Veterans with HIV may have different rates of Medicare and Medicaid enrollment and may be at greater risk of poor outcomes related to non-VA use. This study compares the frequency and factors associated with Medicare and/or Medicaid enrollment and non-VA use in an HIV-infected and uninfected population of veterans. METHODS: We used data from the VA and Center for Medicare & Medicaid Services from 2004 and 2005 to determine the frequency of Medicare and/or Medicaid enrollment among a cohort of HIV-infected and uninfected veterans engaged in VA care. We then restricted the cohort to veterans enrolled in fee-for-service (FFS) Medicare and/or Medicaid with at least one hospitalization and identified characteristics associated with non-VA hospital admissions. RESULTS: HIV-infected veterans had higher rates of Medicare and/or Medicaid enrollment than uninfected veterans (38% vs. 33%, p < 0.01), though the opposite was true when our sample was limited to veterans 65 years and older (53% vs. 70%, p < 0.0 1). Among veterans enrolled in the VA and FFS Medicare and/or Medicaid, veterans with HIV had greater illness severity and more frequent hospitalizations, but were less likely to be hospitalized outside the VA (48% vs. 54%, p < 0.01). HIV infection was associated with lower odds of outside hospitalization (OR = 0.76 [95% CI: 0.68, 0.85]). CONCLUSIONS: Veterans with HIV have higher rates of Medicare and/or Medicaid enrollment, but lower odds of non-VA hospitalization. The VA integrated model of HIV care may discourage outside use among HIV-infected veterans.

Socio-Demographic and Adherence Factors Associated with Viral Load Suppression in HIV-Infected Adults Initiating Therapy in Northern Nigeria: A Randomized Controlled Trial of a Peer Support Intervention.

BACKGROUND: Virological suppression is the main goal of antiretroviral therapy. To achieve this goal, efficient interventions that promote treatment adherence are needed. This study was aimed at exploring the impact of peer-education on virological outcomes in Northern Nigeria. METHODS: A randomized controlled trial (RCT) among patients receiving antiretroviral treatment was conducted in 2 phases between August 2006 and January 2008 in the "largely Muslim" Northern Nigeria. Participants were randomized into one of three intervention arms: standard of care arm, a second arm which included daily reminders via alarm and follow-up calls from peer-educators, and adherence support by a home-based treatment partner; and a third arm which included second arm activities, plus home visits by peer-educators. We evaluated sociodemographic factors and adherence levels, measured using self-report and pharmacy (Rx) refill rates, as risk factors for viral load (VL) suppression. RESULTS: Of the 600 participants (43% males), 276 were observed till the end of the study. There were no significant differences in mean log 10 VL between the intervention groups. At the end of entire follow-up period, 83% (229/276) who were not lost to follow-up achieved undetectable VL (< 400 copies/ml). In the multivariable analysis, age between 30-34 years (vs 18-24 years) and both baseline CD4 ranges between 100-199 cells/mm(3) or 200-349 cells/mm(3) (vs CD4 <100 cells/mm(3)) as positively associated with VL suppression while poor self-reported adherence and <95% Rx refill rates were negatively associated with VL suppression. CONCLUSION: High levels of viral suppression and low prevalence of drug resistance mutations (DRMs) were seen in this cohort participating in an ART adherence study in Northern Nigeria. Self-reported good adherence and optimal Rx refill rates were reported as significant predictors of VL suppression. Our findings indicate that ART adherence will improve significantly regardless of whether HIV-infected adults received peer-education-based medication adherence interventions or standard of care services.

Successful management of latent tuberculosis infection in an underserved community by a student-run free clinic.

The management of latent tuberculosis infection (LTBI) most commonly consists of a nine-month course of isoniazid (INH) therapy and is complicated by low adherence and completion rates. The Latent Tuberculosis Initiative at the HAVEN Free Clinic was developed to provide LTBI treatment to an underserved, high-risk, foreign-born population. We conducted a retrospective chart review to evaluate the program. Of 39 patients enrolled, 26 (67%) successfully completed nine months of INH, eight (21%) discontinued, and five (12%) were lost to follow-up. Patients had a median of nine encounters during the course of treatment and mean self-reported medication adherence was 29/30 pills/month (96%). Median days-of-treatment was 273, 95, and 63 among completion, discontinuation, and lost to follow-up groups, respectively (p < .0001). There was one death in the program, related to a complication of a diagnostic procedure in a patient who had developed INH toxicity. These results are comparable to the most successful published programs (50-65% six-month completion rates), suggesting that student-run clinics serving high-risk populations may contribute to LTBI management and TB control efforts.

Improving quality of preventive care at a student-run free clinic.

UNLABELLED: Student-run clinics increasingly serve as primary care providers for patients of lower socioeconomic status, but studies show that quality of care at student-run clinics has room for improvement. PURPOSE: To examine change in provision of preventive services in a student-run free clinic after implementation of a student-led QI intervention involving prompting. METHOD: Review of patient charts pre- and post-intervention, examining adherence to screening guidelines for diabetes, dyslipidemia, HIV, and cervical cancer. RESULTS: Adherence to guidelines among eligible patients increased after intervention in 3 of 4 services examined. Receipt of HIV testing increased from 33% (80/240) to 48% (74/154; p = 0.004), fasting lipid panel increased from 53% (46/86) to 72% (38/53; p = 0.033), and fasting blood glucose increased from 59% (27/46) to 82% (18/22; p = 0.059). CONCLUSIONS: This student-run free clinic implemented a student-led QI intervention that increased provision of prevention. Such a model for QI could extend to other student-run clinics nationally.

Tenofovir-based regimens associated with less drug resistance in HIV-1-infected Nigerians failing first-line antiretroviral therapy.

BACKGROUND: In resource-limited settings, HIV-1 drug resistance testing to guide antiretroviral therapy (ART) selection is unavailable. We retrospectively conducted genotypic analysis on archived samples from Nigerian patients who received targeted viral load testing to confirm treatment failure and report their drug resistance mutation patterns. METHODS: Stored plasma from 349 adult patients on non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens was assayed for HIV-1 RNA viral load, and samples with more than 1000 copies/ml were sequenced in the pol gene. Analysis for resistance mutations utilized the IAS-US 2011 Drug Resistance Mutation list. RESULTS: One hundred and seventy-five samples were genotyped; the majority of the subtypes were G (42.9%) and CRF02_AG (33.7%). Patients were on ART for a median of 27 months. 90% had the M184V/I mutation, 62% had at least one thymidine analog mutation, and 14% had the K65R mutation. 97% had an NNRTI resistance mutation and 47% had at least two etravirine-associated mutations. In multivariate analysis tenofovir-based regimens were less likely to have at least three nucleoside reverse transcriptase inhibitor (NRTI) mutations after adjusting for subtype, previous ART, CD4, and HIV viral load [P < 0.001, odds ratio (OR) 0.04]. 70% of patients on tenofovir-based regimens had at least two susceptible NRTIs to include in a second-line regimen compared with 40% on zidovudine-based regimens (P = 0.04, OR = 3.4). CONCLUSIONS: At recognition of treatment failure, patients on tenofovir-based first-line regimens had fewer NRTI drug-resistant mutations and more active NRTI drugs available for second-line regimens. These findings can inform strategies for ART regimen sequencing to optimize long-term HIV treatment outcomes in low-resource settings.