The proportion of overweight and obese adults in the United States and Canada has increased over the past decade, but temporal trends in body mass index (BMI) and weight gain on antiretroviral therapy (ART) among HIV-infected adults have not been well characterized. We conducted a cohort study comparing HIV-infected adults in the North America AIDS Cohort Collaboration on Research and Design (NA-ACCORD) to United States National Health and Nutrition Examination Survey (NHANES) controls matched by sex, race, and age over the period 1998 to 2010. Multivariable linear regression assessed the relationship between BMI and year of ART initiation, adjusting for sex, race, age, and baseline CD4+ count. Temporal trends in weight on ART were assessed using a generalized least-squares model further adjusted for HIV-1 RNA and first ART regimen class. A total of 14,084 patients from 17 cohorts contributed data; 83% were male, 57% were nonwhite, and the median age was 40 years. Median BMI at ART initiation increased from 23.8 to 24.8 kg/m2 between 1998 and 2010 in NA-ACCORD, but the percentage of those obese (BMI ≥30 kg/m2) at ART initiation increased from 9% to 18%. After 3 years of ART, 22% of individuals with a normal BMI (18.5–24.9 kg/m2) at baseline had become overweight (BMI 25.0–29.9 kg/m2), and 18% of those overweight at baseline had become obese. HIV-infected white women had a higher BMI after 3 years of ART as compared to age-matched white women in NHANES (p = 0.02), while no difference in BMI after 3 years of ART was observed for HIV-infected men or non-white women compared to controls. The high prevalence of obesity we observed among ART-exposed HIV-infected adults in North America may contribute to health complications in the future.

Respiratory syncytial virus (RSV) infects polarized epithelia, which have tightly regulated trafficking because of the separation and maintenance of the apical and basolateral membranes. Previously we established a link between the apical recycling endosome (ARE) and the assembly of RSV. The current studies tested the role of a major ARE-associated protein, Rab11 family interacting protein 2 (FIP2) in the virus life cycle. A dominant-negative form of FIP2 lacking its N-terminal C2 domain reduced the supernatant-associated RSV titer 1,000-fold and also caused the cell-associated virus titer to increase. These data suggested that the FIP2 C2 mutant caused a failure at the final budding step in the virus life cycle. Additionally, truncation of the Rab-binding domain from FIP2 caused its accumulation into mature filamentous virions. RSV budding was independent of the ESCRT machinery, the only well-defined budding mechanism for enveloped RNA viruses. Therefore, RSV uses a virus budding mechanism that is controlled by FIP2.Pneumovirinae ͉ Rab11 protein ͉ virus replication ͉ virus shedding R espiratory syncytial virus (RSV) is the most common viral cause of serious lower respiratory tract illness in infants and children worldwide. RSV is a negative-sense, single-stranded RNA virus of the Paramyxoviridae family, which encodes 11 proteins. Infection is limited to the most superficial layer of polarized ciliated cells in the respiratory tract epithelium, entering through the apical surface (1, 2). Late steps of the RSV life cycle include assembly and budding of the virus, which also occur at the apical membrane in polarized cells (3).RSV virions are pleomorphic, with a spherical form varying in size from 150 to 250 nm in diameter. The filamentous form of the virus has a smaller diameter of 50 nm and can have a length from 1 to 10 microns, depending on the cell line in which virus is grown (4). Filamentous RSV has been observed budding and fusing with cells during the spread of RSV infection (5). These long filaments destabilize into spherical forms that can be similar to the size of spherical particles collected during infection (4). Other related viruses also make filamentous virions such as influenza, Ebola, and parainfluenza viruses (6,7,8). In polarized cell culture monolayers, influenza virus is predominantly filamentous, and this filamentous form has a higher specific infectivity (9). A previous analysis of the RSV cell-surface filaments in live infected cells showed that these filaments are dynamic, demonstrating rotation, directed motion, and diffusion (10).The minimal viral protein requirements for budding of RSV virus-like particles (VLPs) are fusion (F), matrix (M), nucleoprotein (N), and phosphoprotein (P) (11). The F protein follows the secretory pathway through the endoplasmic reticulum and Golgi and is directed to the apical membrane through a lipid raft-associated mechanism (12). The other viral structural proteins and the RNA genome must also traffic to the apical membrane from the cytoplasm and viral inc...

Background With the introduction of integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART), persons living with HIV have a potent new treatment option. Recently, providers at our large treatment clinic noted weight gain in several patients switched from efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) to dolutegravir/abacavir/lamivudine (DTG/ABC/3TC). In this study, we evaluated weight change in patients with sustained virologic suppression switched from EFV/TDF/FTC to an INSTI-containing regimen. Methods We performed a retrospective observational cohort study among adults on EFV/TDF/FTC for at least two years who had virologic suppression. We assessed weight change over 18 months in patients who switched from EFV/TDF/FTC to an INSTI-containing regimen or a protease inhibitor (PI)-containing regimen versus those on EFV/TDF/FTC over the same period. In a sub-group analysis, we compared patients switched to DTG/ABC/3TC versus raltegravir- or elvitegravir-containing regimens. Results A total of 495 patients were included: 136 switched from EVF/TDF/FTC to an INSTI-containing regimen and 34 switched to a PI-containing regimen. Patients switched to an INSTI-containing regimen gained an average of 2.9 kg at 18 months compared to 0.9 kg among those continued on EFV/TDF/FTC (p=0.003), while those switched to a PI regimen gained 0.7 kg (p=0.81). Among INSTI regimens, those switched to DTG/ABC/3TC gained the most weight at 18 months (5.3 kg, p=0.001 compared to EFV/TDF/FTC). Conclusion Adults living with HIV with viral suppression gained significantly more weight after switching from daily, fixed dose EFV/TDF/FTC to an INSTI-based regimen compared to those remaining on EFV/TDF/FTC. This weight gain was greatest among patients switching to DTG/ABC/3TC.

We study the application of a widely used ordinal regression model, the cumulative probability model (CPM), for continuous outcomes. Such models are attractive for the analysis of continuous response variables because they are invariant to any monotonic transformation of the outcome and because they directly model the cumulative distribution function from which summaries such as expectations and quantiles can easily be derived. Such models can also readily handle mixed type distributions. We describe the motivation, estimation, inference, model assumptions, and diagnostics. We demonstrate that CPMs applied to continuous outcomes are semiparametric transformation models. Extensive simulations are performed to investigate the finite sample performance of these models. We find that properly specified CPMs generally have good finite sample performance with moderate sample sizes, but that bias may occur when the sample size is small. CPMs are fairly robust to minor or moderate link function misspecification in our simulations. For certain purposes, the CPM are more efficient than other models. We illustrate their application, with model diagnostics, in a study of the treatment of HIV. CD4 cell count and viral load 6 months after the initiation of antiretroviral therapy are modeled using CPMs; both variables typically require transformations and viral load has a large proportion of measurements below a detection limit.

Objectives-HIV-infected women living in resource-constrained nations like Zambia are now accessing antiretroviral therapy and thus may live long enough for HPV-induced cervical cancer to manifest and progress. We evaluated the prevalence and predictors of cervical squamous intraepithelial lesions (SIL) among HIV-infected women in Zambia.Methods-We screened 150 consecutive, non-pregnant HIV-infected women accessing HIV/AIDS care services in Lusaka, Zambia. We collected cervical specimens for cytological analysis by liquidbased monolayer cytology (ThinPrep Pap Test®) and HPV typing using the Roche Linear Array® PCR assay.Results-The median age of study participants was 36 years (range 23-49 years) and their median CD4+ count was 165/μL (range 7-942). The prevalence of SIL on cytology was 76% (114/150), of which 23.3% (35/150) women had low-grade SIL, 32.6% (49/150) had high-grade SIL, and 20% (30/150) had lesions suspicious for squamous cell carcinoma (SCC). High-risk HPV types were present in 85.3% (128/150) women. On univariate analyses, age of the participant, CD4+ cell count, and presence of any high-risk HPV type were significantly associated with the presence of severely abnormal cytological lesions (i.e., high-grade SIL and lesions suspicious for SCC). Multivariable logistic regression modeling suggested the presence of any high-risk HPV type as an independent predictor of severely abnormal cytology (adjusted OR: 12.4, 95% CI 2.62-58.1, p=0.02).Conclusions-The high prevalence of abnormal squamous cytology in our study is one of the highest reported in any population worldwide. Screening of HIV-infected women in resourceconstrained settings like Zambia should be implemented to prevent development of HPV-induced SCC.