Susheel Reddy

Risk Factors for Oral HPV Infection among a High Prevalence Population of HIV-Positive and At-Risk HIV-Negative Adults

Introduction: Human papillomavirus (HPV) is an important risk factor for oropharyngeal cancer. Individuals with human immunodeficiency virus (HIV) have higher oral HPV prevalence but the risk factors for oral HPV infection are not well understood for either HIV-positive or HIV-negative individuals. Methods: This study was nested within the Multicenter AIDS Cohort Study (MACS; men) and Women Interagency HIV Study (WIHS; women) cohorts. Exfoliated oral epithelial cells were collected from 379 HIV-positive and 266 at-risk HIV-negative individuals using a rinse and gargle with Scope mouthwash. Samples were tested for 36 types of HPV DNA using PGMY09/11 consensus primers and reverse line blot hybridization. Risk factors for oral HPV infection were explored using logistic regression with generalized estimating equations in this cross-sectional analysis. Results: Prevalent oral HPV infection was common (34%), including HPV16 infection in 5.7% of participants. HIV-positive individuals had increased odds of prevalent oral HPV infection compared with HIV-negative individuals [adjusted OR = 2.1; 95% confidence interval (CI), 1.6–2.8]. Risk factors for prevalent oral HPV differed in HIV-positive and HIV-negative participants. Among HIV-negative individuals, higher number of recent oral sex or rimming partners were strong risk factors for prevalent oral HPV infection (each Ptrend < 0.01). In contrast, among HIV-positive individuals, lower CD4 T-cell count (Ptrend < 0.001) and higher number of lifetime sexual partners (Ptrend = 0.03) were strong risk factors. Conclusions: Oral HPV prevalence was elevated in HIV-positive individuals after controlling for differences in cigarette smoking and sexual behavior, supporting the possibility that HIV may affect the natural history of oral HPV. Impact: Immunosuppression may contribute to increased persistence or progression of oral HPV infection. Cancer Epidemiol Biomarkers Prev; 21(1); 122–33. ©2011 AACR.

Indirect Protection of Adults From Rotavirus by Pediatric Rotavirus Vaccination

BACKGROUND Pediatric vaccination has resulted in declines in disease in unvaccinated individuals through decreasing pathogen circulation in the community. About 2 years after implementation of pediatric rotavirus vaccination in the United States, dramatic declines in rotavirus disease were observed in both vaccinated and unvaccinated children. Whether this protection extends to adults is unknown. METHODS The prevalence of rotavirus, as determined by Rotaclone enzyme immunoassay, in adults who had stools submitted for bacterial stool culture (BSC) between February to May to Northwestern Memorial Hospital, Chicago, was compared between the prepediatric impact era (2006-2007) and the pediatric impact era (2008-2010). Isolates were genotyped and clinical characteristics of those with rotavirus were compared. RESULTS Of the 5788 BSC sent, 4725 met inclusion criteria and 3530 of these (74.7%) were saved for rotavirus testing. The prevalence of rotavirus among adults who had stool sent for BSC declined from 4.35% in 2006-2007 to 2.24% in 2008-2010 (a relative decline of 48.4%; P = .0007). The decline in the prevalence of rotavirus was of similar significant magnitude in both outpatients and inpatients. Marked year-to-year variability was observed in circulating rotavirus genotypes, with strain G2P[4] accounting for 24%; G1P[8], 22%; G3P[8], 11%; and G12P[6], 10% overall. About 30% of adults from whom rotavirus was isolated were immunocompromised and this remained constant. CONCLUSIONS Pediatric rotavirus vaccination correlated with a relative decline of almost 50% in rotavirus identified from adult BSC during the peak rotavirus season, suggesting that pediatric rotavirus vaccination protects adults from rotavirus.

Comparison of Clinical Features, Virulence, and Relapse among Mycobacterium avium Complex Species

RATIONALE Traditionally, Mycobacterium avium complex (MAC) has been composed of M. avium and M. intracellulare; however, advances in genetic sequencing have allowed discovery of several novel species. With these discoveries, investigation of differences in risk factors, virulence, and clinical outcomes have emerged. OBJECTIVES We conducted a retrospective cohort study evaluating all MAC isolates obtained from pulmonary specimens at our institution from 2000 to 2012 and investigated the clinical courses associated with distinct MAC species. METHODS To classify isolates into distinct species, a multilocus sequence analysis using rpoB and internal transcribed spacer (ITS) as targets was performed. We reviewed patient medical records to analyze clinical characteristics and outcomes for the cohort. MEASUREMENTS AND MAIN RESULTS Of the isolates from the 448 included patients, 54% were M. avium, 18% were M. intracellulare, and 28% were M. chimaera. Using American Thoracic Society/Infectious Diseases Society of America criteria, patients whose isolates were identified as M. avium (adjusted odds ratio [AOR], 2.14; 95% confidence interval [CI], 1.33-3.44) or M. intracellulare (AOR, 3.12; 95% CI, 1.62-5.99) were more likely to meet criteria for infection than patients with M. chimaera. Patients infected with M. chimaera were more likely to be prescribed an immunosuppressant compared with all other patients (AOR, 2.75; 95% CI, 1.17-6.40). Patients treated for infections with M. avium (AOR, 5.64; 95% CI, 1.51-21.10) and M. chimaera (AOR, 4.47; 95% CI, 1.08-18.53) were more likely to have a clinical relapse/reinfection than those with M. intracellulare. CONCLUSIONS Our findings suggest that specific MAC species have varying degrees of virulence and classifying MAC isolates into distinct species aids in identifying which patients are at higher risk of clinical relapse/reinfection.

Preservation of Tetherin and CD4 Counter-Activities in Circulating Vpu Alleles despite Extensive Sequence Variation within HIV-1 Infected Individuals

The HIV-1 Vpu protein is expressed from a bi-cistronic message late in the viral life cycle. It functions during viral assembly to maximise infectious virus release by targeting CD4 for proteosomal degradation and counteracting the antiviral protein tetherin (BST2/CD317). Single genome analysis of vpu repertoires throughout infection in 14 individuals infected with HIV-1 clade B revealed extensive amino acid diversity of the Vpu protein. For the most part, this variation in Vpu increases over the course of infection and is associated with predicted epitopes of the individuals MHC class I haplotype, suggesting CD8+ T cell pressure is the major driver of Vpu sequence diversity within the host. Despite this variability, the Vpu functions of targeting CD4 and counteracting both physical virus restriction and NF-κB activation by tetherin are rigorously maintained throughout HIV-1 infection. Only a minority of circulating alleles bear lesions in either of these activities at any given time, suggesting functional Vpu mutants are heavily selected against even at later stages of infection. Comparison of Vpu proteins defective for one or several functions reveals novel determinants of CD4 downregulation, counteraction of tetherin restriction, and inhibition of NF-κB signalling. These data affirm the importance of Vpu functions for in vivo persistence of HIV-1 within infected individuals, not simply for transmission, and highlight its potential as a target for antiviral therapy.

A longitudinal study of human papillomavirus 16 L1, e6, and e7 seropositivity and oral human papillomavirus 16 infection.

Background Individuals with human papillomavirus (HPV) infections can develop IgG antibodies to HPV proteins including the L1 capsid and E6 and E7 oncoproteins. Evidence on whether L1 antibodies reduce the risk of cervical HPV infection is mixed, but this has not been explored for oral HPV infections. Antibodies to HPV16’s E6 oncoprotein have been detected in some oropharyngeal cancer cases years before cancer diagnosis, but it is unknown if these antibodies are associated with oral HPV16 DNA. Methods Enzyme-linked immunosorbent assays tested for serum antibodies to HPV16’s L1 capsid in 463 HIV-infected and 293 HIV-uninfected adults, and for antibodies to recombinantly expressed E6 and E7 oncoproteins to HPV16 in 195 HIV-infected and 69 HIV-uninfected cancer-free participants at baseline. Oral rinse samples were collected semiannually for up to 3 years and tested for HPV DNA using PGMY 09/11 primers. Adjusted Poisson, logistic, and Wei-Lin-Weissfeld regression models were used. Results Human papillomavirus 16 L1 seroreactivity did not reduce the subsequent risk of incident oral HPV16 infection in unadjusted (hazard ratio, 1.4; 95% confidence interval, 0.59–3.3) or adjusted (adjusted hazard ratio = 1.1; 95% confidence interval, 0.41–3.0) analysis. Antibodies to HPV16 E6 and E7 oncoproteins were detected in 7.6% and 3.4% of participants, respectively, but they were not associated with baseline oral HPV16 DNA prevalence or oral HPV16 persistence (each P > 0.40). Conclusions Naturally acquired HPV16 L1 antibodies did not reduce the risk of subsequent oral HPV16 infection. Human papillomavirus 16 E6 and E7 seropositivity was not a marker for oral HPV16 infection in this population without HPV-related cancer.

High Oral Human Papillomavirus Type 16 Load Predicts Long-term Persistence in Individuals With or at Risk for HIV Infection

The association between oral human papillomavirus 16 (HPV16) DNA load and infection clearance was evaluated among 88 individuals with oral HPV16 infection who were identified within a prospective cohort of 1470 HIV-infected and uninfected individuals. Oral rinse specimens were collected semiannually for up to 5 years. The oral HPV16 load at the time of the first positive test result was significantly associated with the time to clearance of infection (continuous P trends <.01). Notably, clearance rates by 24 months were 41% and 94% in the highest and lowest HPV16 load tertiles (P = .03), respectively. High oral HPV16 load warrants consideration as a biomarker for infection persistence, the presumed precursor of HPV16-associated oropharyngeal cancer.

Anal Cancer Screening in Men Who Have Sex with Men in the Multicenter AIDS Cohort Study

Objective:To evaluate the prevalence of anal cytology (ACyt) abnormalities among HIV-infected and HIV-uninfected men who have sex with men (MSM). Design:Multicenter cohort study of 723 HIV-infected and 788 HIV-uninfected MSM with ACyt, with a second ACyt collected 2 years later. A referral for high-resolution anoscopy was suggested for abnormal ACyt. Methods:ACyt samples were collected using a polyester swab and liquid cytology media and read in a central laboratory. Results:Prevalence of any abnormal ACyt was 25% in HIV-uninfected MSM and increased to 38%, 41%, and 47% among HIV-infected MSM with current CD4+ T-cell counts ≥500, 350–499, and <350 cells/mm3 (P < 0.001), respectively. Anal HPV16 DNA was also more common in HIV-infected than HIV-uninfected MSM (25% versus 16%, P < 0.001). Abnormal baseline ACyt together with prevalent HPV16 DNA detection was present in only 7% of HIV-uninfected MSM compared to 18% of HIV-infected MSM with current CD4 < 350, P < 0.001. Among HIV-infected men, 56% of the men with atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions ASCs-US/LSILs and 81% of men with atypical squamous cells cannot exclude high-grade (ASC-H/)/high-grade squamous intraepithelial lesions (HSIL) had lower grade ACyt findings 18–30 months later (“regressed”). However, 19% of untreated HIV-infected men with ASC-H/HSIL cytology maintained that same grade of cytology in their second test approximately 2 years later, and 15% with ASC-US/LSIL “progressed” to ASC-H/HSIL. Abnormal ACyt had high sensitivity (96%) but low specificity (17%) for biopsy-proven HSIL. Conclusions:Prevalence of abnormal ACyt remains elevated in HIV-infected men during the current antiretroviral therapy era.

Improved estimation of the distribution of suppressed plasma HIV-1 RNA in men receiving effective antiretroviral therapy.

Abstract:Plasma HIV-1 RNA was measured in 306 samples, collected from 273 highly active antiretroviral therapy–experienced men, using both the Roche COBAS TaqMan (limit of detection = 20 copies per milliliter) and Roche Amplicor (limit of detection = 50 copies per milliliter) assays. Mixtures of Gaussian distributions incorporating left-censored data were used in analyses. The more sensitive TaqMan assay estimated that 23% and 0.0003% of HIV-1 RNA values would be below 1 copy per milliliter and 1 copy per 3 L, respectively. This is in sharp contrast to the overestimation provided by the less sensitive Amplicor assay, whereby the corresponding predicted percentages were 51% and 1%. Both assays appropriately characterized suboptimal virologic response as the rightmost peaks of both distributions provided an excellent fit to the observed data. Our results based on a widely available 20 copies per milliliter sensitive assay reproduce those obtained using customized assays that quantified HIV-1 RNA values as low as 1 copy per milliliter.

Human Papillomavirus (HPV) 16 E6 seropositivity is elevated in subjects with oral HPV16 infection

INTRODUCTION Human Papillomavirus (HPV) 16 E6 serum antibodies are common in people with HPV-related oropharyngeal cancers (HPV-OPC), but not the general population. We explored HPV16 seroprevalence in people with and without oral HPV16 infection, the cause of HPV-OPC. METHODS Oral rinse samples were collected semiannually and tested for 36 types of HPV DNA by PCR. HPV16 E6 serum antibodies were tested at the visit of first oral HPV detection in participants with prevalent (n=54), or incident (n=39) oral HPV16 DNA; or at baseline in matched participants with no oral HPV16 DNA (n=155) using multiplex serology assay. Predictors of seropositivity were examined using logistic regression. RESULTS HPV16 E6 seropositivity (7.5% vs 0.7%; p=0.005) but not seropositivity to the other HPV16 antigens, was significantly more common in those with than without oral HPV16 infection. There were only 8 HPV16 E6 seropositive participants, but oral HPV16 DNA remained a strong predictor of E6 seropositivity after adjustment for other risk factors (aOR=14.6 95%CI, 1.7-122.5). Seroprevalence was similar in those with prevalent (7.4%; 4/54), and incident (7.7%; 3/39) oral HPV16 infection (p=1.00). E6 seroprevalence was associated with reduced oral HPV16 clearance, but was not statistically significant (HR=0.65 95% CI, 0.16-2.70). Seropositive participants were primarily male (87.5%), HIV-positive (75.0%; median CD4 cell-count of 840) and had oral HPV16 DNA (87.5%). History of an HPV-related cancer (0/8) or HPV-related anogenital dysplasia (1/8) was rare, and 4 participants had recent screening showing no anogenital dysplasia. DISCUSSION HPV16 E6 seropositivity was higher among people with than without oral HPV16 infection, despite no known anogenital disease in these participants.

Indirect Protection and Indirect Measures of Protection From Rotavirus in Adults

TO THE EDITOR—We read with interest the recent article by Lopman et al [1], who used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM) data from the Nationwide Inpatient Sample (NIS) to document a decline in rotavirus and cause-unspecified gastroenteritis in 2008 in patients <24 years of age following widespread implementation of pediatric rotavirus vaccination. Despite the fact that administrative coding (ICD-9CM) data have been widely used [1–6], we are unaware of data regarding how well these codes identify hospitalized adults with all-cause gastroenteritis. In addition, important differences exist in the ICD-9CM codes used in studies, depending on whether the focus was on foodborne illness or all-cause gastroenteritis. Analysis of administrative data that was performed for rotavirus in children showed an underestimation of rotavirus in that population [7]. As part of an institutional review board–approved study of the prevalence of rotavirus among adults hospitalized at Northwestern Memorial Hospital (Chicago, Illinois) from 1 December 2005 through 30 November 2006, who had a stool specimen submitted for bacterial stool culture (BSC) [8], we compared how well ICD9CM codes were able to identify patients with gastroenteritis when compared with having a BSC obtained, a surrogate for a clinical diagnosis of gastroenteritis. We used the criteria from the sentinel study of Mounts et al [3]. Any patient with an ICD-9CM code of 008.45 (Clostridium difficile) was reviewed and Table 1. Comparison Between Patients With an ICD-9CM Code Consistent With Gastroenteritis and Those Who Have a Bacterial Stool Culture Saved