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1.  Natural History of Anal Dysplasia in an HIV-Infected Clinical Care Cohort: Estimates Using Multi-State Markov Modeling 
PLoS ONE  2014;9(8):e104116.
Objectives
(1) To model the natural history of anal neoplasia in HIV-infected patients using a 3-state Markov model of anal cancer pathogenesis, adjusting for cytology misclassification; and (2) to estimate the effects of selected time-varying covariates on transition probabilities.
Design
A retrospective cytology-based inception screening cohort of HIV-infected adults was analyzed using a 3-state Markov model of clinical pathogenesis of anal neoplasia.
Methods
Longitudinally ascertained cytology categories were adjusted for misclassification using estimates of cytology accuracy derived from the study cohort. Time-varying covariate effects were estimated as hazard ratios.
Results
(1) There was a moderate to high probability of regression of the high grade squamous intraepithelial lesion (HSIL) state (27–62%) at 2 years after initial cytology screening; (2) the probability of developing invasive anal cancer (IAC) during the first 2 years after a baseline HSIL cytology is low (1.9–2.8%); (3) infrared coagulation (IRC) ablation of HSIL lesions is associated with a 2.2–4.2 fold increased probability of regression to
Conclusions
The finding of moderate to high rates of regression of the HSIL state accompanied by low rates of progression to IAC should inform both screening and precursor treatment guideline development. There appears to be a consistent and robust beneficial effect of antiretroviral therapy, suppressed viral load, and higher CD4 on the transition from the
doi:10.1371/journal.pone.0104116
PMCID: PMC4125167  PMID: 25101757
PLoS ONE  2014;9(7):e102883.
Background
The aims were to investigate the hepatitis C (HCV) cascade of care among HIV-infected patients and to identify reasons for not referring for and not initiating HCV therapy after completion of HCV treatment staging.
Design and Methods
Retrospective cohort analysis of HIV-infected patients under care at the University of California, San Diego (UCSD). We identified patients screened for and diagnosed with active HCV infection. Logistic regression analyses were used to identify factors associated with lack of referral for HCV therapy. Electronic medical records were reviewed to ascertain reasons for not initiating HCV therapy.
Results
Between 2008 and 2012, 4725 HIV-infected patients received care at the UCSD Owen clinic. Most patients [4534 (96%)] were screened for HCV, 748 (16%) patients had reactive serum HCV antibodies but only 542 patients had active HCV infection. Lack of engagement in care was the most important predictor of non-referral for HCV therapy [odds ratio (OR): 5.08, 95% confidence interval 3.24–6.97, p<0.00001]. Other significant predictors included unstable housing (OR: 2.26), AIDS (OR: 1.83), having a detectable HIV viral load (OR: 1.98) and being non-white (OR: 1.67). The most common reason (40%) for not initiating or deferring HCV therapy was the presence of ongoing barriers to care.
Conclusions
Screening for HCV in HIV-infected patients linked to care is high but almost half of patients diagnosed with HCV are not referred for HCV therapy. Despite improvements in HCV therapy the benefits will not be realized unless effective measures for dealing with barriers to care are implemented.
doi:10.1371/journal.pone.0102883
PMCID: PMC4103859  PMID: 25036553
Background
Access to Hepatitis C (HCV) care is low among HIV-infected individuals, highlighting the need for new models to deliver care for this population.
Methods
Retrospective cohort analysis that compared the number of HIV patients who initiated HCV therapy: hepatology (2005–2008) vs. HIV primary care model (2008–2011). Logistic-regression modeling was used to ascertain factors associated with HCV therapy initiation and achievement of sustained viral response (SVR).
Results
Of 196 and 163 patients that were enrolled in the HIV primary care and hepatology models, 48 and 26 were treated for HCV, respectively (p = 0.043). The HIV/HCV-patient referral rate did not differ during the two study periods (0.10 vs. 0.12/patient-yr, p = 0.18). In unadjusted analysis, predictors (p < 0.05) of HCV treatment initiation included referral to the HIV primary care model (OR: 1.7), a CD4+ count ≥400/mm3 (OR: 1.8) and alanine aminotranferase level ≥63U/L (OR: 1.9). Prior psychiatric medication use correlated negatively with HCV treatment initiation (OR: 0.6, p = 0.045). In adjusted analysis the strongest predictor of HCV treatment initiation was CD4+ count (≥400/mm3, OR: 2.1, p = 0.01). There was no significant difference in either clinic model (primary care vs. hepatology) in the rates of treatment discontinuation due to adverse events (29% vs. 16%), loss to follow-up (8 vs. 8%), or HCV SVR (44 vs. 35%).
Conclusions
Using a HIV primary care model increased the number of HIV patients who initiate HCV therapy with comparable outcomes to a hepatology model.
doi:10.1186/1742-6405-10-9
PMCID: PMC3620560  PMID: 23537147
HIV; HCV treatment; Primary care; Hepatology
Summary
We assessed the effect of herpes simplex virus type 2 (HSV-2) acquisition on the plasma HIV RNA and CD4 cell levels among individuals with primary HIV infection using a retrospective cohort analysis. We studied 119 adult, antiretroviral-naive, recently HIV-infected men with a negative HSV-2–specific enzyme immunoassay (EIA) result at enrollment. HSV-2 acquisition was determined by seroconversion on HSV-2 EIA, confirmed by Western blot analysis. Ten men acquired HSV-2 infection a median of 1.3 years after HIV infection (HSV-2 incidence rate of 7.4 per 100 person-years of follow-up). The median time of follow-up after acquiring HSV-2 infection was 303 days. All men except 1 were asymptomatic during HSV-2 acquisition, and only 1 HSV-2 seroconverter, who was asymptomatic, had a transient increase in blood HIV load (0.5 log10 copies/mL over 11 days). The HSV-2 incidence rate was high in our cohort of recently HIV-infected individuals; however, HSV-2 acquisition did not significantly change the plasma HIV dynamics and CD4 cell levels.
doi:10.1097/QAI.0b013e318163bd87
PMCID: PMC2630881  PMID: 18197122
HIV RNA; incident herpes simplex virus-2; viral dynamics
PLoS ONE  2012;7(7):e38956.
Background
We recently reported, using a receiver operating characteristic area metric, the first meta-analytic comparison of the relative accuracy of cervical and anal cytology in detecting moderate or severe histopathologic lesions by magnification directed punch biopsy. The aim of the present research was to meta-analytically examine cut-point specific operating characteristics (sensitivity, specificity) of cervical and anal cytology in detecting high grade squamous intraepithelial lesion (HSIL) histopathology by colposcope directed punch biopsy.
Methodology/Principal Findings
The primary eligibility requirement was availability of tabulated cytology (normal, atypical cells of unclear significance [ASCUS], low grade squamous intraepithelial lesion, HSIL or atypical squamous cells cannot rule out high grade [ASC-H]) and biopsy (
Conclusions/Significance
Using a cytology cut-point of HSIL or ASC-H, anal cytology is less sensitive but comparably specific to cervical cytology. However, using a cut-point of ASCUS, differences in accuracy were of borderline significance.
doi:10.1371/journal.pone.0038956
PMCID: PMC3405082  PMID: 22848345
Aims
To describe: 1) our cohort of patients diagnosed with NCPH in a HIV academic clinic in North America, and 2) longitudinal follow-up and outcomes of patients following NCPH diagnosis.
Study design
Retrospective case series.
Place and Duration of Study
Owen clinic, University of California, San Diego, United States, between October 1990 and December 2010.
Methodology
We describe a cohort of patients diagnosed with NCPH in a HIV academic clinic with emphasis on their follow-up and outcomes after NCPH diagnosis.
Results
During the study period, eight HIV-infected men were diagnosed with NCPH. All patients were exposed to Didanosine (ddI) for a median of 37 months. One patient died soon after NCPH diagnosis due to a condition unrelated to NCPH. The other seven patients have received B-blocker therapy and annual esophago-gastro-duodenectomy screenings with banding of esophageal varices when indicated and remain still alive. Three patients were on ddI at the time of NCPH diagnosis. In one patient ddI was discontinued shortly after NCPH diagnosis. The other two patients continued to use ddI after NCPH diagnosis and developed recurrent upper gastrointestinal bleeding in the subsequent 2 years, requiring revascularization interventions. The four patients that were already off ddI at the time of NCPH diagnosis have been followed for a median of 6 years. These four patients remained minimally symptomatic for up to 16 years of follow-up from NCPH diagnosis.
Conclusion
When ddI was discontinued before portal hypertension was clinically apparent the progression of NCPH appeared to subside without major clinical complications.
PMCID: PMC3261794  PMID: 22268001
Noncirrhotic portal hypertension; HIV; didanosine
Background
We aimed to determine the reliability and validity of a hepatitis symptom inventory and to identify predictors of hepatitis C (HCV) treatment initiation in a cohort of HIV-infected patients.
Methods
Prospective clinic based study that enrolled patients referred for HCV therapy consideration. A hepatitis symptom inventory and the Center for Epidemiologic Studies Depression Scale (CES-D) were administered to HIV/HCV individuals. The symptom inventory was factor analyzed and subscale reliability estimated with Cronbach's alpha. Predictive validity was evaluated using generalized estimating equations (GEE). Predictors of HCV treatment were identified using logistic regression.
Results
Between April 2008 to July 2010, 126 HIV/HCV co-infected patients were enrolled in the study. Factor analysis using data from 126 patients yielded a three-factor structure explaining 60% of the variance for the inventory. Factor 1 (neuropsychiatric symptoms) had 14 items, factor 2 (somatic symptoms) had eleven items, and factor 3 (sleep symptoms) had two items, explaining 28%, 22% and 11% of the variance, respectively. The three factor subscales demonstrated high intrinsic consistency reliability. GEE modeling of the 32 patients who initiated HCV therapy showed that patients developed worsening neuropsychiatric and somatic symptoms following HCV therapy with stable sleep symptoms. Bivariate analyses identified the following as predictors of HCV therapy initiation: lower HIV log10 RNA, lower scores for neuropsychiatric, somatic and sleep symptoms, lower CES-D scores and white ethnicity. In stepwise multiple logistic regression analysis, low neuropsychiatric symptom score was the strongest independent predictor of HCV therapy initiation and HIV log10 RNA was inversely associated with a decision to initiate HCV treatment.
Conclusions
A 41-item hepatitis-related symptom inventory was found to have a clinically meaningful 3-factor structure with excellent internal consistency reliability and predictive validity. In adjusted analysis, low neuropsychiatric symptom scores and controlled HIV infection were independent predictors of HCV treatment initiation. The usefulness of the HCV symptom inventory in monitoring HCV treatment should be evaluated prospectively.
doi:10.1186/1742-6405-8-29
PMCID: PMC3163174  PMID: 21831314
PLoS ONE  2010;5(8):e12284.
Background
The study aim is to estimate sensitivity and specificity of anal cytology for histologic HSIL in analyses adjusted for the imperfect biopsy reference standard.
Methods and Principal Findings
Retrospective cohort study of an anal dysplasia screening program for HIV infected adults. We estimated the prevalence of histologic HSIL by concurrent cytology category and the associated cytology ROC area. Cytology operating characteristics for HSIL were estimated and adjusted for the imperfect reference standard by 3 methodologies. The study cohort included 261 patients with 3 available measures: (1) referral cytology; (2) HRA cytology; and (3) HRA directed biopsy. The prevalence of biopsy HSIL varied according to the concurrent HRA cytology result: 64.5% for HSIL or ASC-H, 12.6% for LSIL, 10.9% for ASCUS, and 6.3% for no abnormality. The cytology ROC area was 0.78. The observed prevalence of HSIL was 37% (referral cytology), 24% (HRA cytology), and 24% (HRA biopsy). Unadjusted estimates of sensitivity and specificity of cytology were 0.66 and 0.90, respectively. Adjusted estimates varied from 0.47–0.89 (sensitivity) and 0.89—1.0 (specificity).
Conclusions
Analysis of a single dataset yields widely different estimates of anal cytology operating characteristics that depend on difficult to verify assumptions regarding the accuracy of the imperfect reference standard.
doi:10.1371/journal.pone.0012284
PMCID: PMC2924391  PMID: 20808869
Background
This study aimed to evaluate the prevalence and predictors of AIDS-related complicated cryptococcal meningitis. The outcome was complicated cryptococcal meningitis: prolonged (≥ 14 days) altered mental status, persistent (≥ 14 days) focal neurologic findings, cerebrospinal fluid (CSF) shunt placement or death. Predictor variable operating characteristics were estimated using receiver operating characteristic curve (ROC) analysis. Multivariate analysis identified independent predictors of the outcome.
Results
From 1990-2009, 82 patients with first episode of cryptococcal meningitis were identified. Of these, 14 (17%) met criteria for complicated forms of cryptococcal meningitis (prolonged altered mental status 6, persistent focal neurologic findings 7, CSF surgical shunt placement 8, and death 5). Patients with complicated cryptococcal meningitis had higher frequency of baseline focal neurological findings, head computed tomography (CT) abnormalities, mean CSF opening pressure, and cryptococcal antigen (CRAG) titers in serum and CSF. ROC area of log2 serum and CSF CRAG titers to predict complicated forms of cryptococcal meningitis were comparable, 0.78 (95%CI: 0.66 to 0.90) vs. 0.78 (95% CI: 0.67 to 0.89), respectively (χ2, p = 0.95). The ROC areas to predict the outcomes were similar for CSF pressure and CSF CRAG titers. In a multiple logistic regression model, the following were significant predictors of the outcome: baseline focal neurologic findings, head CT abnormalities and log2 CSF CRAG titer.
Conclusions
During initial clinical evaluation, a focal neurologic exam, abnormal head CT and large cryptococcal burden measured by CRAG titer are associated with the outcome of complicated cryptococcal meningitis following 2 weeks from antifungal therapy initiation.
doi:10.1186/1742-6405-7-29
PMCID: PMC2922885  PMID: 20682061
PLoS ONE  2009;4(12):e8504.
Background
The Centers for Disease Control recommend screening for asymptomatic sexually transmitted infection (STI) among HIV-infected men when there is self-report of unprotected anal-receptive exposure. The study goals were: (1) to estimate the validity and usefulness for screening policies of self-reported unprotected anal-receptive exposure as a risk indicator for asymptomatic anorectal infection with Neisseria gonorrhoeae (GC) and/or Chlamydia trachomatis (CT). (2) to estimate the number of infections that would be missed if anal diagnostic assays were not performed among patients who denied unprotected anorectal exposure in the preceding month.
Methods and Findings
Retrospective analysis in HIV primary care and high resolution anoscopy (HRA) clinics. HIV-infected adult men were screened for self-reported exposure during the previous month at all primary care and HRA appointments. Four sub-cohorts were defined based on microbiology methodology (GC culture and CT direct fluorescent antibody vs. GC/CT nucleic acid amplification test) and clinical setting (primary care vs. HRA). Screening question operating characteristics were estimated using contingency table methods and then pooled across subcohorts. Among 803 patients, the prevalence of anorectal GC/CT varied from 3.5–20.1% in the 4 sub-cohorts. The sensitivity of the screening question for self-reported exposure to predict anorectal STI was higher in the primary care than in the HRA clinic, 86–100% vs. 12–35%, respectively. The negative predictive value of the screening question to predict asymptomatic anorectal STI was ≥90% in all sub-cohorts. In sensitivity analyses, the probability of being an unidentified case among those denying exposure increased from 0.4–8.1% in the primary care setting, and from 0.9–18.8% in the HRA setting as the prevalence varied from 1–20%.
Conclusion
As STI prevalence increases, denial of unprotected anal-receptive exposure leads to an increasingly unacceptable proportion of unidentified asymptomatic anorectal STI if used as a criterion not to obtain microbiologic assays.
doi:10.1371/journal.pone.0008504
PMCID: PMC2794382  PMID: 20041143
AIDS (London, England)  2008;22(13):1667-1671.
Objective
Human immunodeficiency virus type 1 blood plasma viral load is correlated with the sexual transmission of HIV, although transmission from men involves virus from semen instead of blood. We quantified HIV-1 RNA in the blood and semen of men who did or did not transmit HIV to their sex partners. We compared the relationships of HIV-1 transmission risk with blood plasma viral load, seminal plasma viral load, herpes simplex virus 2 serostatus and other factors.
Design
A case–control study.
Methods
Participants were men evaluated for primary HIV infection and their recent male sex partners. They were interviewed, and clinical specimens were collected. Epidemiologic and phylogenetic linkages were determined by history and molecular techniques. Couples were grouped on the basis of transmission after exposure. Fisher’s exact test and Wilcoxon tests were used for comparisons between groups. Multivariable logistic regressions were fit to identify independent predictors of transmission.
Results
HIV-transmitting partners (n=15) had a higher median seminal plasma viral load (P<0.015) and median blood plasma viral load (P<0.001) than nontransmitting partners (n=32). Herpes simplex virus 2 serostatus was associated with transmission only when the HIV-infected source partner was herpes simplex virus 2 seropositive and the HIV-exposed partner was not (odds ratio 16, P<0.03). Adjusting for other factors, HIV transmission was significantly associated with blood plasma viral load (odds ratio 13.4, P<0.02) but not seminal plasma viral load (odds ratio 0.69, P=not significant).
Conclusion
Blood and seminal plasma viral load were both associated with human immunodeficiency virus type 1 transmission, but blood plasma viral load was the stronger predictor in this cohort. Herpes simplex virus 2 coinfection was associated with the risk of transmission but not acquisition of human immunodeficiency virus type 1.
doi:10.1097/QAD.0b013e32830bfed8
PMCID: PMC2653089  PMID: 18670228
herpes simplex virus 2; HIV; men who have sex with men; seminal viral load; transmission
The open AIDS journal  2007;1(1):11-20.
Background
Screening for invasive anal cancer and its precursors is being increasingly advocated as a response to increasing incidence among HIV-infected persons. We implemented a comprehensive screening program in 2001 and report our early experience to inform monitoring and evaluation of such programs. Our research aims were: (1) to estimate incidence of and mortality from invasive anal cancer (IAC) before (1995-2000) and after (2001-2005) screening program implementation and (2) to examine potential screening program quality indicators.
Methods
The study cohort included all patients under care for HIV infection at UCSD Owen Clinic between 1995-2005. Person-time incidence rates (IR) and case survival of IAC were estimated for the pre-screening (1995-2000) and post-screening (2001-2005) periods. High resolution anoscopy (HRA) operator accuracy was estimated by kappa agreement between cyto-histologic comparisons. Program quality indicators included: (1) screening coverage; (2) percent technically unsatisfactory cytology smears; (3) time between 1st abnormal cytology and 1st HRA; and (4) time between last clinic visit and last cytology.
Results
28 cases of IAC and 13,411 person-years were observed between 1995-2005. IRs (95% CI) pre-screening and post-screening were 199 and 216 per 100,000 person-years, respectively. There was no routine treatment of high grade squamous intraepithelial lesions (HSIL) during the study period. The percent of patients with IAC requiring chemoradiation decreased from 90.9% to 70.6% (p=0.36). There was a significant improvement in cyto-histologic agreement at HRA with increasing operator experience (r=0.92, p=0.025). Screening coverage was 73% of the target population. Among 14 providers, the percent unsatisfactory cytology smears averaged 27% but varied from 0 – 62%. The median time from 1st abnormal cytology to 1st HRA was 258 days. The median interval between the last cytology and the last clinic visit was 207 days.
Conclusions
(1) The overall IR of IAC did not decline in the screening era and was higher than previous estimates for HIV cohorts; (2) stage shift to IAC of more favorable prognosis is a reasonable screening goal; (3) HRA accuracy varied by provider experience; (4) because of delay in access to HRA, digital rectal exam should be combined with cytology screening to detect palpable disease.
doi:10.2174/1874613600701010011
PMCID: PMC2530895  PMID: 18776956
Anal dysplasia; screening; HIV
The Open AIDS Journal  2007;1:5-10.
Background:
Frequent methamphetamine use among recently HIV infected individuals is associated with transmitted drug resistance (TDR) to non-nucleoside reverse transcriptase inhibitors (NNRTI); however, the reversion time of TDR to drug susceptible HIV may exceed 3 years. We assessed whether recreational substance use is associated with detectable TDR among individuals newly diagnosed with HIV infection of unknown duration.
Design:
Cross-sectional analysis.
Methods:
Subjects were enrolled at the University California, San Diego Early Intervention Program. Demographic, clinical and substance use data were collected using structured interviews. Genotypic resistance testing was performed using GeneSeq™, Monogram Biosciences. We analyzed the association between substance use and TDR using bivariate analyses and the corresponding transmission networks using phylogenetic models.
Results:
Between April 2004 and July 2006, 115 individuals with genotype data were enrolled. The prevalence of alcohol, marijuana and methamphetamine use were 98%, 71% and 64% respectively. Only active methamphetamine use in the 30 days prior to HIV diagnosis was independently associated with TDR to NNRTI (OR: 6.6; p=0.002).
Conclusion:
Despite not knowing the duration of their HIV infection, individuals reporting active methamphetamine use in the 30 days prior to HIV diagnosis are at an increased risk of having HIV strains that are resistant to NNRTI.
doi:10.2174/1874613600701010005
PMCID: PMC2556194  PMID: 18923691
HIV; NNRTI; transmitted drug resistance; methamphetamine.
The Open AIDS Journal  2007;1:11-20.
Background:
Screening for invasive anal cancer and its precursors is being increasingly advocated as a response to increasing incidence among HIV-infected persons. We implemented a comprehensive screening program in 2001 and report our early experience to inform monitoring and evaluation of such programs. Our research aims were: (1) to estimate incidence of and mortality from invasive anal cancer (IAC) before (1995-2000) and after (2001-2005) screening program implementation and (2) to examine potential screening program quality indicators.
Methods:
The study cohort included all patients under care for HIV infection at UCSD Owen Clinic between 1995-2005. Person-time incidence rates (IR) and case survival of IAC were estimated for the pre-screening (1995-2000) and post-screening (2001-2005) periods. High resolution anoscopy (HRA) operator accuracy was estimated by kappa agreement between cyto-histologic comparisons. Program quality indicators included: (1) screening coverage; (2) percent technically unsatisfactory cytology smears; (3) time between 1st abnormal cytology and 1st HRA; and (4) time between last clinic visit and last cytology.
Results:
28 cases of IAC and 13,411 person-years were observed between 1995-2005. IRs (95% CI) pre-screening and post-screening were 199 and 216 per 100,000 person-years, respectively. There was no routine treatment of high grade squamous intraepithelial lesions (HSIL) during the study period. The percent of patients with IAC requiring chemoradiation decreased from 90.9% to 70.6% (p=0.36). There was a significant improvement in cyto-histologic agreement at HRA with increasing operator experience (r=0.92, p=0.025). Screening coverage was 73% of the target population. Among 14 providers, the percent unsatisfactory cytology smears averaged 27% but varied from 0 – 62%. The median time from 1st abnormal cytology to 1st HRA was 258 days. The median interval between the last cytology and the last clinic visit was 207 days.
Conclusion:
(1) The overall IR of IAC did not decline in the screening era and was higher than previous estimates for HIV cohorts; (2) stage shift to IAC of more favorable prognosis is a reasonable screening goal; (3) HRA accuracy varied by provider experience; (4) because of delay in access to HRA, digital rectal exam should be combined with cytology screening to detect palpable disease.
doi:10.2174/1874613600701010011
PMCID: PMC2530895  PMID: 18776956
Anal dysplasia; screening; HIV.

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