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1.  Critical Care of Persons Infected with the Human Immunodeficiency Virus 
Clinics in chest medicine  2013;34(2):307-323.
doi:10.1016/j.ccm.2013.01.011
PMCID: PMC3786408  PMID: 23702179
ICU; HIV; AIDS; Antiretroviral therapy
2.  Evaluation for a Novel Methicillin Resistance (mecC) Homologue in Methicillin-Resistant Staphylococcus aureus Isolates Obtained from Injured Military Personnel 
Journal of Clinical Microbiology  2013;51(9):3073-3075.
A total of 102 methicillin-resistant Staphylococcus aureus (MRSA) isolates collected from 50 injured service members (June 2009 to December 2011) at U.S. military treatment facilities were analyzed for the conventional mecA gene and mecC homologue by using standard PCR-based methods. The prevalence of the mecC homologue was zero.
doi:10.1128/JCM.01516-13
PMCID: PMC3754630  PMID: 23784136
3.  Race/ethnicity and HAART initiation in a military HIV infected cohort 
Background
Prior studies have suggested that HAART initiation may vary by race/ethnicity. Utilizing the U.S. military healthcare system, which minimizes confounding from healthcare access, we analyzed whether timing of HAART initiation and the appropriate initiation of primary prophylaxis among those at high risk for pneumocystis pneumonia (PCP) varies by race/ethnicity.
Methods
Participants in the U.S. Military HIV Natural History Study from 1998-2009 who had not initiated HAART before 1998 and who, based on DHHS guidelines, had a definite indication for HAART (CD4 <200, AIDS event or severe symptoms; Group A), an indication to consider HAART (including CD4 <350; Group B) or electively started HAART (CD4 >350; Group C) were analyzed for factors associated with HAART initiation. In a secondary analysis, participants were also evaluated for factors associated with starting primary PCP prophylaxis within four months of a CD4 count <200 cells/mm3. Multiple logistic regression was used to compare those who started vs. delayed therapy; comparisons were expressed as odds ratios (OR).
Results
1262 participants were evaluated in the analysis of HAART initiation (A = 208, B = 637, C = 479 [62 participants were evaluated in both Groups A and B]; 94% male, 46% African American, 40% Caucasian). Race/ethnicity was not associated with HAART initiation in Groups A or B. In Group C, African American race/ethnicity was associated with lower odds of initiating HAART (OR 0.49, p = 0.04). Race and ethnicity were also not associated with the initiation of primary PCP prophylaxis among the 408 participants who were at risk.
Conclusions
No disparities in the initiation of HAART or primary PCP prophylaxis according to race/ethnicity were seen among those with an indication for therapy. Among those electively initiating HAART at the highest CD4 cell counts, African American race/ethnicity was associated with decreased odds of starting. This suggests that free healthcare can potentially overcome some of the observed disparities in HIV care, but that unmeasured factors may contribute to differences in elective care decisions.
doi:10.1186/1742-6405-11-10
PMCID: PMC3922739  PMID: 24460764
HIV; HAART; Race; Ethnicity; Indications for HIV treatment; Disparities in care; African Americans
4.  Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons 
Neurology  2013;80(4):371-379.
Objective:
To describe the prevalence of neurocognitive impairment (NCI) among early diagnosed and managed HIV-infected persons (HIV+) compared to HIV-negative controls.
Methods:
We performed a cross-sectional study among 200 HIV+ and 50 matched HIV-uninfected (HIV−) military beneficiaries. HIV+ patients were categorized as earlier (<6 years of HIV, no AIDS-defining conditions, and CD4 nadir >200 cells/mm3) or later stage patients (n = 100 in each group); both groups were diagnosed early and had access to care. NCI was diagnosed using a comprehensive battery of standardized neuropsychological tests.
Results:
HIV+ patients had a median age of 36 years, 91% were seroconverters (median window of 1.2 years), had a median duration of HIV of 5 years, had a CD4 nadir of 319, had current CD4 of 546 cells/mm3, and 64% were on highly active antiretroviral therapy (initiated 1.3 years after diagnosis at a median CD4 of 333 cells/mm3). NCI was diagnosed among 38 (19%, 95% confidence interval 14%–25%) HIV+ patients, with a similar prevalence of NCI among earlier and later stage patients (18% vs 20%, p = 0.72). The prevalence of NCI among HIV+ patients was similar to HIV− patients.
Conclusions:
HIV+ patients diagnosed and managed early during the course of HIV infection had a low prevalence of NCI, comparable to matched HIV-uninfected persons. Early recognition and management of HIV infection may be important in limiting neurocognitive impairment.
doi:10.1212/WNL.0b013e31827f0776
PMCID: PMC3589242  PMID: 23303852
5.  Results of a 25 Year Longitudinal Analysis of the Serologic Incidence of Syphilis in a Cohort of HIV Infected Patients with Unrestricted Access to Care 
Sexually transmitted diseases  2012;39(6):10.1097/OLQ.0b013e318249d90f.
Background
The well described biological and epidemiologic associations of syphilis and HIV are particularly relevant to the military, as service members are young and at risk for sexually transmitted infections. We therefore used the results of serial serologic testing to determine the prevalence, incidence, and risk factors for incident syphilis in a cohort of HIV-infected Department of Defense beneficiaries.
Methods
Participants with a positive non-treponemal test at HIV diagnosis that was confirmed on treponemal testing were categorized as prevalent cases, whereas participants with an initial negative non-treponemal test who subsequently developed a confirmed positive non-treponemal test as incident cases.
Results
At HIV diagnosis the prevalence of syphilis was 5.8% (n=202). 4239 participants contributed 27,192 person years (PY) to the incidence analysis and 347 (8%) developed syphilis (rate 1.3/100 PY; [1.1, 1.4]). Syphilis incidence was highest during the calendar years 2006 - 2009 (2.5/100 PY; [2.0, 2.9]). In multivariate analyses, younger age (per 10 year increase HR 0.8;[0.8-0.9]); male gender (HR 5.6; [2.3-13.7]); non European-American ethnicity (African-American (HR 3.2; [2.5-4.2]; Hispanic HR 1.9; [1.2-3.0]); history of hepatitis B (HR 1.5; [1.2-1.9]) or gonorrhea (HR 1.4; [1.1 −1.8]) were associated with syphilis.
Conclusions
The significant burden of disease both at and after HIV diagnosis, observed in this cohort, suggests that the cost-effectiveness of extending syphilis screening to at risk military members should be assessed. In addition, HIV infected persons continue to acquire syphilis, emphasizing the continued importance of prevention for positive programs.
doi:10.1097/OLQ.0b013e318249d90f
PMCID: PMC3846570  PMID: 22592829
Seroincidence; Seroprevalence; Risk Factors; Syphilis; HIV infected persons
6.  Invasive Mold Infections Following Combat-related Injuries 
Trauma-related invasive mold infections are an emerging threat among US military personnel. Early identification of suspicious wounds, based on injury profile and tissue-based diagnosis, require aggressive surgical and empiric antifungal therapy (liposomal amphotericin B and voriconazole pending histopathology and cultures).
Background. Major advances in combat casualty care have led to increased survival of patients with complex extremity trauma. Invasive fungal wound infections (IFIs) are an uncommon, but increasingly recognized, complication following trauma that require greater understanding of risk factors and clinical findings to reduce morbidity.
Methods.  The patient population includes US military personnel injured during combat from June 2009 through December 2010. Case definition required wound necrosis on successive debridements with IFI evidence by histopathology and/or microbiology (Candida spp excluded). Case finding and data collected through the Trauma Infectious Disease Outcomes Study utilized trauma registry, hospital records or operative reports, and pathologist review of histopathology specimens.
Results. A total of 37 cases were identified: proven (angioinvasion, n = 20), probable (nonvascular tissue invasion, n = 4), and possible (positive fungal culture without histopathological evidence, n = 13). In the last quarter surveyed, rates reached 3.5% of trauma admissions. Common findings include blast injury (100%) during foot patrol (92%) occurring in southern Afghanistan (94%) with lower extremity amputation (80%) and large volume blood transfusion (97.2%). Mold isolates were recovered in 83% of cases (order Mucorales, n = 16; Aspergillus spp, n = 16; Fusarium spp, n = 9), commonly with multiple mold species among infected wounds (28%). Clinical outcomes included 3 related deaths (8.1%), frequent debridements (median, 11 cases), and amputation revisions (58%).
Conclusions. IFIs are an emerging trauma-related infection leading to significant morbidity. Early identification, using common characteristics of patient injury profile and tissue-based diagnosis, should be accompanied by aggressive surgical and antifungal therapy (liposomal amphotericin B and a broad-spectrum triazole pending mycology results) among patients with suspicious wounds.
doi:10.1093/cid/cis749
PMCID: PMC3657499  PMID: 23042971
7.  Prevalence and Factors Associated With Sleep Disturbances Among Early-Treated HIV-Infected Persons 
Persons infected with human immunodeficiency virus (HIV) have a high prevalence of insomnia (46%) and daytime drowsiness (30%). Factors associated with insomnia among patients with HIV infection include depression and increased waist size. Screening for sleep disturbances should be considered among HIV-infected persons.
Background. Sleep disturbances are reportedly common among persons infected with human immunodeficiency virus (HIV), but recent data, including comparisons with HIV-uninfected persons, are limited.
Methods. We performed a cross-sectional study among early-treated HIV-infected military beneficiaries (n = 193) to determine the prevalence and factors associated with insomnia (Pittsburgh Sleep Quality Index [PSQI]) and daytime sleepiness (Epworth Sleepiness Scale [ESS]). Data were compared with HIV-uninfected persons (n = 50) matched by age, sex, race or ethnicity, and military rank.
Results. Forty-six percent of HIV-infected persons had insomnia (PSQI >5), and 30% reported daytime drowsiness (ESS ≥10). The prevalence of insomnia and daytime sleepiness was not significantly higher compared with the HIV-uninfected group (38% [P = .30] and 20% [P = .18], respectively). In the multivariate model, factors associated with insomnia among HIV infected patients included depression (odds ratio [OR], 16.8; 95% confidence interval [CI], 2.0–142.1; P = .01), increased waist size (OR, 2.7; 95% CI, 1.4–5.1; P = .002), and fewer years of education (OR, 0.8; 95% CI, .7–.95; P = .006). Neurocognitive impairment (diagnosed in 19% of HIV-infected participants) was not associated with insomnia; however, HIV-infected persons with insomnia were 3.1-fold more likely to have a decline in activities of daily living than those without insomnia (23% vs 9%; P = .01). Only 18% of HIV-infected persons reported using a sleep medication at least weekly.
Conclusions. HIV-infected persons have a high prevalence of insomnia, but among an early-treated cohort this rate was not significantly higher compared with HIV-uninfected persons. Factors associated with insomnia among HIV-infected patients include depression and increased waist size. Prompt diagnosis and treatment of sleep disturbances are advocated and may improve quality of life.
doi:10.1093/cid/cis192
PMCID: PMC3334363  PMID: 22431801
8.  Early immunologic correlates of HIV protection can be identified from computational analysis of complex multivariate T-cell flow cytometry assays* 
Bioinformatics  2012;28(7):1009-1016.
Motivation: Polychromatic flow cytometry (PFC), has enormous power as a tool to dissect complex immune responses (such as those observed in HIV disease) at a single cell level. However, analysis tools are severely lacking. Although high-throughput systems allow rapid data collection from large cohorts, manual data analysis can take months. Moreover, identification of cell populations can be subjective and analysts rarely examine the entirety of the multidimensional dataset (focusing instead on a limited number of subsets, the biology of which has usually already been well-described). Thus, the value of PFC as a discovery tool is largely wasted.
Results: To address this problem, we developed a computational approach that automatically reveals all possible cell subsets. From tens of thousands of subsets, those that correlate strongly with clinical outcome are selected and grouped. Within each group, markers that have minimal relevance to the biological outcome are removed, thereby distilling the complex dataset into the simplest, most clinically relevant subsets. This allows complex information from PFC studies to be translated into clinical or resource-poor settings, where multiparametric analysis is less feasible. We demonstrate the utility of this approach in a large (n=466), retrospective, 14-parameter PFC study of early HIV infection, where we identify three T-cell subsets that strongly predict progression to AIDS (only one of which was identified by an initial manual analysis).
Availability: The ‘flowType: Phenotyping Multivariate PFC Assays’ package is available through Bioconductor. Additional documentation and examples are available at: www.terryfoxlab.ca/flowsite/flowType/
Supplementary information: Supplementary data are available at Bioinformatics online.
Contact: rbrinkman@bccrc.ca
doi:10.1093/bioinformatics/bts082
PMCID: PMC3315712  PMID: 22383736
9.  Hepatitis B Virus Coinfection Negatively Impacts HIV Outcomes in HIV Seroconverters 
The Journal of Infectious Diseases  2011;205(2):185-193.
(See the editorial commentary by Peters and Marston, on pages 166–8.)
Background. Understanding the impact of hepatitis B virus (HBV) in human immunodeficiency virus (HIV) coinfection has been limited by heterogeneity of HIV disease. We evaluated HBV coinfection and HIV-related disease progression in a cohort of HIV seroconverters.
Methods. Participants with HIV diagnosis seroconversion window of ≤3 years and serologically confirmed HBV infection (HB) status were classified at baseline into 4 HB groups. The risk of clinical AIDS/death in HIV seroconverters was calculated by HB status.
Results. Of 2352 HIV seroconverters, 474 (20%) had resolved HB, 82 (3%) had isolated total antibody to hepatitis B core antigen (HBcAb), and 64 (3%) had chronic HB. Unadjusted rates (95% confidence intervals [CIs]) of clinical AIDS/death for the HB-negative, resolved HB, isolated HBcAb, and chronic HB groups were 2.43 (2.15–2.71); 3.27 (2.71–3.84); 3.75 (2.25–5.25); and 5.41 (3.41–7.42), respectively. The multivariable risk of clinical AIDS/death was significantly higher in the chronic HB group compared to the HB-negative group (hazard ratio [HR], 1.80; 95% CI, 1.20–2.69); while the HRs were increased but nonsignificant for those with resolved HB (HR, 1.17; 95% CI, .94–1.46) and isolated HBcAb (HR, 1.14; 95% CI, .75–1.75).
Conclusions. HBV coinfection has a significant impact on HIV outcomes. The hazard for an AIDS or death event is almost double for those with chronic HB compared, with HIV-monoinfected persons.
doi:10.1093/infdis/jir720
PMCID: PMC3244364  PMID: 22147794
10.  Identification of an Abbreviated Test Battery for Detection of HIV-Associated Neurocognitive Impairment in an Early-Managed HIV-Infected Cohort 
PLoS ONE  2012;7(11):e47310.
Background
HIV-associated neurocognitive disorders (HAND) remain prevalent despite improved antiretroviral treatment (ART), and it is essential to have a sensitive and specific HAND screening tool.
Methods
Participants were 200 HIV-infected US military beneficiaries, managed early in the course of HIV infection, had few comorbidities, and had open access to ART. Participants completed a comprehensive, seven-domain (16-test), neuropsychological battery (∼120 min); neurocognitive impairment (NCI) was determined using a standardized score derived from demographically adjusted T-scores (global deficit score ≥0.5). Restricting the estimated administration time of the screening battery to < = 20 minutes, we examined the sensitivity and specificity of detecting NCI for all possible combinations of 2-, 3-, and 4- tests from the comprehensive battery.
Results
Participants were relatively healthy (median CD4 count: 546 cells/mm3) with 64% receiving ART. Prevalence of NCI was low (19%). The best 2-test screener included the Stroop Color Test and the Hopkins Verbal Learning Test-Revised (11 min; sensitivity = 73%; specificity = 83%); the best 3-test screener included the above measures plus the Paced Auditory Serial Addition Test (PASAT; 16 min; sensitivity = 86%; specificity = 75%). The addition of Action Fluency to the above three tests improved specificity (18 min; sensitivity = 86%; specificity = 87%).
Conclusions
Combinations of widely accepted neuropsychological tests with brief implementation time demonstrated good sensitivity and specificity compared to a time intensive neuropsychological test battery. Tests of verbal learning, attention/working memory, and processing speed are particularly useful in detecting NCI. Utilizing validated, easy to administer, traditional neuropsychological tests with established normative data may represent an excellent approach to screening for NCI in HIV.
doi:10.1371/journal.pone.0047310
PMCID: PMC3493574  PMID: 23144815
11.  Elevated CD8 Counts During HAART are Associated with HIV Virologic Treatment Failure 
Objective
To evaluate whether elevated CD8 counts are associated with increased risk of virologic treatment failure in HIV-infected individuals.
Design
Retrospective cohort study.
Methods
U.S. Military HIV Natural History Study participants who initiated HAART in 1996-2008, had 6- and 12-month post-HAART HIV RNA <400 c/ml, ≥2 subsequent HIV viral loads and a baseline CD8 count were eligible (n=817). Baseline was 12 months after HAART start, virologic failure was defined as confirmed HIV RNA ≥400 c/ml, and CD8 counts ≥1200 cells/mm3 were considered elevated. Cox models were used to examine the effect of baseline and time-updated CD8 counts on virologic failure.
Results
There were 216 failures for a rate of 5.6 per 100 person-years (95% confidence interval [CI] 4.9-6.4). Among those initiating HAART in 2000-2008, participants with elevated baseline CD8 counts had significantly greater risk of virologic failure compared to those with baseline CD8 counts ≤600 cells/mm3 (hazard ratio [HR] = 2.68, 95% CI 1.13 – 6.35). Participants with elevated CD8 counts at >20% of prior 6-month follow-up visits had greater risk of failure at the current visit than those who did not (HR = 1.53, 95% CI 1.14 - 2.06). Those with CD8 counts that increased after HAART start had greater risk of failure than those with CD8 counts that decreased or remained the same (HR = 1.59, 95% CI 1.19 – 2.13).
Conclusions
Initial or serial elevated CD8 counts while on HAART or an increase in CD8 counts from HAART initiation may be early warnings for future treatment failure.
doi:10.1097/QAI.0b013e318221c62a
PMCID: PMC3173352  PMID: 21602694
Human immunodeficiency virus; CD8 count; antiretroviral therapy; HIV viral load suppression; HIV virologic failure
12.  Long-term Durability of Immune Responses After Hepatitis A Vaccination Among HIV-Infected Adults 
The Journal of Infectious Diseases  2011;203(12):1815-1823.
Background.  Vaccination provides long-term immunity to hepatitis A virus (HAV) among the general population, but there are no such data regarding vaccine durability among human immunodeficiency virus (HIV)–infected adults.
Methods.  We retrospectively studied HIV-infected adults who had received 2 doses of HAV vaccine. We analyzed blood specimens taken at 1 year, 3 years, and, when available, 6–10 years postvaccination. HAV immunoglobulin G (IgG) values of ≥10 mIU/mL were considered seropositive.
Results.  We evaluated specimens from 130 HIV-infected adults with a median age of 35 years and a median CD4 cell count of 461 cells/mm3 at or before time of vaccination. Of these, 49% had an HIV RNA load <1000 copies/mL. Initial vaccine responses were achieved in 89% of HIV-infected adults (95% confidence interval [CI], 83%–94%), compared with 100% (95% CI, 99%–100%) of historical HIV-uninfected adults. Among initial HIV-infected responders with available specimens, 90% (104 of 116; 95% CI, 83%–95%) remained seropositive at 3 years and 85% (63 of 74; 95% CI, 75%–92%) at 6–10 years. Geometric mean concentrations (GMCs) among HIV-infected adults were 154, 111, and 64 mIU/mL at 1, 3, and 6–10 years, respectively, compared with 1734, 687, and 684 mIU/mL among HIV-uninfected persons. Higher GMCs over time among HIV-infected adults were associated with lower log10 HIV RNA levels (β = −.12, P = .04).
Conclusions.  Most adults with well-controlled HIV infections had durable seropositive responses up to 6–10 years after HAV vaccination. Suppressed HIV RNA levels are associated with durable HAV responses.
doi:10.1093/infdis/jir180
PMCID: PMC3100512  PMID: 21606540
13.  DURABILITY OF ANTIBODY RESPONSES AFTER RECEIPT OF THE MONOVALENT 2009 INFLUENZA A (H1N1) VACCINE AMONG HIV-INFECTED AND HIV-UNINFECTED ADULTS 
Vaccine  2011;29(17):3183-3191.
Background
Human immunodeficiency virus (HIV)-infected persons are at risk for severe influenza infections. Although vaccination against the H1N1 pandemic influenza strain is recommended, currently, there are no data on the durability of post-vaccination antibody responses in this population.
Methods
HIV-infected and HIV-uninfected adults (18–50 years old) received a single dose of monovalent 2009 influenza A (H1N1) vaccine (strain A/California/7/2009H1N1). Antibody levels to the 2009 H1N1 pandemic strain were determined at day 0, day 28, and 6 months by hemagglutination-inhibition assay. A seroprotective response was a post-vaccination titer of ≥1:40 among those with a pre-vaccination level of ≤1:10. Geometric mean titers (GMT) and factors associated with higher levels were also evaluated.
Results
We studied 127 participants with a median age of 35 (interquartile range (IQR) 28, 42) years. Among the HIV-infected arm (n=63), the median CD4 count was 595 (IQR 476, 819) cells/mm3 and 83% were receiving HAART. Thirty-five percent of all participants had a pre-vaccination level of >1:10. HIV-infected compared to HIV-uninfected adults were less likely to generate a seroprotective response at day 28 (54% vs. 75%, adjusted OR 0.23, p=0.021) or have a durable response at 6 months post-vaccination (28% vs. 56%, adjusted OR 0.19, p=0.005). Additionally, although pre-vaccination GMT were similar in both arms (median 7 vs. 8, p=0.11), the GMT at 6 months was significantly lower among HIV-infected versus HIV-uninfected adults (median 20 vs. 113, p=0.003). Among HIV-infected persons, younger age (p=0.035) and receipt of HAART (p=0.028) were associated with higher GMTs at 6 months.
Conclusions
Despite vaccination, most HIV-infected adults do not have durable seroprotective antibody responses to the 2009 influenza A (H1N1) virus, and hence may remain vulnerable to infection. In addition to HAART use, more immunogenic vaccines are likely needed for improving protection against influenza in this population.
doi:10.1016/j.vaccine.2011.02.040
PMCID: PMC3078993  PMID: 21371580
influenza; pandemic 2009 H1N1; vaccine responses; HIV; durability; long-term immunity
14.  Long-Term Safety and Serologic Response to Measles, Mumps, and Rubella Vaccination in HIV-1 Infected Adults 
Vaccine  2011;29(16):2874-2880.
We analyzed HIV viral load (VL) and CD4 count changes, and antibody responses following MMR vaccination of individuals in the U.S. Military HIV Natural History Study cohort. Cases receiving at least one dose of MMR vaccine after HIV diagnosis were matched 1:2 to HIV-positive controls not receiving the vaccine. Baseline was defined as time of vaccination for cases and indexed and matched to the time post-HIV diagnosis for controls. Changes in CD4 count and VL at 6, 12, 18 and 24 months were compared between cases and controls using a general linear model. Available sera from cases were tested for MMR seropositivity at baseline and post-vaccination at 6, 12, 18, and 24 months. Overall mean CD4 count change from baseline through 24 months was 20 (±23) cells/μL greater for cases than controls (p=0.39). Similar non-significant changes in CD4 cell count were seen in the subset of those not on HAART at baseline. VL changes were small and similar between groups (mean differential change −0.04 (±0.18) log10 copies/mL; p=0.84). Of 21 vaccinated participants with baseline serologic testing, 14 (67%) were reactive to measles, 19 (91%) to mumps, and 20 (95%) to rubella. Three (43%) of 7 participants nonreactive to measles developed measles IgG; for mumps, 1 (50%) of 2 developed mumps IgG; for rubella, 1 (100%) developed rubella IgG. MMR vaccination did not result in detrimental immunologic or virologic changes through 24 months post-vaccination.
doi:10.1016/j.vaccine.2011.02.013
PMCID: PMC3073409  PMID: 21352938
Measles; Mumps; MMR Vaccine; Human Immunodeficiency Virus; Vaccines; Vaccination
15.  Hepatitis B Vaccine Antibody Response and the Risk of Clinical AIDS or Death 
PLoS ONE  2012;7(3):e33488.
Background
Whether seroresponse to a vaccine such as hepatitis B virus (HBV) vaccine can provide a measure of the functional immune status of HIV-infected persons is unknown.This study evaluated the relationship between HBV vaccine seroresponses and progression to clinical AIDS or death.
Methods and Findings
From a large HIV cohort, we evaluated those who received HBV vaccine only after HIV diagnosis and had anti-HBs determination 1–12 months after the last vaccine dose. Non-response and positive response were defined as anti-HBs <10 and ≥10 IU/L, respectively. Participants were followed from date of last vaccination to clinical AIDS, death, or last visit. Univariate and multivariable risk of progression to clinical AIDS or death were evaluated with Cox regression models. A total of 795 participants vaccinated from 1986–2010 were included, of which 41% were responders. During 3,872 person-years of observation, 122 AIDS or death events occurred (53% after 1995). Twenty-two percent of non-responders experienced clinical AIDS or death compared with 5% of responders (p<0.001). Non-response to HBV vaccine was associated with a greater than 2-fold increased risk of clinical AIDS or death (HR 2.47; 95% CI, 1.38–4.43) compared with a positive response, after adjusting for CD4 count, HIV viral load, HAART use, and delayed type hypersensitivity skin test responses (an in vivo marker of cell-mediated immunity). This association remained evident among those with CD4 count ≥500 cells/mm3 (HR 3.40; 95% CI, 1.39–8.32).
Conclusions
HBV vaccine responses may have utility in assessing functional immune status and risk stratificating HIV-infected individuals, including those with CD4 count ≥500 cells/mm3.
doi:10.1371/journal.pone.0033488
PMCID: PMC3310879  PMID: 22457767
16.  High Dose Atorvastatin Decreases Cellular Markers of Immune Activation Without Affecting HIV-1 RNA Levels: Results of a Double-blind Randomized Placebo Controlled Clinical Trial 
The Journal of Infectious Diseases  2011;203(6):756-764.
(See the editorial commentary by Carr, on pages 751–2.)
Background. 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) exhibit antiviral activity against human immunodeficiency virus type 1 (HIV-1) in vitro and may modulate the immune response to HIV infection. Studies evaluating the antiviral activity of statins have yielded conflicting results.
Methods. We conducted a randomized, double-blind, placebo-controlled crossover trial to investigate the effect of atorvastatin on HIV-1 RNA (primary objective) and cellular markers of immune activation (secondary objective). HIV-infected individuals not receiving antiretroviral therapy were randomized to receive either 8 weeks of atorvastatin (80 mg) or placebo daily. After a 4–6 week washout phase, participants switched treatment assignments. The study had 80% power to detect a 0.3 log10 decrease in HIV-1 RNA level. Expression of CD38 and HLA-DR on CD4+ and CD8+ T cells was used to measure immune activation.
Results. Of 24 randomized participants, 22 completed the study. Although HIV-1 RNA level was unaffected by the intervention (–0.13 log10 copies/mL; P = .85), atorvastatin use resulted in reductions in circulating proportions of CD4+ HLA-DR+ (–2.5%; P = .02), CD8+ HLA-DR+ (–5%; P = .006), and CD8+ HLA-DR+ CD38+ T cells (–3%; P = .03). Reductions in immune activation did not correlate with declines in serum levels of low-density lipoprotein cholesterol.
Conclusions. Short-term use of atorvastatin was associated with modest but statistically significant reductions in the proportion of activated T lymphocytes.
doi:10.1093/infdis/jiq115
PMCID: PMC3071124  PMID: 21325137
17.  Hepatitis E Virus Infection in HIV-infected Persons 
Emerging Infectious Diseases  2012;18(3):502-506.
To determine whether hepatitis E virus (HEV) is a cause of hepatitis among HIV-infected persons, we evaluated 1985–2009 data for US military beneficiaries. Evidence of acute or prior HEV infection was detected for 7 (4%) and 5 (3%) of 194 HIV-infected persons, respectively. HEV might be a cause of acute hepatitis among HIV-infected persons.
doi:10.3201/eid1803.111278
PMCID: PMC3309581  PMID: 22377220
Hepatitis E virus; HIV; epidemiology; hepatitis; military; viruses
18.  Clinical, demographic and laboratory parameters at HAART initiation associated with decreased post-HAART survival in a U.S. military prospective HIV cohort 
Background
Although highly active antiretroviral therapy (HAART) has improved HIV survival, some patients receiving therapy are still dying. This analysis was conducted to identify factors associated with increased risk of post-HAART mortality.
Methods
We evaluated baseline (prior to HAART initiation) clinical, demographic and laboratory factors (including CD4+ count and HIV RNA level) for associations with subsequent mortality in 1,600 patients who began HAART in a prospective observational cohort of HIV-infected U.S. military personnel.
Results
Cumulative mortality was 5%, 10% and 18% at 4, 8 and 12 years post-HAART. Mortality was highest (6.23 deaths/100 person-years [PY]) in those with ≤ 50 CD4+ cells/mm3 before HAART initiation, and became progressively lower as CD4+ counts increased (0.70/100 PY with ≥ 500 CD4+ cells/mm3). In multivariate analysis, factors significantly (p < 0.05) associated with post-HAART mortality included: increasing age among those ≥ 40 years (Hazard ratio [HR] = 1.32 per 5 year increase), clinical AIDS events before HAART (HR = 1.93), ≤ 50 CD4+ cells/mm3 (vs. CD4+ ≥ 500, HR = 2.97), greater HIV RNA level (HR = 1.36 per one log10 increase), hepatitis C antibody or chronic hepatitis B (HR = 1.96), and HIV diagnosis before 1996 (HR = 2.44). Baseline CD4+ = 51-200 cells (HR = 1.74, p = 0.06), and hemoglobin < 12 gm/dL for women or < 13.5 for men (HR = 1.36, p = 0.07) were borderline significant.
Conclusions
Although treatment has improved HIV survival, defining those at greatest risk for death after HAART initiation, including demographic, clinical and laboratory correlates of poorer prognoses, can help identify a subset of patients for whom more intensive monitoring, counseling, and care interventions may improve clinical outcomes and post-HAART survival.
doi:10.1186/1742-6405-9-4
PMCID: PMC3320559  PMID: 22339893
Highly active antiretroviral therapy; mortality; CD4+ lymphocyte count
19.  The Timing of Hepatitis B Virus (HBV) Immunization Relative to Human Immunodeficiency Virus (HIV) Diagnosis and the Risk of HBV Infection Following HIV Diagnosis 
American Journal of Epidemiology  2010;173(1):84-93.
To assess associations between the timing of hepatitis B virus (HBV) immunization relative to human immunodeficiency virus (HIV) diagnosis and vaccine effectiveness, US Military HIV Natural History Study cohort participants without HBV infection at the time of HIV diagnosis were grouped by vaccination status, retrospectively followed from HIV diagnosis for incident HBV infection, and compared using Cox proportional hazards models. A positive vaccine response was defined as hepatitis B surface antibody level ≥10 IU/L. Of 1,877 participants enrolled between 1989 and 2008, 441 (23%) were vaccinated prior to HIV diagnosis. Eighty percent of those who received vaccine doses only before HIV diagnosis had a positive vaccine response, compared with 66% of those who received doses both before and after HIV and 41% of those who received doses only after HIV (P < 0.01 for both compared with persons vaccinated before HIV only). Compared with the unvaccinated, persons vaccinated only before HIV had reduced risk of HBV infection after HIV diagnosis (hazard ratio = 0.38, 95% confidence interval: 0.20, 0.75). No reduction in HBV infection risk was observed for other vaccination groups. These data suggest that completion of the vaccine series prior to HIV infection may be the optimal strategy for preventing this significant comorbid infection in HIV-infected persons.
doi:10.1093/aje/kwq326
PMCID: PMC3025642  PMID: 21051446
hepatitis B vaccines; hepatitis B virus; HIV; immunization; vaccination
20.  Immunogenicity of a Monovalent 2009 Influenza A (H1N1) Vaccine in an Immunocompromised Population: A Prospective Study Comparing HIV-Infected Adults with HIV-Uninfected Adults 
Background. Limited data exist on the immunogenicity of the 2009 influenza A (H1N1) vaccine among immunocompromised persons, including those with human immunodeficiency virus (HIV) infection.
Methods. We compared the immunogenicity and tolerability of a single dose of the monovalent 2009 influenza A (H1N1) vaccine (strain A/California/7/2009H1N1) between HIV-infected and HIV-uninfected adults 18–50 years of age. The primary end point was an antibody titer of ≥1:40 at day 28 after vaccination in those with a prevaccination level of ≤1:10, as measured by hemagglutination-inhibition assay. Geometric mean titers, influenza-like illnesses, and tolerability were also evaluated.
Results. One hundred thirty-one participants were evaluated (65 HIV-infected and 66 HIV-uninfected patients), with a median age of 35 years (interquartile range, 27–42 years). HIV-infected persons had a median CD4 cell count of 581 cells/mm3 (interquartile range, 476–814 cells/mm3) , and 82% were receiving antiretroviral medications. At baseline, 35 patients (27%) had antibody titers of >1:10. HIV-infected patients (29 [56%] of 52), compared with HIV-uninfected persons (35 [80%] of 44), were significantly less likely to develop an antibody response (odds ratio, .20; P = .003). Changes in the median geometric mean titer from baseline to day 28 were also significantly lower in HIV-infected patients than in HIV-uninfected persons (75 vs 153; P = .001). Five influenza-like illnesses occurred (2 cases in HIV-infected persons), but none was attributable to the 2009 influenza H1N1 virus. The vaccine was well tolerated in both groups.
Conclusions. Despite high CD4 cell counts and receipt of antiretroviral medications, HIV-infected adults generated significantly poorer antibody responses, compared with HIV-uninfected persons. Future studies evaluating a 2-dose series or more-immunogenic influenza A (H1N1) vaccines among HIV-infected adults are needed (ClinicalTrials.gov NCT00996970).
doi:10.1093/cid/ciq019
PMCID: PMC3060889  PMID: 21148532
21.  Impact of Weight on Immune Cell Counts among HIV-Infected Persons▿ 
Prior studies have shown that weight may impact immune cell counts. However, few data exist about the relationship of weight and immune cell counts among HIV-infected patients. We examined documented HIV seroconverters (mean window, 15.7 months) in a prospective U.S. Military HIV Natural History Study (1 January 1986 to 20 January 2010). We estimated the association of the time-updated body mass index (BMI) category with changes in immune cell counts from HIV diagnosis across time (mean follow-up of 5.1 years) using multiply adjusted longitudinal linear mixed-effects models. Of 1,097 HIV seroconverters, 448 (41%) were overweight and 93 (8%) were obese at HIV diagnosis. Immune cell counts at HIV diagnosis did not significantly differ by BMI category. In the longitudinal models for those diagnosed before the advent of the highly active antiretroviral therapy (HAART) era, mean postdiagnosis decreases in the white cell count, total lymphocyte count, CD4 count, CD4 percentage, and CD4/CD8 ratio were less as the BMI category increased (all with P values of <0.05). Among HIV seroconverters diagnosed in the HAART era, obese compared to normal-weight patients had significantly smaller increases in CD4 counts, CD4 percentages, and the CD4/CD8 ratio (all with P values of <0.05). Similar findings were also noted among underweight versus normal-weight patients. In conclusion, although BMI was not associated with immune cell levels at the time of HIV diagnosis, weight appears to affect immune cells counts over the course of infection. In the HAART era, being either underweight or obese was associated with smaller increases in several important immune cell levels, including the CD4/CD8 ratio.
doi:10.1128/CVI.00020-11
PMCID: PMC3122603  PMID: 21525303
22.  Is Kaposi’s Sarcoma Occurring at Higher CD4 Counts Over the Course of the HIV Epidemic? 
AIDS (London, England)  2010;24(18):2881-2883.
We evaluated longitudinal rates of Kaposi sarcoma (KS) and trends in CD4 counts at the time of KS diagnosis during the HIV epidemic (1985–2008). Although rates of KS have decreased, cases are now occurring at higher CD4 counts over time, with more than a third of cases diagnosed in 2002–2008 occurring at CD4 counts ≥350 cells/mm3. These data support future studies evaluating the impact of HAART initiation at higher CD4 counts to further reduce KS.
doi:10.1097/QAD.0b013e32833f9fb8
PMCID: PMC2978255  PMID: 20827160
23.  The Association of Ethnicity with Antibody Responses to Pneumococcal Vaccination among Adults with HIV Infection 
Vaccine  2010;28(48):7583-7588.
Ethnicity may be associated with the incidence of pneumococcal infections and the frequency of protective vaccine responses. Earlier studies have suggested that HIV-infected persons of black ethnicity develop less robust immune responses to pneumococcal vaccination that may relate to their higher incidence of invasive disease. We evaluated the association of ethnicity with capsule-specific antibody responses to pneumococcal revaccination, with either the pneumococcal conjugate (PCV) or polysaccharide (PPV) vaccines among 188 HIV-infected adults. The proportion of the 77 African Americans (AA) and 111 Caucasians with comparable virologic and immunologic parameters who achieved a positive immune response (≥2-fold rise in capsule-specific IgG from baseline with post-vaccination value ≥1 µg/mL for ≥2 of 4 serotypes) at day 60 after revaccination was similar (43% vs. 49%, respectively, p=0.65). Results were also similar when vaccine types (PPV and PCV) were examined separately. Mean changes in log10 transformed IgG levels from baseline to days 60 and 180 post-vaccination were also not significantly different between AA and Caucasians. In summary, in this ethnically diverse cohort with equal access to care, we did not observe differential antibody responses between AA and Caucasian HIV-infected adults after pneumococcal revaccination.
doi:10.1016/j.vaccine.2010.09.056
PMCID: PMC2981674  PMID: 20887830
24.  A Randomized Clinical Trial Comparing Revaccination with Pneumococcal Conjugate Vaccine (PCV) to Polysaccharide Vaccine (PPV) among HIV-Infected Adults 
The Journal of infectious diseases  2010;202(7):1114-1125.
Background
The risk of pneumococcal disease persists and antibody responses to revaccination with the 23-valent polysaccharide vaccine (PPV) are low among HIV-infected adults. We determined whether revaccination with the 7-valent pneumococcal conjugate vaccine (PCV) would enhance these responses.
Methods
In a randomized clinical trial, we compared the immunogenicity of revaccination with PCV (n=131) or PPV (n=73) among HIV-infected adults (median CD4 count 533 cells/mm3) vaccinated with PPV 3–8 years earlier. HIV-uninfected adults (n=25) without prior pneumococcal vaccination received one dose of PCV. A positive response was defined as a ≥2-fold rise (baseline to day 60) in capsule-specific IgG with a post-vaccination level value ≥1000 ng/ml for at least 2 of the 4 serotypes.
Results
HIV-infected persons demonstrated a higher frequency of positive antibody responses to PCV vs. PPV (57% vs. 36%, p=0.004) and greater IgG concentration mean changes from baseline to day 60 for serotypes 4, 9V, and 19F (all p<0.05), but not for serotype 14. However by day 180 both outcomes were similar. Responses to PCV were greater in frequency and magnitude for all serotypes in HIV-uninfected compared with those in HIV-infected adults.
Conclusions
Among persons with HIV infection, revaccination with PCV was only transiently more immunogenic than PPV, and responses were inferior to those in HIV-uninfected subjects with primary vaccination. Pneumococcal vaccines with more robust and sustained immunogenicity are needed for HIV-infected adults.
doi:10.1086/656147
PMCID: PMC2932785  PMID: 20795819
25.  Are HIV-Positive Persons Progressing Faster After Diagnosis Over the Epidemic? 
doi:10.1097/QAI.0b013e3181e2d6c1
PMCID: PMC2901894  PMID: 20611033
HIV; epidemiology; progression; CD4 counts

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