John D. Hamilton

Dendritic Cell Responses to Early Murine Cytomegalovirus Infection Subset Functional Specialization and Differential Regulation by Interferon α/β

Differentiation of dendritic cells (DCs) into particular subsets may act to shape innate and adaptive immune responses, but little is known about how this occurs during infections. Plasmacytoid dendritic cells (PDCs) are major producers of interferon (IFN)-α/β in response to many viruses. Here, the functions of these and other splenic DC subsets are further analyzed after in vivo infection with murine cytomegalovirus (MCMV). Viral challenge induced PDC maturation, their production of high levels of innate cytokines, and their ability to activate natural killer (NK) cells. The conditions also licensed PDCs to efficiently activate CD8 T cells in vitro. Non-plasmacytoid DCs induced T lymphocyte activation in vitro. As MCMV preferentially infected CD8α+ DCs, however, restricted access to antigens may limit plasmacytoid and CD11b+ DC contribution to CD8 T cell activation. IFN-α/β regulated multiple DC responses, limiting viral replication in all DC and IL-12 production especially in the CD11b+ subset but promoting PDC accumulation and CD8α+ DC maturation. Thus, during defense against a viral infection, PDCs appear specialized for initiation of innate, and as a result of their production of IFN-α/β, regulate other DCs for induction of adaptive immunity. Therefore, they may orchestrate the DC subsets to shape endogenous immune responses to viruses.

A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. Results of the Veterans Affairs Cooperative Study.

BACKGROUND Zidovudine is recommended for asymptomatic and early symptomatic human immunodeficiency virus (HIV) infection. The best time to initiate zidovudine treatment remains uncertain, however, and whether early treatment improves survival has not been established. METHODS We conducted a multicenter, randomized, double-blind trial that compared early zidovudine therapy (beginning at 1500 mg per day) with late therapy in HIV-infected patients who were symptomatic and had CD4+ counts between 0.2 x 10(9) and 0.5 x 10(9) cells per liter (200 to 500 per cubic millimeter) at entry. Those assigned to late therapy initially received placebo and began zidovudine when their CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter) or when the acquired immunodeficiency syndrome (AIDS) developed. RESULTS During a mean follow-up period of more than two years, there were 23 deaths in the early-therapy group (n = 170) and 20 deaths in the late-therapy group (n = 168) (P = 0.48; relative risk [late vs. early], 0.81; 95 percent confidence interval, 0.44 to 1.59). In the early-therapy group, 28 patients progressed to AIDS, as compared with 48 in the late-therapy group (P = 0.02; relative risk, 1.76; 95 percent confidence interval, 1.1 to 2.8). Early therapy increased the time until CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter), and it produced more conversions from positive to negative for serum p24 antigen. Early therapy was associated with more anemia, leukopenia, nausea, vomiting, and diarrhea, whereas late therapy was associated with more skin rash. CONCLUSIONS In symptomatic patients with HIV infection, early treatment with zidovudine delays progression to AIDS, but in this controlled study it did not improve survival, and it was associated with more side effects.

Changes in Plasma HIV RNA Levels and CD4+ Lymphocyte Counts Predict Both Response to Antiretroviral Therapy and Therapeutic Failure

Disease resulting from human immunodeficiency virus (HIV) infection typically evolves over several years [1]. The goal of current antiretroviral therapy is to halt viral replication and, it is hoped, produce modest immune restoration and clinical stabilization or improvement. Treatment with combinations of antiretroviral drugs can reduce levels of viral replication more substantially than monotherapy can [2-4] and is associated with improved clinical outcome [2, 4-6]. Unfortunately, the duration of benefit derived from antiretroviral therapy has been limited, at least in part, by the emergence of resistance to this therapy [7]. An increasing array of antiretroviral agents available for the treatment of HIV infection has resulted in many potential therapeutic regimens. Thus, to optimize therapy, we need to develop markers that can identify drug failure before clinical progression. The CD4+ lymphocyte count is one such surrogate, but it has been shown to be an incomplete marker of initial antiretroviral response [8] and does not reflect the level of viral load [9, 10]. Direct and sensitive measures of plasma HIV RNA have recently become available, and these hold promise as a method for guiding antiretroviral therapy [11-13]. A single measurement of the plasma HIV RNA level has important prognostic value [9, 10] and is strongly correlated with rates of progression to the acquired immunodeficiency syndrome (AIDS), regardless of treatment. In general, low levels of plasma HIV RNA (<5000 to 10 000 copies/mL) are associated with relatively low rates of progression to AIDS, although progression does occur in some persons with very low baseline levels [9, 13, 14]. In a previous study [10], we showed that antiretroviral treatment-induced changes in plasma HIV RNA levels were the best indicators of drug efficacy. In the present study, we used samples and data from the completed Veterans Affairs Cooperative Study Program 298 (VACSP 298), which showed that rates of progression to AIDS were reduced in patients randomly assigned to immediate zidovudine therapy compared with patients randomly assigned to placebo [15]. In VACSP 298, a 75% reduction in plasma HIV RNA level explained 59% of the clinical benefit seen with immediate zidovudine treatment [10]. Here, we evaluate 1) how changes in plasma HIV RNA levels and CD4+ lymphocyte count correlate with progression to AIDS and 2) the usefulness of these measures in assessing antiretroviral drug failure during the course of therapy. Methods The details of VACSP 298, including the techniques for collecting and analyzing serum specimens, have been described elsewhere [10, 15, 16]. Clinical events and CD4+ lymphocyte counts were monitored during the original study [15, 16]; plasma HIV RNA levels were measured by Amplicor HIV-1 Monitor (Roche Diagnostic Systems, Branchburg, New Jersey) retrospectively in stored specimens for the second study [10]. A subset of participants from the second study was eligible for longitudinal analysis of markers if the participants had at least four plasma samples, obtained over at least 1 year, available for quantitative HIV RNA determination and if they had had CD4+ lymphocyte counts measured at least four times during the same period. Baseline characteristics were compared by using the chi-square test or the Fisher exact test for discrete variables and the Wilcoxon rank-sum test for continuous variables. As in our previous work [10], all RNA values were log10-transformed before analysis. The initial response to treatment was determined by averaging all measurements of plasma HIV RNA level or CD4+ lymphocyte count obtained during the first 6 months of treatment and comparing these average values with the one or two baseline, prerandomization values that were available. Treatment failure was defined as progression to AIDS according to the 1987 criterion [17]. The two measures examined as surrogate markers of treatment failure were 1) return to baseline values within 6 months and 2) changes in values within 18 months after the initial 6-month response to treatment. Clinical follow-up was limited to 60 months. Analyses of the time to progression to AIDS were conducted using Cox proportional-hazards modeling procedures [18]. Time-dependent analyses are Cox models in which the marker values are entered into the model at the time they are measured and are assumed to be constant until remeasured. In the present study, only measurements obtained within the first 24 months of the study and before the occurrence of AIDS were considered. We used SAS software, versions 6.09/6.11 (SAS Institute, Cary, North Carolina), for statistical analysis. Glaxo-Wellcome, Inc., did not participate in the design or writing of this study and had no control over the decision to publish this report. Results Patient Characteristics The 270 patients from VACSP 298 who had samples available for plasma HIV RNA analysis are described elsewhere [10]. The patients in the two treatment groups (the immediate treatment group and the deferred treatment group) did not differ significantly in age, race, CD4+ lymphocyte count, or plasma HIV RNA level at entry. A trend toward a difference in mean baseline plasma HIV RNA levels was seen: Levels were higher in the immediate therapy group than in the deferred therapy group (4.04 log10 copies/mL compared with 3.89 log10 copies/mL; P = 0.07). The 70 patients in the immediate therapy group who were suitable for longitudinal HIV marker analysis had a median duration of clinical follow-up of 54 months (range, 18 to 60 months), a median age of 41 years, a median plasma HIV RNA level of 4.23 log10 copies/mL, and a median CD4+ lymphocyte count of 374 cells/mm3. Baseline characteristics in this subset, including body weight, percentage of CD3+ lymphocytes that were CD4+ cells, CD8+ lymphocyte count, and 2-microglobulin, did not differ from those in patients who were not selected. HIV Marker Response to Antiretroviral Treatment and Progression to AIDS For all 270 patients, regardless of treatment, if the postrandomization response is measured by the mean levels of the markers over the first 6 months of the study, the relative risk (RR) for progression to AIDS is 0.67 (95% CI, 0.56 to 0.80; P < 0.001) for each decrease of 0.5 log10 copies/mL in HIV RNA level from baseline (Table 1, model 1). The relative risk for each 10% increase in CD4+ lymphocyte counts from baseline (model 2) is 0.82 (CI, 0.76 to 0.89; P < 0.001). If changes in both markers are considered together in the same model (model 3), then the relative risk for each decrease of 0.5 log10 copies/mL in HIV RNA level is 0.70 (CI, 0.59 to 0.84) and the relative risk for each 10% increase in CD4+ lymphocyte count is 0.85 (CI, 0.78 to 0.92). This means that, after adjustment for the changes in CD4+ lymphocyte count, each decrease of 0.5 log10 copies/mL in HIV RNA level decreases the risk for progression to AIDS by about 30%. After adjustment for the changes in HIV RNA level, each 10% increase in CD4+ lymphocyte count decreases the risk for progression to AIDS by about 15%. The interaction between plasma HIV RNA level and CD4+ lymphocyte count was not significant (P > 0.2). In patients who had both a decrease of 0.5 log10 copies/mL in HIV RNA level and a 10% increase in CD4+ lymphocyte count, the relative risk for progression to AIDS was 0.33 (P = 0.019) compared with persons who did not have both of these changes. In patients who had neither of these changes, the risk for progression was significantly increased compared with the group in which at least one of these changes did occur (RR, 2.3; P = 0.001) and did not differ from the group that did not receive immediate therapy. Table 1. Mean Change in Markers from Baseline over 6 Months and Progression to AIDS* Durability of HIV Marker Changes over Time and Progression to AIDS After the initial changes in markers seen after the start of zidovudine therapy in the selected subset (n = 70), most patients experienced a return to baseline levels; 23 of these patients progressed to AIDS within 60 months. We examined the relation between the rate of return toward baseline values from the initial post-treatment level and progression to AIDS. Plasma HIV RNA levels returned to baseline within 6 months in 32 patients (46%), 13 of whom had progression to AIDS; CD4+ lymphocyte counts returned to baseline within 6 months in 49 patients (70%), 17 of whom had progression to AIDS. Using Cox regression and adjusting for baseline values, we found that persons whose plasma HIV RNA levels returned to baseline within 6 months had a greater risk for progression to AIDS (RR, 4.28 [CI, 1.59 to 11.6]; P = 0.004) than did those whose levels returned to baseline after 6 months (Figure 1). Return of the CD4+ lymphocyte count to baseline within 6 months did not distinguish patients who progressed to AIDS from those who did not (RR, 1.62 [CI, 0.63 to 4.15]; P > 0.2). The relative risk for each individual marker was essentially unaffected if we adjusted for a return to baseline of the other marker in the Cox regression analysis. Figure 1. Kaplan-Meier analysis of the time to progression to the acquired immunodeficiency syndrome (AIDS) in 70 patients whose human immunodeficiency virus (HIV) RNA plasma levels did or did not return to baseline (left) or whose CD4+ lymphocyte counts did or did not return to baseline (right) in less than 6 months. P Changes in markers from the 6-month post-treatment mean values were also examined as potential indicators of drug failure. Analysis of marker values was limited to the first 24 months after randomization, during which time a median of 8 plasma HIV RNA measurements (range, 3 to 14 measurements) and a median of 8 CD4+ lymphocyte counts (range, 3 to 11 counts) were performed. After adjustment for the initial response, a decrease in CD4+ lymphocyte count of 30% or more during this 18-month period (months 6 to 24 of follow-up after initiation of tre

Multicenter seroepidemiologic study of the impact of cytomegalovirus infection on renal transplantation

The effects of cytomegalovirus (CMV) infection on patient and allograft survival were determined in 1245 renal transplant recipients from 46 transplant centers. When an antilymphocyte preparation was administered to cadaveric allograft recipients, those at risk for primary CMV had a worse outcome than similar patients treated with prednisone and azathioprine (53.1% alive at 6 months with a functioning allograft vs. 70.8%, P=.05) or patients at risk for reactivation CMV (53.1% vs. 71.1%, P=.035). Patients at risk for reactivation CMV had a better outcome if they recieved an antilymphocyte preparation (71.1% vs. 60.8%, P<.01). The type of immunosuppression had no effect on patients without CMV. Living-related donor transplantation was not significantly influenced by CMV or type of immuno-suppression. We conclude that CMV infection is strongly influenced by the form of immunosuppression employed, and that both are important determinants of the outcome of cadaveric renal transplantation.

Economic Analysis of Influenza Vaccination and Antiviral Treatment for Healthy Working Adults

Context Strategies to decrease the adverse consequences of influenza include vaccination and antiviral therapy. No previous study has compared these two strategies in healthy working adults. Contribution In this costbenefit analysis, vaccination strategies resulted in higher net benefits than strategies that did not include vaccination. The health benefits of most antiviral treatments equaled or surpassed their costs. Clinical Implications Vaccinating healthy working adults against influenza is an economically attractive strategy for preventing the adverse consequences of influenza. Antiviral treatment for persons infected with influenza also saves money, but head-to-head comparisons of the available therapies are needed to define the most cost-effective regimen. The Editors Each year, influenza affects 10% to 20% of the U.S. population (1). In high-risk populations, such as elderly persons, influenza causes up to 20 000 deaths per year (2). Even in young healthy persons, influenza significantly affects direct health care costs, losses in worker productivity, and quality of life (3). In terms of therapy, yearly vaccination can reduce the risk for influenza, and various antiviral medications (for example, amantadine, rimantadine, zanamivir, and oseltamivir) can decrease the duration of illness for a person with influenza. However, yearly vaccination of healthy adults is not absolutely recommended, and it remains unclear whether the benefits of anti-influenza medications justify the costs (4, 5). We compared the costs and benefits of contemporary preventive and treatment strategies for influenza in a sample of healthy working adults. We conducted our study as a costbenefit analysis because most effects of influenza in a healthy adult sample (work-days lost and symptoms) are noncatastrophic. Using a decision model, we compared competing strategies by incorporating influenza vaccination versus nonvaccination and antiviral therapy (zanamivir, oseltamivir, rimantadine, and amantadine) for infected patients. This decision model considered the direct costs (for example, medication costs) and indirect costs (for example, lost wages) associated with each treatment strategy. In addition, our model incorporated the patient-determined relative value for relief from influenza symptoms and for avoiding medication side effects. To measure these variables, we used survey data and a conjoint analysis by using a utility valuation approach. Finally, we used sensitivity analysis to identify factors that could affect the optimal strategy. Our work adds to previous studies in considering antiviral strategies for influenza infection. Methods Model Overview We used a decision tree to model the choices of whether to vaccinate and whether to treat influenza (if influenza infection occurred) with one of several agents (Figure). The decision model was constructed for healthy persons 18 to 50 years of age without any significant comorbid conditions. All costs and benefits were framed from a societal perspective, which we defined as the perspective on outcomes of an intervention that accounts for all health effects (harms and benefits) and all costs (regardless of whether a monetary transaction occurs and who pays). We used the following equation to calculate our costbenefit analysis: Figure. Decision tree showing the strategies for influenza prevention and treatment net benefit (cost) = benefits of vaccination and treatment costs of vaccination and treatment. The Appendix provides the details of the equation and model. In brief, we included in the model eight treatment optionsthe eight possible combinations of influenza vaccination before infection (yes or no) and antiviral therapy if infection developed (using rimantadine, oseltamivir, or zanamivir or no treatment). We initially considered amantadine therapy as a possible treatment option, but because amantadine has a higher incidence of side effects than rimantadine and amantadine was less efficacious, amantadine was dominated by rimantadine in all subsequent analyses and was excluded. Because we were considering a healthy young population, we did not assume that vaccination or antiviral therapy would affect mortality or provide any long-term health benefits. Although these assumptions are conservative, they are consistent with the results of previous trials in healthy young persons (3, 6). We programmed the model using DATA software, version 3.5 (Treeage Software, Williamstown, Massachusetts). Probabilities Table 1 shows the value estimates used in the base case and the ranges evaluated in our sensitivity analysis. For a healthy adult, the probability of contracting influenza during an influenza season has been estimated to be 15% (range, 1% to 35%) (6-9). Vaccine efficacy for preventing influenza infection was estimated to be 68% (range, 50% to 86%) (6). Because rimantadine is effective only against influenza A and because oseltamivir and zanamivir are each effective against influenza A and influenza B, the prevalence of influenza B is important in determining the optimal antiviral therapy. The baseline prevalence of influenza B among influenza strains in a given year was assumed to be 16.3% (range, 1% to 86%) on the basis of the average yearly rate for prevalence of influenza in the United States over the past 10 years (Unpublished data). In terms of side effects, we considered the probability that rimantadine caused side effects of the central nervous system (characterized as dizziness, nervousness, and anxiety) in 2% of patients and gastrointestinal side effects (characterized as nausea) in 1% of patients (2, 3). For oseltamivir therapy, the probability of gastrointestinal side effects (characterized as nausea) was considered to be 9% (29). Because significant side effects rarely occur with use of influenza vaccine or zanamivir, the probabilities for these variables were not included in the base-case model (3, 6, 9, 13). Finally, on the basis of a previous study (14), we assumed that 17% of patients who developed influenza infection would receive antibiotic therapy (at a drug cost of

Role of Clinical Microbiology Laboratories in the Management and Control of Infectious Diseases and the Delivery of Health Care

17.50) (12). This figure was reduced to 11% in infected patients who received antiviral medication, based on data from a previous study (14). Table 1. Base-Case Values and Ranges Costs All costs and benefits are expressed in 2001 U.S. dollars. We calculated these dollar figures on the basis of 2001 medical cost and wage index data (28). The cost of vaccination, including the cost of administration, was

Human immunodeficiency virus type 1 RNA level and CD4 count as prognostic markers and surrogate end points: A meta-analysis

10.41 (15); a 5-day course of rimantadine therapy was

Race and Stress in the Incidence of Herpes Zoster in Older Adults

17.50 (19), and 5-day courses of zanamivir and oseltamivir therapies were

A Lymphotoxin-IFN-β Axis Essential for Lymphocyte Survival Revealed during Cytomegalovirus Infection

47.50 and

The Diagnostic Accuracy of Barium Studies of the Stomach and Duodenum—Correlation with Endoscopy

57.22, respectively (30, 31). The cost of a physician visit was assumed to be