Risk of subsequent SARS-CoV-2 infection among vaccinated employees with or without hybrid immunity acquired early in the Omicron-predominant era of the COVID-19 pandemic.

BACKGROUND: Hybrid immunity, from COVID-19 vaccination followed by SARS-CoV-2 infection acquired after its Omicron variant began predominating, has provided greater protection than vaccination alone against subsequent infection over 1-3 months of observation. Its longer-term protection is unknown. METHODS: We conducted a retrospective cohort study of COVID-19 case incidence among healthcare personnel (HCP) mandated to be vaccinated and report on COVID-19-associated symptoms, high-risk exposures, or known-positive test results to an employee health hotline. We compared cases with hybrid immunity, defined as incident COVID-19 during the first 6 weeks of Omicron-variant predominance (run-in period), to those with immunity from vaccination alone during the run-in period. Time until COVID-19 infection over 13 subsequent months (observation period) was analyzed by standard survival analysis. RESULTS: Of 5867 employees, 641 (10.9%, 95% confidence interval [CI]: 10.1%-11.8%) acquired hybrid immunity during the run-in period. Of these, 104 (16.2%, 95% CI: 13.5%-19.3%) experienced new SARS-CoV-2 infection during the 13-month observation period, compared to 2177 (41.7%, 95% CI: 40.3%-43.0%) of the 5226 HCP without hybrid immunity. Time until incident infection was shorter among the latter (hazard ratio: 3.09, 95% CI: 2.54-3.78). CONCLUSIONS: In a cohort of vaccinated employees, Omicron-era acquired SARS-CoV-2 hybrid immunity was associated with significantly lower risk of subsequent infection over more than a year of observation-a time period far longer than previously reported and during which three, progressively more resistant, Omicron subvariants became predominant. These findings can inform institutional policy and planning for future COVID-19 additional vaccine dosing requirements for employees, for surveillance programs, and for risk modification efforts.

Incidence and Characteristics of Delayed Injection Site Reaction to the mRNA-1273 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine (Moderna) in a Cohort of Hospital Employees.

BACKGROUND: mRNA SARS-CoV-2 vaccines are administered to 2 million individuals per day in the United States under US Food and Drug Administration emergency use authorization. METHODS: Observational cohort study of hospital employees who received their first SARS-CoV-2 mRNA vaccination between 14 December 2020 and 8 January 2021, including employees who reported onset of an injection site reaction ≥48 hours after administration of their first or second dose to an employee hotline. RESULTS: Thirteen female employees who received the mRNA-1273 vaccine (Moderna) during the first 3 weeks of the SARS-CoV-2 vaccine rollout at San Francisco General Hospital reported a pruritic rash at the injection site appearing 3 -9 days after receipt of their initial dose. Five had milder or similar reactions with earlier onset after the second dose. One additional female employee reported this delayed reaction only after the second dose. None reported serious adverse events or had symptoms severe enough to seek medical attention. These cases represented 1.1% of the 1275 female employees who received their first mRNA-1273 dose and 2.0% of the 557 who were aged 31 -45 years during this initial vaccine rollout. None of 675 males who initiated mRNA-1273 or 3612 employees of any sex who initiated BNT162b (Pfizer) vaccination during this period reported delayed-onset reactions. CONCLUSIONS: These results suggest that delayed-onset, injection site pruritic rashes after mRNA-1273 SARS-CoV-2 vaccine administration, lasting up to 1 week, occur commonly in females, do not lead to serious sequela, and should not deter receipt of the second vaccine dose.

A Rapid Nucleic Acid Amplification Test-Based, Conditional Release-to-Work Policy for Health Care Personnel With Symptoms Consistent With COVID-19.

OBJECTIVE: Most health care personnel (HCP) reporting symptoms consistent with COVID-19 illness are assessed by high-accuracy SARS-CoV-2 assays performed in clinical laboratories, but the results of such assays typically are not available until the following day. METHODS: This is an observational study over 16 weeks of a rapid nucleic acid amplification test (NAAT) performed at point of contact. The benchmark for comparison was a simultaneously obtained specimen assayed by a routine NAAT assay performed in a clinical laboratory. RESULTS: There were 577 paired rapid and routine NAAT results. Rapid test positive predictive value was 90.0% (95% confidence interval = 88.8%-91.2%), and negative predictive value was 95.2% (95% confidence interval = 93.5%-96.9%). The rapid test avoided an estimated 160 to 184 lost work shifts over 4 months. CONCLUSIONS: A rapid NAAT test-based strategy proved effective in safely clearing symptomatic employees without infection for earlier return to work.

Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy.

BACKGROUND: Elevated immune activation persists during treated human immunodeficiency virus (HIV) infection and is associated with blunted CD4 recovery and premature mortality, but its causes remain incompletely characterized. We hypothesized that asymptomatic cytomegalovirus (CMV) replication might contribute to immune activation in this setting. METHODS: Thirty antiretroviral therapy-treated HIV-infected CMV-seropositive participants with CD4 counts <350 cells/mm(3) were randomized to receive valganciclovir 900 mg daily or placebo for 8 weeks, followed by an additional 4-week observation period. The primary outcome was the week 8 change in percentage of activated (CD38(+) HLA-DR(+)) CD8(+) T cells. RESULTS: Fourteen participants were randomized to valganciclovir and 16 to placebo. Most participants (21 [70%] of 30) had plasma HIV RNA levels <75 copies/mL. The median CD4 count was 190 (IQR: 134-232) cells/mm(3), and 12 (40%) of 30 had detectable CMV DNA in saliva, plasma, or semen at baseline. CMV DNA continued to be detectable at weeks 4-12 in 7 (44%) of 16 placebo-treated participants, but in none of the valganciclovir-treated participants (P = .007). Valganciclovir-treated participants had significantly greater reductions in CD8 activation at weeks 8 (P = .03) and 12 (P = .02) than did placebo-treated participants. These trends were significant even among those with undetectable plasma HIV RNA levels. CONCLUSIONS: CMV (and/or other herpesvirus) replication is a significant cause of immune activation in HIV-infected individuals with incomplete antiretroviral therapy-mediated CD4(+) T cell recovery. CLINICAL TRIALS REGISTRATION: NCT00264290.

Temperature Screening of Healthcare Personnel Is Ineffective in Controlling COVID-19.

OBJECTIVE: Our aim was to describe the effectiveness of employee temperature screening at a public hospital in San Francisco during the COVID-19 pandemic. METHODS: An estimated 6000 health care personnel (HCP) underwent daily screening before entry to campus. Logs of failed employee entrance temperature screenings from March 2020 through March 2021 were reviewed. RESULTS: From March 2020 through March 2021, only one employee, who reported no symptom that could bar their entry to work, had an elevated temperature on screening. On re-check with an oral thermometer, that individual's temperature was normal. CONCLUSIONS: While the rationale to continue temperature screening may be rooted in beliefs it will increase employee reporting of symptoms or exposures, our results indicates that such screening of HCP at large US hospitals has no utility in detecting COVID-19 or controlling its transmission.

Development of cytomegalovirus (CMV) immune recovery uveitis is associated with Th17 cell depletion and poor systemic CMV-specific T cell responses.

BACKGROUND: the immune reconstitution inflammatory syndromes (IRIS) are a spectrum of inflammatory conditions associated with opportunistic infections and occurring in approximately16% of human immunodeficiency type 1 (HIV-1)-infected patients given antiretroviral therapy. It has been proposed that these conditions are linked by a dysregulated immune system that is prone to exaggerated responses. However, immunologic studies have been limited by the availability of longitudinal samples from patients with IRIS and appropriate matched control subjects. Cytomegalovirus (CMV) immune recovery uveitis (IRU) is an IRIS occurring in up to 38% of patients with CMV retinitis. Although the pathologic immune responses occur in the eye, immune dysregulation that allows for development of pathologic responses is presumably caused by faulty systemic immune cell reconstitution. METHODS: we examined CMV-specific T cell responses, regulatory T (T(reg)) cell function and polyclonal T cell responses, including IL-17 production, in 25 patients with CMV IRU and 49 immunorestored control subjects with CMV retinitis who did not develop IRU. RESULTS: patients with CMV IRU had poor CMV-specific CD4(+) T cell responses, as compared with control subjects, whereas CD8(+) T cell responses were comparable. Patients with CMV IRU were characterized by smaller numbers of circulating Th17 cells. Deficiency in anti-CMV responses was not associated with differences in T(reg) cell function. CONCLUSIONS: the T(reg) cell compartment is intact in patients with CMV IRU, and these patients do not develop exaggerated systemic CMV-specific or polyclonal immune responses. Cases are instead characterized by more profound depletion of Th17 cells and poor antiviral immune responses. CMV IRU may be most likely to develop in persons experiencing the greatest degree of immune dysfunction before initiating highly active antiretroviral therapy.

Poor predictive value of cytomegalovirus (CMV)-specific T cell assays for the development of CMV retinitis in patients with AIDS.

BACKGROUND: We examined the potential clinical utility of using a cytomegalovirus (CMV)-specific T cell immunoassay to determine the risk of developing new-onset CMV retinitis (CMVR) in patients with acquired immunodeficiency syndrome (AIDS). METHODS: CMV-specific T cell assays were performed by multiparameter flow cytometry using stored peripheral blood mononuclear cells that had been obtained in an observational study 2-6 months before new-onset CMVR was diagnosed in case patients (at a study visit during which a dilated ophthalmologic examination revealed no evidence of CMVR) and at the same study visit in control subjects (matched by absolute CD4(+) T cell count at entry) who did not subsequently develop retinitis during 1-6 years of study follow-up. RESULTS: There were no significant differences in CMV-specific CD4(+) or CD8(+) T cell interferon-gamma or interleukin-2 expression in peripheral blood mononuclear cells from case patients and control subjects. Although there were trends toward lower percentages and absolute numbers of CMV-specific, cytokine-expressing CD8(+) T cells with a "late memory" phenotype (CD27(-)CD28(-)) as well as with an "early memory" phenotype (CD27(+)CD28(+)CD45RA(+)) in case patients than in control subjects, these differences were not statistically significant. CONCLUSIONS: Many studies have reported that CMV-specific CD4(+) and CD8(+) T cell responses distinguish patients with active CMVR (i.e., who lack CMV-protective immunity) from those with inactive CMVR after immune restoration by antiretroviral treatment (i.e., who have CMV-protective immunity). However, the multiple CMV-specific immune responses we measured do not appear to have clinical utility for predicting the risk for patients with AIDS of developing new-onset CMVR with sufficient accuracy to be used in guiding therapeutic management.

Loss of T cell responses following long-term cryopreservation.

Although cryopreservation of peripheral blood mononuclear cells (PBMC) is a commonly used technique, the degree to which it affects subsequent functional studies has not been well defined. Here we demonstrate that long-term cryopreservation has detrimental effects on T cell IFN-gamma responses in human immunodeficiency virus (HIV) infected individuals. Long-term cryopreservation caused marked decreases in CD4(+) T cell responses to whole proteins (HIV p55 and cytomegalovirus (CMV) lysate) and HIV peptides, and more limited decreases in CD8(+) T cell responses to whole proteins. These losses were more apparent in cells stored for greater than one year compared to less than six months. CD8(+) T cell responses to peptides and peptide pools were well preserved. Loss of both CD4(+) and CD8(+) T cell responses to CMV peptide pools were minimal in HIV-negative individuals. Addition of exogenous antigen presenting cells (APC) did not restore CD4(+) T cell responses to peptide stimulation and partially restored T cell IFN-gamma responses to p55 protein. Overnight resting of thawed cells did not restore T cell IFN-gamma responses to peptide or whole protein stimulation. A selective loss of phenotypically defined effector cells did not explain the decrement of responses, although cryopreservation did increase CD4(+) T cell apoptosis, possibly contributing to the loss of responses. These data suggest that the impact of cryopreservation should be carefully considered in future vaccine and pathogenesis studies. In HIV-infected individuals short-term cryopreservation may be acceptable for measuring CD4(+) and CD8(+) T cell responses. Long-term cryopreservation, however, may lead to the loss of CD4(+) T cell responses and mild skewing of T cell phenotypic marker expression.

Effect of a four-week course of interleukin-10 on cytokine production in a placebo-controlled study of HIV-1-infected subjects.

Interleukin (IL)-10 suppresses synthesis of the pro-inflammatory cytokines tumor necrosis factor (TNF)alpha, IL-1beta, and interferon (IFN)gamma. Since pro-inflammatory cytokines have been implicated in the production of human immunodeficiency virus type 1 (HIV-1), cytokine synthesis in whole blood cultures were determined during a 4-week course of subcutaneous IL-10 injections in 33 HIV-1-infected patients. Patients were randomized into four groups: placebo (nine), IL-10 at 1 microg/kg/day (nine), IL-10 at 4 microg/kg/day (six) and IL-10 at 8 microg/kg three times per week (nine). Whole blood was obtained at the beginning and conclusion of the study and was stimulated for 24 hours with the combination of IL-18 plus lipopolysaccharide. TNFalpha production in stimulated whole blood was reduced three and six hours after the first injection of IL-10 compared to subjects injected with the placebo. After four weeks of treatment, production of IFNgamma was suppressed in a greater number of patients in the IL-10 treatment groups compared to subjects in the placebo group. Similarly, IL-1beta production was lower in the IL-10 treatment groups compared to subjects receiving placebo. In contrast, after four weeks of IL-10, circulating levels of the anti-inflammatory TNF soluble receptor p55 increased dose-dependently compared to placebo subjects. Patient heterogeneity and small sample size presented difficulties in establishing statistical significance. Although the cytokine changes in our study did not demonstrate statistically significant changes, the data nevertheless reveal that four weeks of IL-10 therapy in HIV-1 infected subjects produced the anticipated suppression of pro-inflammatory cytokines.

Antigen-specific T cell responses induced by Towne cytomegalovirus (CMV) vaccine in CMV-seronegative vaccine recipients.

BACKGROUND: Towne cytomegalovirus (CMV) vaccine is safe and immunogenic, though its protective efficacy has yet to be optimized. OBJECTIVE: Describe antigen-specific T cell responses to Towne vaccination. STUDY DESIGN: 3000 pfu Towne CMV vaccine were given to 12 CMV-seronegative volunteers. CMV-specific CD4+ and CD8+ T cell proliferation and IFNgamma expression were measured by flow cytometry after stimulation with CMV lysate or peptides. RESULTS: All vaccinees developed CD4+ and CD8+ T cell proliferation and CD4+ T cell IFNgamma responses to multiple CMV antigens, but their CD8+ T cells had low or undetectable IFNgamma responses to pp65 peptide pool. The seven HLA-A2+ subjects had higher CD8+ T cell proliferation and IFNgamma responses to IE than pp65, and two never developed CD8+ T cell IFNgamma responses to pp65. Peak CD4+ T cell IFNgamma responses to CMV lysate were lower than values observed in natural CMV seropositives. Initial CD4+ and CD8+ T cell responses to lysate and pp65 waned after 12 months to levels that were lower than those in healthy CMV seropositives, while vaccinees' CD8+ T cell responses to IE were robust and prolonged. CONCLUSION: Correlating CMV antigen-specific T cell responses with clinical protective efficacy may facilitate future CMV vaccine development.

Human papillomavirus infection in the oral cavity of HIV patients is not reduced by initiating antiretroviral therapy.

OBJECTIVE: The incidence of human papillomavirus (HPV)-related oral malignancies is increasing among HIV-infected populations, and the prevalence of oral warts has reportedly increased among HIV patients receiving antiretroviral therapy (ART). We explored whether ART initiation among treatment-naive HIV-positive adults is followed by a change in oral HPV infection or the occurrence of oral warts. DESIGN: Prospective, observational study. METHODS: HIV-1 infected, ART-naive adults initiating ART in a clinical trial were enrolled. End points included detection of HPV DNA in throat-washes, changes in CD4 T-cell count and HIV RNA, and oral wart diagnosis. RESULTS: Among 388 participants, 18% had at least one HPV genotype present before initiating ART, and 24% had at least one genotype present after 12-24 weeks of ART. Among those with undetectable oral HPV DNA before ART, median change in CD4 count from study entry to 4 weeks after ART initiation was larger for those with detectable HPV DNA during follow-up than those without (P =  0.003). Both prevalence and incidence of oral warts were low (3% of participants having oral warts at study entry; 2.5% acquiring oral warts during 48 weeks of follow-up). CONCLUSION: These results suggest: effective immune control of HPV in the oral cavity of HIV-infected patients is not reconstituted by 24 weeks of ART; whereas ART initiation was not followed by an increase in oral warts, we observed an increase in oral HPV DNA detection after 12-24 weeks. The prevalence of HPV-associated oral malignancies may continue to increase in the modern ART era.

Risk factors for mortality in patients with AIDS in the era of highly active antiretroviral therapy.

OBJECTIVE: To evaluate risk factors for mortality among patients with AIDS in the era of highly active antiretroviral therapy (HAART), particularly the effect of cytomegalovirus (CMV). DESIGN: Prospective cohort study of patients with AIDS, conducted from 1998 through 2003. PARTICIPANTS: One thousand five hundred eighty-three patients with AIDS, of whom 374 had CMV retinitis. METHODS: Patients were contacted every 3 months, with examinations at least every 6 months, in which standardized data were collected on AIDS history and treatment, eye examinations, and hematologic, virologic, and immunologic laboratory data. MAIN OUTCOME MEASURE: Mortality. RESULTS: The overall mortality rate was 0.07 deaths/person-year. In a multivariate analysis, the following baseline risk factors were associated with an increased mortality: higher human immunodeficiency virus (HIV) viral load (relative risk [RR] = 4.6 for HIV viral load >100,000 copies/ml vs. <400 copies/ml; P<0.0001), lower CD4+ T-cell count at enrollment (RR = 3.8 for CD4+ T cell count 0-49 cells/microl vs. > or = 200 cells/microl; P<0.0001), CMV viral load > or = 400 copies/ml (RR = 1.9; P = 0.002), lower hemoglobin (RR = 1.7 for hemoglobin <10 g/dl; P = 0.009), a history of cryptococcal meningitis (RR = 1.7; P = 0.02), CMV retinitis (RR = 1.6; P = 0.0002), and Karnofsky score < or = 80 (RR = 1.4; P = 0.008). CONCLUSIONS: In the era of HAART, CMV disease as manifested by CMV retinitis and a detectable CMV viral load were associated with an increased risk for mortality, even after adjusting for demographic, treatment, immunologic, and HIV virologic factors.

Pharmacokinetics of clarithromycin extended-release (ER) tablets in patients with AIDS.

BACKGROUND: Clarithromycin is a key agent in effective antimycobacterial therapy and prophylaxis for AIDS-related disseminated Mycobacterium avium complex (dMAC) infection. Immediate-release (IR) clarithromycin tablets are dosed at 500 mg bid for these indications. A new extended-release (ER) tablet of clarithromycin has been developed and approved at a dosing interval of once every 24 hours for treatment of respiratory tract bacterial infections. However, the pharmacokinetics of clarithromycin ER in AIDS patients with or at risk for dMAC has not been previously investigated. METHOD: We conducted a randomized, crossover trial in which 14 AIDS patients received clarithromycin ER, 1000 mg once daily, and clarithromycin IR, 500 mg bid, each for 1 week, with pharmacokinetic sampling at the end of each week. RESULTS: The mean of the individual AUC ratios for clarithromycin ER vs. IR was 1.09 (90% CI, 0.94-1.24). Adverse events were no more severe or frequent with clarithromycin ER than IR. CONCLUSION: Clarithromycin ER is a once-daily regimen that is as well tolerated as standard bid IR clarithromycin dosing and has average bioequivalence to the IR formulation in patients with AIDS.

A Phase I, placebo-controlled trial of multi-dose recombinant human interleukin-12 in patients with HIV infection.

OBJECTIVES: Interleukin (IL)-12 is a cytokine that stimulates T lymphocytes and natural killer cells to generate a Type 1 T-helper lymphocyte immune response. The primary objective of this study was to determine the safety and immunologic activity of repeated recombinant human IL-12 (rhIL-12) dosing in HIV-infected patients over a broad range of the HIV disease spectrum. DESIGN: A randomized, placebo-controlled, Phase 1 trial design was chosen to control for the effects of HIV disease alone on safety and immunologic measurements. METHODS: HIV-infected patients on antiretroviral therapy received rhIL-12 or placebo twice weekly for 4 weeks. Subjects were monitored for safety and changes in absolute lymphocyte subset number, serum interferon (IFN)gamma and neopterin levels, plasma HIV RNA level, peripheral blood mononuclear cell (PBMC)-inducible IFNgamma responses to mitogen, and PBMC proliferative responses to phytohemagglutinin, tetanus, Candida, Mycobacterium avium complex, streptokinase, and HIV p24 and gp160 antigens. RESULTS: rhIL-12 was well tolerated at doses up to 100 ng/kg in subjects enrolled with CD4 cell counts < 50 x 10(6) cells/l and at all doses in subjects with CD4 cell counts of 300 x 10(6)-500 x 10(6) cells/l. rhIL-12 resulted in dose-related increases in serum neopterin (particularly in subjects with baseline CD4 cell counts of 300-500 x 10(6) cells/l) but in no significant changes in other immunologic measurements or plasma HIV RNA levels. CONCLUSIONS: rhIL-12 dosed twice weekly at < or = 100 ng/kg was well tolerated in HIV-infected patients and resulted in dose-related increases in serum neopterin (possibly reflecting the effect of some degree of IFNgamma induction). However, there was no evidence of improvement in antigen-specific immune response.

Avidity of antibodies to cytomegalovirus in HIV-seropositive patients with and without CMV retinitis.

Antibodies of high avidity may protect the fetus from CMV infection, but the association of avidity with other CMV infections is unknown. To determine if anti-CMV antibody avidity is altered in HIV-seropositive patients, either untreated or treated with HAART, and to determine if alterations in avidity are associated with CMV retinitis, we obtained sera from 164 CMV-seropositive adults: 68 were HIV-seronegative healthy adults and 96 were HIV seropositive. Of the HIV-positive, 57 had no current or prior evidence of CMV retinitis (29 were being treated with HAART, and 28 were receiving no therapy when sampled), and 39 had either active CMV retinitis or were immunorestored by HAART with quiescent CMV retinitis. IgG antibody avidity was determined for each serum run in duplicate using an EIA assay and 5M urea as a dissociating agent. After correction for the significantly higher levels of IgG antibodies to CMV in the HIV-seropositive sera as compared to the normal healthy individuals, both HIV-infected and HIV-uninfected individuals had nearly identical average avidity indices (avidity index = 76). There was also no significant difference in average avidity index between HAART-treated and untreated patients, or between patients with active and immunorestored, quiescent CMV retinitis). These results indicate antibody avidity is unaltered in HIV disease and does not play an important role in the pathogenesis of AIDS-related CMV disease.

CMV antigen-specific CD4+ and CD8+ T cell IFNgamma expression and proliferation responses in healthy CMV-seropositive individuals.

CMV-specific CD4+ and CD8+ T cell IFNgamma expression and proliferation were measured in healthy volunteers by flow cytometry after CMV lysate or CMV pp65 or IE peptide pool stimulation. Cutoff values were set to maximize specificity (i.e., no false positive CMV-seronegatives). Sensitivity (defined as a positive response in CMV-seropositives to at least one of the 3 antigen preparations used) was 100% for CMV-specific CD4+ and CD8+ T cell IFN expression and CD4+ T cell proliferation and 95.4% for CMV-specific CD8+ T cell proliferation. All 22 CMV-seropositive individuals had positive responses by at least three of these four measurements. These findings support the concept that a multiplicity of antigen-specific functional immune responses and persistence of robust virus-specific CD4+T cells are important components of protective immunity in this chronic viral infection.

Regulatory T cells and the risk of CMV end-organ disease in patients with AIDS.

OBJECTIVES: Cytomegalovirus (CMV)-specific T-cell effectors (CMV-Teff) protect against CMV end-organ disease (EOD). In HIV-infected individuals, their numbers and function vary with CD4 cell numbers and HIV load. The role of regulatory T cells (Treg) in CMV-EOD has not been extensively studied. We investigated the contribution of Treg and Teff toward CMV-EOD in HIV-infected individuals independently of CD4 cell numbers and HIV load and controlling for CMV reactivations. DESIGN: We matched 43 CMV-EOD cases to 93 controls without CMV-EOD, but with similar CD4 cell numbers and HIV plasma RNA. CMV reactivation was investigated by blood DNA polymerase chain reaction over 32 weeks preceding the CMV-EOD in cases and preceding the matching point in controls. METHODS: CMV-Teff and Treg were characterized by the expression of interferon-γ (IFN-γ), interleukin 2, tumor necrosis factor α (TNFα), MIP1ß, granzyme B (GrB), CD107a, TNFα, FOXP3, and CD25. RESULTS: Sixty-five percent cases and 20% controls had CMV reactivations. In multivariate analyses that controlled for CMV reactivations, none of the CMV-Teff subsets correlated with protection, but high CMV-GrB enzyme-linked immunosorbent spot responses and CMV-specific CD4FOXP3+%, CD4TNFα+%, and CD8CD107a% were significant predictors of CMV-EOD. CONCLUSIONS: Because both FOXP3 and GrB have been previously associated with Treg activity, we conclude that CMV-Treg may play an important role in the development of CMV-EOD in advanced HIV disease. We were not able to identify a CMV-Teff subset that could be used as a surrogate of protection against CMV-EOD in this highly immunocompromised population.

The clinical impact of continuing to prescribe antiretroviral therapy in patients with advanced AIDS who manifest no virologic or immunologic benefit.

INTRODUCTION: Despite the efficacy and tolerability of modern antiretroviral therapy (ART), many patients with advanced AIDS prescribed these regimens do not achieve viral suppression or immune reconstitution as a result of poor adherence, drug resistance, or both. The clinical outcomes of continued ART prescription for such patients have not been well characterized. METHODS: We examined the causes and predictors of all-cause mortality, AIDS-defining conditions, and serious non-AIDS-defining events among a cohort of participants in a clinical trial of pre-emptive therapy for CMV disease. We focused on participants who, despite ART had failed to achieve virologic suppression and substantive immune reconstitution. RESULTS: 233 ART-receiving participants entered with a median baseline CD4+ T cell count of 30/mm(3) and plasma HIV RNA of 5 log10 copies/mL. During a median 96 weeks of follow-up, 24.0% died (a mortality rate of 10.7/100 patient-years); 27.5% reported a new AIDS-defining condition, and 22.3% a new serious non-AIDS event. Of the deaths, 42.8% were due to an AIDS-defining condition, 44.6% were due to a non-AIDS-defining condition, and 12.5% were of unknown etiology. Decreased risk of mortality was associated with baseline CD4+ T cell count ≥25/mm(3) and lower baseline HIV RNA. CONCLUSIONS: Among patients with advanced AIDS prescribed modern ART who achieve neither virologic suppression nor immune reconstitution, crude mortality percentages appear to be lower than reported in cohorts of patients studied a decade earlier. Also, in contrast to the era before modern ART became available, nearly half of the deaths in our modern-era study were caused by serious non-AIDS-defining events. Even among the most advanced AIDS patients who were not obtaining apparent immunologic and virologic benefit from ART, continued prescription of these medications appears to alter the natural history of AIDS--improving survival and shifting the causes of death from AIDS- to non-AIDS-defining conditions.