Risk Of Cytomegalovirus Disease Research Articles

Valganciclovir for cytomegalovirus prevention in solid organ transplant patients: an evidence-based reassessment of safety and efficacy.

BackgroundSeveral anti-viral drugs have demonstrated efficacy in preventing Cytomegalovirus (CMV) infections in solid organ transplant (SOT) patients. The recently approved valganciclovir is the most commonly used and most expensive drug for CMV prevention. The safety and efficacy data have been drawn from a single trial. We hypothesized that valganciclovir may not be as safe as nor more effective than other therapies for CMV prevention.MethodsAll experimental and analytical studies that compared valganciclovir with other therapies for prevention of CMV infection after SOT were selected. Based on meta-analytic and multivariate regression methodologies we critically analyzed all available evidence.FindingsNine studies were included (N = 1,831). In trials comparing valganciclovir with ganciclovir, the risk for CMV disease is 0.98 (95% Confidence Interval (95%CI) 0.67 to 1.43; P = 0.92; I2 = 0%). Valganciclovir was significantly associated with the risk of absolute neutropenia (<1,500/mm3) compared with all therapies (Odds Ratio (OR) 3.63 95%CI 1.75 to 7.53; P = 0.001; I2 = 0%); with ganciclovir only (OR 2.88, 95%CI 1.27 to 6.53; P = 0.01; I2 = 0%); or with non-ganciclovir therapies (OR 8.30, 95%CI 1.51 to 45.58; P = 0.01; I2 = 10%). For a neutropenia cut-off of <1,000/mm3, the risk remained elevated (OR 1.97, 95%CI 1.03 to 3.67; P = 0.04; I2 = 0%). For every 24 patients who receive valganciclovir prophylaxis, one more will develop neutropenia compared to other therapies. The risk of late-onset CMV disease with valganciclovir was similar to ganciclovir and higher than those with non-ganciclovir therapies (OR 8.95, 95%CI 1.07 to 74.83; P = 0.04; I2 = 0%]. One more patient will develop late-onset CMV disease for every 25 who receive valganciclovir compared to treatment with non-ganciclovir therapies. The risk of CMV tissue-invasive disease in liver recipients receiving valganciclovir was 4.5 times the risk seen with ganciclovir [95%CI 1.00 to 20.14] (p = 0.04). All results remained consistent across different study designs, valganciclovir doses, and CMV serostatus.ConclusionsValganciclovir shows no superior efficacy and significantly higher risk of absolute neutropenia, CMV late-onset disease, and CMV tissue-invasive disease compared to other standard therapies. Due to the availability of efficacious, safer, and lower cost drugs (high-dose acyclovir, valacyclovir, ganciclovir), our results do not favor the use of valganciclovir as a first-line agent for CMV preemptive or universal prophylaxis in SOT patients.

Regimen-Related Mucosal Injury of the Gut Increased the Incidence of CMV Disease after Allogeneic Bone Marrow Transplantation

Cytomegalovirus (CMV) infection is 1 of the major causes of morbidity in patients undergoing allogeneic stem cell transplantation (allo-SCT). The incidences of CMV antigenemia and CMV disease in 43 patients who received allogeneic bone marrow transplantation (BMT) using a reduced-intensity conditioning (RIC) regimen, which mainly consisted of fludarabine (Flu), busulfan (Bu), and total body irradiation (TBI), were compared with those in 68 patients who received a myeloablative conditioning (MAC) regimen, and risk factors for CMV antigenemia and CMV disease were identified. Before engraftment, grade 3-4 mucosal injury because of the conditioning regimen was significantly decreased in RIC patients (stomatitis: P = .02; diarrhea: P < .01). Rate of engraftment, incidences of acute graft-versus-host disease (aGVHD), and rate of corticosteroid administration were not different in RIC patients and MAC patients. Although the incidences of CMV antigenemia were not significantly different in RIC patients and MAC patients (64.1% versus 57.8%, log rank, P = .59), the incidence of CMV disease was significantly decreased in RIC patients (5.4% versus 20.3%, log rank, P = .04). CMV seropositivity in the patients (P < .01) and corticosteroid administration (P < .01) were revealed by multivariate analysis to be significant risk factors for CMV antigenemia. Grade II-IV aGVHD (P = .02) and grade 3-4 diarrhea before engraftment (P = .04) were revealed to be risk factors for CMV disease. The present study is the first study to show that severe diarrhea before engraftment is a significant risk factor for CMV disease. In summary, risk of CMV disease was significantly decreased in patients without severe mucosal injury of the gut because of the conditioning regimen before engraftment.

Immune monitoring of anti cytomegalovirus antibodies and risk of cytomegalovirus disease in heart transplantation

We sought to determine whether quantitative assessment of anti-cytomegalovirus (CMV) antibodies could be useful to identify patients at risk of cytomegalovirus (CMV) disease after heart transplantation (HT). 75 patients who underwent HT at a single health care center were prospectively studied. Induction therapy included 2 doses of daclizumab and maintenance tacrolimus ( n = 42) or cyclosporine ( n = 29), mycophenolate mofetil and prednisone. All patients received prophylaxis with gancyclovir or valganciclovir. Anti-CMV intravenous immunoglobulin (CMV-IG) was added in high risk patients (CMV D+/R − serostatus). Serial determinations of anti-CMV antibodies, immunoglobulins (IgG, IgA, IgM) and IgG-subclasses were analysed. CMV infection was based on detection of the virus by antigenemia. CMV disease consisted of detection of signs or symptoms attributable to this microorganism. Ten patients (13.3%) developed CMV disease. Mean time of development of CMV disease was 3.4 ± 1.6 months. In Cox regression analysis, patients with low baseline anti-CMV titers (< 4.26 natural logarithm of titer, RH: 8.1, 95%CI: 1.93–34.1, p = 0.004) and recipients with 1-month post-HT IgG hypogammaglobulinemia (IgG < 500 mg/dl, RH: 4.49, 95%CI: 1.26–15.94, p = 0.02) were at higher risk of having CMV disease. Despite use of prophylactic CMV-IG, D+/R − patients showed significantly lower titers of anti-CMV antibodies at 7 d, 30 d and 90 d post HT as compared with HT recipients without infections. Four out of 6 of these patients developed late CMV disease. Monitoring of specific anti-CMV antibodies on the bedside warrants further evaluation as a potential tool to identify heart transplant recipients at higher risk of CMV disease.

Viral Genome Scan for Analysis of CMV-Specific CD8+ T Cells in Normal and Immunocompromised Individuals.

Human cytomegalovirus (CMV) may cause severe disease in immunosuppressed hosts including hematopoietic stem cell transplant recipients. The components of host immunity that provide protection from progressive infection have not been completely defined. Studies in immunocompromised CMV-infected humans, and in mice infected with murine cytomegalovirus (mCMV), have shown that recovery of class I major histocompatibility complex (MHC) restricted CD8+ cytotoxic T lymphocytes (CTL) that recognize viral peptides play a key role in containing viral replication. The importance of CTL specific for individual antigens in immune control of CMV has been difficult to determine because cells permissively infected with human CMV express over 160 viral proteins during the (IE), early (E), and late (L) phases of replication. Recent studies in immunocompetent humans have identified significant frequencies of CTL specific for multiple CMV antigens expressed at all stages of viral replication, despite the presence of viral proteins that interfere with class I antigen presentation. Thus, analysis of CMV-specific T cell immunity using one or a few peptides is likely to underestimate the magnitude and diversity of the host response. We have developed a genetic approach for characterizing CMV antigens that concurrently identifies the HLA restricting allele and enables rapid determination of the minimal epitope derived from any CMV gene. To evaluate this approach, PBMC from seropositive individuals were stimulated once in vitro with autologous fibroblasts infected with the RV798 strain of CMV, which lacks all class I immune evasion genes and enables display of all potentially antigenic peptides. The T cells were then screened against a panel of COS cells transfected with a plasmid library containing a majority of CMV ORFs and with each of the HLA alleles of the donor. Twenty-two CMV genes that were predominantly expressed at IE or E stages of infection were identified to encode antigens recognized by CTL from 4 normal donors. The median number of antigens recognized in each donor was 8 (range 4–12). Seventeen CMV peptides presented by a variety of common HLA class I molecules including HLA-C were subsequently mapped and two epitopes were found to be derived from alternative translation products or processing mechanisms. Memory T cells from other CMV seropositive individuals that shared the HLA restricting allele also recognized these novel epitopes. This genome scan was used successfully to identify the repertoire of CMV antigens recognized by CMV-specific CTL generated from CMV seropositive hematopoietic stem cell transplant donors and to determine which responses were transferred to the respective recipient post transplant. CTL specific for a broad repertoire of viral antigens comparable to that in the donor were found in some transplant recipients, while in others the response was dramatically restricted compared to the donor. These results further define the broad specificity of the CMV-specific CTL response in seropositive donors, enable comprehensive monitoring of the recovery of CMV-specific CTL in immunocompromised patients at risk for CMV disease, and may be useful for defining the specificity of CTL responses that correlate with control of virus replication.

Immunoglobulins, vaccines or interferon for preventing cytomegalovirus disease in solid organ transplant recipients

Cytomegalovirus (CMV) is the most common virus causing disease and death in solid organ transplant recipients during the first six months post-transplant. Previous systematic reviews have demonstrated the efficacy of antiviral medications used prophylactically or pre-emptively in preventing CMV disease. In this review the efficacy of older agents (immunoglobulins (IgG), anti CMV vaccines and interferon) are examined. To assess the benefits and harms of IgG, anti CMV vaccines or interferon for preventing symptomatic CMV disease in solid organ transplant recipients. We searched the Cochrane Renal Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library), MEDLINE, EMBASE, reference lists and abstracts from conference proceedings without language restriction. Date of last search: December 2005 Randomised and quasi-randomised controlled trials comparing IgG, anti CMV vaccine or interferon with placebo or no treatment, IgG alone or combined with antiviral medications with antiviral medications or IgG alone in recipients of any solid organ transplant. Two of four authors independently assessed trial quality and extracted data from each trial. Statistical analyses were performed using the random effects model and results expressed as relative risk (RR) for dichotomous outcomes with 95% confidence intervals (CI). Thirty seven trials (2185 participants) were included in this review. There was no significant difference in the risk for CMV disease (16 trials, 770 patients: RR 0.80, 95% CI 0.61 to 1.05), CMV infection (14 trials, 775 patients: RR 0.94, 95% CI 0.80 to 1.10) or all-cause mortality (8 trials, 502 patients: RR 0.57, 95% CI 0.32 to 1.03) with IgG compared with placebo/no treatment. However IgG significantly reduced the risk of death from CMV disease (6 trials, 346 patients: RR 0.33, 95% CI 0.14 to 0.80). There was no difference in the risk for CMV disease (4 trials, 298 patients: RR 1.17, 95% CI 0.74 to 1.86), CMV infection (4 trials, 298 patients: RR 1.16, 95% CI 0.89 to 1.52) or all-cause mortality (2 trials, 217 patients: RR 0.92, 95% CI 0.37 to 2.29) between antiviral medication combined with IgG and antiviral medication alone. There was no significant difference in the risk of CMV disease with anti CMV vaccine or interferon compared with placebo or no treatment. Currently there are no indications for IgG in the prophylaxis of CMV disease in recipients of solid organ transplants.

Is Double Renal Transplantation a Risk Factor for Cytomegalovirus Disease?

We performed a retrospective study to identify the risk factors for cytomegalovirus (CMV) disease among 570 renal transplant recipients. By means of a multivariate analysis we identified antilymphocyte antibody therapy (odds ratio [OR]: 4.6; 95% confidence interval [CI]: 2.0 to 10.6), high doses of corticosteroids (OR: 3.4; 95% CI: 1.2 to 10.1), and double renal transplant (OR: 4.1; 95% CI: 1.5 to 11.5). To the best of our knowledge, this is the first study to suggest that in addition to other well-known risk factors for CMV disease (ie, therapy with anti-lymphocyte antibodies or high doses of corticosteroids), the use of double renal transplantation appears to increase the risk of CMV disease in this population.

Reconstitution of HLA-A*2402-Restricted Cytomegalovirus-Specific T-Cells following Stem Cell Transplantation

Cytomegalovirus (CMV)-specific immune reconstitution early after stem cell transplantation (SCT) was evaluated prospectively by detecting CD8+ T-cells, which recognize the peptide QYDPVAALF in the context of HLA-A*2402. Fifteen allogeneic SCT recipients were included in the study. All recipients and donors were seropositive for CMV and had the HLA-A*2402 allele. CMV-specific T-cells were detected as early as 1 month after transplantation, and their numbers increased to peak levels 2 to 5 months after transplantation. The numbers of CMV-specific T-cells in patients who developed grade II to IV acute graft-versus-host disease (GVHD) and received corticosteroids for acute GVHD were low in the early period after allogeneic SCT. There was a trend toward earlier reconstitution of CMV-specific CD8+ T-cells in allogeneic peripheral blood SCT (PBSCT) patients than in allogeneic bone marrow transplantation patients. The contribution of T-cells in the graft to the recovery of CMV-specific immune responses was also suggested by the finding that the reconstitution of CMV-specific CD8+ T-cells was delayed in CD34-selected autologous PBSCT compared with unpurged autologous PBSCT. The reconstitution of CMV-specific CD8+ T-cells was delayed in patients with CMV disease or recurrent CMV reactivation. These observations suggest that the detection of CMV-specific T-cells with an HLA-peptide tetramer is useful to assess immune reconstitution against CMV and to identify patients at risk for CMV disease or recurrent CMV reactivation after SCT.

Efficacy and Safety of Low‐Dose Valganciclovir for Prevention of Cytomegalovirus Disease in Renal Transplant Recipients: A Single‐Center, Retrospective Analysis

To evaluate the safety and efficacy of valganciclovir 450 mg/day for 6 months for cytomegalovirus (CMV) prophylaxis in renal transplant recipients. Single-center, retrospective analysis. Urban, academic medical center. Fifty-eight patients who received de novo renal transplants from August 1, 2001-November 21, 2002. Valganciclovir 450 mg/day was administered to all renal transplant recipients at risk for CMV disease. Therapy was begun postoperatively and was dose adjusted to renal function. Data collected from renal transplant recipients were demographics, immunosuppressive and antiviral drug therapy, and occurrence of CMV disease, acute rejection, allograft loss, and hematologic adverse events. Donor (D)/recipient (R) CMV serostatus was 37.9% D+/R+, 29.3% D-/R+, 17.3% D+/R-, and 15.5% D-/R-. Antithymocyte globulin (ATG) was administered to 62.1% of patients. Most of the transplant recipients received triple immunosuppression as maintenance therapy. Median follow-up was 20 months. The frequency of CMV disease was 1.7% within 6 months after transplantation and 5.2% at any point after transplantation. All patients who developed CMV disease were D+/R- and had received ATG. Leukopenia and thrombocytopenia associated with valganciclovir were seen in 28% and 24% of patients, respectively. One patient developed acute cellular rejection. No graft losses or deaths occurred. Early discontinuation of valganciclovir occurred in 20% of patients secondary to severe, persistent leukopenia, thrombocytopenia, and/or diarrhea. None of these patients developed CMV disease. A high rate of CMV disease was noted among the D+/R- population. Administration of ATG as an induction agent also increased the frequency of CMV disease. Despite the low dosage of valganciclovir, hematologic adverse events were common. However, valganciclovir, administered at 450 mg/day for 6 months, was effective and relatively safe for prophylaxis of CMV disease in renal transplant recipients.

Canadian consensus guidelines for the management of cytomegalovirus disease in HIV/AIDS.

The management of HIV-infected patients with cytomegalovirus (CMV) disease has changed significantly with the availability of highly active antiretroviral therapy (HAART). These updated guidelines are intended to provide practical help to physicians managing HIV-positive patients with or at risk for CMV disease. The 10 members of the Canadian CMV Disease in HIV/AIDS Consensus Group were infectious disease specialists, a primary care physician and ophthalmologists with expertise in HIV and CMV infection. Financial support by Hoffmann-La Roche Canada Ltd was unrestricted, and was limited to travel expenses and honoraria. The consensus group met in June and October 2002. Key areas to be considered were identified, and group members selected, reviewed and presented relevant recent literature for their assigned section for the group's consideration. Evidence was assessed based on established criteria, which were expert opinions of the members. Draft documents were circulated to the entire group and modified until consensus was reached. The final guidelines represent the group's consensus agreement. The guidelines were approved by the Canadian Infectious Disease Society. The guidelines address symptom monitoring, screening for early detection and prevention, and treatment using oral, intravenous and intraocular anti-CMV therapies in conjunction with HAART.

Formulary considerations for drugs used to prevent cytomegalovirus disease.

Four types of therapeutic strategies for managing cytomegalovirus (CMV) in solid organ transplant recipients, the mechanisms of action and efficacy of drugs used for prophylaxis, and the criteria for evaluating drugs for inclusion in a formulary are described. Universal and selective prophylaxis are simple to implement and effective for CMV prophylaxis, but they are costly and patient nonadherence and viral resistance can develop. Preemptive therapy may cause less resistance and cost less, but it is more complex and associated with a higher incidence of infection, which may have no effect on secondary effects from CMV infection, and higher recurrence of disease than prophylactic therapy. Treatment of active disease may be less costly for the drug than other approaches, but intravenous access is required and the rates of infection recurrence and mortality are higher compared with prophylaxis and preemptive therapy. Criteria for deciding which CMV prophylactic drugs to include in a formulary include efficacy, safety, convenience, and cost. CMV immune globulin i.v. is costly and exhibits reduced efficacy when used alone in patients at high risk for CMV disease. Intravenous ganciclovir is effective, but it is costly because of infusion costs. Intravenous drug therapies are inconvenient and associated with a risk of bacterial and fungal infection. Oral acyclovir is safe to use and inexpensive (since a genetic exists), but it has poor efficacy and is inconvenient because of the need for four large daily doses. Valacyclovir is more convenient and with similar safety and probably better efficacy than acyclovir, but it is more costly. Oral ganciclovir and oral valganciclovir have similar safety and costs, with greater efficacy than acyclovir. The single daily dose and lack of resistance to valganciclovir are advantages over oral ganciclovir, which requires three daily doses and can result in the development of resistance.

CMV infection of the renal allograft is much more common than the pathology indicates: a retrospective analysis of qualitative and quantitative buffy coat CMV-PCR, renal biopsy pathology and tissue CMV-PCR.

Quantitative blood polymerase chain reaction (PCR) for cytomegalovirus (CMV) is used to direct therapy in kidney transplant patients, but cytomegalic inclusions are rarely found in allograft renal biopsies even with an elevated serum creatinine and apparent CMV disease. The relationship between quantitative blood CMV and renal allograft pathology is unknown. Thirteen biopsy samples were available for analysis from patients suspected of CMV disease, who had a buffy coat CMV-PCR drawn within 2-5 days of a renal allograft biopsy for an elevated creatinine. All were evaluated for CMV pathologically, by light microscopy, immunohistochemistry, in situ hybridization and tissue PCR. Qualitative and quantitative buffy coat CMV-PCR were positive in 10/13 (77%) patients. Tissue CMV-PCR was positive in five (50%) biopsies, including two with CMV inclusions and three with no inclusions. Quantitative buffy coat CMV-PCR levels did not correlate with detection of CMV inclusions in renal tissue. Paradoxically, quantitative buffy coat CMV-PCR was low (239 and 538 copies/microg of DNA) when CMV inclusions were detected. All five biopsies with acute rejection were associated with CMV viraemia and two of the five with allograft CMV inclusions. A quantitative buffy coat CMV-PCR of <100 copies/microg of DNA ruled out disease with CMV inclusions. CMV nephropathy is much more common than previously reported when sensitive techniques are used for detection in tissue. Acute rejection and CMV viraemia occur commonly together in patients at risk for CMV. Quantitative buffy coat CMV-PCR does not correlate with the presence of CMV inclusions. These findings have implications for management of patients who have elevated serum creatinine and are at risk for CMV disease.

Quantification du CMV : méthodes, intérêt, applications

Cytomegalovirus (CMV) causes significant morbidity and mortality in immunocompromised individuals, whereas infection is often asymptomatic in immunocompetent patients. To identify patients at risk for CMV disease, several methods have been developed for viral quantitation in clinical samples. These methods are based on antigen detection or molecular biology. The pp65 quantitative antigenemia is a sensitive assay for estimating the viral load, but it has an important disadvantage : the need of rapid processing of the sample. For the molecular methods, several kits are available; they are based on hybridization (Murex Hybrid Capture ® System), Branched DNA (Quantiplex bDNA CMV Test ®), PCR (Cobas Amplicor CMV™ Monitor-Test) and NASBA. These kits give concordant results with antigenemia. The real-time PCR-based methods that have been recently developed, are now widely used for quantification of CMV viral load. These methods are rapid and avoid post-amplification contamination. Their major disadvantages are the cost of the PCR apparatus and the non-standardization of the assays. Utility of CMV viral load measurement for the follow-up of immunocompromised patients is now well-established. The choice of the best method for a laboratory depends on the type of patients, the number of samples received per day and the financial resources.

Pediatric cytomegalovirus infections

Cytomegalovirus (CMV) is a frequent infection, which is usually asymptomatic however, infection of the fetus in utero, can cause severe disease and death. Premature and young infants, immunosuppressed children who receive transplants and children with human immunodeficiency virus (HIV) infection are also at risk for significant disease due to CMV. The diagnosis of infection in pregnant women and children requires the use of serology and/or detection of the virus. Serological tests are available for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody however, these tests have important limitations. The virus can be detected by tissue culture using the shell vial and centrifugation method or by identification of CMV deoxyribonucleic acid (DNA) or messenger ribonucleic acid (mRNA). These tests also have some limitations. Additional laboratory tests have been reported to improve the accuracy of diagnosis but require further evaluation. Treatment with ganciclovir or foscarnet may be beneficial. Approaches to prevention of infections associated with transfusions include the use of CMV-IgG antibody negative blood or leukoreduction. Recipients of stem cell transplants can also be given high titered antibody to CMV. Children with HIV and severe immunosuppression can now receive highly active retroviral therapy, which may reduce the immunosuppression and the risk for CMV disease.

Multiplex, quantitative, real-time PCR assay for cytomegalovirus and human DNA.

We created a multiplex, quantitative, real-time PCR assay that amplifies cytomegalovirus (CMV) and human DNA in the same reaction tube, allowing for a viral load determination that is normalized to measured human DNA. The assay targets a conserved region of the CMV DNA polymerase gene that is not affected by known drug resistance mutations. All 36 strains of CMV detected by culture or qualitative PCR in a population of lung transplant recipients were detected. The assay detected 1 to 10 copies of CMV plasmid DNA. The analytic sensitivity was not affected by the presence of DNA from 10(6) human cells but was reduced approximately 10-fold by alkaline lysates of leukocyte preparations. CMV quantitation was linear over a range of 10(1) to 10(6) copies. The intraassay and interassay coefficients of variation were 29 and 40%. Human DNA was regularly detected in patient plasma samples, and the amount was increased by storage of blood at room temperature before plasma separation and by plasma separation techniques that allowed leukocyte contamination. Applied to whole blood, the assay provides a measurement of CMV DNA in relation to cellular content without a need for cell counting procedures. Applied to plasma, the assay can reveal artifactual increases in plasma CMV levels resulting from leukocyte contamination. Further study of the utility of this assay to monitor patient populations at risk for CMV disease is warranted.

Cytomegalovirus Infection

Cytomegalovirus Infection

Risk for cytomegalovirus disease in patients receiving polymerase chain reaction-based preemptive antiviral therapy after allogeneic stem cell transplantation depends on transplantation modalityH. Hebart, W. Brugger, U. Grigoleit, et al. Blood 97:2183–2185, 2001

Risk for cytomegalovirus disease in patients receiving polymerase chain reaction-based preemptive antiviral therapy after allogeneic stem cell transplantation depends on transplantation modalityH. Hebart, W. Brugger, U. Grigoleit, et al. Blood 97:2183–2185, 2001

Quantification of cytomegalovirus (CMV) viral load by the hybrid capture assay allows for early detection of CMV disease in lung transplant recipients

Background: We prospectively compared the hybrid capture system (HCS) assay with conventional cell culture and shell vial assay for the detection of cytomegalovirus (CMV) infection and disease in the lung transplant population. Methods: Between January 1999 and February 2000, 34 lung transplant patients at Loyola University Medical Center, who were considered to be at risk for CMV disease, underwent surveillance testing for CMV cell culture, shell vial assay and HCS assay according to a pre-determined schedule. In addition, bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy were performed at regular intervals and for clinical indications. All BAL samples were sent for CMV cultures and biopsy specimens were analyzed for histopathologic evidence of CMV by immunoperoxidase staining using antibody to early immediate nuclear antigen. Results: Ten patients developed CMV disease/syndrome during the course of the study. The sensitivity, specificity, positive predictive value and negative predictive value were >90% for the HCS assay. The sensitivity of the HCS assay (90%) was statistically significantly higher than the sensitivity of either the SV assay (40%) or the cell culture (50%). In addition, the HCS assay was able to detect CMV 50 ± 67 days prior to clinical evidence of CMV disease and an average of 36 days prior to the other detection techniques. Conclusion:The HCS assay is a sensitive diagnostic technique able to reliably detect CMV disease earlier than other diagnostic methods in the lung transplant population. Future studies may be able to evaluate whether pre-emptive anti-viral therapy targeted to specific viral loads using the HCS assay will be beneficial in preventing morbidity associated with CMV disease.

Correlates of Change in Cytomegalovirus Viremia in Patients with Advanced Human Immunodeficiency Virus Infection Who Require Transfusion

The Viral Activation Transfusion Study compared leukocyte-reduced to unfiltered red blood cell transfusions in human immunodeficiency virus (HIV)- and cytomegalovirus (CMV)-coinfected patients. Relationships between serially measured plasma CMV load and clinical and laboratory outcomes over a median of 12 months were examined in 511 subjects. At baseline, subjects had a median of 15 CD4(+) cells/mm(3), 25% had CMV disease, and 21.5% were viremic. No relationship was found between changes in CMV viremia and changes in HIV RNA. Increased CMV viremia was associated with a concomitant fall in Karnofsky score. Highly active antiretroviral therapy (HAART) led to a decrease in CMV viremia after a 90-day delay. After adjustment for HIV load and CD4(+) cell count, CMV viremia remained associated with an increased risk of CMV disease (relative hazard, 5.78). In late-stage HIV-infected patients, CMV viremia was associated with lower functional status and increased risk of CMV disease. HAART suppressed CMV viremia only after a delay of several months.

Incremental cost effectiveness of prophylaxis for cytomegalovirus disease in patients with AIDS.

Cytomegalovirus (CMV) disease, an opportunistic complication in patients with AIDS, causes substantial morbidity and has high treatment costs. Although prevention of this disease is highly desirable, incremental cost-effectiveness estimates for proposed prophylactic strategies in the era prior to the availability of highly active antiretroviral therapy (HAART) were unfavourable relative to other specific antimicrobial prophylactic strategies in patients with AIDS. With the availability of HAART, several inputs upon which previous estimates of the incremental cost-effectiveness ratio for anti-CMV prophylaxis were based probably changed substantially. To assess the incremental cost effectiveness of prophylaxis in the HAART era, data are needed on visual outcomes and utility for patients with CMV retinitis and AIDS, on better strategies for identifying subpopulations at high risk for CMV disease and on the prophylactic efficacy of valganciclovir. Cost-effectiveness analysis could potentially contribute by exploring thresholds of population risk, prophylactic effectiveness, and drug pricing in order to identify conditions under which prophylaxis for CMV disease in patients with AIDS could potentially become cost effective.

Cytomegalovirus (CMV) DNA load in plasma for the diagnosis of CMV disease before engraftment in hematopoietic stem-cell transplant recipients.

Among hematopoietic stem-cell transplant (HSCT) recipients, cytomegalovirus (CMV) disease before engraftment is rare but often fatal, and cell-based diagnostic tests have low sensitivity in this clinical setting. We used the quantitative real-time polymerase chain reaction (PCR) assay to test for CMV DNA in plasma samples from 15 HSCT recipients who developed CMV disease before engraftment and from 33 matched control patients. CMV DNA was detected in plasma in 14 (93.3%) of the 15 patients who had CMV disease before engraftment, compared with 5 (15.2%) of 33 control patients (P<.001). CMV DNA was detected a median of 13 days before the onset of CMV disease (range, 0-35 days). The maximum CMV virus load in plasma was >1 log(10) higher among case patients than among control patients (median, 1700 [range, 50 to 5.5x107] vs. <50 [range, <50-350] CMV DNA copies/mL plasma, respectively; P<.001). Quantitative PCR for CMV DNA in plasma appears to be useful for the identification of HSCT recipients at risk for CMV disease before engraftment.