Management of CMV infection and disease in transplant patients. 27-29 February 2004

The International Herpes Management Forum (IHMF) has published guidelines for the diagnosis and management of cytomegalovirus (CMV) infection and disease in solid organ (SOT) and haematopoietic stem cell transplant (HSCT) recipients. These recommendations have been updated to include, among others: (1) use of whole blood for the polymerase chain reaction (PCR) diagnosis of CMV infection; (2) CMV load measurements for prognostication and for monitoring response to anti-CMV therapy; (3) valganciclovir prophylaxis in CMV donor-positive/recipientnegative (D+/R-) SOT patients for prevention of CMV disease; (4) oral ganciclovir prophylaxis, in preference to aciclovir, to reduce incidence of CMV disease in SOT patients; (5) pre-emptive therapy with oral ganciclovir to reduce incidence of CMV disease and viraemia in liver transplant patients; (6) valaciclovir prophylaxis, in preference to high-dose oral aciclovir, to prevent CMV infection in allogeneic HSCT patients; and (7) foscarnet as an alternative to intravenous ganciclovir for pre-emptive treatment of CMV infection in allogeneic HSCT patients. New developments in the field requiring further research were highlighted, including: optimal frequency of CMV monitoring in CMV D+/R- SOT patients; optimal duration of prophylaxis for the prevention of late CMV disease; need for an acceptable viral threshold for initiation of pre-emptive therapy; and assessment of the clinical efficacy of valganciclovir for the treatment of CMV disease and as pre-emptive therapy in SOT and HSCT patients. This article presents supporting evidence for these recommendations and statements.     

Prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplants

The main risk factors for cytomegalovirus (CMV) disease in recipients of allogeneic stem cell transplants (SCT) are recipient CMV seropositivity and acute graft-versus-host disease. Currently, two antiviral strategies, prophylactic or preemptive antiviral treatment, are used for prevention of CMV disease. Preemptive treatment is most favorable when short-term (14-day) treatment is applied. Several methods are available for monitoring of CMV reactivation. PCR-based CMV DNA detection assays are the most sensitive methods; however, the clinical benefit of this high sensitivity is unclear. Even more, there is lack of clarity whether PCR tests can better be performed with plasma, whole blood, or peripheral blood leukocyte samples. Recovery of a CMV-specific CD8(+) cytotoxic-T-lymphocyte (CTL) response is necessary for preventing CMV reactivation and disease. Reconstitution of absolute CMV-specific CTL counts to values above 10 x 10(6) to 20 x 10(6) CTLs/liter is associated with protection from CMV disease. In the near future, preemptive therapy might be withheld in patients with CMV reactivation who are shown to have adequate CMV-specific cytotoxic T-cell levels. Antiviral therapy with (val)acyclovir has been studied only as prophylactic treatment for prevention of CMV infection. High-dose oral valacyclovir is more effective than acyclovir when used in addition to preemptive treatment of CMV reactivation with ganciclovir or foscarnet. Three antiviral drugs have been tested for preemptive therapy of CMV reactivation and/or treatment of CMV disease. Although intravenous ganciclovir is considered the drug of choice, foscarnet has similar efficacy and less toxicity, especially hematologic toxicity. Cidofovir has not been tested extensively, but so far the results are disappointing. Oral valganciclovir for preemptive treatment of SCT recipients is currently being studied. In addition to antiviral therapy, adoptive immunotherapy with CMV-specific cytotoxic T cells as prophylactic or preemptive therapy is a very elegant strategy; however, generation of these cells is expensive and time-consuming, and therefore the therapy is not available at every transplantation center. Magnetic selection of CMV-specific CD8(+) T cells from peripheral blood by using HLA class I-peptide tetramers may be very promising, making this strategy more accessible.     

Recent advances in the therapy and prevention of CMV infections.

The introduction of highly active antiretroviral therapy (HAART) for HIV has had a major impact on the treatment of CMV disease in HIV-infected individuals. There is mounting evidence that in patients with CMV retinitis who have a sustained response to HAART, CMV maintenance treatment can be discontinued without relapse of retinitis. In HAART-na?ve individuals with newly diagnosed CMV retinitis, the optimal timing for the initiation of HAART relative to the start of anti-CMV treatment is currently unknown. New local therapies for CMV retinitis (e.g. ganciclovir implant, the new antisense compound fomivirsen) provide treatment options in situations where high local drug delivery is warranted. A treatment algorithm for CMV disease in the HAART era is proposed. In the transplant setting, ganciclovir and foscarnet remain the major compounds used for treatment of CMV disease. In marrow and stem cell transplant recipients, CMV pneumonia still carries a high mortality. Ganciclovir in combination with CMV-specific immunoglobulin or regular intravenous IG remains the treatment of choice for CMV pneumonia; extended antiviral maintenance for several months is recommended in patients with continued immunosuppression. Preemptive treatment based on virologic markers (e.g. pp65 antigenemia, CMV DNA) has been very successful in reducing the incidence of early CMV disease in the transplant setting. The duration of preemptive treatment should be guided by the underlying immunosuppression and virologic markers. Late CMV disease is a challenge in marrow and stem cell transplant recipients, and occurs increasingly in highly immunosuppressed solid organ transplant recipients as well. Recent advances in prophylaxis strategies include oral ganciclovir for liver transplant recipients and valacyclovir for kidney transplant recipients.     

CMV Infection in Bone Marrow and Solid Organ Transplant Patients in the Era of Antiviral Prophylaxis

Recent developments in the diagnosis and therapy of cytomegalovirus (CMV) infection have helped to reduce CMV-associated morbidity and mortality following allogeneic bone marrow and solid organ transplantation. The clinical symptoms of active CMV infection and the prevalence of life-threatening CMV disease vary widely between different patient populations according to the type of transplant and the intensity of immunosuppression employed. Antiviral prophylaxis with aciclovir, valaciclovir and ganciclovir has been shown to reduce CMV infection and disease following organ transplantation. Antiviral drugs, in particular ganciclovir and foscarnet, have varying sideeffects, however, and antiviral resistance due to prolonged administration of ganciclovir and foscarnet has been reported recently. Short courses of pre-emptive antiviral therapy for documented CMV infection help to reduce the duration and sideeffects of therapy, offering an alternative strategy to antiviral prophylaxis. Studies are required to compare the efficacy and costs of antiviral prophylaxis with pre-emptive therapy.     

Case study: rapid emergence of a cytomegalovirus UL97 mutant in a heart-transplant recipient on pre-emptive ganciclovir therapy

A cytomegalovirus (CMV) strain containing a mutation in the UL97 gene (Leu595Ser), which is known to confer ganciclovir resistance, emerged rapidly in a heart-transplant recipient after 54 days of antigenaemia-guided ganciclovir therapy. The emergence of this viral mutant, while the patient was receiving oral ganciclovir 1000 mg three times daily, was associated with increasing CMV pp65 antigenaemia levels despite the re-instatement of intravenous ganciclovir 5 mg/kg twice daily. The antiviral regimen was then switched to intravenous foscarnet 90 mg/kg, administered either twice daily, once daily or every other day, which resulted in a rapid decrease of CMV antigenaemia levels and prevented the development of CMV-associated disease. Frequent monitoring of the CMV viral load and/or mutational studies are warranted in highly immunocompromised transplant recipients to prevent the development of CMV disease caused by ganciclovir-resistant strains.     

Cytomegalovirus infection of the central nervous system

Studies report that 40-100% of the general population are infected with cytomegalovirus (CMV), a virus associated with severe neurological conditions, such as CMV encephalitis, and which may have a role in some cases of Guillain-Barre syndrome. CMV infection is a particular concern among individuals with HIV, as almost all are co-infected with it. The introduction of highly active antiretroviral therapy (HAART) has provided a means of reconstituting the immune system of those with HIV/AIDS in such a way as to allow CMV infection to be controlled. In doing so, HAART has done much to reduce the mortality rate associated with CMV disease in such patients. Despite this, response to treatment in these patients remains suboptimal and many do not have access to such therapy, so, efforts to improve the treatment of CMV have been a priority. The International Herpes Management Forum (IHMF) has developed management guidelines to promote the improved diagnosis and treatment of CMV disease of the central nervous system (CNS). It is recommended that polymerase chain reaction (PCR) for viral DNA should be performed on CSF as a means of diagnosing CMV infection of the CNS. As CMV disease is always preceded by viraemia, treatment should be directed toward the prevention of CMV disease. However, if CMV disease develops, ganciclovir is recommended as therapy and continued in a maintenance fashion, which can be discontinued should CD4 count remain above 100 cells/mm3 for 6 months. In many circumstances, valganciclovir may be preferred, depending on the level of function in the patient, their ability to take oral therapy and the severity of disease. Use of foscarnet should be limited to ganciclovir-resistant cases due to the high level of toxicity associated with the drug and its intravenous mode of administration.     

Cytomegalovirus appendicitis in solid organ transplant patients,two cases and a review

Cytomegalovirus (CMV) disease is a common complication following solid organ transplantation with a variety of gastrointestinal (GI) tract manifestations. CMV appendicitis, however, is a rare complication in a solid organ transplant patient, having been reported only once previously. We have recently seen two cases in solid organ transplant recipients at our institution, one a liver recipient and the other a heart recipient. Both patients underwent surgical resection. Pathologic evaluation of both resected appendices as well as polymerase chain reaction (PCR) amplification for CMV from the serum revealed the virus as the etiology. Both patients received induction intravenous ganciclovir followed by oral valganciclovir and have done well post-operatively. Tissue-invasive CMV disease should be considered in the differential diagnosis for solid organ transplant patients with symptoms suggesting acute or chronic appendicitis. Both PCR testing as well as pathologic review of tissue specimens should be considered to ensure accurate diagnosis and management.     

Qualitative Plasma PCR Assay (AMPLICOR CMV Test) versus pp65 Antigenemia Assay for Monitoring Cytomegalovirus Viremia and Guiding Preemptive Ganciclovir Therapy in Allogeneic Stem Cell Transplantation

The performances of a commercially available qualitative plasma PCR assay (AMPLICOR CMV test; Roche Diagnostics) and the pp65 antigenemia assay (AG) were evaluated for the monitoring of cytomegalovirus (CMV) viremia in 43 allogeneic stem cell transplant recipients. In addition, the suitabilities of both assays for triggering the initiation of preemptive ganciclovir therapy were assessed. A total of 37 CMV viremic episodes were detected in 28 patients. Positivity of plasma PCR testing in one or more consecutive specimens was the only marker of CMV viremia in 18 of the 37 episodes (PCR positive and AG negative, n = 50 specimens). Five episodes were diagnosed on the basis of a single positive AG result (AG positive and PCR negative, n = 5 specimens); both assays were eventually positive (PCR positive and AG positive, n = 27 specimens) for 14 viremic episodes; for these episodes, conversion of the PCR assay result to a positive result occurred an average of 1 week before conversion of the AG result. Overall, the concordance between the two methods was 90%, and the sensitivities of the plasma PCR assay and AG for the detection of CMV viremic episodes were 86.5 and 51.3%, respectively. Two patients who tested positive by both assays simultaneously progressed to CMV end-stage organ disease, despite the initiation of preemptive ganciclovir therapy. Conversion of the AG result to a negative result upon administration of preemptive ganciclovir therapy occurred a median of 7.5 days earlier than conversion of the plasma PCR assay result. Nineteen of the 28 patients with CMV viremia received AG-guided preemptive ganciclovir therapy; had the positivity of the plasma PCR assay triggered the initiation of preemptive therapy, 9 additional patients would have been unnecessarily treated since none of them developed CMV end-stage organ disease. Although the AMPLICOR CMV assay is more sensitive than AG, the latter appears to be more suitable both for guiding the initiation of preemptive therapy and for monitoring a patient's response to antiviral therapy.     

A comparative randomised study of valacyclovir vs. oral ganciclovir for cytomegalovirus prophylaxis in renal transplant recipients

An open, prospective, randomised study was conducted to compare the safety and efficacy of valacyclovir vs. oral ganciclovir for cytomegalovirus (CMV) prophylaxis in renal transplant recipients. Eighty-three renal transplant recipients were assigned randomly to receive valacyclovir (n=43) or oral ganciclovir (n=40) for the first 3 months after transplantation. Both groups were similar in terms of demographics, primary renal disease, graft source, HLA matching, immunosuppressive therapy and donor-recipient CMV antibody status. CMV infection was diagnosed by detection of virus DNA in plasma with the Amplicor CMV Test. CMV disease was observed in only one patient belonging to the ganciclovir group, who developed enterocolitis 6 months post-transplantation. No difference was observed between the two treatment groups with respect to detection of CMV DNA, virus infections other than CMV, acute rejection episodes, and serum creatinine levels at 3 and 6 months following transplantation. An increased number of bacterial infections was noted in the ganciclovir group (p 0.003). No adverse reactions with either treatment were reported. The estimated cost of valacyclovir treatment was 20% higher than that of ganciclovir treatment. Overall, both valacyclovir and oral ganciclovir were found to be effective and safe for CMV prophylaxis in renal transplant recipients. Decisions regarding prophylactic regimens should include additional criteria, such as cost or possible development of resistance.     

Management of allogeneic bone marrow transplant recipients at risk for cytomegalovirus disease using a surveillance bronchoscopy and prolonged pre-emptive ganciclovir therapy.

BACKGROUND: Patients undergoing allogeneic bone marrow transplant (BMT) are considered to be at increased risk of cytomegalovirus (CMV) disease if they and/or their donor are CMV seropositive pre-transplant. Although several pre-emptive strategies have been shown to be effective in preventing early CMV disease, the ability of pre-emptive strategies using prolonged ganciclovir therapy to reduce the incidence of late-onset CMV infection, disease and mortality has not been fully evaluated. OBJECTIVE: To assess the efficacy of 18 weeks of pre-emptive ganciclovir therapy in preventing late-onset (> 100 days post-transplant) CMV disease when administered to asymptomatic BMT patients found to have CMV in bronchoalveolar lavage (BAL) fluid obtained during a surveillance bronchoscopy approximately 35 days post-transplant. To determine whether or not survival of BMT recipients is influenced by pre-transplant donor and recipient CMV serostatus in the context of this pre-emptive ganciclovir strategy. STUDY DESIGN: Consecutive patients undergoing allogeneic BMT were assessed for their risk of developing CMV disease based on their pre-transplant CMV serostatus and that of their donor. Patients who were CMV seropositive and/or received marrow from a CMV seropositive donor underwent a surveillance bronchoscopy and BAL approximately 35 days post-transplant. Patients with positive BAL fluid for CMV received pre-emptive ganciclovir therapy for 18 weeks at decreasing dose levels. Patients considered to be at low risk for the development of CMV disease (donor and recipient CMV seronegative) were followed without intervention. RESULTS: Of 98 consecutive patients, 55 were considered to be at risk for CMV disease and underwent a surveillance bronchoscopy. Sixteen (29%) patients had a positive BAL fluid for CMV and were started on pre-emptive ganciclovir therapy. Two patients progressed and died with CMV-related pneumonia. One additional patient developed CMV-related enteritis on day 42 post-transplant and recovered with continuing ganciclovir treatment. Of the 39 patients with a negative BAL fluid for CMV, one developed a fatal CMV pneumonia 150 days post-transplant and two additional patients developed gastrointestinal CMV disease 28 and 57 days post-BMT, respectively. None of the patients in the low risk group developed CMV disease. CONCLUSIONS: The strategy utilizing a surveillance bronchoscopy for CMV and initiating prolonged (18 weeks) pre-emptive ganciclovir therapy for patients with a positive BAL fluid for CMV resulted in a low incidence of CMV-related post-transplant complications. After a minimum follow-up of 16 months, late CMV reactivations (occurring > 100 days post-transplant) were not observed in the group of individuals pre-emptively treated with ganciclovir. This observation suggests that prolonged therapy with a reduced dose of ganciclovir may be important in the prevention of CMV reactivation. The CMV serostatus of donors and recipients prior to BMT did not correlate with survival.     

Antiviral Immunotherapy

Unselected intramuscular (IM) and intravenous (IV) immunoglobulins, as well as virus-specific hyperimmune globulins, occupy important roles as immunotherapy for viral infections. Standard IM immunoglobulins may be utilised in selected, susceptible patients for the prevention of hepatitis A and measles. Hyperimmune globulins to varicella zoster virus (VZV), hepatitis B virus and rabies have established indications for use as post-exposure prophylaxis. Cytomegalovirus (CMV) hyperimmune globulin has an indication for the prevention of primary CMV-associated disease in kidney transplantation and has been shown to decrease severe CMV-associated disease in liver transplantation. More recently, respiratory syncytial virus (RSV) hyperimmune globulin has been developed and is being utilised to prevent RSV disease in high risk infants and children during months of maximum risk for RSV infection. Unselected IV immunoglobulins (IVIg) have proven beneficial in preventing CMV-associated disease and graft-versus-host-disease in allogeneic bone marrow transplant recipients. In addition, IVIg plus ganciclovir is effective therapy for established CMV disease in both bone marrow and solid organ transplantation. IVIg for chronic anaemia associated with parvovirus B19 infection is gaining acceptance, as is the use of IVIg and intraventricular immunoglobulin for chronic meningoencephalitis associated with agammaglobulinaemia. Immunotherapy for the prevention or treatment of several other viral infections has been explored, but without clear conclusions. The use of human immunodeficiency virus (HIV) hyperimmune globulins in HIV-infected patients has yielded inconsistent results and the role of such therapy in the era of highly active antiretroviral therapy is uncertain. Oral immunoglobulins appear successful for rotaviral infections, but their exact use requires further clarification. Other immunotherapeutic modalities, such as monoclonal antibodies against CMV, RSV and HIV, have been developed but these agents have not undergone extensive clinical evaluation.     

The eyes have it, too

Eye problems are a significant concern for HIV-positive patients, in whom CMV blindness and vision loss is a devastating side effect. CMV retinitis is the most common eye disease in people with HIV, affecting up to 45 percent of people with AIDS. CMV retinitis is treated with oral or intravenous ganciclovir, although some patients have difficulty absorbing the drug, and an eye implant has been developed. Foscarnet is also used in combination therapy. The Food and Drug Administration (FDA) recommends beginning prophylaxis when CD4 counts drop below 50.     

Ganciclovir for Severe Cytomegalovirus Primary Infection in an Immunocompetent Child

Described here is the unusual case of a previously healthy 17-month-old girl who developed severe cytomegalovirus (CMV) disease with prolonged fever and hepatitis. The severity of her illness required hospitalization and prompted antiviral treatment. Short-term intravenous ganciclovir treatment was associated with immediate and sustained resolution of the symptoms as well as a sharp decrease of CMV viremia. This observation suggests that antiviral therapy might be considered in select cases of severe primary CMV infection in immunocompetent children.     

Nonpulmonary manifestations of cytomegalovirus infection in immunocompromised patients.

Nonpulmonary manifestations of cytomegalovirus (CMV) infection in immunocompromised patients include chorioretinitis, gastrointestinal infection, and central nervous system disease. Diagnosis of end organ disease, especially in the gastrointestinal tract, is best substantiated by histologic evidence of CMV inclusions. Positive cultures of CMV provide evidence for supporting infection but do not define actual end organ disease. Satisfactory treatment of the disease can be accomplished with ganciclovir or foscarnet, although these agents only suppress virus replication. In many instances, severe CMV-induced end organ disease in immunocompromised patients will progress despite treatment. In some instances, resistance to the antiviral agent is the basis for drug failure. Patients at high risk for CMV disease can be identified, and studies of prophylaxis are in progress.     

Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. Roche Ganciclovir Study Group

BACKGROUND: The intraocular ganciclovir implant is effective for local treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS), but it does not treat or prevent other systemic manifestations of cytomegalovirus infection. METHODS: Three hundred seventy-seven patients with AIDS and unilateral cytomegalovirus retinitis were randomly assigned to one of three treatments: a ganciclovir implant plus oral ganciclovir (4.5 g daily), a ganciclovir implant plus oral placebo, or intravenous ganciclovir alone. The primary outcome measure was the development of new cytomegalovirus disease, either contralateral retinitis or biopsy-proved extraocular disease. RESULTS: The incidence of new cytomegalovirus disease at six months was 44.3 percent in the group assigned to the ganciclovir implant plus placebo, as compared with 24.3 percent in the group assigned to the ganciclovir implant plus oral ganciclovir (P=0.002) and 19.6 percent in the group assigned to intravenous ganciclovir alone (P<0.001). As compared with placebo, oral ganciclovir reduced the overall risk of new cytomegalovirus disease by 37.6 percent over the one-year period of the study (P=0.02). However, in the subgroup of 103 patients who took protease inhibitors, the rates of new cytomegalovirus disease were low and of similar magnitude, regardless of treatment assignment. Progression of retinitis in the eye that initially received an implant was delayed by the addition of oral ganciclovir, as compared with placebo (P=0.03). Treatment with oral or intravenous ganciclovir reduced the risk of Kaposi's sarcoma by 75 percent (P=0.008) and 93 percent (P<0.001), respectively, as compared with placebo. CONCLUSIONS: In patients with AIDS and cytomegalovirus retinitis, oral ganciclovir in conjunction with a ganciclovir implant reduces the incidence of new cytomegalovirus disease and delays progression of the retinitis. Treatment with oral or intravenous ganciclovir also reduces the risk of Kaposi's sarcoma.     

High dose oral ganciclovir treatment for cytomegalovirus retinitis.

BACKGROUND: The oral formulation of ganciclovir is approved at a dose of 3.0 g/day for maintenance treatment of cytomegalovirus (CMV) retinitis following an initial induction course of intravenous (IV) anti-CMV therapy. Median time to progression of CMV retinitis is 12-20 days shorter with oral compared to IV ganciclovir maintenance, likely due to the limited oral bioavailability of ganciclovir. OBJECTIVES: We hypothesized that higher systemic drug exposures associated with increased doses of oral ganciclovir would be associated with increased efficacy. STUDY DESIGN: Maintenance treatment of CMV retinitis with higher than standard doses of oral ganciclovir (>3.0 g/day) was studied in 281 AIDS patients with previously treated, stable retinitis randomized to 3.0, 4.5 or 6.0 g/day oral, or 5 m/kg/day IV ganciclovir. Graders unaware of treatment assignments determined retinitis progression using fundus photographs. Vision, other ophthalmic measures and safety were assessed open-label. RESULTS: Median days to photographic progression were 41, 50, 57 and 70, respectively (P=0.052; 3.0 g vs. IV). Hazard ratios for progression relative to IV were 1.66, 1.28 and 1.19 (P=0.016 for 3.0 g). NONMEM-modeled estimates of average serum ganciclovir concentration area under the curve (AUC(0-24)) correlated best with time to progression (P=0.0019). Six grams per day oral ganciclovir was most similar in efficacy to IV, although broad confidence intervals prevented a conclusive comparison. Patients receiving oral ganciclovir had a lower frequency of sepsis and IV catheter events. CONCLUSIONS: This study suggests that the efficacy of ganciclovir for the maintenance treatment of CMV retinitis improves with increasing total drug exposure (measured as average serum concentration AUC(0-24)). All four regimens of ganciclovir were reasonably well tolerated, with safety profiles similar to what has been reported in prior work.     

Intravenous immunoglobulin: appropriate indications and uses in hematopoietic stem cell transplantation.

Intravenous immune globulin (IVIG) therapy has been prescribed in many different disease states. Hyperimmune products are also available. Recently, routine use for many indications has come under scrutiny secondary to high cost, limited supply, and unclear benefit. IVIG is U.S. Food and Drug Administration-approved for application in hematopoietic stem cell transplantation (HSCT), a very common indication for its use. In an attempt to clarify the most appropriate indications and doses in HSCT recipients, we conducted a MEDLINE search in which we reviewed all relevant articles from 1966 to the present. Search terms included bone marrow transplantation, intravenous immune globulin, hyperimmune globulin, GVHD, and cytomegalovirus (CMV). Also, the references of all pertinent studies and review articles were scanned for studies missed via MEDLINE. CMV prophylaxis/treatment and GVHD prophylaxis are the 2 indications with the most significant clinical support, but there are very few prospective, randomized, controlled trials reported. Furthermore, sample size usually was small, included heterogeneous patient populations, and employed different primary end points. Several reports support IVIG therapy in combination with ganciclovir for prevention and treatment of CMV infection, whereas others have shown ganciclovir monotherapy to be effective, blurring the benefit of IVIG administration. CMV IgG data are also imprecise and difficult to interpret. The role of IVIG therapy in prevention and treatment of GVHD also is vague. Only 1 randomized investigation showed a benefit in the prevention of acute GVHD, and no studies showed efficacy in chronic GVHD prophylaxis and therapy. Reports examining the utility of IVIG or CMV IgG in HSCT are hampered by marked variation in trial design and dosing and diverse patient characteristics. Although IVIG may be useful as a component of preemptive therapy and treatment of CMV disease, its contribution to the prevention of reactivation of CMV infection is dubious. Extended IVIG therapy during GVHD prevention may impair recovery of humoral immunity, and its role in prophylaxis and therapy of GVHD has not been clearly defined. Hospital monitoring programs may be a valuable way to detect areas of high use and allow for streamlining of prescribing.     

Cytomegalovirus disease in the era of highly active antiretroviral therapy (HAART).

Cytomegalovirus (CMV) infection was one of the most important opportunistic infections in HIV-infected patients before the introduction of highly active antiretroviral therapy (HAART), i.e. the combination of at least three antiretroviral drugs of different classes. Thereafter, life expectancy and quality of life increased dramatically with the persistent suppression of HIV viremia and a significant reduction in incidence of CMV disease. Nevertheless, evidence for a multitude of direct and indirect effects of CMV on HIV progression is accumulating. Even in the era of HAART, a considerable number of HIV-infected patients have a CD4 cell count below <100 mm(-3), which involves a high risk for CMV disease. The focus of the present review is on interpretation of test results, their predictive value for CMV disease, and guidance for the rational use of diagnostic assays in HIV-infected patients. Identification of patients at immediate risk for CMV disease may be accomplished by detection of CMV-DNA in leucocytes or plasma. Evidence is growing that CMV genotypes may be also relevant for the risk of CMV disease. Diagnosis of CMV disease requires in most instances demonstration of virus in biopsy specimen from the affected organ because presence of CMV in blood may not be causally related to symptoms observed. Clinical symptoms and patient characteristics are essential in the interpretation of laboratory test results and may guide the rational collection of clinical specimen and use of laboratory assays. As a consequence, a reliable diagnosis of CMV disease and early identification of patients at high risk for CMV disease requires an integrated interpretation of clinical and virological information.