Management of human cytomegalovirus infection and disease after allogeneic bone marrow transplantation.
(1/256)
BACKGROUND AND OBJECTIVE: Human cytomegalovirus (HCMV) infection and disease remain a major cause of morbidity and mortality after bone marrow transplantation. HCMV disease, especially pneumonitis, may be treated with ganciclovir and immunoglobulin but even so the outcome is poor with mortality rates of 30-70%. It is therefore imperative to treat HCMV infection before it develops into disease. The aim of this article is to describe the main strategies used to prevent HCMV infection and to improve the survival after CMV disease in bone marrow transplant recipients. INFORMATION SOURCES: In the present review, we examined personal papers in this field and articles published in journals covered by the Science Citation Index and Medline. STATE OF THE ART: Major advances have been made in preventing HCMV infection and disease through two different approaches, both of which reduce HCMV induced morbidity and mortality: In pre-emptive therapy, patients are given ganciclovir when HCMV infection is first identified and this is continued 3-4 months after transplantation; in prophylactic therapy ganciclovir is given to all patients at risk of HCMV disease from engraftment up to 3-4 months post transplantation. Each strategy has advantages and disadvantages and there is no evidence for the superiority of one over the other since the overall survival is the same and the incidence of death from HCMV disease is similar. PERSPECTIVES: The use of more sensitive tests such as HCMV PCR or antigenemia may improve the outcome but probably will not eradicate all HCMV disease. Future possible strategies could include adoptive transfer of CD8+ HCMV-specific cytotoxic T lymphocytes clones derived from the donor marrow or boosting donor or patient immunity using subunit anti-HCMV vaccines such as gB or pp65. (+info)
Expression of the late cytomegalovirus (CMV) pp150 transcript in leukocytes of AIDS patients is associated with a high viral DNA load in leukocytes and presence of CMV DNA in plasma.
(2/256)
The expression of a late cytomegalovirus (CMV) transcript (pp150) was sought in peripheral blood leukocytes (PBL) of subjects with AIDS and correlated with the amounts of CMV DNA in PBL and plasma, by means of quantitative polymerase chain reaction (PCR). The detection of the late CMV transcript was associated with a high number of CMV DNA copies in PBL (P=.0015) and with a positive CMV PCR assay in plasma (P<.001). Expression of CMV pp150 mRNA was best predicted by viral DNA thresholds corresponding to 7058 and 30 copies in PBL and plasma, respectively. The detection of CMV pp150 mRNA was associated with the presence of CMV disease in a univariate analysis but not in a multivariate analysis after controlling for the viral DNA load in PBL. Thus, active viral replication as determined by a high CMV DNA load in PBL is reflected by expression of the late CMV transcript in the same cells and by the presence of CMV DNA in plasma. (+info)
Late cytomegalovirus pneumonia in adult allogeneic blood and marrow transplant recipients.
(3/256)
To assess the impact of antiviral prophylaxis during the first 3 months after transplantation on the frequency, timing, and outcome of cytomegalovirus (CMV) pneumonia during the first year, 541 adult allogeneic blood and marrow transplant recipients were evaluated. Thirty-four patients (6.3%) developed 35 episodes of CMV pneumonia at a mean of 188 days after transplantation, with an associated mortality rate of 76%. Twenty-six episodes (74%) occurred late (after day 100). Of the patients with late CMV pneumonia almost all (92%) had chronic graft vs. host disease or had received T cell-depleted transplants. Fourteen late CMV pneumonias (54%) were associated with serious concurrent infections, and 100% of these episodes were fatal. In conclusion, although the frequency of CMV pneumonia in the early posttransplantation period may be substantially reduced by prophylaxis, CMV continues to be a major cause of morbidity and mortality in the late period. Some subsets of patients need more prolonged surveillance and prophylaxis and/or preemptive therapy. (+info)
Interstrain variation in the human cytomegalovirus DNA polymerase sequence and its effect on genotypic diagnosis of antiviral drug resistance. Adult AIDS Clinical Trials Group CMV Laboratories.
(4/256)
The polymerase (pol) coding sequence was determined for 40 independent clinical cytomegalovirus isolates sensitive to ganciclovir and foscarnet. Sequence alignments showed >98% interstrain homology and amino acid variation in only 4% of the 1, 237 codons. Almost all variation occurred outside of conserved functional domains where resistance mutations have been identified. (+info)
Intravitreal toxicology in rabbits of two preparations of 1-O-octadecyl-sn-glycerol-3-phosphonoformate, a sustained-delivery anti-CMV drug.
(5/256)
PURPOSE: To determine intraocular toxicity and efficacy of the lipid prodrug of foscarnet, 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA), as a long-acting, nontoxic intravitreous injectable drug delivery system for cytomegalovirus (CMV) retinitis. METHODS: ODG-PFA was synthesized by coupling the phosphonate residue of PFA to the 3 hydroxyl of 1-O-octadecyl-sn-glycerol and formulated as micelles and liposomes at concentrations so that, after injection into the rabbit vitreous, the resultant intravitreal concentrations were 0.2 mM, 0.63 mM, and 2 mM in micellar formulation and 0.02 mM, 0.063 mM, 0.2 mM, and 0.63 mM for liposomal formulation. The compounds were injected, and toxicology evaluations were performed. RESULTS: Intravitreal injections of micellar ODG-PFA resulted in aggregation of the material in vitreous and variable local retinal damage. Intravitreal injections of the liposomal ODG-PFA revealed even dispersion of the compounds and a clear vitreous, using final concentration in the vitreous of 0.2 mM. No intraocular toxicity was found with the 0.632 mM final concentration. The 50% inhibitory concentration (IC50) for CMV of ODG-PFA was 0.43+/-0.27 microM, and the therapeutic index of ODG-PFA after intravitreal injection was estimated to be 1470:1. CONCLUSIONS: Lipid-derivatized foscarnet liposome formulations may be a useful long-acting delivery system for the therapy of CMV retinitis. (+info)
Identification and rapid quantification of early- and late-lytic human herpesvirus 8 infection in single cells by flow cytometric analysis: characterization of antiherpesvirus agents.
(6/256)
Human herpesvirus 8 (HHV-8) infection is associated with Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. In this study, we used monoclonal antibodies (MAbs) directed against HHV-8 lytic cycle-associated proteins encoded by open reading frame (ORF) 59 (nuclear PF-8 protein) and ORF K8.1 (viral envelope glycoprotein K8.1 [gpK8.1]) to investigate HHV-8 lytic infection in single cells. Lytically infected cells were labeled with MAbs, stained with fluorescently conjugated secondary Abs, and analyzed by flow cytometry. A 3-day stimulation of HHV-8-positive PEL cell lines (BCBL-1 and BC-3) with 12-O-tetradecanoylphorbol-13-acetate (30 nM) or n-butyric acid (0.3 mM) maximized the expression of lytic-phase viral proteins and minimized cell toxicity. The absolute number of expressing cells was inducer and cell line dependent. Expression of PF-8 occurred earlier and more frequently (in up to 20% of cells) than did expression of gpK8.1. A subset of PF-8 positive cells (25%) co-expressed gpK8.1, representing the majority of gpK8.1 expressing cells. Acyclovir, foscarnet, cidofovir, and PMEA reduced the number of cells expressing gpK8.1, but not the number expressing the nonstructural early lytic gene product PF-8. By contrast, alpha interferon (IFN-alpha) and IFN-beta reduced expression of both PF-8 and gpK8.1, implying an overall inhibitory effect on viral gene transcription or translation. In summary, we have characterized and quantified HHV-8 lytic infection in single cells by dual measurement of early- and late-lytic-cycle HHV-8 protein expression. This technique should prove useful for screening of possible antiherpesvirus agents and for detailed phenotypic characterization of HHV-8-infected cells in vitro and in patients with HHV-8-associated diseases. (+info)
Characterization of the DNA polymerase and thymidine kinase genesof herpes simplex virus isolates from AIDS patients in whom acyclovirand foscarnet therapy sequentially failed.
(7/256)
Herpes simplex virus (HSV) isolates were characterized from 8 AIDS patients in whom acyclovir and foscarnet therapy sequentially failed. The 6 postacyclovir (prefoscarnet) HSV isolates were resistant to acyclovir and susceptible to foscarnet. Of the 9 postfoscarnet isolates, 8 were foscarnet-resistant and acyclovir-susceptible, 1 was resistant to both drugs. Acyclovir- or foscarnet-resistant isolates retained susceptibility to cidofovir. The acyclovir-resistant isolates contained single-base substitutions or frameshift mutations in G or C homopolymer nucleotide repeats of the thymidine kinase gene. In contrast, the foscarnet-resistant strains contained single-base substitutions in conserved (II, III, or VI) or, more rarely, nonconserved (between I and VII) regions of the DNA polymerase (pol) gene. The single isolate exhibiting resistance to acyclovir and foscarnet contained mutations in both genes. In this study of clinical HSV isolates, DNA pol mutations conferring foscarnet resistance were not associated with decreased acyclovir or cidofovir susceptibility. (+info)
Cytopathic effect inhibition assay for determining the in-vitro susceptibility of herpes simplex virus to antiviral agents.
(8/256)
We compare a rapid dilution method for the determination of antiviral susceptibility of herpes simplex virus (HSV) with the plaque reduction assay. A total of 84 HSV clinical isolates were studied by both methods to detect in-vitro resistance to acyclovir and foscarnet. The rapid method showed for the detection of HSV isolates resistant to acyclovir and foscarnet, a sensitivity of 96. 8% and 100% and specificity of 100% and 100%, respectively. This method provides an easy and accurate screening procedure for the susceptibility testing of HSV to antiviral agents. (+info)