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CMV INFECTION IN BMT PATIENTS
JOYDEEP GHOSH
REGISTRAR
BMT UNIT
CYTOMEGALOVIRUS
• Cytomegalovirus (CMV) is a double-stranded DNA virus and is a member of the Herpesviridae family
• Human CMV grows only in human cells and replicates best in human fibroblasts
• Seroprevalence : – At least 60% of the US population (1) – more than 90% in India (2)
1-- J Infect Dis. Apr 1995;171(4):1002-62-- Kothari et al, J Health Popul Nutr. 2002;20: 348-351
Introduction
• Cytomegalovirus (CMV) remains one of the most important complications after Allogeneic hematopoietic stem cell transplantation (HCT)
• It can cause multiorgan disease including – pneumonia,
– hepatitis, gastroenteritis,
– retinitis, and
– encephalitis,
• can develop both early and late after the transplantation procedure
CMV interacts with immune system…
• Increased prevalence of other bacterial and fungal infections
• Acts as a risk factor for acute GVHD in T-cell depleted transplants as well as chronic GVHD(1)
• Acute GVHD itself is a risk factor for CMV reactivation (2)
1-- Transplantation. 2004;77:526-531
2-- Haematologica. 2006;91:78-83
PREVENTION OF PRIMARY CMV INFECTION
• PRE-TRANSPLANT STRATEGIES
– CMV seronegative blood products for seronegative patients
– Preferably a CMV seronegative donor
• POST-TRANSPLANT STRATEGIES
– Use of seronegative/ leucodepleted blood products
– Monitoring of CMV copies
For CMV seropositive recipients
• CMV-seropositive patients with CMV-seronegative donors ---
– increased risk of both repeated CMV reactivations and for CMV disease.
• So, seropositive recipients should get seropositive donors
• Boeckh M, Nichols WG. Blood. 2004;103:2003-2008
For CMV seronegative recipients
• Risk of transmission of CMV by the stem cell product to the recipient is approximately 20% to 30%
• In a randomized study, the risk of primary infection was 16% in patients receiving high-dose valacyclovir and 26% in patients receiving high-dose acyclovir.
Ljungman P et al. Blood.2002;99:3050-3056.
Why CMV has poor outcome?
• Before introduction of Ganciclovir (GCV), CMV infection -38%
Pneumonia - 17%,
mortality due to CMV pneumonia - 85%
• Occurred mainly in CMV-seropositive patients, with acute graft-versus-host disease being the most important risk factor
• Treatment with GCV and immunoglobulin –mortality to 30 to 50%
Antiviral strategies
• Prophylactic: – anti-viral therapy started at engraftment and
continued until at least day 100 post transplant
• Pre-emptive:– Pre-emptive therapy is defined as antiviral
treatment initiated based on the detection of primary or reactivated CMV infection by • positive CMV cultures,
• a positive antigenemia (Ag) assay, or
• positive molecular assays
• Introduction of pre-emptive antiviral therapy has greatly reduced the incidence and mortality rate of CMV disease
• Prophylactic treatment has no advantage over pre-emptive treatment
• Moreover, if Ganciclovir is used, it results in an increased incidence of bacterial and fungal infections and late CMV disease, due to neutropenia
• Pre-emptive treatment based on the Ag assay or PCR tests is superior to culture or BAL fluid-based strategies.
• Short-term (14-day) antiviral treatment is the most favourable approach for prevention of CMV disease, followed by maintenance at a lower dose
Ag assay or CMV PCR?
When to start pre-emptive?
Drugs
• Valacyclovir {(V)ACV} has been studied only as prophylactic therapy for prevention of CMV reactivation or disease and not as a (pre-emptive) treatment
• In a large randomized multicenter study, oral VACV was shown to be more effective in preventing CMV viremia in SCT recipients than oral ACV, – although the overall survival and the incidence of
CMV disease did not differ between the two groups (75 versus 76% and 5.5 versus 3.5% for the ACV and VACV groups, respectively [no significant difference])
Foscarnet
• Intravenous foscarnet is considered second-line therapy for CMV reactivation or disease; however, for patients developing dose-limiting neutropenia or CMV strains resistant to GCV, it is the drug of choice
• Similar efficacy compared to GCV(1)
• Toxicity: renal
1 -- Reusser, P. Et al, Blood 99:1159–1164.
Cidofovir
• Toxicity is a major concern:– Nausea, vomiting, thrombocytopenia,
– Neuro/ophthalmologic toxicity
• Less favorable outcome
• Some studies have shown around 58% response rate with significant amount of toxicities(1)
• 1– Ljungman. Blood 97:388–392
Drug resistance
• When prolonged antiviral therapy (100 days) is given, drug resistance may develop
• Overall, antiviral drug resistance in adult SCT recipients has been reported only sporadically
• In clinical CMV strains, resistance to antiviral agents has been associated with– mutations in the viral protein kinase UL97 (for GCV only)
and
– viral DNA polymerase UL54 (for GCV, foscarnet, and CDV) genes
• Labs: – Phenotypic- based on MICs
– Genotypic: base on the above genes
• Erice A. Resistance of human cytomegalovirus to antiviral drugs.
Clin Microbiol Rev 1999; 12: 286–297
To summarize …
• In the era before the introduction of pre-emptive antiviral therapy, high-dose prophylactic ACV was shown to be effective in reducing the CMV-associated mortality rate
• When pre-emptive treatment with GCV or foscarnet was used, VACV proved to be more effective as prophylaxis
• Currently it is not clear whether VACV prophylaxis combined with a pre-emptive antiviral strategy is better than pre-emptive therapy alone
• Although intravenous GCV is considered the drug of choice for (pre-emptive) treatment of CMV reactivation or disease, foscarnet has similar efficacy and less hematologic toxicity
Thank you…