Cmv infection in hct patients

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CMV INFECTION IN BMT PATIENTS JOYDEEP GHOSH REGISTRAR BMT UNIT

Transcript of Cmv infection in hct patients

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CMV INFECTION IN BMT PATIENTS

JOYDEEP GHOSH

REGISTRAR

BMT UNIT

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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

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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

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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

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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

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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

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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.

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Why CMV has poor outcome?

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• 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%

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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

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• 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

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• 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

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Ag assay or CMV PCR?

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When to start pre-emptive?

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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])

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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.

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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

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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

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• 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

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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

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• 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

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Thank you…