Cytomegalovirus (CMV) is an important infection after allogeneic hematopoietic stem cell transplantation that can cause multiorgan disease. It interacts with the immune system and is a risk factor for acute and chronic graft-versus-host disease. Prevention strategies include using CMV-seronegative blood products for seronegative patients and a seronegative donor when possible. For seropositive patients and recipients, pre-emptive antiviral therapy based on CMV antigenemia or PCR testing is superior to prophylaxis and has reduced CMV-associated mortality. Ganciclovir is the standard treatment but foscarnet is used if resistance or toxicity develops.

1. CMV INFECTION IN BMT
PATIENTS
JOYDEEP GHOSH
REGISTRAR
BMT UNIT

2. 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):1002-6
2-- Kothari et al, J Health Popul Nutr. 2002;20: 348-351

3. 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

4. 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

5. 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

6. 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

7. 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.

8. Why CMV has poor outcome?

9. • 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%

10. 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

11. • 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

12. • 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

14. Ag assay or CMV PCR?

15. When to start pre-emptive?

16. 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])

17. 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.

18. 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

20. 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

21. • 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

22. 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

23. • 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

24. Thank you…