Advances in the Prevention and Treatment of CMV

1
Advances in the Prevention and Treatment of CMV

• Raymund R Razonable, M.D.
• Mayo Clinic College of Medicine
• Rochester, Minnesota
• The 11th Annual Meeting of the IHMF
• The Netherlands. February 27-29, 2004.

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Prevention of CMV Disease
3
Prophylaxis vs Pre-emptive Therapy
100 25
Prophylaxis
PCR pp65
Pre-emptive therapy
1
2
3
Months after transplantation
Among HSCT patients, ganciclovir prophylaxis is
initiated after engraftment Routine
surveillance for CMV with sensitive assay is
essential for pre-emptive therapy Shorter
course antiviral therapy
4
Antiviral Prophylaxis for the Prevention of CMV
Disease after Solid Organ Transplantation (SOT)

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Oral Ganciclovir vs Acyclovir ProphylaxisIn CMV
D/R- SOT Recipients

• A randomized controlled multicenter trial of 115
  CMVD/R- SOT patients
• After receiving IV ganciclovir, 5 mg/kg/d for
  5-10 days, patients were randomized to receive
  oral ganciclovir, 1 g PO TID, or oral aciclovir,
  400 mg PO TID, for 12 weeks

• For CMV D/R- SOT patients who have received 5-10
  days of IV ganciclovir prophylaxis, oral
  ganciclovir prophylaxis should be offered, in
  preference to oral aciclovir, to reduce the
  incidence of CMV disease (Category 1
  recommendation)

Rubin RH Transplant Infect Dis 20002112
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Oral Ganciclovir vs Aciclovir ProphylaxisIn
CMV-seropositive Liver Transplant Recipients

• A randomized controlled trial of 219 CMV R liver
  transplant patients
• After receiving IV ganciclovir, 6 mg/kg/d from
  day 1-14, patients were randomized to receive
  oral GCV or oral ACV from D15-100

• To reduce the incidence of CMV disease,
  CMV-seropositive liver transplant patients should
  be offered oral ganciclovir prophylaxis in
  preference to oral aciclovir (Category 1
  recommendation)

Winston DJ and Busuttil RW. Transplantation
200375229-33
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Oral vs Intravenous Ganciclovir ProphylaxisIn
CMV D/R- Liver Transplant Recipients

• A randomized controlled trial of 64 CMV D/R-
  liver transplant patients
• After receiving IV ganciclovir, 6 mg/kg/d from
  day 1-14, patients were randomized to receive
  oral GCV or ACV from D15-100

• Oral ganciclovir prophylaxis is as effective as
  intravenous ganciclovir for the prevention of CMV
  disease in CMV D/R- liver transplant patients
  who had received IV ganciclovir during the
  initial 14 days after transplantation (Category 1
  recommendation)

Winston DJ and Busuttil RW. Transplantation
200473305-308
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Oral Ganciclovir vs Valganciclovir ProphylaxisIn
CMV D/R- SOT Patients
372 D/R- SOT (liver, kidney, heart, pancreas),
gt13 y, 57 sites
21 randomization
No significant difference between 2 groups at 12
months Paya CV Am J Transpl (In Press)
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Valganciclovir Prophylaxis in SOT
PatientsPV16000 Study Primary Endpoint Analysis
Tissue invasive disease 16/118 (14) VGCV vs
2/59 (3) OGCV Paya CV. Am J Transpl (In Press)
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CMV Disease in CMV D/R- SOT Patients
Valganciclovir vs Oral Ganciclovir Prophylaxis

• Valganciclovir prophylaxis for 100 days is as
  effective as oral ganciclovir for the prevention
  of CMV disease in CMV D/R- SOT patients
  (Category 1 recommendation)

Data from Paya CV Am J Transplant (In Press)
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Valganciclovir Prophylaxis in SOT
PatientsPV16000 Study Secondary Endpoint
Analysis
P0.001 Trend towards reduced peak viral load
at time of suspected CMV disease

• Compared to oral ganciclovir, valganciclovir
  prophylaxis is associated with a lower incidence
  of CMV viremia during prophylaxis and a later
  onset of CMV viremia after completion of
  prophylaxis (Category 1 statement)

Paya CV. Am J Transplant (In Press)
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Valganciclovir Prophylaxis in SOT
PatientsPV16000 Study Adverse Events

• The incidence of neutropenia is higher during
  valganciclovir compared to oral ganciclovir
  prophylaxis (Category 2 statement)

Paya CV. Am J Transplant (In Press)
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CMV D/R- SOT Patients Remain at Risk of CMV
Disease after Completing 100 Days of Antiviral
Prophylaxis
Cumulative percentage of patients with CMV during
the first year post-transplant
Valganciclovir Ganciclovir
Ganciclovir

• The optimal duration of antiviral prophylaxis for
  the prevention of late CMV disease needs to be
  assessed in a controlled clinical trial (Research
  need)

Razonable J Infect Dis 20011841461 Razonable
ICAAC 2003 Abstract V-1288
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Pre-emptive Therapy for the Prevention of CMV
Disease after Solid Organ Transplantation
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Pre-emptive Therapy with Oral GanciclovirA
Randomized Placebo-controlled Trial in Liver
Recipients
CMV disease or viremia
CMV PCR positive in 86 patients
168 D/R- or R liver transplant patients
Weekly qualitative CMV PCR for 8 weeks
CMV disease or viremia prior topre-emptive
therapy in 17 (25) patients
Persistent CMV replication in 6 patients on oral
GCV therapy

• Due to the rapid dynamics of CMV, a randomized,
  controlled trial is needed to assess whether
  twice weekly sampling is superior to once weekly
  (Research need)

Paya CV J Infect Dis 2002185854 Razonable RR J
Infect Dis 20031871801
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Pre-emptive Therapy with Oral Ganciclovir

• Pre-emptive therapy with oral ganciclovir (1g tid
  for 8 weeks), upon the detection of CMV DNA,
  reduces the incidence of CMV disease and viremia
  in liver transplant patients (Category 1
  recommendation)

Paya CV. J Infect Dis 2002185854-60
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Antiviral Prophylaxis for the Prevention of CMV
Disease after Hematopoietic Stem Cell
Transplantation

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Valaciclovir Prophylaxis in HSCTA Randomized
Comparison with Oral Aciclovir

• 748 CMV-seropositive (R or D) allogeneic bone
  marrow transplant patients

• IV aciclovir 500 mg/m2 every 8 hours from D-5 to
  discharge or D28

• Randomization

• Oral aciclovir 800 mg QID until week 18 (n372)

Valaciclovir 2000 mg QID until week 18 (n376)

• In allogeneic HSCT patients, valaciclovir
  prophylaxis should be offered, in preference to
  high-dose oral aciclovir, to reduce CMV infection
  and disease (Category 1 recommendation)

Hazard ratio 0.59 (95CI, 0.46-0.76)
Plt0.0001) Ljungman P. Blood 2002993050-3056
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Valaciclovir Prophylaxis in HSCTA Randomized
Comparison with Oral Aciclovir
Hazard ratio 0.57 (95CI, 0.43-0.75)
Plt0.0001) Indications for use of ganciclovir or
foscarnet Preemptive therapy (88) Presumed
CMV disease (5) Confirmed CMV disease (7)
Ljungman P. Blood 2002993050-3056
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Valaciclovir Prophylaxis in HSCTA Randomized
Comparison with Intravenous Ganciclovir
168 CMV-seropositive allogeneic bone marrow
transplant patients IV aciclovir 500mg/m2 every 8
hours from D0 to engraftment
Randomization
Oral valaciclovir 2000 mg q6h until D100 (n83)
IV ganciclovir 5 mg/kg q12h x 1 week then 6 mg/kg
q24h for 5 d/week until D100 (n85)

• After engraftment, valaciclovir prophylaxis is as
  effective as IV ganciclovir in reducing CMV
  infection and disease but is associated with
  higher rates of therapeutic interventions
  (Category 1 statement)

Hazard ratio 1.042 (95CI, 0.391, 2.778)
P0.934 P0.588 P0.268 P0.039 Winston DJ
Clin Infect Dis 200336749-58
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Valaciclovir Prophylaxis in HSCTA Randomized
Comparison with Intravenous Ganciclovir
P0.007 PNS P0.001 Winston DJ Clin Infect
Dis 200336749-58
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Pre-emptive Anti-CMV Therapy for the Prevention
of CMV Disease after Hematopoietic Stem Cell
Transplantation
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Foscarnet for Pre-emptive Therapy in HSCTA
Randomized Comparison with IV Ganciclovir
A randomized comparison of foscarnet and
ganciclovir for antigenemia-directed pre-emptive
therapy for 15 days in patients undergoing
allogeneic HSCT
Moretti S. Bone Marrow Transplant 199822175-80
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Foscarnet for Pre-emptive Therapy in HSCTA
Randomized Comparison with IV Ganciclovir
A prospective randomized open-label comparison of
foscarnet and ganciclovir for pre-emptive
anti-CMV therapy (induction X 2 wks, maintenance
X 2 wks)

• Foscarnet vs ganciclovir Odds Ratio 0.74 (95 CI
  0.40-1.34)
• Pre-emptive therapy with foscarnet is as
  effective as IV ganciclovir for the prevention of
  CMV disease in allogeneic HSCT patients (Category
  1 recommendation)

Reusser P et al. Blood 2002991159
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Foscarnet for Pre-emptive Therapy in HSCTA
Randomized Comparison with IV Ganciclovir
Reusser P et al. Blood 2002991159
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Treatment of CMV Disease

• IHMF Guidelines (November 9-11, 2000)
• Combination therapy with foscarnet and
  ganciclovir should be fully investigated in
  randomized, controlled trials (Research need)
• NOW MET!! (Category 1)
• Research Needs
• Valganciclovir appears an appropriate way of
  delivering high dose ganciclovir for the
  treatment of established disease. Clinical trials
  are required to ensure adequate therapeutic
  levels are achieved in patients with poor
  absorption, e.g. in patients with
  gastrointestinal GVHD (Research need)
• Further studies are required to define how GCV
  doses can be modified to deliver appropriate
  control of CMV, especially in patients with renal
  dysfunction (Research need)

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Summary and Management Recommendations

• Raymund R Razonable, M.D.
• Mayo Clinic College of Medicine
• Rochester, Minnesota

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Proposed Updates to IHMF Guidelines on CMV
Diagnosis and Treatment

• Diagnosis of CMV infection and disease
• CMV DNA levels in whole blood are significantly
  higher than those present in plasma, so whole
  blood should become the sample of choice
  (Category 1 recommendation)
• An international quantitation standard is
  required to compare studies using different
  PCR-based systems and to facilitate patient
  management at multiple care centres (Research
  need)
• Treatment of CMV disease
• The clinical efficacy of valganciclovir for the
  treatment of established CMV disease needs to be
  evaluated in a prospective, randomized clinical
  trial (Research need)

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Proposed Updates to IHMF Guidelines on Prevention
of CMV in Solid OrganTransplantation

• Antiviral Prophylaxis in Solid Organ
  Transplantation
• For CMV D/R- solid organ transplant (SOT)
  patients who have received 510 days of IV
  ganciclovir prophylaxis, oral ganciclovir
  prophylaxis should be offered, in preference to
  oral aciclovir, to reduce the incidence of CMV
  disease (Category 1 recommendation)
• To reduce the incidence of CMV disease,
  CMV-seropositive liver transplant patients should
  be offered oral ganciclovir prophylaxis in
  preference to oral aciclovir (Category 1
  recommendation)
• Oral ganciclovir prophylaxis is as effective as
  intravenous (IV) ganciclovir for the prevention
  of CMV disease in CMV D/R- liver transplant
  patients who had received IV ganciclovir during
  the initial 14 days after transplantation
  (Category 1 recommendation)
• Valganciclovir prophylaxis for 100 days is as
  effective as oral ganciclovir for the prevention
  of CMV disease in CMV D/R- SOT patients
  (Category 1 recommendation)
• Compared with oral ganciclovir, valganciclovir
  prophylaxis is associated with a lower incidence
  of CMV viraemia during prophylaxis and a later
  onset of CMV viraemia after completion of
  prophylaxis (Category 1 statement)

30
Proposed Updates to IHMF Guidelines on Prevention
of CMV in SOT

• Antiviral prophylaxis in Solid Organ
  Transplantation (contd)
• The incidence of neutropenia is higher during
  valganciclovir compared with oral ganciclovir
  prophylaxis (Category 2 statement)
• CMV D/R- SOT patients remain at risk of CMV
  disease after completing 100 days of antiviral
  prophylaxis (Category 1 statement)
• The optimal duration of antiviral prophylaxis for
  the prevention of late CMV disease needs to be
  assessed in a controlled clinical trial (Research
  need)
• Pre-emptive therapy in Solid Organ
  Transplantation
• Due to the rapid dynamics of CMV, a randomized,
  controlled trial is needed to assess whether
  twice-weekly sampling is superior to once- weekly
  sampling (Research need)
• Pre-emptive therapy with oral ganciclovir (1 g
  3x/day for 8 weeks), upon the detection of CMV
  DNA, reduces the incidence of CMV disease and
  viraemia in liver transplant patients (Category 1
  recommendation)

31
Proposed Updates to IHMF Guidelines on Prevention
of CMV in Haemotopoietic Stem Cell Transplantation

• Antiviral prophylaxis in haemotopoietic stem cell
  transplant patients
• In allogeneic haemotopoietic stem cell transplant
  (HSCT) patients, valaciclovir prophylaxis should
  be offered, in preference to high-dose oral
  aciclovir, to reduce CMV infection and disease
  (Category 1 recommendation)
• After engraftment, valaciclovir prophylaxis is as
  effective as IV ganciclovir in reducing CMV
  infection and disease but is associated with
  higher rates of therapeutic interventions
  (Category 1 statement)
• Pre-emptive therapy in HSCT patients
• Pre-emptive therapy with foscarnet is as
  effective as IV ganciclovir for the prevention of
  CMV disease in allogeneic HSCT patients (Category
  1 recommendation)
• Electrolyte abnormalities are common during
  therapy with foscarnet. Routine monitoring for
  serum electrolytes is essential and abnormalities
  should be corrected accordingly (Category 1
  recommendation)

32
Research Needs

• Valganciclovir appears an appropriate way of
  delivering high dose ganciclovir for the
  treatment of established disease. Clinical trials
  are required to ensure adequate therapeutic
  levels are achieved in patients with poor
  absorption, e.g. in patients with
  gastrointestinal GVHD (Research need)
• Further studies are required to define how GCV
  doses can be modified to deliver appropriate
  control of CMV, especially in patients with renal
  dysfunction (Research need)