Side effects of either preparation include bone marrow suppression – including neutropenia, thrombocytopenia, hepatotoxicity and anaemia. Neutropenia is the most important and most frequent side effect and may require reduction or cessation of therapy. It is usually reversible with reduction or brief cessation of therapy and is most common in the first 6 weeks of treatment. It is more prevalent in IV therapy (65% v 21%). Note that neutropenia also occurs in congenital CMV without treatment.
Hepatic involvement is more common after the fourth month but is usually mild and reversible on stopping therapy. Renal impairment may also be seen but is rare and reversible on stopping therapy.
Animal studies show reversible testicular damage and reduced sperm viability and there may be carcinogenic effects. These effects have not been shown in human studies but long term follow up data is lacking.
Oral treatment is generally well tolerated
The timings of treatment monitoring are different for the 2 groups of patients and depend on whether treatment is oral or IV.
Managing acutely unwell infants with multisystem involvement
For this group of patients it is important to achieve maximal suppression of viral load to control the clinical symptoms. This will require regular monitoring of viral load and may require adjustment of the dose of ganciclovir, or adjunctive therapy, if this goal is not achieved. This group will also be more vulnerable to the potential side effects as outlined above.
Monitoring
- FBC, U+E, and LFTs - 2-3 x /week for 3 weeks and at least once per week thereafter for the duration the baby is on ganciclovir. Once converted to valganciclovir follow well child monitoring.
- CMV viral load (0.5ml EDTA) – Day 3, then weekly through the course of treatment for the first 6 weeks then monthly (this will depend on how unwell the child is and how important it is to maximally suppress)
- Therapeutic drug monitoring is only required in the following circumstances
- Failure of fall in viral load by 1-2 logs
- Suspicion of toxicity
- Abnormal renal function
It should also be considered in premature infants
Trough levels should be taken 1hr prior to administration. Peak levels should be taken 1 hr after the dose. Levels require 0.5 ml in Serum Gel or Plain Clotted tube. Results can take up to 1 week.
Action:
Neutropenia <0.5x10/L – Stop ganciclovir until recovery to >0.75x10/L. Drug is then resumed at normal level. Repeat WCC at 3 days and 7 days and if level falls below 0.75 within 1 week reduce drug dose by 50% and continue.
Consider the use of granulocyte colony- stimulating factor in cases of persistent neutropenia.
Thrombocytopenia <50x109/L - Stop ganciclovir until recovery to >50x109/L and restart dose at previous level. If platelets were less then 10 x109 at diagnosis, hold dose if level falls by 50%. Recheck FBC at 3 and 7 days.
Acute Hepatitis – This may be due to the disease itself or due to the ganciclovir therapy. Decisions about ongoing treatment will need to be made clinically (advice may be sought from the consultant in Virology or Infectious Diseases). In the Kimberlin study the treatment was stopped if the ALT rose to 10x the baseline level and only restarted when ALT fell to < 5x the baseline level
Renal impairment - If there is evidence of worsening renal function (oliguria or rising serum creatinine) then the ganciclovir dose may require to be decreased as it is renally excreted. Therapeutic drug monitoring should be undertaken and dose adjusted according to levels. (Seek advice from pharmacy)
Failure of responseto treatment– Blood CMV viral loads usually drop at least 1 and 2 logs during treatment. If no drop in viral load is seen with ganciclovir treatment, or if severe symptomatology persists, therapeutic drug monitoring should be undertaken as the drug dosage may need to be adjusted or an alternative treatment sought. In this instance there should be a discussion with both a consultant virologist and hospital pharmacist. There should be consideration of resistance testing. (see notes) Options may include:
- Optimisation of serum ganciclovir levels Trough – 0.5 – 1.0 mg/L. Peak – 7-9 mg/L
- Viral Sensitivity Studies
- Adjunctive therapy with CMV specific Immunoglobulin
Managing well infant with CNS involvement but no systemic disease
As these infants are not systemically unwell the goal of treatment is not to completely suppress viral replication but rather to reduce the viral load during the period of treatment. It is therefore possible to complete their therapy as outpatients and less monitoring is required.
Monitoring
If the child is on IV ganciclovir follow monitoring schedule for unwell child.
- FBC, LFTs and U&E weekly for the first 4 weeks and then monthly until end of treatment
- Viral load fortnightly for 4 weeks and then monthly
- Weight and review of dosage at time of blood sampling
If viral loads are increasing check for compliance and then consider resistance testing. If the child is difficult to bleed the priority should be FBC followed by biochemistry followed by viral loads.
Drug levels are not required for valganciclovir
Actions
Neutropenia <0.5x10/L – Stop valganciclovir until recovery to >0.75x10/L. Drug is then resumed at normal level. Repeat levels at 3 days and 7 days and if level falls below 0.75 within 1 week reduce drug dose by 50% and continue.
Thrombocytopenia <50x109/L - Stop valganciclovir until recovery to >50x109/L and restart dose at previous level. If platelets were less then 10 x109 at diagnosis hold dose if level falls by 50%. Repeat FBC at 3 and 7 days.
Acute Hepatitis – This may be due to the disease itself or due to the therapy. Decisions about ongoing treatment will need to be made clinically (advice may be sought from the consultant in Virology or Infectious Diseases). In the Kimberlin study the treatment was stopped if the ALT rose to 10x the baseline level and only restarted when ALT fell to < 5x the baseline level
Renal Impairment – If there is evidence of worsening renal function (oliguria or rising serum creatinine) then the valganciclovir dose may require adjustment. Consider reducing to once daily dosing until renal function improves. In severe renal impairment the drug should be stopped. For further advice on dosage adjustment in renal impairment refer to monograph.
Viral Load– The aim with this group of patients is to reduce the viral load by 1-2 logs. Dose adjustments are not required to achieve further suppression if this goal is achieved. If no response is seen advice should be sought from the consultant Virologist or Infectious Disease specialist
Notes
As the drugs are renally excreted drug levels often fall during therapy due to newborn renal maturation increasing drug clearance. This is a problem with ganciclovir rather than valganciclovir as oral bioavailability increases in early infancy which “compensates” for increased drug clearance therefore making valganciclovir a more stable method of treatment.
Resistance due to gene mutations can occur in CMV. Treatment failure and the emergence of some resistant mutations have been associated with the use of valganciclovir and ganciclovir. If persistent high levels of viraemia are seen, advice should be sought from a consultant virologist to consider performing resistance assays for common gene mutations, and alternative treatment.