Type of intervention Primary prevention. Economic study type Cost-effectiveness analysis.

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A randomized prospective controlled trial of oral ganciclovir versus oral valacyclovir for prophylaxis of cytomegalovirus disease after renal transplantation

Reischig T, Opatrny K, Bouda M, Treska V, Jindra P, Svecova M

Record Status

This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.

Health technology

The health technologies studied were oral ganciclovir (dosage of 1g tid (Cymevene; Hoffman-La Roche, UK)), and oral valacyclovir (dosage of 2g qid (Valtrex; Glaxo Wellcome, UK)). These were then compared to deferred therapy with no prophylaxis (i.e. frequent monitoring by highly sensitive nested PCR for cytomegalovirus (CMV) DNA for whole blood and early therapy of CMV symptomatic infections).

Type of intervention Primary prevention.

Economic study type Cost-effectiveness analysis.

Study population

The study population comprised all adult renal graft recipients with serologic donor (D) and recipient (R) D+ R-, D+

R+, and D- R+ status. The following patients were not eligible for the study: those with unknown or D- R- CMV serology prior to RTx, those with active viral infection, patients with leucopoenia of below 4.0x109/1, those with thrombocytopenia of below 150x109/1, patients with a known allergy to ganciclovir or acyclovir, and patients using systemic antiviral agents.

Setting

The setting was tertiary care. The economic study was conducted at the Charles University Teaching Hospital, Pilsen, Czech Republic.

Dates to which data relate

The effectiveness and resource use data were gathered in the period from April 1999 to December 2000. 2001 prices were used.

Source of effectiveness data

The evidence for the final outcomes was derived from a single study.

Link between effectiveness and cost data

The costing was undertaken prospectively on the same patient sample as that used in the effectiveness study.

Study sample

No power calculations were reported and no specific sample size was planned. The method of sample selection was also

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not reported. 38 patients were included in the study and randomised at a 1:1:1 ratio to a 3-month treatment. Of these, 14 received ganciclovir (GAN group), 12 received valacyclovir (VAL group), and 12 patients were given no prophylaxis (C group) and their condition was managed by deferred therapy. The GAN group was composed of 10 males (71.4%) and 4 females (28.6%) with a mean age of 44 (+/- 11.6) years. The VAL group was composed of 10 males (83.3%) and 2 females (16.7%) with a mean age of 47.8 (+/- 12.4) years. The C group had 8 males (66.7%) and 4 females (33.3%) with a mean age of 46 (+/- 13.1) years.

Study design

The study was a randomised controlled trial (RCT) carried out in a single centre. The unit and method of randomisation were not reported in the study. Patients were prospectively monitored clinically and by laboratory tests for six months post-renal transplantation or until death. However, because of the tendency of CMV viremia to increase after the end of prophylaxis, patients were followed up for up to 12 months post-renal transplantation to undergo checks for the occurrence of late CMV disease. One patient from the GAN group was lost to follow up as he lost his graft due to renal vein thrombosis on day eight post-transplantation.

Analysis of effectiveness

The analysis of the effectiveness study was based on intention to treat. The primary health outcomes were: the

incidence of CMV disease, the incidence of CMV viremia, patient and graft survival, graft function and safety profile, incidence of acute rejections, and other infections. The patient who was lost to follow up was assessed in the intention- to-treat analysis only. The groups were shown to be comparable in basic demographic and immunological

characteristics, donor and recipient pre-transplantation, CMV serology and in immunosuppression therapy.

Effectiveness results

Six months after transplantation, the GAN group had a significantly lower incidence rate of CMV viremia than the C group, (p=0.001).

No case of CMV disease was seen in either the GAN or the VAL group, but 8 (66.7%) cases were observed for the C group.

Both the GAN and the VAL group had a significantly lower incidence rate of CMV disease than the C group (p=0.0005 for GAN versus C; p=0.001 for VAL versus C).

However, in the 12 months post-transplantation, CMV disease was observed in two (15.4%) patients in the GAN group and in one (8.3%) patient in the VAL group.

Even though the C group had no cases of late CMV disease, the incidence of CMV remained significantly lower in both the VAL and GAN groups compared with the C group (p=0.015 for GAN versus C; p=0.009 for VAL versus C).

Both the GAN and the VAL groups had a significantly lower rate of cumulative rate of treatment failure at month six (14.3% and 0% respectively) than the C group (66.7%).

Patient and graft survival did not differ significantly across the groups, nor did the incidence of acute rejection episodes.

Clinical conclusions

The study demonstrated a high efficacy of 3-month therapy with both oral ganciclovir and valacyclovir in the prophylaxis of CMV disease in patients after transplantation treated with mycophenolate mofetil.

Measure of benefits used in the economic analysis

No summary benefit measure was used in the economic analysis. As such, a cost-consequences approach was adopted.

NHS Economic Evaluation Database (NHS EED) Produced by the Centre for Reviews and Dissemination

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Direct costs

Resource quantities and costs were not reported separately. The direct costs included in the analysis were the mean CMV-associated cost per patient over the 6-month post-renal transplantation period and expressed as means +/- standard deviation (SD). There was no detailed breakdown of costs. The cost calculations were undertaken from a hospital point of view. The source of the direct cost data was not stated. No discounting was carried out as costs were incurred in a period of less than one year. 2001 prices were used.

Statistical analysis of costs

Kruskal-Wallis analysis of variance was used to compare the mean costs between the three groups.

Indirect Costs

Indirect costs were not included.

Currency Euros (Euro).

Sensitivity analysis

No sensitivity analysis was performed.

Estimated benefits used in the economic analysis Please refer to the effectiveness results reported previously.

Cost results

The 6-month post-transplantation period mean associated costs per patient were Euro 2,449 (+/- 1,178) in the GAN group, Euro 2,485 (+/- 581) in the VAL group, and Euro 4,259 (+/- 4,616) in the C group (including patients both with and without CMV disease).

This resulted in savings of 42.5% and 41.7% of costs in the GAN and VAL groups compared to patients in group C.

Synthesis of costs and benefits

The synthesis of costs and benefits was not relevant as a cost consequences analysis was carried out.

Authors' conclusions

The results of the study show that oral ganciclovir and valacyclovir are equally effective in the prophylaxis of CMV disease in patients undergoing renal transplantation, and not only decrease the incidence, but also delay the onset of CMV disease. The study also found that both drugs are safe, and cost-effective in saving over 40% of CMV-associated costs over the first 6 months post- transplantation.

CRD COMMENTARY - Selection of comparators

A justification was given for the comparator (no prophylaxis) used. For the third group, deferred therapy was used for the sake of maximum safety and because some authors suggest that this therapy can be employed to control CMV infection and may be even less costly than pre-emptive therapy. You, as a user of this database, should decide whether they represent valid comparators in your setting.

Validity of estimate of measure of effectiveness

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The analysis of effectiveness was based on a randomised control trial, which was appropriate for the study question as well-conducted RCTs are the gold standard study design when comparing different health technologies. The study groups were shown to be comparable at analysis. However, even though the analysis was based on an RCT and outcomes were analysed on an intention-to-treat basis, the internal validity of the study would have been enhanced had the authors reported how participants were randomised to the three study groups.

Validity of estimate of measure of benefit

No summary benefit measure was used and the analysis was based on a cost-consequences analysis.

Validity of estimate of costs

All categories of cost relevant to the perspective adopted (hospital) were included in the analysis. However, because there was no detailed breakdown of costs it is not possible to say if all relevant costs for each category of cost were included in the analysis. Thus it is not possible to determine if important omissions in costs were made that could have affected the authors' conclusions. Furthermore costs and quantities were not reported separately. These features tend to limit the generalisability of the cost results to other settings.

Resource use quantities were taken from a single study. Statistical analysis of quantities was performed using Kruskall- Wallis analysis of variance. However, the authors did not state the source of the prices. Prices were given in 2001 Euros, but no currency conversions were reported, even though the Czech Republic does not use the Euro. Since all costs were incurred over a period of less than one year, discounting was unnecessary.

Other issues

The authors made appropriate comparisons of their findings with those from other studies and the issue of

generalisability to other settings was addressed. The authors' conclusions reflected the scope of the analysis, and the authors noted that their results should not be automatically extrapolated to D+ R- patients, as there were only 2/38 (5%) in their series. The authors reported a further limitation to their study, namely that the study was not powered to demonstrate that the incidence of acute rejection episodes in patients in the VAL and GAN groups was different than those in the C group.

Implications of the study

The authors reported no clear implications of the study, but appear to imply that oral ganciclovir or oral valacyclovir should be routinely used in the prophylaxis of CMV disease after renal transplantation.

Source of funding

Supported by Research Project Number 20632 (111400002) awarded by the Ministry of Education, Youth and Physical Training of the Czech Republic

Bibliographic details

Reischig T, Opatrny K, Bouda M, Treska V, Jindra P, Svecova M. A randomized prospective controlled trial of oral ganciclovir versus oral valacyclovir for prophylaxis of cytomegalovirus disease after renal transplantation. Transplant International 2002; 15(12): 615-622

PubMedID 12478408 DOI

10.1007/s00147-002-0475-0

Other publications of related interest

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Ahsan N, Holman M J, Yang H C. Efficacy of oral ganciclovir in prevention of cytomegalovirus infection in post- kidney transplant patients. Clinical Transplants 1997;11:633-639.

Brennan D C, Garlock K A, Singer G G, Schnitzler M A, et al. Prophylactic oral ganciclovir compared with deferred therapy for control of cytomegalovirus in renal transplant recipients. Transplantation 1997;64:1843-1846.

Lowance D, Neumayer H H, Legendre C M, et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. New England Journal of Medicine 1999;340:1462-1470.

McCarthy J M, Karim M A, Krueger H, Keown P A. The cost impact of cytomegalovirus disease in renal transplant recipients. Transplantation 1993;555:1277-1282.

Indexing Status

Subject indexing assigned by NLM MeSH

Acyclovir /administration & dosage /analogs & derivatives /therapeutic use; Administration, Oral; Adult; Antiviral Agents /administration & dosage /therapeutic use; Cadaver; Cytomegalovirus Infections /prevention & control; Dose- Response Relationship, Drug; Female; Ganciclovir /administration & dosage /therapeutic use; Humans; Kidney Diseases /classification /surgery; Kidney Transplantation /adverse effects; Living Donors; Male; Middle Aged;

Postoperative Complications /prevention & control /virology; Prospective Studies; Renal Insufficiency /etiology /surgery; Tissue Donors; Valine /administration & dosage /analogs & derivatives /therapeutic use

AccessionNumber 22003000157

Date bibliographic record published 31/01/2004

Date abstract record published 31/01/2004

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