Assessing the economic merits of managing cytomegalovirus infection in organ and stem cell transplantation

Abstract

Two preventative approaches exist to manage cytomegalovirus (CMV), a common infection in recipients of organ and stem cell transplants: prophylaxis – the prevention of viraemia – and pre-emptive therapy – the prevention of manifestation of disease in patients who have viraemia. Economic evaluation may provide a helpful framework to inform the choice between these two approaches. However, several issues arise. Direct comparisons of prophylaxis and pre-emptive therapy are rare and there are few epidemiological data that depict the full natural history of CMV infection and disease. There is a need for large, prospective randomised trials that directly compare these two strategies and are of sufficient duration to assess their overall impact on direct and indirect effects of CMV as well as patient quality of life. These methodological issues are relevant to the economic evaluation of preventative measures in other clinical settings and highlight the need for a rigorous evaluative framework to best inform decision making about the optimal strategy for patients.

Keywords::

• cytomegalovirus
• economic evaluation
• pre-emptive
• prevention
• prophylaxis
• transplantation

Introduction

The public health community, journalists and politicians have been calling for a focus on the prevention of disease since the early 1980s^1–4. Indeed, it is often assumed that prevention is not only better but also cheaper than cure. In Is Prevention Better than Cure, economist Louise Russell cautioned that this blanket assumption may lead one to ‘take the untenable position of arguing that a preventative measure is a good investment only if it saves money’⁵, when in reality prevention usually adds to medical expenditure⁶.

Russell, as have other authors, calls for the rigorous evaluation of all preventative measures⁷. Russell proposes a standard economic framework to this effect and suggests that one must firstly consider the health benefits that a preventative measure confers; secondly, whether the costs incurred represent a good investment for those benefits; and thirdly, whether the balance of costs and benefits is acceptable. Russell's work is focused on primary prevention; however, her arguments apply equally to the prevention of disease within clinical settings. One such example is the prevention of cytomegalovirus infection (CMV) in organ and stem cell transplantation.

Prevention of infections has been the cornerstone of organ and stem cell transplantation for over 20 years. Although transplant patients benefit greatly from immunosuppressive therapy, it unfortunately renders them more susceptible to a number of infections. CMV is one of the most common of such infections and is the cause of significant morbidity and mortality in both stem cell transplant (SCT) and solid organ transplant (SOT) recipients^8–10.

Since the early 1990s, improved management of CMV has become possible through the advent of antiviral agents^11,12. Two preventative approaches are commonly used to combat CMV: firstly prophylaxis, where all patients at risk of CMV infection or CMV reactivation are given antiviral therapy for a period of usually 3 months (prevention of viraemia), and secondly, pre-emptive therapy, where all patients at risk are monitored regularly for CMV viral replication and those who develop viraemia are given antiviral therapy to prevent disease¹³. A third option, rarely followed, is to only treat CMV disease cases upon presentation of symptoms (often referred to as the ‘wait and treat’ approach).

The objective of this paper is to explore the issues arising in the economic evaluation of preventative strategies for CMV management in transplant patients. The paper first presents the background on CMV and explores the underlying rationale behind prophylaxis and pre-emptive therapy in transplantation. Secondly, data on effectiveness, patient outcomes and cost effectiveness of these approaches is discussed based on a pragmatic review of the literature. Using Russell's evaluative framework, we then review some of the issues pertinent to the economic evaluation of preventative approaches of CMV in transplantation and conclude with a broader discussion of some of the methodological considerations for the economic evaluation of preventative approaches in general.

For the purposes of this paper, findings are presented in general terms of prophylaxis versus pre-emptive therapy and specific findings on the relative merits of different antiviral agents are not discussed. This review is also restricted to the renal, liver and stem-cell transplant settings.

Background: CMV in transplantation

The clinical and economic burden of CMV in organ and stem cell transplantation

The prevention of CMV infection in transplant patients is critical to the success of organ and stem cell transplantation. If not prevented, 30–75% of transplant recipients will develop a CMV infection, and 8–30% of transplant recipients will develop CMV disease¹³. Key definitions in the natural history of CMV (infection, viraemia, disease) are provided in Table 1. CMV causes both direct and indirect effects, the exact nature of which depends on the type of organ transplanted. These are outlined in Table 2. Direct effects result from viral replication of CMV in specific organs, whereas indirect effects include modulation of transplant recipients' immune response, alterations of basic metabolic functions including glucose control, as well as impact on graft survival and function and an increase in opportunistic infections^14,15.

CMV infection and disease are costly to treat. Legendre et al estimated that the average costs of treating CMV syndrome and tissue-invasive disease in renal transplant recipients were €10,852 and €15,431, respectively¹³. In a 1997 study of liver transplant recipients, Falagas et al found that CMV disease was associated with a median increase in length of hospital stay of 30 days (64 vs. 34 days) and an increased cost of about $58,000 in liver transplant patients¹⁶. Paya found that CMV disease was one of the most significant independent determinants of longer hospital stays and increased length of stay by up to 1.7-fold in liver transplant patients¹⁷. McCarthy et al confirmed these findings and found that patients with CMV disease had institutional costs that were 2.5 times higher than those without CMV disease¹⁸. Although the average lengths of hospital stay are likely to have decreased since the publication of some of these studies, the negative impact of CMV disease on resource use and hospital length of stay is widely recognised^19–21.

Prevention of infections in clinical transplantation

Prophylaxis, or prevention, against a number of infections has been shown to be both clinically- and cost-effective and to improve overall patient outcomes in stem cell and solid organ transplantation^22–24. For example, antifungal prophylaxis is commonly used in bone marrow transplantation, where up to 30% of patients can develop invasive fungal infections resulting in mortality rates of 70–90%²⁵. Similarly, antibiotics are given empirically to prevent infection, sepsis and death in patients who develop febrile neutropenia during high-dose chemotherapy or bone-marrow transplantation^26,27. Prevention of herpes zoster virus using targeted antiviral agents is also common practice in transplant patients^28,29. There are broader reasons why the prevention of infections is so critical in transplantation. Transplant patients usually spend a long time on waiting lists before receiving a donor organ, thus there is a clinical imperative to maximise the success of the transplant. Preventing viraemia can help protect the integrity of the graft and optimise the overall clinical outcome for patients. Prevention is also important from an economic standpoint, as the costs of transplantation are considerable, particularly if one includes the costs of organ procurement^30,31.

Prevention of CMV in transplantation

Prophylaxis and pre-emptive therapy both represent preventative approaches to CMV; however, they differ in terms of the timing of intervention in the natural history of CMV: prophylaxis targets all patients at risk and aims to prevent CMV viraemia or viral replication, either by preventing primary viraemia or reactivation of CMV infection in a previously exposed individual. Pre-emptive therapy monitors all patients at risk but only provides antiviral therapy to patients who show evidence of viraemia, thus focusing on the prevention of disease (Figure 1).

The choice between prophylaxis and pre-emptive therapy in transplantation may be summarised as follows³²: in solid organ transplantation, prophylaxis has been found to be the most effective strategy at reducing CMV disease in high-risk patients; however, it may expose a certain proportion of patients who would never have developed CMV to a prolonged course of antiviral therapy. This in turn can be costly and cause adverse events in otherwise very sick patients. Moreover, there is the risk that extended prophylaxis may select for viral resistance, lead to late-onset disease and cause delayed CMV-specific T-cell responses^33,34. On the other hand, prophylaxis reduces the risk of indirect effects of CMV infection, including acute and chronic graft rejection, increased opportunistic infections and decreased patient survival^35,36.

Pre-emptive therapy takes a more targeted approach. Antiviral agents are administered for a shorter period of time, thus drug costs and toxicity effects may be lower. However, these lower costs may be offset by the high costs of surveillance prior to administration of therapy. Pre-emptive therapy leaves patients exposed to asymptomatic CMV replication, which has been shown to increase the risk of rejection, allograft dysfunction, opportunistic infections and mortality across a number of transplant settings^37,38.

Protocols and clinical guidelines for CMV usually base the choice of CMV management strategy on the estimated underlying risk of CMV disease. For example, in allogeneic SCT, risk factors for disease include the host (older age), transplantation factors (conditioning regimen, unrelated or mismatched donor source, T-cell depletion) and viral factors (seropositivity, of recipient and donor, viraemia and high viral load)^39,40. Yet there is significant debate within the transplant community as to the ideal strategy for different risk groups. Prophylaxis of CMV is common practice in at-risk solid organ transplants. In SCT, toxicity associated with some of the antiviral agents has limited the use of prophylaxis; however, the development of new antiviral agents with lesser toxicity may change this^41,42.

What is the relative effectiveness of preventative approaches to CMV?

The most important goal in selecting a preventative approach to CMV management is to optimise long-term patient outcomes and the overall success of transplan-tation¹³. Guidelines for the appropriate management of CMV infection and disease have been published internationally^43,44. Both approaches ultimately aim to prevent CMV disease, however they target different points of intervention. The rationale behind prophylaxis is to prevent primary CMV infection or CMV reactivation as well as disease by administering antiviral medication immediately after transplantation for a defined period (usually 3 months) prior to any sign of viraemia, as this alone may mitigate the indirect effects associated with CMV infection as well as the direct effects of CMV disease. With pre-emptive therapy, on the other hand, one waits until CMV viraemia is detected and antiviral therapy is then administered to stop development of CMV disease.

There are a number of meta-analyses that have looked at the relative merits of prophylaxis, pre-emptive therapy versus standard therapy and antiviral agents used in solid organ transplantation for prophylaxis⁴⁵. One meta-analysis compared prophylaxis and pre-emptive therapy and showed that, whilst both approaches prevented CMV disease, only prophylaxis resulted in better patient survival and reduced rates of bacterial and fungal infections in SOT patients³⁸. The underlying rationale behind prophylaxis is also supported by evidence that primary CMV infection is an independent risk factor for graft rejection and allograft loss after solid organ transplantation^46,47, and CMV serostatus is an independent risk factor for overall mortality after liver transplantation⁴⁸. Further, asymptomatic CMV antigenaemia was found to reduce graft survival and increase overall mortality in kidney transplant patients⁴⁹. Prophylaxis has also been shown to improve patient survival in renal⁵⁰ and heart transplant patients⁵¹.

Only one large prospective study has looked specifically at graft survival as the primary endpoint in a direct comparison of prophylaxis and pre-emptive therapy in renal transplant patients⁵². The authors found that prophylaxis improved graft survival after 3–5 years post-transplant compared to pre-emptive therapy; however, there was no difference in overall mortality between the two groups. Short-term (1 year) graft survival was equivalent between the two treatment groups^52,53. These results raise three important issues for consideration in the design of clinical trials and economic evaluations of CMV prevention: what should the duration of studies be to be able to capture all relevant outcomes? How can studies influence CMV management strategies on indirect effects such as survival and opportunistic infections? And finally, which are the most meaningful outcomes to be evaluated and by whom?

Impact on quality of life

Another important outcome to consider in the comparison of prevention strategies targeting CMV is health-related quality of life. We found no studies that included measures of health-related quality of life or utilities in the management of CMV in transplantation. One study compared oral to intravenous ganciclovir in patients with AIDS-related cytomegalovirus retinitis and found a distinct preference for oral treatment⁵⁴. However, this is a distinctly different patient population from the transplantation setting. It should be mentioned that some of the reluctance to use antiviral agents prophylactically, particularly in SCT patients, stems from the fact that some intravenous agents are associated with significant neutropenia and other toxicities.

Clearly, future studies are needed that include specific health-related quality of life measured over a long enough timeframe to be able to elucidate the impact of different management strategies on patient outcomes both during and following the administration of different antiviral agents. Selected instruments need to be sensitive enough to reflect differences in quality of life over the various health states that patients encounter in their pathway.

Which approach is the most cost effective?

Most published economic evaluations of CMV prevention compare the relative cost effectiveness of prophylaxis and pre-emptive therapy to a ‘wait-and-treat’ approach. In the absence of randomised comparative trials of CMV prophylaxis versus pre-emptive therapy, most comparisons of the two preventative approaches are indirect and rely on substantial modelling⁵⁵.

Annemans et al ⁵⁶ developed a decision model to assess the cost effectiveness of different management strategies for CMV in liver transplantation and found that prophylaxis using oral ganciclovir was either dominant or had a small incremental cost effectiveness (<€6,000 per case avoided) when compared to pre-emptive therapy. Underlying assumptions were based mostly on expert clinical opinion and results were pooled across European countries. The authors presented findings for an ‘average risk’ patient and found that results were very sensitive to patients’ baseline risk of CMV. Results were most sensitive to the cost of the drug and hospital drug administration costs, the efficacy of prophylaxis and the specificity of CMV monitoring tests. Hospital length of stay was the major cost component. The authors conclude that avenues to improve the cost effectiveness of CMV management strategies include the optimisation of CMV surveillance, better safety and efficacy of antiviral agents and oral formulations that may allow the length of hospital stay to be decreased.

Legendre et al⁵⁷ developed a decision model that compared oral prophylaxis using valaciclovir and ganciclovir to pre-emptive therapy using intravenous ganciclovir and wait-and-treat strategies. The analysis was conducted from the perspective of the French healthcare system and found that prophylaxis was the most clinically and cost-effective strategy for managing CMV in high-risk (D+/R–) and medium-risk (R+) renal transplant patients. The authors cautioned that robust data on the underlying risk levels of CMV by serostatus was very limited. Also, their analyses only covered a 6-month period, thus possibly not reflecting late-onset CMV disease. Finally, their cost analyses only included direct effects of CMV and did not look at the possible impact of CMV management strategies on opportunistic infections or graft survival. Quality of life was also not factored into analyses⁵⁷.

Khoury et al⁵² performed one of the few randomised studies that look at the economic and clinical consequences of prophylaxis versus pre-emptive therapy for CMV in kidney transplant patients. Their overall conclusion was that both strategies are equally effective in preventing symptomatic CMV at a similar cost. However, the costs of pre-emptive treatment were highly sensitive to the costs of monitoring, whereas the costs of prophylaxis were very sensitive to drug costs. The authors' conclusion was that the best candidate from an economic standpoint ‘remains institution and resource dependent’⁵². In a more recent direct comparison between prophylaxis and pre-emptive therapy, prophylaxis was found to be more cost effective than pre-emptive therapy and was associated with a 50% reduction in overall costs⁵⁸. Neither study looked at the impact of CMV management strategies on the indirect effects of CMV.

A further study by Dmitrienko et al ²¹ was conducted to determine the impact on probabilities of events, clinical outcomes and costs of implementing the Canadian consensus guidelines in kidney transplant patients. The authors developed a decision-analysis model to compare different scenarios and found that different strategies, specifically in terms of extending prophylaxis to different risk groups, had a significant bearing on the relative ratio of costs-to-effects²¹.

Discussion

Methodological issues in the economic evaluation of CMV prevention in transplantation

The choice between prophylaxis and pre-emptive therapy represents a decision between two preventative approaches; however, the difference lies in defining the appropriate timepoint for prevention (viraemia versus disease) and the size of the population to benefit from intervention. This choice is not dissimilar to prevention of HIV/AIDS: whereas prevention of viraemia (HIV) is achieved through population-wide primary preventative measures such as condom use, prevention of the disease (AIDS) is achieved through retroviral therapy, and triple therapy options are offered only to those who are HIV-positive. Another example is the choice between giving all patients at risk of heart disease statins prophylactically versus reserving treatment to those who have already presented with a myocardial infarction. In all of these cases, the choice lies in the relative balance of risks, anticipated health outcomes and costs. Economic evaluation may provide a helpful framework to guide decision making towards the strategies that present the greatest value in terms of the balance between these factors.

There is a growing clinical and economic literature comparing the relative merits of prophylaxis and pre-emptive therapy for CMV in transplantation. However, there is an unfortunate lack of large, prospective, randomised clinical trials that make direct comparisons between prophylaxis and pre-emptive therapy in transplant patients⁴⁵. Clinical protocols and guidelines still differ in terms of which strategy they advocate for particular risk groups. The purpose of this paper is to raise some of the issues emerging from this literature that are relevant to the economic evaluation of these preventative approaches. Consideration of these issues will become increasingly important as new antiviral therapies emerge and treatment effects are translated into broader patient outcomes.

To facilitate this discussion, we follow the evaluative framework proposed by Russell⁵. The components of this framework are discussed individually below.

The size of the population at risk

It is widely recognised that CMV infection and disease may severely compromise the outcomes of transplantation as well as lead to increased length of hospital stay in transplant patients^{16,17,35–37} As a result, prevention of CMV is common practice across most transplantation centres. Where guidelines and practices differ, however, is in the selection of patients deemed ‘at risk’ for CMV to whom prophylaxis or pre-emptive therapies are offered⁴⁷. For example, some centres may advocate restricting prophylaxis only to high-risk patients, whilst others may adopt prophylaxis for intermediate and high-risk patients⁴⁵. Risk is also defined differently for SOT and SCT patients.

Reliable data on the risks for CMV infection in different transplant settings are needed if we are to hope for the convergence of guidelines and practices to offer patients as much protection against CMV as possible.

The size of the risk of disease

There is still a need for better understanding of the links between CMV infection, viraemia and disease and of the impact of CMV management approaches on the natural history of CMV. Further reliable epidemiological data on CMV in transplantation are needed if we are to understand – and model credibly in economic evaluations – the impact of prophylaxis and pre-emptive therapy on direct and indirect effects of CMV. Moreover, there is not always uniformity in the underlying definitions for clinical endpoints used in clinical trials, making direct comparisons of the relative impact of different antiviral agents occasionally challenging.

The relative timing of events

There are a number of uncertainties related to the appropriate duration of clinical trials in order to capture the different events that take place between CMV infection, viraemia, and onset of disease. An ongoing concern with prophylaxis is whether it merely delays the onset of CMV disease and thus results in late-onset CMV disease. Thus, trials must be long enough to capture late-onset disease, should it occur. Most clinical trials limit the duration of prophylaxis to 100 days; however, it has been suggested that longer antiviral administration may be of benefit and reduce costs, particularly in high-risk patients, as the added cost of treatment is offset by decreased costs associated with prevented cases of CMV disease^59–61. Some authors have also suggested that prolonged prophylaxis may confer benefits in terms of overall survival¹³. A related issue is whether monitoring for CMV is necessary after prophylaxis is stopped and for how long the results of monitoring should be studied to ensure that a complete clinical picture on CMV is obtained from all patients⁵³.

The uncertainties associated with risk of disease

One of the ongoing uncertainties associated with prevention of CMV is the relative impact of prophylaxis and pre-emptive therapy on long-term effects of CMV. Ideally, one would want clinical trials and prospective observational studies to be long enough to allow for a thorough evaluation of the impact of preventative approaches on both direct and indirect effects of CMV. Most clinical trials lack the statistical power to compare indirect effects of CMV, particularly overall mortality. Nonetheless, inclusion of these outcomes into clinical trials would shed light on the relative value of different prevention strategies beyond their immediate impact on CMV disease.

The costs and cost-offsets of prevention and curative approaches

Economic studies of CMV differ in terms of which costs they include in their analyses. None of the studies reviewed consider costs associated with the indirect effects of CMV. Many studies limit the cost of drugs to acquisition costs and fail to factor in preparation costs for drug administration, pharmacy time, and nursing supervision⁶⁰. Direct costs associated with CMV diagnosis and treatment also vary significantly from one country to another, reflecting heterogeneity of practice. This is particularly true for the cost of CMV monitoring, given different diagnostic techniques and use of personnel⁵⁶. These differences led Khoury et al to conclude that ‘for now, the best approach to control CMV after solid organ transplantation remains institution- and resource-dependent’⁵².

Individual values placed on the balance of risks and benefits

As mentioned previously, there are no data on the quality of life or utility associated with different antiviral therapies or their use in the prevention of CMV. Given the morbidity associated with organ and stem cell transplantation and the toxicities linked to some of the antiviral therapies, it is essential that future studies include the measurement of these patient outcomes at appropriate time points over the duration of the trial. The selection of sensitive and reliable instruments to measure patient quality of life is also a critical issue. Much like the selection of clinical trial endpoints, these data should be considered as an integral part of the evaluation of new therapies.

Implications for the economic evaluation of preventative interventions

The choice between prophylaxis and pre-emptive therapy for CMV in transplantation represents a choice between two forms of prevention. The difference between these approaches lies in the point at which one intervenes to limit the risks and sequelae of CMV – in prophylaxis, the goal is to prevent viraemia, whereas in pre-emptive therapy, it is to prevent disease. The issues raised in the comparison of these two approaches are applicable to a broader assessment of preventative interventions, regardless of whether they are compared to other preventative measures or to curative interventions.

One of the main challenges in the evaluation of preventative and treatment interventions is how to integrate the results from randomised clinical trials into economic models aimed at depicting the impact of interventions in clinical practice. Randomised clinical trials are considered the ‘gold standard’ source of data on treatment effects to inform economic evaluations; however, their short duration, the use of intermediary outcomes and other aspects of trial design often preclude the possibility of collecting all necessary data to inform decisions about clinical management in naturalistic settings⁶². As a result, health economists interested in depicting the impact of preventative and treatment effects in an actual patient population resort to modeling approaches – economic modeling in fact becomes ‘an unavoidable fact of life’⁶³. Economic models are designed to offer an objective, structured and (hopefully) transparent framework for presenting the components of complex questions⁶². However, decision models are both defined and limited by their data inputs and underlying assumptions and, as a result, must be interpreted with caution.

One of the challenges evident in the case of CMV is the relative paucity of reliable, longitudinal epidemiological data from large datasets that help determine the impact of prevention strategies on the natural history of disease. Economic models must often rely on different sources of data to estimate risk levels of disease and complications. For example, relative risk estimates of treatment effect may be obtained from randomised clinical trials, yet absolute risk ratios can often be obtained from longitudinal series or observational studies. The combination of these data makes the conduct of rigorous and thorough sensitivity analyses essential in economic evaluations in order to test the robustness of results to different input parameter values.

Finally, this review underlines the lack of quality of life data from clinical trials. In this indication, as in many others, future studies are needed that include specific health-related quality of life measures over a long enough timeframe to be able to elucidate the impact of different management strategies on patient outcomes both during and following the administration of treatment. These data provide an important perspective of the patient experience and efforts should be made to include them in economic evaluations as well as in clinical publications on the impact of new interventions. Selection of instruments that are acceptable to the regulatory and clinical communities is an important step in ensuring that quality of life data is considered when choosing between different interventions. Increasingly, quality of life data have been used to show the potential risk benefit trade-offs of alternative treatments⁶⁴.

In conclusion, there is a need for large, prospective randomised trials that allow for direct comparisons of the impact of prophylaxis and pre-emptive therapy on direct and indirect effects of CMV and relevant patient outcomes over a sufficient period of time. This paper has attempted to highlight some of the issues and uncertainties involved in the economic evaluation of these two approaches. Further studies are eagerly awaited to shed light on some of these uncertainties and address some of the remaining questions regarding the optimal prevention strategy against CMV in transplant patients.

Figure 1. Stage of antiviral therapy.

Table 1. Key definitions of CMV in transplantation⁶⁵.

Term	Definition
CMV infection	The presence of CMV in body fluid or a tissue specimen as determined by DNA techniques, culture or antigen tests
CMV viraemia	Viraemia is defined as the isolation of CMV in the blood by culture that involves the use of either standard or shell vial techniques.
CMV disease (tissue-invasive CMV disease or end-organ disease)	CMV detected from an organ by biopsy or other invasive procedure with a test with appropriate sensitivity and specificity together with symptoms and/or signs from the affected organ.

Table 2. Direct and indirect effects of CMV^15,66,67.

Direct effects	Indirect effects
Hepatitis	Increase in opportunistic fungal and bacterial infection
Nephritis	Increased graft rejection
Carditis	Increased graft dysfunction
Colitis	Atherosclerosis
Pneumonitis	Altered metabolic processes, e.g. diabetes
Retinitis
Encephalitis

Acknowledgements

Suzanne Wait and Primrose Musingarimi are consultants to ViroPharma Limited. Glenn Tillotson is an employee of Viropharma Incorporated. Andrew Briggs is funded by the William R Lindsay Chair in Health Policy & Economic Evaluation at the University of Glasgow and did not receive specific funding for his part in this publication.