The Pharmaceutical Journal
Vol 269 No 7223 p688-689
9 November 2002

This article
Reprint
Photocopy

PDF 65K

Interscience conference on antimicrobial agents and chemotherapy

Prophylaxis or pre-emptive therapy for CMV in solid organ transplantation?

The controversy over whether cytomegalovirus (CMV) infection in solid organ transplantation is optimally prevented by employing prophylactic or pre-emptive therapy strategies has been debated recently, in full.^1,2 This controversy was fuelled by a series of presentations given at the Interscience Conference on Antimicrobials and Chemotherapy. Cytomegalovirus (CMV) infection in solid organ transplantation is associated with significant morbidity and some mortality. Without treatment, the frequency of disease is around 8 per cent of renal transplants, 29 per cent of liver, 25 per cent of heart and 39 per cent of heart/lung transplants.³ Primary infection causes general symptoms such as fever, night sweats, fatigue and myalgia. Gastrointestinal disease with nausea, abdominal pain and diarrhoea occurs frequently. The lungs and retina can be damaged. CMV disease can also suppress the immune system and allow coincident infection with other viral, bacterial, protozoal or fungal organisms. Furthermore, it is well recognised that CMV infection is associated with acute allograft rejection. Single studies and large registry data show that in individuals who experience CMV disease, a reduced graft and patient survival can be expected.

Prophylactic therapy

Because of the frequency of CMV infection and its associated morbidity and mortality, much research has focused on the most effective use of prophylactic treatment against CMV.

Prophylaxis has been shown through many studies to be effective and cost effective. A growing body of evidence also suggests that prophylactic therapy may have a positive effect on organ rejection and other outcomes. This year, the British Transplantation Society published guidelines recommending that patients at high risk of CMV disease should be offered prophylaxis against primary infection and reviewing the various options for prophylactic treatment covered by the published literature.⁴

Oral versus IV ganciclovir

Noting that there is no definitive consensus on the best approach to preventing CMV disease in lung transplant patients, Dr Joan Gavalda, Hospitals Vall d'Hebron, Barcelona, Spain, presented a study from which she and co-workers concluded that a long course of IV ganciclovir may be more effective than oral ganciclovir in the prevention of CMV disease after lung transplantation. The study compared the efficacy of oral ganciclovir and intravenous (IV) ganciclovir as prophylaxis of CMV disease in 60 CMV positive patients who were randomised to receive IV ganciclovir 5mg/kg/12 hours for 1 to 21 days post transplant and 6mg/kg/24 hours for days 22 to 45 days post transplant, or to receive oral ganciclovir 5mg/kg/12 hours for one to 21 days post transplant and then 3g/24 hours for days 22 to 90 days. Results showed that at one year after transplantation, IV ganciclovir decreased the risk of CMV disease (IV ganciclovir versus oral ganciclovir: 17.9 per cent versus 40.6 per cent; P<0.05) and increased mean time to diagnosis compared with oral ganciclovir (209.6 days versus 167.5 days oral ganciclovir).

Valganciclovir has a more convenient dosing regimen

It is broadly accepted that for any prophylactic strategy to be effective, it relies to varying degrees on good patient compliance. A further study presented at the conference showed that valganciclovir, a new, highly bioavailable pro-drug of ganciclovir, was comparable to oral ganciclovir as prophylactic treatment for CMV disease prevention.

The study was presented by CARLOS Paya on behalf of the Valganciclovir Solid Organ Transplant Study Group, Rochester, US. It involved 364, donor positive to recipient negative, solid organ transplant patients, randomised to receive 900mg valganciclovir once daily or 1,000mg oral ganciclovir three times daily within 10 days of transplantation. Treatment continued through to day 100 post transplant with follow up to six months. The primary analysis was for non-inferiority. The study showed that valganciclovir was comparable to oral ganciclovir in preventing CMV with a similar safety profile and a more convenient dosing regimen. Incidence of CMV disease was 12.1 per cent with valganciclovir compared with 15.2 per cent with ganciclovir during the first six months (95 per cent CI -0.04, 0.11). During the treatment period, the number of patients with measurable viral load of more than 400 copies/ml was significantly lower in the valganciclovir group than in the oral ganciclovir group (2.5 per cent versus 10.4 per cent, respectively) but was comparable by six months post-transplant (40 per cent with valganciclovir versus 43 per cent with ganciclovir).

Since CMV infection has been linked to allograft dysfunction, rates of acute rejection were also examined. A slightly lower incidence of acute allograft rejection was seen with valganciclovir compared with oral ganciclovir, with 29.7 per cent of patients and 36 per cent, respectively, experiencing at least one episode of acute rejection in the first six months after transplantation (p= NS). Both drugs were well tolerated.

Improving pre-emptive prophylactic strategies

On the other side of the debate, pre-emptive therapy has the benefit of only targeting patients at high risk of future CMV disease and minimises over-treatment while maximising cost-benefit. It is recognised that universal prophylaxis for CMV infection does not allow the immune stimulation or priming that is important for future control of CMV replication. Late onset CMV can be a significant complication in transplant recipients receiving prophylaxis with oral ganciclovir. Therefore, there is also continued interest in improving pre-emptive prophylactic approaches.

One study aimed to assess the use of viral load in predicting persistent CMV replication or disease during pre-emptive therapy. RAYMOND Razonable and colleagues, from the Mayo Clinic, Rochester, US, monitored 140 patients using weekly qualitative polymerase chain reaction (PCR) on peripheral blood leukocyte (PBL) samples for eight weeks. Fifty-seven patients (41 per cent) with positive PCR were randomised either to placebo (n=28) or to oral ganciclovir (n=29) for eight weeks and weekly PBL samples were collected. Viral load at randomisation was similar between the two groups (p=0.78) but only two out of 29 treated with oral ganciclovir developed CMV disease compared with seven out of 28 placebo-treated patients. Six patients with high viral load of 2,820 to 23,200 copies/106 had persistent CMV replication despite oral ganciclovir use and two of these patients developed CMV disease. The authors noted that compared with patients with undetectable viral load, those with a viral load of less than 2,869 and greater than 2,860 copies/106 PBL had a relative risk of developing CMV disease of 8.8 (p>0.0001) and 51.5 (p>0.0001), respectively. They concluded that this indicates the need for an agent with improved bioavailability for those patients with a viral load greater than 2,860 copies/106 and that those patients with persistently unquantifiable viral load may not need drug intervention. The majority of patients (89 per cent) with unquantifiable viral load did not develop CMV disease whereas all except two out of the seven placebo-treated patients who developed CMV disease did have a quantifiable viral load in the range 290 to 15,900 copies/106.

In a further study, NINA Singh et al, VA Medical Centre, Pittsburgh, US, reviewed for the first time the frequency of late onset CMV in transplant recipients receiving pre-emptive treatment with ganciclovir and found that it was efficacious. The study involved 76 liver transplant recipients who received pre-emptive therapy with oral ganciclovir for six weeks on detecting circulating blood levels of the dominant CMV antigen pp65, to prevent progression to disease. Mean follow up was 2.5 years and ranged up to 5.9 years. A total of 44 per cent of patients experienced at least one episode of shedding a median of 28 days after transplantation. There were no reported cases of CMV disease at 189.3 person-years of follow up confirming that pre-emptive therapy with oral ganciclovir was efficacious when guided by antigenaemia. The zero (0/76) incidence of late-onset CMV disease in this patient group was significantly lower than the 5.5 per cent (6/108) in previously reported studies of liver transplant patients who had received ganciclovir for 100 days (p=0.048).

The debate continues

The debate over whether to use prophylactic or pre-emptive strategies for CMV disease management will continue to be controversial. The results of the published controlled trials and those reported at the meeting confirm that each strategy can be used to protect patients from the effects of CMV. The choice for each transplant centre will probably be made after reviewing the practicalities of implementing and auditing the agreed management strategy. Pharmacists should be aware of this current debate and be prepared to address questions of cost and cost-effectiveness.