There is no evidence that intravenous immunoglobulin (IVIG), CMV-specific hyperimmune immunoglobulin or anti-CMV monoclonal antibodies are useful alone or in combination with antiviral agents in primary prophylaxis against CMV infection (Bowden et al, 1991; Ruutu et al, 1997; Boeckh et al, 2001). A recent Cochrane review in solid organ transplant did not recommend prophylactic immunoglobulin (Hodson et al, 2007).
There have been several small studies published using CD4 or CD8 T cells (Walter et al, 1995; Einsele et al, 2002; Peggs et al, 2003, 2009; Hanley et al, 2011; Sili et al, 2012), or CMV peptide-loaded dendritic cell vaccination (Grigoleit et al, 2007) for treatment or prophylaxis of CMV infection, but too little evidence currently exists to make any recommendation at present although ongoing prospective studies are addressing this issue.
Aciclovir prophylaxis has been extensively studied post-HSCT. A large randomized trial of 310 patients initially appeared to suggest a reduced incidence and delayed onset of CMV infection as well as a significant improvement in survival. More mature follow up has shown no significant difference in CMV reactivation between groups, although reactivation did occur later in the prophylactic group. A modest survival benefit was still seen in the most aggressively treated patients, though it is difficult to attribute this to anti-CMV activity alone (Prentice et al, 1994, 1997). Improved survival in allograft patients who received aciclovir prophylaxis post-engraftment was also shown in a meta-analysis in which the vast majority of donor/recipient pairs were CMV IgG-positive (Yahav et al, 2009). However, the impact of aciclovir on CMV reactivation/disease rates in the studies included was again minimal and survival advantage was potentially mediated through anti-herpes simplex effects. Subsequently, valaciclovir, 2 g four times a day, was compared with oral aciclovir at 800 mg four times a day, in 727 patients following high dose intravenous (iv) aciclovir in the immediate post-transplant period (Ljungman et al, 2002c). In this study, valaciclovir significantly reduced CMV infection and disease rates (P < 0·0001). There was a 50% reduction in the use of pre-emptive therapy although there was no difference in overall survival (Ljungman et al, 2002c). Similar results were shown in a smaller case controlled study using valaciclovir at a dose of 1 g three times a day (Vusirikala et al, 2001). The studies described above predominantly used myeloablative conditioning and T-cell-replete BM as the stem cell source. Studies in PBSC recipients, though smaller, suggested that the beneficial effects of high dose aciclovir prophylaxis appeared to be maintained (Verma et al, 2003; Hazar et al, 2004). However, aciclovir was shown to be significantly less effective in T-cell-depleted BM transplant recipients, where 83% of T-cell-depleted recipients still had a CMV reactivation compared to 41% of unmanipulated stem cell sources (P < 0·0001) (Nakamura et al, 2002). As most of these studies predated widespread use of pre-emptive therapy based on quantitative PCR, their significance is questionable in terms of current management of CMV, though a compelling argument can be made for its use for suppression of herpes simplex virus infection.
Ganciclovir prophylaxis significantly reduced the incidence of CMV infection and disease during the period of prophylaxis (Goodrich et al, 1993; Boeckh et al, 1996). However neutropenia occurred in up to 30% of cases treated (Salzberger et al, 1997) and infective complications were increased (Boeckh et al, 1996). Ganciclovir was less effective in T-cell-depleted transplants and heavily immunosuppressed recipients (Maltezou et al, 1999). In a prospective randomized trial of ganciclovir versus aciclovir, cumulative rates of CMV disease were equivalent, although more patients in the aciclovir group required pre-emptive therapy (P = 0·2) (Burns et al, 2002). Post-prophylaxis, late onset CMV disease remained a problem (Boeckh et al, 2003) and prolonged exposure of CMV to ganciclovir, especially in the setting of T-cell depletion may encourage resistance, as occurs in solid organ transplantation (Eid et al, 2008). Valganciclovir prophylaxis has been reported to reduce risk of CMV disease in cord blood transplants (Montesinos et al, 2009).
More intensive prophylactic regimens involving pre-transplant ganciclovir combined with high dose aciclovir prophylaxis or a combination of ganciclovir and foscarnet have been employed in high-risk paediatric and cord blood transplants where both have been reported to be successful in reducing CMV infection and disease (Shereck et al, 2007; Milano et al, 2011).
Maribavir, when given from engraftment, initially showed favourable results in phase II studies; but, at the dose chosen, failed to show any effect on CMV disease or initiation of CMV pre-emptive therapy compared to placebo in a larger phase III study. There was a small impact on CMV DNA loads in plasma (Winston et al, 2008; Marty et al, 2011). Letermovir (AIC246), a maturation inhibitor of CMV, has been studied in phase 2 trials as anti-CMV prophylaxis in 133 HSCT patients with potentially encouraging results (Goldner et al, 2011). Neither of these drugs can be recommended for prophylaxis at present.
In summary, post-HSCT, in contrast to solid organ transplantation, ganciclovir-induced myelosuppression limits its use for prophylaxis. Routine use of aciclovir or valaciclovir is relatively non-toxic but will result in some patients being overtreated and the effect in T-cell-depleted transplants is small. However, the potential benefits of prophylaxis using these drugs in selected patients include reducing the need for hospital admission, for iv pre-emptive therapy, reducing indirect effects of CMV reactivation on immune status post-transplant and delaying CMV reactivation until the patient has recovered from the toxicity associated with the transplant and is no longer on immunosuppression.