CMV Hyperimmune Globulin Data Inconclusive but New Drug Shows Promise

Treating CMV was never easy making prophylaxis the preferred approach for HSCT patients. Since the late 80ies, trials using hyperimmune globulin have come up with mixed results. While treatment was usually safe, efficacy was a lot much harder to prove.  More specific monoclonal ab preparations directed against immunodominant surface
glycoproteins did not fair any better. With neutralizing activity a. gainst gD, gH, gI or a mixture of these targets , these preparations held great promise based on findings in cell-based assays, however, efficacy in clinical trials proved elusive.

Then, the field got energized by a report from Nigro’s group claiming that immunoprophylaxis in pregant women with recent CMV seroconversion reduced the frequency of congenital CMV infection and disease considerably (NEJM 2005;353).
Many clinicians were swayed by the data despite some blatant design issues, like the lack of randomization.  Given the fact that trials in pregnancy are notoriously difficult to
to conduct in a scientifically rigorous way, these data were welcome though not ultimately convincing.

Hence, it was important to get confirmation.

Setting a 50% benefit treshhold, another Italian collaborative group set out to do just that (Revello, NEJM 2014; 370:1316).  When the study was unblinded after the enrollment of 124 patients, only a non-significant benefit was seen in the Ig treatment group.
In other words, the study failed to meet the prespecified criteria for efficacy.  There was a noteworthy numerical benefit with hyper-Ig, just not as impressive as the Nigro data had suggested and the study authors had felt was the minimally acceptable benefit.

Now a report in the NEJM shows us that direct antivirals can do what immunoglobulins can not (NEJM 2014; 370:1781).  Letermovir (formerly AIC246) is a non-nucleoside with a novel MoA targeting the CMV terminase.  Dose-dependent prophylactic/pre-emptive efficacy was shown in patients receiving the drug post-engraftment. Importantly, side effects were almost indistinguishable from placebo and events typical for  ganciclovir on bone marrow and renal system were not observed.

This elegantly designed trial should pave the way for registration trials as prophylaxis starting right after transplantation.

Clearly, there is still much to be learned about Letermovir, to be addressed in future trials. How about the emergence of resistance with longer-term
exposure?  Lab data suggest a low frequency for mutations. Clearly, cross-resistance to ganciclovir, cidofovir or foscarnet would not be expected.  Combination therapy with any of these drugs would be another area to explore, maybe for established CMV disease like CMV pneumonia.

The other big question is related to efficacy compared to ganciclovir.
If Letermovir is equally potent while offering a better safety profile, the CMV treatment guidelines will have to be rewritten.

Exciting days for CMV! And a toast to well-controlled RCTs!

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