Treating CMV was never easy making prophylaxis the preferred approach for HSCT patients. Since the late 80ies,\u00a0trials using hyperimmune globulin have come up with mixed results. While treatment was usually safe,\u00a0efficacy was a lot much harder to prove. \u00a0More specific monoclonal ab preparations directed against immunodominant surface
\nglycoproteins did not fair any better. With neutralizing activity a. gainst gD, gH, gI or a mixture of these targets , these preparations\u00a0held great promise based on\u00a0findings in cell-based assays, however, efficacy in clinical trials proved elusive.<\/p>\n
Then, the field got energized by a report from Nigro’s group claiming that immunoprophylaxis in pregant women with\u00a0recent CMV seroconversion reduced the frequency of congenital CMV infection and disease considerably (NEJM 2005;353).
\nMany clinicians were swayed by the data despite some blatant design issues, like the lack of randomization. \u00a0Given the fact\u00a0that trials in pregnancy are notoriously difficult to
\nto conduct in a scientifically rigorous way, these data were welcome though not ultimately\u00a0convincing.<\/p>\n
Hence, it was important to get confirmation.<\/p>\n
Setting a 50% benefit treshhold, another Italian collaborative group set out to do just that (Revello, NEJM 2014; 370:1316). \u00a0When the study was unblinded after the enrollment of 124 patients, only a non-significant benefit was seen in the Ig treatment group.
\nIn other words, the study failed to meet the prespecified criteria for efficacy. \u00a0There 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.<\/p>\n
Now a report in the\u00a0NEJM shows us that direct antivirals can do what immunoglobulins can not (NEJM 2014; 370:1781). \u00a0Letermovir (formerly\u00a0AIC246) is a non-nucleoside\u00a0with a novel MoA targeting the CMV terminase. \u00a0Dose-dependent prophylactic\/pre-emptive efficacy was shown in patients receiving the drug post-engraftment. Importantly, side effects were almost indistinguishable from\u00a0placebo and events typical for \u00a0ganciclovir on bone marrow and renal system were not observed.<\/p>\n
This elegantly designed trial should pave the way for registration trials as prophylaxis starting right after transplantation.<\/p>\n
Clearly, there is still much to\u00a0be learned about Letermovir, to be addressed in future trials. How\u00a0about the emergence of resistance with\u00a0longer-term
\nexposure? \u00a0Lab data suggest a low frequency\u00a0for mutations. Clearly, cross-resistance to ganciclovir, cidofovir or foscarnet would not be expected. \u00a0Combination therapy with any of these drugs would be another area to explore, maybe for established CMV disease like CMV pneumonia.<\/p>\n
The other big question is related to efficacy compared to ganciclovir.
\nIf Letermovir is equally potent while offering a better safety profile, the CMV treatment guidelines will have to be rewritten.<\/p>\n
Exciting days for CMV! And a toast to well-controlled RCTs!<\/p>\n","protected":false},"excerpt":{"rendered":"
Treating CMV was never easy making prophylaxis the preferred approach for HSCT patients. Since the late 80ies,\u00a0trials using hyperimmune globulin have come up with mixed results. While treatment was usually safe,\u00a0efficacy was a lot much harder to prove. \u00a0More specific monoclonal ab preparations directed against immunodominant surface glycoproteins did not Continue reading CMV Hyperimmune Globulin Data Inconclusive but New Drug Shows Promise<\/span>