Episode #33 – Troll of Transplantation Part 1

Treating CMV disease in transplant recipients!  What are the treatment regimens?  What is induction vs maintenance therapy?  When can we make the transition between induction/maintenance?

First let’s talk about the available agents: 

• First line agents are ganciclovir 5 mg/kg IV q12h or valganciclovir 900 mg PO q12h for patients with normal renal function
  • • It is recommended to preferentially use IV ganciclovir for patients with severe or life-threatening disease, those with a very high viral load, and those with questionable GI absorption
    • For mild-to-moderate disease, oral valganciclovir and IV ganciclovir are considered equally effective
      • • You can refer to this RCT establishing this here: Asberg A, Humar A, Rollag H, et al. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2007;7(9):2106-2113. doi:10.1111/j.1600-6143.2007.01910.x
• For the patients who cannot tolerate ganciclovir or valganciclovir (usually due to cytopenias) or those who fail to respond to these agents (here we are going into the refractory/resistant CMV chapter – stay tuned for part 2) →  second line agents include foscarnet or cidofovir
  • • These agents are reserved for the second line use due to their significant nephrotoxicity
      • • Joseph referred to this study that showed that 50% of the patients who received foscarnet for refractory/resistant CMV developed renal dysfunction by the end of treatment, and 28% after 6 months: Gardiner BJ, Chow JK, Price LL, Nierenberg NE, Kent DM, Snydman DR. Role of Secondary Prophylaxis With Valganciclovir in the Prevention of Recurrent Cytomegalovirus Disease in Solid Organ Transplant Recipients. Clin Infect Dis. 2017;65(12):2000-2007. doi:10.1093/cid/cix696
    • A newer agent, maribavir, was recently approved by the FDA in November 2021, with a much better safety profile, so that’s an exciting development! 
    • There have been case reports using letermovir as a second line agent off-label, but most experts would not use it in the setting of active viral replication due to the high risk of resistance development

There are two stages of therapy, which includes the induction phase and then maintenance.

• Induction is the full-dose therapy stage, as Joseph described it.  Administer antivirals at the full therapeutic dose mentioned previously.  This is followed by maintenance, which is essentially a secondary prophylaxis phase to prevent early recurrence of CMV
• There is no preset duration for induction therapy. The AST ID COP guidelines list 3 criteria to meet before ending induction therapy:
  • • Resolution of clinical symptoms
    • Virologic clearance below a threshold negative value (test-specific) based on weekly lab monitoring with CMV qNAT or pp65 antigenemia – Two consecutive results, or a single negative with highly sensitive assays
    • Minimum of 2 weeks of antiviral treatment
• Once full-dose antiviral treatment is completed, the guidelines state that secondary prophylaxis may be considered in certain high-risk patients
  • • Here we transition to prophylaxis dosing as compared to therapeutic doses
    • The duration of antivirals in this stage is not defined by the guidelines and different centers use different approaches, some use 1 to 3 months. 
    • Duration also depends on the individual patient situation, particularly in regards to lymphopenia and CMV-CMI. 
• There was a retrospective study published in CID in 2017 looking at secondary prophylaxis with valganciclovir and it showed a reduction in relapse with a hazard ratio of 0.19 in the first 6 weeks following treatment completion. This benefit did not extend beyond 6 weeks of secondary prophylaxis: Gardiner BJ, Chow JK, Price LL, Nierenberg NE, Kent DM, Snydman DR. Role of Secondary Prophylaxis With Valganciclovir in the Prevention of Recurrent Cytomegalovirus Disease in Solid Organ Transplant Recipients. Clin Infect Dis. 2017;65(12):2000-2007. doi:10.1093/cid/cix696
  • • This is still an area that deserves more investigation to determine the optimal approach and how to incorporate the use of CMV-CMI and allow for CMV-specific T-cell immune reconstitution.

Lastly, don’t forget about other important interventions and notes mentioned on the episode:

• • Cautious reduction in immunosuppression should be considered, especially in moderate to severe disease
  • Can switch from IV ganciclovir to oral valganciclovir once there is clinical and virological improvement and no concerns for GI malabsorption
  • You should dose adjust the drugs based on renal function, but you should not adjust down due to leukopenia or pancytopenia → underdosing is a risk factor for resistance
  • IVIg or CMV-specific Ig may be considered for patients with life-threatening disease, CMV pneumonitis, or those with hypogammaglobulinemia.