Medical Care
There are various CMV-treatment approaches based on patient’s CMV-status and co-morbidities. Some patients receive prophylaxis while some receive preemptive therapy. Prophylaxis is given to a patient to prevent primary, reactivation or recurrent infection. Preemptive therapy is given to an asymptomatic CMV-infected patients with CMV detected by screening tests. Some studies have shown that high-dose acyclovir or valacyclovir prophylaxis markedly reduces CMV infection in allo-HSCT recipients. Intravenous ganciclovir has been also tested, with some reduction in CMV infection, however this did not provide overall survival benefit and was also associated with bone marrow suppression (ganciclovir-induced neutropenia). [43]
Letermovir, a CMV terminase inhibitor, has been used for primary prevention of CMV in sero-positive allo-HSCT recipients. Some studies such as Marty et al, have demonstrated efficacy of it’s use, with a 23.5% reduction of CMV infection at week 24 after transplantation. This may also reduce mortality by preventing or delaying clinically significant CMV infection in these patients. [19, 61, 62]
Ganciclovir treatment
The drug of choice for treatment of CMV disease is intravenous ganciclovir, although valganciclovir may be used for nonsevere CMV treatment in selected cases.
Ganciclovir is a nucleoside analogue that inhibits DNA synthesis in the same manner as acyclovir. The major difference is that CMV does not contain a thymidine kinase.
Protein UL97 phosphorylates ganciclovir to ganciclovir monophosphate. One of the mechanisms of ganciclovir resistance is a change in UL97. Mutations at codon 460 and 520 and mutations or deletions around codons 590-596 in UL97 cause most ganciclovir resistance, although other resistance mechanisms may be present.
Ganciclovir has activity against CMV, HSV, VZV, and HHV-6, HHV-7, and HHV-8. However, one of the other nucleoside analogues (eg, famciclovir, penciclovir, acyclovir) is preferred to treat VZV and herpes simplex infections.
The major adverse effects of ganciclovir therapy include fever, rash, diarrhea, and hematologic effects (ie, neutropenia, anemia, thrombocytopenia). Neutropenia is managed by dose reduction and/or the addition of growth factors (ie, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]).
Oral ganciclovir results in serum levels that are 5-10 times less than intravenous ganciclovir, making oral ganciclovir a less-than-optimal agent for the management of active disease. Valganciclovir hydrochloride, an oral version (L-valyl ester) of ganciclovir, has been approved for the treatment of CMV retinitis in HIV-positive patients.
A randomized trial of patients with CMV retinitis showed that oral valganciclovir was as effective as intravenous ganciclovir when used as an initial treatment. [63] Although no trials have compared oral valganciclovir as a maintenance treatment, pharmacokinetic studies suggest valganciclovir is approximately as effective as intravenous ganciclovir
See the Medication section for dosing.
In the treatment of CMV pneumonia, ganciclovir is administered with CMV-specific immune globulin (dosing in Medication section). [44] However, it is unknown how immune globulin facilitates ganciclovir so that it leads to a better outcome in CMV pneumonia.
The length of treatment varies. Some clinicians have administered ganciclovir for as long as 2-4 weeks from the end of the induction period, depending on the clinical status of the patient. Recently, investigators have studied shorter courses of intravenous ganciclovir therapy for CMV infection and disease, followed by transition to oral valganciclovir. [64] If effective, this may help to improve patient quality of life and to reduce the length of hospital stay. [64]
Other uses of ganciclovir include treatment of GI disease in transplant recipients and in patients who are HIV positive. Ganciclovir has also been used to treat CMV esophagitis in both of these patient populations.
The drug is also used to treat diarrhea secondary to colitis or enteritis in patients positive for HIV after tissue biopsy and confirmation of CMV disease. Because of the high probability of CMV disease relapse (50%), maintenance therapy should be offered to most patients. [65]
Ganciclovir has also been used to treat CNS disease, including encephalitis and neuropathy, with mixed results.
Valganciclovir
Valganciclovir is a prodrug of ganciclovir that is activated in the gut and liver to ganciclovir.
Valganciclovir has 60% bioavailability. Valganciclovir 900 mg orally once daily is equivalent to once-daily intravenous ganciclovir 5 mg/kg.
One meta-analysis showed equivalent efficacies between 900 mg of valganciclovir and 450 mg for cytomegalovirus prophylaxis in transplantation, though the 900 mg daily was associated with 3 times increased risk of leucopenia and 2 times increased risk of rejection. [66, 67]
Valganciclovir is used for treatment in selected CMV cases. [68] Most experience has been established in renal and pancreas transplant recipients and patients with AIDS who have CMV retinitis.
It is also the drug of choice now for preemptive or universal CMV prophylaxis. [2] Routine valganciclovir prophylaxis was favored over preemptive therapy in a randomized controlled trial of CMV-positive renal allograft recipients.
A glomerular filtration rate (GFR) below 10 is a contraindication to valganciclovir use.
Ganciclovir prophylaxis
A major successful use of ganciclovir has been prophylactic or preemptive treatment of CMV disease in transplant recipients. Without preventive CMV therapy, 30%-75% of transplant recipients develop CMV infection, and 8%-30% develop CMV disease. [68, 69]
Oral ganciclovir has been replaced by valganciclovir for prophylaxis and preemptive therapy because of bioavailability issues.
Prophylaxis is provided to all patients who have positive CMV serology results. Positive findings on blood cultures, pp65 antigenemia, and CMV PCR have been used as markers for the initiation of therapy. Both the prophylactic and the preemptive approaches have been used, and both have been found to decrease CMV disease in bone marrow or solid organ transplants recipients. The choice of the appropriate regimen may be determined by the adverse effects of the drugs and the abilities of the microbiology laboratory. Universal prophylaxis versus preemptive therapy as the best approach remains a matter of debate and varies among institutions. Recent data favor universal prophylaxis with either ganciclovir or valganciclovir in high-risk liver transplant recipients. [70]
Preemptive therapy is attractive because it restricts the use of ganciclovir to a select population at high risk for CMV disease, eliminates toxicity in most patients who would not be diagnosed with CMV disease, and decreases the cost of medical care.
A study compared 96 renal transplant recipients in Italy between May 2006 and December 2007, all of whom received preemptive therapy with ganciclovir and/or valganciclovir, with 100 controls who received CMV prophylaxis. Serial quantitative viral loads were obtained weekly during the first 4 months. Asymptomatic patients, with a viral load DNA of more than 100,000 copies/mL determined using PCR, were treated with for 3 months or until resolution of viral replication. Among the 96 transplant recipients, blood CMV viral loads were elevated in 14 asymptomatic patients, who were treated with oral valganciclovir for 3 months. After a median follow-up period of 13.3 months, none of the 14 patients who received valganciclovir developed CMV disease, leading the authors to conclude that valganciclovir administered as preemptive therapy was safe and efficacious in preventing CMV disease. [71]
Conversely, a study using CMV pp65 antigenemia as the trigger for treatment found prophylaxis to be more effective than preemptive therapy for preventing CMV pneumonia in marrow transplant recipients. [72] At the same time, however, ganciclovir at engraftment was associated with more early invasive fungal infections and more late CMV disease. [72]
Some experts believe CMV prophylaxis in solid organ transplant recipients may protect against indirect CMV effects not measurable by levels, such as graft rejection, opportunistic infections, and transplant-associated vasculopathy. [68]
Prophylactic approaches have also been very successful in eliminating CMV disease; however, toxicities are increased with this approach because patients without viral reactivation may be exposed to antiviral therapy. Many transplantation centers reserve prophylactic therapy for patients most at risk (CMV-positive donors/CMV-negative recipients) for disease reactivation and use antigen assays to institute preemptive therapy in other patients.
Some experts recommend extending the duration of CMV prophylaxis to the period of reduced immunosuppression. They feel this may protect patients from late-onset CMV disease. [68]
Prolonged ganciclovir use has been associated with development of resistance.
Letermovir prophylaxis
Letermovir is an anti-CMV drug that was approved by the FDA in November 2017. It inhibits the CMV DNA terminase complex (pUL51, pUL56, and pUL89), which is required for viral DNA processing and packaging by affecting the production of proper unit length genomes and interfering with virion maturation. Approval of letermovir was based on a phase 3 clinical trial (n=565). In this study, significantly fewer patients developed clinically significant CMV infection in the letermovir group (38%, n=122/325) compared to the placebo group (61%, n=103/170). In addition, fewer patients discontinued treatment or had missing data through week 24 post-HSCT (P< 0.0001), the primary efficacy endpoint.
All-cause mortality in patients receiving letermovir was lower compared to placebo, 12% versus 17% at week 24 posttransplant. The incidence of bone marrow suppression in the letermovir group was comparable to that of the placebo group. The median time to engraftment was 19 days in the letermovir group and 18 days in the placebo group. [61]
Foscarnet
Foscarnet is a DNA chain inhibitor of phosphorylation. It has been used to treat resistant HSV and ganciclovir-resistant viruses. It is an effective antiviral.
Meticulous attention must be paid to the patient's renal function. Small changes in creatinine levels require new calculations for renal clearance. Foscarnet is nephrotoxic. The patient must be well hydrated.
Foscarnet may cause changes in calcium and phosphorus metabolism. Other adverse effects include neurological toxicities, anemia, headache, and nausea. It can cause a fixed drug reaction on the penis.
See the Medication section for dosing.
Foscarnet does not require intracellular phosphorylation. Foscarnet resistance is secondary to mutations of the viral DNA polymerase involving codons from 696-845.
Acyclovir prophylaxis
High-dose valacyclovir, penciclovir, famciclovir, and acyclovir have been used for CMV prophylaxis in organ transplant recipients. The results have been mixed and depend on the transplant population.
European transplant groups are more likely to use acyclovir or valacyclovir for CMV prophylaxis than their US counterparts.
In vitro assays have shown that some strains of CMV may be susceptible to acyclovir.
Overall, acyclovir prophylaxis is not as effective as prophylaxis with ganciclovir.
Cidofovir prophylaxis
Cidofovir is a nucleotide that inhibits DNA replication.
It is effective against a broad range of viruses. It has been used for the treatment of refractory CMV retinitis in HIV-positive patients.
Ganciclovir resistance does not necessarily preclude the use of cidofovir.
See the Medication section for dosing.
The patient must be hydrated, and the drug must be administered with probenecid to protect the renal tubules
Maribavir
Maribavir has significant activity against both human cytomegalovirus (CMV) and Epstein-Barr virus, but not other herpesviruses.
Maribavir is a benzimidazole nucleoside and prevents viral DNA synthesis, as well as capsid nuclear egress.
Unlike ganciclovir, which requires phosphorylation by UL 97 kinase to become an active inhibitor of DNA polymerase, maribavir directly inhibits UL 97 kinase.
Maribavir's bioavailability is greater than that of oral ganciclovir, but less than that of valganciclovir.
It may be useful for CMV resistant to ganciclovir, foscarnet, or cidofovir; however, the optimal dose, treatment duration, and use in combination versus monotherapy are currently undefined. [73] In a study of 6 patients treated with maribavir after failing to respond to other therapies and/or with known ganciclovir-resistant CMV, 4 patients achieved undetectable viral loads. [73] No significant adverse effects attributable to MBV were observed.
No efficacy was demonstrated in a phase 3, double-blind, placebo-controlled, randomized trial of 681 allogeneic stem cell transplant recipients who received maribavir to prevent CMV disease. [74]
Maribavir differs from current CMV antiviral agents in its adverse event profile. It is not associated with nephrotoxicity or hematologic toxicity, but has been associated with taste disturbances. [75]
Leflunomide
Leflunomide is an antimetabolite used as a disease-modifying agent in rheumatoid arthritis. It has also been successfully used off-label in both CMV disease treatment and prophylaxis. [76, 77, 78]
Leflunomide failure has been reported in hematopoietic stem cell transplant recipients. [79]
See the Medication section for dosing.
Cytomegalovirus immune globulin
CMV immune globulin has been approved by the US Food and Drug Administration for the prophylaxis of CMV disease in high-risk lung transplant recipients when given in conjunction with ganciclovir. In a retrospective study of cardiothoracic transplant recipients, those who received CMV immune globulin plus ganciclovir had a higher disease-free incidence of CMV, less rejection, higher survival rate, and reduced coronary intimal thickening compared with patients who received ganciclovir alone. [80] A prospective randomized study is required to confirm these observations.
CMV immune globulin is used in combination with ganciclovir to treat CMV pneumonia.
See the Medication section for dosing.
Consultations
Infectious diseases specialist
Obtaining a consultation with an infectious disease specialist in patients with CMV viremia or pneumonia is prudent. This is particularly true in patients who are HIV positive, patients who have received organ transplants, and individuals who are immunocompromised in any other way (eg, heavy steroid use, tumor necrosis antagonists)
Current antiviral medications have many adverse effects that are best managed by a physician who has experience using these drugs.
Cidofovir and foscarnet have significant toxicity, including acute permanent renal failure. These drugs should be administered in conjunction with a clinician experienced in their usage.
Hematologist
CMV infection may cause hemolytic anemia and thrombocytopenia.
A hematologist may be consulted in severe cases.
Neurologist
CMV may cause aseptic meningitis, encephalitis, polyneuritis, and Guillain-Barré syndrome.
A neurologist may be helpful in the management of these diseases.
Ophthalmologist
Chorioretinitis may be observed in immunocompromised hosts.
In addition, consultation with an ophthalmologist is important in monitoring patients with HIV for opportunistic infections, especially patients with a CD4 cell count of fewer than 100 cells/µL.
Activity
Patients with CMV infection commonly ask when they can resume their usual activities. The most common symptom after resolution of the acute phase of CMV infection is fatigue, which may persist up to 18 months after the primary infection but is usually much shorter. Some patients resume their usual activities almost immediately, but the average time to recovery from fatigue is 1-2 months. Patients should resume activity as they can tolerate.
Prevention
See Medical Care for a discussion about early treatment versus prophylaxis with ganciclovir.
Other drugs have been used for CMV prophylaxis, but none is as effective as valganciclovir (drug of choice) [2] or ganciclovir. Acyclovir and valacyclovir have been used for prophylaxis and early treatment in allogeneic marrow transplant recipients. Acyclovir has also been used in recipients of other types of transplants.
CMV remains the most common viral cause of severe disease in the transplant population, with significant associated morbidity and mortality. This, together with the issue of drug treatment toxicities and drug interactions, makes the development of a successful vaccine a high priority. [81] A CMV glycoprotein-B vaccine containing an MF59 adjuvant is currently in a phase 2 randomized placebo-controlled trial in transplant recipients. [82]
Congenital CMV infection is an important cause of hearing, cognitive, and motor impairments in newborns. A phase 2, placebo-controlled, randomized, double blind trial by Pass et al (2009) evaluated a recombinant CMV vaccine (envelope glycoprotein B with MF59 adjuvant). Three doses of the CMV vaccine or placebo were administered at 0, 1, and 6 months to 464 CMV-seronegative women within 1 year after they had given birth. After a minimum follow-up period of 1 year, 49 confirmed CMV infections were reported—18 in the vaccine group and 31 in the placebo group. One infant in the vaccine group was found to have congenital CMV infection, while 3 infants from the placebo group were infected. Ongoing research continues to evaluate the potential for a CMV vaccine to decrease maternal and congenital CMV infection. [83]
Further Outpatient Care
When ganciclovir is administered on an outpatient basis for the treatment of CMV retinitis, follow-up with a CBC count once per week (monitoring for hematological toxicity) is necessary. Monitoring electrolytes at the same time is prudent. Ganciclovir therapy should be stopped when neutrophil counts are less than 500 cells/µL. Starting growth factors, such as GM-CSF or G-CSF, may be necessary. A switch to foscarnet may be required at this time.
Patients with CMV retinitis should undergo regular ophthalmological examinations.
Further Inpatient Care
Patients with cytomegalovirus (CMV) disease must be well hydrated.
Nutrition is an important factor because many patients are debilitated by transplant or HIV disease.
As with any patient, attention must be focused on avoiding iatrogenic infections and problems.
Patients who develop CMV disease are immunocompromised, meaning that they at greater risk for bacterial and fungal infections. If possible, the patient's level of immunosuppression should be lowered.
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Here, using immunofluorescent technique, a specimen of human embryonic lung (25X) reveals the presence of cytomegalovirus. Courtesy of the CDC and Dr Craig Lyerla.
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Hematoxylin-eosin–stained lung section showing typical owl-eye inclusions (480X). Courtesy of Danny L Wiedbrauk, PhD, Scientific Director, Virology & Molecular Biology, Warde Medical Laboratory, Ann Arbor, Michigan.
