Ganciclovir-Resistant Cytomegalovirus Encephalitis in a Patient With AIDS

Authors: 
Niel N. Shah, MBBS; Shuchi Pandya, MD; Sowmya Nanjappa, MBBS, MD; Ana P. Velez, MD; and John N. Greene, MD

Citation: 
Consultant. 2018;58(1):22-26.

Cytomegalovirus (CMV) neurologic disease is a complication of advanced AIDS and can cause fatal encephalitis. CMV neurologic disease occurred in as many as 2% of patients with AIDS prior to the availability of antiretroviral therapy (ART), especially in patients with a CD4 cell count of less than 50/µL.¹ The incidence of CMV neurologic disease has decreased since ART became available.^2,3

Some patients do not adhere to ART and, upon restarting it, may develop immune reconstitution inflammatory syndrome (IRIS). However, IRIS can develop in any HIV-positive patient who starts ART, irrespective of drug adherence. Usually, CMV disease can be treated with intravenous (IV) ganciclovir or oral valganciclovir. However, in cases of CMV resistant to these medications, treatment can be challenging.

We present a case of a patient with AIDS who developed ganciclovir-resistant CMV encephalitis, possibly as part of IRIS. 

Case Presentation

A 52-year-old woman with AIDS with a CD4 cell count of 30/µL presented with altered mental status and failure to thrive. Because she was slow to speak and somnolent, it was difficult to obtain information from a review of systems, other than the fact that she had experienced decreased oral intake and confusion. This change in mental status had recently been noted by her family members shortly after she had begun outpatient ART.

History. Her history was significant for HIV-associated non-Hodgkin lymphoma, herpes simplex virus (HSV) encephalitis, CMV encephalitis, and CMV retinitis. At presentation, she was on ART consisting of darunavir boosted with ritonavir and emtricitabine-tenofovir. She was also on prophylactic azithromycin for Mycobacterium avium complex (MAC) infection, trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis jiroveci pneumonia (PCP), and valganciclovir for CMV infection. She had been nonadherent with ART and had recently restarted the regimen. She had no drug allergies, and her family history was noncontributory. There was no history of alcohol abuse or IV drug use, and she had quit tobacco many years prior.

Physical examination. At presentation, the woman was afebrile with a blood pressure of 112/77 mm Hg and a heart rate of 99 beats/min. She had bilateral nystagmus and was unable  to close her right eye. She was able to follow simple commands but was not oriented to person, place, or time. Otherwise, she was somnolent and in no acute distress. No other neurologic deficits were noted. Prior to admission, her mental status had been declining gradually over a few months.

Diagnostic tests. Laboratory test results showed pancytopenia, with a white blood cell (WBC) count of 950/µL, an absolute neutrophil count (ANC) of 430/µL, and a lymphocyte count of 480/µL. The HIV viral load was 350 copies/mL, and the CD4 cell count was 60/µL (compared with 30/µL at the time of HIV infection diagnosis).

Cerebrospinal fluid (CSF) analysis revealed a glucose level of 48 mg/dL, a protein level of 38 mg/dL, a WBC count of 51/µL comprising 1% neutrophils and 97% lymphocytes. CSF Gram stain and fungal stain were negative for bacteria.

Magnetic resonance imaging (MRI) of the brain showed diffuse, relatively symmetric, nonenhancing increased signal throughout the white matter of both hemispheres above the tentorium (Figure). It also revealed small areas of focal signal intensity and subtle restriction of diffusion in the ependymal location lateral to the atrium of the right lateral ventricle and in the splenium of the corpus callosum. These changes were thought to represent an unusual form of a nonenhancing localized ischemic process.

Figure: MRI of the brain showing diffuse, symmetric, nonenhancing increased signal throughout the white matter of both hemispheres.

The MRI findings raised suspicion for HSV-related encephalitis; hence, IV acyclovir was started initially at 10 mg/kg every 8 hours, but shortly after, the acyclovir was changed to IV ganciclovir out of concern for CMV encephalitis.

Further CSF studies revealed negative polymerase chain reaction (PCR) test results for Treponema pallidum, Toxoplasma gondii, Epstein-Barr virus, Cryptococcus species, and HSV, as well as negative bacterial, fungal, and acid-fast bacillus cultures. The CSF fluid was positive for more than 300,000 copies/mL of CMV, a surprising finding given that she had been on oral valganciclovir, 450 mg twice a day, for CMV infection prophylaxis for 6 months prior to presentation. The CSF sample was tested for genotype; while awaiting results, ganciclovir was switched to IV foscarnet. A blood sample was sent for PCR testing for CMV, and the CSF was tested for HIV viral load.

Genotype tests of the CMV in the CSF revealed mutations of UL97 and UL54. PCR results showed an elevated blood CMV level of 600 copies/mL. The CSF HIV viral load was found to be 1000 copies/mL.

Due to high viral load of HIV in the CSF, raltegravir was added to the ART regimen after discussion with her HIV physician. Meanwhile, her pancytopenia improved due to the discontinuation of ganciclovir. Induction therapy was started with IV foscarnet at 90 mg/kg every 12 hours for 21 days, followed by maintenance therapy with IV foscarnet, 90 mg/kg every 24 hours, for the next 21 days. After completion of foscarnet therapy, the plan was to start oral valacyclovir, 1 g every 6 hours, until her CD4 cell count was found to be more than 200/µL. The CD4 cell count during hospitalization was 60/µL (1 month prior, it had been 65/µL), and the HIV viral load was 330 copies/mL (1 month prior, it had been 645 copies/mL).

The patient began to show overall symptomatic and mental status improvement on foscarnet therapy. She was noted to have better oral intake and also was found to be alert, awake, and oriented to person, place, and time. She was discharged without further complications on day 21 of hospitalization.

Laboratory test results at discharge included a WBC count of 1720/µL, an ANC of 580/µL, a urea nitrogen level of 7 mg/dL, and a creatinine level of 0.5 mg/dL. Results of PCR tests of CMV in blood while on foscarnet therapy had improved from 600 copies/mL at admission to less than 300 copies/mL. PCR testing of CSF for CMV was unable to be performed.

The discharge medications included IV foscarnet, ART, PCP prophylaxis with TMP-SMX, and MAC prophylaxis with azithromycin. To improve her prognosis, we counseled her on adherence to all the prescribed medications and referred her to our dementia institute. However, the overall prognosis was poor due to AIDS and the second episode of CMV encephalitis. Thus, her family requested home hospice care after she completed foscarnet therapy.

NEXT: Discussion, Diagnosis, and Treatment

Discussion

CMV neurologic disease can involve the brain, spinal cord, dorsal column nerve roots, or peripheral nerves. CMV inclusions have been identified in neurons, astrocytes, oligodendrocytes, and capillary endothelia of neural tissue. Neurologic disease resulting from CMV occurs primarily in immunocompromised persons. For example, in one review of 676 patients with CMV encephalitis, 85% were HIV-positive and 12% had other causes of immunosuppression, while only 3% were immunocompetent.⁴ CMV end-organ disease results from the hematogenous spread of CMV. In patients with AIDS, the major risk factor for the development of CMV disease is the presence of CMV in blood that can be detected by culture testing, CMV DNA amplification, or antigen detection.⁵ Studies of transplant recipients and of patients with AIDS have indicated that CD4-dependent, CMV-specific, cytotoxic T-lymphocyte activity is critical for preventing CMV replication and end-organ disease.^6-8

Several cases of IRIS have been reported after initiation of potent ART in which encephalitis was the clinical manifestation and CMV infection of the central nervous system was the antigenic stimulus.^9,10 Our patient’s case would be an addition to these. Our patient was nonadherent with ART and developed CMV encephalitis only after a short period of restarting ART. Several small study series have shown that prior to the introduction of potent ART, the median survival of patients with CMV neurologic disease was less than 3 months.¹¹ Over several decades, ART has altered the natural history of CMV neurologic disease, with prolonged median survival reported in some patients, even if they initiate ART after receiving a diagnosis of CMV disease.¹²

CMV encephalitis usually presents with altered mental status that is very difficult to distinguish clinically from the dementia caused by HIV infection itself.⁴ However, delirium, confusion, and focal neurologic abnormalities are more commonly associated with CMV-related encephalitis rather than HIV-related dementia.¹¹ Patients with CMV ventriculoencephalitis present with a more acute onset of lethargy and confusion that is often accompanied by cranial nerve involvement. CMV neurologic disease should be considered in patients with AIDS who have a CD4 cell count below 50/µL and who present with these clinical features and/or have CMV infection elsewhere in the body. In patients with AIDS, it is common for CMV to involve the entire gastrointestinal (GI) tract. Patients with upper GI tract esophageal disease can present with painful dysphagia, while patients with lower GI tract involvement may present with colitis. In upper GI tract involvement, CMV can be isolated from esophageal ulcers, gastric ulcers, and duodenal ulcers. CMV colitis frequently affects only the right colon, necessitating full colonoscopy and multiple biopsies for accurate diagnosis.¹³

The evaluation typically includes MRI or contrast computed tomography (CT) of the brain, as well as CSF analysis (if there are no contraindications to lumbar puncture) for appearance, cell count, protein level, glucose level, and the presence of CMV DNA or antigen. Blood assays have poor sensitivity and specificity in detecting CMV DNA or antigen are not usually helpful.¹⁴ As was the case in our patient, many patients with extraocular CMV disease have prior or concurrent CMV retinitis. Thus, it is advisable for those diagnosed with CMV neurologic disease who are not already known to have retinitis to undergo ophthalmologic screening for retinitis. Examinations should be repeated at 6-month intervals until the patient’s absolute CD4 cell count has been restored to 100/µL or more on ART.

Diagnosis

The diagnosis of CMV-related disease is based on the clinical presentation and is supported by MRI or CT findings and/or the presence of CMV infection in the CSF through PCR assays or antigen testing. MRI or contrast CT must be performed to rule out toxoplasmosis, lymphoma, progressive multifocal leukoencephalopathy, or other intracranial pathology.¹⁵ Although it is not specific for CMV encephalitis, evidence of periventricular inflammation or meningeal enhancement on MRI supports the diagnosis. Case reports have demonstrated that MRI is not always sensitive enough to detect the presence of CMV encephalitis, even in severe cases.¹⁵ On the other hand, CMV DNA or CMV antigen detection (by PCR) in the CSF is highly sensitive and specific for CMV neurologic disease involving the brain.^16-18

Treatment

The initial treatment of patients with CMV neurologic disease depends on the degree of neurologic impairment as well as the patients’ ability to tolerate the regimen. For patients with severe CMV neurologic disease (eg, CMV encephalitis in a patient who is obtunded), the initial therapy should be IV ganciclovir and IV foscarnet dual therapy.¹⁴ The benefit of dual therapy for patients with severe CMV neurologic disease is based on findings of a trial showing better outcomes with combined ganciclovir and foscarnet in patients with relapsed CMV retinitis compared with patients who received monotherapy with either of these agents.¹⁹ The initial treatment of patients with mild CMV neurologic disease (eg, a patient with CMV polyradiculopathy or mononeuritis multiplex who has mild motor deficits) should include monotherapy with oral valganciclovir.¹⁴ Patients who are not able to tolerate oral medications should be given monotherapy with IV ganciclovir or IV foscarnet. Similarly, for individuals with severe disease who cannot tolerate dual therapy, monotherapy with IV ganciclovir or IV foscarnet should be considered, depending on which drug is better tolerated.¹⁴

Our patient had the UL97 and the UL54 mutations and thus was likely to be resistant to ganciclovir, as was proved by laboratory test results and the recurrent CMV infection while on a maintenance dose of valganciclovir; accordingly, we started her on IV foscarnet with a standard dosage schedule of 90 mg/kg every 12 hours.

Cidofovir is an alternative therapy for the treatment of CMV neurologic disease in patients who cannot tolerate ganciclovir, valganciclovir, and foscarnet.¹⁴ The drug regimens used for the treatment of CMV neurologic disease are described in Table 1. To reduce the risk of serious renal injury by cidofovir, saline hydration and high-dose probenecid therapy (which can block cidofovir uptake by proximal renal tubular cells) should be administered concomitantly with cidofovir.^20,21 The major adverse effects of the drugs used in the treatment of CMV neurologic disease are described in Table 2.

Continuing initial therapy with ganciclovir and/or foscarnet is recommended until significant improvement has occurred in the patient’s neurologic symptoms, which typically occurs after several weeks of treatment.²² After the patient has improved, anti-CMV treatment can be simplified to valganciclovir monotherapy, 900 mg/d.¹⁴ Several observational studies regarding the duration of maintenance therapy for patients with CMV retinitis have suggested that valganciclovir should be continued until the patient’s viral load has been suppressed and the CD4 cell count has increased to 100/µL or greater for at least 6 months.^23-26 Patients such as ours who are receiving foscarnet or cidofovir as initial therapy due to ganciclovir-resistant CMV infection should be rechallenged with oral valganciclovir for maintenance therapy if no severe complications developed related to ganciclovir (ie, hypersensitivity reaction, refractory bone marrow suppression, and nephrotoxicity).¹⁴ In our patient’s case, severe bone marrow suppression due to ganciclovir resulted in an improvement in cell counts after switching from ganciclovir to foscarnet. Therefore, valganciclovir was relatively contraindicated for maintenance therapy.

Patients who are receiving foscarnet as initial therapy and who are unable to tolerate valganciclovir should receive maintenance doses of foscarnet (90-120 mg/kg/d as a single infusion).¹⁴ Our patient was treated according to this guideline. Individuals receiving cidofovir as initial therapy should continue therapy every other week as long as no evidence of nephrotoxicity develops.¹⁴ According to the results of one recent study, high-dose valacyclovir can be a safe and cost-effective option for the preemptive treatment of CMV antigenemia in patients who have cytopenia, who are not eligible for ganciclovir, or who prefer outpatient treatment.²⁷

Other options for drug-resistant CMV infections are artesunate, maribavir, and leflunomide. Case reports indicate these drugs may result in viral suppression and clinical improvement in transplant patients with drug-resistant CMV infection.

The first evidence of the successful treatment of drug-resistant CMV infection with artesunate was reported in a 12-year-old hematopoietic stem cell transplant recipient, in whom the dose was 100 mg/d.²⁸ The authors of the report noted a 1.7- to 2.1-log reduction in the CMV viral load by treatment day 7. Artesunate may have inhibitory activity against nuclear factor κB and thus inhibit replication of CMV.²⁹

Maribavir is a direct UL97 kinase inhibitor and is not associated with hematologic or renal toxicity, unlike ganciclovir and foscarnet.³⁰ In a phase 2 study of maribavir prophylaxis for CMV infection in hematopoietic stem cell transplant recipients, patients receiving maribavir had a lower incidence of CMV antigenemia.³¹

Leflunomide is an immunosuppressive agent approved for the treatment of rheumatoid arthritis. It appears to inhibit virion assembly rather than DNA synthesis.³² One group of authors reported the successful use of leflunomide in a kidney transplant recipient with documented drug-resistant CMV retinitis.³³

NEXT: The Take-Home Message & References

The Take-Home Message

CMV encephalitis is one of the major causes of morbidity and mortality in patients who have AIDS or are otherwise immunocompromised. In our patient’s case, the development of CMV encephalitis as part of IRIS after restarting ART and the presence of recurrent CMV and HSV infections due to nonadherence to ART emphasize the importance of adherence to the ART regimen. We used several diagnostic modalities, such as brain MRI and CSF PCR assays for CMV, to support the clinical presentation.

Our patient developed recurrent CMV infection even while on prophylactic valganciclovir; when her CSF was tested for drug resistance pattern, she was found to have ganciclovir-resistant CMV encephalitis. We switched ganciclovir to foscarnet, and her pancytopenia began to improve. She was also started on raltegravir due to the high HIV viral load in her CSF sample. With foscarnet therapy, she began to show improvement of mental status and physical symptoms.

We conclude that foscarnet is an alternative treatment option for immunocompromised patients with ganciclovir-resistant CMV encephalitis. Agents such as cidofovir, artesunate, maribavir, and leflunomide can be considered when foscarnet is contraindicated. 

Niel N. Shah, MBBS, is at the Moffitt Cancer Center and Research Institute in Tampa, Florida.

Shuchi Pandya, MD, is an infectious disease fellow at the University of South Florida (USF) Morsani College of Medicine in Tampa, Florida.

Sowmya Nanjappa, MBBS, MD, is an assistant professor of internal medicine at the Moffitt Cancer Center and Research Institute and at the USF Morsani College of Medicine in Tampa, Florida.

Ana P. Velez, MD, is an associate professor of medicine at the Moffitt Cancer Center and Research Institute and at the USF Morsani College of Medicine in Tampa, Florida.

John N. Greene, MD, is a professor of medicine, chief of Division of Infectious Diseases and Tropical Medicine, and a hospital epidemiologist at Moffitt Cancer Center and Research Institute in Tampa, Florida.

References:

1. Gallant JE, Moore RD, Richman DD, Keruly J, Chaisson RE; Zidovudine Epidemiology Study Group. Incidence and natural history of cytomegalovirus disease in patients with advanced human immunodeficiency virus disease treated with zidovudine. J Infect Dis. 1992;166(6):1223-1227.
2. Baril L, Jouan M, Caumes E, Mengual X, Bricaire F, Katlama C. The impact of highly active antiretroviral therapy on the incidence of CMV disease in AIDS patients. In: Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 28-October 1, 1997; Toronto, Canada. Abstract I-31.
3. Hammer SM, Squires KE, Hughes MD, et al; AIDS Clinical Trials Group 320 Study Team. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med. 1997;337(11):725-733.
4. Arribas JR, Storch GA, Clifford DB, Tselis AC. Cytomegalovirus encephalitis. Ann Intern Med. 1996;125(7):577-587.
5. Shinkai M, Bozzette SA, Powderly W, Frame P, Spector SA. Utility of urine and leukocyte cultures and plasma DNA polymerase chain reaction for identification of AIDS patients at risk for developing human cytomegalovirus disease. J Infect Dis. 1997;175(2):302-308.
6. Rook AH, Manischewitz JF, Frederick WR, et al. Deficient, HLA-restricted, cytomegalovirus-specific cytotoxic T cells and natural killer cells in patients with the acquired immunodeficiency syndrome. J Infect Dis. 1985;152(3):​627-630.
7. Walter EA, Greenberg PD, Gilbert MJ, et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995;333(16):1038-1044.
8. Jacobson MA, Maecker HT, Orr PL, et al; Adult AIDS Clinical Trials Group and the Studies of Ocular Complications of AIDS Research Group. Results of a cytomegalovirus (CMV)-specific CD8⁺/interferon-γ⁺ cytokine flow cytometry assay correlate with clinical evidence of protective immunity in patients with AIDS with CMV retinitis. J Infect Dis. 2004;189(8):1362-1373.
9. French MA, Lenzo N, John M, et al. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Med. 2000;1(2):107-115.
10. Aboulafia DM, Taylor L. Vacuolar myelopathy and vacuolar cerebellar leukoencephalopathy: a late complication of AIDS after highly active antiretroviral therapy-induced immune reconstitution. AIDS Patient Care STDs. 2002;​16(12):579-584.
11. McCutchan JA. Cytomegalovirus infections of the nervous system in patients with AIDS. Clin Infect Dis. 1995;20(4):747-754.
12. Silva CA, Penalva de Oliveira AC, Vilas-Boas L, Fink MCDS, Pannuti CS, Vidal JE. Neurologic cytomegalovirus complications in patients with AIDS: retrospective review of 13 cases and review of the literature. Rev Inst Med Trop Sao Paulo. 2010;52(6):305-310.
13. Dieterich DT, Rahmin M. Cytomegalovirus colitis in AIDS: presentation in 44 patients and a review of the literature. J Acquir Immune Defic Syndr. 1991;​4(suppl 1):S29-S35.
14. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Rockville, MD: AIDSinfo, US Dept of Health and Human Services. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Updated October 18, 2017. Accessed December 12, 2017.
15. Clifford DB, Arribas JR, Storch GA, Tourtellote W, Wippold FJ. Magnetic resonance brain imaging lacks sensitivity for AIDS associated cytomegalovirus encephalitis. J Neurovirol. 1996;2(6):397-403.
16. Revello MG, Percivalle E, Sarasini A, Baldanti F, Furione M, Gerna G. Diagnosis of human cytomegalovirus infection of the nervous system by pp65 detection in polymorphonuclear leukocytes of cerebrospinal fluid from AIDS patients. J Infect Dis. 1994;170(5):1275-1279.
17. Arribas JR, Clifford DB, Fichtenbaum CJ, Commins DL, Powderly WG, Storch GA. Level of cytomegalovirus (CMV) DNA in cerebrospinal fluid of subjects with AIDS and CMV infection of the central nervous system. J Infect Dis. 1995;172(2):527-531.
18. Flood J, Drew WL, Miner R, et al. Diagnosis of cytomegalovirus (CMV) polyradiculopathy and documentation of in vivo anti-CMV activity in cerebrospinal fluid by using branched DNA signal amplification and antigen assays.J Infect Dis. 1997;176(2):348-352.
19. Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. Combination foscarnet and ganciclovir therapy vs monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS: the Cytomegalovirus Retreatment Trial. Arch Ophthalmol. 1996;114(1):23-33.
20. Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC Peripheral Cytomegalovirus Retinitis Trial: a randomized, controlled trial. Ann Intern Med. 1997;126(4):264-274.
21. Lalezari JP, Stagg RJ, Kuppermann BD, et al. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS: a randomized, controlled trial. Ann Intern Med. 1997;126(4):257-263.
22. Whitley RJ, Jacobson MA, Friedberg DN, et al; International AIDS Society-USA. Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. Arch Intern Med. 1998;158(9):957-969.
23. Jabs DA, Bolton SG, Dunn JP, Palestine AG. Discontinuing anticytomegalovirus therapy in patients with immune reconstitution after combination antiretroviral therapy. Am J Ophthalmol. 1998;126(6):817-822.
24. Macdonald JC, Karavellas MP, Torriani FJ, et al. Highly active antiretroviral therapy–related immune recovery in AIDS patients with cytomegalovirus retinitis. Ophthalmology. 2000;107(5):877-881.
25. Whitcup SM, Fortin E, Lindblad AS, et al. Discontinuation of anticytomegalovirus therapy in patients with HIV infection and cytomegalovirus retinitis. JAMA. 1999;282(17):1633-1637.
26. Macdonald JC, Torriani FJ, Morse LS, Karavellas MP, Reed JB, Freeman WR. Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy. J Infect Dis. 1998;​177(5):1182-1187.
27. Ong S-Y, Truong H-T-T, Diong CP, et al. Use of valacyclovir for the treatment of cytomegalovirus antigenemia after hematopoietic stem cell transplantation. BMC Hematol. 2015;15:8. doi:10.1186/s12878-015-0028-2
28. Shapira MY, Resnick IB, Chou S, et al. Artesunate as a potent antiviral agent in a patient with late drug-resistant cytomegalovirus infection after hematopoietic stem cell transplantation. Clin Infect Dis. 2008;46(9):1455-1457.
29. Efferth T, Romero MR, Wolf DG, Stamminger T, Marin JJG, Marschall M. The antiviral activities of artemisinin and artesunate. Clin Infect Dis. 2008;​47(6):804-811.
30. Trofe J, Pote L, Wade E, Blumberg E, Bloom RD. Maribavir: a novel antiviral agent with activity against cytomegalovirus. Ann Pharmacother. 2008;​42(10):1447-1457.
31. Winston DJ, Young J-AH, Pullarkat V, et al. Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-​ranging study. Blood. 2008;111(11):5403-5410.
32. Chacko B, John GT. Leflunomide for cytomegalovirus: bench to bedside. Transpl Infect Dis. 2012;14(2):111-120.
33. Levi ME, Mandava N, Chan LK, Weinberg A, Olson JL. Treatment of multidrug-resistant cytomegalovirus retinitis with systemically administered leflunomide. Transpl Infect Dis. 2006;8(1):38-43.