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Research Letter |

Long-term Suppression of Multidrug-Resistant Cytomegalovirus Retinitis With Systemically Administered Leflunomide FREE

Jeffrey H. Dunn, MD1; Adriana Weinberg, PhD2,3; Larry K. Chan, MD4; Naresh Mandava, MD1; Marilyn E. Levi, MD2; Jeffrey L. Olson, MD1
[+] Author Affiliations
1Department of Ophthalmology, Rocky Mountain Lions Eye Institute, University of Colorado School of Medicine, Aurora
2Division of Infectious Diseases, Department of Medicine, University of Colorado School of Medicine, Aurora
3Clinical Virology Laboratory, University of Colorado School of Medicine, Aurora
4Division of Renal Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora
JAMA Ophthalmol. 2013;131(7):958-960. doi:10.1001/jamaophthalmol.2013.1589.
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Cytomegalovirus (CMV) infection continues to affect outcomes in transplant recipients. Typical CMV antivirals, including ganciclovir sodium and its oral prodrug valganciclovir hydrochloride, foscarnet sodium, and cidofovir, are DNA polymerase inhibitors. Resistance of CMV to this class of drugs is an ongoing challenge. Alternative CMV antivirals include leflunomide and cytomegalovirus immunoglobulin.13

We report the follow-up of a renal transplant recipient who developed bilateral ganciclovir-resistant CMV retinitis that has been treated with leflunomide since July 2004.4

In March 2002, a 43-year-old CMV IgG–negative woman underwent cadaveric renal transplantation from a CMV IgG–positive donor. Despite valganciclovir prophylaxis, she developed CMV viremia with retinitis. She was placed on treatment doses of valganciclovir and was stable for 14 months. At month 18 following transplantation, she developed bilateral uveitis and reactivation CMV retinitis.

She was referred to the infectious diseases clinic at the University of Colorado and was initially treated with intravenous ganciclovir and CMV immunoglobulin. Intravenous foscarnet, oral valganciclovir, and weekly CMV immunoglobulin were initiated, with remission of the retinitis. Subsequent reactivation retinitis was treated with ganciclovir implantation5 without response. Weekly bilateral intraocular foscarnet injections were successful in the right eye only. Genotyping of the CMV showed UL97 and UL54 mutations, indicating resistance to ganciclovir, foscarnet, and cidofovir.6

The patient was placed on oral leflunomide, 20 mg/d, with persistent CMV retinitis in the left eye. The leflunomide dosage was increased to 40 mg/d, and fomivirsen sodium injections were administered in the left eye and continued weekly intravitreal foscarnet injections were administered in the right eye. Random serum and vitreous leflunomide levels were measured, at 24.2 and 4.1 µg/mL, respectively. She ultimately responded to leflunomide, 60 mg/d, with no further progression of CMV retinitis.

Weekly intravitreal foscarnet injections into her right eye and intravenous CMV immunoglobulin continued until May 2006, with resolution of retinitis. The leflunomide dosage was decreased to 40 mg/d. She underwent an uneventful cataract extraction in the right eye.

In September 2006, the patient presented with ocular inflammation that manifested as anterior chamber reaction and macular edema, thought to be immune recovery uveitis in the absence of CMV retinitis. She was treated with topical steroid eyedrops twice daily, an increased prednisone dosage to 60 mg/d, and an increased leflunomide dosage to 60 mg/d.

In April 2007, she developed an acute decrease in visual acuity of the right eye without floaters or pain. Her visual acuity without correction was 20/200 OD. Optical coherence tomography demonstrated an increase in macular edema on the right. The leflunomide dosage was increased to 80 mg/d and eventually 100 mg/d without improvement in macular edema, so the leflunomide dosage was decreased back to 60 mg/d.

In April 2010, she developed an acute decrease in visual acuity of the right eye from 20/200 to 20/400 due to an inferiorly dislocated intraocular lens. She underwent intraocular lens surgery and had stable vision as of April 2011 and no CMV reactivation or recurrent inflammation.

Multidrug-resistant CMV infection is a significant cause of morbidity and mortality among transplant recipients.4 Leflunomide has demonstrated activity against CMV2,3 and is also an immunosuppressive agent that may prevent solid-organ rejection.7 Leflunomide inhibits viral nucleocapsid and tegument development, suggesting that it is unlikely to share cross-resistance with DNA polymerase antivirals.2 Adverse reactions to leflunomide include hepatotoxic effects and immunosuppression.4 Our patient has tolerated this drug well with no reactivation of CMV retinitis for a 7-year period. The Table provides details of her clinical course.

Table Graphic Jump LocationTable.  Summary of Management of Cytomegalovirus Retinitis With Leflunomide in a Renal Transplant Recipient

Leflunomide monitoring is essential owing to significant variation in the terminal half-life of the active metabolite (A77 1726).4 Recommended serum levels range from 25 ng/mL to 80 µg/mL.1,2 We were able to demonstrate vitreous leflunomide levels correlating with suppression of CMV retinitis.

Corresponding Author: Marilyn E. Levi, MD, Division of Infectious Diseases, University of Colorado School of Medicine, 12700 E 19th Ave, Campus Box B168, Aurora, CO 80045 (marilyn.levi@ucdenver.edu).

Author Contributions:Study concept and design: Weinberg, Chan, Mandava, Levi.

Acquisition of data: Dunn, Weinberg, Chan, Levi.

Analysis and interpretation of data: Dunn, Weinberg, Chan, Levi, Olson.

Drafting of the manuscript: Dunn, Weinberg, Chan, Levi.

Critical revision of the manuscript for important intellectual content: Dunn, Chan, Mandava, Levi, Olson.

Statistical analysis: Chan.

Administrative, technical, and material support: Mandava, Olson.

Study supervision: Mandava, Levi.

Conflict of Interest Disclosures: None reported.

John  GT, Manivannan  J, Chandy  S,  et al.  A prospective evaluation of leflunomide therapy for cytomegalovirus disease in renal transplant recipients. Transplant Proc. 2005;37(10):4303-4305.
PubMed   |  Link to Article
Waldman  WJ, Knight  DA, Lurain  NS,  et al.  Novel mechanism of inhibition of cytomegalovirus by the experimental immunosuppressive agent leflunomide. Transplantation. 1999;68(6):814-825.
PubMed   |  Link to Article
Avery  RK, Mossad  SB, Poggio  E,  et al.  Utility of leflunomide in the treatment of complex cytomegalovirus syndromes. Transplantation. 2010;90(4):419-426.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
Kuo  IC, Imai  Y, Shum  C, Martin  DF, Kuppermann  BD, Margolis  TP.  Genotypic analysis of cytomegalovirus retinitis poorly responsive to intravenous ganciclovir but responsive to the ganciclovir implant. Am J Ophthalmol. 2003;135(1):20-25.
PubMed   |  Link to Article
Drew  WL.  Cytomegalovirus resistance testing: pitfalls and problems for the clinician. Clin Infect Dis. 2010;50(5):733-736.
PubMed   |  Link to Article
Williams  JW, Javaid  B, Kadambi  PV,  et al.  Leflunomide for polyomavirus type BK nephropathy. N Engl J Med. 2005;352(11):1157-1158.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable.  Summary of Management of Cytomegalovirus Retinitis With Leflunomide in a Renal Transplant Recipient

References

John  GT, Manivannan  J, Chandy  S,  et al.  A prospective evaluation of leflunomide therapy for cytomegalovirus disease in renal transplant recipients. Transplant Proc. 2005;37(10):4303-4305.
PubMed   |  Link to Article
Waldman  WJ, Knight  DA, Lurain  NS,  et al.  Novel mechanism of inhibition of cytomegalovirus by the experimental immunosuppressive agent leflunomide. Transplantation. 1999;68(6):814-825.
PubMed   |  Link to Article
Avery  RK, Mossad  SB, Poggio  E,  et al.  Utility of leflunomide in the treatment of complex cytomegalovirus syndromes. Transplantation. 2010;90(4):419-426.
PubMed   |  Link to Article
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.
PubMed   |  Link to Article
Kuo  IC, Imai  Y, Shum  C, Martin  DF, Kuppermann  BD, Margolis  TP.  Genotypic analysis of cytomegalovirus retinitis poorly responsive to intravenous ganciclovir but responsive to the ganciclovir implant. Am J Ophthalmol. 2003;135(1):20-25.
PubMed   |  Link to Article
Drew  WL.  Cytomegalovirus resistance testing: pitfalls and problems for the clinician. Clin Infect Dis. 2010;50(5):733-736.
PubMed   |  Link to Article
Williams  JW, Javaid  B, Kadambi  PV,  et al.  Leflunomide for polyomavirus type BK nephropathy. N Engl J Med. 2005;352(11):1157-1158.
PubMed   |  Link to Article

Correspondence

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