International http://std.sagepub.com/ Journal of STD & AIDS

Management of ganciclovir-resistant cytomegalovirus retinitis in HIV infection in the era of antiretroviral therapy Hugh Adler, Cillian F De Gascun, Fionnuala McSweeney, Robert W Acheson, Eimear T Brannigan, Margaret Duffy, David J Keegan and John S Lambert Int J STD AIDS 2014 25: 827 originally published online 10 February 2014 DOI: 10.1177/0956462414522773 The online version of this article can be found at: http://std.sagepub.com/content/25/11/827

Published by: http://www.sagepublications.com

Additional services and information for International Journal of STD & AIDS can be found at: Email Alerts: http://std.sagepub.com/cgi/alerts Subscriptions: http://std.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav

>> Version of Record - Sep 22, 2014 OnlineFirst Version of Record - Feb 10, 2014 What is This?

Downloaded from std.sagepub.com at Univ of Illinois at Chicago Library on November 11, 2014

Case report

Management of ganciclovir-resistant cytomegalovirus retinitis in HIV infection in the era of antiretroviral therapy

International Journal of STD & AIDS 2014, Vol. 25(11) 827–829 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462414522773 std.sagepub.com

Hugh Adler1, Cillian F De Gascun2,3, Fionnuala McSweeney1, Robert W Acheson4, Eimear T Brannigan1, Margaret Duffy2, David J Keegan4 and John S Lambert1,3

Abstract The incidence of cytomegalovirus retinitis has decreased significantly since the advent of antiretroviral therapy. However, it remains an important problem in both the developed and developing worlds. Furthermore, long-term antiviral suppression is associated with a significant increase in viral resistance. We present the case of a 46-year-old man who developed cytomegalovirus retinitis one year after being diagnosed with HIV. While he initially demonstrated an excellent clinical response to ganciclovir, his cytomegalovirus viral load remained persistently elevated. Over the subsequent years, his virus developed ganciclovir resistance with a concomitant deterioration in his visual acuity. He responded poorly to salvage therapy with foscarnet and cidofovir. This case highlights the ongoing difficulty of managing cytomegalovirus disease nearly two decades into the era of antiretroviral therapy and underlines the need to develop new treatment strategies.

Keywords Cytomegalovirus, resistance, ganciclovir, retinitis, opportunistic infection, CMV, HIV, AIDS, treatment Date received: 11 November 2013; accepted: 2 January 2014

Background Prior to the advent of antiretroviral therapy (ART), cytomegalovirus (CMV) caused systemic disease in up to 30% of AIDS patients.1 The availability of ART has resulted in an 80% decrease in incidence of CMV retinitis since 1996. There is a lifelong risk of viral reactivation and disease recurrence in patients with low CD4 counts, necessitating long-term maintenance antiviral therapy, which in turn may lead to the development of drug-resistant CMV.2,3 We present a case that highlights the ongoing difficulty in managing such patients 17 years into the era of ART.

Case A 46-year-old Irish man presented with pyrexia and diarrhoea. One year before he had been diagnosed with HIV following an initial diagnosis of nonHodgkin’s lymphoma; he was taking tenofovir,

emtricitabine and efavirenz as well as co-trimoxazole and azithromycin prophylaxis. CD4 count was 8 cells/mm3, with an HIV viral load (VL) of 91 copies/ml (cpm). Blood, sputum, urine, stool and cerebrospinal fluid were cultured; all were negative. Plasma CMV DNA testing revealed a significant VL of 161,000 cpm (log 5.2). No visual symptoms were reported, visual acuity (VA) was 6/9 bilaterally but ophthalmology 1 Department of Infectious Diseases, Mater Misericordiae University Hospital, Dublin, Ireland 2 National Virus Reference Laboratory, University College Dublin, Ireland 3 School of Medicine and Medical Science, University College Dublin, Ireland 4 Department of Ophthalmology, Mater Misericordiae University Hospital, Dublin, Ireland

Corresponding author: John S Lambert, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland. Email: [email protected]

Downloaded from std.sagepub.com at Univ of Illinois at Chicago Library on November 11, 2014

828

International Journal of STD & AIDS 25(11)

review confirmed a diagnosis of CMV retinitis (most prominent in the right inferotemporal quadrant) and bilateral HIV retinopathy. Ganciclovir (GCV) 5 mg/kg BD was administered intravenously (IV) for 21 days followed by oral valganciclovir (VGCV) maintenance of 900 mg BD orally. Subsequent review by ophthalmology documented resolving inflammatory exudate, but no evidence of active retinitis or recent haemorrhage. CD4 count was 57 and HIV VL undetectable, but CMV VL remained significant at 52,100 cpm (log 4.7) – hence, prophylactic oral VGCV was continued. Two years later, his vision deteriorated to VA 6/24 bilaterally and ophthalmology review revealed uveitis and bilateral retinal changes consistent with reactivation of CMV. CD4 count was 86, HIV was undetectable; CMV VL was 4685 cpm (log 3.7). Antiviral resistance was suspected at this time, and UL97 gene sequencing revealed an L595S mutation conferring resistance to GCV. IV foscarnet 5 g BD was administered for 21 days, and a GCV implant was inserted into the left eye. CMV VL after three weeks of therapy was 74 cpm (log 1.9). Attempted weekly cidofovir maintenance was unsuccessful due to nephrotoxicity, and the patient declined a GCV implant in the contralateral eye, so oral VGCV was recommenced. However, CD4 count failed to rise above 100 cells/mm3. VGCV-induced myelosuppression was suspected and VGCV was empirically discontinued; CD4 count subsequently rose to >300 cells/mm3, obviating the need for long-term prophylaxis. Seven years after his diagnosis, he remains functionally blind (VA 6/60 in the right eye, 6/24 in the left), with both HIV and CMV virally suppressed.

Discussion Reports of drug-resistant clinical isolates of CMV first appeared in 1989, and studies subsequently identified resistance-associated mutations in both the UL97 kinase gene and the UL54 Pol gene. Over 90% of clinical GCV-resistant isolates contain mutations at one or more of the following UL97 codons: 460; 520 or 591 to 607, including the L595S mutation seen in our patient.4 Mutations in the UL54 Pol gene may confer resistance to different antivirals. GCV (and cidofovir) resistance is seen with mutations N408D, F412C, D413E, L501F/I, K513R/E and A987G, and foscarnet resistance with T700A, V715M, V781I, L802M and A809V (among others). Some Pol mutations – at positions 782, 802 and 809 – confer resistance to both foscarnet and GCV. By the mid-1990s, the incidence of GCV resistance was 25% at one year after diagnosis of retinitis in patients with AIDS, the rate of resistance increasing with duration of therapy.4 ART reduced the incidence of CMV by 80% and of resistance by 67%.1 It also reduced the rates of CMV disease progression, second

eye involvement, retinal detachment and blindness.3 The GCV vitreous implant was approved in 1996, resulting in a significantly longer time to first progression when compared with IV GCV.1 By delivering highdose GCV directly to the retina, the GCV implant appears to reduce retinitis progression even in the presence of systemic GCV-resistant CMV.5 One hypothesis proposed to explain this effect is that there may be multiple circulating CMV strains, some of which remain GCV-susceptible.6 However, the implant is no longer available. Foscarnet and cidofovir are well-established secondline treatments for CMV retinitis.7 There are few options available in patients who do not tolerate these agents. While both can be administered as intravitreal injections, these preparations are not licensed in our jurisdiction and our unit had no experience with them at the time of our patient’s presentation. In addition, our patient declined further intraocular treatment following his first GCV implant. Therefore, in order to provide ongoing systemic anti-CMV coverage, we elected to continue oral VGCV, although we were uncertain how effective this would prove, and indeed full immune recovery did not occur until VGCV was discontinued for good. Immune recovery is the ultimate goal of treating CMV retinitis in HIV patients, as maintenance therapy can be discontinued in patients whose CD4 counts increase to >100 cells/mm3 for a sustained period.8 While CMV retinitis may still reactivate in a small proportion of these patients, the risk is low (0.03 events/ person-year).9 In these individuals, there seems to be a selective loss of immunity to CMV, as evidenced by the absence of an immune response to CMV antigens,10 and also by the fact that there appears to be no level of CD4 count above which CMV reactivation cannot occur.3 In the case presented here, the commencement of antivirals resulted in rapid improvement in retinitis. However, the drop in CMV VL following three weeks of GCV was sub-optimal. While we acknowledge routine CMV VL monitoring is not recommended,11 we believe this should be the case in the early stages of treatment – both to document a definitive response to antiviral therapy and to alert treating physicians to the possibility of treatment failure and/or the occurrence of resistance. This issue has substantial global implications. CMV is absent from current World Health Organisation guidelines for the management of HIV in resourcelimited settings, despite CMV disease manifestations in 5% to 25% of HIV-infected individuals in the developing world.12,13 Strategies involving the provision of GCV, VGCV and newer anti-CMV agents to patients in the developing world need to be devised.

Downloaded from std.sagepub.com at Univ of Illinois at Chicago Library on November 11, 2014

Adler et al.

829

Conclusions Significant advances in HIV have been made in the management of CMV retinitis and other opportunistic infections since the introduction of ART. However, we believe it is important that CMV retinitis and systemic disease due to drug-resistant virus be identified as a significant issue that needs to be comprehensively addressed, as it is a re-emerging pathogen in both the developed and developing worlds. Conflict of interest The authors declare no conflict of interest.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References 1. Holland GN. AIDS and ophthalmology: the first quarter century. Am J Ophthalmol 2008; 145: 397–408. 2. Jabs DA, Martin BK, Ricks MO, et al. Detection of ganciclovir resistance in patients with AIDS and cytomegalovirus retinitis: correlation of genotypic methods with viral phenotype and clinical outcome. J Infect Dis 2006; 193: 1728–1737. 3. Jabs DA, Van Natta ML, Thorne JE, et al. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: 1. Retinitis progression. Ophthalmology 2004; 111: 2224–2231. 4. Lurain NS and Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev 2010; 23: 689–712. 5. Jabs DA, Martin BK, Forman MS, et al. Cytomegalovirus resistance to ganciclovir and clinical outcomes of patients with cytomegalovirus retinitis. Am J Ophthalmol 2003; 135: 26–34.

6. Bakshi NK, Fahle GA, Sereti I, et al. Cytomegalovirus retinitis successfully treated with ganciclovir implant in a patient with blood ganciclovir resistance and ocular ganciclovir sensitivity. Eye (London, England) 2012; 26: 759–760. 7. 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, http://aidsinfo.nih.gov/contentfiles/lvguidelines /adult_oi.pdf (accessed 17 December 2013). 8. Jouan M, Saves M, Tubiana R, et al. Discontinuation of maintenance therapy for cytomegalovirus retinitis in HIV-infected patients receiving highly active antiretroviral therapy. AIDS (London, England) 2001; 15: 23–31. 9. Walmsley SL, Raboud J, Angel JB, et al. Long-term follow-up of a cohort of HIV-infected patients who discontinued maintenance therapy for cytomegalovirus retinitis. HIV Clin Trials 2006; 7: 1–9. 10. Johnson SC, Benson CA, Johnson DW, et al. Recurrences of cytomegalovirus retinitis in a human immunodeficiency virus-infected patient, despite potent antiretroviral therapy and apparent immune reconstitution. Clin Infect Dis 2001; 32: 815–819. 11. Jabs DA, Martin BK, Forman MS, et al. Cytomegalovirus (CMV) blood DNA load, CMV retinitis progression, and occurrence of resistant CMV in patients with CMV retinitis. J Infect Dis 2005; 192: 640–649. 12. Heiden D, Ford N, Wilson D, et al. Cytomegalovirus retinitis: the neglected disease of the AIDS pandemic. PLoS Med 2007; 4: e334. 13. Ford N, Shubber Z, Saranchuk P, et al. Burden of HIVrelated cytomegalovirus retinitis in resource-limited settings: a systematic review. Clin Infect Dis 2013; 57: 1351–1361.

Downloaded from std.sagepub.com at Univ of Illinois at Chicago Library on November 11, 2014

Management of ganciclovir-resistant cytomegalovirus retinitis in HIV infection in the era of antiretroviral therapy.

The incidence of cytomegalovirus retinitis has decreased significantly since the advent of antiretroviral therapy. However, it remains an important pr...
110KB Sizes 0 Downloads 0 Views