An interesting case of first presentation CMV retinitis.

INTRODUCTION

Before the widespread introduction of highly active antiretroviral therapy (HAART), cytomegalovirus (CMV) retinitis was a frequent opportunistic infection in patients with advanced HIV infection [1,2]. CMV is a DNA herpesvirus, which can reactivate causing disease, but typically only at CD4 cell counts less than 50 cells/[mm.sup.3]. CMV retinitis is associated with a high mortality [3]. With the availability of HAART in developed nations, the incidence has now decreased. For patients with low CD4 cell counts, it remains an important cause of morbidity [4]. We present an unusual case of CMV retinitis occurring less than 6 weeks after commencing HAART, in a patient with no signs of CMV disease at baseline ophthalmology assessment, and with a CD4 count of 280 cells/[mm.sup.3] at the time of presentation.

CASE REPORT

A 37-year-old homosexual man, living in London, presented to a sexual health clinic in 2006 complaining of rectal pain. He was diagnosed clinically with herpes proctitis and treated with aciclovir tablets. As he had never previously had an HIV test, it was suggested that he had a rapid point-of-care HIV test (POCT, Abbott Diagnostics). This test was reactive and HIV-1 infection was confirmed on further antibody tests.

Baseline investigations revealed a CD4 count of 110 cells/[mm.sup.3] (19%) and HIV viral load (HIV VL) of 149,267 copies/ml. An HIV genotype test showed no evidence of transmitted drug resistance and an HLA-B*5701 allele test was negative. Other routine blood tests (including renal, liver, bone profile and full blood count analyses) were unremarkable.

The following week, he complained of a painless rash that had developed on his trunk and limbs over the past 2 months. On examination he had five purple, shiny, raised lesions on the shoulder, chest, and hard palate. These were consistent with a clinical diagnosis of Kaposi's sarcoma (however, no biopsy was taken).

A routine ophthalmology assessment (with dilated fundoscopy), arranged due to his low baseline CD4 cell count, found visual acuity (VA) of 6/9 bilaterally and a small cotton-wool spot on the right side. No active disease was noted.

The patient commenced Kivexa (abacavir and lamivudine) one tablet once daily, and Kaletra (lopinavir/ritonavir) two tablets twice daily. He was monitored for adherence and signs of toxicity.

Five weeks after starting HAART his CD4 lymphocyte count had increased to 280 cells/[mm.sup.3] (33%). His HIV VL had fallen to 1011 copies/ml. He presented at this stage complaining of a 5-day history of blurred vision, flashing lights and a new 'blind spot'. He had no neurological signs on examination, but ophthalmological assessment found a large upper central scotoma on the right side. Visual acuity was now 6/18 on this side. Dilated fundoscopy revealed a new large infero-temporal area of haemorrhagic retinitis, with exudates and vasculitis (Figure 1). The left side was clear. These appearances were consistent with a first presentation of CMV retinitis. Blood CMV PCR was 332,648 copies/ml (this had not previously been tested).

He was commenced on fortnightly intravenous cidofovir infusions (three doses, each at 5mg/kg) and his renal function remained stable. HAART was continued throughout. After completing this treatment, the area of retinal scarring had regressed (Figure 2) and he commenced valganciclovir maintenance therapy 900mg once daily. His CD4 count was 350 cells/[mm.sup.3] (25%) and HIV VL 361 copies/ml. The presumed Kaposi's sarcoma lesions had entirely resolved.

Unfortunately, the following month, due to a combination of personal factors (bereavement) and troublesome diarrhoea, the patient elected to stop taking all therapy. Within 4 weeks of stopping HAART, his CD4 count decreased to 220 cells/[mm.sup.3] (17%) and HIV VL rebounded to 138,274 copies/ml. There was no demonstrable drug resistance on HIV genotype testing. He began to notice flashing lights again, accompanied by visual 'floaters'. Ophthalmology review revealed no progression or reactivation of the scarred areas.

He restarted CMV secondary prophylaxis and HAART. Initially this was Kivexa (abacavir and lamivudine) with efavirenz, but this was changed due to central nervous system (CNS) side-effects (vivid dreams, disturbed sleep and morning dizziness). He was switched to nevirapine therapy and within 12 weeks had an HIV VL of <50 copies/ml and a CD4 count of 700 cells/[mm.sup.3] (30%). At this stage he discontinued valganciclovir prophylaxis having received it for 6 months in total.

DISCUSSION

CMV retinitis usually occurs in patients with CD4 counts less than 50 cells/[mm.sup.3] and is rare at CD4 counts over 100 cells/[mm.sup.3] [5]. It generally causes a progressive necrotising retinitis with mild inflammation. Without treatment it can eventually cause blindness, scarring and retinal detachment [6].

[FIGURE 1 OMITTED]

In the pre-HAART era treatment involved the prompt use of drugs with anti-CMV activity. This was initially successful in the majority of cases. However, without treatment of the underlying immunosuppression, most cases relapsed (even in the presence of secondary prophylaxis) [6]. Despite re-treatment many patients deteriorated and retinal detachment occurred in up to 28% of patients [3,7].

The widespread availability of HAART has significantly decreased the rates of opportunistic infections, including CMV retinitis [3]. Patients usually receive treatment before their CD4 count falls below 50 cells/[mm.sup.3], even if diagnosed with another AIDS-defining event. HAART has also enabled secondary CMV prophylaxis to be discontinued (depending on clinical progress), and this decision is usually guided by a sustained CD4 count of greater than 100 cells/[mm.sup.3] for at least 3 months [8,9].

The use of HAART has also led to increased reports of immune recovery uveitis (IRU), which behaves as an immune restoration disorder [10]. This is an inflammatory condition, characterised by vitritis, and can cause optic nerve and macular oedema. It is associated with the rapid decline in HIV VL and increase in CD4 cell count, which can occur soon after starting HAART. In such cases, eyes with underlying inactive, or previously treated, CMV retinitis develop intraocular inflammation causing visual deterioration or floaters [11]. Such patients do not usually have a positive serum CMV PCR at the time of diagnosis [12].

In this case several factors suggest this was a first presentation of CMV retinitis, 5 weeks after commencing HAART, rather than IRU. First, the patient had no prior history of CMV retinitis or treatment, before starting HAART, and a sole cotton-wool spot was found on baseline assessment. When he developed visual symptoms a haemorrhagic retinitis was found (rather than vitritis and inflammation). Furthermore he had a positive blood CMV PCR. It is, however, most unusual for a first presentation of CMV end-organ disease to occur at this CD4 count of 280 cells/[mm.sup.3].

[FIGURE 2 OMITTED]

Treatment of CMV retinitis requires an agent with anti-CMV activity (both as primary treatment and then secondary prophylaxis), and also adherence to HAART. Anti-CMV therapy exists in various forms (intravenous, oral and intravitreal) and includes ganciclovir, valganciclovir, foscarnet and cidofovir. Selection is based on extent/severity of eye lesion(s), renal and haematological profile, and should be reviewed regularly in conjunction with an ophthalmologist.

In this case adherence to HAART was probably negatively affected by the dramatic clinical deterioration occurring so soon after initiation of treatment. The patient associated his visual loss with antiretroviral therapy. Also the decision to discontinue secondary prophylaxis was difficult, as the usual CD4 cell count guide could not be followed. Instead the decision was made clinically, when all areas of retinitis had regressed, and by which stage the patient's CD4 count was greater than 500 cells/[mm.sup.3].

Incidence of CMV retinitis in the developed world is decreasing and treatment including HAART is effective. However, clinicians should remain vigilant to this debilitating disease in late-presenters and patients unable to adhere to HAART. Clinicians should also consider the complication of IRU in any patient with new visual disturbance in the months after starting HAART. This case illustrates the unpredictable nature of opportunistic infections, and reminds us that the plasma CD4 cell count is not always an accurate predictor of underlying immune status and risk of disease. New visual symptoms in an HIV-positive patient, particularly visual loss, blurring or floaters should continue to warrant urgent ophthalmological assessment, regardless of CD4 cell count. Furthermore, it re-emphasises the need for patients with an AIDS-defining event, or low CD4 cell count at presentation, to have an ophthalmological review as part of routine care.

REFERENCES

[1.] Gallant JE, Moore RD, Richman DD et al. Incidence and natural history of cytomegalovirus disease in patients with advanced human immunodeficiency virus disease treated with zidovudine. J Infect Dis, 1992, 166, 1223-1227.

[2.] Jabs DA. Ocular manifestations of HIV infection. Trans Am Ophthalmol Soc, 1995, 93, 623-683.

[3.] Hoover DR, Peng Y, Saah A et al. Occurrence of cytomegalovirus retinitis after human immunodeficiency virus immunosuppression. Arch Ophthalmol, 1996, 114, 821-827.

[4.] Salmon-Ceron D, Mazeron MC, Chaput S et al. Plasma cytomegalovirus DNA, pp65 antigenaemia and a low CD4 cell count remain risk factors for cytomegalovirus disease in patients receiving highly active antiretroviral therapy. AIDS, 2000, 14, 1041-1049.

[5.] Kuppermann BD, Petty JG, Richman DD et al. Correlation between CD4+ counts and prevalence of cytomegalovirus retinitis and human immunodeficiency virus-related noninfectious retinal vasculopathy in patients with acquired immunodeficiency syndrome. Am J Ophthalmol, 1993, 115, 575-582.

[6.] Williams IG. Management of CMV disease in HIV infection. Int J STD AIDS, 1999, 10, 211-218.

[7.] Sandy CJ, Bloom PA, Graham EM et al. Retinal detachment in AIDS-related cytomegalovirus retinitis. Eye, 1995, 9, 277-281.

[8.] Whitcup SM. Cytomegalovirus retinitis in the era of highly active antiretroviral therapy. J Am Med Assoc, 2000, 283, 653-657.

[9.] Berenguer J, Gonzalez J, Pulido F, et al.; Madrid Group for the Study of Discontinuation of Secondary Prophylaxis in Patients with CMV Retinitis. Discontinuation of secondary prophylaxis in patients with cytomegalovirus retinitis who have responded to highly active anti-retroviral therapy. Clin Infect Dis, 2002, 34, 394-397.

[10.] Holland GN. Immune recovery uveitis. Ocul Immunol Inflamm, 1999, 7, 215-221.

[11.] Karavellas MP, Lowder CY, Macdonald C et al. Immune recovery vitritis associated with inactive cytomegalovirus retinitis: a new syndrome. Arch Ophthalmol, 1998, 116, 169-175.

[12.] Kempen JH, Min YI, Freeman WR et al. Risk of immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis. Ophthalmology, 2006, 113, 684-694.

Correspondence to: Dr Lucy Garvey, The Jefferiss Wing, St Mary's Hospital, Praed St, London W2 1NY, UK. Email: [e-mail]