5.5 CMV RETINITIS AND OTHER DISEASES
I. Epidemiology and clinical course
Cytomegalovirus (CMV) disease is a common and potentially debilitating condition, occurring in 21-44% of AIDS patients in western countries before the era of highly active antiretroviral therapy (HAART). The most frequent presentation is retinitis which accounted for 75-85% of the diseases1 while gastrointestinal (colitis, esophagitis), respiratory (pneumonitis), and neurological (encephalitis, polyradiculopathy) diseases can also occur. However, similar to most opportunistic infections occurring in HIV-infected patients, the incidence of CMV retinitis has come down after the institution of HAART.
Floaters, loss of visual fields, and blurring of vision are the commonest presentations of CMV retinitis, which mostly occur in patients with CD4 count <50-100/ul.2 Without CMV-specific treatment the retinitis invariably progresses and it can lead to blindness.3 Blindness can result from macular involvement or retinal detachment that is caused by extensive peripheral retinitis.4
There have been reports of CMV retinitis presenting soon after the initiation of HAART, which may be due to the unmasking of subclinical CMV retinal infection by a HAART-induced immune inflammatory response.5 In addition, sight-threatening immune recovery vitritis has been described in HAART responders with inactive CMV retinitis.6
In Hong Kong, CMV diseases, primarily retinitis, contributed to some 5-6% of the primary AIDS-defining illnesss (ADI) and was the commonest subsequent ADI.7
II. Diagnosis of CMV retinitis
II.A High index of suspicion
Owing to the potential serious impact on vision, prompt diagnosis followed by treatment is essential, especially for patients with near macular involvement of the retinitis. Diagnosis of CMV diagnosis is a clinical one. Health care providers should be on the alert for symptoms and signs of CMV retinitis, more so if the patient has visual complaints or the CD4 count is <50-100/ul.
Primary prophylaxis against CMV is currently unavailable. All HIV-infected patients shall learn about the symptoms of CMV retinitis during their early visits and the need to inform their health care providers should such symptoms arise. They are to be reminded again if their CD4 count falls below 50-100/ul. In this case, regular indirect ophthalmoscopy by an ophthalmologist shall be considered.8 Also, it is necessary to look out for "precipitation" of CMV retinitis after initiation of HAART in advanced HIV disease patients.
II.B Differential diagnosis
When CMV retinitis is suspected, urgent referral for ophthalmologist assessment and confirmation is warranted before initiating anti-CMV treatment. The objective is to primarily establish a baseline to monitor treatment and to exclude conditions such as herpetic retinal necrosis, toxoplasma retinochoroiditis, cryptococcal choroiditis, large cell lymphoma, candidiasis, syphilitic uveitis and Pneumocystis carinii choroiditis.
III. Treatment of CMV retinitis
Despite the threats associated with CMV disease, several effective drugs are available for its treatment and prevention of relapse. Also, the advent of HAART has modified the management (besides its natural history) of CMV disease in HIV-infected patients.
III.A Treatment goal
The objectives of managing CMV retinitis are to minimize its potential morbidity, mortality and impact to the quality of life (especially blindness/impaired vision) of the patient. This could be achieved through early diagnosis, timely treatment, appropriate maintenance therapy and monitoring for relapse of the disease.
III.B Treatment modalities
The benefit of drug treatment of CMV retinitis has to be balanced against its side effects and tolerance of patient. Standard treatment starts with induction therapy of anti-CMV drugs to halt progression and induce resolution of the retinitis. It aims at preserving vision and preventing complication of retinitis, in particular retinal detachment. Maintenance therapy generally follows to prevent further retinal necrosis, which can occur in 2-6 weeks if therapy is stopped.9
Based on the managing principles, care of each patient should be tailored according to his/her specific needs. Treatment regimen shall be discussed with the patient and chosen according to characteristics of the retinitis, patient's work and living conditions, family support, concomitant drugs, and contraindications to each potential drug. The features of various anti-CMV drugs are listed (see Box 5.8). In general, IV ganciclovir, IV foscarnet and IV cidofovir are all appropriate initial choices for induction and maintenance therapy. However, cidofovir is a more convenient first line drug as it requires only weekly induction, followed by bi-weekly maintenance administration. This obviates the need of having long-term intravenous access as is the case with IV ganciclovir or foscarnet. If IV foscarnet is used for maintenance, the patient should have access to an infusion pump to avoid dangerous electrolyte disturbance.
Oral ganciclovir alone should not be used for induction treatment. However, it can be considered for maintenance therapy when other options are not feasible. And it should be considered only for cases with peripheral retinitis under regular ophthalmologic supervision. Those with single eyes should not rely on oral ganciclovir. The concern is the poor bioavailability of oral ganciclovir.
Treatment response to the anti-CMV drugs should be assessed by the ophthalmologist. A course of 2- to 3-week induction treatment shall be given until satisfactory response is noted. Maintenance therapy follows. Close monitoring for relapse of retinitis or involvement of the fellow eye (if not yet affected) by the ophthalmologist is a must. The sequelae of retinitis and impact on work and daily living activities of the patient shall be assessed. It is useful to maintain good communication with the ophthalmologist for joint management of patients with CMV retinitis. The nursing team can definitely help in clinical care, health counseling and psychological support of the patient. Medical social worker comes in for mobilization of community resources.
Ganciclovir implant is a useful alternative for those who cannot tolerate systemic treatment. By releasing a high local concentration of ganciclovir, it controls CMV retinitis with little toxicity. The drawbacks are:
III.C Relapsing/refractory retinitis
Prior to the era of HAART, almost all patients had relapse of CMV retinitis despite long term suppressive therapy. Others might have disease refractory to initial CMV treatment. Management of relapsing or refractory retinitis is difficult and should be individualized according to initial/previous response to therapy, concomitant medical conditions, characteristics of retinitis, immunologic and virologic status, and expertise of specialized treatment available. Adherence to maintenance therapy should be reassessed for relapsed cases.
For relapse while on IV ganciclovir or foscarnet maintenance, re-induce with the maintenance drug or switch to the other drug has similar efficacy.10 Re-induction with cidofovir is also effective for relapse on maintenance with IV ganciclovir, IV foscarnet or cidofovir maintenance.
Refractory disease during initial treatment or upon relapse with monotherapy requires combination therapy. Combination of IV ganciclovir and foscarnet has been shown to be superior to using either alone in treating relapse.9 In vitro data suggests synergistic inhibition of CMV when cidofovir is combined with ganciclovir or foscarnet.9 Ganciclovir ocular implant or intravitreal ganciclovir/foscarnet injection can be considered if expertise for such treatment is available. Either of these two treatments can be given alone or in supplementation to IV therapy.
III.D Discontinuation of maintenance therapy
Evidence is strong that maintenance therapy can be stopped in patients who responded to HAART with good CD4 response (>100/ul).11,12 Withdrawal of maintenance therapy may thus be considered if all of the following criteria are met: (a) CD4 count >100-150/ul for 3-6 months, (a) vision adequate in contralateral eye, (c) undetectable plasma viral load for >3-6 months, (d) patient can attend regular ophthalmic examination.7 Of course, the CD4 and plasma viral load of the patients should be regularly monitored too. Risks and benefits of withdrawing secondary prophylaxis need to be explained to the patient. Some doctors may prefer a higher threshold of CD4, e.g. >200/ul for > 6 months, and an adequate vision (after treatment) of both eyes before withdrawing maintenance therapy.
IV. Other CMV diseases
CMV diseases of gastrointestinal tract, respiratory tract and central nervous system are to be suspected when clinical presentation is suggestive. Definitive diagnosis of end-organ CMV diseases is evidenced by the presence of CMV inclusion bodies and/or tissue damage in biopsy specimens. In these circumstances the risk of CMV retinitis is high and ophthalmologic assessment is indicated even when there are no visual symptoms.
Induction treatment with IV ganciclovir or foscarnet for 3-6 weeks is often indicated. A combination of the two drugs may be considered for CMV encephalitis or polyradiculopathy and in patients who have received prior anti-CMV therapy.13 Maintenance therapy is generally not necessary for non-retinal CMV diseases unless there is relapse.
References