Part 4 • Infectious Uveitic Conditions

Chapter 11 Acquired Immunodeficiency Syndrome

through the pars plana. The mean time to progression with this implant is 226 days, with about 50% of untreated contralateral eyes developing CMV retinitis during the study.31 The efficacy of this device for treating local CMV retinitis is clear, but the implant does not treat systemic CMV infection or prevent occurrence in the contralateral eye; therefore, systemic treatment is often required in addition to the ganciclovir implant. Combinations of the ganciclovir implant with systemic therapy, such as oral ganciclovir, may treat both local and systemic infection while avoiding daily systemic infusions. In a multicenter clinical trial, 377 patients with unilateral CMV retinitis were randomly assigned to receive the ganciclovir implant with placebo, the ganciclovir implant with oral ganciclovir, or intravenous ganciclovir.55 The primary endpoint was time to new CMV disease, defined as contralateral CMV retinitis or extraocular CMV disease proven on biopsy. At 6 months new CMV disease occurred in 44.3% of patients receiving the ganciclovir implant with placebo, 24.3% receiving the ganciclovir implant with oral ganciclovir, and 19.6% receiving intravenous ganciclovir. Interestingly, new CMV retinitis or extraocular CMV disease was rare in patients taking protease inhibitors, regardless of treatment group.

Historically, intravitreal injections of ganciclovir,56 foscarnet,57 or cidofovir were used to treat CMV retinitis.58,59 We previously used injections of ganciclovir or foscarnet to treat recurrent CMV infection, especially in patients resistant to or intolerant of systemic therapy. However, in the era of HAART and the ganciclovir implant, this approach is rarely used.

Oral formulations of ganciclovir have been developed. A randomized controlled trial showed that once-daily oral valganciclovir was as clinically effective and well tolerated as oral ganciclovir three times daily for CMV prevention in high-risk sold organ transplant recipients.60 Valganciclovir is an orally administered prodrug that is rapdily hydrolysed to ganciclovir and is now the formulation most commonly used. The recommended dose for newly diagnosed CMV retinitis is 900 mg twice daily for 2–3 weeks, followed by 900 mg once daily. If used in combination with a ganciclovir implant, the dose of valganciclovir is usually 900 mg once daily. Orally administered valganciclovir apears to be as effective as intravenous ganciclovir for induction treatment and effective for long-term maintentnace therapy for CMV retinitis in patients with AIDS.61 As with intravenous ganciclovir, the major toxicity is bone marrow suppression with neutropenia and thrombocytopenia.

Current therapeutic approach to CMV retinitis in the era of HAART

How has HAART altered the treatment strategy for CMV retinitis? First, we now know that immune recovery following HAART has reduced the incidence of opportunistic infections and can also control pre-existing infections, including CMV retinitis. As a result, lifelong anti-CMV therapy is no longer required for most patients who have documented improvements in CD4+ T-cell counts following HAART. In fact, we currently consider stopping maintenance anti-CMV therapy in patients with stable CMV retinitis if CD4+ cell counts are stable or increasing and have been >100 cells/ L for at least 3 months. Freedom from anti-CMV therapy has

Table 11-1  Therapeutic approach for CMV retinitis

HAART Naïve or Receiving HAART for Less Than 3 Months

HAART for more than 3 months

improved the quality of life of our patients. Nevertheless, they must be closely followed for reactivation of retinitis or the development of extraocular disease. If the CD4+ count falls to <50 cells/ L, the clinician should consider restarting anti-CMV therapy or, at least, plan to re-examine the patient more frequently.

The therapeutic approach to CMV retinitis is now based on the patient’s immune status in relation to HAART, the location of CMV retinitis in the eye, and patient input (Table 11-1). Because we know that CMV can be effectively controlled with an improved immune status following HAART, if CMV retinitis occurs in a paitent who is HAART naïve, the goal is to control the CMV disease until the CD4+ counts rise. However, if a patient has failed to have a significant improvement in CD4+ counts despite HAART, one must assume that anti-CMV therapy will be required for longer than several months, and this will alter the therapeutic approach. Similarly, the approach to patients with CMV retinitis in zone 1, an area of the retina that extends 3000 m from the center of the fovea or 1500 m from the edge of the optic nerve, is different from that for patients who have more peripheral and less immediately sight-threatening disease.

Again, the main treatment goal for patients who are HAART naïve or who have started HAART within the last several months is to limit the CMV infection until the immune system improves and controls the infection on its own. For zone 1 disease, most clinicians still recommend a sustained-release ganciclvoir implant in combination with valganciclovir, regardless of whether patients are HAART naïve or HAART experienced.62 This regimen provides the best ocular drug levels to control the CMV retinitis and prevent potentially sight-threatening disease progression, and also controls systemic CMV disease. Some patients refuse intravitreal therapy, and these patients are treated with higher induction doses of valganciclovir and watched very carefully for disease progression. For

patients who have been receiving HAART for longer than 3 months we recommend a combination of a ganciclovir implant with valganciclovir for zone 1 disease; if they have zone 2 or 3 disease we will combine a ganciclovir implant with valganciclovir 900 mg once daily, or just valganciclovir 900 mg twice daily for 3 weeks followed by 900 mg once daily.

Previously, National Institutes of Health (NIH) guidelines on the therapy of HIV infection recommended that use of prophylactic medications be continued even if CD4+ cell counts increase above threshold levels.63 Because of the clonal nature of the antigen-specific immune response, it is possible that the increased T-cell numbers after HAART may not restore adequate protection against opportunistic pathogens such as CMV. Current data now suggest that immune recovery after HAART is effective in controlling opportunistic infections, even in patients with a history of severe immunosuppression. Therefore, more recent NIH guidelines address discontinuation of maintenance anti-CMV therapy in patients receiving HAART who demonstrate immune recovery.64

Oral formulations of ganciclovir can be used for maintenance therapy for CMV retinitis but may be somewhat less effective than intravenous therapy. In an open-label study, after induction therapy with intravenous ganciclovir, patients were randomly assigned to receive maintenance intravenous ganciclovir or oral ganciclovir at a dose of 1000 mg three times a day.65 Although the mean time to progression of retinitis was 62 days with intravenous therapy and 57 days with oral therapy, the median time to progression was 49 days with intravenous and 29 days with oral treatment. Valganciclovir, the orally administered prodrug of ganciclovir, appears to be as effective as intravenous ganciclovir for induction treatment and may be effective for the long-term management of CMV retinitis in patients with AIDS.66 The usual dose is 900 mg once daily. An effective oral preparation of foscarnet is not available.

Retinal detachment

Retinal detachment develops in approximately 20% of patients with retinitis, 50% of these patients developing detachment in the second eye if it is involved with retinitis. Approximately 11% of patients with retinitis will experience a retinal detachment 6 months after diagnosis, and 24% will have detachment over the first year after diagnosis in the first eye.67 The greater the amount of peripheral retinal involvement, the greater the risk of retinal detachment. Compared to eyes with 10% of the peripheral retina involved, eyes with more than 25% of involvement had a fivefold increase in detachment rate. This risk increased to 24-fold if active retinitis also was present.

Because the mechanism of retinal detachment in CMV retinitis is vitreous traction on the thinned, atrophic retina, multiple retinal breaks are usually present and large, relatively posterior breaks can occur. Tears can occur at the edge of the normal retina, but also throughout the atrophic areas. The risk of retinal detachment is increased if the patient with CMV retinitis is myopic. The posterior vitreous usually adheres to the retina, and the combination of low-grade vitritis with a thinned retina allows the vitreous to pull the retina forward, causing it to detach. The rate of growth of

Cytomegalovirus retinitis

the detachment is variable and depends on the extent of traction and location within the eye.

The standard surgical approach for retinal detachment is not optimal for eyes with CMV retinitis. Scleral buckling is appropriate when retinal breaks are located near the vitreous base. The breaks in eyes with CMV retinitis often are more posterior and multiple. Scleral buckling may be successful in selected patients, but a more effective approach is vitrectomy, endolaser surgery, and the application of silicone oil tamponade. Head position can be more normal, although the patient still cannot lie on his or her back. Vision can be rehabilitated in a few days. The surgery can be performed as a local, outpatient procedure with minimal postoperative discomfort.

The major disadvantage of silicone oil is the induced hyperopia of 5 to 6 diopters, which, unless a contact lens is worn, will produce diplopia if surgery has been performed on only one eye. Both gas bubbles and silicone oil are associated with an increased risk of cataract formation. These cataracts commonly become visually significant 1 year after the surgery. Older patients may have a greater chance of cataract development than younger patients. As survival with CMV retinitis increases, more cataracts will need to be removed in this patient population. Of interest is the fact that the oil causes a hyperopic shift of approximately 1 to 2 diopters with a posterior chamber intraocular lens as opposed to the 5- to 6-diopter change in the phakic eye. One additional potential disadvantage of silicone oil is that intravitreal drug injections are more difficult and the therapeutic result is unpredictable.

The use of laser surgery to demarcate areas of retinitis and thereby prevent detachment has been suggested. A similar approach is often used in acute retinal necrosis due to herpes zoster infection. Although there is evidence in the literature to support this approach, it is not uniformly successful, and because CMV retinitis often continues to progress through a barrier of laser burns, this approach will not prevent either spread or detachment in all patients. It is unclear whether this approach should be widely utilized, but it may be possible to study this question and identify high-risk groups for whom prophylactic laser will be useful.

Prognosis

Advances in the drugs we use to treat both HIV and CMV disease have greatly improved the visual prognosis for patients with CMV retinitis. Reduced complications, including destruction of the macula from disease progression and retinal detachment, are a welcome outcome from improved treatment. Recent data suggest that patients with CMV retinitis have visual impairment at a rate of 0.10 case/eye-year and blindness at a rate of 0.06 case/eye-year.68

Immune recovery uveitis

Although HAART-associated improvements in immune function have improved the clinical course of CMV retinitis, immune restoration has also led to a change in the clinical manifestations of the disease. Vitritis was reported in immunocompromised patients with CMV retinitis before HAART.69 However, more profound intraocular inflammation is occurring in patients with CMV retinitis receiving HAART.38,42,70–73 Initially, this syndrome was referred to as immune recovery

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