• Introduction
• Chapter 1
• Chapter 2
• Chapter 3
• Chapter 4
• References

While this study demonstrated the superiority of oral ganciclovir in conjunction with the implant in reducing the development of progressive CMV retinitis, perhaps more significantly, treatment with oral or intravenous ganciclovir reduced the risk of Kaposi's sarcoma by 75% (P=0.008) and 93% (P<0.001), respectively, compared with placebo. This may be the first report of the use of an antiviral agent to prevent the development of a malignancy.
 

Initial Therapy
Initial therapy for CMV retinitis should now make every effort to optimize therapy for HIV infection. Patients who have failed HAART and who are unlikely to reconstitute their immune response to CMV (see below) will probably need lifetime chronic suppressive maintenance therapy. Intravenous ganciclovir, intravenous ganciclovir followed by oral ganciclovir, intravenous foscarnet, intravenous cidofovir, valganciclovir (the valine ester of ganciclovir), and the ganciclovir intraocular implant (coupled with either oral ganciclovir or valganciclovir) have all been shown to be effective.

Oral ganciclovir maintenance is less effective than daily intravenous ganciclovir maintenance, and probably should not be used now that valganciclovir is available.⁵ For patients without immune reconstitution, the ganciclovir implant is superior to intravenous ganciclovir for preventing relapse of retinitis.^1,6 For patients with vision-threatening lesions adjacent to the optic nerve or fovea,ganciclovir implant + valganciclovir may be the preferred therapy. For peripheral lesions that are not immediately vision threatening, any of the treatment regimens may be chosen.⁷ Oral administration of valganciclovir may be preferable to infusing ganciclovir or foscarnet through a central venous catheter.

Patients with CMV retinitis who have never received HAART, or those who have had a temporary interruption of antiretroviral therapy, may only need treatment for 6 months, until there is sufficient immune reconstitution to allow discontinuation of CMV therapy. Patients with immediately vision-threatening lesions still need prompt anti-CMV therapy to prevent progression of the retinitis. The ganciclovir implant and its superior ability to control retinitis progression may be most appropriate, but routine replacement may not be necessary. The ganciclovir implant ordinarily should be combined with valganciclovir.

Immune Recovery Uveitis
Immune recovery uveitis (IRU) is an immunological reaction to CMV, characterized by inflammation in the anterior chamber and/or vitreous in the setting of immune reconstitution, that has been recognized since the monograph was originally published.^8-13 The reported incidence of IRU has varied from 0.11/person-years to 0.85/person-years, with lower rates seen where more aggressive anti-CMV therapy is used. Ocular complications of IRU include macular oedema and epiretinal membranes, which can cause loss of vision. IRU is usually treated with periocular corticosteroids or short courses of prednisone, with estimated response rates of 50%. IRU is most often described in persons with quiescent retinitis. It may not be necessary to treat small peripheral CMV retinitis lesions, since immune recovery may ultimately control the retinitis. However, IRU may be more common in patients given less aggressive anti-CMV therapy,¹³ so treating CMV retinitis until there is sufficient immune recovery is still preferred.

Relapse
Without immune reconstitution on chronic suppressive maintenance therapy with systemic anti-CMV drugs, relapse of the retinitis will occur in most patients. Early relapses are generally due to the limited intraocular penetration of systemically administered drugs.^14-16 Reinduction with the same drug followed by reinstitution of maintenance therapy can control the retinitis, but for progressively shorter time-periods.¹⁷ Changing to an alternative drug at the time of first relapse typically does not result in better control of the retinitis.¹⁷ Because of the greater drug levels in the eye, the placement of the ganciclovir implant in a patient who has relapsed while on systemic ganciclovir will often control the retinitis for 6-8 months, until the implant is depleted of drug.^18,19 The combination of ganciclovir and foscarnet is superior to systemic therapy with either agent alone for patients with relapsed retinitis.²⁰    

Immune Recovery and Treatment Discontinuation
Prior to 1996 and the introduction of potent antiretroviral therapy, people with CMV retinitis required lifelong therapy with specific anti-CMV agents, as discussed in the monograph. Now, people on HAART may have specific immunity to CMV restored.²¹ Recovery of CD4+ T cell counts, to greater than 100-150 cells/µl for 3–6 months, appears adequate to control CMV retinitis in most patients.^22-27 In these patients, anti-CMV therapy may be discontinued. Relapse of CMV retinitis typically occurs when CD4+ T cell counts fall below 50 cells/µl27 and maintenance therapy should start when the CD4+ T cell counts decline to that level, before relapse occurs. Rare patients may experience generalized immune recovery but lack the recovery of specific immunity to CMV: these people still require chronic suppressive anti-CMV therapy despite elevated CD4+ T cell counts. Because of the rapid relapse of the retinitis when CD4+ T cell counts decline, and the rapid decline of CD4+ T cell counts with interruption of HAART, patients with immune reconstitution not receiving CMV maintenance therapy should still receive ophthalmologic follow-up.
 

Early relapse in patients receiving systemic anti-CMV therapy is usually caused by inadequate drug dosing levels rather than drug resistance. Monitoring patients for CMV viral load in the blood and presumed re-infection in the eye may be helpful in detecting those patients who develop CMV resistance.⁴³ Similarly, because patients with resistant CMV nearly always have mutations in the CMV UL97 gene, it may be possible to monitor patients being treated for CMV retinitis using blood specimens for PCR amplification of CMV DNA and sequencing for CMV UL97 mutations or using the point mutation assay.^44,45 Patients with low-level ganciclovir resistant isolates in the eye may respond to the ganciclovir implant, given the greater levels of ganciclovir attained by this form of therapy. However, patients harbouring high-level ganciclovir resistant isolates typically will not respond, and will require either a switch to foscarnet or combination therapy. Repetitive intravitreous injections of fomivirsen may be used for relapsed retinitis,46 but should be combined with systemic therapy.⁴⁷
 

Michael A Polis
National Institute of Allergy and Infectious Diseases
Bethesda
Maryland, USA

The opinions reflected herein are those of Dr Polis in his private capacity and do not necessarily reflect the opinion of the US
Government.