Ocular Complications of HIV/AIDS in the Era of HAART

Millena G Bittencourt; Owhofasa O Agbedia; Hong T Liu; Rachel Annam; Yasir J Sepah; Henry Alexander Leder; Raafay Sophie; Mohamed Ibrahim; Abeer Akhtar; Anam Akhlaq; Diana V Do; Quan Dong Nguyen


Expert Rev Ophthalmol. 2012;7(6):555-564. 

In This Article

Modifications in the Management of CMVR

The AIDS pandemic witnessed a turning point in 1996 with the introduction of HAART. Prior to 1996, CMVR was treated with drugs introduced in the late 1980s, including ganciclovir sodium (Cytovene®, Roche Pharmaceuticals, NJ, USA; approved in 1989) and foscarnet sodium (Foscavir®; AstraZeneca LP, DE, USA; approved in 1991). Drugs used in the management of CMVR after 1996 include: cidofovir (Vistide®, Gilead Sciences, Inc., CA, USA; approved in 1996) and fomivirsen sodium (Vitravene®, Novartis Ophthalmics AG, Bulach, Switzerland, and Isis Pharmaceuticals, Inc., CA, USA; approved in 1998).[27,29] Treatment was divided into two phases: induction therapy and maintenance therapy (secondary prophylaxis). High doses of ganciclovir were administered intravenously for 2–3 weeks as an induction therapy and until a regression of the CMVR was observed.[29,30] After induction therapy, maintenance therapy was initiated with lower doses of the antivirus administered orally and the patient was followed up on a weekly basis until the retinitis resolved; allowing for intermittent reinduction if recurrence occurred.[29,31–35] Foscarnet was found to be as efficacious as ganciclovir and potentiates the activity of ganciclovir when administered in combination.[36,37] Cidofovir, a CMV DNA polymerase inhibitor and potent anti-CMVR drug, could be administered either locally or systemically.[32,38,39] The most common ocular side effects of cidofovir included hypotony and iritis.[40,41]

Prior to HAART, CMVR had a recurrence rate of 30–50% within 3–4 months of remission.[18,42–45] The high recurrence rates were probably due to subtherapeutic drug levels in the vitreous. Relapses were measured by centrifugal advancement of the active lesion border (termed progression), and could be treated with reinduction therapy, but the pace of relapse appeared to accelerate over time. To improve the bioavailability of the drug in the retina, ganciclovir and foscarnet were administered intravitreally. A ganciclovir sustained-release eye implant (Vitrasert®; Bausch & Lomb Inc., CA, USA) that provides anti-CMV effect over 5–8 months was approved by the US FDA in 1996. The implant may be replaced every 7–8 months if further anti-CMV treatment is required. This approach of local administration often resulted in the development of CMVR in the contralateral eye, visceral disease and increased mortality.[27] Therefore, the implant was usually used in combination with oral ganciclovir for systemic effects. In a study to determine the clinical outcomes achieved with ganciclovir implant in the treatment of CMVR, Oktavec et al. measured the rate of complications of ganciclovir implant to be 0.19/EY. The most common complications were cataract, vitreous hemorrhages and retinal detachment. Severe vision loss occurred at a rate of 0.005/EY. The presence of immune recovery was associated with a lower rate of ocular complications and a statistically significant reduction in the occurrence of retinal detachment. Ocular complications were relatively common after ganciclovir implant but severe vision loss was low.[14]

Early relapses were mostly attributed to limited intraocular drug levels with systemic therapy, whereas later relapses (beyond 3 months) were associated with resistance to the administered anti-CMV drugs.[46–50] The estimated rates of resistance for ganciclovir and foscarnet were 0.25 cases/PY and the occurrence of resistance was associated with adverse ocular outcomes, including increased retinitis progression, increased loss of retinal area and increased rate of visual impairment.[27,48–50] As the treatment was 'virostatic', clearance of the virus was not possible: this explains the recurrence in cases with immunosuppression and the phenomena of progressively shortening relapse time following repeated cycles of induction and maintenance.[51] Some strains of CMV have shown resistance to oral ganciclovir therapy. Ganciclovir implant is efficacious when the resistance to oral ganciclovir is identified genotypically, such as in the cases of UL97 and UL54 gene mutations.[52]

Since the inception of HAART in 1996, two new antiviral agents have been introduced for the treatment of CMVR, valganciclovir (valcyte) and formivirsen. Studies have shown that oral valganciclovir is as effective as intravenous ganciclovir for induction therapy of CMVR and resolution of CMVR has been shown to be similar with both agents.[53] In addition, valganciclovir has an excellent bioavailability when given orally, which makes it the drug of choice for induction and maintenance therapy of CMVR. Fomivirsen is administered intravitreally; a dose of 165 mg once weekly for 3 weeks and then every second week is efficacious for treating new CMVR and preventing progression.[54–56] Fomivirsen is used as a fourth line agent in the treatment of CMVR owing to its associated complications, including uveitis and retinal pigment epithelial degeneration.[53]

Several principles guide the treatment of CMVR. As the infection is systemic, all patients with CMV infection who can tolerate systemic therapy should receive systemic therapy. Oral valganciclovir is a good option owing to its sufficient bioavailability. For patients with zone 1 disease (lesions within the retina extending 3000 μm from the center of the fovea or 1500 mm from the edge of the optic nerve), who are at risk for immediate and permanent visual loss, the addition of the ganciclovir implant along with valganciclovir is often preferred.[57] This combination therapy is associated with a better control of retinitis and lower rates of retinitis progression compared with systemic therapy alone.[58] Patients that relapse or progress before immune recovery and patients with poor compliance to HAART therapy should also be considered for ganciclovir implant. Zone 2 disease extends from the edge of zone 1 anteriorly to a circle identified by the vortex vein ampullae and zone 3 extends from the edge of zone 2 to the ora serrate.[7] In cases of Zones 2 and 3, naive patients can be treated with oral valganciclovir, while HAART-experienced patients should be treated as zone 1 disease patients. Because the recovery of specific immunity to CMV requires approximately 3–6 months after the initiation of HAART, HAART-naive patients require treatment for a minimum of 6 months prior to an attempt to discontinue therapy after immune recovery.[59,60]

HAART-experienced patients usually require longer periods of anti-CMV therapy before their immune system recovers sufficiently to allow clearance of the drugs.[24] In patients on HAART, if the CD4 count remains consistently above 100 cells/µl as measured on two consecutive occasions 3 months apart, and the CMVR is inactive for more than 4 months, then anti-CMV therapy may be discontinued. However, these patients require close and long-term monitoring for recurrence, usually at 3 monthly intervals, as CMVR progresses at a rate of 0.02–0.03 PY in immune-recovered patients and no CD4+ level can be considered as completely safe.[61] Therefore, maintenance therapy in patients with regressed CMVR can be safely terminated after HAART immune recovery, eliminating the need for lifelong maintenance therapy.[24]