Ophthalmology

The best news for patients with CMV retinitis came shortly before the XI International Conference on AIDS, when the FDA gave full approval to the use of cidofovir (Vistide), a nucleotide analogue made by Gilead. Because of its long half-life, cidofovir can be given as an intravenous infusion every two weeks for maintenance therapy for CMV retinitis and, therefore, does not require placement of a permanent central catheter. Unlike nucleoside analogues such as ganciclovir, nucleotide analogues do not require an initial phosphorylation before the drug is taken up into cells. Since resistance to ganciclovir is usually due to viral mutations that reduce this phosphorylation step, there is hope that cidofovir will be effective not only as first-line therapy but also for patients with ganciclovir resistance. However, concerns remain about the renal toxicity of cidofovir as well as the potential side effects (nausea, fatigue, rash) of probenecid, which must be taken with cidofovir to reduce renal toxicity. Logistic problems will also need to be worked out. The infusion is lengthy because of the large volumes of saline hydration given with cidofovir, and it is not clear whether home infusion is feasible for many patients. Data presented at Vancouver indicated that cidofovir is effective for relapsing CMV retinitis and that the 5 mg/kg dose every two weeks is more effective than the 3 mg/kg dose, with no significant difference in side effects (proteinuria, elevated creatinine, or neutropenia).

While no new treatment breakthroughs for CMV retinitis were announced in Vancouver, some interesting data were presented, including subgroup analyses from the CPCRA and Syntex 1654 studies, which have shown contradictory results concerning the efficacy of oral ganciclovir for prevention of CMV retinitis. The CPCRA study data failed to show a benefit from prophylaxis, even when a cohort of patients similar to those in the Syntex 1654 study were analyzed (i.e., limited to those with CD4 counts <50/mm3 or those with CD4 counts >50/mm3 but with prior opportunistic infections). Interestingly, patients given oral ganciclovir who had been treated with ddI were more likely to get CMV disease, suggesting an inhibitory drug effect. However, the Syntex 1654 study did not show any such ganciclovir-ddI interaction.

Perhaps the most intriguing report from the CMV sessions in Vancouver was Stephen Spector's data from the Syntex 1654 study which looked at a subgroup of patients who had qualitative and quantitative plasma PCR testing for CMV. Since nearly everyone agrees that oral ganciclovir prophylaxis is too expensive to use in all patients, the surprising finding from this analysis was that the most cost-effective use of the drug may be in patients formerly considered to be at lower risk of the disease. The most striking reduction in CMV retinitis at one year occurred in patients who were PCR-negative prior to oral ganciclovir prophylaxis (1% vs. 14% in controls). Patients who were PCR-positive prior to therapy had a reduction in CMV retinitis from 43% to 26%. Similarly, reduction in CMV retinitis was also more pronounced in patients with low rather than high quantitative levels of CMV PCR at baseline.

The sensitivity, specificity, and cost-effectiveness of various techniques that measure CMV, including DNA hybridization, pp65 antigenemia, PCR, and blood or urine cultures, will require much more extensive study before their clinical value is known. Data presented at Vancouver showed clearly that the peak activity of CMV assays does not always occur at the time of CMV disease. Serial assays are therefore necessary, potentially limiting the usefulness of CMV testing.