GMHC Treatment Issues, Vol. 10, No. 3 - March 1996
Theo Smart

New Products

The approval for the implants comes roughly three months after the application was reviewed. Chiron Vision and Hoffmann-La Roche are co-marketing and sharing the profits from the ganciclovir implants, which cost $4,000 per device (not including the cost of surgically fastening the device within the eye, which ranges from $3,000 to $6,000). The product's labeling recommends replacing the implants every six months. (The implants' useful lifespan has been a matter of concern due to their variable drug release rate.) No mention is made in the labeling of the need for backup systemic therapy. Such therapy may be advisable to reduce the risk of developing CMV disease in other parts of the body, including the unaffected eye. Roche is addressing this issue with an ongoing study of oral ganciclovir in combination with the implants.

The advisory panel recommended approving cidofovir as systemic treatment for new or relapsing CMV retinitis in people with AIDS. This application was supported by three studies (see January's Treatment Issues, pages 5-7), two with newly released findings.

One dose-ranging study compared two doses of cidofovir, 3 and 5 mg per kg of body weight once weekly for induction and then every other week for maintenance therapy. All patients had recurrent retinitis (the median number of prior relapses was four). The higher dose worked much better, significantly delaying retinitis progression by 115 days, compared to 49 days on the low dose.

On March 11, recruitment stopped for the latest of two trials comparing immediate cidofovir to deferred therapy in new CMV retinitis. Those in whom therapy was postponed progressed significantly faster than those receiving 3 mg cidofovir/kg of body weight -- a median delay of 69 days for immediate cidofovir arm versus 21 days for deferred therapy. (This trial also had a 5 mg/kg arm, but too little data has been collected to calculate the delay in CMV progression for this dose.)

The FDA's more conservative analysis found shorter times to CMV progression. The agency did not argue with the cidofovir studies' overall conclusions, however.

Until formal FDA approval occurs, patients can still receive cidofovir free through the expanded access programs (more than 250 people now enrolled) or as follow-up to the clinical trials. To be eligible for expanded access, applicants must have experienced a CMV relapse on either ganciclovir or foscarnet. To enroll, call 800/Gilead-5.

Also of interest, Gilead says that it has confirmed that cidofovir has anti-CMV activity when administered by injections into the eye. The company's results do not match the degree of safety or activity reported by William Freeman, M.D., of University of California San Diego. (Dr. Freeman administers intraocular injections only once every six weeks -- see Treatment Issues, July/August, 1995, pages 5-6.) Gilead has placed the study on hold while its Data and Safety Monitoring Board (DSMB) looks at the data. Depending on the DSMB's recommendation, the company may amend its protocol to more closely resemble Dr. Freeman's protocol.

Oral Ganciclovir and Drug Resistance

Data from two separate analyses of the Roche oral ganciclovir prophylaxis study presented at the Third Conference on Retroviruses and Opportunistic Infections may ameliorate some of the concerns over the use of this drug. Many fear that the levels of ganciclovir reaching the eye during prophylaxis with oral ganciclovir are suboptimal and that such low-level exposure may induce ganciclovir-resistance in whatever CMV is present. Patients' future response to treatment with intravenous ganciclovir for breakthrough CMV retinitis might then be compromised. Two reports at the Third Conference on Retroviruses argued against this inference.

W. Lawrence Drew, M.D., presented data from 39 CMV isolates cultured from the urine and sometimes the blood or semen of patients on oral ganciclovir. He believes his observations suggest that resistance is a very rare occurrence (abstract LB16). After a mean of 8.3 months on oral ganciclovir in a Roche Bioscience prophylaxis trial, the only resistant isolates were from two patients who subsequently were not responsive to intravenous ganciclovir therapy.

Dr. Drew's study was much criticized, though, because CMV could be cultured from only a very small percentage of the study cohort of 925 people. No one knows how well drug- resistance of CMV in bodily fluids correlates with the state of CMV in the retina, which obviously cannot be sampled for analysis.

Another analysis of the Roche prophylaxis trial (abstract 9) reported on the clinical response to intravenous ganciclovir treatment among trial participants who did develop retinitis. Response to IV therapy was not significantly different between those randomized to prophylaxis and those on placebo. CMV retinitis in the placebo group was more often sight- threatening. Drug resistance, if any, seemed clinically irrelevant here.

Improving Current IV Therapy

Even when there is retinitis progression on maintenance doses of intravenous ganciclovir (which achieves greater blood levels of drug than the poorly absorbed oral ganciclovir), the condition generally responds to the higher doses of ganciclovir used during induction therapy. Data from a study of 279 patients who had failed maintenance therapy (abstract LB15 and also Archives of Ophthalmology, January, 1996, pages 23-33) show that people who had retinitis progression while on ganciclovir maintenance therapy and then were randomized to ganciclovir induction therapy did as well as those that were switched to foscarnet therapy.

Trial participants who were assigned to ganciclovir/foscarnet combination therapy experienced a significantly longer delay of retinitis progression (median time to progression was 60 days for the ganciclovir arm, 39 days for foscarnet and 129 days for the combination). Given the added annoyance, toxicity and cost of combination therapy, it is not clear how many patients will benefit from this finding. (It also is noteworthy that the study found no difference in survival between the study arms, contradicting an earlier study that found a survival benefit for foscarnet.)

A Canadian observational study reported at the Retroviruses Conference found improved results for intravenous ganciclovir or foscarnet by using induction regimens longer than the standard two weeks (abstract 165). One hundred and five patients were treated with open-label foscarnet or ganciclovir until their CMV was deemed stable upon ophthalmologic examination. Of the 79 patients achieving such stability, CMV relapse occurred on maintenance therapy in 51, at an average of 109 days. Comparison of these results with those found in rigorously controlled trials is of course difficult, and again, any added benefit from the extra ganciclovir has to be balanced against the added hazards and expense.

Since most early CMV breakthroughs can be controlled by higher ganciclovir induction doses, progression on maintenance therapy seems to be due to suboptimal dosing of the drug rather than to resistance. This problem could be largely addressed by the localized therapy that ganciclovir implants offer. Resistance more commonly stems from long-term systemic treatment of active CMV disease. It results from repeatedly introducing low-dose ganciclovir maintenance therapy after courses of induction therapy that incompletely suppress the CMV infection. Should widespread ganciclovir resistance occur, new agents such as cidofovir increase the therapeutic alternatives so that it will not entirely derail CMV treatment.

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