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Gay Men's Health Crisis
Finding a Place for Cidofovir
Theo Smart
January 1, 1996
GMHC Treatment Issues 1996 Jan 1; 10(1): 2

Gilead Sciences has asked the Food and Drug Administration to approve intravenous cidofovir (brand name: Vistide) as a therapy for CMV retinitis. Cidofovir's primary advantage is that it need only be infused into patients on a weekly or biweekly basis compared to once or twice daily for current medications (ganciclovir and foscarnet). This dosing schedule furthermore removes the need for the in-dwelling catheter used with ganciclovir and foscarnet. If Gilead's application is accepted without modification, cidofovir would be on a par with the two older drugs and could be administered either as initial treatment or as a salvage therapy.

The case for the new drug application rests on data from two company-sponsored studies. One compares immediate treatment with cidofovir to deferred treatment. The other is a dose comparison study.

The first study enrolled 48 patients with CMV retinitis and no systemic CMV disease. Retinitis progression was defined as advancement of the edge of an existing lesion by 750 microns or the occurrence of a new lesion 750 microns or larger in diameter. Most of those randomized to deferred therapy experienced progression of their retinitis after a median 22 days, and were then crossed over to treatment. Those who received cidofovir immediately and who remained on treatment throughout the trial did not progress for a median of 120 days.

Many patients discontinued the study prior to progression and were not counted in calculating progression rates. According to Gilead's Vice President of Clinical Research, Howard Jaffe, M.D., though, even if those who discontinued were assumed to have progressed, the median time to progression would have been approximately 70 days at worst. The median time to progression had not yet been reached in the sixteen patients crossed-over to treatment from the deferred therapy arm, but, again, many patients have discontinued therapy.

The dose comparison study includes 100 people with relapsing CMV retinitis or intolerance to standard therapies. Although an interim analysis of data from the first sixty patients last April did not at that time show a statistically significant difference between the two doses (three mg/kg of body weight vs. five mg/kg), the median time to first progression was 49 days on the three mg/kg arm vs. 115 days on the five mg/kg arm. Complete data from this study should be ready sometime in February -- if there is a statistically significant difference between the doses, the case for approval of cidofovir will be stronger.

One other study and a treatment IND (expanded access) program provide additional data for the cidofovir application. The SOCA (Studies of the Ocular Complications of AIDS) network is running a three arm trial in 90 volunteers comparing two different regimens of cidofovir and deferred treatment. It is unlikely that any efficacy data from this study will be ready by the time the FDA reviews Gilead's application, but some safety data will be available. Adverse events also are being actively monitored in the treatment IND program as physicians must submit a report with every two doses of drug. At press time, 146 patients have re istered in the protocol. (For TIND information, call 415/573-4700.) Toxicity and Drug Interactions All three systemic intravenous CMV therapies are toxic. Like foscarnet, cidofovir can cause irreparable, life-threatening kidney damage. A few years ago, it appeared too dangerous to be useful as a systemic therapy until researchers learned that the toxicity could be attenuated with hydration therapy and four grams of probenecid on the day of the infusion. (Probenecid helps the kidneys excrete cidofovir safely. Researchers also reduced the cidofovir regimen.) Even with probenecid and hydration, the drug at standard dose should not be administered to patients with proteinuria (high levels of protein in the urine) or elevated serum creatinine levels, both indications of kidney impairment. Dose reduction studies are underway in patients with compromised kidney function.

Probenecid produces its own side effects, including transient (lasting one to two days) fevers, nausea and rashes in about fifty percent of the patients in the Gilead studies. A few patients can have life-threatening allergic reactions. In the dose-ranging study, at least two patients required resuscitation and hospitalization within hours of treatment.

One had a major drop in blood pressure and the other had a fever of 104� F, low blood pressure and severe shortness of breath. Both patients had a history of reactions to sulfa drugs (to which probenecid is structurally related). Many investigators have been giving antihistamines along with the probenecid. Discontinuing pro-benecid or lessening the dose is not an option since cidofovir's kidney toxicity is so severe.

There is little drug interaction data available for cidofovir. There seems to be no interaction with AZT. Interaction studies with ddI and Bactrim will begin soon, and other studies are being designed.

Comparison with Other CMV Drugs Some in the community are concerned that if the FDA approves cidofovir, people may opt to use this drug before the better characterized ganciclovir or foscarnet because the dosing regimen is so much easier on patients than the daily regimens and indwelling catheters of the two older intravenous therapies. But the lack of studies directly comparing cidofovir to ganciclovir or foscarnet makes it difficult to determine which drug should be used when.

The picture is further complicated by the new availability of oral ganciclovir and the ganciclovir intraocular implants. These two approaches in combination may represent another attractive option. The implant would provide the advantages of localized therapy against CMV retinitis in the treated eye while the oral drug may provide a cover against breakthrough infections in the uninvolved eye or elsewhere in the body.

Hard data on this combination will be available from an ongoing trial comparing the ganciclovir implant-oral ganciclovir combination to standard intravenous regimens. In the future, intraocular injections of cidofovir promises to provide another effective localized therapy against CMV retinitis. (For a review of the many new CMV treatments, see the July-August, 1995 Treatment Issues.) The lack of comparative data is not an argument against FDA approval of cidofovir. Cidofovir appears to show clear clinical benefit in people who can tolerate it. But unless intravenous cidofovir is shown to be superior to other CMV therapies, or until there is more clinical experience with the drug most clinicians will relegate it to second or third CMV therapy, to be used when other approaches are failing.

FDA to Review Two NNRTIs Boehringer Ingelheim and the newly combined entity Pharmacia & Upjohn have announced that they will soon file New Drug Applications with the FDA this spring for their respective experimental antiretroviral drugs, nevirapine and delavirdine. Both drugs are nonnucleoside reverse transcriptase inhibitors (NNRTIs) that block the action of HIV's reverse transcriptase enzyme (see the September, 1995 Treatment Issues, pages 8-9). Expanded access programs for both drugs are also in the works.

As Treatment Issues went to press, Upjohn announced interim results from two large clinical studies of delavirdine. The data form one trial indicate that the combination of delavirdine and AZT provides more sustained responses in CD4 cell counts and viral load than either drug alone. In another trial, involving participants with more advanced disease, delavirdine plus ddI improved on the response to ddI alone only for several months. The company is now transforming its AZT plus delavirdine trial to include an AZT/3TC/delavirdine arm. (Call 800/432-4702.) Upjohn believes its data show that even modest 70 percent (0.5 log) reductions in HIV levels achieved after eight weeks of treatment are predictive of substantially reduced disease progression for at least a year. This observation underlines the importance of mild enhancements delavirdine brings to existing nucleoside analog therapy. It provides support as well for choosing treatments on the basis of viral load response.

The company plans to initiate an expanded access program for delavirdine that will enroll up to 800 persons per month starting in March. For more information on the program, call 800/779-0070.

Boehringer Ingelheim has announced a 2,000 person clinical endpoint study of nevirapine for people with CD4 counts of 200 or below. Participants will be randomized to nevirapine or placebo. All will receive 3TC and may take whatever other nucleoside analogs they wish in combination with 3TC. For enrollment information call 617/487-9900.

The company will be meeting with community representatives over the next few weeks to work out the details for the expanded access program.