Gilead Sciences of Foster City, CA, has developed the antiviral drug cidofovir as an intravenous injectable liquid (Vistide) for treating cytomegalovirus (CMV) retinitis, a sight-threatening infection of the inner eye, and as a topical gel (Forvade) for treating herpes simplex blisters and sores that do not respond to standard acyclovir (Zovirax) treatment. The gel has also been studied for treating genital warts caused by human papillomavirus infection, for molluscum contagiosum and for Kaposi's sarcoma lesions.
Cidofovir has been proposed as a treatment for progressive multifocal leukoencephalopathy (PML; see BETA September 1997). Cidofovir is also being developed in Europe for intraocular (into the eye) injection to treat CMV retinitis and as an ophthalmic solution (eye drops) for the redness, swelling and destruction of the tissue in the corners of the eye called viral keratoconjunctivitis. The product manufactured by Gilead Sciences is not intended for intraocular injection.
The retina is the light-sensitive membrane that lines the back inner surface of the eye. Nerve cells in the retina (rods and cones) convert light into electrical impulses that travel along the optic nerve to the brain. Retinitis is inflammation of the retina. CMV infection can progressively destroy retinal tissue, resulting in permanently decreased vision or blindness. CMV retinitis is most often associated with HIV infection and very low CD4 T-cell counts, usually fewer than 50 cells/mm3. Retinitis usually appears first at the border of the retina and moves toward the center of the retina (called the macula), progressively decreasing visual acuity. CMV can also cause gastrointestinal disease, neurologic disease, peripheral neuropathy and pneumonia. For more information on managing CMV infection, see Research Notes, this issue.
Treatment for CMV retinitis with cidofovir consists of 5 mg of cidofovir per kilogram of weight given intravenously at a constant rate over 1 hour once a week for 2 weeks. Then intravenous infusions are given every other week. People with decreased kidney function should take less cidofovir per kg of weight. The usual recommendation is 3 mg per kg of weight. To protect patients against possible kidney damage, an oral drug called probenecid and an infusion of saline (salt water) are given before starting an infusion of cidofovir. Patients take 2 grams of probenecid 3 hours before each cidofovir infusion and 1 gram at 2 and again at 8 hours after the infusion is completed (a total of 4 grams of probenecid).
Other available approved treatments for CMV retinitis include ganciclovir (Cytovene) and foscarnet (Foscavir). Both require daily intravenous administration. These drugs are more commonly used because of the risk of irreversible kidney damage from cidofovir.
Cidofovir interferes with the ability of CMV to reproduce. Certain enzymes are responsible for precisely assembling nucleotides, the building blocks of DNA, into a long chain. A complete chain of CMV DNA contains all the genetic instructions that allow the virus to infect and destroy tissue. When a metabolized form of cidofovir is inserted into a growing DNA chain in place of a nucleotide, the rate of synthesis of new viral DNA slows down. This results in reduced numbers of new CMV virus particles and decreased inflammation of retinal, lung or intestinal tissues.
A difference between cidofovir and other currently approved treatments for CMV infection is that cidofovir remains inside cells longer than the other drugs and therefore requires less frequent administration. Maintenance therapy requires 2 doses of cidofovir per month compared to 42 or more doses of either ganciclovir or foscarnet.
The efficacy of treatments for CMV retinitis is evaluated based on the length of time before any further retinal destruction is observed. Retinal photographs are taken before treatment starts and at regular intervals during treatment. One reported study comparing delayed treatment to immediate cidofovir therapy showed that the 23 patients who received delayed treatment for progressive retinitis (treatment was delayed until progression was seen) progressed in an average of 22 days, while those treated immediately with cidofovir (25 patients) progressed after an average of 120 days. Once researchers had evidence of progression, any patient who had been in the delayed treatment group was immediately treated with cidofovir.
Negative Side Effects
Nephrotoxicity (kidney damage) as measured by urine tests for protein and blood tests for serum creatinine occurred in 53% of patients involved in clinical studies of cidofovir. Adequate water intake may help prevent kidney damage; people who are taking the protease inhibitor indinavir (Crixivan) and receiving infusions of cidofovir should be extra careful to drink many glasses of water throughout the day to prevent kidney problems. Probenecid is given before and after administration of cidofovir to help prevent kidney damage. Probenecid hypersensitivity is a frequent cause for discontinuing cidofovir therapy. Most cases of probenecid hypersensitivity involve mild skin rashes and low-grade fever; however more serious rashes have been reported.
Neutropenia (low counts of neutrophils, a type of white blood cell) occurred in 20% of patients who were studied. They were most often treated with granulocyte colony-stimulating factor to increase their white blood cell counts. See Blood Cell Deficiencies, this issue, for more information.
Ocular hypotony (low pressure inside the eyeball) is rarely reported (<1%) and has been associated with diabetes. In such cases, the drug should be stopped.
Metabolic acidosis, which occurs when the kidneys are not able to process and eliminate normal amounts of acid generated by the body, is reported in 2% of patients who receive cidofovir. Metabolic acidosis means that the blood is more acidic and the urine is less acidic than usual. If the acid balance is not corrected, excess acid may cause softening of the bones, kidney stones, hardening of the kidneys and low levels of blood potassium. Hospitalization is usually required to manage this side effect.
Finally, when cidofovir is given intravenously, there is a small increased risk of infection at the infusion site if the skin, needle and dressings are not sterile. Sepsis (blood poisoning that results from multiplication of bacteria in the blood) may result, and is usually treated with intravenous antibiotics. The use of cidofovir does not require an indwelling catheter (one that is surgically implanted), but can be delivered to the blood through a temporary intravenous line.
Because cidofovir must be preceded and followed by the drug probenecid, physicians must guard against many possible drug interactions with probenecid. For example, doses of AZT should be reduced by 50% when taking probenecid. Cidofovir may interact with the protease inhibitor ritonavir (Norvir). Physicians are advised to closely monitor kidney function tests (such as routine urinalysis and blood serum creatinine measures) and maintain adequate hydration in patients who are taking both drugs.
Probenecid may increase the blood levels of many common drugs, including acyclovir, barbiturates (sedatives) and non-steroidal anti-inflammatory agents such as ibuprofen or naproxen. High levels of these drugs may cause unwanted side effects and may be health- or life-threatening.
Patient Assistance Program and Reimbursement Assistance Program
Gilead Sciences helps patients and providers obtain reimbursement from third party payers and offers direct assistance to U.S. citizens who earn no more than 200% of the federal poverty level (this calculation is currently $15,960 for unmarried individuals) and who cannot obtain cidofovir through state-run AIDS drug assistance programs (ADAP), private insurance or Medicare. Physicians or patients may call 800-445-3235 to request a 3-month supply.
Mark Bowers is Managing Editor of treatment publications at the San Francisco AIDS Foundation.
Lalezari J and others. Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus in patients with AIDS. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. 17:339-344. April 1, 1998.
Lalezari J and others. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. Annals of Internal Medicine 126:257-263. February 15, 1997.
Lalezari J. Cidofovir: a new therapy for cytomegalovirus retinitis. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 14:S22-S26. 1997.
Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC peripheral cytomegalovirus retinitis trial. Annals of Internal Medicine. 126:264-274. February 15, 1997.
Vistide (cidofovir injection) package insert. Gilead Sciences, Inc. September 1996.