AIDS INFORMATION NEWSLETTER Michael Howe, MSLS, Editor AIDS Information Center VA Medical Center, San Francisco (415) 221-4810 ext 3305 January 26, 1996 Opportunistic Infections (Part XVIII) Cytomegalovirus (CMV) [Harvey S. Bartnof, MD. Treatment for Opportunistic Infections. AIDS Treatment Highlights from the 35th ICAAC Conference in San Francisco. Headline Treatment News. BETA - Bulletin of Experimental Treatments for AIDS. Published by the San Francisco AIDS Foundation. October, 1995.] IV cidofovir (Vistide) prevented progression of CMV retinitis for 115 days among patients failing or intolerant to the standard IV therapies of ganciclovir and foscarnet. The dose was once weekly for 2 weeks, then once every other week (J. Lalezan, abstract LB-9, University of California at San Francisco). NOTE: Gilead Sciences has submitted an application to FDA for approval of Vistide for first line IV treatment of CMV retinitis, both as initial and maintenance therapy. Vistide is currently available free-of-charge through an expanded access program (treatment IND) for people who fail either ganciclovir or foscarnet (call 1-800- 445-3235 for more information). Valaciclovir (Valtrex) primary prophylaxis for CMV decreased retinitis by a third when compared with either of 2 doses of acyclovir. The 21-month study of 1,227 patients resulted in retinitis among 18% of those treated daily with either 800 mg or 3,200 mg acyclovir, compared to 12% among those treated with 8 grams of valaciclovir daily (J. Feinberg, abstract I214, Johns Hopkins University). Ganciclovir eye implants led to a 2.5 times longer time to progression of CMV retinitis among 125 patients when compared with IV ganciclovir. Implant patients experienced progression after a median of 194 days, compared with a median time of 72 days for IV ganciclovir patients. Treatable retinal detachments occurred in 12% and eye infections (endophthalmitis) occurred in 2%. (B. Kupperman, abstract I215, Chiron Ganciclovir Implant Study Group). Fifteen months of oral ganciclovir (Cytovene), 1 gram 3 times a day, did not lead to a statistically significant decrease in CMV retinitis among high-risk patients. The CPCRA 023 Study of 994 patients did find a non-significant 16% reduction in the disease among those taking the drug. These results conflict somewhat with those of the Syntex 1654 oral ganciclovir study, although the 2 studies are not identical. Syntex 1654 did find a significant 49% decrease in the rate of CMV disease, leading to an early discontinuation of the study. Differences in the 2 studies include patients' entry CD4 counts, study duration and study endpoints used to define CMV disease (C. Brosgart, abstract LB-10, University of California at San Francisco). Advances in Treatments for Cytomegalovirus Retinitis by Mark Bowers (Mark Bowers is the Treatment Hotline Manager at Project Inform and a frequent contributor to BETA.) [Bulletin of Experimental Treatments for AIDS (BETA), No. 26 - September 1995, at p. 13; published by the San Francisco AIDS Foundation, BETA Subscriber Services, Infocom Group, 1250 45th Street, Suite 200, Emeryville, CA 94608-2924.] Cytomegalovirus (CMV) belongs to the same family as other herpes viruses (such as herpes simplex and varicella zoster). Herpes viruses can remain latent in humans for their entire lifetimes, and are more active when the human immune system is somehow impaired. CMV is usually only a problem for people who undergo deliberate immunocompromise prior to organ transplantation or for people with AIDS, particularly those with fewer than 100 CD4 cells/mm3. Seventy-five percent (75%) of CMV retinitis cases are found in people who have fewer than 75 CD4 cells/mm3. Statistically, nearly 55% of all Americans and almost 100% of all gay men carry latent CMV. CMV is primarily a sexually transmitted virus, but it can also be transmitted congenitally (from mother to child at birth), by close personal contact and through blood transfusion and organ transplantation. The clinical manifestations of CMV and the drugs used to treat them are very different from those of the other herpes viruses. The usuual diseases associated with CMV are retinitis, encephalitis, esophagitis, colitis, polyradiculopathy (a kind of peripheral neuropathy) and pneumonitis. Of these, the most common and most dreaded is retinitis, which leads to blindness if untreated and seldom strikes without some loss of eyesight. CMV disease is one of the most common opportunistic infections (OI) in people with AIDS, affecting 25-40%. The greatest amount of clinical research on CMV disease has been done on the prevention and treatment of CMV retinitis, which affects up to 15% of all PWA's. New technologies have been tested and new drugs are finding their place in the treatment of CMV retinitis. But while acyclovir effectively controls herpes simplex outbreaks with comparatively few side effects, the drugs that are active against CMV require careful evaluation of their toxicities before they can be used for treatment or prevention. Such an evaluation includes carefully weighing the disease management factors articulated by Mark Jacobson, MD, of the University of California at San Francisco: individualizing therapy, balancing side effects and different routes of drug administration and considering the cost of treatment. Intravenous Ganciclovir and Foscarnet The 2 drugs that are currently licensed by the Food and Drug administration (FDA) for the treatment of CMV retinitis are ganciclovir (Cytovene) and foscarnet (Foscavir). For this indication, both drugs require intravenous (IV) administration for initial treatment, usually through a surgically implanted central access catheter in the chest. After initial treatment (called induction) to stop the progression of retinal deterioration, a maintenance treatment period follows. Maintenance therapy continues for life. The FDA-approved choices for maintenance are continuing the IV drug or switching to oral ganciclovir. The choice of induction therapy is individualized. Ganciclovir is infused for one hour at 5 mg/kg every 12 hours for 2-3 weeks, then maintenance is given indefinitely at 6 mg/kg a day 5 days per week. At the maintenance therapy dose, the half-life of ganciclovir allows 2 days per week to be skipped; this is not true for foscarnet, which must be infused 2-3 times daily. The normal intravenous dose for induction treatment with foscarnet is 60 mg/kg every 8 hours or 90 mg/kg every 12 hours for 2-3 weeks at a constant rate over 2 hours, requiring the use of an infusion pump. Renal toxicity must be constantly monitored, and adequate hydration using saline solution is important to protect the kidneys from damage by the drug. Maintenance therapy is usually at 90 mg/kg daily. Ganciclovir and foscarnet interact with many drugs commonly used in the treatment of HIV disease or associated opportunistic infections. Ganciclovir is bone marrow suppressive. About 30% of people receiving ganciclovir experience significant neutropenia (fewer than 1,000 neutrophils/mm3). Neutrophil and platelet counts should also be closely monitored. Neutropenia can be corrected by using colony-stimulating factors (G-CSF [Neupogen] or GM-CSF [Leukine]). Clinicians at San Francisco General Hospital recommend 300 mcg (one vial) of Neupogen 3-7 times per week until counts rise above 1,000 cells/mm3. Other drugs that are bone marrow suppressive are often discontinued when ganciclovir is being used, including AZT (Retrovir), trimethoprim-sulfamethoxazole (Bactrim or Septra) and pyrimethamine (Daraprim), all commonly taken by people with AIDS. Normal neutrophil production usually returns within 22 days of stopping ganciclovir therapy or switching to foscarnet. Foscarnet is potentially nephrotoxic (damaging to the kidneys). This is why patients are pre-treated with 1 liter of normal saline solution before being infused with foscarnet, and also why an infusion pump is needed to control the rate of infusion. Other nephrotoxic drugs may interact with foscarnet, including amphotericin B, aminoglycosides and pentamidine. Foscarnet leaves the body exclusively through the kidneys. Creatinine, a test of kidney function, must be monitored when foscarnet is in use. Concentrated foscarnet in the urine can cause ulcers on the genitals (penis, vulva) if excess urine is not blotted from the skin. The use of IV pentamidine and foscarnet at the same time increases the risk of hypocalcemia (abnormally low levels of calcium in the blood), which may have fatal consequences. Foscarnet and AZT used together increases the risk of anemia. Foscarnet has anti-HIV effects of its own, so the discontinuation of AZT may not be as problematic with foscarnet as it may be with ganciclovir. Alternating Foscarnet and Ganciclovir The Studies of the Ocular Complications of AIDS (SOCA) is a network of 11 university research sites with resident ophthalmologists, set up to conduct clinical research on CMV retinitis. SOCA recently completed a retreatment study designed to see if the combination of ganciclovir and foscarnet was better at preventing CMV disease progression than either drug alone. All participants had previously relapsed while on one therapy or the other. A total of 271 people received 1 of 3 treatments: (1) IV foscarnet (90 mg/kg twice daily for 2 weeks followed by maintenance at 120 mg/kg once daily); (2) IV ganciclovir (5 mg/kg twice daily for 2 weeks followed by maintenance at 5 mg/kg once daily); or (3) the combination (continuation of previous therapy with the addition of induction with the other therapy for 2 weeks followed by maintenance at 5 mg/kg daily of ganciclovir and 90 mg/kg daily of foscarnet). The standard of comparison in most CMV retinitis studies is time to disease progression, defined as a 750 micron advance on the retina of the area affected by CMV. The median time to progression was 4.8 months on the combination, compared to 1.6 months for those on only foscarnet and 2.1 months for those on only ganciclovir. A significantly longer time to progression for those on the combination must be weighed against the associated decrease in quality of life, in part because of long daily infusion times and in part due to the combined toxicities of the 2 drugs. No study group enjoyed any survival advantage over any other. Oral Ganciclovir Maintenance and Expected Approval for Prophylaxis Oral ganciclovir was approved for maintenance therapy (following IV induction) in January 1995. A Phase I/II safety and efficacy study of oral ganciclovir for maintenance was conducted by the AIDS Clinical Trials Group (ACTG) and the Cytomegalovirus Cooperative Study Group (CCSG). Oral bioavailability, a measure of how much drug taken orally gets into the bloodstream compared with intravenous administration, ranged from 2.6% to 7.3%. The data suggest that oral absorption is prolonged at higher doses and that serious adverse events are rare. (Current European studies of high dose oral ganciclovir are expected to confirm these observations.) Time to disease progression was compared for 50 people on 4 different doses: 62 days for those taking 1g every 8 hours, 148 days for those taking 500 mg every 3 hours, 75 days for those taking 750 mg every 3 hours, 148 days for those taking 1 g every 3 hours, and 139 days for those taking 2 g every 8 hours. Nineteen (19) people who had positive cultures for CMV but no evid ence of disease or prior anti-CMV treatment were also given oral ganciclovir as prophylaxis. A Roche Bioscience (formerly Syntex) study of oral ganciclovir was stopped by its Data Safety and Monitoring Board (DSBM) because of the significant benefit experienced by the group treated with oral ganciclovir. All study participants taking placebo were offered the drug. A new drug application for prophylaxis was filed in May and FDA approval is expected this year. Cidofovir (Vistide) Cidofovir has been evaluated for use in treating retinitis by 2 groups using 2 different formulations. Gilead Sciences holds the license for the development of cidofovir in the United States. Recently published data from a study at the University of California at San Diego (UCSD) show that single injections of cidofovir into the eyes of 65 people with CMV retinitis results in a delay of disease progression similar to that seen with IV drugs. Although the study was uncontrolled, the results indicate that retinitis was controlled for 6 to 8 weeks. Some community ophthalmologists who are familiar with intraocular infections caution that side effects of the procedure, such as retinal detachment, are an increased risk. Gilead Sciences will offer intravitreal injections of cidofovir to people who have failed or who are intolerant to ganciclovir and/or foscarnet beginning in August, 1995 (call Gilead at 415-476-6356). For more information see the June 1995 issue of BETA, pages 52-55. Intravenous cidofovir offers an advance over IV ganciclovir and foscarnet, in that dosing is needed only once weekly or less. The most important adverse side effect of cidofovir is kidney damage, which can be minimized by IV hydration similar to that required prior to the administration of foscarnet. The use of the drug probenecid increases the concentration of cidofovir and allows for less frequent dosing while protecting agaist kidney damage. (For an in-depth discussion of recent studies of IV cidofovir, see BETA, June 1995, pp. 54-55.) Gilead has filed for Treatment Investigational New Drug (TIND) status for IV cidofovir for the treatment of CMV retinitis. TIND status would provide the drug free to qualified patients under the supervision of their physician(s). Call Gilead after October 1 for more information. Ocular Implants Implants of a small device that releases ganciclovir into the vitreous humor of the eye continuously for 6 months have been clinically tested in a Phase I study at the National Eye Institute (NEI). Thirty eyes (belonging to 26 volunteers who had non-sight-threatening CMV retinitis) were either implanted with the devices or received deferred therapy. The time to disease progression was 15 days for the deferred therapy group and 226 days for the implanted group. Participants experienced no systemic toxicities nor any catheter-related toxicities, which are a risk when receiving infusions. There are risks from the implanting procedure, including bleeding and reduced vision. A second study of the ganciclovir implants, manufactured by Chiron Vision, compared the effectiveness of 2 different release rates of the implant to IV ganciclovir in 180 people with previously untreated CMV retinitis. The median time to progression for the IV group was 72 days compared to 186 days for the implants. No difference was seen in time to progression between the 2 release rates. Those in the IV group who experienced disease progression were given implants. There was no difference among the groups in the rate of development of CMV disease outside the eye. Chiron Vision has applied for approval from FDA. Implants offer a true advance in the treatment of retinitis: time to progression is 2-3 times longer than with currently approved therapies. The operation to implant the ganciclovir device is performed under local anesthesia on an outpatient basis, and surgical complications are not common. No central venous access is needed, and any extraocular disease that develops might be treated (off-label) with oral ganciclovir. An expanded access program is open only to those who have failed or cannot tolerate IV ganciclovir or foscarnet. Chiron Vision can be contacted at 800-244-7668. Roche Bioscience, manufacturer of ganciclovir, is currently sponsoring a study to compare implants to implants plus oral ganciclovir and to IV ganciclovir alone. The study recruits both newly diagnosed and previously treated individuals who have CMV retinitis. For more information, see the March 1995 issue of BETA, page 73. Ocular Injections In addition to the injections done with cidofovir, ophthalmologists have been injecting either ganciclovir or foscarnet directly into affected eyes for many years. One French study highlighted the drawbacks to such injections: 141 of 151 eyes that were injected experienced some scarring. There are no controlled data to indicate that the incidence of retinal detachment with injections is higher than the statistical average, but this is nonetheless a concern. Antisense Drug Isis Pharmaceuticals has been clinically testing an antisense drug for CMV. An antisense drug is designed to bind the messenger RNA made by CMV. If the RNA is bound and degraded, the virus cannot replicate. Twenty-two volunteers who had failed intravenous foscarnet or ganciclovir received injections every 2 weeks in a safety study. Last December, Isis began 3 larger efficacy studies, one of which is still open to volunteer participants. Two of the studies were halted because 4 of 23 eyes treated with ISIS 2922 developed stippling (retinal spots), possibly due to a previously undetected toxicity of the antisense drug. The study that remains open offers weekly injections of ISIS 2922 followed by injections every other week to people who have failed other CMV treatment options. Contact ISIS at 619-929-3898 and ask about study CS7. This has been a watershed year for advances in the treatment and prevention of CMV retinitis. More options are available than ever before, and the drugs now available offer a longer period of time without advancement of retinitis. Cidofovir can be administered less frequently by the IV route than currently approved drugs, and its protection is longer lasting. Oral ganciclovir will soon be approved for primary prevention of retinitis, which will allow those who are already using the drug to be reimbursed by insurance plans. Eye implants offer longer lasting protection from advances in retinitis than any other treatment to date. Finally, combination strategies will be available that may be better than previous combinations (IV ganciclovir and IV foscarnet) and will have fewer, more tolerable side efects. Sources Jacobson MA and others. Current management of cytomegalovirus disease in patients with AIDS. AIDS Research and Human Retroviruses 10: 917-22, 1994. Jacobson MA and others. Randomized Phase I trial of two different combination foscarnet and ganciclovir chronic maintenance regimens for AIDS patients with cytomegalovirus retinitis: AIDS Clinical Trials Group protocol 151. Journal of Infectious Diseases 170: 189-93, 1994. Kirsch LS and others. Intravitreal cidofovir (HPMPC) treatment of cytomegalovirus retinitis in patients with AIDS. Ophthalmology 102: 533-42, 1995. Martin DF and others. Treatment of cytomegalovirus with an intraocular sustained-release ganciclovir implant: a randomized controlled clinical trial. Archives of Ophthalmology 112: 1531-39, 1994. Reese RE and others. Handbook of Antibiotics. Little, Brown and Company, Boston. 1993. Spector SA and others. Pharmacokinetic, safety, and antiviral profiles of oral ganciclovir in persons infected with HIV: a Phase I/II study. Journal of Infectious Diseases 171: 1431-7, 1995. Copyright (c) 1995 - San Francisco AIDS Foundation. Reproduced with permission. Reproduction of this article (other than one copy for personal use) must be cleared through BETA, email beta@sfsu.edu. Chiron Vision Files FDA Application to Market Intraocular Implant for CMV Retinitis Chiron Corporation and Hoffmann-La Roche announced on July 5, 1995, that Chiron's ophthalmic business, Chiron Vision, has filed a New Drug Application (NDA) with the US Food and Drug administration (FDA) to market Vitrasert, its intraocular implant which delivers ganciclovir directly to the eye for treatment of cytomegalovirus (CMV) retinitis. The NDA filing is based on results of two independent phase III clinical trials conducted by Chiron Vision and the National Eye Institute (NEI). The studies demonstrated that the Vitrasert ganciclovir implant offers a clinical improvement versus intravenous ganciclovir in further delaying progression of CMV retinitis in the treated eye. Chiron Vision and Hoffmann-La Roche, Inc., will collaborate on the marketing of Vitrasert, Chiron Vision developed the Vitrasert implant technology and Hoffmann-La Roche currently markets Cytovene (ganciclovir), the drug used in the implant. Roche will provide ganciclovir, which was discovered and developed by Roche Bioscience (formerly Syntex), another member of the Roche Group, on an exclusive, worldwide basis for use in the eye implant. In the collaboration, Chiron Vision will develop, manufacture, and sell the Vitrasert for CMV retinitis. The two companies will co- promote the Vitrasert, with Chiron Vision focusing on the ophthalmic surgeon and Hoffmann-La Roche focusing on the primary care and infectious disease physicians. Data from a planned interim analysis of the multicenter, controlled, randomized Chiron Vision study, testing the implant in 188 AIDS patients with newly diagnosed CMV retinitis, were reported January 31, 1995, at the National Conference on Human Retroviruses and Related Infections in Washington, DC. The study demonstrated that the median time to progression of CMV retinitis was 186 days for eyes receiving Chiron Vision ganciclovir intraocular implants compared to 72 days for eyes receiving intravenous ganciclovir therapy (P less than 0.0001). The incidence of extraocular CMV disease was 12 percent in the implant arms versus 0 percent for IV ganciclovir. There were few serious surgical complications. The firms' complete analysis of the data, upon which Chiron Vision's FDA submission is based, confirmed these results. Study participants were assigned randomly to an IV ganciclovir group or one of two implant groups (1 microgram/hour or 2 micrograms/hour), and were followed for eight months or until progression of retinitis or death. Progression of retinitis was determined by a central masked Fundus Photograph Reading Center at the University of Wisconsin. Results of the NEI study, published in the December 14, 1994 issue of Archives of Ophthalmology, showed that AIDS patients had no progression of newly diagnosed, peripheral CMV retinitis for about eight months using the ganciclovir implant. Among those who received no immediate treatment, the eye infection worsened in about 15 days. The study evaluated 26 patients, of which 30 eyes were randomly assigned to either immediate treatment (patients received an implant within 48 hours of study enrollment) or deferred treatment (patients were evaluated until progression of CMV retinitis was noted). The study found that in people who received immediate treatment (within 48 hours of enrollment), the ganciclovir implant eliminated all signs of active infection for a median of 226 days, or about eight months. Among study participant in the deferred treatment group, the median time to CMV retinitis progression was 15 days. During the study, most participants enjoyed good vision with the implant. By the final follow-up eye examination, 34 of the 39 eyes treated with the implant had nearly perfect vision (20/25 or better). However, nearly all affected eyes had blurred vision immediately after receiving the ganciclovir implant, and 18 percent of the eyes experienced retinal detachment, a common problem for people with AIDS with CMV retinitis. Chiron Vision's intraocular implant contains ganciclovir embedded in a polymer-based system that slowly releases the drug into the eye for up to eight months. The implant is placed into the posterior segment of the eye through a 5 to 6 mm incision during a one-hour surgery performed under local anesthesia. The implant can be removed and replaced when depleted of drug. Chiron Vision is preparing applications to market Vitrasert in additional countries. At the Journal's press time, the company plans to file such an application in the first of these countries, Canada, in July, followed by applications in several European countries this fall. Currently, two additional clinical trials are underway to further evaluate the ganciclovir implant for CMV retinitis. Enrollment in these studies is limited to patients who meet certain eligibility criteria. For more information on these studies, contact the Professional Services Group at Chiron Corporation. The number is 1-800-244-7668, select 2. (Journal of the International Association of Physicians in AIDS Care. 1995 July;1(6):37.) [Editor's Note: See also, Martin DF et al. Treatment of Cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant: A randomized controlled clinical trial. Arch Ophthalmol. 1994;112:1531-1539.] New Chiron Method for Treating AIDS-Related Illness Wins OK An advisory panel to the U.S. Food and Drug Administration recommended on Friday the approval of Chiron Corp.'s Vitrasert, an implant that would directly administer to the eye drugs for a potentially blinding disease in AIDS patients. Cytomegalovirus (CMV) retinitis affects as many as 40 percent of all AIDS patients, often when they have less than one year to live. Vitrasert would deliver Roche Holding AG's Cytovene (ganciclovir) via a time-release delivery system implanted in the eye. The panelists recommended that Chiron undertake further studies to determine how the implant might be used with other drugs to treat CMV symptoms throughout the body. They also voiced concerns about a side effect, which caused some patients' retinas to detach from their eyes. Related Stories: Wall Street Journal (12/11) P. B6; Boston Globe (12/09) P. 40 (Investor's Business Daily (12/11/95) P. A17.) Cytovene Capsules Approved Cytovene (ganciclovir) capsules were approved by the Food and Drug Administration on December 22, 1994 as an alternative to the intravenous formulation for maintenance therapy of CMV retinitis in patients with HIV disease. The approved use of the drug is further limited to patients whose retinitis is stable following appropriate IV induction therapy, where the risk of more rapid disease progression is balanced by the benefit associated with the avoidance of daily infusion. The FDA approval allows physicians to prescribe the capsules off-label as a prophylaxis against CMV retinitis. (See JPAAC, November 1994.) In clinical studies comparing cytovene capsules to the IV formulation, progression of CMV retinitis in patients on the oral formulation occurred moderately faster. The mean time to disease progression was 5-12 days faster for patients on the oral formulation. As with the IV formulation, the major side effects of Cytovene capsules are granulocytopenia, anemia, and thrombocytopenia. The most common side effects experienced by clinical trial subjects taking the capsules, compared with those on the IV formulation, were: diarrhea (41 vs 44 percent), fever (38 vs 48 percent), leukopenia (29 vs 41 percent), and nausea (26 vs 25 percent). The benefits of Cytovene capsules over the oral formulation as shown in clinical trials included fewer serious incidents of sepsis (4 vs 15 percent), fewer catheter-related infections (6 vs 22 percent), and a lower incidence of anemia (19 vs 25 percent) and leukopenia (29 vs 41 percent). [Journal of the Physicians Association for AIDS Care. 1995 January;2(1):15.] [Editor's Note: See also: The Oral Ganciclovir European and Australian Cooperative Study Group. Intravenous versus oral ganciclovir: European/Australian comparative study of efficacy and safety in the prevention of cytomegalovirus retinitis recurrence in patients with AIDS. AIDS. 1995;9(5):471-477.] Ganciclovir Approved to Prevent CMV [Dave Gilden. GMHC Treatment Issues. 1995 Nov;9(11):3.] Hoffmann-La Roche received FDA approval last last month to market its capsule form of ganciclovir for preventing CMV infection in people with "advanced HIV infection at risk for developing CMV disease." Oral ganciclovir (brand name:Cytovene) already had approval as a maintenance therapy for CMV retinitis. It could be taken after the infection had been brought under control by two to three weeks of daily infusions with the older intravenous formulation of ganciclovir. Approval of ganciclovir prophylaxis was based on an eighteen- month study conducted by its manufacturer, Roche Bioscience (formerly Syntex Laboratories). This trial found that oral ganciclovir reduced the incidence of CMV retinitis by half (39 percent of participants on placebo contracted the disease compared to 18 percent on oral ganciclovir). Countering the Roche Bioscience trial was one conducted by the community Programs for Clinical Research on AIDS (CPCRA), which found no benefit from oral ganciclovir in terms of preventing symptomatic CMV. But critics have complained that the CPCRA study was not sensitive enough to detect a benefit within its alloted time period. (See Treatment Issues, Octobver, 1995, page 10). The indication approved by the FDA is vaguely worded, reflecting the unresolved question of who should take oral ganciclovir prophylactically. The drug costs $47 a day wholesale and can cause some serious side effects (in particular, suppression of blood cell production by the bone marrow) while only cutting the incidence of CMV by half for the first eighteen months (what happens after that is unknown). CMV normally appears in people with very advanced AIDS. Only those with CD4 counts less than 50 and positive CMV test results may be appropriate for the drug. Alternatively, a history of other opportunistic infections associated with severe immune suppression may be useful in assessing riks. Those who had had mycobacterium avium cmplex (MAC), for example, experienced a four-fold increased risk of CMV in one study (presented last January at the Second Annual Human Retrovirus Conference, abstract 290). CYTOVENE (GANCICLOVIR CAPSULES) From Roche Laboratories (A Member of the Roche Group) Indications: An alternative to CYTOVENE-IV (ganciclovir sodium for injection) for the maintenance treatment of immunocompromised patients, including patients with AIDS, in whom retinitis is stable following appropriate induction therapy and for whom the risk of more rapid progression is balanced by the benefit associated with avoiding daily intravenous infusions. DOSAGE: The recommended maintenance dose of CYTOVENE capsules is 1000 mg tid with food. To maximize bioavailability, it is important to take CYTOVENE capsules with food. Reinduction: For patients who experience progression of CMV retinitis while receiving maintenance treatment with either formulation of CYTOVENE reinduction treatment is recommended. Follow-up examinations: Patients should be advised to have ophthalmologic follow-up examinations at a minimum of every 4 to 6 weeks while being treated with CYTOVENE. Some patients will require more frequent follow-up. How supplied: CYTOVENE (ganciclovir capsules) 250 mg is supplied in bottles of 180. Important safety information: The most serious side effects associated with the use of CYTOVENE are granulocytopenia (neutropenia), anemia and thrombocytopenia. CYTOVENE should not be administered if the absolute neutrophil count is <500 cells per milliliter or the platelet count is <25,00 cells per milliliter. Transient elevation of serum creatinine levels were observed in clinical studies of CYTOVENE. Careful monitoring for renal function should be undertaken while patients are receiving CYTOVENE. Patients receiving CYTOVENE capsules should be advised of the risk of more rapid progression of CMV retinitis when taking the capsules versus daily intravenous infusions. Preventing and Treating CMV Retinitis - Oral Ganciclovir Unlike previous reports, a new study has concluded that oral ganciclovir does not significantly delay the onslaught of cytomegalovirus (CMV) retinitis in HIV-infected individuals. But, "most people feel oral ganciclovir offers protection," said Henry Masur at a recent staff conference at the National Institutes of Health Clinical Center. "Was it a careful study?," Masur questioned. The meeting focused on how sight can be preserved if the infection is identified and treated before symptoms become obvious. Still, many of the newly-available laboratory tests are limited, and oral prophylaxis is expensive and offers no long-term survival benefit. (Lancet (10/28/95) Vol. 346, No. 8983, P. 1153; Rowe, Paul M.) [Editor's note: But see also, Spector S et al. A randomized, double-blind study of the efficacy and safety of oral ganciclovir for the prevention of CMV disease in HIV-infected patients. 35th Interscience Conference on ANtimicrobial Agents and Chemotherapy, San Francisco, 1995.] Cidofovir Available Under Treatment IND for CMV Retinitis FDA has designated the investigational drug cidovir (Vistide) for use in treatment of HIV-infected persons with relapsing cytomegalovirus (CMV) retinitis that has progressed despite treatment. the treatment IND program enables patients with serious or life-threatening conditions who have exhausted existing treatments or have no satisfactory treatment to be treated with promising investigational drugs. Further information on access under the Treatment IND may be obatained from the sponsor, Gileas Sciences Inc of Foster City, Calif. Telephone: (800-GILEAD 5 from 8:00 AM to 6 PM EST. [From the food and Drug Administration. JAMA. 1995;274(14):1109.] New CMV Treatment - Cidofovir Gilead Sciences, Inc., announced in late August that it has begun a Phase II study of an intravitreous formulation of cidofovir for the treatment of relapsing cytomegalovirus (CMV) retinitis. This randomized, controlled, multicenter study is designed to deterine the safety, tolerance and efficacy of various dose levels of cidofovir whlen administered locally by direct injection into the vitreous or inner chamber of the eye. The study is designed to enroll up to 90 patients with relapsing CMV retinitis that has progressed despite treatment with a currently approved systemic therapy. CMV retinitis occurs in approximately 15% to 40% of patients with AIDS. CMV is a syustemic disease and the most common viral opportunistic infection occurring in approximately 95% of AIDS patients. CMV can infect several sites in the body and when it invades the retina, lesions form on the light-sensitive layer of cells at the back of the eye that transmits images to the brain. As these CMV lesions progress, the patients's vision deteriorates. Currently approved therapeutics for CMV retinitis are administrered as systemic agents. Some patients, however, may benefit from local therapy administered directly to the eye. Patients enrolled in this study will receive a single injection of intravitreous cidofovir at one of three dose levels in each infected eye. Patients may continue to receive one or more subsequent injections as maintenance therapy. In April, results from two investigator-sponsored clinical studies using intravitreous injections of HPMPC, the active ingredient in intravitreous cidofovir were published. The data was encouraging in that it suggests the intravitreous HPMPC may be beneficial in delaying the time to progression of CMV retinal lesions and that further investigation is merited. This is the purpose of the Gilead-spnosored trials that are currently underway. (NAPWA Medical Alert. 1995 Nov/Dec;3(5):5.) ---------------------------------------------------------------- Information Sheet for Patient Education June 16, 1995 [Editor's Note: Belos is one of a series of Information Sheets prepared by the National AIDS Treatment Information Project (NATIP) with funding from the Henry J. Kaiser Family Foundation. The materials are designed for self-education by HIV-infected persons and for counseling by community advisors, case managers, social workers, and clinicians. For more information about NATIP, call 617-667-5520 or write: Helen E. Woods Wogan, Project Manager, Libby 317, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215. Fax: 617-667-2885. Internet: hwoods@bih.harvard.edu] What is cytomegalovirus? Cytomegalovirus (CMV) is a virus that infects more than half of all adults but rarely causes significant disease unless there is damage to the person's immune system. Health adults usually become infected by CMV through close personal and sexual contact with others. After CMV infects a healthy person, the immune system keeps virus from spreading and causing disease but never completely eliminates CMV from the body. How does it affect HIV-infected persons? Since CMV is spread in a similar fashion to HIV, it often infects persons with HIV disease. After HIV infection has progressively damaged the immune system over a period of years, your body may no longer be able to control CMV, and the virus may cause disease. CMV disease is rare until the T-cell count is below 100. In this setting, CMV may cause disease in the eye (retinitis), the gut (esophagitis, colitis), and occasionally the nervous system, liver, and lungs. What are the symptoms and signs of CMV disease? The symptoms of CMV disease depend on the part of the body affected by the disease, and similar symptoms can be caused by other conditions. People with CMV retinitis may have blurry or lost vision, or they may see small moving spots called "floaters" or shadows as if a shade is drawn over the eye. Early retinitis is often without any symptoms whatsoever. CMV esophagitis usually causes pain or discomfort in the mid-chest when swallowing food. People with CMV colitis may have fever, loss of appetite, abdominal pain, and diarrhea. CMV can also cause painful tingling or pain in the legs, hands or feet (neuropathy), yellow eyes and skin (jaundice), or pneumonia. How is CMV disease diagnosed? CMV retinitis has a typical appearance on examination with an ophthalmoscope, an instrument which the doctor uses to look in the back of your eyes. Detection of early disease requires dilating your pupils with eye drops. To diagnose CMV disease in other parts of the body, your doctor must perform a biopsy (take samples of tissue), which is cultured (placing it in a laboratory container to try to grow the virus) and examined under the microscope. Small numbers of CMV may be present in the body fluids even in persons without symptoms, and the virus can often be detected by culture. A positive culture, however, means that CMV is present in the body but does not prove that it is causing disease. How is CMV disease treated? There are two standard treatments for CMV disease: ganciclovir and foscarnet. Neither of these drugs will cure CMV, but they often suppress the disease, improve symptoms, and prevent further damage to the body. High-dose therapy with one of the medications is generally provided for 2-3 weeks, followed by a reduced daily dose once the infection has stabilized. Both drugs require a daily infusion, and they have to be given through the vein (intravenously) every day for about 2 to 4 hours. CMV treatment is usually infused through a small tube called a catheter (Hickman or Portacath) inserted into the chest or arm (a PICC line) that makes it easier and safer to give the infusion. The catheter must be bandaged and kept clean and dry. Because drugs only slow down CMV but do not eliminate it from the body, treatment must continue indefinitely. You must also see your doctor regularly to make certain that the CMV disease is not getting worse and that the medicine is not causing serious side effects. It is possible that these drugs will not work well or have side effects that make you feel sick and that your doctor will need to change your regimen. While there has been one study suggesting that foscarnet therapy may be associated with slightly longer life expectancy than ganciclovir, foscarnet can also have more serious side effects and require a more lengthy daily infusion. In patients with CMV retinitis who are unable to tolerate either medication, ganciclovir implants or injections have been used with some success. An oral form of ganciclovir is now also available, although it is still unclear in what situations it might be useful. Other medications, which might be more effective and easier to take, are also being evaluated in clinical trials. What are side effects of the treatments? The most common side effect from ganciclovir is low white blood cell count (neutropenia), which generally does not cause symptoms. The neutropenia will usually go away if you stop taking the drug. Neutropenia can also be treated with a medication called G-CSF (Neupogen), which is given by injection under the skin (subcutaneous). AZT can also cause neutropenia, and, because of this, taking AZT and ganciclovir together is usually not recommended. Other side effects from ganciclovir may include anemia, fever, rash, gastrointestinal disturbances (nausea, vomiting, diarrhea), and abnormal liver function tests. Foscarnet can cause serious metabolic disturbances (low blood calcium, magnesium, phosphorus, and potassium), kidney damage, and skin ulceration. Another very difficult side effect of both drugs is the possibility of developing an infection from the catheter. Symptoms may include fever, redness or soreness at the catheter site, or difficulty with infusing fluids. It is very important to keep the catheter clean and dry and to change the bandage that covers it regularly. Catheter infections can be very dangerous and should be treated immediately by your doctor. Can CMV disease be prevented? There are no medicines proven to prevent CMV from causing disease in HIV-infected persons, although oral ganciclovir is currently being evaluated. Regular eye examinations may be useful in detecting early CMV retinitis in those at risk.