December 1997/January 1998
Chiron Vision's Vitrasert eye implant has been an important addition to the anti-CMV armamentarium because of its ability to deliver higher concentrations of ganciclovir directly to the infected retina (see Treatment Issues, April/May 1997). However, the implant does not protect the rest of the body from new CMV disease. For this reason, many patients consider using systemic medication, such as oral or IV ganciclovir, to prevent the spread of disease. The choice of which prophylactic agent to use and at what dose, however, has been in question. Daniel Martin, M.D., of Emory University in Atlanta, Georgia, reported the long-awaited results of Roche's protocol 2304 at the late-breaker session at ICAAC (LB-9). This study compared the implant plus 4.5 grams daily of oral ganciclovir (Cytovene capsules) versus the implant plus oral placebo versus IV ganciclovir alone.
Between May 1994 and July 1996, 377 patients were randomized to one of the three treatment groups. Investigators found that participants on oral ganciclovir plus implant remained on treatment longer (follow-up for the oral ganciclovir plus implant group was 251 days as opposed to 176 days for the IV alone group). At six months, the incidence of CMV appearing beyond the originally affected eye was 44.3% in the placebo plus implant group, 24.3% in the oral ganciclovir plus implant group and 19.6% in the IV ganciclovir group. The time to development of such "new" CMV disease (25% incidence) was 84 days in the placebo and implant group, 184 days in the oral ganciclovir and implant group and 223 days in the IV ganciclovir group. Oral ganciclovir reduced the overall risk for the development of new CMV disease by 37.6%. Where oral ganciclovir plus the implant really stood out was in preventing disease progression in the infected eye: Time to CMV progression in the implant-treated eye (25% incidence) was 180 days in the placebo plus implant group, 267 days in the oral ganciclovir plus implant group and only 39 days in the IV only group. In a subgroup receiving concomitant protease inhibitor treatment, incidence rates of new CMV were low in all groups.
Oral ganciclovir was associated with a reduction in the number of hospitalizations, days spent in the hospital and incidence of new AIDS-associated conditions, particularly KS. Dr. Martin speculated that ganciclovir inhibits herpes virus 8 (HHV8), which appears to trigger KS. Survival rates favored oral over IV ganciclovir but did not achieve statistical significance. Adverse events were similar among treatment groups except for neutropenia (low white blood cells), which occurred more frequently in the two cohorts receiving systemic ganciclovir, and sepsis (blood infection), which was more common in the IV group. Dr. Martin concluded that 4.5 grams of oral ganciclovir daily, used in conjunction with the implant, delays the onset of new CMV disease and progression of CMV retinitis and reduces the incidence of KS.
Of note, the FDA-approved dose of oral ganciclovir is 3 grams per day for maintenance and prophylaxis. However the 3 gram dose was not used in protocol 2304. This was because of data from two studies: Roche study 1653 indicated that IV ganciclovir was more effective than 3 grams of oral in preventing the spread of CMV disease while Syntex/Roche study 2226 demonstrated that 4.5 grams/day of oral was closer in efficacy to IV (and 6 grams was even better -- see Treatment Issues, Sept. 1996 ).
Roche is not seeking FDA approval to increase the dose listed in the package insert. According to Bob Posch, HIV Community Development Director, the 4.5 gram dose was used in this study because there was no induction phase in the implant arms. Roche recommends induction with IV ganciclovir for 21 days followed by the standard 3 gram oral ganciclovir maintenance regimen. Those who choose not to use IV, but instead opt for the 4.5 gram oral dose, will need to take 18 Cytovene capsules per day and will incur high annual costs that may not be completely reimbursable. (In fact, the combination of oral ganciclovir and implant used in the 2304 study costs well over $20,000 per year.)
The other reason why Roche is not pursuing a change in the dosing with the FDA is that the company is proceeding with the development of its oral ganciclovir prodrug (RS79070), which will be an improvement over even the highest 6 gram dose of Cytovene capsules.
Roche's ganciclovir prodrug is over 50% more bioavailable than the current oral formulation. The prodrug is more readily absorbed by the gut and then broken down into active ganciclovir once in the body. In addition, the same serum levels of ganciclovir can be achieved with the prodrug as with IV ganciclovir. As reported in previous issues, Roche put the prodrug program on hold this spring (see Treatment Issues, April/May 1997 , and Sept. 1997). When pressed, Roche assured community activists that a decision would be made on the future of the program by year's end. And at the end of October, Roche announced it would go forward with a new development plan for the prodrug, now known as valganciclovir.
Negotiations with the FDA have enabled Roche to expand its only existing trial, WV 15376 (376), from 18 to 50 sites worldwide and from 70 to about 150 participants. Protocol 376 will now become the pivotal efficacy trial for FDA approval. It compares valganciclovir to IV ganciclovir as induction therapy for newly diagnosed peripheral CMV retinitis. The benefit of valganciclovir over IV ganciclovir is considerable: Induction with the prodrug requires taking only two 450 mg pills twice a day for three weeks, followed by just two 450 mg pills once a day for maintenance.
Even though the 376 trial is only four weeks long, it will still take some time to get valganciclovir to market. Enrollment in this trial may not be complete until 1999 if the accrual rate does not pick up. When FDA approval does come, the indication will be for treatment only in HIV patients. Roche is working with the NIH's AIDS Clinical Trials Group to design prevention trials, but these will be larger and longer studies. In order to be a viable, cost-effective option for CMV prevention, valganciclovir will need to be more effective and priced lower than the hugely expensive Cytovene capsules. Anyone interested in participating in 376 may call 800/TRIALS-A.