Adefovir Dipivoxil (Preveon)
Recently, Gilead Sciences reported raw and preliminary data in a press release from two ongoing just recently unblinded studies. NATAP does not usually report data from a press release but it is the only new data available on adefovir. Since the drug is available through expanded access, this information may be helpful. 160 treatment naive individuals in study GS 411 received indinavir with NRTI therapy with or without adefovir. At 20 weeks, Gilead reported about 80% treated with an adefovir regimen had <400 copies/ml, a median CD4 increase of 92 cells, and a median decrease in viral load of 2.1 to 2.5 log. The control group also had 80% with <400 copies/ml, a median increase of 66 CD4, and a median decrease in viral load of 2.15 log. This data suggests that adefovir could be substituted for a NRTI with equal improvement in CD4s and viral load, but the data has not been adequately broken down enough to sort it out. Grade 3 or 4 LFT elevations were 8% in the adefovir group vs 5% in the non-adefovir group. Also, Gilead reported 24 week data released from GS 408 saying that the adefovir treatment group had a -0.39 log reduction from baseline compared to a -0.01 log reduction for the comparison group not receiving adefovir. But, the study design makes it difficult to sort out adefovirs effect on viral load in this study. NATAP will report additional analysis of the data when available.
Subsequent to releasing the above information, Gilead Sciences recently reported adverse events from the adefovir GS 408 study and other studies. As of March 1, 1998, more than 3000 patients have been treated with Preveon in clinical trials and more than 500 patients have been treated for greater than or equal to 6 mos. 4% (n=18) of individuals in study GS 408 who received adefovir 120 mg per day for up to one year experienced grade 3 or 4 lab abnormalities, which were generally asymptomatic related to renal (kidney) dysfunction. And, 38.6% of participants in GS 408 (receiving drug for 6 mos or more ) were noted to have moderate (grade 1 or 2) changes in lab abnormalities in 3 out of 5 markers of renal function. It appears as if these adverse events do not emerge until 6 months on drug. The 5 markers are hypophosphohemia (decreased phosphate), decreased serum bicarbonate, elevated sugar in the urine, elevated protein in the urine, and elevated serum creatinine. Such an experience may predict development of a serious renal complication. As a result of developing these renal complications, individuals are either coming off drug or downdosing to 60 mg. In some cases, downdosing to 60 mg resolves the problem and in some cases it doesnt. It may be preferable to come off drug until the adverse events resolve. Of those 18 individuals mentioned above who experienced the grade 3 or 4 changes, all patients with followup of greater than or equal to 2 months have had complete or partial resolution of the lab abnormalitities. Gilead says it is unlikely that the abnormalties will not resolve. Individuals can be treated with potassium if they have low potassium or phosphate if they have low phosphate.
Gilead says, the company is discussing strategies to address these developments. Within a few weeks Gilead expects to have 20 week safety and efficacy data for the 60 mg dose of Preveon from study GS 417. Gilead will look to see if there is antiviral activity from the 60 mg dose and a reduction in the potential for adverse events. Gilead has had close monitoring of these markers for more than 1 year, and will continue to identify early signs that can predict potential problems. Patients currently receiving Preveon in studies are having certain lab tests monitored closely to observe for lab abnormalities. Better understanding of early signs would allow improvement in the toxicity management guidelines. Studies planned to begin will also have these close monitoring guidelines as well as incorporate other approaches to address these concerns.