A Rocky Road for Nucleotide Analogs
Nucleotide Analogs' Toxic Side Effects
Gilead Science has been developing a class of broad-spectrum antiviral agents called nucleotide analogs for over five years. To date, cidofovir (Vistide) has been approved for the treatment of AIDS-related CMV retinitis and adefovir (Preveon) is in an expanded access program for the treatment of HIV. Both compounds have proven antiviral activity and long half-lives in the body, which allow for less-frequent dosing. Unfortunately, both compounds are also associated with the development of potentially serious side effects, including damage to the kidneys.
More Problems with Cidofovir
Continuing reports of adverse events associated with cidofovir use prompted Gilead to distribute a letter to health care providers and community members in August, reinforcing the importance of following strict treatment guidelines when administering the drug. Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred after as few as one to two doses of cidofovir. Anyone with impaired renal function should not receive the drug. Patients should avoid other agents with nephrotoxic (kidney-damaging) potential, such as foscarnet.
Intravenous hydration with at least one liter of saline solution should be administered prior to each infusion of cidofovir. Three doses of oral probenecid must be administered the day of the infusion. (Probenecid is a drug that prevents the kidneys from absorbing the cidofovir.) Renal function must be monitored 48 hours prior to every dose. In the event that serum creatinine and urine protein levels are elevated, cidofovir dosing should be reduced or discontinued. If all of these guideline are rigorously followed each time the drug is administered, the risk of renal toxicity is reduced.
In addition to the high incidence of kidney problems, a higher rate of uveitis (inflammation of the eye) has been reported than had been anticipated based upon clinical trial experience. The rate of eye inflammation was under 5% in trial participants, but since the drug was approved, ophthalmologists from three university clinics have reported rates of 50% in patients receiving cidofovir therapy for 125 days (JL Davis et al. Archives of Ophthalmology. June 1997; 115(6):733-7). Patients with more advanced CMV disease are more prone to uveitis.
Any eye inflammation after an infusion should be reported to the ophthalmologist immediately, as continued dosing with full-strength cidofovir can exacerbate the situation. Uveitis can lead to scarring and loss of sight. Although it can be treated with topical steroids, there is a risk for the development of cataracts. Hypotony, a serious condition of reduced pressure in the eyeball, can also occur, so intraocular pressure should be monitored.
Finally, three cases of hearing loss associated with cidofovir have been reported. Upon discontinuation of therapy, the hearing impairment abated. Janet Davis, M.D., of the University of Miami, summed things up by stating, "I think cidofovir is an excellent drug -- it works for the retinitis -- but it is very, very toxic. It has to be treated with extreme respect."
Adefovir Dosing: How Low Can You Go?
The development of renal toxicity has been associated with the use of Gilead's other nucleotide analog, the anti-HIV agent, adefovir. While the onset of kidney problems is very rapid with cidofovir, it is much more gradual, and thus far less severe, with adefovir. As TI reported in April, 40% of people on the 120 mg/day adefovir dose for over six months were developing signs of incipient kidney tube damage ("Fanconi-like" syndrome -- see Treatment Issues, April 1998). Gilead has recently amended its expanded access program to include dose reductions. Under the revised protocol, newly enrolled patients will be randomized to either 60 mg or 120 mg doses. All patients receiving 120 mg will have their dose reduced to 60 mg after 16 weeks of treatment. Patients receiving 60 mg of adefovir who experience treatment-related adverse events will have the option to either permanently discontinue treatment or reduce the dose to 30 mg daily.
There is only preliminary data to support the efficacy of the 60 mg dose and none to support the 30 mg dose. The data available on 60 mg comes from Protocol 417, which compares doses of 60 mg and 120 mg in combination with other antiretroviral agents, including protease inhibitors. Since the study is still ongoing, investigators do not know which dose participants are taking. After 20 weeks of therapy, efficacy results are comparable between the two groups, but the potent antiviral effect of the protease inhibitors might obscure any impact from either dose of adefovir. One dose level does appear to be better tolerated with respect to renal toxicities. Gilead is betting that this is the 60 mg dose.
Monthly lab tests are required to monitor creatinine, electrolytes, liver function, urine protein and glucose. It remains to be seen whether Gilead can find a dose of adefovir that is both potent and well tolerated. Until then, patients will have to decide whether the benefits of adefovir, especially at lower doses, are worth the potential toxicities.
As TI went to press, Gilead announced that the large CPCRA 039-adefovir protocol was terminated by the trial's Data and Safety Monitoring Board. Safety concerns did not trigger this decision. Rather, 039 was unable to accrue enough participants to answer its primary question: is there a survival benefit for the adefovir group? The study was not designed to look at virologic markers (changes in viral load, percent below detection) as the main proof of the drug's impact. In fact, the data that were collected indicated no differences between 120 mg of adefovir and placebo on HIV viral load. Adefovir's relatively moderate antiviral effect would have been obscured in any case since participants were permitted to change their other drugs at will.
Adefovir for AZT/3TC Users
A major remaining question is whether there are subpopulations that can obtain enhanced benefit from adefovir. A genotypic substudy was conducted on 142 participants from Protocol 408 -- Gilead's pivotal trial that supplemented participants' existing therapy with adefovir or placebo for 24 weeks. Mean baseline viral load was 25,120 copies/ml. Results of the substudy were reported this summer at the 2nd International Workshop on HIV Drug Resistance and Treatment Strategies in Italy.
Participants were broken down by baseline genotypic resistance mutations. Between 70% and 90% had previously used 3TC and over 90% had previously used AZT for an average of three years. In this heavily pretreated group, 76% at baseline had the codon 184 mutation associated with 3TC resistance. All participants in the substudy continued using 3TC in their regimens. The participants with the 184 mutation alone achieved a 0.94 log (88%) decrease in viral load at week 24. Participants with the 184 mutation plus high-level AZT resistance (as defined by mutations at codons 41 and 215) experienced a 0.51 log (69%) reduction in viral load. Confirming that adefovir is ineffective against AZT-resistant HIV, the worse antiretroviral response, an average 0.05 log (11%) reduction, was seen in participants with high-level AZT resistance without the 184 mutation. (The few study participants with none of these mutations experienced a 0.65 log (78%) viral load reduction.)
The addition of the 184 mutation seems to increase HIV's sensitivity to adefovir, although the durability of this effect is unknown because of HIV's propensity to develop further compensating mutations. Still, Gilead may position adefovir as salvage therapy for the large AZT/3TC experienced population with few other treatment options. Although the viral load reductions are not huge in this group, they are better than the 0.39 log (59%) reductions seen by the 408 cohort as a whole. Choosing a drug based on the presence of specific resistance mutations is a novel concept, but as more is learned about the significance of genotyping, this may become a useful means for tailoring treatment regimens.