T-20 and Adefovir for Salvage Therapy -- Expect No Miracles

An experimental agent that promises to augment treatment strategies without running into cross-resistance with present antivirals is now entering phase II clinical trials. Trimeris Corporation's T-20 is a 36-amino acid peptide that forms part of the gp41 protein on HIV's outer coat. gp41 facilitates virus-cell fusion by extending outward and penetrating cell membranes, in a manner analogous to a three-pronged harpoon. T-20 binds onto the gp41, preventing this harpoon-like action.

Last fall Trimeris presented data on a pilot T-20 trial utilizing four doses infused intravenously twice a day. Not much happened in the 12 volunteers receiving the three lower doses, but the four receiving 100 mg twice a day saw their viral loads plummet by at least 97% in a mere two weeks. Trimeris' two upcoming trials will test T-20 in 72 people who have failed to have a stable response to indinavir, ritonavir or nelfinavir. Rather than intravenous infusion, the trials will employ a portable subcutaneous infusion pump of the type at present used by many diabetics to receive insulin. During the trials' first ten days, T-20 will be administered as monotherapy to compare the response to five different doses, four using the pump and one delivered by twice-a-day subcutaneous injection. The 24-week extension phase will continue all participants on the infusion pump and add a combination of efavirenz and nelfinavir plus either saquinavir (for those previously on indinavir and ritonavir) or ritonavir (for those previously on nelfinavir).

All trial volunteers must be NNRTI-naïve, so at least the T-20 and the efavirenz, both highly potent drugs, will be active. Still, the use of T-20 at possibly suboptimal doses does give one pause. As persons with a history of protease inhibitor failure, the trial participants who develop T-20-resistant HIV will have lost one of their few remaining treatment options.

An article published in the February, 1998 Journal of Virology described the ease with which HIV in cell cultures can mutate to resist T-20. All that is required is two point mutations on the genetic sequence for gp41. The mutated HIV produced in these experiments did not seem substantially impaired in any way. HIV's capacity for escaping T-20 in the human body remains to be documented, but the cell culture results are comparable to what is seen with protease inhibitors.

T-20's other main strengths and drawbacks stem from its peptide structure. Since it is a protein fragment, common enzymes easily break it down in the digestive track and the blood. This is the reason it cannot be administered orally and has a half-life of only about two hours once in the bloodstream. But T-20's non-oral administration plus the lack of kidney or liver involvement in its metabolism also means that it avoids many of the major toxicities of current antiviral drugs.

The portable pump ensures a constant level of T-20 in the body, which periodic infusion could not achieve. Although it is a very small removable device that delivers drug through a thin tube inserted just under the skin, many persons with HIV question its practicality. Also, a new pump needs to be purchased every five years for about $4,500, and supplies add another $1,000 per year. This expense is on top of the anticipated high cost of T-20 itself, which presents a manufacturing challenge due to its lengthy, specific amino acid sequence.

Adefovir -- Just Like a Nuke

Because of its drawbacks, Trimeris is concentrating on developing T-20 as salvage therapy, where lack of treatment options would make its shortcomings acceptable. To demonstrate T-20's benefits in this arena, the company ultimately will have to conduct a randomized trial in which participants' personal standard combination regimens are supplemented by either T-20 or placebo.

This sort of trial is now underway for Gilead Sciences' nucleotide analog adefovir. Preliminary results were presented in April at the 11th International Conference on Antiviral Research (ICAR). "Protocol 408" is a 442 person, 12-month trial that enrolled people with viral loads greater than 2,500 copies/ml and CD4 counts over 200. It found that those on adefovir plus standard drugs exhibited an viral load drop averaging 0.39 log (41%) at six months. Those who received only their choice of standard drugs had no change in viral load over this period. CD4 count changes in both groups were negligible on average.

Gilead is quick to point out that these results are similar to those obtained with the nucleoside analogs now on the market, confirming what the company has argued all along. The impression that adefovir adds another option to the available gamut of nucleoside analogs was furthered by another trial presented at ICAR, which compared various combinations of the drugs adefovir, AZT, 3TC and indinavir in 85 treatment-naïve volunteers. All of the three and four drug combinations effected a greater than two log (90%) drop in viral load at week 20, with about 80% of the participants in each treatment arm below 400 copies/ml, the limit of quantification. CD4 counts were up 89 to 129 in the adefovir-containing arms compared to 66 in the AZT/3TC/indinavir arm. (Also presented at ICAR were data indicating that adefovir is highly effective at suppressing hepatitis B virus.)

Adefovir resembles the approved nucleoside analogs in other ways, too. According to yet another ICAR presentation, the most frequent HIV mutations arising in protocol 408 participants were those most commonly associated with AZT resistance. HIV with an AZT-resistance profile is about six to eight times less susceptible to adefovir and grows as well as wild type, nonmutated virus. Gilead has further studied the behavior of the HIV in four of the trial participants who had AZT-resistance mutations at baseline and later developed the codon 184 mutation associated with 3TC resistance. Special lab tests indicated that the codon 184 mutation resensitizes AZT-resistant HIV to adefovir, as it does to AZT sometimes (and did in these four individuals). Gilead scientists think that this means that adefovir will be a good salvage therapy for those with AZT/3TC experience. The company is now analyzing individuals who participated in protocol 408 to see if this resensitization is reflected in the response to adefovir in the human body. It is now well known, though, that when the codon 184 mutation resensitizes HIV to AZT, the effect is temporary and leads to further compensating mutations. The same could be true for adefovir.

Meanwhile, Gilead has embarked on an enlarged expanded access program for adefovir. Adefovir is now available to anyone who has failed combination therapy with at least two commercially available nucleoside analogs and at least one protease inhibitor, whatever that person's CD4 count or viral load. Enrollees will be assigned to receive either 60 mg/day of adefovir or 120 mg, the dose used in most of the trials -- or they can choose to obtain the higher dose.

Warning: The main reason for trying the lower dose is that Gilead has found that 40% of the people on 120 mg/day for over six months are developing signs of incipient renal tubule damage (Fanconi-like syndrome). Preliminary data suggest that the 60 mg dose has the same anti-HIV effect as 120 mg and is much safer. Still, one wonders whether adefovir is suffering from the d4T or ddC syndrome, in which toxicity-induced dose reductions sapped the drugs' antiviral potency.

Treatment Issues will provide more information about the adefovir-kidney situation as it becomes available. In the meantime, anyone taking adefovir is urged to rigorously adhere to the monthly kidney test schedule that Gilead requires.