GMHC Treatment Issues, Volume 10, Number 5 - May 1995

Responding to a campaign by Project Inform and the company's own Community Advisory Board, Glaxo Wellcome has broadened the financial assistance program for its new popular antiviral 3TC. Previously, Glaxo refused to provide free or discounted 3TC to anyone covered by a state ADAP (AIDS Drug Assistance Program) that refused to include the drug in its formulary. (ADAPs, which serve 62,000 people nationwide, pay medicine costs for uninsured people with HIV of low or moderate income.) Glaxo refused to be the reimburser of last resort, but that stance left people without access to 3TC in the eleven states whose ADAPs did not include 3TC. With ADAPs across the country facing a financial crunch (see Treatment Issues, February 1996, pages 11-12), these people were unlikely to obtain 3TC any time soon, no matter how much pressure Glaxo's policy put on the states.

In announcing the change, Glaxo vice president Steve Skolsky noted that Glaxo will not necessarily back up everyone eligible for state ADAPs, only those who also meet Glaxo's criteria for financial assistance.

Merck & Co. has also come under sharp criticism for a similar policy in regard to financial assistance for indinavir. Only three ADAPs (Maryland, North Dakota and Washington) now pay for this protease inhibitor, and only seven others were expected to add it soon.

Fortunately, as part of the Ryan White Care Act extension passed by Congress in May, an extra $52 million will be available this year for ADAP expenses. New York and California ADAPs have already decided to cover protease inhibitors starting in July. Funding is still short, though, and it remains to be seen how well the ADAPs can keep up with the costs of the new anti-HIV treatments.

** DMP 266: Keep the Drug but Dump the Trial?

"DMP 266" is a nonnucleoside reverse transcriptase inhibitor (NNRTI) like nevirapine or delavirdine that was originally created by Merck but languished when that company decided to concentrate on its protease inhibitor program. It was recently bought by DuPont Merck, a joint venture owned by DuPont and Merck. In its first human trials DMP 266 by itself reduced plasma HIV levels (viral load) in 20 volunteers by a median of over 1.4 logs, or greater than 96 percent.

Such figures make DMP 266 one of the most potent anti-HIV agents ever tried in humans. But previous NNRTIs are notorious for the speed with which HIV develops resistance to them, through a single point mutation in the virus's reverse transcriptase enzyme. The duration of DMP 266's effect remains unknown. Several mutations in reverse transcriptase appear necessary for high-level resistance to emerge. Researchers hope HIV strains resistant to DMP 266 are less likely to exist prior to treatment and will be slower to evolve after therapy commences. To ensure stability of response, though, future trials will test the compound only in combination with other drugs except for short two-week intervals.

Two new trials are about to begin: One tests DMP 266 in combination with indinavir while the other is a study of DMP 266 plus AZT and 3TC. Details on the second trial have yet to be released, but the first study is a fourteen-week, placebo- controlled trial taking place at ten East Coast sites. The 360 participants must have CD4 cell counts of between 100 and 500 and viral loads exceeding 20,000.

The DMP 266/indinavir trial is a step toward creating simpler, more "compact" drug combinations that strongly suppress HIV while having fewer toxicities and simpler dose schedules than current combination therapies. But this trial has already aroused some criticism in the AIDS community: over 100 participants in the trial's control arms will receive indinavir monotherapy (800 or 1,000 mg three times a day) for twelve to fourteen weeks.

Indinavir monotherapy is generally not advised for fear that HIV resistant to it will easily evolve, especially in people with high baseline viral loads. Volunteers assigned to this therapy risk not being able to receive full benefit from indinavir and other protease inhibitors that trigger similar resistance mutations -- ritonavir, for example.

** PMPA Beats SIV Again

Gilead Sciences' drug PMPA can prevent mucosal transmission of simian immunodeficiency virus (SIV) and potently reduce SIV burden in infected macaques, according to data presented at the Ninth International Conference on Antiviral Research, held in Japan on May 19 to 24. These studies follow earlier data showing that administering PMPA could protect uninfected macaques against injected SIV (see Treatment Issues, December 1995, page 3).

In the treatment study, ten macaques infected with SIV were injected for four weeks with two different daily doses of PMPA. Levels of the virus in the monkeys were reduced 100- to 1000-fold while viral load increased in two untreated macaques. Viral load became undetectable in eight out of ten of the treated monkeys, although SIV DNA (a measure of infected cells rather than free virus) was still detectable in most. After four weeks, treatment was discontinued and SIV levels rebounded to baseline.

There appeared to be no toxicity at the low dose, but the higher dose caused slight reductions in red blood cells, hemoglobin and phosphates, all of which reversed when treatment stopped. Studies of PMPA's effect in humans are expected to begin sometime this year.

Researchers in the transmission study treated four monkeys with an intravaginal topical gel containing ten percent PMPA. After intravaginal inoculation with SIV, the team performed weekly viral detection tests to see whether the macaques had become infected. All remained free from infection. After eight weeks of follow-up, the monkeys were still SIV- negative. Similar studies with microbicides such as the commercially available nonoxynol-9 have found that only one- third of treated monkeys were protected from SIV exposure.

** Oxymetholone Adds Weight

People with HIV experienced dramatic weight gains in a recently published German study of the oral anabolic steroid oxymetholone and the antihistamine ketotifen (see the British Journal of Nutrition, January 1996; 75(1):129-38). Ketotifen is thought to increase weight by lowering the body's production of tumor necrosis factor (see Treatment Issues, May 1995, page 7), but it seemed to add nothing to the observed benefit from oxymetholone. Marketed in Europe, both drugs are available in the United States only through unofficial channels.

The 60-person, 30-week study followed volunteers who had lost more than ten percent of their body weight within the previous four months. Persons who had had an active opportunistic infection in the previous six months were excluded, as were those whose weight loss due to chronic fever and diarrhea with no known cause.

Thirty trial participants were randomized to two treatment arms. One group received 50 mg of oxymetholone three times a day. The other took the same dose of oxymetholone plus 50 mg twice a day of ketotifen. The remaining 30 participants went untreated and served as controls.

Within four weeks, those on both treatments began to gain weight. At thirty weeks, treated volunteers had increased their weight by ten percent whereas untreated volunteers had lost four percent. By the crude Body Mass Index, treatment led to an increase in lean body mass. Appetite and quality of life improved in the treated patients. Both agents were well tolerated.

** Anti-CMV Drug Trials Back On-Line

Fomivirsen (formerly ISIS 2922) is an antisense RNA molecule designed to attack CMV. It is under study as an intraocular injection for CMV retinitis. Last year, Isis Pharmaceuticals placed fomivirsen trials on hold when the dose under evaluation, 330 mg, was found to cause a loss of peripheral vision in twenty percent of the patients with early stage disease (see Treatment Issues, July/August 1995). This side effect only occurred in one out of forty patients with more advanced retinitis, though, so the company continued testing fomivirsen in that population.

The company then performed a dose escalation study in twelve patients with early stage retinitis, starting with a 75 mg dose. There was no toxicity and little treatment effect, so the researchers increased the dose to 150 mg. This dose has produced none of the undesirable effects, and the company claims it has produced prolonged responses in a larger percentage of patients (although it is vague about both the number of responders and the duration of benefit).

Isis has now reinstated trials at the lower, safer dose in persons with early, non-sight threatening (peripheral) CMV retinitis. The study compares the time to progression in patients who are immediately treated to that of patients who do not receive treatment until after progression. Enrollment has not been rapid due to the earlier problems. The same is true of a second trial that compares fomivirsen plus oral ganciclovir to induction therapy with intravenous ganciclovir followed by oral ganciclovir maintenance therapy. (Adding oral ganciclovir to the intraocular fomivirsen injections addresses the threat of CMV breakthrough in the other eye or elsewhere.)

Two other studies have been opened. One is for patients with advanced CMV retinitis and compares two different dosing regimens. The second is for patients who have failed the other antiviral therapies and have no remaining therapeutic options. One of fomivirsen's key selling points is that there is no cross-resistance to other anti-CMV drugs, so there is a possibility that the drug can offer benefit in otherwise untreatable patients. For information about the location of trial sites near you, call 800/679-4747.

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