GMHC Treatment Issues; Vol 9, Number 9 - September 1995
Theo Smart

Protease Inhibitors

AG1343 (VIRACEPT): British researcher Michael Youle, M.D., reported the complete results from the first clinical trial of AG1343, Agouron Pharmaceutical's protease inhibitor (abstract 2160). Although all the people treated with AG1343 experienced a substantial reduction in viral load and increases in CD4 cell counts, the surrogate marker responses were not as impressive as those for the first patient to complete the study (see Treatment Issues, June, 1995, page 4).

The 28-day study evaluated two doses, 300 and 600 mg, in twenty HIV-positive men with CD4 cell counts above 200. The drug seemed to be well tolerated, although diarrhea, nausea, mild fatigue and poor concentration were reported in some trial participants.

Certain individuals did experience a greater than 99 percent (two log) reduction in HIV RNA in each arm of the study, but the average maximum decrease was 80 percent in the low dose, and 91 percent in the high dose. The average increase in CD4 cell counts was 140 (one patient had an increase of almost 500 CD4 cells). Given the size and short duration of the study, it is hard to determine whether the antiviral effect is sustained -- at the end of twenty days the viral load seemed to be increasing slightly in most patients. It is unclear whether this trend represents decreasing antiviral activity or natural variation in the HIV RNA marker.

Another confounding variable was that the study was plagued by poor compliance, according to Donna Nichols, Agouron's director of communication. Far more patients were lax about taking drug and showing up for appointments than the company expected, given how well the drug supposedly is tolerated.

Data out to three months on the low dose were presented on two people who experienced a greater than one log (90 percent) reduction in viral load within the 28-day study and were then offered extended treatment. Although there may have been a slight increase in viral load by day 90, these patients' RNA levels were still more than 96 percent below baseline.

A dose-ranging study using a new formulation (and higher doses) is currently on-going in the U.S. Reports of good viral load and CD4 count responses in trial participants already are circulating. There also have been complaints that mild diarrhea is a more common side effect than previously reported (according to Ms. Nichols, diarrhea has occurred in six out of 30 patients). Three phase II/III studies are expected to begin sometime this October or November. The largest of these will be a clinical endpoint study of AG1343 plus standard of care (any approved drugs that people wish to take) vs. standard of care alone in people with less than 50 CD4 cells.

Palinavir or BILA-2011 BS: Palinavir, a new protease inhibitor made by Boehringer Ingelheim, should be in clinical trials in the Netherlands by the end of the year. Researchers characterized the drug as having excellent antiviral activity, good bioavailability and an acceptable safety profile in animals (abstract 0496).

The drug suffers from some of the same problems as other protease inhibitors in development: palinavir is a complex molecule and will probably be difficult to manufacture. It also binds to alpha acid glycoprotein, the naturally occurring blood protein that was found last year to bind to and inactivate Searle's protease inhibitor. Unlike the Searle compound, plasma levels of free drug should still be high enough to suppress HIV -- assuming that palinavir is absorbed by the intestines in humans as well as it is in animals. HIV does become resistant to the compound in lab cultures. One mutation occurs that makes the virus slightly less susceptible to palinavir, but a second mutation is required to develop substantial resistance. One of these mutations is unique to palinavir while the other is also seen in lab cultures treated with the Agouron drug, AG1343. The mutant virus is not cross-resistant with Roche's saquinavir, but there does appear to be some decreased susceptibility to the Merck protease inhibitor.

An intriguing laboratory finding is that after repeated exposure to increasing concentrations of palinavir and the development of mutations in the protease enzyme, a new mutation occurs not in the protease itself but in the polyprotein that the protease cleaves in order to make new infectious HIV particles. It is not clear whether this mutation will emerge in humans or whether this is a good or bad development.

Daniel Lamarre, M.D., of Boehringer's Canadian subsidiary Bio-Mega, believes that the change in the polyprotein shows that the enzyme's activity is greatly compromised by the mutations palinavir induces. Dr. Lamarre speculates that perhaps the right combination of protease inhibitors might force mutations that dramatically impair the virus's ability to reproduce.

PRO 2000

Martin Hirsch, M.D., presented the initial human data on PRO 2000, a new antiviral produced by a small company called Procept (abstract 0380). This compound blocks infection of CD4 cells by interfering with the binding of HIV's outer protein gp120 to cells' CD4 receptors. Preliminary pharmacokinetic studies of single doses of the drug have already been performed in HIV-negative people. Though the drug seems safe thus far, there are some potential problems with long-term administration (in studies with monkeys, high doses of the drug impaired blood coagulation). Dose-ranging studies in people with HIV are now beginning in the Netherlands.

Liposomal Exonuclease VII

Researchers from the University of Turin presented novel work with a cellular enzyme, exonuclease VII, that degrades single strands of DNA (abstract 0631). Most exonucleases also degrade cellular RNA, which is always single-stranded and orchestrates cellular metabolism. Destroying too much RNA is fatal to most cells.

Exonuclease VII, in contrast, only targets single strands of the usually double-stranded DNA. Exonuclease VII also is large for such an enzyme -- too large to pass through the pores of the nuclear membrane or mitochondria, where the host cell's DNA is located. Exonuclease VII can only chew up single strands of foreign DNA, including HIV's, that it encounters in the cytoplasm outside the nucleus. (HIV DNA exists temporarily in the cytoplasm as a single-stranded molecule. This occurs while it is being constructed by reverse transcriptase from the genes in an invading HIV particle, which are in RNA form.)

The Italian researchers found that when the enzyme is introduced enclosed within a liposome (fat globule), it blocks HIV infection in cell cultures without harming the cells. Such liposomes would isolate the enzyme until they contact one of the immune cells serving as reservoirs for HIV.

Liposomal Foscarnet

Scientists from Montreal have conducted experiments with liposomal foscarnet in mice (abstract 0636). These fat globules dramatically increase foscarnet's plasma half-life as well as its uptake into macrophages and lymphoid organs. More importantly, the liposomes substantially lower accumulation of the drug in the kidneys, whose functioning foscarnet greatly impairs. Administration of liposomal foscarnet may therefore increase the drug's effect while decreasing its toxicity. Although liposomes are generally too large to cross the barriers between the blood and the brain and the retina, which is necessary in order to treat CMV encephalitis or retinitis, free drug concentrations in the brain and retina were higher in the mice injected with the liposomal drug than in the mice administered the non- liposomal product. This was possibly due to foscarnet's increased half-life.

Liposomal encapsulation can also increase foscarnet's antiviral activity against both CMV and HIV. Michel Bergeron, M.D., the researcher from the UniversitÄ Laval in Quebec City who is developing and has patented the product (and who also organized the ICC conference), says that his primary focus is to use this formulation to treat HIV in the lymph nodes and macrophages that act as reservoirs for the virus. If the pharmacokinetics are as good in humans as they are in mice, it may be possible to administer the drug as a subcutaneous injection on a daily or perhaps even weekly basis. Another possibility is that the drug can be administered through a slow-releasing subcutaneous implant.

Presently, Dr. Bergeron's team is focusing on the toxicology studies in animals. "I hope to move into patients within a year," says Dr. Bergeron. "The first study we're going to do is a phase I in HIV-negative patients." Then he plans to do a study in patients with HIV and lymphadenopathy. A subset of the patients in these studies will be monitored for progression to CMV disease, and other herpes virus infections. Part of Dr. Bergeron's interest in foscarnet is that "it is a broad spectrum antiviral." He will probably need a pharmaceutical company to help with the development costs, since manufacturing liposomal drugs is expensive.

Roxithromycin for Cryptosporidiosis

Two clinical studies from Brazil evaluated the safety and efficacy of roxithromycin, a macrolide antibiotic like clarithromycin and azithromycin, in the treatment of the intestinal parasite cryptosporidium.

In one of the studies (abstract 2148), 300 mg of oral roxithromycin was administered twice daily for four weeks to 22 people with HIV and cryptosporidium. Eleven patients were cured, six had partial responses and one patient failed to respond. Four did not complete treatment (two dropped out due to toxicity). An increase in blood levels of liver enzymes, an indication of liver damage, was the most commonly seen complication. Although these results are better than most seen for cryptosporidia treatment, the trial participants had a high CD4 cell count (mean 257). Individuals with CD4 cell counts over 200 may clear cryptosporidia even without treatment.

Another Brazilian study of roxithromycin (abstract 2158) involved eighteen persons with somewhat lower CD4 cell counts (an average of 187 and a range of 20 to 349) taking 300 mg of roxithromycin twice daily for four weeks. Ten of these individuals had a complete response, four had a partial response and four failed treatment. These researchers found no difference in response to treatment based on CD4 cell count. Once again, an increase in blood levels of liver enzymes was the most frequent side effect.

The FDA has not approved roxithromycin for sale in this country. The drug is currently in phase III clinical trials for various bacterial infections and is sold unofficially by the PWA Health Group in New York.

Imiquimod for Genital Warts

Imiquimod is a drug that induces the local production of alpha interferon. In double blind placebo controlled studies of 311 persons with genital warts (abstract 0185), imiquimod treatment (five percent in a cream base, self-administered) cured 56 percent of the patients (warts resolved in fourteen percent of those on placebo). Alvin Friedman-Kien, M.D., of New York City, is currently studying imiquimod in people with HIV and ano-genital warts.

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