Subject: New Antiviral Update Date: Feb 1993 (258 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Project Inform P E R S P E C T I V E &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Permission granted for non-commercial use. New Antiviral Update The saga continues as to the best use of AZT, ddI and ddC, in which combination, at what dose, and for how long. Throughout the course of debate, one issue becomes clear there is an urgent need for more and better antiviral options. Fortunately, there are a number of promising antiviral therapies in the pipeline, some of which are available through larger trials or expanded access, such as d4T. Others are expected to enter larger scale testing this year, such as 3TC. Novel approaches to blocking HIV replication are also being pursued, with drugs which block HIV at different parts of its life cycle, such as proteinase and tat inhibitors. Additionally, new information on innovative strategies for controlling HIV, by targeting the destruction of HIV-infected cells or manipulating the immune system to help inhibit HIV replication, are encouraging and hold great promise. Nucleoside Analogs There are a number of nucleoside analogs, similar to AZT, ddI and ddC, which are still in the development pipeline. These include d4T, 3TC, and FLT. All nucleoside analogs are not the same. Just as the three currently approved antivirals have a different set of toxicities and indications for use, so too the antivirals on the horizon have unique features which make them more and less attractive. While d4T, for example, seems to occasionally cause the same type of peripheral neuropathy seen with ddI, the early information suggests d4T may be more potent than the existing antivirals. Preliminary results of early studies indicate that some study participants experienced 50% CD4 cell count increases which were sustained for one year. 3TC on the other hand, does not demonstrate the anti-HIV activity of other drugs but early results of study show that it is virtually nontoxic. While 3TC may never have its place among the ranks of first line antiviral therapies, it may prove to have an important role in combination approaches or for people who cannot tolerate other antivirals. d4T In October of 1992, Bristol-Myers began an expanded access program for d4T, which is now in large efficacy trials at many sites around the country. (For information on entering these trials, call 1-800-TRIALS-A.) In uncontrolled studies, d4T has indicated clear anti-HIV activity and the ability to produce rises in CD4 counts lasting much longer than rises produced by other single nucleosides. The drug's only serious potential toxicity seems to be peripheral neuropathy, which, as with ddI, has sometimes been successfully managed by cutting the doses in half. In one study d4T produced improvements in neurocognitive functioning equal to those produced by AZT, suggesting that it may be helpful to some people with HIV-related dementia (and of special importance to such people if they can't tolerate AZT. The expanded access program provides d4T to people who are intolerant of both AZT and ddI, or who have failed both drugs. For more information on d4T and the expanded-access program, a d4T Fact Sheet is available through Project Inform's toll free hotline. A point to remember is that, although the expanded access program focuses attention on the use of d4T in a specialized, mostly later stage group, the drug may ultimately take its place among the currently approved drugs, to be used in ways that can't be foreseen. It may end up being used in late disease, in early disease, as first line therapy, as fall back therapy, alone or in one or more combinations. 3TC Early results from a phase I dose ranging study evaluating the safety of 3TC were discouraging. Upon closer analysis of the data, however, poor results were attlibuted to subclinical doses, meaning the doses used in the trial were too low to be effective. The sponsor, Glaxo, subsequently raised the doses of drug in the trial. As the doses were increased, so was the anti-HIV activity of the drug, although never to the level of other approved antivirals. Despite increasing doses, toxicities were not apparent.3TC is expected to go into larger scale testing this year. The other nucleoside currently in trials, FLT, produced serious toxicities, adversely affecting red cells, white cells, and platelets. Trials have been on hold, after two deaths that may or may not be FLT-related, and the future of the drug is unclear. In general, everyone wants to move beyond nucleosides to other kinds of drugs. But if d4T and 3TC are in certain ways better than AZT, ddI and ddC, there could be quite a lot done with five nucleosides to mix and match. As more nucleosides show efficacy, alone and in combination, people may become anxious about which is the best option, since there have been no studies comparing the most promising therapies to each other. Although several important studies will report data in the coming months, the aggregate results are unlikely to produce accord on any single superior therapy. A scientific consensus has developed that combination antivirals are more effective than monotherapy, but, due to problems with intolerance or access, a single drug like AZT or d4T may sometimes still be a better option. There may in the end be a number of valid antiviral strategies, none dramatically superior to the others. Doctors and patients should always be flexible, willing to alter therapy according to individual response and in light of new evidence as it appears. Other Antivirals...GLQ223 Two studies of GLQ-223 (compound Q, or trichosanthin) were presented at the International AIDS Conference in Amsterdam, one from Project Inform and one from the manufacturer, Genelabs (including data from San Francisco General Hospital and several other sites). The Project Inform study of 29 volunteers, which has completed,reported on doses escalating to 100 micrograms/kg., over a 2-year period. The Genelabs study of 54 study participants reported on doses escalating to 200 mcg./kg., over the same time. The Project Inform study allowed simultaneous use of AZT, ddI, ddC, PCP prophylaxis and acyclovir; the Genelabs study allowed only Q initially, and later added AZT. Both studies showed that, as doses increased, and as the total dose each volunteer had taken increased, there tended to be rises in CD4 and CD8 cells, with a concurrent trend to improved general health. The positive correlation was almost identical in the two studies. An interesting feature of the Project Inform study (which included people defined as having AIDS or ARC) was the virtual absence of severe side effects not just to Q, but to any of the other drugs people were on. None of this is really new, and the Genelabs study has since gone on to higher doses of 500 mcg/ kg. The principal measure of the efficacy of aLQ-223 will come from the current controlled trial, now under way in San Francisco and other cities. Pentoxifylline Pentoxifylline (Trental) is a prescription drug that reduces a natural substance called tumor necrosis factor (TNF), which is elevated in people with HIV. High TNF levels are associated with increased HIV replication and with decreased activity of concurrent nucleoside analogs. In Amsterdam a study of 25 people on pentoxifylline reported reduced TNF (but not below normal levels) and HIV titers. There was no reported increase in CD4 counts. Since there were no severe side effects, the next round of trials will double the dose (from 1200 mg to 2400 mg per day) to look for stronger anti-HIV action. There are some east coast cities where pentoxifylline is a relatively popular community drug. It's a blood thinner, used mostly for leg cramps in older people, and is a reasonable alternative for people looking for something different and easily available, with some science behind it. Because pentoxifylline is approved, people considering off-label use of the drug should talk to their doctor and continue careful monitoring. A plan for a larger study of pentoxifylline is in the works. Another compound in human trials, N-acetylcysteine (NAC), has also been shown to reduce TNF levels in laboratory studies. The major rationale behind the development of this compound, however, is to raise glutathione levels, which may be decreased in people in later stages of HIV- infection. A more in-depth analysis of NAC is warranted, but for lack of space in this issue of the PI Perspective, people interested more in this subject should call the Project Inform Hotline. Proteinase and Tat Inhibitors Proteinase inhibitors and TAT inhibitors are new kinds of antivirals that have been widely publicized for years without moving along very quickly. Hoffman LaRoche has both a TAT inhibitor and a proteinase inhibitor, and both have been in safety and pharmacokinetics trials for some time, in both the United States and Europe. Hoffman LaRoche says that there are no data at all on whether either drug has any antiviral effect in humans, but trials to determine efficacy are expected to begin shortly. Thus far it is believed that if Hoffman really had something with their proteinase, they would be forthcoming with information. Other companies, including Abbott Laboratories and Merck, have proteinase inhibitors in development as well. Abbott's intravenous (IV) proteinase, which was under study in the Netherlands, ran into difficulties due to side affects, most notably liver toxicities. While Abbott will continue the study at lower doses in hopes of answering some pathogenic questions about proteinase in humans, they have decided to abandon their IV proteinase program. Abbott will still continue their efforts on an oral proteinase inhibitor, however, which is expected to enter human studies, in Amsterdam and Paris, in April of this year. Ateviridine Upjohn's BHAP-compound, U-87201E, is a non-nucleoside reverse transcriptase inhibitor. A small trial of U-87201E, which has recently been given the generic name ateviridine, has, as we go to press, just completed. This study was small and involved 15 volunteers, with CD4 cell counts less than 500. The goal of the study was to determine the safety and pharmacokinetics of ateviridine in combination with AZT, and to determine if resistance to ateviridine develops if taken in combination with AZT. More information about this study will be available soon. In test tubes ateviridine has an antiviral effect, but it's unknown whether it does much in people. Further small studies are proceeding. Three-Drug Combinations A current trial is combining AZT, ddC, and alpha interferon, based on laboratory studies of increased anti-HIV effect with the three drug combination. Two-drug combinations with alpha interferon have never shown much increased efficacy (nothing that most people would consider justification for using an expensive injectable drug with unpleasant side effects). These drugs are all approved, and some doctors have been experimenting with AZT/ddC/alpha interferon or AZT/ddI/alpha interferon, but none have reported their results. The trial is using standard doses of AZT and ddC and 3 million units a day of alpha interferon, which is low but not low enough to escape side effects. The idea of three-drug combinations may be on the cutting edge of future research. If two drugs work significantly better than one, then three or more may work significantly better than two. A laboratory study presented at the International AIDS Conference in Amsterdam showed that a combination of AZT, ddI and a non-nucleoside reverse transcriptase inhibitor, nevirapine, hitting the virus at essentially the same point (the formation of reverse transcriptase), caused the virus to mutate in away that rendered it completely inactive, even after the drugs were withdrawn. It is unclear whether this would happen in humans, but it's another possible path, and could represent a use for the otherwise disappointing non-nucleoside reverse transcriptase inhibitors. As we go to press, a study of this three drug combination is about to begin in humans, through the AIDS Clinical Trials Group (ACTG). The other three-drug combination reported at the conference featured AZT and alpha interferon, plus thymosin, a thymic peptide that's also been studied for use against hepatitis. A small Italian study of people with up to 500 CD4 cells compared AZT alone to AZT plus alpha interferon to AZT plus alpha interferon plus thymosin; after 18 months, the one-drug and two- drug groups were below baseline in CD4 counts, while the three- drug group showed "a substantial and sustained increase" from a mean of 324 to a mean of 582. This three-drug group also showed greater decreases in viral load and increases in measures of CD4-cell function. This particular study is really too small to be considered conclusive, but clearly the idea of combining antivirals with immune-based therapies represents, as Project Inform has long maintained, a major area for further research. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display