Being Alive; August 1996
Henry E. Chang

Nucleotide Analogues

Nucleotides are the building blocks of genetic information in cells and viruses. Researchers have developed ways to chemically alter natural nucleotides which lead to the creation of false genetic building blocks, known as nucleotide analogues, that can inhibit viral reproduction. Gilead Sciences is the industry pioneer and leader in the field of antiviral nucleotide development and has recently received FDA clearance to market the first-ever nucleotide analogue, Vistide (cidofovir, HPMPC), for the treatment of CMV retinitis in people with AIDS.

Unlike the existing antiviral nucleosides, such as AZT, ddI, ddC, d4T and 3TC, nucleotides persist in cells for longer periods of time because they carry a negatively charged phosphate component. Thus, nucleotides have a more favorable half-life and are able to form a drug reservoir inside the cell which allows for an infrequent dosing schedule. By contrast, most nucleoside analogues must be administered multiple times each day. Gilead Sciences is conducting clinical studies of two of its antiviral nucleotide analogues, PMEA and bis-POM PMEA (or adefovir dipivoxil), and is soon to position its third compound, PMPA, for clinical evaluation.

In laboratory experiments, PMEA has demonstrated additive antiviral activity when combined with ddI, 3TC, ritonavir and saquinavir and modest to minor synergistic effect when combined with AZT, ddC, and d4T. In a comparative study with ganciclovir, PMEA has produced statistically significant reduction in death rate in a murine CMV animal model. Results from preliminary studies of PMEA in HIV-infected individuals have shown encouraging safety and activity profiles which justify further clinical evaluation. So far, viral resistance to PMEA has been difficult to establish in cell cultures. Dr. Julie Cherrington's group at the company has recently reported that two mutations in the reverse transcriptase enzyme (positions 65 and 70) lead to a ten-fold reduction in the viral sensitivity to PMEA. Importantly, no significant cross-resistance to AZT-resistant or 3TC-resistant strains has been observed.

An oral prodrug of PMEA, bis-POM PMEA (or adefovir dipivoxil), has also entered clinical testing in HIV-infected individuals. Bis-PLM PMEA has been shown to inhibit a broad spectrum of viruses including HIV, herpesviruses, and hepatitis B virus. Like PMEA, bis-POM PMEA resistant viruses have been difficult to establish in cultures. The compound has a bioavailability or absorption rate of 40% in humans and has a convenient once daily dosing schedule due largely to its prolonged half-life inside cells.

In a Phase I/II study conducted in antiretroviral-experienced people with CD4 counts of greater than 200, bis-POM PMEA alone has demonstrated statistically significant sustained reductions of viral load in the bloodstream by about 70% over 12 weeks. Statistically significant increases in CD4 cells were also noted. Gilead is now recruiting HIV-infected individuals with CD4 counts between 200 and 500 to participate in a new bis-POM PMEA study designed to assess the safety and efficacy of adding bis-POM PMEA to existing antiretroviral therapy. Interested individuals are encouraged to contact the company for study eligibility criteria and the nearest study centers by calling 1.800.445.3235.

Another nucleotide analogue, PMPA in a topical formulation, has been shown to completely protect against vaginal transmission of SIV in primates. SIV or simian immunodeficiency virus infection in primates is a model for HIV. In addition, subcutaneously injected PMPA provided complete protection against the development of SIV infection in all primates treated for 4 weeks either shortly before or after exposure to the virus. The company is expected to soon file an investigational new drug application with the FDA to initiate the clinical testing of PMPA in HIV-infected individuals.

Nucleoside Analogues

There are a number of nucleoside analogues in early stage development. In particular, two nucleosides have recently captured people's attention due to their early encouraging safety and efficacy profiles-Glaxo Wellcome's 1592U89 and Bristol-Myers Squibb's lobucavir.

1592U89 is a nucleoside reverse-transcriptase inhibitor. In a study conducted in HIV-infected individuals with limited prior antiretroviral exposure having CD4 counts of between 200 and 500, different doses of 1592U89 alone and in combination with AZT produced a marked reduction of viral load in the range of 1.8 to 2.1 log or about 99% after 12 weeks of therapy. CD4 counts were increased by 63 to 126 cells over the same time period. The company has a very aggressive program to evaluate 1592U89 in combination with inhibitors of reverse transcriptase and protease in both acutely and chronically infected individuals.

Bristol-Myers Squibb presented preliminary data on its nucleoside reverse transcriptase inhibitor, lobucavir, at the International Conference on AIDS in Vancouver. Lobucavir has broad-spectrum antiviral activity and has been shown to inhibit cytomegalovirus, herpes simplex virus, hepatitis B, varicella zoster virus, Epstein-Barr virus, and HIV. Lobucavir has good oral bioavailability and is well tolerated thus far. The compound has exhibited acute potent antiviral activity with reductions in viral load by as much as 1.5 log or greater than 90% after 28 days of therapy. In addition, a dose-related anti-CMV activity has been noted in HIV+, CMV-infected individuals.

(Henry E. Chang is Research Director of AIDS Healthcare Foundation, the nation's largest community-based HIV/AIDS medical service provider. He can be reached at 213.468.1351.)

960810
BA960803

Copyright © 1996 - Beings Alive. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used. Subscription lists are kept confidential. Being Alive, 621 N. San Vicente Blvd., West Hollywood, CA 90069, Tel - 310.289.2551; FAX - 310.289.9866; Email: BeiAlive@aol.com  http://www.beingalivela.org/