SANTA MARGHERITA DI PULA, SARDINIA A new class of antiretrovirals known as protease inhibitors appear to offer promise in bolstering the treatment of patients with AIDS, according to reports at an investigators meeting here.

The initial enthusiasm that greeted the development of zidovudine (AZT), the first antiretroviral treatment for AIDS, turned to frustration with the realization that HIV quickly developed resistance to the drug. The basic problem is that rapid mutations in the RT (reverse transcriptase) gene confer resistance to this and similar drugs (known as nucleoside analogues). The problems of resistance and cross-resistance among nucleoside and non-nucleoside inhibitors of reverse transcriptase have become a major obstacle in the treatment of AIDS.

Early studies with a second class of antiretrovirals, the protease inhibitors, also raised concerns about resistance. However, several studies presented at the conference appear to provide some cause for hope regarding more effective antiretroviral treatment of HIV disease with optimal combinations of drugs from both classes.

The results of a randomized trial indicated that combination therapy with a protease inhbitor, saquinavir and a nucleoside analogue, zidovudine was more effective than either drug alone. The effects of the drugs were measured in terms of CD4 cell counts, reduction in HIV viral load and the emergence of resistance, reported Stefano Vella M.D., Director, Retrovirus Section, Instituto di Sanita, Rome.

"These results suggest that the combination of saquinavir and zidovudine may delay the emergence of resistance to either drug," he said.

Genotypic analysis of phase I/II trial data on saquinavir alone and in combination with AZT, or in triple combination with AZT and DDC (a drug in the same class as AZT) , also indicates that patients appear to respond best to the combination therapies, and that this correlates with the absence of genotpyic resistance.

An extensive analysis of clinical and in vitro data by Dr. Jacobsen and colleagues has led to the identification of two mutations commonly seen in association with saquinavir in about 50% of cases after one year. Moreover, a study of 1,500 protease sequences showed that saquinavir does not produce HIV species that are cross resistant to other protease inhibitors.

This suggests that patients who develop resistance to saquinivair could be switched to other protease inhibitors since saquinavir resistant HIV variants would still respond to other drugs in the same class, explained Dr. Jacobsen. The identification of these mutations should also make it easier to select patients who are most likely to respond to saquinavir, he noted.

Further analysis of data from clinical trials suggests that resistance to saquinavir develops less quickly and to a lesser extent that seen with other protease inhibitors. The lack of observable resistance in some patients treated for as long as three years was also cited by researchers as an encouraging observation.

"For people with AIDS, these new findings are significant," said Dr. Vella. "First, it tells us that administration of saquinavir does not appear to prejudice the efficacy of other protease inhibitors in development. Second, it appears that saquinavir used in combination with other anti-HIV drugs may reduce the risk of resistance."

Taken together, these finding appear to suggest an improvement in the treatment of HIV with antiretrovirals, concurred Graeme Moyle, M.D., MRC Senior Research Fellow, Chelsea and Westminister Hospital London, the largest AIDS clinic in Europe.

"We still don't have any long term clinical endpoint data on protease inhibitors. The data we do have suggests combination therapy with two or more agents from different classes may delay development of resistance. Careful selection of dosage, the alternating use of different inhibitors not subject to cross resistance, and tailored combination therapies may offer ways to prevent or delay the onset of clinical resistance," he noted.

BACKGROUND--

HIV protease (also called proteinase) enzyme is responsible for the maturation of specific polyproteins into HIV active structural proteins and essential viral enzymes, particularly RT. Since one class of drugs targets one enzyme and another a different enzyme, cross resistance has not been observed between nucleoside analogue reverse transcriptase inhibitors (such as AZT) and protease inhibitors.

Much remains unknown in the field of HIV drug resistance. For example, little is known about the frequency of mutations during therapy, pathogenicity of different resistant strains, role of these strains in disease progression. There is also very little data on the relationship between development of resistance to individual drugs and clinical outcome.

Saquinavir is in the most advanced stages of clinical trials with FDA approval expected later this year. Several other protease inhibitors are also under development.

These studies were presented (and interviews conducted) at the 4th International Workshop on HIV Drug Resistance Conference in Sardinia, Italy, in July 1995.