Business Wire - Wednesday, January 20, 1999

HIV drugs developed in this country are only tested against subtype B, the version of HIV-1 that is most common in the United States. So scientists have not known if protease inhibitors, the newest class of HIV drugs, might be effective in treating different viral subtypes that are predominant elsewhere in the world, said Robert Shafer, MD, clinical assistant professor of medicine at Stanford and first author of the latest study.

Shafer and his colleagues did laboratory testing on blood samples from African patients with the highly prevalent subtype C virus to determine if this version of HIV would respond to the new drugs. Subtype C is responsible for the pandemic in southern Africa and India, where millions of people are infected with HIV, and is the cause of 90 percent of all new infections worldwide, according to Shafer and David Katzenstein, MD, an associate professor of medicine and senior author of the study.

"We've shown that all the (protease inhibitor) drugs are highly effective against the subtype C virus, even though they weren't designed for it," Shafer said. "This has relevance to people in developed countries with subtype C and also could be applicable to under-developed countries, should treatment become available."

The latest study appears in the January 1 issue of the journal AIDS Research and Human Retroviruses. The Stanford researchers conducted a similar study last year involving reverse transcriptase inhibitors, the earlier class of AIDS drugs, and found that these drugs were also very effective against subtype C. That study appeared in the July 1997 issue of the Journal of Virology.

These laboratory studies have given impetus to a new treatment program designed by Katzenstein, who plans to use two reverse transcriptase inhibitors -- AZT and nevirapine -- in HIV-infected women and their infants in Zimbabwe. The goal is to prevent mother-to- child transmission of HIV during breast-feeding.

Katzenstein, who spent two years teaching virology and treating AIDS patients in the African nation, said studies suggest that 5 to 10 percent of mother-to-child HIV transmissions occur as a result of breast-feeding. In his planned study of 100 women, the mothers will receive AZT before and during delivery, while the infants will receive nevirapine at regular intervals while they are being breast-fed.

"In the long run, we may be able to develop a strategy to prevent transmission of HIV to kids with a small amount of the drug," which is relatively inexpensive, Katzenstein said.

He said the laboratory studies were valuable because they confirmed that these drugs would be effective in the Zimbabwean patients.

"It was important to do these studies so that we could feel comfortable in committing to use of these drugs in people who are not part of clinical trials in the United States," Katzenstein said.

In the two laboratory studies of the AIDS drugs, the researchers used blood samples obtained by Katzenstein in 1995 from 12 factory workers (11 men and one woman) in Zimbabwe who had been infected within the previous six months with a form of the virus identified as subtype C. Katzenstein brought the samples to Stanford, where they were cultured and then subjected to genetic sequencing to determine how much this version of the virus differed from the more common B version in the United States.

The researchers also exposed the C viral samples to four different protease inhibitors to see how well they would respond. In all cases, the C samples were found to be highly sensitive to treatment, responding much in the same way as B viruses do, Shafer said.

Shafer and Katzenstein also reported finding that the primary targets of antiretroviral therapy -- the protease and reverse transcriptase genes -- are among the most conserved parts of the HIV-1 genome.

Previous studies have shown that the envelope genes (which are relevant to the design of vaccines) of global HIV-1 isolates may differ from one another by about 30 percent, whereas the reverse transcriptase genes and protease genes of global isolates generally differ from one another by no more than 10 to 12 percent. Shafer said it appears that as the virus has evolved during its spread among humans it has not changed enough to elude current drug treatments.

"I think the drugs target something that is very well-conserved. And that is good news," he said. "I think we'll find that drugs work against worldwide strains. There is the bigger issue of getting those drugs to the people who need it."

Protease inhibitors are expensive, with a year's therapy costing between $2,000 and $4,000, he said. The cost of AIDS drugs generally has been a major obstacle to treatment of patients in under-developed countries, such as Zimbabwe, Shafer and Katzenstein noted.

In addition to Katzenstein, Shafer's colleagues in the study are Teddy K. Chuang and Philip Hsu, both 1997 graduates of Stanford, and Camille Bodley White, PhD, a Stanford research associate.

The study was funded by the National Institutes of Health.

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CONTACT: Stanford University Medical Center Ruthann Richter, 650/723-6911 (Media) Robert Shafer, MD, 650/725-2946 (Comment) David Katzenstein, MD, 650/725-8304 (Comment) http://www-med.stanford.edu/center/communications

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