Protease inhibitors, routinely used to treat the human
immunodeficiency virus (HIV) in the United States, are highly
effective against the subtype C viral strain thought to be most
prevalent worldwide, report Stanford researchers.
Drugs against HIV developed in the United States are tested only
against subtype B, the version of HIV-1 that is most common in this
country. However, scientists have not known whether protease
inhibitors would 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 study.
Both Protease Inhibitors and Reverse Transcriptase Inhibitors Effective
Dr. Shafer and his colleagues did laboratory tests on blood samples
from African patients infected with the subtype C virus to determine
whether this version of HIV would respond to the new drugs. According
to Dr. Shafer and David Katzenstein, MD, associate professor of
medicine and senior author of the study, subtype C is responsible for
the pandemic in southern Africa and India and is the cause of 90% of
all new infections worldwide.
Weve shown that all the [protease inhibitor] drugs are
highly effective against the subtype C virus, even though they
werent designed for it, said Dr. Shafer. This has
relevance to people in developed countries with subtype C and also
could be applicable to underdeveloped countries, should treatment
The study appeared in the January 1 issue of AIDS Research and Human
Retroviruses. The Stanford researchers conducted a similar study last
year involving reverse transcriptase inhibitors 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.
New Treatment Program to Prevent Mother-to-Child Transmission
These laboratory studies have given impetus to a new treatment
program designed by Dr. Katzenstein. The program calls for the use of
two reverse transcriptase inhibitorszidovudine (AZT [Retrovir])
and nevirapine (Viramune) in HIV-infected women and their
infants with the goal of preventing mother-to-child transmission of
HIV during breast-feeding.
Dr. Katzenstein, who spent 2 years teaching virology and treating
AIDS patients in African, said studies suggest that 5% to 10% of
mother-to-child HIV transmissions occur as a result of
breast-feeding. In his planned study of 100 women, mothers will
receive AZT before and during delivery of breast milk, while infants
will receive nevirapine at regular intervals as 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, said Dr. Katzenstein.
In the two laboratory studies of the AIDS drugs, the researchers used
blood samples obtained by Dr. Katzenstein in 1995 from 12 factory
workers (11 men and 1 woman) in Zimbabwe who had been infected with
the subtype C virus within the previous 6 months. Dr. 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 subtype 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 the B
viruses do, said Dr. Shafer.
Drs. Shafer and Katzenstein also reported that the primary targets of
antiretroviral therapythe protease and reverse transcriptase
genesare 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%, whereas the reverse
transcriptase genes and protease genes of global isolates generally
differ from one another by no more than 10% to 12%. Dr. 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.
Drug Costs Still a Big Issue
I think the drugs target something that is very well-conserved.
And that is good news, he said. I think well find
that drugs work against worldwide strains. There is the bigger issue
of getting those drugs to the people who need them.
Protease inhibitors are expensive, with a years therapy costing
between $2,000 and $4,000. The cost of AIDS drugs generally has been
a major obstacle to treatment of patients in underdeveloped
countries, such as Zimbabwe, noted Drs. Shafer and Katzenstein.
In addition to Katzenstein, Shafers 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.