San Francisco Chronicle; Wednesday, July 1, 1998
David Perlman, Chronicle Science Editor

Scientists at the 12th World AIDS Conference in Geneva said the case could mark an ominous new turn in the global epidemic that has already claimed more than 10 million lives.

The mutated strain of the AIDS virus, seemingly impervious to protease inhibitors and older anti-virals now in use, was found in a newly infected patient at San Francisco General Hospital.

"We may be seeing an emerging and dangerous edge to the epidemic," said Dr. Frederick Hecht of the University of California at San Francisco, who delivered the report on the disheartening case.

A study conducted by researchers at the University of Geneva found similar drug-resistant strains of HIV in six of 57 male patients, who, like the San Francisco patient, contracted the virus through unprotected sex. A report on those cases was presented by Dr. Sabine Yerly of the university's virology laboratory.

The discoveries "should deliver a loud wake-up call on multiple fronts in the battle against AIDS," said Dr. Anthony Fauci, a pio neer AIDS fighter who directs the National Institute of Allergy and Infectious Diseases in Washington.

The San Francisco case, confirmed through genetic analysis, was a middle-aged patient of Hecht's. The man was recently infected during unprotected sex with his HIV-positive partner, whose virus became resistant after he was infected -- until now the only way drug resistance was known to originate.

The blood of both men is resistant to all four of the protease inhibitors now in use, as well as to two older, widely used AIDS drugs, AZT and 3TC. Protease inhibitors have generated huge excitement for the past two years because they can reduce HIV to undetectable levels in the blood. Taken in "cocktails" with other traditional AIDS drugs, they have brought thousands of patients back to good health, although patients must take the complex and costly combinations on a daily basis for the therapy to work.

Drug resistance to the older AIDS medicines like AZT has emerged after long-term use, and has been caused by the tendency of the AIDS virus to undergo mutation.

Only one or two mutations are needed for the wily virus to escape the killing effect of the older drugs, which attack HIV by disabling an enzyme --reverse transcriptase -- that the virus requires to reproduce. The newer protease inhibitor drugs block a different enzyme. Based on the extraordinary success of multiple-drug cocktails in clinical tests, the protease inhibitors generated high hopes at the last World AIDS conference in Vancouver two years ago. Scientists at the Vancouver meeting theorized that it would be difficult for the AIDS virus to develop resistance to the new anti-virals.

RAPID MUTATIONS

Now, however, Hecht and his colleagues have found that HIV can quickly undergo genetic mutations many times. In the new case, it took seven successive mutations for the virus to escape the effects of the protease inhibitors, Hecht said. The new drug resistance, he said, was detected by scientists at Virologic Inc., a small biotechnology firm in South San Francisco. Hecht's report evoked widespread interest and concern among many of the 12,000 scientists and AIDS activists at the Geneva conference. Full details are being published in the New England Journal of Medicine, along with an editorial by Fauci.

As Fauci commented yesterday, "This report of another case of drug resistance is not surprising, and people must assume that if they get infected now, it's just the same as if they were a person who got infected in 1983 before there were any AIDS drugs available."

The protease inhibitor drugs have proved a "welcome advance and have rapidly improved the prognosis" for many patients infected with HIV, Fauci said.

GENETIC `PLASTICITY'

But doctors and patients must expect that the virus will show enough genetic "plasticity" to develop resistance as long as even the best drugs cannot completely suppress the ability of the virus to reproduce itself, he added. The danger is that resistance to the protease inhibitors may spread rapidly from a very few early cases like the one Hecht reported in Geneva. Another lesson also is obvious: The new drug combinations, which involve many pills that must be taken in a rigorous regimen, can induce HIV resistance if patients skip or discontinue their scheduled doses of medicine.

"This study shows that we can do more harm than good if we don't help patients take their medications correctly," said Hecht's colleague, Dr. Margaret Chesney, a co-author of the report. "The bottom line is that helping patients stick to these difficult regimes is as important as the drugs themselves."

To Hecht, a major lesson of the case he reported is the increasing need to test patients for drug resistance before beginning therapy. In his own case, he said, 35 patients were tested before discovering the first patient who was infected with a virus resistant to all four of the protease inhibitors now in use -- saquinavir, ritonavir, indinavir and nelfinavir. In other studies at UCSF, he said, 16 percent of newly infected AIDS patients were resistant to the standard drug AZT, and 8 percent proved resistant to 3TC, another drug frequently used in combination with one or more protease inhibitors.

DRUGS RENDERED USELESS

"Part of our concern," he said, "is that all of these drugs could become useless because of resistance by the virus -- very much as tuberculosis has become resistant to so many once-useful drugs. These are warning signs." In the case Hecht reported, the previously uninfected patient had engaged in unprotected, receptive anal intercourse with a partner who had been infected since 1990 and had been sporadically treated with nine different anti-viral drugs, including protease inhibitors.

The infected partner did not ejaculate during intercourse -- a practice believed by many gay men to be a relatively safe type of sex. After not responding to protease drugs, the patient then began treatment with several other anti- virals, but when they did not work as well as in other patients, he took himself off all drug therapy and so far does not seem ill, Hecht said.

"This case doesn't mean that combination therapy is not a good thing, said Thomas Coates, director of the UCSF AIDS Research Institute. "A lot of people are living longer and better lives due to combination therapies, but it is clearly not the final answer. We have to help afflicted communities understand that transmission of resistant virus strains is possible, even by a (sex) practice not considered to be very risky."

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