COURSE OF HIV INFECTION. New treatment strategies aim to keep the viral load (orange) low and the CD4 T cell count (blue) high so as to delay the onset of AIDS.

One message at the 12th World AIDS Conference last week in Geneva was frighteningly clear: although protease inhibitors have brought about a dramatic decline in AIDS-related deaths since their approval two years ago, these medications are not cause for complacency.

Protease inhibitors prevent the HIV virus from constructing proteins it needs to replicate. As such, they have proved to be potent ingredients in so-called drug cocktails known as highly-active antiretroviral therapy (HAART). These three- or four-drug mixes aim to keep viral levels at a minimum and so forestall the onset of AIDS.

But on Wednesday, researchers from the University of California at San Fransisco (UCSF), the Centers for Disease Control and Prevention and ViroLogic, Inc., led by UCSF-San Francisco General Hospital medical professor Frederick Hecht, reported the transmission of an HIV strain that is resistant to six of the 11 available antiretroviral medications, including all four protease inhibitors: saquinavir, ritonavir, indinavir and nelfinavir. The results are to be published in the New England Journal of Medicine.

It was largely inevitable that an HIV strain would become resistant to protease inhibitors. The virus is notoriously capable of shuffling its genetic deck to stack the cards in its favor. But it is surprising that it happened in only two years. Although several strains are resistant to reverse transcriptase inhibitors, the other antiretrovirals used in HAART, these medications have been in use for more than 10 years.


DRUG RESISTANCE. In the absence of medication, many HIV variants coexist in a patient (left). If a replication-blocking drug is given, it will halt replication of susceptible variants (top) but will essentially be ignored by resistant versions (bottom), which will continue multiplying after the drug-sensitive versions have stopped.

The main problem contributing to the emergence of multi drug resistant strains appears to be adherence. Patients often stop taking HAART drugs due to unpleasant gastrointestinal and systemic side effects. One study reported at the conference last week found that about 40 percent of 151 patients who had tried one or more of the four available protease inhibitors had eventually discontinued taking the drug.

Doing so essentially selects those strains resistant to the drug for survival--making later rounds of treatment less likely to succeed. And in fact, the newly found HIV strain that is resistant to protease inhibitors was transmitted by a man who had been sporadically treated with nine different antiretrovirals since 1990.

"The bottom line is that helping patients stick to these difficult regimens is as important as the drugs themselves," commented Margaret Chesney, a co-investigator at UCSF. "We can do more harm than good if we don't help patients take the medications correctly."

The good news is that some seem to be aware of the risk of interrupting treatment. On Wednesday, other UCSF scientists led by Joseph A. Catania reported that despite the availability of HAART drugs, many HIV-positive gay men were opting to delay treatment until the later stages of infection. The team surveyed 500 randomly selected HIV-infected men in New York, Los Angeles, Chicago and San Fransisco by telephone and found that only 56 percent were currently using HAART.

"These men are aware that once they start drug therapy, they can never stop," noted Ron Stall, who presented the findings in Geneva. "Someone not prepared to make that commitment is better off delaying therapy than following it inconsistently, possibly creating resistant strains. From an adherence standpoint, it is probably better if someone who's not sure waits to begin therapy."

Even so, the two-year old International AIDS Society-USA-continues to advocate early and potent combination therapies. Their revised recommendations--announced in Geneva last week and published in the July 1 issue of the Journal of the American Medical Association--hail HAART as the best hope against AIDS, at least for now.