Despite its high cost and cumbersome daily dosing schedule, the triple-drug anti-HIV cocktail is popularly hailed as the most effective therapy yet against AIDS.

So, it may come as a surprise that the treacherous HIV pathogen has mounted a counterattack, in the form of multidrug resistance to that cocktail of retroviral and protease inhibitors. The mutated resistant viral strains include those less likely to roll over dead when dosed by a spectrum of front-line AIDS medications including zidovudine (known as ZDV), didanosine (ddi) and lamivudine (3TC), for example.

The October 1998 issue of the British journal AIDS, to be published Thursday, carries a report titled "Resistance of HIV-1 to antiretroviral agents in blood and seminal plasma: implications for transmission." Its senior author is infectious disease specialist Myron Cohen, a professor of medicine, microbiology and immunology at the University of North Carolina, in Chapel Hill.

Cohen heads an international consortium of some 30 virologists, epidemiologists and other specialists, he told BioWorld Today, "who are working on HIV prevention strategies in the U.S. and other countries."

"In the context of this approach," he said, "we've done lots of studies on HIV and semen, and to a lesser extent on female genital secretions. Ejaculate is the problem with sexual transmission of HIV. There's little doubt about that.

"When you get that far," Cohen continued, "the antiviral drugs become an important issue, especially in developed countries where they're widely available. Most of the antiviral drugs are perceived, and rightly so, as a route to the treatment of HIV disease. And that gets a lot of hype.

"But when you're dealing with communicable diseases, then the therapy you give has a public-health implication, for which there are two sides to the coin. One side is that, as the drugs prove effective and reduce the concentration of the infectious agent in a secretion such as blood or semen, the secretion ought to be less infectious. That's exactly what's happened with the use of antiviral drugs in pregnant women. [They] reduce the vertical transmission of HIV from mother to child."

But then Cohen cited the flip side of the coin: "It's also obvious that as people have trouble taking their multidrugs, those drugs don't penetrate all of the body compartments very well," he said. "You end up with a situation that tends to promote the drug-resistant HIV isolates. And if these were transmitted to the next person and could sustain their resistance in him or her, then the consequences would be dramatic loss of efficacy of the available drugs."

Cohen described his AIDS journal report as "the biggest study to date that tries to put some sort of an estimate on the magnitude of this multidrug resistance problem, as it relates to HIV transmission." He added, "The good news is that most people who take the drugs have a very positive response to therapy, with reduced viral burden. However, we would never tell such people that they're no longer contagious, as we don't know how little HIV is required for transmission."

Fate Of 44 Blood And Semen Donors

The co-authors collected blood and semen at intervals from 44 men in North Carolina and Switzerland. "The point is that 44 men is a lot of men to donate ejaculate," he said. "And the majority of those 44 studied over a period of time, three-fourths of them, had a drastic reduction in the HIV in their ejaculate. So, it's only 25 percent -- 11 men -- in whom we could continue to recover HIV."

Five of the 11 had never taken the antiviral drugs. Six had received treatment with reverse transcriptase blockers, designed to prevent the virus from dumping its DNA into infected cells. From the start of the study, all 11 went on therapeutic regimens including a variety of antiviral AIDS drugs. Periodically, for up to 58 weeks, the investigators measured the HIV load in blood and semen samples.

"What we showed," said the paper's lead author, virologist Joseph Eron, "was that men who had previous treatment already had evolved virus in their blood and genital tract that contained mutations known to decrease the susceptibility of that particular virus strain to the available drugs." That is, the HIV strains were resistant.

Moreover, when the co-authors followed men with drug-resistant HIV in their secretions, they continued to acquire higher levels of resistance while receiving antiviral therapy.

"There are two issues here," Cohen said. "One [is that] the drug resistance isn't the same in the blood and in the semen, which tells you that the genital tract is a unique compartment of the body. Different amounts of the drugs are concentrating in that compartment, and evolution of resistance may be going along different pathways. You've got a different amount of selective pressure in those two compartments.

Viral Drug Resistance Hypothesis

"And the second thing is," he went on, "that we did see resistance to the nucleoside drugs -- the retroviral inhibitors -- so that represents an obvious concern, because those drugs are so popular. But we didn't observe resistance in the semen to the protease inhibitors. It's possible that resistance requires a sub-lethal concentration getting into the secretion. If nothing gets into it, no resistance evolves at all. So, the hypothesis we're trying to test now is that the protease inhibitors may not get into the genital tract very well.

"Our goal is prevention of HIV transmission," Cohen said. "It's a little bit different from the traditional model. The traditional model says, 'OK, we're going to prevent HIV; let's make a vaccine.' So, then you have a biologist who makes a vaccine and worries about testing it. But we're coming at this quite differently. Though some people in our group are vaccinologists, we're much more interested in understanding the underpinnings of HIV transmission, and then we'll work our way backwards."

Cohen concluded: "I think the pharmaceutical industry is not worrying enough about the marketing issues that relate to HIV resistance patterns. If a particular drug promotes resistance that goes to the next person, that drug would suddenly become unpopular. In the end, the marketing and sales are going to depend not just on their effect on the individual's health, but on our species." *