From his own clinical experience, McMeeking agrees that heart disease, certain cancers, and liver and kidney disease do seem to pose a greater threat to his HIV-infected patients than might otherwise be expected in a comparable uninfected population. “I still expect most of my patients to live a normal life expectancy,” he says, “but they may do so with a bit more nips and scrapes.”
The third group of HIV-infected individuals consists of those in the middle of the two extremes. HAART, in these cases, has literally been a life saver, but has not guaranteed a normal life expectancy. These are the patients, like Bob Hattoy, who were diagnosed with AIDS in the late eighties or early nineties, before the advent of HAART. They began on one drug (AZT, for instance) and then stayed alive long enough to get on protease inhibitors and the HAART cocktails. These patients were on the cusp of the HIV transformation from a deadly to a chronic-disease epidemic; they were infected late enough to survive but too early to derive all the benefits from HAART.
The anti-retroviral drugs of HAART work by attacking the life cycle of the virus. The earliest generation of HAART drugs attacked the enzymes that the virus uses to reproduce in the cells. (Protease inhibitors, for instance, go after an enzyme called HIV-1 protease, which the virus uses to assemble itself during reproduction.) The latest drugs go after the methods that the virus uses to enter cells in which it will replicate. The key to the effectiveness of HAART, as researchers discovered in the mid-nineties, was to include at least three drugs in the cocktail to which the patient’s specific virus had no resistance. This would suppress viral replication sufficiently so that the virus wouldn’t be able to mutate fast enough to evolve resistance to any of the drugs. But patients who began on one or two anti-AIDS drugs and only then moved to HAART already had time to evolve resistance to a few of the drugs in the cocktail. This made the entire package less effective and increased the likelihood that they would evolve resistance to the other drugs as well.
“We call it ‘sins of the past,’ ” says Mullen. “We gave these patients sequential monotherapy; it was state-of-the-art at the time, and a lot of those people are alive today because of that. It got them through until HAART came along, but their HAART is not highly active, only fairly active. Their virus has baseline mutations that interfere with the response.” This group of patients also includes those who were infected initially with a strain of HIV already resistant to one or several of the components of HAART, or those patients who were less than 99 percent faithful in taking the regimen of pills that constitute HAART. Anything less than that and the virus has the opportunity to evolve resistance.
Perhaps a quarter of all new cases, says Mullen, are infected with a strain of the virus resistant to one or more drugs in the HAART cocktail. “You can’t use the frontline regimen, because the virus has already seen those drugs,” he says. “You have to go to more complicated regimens. This is why we do resistance testing before we start a person on medication. We see what drugs the virus has seen or is resistant to and can take that into account.”
Sins-of-the-past patients have to have faith that the pharmaceutical industry can stay one step ahead of their disease. The prognosis, at the moment, is promising. There are several entirely new classes of AIDS drugs, including one by Merck, called an integrase inhibitor, that was just approved by the FDA last October. A recent report of the discovery of 270 new human proteins employed by the AIDS virus to hijack cells and start replicating—the definition of a successful infection—means the pharmaceutical industry will not run out of new targets to block the infection in the near future.
Still, some sins-of-the-past patients simply do worse than others, and the occasional patient will lose the battle before new drugs come along or simply give up. “I had a friend who died last week,” one sins-of-the-past patient told me recently. “He just lost faith. He would get sick a lot, would get better, then sick again. Finally he decided to try Eastern medicine, and stopped taking his [HAART] medications entirely. It killed him. It’s not a good example, other than to show that people can reach their breaking point.”