By Jim Lebret

What kind of an effect has this new class of AIDS wonder drugs had on the disease and those who live with it? Our writer takes a look at the modern fight against AIDS.

    After years of ho-hum progress, AIDS research has reentered the public eye. For what seemed like eons, news about new treatments for the disease degenerated into nothing but a series of false hopes. The slow pace of progress lulled people to sleep. Then, suddenly, a class of drugs called protease inhibitors caught the world napping.

    These new drugs, taken in combination, issue what represents at least a temporary knockout punch for HIV, the Human Immunodeficiency Virus that causes AIDS. While they have not yet cured anyone of AIDS, the drugs have allowed people apparently at death’s door to resume normal, healthy lives.

    As big a discovery as a new and powerful AIDS-fighting drug might be, news of the latest AIDS breakthrough took some time to rise from the well-worn ruts of AIDS complacency and make it into print, probably because few people wanted another alleged “wonder drug” to become a letdown. Protease inhibitors were actually found to work in laboratory settings as early as winter of 1992, although they have undergone tremendous modification since then. Finally by December of 1996, all three major news magazines—Time, Newsweek, and U.S. News and World Report—had run cover stories on protease inhibitors. Time even named AIDS researcher Richard Ho “Man of the Year.”

    It seemed that as these media outlets—and others that subsequently picked up on the medical event—sought out information about the new drug, they found that protease inhibitors were not entirely the miraculous cure to AIDS their audiences would want to hear about. The usual sound bite bottom line came with difficulty, so most stories dealt with the optimistic aspects instead of the indecisive issues. The typical conclusion in these publications: although protease inhibitors do not represent a definitive cure for AIDS, their discovery was hardly a failure.

Bio 101
    The process by which AIDS takes on the body’s defenses begins when the HIV virus binds itself to a receptor on the membrane of a T4 lymphocyte—a helper T cell—and enters the cell. Helper T cells are blood cells that play a crucial role in the body’s fight against infections.

    After a few tricks involving the surface proteins—which make the invaded cell think that HIV will prove a friend—the virus sheds its protective coat and releases both RNA, a single-stranded nucleic molecule involved in protein synthesis whose structure is determined by the double-stranded genetic material DNA, and reverse transcriptase (RT), an enzyme that uses RNA as a template for making new DNA. The virus then can make its own DNA, which becomes incorporated into the host cell’s DNA, rendering it an active part of the cell. At this point the virus rules the host cell’s machinery and produces viral copies. Eventually, both HIV RNA and protein coats cavort into new HIV viruses and the cycle of infection repeats itself.

The Drugs
    Early treatments, which regarded HIV as a simple bacterial infection, proved ineffective. Scientists discovered numerous places where the virus could mutate its way out of all sorts of problems.

    That’s why current treatments involve a “cocktail” of medications that aggressively pursue different points of vulnerability during the virus’ infection process. In general, scientists have decided that these are the points at which the virus releases protease enzymes and beginning of reverse transcription. Since HIV assaults cells the same way every time, scientists can target a point in the virus’ assembly-line means of self-propagation for a counterattack. Thus, HIV, for all of its diabolical campaigning, has two Achilles heels for medications to exploit, the first of which is reverse transcriptase.

    During reverse transcription, as the RNA sprawls out in efforts to copy itself, drugs like AZT, DDI, DDC, D4T, and 3TC throw monkey wrenches into the usual smooth and zipper-like transcription process. By binding with the RT enzyme, the drugs make sure that the virus turns out only molecular duds. As a result, HIV’s progress slows.

    But HIV proves tricky: it outsmarts these medications within a short time—sometimes just a few weeks—by changing its own genetic structure. As a result, the virus shackles the immune system once again. This characteristic of HIV worried scientists in the late 1980s when they became afraid of a “super virus” entirely immune to the commonly used AZT, the first AIDS drug the FDA approved.

    As a result, researchers increased efforts to create more RT blockers. Alone, these new drugs had few effects. When researchers combined 3TC, a new drug, with AZT, it proved a remarkably potent combination. The combination worked because the mutations that helped the virus endure one drug left it defenseless to the other. But even this did not last forever: the virus kept on mutating and, in time, overcame the “wonder treatment.”

The Good
    Enter protease inhibitors.

    Our present heroes in the AIDS war are protease inhibitors, famed for reducing the viral loads in bloodstreams of some individuals by up to 99 percent, and providing hope for millions of AIDS victims. How do the drugs work? Simply put, protease inhibitors hit the viruses at a later stage in the infection, rendering them sterile.

    The process by which the drugs work begins when the virus, nearing the end of a replication, produces two long pro-proteins resembling pearl necklaces. Each strand includes every viral protein essential for the virus’ offsprings’ successful infection of other cells. An enzyme called protease must cut the extraneous matter from around the particles for inclusion in the finished virus. Protease is HIV’s other Achilles heel.

    This is where the protease inhibitors step in. Protease inhibitors squeeze into the protease enzyme, preventing it from doing any cutting. As a result, the new and awkward viruses contain bulky pro-proteins in lieu of the protein “bullets” so lethal to receptors on helper T cells. Such molecular victories prevent cell death and, subsequently, can keep the immune system humming along.

    Indeed, there is evidence of the strength of protease inhibitors: take, for instance, Jim Howley’s example. Thirteen years ago he tested positive for HIV. Full blown AIDS followed close behind. With an estimated year and a half to live, he fell into despair and became a cocaine addict as his T-cell count rapidly declined. His hair began falling out, his weight plummeted, and the deadly cancer Kaposi’s sarcoma covered him with purple splotches. Then, in September of 1995, two new protease inhibitors, Norvir and Saquinavir, turned him around. His T-cell count jumped almost 200 percent in a matter of months and he started an exercise routine. Today, Howley participates in marathons and has spread his story through newspapers and magazines.

The Bad
    Unfortunately, however, protease inhibitors haven’t worked so favorably for everyone who has tried them: Paul Forgetta is quite a different example. Stuck in the bitter reality of full blown AIDS and the accompanying opportunistic diseases, he now has little more than hope after sampling the latest protease inhibitors, all to no avail. The miracle experienced by Jim Howley passed up Forgetta as unhindered HIV viruses still rage through his immune system.

    Despite the optimistic drumbeat of articles relating stories like Howley’s, negative stories like Forgetta’s abound: 30 percent of people who try them never respond to protease inhibitors. And those taking protease inhibitors often face obstacles from diarrhea to bone marrow suppression.

    Possibly just as daunting are the psychological aspects of AIDS treatments for those who recover. It is often difficult for some to share the media’s trumpeting euphoria of extended life when the prospect of life creates a slew of new problems exhausting for recovering sufferers. Previously, AIDS has been a one way ticket to the grave. Now, miracle drugs have thrown some of those expecting to die young into a confusing depression.

    Many have lost friends, bade farewell to families, and even run up enormous credit card bills with no intentions of paying them back: they prepared for death, but medical advances canceled the event. So with a tackle-box full of pills, some people with AIDS approach the future with uncertainty.

    For those who can afford the $17,000-a-year treatment, some will find the regimen of up to ninety pills a day for a lifetime too difficult to stomach. Others will find them literally hard to stomach. Many will survive for a time, though others will provide the virus ample time to mutate by missing too many doses. Indeed, fear of viral mutations has led doctors to deny prescriptions for protease inhibitors to some people, particularly those receiving Medicare, who they do not trust to keep taking the pills.

The Ugly
    Looking beyond the United States, AIDS has an intense grip on people elsewhere in the world. Poverty unimaginable to the Western world prevents even the most conventional of AIDS drugs from reaching the masses of developing countries. When getting enough to eat is the first priority for these people, expensive medication like protease inhibitors is nowhere near reality for the majority of the world’s AIDS patients.

    In the United States and most of the West, AIDS, despite its growth among middle class heterosexuals and women, remains mostly confined to gay men, drug addicts, and the extremely poor. In countries like Uganda, however, AIDS has become an equal opportunity killer and is spread mostly through heterosexual sex. In these countries, it is difficult for people to afford condoms and other prophylactics: the thousands of dollars a year needed to purchase protease inhibitors are out of nearly everyone’s reach.

    It is a dismal fact of life that so many suffer so in poorer countries, but equally as distressing is the truth that scant portions of the affluent nations know of their pain. The media, running and re-running now-clichéd articles on AIDS and protease inhibitors, mention little about the Third World inhabitants who total 90 percent of all AIDS victims.

    As if the media’s neglect is insufficient, drug companies likewise divert their efforts to combat AIDS between designing drugs that temporarily halt the virus’ damage—a reality only for those in wealthy countries—and developing a widely-accessible vaccine. Logically and biologically it makes more sense to invest most time, effort, and money into finding a cheap and efficient cure; such a vaccine represents the only real hope for the countries with the highest percentages of AIDS infection.

The Future
    Protease inhibitors have yet to cure any patient of AIDS. While Ho plans to eventually determine if protease inhibitor treatment can safely be stopped and AIDS still remain undetectable, such trials have been pushed back.

    One scientist likened AIDS to a fire with protease inhibitors as extinguishers. AIDS has a long history of laughing last and, like those sadistic “magic” birthday candles, it only takes an ember—or a single virus hidden in the neural tissue—to reignite the whole problem.

    All the while, new drugs continue to hit the market. RT inhibitors like 1592, with ten times the power of AZT and Delavirdine (an AZT-like treatment without side effects), will be available soon. In the protease inhibitor world, ABT-378 should outshine its predecessors when the FDA approves it within the next few years. As researchers race to improve the formidable array of reverse transcriptase and protease-targeting drugs, a new kind called integrase inhibitors may join the barrage of pharmaceutical weaponry. These substances assume the role of an important protein slicer which, if impeded, hinders viral replication much the same way protease inhibitors do. Maybe then adequate hurdles can tie up HIV enzymes long enough to deem AIDS a manageable, yet chronic, illness. Not yet.

    As the topsy-turvy ride with AIDS moves along, public feeling frequently changes from hope to apprehension to elation. Perhaps the starts and jumps will level out soon with the help of new drug technologies. In this time of a lurch forward, we can only learn from the pros and cons of the past year and hope that the protease inhibitors have touched off a beginning to the end of AIDS.