Life, Death or Limbo
The Successes and Failures of the AIDS Cocktail
By John Caldwell from Frontiersweb
After eight years of work at AIDS Project Los Angeles, watching people suffer and die from the devastating effects of AIDS, Chris Bennett readily accepted the reality of his own diagnosis in 1993. He was positive and he would die, shortly and without question.
But that fate, and his whole world, drastically changed when he went on the AIDS cocktail in 1996. Having already made plans for his own death, he now faced a nebulous future--a drug-supported state of limbo.
"In a strange way, the hopefulness was harder to take," Bennett says. "All of a sudden the rules had changed. Suddenly I wasn't looking at a shortened life span."
But a new reality quickly set in: the guilt of surviving legions of friends and acquaintances who succumbed to the disease during a time when treatment meant little more than managing an inevitable and difficult course toward death. "That adjustment, after seeing so many people around me die, was difficult," Bennett admits.
Bennett, 42, a resident of Los Angeles, has since turned out to be somewhat of a poster child for the success of the cocktail. His five years of treatment have yielded few of the debilitating side effects now common among large numbers of people on the cocktail, clinically known as "Highly Active Anti-Retroviral Therapy," or HAART. Like many of his friends, his T-cell count is way up and his viral load is undetectable. But they are dealing with immense complications and he is not.
"Most everyone I know is having serious problems," Bennett says. "I'm just thriving and people around me can barely summon the strength to see their doctors."
For many patients, the cocktail therapy, which usually consists of taking a combination of two reverse transcriptase inhibitors and one protease inhibitor several times a day, has been difficult due to overwhelming side effects. A large percentage of HIV patients like Bennett, however, are experiencing few complications and have had their viral loads suppressed to undetectable levels. According to Martin Delaney, founding director of Project Inform, an AIDS awareness organization in San Francisco, if a patient makes it past the first few years without major side effects, they are likely to do well indefinitely. For them, life resumes without the threat of any known end point to the cocktail's effectiveness. For everyone else, life has become a daily battle not with the disease, but with the cure. Some are managing the side effects and some are still dying, but far fewer than before.
"I'm still in awe as to how these medications have changed HIV," says Dr. David Bangsburg, primary care clinician at San Francisco General Hospital. "Before '96, my practice was death management."
A study published July 3 in the Annals of Internal Medicine by Dr. Edward Murphy, a professor of medicine at the University of California, San Francisco (UCSF), reports that the AIDS death rate has been reduced to about one-third of what it was before the cocktail. The study examined patients during a momentous period of change between 1995 and 1999 and confirmed that the cocktail even works for those who start with extremely low T-cell counts. The study also found that the cocktail reduced the rate of most opportunistic infections by about two-thirds.
According to Dr. Peter Ruane, who works with HIV patients at Tower ID Medical Associates on the Cedars Sinai campus in Los Angeles, old symptoms of AIDS such as CMV, a virus that attacks the eyes, and PCP, an opportunistic pneumonia, have all but disappeared, while Kaposi's sarcoma, a skin cancer, has been reduced to mere occasional cases. Before the cocktail, at any given time, his group alone was treating 10 patients in the hospital and 50 in home care. Now, they typically see only one in the hospital and one at home.
But in the last few years, the appearance of many long-term and troublesome complications have dampened the success of the cocktail. Since the introduction of HAART, the number of side effects has steadily increased and their effects have become more complicated.
"There are mounting side effects," Murphy says. "Even though your T-cell count may be getting better, there are still problems. Life is by no means normal."
In addition to the initial symptoms of diarrhea and nausea, the most prevalent long-term complications include: neuropathy, in which nerve abnormalities cause pain and burning, preventing some people from walking; liver toxicity, resulting in numerous liver complications, particularly in people with hepatitis C; and lipodystrophy, in which fat is redistributed throughout the body, posing long-term risks for heart disease due to cholesterol imbalances. Other, more recent, side effects are a thinning of the bones, resulting in some fractures, and lactic acidosis, a buildup of lactate in the cells, which can lead to organ failure.
Despite the continued success of the cocktail to prolong life, the increasingly complicated side effects are having a severely adverse effect on the quality of many lives, even in those who seem to be doing well.
"It's difficult for me to leave the house sometimes," Bennett says, his voice cracking as he points out his basketball-size stomach, a result of lipodystrophy. "I feel like a pariah. It's something I can't hide. I think my body is grotesque sometimes."
Lipodystrophy causes a loss of fat in the face, arms and legs, and redistributes it in lumps on the back of the neck, labeled "buffalo humps" by some, or other clearly distinguishable places on the body. The condition makes hiding HIV status difficult and has an adverse psychological effect on some members of a culture that places a premium on physical appearance.
Many physicians are not sure if the side effects are caused by the drugs or the disease and are advising their patients to start therapy later, abandoning the previously lauded practice of hitting patients as early as possible with the cocktail. By delaying treatment, they can delay potential suffering as a result of the side effects in their patients, who will typically still get a reasonable response to the drugs when they do start.
"Clearly, a lot of people were pushed into therapy too early," Delaney says. He adds that numerous things have been learned since the introduction of HAART. In 1996, if a patient on HAART had a viral load that became detectable, they were told to change at least two drugs in their regime. But it has since been learned that usually only one drug is failing, and occasional reappearances of the viral load don't always mean that any drugs are failing at all.
"The meds we have now are better," Bangsburg says. "By delay you get clinicians who better know how to use those drugs. It's become quite a juggling act."
For those patients who found the "right" regime early on and had viral loads that were completely suppressed, the virus doesn't have a chance to evolve a resistance and they live well, Ruane says. But for some, there is no optimal regime and the virus builds a strong resistance, limiting their benefit. But even when death is likely, they still live longer because of the cocktail. Many, however, deal with serious depression as they wait to see what's around the corner, not knowing if it's life, death or a continued limbo in which side effects dominate. "They're not back in life again, but they're not dying," Ruane says.
Some patients struggling with overwhelming side effects are employing "drug holidays." By voluntarily interrupting their drugs regimes, HIV patients may get a much-needed reprieve. Delaney stresses the need for research in this area, saying the real test is in advanced cases in which it appears to be detrimental for patients to stay on the cocktail. But in the absence of research on drug holidays, most doctors are scoffing.
"I don't recommend it in my patients," Bangsburg said, expressing concern that his patients could potentially lose ground in their fight against the virus. "I don't have a good understanding of the long-term effects."
Those patients who embark on the holiday, known by some doctors as Strategic Treatment Interruption, usually experience an explosion in their viral loads. But without any other immediate and negative effects, the benefit can seem enticing--a break from the dogged complications and fatigue that have ruled their lives.
"I think drug holidays are a good thing," says Jay Wonacott, a San Francisco resident who has lived through a hard-fought battle with the disease, the cocktail's inability to keep his viral load down and difficult side effects. "During that time I felt better. My life became easier. It really did feel like a vacation."
Wonacott is adamant about the importance of only taking drug holidays under the supervision of a physician. He went on his holiday per the instruction of his doctor who, perplexed by the absence of any combination of drugs that seemed to work in his case, thought it might be best for him to wait a little while. After four months, his blood work showed a viral load that had exploded. He was fortunate, however, to be able to enter a new drug study at that time, which put him on a cocktail that has since kept his viral load undetectable.
"People can get away with it for short periods because there's a lag time," Murphy says. "The one potential benefit is that the virus goes back to its original [non-resistant] version."
The fact that the virus reverts back to its original strain means it has not mutated, reducing the possibility of some additional complications. But once therapy is resumed, Murphy adds, the virus does go back to the resistant strain found in all cocktail recipients, even when the drugs are successfully supressing it. He admits that some holiday takers do feel better, but he also does not recommend it to his patients. Instead, he, and most other physicians, recommend strict adherence to drug regimens.
As doctors learn more about the effects of the cocktail on HIV, adherence becomes increasingly important. According to Michael Crosby, who is conducting a study at UCSF's Center for AIDS Prevention Studies to look at the effects of alcohol and drugs on a patient's ability to adhere, those who adhere live better lives.
"If men and women are not adherent, they are likely to develop resistant strains of HIV," Crosby says, adding that drug mutations can lead to the failure of the cocktail, and pose an increased threat to the community when they are spread. "Alcohol and drug users are particularly vulnerable to not adhering."
Arguably, all HAART recipients are vulnerable to lapses in adherence. The drug regimen involves a cumbersome program in which numerous pills must be taken at precise times during the day. Patients must watch the clock religiously and can never forget to bring their pills with them wherever they go.
"The problem is the strictness of the regimen," Bennett says, "even with a little alarm on my watch going off every eight hours."
Breakthroughs in drug combinations are reducing the adherence problem for some patients. Bennett recently started taking Ritonavir, a protease inhibitor, in conjunction with Crixivan, another protease inhibitor, a combination that allowed him to reduce his dosage to twice a day.
The literally dozens of combinations now possible with the ever-increasing aggregate of HAART drugs have become a complex puzzle in which physicians must place and then pull the pieces apart in a frustrating effort to figure out which seem to fit together. Only now are they learning how individual drugs affect the level of other drugs in the system (one transcriptase inhibitor may reduce or increase the amount of another that is absorbed by the body).
"It is very hard to keep up-to-date with all these possible combinations," says Dr. Scott Hitt, president of the American Academy of HIV Medicine. "The cocktail sounds so easy, but it isn't that way."
All this complex and groundbreaking science in the treatment of HIV with an ever-expanding inventory of drugs has Hitt and other doctors advising consumers to see only those physicians who have solid experience treating HIV. His organization has set up criteria for the certification of doctors as HIV specialists.
"Twenty years ago, we ran around saying this is a disease all doctors should know how to treat," Hitt says, explaining how many in the medical profession are now referring to HIV treatment as a specialty.
The obvious physician learning curve is causing many cocktail patients to educate themselves. Organizations like Project Inform and HIVResistanceWeb, a Web site that provides up-to-date data on drugs and their interactions, are helping patients learn in concert with their doctors. Together, they are helping to make the cocktail as effective and bearable as possible.
"I have used every drug that has ever been created for HIV," Wonacott says. In the end, it's made things better to have accepted that both the cocktails and their side effects are now part of his life.