Starting Treatment, Staying on Therapy

January/February 2005

This article is part of The Body PRO's archive. Because it contains information that may no longer be accurate, this article should only be considered a historical document.

Starting Treatment, Staying on Therapy
John is a 45-year-old man who recently learned that he is HIV positive. He has a CD4 count of 350 cells and a viral load of 60,000 copies. What should he do?

Despite two decades of intensive research, the publication of hundreds, if not thousands, of studies in respected journals, and the development of treatment guidelines by a panel of experts in HIV disease, there is no best answer. In fact, if John consults ten physicians specializing in the treatment of HIV, he's likely to get ten somewhat different opinions about his next course of action. And they'll probably all be right.

In 2005, the management of HIV/AIDS is still more of an art than a science, no matter what the experts tell us. No two HIV-positive patients are alike; and decisions about their care must be individually tailored. This will continue to be the state of things until a cure is discovered and all controversy about HIV treatment will end.

Before proceeding further, I want to emphasize two important points. First, if left untreated, 95% of people infected with HIV will die of AIDS. Second, HIV infection is a manageable problem -- that is, it can now be considered a chronic disease, like diabetes (at least in the developed world). It's conceivable that a person can live a normal lifespan with his or her HIV infection as long as he or she adheres to his or her therapy.

Not enough time has passed to know if people can remain on antiretroviral therapy for 20, 30 or 40 years. However, we know that people can be treated with the same regimen successfully for at least a decade and probably for much longer. The usual reason for the failure of therapy is not the sudden ineffectiveness of the medications but patient noncompliance. It takes a lot of energy and dedication not to skip doses. Unlike diabetes, if you skip doses of your HIV meds, you can't "catch up." Doctors must be cheerleaders as well as practitioners.

How HIV Works

Scientists have long understood the natural history of HIV infection, which has not changed since the first reports of AIDS in 1981. On average, a decade passes from the time of infection to the time of death. Some people die within one to two years of infection, others will die 15 to 20 years after being infected -- it's a bell-shaped curve. But again, less than 5% of people will survive their HIV infection if untreated.

There are people who believe that because they are HIV negative despite unsafe sexual behavior they are somehow immune to HIV. This is a fallacy: we do not yet have a test to identify those with an innate resistance to the disease. One can have a single sexual encounter and get infected or a hundred and not get infected. Sooner or later, the vast majority of those playing Russian roulette with the virus will get infected. Therefore, all people must consider themselves to be at risk for acquiring HIV and should take the proper precautions to avoid infection.

They should know that, except for rabies, which has a mortality rate of 98%, no other disease -- not the plague, not Ebola virus, not anthrax, not smallpox -- approaches the mortality rate of HIV infection. Because HIV/AIDS plays out over such a long period of time, people take it less seriously. The public reacts with greater fear to a potential act of bioterrorism than to the real threat of HIV/AIDS. Billions of dollars are being spent to prevent a hypothetical bioterrorist attack, while the world continues to debate the merits of allocating sufficient resources to confront a real disease that has already killed, and will continue to kill, more people than any act of bioterrorism act ever will.

On a more optimistic note, studies have proven that people with advanced HIV disease -- those with CD4 counts well under 200 cells or with a history of an opportunistic infection like pneumocystis pneumonia or cytomegaloviral retinitis, for example -- have benefited from HIV medications. We all know people who were plucked from the jaws of death and lived to tell their tales because of the timely administration of life-saving therapies. Thousands of people with CD4 counts once hovering near zero have resumed near-normal, productive lives. Yet the prospect of taking lifelong medications often terrifies people more than the prospect of death from AIDS. What have we done wrong?

Treating HIV

The story of HIV treatment is the classic tale of hype and hope, of high expectation and inevitable disappointment. When AZT first became available in 1987, a period of darkness seemed to be ending; but the punishing schedule (two pills every four hours around the clock), the significant adverse effects (headaches, nausea and vomiting, and severe anemia requiring blood transfusions), and ultimate failure to improve life expectancy beyond a few extra months, created a widespread distrust in the medical community that persists today. The inability to convince some HIV-infected individuals to take far less noxious regimens can be traced to the early horrors of high-dose AZT, a time when the term "toxicity" became a synonym for poison in the minds of many.

In the mid-1990s, expectations were raised once again with the development of HAART (highly active antiretroviral therapy), which consisted of a "cocktail" of three different drugs in mind-boggling pill quantities and with annoying food restrictions. At first, only patients with advanced disease received treatment, with brilliant success, which prompted the recommendation that treatment be offered to people in the earlier phases of their infection, before symptoms developed. Studies soon focused on those who had just become infected: it was theorized that after only two or three years of treatment, HIV could be eradicated and a person thus cured. Hit hard and hit early became the mantra of the day.

Pressured by health professionals and AIDS activists, the insurance industry and governmental programs like ADAP (AIDS Drug Assistance Program) quickly relented and permitted access to therapy for all HIV infected individuals. No longer did ignorance of one's HIV status seem reasonable. Moreover, studies bolstered the cost-effective strategy of treating HIV infection long before the development of opportunistic infections. With greater confidence we coaxed our patients to get tested; and those who tested positive we urged to consider treatment. Even people with CD4 counts in the normal ranges (above 500 cells) who had little likelihood of becoming ill for a decade were often prescribed HAART.

The bubble burst when researchers discovered that current treatments didn't cure HIV. The virus disappeared into hidden reservoirs that have yet to be discovered -- cessation of therapy results in rebound of the virus to pretreatment levels and renewed destruction of the immune system. Far worse than this discovery, however, was the recognition of bizarre, unexpected side effects that, because of the rush to bring effective therapies to market, were not reported in clinical trials.

Some people noticed that their faces were shriveling; others complained of disfiguring deposits of fat on the backs of their necks; still others developed protuberant abdomens, skinny arms and skinny legs. Doctors also diagnosed more cases of diabetes than expected or alarming elevations of serum cholesterol and the so-called bad cholesterol, LDL. A new disorder had emerged, lipodystrophy syndrome, one that was easy to identify but hard to define because of the lack of objective criteria.

At first Crixivan, a protease inhibitor, was blamed as the cause of the syndrome ("Crix belly" it was called) -- at the time, Crixivan was the most popular protease inhibitor prescribed. Soon, however, the syndrome occurred with other regimens. Today, Zerit, Videx and Retrovir, the so-called thymidine analog nucleoside reverse transcriptase inhibitors (NRTIs), have been implicated as the main culprits because of their effects on the machinery of mitochondria, microscopic bodies found in every cell. (Mitochondria are known as the cells' powerhouse because they convert food into energy.)

But by what mechanism HIV drugs cause this syndrome is still unknown. Stopping therapy or switching to another regimen doesn't reverse the syndrome. Moreover, no one can claim with absolute certainty that the syndrome won't occur with every combination of current HIV medications, even if thymidine analogs and protease inhibitors are excluded from the regimen.

Suddenly, the hit early, hit hard game plan came under fire. Patients questioned the wisdom of starting therapy so early in the course of their disease. Those already on treatment wondered if intermittent therapy might minimize long-term side effects without compromising the effectiveness of medication. A minority failed to recognize any benefit of HIV treatment, preferring to take their chances and hold out for therapies with far fewer adverse effects rather than suffer permanent disfigurement and impaired quality of life.

What Next?

As always, scientists and physicians hesitated to revise their recommendations, warning of the dire consequences of any modification in the management of HIV infection. Today, we often wait as long as possible to initiate therapy, prescribing medications when the benefits of treatment outweigh the downside of treatment. As the CD4 count approaches 200 cells, the risk of developing an HIV-related problem increases; and the higher the viral load, the faster that person will reach that 200 CD4 count. A person with a viral load of 100,000 will get sicker faster than a person with a viral load of 2,000.

So, what can we advise John to do? He should probably repeat his CD4 count and viral load before making any decision. However, let's assume that he gets similar results. He has four options. According to the NIH guidelines for using antiretroviral agents among HIV-infected adults and adolescents, he could begin therapy now because he has a greater than 60% chance of progressing to AIDS in the next three years. Once he has started medications, he should consider his treatment to be lifelong.

On the other hand, he has a 40% chance of not progressing to AIDS in the next three years; and, with a CD4 count well above 200 cells, he's not in any immediate danger. Therefore, he could opt to monitor his CD4 counts and viral levels closely until he feels that it's no longer prudent to wait.

Third, if the opportunity is available to him, he could enroll in the SMART trial, an international trial funded by the NIH and conducted jointly with community-based HIV medical practices. In this study, patients with CD4 counts of 350 or above are randomized to one of two groups: group one, in which patients begin standard anti-HIV therapy as soon as they enroll in the study, no matter how high their CD4 count; and group two, in which patients delay therapy until their CD4 count drops to 250. Those assigned to the latter group take their medications until their CD4 counts rise above 350, at which point they stop their therapy, resuming when their counts drop back down to 250. This study hopes to answer the following questions. Is their any disadvantage to delaying therapy until a near-AIDS level CD4 count? Is their any advantage to intermittent therapy -- that is, do patients who interrupt their therapy have fewer side effects but the same long-term benefits as those who remain on indefinite treatment?

A final option for John is to do nothing and avoid doctors until he becomes ill. A fraction of patients are so fearful of medications and doctors that they evade the health care system until they've developed an opportunistic infection. Although many opportunistic infections are treatable, some are not; or multiple infections may develop in a single individual, leading to prolonged hospitalization and complex treatment regimens with horrible side effects; or the patient may die during the course of treatment. Few doctors or patients would choose this course.

However, if John fits this patient description, he might be better off delaying his therapy until the last possible moment rather than risking the development of multiple drug resistance because of poor compliance. Sometimes it takes a brush with death to convince a person to treat his or her HIV infection.

For the majority of people, however, it's not "if" he or she will be treated but "when." Unlike people with other life-threatening diseases like cancer, who must undergo treatment as soon as possible, those with HIV infection usually have months or years to ponder their options, jointly deciding with their doctors not only when to start treatment but also what particular regimen will work best for them.

Ross Slotten, M.D., M.P.H., is a board certified family practitioner in Chicago who has been caring for people with HIV since 1981. His three-physician group, Klein and Slotten Medical Associates, treats mainly gay men and is among the largest private HIV practices in the Midwest. He is currently a consultant for AEGIS, the biggest free-access HIV/AIDS knowledge base on the Web. Since 1989, he has been a member of CPCRA (Community Programs for Clinical Research on AIDS), a community-based national clinical trial network sponsored by the National Institutes of Health. Dr. Slotten can be reached at (no spaces) or 1-312-280-0996.

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