PI Perspective #29

April 2000     View PDF     En español

Millennial Heresy

Beginning in 1996, protease inhibitors and three-drug combination therapy revolutionized HIV treatment. At least in the developed world, a new highly aggressive treatment standard emerged almost overnight. Not surprisingly, four years of experience with the new therapies have shown a few cracks in that standard and it may be time to reconsider some of the common beliefs about therapy.

Raising such questions is not a condemnation of past practices or a sudden declaration that everyone should abruptly change strategies. It is instead a statement that our knowledge is advancing—a sign of progress not retreat. Many of these concerns have been raised all along—what’s different now is that more people are speaking out. These concerns should not be misunderstood to suggest that people are suddenly worse off than before. By any measure, most people with HIV and AIDS continue to do far better than they did just a few short years ago.

The Questions
Seemingly heretical answers are being proposed for a variety of questions, including:

• When should people start therapy? Is there such a thing as too early?
• Must people stay on treatment permanently?
• Must every combination include a minimum of three drugs, two of them from the class of drugs known as nucleoside analogues?
• Have we overlooked other options?
• Are some of our most popular drugs as good as we have been led to believe?

Is the pursuit of undetectable viral load—at any cost—a necessary medical goal or a growing part of what threatens people with HIV?
What’s at stake in getting the answers to these and similar questions is whether advances in therapy will provide an entire lifetime of benefit, or just a few years respite from HIV.

When to Start?
When talk of the eradication of HIV accompanied the new therapies, the slogan “Hit it hard and hit it early” became the mantra of virologists and clinical researchers. If HIV would soon be eradicated, it seemed to make sense to beat the virus into submission as quickly as possible. Sensationalist media reports ignored the fact that researchers were only raising the hope of eradication as a possible goal for people who went on treatment mere days or weeks after being infected. No one suggested it would be achieved any time soon for the typical, chronically infected person.

“Hit it hard and hit it early” was incorrectly translated into meaning that everyone who was HIV-positive, regardless of stage of disease, should be permanently put on an intensive, three-drug regimen now. Accepting this was easier at the time since some of the long-term toxicities of aggressive treatment were not yet apparent. Lipodystrophy was not yet a household word, nor were reports being received about possible dangers of heart, kidney and liver disease, the high rate of HIV/hepatitis co-infections, or the previously overlooked problems of mitochondrial damage and lactic acidosis. Although the incidence of such problems is unclear and frequently overstated, they have clearly become more common in this era of aggressive treatment.

We quickly learned that aggressive treatment also set HIV-positive people on paths that risked developing resistance to the drugs. After only a few rounds of treatment failure, people sometimes acquired resistance to almost every available drug.

There’s no doubt the new drugs can make a profound, life-or-death difference, especially for people with advanced disease. However, people in much earlier stages of disease were now being put on treatment. Many who were healthy and may have remained healthy for many years before developing AIDS suddenly found themselves coping with drug side effects, along with adherence and resistance problems.

The present debate is not about whether to use treatment, but when. No one disputes that people with CD4+ cell counts below 200 should be on treatment. Getting people into care and starting therapy before the onset of opportunistic infections remains one of the great challenges of the public health system in the U.S. At the other extreme, there’s no clear evidence that starting treatment in people with very high CD4+ counts—above 500—provides any proven benefit, though it exposes them to the risk of side effects and resistance—possibly long before necessary.

In between these extremes, the picture is muddy. Some studies have shown benefits from treatment in people who started with CD4+ cell counts of 350 or below. There is less clear evidence for people with counts between 350 and 500. Ironically, the success of the new drugs in restoring the immune system has complicated this debate. Before, it was easier to recommend early treatment because there was evidence of significant early damage to the immune system. Today’s treatment strategies are remarkably effective in repairing much of the apparent damage—making it easier, in theory, to delay treatment.

But early treatment, at almost any stage of progression, may still be proven beneficial in future studies. There may be advantages to starting therapy early, but the effects may not be readily apparent because we don’t yet know how to measure them. We simply don’t know which is best today, and there isn’t much hope of getting a clear answer anytime soon. Even if needed studies begin tomorrow, they will take several years to complete. Unfortunately, the constantly changing standards of treatment have caused many researchers to despair about ever being able to design proper trials to answer these questions.

People with HIV and their doctors must recognize that there’s no one right answer to this question. For now, what counts most is making sure everyone is given the knowledge and opportunity to make this choice for him or herself.

Must Treatment be Permanent?
Until recently, treatment was assumed to be permanent once begun, a factor that weighed heavily in the decision to start treatment. While many researchers assume that a lifetime of uninterrupted therapy is necessary, others are experimenting with intermittent therapy options, known as Structured Treatment Interruption (STI). This research has produced a handful of people who, after a few repeated cycles of therapy interruption, have apparently strengthened their natural immune response against HIV so much that they no longer need drugs to keep their viral load below the limit of detection. If this could be routinely achieved, it would make many of the other dilemmas of treatment disappear, like long-term side effects or treatment fatigue.

Other recent research has begun to confirm earlier findings that treatment interruptions can sometimes reverse drug resistance. While the reversal may not be complete or permanent, it often seems sufficient to permit a new regimen to work long enough to get viral load under control and keep it there for long periods of time.

Perhaps the most important but elusive question is whether or not people can safely take time off from therapy at various stages of HIV infection. Researchers have historically looked only at the harm it might do: increased viral load, reduced CD4+ cell counts, possible loss of some of the gains achieved by therapy. But we must also ask how much good STI might do (and how much harm constant therapy might be doing to some). Can people live longer, more comfortable lives with an occasional STI? No one yet knows, but there is growing evidence that people won’t be able to sustain constant therapy for the rest of their lives. Side effects, organ and tissue damage, viral resistance, treatment fatigue and obstacles to adherence accumulate over time and will take their toll. (For more information about STI research, call Project Inform’s Hotline).

The Three-drug, Two- “nuke” Minimum
One of today’s most sacred rules is that every regimen must include at least three drugs, typically a combination of a protease inhibitor or non-nucleoside (“non-nuke”) plus two of the nucleoside analogue (“nuke”) drugs. While using two nucleosides may have been the best choice in 1995, it may not be the best we can do today. In light of recent findings of previously unrecognized toxicity associated with the nucleoside analogue drugs, it seems critically important to know whether or not people always need two of them, or need them at all.

Why were two nucleoside analogues always recommended instead of one? Primarily because they are weak drugs and it took two to make a substantial contribution to therapy. Of the available nucleosides, 3TC was probably the most potent, so it quickly became a standard element in most combinations (even though later data showed that resistance to 3TC quickly developed and was the most common cause of failure of three-drug regimens). A new generation of this class of drugs, represented by abacavir (Ziagen), offer potency far exceeding that of previous nucleosides.

Unfortunately, most people had already used the older nucleoside drugs for years, often to the point of resistance. Thus, the benefits seen in studies of people starting treatment for the first time overstated the results people would get if they had used the older drugs before, while perhaps understating the long-term toxicity.

A number of other alternatives to the dual nucleoside standard have yet to be considered or tested, and some that have proven themselves have had a very difficult time being accepted. The most obvious overlooked combination was two protease inhibitors. This option was studied from the beginning, but only to save saquinavir from the dump heap. Studies using a ritonavir/saquinavir combination without nucleosides show it is at least, if not more, potent and durable than standard three-drug combinations. The advantages include eliminating the side effects of nucleoside analogue drugs and simplifying the regimen.

Once non-nucleoside analogue drugs and higher potency, second generation nucleosides were available, other combinations became possible. The list of possible combinations has grown each year, yet little effort has been made to challenge the old standard of care. Its time is overdue.

A European Perspective
Perhaps the most heretical view of all is that of some European and American researchers argue that aggressive therapy—a three-drug combination—isn’t necessary for everyone. They believe that for at least some people, notably those with very low viral loads, simpler two-drug combinations may be sufficient, even if they don’t always result in sustained, undetectable viral load. They also argue that three-drug regimens are seldom feasible in developing nations and that in these situations a two-drug regimen is better than nothing.

Most U.S. researchers scoff at this, saying studies have proven three-drug therapy is superior. However, the studies that “proved” this point included people with widely varying CD4+ cell counts and viral loads, who took either two or three drugs. In these settings, three-drug therapy always looks better, but only because people with the most advanced disease typically decline on two-drug combinations. This conclusion overlooks the fact that many do very well for long periods on the two-drug regimens. People with high CD4+ counts and low viral load often maintain undetectable viral load status for long periods—on just two drugs. It’s unclear whether more aggressive therapy is warranted for such people.

If two-drug therapy were proven sufficient for at least some people, it would save a great deal of money and a lot of anguish, side effects, and effort. Nonetheless, dogma perseveres and in the U.S., almost any doctor who puts a patient on a two-drug therapy for any reason runs the risk of being accused of medical mismanagement. The three-drug standard is “locked in” because any study that proposes to use two drugs is branded as “unethical.”

How Good are the Most Popular Drugs?
Our perceptions of the value of drugs are based on many perspectives, not all of them balanced and unbiased. The results of independent studies get blended with those conducted by a drug’s sponsor. Drug company analyses are sometimes massaged by their marketing departments and almost never find fault with the sponsor’s drug. Doctors also develop their own favorites, which may be influenced by the hard sell tactics of manufacturers. People hear the preferences and beliefs of their friends, along with the views of community newsletters, magazines, the press and treatment educators.

The only real way to sort out the net value of a drug is to follow the results of studies over time. Good drugs stand the test of time, while mediocre ones may not. Although people often need to make decisions based on short-term studies, they need to keep an open mind and be prepared to change their beliefs as the long-term picture emerges.

This long term view has begun to raise doubts about the most widely used protease inhibitor, nelfinavir (Viracept), a drug often chosen for its relatively limited side effects, ease of use, and some debatable beliefs about its role in viral resistance. Despite this, three recent studies have raised serious concerns about whether it meets the standards of potency established by some other protease inhibitors. (For more information, read Nelfinavir Potency Concerns.)

Over time, we may see similar concerns raised about other drugs; but conversely, we may also see the reputations of some drugs improve. Two non-nucleoside analogue drugs, nevirapine (Viramune) and delavirdine (Rescriptor), were initially viewed as having only modest activity, but this was largely a remnant from when they were only tested in two-drug combinations while being compared to other drugs in three-drug combinations. More recent studies using three-drug combinations have raised the perceived value of nevirapine, and a similar process is now taking place with delavirdine.

Undetectable Viral Load
While the hope of eradication thrived, keeping viral load as low as possible for as long as possible made sense as a step toward that goal. Even though eradication is not currently considered feasible, most researchers still seem wedded to the pursuit of undetectable viral load at any cost. It is not clear that this is always in the patient’s best interest.

Perhaps the most compelling argument for undetectable viral load is that it may present the greatest obstacle to developing drug resistance. At least in theory, once viral load becomes detectable and a person continues using an anti-HIV drug, it will cause the development of ever more mutations and thus resistance, crippling the potential for future drugs to work. But it doesn’t always seem to work that way in the real world. Many people, including some researchers, report that viral load often becomes detectable despite continued anti-HIV therapy, but it stays at a stable level while people thrive and their immune systems continue to improve.

Others believe that if eradication isn’t possible, the best balance between the immune system and the virus may be one that permits enough HIV replication to keep stimulating a natural immune response, but not enough to do much harm. At the very least the perceived value of keeping viral load undetectable must be measured against the price paid to achieve it. When the price is too high in terms of toxicity and treatment fatigue, it’s important to remember that people can live long and well despite measurable viral load.

Where Does the Road Lead?
These and other concerns are causing the first serious rethinking of the goals and tactics of HAART (Highly Active AntiRetroviral Therapy). HAART may still be the preferred approach for people with serious immune deficiency, or even for those with modest degrees of immune dysfunction, but that doesn’t mean it’s right for everyone. As long as drugs can cause serious side effects in some people, there will be room for debate over just when and how to use them.

For many, HIV disease is a long slow process, not the titanic daily battle between massive amounts of virus and the valiant drugs envisioned in 1996. On the contrary, for some, the rate of viral reproduction is relatively low and stable, at least compared to truly aggressive viruses. Keeping it sufficiently, if not completely suppressed, may be easier than previously thought, and it may be possible to do it at a lower cost and with fewer side effects and adherence demands. The coming period of rethinking and change should be welcomed, and we can only hope that the researchers who promoted HAART will not view it defensively.

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