New standard sheds little light on best regimens

Best combinations not known for several years

The new clinical practices standard for HIV treatment, due out in May, will reflect basic pathogenic principles of HIV disease that should remain viable for the next several years, say health officials. However, guidelines for when to add or switch antiretroviral drugs remain untested, which poses the greatest problems for clinicians and patients, they add.

"When to switch to an alternative agent and the exact determination of when to use which agent is something I wish we could tell people definitively," said Mark Feinberg, MD, MPH, senior medical officer for the Office of AIDS Research at the National Institutes of Health in Bethesda, MD. "But if we did, it would be more our guess than documented knowledge. This is all uncharted territory, and the true answers won’t come in for a couple of years."

Speaking at a recent teleconference presented by the San Francisco AIDS Foundation, Feinberg outlined issues faced by two panels drawing up clinical guidelines and principles for HIV treatment. The NIH and the National Institutes of Allergy and Infectious Diseases convened the panels last year with support from the Kaiser Family Foundation in Menlo Park, CA. The recommendations are based on recent advances in HIV pathogenesis suggesting that previously untreated patients are most likely to benefit from antiretroviral treatment, and that initial treatment decisions are the most important.

"Someone who has not received antiviral therapy is unlikely to have significant levels of drug-resistant virus," Feinberg explained. "But because the option you choose at any one point is going to affect your future choices, it is important that you make the right choices up front."

A preliminary draft of the guidelines calls for triple-drug combination treatment as initial therapy. (See related story in AIDS Alert, May 1996, p. 49.) However, because long-term studies of protease inhibitors are still under way, it is difficult to recommend which specific drugs are best for initial treatment, Feinberg said. The only clear answer is that any drug alone is now considered inadequate.

"No matter how potent any of the protease inhibitors, none in and of themselves have been shown to give rise to durable suppression of virus replication in significantly large numbers of patients," he said.

With the recent FDA approval of a fourth protease inhibitor, nelfinavir, clinicians and patients have an ever-growing spectrum of drug combinations to choose from — but little data to predict their long-range efficacy. (See related story on nelfinavir, p. 68.) Guidance must come from a well-defined goal of therapy, whether it be hitting hard and early or developing a strategy in which a sequence of drug combinations are recommended based on symptoms, CD4 count, viral load, and previous treatment.

"With respect to virologic effect, I would be hard-pressed to say one is better than another," Feinberg says. Any decision also must consider a patient’s tolerance and lifestyle, he said.

Once a treatment plan is established, clinicians and patients also must discuss how progress will be monitored and what the next step is if treatment doesn’t meet those goals, added Eric Goosby, MD, acting director of the White House Office of AIDS Policy.

"I really believe a discussion at the point of initiation of therapy should be directed toward defining at what point we consider switching and what that process would look like," he said.

As an example of confounding variables that could alter a plan, he mentioned how a patient developing an opportunistic infection might require a change of not just one or two but possibly three new drugs. And for previously treated patients, the failure of a regimen may mean dropping those drugs completely, if not indefinitely.

You may as well call it monotherapy

Indeed, too many clinicians are simply adding a protease inhibitor to one or two non-nucleoside reverse transcriptase inhibitors after they have lost their effectiveness.

"The most common mistake I have seen is practitioners who are just adding protease inhibitors to an already existing nucleoside regimen that is not changed when the protease is added," Goosby explained. This means the patients are being treated with only one effective drug, which essentially means they are receiving monotherapy.

Until recently, AIDS researcher and clinician Ken Mayer, MD, was still comfortable initially treating patients with two drugs rather than three. After all, studies had shown that two drugs were enough to suppress virus in about half the patients who had viral loads between 10,000 and 100,000 copies, he notes.

"The thinking was, why not just give two drugs and see if the patients are among those lucky 50%, and then add a third drug if they aren’t," he tells AIDS Alert. "Now the tendency is to be more cautious and start with three drugs and hedge your bets, so that you are well over 90% likely to get someone who is asymptomatic with modest viral load to complete suppression."

Mayer, who is director of the Brown University AIDS program in Providence, RI, agrees that knowing when to change a failing regimen is easier than knowing how to change it. Although some clinicians feel sometimes as if "we are making it up as we go along," there are data out now on two different combinations of protease inhibi tors (saquinavir/ritonavir and nelfinavir/indinavir), as well as on two non-nucleoside reverse transcriptase inhibitors (nevirapine and Dupont Merck’s DMP 266) in combination with protease inhibitors.

"I can’t think of anyone I have run out of options with if they are willing to work with us," he adds.

Compliance an ethical decision

Compliance is another factor that has been raised in making treatment decisions for these difficult new regimens. Both Feinberg and Goosby noted that the panels agreed it was an ethical decision that didn’t belong in a provider’s initial consideration for making a therapeutic intervention.

"The consensus of both groups was the offering of combination therapy to any given individual is not something attendant on or determined by one socioeconomic class or risk factor for HIV or the ability to adhere to a preconceived ideal that a provider may have," Goosby says.

At the same time, clinicians must make their patients understand how the therapies work and why failure to follow a regimen is a serious problem. "It must be clearly laid out that you really get one best shot and subsequent shots may not be good enough, so you must try to get it right the first time," Feinberg said. "This is not just a single discussion, but an ongoing one that needs to take place with the physician, the health team, and the patient’s family."

Patients also should be encouraged to find creative ways to assure compliance, such as having back-up systems if they are forgetful, keeping drugs at the office or in the car, or having friends check up on your progress, Goosby said.

Goosby also noted that patients should be informed that if they do fail to take one drug of a multiple-drug regimen, they should stop all three drugs at the same time until they are ready to comply again, rather than just stop that one drug.

"My experience with a large IDU [injection drug user] population is that when patients understand the importance of it [compliance] and you are consistent with them and available to hear their concerns, you can get a high degree of adherence out of anybody," he added.

Both Feinberg and Goosby outlined the theoretical reasons for the new push to treat patients as early as possible, ideally as soon after infection as possible. Although the long-term effects of treatment during primary infection (the first month or so after the virus has established a foothold) are not known, some researchers say this approach offers the best possibility for a cure.

One advantage of treating the virus at initial infection is that it is genetically homogenous. By having none or few of the variations found in the virus population once the virus is established, there is less possibility of resistance and more possibility of total suppression of HIV, Feinberg noted.

Second, by blunting active replication at the outset, the immune system would likely sustain less damage than if the virus were not thwarted.

A third, less well-known reason is a phenomenon called the viral set point. Viral activity during primary infection is so frenzied that viral load can measure as high as 10 million copies in plasma RNA before it levels out at around 100,000 copies. After fluctuating for about six to 12 months, the viral infection seems to hit a set point, or a level at which it will remain for months or years, Feinberg explained. Recent studies have shown that patients with higher set points progress to disease more rapidly than those with lower ones. Treatment during the primary phase of infection may result in a lower set point, he added.

The growing recognition of the benefits of early treatment makes it important for clinicians and patients to recognize the flu-like symptoms of primary infection, which may include rash, headache, fatigue, sore throat, and muscle ache.

"It is important for physicians to take a thorough history on patients who present with these symptoms because recent evidence, albeit limited, suggests that they may derive substantial clinical benefit," Feinberg added.