First once-daily drug simplifies dosing, offers new options in HIV-1 treatment
First once-daily drug simplifies dosing, offers new options in HIV-1 treatment
Side effects, risks of cross-resistance remain, as with other therapies
The U.S. Food and Drug Administration has approved the first once-daily antiretroviral drug — efavirenz (Sustiva), a non-nucleoside reverse transcriptase inhibitor (NNRTI) — to treat HIV-1 infection in adults and children. Although the drug is being touted as highly potent and more convenient than other therapies, it is not without side effects or risk of cross-resistance, like other anti-HIV drugs.
"We . . . welcome the introduction of this much-needed once-daily anti-HIV drug," says A. Cornelius Baker, executive director of the National Association of People with AIDS in Washington, DC. "The clinical trial results suggest that [efavirenz], when used in combination with other antiretroviral agents, may not only simplify dosing and reduce patients’ pill burden, but its potency and tolerability may also offer physicians and patients, including children, new treatment options."
At the 12th World AIDS Conference in Geneva earlier this year, investigators presented data that compared various combinations of efavirenz, zidovudine (AZT, Retrovir), lamivudine (3TC, Epivir), and indinavir (Crixivan) in patients with asymptomatic or minimally symptomatic HIV disease who hadn’t received lamivudine, any of the NNRTIs, or protease inhibitors. Data from 450 patients studied over 24 weeks were presented. Patients on the efavirenz/lamivudine/ zidovudine regimens performed statistically significantly better than patients on regimens containing indinavir/zidovudine/lamivudine or indinavir plus efavirenz. HIV-1 RNA levels were below 400 copies in 74.7% of patients on efavirenz/lamivudine/zidovudine, compared to 56.2% of patients on indinavir/lamivudine/zidovudine.
Adverse events vary among study groups
In addition, patients on efavirenz had fewer side effects than patients on the other triple-therapy regimen. Patients on indinavir/zidovudine/ lamivudine were most likely to experience adverse events (26 of 148 patients), compared to 10 of 154 patients on efavirenz/zidovudine/ lamivudine and seven of 148 patients on efavirenz and lamivudine.
"That trial has been criticized because the superiority of Sustiva can probably be attributed to patients stopping their indinavir because of side effects," says David Margolis, MD, assistant professor at the Institute for Human Virology at the University of Maryland in Baltimore. "So it can’t be definitely said that Sustiva triple-combination is better or more potent than the indinavir triple combination or a protease inhibitor triple combination. But it certainly is potent, it certainly has good effect, and it certainly is well tolerated. So I think it presents a very exciting new alternative for potent triple therapy for patients."
However, Margolis says it remains to be seen whether the triple combination therapy with efavirenz will be used as first-line therapy. One problem is that patients who are on any type of drug that affects the central nervous system (CNS), such as methadone or anxiolytics, may have more CNS side effects from efavirenz, such as irritability or sleepiness.
"There are some reports of patients with underlying psychiatric disorders that may be occasionally exacerbated by exposure to Sustiva," Margolis notes. "But the bottom line is, there is some reason to be a little cautious in people whose thinking is challenged in some way."
He says he has only been using efavirenz as second-line therapy because of his involvement in the expanded access program for the drug at the University of Maryland.
"I’ve only [used] it so far in patients who have failed or can’t tolerate other potent therapy, and I’ve used it in some of my protease inhibitor patients who have gotten the belly’ or other protease side effects," Margolis says. "Over the short term, their clinical effect has been maintained, so that’s been encouraging." (For more information on problems with body fat redistribution in patients taking protease inhibitors, see AIDS Alert, September 1998, p. 101.)
Watch out for cross-resistance
Margolis warns of cross-resistance between efavirenz and the two other available NNRTIs, nevirapine (Viramune) and delavirdine (Rescriptor).
"[Cross-resistance] is not all across the class," he says. "Some viruses will be resistant to all three drugs. Some viruses, from people who have been exposed to either Rescriptor or Viramune, will not be completely resistant to Sustiva, although just like the protease inhibi tors, I think you need to be concerned that the first time you’re exposed to a drug of a certain class, it’s going to be your best response."
However, it appears that resistance with efavirenz may take longer to develop.
"So I think for a lot of reasons, most of the market for non-nucleoside reverse transcriptase inhi bitors will go to Sustiva," Margolis adds.
Also, there are "very limited data" on efavi renz and fetal toxicity, so women of childbearing age should be counseled carefully before they take the drug, he says.
In patients with low CD4 counts and high viral loads, Margolis says he would use efavirenz "cautiously" in certain circumstances.
"I would have some concern using simply Sustiva and two nucleosides at this point," he notes. "I might use it cautiously in them if I thought they would have trouble taking two protease inhibitors, for example. I would want to follow them closely to see whether or not [the drugs] are working."
Margolis checks viral load within two to three weeks after starting a regimen, then one month later, and finally monthly for two months until patients are stable.
Potency similar to protease inhibitors
Steven Johnson, MD, associate professor of medicine and director of the HIV/AIDS Clinical Program at University Hospital in Denver, says efavirenz is as potent as a protease inhibitor.
"This is an exciting new drug," he notes. "Even removing some of the company-sponsored activism about the drug, we’re really very excited to be able to have it."
Typically, efavirenz is used as part of a three-drug regimen, says Johnson. Although it was studied in premarketing trials with zidovudine and lamivudine and was found to be highly effective, it also has been found effective in combination with protease inhibitors.
"So I think one of the open questions with its licensure is what precisely is the best combination to use in terms of effectiveness and tolerability," Johnson says. "It’s a consequence of our rapid licensure of medications that the first four [anti-HIV] drugs that were licensed were licensed over about eight years, and now the last eight drugs have been [licensed] over the last three years. So we’ve rapidly licensed new drugs, and obviously have had great effects with them, but what has happened is that these drugs have emerged so rapidly that we don’t precisely know the comparability of every different combination of these medications. There are literally thousands of combinations at this point."
He estimates that 10% of patients at the clinic have been on efavirenz as part of clinical trials and the expanded access program. Although he says there is no "cookbook approach" to antire troviral drug therapy, patients generally receive three or more drugs.
"We usually base decisions on prior drug experience, so [with] people who have been on drugs before, our concern might be resistance to therapy, [so] we may choose drugs they haven’t been on before," Johnson explains. "That’s certainly an important role for efavirenz. For people who have some degree of resistance to the licensed drugs, Sustiva can be part of the new regimen that would hopefully be effective against resistant virus."
What about compliance?
With current regimens requiring patients to take many pills, compliance with drug therapy isn’t always optimal. Efavirenz should help that problem somewhat, says Johnson, because it lowers the number of pills patients must take.
"We think the less frequently you dose a drug during the day, the more likely it is to lead to adherence," Johnson says. "A three-times-a-day drug is taken less consistently than a two-times-a-day drug. So a once-a-day drug is probably going to be easier to take than a three-times-a-day drug."
Another advantage of efavirenz is that there are no dietary restrictions associated with it. For example, indinavir should be taken on an empty stomach.
"The simpler the better, because the more adherent people are, the more likely that the virus will be suppressed and the immune system will recover to the greatest extent possible," Johnson says.
The regimen found to be most effective in premarketing trials — efavirenz, zidovudine, and lamivudine — will be five pills daily, he adds. Zidovudine and lamivudine must be taken as a combination pill twice daily, and three efavirenz pills are taken at bedtime. Another regimen that requires fewer pills is indinavir, zidovudine, and lamivudine, which requires eight pills daily. But some regimens require 20 or more pills daily.
James Hellinger, MD, associate research director of Community Research Initiative of New England in Boston, agrees that having to take fewer pills means efavirenz may increase compliance.
"The most important thing is that the medication combinations that work best are the ones patients can take," he notes. "A drug can be unbelievably potent, but if it’s got intolerable short-term effects that develop immediately or side effects that accumulate and develop over a longer term, that can create problems resulting in people not wanting to take their meds. So far, the studies suggest that combinations including Sustiva look to be very potent and very tolerable in both the short term and the long term. So people who start them stay on them."
Efavirenz can be used in many combinations of other drugs. "There’s enough background for the use of medications of this class together with nucleosides — for example, the class of nucleosides that includes Retrovir and Epivir," says Hellinger.
"There’s enough background that the overwhelming likelihood is that one could probably combine Sustiva with nucleosides and achieve a comparable effect, but those studies are in pro gress and haven’t yet been reported. Sustiva also has been studied with single protease inhibitors such as nelfinavir together with nucleosides. [It also has been studied] with nelfinavir alone or indinavir alone. It looks like Sustiva will be a valuable agent when combined with all of those other classes," he says.
Nevirapine works well in combinations
Another NNRTI, nevirapine (Viramune), also is highly effective in three- or four-drug combinations, says Hellinger. He says it has been "underutilized" because it was studied as a single-drug therapy in preclinical trials.
"But when it has been combined with three- and four-drug combinations, it’s been extremely active," he says. "One of the key differences, though, is that Viramune has a somewhat higher — at least twofold — rate of developing rash. So it can be harder to start that medication. In contrast, Sustiva has about half the incidence of rash [of Viramune], but a much higher rate of CNS side effects such as dizziness or grogginess."
With nucleosides, it appears that patients can start on one agent in the class and follow with one or two different agents in the class and still have an effect, says Hellinger.
"But with the non-nucleoside that Sustiva is a part of, it looks like that doesn’t work," he notes. "There’s no class-bearing benefit. If you started with something in the class, nothing else is going to work. But with the other classes, you might be able to do a sequencing approach where you start with something and switch to alternatives in the class and still have some benefit."
Side effects lessened at bedtime
Johnson says some of his patients complain of dizziness or lightheadness with efavi renz, but because it is taken at bedtime, symptoms are less noticeable because patients go to sleep and the effects of the drug wear off after about two hours.
Efavirenz also can lower the plasma level of other drugs such as saquinavir (Invirase) and indinavir.
"So what that means is that in regimens that combine those, the physician may increase the dose of the protease inhibitor to compensate for it," Johnson explains.
He says he is optimistic about the approval of efavirenz.
"This field is more complex now than it’s ever been," Johnson notes. "So an important part of the success of this drug is that it be in the hands of people who understand its limitations, its effectiveness, its drug interactions, and its side effects."
Hellinger says efavirenz is appropriate for patients who have been in long-term drug therapy or for those who are just starting it.
"I think it’s likely to be extremely useful for people who have never had medication, whether they have high or low CD4 counts," he notes. "It’s likely to have an important role in people who have had medications, have had partial or no effect, and then have had an adjustment and a Sustiva combination added. So it’s likely to be useful at all points along the spectrum of HIV infection."
(Editor’s note: To obtain more information about efavirenz, including product labeling, visit the Web site maintained by the drug’s manufacturer, DuPont Pharmaceuticals in Wilmington, DE. Address: www.sustiva.com.)
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