A new HAART on the horizon says the proof is in the potency

Studies show a new regimen has better compliance

Research proving that HIV-1 originated in West African chimpanzees may have grabbed most of the national headlines at the recent 6th Conference on Retroviruses and Opportunistic Infections in Chicago. But some clinicians were more interested in studies that claim highly active antiretroviral therapy (HAART) need not involve protease inhibitors to achieve positive results.

The conference buzz over non-protease inhibitor therapies brings HIV treatment full circle, proving that protease inhibitors are not the magic bullet and it’s potency that matters most.

"When there was all the hoopla two or three years ago with protease inhibitors, the point was we finally had extremely potent therapies that, in combination with existing ones, could suppress the virus below our ability to detect it," says Daniel R. Kuritzkes, MD, associate professor of medicine at the University of Colorado Health Sciences Center in Denver. Kuritzkes also is the co-director of the Colorado AIDS Clinical Trials Unit in Denver.

Protease inhibitors were never the only option

Although therapies with protease inhibitors quickly became the gold standard, they were never meant to be the only option, Kuritzkes says. "Even when they were introduced, people who were a little more forward-looking in their view were saying it’s not the protease inhibitors per se, it’s the potency," he says.

Other drug combinations — whether two, three, or more drugs — also should be able to succeed in suppressing HIV, he adds.

The latest research brings good news for clinicians, especially if they have patients who are having difficulty tolerating protease inhibitors, says Kenneth Mayer, MD, chief of the infectious disease division of Memorial Hospital in Pawtucket, RI. "Because there are all these meta bolic side effects, clinicians have been concerned about [protease inhi bi tor] use, and now we have data on alternative regimens," Mayer says.

Researchers at the February retrovirus conference presented data showing successful results with an all-nucleoside reverse transcriptase inhibitor combination of Ziagen (abacavir sulfate), Retrovir (zidovudine, AZT), and Epivir (lamivudine, 3TC). Ziagen, manufactured by Chicago-based Glaxo Wellcome, received accelerated approval by the Rockville, MD-based Food and Drug Administration (FDA) on Dec. 17, 1998, for use in combination with other antiretroviral agents for treatment of HIV-1 infection.

The Ziagen study showed a 74% probability of keeping a patient’s viral load to undetectable levels for 48 weeks on the Ziagen triple-drug regimen. Also, 92% of the patients (48 out of 52) who remained on the Ziagen+Epivir+Retrovir arm for the entire 48 weeks achieved undetectable levels of HIV.1

Abacavir combination holds promise

The abacavir study is encouraging because it provides clinicians with an option of a protease-sparing regimen that appears to have equivalent results, says Joseph J. Eron, MD, an associate professor of medicine at the University of North Carolina at Chapel Hill. Eron also is the co-investigator of the AIDS Clinical Trial Unit in Chapel Hill.

Also, a late-breaking session presented by Karen Tashima, MD, provided impressive data on the non-nucleoside reverse transcriptase inhibitor Sustiva, Eron says. "They had 48 weeks’ data from their trial that showed very potent activity and a very low drop-out rate when compared with the control arm," Eron says.

Sustiva (efavirenz), manufactured by DuPont Pharmaceuticals in Wilmington, DE, was studied in a combination with zidovudine/AZT and 3TC. The combination was found to reduce viral load in 98% of patients, compared to reduced viral loads in 86% of patients on the protease inhibitor Crixivan plus AZT and 3TC.2

The Sustiva combination also had a lower discontinuation rate in a 48-week study, with 25% of patients discontinuing use, as compared with 42% of patients discontinuing use of the protease inhibitor Crixivan (indinavir) used with AZT and 3TC.

Sustiva, approved by the FDA on Sept. 18, 1998, was selected in December to be included in an update of "Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents," developed by the Panel on Clinical Practices for Treatment of HIV Infection convened by the Department of Health and Human Services in Washington, DC, and the Henry J. Kaiser Family Foundation.

A Sustiva combination could be an effective alternative for patients who have become noncompliant with their HAART because of side effects caused by the protease inhibitor.

"Then we can use the protease inhibitors later on if needed, and avoid some of the side effects," says Tashima, who was a principal investigator in the Sustiva study and is an assistant professor of medicine at the Miriam Hospital of Brown University in Providence, RI.

"The drug itself is easy to take because it’s just three pills at night with no food restrictions," Tashima adds. "Once-a-day drugs are the way we’re going to improve patients’ adherence to medications."

A British study of Sustiva found that patients who had experienced peripheral fat wasting (lipodystrophy) while on protease inhibitor therapy experienced various physical improvements after their regimen was changed to Sustiva plus two nucleoside reverse transcriptase inhibitors. These positive results included a significant weight gain at 12 and 24 weeks, a modest reduction in abdominal circumference, and a general improvement in appearance.3

48-week trial demonstrates durability

First introduced as a 24-week study at the 12th World AIDS Conference in Geneva in June 1998, the Sustiva study was expanded to 48 weeks, meaning its success rate has held up over nearly a year’s time.

"The 48-week trial is important because one worry about the non-nucleoside class, such as efavirenz, is that, yes, they are potent, but how durable would they be, and how long would the potent activity last?" Eron says.

"This was the first time ever a large randomized study showed that a regimen without a protease inhibitor could be as successful as those with it," says Laurent Fischer, MD, senior vice president of the virology group at DuPont. "Using it once daily, Sustiva is a much more convenient and better tolerated drug," he says.

The protease inhibitor Crixivan reportedly has adverse effects of gastrointestinal intolerance, nausea, headache, blurred vision, dizziness, rash, hyperglycemia, fat redistribution, and lipid abnormalities.

Research showed that Sustiva’s most alarming side effects were a rare rash and central nervous system symptoms such as insomnia, vivid dreaming, confusion, and impaired concentration.4 Some patients also experienced dizziness. "Those side effects are seen early in treatment and disappear in a matter of weeks," he adds.

Also, pregnant women should not be given Sustiva because birth defects have been observed in animals that received the drug.

DuPont recommends that patients take the drug at night a few hours before they go to bed and to begin on a Friday night, so they have the weekend to adjust to it. Some physicians have been splitting the dose, having patients take half in the morning and half at night, although that has not helped to reduce the symptoms or affect the efficacy, Fischer says.

"We put a lot of emphasis on how it was important to educate patients about the side effects before they started treatment," Fischer says.

With a price tag of about $3,900 a year, Sustiva is 28% to 38% cheaper than protease inhibitors, Fischer says.

A minor problem with the Sustiva study is that it was not a blinded study with a placebo, Kuritzkes and Eron note. Patients knew whether they were getting efavirenz or a protease inhibi tor because the regimens are so different that patients would have known which drug they were taking in any event.

The analysis indicated that most of the patients who dropped out of the study did so because of drug-related toxicity. "But it’s hard to evaluate toxicities objectively when patients know what drug they’re on," Kuritzkes says.

Some additional Sustiva trials included the drug as part of a protease-inclusive or protease-sparing regimen, and found that 66% of patients given a combination of Sustiva and indinavir maintained undetectable levels of HIV at 108 weeks.

On the bright side, both the Sustiva and abacavir studies mean clinicians will have more choices for HAART, Eron says.

"I think we can tailor or adapt our treatment regimens to fit our patients even better now," Eron says. "And I think in general what we’re going to see over the next year is that more patients are started on treatments that do not contain protease inhibitors."

References

    1. Fischl M, Greenberg S, Clumeck N, et al. Ziagen (Abacavir, ABC, 1592) combined with 3TC & ZDV is highly effective and durable through 48 weeks in HIV-1 infected antiretroviral-therapy-naive subjects (CNAA3003) [abstract 19]. Presented at the 6th Conference on Retroviruses and Opportunistic Infections. Chicago; Feb. 1-5, 1999.

    2. Tashima K, Staszewski S, Morales-Ramirez J, et al. A phase III, multicenter, randomized, open-label study to compare the antiretroviral activity and tolerability of efavirenz (Sustiva, EFV) + zidovudine (ZDV) + lamivudine (3TC), versus indinavir (IDV) + ZDV + 3TC, versus EFV + IDV (Study 006); January 1997-October 1998. Presented at the 6th Conference on Retroviruses and Opportunistic Infections. Chicago; Feb. 1-5, 1999.

    3. Moyle G, Baldwin C, Dent N, Gazzard B. Management of protease inhibitor-associated metabolic changes by substitution with efavirenz in virologically controlled HIV-1 RNA- positive patients [abstract 669]. Presented at the 6th Conference on Retroviruses and Opportunistic Infections. Chicago; Feb. 1-5, 1999.

    4. Ruiz NM, Bessen LJ, Manion DJ, et al. Potential adverse experiences associated with efavirenz (Sustiva) in adults [abstract 655]. Presented at the 6th Conference on Retroviruses and Opportunistic Infections. Chicago; Feb. 1-5, 1999.