Two-protease regimens may work better than one

Drug combo good alternative for some patients

While some recent studies have followed patients on drug combinations that have no protease inhibitors, additional research is showing positive results from combinations that include two protease inhibitors and a nucleoside. Research also is being conducted on regimens consisting of two protease inhibitors without other antiretroviral medications.

The studies show that patients tolerate the protease inhibitor combinations very well, says Cassy Workman, MMBS, an associate director of AIDS Research Initiative and director of Ground Zero Medical in Sydney, Australia.

Workman’s research has involved giving patients the protease inhibitors ritonavir and indinavir, along with two nucleoside reverse transcriptase inhibitors (NRTIs). She gave patients twice-daily doses of 400 mg of ritonavir/ Norvir and twice-daily doses of 400 mg of indinavir/ Crixivan. The doses are not 12-hour regimens, so patients can easily take one dose in the morning and one in the evening. They also can take the doses without food restrictions and additional hydration. This regimen compares with the more typical daily dose of 1600 mg-2400 mg of indinavir, plus ritonavir and two NRTIs.

A second study assessed the new advanced-generation protease inhibitor ABT-378, manufactured by Abbott Laboratories in Abbott Park, IL, combined with ritonavir, stavudine, and lamivudine. Clinical tests of ABT-378 are continuing, and the drug has not yet received approval from the Food and Drug Administration.

ABT-378 is taken with a small amount of ritonavir and is well-tolerated, says Robert Murphy, MD, an associate professor of medicine and director of the HIV Treatment Clinic at Northwestern University in Chicago.

Patients ultimately will be able to take the ABT-378/ritonavir combination in the form of three capsules twice daily that can be taken without food restrictions. The most common side effects observed in the study were diarrhea, asthenia, and headache.1

The 24-week study treated 101 patients with four different dosage combinations of ABT-378 and ritonavir. "Only four people have discontinued the study, and none did so because of any side effects," Murphy says. "It’s very well-tolerated, and some patients actually thought they were taking a placebo."

All patients received some treatment with ABT-378, although some received smaller doses of the drug, he adds.

Another study assessed the tolerability and antiviral activity of a two-protease inhibitor combination of ritonavir and saquinavir.

"It’s been successful in potency, and most of the people who started the trial three years ago are still in it," says Calvin Cohen, MD, research director at CRI New England in Brookline, MA. "While not everyone can tolerate all the drugs, most people are staying with it."

Clinicians gave patients 400 mg twice a day of each drug instead of a full dose of 600 mg twice a day. "That clearly helps people tolerate the drug ritonavir," Cohen says.

The lower dose is potent because the ritonavir prevents patients’ livers from breaking down the saquinavir as quickly, so more of the saquinavir remains in their bloodstream, Cohen says.

"We’re in year three, and people who had viral suppression two and a half years ago still have it now," Cohen says. "For some people, these two drugs are enough, and this is particularly important because some patients have taken the other compounds and are no longer responding to them."

The two-protease inhibitor combination is a good option for patients who cannot rely on other medications, he adds.

The open-label randomized study included protease inhibitor-naive HIV-infected patients, who had CD4 counts of 100 to 500 cells/mL.2 After 12 weeks of dual protease inhibitor therapy, clinicians gave reverse transcriptase inhibitors to patients whose viral load maintained more than 200 copies/mL. About 70% of patients remained in the study at week 96.

Combining ritonavir with indinavir also solved some of the problems of intolerance seen with these drugs in Workman’s study. For instance, patients on ritonavir often have gastrointestinal side effects, and patients on indinavir may have problems with kidney stones. Patients on the ritonavir/indinavir combination studied in Australia didn’t have these side effects, even though patients were told not to increase fluid intake, Workman says.

Workman’s study of 57 patients on the indinavir/ritonavir combination examined patient records for incidences of nephrolithiasis and found no cases of it.3

In addition, the two-protease inhibitor combination is easier to take and tolerate. For example, a single-protease inhibitor regimen of indinavir requires patients to take the protease inhibitor three times a day, and it must be timed perfectly to keep the patient’s drug levels high enough to be effective. Also, patients are not able to eat for a three-hour window with each dose of indinavir.

The dual protease inhibitor combination requires none of those restrictions, and the ritonavir is soon expected to be available in capsule form, Workman says. The combination still is potent, providing strong viral suppression and significant CD4 count increases, Workman says.

Few patients had adverse effects

Cohen’s study of a ritonavir and saquinavir combination found that a few patients experienced some initial side effects of nausea, upset stomach, vomiting, and diarrhea. For most patients, these side effects wore off in about a month.

Although the protease inhibitors are thought to be related to long-term side effects of increased cholesterol and triglycerides and lipodystrophy, Cohen’s study found little evidence of these bodily changes.

Patients take the dual protease inhibitor combination twice a day, about 12 hours apart. "If people are out and doing whatever they do in the day, then they take the medication before they leave home and when they come home," Cohen says.

The ritonavir needs no refrigeration, but the saquinavir is best if it’s refrigerated, although patients conceivably could carry it around with them all day and it would still be potent, he adds.

The studies show that protease inhibitor combinations need not be poorly tolerated, and that combinations of two protease inhibitors in smaller daily doses are as effective in suppressing HIV as drug combinations of one protease inhibitor and two NRTIs, the researchers say.

"I think it’s important we have as many alternatives as possible," Murphy says.

Plus, if clinicians start with a protease inhibitor combination, they still will have good treatment options available later if necessary. "But the aim should be to get it right the first time by selecting a potent, well-tolerated regimen that matches the patient’s lifestyle," Workman says.

Because of the dual protease inhibitor combination’s potency, convenience, and tolerability, it has the potential to last for decades, Cohen says. "Dual protease combinations can be used with any patient, and it’s a critical option for patients who have taken some of the nucleosides in the past."

References

1. Murphy R, King M, Brun S, et al. ABT-378/ritonavir therapy in antiretroviral-naive HIV-1 infected patients for 24 weeks. Abstract presented at the 6th Conference on Retrovi ruses and Opportunistic Infections. Chicago; Jan. 31-Feb. 4, 1999.

2. Cohen C, Japour A, Cameron W, et al. Long term, open-label ritonavir-saquinavir (RTV-SQV) safety and durability in protease inhibitor-naive patients. Abstract presented at the 6th Conference on Retroviruses and Opportunistic Infections. Chicago; Jan. 31-Feb. 4, 1999.

3. Workman C, Whittaker W, Dyer W, et al. Combining ritonavir (RTV) and indinavir (IDV) decreases IDV-associated nephrolithiasis. Abstract presented at the 6th Conference on Retroviruses and Opportunistic Infections. Chicago; Jan. 31-Feb. 4, 1999.