Study evaluates effectiveness of LEXIVA/ritonavir and Lopinavir/ritonavir in protease inhibitor

Jul 12 2004

HIV treatment regimens containing the protease inhibitor (PI) LEXIVA® (fosamprenavir calcium) dosed with ritonavir (LEXIVA/r) or lopinavir (LPV) and ritonavir (LPV/r) were effective in suppressing HIV in patients who had failed prior PI-containing regimens, according to information presented at the International AIDS Conference (IAC).

Lexiva was co-discovered by GlaxoSmithKline and Vertex Pharmaceuticals.

The data are based on 48-week results of the CONTEXT study, a Phase III clinical trial that enrolled patients who had experienced virologic failure (VF) while receiving one to two prior PI regimens. Patients were randomized to take one 700mg LEXIVA tablet and one 100mg capsule of ritonavir (LEXIVA/r) twice a day (BID) (four capsules daily), 1400mg Lexiva plus 200mg ritonavir once a day (QD), or three LPV/r capsules, each combining 400mg LPV and 100mg of ritonavir BID (six capsules daily). PIs were taken in combination with two nucleoside reverse transcriptase inhibitors (NRTIs).

LEXIVA is indicated for the treatment of HIV infection in adults in combination with other antiretroviral medications. The following points should be considered when initiating therapy with LEXIVA/r in PI-experienced patients: the PI-experienced patient study was not large enough to reach a definitive conclusion that LEXIVA/r and LPV/r are clinically equivalent.

Once-daily administration of LEXIVA dosed with ritonavir is not recommended for PI-experienced patients, who are advised to take one 700mg tablet of LEXIVA BID in combination with one 100mg capsule of ritonavir BID.

At 48-weeks, 58 percent (62 of 107 patients) taking LEXIVA/r BID achieved viral loads (VL) below 400 copies/mL, and 46 percent (49) had VL below 50 copies/mL. Of 103 patients who took LPV/r BID, 61 percent (63) achieved VL below 400 copies/mL and 50 percent (52) had VL below 50 copies/mL.

At baseline, patients in both treatment arms had similar viral loads, CD4 cell counts, and PI-associated resistance mutations. Prior NRTI experience and the presence of RT-associated mutations, however, were higher at baseline in patients who subsequently were randomized to the study arm that included LEXIVA/r compared to the group assigned to the study arm containing LPV/r. There was a higher incidence of NRTI mutations in the LEXIVA/r BID group (mean 1.7) compared to the group taking LPV/r BID (1.4). This was primarily due to a higher number of subjects harboring virus with three or more thymidine analogue mutations (TAMS) in the LEXIVA/r BID group (38 percent), compared to 24 percent in the group taking LPV/r BID.

“There was no difference between the LEXIVA/r BID and lopinavir/r BID study arms in the proportion of patients with virologic failure with 29 percent versus 27 percent respectively,” said Edwin DeJesus, M.D., Infectious Disease Consultants, Altamonte Springs, FL.

Mutations Present at Baseline
The most common protease-associated resistance mutations seen at baseline among the 210 patients included in the study were:

• L90M in 63 patients (30 percent)
• M46I/L in 48 patients (23 percent)
• D30N in 45 patients (21 percent)

“There was no significant difference between the two study arms in the virologic responses of patients who had these mutations present at baseline,” said Rob Elston, GSK scientist and study presenter.

Viral suppression in the presence of L90M was achieved in 16 of 31 patients (52 percent) taking LEXIVA/r, and in 17 of 28 patients (61 percent) taking LPV/r. Among patients with M46I/L mutations, 11 of 22 (50 percent) taking LEXIVA/r and 12 of 24 (50 percent) taking LPV/r responded to treatment, while 21 of 22 patients (95 percent) with D30N mutations responded in the arm containing LEXIVA/r compared to 17 of 18 (94 percent) in the arm containing LPV/r.

Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored, it is unknown what effect therapy with LEXIVA will have on the activity of subsequently administered protease inhibitors. Clinical relevance of resistance data is currently being evaluated.