By Liz Highleyman

HIV treatment guidelines recommend that protease inhibitors (PIs) should be used with a small amount of ritonavir (Norvir) in order to "boost" levels of the main PI in the body. However, ritonavir is associated with a variety of side effects, including elevated blood lipid levels.

At the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008) last week in Washington, DC, researchers presented data from 2 studies looking at the safety and efficacy of reducing the ritonavir boosting dose from 200 mg to 100 mg when used with fosamprenavir (Lexiva). Fosamprenavir/ritonavir at a dose of 1400/100 mg once-daily was recently approved by the U.S. Food and Drug Administration for treatment-naive patients.

LESS is More

In the open-label Phase 3b LESS trial (Lexiva Simplification Study), patients who achieved HIV suppression < 400 copies/mL for at least 3 months while taking a fosamprenavir regimen boosted with 200 mg ritonavir (once-daily [QD] 1400/200 mg or twice-daily [BID] 700/200 mg) were randomized 2:1 to either decrease their ritonavir dose to 100 mg or continue on the original regimen.

The 209 participants included in the intent-to-treat population were mostly men (about 80%), 67% were white, the median age was 44 years, and the median CD4 count was about 435 cells/mm3. The most common nucleoside/nucleotide reverse transcriptase (NRTI) backbone was abacavir (Ziagen) + lamivudine (3TC; Epivir) at about 45%, followed by tenofovir (Viread) + emtricitabine (Emtriva) at about 25%, and zidovudine (AZT; Retrovir) + lamivudine at about 19%.

Results

• At week 24, 92% of 140 patients in the 100 mg ritonavir arm and 94% of 69 in the 200 mg arm had not experienced viral rebound to > 400 copies/mL (not a statistically significant difference).

• In a "time to loss of virological failure" (TLOVR) analysis, 83% of patients in the 100 mg ritonavir arm and 85% in the 200 mg arm achieved HIV RNA < 50 copies/mL.

• Proportions achieving viral load < 400 copies/mL were 92% and 94%, respectively.

• Median CD4 cell increases were 446 and 438 cells/mmm3, respectively.

• 34% of patients taking 100 mg ritonavir experienced any grade 2-4 adverse events (AEs), compared with 36% of those taking 200 mg.

• The proportions of patients who experienced drug-related grade 2-4 AEs were 4% and 7% respectively.

• The most common AE was diarrhea, occurring in 1% and 3%, respectively.

• No patient in either arm experienced treatment-related serious AEs.

• No patient in the 100 mg group and 2 people in the 200 mg group experienced hypercholesterolemia (elevated cholesterol).

• Overall median changes in lipid parameters at week 24 were similar in the 100 and 200 mg ritonavir dose arms.

• However, patients taking 100 mg ritonavir had a significantly larger decrease in triglycerides (-21 vs -1 mg/dL).

These findings led the investigators to conclude that, "A regimen of fosamprenavir 1400 mg + ritonavir 100 mg demonstrated non-inferiority to full boosted fosamprenavir/ritonavir (700/100 mg BID or 1400/200 mg QD) over a 24 week period in virologically stable subjects."

"These results support the safety and efficacy of the once-daily treatment option of Lexiva and 100 mg dose of ritonavir for patients with HIV/AIDS," said Mark Shaefer, PharmD, Director of Clinical Development at GlaxoSmithKline in a press release issued by the company. "Once-daily dosing with 100 mg of ritonavir not only reduces the pill burden on patients but also simplifies the treatment regimen."

Community Res. Initiative, Boston, MA; Orlando Immunology Ctr., Orlando, FL; Therafirst Med. Ctr., Fort Lauderdale, FL; North Texas IDC, Dallas, TX; Univ. of Colorado, Denver, CO; GlaxoSmithKline, Research Triangle Park, NC.

Long-term Safety and Efficacy at 96 Weeks

In a related study, COL100758, researchers compared the safety and efficacy of 100 vs 200 mg doses of ritonavir to boost 1400 mg once-daily fosamprenavir; in this trial, all patients received abacavir/lamivudine as their NRTI backbone.

This randomized, open-label trial enrolled 115 participants. Most (81%) were men, 53% were black, 41% were white, 16% were Hispanic/Latino, and the median age was 39 years. The median baseline CD4 count was higher in the 100 mg ritonavir arm (259 vs 179 cells/mm3).

Results

• 46 of 58 patients (79%) in the 100 mg ritonavir arm and 33 of 57 (58%) in the 200 mg arm completed the study.

• At 96 weeks, 66% in the 100 mg arm and 53% in the 200 mg arm had HIV RNA < 50 copies/mL in an intent-to-treat "missing = failure" analysis (not a statistically significant difference).

• In an observed (as-treated) analysis, the corresponding percentages were 83% and 94%, respectively.

• In a TLOVR < 50 copies/mL analysis, the proportions were 57% and 49%, respectively.

• Median CD4 cell increases were 265 in the 100 mg arm and 260 in the 200 mg arm.

• 41% and 44%, respectively, experienced any grade 2-4 treatment-related AEs.

• 14% and 18%, respectively, experienced grade 2-4 diarrhea.

• Low-density lipoprotein (LDL or "bad") cholesterol and triglycerides increased less in the 100 mg arm than in the 200 mg arm.

• 47% of patients in the 100 mg arm maintained ? 95% adherence, compared with 27% in the 200 mg arm (just shy of statistical significance).

Orlando Immunology Ctr., Orlando, FL; North Texas ID Consultants, Dallas, TX; Comprehensive Care Ctr., Ft. Lauderdale, FL; GlaxoSmithKline, Durham, NC, Duke Univ., Durham, NC.

Fat and Bone Mineral Density

In another analysis of the same study, researchers compared changes in regional fat and bone mineral density (BMD) at 96 weeks. Total body DEXA scans were performed pre-treatment and at week 96; 113 patients had at least 1 scan, and 71 had paired baseline and week 96 scans (40 in the 100 mg ritonavir arm and 31 in the 200 mg arm).

Median percentage changes in fat in the upper and lower limbs and trunk, and median percentage changes in total body and lumbar spine BMD were assessed. Clinically relevant changes in fat mass were defined as > 20% loss of limb fat and/or > 20% gain in trunk fat.

Results

• Median percentage changes in fat mass in the 100 mg and 200 mg arms, respectively, were as follows:

• -1.5% vs +11.6% for upper limbs;

• +10.0% vs +16.3% for lower limbs;

• +14.5% vs +18.5% for trunk.

• 20% fat changes were observed in the following proportions of patients in the 100 mg and 200 mg arms, respectively:

• 18% and 13% with > 20% fat loss in the upper limbs;

• 15% vs 6% with > 20% fat loss in the lower limbs;

• 38% vs 45% with > 20% fat gain in the trunk.

• No patient had both > 20% limb fat loss and > 20% trunk fat gain simultaneously.

• Median total body BMD (g/cm2) percentage changes were -1.05% in the 100 mg arm and -1.04% in the 200 mg arm.

• Among the 27 patients with lumbar spine data available, the changes were -3.0% and -2.2%, respectively.

After 96 weeks treatment with once-daily fosamprenavir plus abacavir/lamivudine, "both limb and trunk fat depots generally increased," the researchers concluded. However, "[t]he median [percentage] change in fat mass in all regions studied was not significantly different" between the ritonavir 100 mg and 200 mg arms. Finally, they noted, "BMD changes were small in both study arms."

Univ of NC, Chapel Hill, NC; Orlando Immun. Ctr., Orlando, FL; North Texas ID Consultants, Dallas, TX; Comprehensive Care Ctr., Ft. Lauderdale, FL; GlaxoSmithKline, Research Triangle Park, NC; Duke Univ, Durham, NC.

11/04/08

References

C Cohen, E DeJesus, A Lamarca, and others. Switching from a 200mg-Ritonavir (RTV, r)-Boosted Fosamprenavir (FPV) Regimen (700mg/200mg BID or 1400mg/200mg QD) to a 100mg RTV-Boosted FPV Regimen (1400mg/100mg QD) Yields Similar Efficacy and Safety. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-1250e.

E DeJesus, l Sloan, M Sension, and others. 96-Week Efficacy/Safety Data Comparing Two Doses of Ritonavir (/r) to Boost Once-Daily (QD) Fosamprenavir (FPV), Used in Combination with Abacavir (ABC)/Lamivudine (3TC). 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-1246.

DA Wohl, E DeJesus, L Sloan, and others. Fat changes by total body DEXA after 96 weeks of treatment with once-daily fosamprenavir with either 100 or 200 mg of ritonavir plus abacavir/lamivudine: COL10075. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-2302.

Other source
GlaxoSmithKline. Data Show that Administration of LEXIVA with Lower Dose of Ritonavir Is Associated with Similar Efficacy and Safety as Higher Dose. Press release. October 26, 2008.