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4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention

Sydney, Australia / July 22-25, 2007

The longest study to date of an antiretroviral therapy (ART) regimen using fosamprenavir (FPV) (1400 mg q.d.) with low-dose ritonavir (100 mg q.d.) (FPV/r) in ART-naïve HIV/AIDS patients has proven its long-term efficacy and safety. Low doses of ritonavir serve to boost the plasma concentration and exposure of concurrently administered FPV to inhibit CYP3A4 metabolism of its active component amprenavir (APV), thereby decreasing APV clearance, prolonging its elimination half-life and enhancing its antiretroviral activity, the study authors stated. But use of ritonavir boosting may be associated with adverse gastrointestinal events and unfavourable lipid changes.

Optimizing Boosted Regimens

The rationale for the study was that as the incidence of ritonavir-related adverse events and lipid elevation is dose-related, using the lowest ritonavir boosting dose to maintain virologic suppression and enhance CD4+ cell count would be expected to optimize the tolerability of boosted FPV-containing regimens. Patients received FPV/r 1400/100 mg q.d. for a median of 2.4 years with some treated for more than three years. To date, no study has evaluated this regimen for longer than 48 weeks.

The retrospective database study was conducted at two U.S. HIV treatment centres to investigate the treatment response of ART-naïve, HIV-seropositive patients who started the FPV and low-dose ritonavir regimen between January 2004 and January 2006 and continued for at least six months. At baseline, patients had to have a viral load (VL) ³1000 c/mL, any CD4+ cell count and no active AIDS-related infections/complications/malignancies. The results presented were derived from 20 patients who were diverse in race and gender (median age 48, range 27 to 65; non-Caucasian 50%; females 25%; median duration HIV-positive status 5.3 years, CD4+ median cell count 327 cells/mm3).

All patients achieved and maintained VL<50 c/mL. The percentage of patients with VL <50 c/mL was greater at seven to nine months (85%) than at four to six months (40%). The CD4+ cell count increased from baseline by a median of 181 cells/mm3 at 2.4 years and 250 cells/mm3 at three years. Changes in median fasting lipids from baseline were as follows: triglycerides increased moderately (121 to 160 mg/dL [1.37 to 1.80 mmol/L]), total cholesterol (TC) increased slightly (162 to 177 mg/dL [4.20 to 4.58 mmol/L]), HDL-C also increased slightly (30 to 37 mg/dL [0.78 to 0.96 mmol/L]) and LDL-C decreased slightly (99 to 96 mg/dL [2.56 to 2.48 mmol/L]).

Treatment was generally well-tolerated with adverse events mostly being mild and self-limiting: diarrhea 30% (grade 1), nausea 20% (grade 1) and vomiting 10% (grade 1-2). There were no virologic failures or discontinuations due to adverse events.

The long-term response findings of this retrospective patient chart review study support the results of clinical efficacy trials that have evaluated FPV/r 1400/100 mg q.d.-containing regimens for up to 48 weeks, the study authors concluded. Although fasting TC and triglyceride concentrations increased, they generally remained within normal limits and below the National Cholesterol Education Program cut-off in most patients in the study, investigators noted. They added that the increase seen in HDL-C, which is associated with reduced cardiovascular risk, has been observed in other studies of FPV/r 1400/100 mg q.d.-containing regimens. According to lead author Dr. Gary Blick, Medical and Research Director, Circle Medical, Norwalk, Connecticut, ART-naïve patients could start on a first regimen that includes FPV 1400 mg and use only 100 mg ritonavir to boost it. “That lowers the pill burden, it should lower the side effect profile and make their lipid profile somewhat better also,” he told delegates. “Everybody responded with undetectable VLs that have been sustained to <400 copies/mL and for a median duration of 2.3 years. The T-cell increase was robust also.” Although the study did not look at adherence, the fact that the patients attained undetectable VLs suggested they were adhering to their regimens, Dr. Blick stated.

Body Fat Composition and Bone Mineral Density

Further efficacy data for the novel boosting dose were presented at the conference in a study that also compared body composition changes with both doses.

Although ritonavir has been linked to a number of metabolic abnormalities, including dyslipidemia and disorders of glucose metabolism, there have been limited data to date about the impact of lower doses on body composition, according to study authors.

Their randomized, open-label, 96-week study used whole- body dual-energy X-ray absorptiometry (DEXA) to determine the differential effects of co-administration of once-daily FPV with 200 mg vs. 100 mg ritonavir on body fat composition and bone mineral density (BMD) in 115 ART-naïve men and women. Results presented at the conference were for 48-week data.

Participants were randomized to receive FPV 1400 mg q.d. along with ritonavir 100 mg (FPV/r100) vs. 200 mg ritonavir (FPV/r200). All received a fixed dose of abacavir 600 mg/lamivudine 300 mg (ABC/3TC) q.d. Seven patients presumed hypersensitive to ABC were switched to zidovudine/3TC. Whole-body DEXA scans were obtained at study entry and at week 48 for 48 patients. Clinically relevant (potentially detrimental) changes in fat mass were defined as >20% loss for limb fat and/or >20% gain in trunk fat. The proportion of patients in each group with >20% combined arm fat decrease, >20% combined leg fat decrease or >20% trunk fat increase were compared.

“Gratifyingly, it looks like the 100-mg boosting dose was at least as effective as the 200-mg dose,” reported study co-author Dr. Charles Hicks, Associate Professor of Medicine, Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina. “If you look at the virologic outcomes, there is a slightly better outcome with the lower dose of ritonavir.” The study found 84% of patients had a VL <400 copies/mL with 100 mg ritonavir compared with 67% of patients who received 200 mg (intent-to-treat, missing equals failure). Seventy-nine per cent of patients had a VL<50 c/mL with 100 mg ritonavir compared with 63% of patients who received 200 mg.

Observations on Adherence and Lipid Profile

“The concern early on had been that maybe 100 mg perhaps wasn’t going to be enough boosting but it looks like it is,” Dr. Hicks commented. “Surprisingly, it looked like the lower dose was doing better and when we looked at explanations for why that may be so, it looks like the adherence was better with the lower dose.”

In the results for body fat changes and lipid data for the first 48 weeks, it was difficult to discern a difference between the two doses of ritonavir, he noted. In all, 88 patients had paired baseline and week 48 DEXA scans. The results are reported as changes from baseline for FPV/r100 (n=44) vs. FPV/r200 (n=44), respectively. Median fat (g) per cent changes were: +7.0% vs. +7.2% for upper limbs (P=0.86), +3.1% vs. +9.9% for lower limbs (P=0.37) and +6.3% vs. +7.0% for trunk (P=0.80). Median total body BMD (g/cm2) per cent changes were -0.60% vs. -0.95% (P=0.09). Clinically relevant fat changes in upper limbs, lower limbs and trunk occurred in 11% vs. 16%, 9% vs.14% and 18% vs. 32% of patients, respectively.

Changes in glucose and insulin were unremarkable and similar. The median TC:HDL-C ratio decreased by 0.25 in both groups. Median fasting triglycerides increased from about 120 to 170 mg/dL (1.35 to 1.92 mmol/L) in the ritonavir 100 mg group and about 120 to 150 mg/dL (1.35 to 1.69 mmol/L) in the 200-mg group. The study authors concluded median limb and trunk fat depots increased similarly when FPV was co-administered with either 100 mg or 200 mg. Clinically relevant changes in fat occurred less frequently in patients assigned to FPV/r100. Total BMD changes were small and not significantly different in both study arms. However, differences in efficacy at week 48 favoured FPV/r100.

“I think the findings are meaningful findings in terms of the cholesterol and triglycerides because usually those changes are apparent in the first six months or so, and I think if there were going to be a meaningful difference, we would already have seen it,” Dr. Hicks told delegates. “However, the body shape changes often require a longer time, sometimes as long as two years.” The lower dose of ritonavir might be associated with diminished body fat and lipid problems but the final results at 96 weeks were needed to confirm this, he concluded.