1 vs 2 PIs after initial PI regimen, CPCRA057 (CROI2004, G Moyle, Natap, 170204)

1 vs 2 Protease Inhibitors in Patients With Viral Failure on Initial PI Regimen: CPCRA 057

Written by Graeme Moyle, MD (Chelsea & Westminster Hospital, London, UK and Jules Levin (NATAP) 11th Annual Retrovirus Conference Feb 8-11, 2004, San Francisco

Jay Kostman reported results at Retrovirus in poster 548 from this multi-center randomized trial conducted between August 1998 and June 2000. This report describes the randomized comparison of open-label regimens containing 1 vs 2 protease inhibitors in combination with 1 NNRTI and NRTI background therapy for patients with inadequate viral suppression on their first PI-containing regimen.

Patients were on their first PI regimen for at least 16 weeks, single PI. They had insufficient viral suppression (>400 copies/ml) after at least 16 weeks, and no prior NNRTI use. Randomization was stratified by PI in failing regimen (NFV vs IDV or RTV) and whether viral load of <500 c/ml had ever been achieved on the failing regimen. The study was designed to enroll 400 patients , but due to slow enrollment was stopped early (n=68). Analysis was intent-to-treat.

BaselineCD4 was 315 viral load was 4.2 log. Viral suppression was 46% in 2 PI regimen and 54% in patients randomized to 1 PI regimen.

At baseline patients had key PI mutations: 30N, 46I/L, 48V, 82A/F/T, 84V, 90M; any of the above 58% (2 PI regimen) -71% (1 PI regimen). Any key NRTI mutations: 41N, 67N, 69D, 70R, 184V, 215F/Y, 219E/Q; any of the above 90-93%.

This study, while some updated in its design and entry criteria, provides valuable insight into the best way to treat after initial PI failure. The study randomised individuals who would failed either nelfinavir (n = 38) or, indinavir or indinavir (n=30) to receive a regimen including new NRTIs, their first NNRTI and either one or two protease inhibitors. The prescribed 2 PI combinations included RTV/SQV (400mg/800mg, 80%), RTV/IDV (400mg/400mg, 9%), SQV/NFV (1000mg/1250mg, 3%). The prescribing NNRTIs was efavrienz (88%) or nevirapine (12%). Single PI were IDV (68%)or amprenavir (21%), in the NFV group, and NFV (93%) or APV (7%) in the I/R group.

Patients included in the study had a medium baseline CD 4 count of 255 to 267 cells/cu mm and a baseline viral load of 4.1-4.2 log copies/ml. Whilst the time to first follow-up viral load greater than 10,000 copies/ml or death (the primary study endpoint) did not differ between groups, result of CD 4 and viral load analyses favoured the use of two protease inhibitors. These data are consistent with previous double PI studies such as SPICE and ACTG398.

The proportion of individuals with a viral load less than 400 copies/ml 12 months after randomisation was 36 percent of individuals who received a single PI and 61 percent of individuals who received two protease inhibitors (p = 0.08). There was this wide difference in percent with HIV RNA <400 c/ml by month 2 on therapy. The log reduction in viral load at months 12 was -0.59 in the single PI group and -1.41 in the double PI group (p = 0.05). The wide difference in viral load change was also apparent by month 2. Regarding CD4 cell count, the single PI group experienced a decline in CD 4 count of 11 cells/cu mm whereas the double PI group experienced a rise of 69 cells/cu mm (p=0.04). This study supports the idea that individuals who experience virological rebound on their first protease inhibitor should include two active protease inhibitors in the next regimen.

The study authors summarized the pharmacological boosting of the second PI with RTV appears to have improved responses compared to the single PI regimen; as well, RTV may also have acted as another potent drug in the2 PI regimen since it was used at a dose of 400 mg twice daily. Suboptimal response in the1 PI treatment group may be dueto lack of pharmacologic boosting or to preexisting resistance. Subgroup analysis within the NFV and IDV or RTV groups showed similat CD4 and HIV RNA trends as the pooled analysis, although differences in CD4 and log HIV RNA were not statistically different. There were 7 patients who experienced grade 4 adverse events (3 in the 1 PI arm and 4 in the 2 PI arm). In the 2 PI arm these were pancreatitis, sepsis, hypertriglyceridemia, and elevated liver enzymes. In the 1 PI group, these were hypertriglyceridemia, mucosal fungal infection, and seizures.