RTV Intensification of IDV

Briefly, this study showed that virologic response (<400 copies/ml) by individuals on IDV/RTV 400/400 was associated with IDV trough concentrations and the number of baseline genotypic resistance mutations.

Andy Zolopa followed up on his initial Retrovirus report of ritonavir intensification of an indinavir regimen at Sitges & Durban. Zolopa set out to test if increased trough of IDV, which results from giving 400/400 RTV/IDV compared to 800 IDV every 8 hrs., produces greater virologic suppression in patients with detectable virus while receiving an IDV based regimen; also to study the effect of baseline genotype on response to IDV intensification with RTV.

The median baseline viral load was 2000 copies/ml (3.3 log) for the 37 individuals in the study, and 24 had baseline viral load between 50-400 copies/ml. Their median CD4 count was 390, and the median IDV experience was 32 months. Investigators used the Roche Ultra-sensitive <50 copy viral load test. During the first 3 weeks of the study the only change in the regimen was the substitution of RTD/IDV 400/400 mg bid for 800 mg every 8 hours using RTV dose escalation. Dose titration was allowed during the first 2 weeks. A substudy (n=16) evaluated IDV PK profiles at baseline and RTV and IDV pk at week 3. Results confirmed what they had previously seen in healthy volunteers: IDV Cmin increased 272%, Cmax decreased 51%, Ctrough (n=27) increased 386%, and AUC-24 increased 11%. 26/27 had increased Ctrough.

At week 24, 52% of the patients remaining on therapy had <400 copies/ml, 44% had <50 copies/ml, and CD4s increased 23. Two patients dose reduced to 300/400 RTV/IDV bid.

The median IDV Ctrough at week 3 was 0.792 ug/mL including all subjects with IDV Ctrough at week 3 (n=32), compared to the median baseline Ctrough of 0.13 (n=27). Interestingly, the median decline in HIV viral load was greater in patients with IDV Ctrough higher than the median. 75% of patients with Ctrough higher than the median at week 24 had <400 copies/ml, while 37% with less than the median trough had <400 copies/ml.

Genotype was available for 30 subjects. Greater than 25% prevalence of PI mutations was found at positions 10, 46, 54, 71, 82, and 90. By on-treatment analysis, at week 24, virologic response (<400 copies/ml) was observed in 77% (10/13) of subjects with 0-3 baseline mutations, and 22% (2/9) with 4-7 baseline mutations in HIV protease (p=0.027). Zolopa also reported that the median decline in viral load over the first 3 weeks of therapy was greater in those subjects with week 3 IDV Ctrough higher than 0.792 ug/mL, regardless of baseline genotype. Zolopa concluded that these data suggest that drug trough concentrations and HIV drug susceptibility are the most important predictors of drug potency with protease inhibitors.

Of the 37 subjects enrolled 11 discontinued, 10 due to adverse events: GI (3), anxiety (1), hypercholesterimia (1), Kidney calculus (1)--patient mistakenly took 800/400 IDV/RTV bid, lactic acidosis (1), lipodystrophy (1), rash (1), somnolence (1). Adverse events reported by 2 or more patients of at least moderate severity and possibly or probably study drug related (n=37): diarrhea (15), hypercholesteremia (9), hyperlipidemia (8), abdominal pain (6), weight loss (5), asthenia (2), nausea (2), somnolence (2). Abnormal labs (n=36) of grade 3 or 4: triglycerides (>750) 18 non-fasting and 11/13 fasting; cholesterol (>300) 14 non-fasting, and 11/12 fasting; Grade 2: AST/ALT (>2.5 x ULN) 6, tota bilirubin (>1.5 x ULN) 1I; there were no reports of grade 3 or more liver function abnormalities.