Treatment intensification is adding an additional drug to a regimen if a person has not reduced their viral load to the expected undetectable response. Treatment intensification is now considered an option for individuals with early virologic failure, or for individuals not showing an adequate virologic response. Intensification can be considered if a person does not reduce viral load <400 copies/ml by week 8, or not reaching below 50 copies/ml within the expected time, which could be 12 or 16 weeks. For the treatment-naÔve individual, several studies have shown that abacavir is a good choice for intensification. An ongoing ACTG study is exploring the use of abacavir for treatment intensification for early virologic failures of first-line therapy. PMPA, a nucleotide not yet FDA approved, is also being studied for use in intensification. For the individual initiating first-line treatment with indinavir and not reaching undetectable within the expected time period, intensifying with ritonavir may be an option for some individuals. Although it's a more complicated situation, treatment intensification can also be considered for the treatment-experienced individual, depending on their situation. Their prior drug experience may present an obstacle to successful intensification.

Prior studies have shown that RTV improves IDV pharmacokinetics. RTV increases the Cmin or trough of IDV while at the same time it decreases the Cmax or peak concentration. Generally, the AUC or general blood levels of indinavir remained about the same.

This study set out to determine the pharmacokinetics of 400/400 RTV/IDV, and to see if an increase in IDV trough concentrations would produce an improved virologic suppression in individuals taking IDV 3X/day who have detectable virus. There were no food or hydration restrictions in this study.

N Shulman, A Zolopa, D Havlir, J Gallant, E DAAR, and others from the M98-985 Study Group, along with D Kempf and E Sun, from Abbott reported on preliminary data (week 16) from this open-label study. Individuals with early treatment failure (viral load of 50 copies/ml to 50,000 copies/ml, 29/35 <10,000 copies/ml) receiving IDV + 2 nucleosides were switched to a combination of RTV+IDV 400mg/400mg twice-a-day by dose escalation. Genotypic/phenotypic resistance was determined at baseline using the Virco assays. For the first two days individuals received 200/400 RTV/IDV and on days 3-5 they received 300/400 RTV/IDV, but the NRTIs they were taking at baseline remained the same. Only the PI regimen was changed. At day 6, the dose was adjusted to 400/400 RTV/IDV. Dose reduction of RTV to 300 mg bid was allowed in patients intolerant of 400 mg. 35 individuals enrolled in this 48 week study. Baseline IDV PK was determined just prior to day 1 dose adjustment. As well IDV PK was determined at week 3 after 15 days on full dose 400/400 RTV/IDV. IDV PK will again be determined at 24 weeks. After three weeks individuals were permitted to change their NRTIs.

At baseline, while still on IDV every 8 hours, the median HIV-RNA was 3.1 log (1250 copies/ml). The range was from 1.7-3.7 log (50-50,000 copies/ml). 9 individuals had viral load between 50-400 copies/ml, and 20 had between 400-10,000 copies/ml. Median CD4 was 424 (range 32-1242).

The analysis of resistance testing may be revealing in understanding why some individuals did not respond to intensifying IDV with RTV.

For the 9 individuals who had <50 copies/ml at week 16, their respective viral loads at baseline were: 53,000, 100, 1074, 726, 146, 79, 104, 243, and 1925 copies/ml. The median Cmin was 0.063 ug/mL. They all had a much higher Cmin at week 3 with a median of 0.87 ug/mL, while their median IDV AUC was 50.5 ug*h/mL at baseline and 45 ug*h/mL at week 3. So the AUC did not change for the better.