Boosted PIs superior to no PIs as salvage therapy in highly PI-experienced

Edwin J. Bernard
Published: 24 April 2004

A small Italian study comparing boosted protease inhibitor (PI) and PI-sparing salvage regimens in the highly PI-experienced has found the former superior in preserving CD4 cell counts to 24 weeks. The results were published in the March 26th issue of the journal AIDS.

Researchers from the Clinic of Infectious Diseases in Milan recruited 40 individuals whose current HAART regimens were failing and whose HIV was resistant to all available PIs (saquinavir, indinavir, ritonavir, nelfinavir, amprenavir and lopinavir) according to genotypic resistance testing. At baseline, study participants had an average of eight protease gene mutations, a CD4 count of 150 cells/mm3 (range 26-236), and a viral load of 4.88 log10 copies/ml.

Twenty-one were assigned to a boosted PI regimen and 19 to a PI-sparing regimen. All 40 also received tenofovir and thirteen (six in the PI and seven in the non-PI group) at least one additional reverse transcriptase inhibitor (RTI). These could have been nucleoside or non nucleoside RTIs -- the researchers did not specify the exact number of drugs, nor name the specific drugs their participants were taking. They only indicated broad classes of drugs.

Although there were no statistically significant differences between the two groups at baseline, those in the boosted PI group had an average CD4 count of 58 cells/mm3 compared with 175 cells/mm3 in the PI-sparing group. Eight individuals in each group took a treatment interruption prior to restarting therapy; there were an average of ten NRTI mutations seen in each member the PI group compared with nine in the PI-sparing group; and fifteen members of each group had mutations associated with reduced tenofovir sensitivity, although none had the 65R mutation.

Significantly, however, only six of the 21 PI-treated individuals received at least one active RTI in the new regimen compared with 16 in the PI-sparing group (p=0.0006). Additionally, only members of the PI-sparing group interrupted their treatment prior to 24 weeks (n=4) due to toxicity. Significant differences between the groups in terms of grade 3/4 laboratory abnormalities were also seen (three individuals in the boosted PI and eight in the PI-sparing group; p=0.08). No statistically significant differences were noted in the cholesterol or triglyceride levels between the groups at week 24, however.

At the end of 24 weeks, the CD4 cell count difference between the two groups was found to be statistically significant (p=0.005). Those receiving a boosted PI regimen gained an average of ten cells/mm3 (ranging from -7 to +55), whereas those receiving the PI-sparing regimen lost an average of 41 cells/mm3 (ranging from -56 to -4).

Although six of the 21 (29%) in the boosted PI group and none of the 15 (0%) in the PI-sparing group achieved less than 400 copies/ml at week 24 (p=0.03), there were no significant differences seen in viral load levels between the two groups as a whole. At week 24, the boosted PI group showed a change of -0.28 log10 copies/ml (ranging from +0.16 to -1.33), and those in the PI-sparing group showed a change of -0.18 log10 copies/ml (ranging from +0.13 to -0.47).

After adjusting for baseline CD4 cell counts and viral loads, age, number of active drugs, total number of reverse transcriptase mutations and treatment interruptions prior to study entry, multivariate analysis showed that the only independent predictor of a change in CD4 cell counts at week 24 was a boosted PI regimen (p=0.048).

Given these results, the authors suggest that a boosted PI regimen “may be worthwhile even in the presence of extensive PI resistance”, since CD4 counts appear to be preserved in the medium term. The authors suggest that the boosted PI regimen might further impair viral replicative capacity by sustaining resistance mutations associated with lower replicative capacity or selecting new ones that augment this effect. Reduced replication capacity has been shown to reduce the CD4 cell-killing effect of HIV.

They also suggest that the presence of a protease inhibitor in the regimen might spare CD4 cells from apoptosis, and that the boosted protease inhibitor might have antiviral activity even in the presence of multiple drug resistance mutations.

Further information on this website

Reference

Gianotti N et al. Boosted protease inhibitor-including regimen versus a protease inhibitor-sparing regimen in protease inhibitor-resistant HIV-infected patients: 24-week immunological outcome. AIDS 18 (5), 821-823, 2004.

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