Efficacy and Treatment-Limiting Toxicity With the Concurrent Use of Lopinavir/Ritonavir and a Third Protease Inhibitor in Treatment-Experienced HIV-Infected Patients

Nathalie C. Casau, Marshall J. Glesby, Simon Paul, Roy M. Gulick


J Acquir Immune Defic Syndr. 2003;32(5) 

In This Article

Summary and Introduction

To investigate the efficacy and tolerability of using lopinavir/ritonavir concurrently with a third protease inhibitor (PI), the authors reviewed the medical records of 47 HIV-infected patients treated with antiretroviral regimens containing lopinavir/ritonavir and amprenavir, saquinavir, indinavir, or nelfinavir. The baseline mean HIV RNA level was 4.6 log10 copies/mL, and the median CD4 cell count was 123/mm3. By week 40, one patient (2%) was lost to follow-up, and 21 (44%) discontinued their lopinavir/ritonavir plus a third PI regimens: 4 (8%) due to virologic failure as determined by the clinician; 13 (28%) due to toxicity; and 4 (8%) due to social reasons. By intent-to-treat analysis, 12 (26%) of 47 patients had an HIV RNA level of less than 400 copies/mL at 40 weeks. By multivariate analysis, factors associated with virologic response were no prior lopinavir exposure (p = .03) and no prior exposure to nonnucleoside reverse transcriptase inhibitors among patients taking a nonnucleoside reverse transcriptase inhibitor (p = .05). Some HIV-infected patients concurrently treated with lopinavir/ritonavir and a third PI have viral suppression; many eventually discontinue therapy because of toxicity or virologic failure.

Despite recent progress with combination antiretroviral therapy,[1] virologic failure eventually occurs in a significant proportion of HIV-infected patients in clinical cohort studies.[2] Data from the EuroSIDA study showed that those patients who had not reached viral suppression during a first protease inhibitor (PI) regimen were less likely to respond virologically to a second PI regimen.[3] Virologic failure is frequent in HIV-infected patients exposed to a series of combination antiretroviral regimens, and better antiretroviral therapies are needed for these highly treatment-experienced individuals.

One approach to optimize response to antiretrovirals is to increase drug concentrations in an attempt to overcome resistance. Ritonavir inhibits the metabolism of PIs and increases the levels of saquinavir, indinavir, amprenavir, and lopinavir;[4,5,6] this approach has become standard practice, but fewer data are available regarding other PI combinations.[7]

Large, prospective, randomized trials have looked at the use of two PIs as part of a salvage regimen for heavily treatment-experienced patients.[6,8,9] In the clinical setting, lopinavir/ritonavir and a third PI have been used in combination for salvage therapy, but there are few data to support the use of this combination in treatment-experienced patients.

In this study, we reviewed the medical records of HIV-infected patients from a large clinical database who, following virologic breakthrough, began treatment with lopinavir/ritonavir and a third PI with nine different nucleoside reverse transcriptase inhibitor/nonnucleoside reverse transcriptase inhibitor (NNRTI) combinations. We examined the safety and efficacy of this novel approach, to identify the correlates of virologic responses.