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 (4–6); 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.
MATERIALS AND METHODS
We identified actively followed HIV-infected patients receiving treatment with lopinavir/ritonavir and a third PI by screening the computer-based medical and prescription records of patients at the Center for Special Studies HIV Clinic at the New York Presbyterian Hospital of the Weill Medical College of Cornell University in the fall of 2001. Patients who had not followed up with their physician for at least one visit after starting this regimen were excluded from further analysis. There were no other exclusion criteria. Medical records were reviewed retrospectively from May 22, 2000 (the date marking the first patient in our clinic to begin treatment with lopinavir/ritonavir and a third PI) until March 1, 2002. By chart review, we evaluated reasons for the discontinuation of the three PI regimens, assessed new cases of hypercholesterolemia (nonfasting cholesterol level, >240 mg/dL) and hypertriglyceridemia (nonfasting triglyceride level, >500 mg/dL), and evaluated for onset of diabetes mellitus (random serum glucose level, >200 mg/dL [on at least one occasion]). Lipodystrophy was defined as any significant change in the body habitus or fat distribution noted by the patient or the clinician and documented in the chart, such as central fat accumulation, dorsocervical fat pad enlargement, and peripheral fat wasting or atrophy. The standard AIDS Clinical Trial Group toxicity table was used to grade elevations of aspartate aminotransferase and alanine aminotransferase levels.
The virologic response was characterized as the proportion of patients with HIV RNA levels of <400 copies/mL (Roche Amplicor; lower limit of detection of 400 copies/mL or ultrasensitive lower limit of detection of 50 copies/mL) at consecutive 8-week intervals (Figure 1). We imputed a missing HIV RNA level occurring between two levels of <400 copies/mL as <400 copies/mL. We reviewed all computerized clinician progress notes from the time patients started treatment with lopinavir/ritonavir and a third PI either until patients discontinued their regimen or, if they remained in the study, until their last clinic visit and last HIV RNA data point available at the time of chart review. Patients who remained on treatment with lopinavir/ritonavir and a third PI and had an undetectable HIV RNA level of <400 copies/mL but who had not reached 40 weeks were censored from the intent-to-treat analysis after their last recorded value. All other patients who had either stopped their regimen for any reason, who had never had an HIV RNA level of <400 copies/mL during their regimen, or who were lost to follow-up were determined to have virologic failures.
Fisher exact test was used to evaluate whether selected prespecified patient characteristics were associated with viral response (prior lopinavir exposure, no prior NNRTI exposure, current NNRTI treatment, or amprenavir as the third PI). We used STATA 7 (STATA, College Station, TX) for statistical analysis. The Institutional Review Board of the Weill Medical College of Cornell University reviewed and approved this study.
We identified 47 patients who began treatment with lopinavir/ritonavir concurrently with a third PI (Table 1). Thirty-two patients (68%) had a history of opportunistic infection. The median nadir CD4 cell count was 47/mm3, and the median baseline CD4 cell count was 123/mm3. The mean baseline HIV RNA level was 4.6 log10 copies/mL. Eight patients (17%) had had documented toxicity from prior antiretrovirals. Twenty-eight patients (60%) had prior exposure to efavirenz, and seven (15%) had prior exposure to lopinavir/ritonavir.
The third PI in the regimens was amprenavir for 27 patients (57%), indinavir for 12 (26%), saquinavir for 6 (13%), and nelfinavir for 2 (4%). Nineteen patients (40%) were receiving NNRTI treatment concurrently with their three-PI regimen, which included delavirdine for 1 (2%), efavirenz for 7 (15%), and nevirapine for 11 (23%). Two patients (4%) were receiving tenofovir treatment (Table 2).
One patient (2%) was lost to follow-up. Twenty-one patients (44%) discontinued their lopinavir/ritonavir plus a third PI regimens prior to 40 weeks: 8% (n = 4) due to virologic failure as determined by the clinician; 28% (n = 13) due to toxicity; and 8% (n = 4) due to other reasons.
At 40 weeks, the median change in CD4 cell count from baseline 76/mm3 (n = 17), and the mean change in HIV RNA level from baseline was −1.08 log10 copies/mL (n = 17). By intent-to-treat analysis, 12 patients (26%) had an HIV RNA level of <400 copies/mL at 40 weeks.
The most frequent toxic effects leading to treatment discontinuation were gastrointestinal (nausea in 7 patients; vomiting, 1; and diarrhea, 6). One patient developed a hypersensitivity reaction to abacavir. Two patients discontinued their regimen secondary to grade 3 elevated liver transaminase levels. There were 10 patients (21%) who developed a cholesterol level of >240 mg/dL, 4 (9%) who developed nonfasting triglyceride levels of >500 mg/dL, and 2 (4%) who developed new onset diabetes mellitus, none of whom discontinued treatment. One patient developed worsening lipodystrophy, grade 2 hypertriglyceridemia, and hypercholesterolemia.
No prior lopinavir exposure (p = .03) and no prior exposure to an NNRTI among patients who received an NNRTI (p = .05) were both significantly associated with an HIV RNA level of <400 copies/mL at least once. The virologic response with amprenavir as the third PI was not different than those with other PIs (p = .5).
This is one of the first studies to characterize the efficacy and toxicity of a three-PI regimen. In our retrospective study of advanced, highly treatment-experienced HIV-infected patients treated with lopinavir/ritonavir and a third PI over 40 weeks, we found an initial virologic response in about one third of the patients that was sustained in a subset of patients. This modest virologic response is likely to be associated with clinical benefit (10); however, a significant proportion of patients eventually discontinued their regimens, primarily due to treatment-limiting toxicity.
In a 12-week prospective pilot study of 28 lopinavir/ritonavir treatment-naive patients, one half of who were also receiving tenofovir, Hellinger et al. (11) found that 18 (65%) who were using lopinavir/ritonavir along with saquinavir had an HIV RNA level of <50 copies/mL by intent-to-treat analysis. Clearly, tenofovir and lopinavir/ritonavir provided significant virologic activity in this pilot study. We observed a lower virologic response rate, but our patients differed in that only 4% received tenofovir and 15% had prior lopinavir/ritonavir exposure.
Although 27 patients (57%) received amprenavir as a third PI, only eight (17%) were receiving extra ritonavir to counteract the negative pharmacokinetic interactions between amprenavir and lopinavir/ritonavir. We initially posited that suboptimal virologic response in our study might have been explained by adverse drug–drug interactions, as prior investigators have reported unfavorable interactions between lopinavir/ritonavir and amprenavir and lowered the concentrations of either one or all PIs (12–14). However, in our study, the virologic response with amprenavir as the third PI was no different than those with other PIs, although the power to detect a difference in subgroup analyses was limited.
We observed a high incidence of treatment-limiting adverse events in our study, with nausea and diarrhea being the most common. Significant gastrointestinal adverse effects were also observed in the pilot trial by Hellinger et al. (11). In our study, the high frequency of adverse effects might have been due to the multidrug salvage regimens that patients were taking. Data from the Swiss HIV Cohort Study suggest that a higher prevalence of adverse events is associated with dual PI-containing regimens and three-class antiretroviral regimens (15). In our study, eight patients (17%) had had adverse effects from prior antiretroviral regimens and therefore might have been more likely to have further toxicity when starting the next regimen.
The effect of several factors on viral response was explored, and of these factors, prior antiretroviral history was most important. Patients who had been exposed to prior lopinavir/ritonavir were less likely to suppress their HIV RNA level to <400 copies/mL. Patients who had not previously taken an NNRTI and added one to their current regimen were more likely to suppress HIV viremia, and the NNRTI likely added significant virologic activity to the regimen. Prior studies showed that patients treated with an NNRTI-containing salvage regimen without prior exposure to an NNRTI had better virologic responses in subgroup analyses (8,9).
Our study has several important limitations. The study was retrospective, and antiretroviral treatment was not randomized, which may have led to bias. Selection of drug regimens, toxicity management, and assessment of virologic failure were done according to the primary care physicians. In addition, patients were taking a number of different antiretroviral regimens, which differed in their composition, introducing heterogeneity. Because of the small sample size, we had limited power to analyze various treatment subgroups.
In summary, in this retrospective analysis, we found overall that 26% of patients taking lopinavir/ritonavir and a third PI regimens had sustained viral suppression but that another 28% discontinued the regimens due to toxicity. Independent factors associated with virologic response included no prior lopinavir/ritonavir exposure and no prior NNRTI exposure when an NNRTI was part of the regimen. Data from prospective studies are required to assess better the efficacy and tolerability of lopinavir/ritonavir and a third PI as part of a strategy for salvage therapy for treatment-experienced HIV-infected patients.
The authors thank the physicians of the Center for Special Studies at the Weill Medical College of Cornell University.
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