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Abstract & Commentary
Synopsis: A protease-inhibitor-based regimen containing lopinavir-ritonavir provided more durable antiviral efficacy than a similar regimen containing nelfinavir in treatment-naïve HIV-infected patients.
Source: Walmsley S, et al. N Engl J Med. 2002;346:2039-2046.
Walmsley and colleagues conducted a double-blind, placebo-controlled, randomized, clinical trial comparing standard-dose nelfinavir (750 mg thrice daily) with one of the newer protease inhibitors, lopinavir-ritonavir (400-100 mg twice daily), in combination with d4T and 3TC, in 653 treatment-naïve HIV-infected patients. The major study end points included the proportion of patients with undetectable plasma viral load (HIV PCR < 400 copies) at 24 weeks of therapy, and the loss of virologic efficacy at 48 weeks of therapy. The 2 groups were remarkably similar at entry to the study, with an average HIV viral load of about 4.9 logs and an average CD4 count of about 260. About 20% of the study participants were female. Both regimens were surprisingly well tolerated and only 3.4% of those randomized to receive lopinavir-ritonavir and 3.7% of those receiving nelfinavir discontinued the study drug because of intolerance.
At week 24 of therapy, a greater proportion of patients treated with lopinavir-ritonavir (79%) had undetectable viral loads (< 400 copies) compared with those receiving the nelfinavir-based regimen (71%) (P < .05). By week 48 of study, the proportion of patients with undetectable viral loads (< 400 copies) in the lopinavir-ritonavir vs. nelfinavir groups was less (75% vs 63% respectively; P < .001). Similarly, by week 48, the proportion of patients with < 50 copies HIV RNA in the lopinavir-ritonavir vs. nelfinavir groups was only 67% vs. 52%, respectively (P < .001). The Kaplan Meier estimates of the sustained virologic response at week 48 for the 2 groups were, respectively, 84% vs. 66% (hazard ratio of 2.0).
Comment by Carol A. Kemper, MD, FACP
HIV clinicians have long debated the virologic potency and durability of nelfinavir relative to the other protease inhibitors, although head-to-head comparative studies are few. Walmsley et al found a statistically significant virologic benefit of an initial regimen containing lopinavir, boosted with ritonavir, over a similar regimen containing nelfinavir. This difference was observed despite the fact that both drugs were similarly well tolerated and overall adherence to each of the regimens was better than 90%. However, examined in a harsher light, one third of treatment-naïve patients receiving lopinavir-ritonavir and one half of those receiving nelfinavir failed to achieve complete suppression of viremia (< 50 copies HIV RNA) at 48 weeks of study despite maximal compliance with the regimens and optimal tolerability. Although it may have proved more effective than nelfinavir, the combination of lopinavir-ritonavir still fell short of that hoped for in a PI. The reasons provided for "treatment failure" at 48 weeks of therapy for patients receiving lopinavir-ritonavir vs. nelfinavir were viral rebound (21 vs 62 patients), failure to achieve initial viral suppression (22 vs 38 patients), discontinuation of the regimen (7 vs 5 patients), and the addition of other antivirals (1 vs 3 patients).
Among patients with detectable viremia (> 400 copies) occurring between weeks 24 and 48 of the study, HIV protease mutations were observed in 25 of 76 patients receiving nelfinavir vs. none of 37 patients "failing" lopinavir-ritonavir. Mutations associated with resistance to 3TC, were also twice as frequent among patients receiving nelfinavir compared with those receiving lopinavir-ritonavir.
Of concern on reviewing these data was the possibility of pre-existing mutations associated with resistance to protease inhibitors in patients receiving nelfinavir—an agent that has been around for much longer than lopinavir but an agent whose use does not commonly confer cross-resistance to this agent. However, none of the 24 patients with baseline virus isolates available for genotype resistance testing have evidence of protease mutations. Nonetheless, the possibility of archived resistance in these subjects cannot be ruled-out, especially in patients who never achieved virologic suppression. Genotype or phenotype resistance testing during the initial few months of therapy may have proved interesting.
The high degree of drug tolerability observed in this study is nothing short of remarkable, in my experience. Diarrhea (15-17%) and other gastrointestinal symptoms were the most frequent side effects of both agents. Unfortunately, fasting lipid levels were not assessed during this trial. Assessment of nonfasting cholesterol and triglyceride levels suggested that lopinavir-ritonavir resulted in higher cholesterol levels and was significantly more likely to cause severe hypertriglyceridemia > 750 mg/dL (9.3% vs 1.3%; P < .001), but this was apparently not believed to be dose-limiting.
The longer-term assessment of lipid effects, the occurrence of lipodystrophy, as well as the addition of therapeutic drug monitoring would have greatly added to this study. Nonetheless, the use of small amounts of ritonavir to pharmacologically boost lopinavir blood levels was more effective as initial therapy than nelfinavir administered as a single agent.
Dr. Kemper, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, is Associate Editor of Infectious Disease Alert.