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First-line efavirenz versus lopinavir-ritonavir-based highly active antiretroviral therapy for naïve patients
 
 
  AIDS: Volume 18(17) 19 November 2004
Research letter
 
Manfredi, Roberto; Calza, Leonardo; Chiodo, Francesco
 
Department of Clinical and Experimental Medicine, Division of Infectious Diseases, University of Bologna 'Alma Mater Studiorum', S. Orsola Hospital, Bologna, Italy.
 
Received: 20 July 2004; accepted: 4 August 2004.
 
Ninety-seven consecutive patients started anti-HIV therapy based on efavirenz (46) or lopinavir-ritonavir (51) in an observational study. Despite the significantly more compromised immunological-clinical baseline conditions of patients starting lopinavir-ritonavir, a mean clinical-laboratory follow-up of 17 months showed a comparable laboratory response and therapy interruption or change rate, although the toxicity profile of the two compounds proved significantly different. Randomized studies comparing these two recommended first-line treatments are warranted, particularly from a pharmacoeconomic viewpoint.
 
The 2002-2004 international guidelines for antiretroviral management consider lopinavir-ritonavir highly active antiretroviral therapy (HAART) or efavirenz-based HAART to be the two alternative first-line choices for HIV-infected antiretroviral drug-naive patients [1,2]. However, no randomized comparative study has been performed until now, dealing with these two profoundly different therapeutic strategies (the first based on a boosterized protease inhibitor, and the second on a non-nucleoside reverse transcriptase inhibitor), with regard to both efficacy and tolerability issues [3-5].
 
The most important variables conditioning both the efficacy and safety parameters of lopinavir-ritonavir and efavirenz-based HAART were assessed in 97 consecutive antiretroviral-naive patients followed since the year 2002 in an open-label observational study conducted at our outpatient reference centre in Bologna, Italy. After giving their written informed consent, 51 consecutive patients treated with lopinavir-ritonavir plus two nucleoside analogues were compared with 46 patients who received efavirenz plus two nucleoside derivatives, selected by the physician in charge from all available molecules (including zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, and tenofovir). At baseline, the two patient groups under consideration were statistically comparable with regard to all demographic and epidemiological features, as well as the mean plasma HIV viraemia (4.5 ± 1.4 versus 4.3 ± 1.6 log10 HIV-RNA copies/ml, for the lopinavir-ritonavir and efavirenz groups, respectively; Table 1). However, a previous or concurrent diagnosis of AIDS (P < 0.0001), or a significantly lower mean CD4 lymphocyte count (P = 0.002), were found among patients who received lopinavir-ritonavir as opposed to efavirenz-treated subjects. During the subsequent follow-up period, which until now ranged from 10 to 33 months (mean 16.8 ± 6.9 months), the laboratory workout showed a comparable virological response (with regard to the time and rate of both viral decay and the rate of viral suppression) in the presence of only one case of virological failure in the efavirenz group (explained by the appearance of a mutation at codons 103 and 181, at genotyping assay), versus no failed patient found in the lopinavir-ritonavir group (ns) (Table 1). Notwithstanding the significantly lower mean initial CD4 lymphocyte count, lopinavir-ritonavir-treated individuals achieved a more rapid and elevated immune recovery (P = 0.011 and P = 0.005, respectively), compared with those who received an efavirenz-based combination. Early (first month) interruptions as a result of a poor tolerability rate proved similar: eight patients were recorded in the lopinavir-ritonavir group, compared with six episodes among efavirenz-treated patients, although short-term untoward events predominanly involved the entire gastrointestinal tract for lopinavir-ritonavir, compared with the central nervous system for efavirenz-containing regimens (P = 0.0011). The overall need for regimen interruption or substitution attributable to toxicity, untoward events, insufficient patient adherence, or laboratory-clinical failure, as measured throughout the entire study period, tested quite low and was comparable between the two study groups (21.6% on the whole), as was the mean time to treatment interruption, but the observed mid-term toxicity rate proved significantly different from a qualitative point of view. Lopinavir-ritonavir-treated patients experienced dyslipidemia in more than 50% of overall cases (serum triglycerides > 200 mg/dl, or cholesterolemia > 220 mg/dl), versus nearly 10% of individuals belonging to the efavirenz group (P = 0.0016; Table 1).
 
Our experience conducted on 97 consecutive antiretroviral-naive patients treated with lopinavir-ritonavir versus efavirenz-based HAART, although limited by its open-label observational design, showed a comparable virological response, although an apparently more potent and rapid immunological recovery was attained in the lopinavir-ritonavir group, even taking into account the more severe initial immunodeficiency and AIDS rate in the latter patient group. On the other hand, although efavirenz-treated patients experienced more infrequent adverse events, and benefited from a low pill burden and an expected improved adherence (three capsules once a day at bedtime for efavirenz, versus three capsules twice a day for lopinavir-ritonavir) [3-5], the rate of early treatment interruptions tested similarly in the two study groups. The last update of international guidelines for antiretroviral treatment proposed either lopinavir-ritonavir or efavirenz-based HAART as equivalent first-line treatments for HIV disease in antiretroviral-naive patients [1,2], but in the absence of randomized comparative studies, the selection of lopinavir-ritonavir or efavirenz-based regimens should take into careful account the initial immunological and disease status of the patient, because lopinavir-ritonavir-based combinations seem to offer a better recovery in this last (more compromised) patient group, although efavirenz is better accepted and is more easy to administer. Further data are strongly warranted on long-term outcomes, the viral resistance burden, and tolerability issues on these two very different antiretroviral regimens proposed as first-line combinations for naive HIV-infected patients [1,2]. Given also the profoundly different expenditures associated with the administration of these two therapeutic strategies [6] (an efavirenz-based combination costs nearly 30% less than a lopinavir-ritonavir regimen in Italy), an appropriate pharmacoeconomic assessment of these two first-line selected regimens also seems highly desirable.
 
Table 1. BASELINE
 
EFV (n=46) LPV/r (n=51)
Males: 31 35
Age: 37 38
IDU/Heter/MSM 15/18/13 15/21/15
Mean VL 4.3 LOG 4.5 log
Mean CD4 293 196
# w/AIDS 10 35
<50 c/ml: 45 51
Mean time to viral suppression 6.8 mo 6.3 mo
Mean time to peak CD4 12 mo 9.4 mo
Mean peak cd4 556 612
Early (first month)
Treatment interrupt
Caused by poor tolerability 6 8
Overall interruptions 10 11
Mean time to interrupt 8.9 mo 9.2 mo
# developing hyperlipiedmia 24 5

 
Our experience conducted on 97 consecutive antiretroviral-naive patients treated with lopinavir-ritonavir versus efavirenz-based HAART, although limited by its open-label observational design, showed a comparable virological response, although an apparently more potent and rapid immunological recovery was attained in the lopinavir-ritonavir group, even taking into account the more severe initial immunodeficiency and AIDS rate in the latter patient group. On the other hand, although efavirenz-treated patients experienced more infrequent adverse events, and benefited from a low pill burden and an expected improved adherence (three capsules once a day at bedtime for efavirenz, versus three capsules twice a day for lopinavir-ritonavir), the rate of early treatment interruptions tested similarly in the two study groups. The last update of international guidelines for antiretroviral treatment proposed either lopinavir-ritonavir or efavirenz-based HAART as equivalent first-line treatments for HIV disease in antiretroviral-naive patients, but in the absence of randomized comparative studies, the selection of lopinavir-ritonavir or efavirenz-based regimens should take into careful account the initial immunological and disease status of the patient, because lopinavir-ritonavir-based combinations seem to offer a better recovery in this last (more compromised) patient group, although efavirenz is better accepted and is more easy to administer. Further data are strongly warranted on long-term outcomes, the viral resistance burden, and tolerability issues on these two very different antiretroviral regimens proposed as first-line combinations for naive HIV-infected patients. Given also the profoundly different expenditures associated with the administration of these two therapeutic strategies (an efavirenz-based combination costs nearly 30% less than a lopinavir-ritonavir regimen in Italy), an appropriate pharmacoeconomic assessment of these two first-line selected regimens also seems highly desirable.
 
 
 
 
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