aHospital Clínic, Barcelona, Spain
bHospital de Bellvitge, L'Hospitalet, Barcelona, Spain
cHospital de Mútua de Terrassa, Terrassa, Spain
dHospital de Vall d'Hebrón, Barcelona, Spain
eHospital de la Santa Creu i Sant Pau, Barcelona, Spain
fHospital del Mar, Barcelona, Spain
gHospital Son Dureta, Palma de Mallorca, Spain
hHospital General de Granollers, Granollers, Spain
iHospital de Mataró, Mataró, Spain.
Received 1 June, 2006
Revised 1 October, 2006
Accepted 15 October, 2006
The concept of simplification emerged as a need for adherent HIV-infected patients receiving successful complex or unconvenient antiretroviral regimens, and it has now been incorporated into the updated recommendations for the use of antiretroviral therapy . The NEFA Study was a multicentre, randomized, open-label clinical trial. Eligible patients were HIV-1-infected adults who were receiving triple antiretroviral therapy consisting of at least one protease inhibitor (PI) plus two nucleoside reverse transcriptase inhibitors (NRTI), who had had plasma HIV-1-RNA levels of less than 200 copies/ml for at least 6 months, and who wished to change the PI component of their regimen. Patients were randomly assigned to receive nevirapine, efavirenz, or abacavir instead of the PI used in their current antiretroviral regimen while their NRTI remained unchanged. The study was initially designed to be a 48-week study , but it was extended to at least 3 years following recommendations from the European health authorities in studies of maintenance therapy with simplified regimens in patients showing adequate virological control .
The primary study endpoint was the occurrence of death, progression to AIDS, or a virological failure throughout the study period. Secondary endpoints were the CD4 cell count, the incidence of side effects, and plasma lipids. According to recently published recommendations on virological-based endpoints in antiretroviral drug switching trials, patients were followed for the entire duration of the trial regardless of the premature discontinuation of assigned therapy . ‘Switching equal to failure’ intent-to-treat (considering as failures all patients who died, progressed to AIDS, had detectable viral loads, discontinued study medication, or were lost to follow-up) and as-treated analyses were performed.
Among 460 patients eligible for the study, 155 were assigned to nevirapine, 156 were assigned to efavirenz, and 149 were assigned to abacavir. The baseline characteristics of the patients were not significantly different among the groups. Approximately half of the patients in each arm had received therapies with one or two NRTI before PI-containing antiretroviral therapy. Indinavir (n = 278) and nelfinavir (n = 135) were the PI withdrawn in 90% of patients. Lamivudine with either stavudine (n = 259, 56%) or zidovudine (n = 145, 32%) were the combinations of NRTI most commonly used. The outcomes of the patients can be seen in Table 1. At 36 months, the Kaplan–Meier estimates to reach a protocol-defined endpoint in the nevirapine, efavirenz and abacavir arms were 33, 46, and 40% according to the intent-to-treat analysis (generalized log-rank test, P = 0.068). According to the intent-to-treat analysis, the Cox's proportional hazards survival regression showed a hazard ratio of failure of 0.817 [95% confidence interval (CI) 0.562–1.187] in the nevirapine arm and of 1.242 (95% CI 0.881–1.749) in the efavirenz arm compared with the reference hazard ratio of 1 in the abacavir arm (P = 0.070). In the as-treated analysis, the Kaplan–Meier estimates to reach a protocol-defined endpoint at 36 months in the nevirapine, efavirenz and abacavir arms were 7, 10, and 22% (generalized log-rank test, P < 0.001), respectively. According to the as-treated analysis, the Cox's proportional hazards survival regression showed a hazard ratio of failure of 0.302 (95% CI 0.153–0.598) in the nevirapine arm and 0.472 (95% CI 0.260–0.858) in the efavirenz arm compared with the reference hazard ratio of 1 in the abacavir arm (P = 0.001).
Among patients who had received previous single or double therapies with NRTI (n = 238), the rate of virological failure while on study medication in the abacavir arm (25 of 69, 36%) was significantly higher that those in the nevirapine (six of 79, 8%) or efavirenz (10 of 90, 11%) arms (P < 0.001). In contrast, there were no differences in the rates of virological failure among the three arms among patients without previous suboptimal therapy with NRTI (n = 222): four of 76 patients (5%) in the nevirapine arm, one of 66 patients (2%) in the efavirenz arm, and four of 80 patients (5%) in the abacavir arm (P = 0.479).
The incidence of adverse events leading to study discontinuation was significantly lower in the abacavir group (n = 13, 9%) than in the nevirapine group (n = 29, 19%) or the efavirenz group (n = 39, 25%; P = 0.005). Adverse effects leading to discontinuation were among those expected for each study drug, and interestingly most of them occurred early after the introduction of each study drug. Sixty-two of the 82 patients (77%) who discontinued study drugs did so in the first 12 months of the study, and most of them in the first weeks of therapy. An interesting observation emerging from the long follow-up in our study was that most adverse effects leading to the discontinuation of study drugs in the cases of nevirapine and abacavir were concentrated almost exclusively in the first weeks of the study. There was only one (1%) case of clinical hepatitis and four (3%) of increased aminotransferase levels leading to discontinuation of study drug in the nevirapine arm, and all these occurred in the first year of the follow-up. Interestingly, nevirapine-related exanthema and hepatitis have been reported less frequently in antiretroviral-experienced patients with virological suppression [5,6]. In the case of patients assigned to efavirenz, neuropsychiatric adverse effects were those most commonly leading to discontinuation, and they were scattered during follow-up. In general, the patients who discontinued efavirenz late during the study did so because of the persistence of neuropsychiatric effects rather than because of its severity. The median fasting plasma triglyceride values at each timepoint were not significantly different between the arms. The median fasting plasma cholesterol values at all but the month 30 follow-up visit (P ≤ 0.012) were significantly lower in the abacavir than in the nevirapine and efavirenz arms.
In summary, simplification of PI-containing HAART in patients with sustained virological response had a higher probability of maintaining the suppression of viral replication after 3 years of follow-up when nevirapine or efavirenz were substituted for PI compared with abacavir. However, the rates of viral suppression among patients who had not had previous suboptimal therapy with NRTI were similar for the three drugs. In contrast, abacavir showed a lower incidence of adverse effects leading to discontinuation and caused a greater decrease in plasma cholesterol.
The NEFA Study: participating centres and investigators (in alphabetical order).
Hospital de Bellvitge, L'Hospitalet (Daniel Podzamczer, Beatriz Rosón).
Hospital Clínic, Barcelona (Esteban Martínez, Ana Milinkovic, José B Pérez-Cuevas, José L. Blanco, Mireia Arnedo, Agathe León, Montserrat Laguno, María Larrouse, Josep Mallolas, Tomás Pumarola, José M. Gatell).
Hospital Creu Roja, L'Hospitalet (Cristina Cortés, Isabel García).
Hospital General de Granollers, Granollers (Enric Pedrol, Carme Font).
Hospital Joan XXIII, Tarragona (Cristóbal Richart, Joaquim Peraire, Consuelo Viladés, Francesc Vidal).
Hospital del Mar, Barcelona (Hernando Knobel, Alicia González).
Hospital de Mataró, Mataró (Luis Force, Pilar Barrufet).
Hospital de Mútua de Terrassa, Terrassa (David Dalmau, Anna Ochoa de Echagüen, Mariona Xercavins).
Hospital Parc Taulí, Sabadell (Ferran Segura, Esperanza Antón).
Hospital Sant Jaume, Calella (Josep M Llibre).
Hospital de la Santa Creu i Sant Pau, Barcelona (Pere Domingo, Montserrat Barceló, Francesc Montero).
Hospital Son Dureta, Palma de Mallorca (Melcior Riera, Maria Leyes).
Hospital de Terrassa, Terrassa (Miquel Aranda).
Hospital Vall d'Hebron, Barcelona (Esteban Ribera, Manuel Crespo).
Hospital de Viladecans, Viladecans (Manuel Javaloyas).
Sponsorship: Supported partly by grants PI02590 from Fondo de Investigaciones Sanitarias and RIS G03/173 from Red Temática Cooperativa de Investigación en SIDA, Ministerio de Sanidad y Consumo (Spain).
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© 2007 Lippincott Williams & Wilkins, Inc.