712 Incidence and Risk Factors for Severe Adverse Events in a Prospective Cohort of HIV-infected Adults Started on a Protease Inhibitor-containing Therapy X. Duval1, V. Journot2, M. Dupon3, F. Saoula4, C. Barennes2, S. Herson5, S. Boucherit1, A. Waldner6, G. Chêne2, F. Raffi*7, and the APROCO Study Group 1CHU Bichat-Claude Bernard, Paris, France; 2INSERM U330, Bordeaux, France; 3CHU Pellegrin, Bordeaux, France; 4CHU Pontchaillou, Rennes, France; 5CHU Pitiè Salpétrière, Paris, France; 6CHU Reims, France; and 7CHRU Hôtel Dieu, Nantes, France
Background: Although the durability of HAART efficacy is markedly dependent on treatment tolerability, a limited number of studies has assessed the incidence and the determinants of unselected severe adverse events (SAE) in the context of routine practice of antiretroviral (ARV) therapy in HIV infected patients (pts).
Objectives: To study the incidence of SAE and their risk factors in a large multicenter cohort including 1,155 pts starting on protease inhibitor (PI) between May 1997 and June 1998.
Methods: SAE (grade 3 or 4 events) were prospectively reported and validated by 2 clinical experts; the likelihood of resulting from ARV treatment was classified as related or unrelated to PI and/or other ARV. This analysis reports data on ARV-related SAE occurring in the first 2 yrs of follow-up.
Results: At baseline, 44% of pts initiated an indinavir-containing regimen: 25% nelfinavir, 16% ritonavir, 11% saquinavir, and 4% other PIs regimen. During a median follow-up of 23 mos (2,142 pt-yrs), 550 events were reported; 235 were related to ARV (incidence density 11% pt-yrs) and 186 to PI (8.7% pt-yrs). Overall, 11% occurred within the first month and 33% within the first 4 months after initiation of therapy. The most frequent SAE involved the liver (29%), the kidney (14%), the hematological system (13%) and metabolic parameters (11%). In a multivariate proportional hazard model, creatininemia > 110 µmol/L (HR = 2.23 (95% Confidence Interval [CI] = 1.1-4.54) p = 0.027), increase of ASAT (for 50 UI/L, HR = 1.21, CI [1.10-1.33], p = 10-4), hepatitis C and/or B co-infection (HR = 1.69, CI [1.18-2.42], p = 0.005), ever taking stavudine use (HR = 2.40, CI [1.50-3.83], p = 0.0002) were associated with an higher risk of SAE whereas polynuclear neutrophil cells > 1000/mm3 (HR = 0.013 [0.00-0.49] p = 0.02), total lymphocyte cells > 1000/mm3 (HR = 0.57, CI [0.39-0.85], p = 0.006), nelfinavir use (HR = 0.52, CI [0.3-0.89], p = 0.01), each additional month on any PI (HR = 0.8 to 0.84 depending on PI, p < 10-4), and on stavudine (HR = 0.93, CI [0.90-0.96], p < 10-4) were associated with a lower risk of SAE.
Conclusions: SAE after the initiation of HAART are frequent and related both to host (renal, hepatic tests, white blood cells count and hepatitis co-infections) and treatments characteristics. Early occurrence of SAE in the course of therapy could involve for some of them a toxic mechanism with decreasing risk over time.