Background of study: The extensive use of protease inhibitors (PIs) in HIV infection therapy has shown up a series of adverse reactions which were only slightly evident in clinical trials, such as, for example, lipodistrophy and other metabolic type alterations (diabetes mellitus, serum lipid abnormalities). Many of these events have been identified through spontaneous reports, in the absence of formal epidemiologic studies.
Objective: The aim of the study is to evaluate the incidence of adverse events during treatment with PI and to show up unexpected adverse events.
Design: Since september 1997 we have been carrying out a cohort multicentre study involving 10 Departments of Infectious Diseases from Northern Italy belonging to the CISAI study group; we planned to enroll 2000 patients starting with PIs. Adverse events are classified according to the ACTG adverse experience grading scales. A total of 1480 patients have been enrolled, having an average age of 37.1 years (SD ± 8.1),1066 are male and the average follow-up time is equal to 22.2 months (range 1 - 30). Average CD4+ lymphocites at enrolment are 265 cell/mmc (SD ± 201). From the beginning of the study to the present day (data refer to september 2000) 506 patients have left the study, 188 have been lost to follow up, 248 have
definitively interrupted the therapy and 23 died.
Results: The incidence rate of adverse events for each single drug is the following: Ritonavir 95.3/100 person-years (95% CI 94.1-96.4), Ritonavir+Saquinavir HGC association 91.9 (90.3-93.4), Indinavir 52.5 (52-53), Nelfinavir 47.2 (46.5-47.9), Saquinavir HGC (SQV-HGC) 34.1 (33.5-34.7). The incidence rate of serious adverse events (grade 3 or 4) is the following: Ritonavir 32.4 (31.7-33.1), Ritonavir+SQV-HGC 26.9 (26.1-27.8), Indinavir 14.4 (14.2-14.7), SQV-HGC 10.6 (10.3-11), Nelfinavir 8.4 (8.1-8.7). Gastrointestinal intolerance is the main side effect in patients treated with Ritonavir (29.4/100 person-years; 95% CI 28.8-30), Ritonavir+SQV-HGC (23.1; 22.3-23.9) while lipodistrophy is the most frequent adverse event in those treated
with Indinavir (17.9; 17.6-18.2), Nelfinavir (16.4; 16-16.8) and SQV-HGC (13.6; 13.2-14). The most important unexpected event reported up to date is osteonecrosis observed in 7 patients.
Conclusion: Ritonavir, either alone or associated with SQV-HGC, is the PI that most frequently generates adverse events in the HAART-treated population, while SQV-HGC is the best in terms of tolerability. If we consider only serious events, Nelfinavir has the lowest incidence rate. We are now particularly focusing our attention on the unexpected and rare adverse events reported in our cohort, such as osteonecrosis, that could lead to serious physical impairment if unrecognized.
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