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Determinants of recurrent toxicity-driven switches of highly active antiretroviral therapy. The ATHENA Cohort

Dieleman, Jeanne P.a; Jambroes, Mariellec,d; Gyssens, Inge C.b; Sturkenboom, Miriam C. J. M.a; Stricker, Bruno H. Ch.a,h; Mulder, Wilhelmina M. C.e; de Wolf, Frankg; Weverling, Gerrit-Janf; Lange, Joep M. A.c,d; Reiss, Peterc,d; Brinkman, Kees*; on behalf of the ATHENA Study Group

Clinical Science

Background: Toxicity is the most important reason for premature switching of highly active antiretroviral therapy (HAART). In order to optimize the benefit–risk ratio of HAART, guidelines for toxicity management are needed.

Objective: An observational cohort study to estimate the incidence and identify determinants of toxicity-driven switches on second-line HAART after having switched first-line HAART despite successful viral suppression.

Methods: Patients were selected from those in the ATHENA cohort (n = 2470) who switched the initial HIV protease inhibitor (PI)-containing HAART while plasma HIV-1 RNA was ≤ 500 copies/ml (n = 775). One-year cumulative incidences of subsequent toxicity-driven switches and adjusted relative risks (RR) for potential determinants were calculated.

Results: The 1-year cumulative incidence of toxicity-driven switches of the second regimen was 24% [95% confidence interval (CI), 21–28], mostly because of gastrointestinal toxicity and neuropathy. Those who had switched from first HAART because of toxicity were at an increased risk of a recurrent toxicity-driven switch (RR, 2.5; 95% CI, 1.7–3.5). Switching from PI to nevirapine while continuing the other antiretroviral drugs was more protective against a subsequent switch because of further toxicity than changing to another PI-containing regimen (RR, 0.2; 95% CI, 0.1–0.6).

Conclusions: As for first-line HAART, toxicity is responsible for the majority of switches during second-line HAART. Prior switching for toxicity increased the risk of having to switch the subsequent regimen for toxicity, but this risk is reduced when switching to nevirapine rather than to an alternative PI. The latter should be taken into account when designing toxicity-management guidelines.

From the the aPharmaco-Epidemiology Unit, Departments of Internal Medicine, and Epidemiology & Biostatistics, and the bDepartments of Microbiology & Infectious Diseases, and Internal Medicine, Erasmus University Medical Centre Rotterdam, the cNational Aids Therapy Evaluation Centre, Amsterdam, the dDepartment of Infectious Diseases, Tropical Medicine and AIDS, the eDepartment of Clinical Pharmacology and Pharmacotherapy, the fDepartment of Clinical Epidemiology and Biostatistics, and the gDepartment of Human Retrovirology, Academic Medical Center, Amsterdam, the hDutch Inspectorate for Health Care, The Hague and iOnze Lieve Vrouwe Gasthuis, Department of Internal Medicine, Amsterdam, the Netherlands. *See the Appendix for members of the ATHENA Study Group.

Requests for reprints to: J. P. Dieleman, Pharmaco-Epidemiology Unit, L-448, Depts of Internal Medicine and Epidemiology & Biostatistics, Erasmus University Medical Centre Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands.

Received: 6 July 2001;

revised: 9 November 2001; accepted: 13 November 2001.

Sponsorship: the ATHENA-project is funded by the Dutch Health Insurance Council, Amstelveen, the Netherlands. J. P. Dieleman was supported by a grant from the Dutch Inspectorate for Health Care, The Hague, the Netherlands.

© 2002 Lippincott Williams & Wilkins, Inc.