Alternation of Antiretroviral Drug Regimens for HIV Infection

A Randomized, Controlled Trial

15 July 2003 | Volume 139 Issue 2 | Pages 81-89

Background: Mathematical modeling has suggested that alternating antiretroviral regimens while patients' viral load remains suppressed would minimize HIV resistance mutations.

Objective: To compare alternation of antiretroviral regimens with the current standard of switching regimens after viral load rebound.

Design: Randomized, multicenter, open-label, pilot trial.

Setting: 15 outpatient HIV clinics in Spain and Argentina.

Patients: 161 HIV-1–infected, antiretroviral-naive persons.

Intervention: Patients were assigned to continuously receive stavudine, didanosine, and efavirenz (standard of care, regimen A) or zidovudine, lamivudine, and nelfinavir (standard of care, regimen B) until virologic failure, or to alternate between those two regimens every 3 months while viral load was suppressed (regimen C).

Measurements: Time to virologic failure, percentage of patients with undetectable plasma viremia over 48 weeks, CD4 and CD8 cell counts, adverse events, emergence of drug resistance, drug adherence, and quality of life.

Results: Patients receiving standard-of-care regimens A and B did not differ. Virologic failure over 48 weeks was delayed in the alternating therapy group compared with the pooled standard-of-care group (incidence rate, 1.2 events/1000 person-weeks [95% CI, 0.3 to 3.6 events/1000 person-weeks] vs. 4.8 events/1000 person-weeks [CI, 2.9 to 7.4 events/1000 person-weeks]; P = 0.01). Genotypic drug resistance emerged in 79% of patients in the standard-of-care group who experienced on-therapy treatment failure. Patients in the standard-of-care and alternating therapy groups had similar CD4 cell counts, frequency of adverse events, reported drug adherence, and quality of life.

Conclusions: Virologic outcome was better with alternating therapy than with the current standard of care, while adverse events and adherence were similar. The strategy of alternating therapy merits further investigation.

*For members of the SWATCH Study Team, see the Appendix.

Editors' Notes Context Although combination antiretroviral therapy slows the clinical progression of HIV-1 infection, drug resistance remains a vexing problem. Some have speculated that alternating between drug regimens on a fixed schedule might forestall drug failure. Contribution This pilot study randomly assigned patients to receive one of two triple-drug regimens (stavudine, didanosine, and efavirenz or zidovudine, lamivudine, and nelfinavir) or to alternate between the two regimens every 3 months. Alternating the regimens delayed virologic failure. Implications Alternating antiretroviral drug regimens may be a promising strategy for delaying failure of therapy for HIV-1 infection. However, this study was small, and improved antiretroviral regimens have become available since the investigators conducted this study. –The Editors

 

Author and Article Information

From IrsiCaixa Foundation and Lluita contra la SIDA Foundation, Hospital Germans Trias i Pujol, Badalona, Spain; Vanderbilt University School of Medicine, Nashville, Tennessee; Huesped Foundation, Buenos Aires, Argentina; Hospital Santa Creu i Sant Pau, Barcelona, Spain; Hospital de Vic, Vic, Spain; Hospital St. Jaume Calella, Calella, Spain; Hospital Virgen del Rocío, Sevilla, Spain; Tibotec-Virco, Mechelen, Belgium; and Utrecht University, Utrecht, the Netherlands.

Acknowledgments: The authors thank the patient volunteers and the study coordinators (Jose Miranda, RN; Juan C. Martinez, RN; and Silvia Gel, RN).

Grant Support: In part by grants PM98-0064 (Spanish Ministry of Science and Technology) and NIH R01AI29193 (National Institutes of Health). Dr. Martinez-Picado was supported by contract FIS 99/3132 from the Fundacio per a la Recerca Biomedica Germans Trias i Pujol in collaboration with the Spanish Department of Health. Roche, Bristol-Myers Squibb, and GlaxoSmithKline provided industry support in the form of unrestricted grants.

Potential Financial Conflicts of Interest:Employment: K. Hertogs (Virco); Consultancies: C. Boucher (Bristol-Myers Squibb, Roche), R.T. D'Aquila (GlaxoSmithKline); Honoraria: J. Martinez-Picado (Roche), P. Domingo (Bristol-Myers Squibb), C. Boucher (Bristol-Myers Squibb, Roche, GlaxoSmithKline), R.T. D'Aquila (Agouron, Bristol-Myers Squibb, Gilead Sciences); Stock ownership or options (other than mutual funds): J.M. Llibre (Bristol-Myers Squibb); Grants received: P. Viciana (GlaxoSmithKline, Roche, Bristol-Myers Squibb, Boehringer), C. Boucher (Bristol-Myers Squibb, Roche, GlaxoSmithKline), R.T. D'Aquila (Bristol-Myers Squibb); Patents received or pending: K. Hertogs.

Requests for Single Reprints: Javier Martinez-Picado, PhD, IrsiCaixa Foundation, Hospital Germans Trias i Pujol, Carretera de Canyet s/n, 08916 Badalona, Spain; e-mail, javiermp{at}ns.hugtip.scs.es.

Current Author Addresses: Drs. Martinez-Picado, Ruiz, and Clotet: IrsiCaixa Foundation, Hospital Germans Trias i Pujol, Carretera de Canyet s/n, 08916 Badalona, Spain.

Dr. Negredo and Ms. Fumaz: Lluita contra la SIDA Foundation, Hospital Germans Trias i Pujol, Carretera de Canyet s/n, 08916 Badalona, Spain.

Dr. Shintani: Center for Health Services Research, Division of General Internal Medicine, Vanderbilt University Medical Center, 6007 Medical Center East, Nashville, TN 37232-8300.

Dr. Zala: Huesped Foundation, Angel Peluffo 3932, C1202ABB, Buenos Aires, Argentina.

Dr. Domingo: Hospital Santa Creu i Sant Pau, Av. St. Antoni Maria Claret 167, 08025 Barcelona, Spain.

Dr. Vilaró: Hospital de Vic, Francesc Pla El Vigatà 1, 08500 Vic, Spain.

Dr. Llibre: Hospital St. Jaume Calella, St. Jaume 209, 08370 Calella, Spain.

Dr. Viciana: Hospital Virgen del Rocío, Av. Manuel Siurot s/n, 41013 Sevilla, Spain.

Dr. Hertogs: Tibotec-Virco, Gen de Wittelaan 11 B4, B-2800 Mechelen, Belgium.

Dr. Boucher: Eijkman-Winkler Institute, Department of Virology, University Medical Centre, Heidelberglaan 100, 3584CX Utrecht, the Netherlands.

Dr. D'Aquila: Division of Infectious Diseases, Vanderbilt University Medical Center, A-4102 Medical Center North, Nashville, TN 37232-2582.

Author Contributions: Conception and design: J. Martinez-Picado, L. Ruiz, C. Boucher, R.T. D'Aquila, B. Clotet.

Analysis and interpretation of the data: J. Martinez-Picado, E. Negredo, A. Shintani, C.R. Fumaz, R. T. D'Aquila.

Drafting of the article: J. Martinez-Picado, E. Negredo, A. Shintani, R.T. D'Aquila.

Critical revision of the article for important intellectual content: J. Martinez-Picado, L. Ruiz, A. Shintani, R.T. D'Aquila.

Final approval of the article: J. Martinez-Picado, E. Negredo, L. Ruiz, A. Shintani, C.R. Fumaz, C. Zala, P. Domingo, J. Vilaró, J.M. Llibre, P. Viciana, K. Hertogs, C. Boucher, R.T. D'Aquila, B. Clotet.

Provision of study materials or patients: E. Negredo, C. Zala, P. Domingo, J. Vilaró, J.M. Llibre, P. Viciana, K. Hertogs, B. Clotet.

Statistical expertise: A. Shintani.

Obtaining of funding: B. Clotet.

Administrative, technical, or logistic support: J. Martinez-Picado.

Collection and assembly of data: J. Martinez-Picado, E. Negredo, C.R. Fumaz.