Alternation of Antiretroviral Drug Regimens for HIV Infection

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 The use of triple-drug antiretroviral therapies for HIV-1 infection can markedly reduce viral load and slow clinical progression (1-4). The goals of therapy are maximal, durable suppression of viral load; restoration or preservation of immunologic function; improved quality of life; and reduced HIV-related morbidity and mortality (5). Although as many as 70% to 90% of antiretroviral drugnaive patients achieve maximal viral load suppression in clinical trials, results can vary and may be less favorable in practice settings (6). Therapy fails because of complex interactions among several factors, including incomplete adherence, inadequate anti-HIV activity or drug exposure, and viral resistance. In standard care, an antiretroviral drug regimen is changed only after it fails. This allows viral replication under the selection pressure of the failing regimen, potentially for prolonged periods, regardless of how failure was initiated. New treatment strategies are being studied to maximize and prolong benefits of current drugs, and improved therapies are under development. Simultaneous use of four or more antiretroviral drugs has been explored (7), but this method may cause greater toxicity and has not yet proved better than standard three-drug regimens (8). Two-drug maintenance regimens following triple-drug induction therapy have not yet been successful (9, 10). In addition, repeated supervised interruptions of antiretroviral treatment, which are intended to bolster immune control of HIV-1, have not yet achieved that goal in most persons with chronic HIV infection (11-15). Analyses of the optimum time to change drug therapy have suggested another strategy (16). Mathematical modeling has been used to evaluate laboratory monitoring methods as triggers for a regimen change. Simulations have indicated that proactively switching regimens while patients' viral load remains suppressed could more effectively shorten the period of virus replication under the selection pressure of a failing regimen and decrease accumulation of resistance mutations compared with changing the regimen after viral load rebound is detected or resistance emerges. This method would also theoretically allow repeated use of drugs (recycling, or drug regimen alternation) and a shorter continuous period of exposure to the same drugs, which may diminish cumulative long-term toxicity. However, changing well-tolerated, successful drugs may increase risk for poor tolerability of and adherence to the next regimen. Our trial, SWATCH (SWitching Antiviral Therapy Combination against HIV-1), was designed to compare proactively alternating two triple-drug regimens every 3 months with continuous administration of either of the same regimens until viral load rebound. Methods Study Participants This randomized, multicenter, open-label trial compared two strategies for switching antiretroviral drug regimens among HIV-infected patients beginning antiretroviral treatment. Study participants were recruited from 15 hospital-based outpatient HIV clinics in Spain and Argentina (Appendix). Institutional review boards at all participating hospitals approved the study, and all eligible patients who presented to the clinics for initial treatment were asked to participate. The inclusion criteria were age of at least 18 years, no previous antiretroviral therapy, and a baseline plasma HIV-1 RNA level of more than 400 copies/mL within 4 weeks before randomization. CD4 cell count was not an entry criterion. Women were required to have a negative result on a urine pregnancy test within 72 hours before the start of therapy with the study medication. Prophylaxis against Pneumocystis carinii was permitted in patients with CD4 cells counts of less than 0.200 cells 109 cells/L or a previous event. Interventions Patients were randomly assigned to one of two strategies for switching antiretroviral regimens: the standard-of-care approach, involving a switch triggered by viral load rebound, or alternation of regimens every 3 months while viral load remained suppressed. Two groups of patients who received different initial regimens were treated with the standard-of-care approach. Regimen A consisted of 400 mg of didanosine once daily (1 hour before or 2 hours after eating), 40 mg of stavudine every 12 hours (30 mg for patients weighing <60 kg), and 600 mg of efavirenz once daily. Regimen B consisted of 300 mg of zidovudine every 12 hours, 150 mg of lamivudine every 12 hours, and 1250 mg of nelfinavir every 12 hours with a meal or light snack. Regimens A and B were each continued until viral load rebounded. Patients who received the alternating regimen (regimen C) alternated between regimens A and B every 3 months, beginning with regimen A. Each regimen was used twice in the alternating therapy group. Use of efavirenz in this group was extended 1 extra week after patients switched to regimen B, and use of nelfinavir was extended 1 extra week after patients switched back to regimen A. The rationale was to maintain antiviral effect during regimen changes until the new drugs reached steady-state levels in the blood. Patients were assessed at enrollment and at weeks 12, 24, 36, and 48. Objectives We wanted to determine whether alternation of two antiretroviral regimens prolonged time to virologic failure of initial treatment compared with the standard-of-care approach. We also tested whether regimen alternation differed from standard of care in adverse events, treatment discontinuations, resistance at time of virologic failure, CD4 cell counts, adherence, perceived effort of therapy, and quality of life. Another aim was to assess whether virologic failure differed when patients began therapy with one rather than the other of the two regimens given using the standard-of-care approach. Outcome Measures The primary outcome measure was time to virologic failure, defined as the first plasma HIV-1 RNA level of 400 copies/mL or greater between weeks 24 and 48 after viral load had decreased to less than 400 copies/mL by week 24. Secondary outcome measures included the percentage of patients in whom viral load was suppressed to undetectable levels over 48 weeks of treatment, using a viral load cutoff of 400 copies/mL or 50 copies/mL. Other secondary outcome measures included time to treatment discontinuation due to all causes, due to causes other than virologic failure, and due to adverse events. Levels of HIV-1 RNA were assessed at each center by using the Amplicor HIV-1 Monitor test (Roche Diagnostics, Indianapolis, Indiana). A level of 400 copies/mL or greater triggered confirmatory testing of a second aliquot of plasma from the same time point. The Amplicor HIV-1 Monitor UltraSensitive test (Roche Diagnostics) was used retrospectively to also detect as few as 50 copies/mL. Absolute counts of CD4 and CD8 cells, as assessed by flow cytometry at 48 weeks, and changes in cell counts between weeks 12 and 48 were also secondary outcome measures. Results of resistance tests performed at virologic failure were compared across groups. Resistance genotyping (Viro-Seq, Applied Biosystems, Barcelona, Spain) was performed on all failure specimens and matching baseline specimens to identify amino acid differences in HIV-1 pol from the reference wild-type sequence, NL4-3. Phenotypic resistance testing with a recombinant virus assay (Antivirogram, Virco, Mechelen, Belgium) determined 50% inhibitory concentrations (17, 18). We assessed adverse events (signs, symptoms, or laboratory abnormalities) that were defined as severe according to World Health Organization guidelines and required discontinuation of treatment. Adherence was self-reported, as described elsewhere (19), and appropriate adherence was defined as consumption of at least 95% of the medication prescribed (20). The perceived effort required to follow study treatment properly was assessed with a 100-mm visual analogue scale effort index (19, 21), ranging from 0 (no effort) to 10 (maximum effort). For self-assessment of quality of life over the 4 weeks preceding each visit, a 5-point scale adapted from the Medical Outcomes StudyHIV questionnaire was used (22). Compared with the previous visit, a score of 1 reflected the greatest reduction in quality of life, a score of 3 indicated no change, and a score of 5 indicated the best possible improvement. A score of 3 was used as the arbitrary baseline value. All patients taking each of the three study regimens received the same supportive instruction at each visit. Patients who discontinued using study medications or withdrew from the protocol for any reason were followed, if possible, for adverse events, clinical outcome, and all protocol testing. The protocol recommended that patients who had viral load rebound or adverse effects while receiving regimen A should be offered regimen B after leaving the study, and vice versa. For patients who had treatment failure with the alternating regimen (regimen C), we provided results of the drug resistance tests to their physicians to assist them in selecting the next treatment. Sample Size We estimated that a sample size of 162 (54 patients for each regimen)