Highly active antiretroviral therapy (HAART) has resulted in dramatic reductions in HIV-1-associated mortality and morbidity.1,2 The US Department of Health and Human Services guidelines currently recommend initiating antiretroviral therapy (ART) with 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus a single nonnucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI) (http://www.aidsinfo.nih.gov/guidelines). These recommendations are based on clinical trials in which 60% to 90% of patients had HIV-1 RNA levels below the assay detection limit at 48 weeks.3-7 Risk factors for treatment failure include high baseline HIV-1 RNA levels, low baseline CD4 cell counts, and poor adherence to ART.8-10 Although highly effective, HAART has been associated with significant short- and long-term toxicities, including hyperlipidemia, insulin resistance, and fat redistribution syndromes, which may be associated with accelerated atherosclerotic cardiovascular disease.11-14 Given these and other toxicities, interest has arisen in reducing prolonged exposure to antiretrovirals. Discontinuation of ART in patients successfully treated for prolonged periods has been associated with rapid virologic rebound and decreasing CD4 cell counts, however.15,16 Treatment strategies that improve initial virologic and immunologic responses while simplifying treatment regimens over the long term remain of great interest. Induction-maintenance is one such strategy.
The term induction-maintenance is borrowed from oncology. Intensive initial therapy is designed to induce a rapid response that may be maintained over the long term with less intense and theoretically less toxic maintenance treatment regimens. To date, 3 HIV trials have tested this concept, and all led to a suboptimal treatment response.17-19 In these trials, patients were treated with triple (2 studies) or quadruple drug therapy for 12 to 26 weeks, followed by simplification to monotherapy or dual combination therapy. Rebound rates ranged from 22% to 31% and were related to poor adherence, poor pharmacokinetic profiles, and baseline viral resistance.17-20 Despite these initial failures, interest in the induction-maintenance concept has persisted.
Here, we describe an induction-maintenance strategy in which patients were induced with a compact quadruple regimen that included a fixed-dose combination of abacavir (ABC), lamivudine (3TC), and zidovudine (ZDV) with efavirenz (EFV) for 48 weeks, followed by randomization to maintenance with ABC/3TC/ZDV or continued quadruple therapy. We hypothesized that 4-drug induction therapy would be effective in patients with diverse baseline HIV-1 RNA levels and CD4 cell counts, well-tolerated, and convenient. Additionally, we anticipated that after 48 weeks of treatment, the residual viral burden would be sufficiently small to allow for the successful removal of 1 agent, EFV, resulting in reduced toxicity and improved adherence while maintaining the desired antiviral and immunologic benefits.
HIV-1-infected adults were eligible if they were antiretroviral naive (<2 weeks of prior treatment with NRTIs and/or PIs and no prior exposure to NNRTIs) and had an HIV-1 RNA level ≥5000 copies/mL. Laboratory exclusion criteria included hemoglobin <10 g/dL (male) or <9 g/dL (female), absolute neutrophil count <1000 cells/mm3, platelet count <75,000 cells/mm3, transaminases >5 times the upper limit of normal (ULN), serum pancreatic amylase >1.5 times the ULN, or estimated creatinine clearance <40 mL/min. Female patients were excluded if they were pregnant or breastfeeding.
ESS40013 was a randomized, open-label, 96-week study conducted at 40 clinical sites in the United States. The study was conducted in 2 phases: induction and maintenance (Fig. 1). Enrollment occurred between March and November 2001.
During the 48-week induction period, all patients were treated with 1 fixed-dose tablet of ABC (300 mg)/3TC (150 mg)/ZDV (300 mg) (Trizivir; GlaxoSmithKline, Research Triangle Park, NC) twice daily and with EFV (600 mg, Sustiva; Bristol-Myers Squibb, New York, NY) once daily. Patients with HIV-1 RNA levels <50 copies/mL at weeks 36 and 44 were eligible for randomization into the 48-week maintenance phase. Randomization was stratified based on an HIV-1 RNA level at study entry (baseline) of <100,000 copies/mL or ≥100,000 copies/mL. Patients were centrally randomized (1:1 ratio) to continue quadruple therapy or to simplify to ABC/3TC/ZDV alone.
Pretreatment evaluations included a clinical assessment and laboratory evaluations (plasma HIV-1 RNA, T-lymphocyte subsets, hematology, clinical chemistries, serum pregnancy test, and collection of a plasma sample later analyzed for viral resistance mutations).
On-study evaluations included clinic visits at baseline and weeks 2, 4, 8, 16, 24, 36, 44, and 48 for the induction phase and at weeks 56, 64, 72, 84, and 96 for the maintenance phase. HIV-1 RNA was assessed at each visit except week 2 using the Roche Amplicor HIV-1 Ultrasensitive Assay, version 1.5 (Roche Diagnostics, Pleasanton, CA). Clinical chemistries, hematology profiles, and T-cell subsets were performed at all visits except weeks 2 and 44. Fasting lipid profiles were measured at baseline and weeks 48 and 96. Serum pregnancy testing was performed at baseline, week 96, and whenever pregnancy was suspected. Samples for possible viral resistance testing were collected at baseline and at confirmation of virologic failure. Safety was assessed through the reporting of adverse clinical events and abnormal laboratory values. The severity of adverse events was assessed by the investigator using the Division of AIDS toxicity grading scale (1992). No substitutions were allowed for ABC/3TC/ZDV. Patients who were intolerant to EFV were able to substitute nevirapine (Viramune; Boehringer Ingelheim, Ridgefield, CT) and remain in the study.
Virologic failure was defined as failure to suppress the HIV-1 RNA level to <50 copies/mL by week 36 or a confirmed HIV-1 RNA level >500 copies/mL after suppression to <50 copies/mL. All patients who met virologic failure criteria were withdrawn from the study. Treatment failure was defined as virologic failure, discontinuation because of toxicity, clinical disease progression, or death.
The protocol and informed consent forms were reviewed and approved by the institutional review boards (IRBs) at each of the participating sites. All patients provided written informed consent.
The primary objective was to compare the durability of HIV-1 RNA suppression with ABC/3TC/ZDV compared with ABC/3TC/ZDV + EFV during the 48-week maintenance phase after a 48-week induction phase with a 4-drug regimen composed of ABC/3TC/ZDV + EFV. The primary end points were the proportions of patients with HIV-1 RNA <50 copies/mL at week 96 and time to treatment failure during the maintenance phase. Secondary objectives included safety and tolerability, efficacy, self-reported medication adherence, and development of viral resistance. A sample size of 280 patients randomized to the maintenance phase provided 80% power to demonstrate noninferiority of triple-nucleoside therapy compared with the quadruple regimen based on proportions of patients with an HIV-1 RNA level <50 copies/mL at week 96 using a noninferiority margin of 12% and a type 1 error rate of 0.05, assuming a success rate of 85% for both treatment groups.
The intent-to-treat (ITT) population was used for all analyses. For the induction phase, the ITT population consisted of all patients enrolled in the study. For the maintenance phase, the ITT population included all randomized patients. Analysis methods for the HIV-1 RNA data were (1) missing equals failure (M = F), which considered all missing data as failures, and (2) observed (Obs), which did not include missing data. Adverse events were coded by an adverse event dictionary (MIDAS), and laboratory testing was performed centrally (Covance Laboratories, Indianapolis, IN and Virco, Mechelen, Belgium). Adherence to therapy was measured using the Patient Medication Adherence Questionnaire, version 3W (PMAQ-3W) at weeks 4, 24, 48, 56, and 96. The questionnaire is a self-reported measure of medication adherence with a recall period of the last 3 days and weekend before the visit.21 Viral resistance testing at baseline and at the time of virologic failure was attempted for all patients who met virologic failure criteria and for patients with an HIV-1 RNA level ≥500 copies/mL at their last study visit. Resistance-associated mutations are those defined by the Drug Resistance Mutations Group of the International AIDS Society.22 All analyses were performed using SAS (version 8; SAS Institute, Cary, NC) on UNIX computers.
Four hundred forty-eight patients were enrolled in the induction phase. As shown in Table 1, patients were predominantly male, approximately half were nonwhite, 56% had a baseline HIV-1 RNA level ≥100,000 copies/mL, and 48% enrolled with a CD4 count <200 cells/mm3. Thirty-seven percent (166 of 448 patients) discontinued treatment during the induction phase (see Fig. 1), primarily because of adverse events (n = 55 [12.3%]), withdrawn consent (n = 33 [7.4%]), and loss to follow-up (n = 28 [6.3%]). Thirty patients (6.7%) were switched from EFV to nevirapine during the induction phase because of intolerability and were included in the analysis.
A total of 282 patients were randomized to continue quadruple therapy (n = 141) or to discontinue EFV (n = 141). Baseline characteristics for the 2 groups are essentially identical and comparable to those of the original population (see Table 1). Most (87%) patients entering the maintenance phase completed the 96-week trial. Rates of discontinuation during the maintenance phase were similar between treatment groups (ABC/3TC/ZDV + EFV = 15%, ABC/3TC/ZDV = 11%; see Fig. 1). More subjects in the quadruple therapy group discontinued the study because of nonvirologic reasons (eg, adverse events, lost to follow-up), and more subjects in the ABC/3TC/ZDV group discontinued because of virologic failure; however, these differences were not statistically significant (P > 0.05).
Virologic and Immunologic Response
Sixty-one percent of patients who entered the induction phase had HIV-1 RNA levels <50 copies/mL at week 48 (ITT M = F; Fig. 2A). Ninety percent of patients who completed the induction phase had HIV-1 RNA levels <50 copies/mL at week 48, consistent with the large number of study discontinuations attributable to nonvirologic reasons. No statistically significant differences in proportions reaching undetectable HIV-1 RNA levels were observed at 48 weeks between different baseline HIV-1 RNA strata, suggesting that the induction regimen was equally effective across diverse baseline HIV-1 RNA levels. The median time to reach an HIV-1 RNA level <50 copies/mL was shorter (approximately 16 weeks) in patients with a baseline HIV-1 RNA level <750,000 copies/mL than in patients in the highest HIV-1 RNA strata (35 weeks), however (see Fig. 2B).
At 96 weeks, 79% of patients receiving quadruple therapy and 77% receiving ABC/3TC/ZDV maintenance therapy had HIV-1 RNA levels <50 copies/mL (ITT M = F; P = 0.7; Figs. 3A, B). This established ABC/3TC/ZDV as noninferior to continued quadruple therapy (95% confidence interval [CI]: −8.6%, 5.7%). No between-treatment difference was observed in time to treatment failure (log-rank test, P = 0.749; see Fig. 3C). Virologic failure was rare in both groups (16 patients in the ABC/3TC/ZDV group, 8 patients in the quadruple therapy group; P = 0.134).
Patients remaining on therapy during the induction phase experienced a median increase of 179 CD4 T cells/mm3. Virologic response rates were influenced by the magnitude of the baseline CD4 count: at week 48, 97% of patients with baseline CD4 cell counts ≥350 cells/mm3 had HIV-1 RNA levels <50 copies/mL compared with 84% of patients with baseline CD4 cell counts <50 cells/mm3 (P = 0.012). No significant difference in virologic response was observed between groups who had an intermediate baseline CD4 cell count (50-199 cells/mm3 and 200-349 cells/mm3).
Median CD4 T-cell counts at the time of randomization to maintenance were 411 cells/mm3 for the ABC/3TC/ZDV group and 395 cells/mm3 for patients remaining on quadruple therapy. CD4 T-cell counts continued to increase during maintenance to median levels of 453 cells/mm3 and 425 cells/mm3 in the respective treatment groups.
Adverse Events and Adherence
Mild to moderate treatment-related adverse events were common during induction, especially nausea (38%), fatigue (24%), vivid dreams (20%), dizziness (18%), rashes (16%), and sleep disturbances (15%) (Table 2). Adverse events leading to discontinuation in >1% of patients were suspected ABC hypersensitivity reaction (32 patients [7%]) and rash (9 patients [2%]). New adverse events were much less common during the maintenance phase, although they were slightly more common in patients continuing quadruple therapy (15% vs. 6%). Treatment discontinuation was more frequent in the quadruple therapy group for reasons other than virologic failure (see Fig. 1).
Total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels all increased during the induction phase (median increases: 30 mg/dL, 15 mg/dL, and 11 mg/dL, respectively). During maintenance, total cholesterol, LDL cholesterol, and triglycerides were persistently elevated in the quadruple therapy group but decreased substantially in the ABC/3TC/ZDV group. At week 96, median changes from week 48 were −22 mg/dL and +3 mg/dL for total cholesterol, −16.5 mg/dL and +1 mg/dL for LDL, and −16 and +5 mg/dL for triglycerides for the ABC/3TC/ZDV and quadruple treatment groups, respectively.
Adherence to therapy was excellent in both treatment groups. At week 96, 88.8% of patients on ABC/3TC/ZDV reported perfect adherence on the PMAQ-3W versus 79.6% of patients in the quadruple therapy group (P = 0.057).
Treatment-Emergent Viral Resistance
Eighteen of 22 patients meeting criteria for virologic failure during the induction phase had plasma samples available for genotypic analysis (Table 3A). Of these, 2 had significant baseline mutations associated with study drugs (M184V [n = 1] and K103N [n = 1]). The most common viral resistance pattern at failure (10 of 18 patients) included point mutations associated with resistance to EFV and/or 3TC (M184V alone [n = 1]; K103N alone [n = 4]; M184V and K103N [n = 1]; M184V, K103N, and Y188L [n = 1]; M184V, K103N, and P225H [n = 2]; and M184V and G190S [n = 1]). Two patients had treatment-emergent mutations associated with resistance to EFV, 3TC, and ZDV (M184V, K103N, M41L, D67N, L210W, and T215Y [n = 1] and M184V, K103N, D67D/N, and V118V/I [n = 1]). Two patients had the K65R mutation selected on therapy (K65R, V118I, and G190S [n = 1] and K65R/K, M184V/M, K103N, and Y188H/Y [n = 1]); both had high baseline HIV-1 RNA levels (952,835 copies/mL and 331,154 copies/mL) and low baseline CD4 cell counts (6 cells/mm3 and 8 cells/mm3).
During maintenance, 24 patients (16 in the ABC/3TC/ZDV group and 8 in the quadruple therapy group; P = 0.134) had confirmed HIV-1 RNA levels >500 copies/mL (n = 10) or levels >500 copies/mL at the last study visit (see Table 3B). Of these patients, 19 had paired genotype samples at baseline and virologic failure. One of the 19 had a significant baseline mutation associated with study drugs (K103N). The most common mutation pattern at virologic failure was M184V alone (6 patients receiving the ABC/3TC/ZDV regimen and 2 receiving the quadruple regimen). M184V and thymidine analogue-associated mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E) were seen in 4 patients in the ABC/3TC/ZDV group (M184V and D67D/N [n = 1]; M184V, D67D/N, and K70R/K [n = 1]; M184V and T215F [n = 1]; and M184V, D67N, K70R/K, and K219E/K [n = 1]). Three patients (1 receiving ABC/3TC/ZDV therapy and 2 receiving quadruple therapy) had HIV variants with EFV resistance mutations (K103N and M184V [n = 1] in the triple therapy group and K103N [n = 1] and K103N and P225P/H [n = 1] in the quadruple therapy group).
This study is the first demonstration of success for an induction-maintenance approach to HIV therapy. ABC/3TC/ZDV therapy successfully maintained virologic and immunologic responses in patients treated for 48 weeks with EFV-based quadruple therapy, which establishes induction-maintenance as a viable treatment option for HIV-1 infection.
We chose a 48-week induction phase for a number of reasons. Given the expectation that patients with high baseline HIV-1 RNA levels would be enrolled, we anticipated that shorter induction periods could limit the number of patients eligible for randomization to maintenance. Furthermore, the induction-maintenance concept is partially predicated on reducing the pool of randomly generated preexisting resistant variants during initial treatment. Given that the half-life of the second phase of HIV-1 RNA decay after HAART initiation is, on average, 2 to 4 weeks,23,24 we hypothesized that treatment of approximately 12 half-lives, or approximately 48 weeks, would result in a substantially reduced residual viral burden at the time of treatment simplification. Additionally, we believe that success in this trial, as compared with previous failures, was achieved by using an effective and well-tolerated triple combination therapy during maintenance.
The large number of treatment discontinuations during induction is problematic. In a recent trial comparing EFV-based HAART with triple-nucleoside therapy for initial treatment of HIV-1, only 7% of patients discontinued therapy by week 32,4 despite one of the treatment groups being ABC/3TC/ZDV plus EFV. A discontinuation rate of 37% in the present study is difficult to explain. That these studies enrolled patients contemporaneously raises the question as to whether there was some selection bias in the selection and referral of patients in these competing trials. The specific 4-drug regimen in this trial failed to improve initial response rates to antiviral therapy, in contrast to established 3-drug regimens.4,6,7 Response rates in patients at all strata of baseline HIV-1 RNA levels were high and demonstrate the potency of this particular combination. We were encouraged by the low rate of virologic failure during induction. Nevertheless, it was surprising that 2 patients experienced failure with viruses that included the K65R mutation despite inclusion of ZDV in the regimen.25 One potential explanation is documented ART nonadherence for both patients, likely resulting in periods of exposure to ABC in the absence of ZDV because of the shorter half-life of ZDV and its anabolites. Additionally, these patients had low baseline CD4 cell counts (<10 cells/mm3) and high HIV-1 RNA levels (>300,000 copies/mL) at treatment initiation, which may increase the risk of K65R emergence.7
In assessing the results of this trial, we must ask what benefits treatment simplification provided. In the short term, a reduction in treatment-related adverse events and improved adherence accompanied triple-nucleoside therapy, as did improvement in fasting lipid profiles. Furthermore, in the face of the emergence of drug-resistant virus, treatment options in all drug classes (NRTI, NNRTI, and PI) remained available for use in most of the ABC/3TC/ZDV-treated patients who experienced virologic failure. It is important to note that during maintenance, treatment-emergent drug resistance was more common in the ABC/3TC/ZDV group than in the quadruple therapy group, although the difference did not reach statistical significance.
Having established the viability of the induction-maintenance approach, we now ask how to incorporate this treatment strategy into current clinical practice. For the regimen used here, much depends on the results of the ACTG 5095 trial, which compares 3TC/ZDV + EFV with ABC/3TC/ZDV + EFV.4 Should the 4-drug regimen prove superior as initial therapy, it would then follow that simplification would be a reasonable option for patients completing 48 weeks of quadruple therapy. Furthermore, this trial should be the impetus to explore induction-maintenance strategies further in treatment-naive and treatment-experienced patients. Within a relatively short time frame, HIV-1 infection has been transformed from a near-uniformly fatal infection to one that is chronic and treatable; thus, it becomes imperative that new and creative ways to manage this condition are explored to optimize therapeutic outcomes.
We are indebted to the participants in this study; to the staff at Clinical Trials Management Services who conducted the study (T. Hardin, N. Hagie, M. Carrier, D. Clendenon, P. Kilgore, S. McKinney, Y. Hoss, S. Edwards, J. Blevins, and B. Simms); and to members of the GlaxoSmithKline study team (B. Wine, S. Gooding, P. Wannamaker, B. Pobiner, H. Hair, J. Hernandez, and J. Royal) who assisted with the design, conduct, and analysis. The other ESS40013 investigators were S. Becker, P. Benson, D. Berger, W. Causey, P. Cimoch, P. Cook, R. Dretler, V. Fainstein, T. File, J. Gathe, F. Haas, K. Henry, J. Hernandez, A. Huang, T. Jefferson, A. Kelly, P. Kumar, C. McDonald, A. Meza, R. Myers, J. Narro, B. Onbirbak, J. Pulvirenti, A. Rodriguez, R. Roland, P. Ruane, P. Salvato, M. Sension, P. Shalit, L. Slater, S. Sotman, S. Sperber, D. Ward, S. Weinroth, D. Wheeler, and J. Zachary.
1. Mocroft A, Vella S, Benfield TL, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet
2. Palella FJ, Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med
3. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med
4. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med
5. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med
6. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med
7. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA
8. Mocroft A, Gill MJ, Davidson W, et al. Predictors of a viral response and subsequent virological treatment failure in patients with HIV starting a protease inhibitor. AIDS
9. Fatkenheuer G, Theisen A, Rockstroh J, et al. Virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients. AIDS
10. Brigido LF, Rodrigues R, Casseb J, et al. Impact of adherence to antiretroviral therapy in HIV-1-infected patients at a university public service in Brazil. AIDS Patient Care STDS
11. Nolan D, Hammond E, Martin A, et al. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS
12. Carr A. Toxicity of antiretroviral therapy and implications for drug development. Nat Rev Drug Discov
13. Nolan D, Hammond E, James I, et al. Contribution of nucleoside-analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level. Antivir Ther
14. Bozkurt B. Cardiovascular toxicity with highly active antiretroviral therapy: review of clinical studies. Cardiovasc Toxicol
15. Davey RT, Jr, Bhat N, Yoder C, et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci USA
16. Markowitz M, Jin X, Hurley A, et al. Discontinuation of antiretroviral therapy commenced early during the course of human immunodeficiency virus type 1 infection, with or without adjunctive vaccination. J Infect Dis
17. Havlir DV, Marschner IC, Hirsch MS, et al. Maintenance antiretroviral therapies in HIV infected patients with undetectable plasma HIV RNA after triple-drug therapy. AIDS Clinical Trials Group Study 343 Team. N Engl J Med
18. Reijers MH, Weverling GJ, Jurriaans S, et al. Maintenance therapy after quadruple induction therapy in HIV-1 infected individuals: Amsterdam Duration of Antiretroviral Medication (ADAM) study. Lancet
19. Pialoux G, Raffi F, Brun-Vezinet F, et al. A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1-infected patients. Trilege (Agence Nationale de Recherches sur le SIDA 072) Study Team. N Engl J Med
20. Descamps D, Flandre P, Calvez V, et al. Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Trilege (Agence Nationale de Recherches sur le SIDA 072) Study Team. JAMA
21. Duong M, Piroth L, Grappin M, et al. Evaluation of the Patient Medication Adherence Questionnaire as a tool for self-reported adherence assessment in HIV-infected patients on antiretroviral regimens. HIV Clin Trials
22. Johnson VA, Brun-Vezinet F, Clotet B, et al. Drug resistance mutations in HIV-1. Top HIV Med
23. Perelson AS, Neumann AU, Markowitz M, et al. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science
24. Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature
25. Lanier ER, Givens N, Stone C, et al. Effect of concurrent zidovudine use on the resistance pathway selected by abacavir-containing regimens. HIV Med
Keywords:© 2005 Lippincott Williams & Wilkins, Inc.
induction-maintenance antiviral therapy; quadruple regimen