Potent combination antiretroviral therapy has been shown to provide dramatic reductions in mortality and morbidity from HIV-1 infection [1–3]. Initial treatment regimens frequently include the combination of one or more protease inhibitors (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTI) [2–5]. The complexity and toxicities associated with initial regimens can affect long-term viral suppression and be associated with adherence difficulties . PI-based and NRTI-containing regimens have also been associated with metabolic perturbations [7,8], including hyperlipidemia, insulin resistance and fat redistribution. There is a need for potent but simplified antiretroviral regimens that address drug class-related toxicities.
The study was designed to assess the safety and efficacy of switching to one of two simplified, potent, class-sparing regimens after successful long-term viral suppression on a first multidrug regimen. Due to the high frequency of durable virologic suppression, with efavirenz (EFV) [5,9,10] and high genetic barrier to viral resistance with lopinavir/ritonavir (LPV/r) [11–13], EFV-based and LPV/r-based regimens were chosen.
Study design and patients
A5116 was a multicenter, randomized, open-label study that compared a simplified NRTI-sparing regimen of LPV/r plus EFV with a PI-sparing regimen of EFV plus two NRTI. Planned duration of follow up was 48 weeks beyond the enrollment of the last patient, which was increased to 72 weeks. Patients were recruited from 30 AIDS Clinical Trials Units in the USA and seven sites in Italy. The study was approved by institutional review boards (IRB) or ethical committees of participating sites. All patients gave written informed consent.
Eligible patients were prior ACTG 388 participants  who had long-term viral suppression (HIV-1 RNA ≤ 200 copies/ml) on a first three- or four-drug regimen of lamivudine, zidovudine and indinavir or lamivudine, zidovudine and indinavir with either EFV or nelfinavir without serious treatment-related toxicity, evidence of virologic failure (VF, two consecutive plasma HIV-1 RNA ≥ 400 copies/ml) or phenotypic viral resistance. Patients with isolated phenotypic lamivudine resistance were eligible as long as they were willing to receive stavudine and didanosine if randomized to the PI-sparing regimen. The study was modified to allow enrollment of non-ACTG 388 patients who were on a stable first three- or four-drug PI-based or NNRTI-based regimen for at least 18 months without documentation of VF or viral resistance and who had a plasma HIV-1 RNA ≤ 200 copies/ml at screening.
All patients had advanced HIV disease (HIV-1 RNA ≥ 80 000 copies/ml or CD4 cells ≤ 200 cells/μl) prior to the initiation of their first thee- or four-drug regimen.
Patients received one of two regimens: EFV (Sustiva, Bristol-Myers Squibb, New York, New York, USA) 600 mg once daily and two NRTI or LPV/r (Kaletra, Abbott Laboratories, Abbott Park, Illinois, USA) 533 mg/133 mg twice daily and EFV 600 mg once daily. The following NRTI combinations were used: lamivudine 150 mg/zidovudine 300 mg as a fixed dose combination (Combivir, GlaxoSmithKline, Research Triangle Park, North Carolina, USA), stavudine 40 mg (Zerit, Bristol Myers-Squibb) and lamivudine 150 mg, didanosine enteric coated (Videx EC, Bristol Myers-Squibb) 400 mg and lamivudine 150 mg, didanosine enteric coated 400 mg and stavudine 40 mg, and didanosine enteric coated 400 mg and zidovudine 300 mg. The substitution of nevirapine (Viramune, Boehringer Ingelheim, Boehringer, Germany) for EFV or an alternative NRTI was permitted in the event of drug-associated toxicity.
Clinical assessments, plasma HIV-1 RNA measurements, CD4 cells and routine laboratory tests were performed at study entry and weeks 4, 8, 16 and every 8 weeks thereafter. Plasma HIV-1 RNA was quantified in two central laboratories using the ultrasensitive Roche Amplicor Monitor System version 1.5 assay (Roche Molecular Systems, Inc., Pleasanton, California, USA), with a lower limit of quantification of 50 copies/ml. Fasting lipid levels [triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol], insulin and lactate levels were performed before study entry, at weeks 8, 24, 48 and every 16 weeks thereafter.
Plasma viral genotype and phenotype were done at the time of confirmed VF by a reference laboratory (Monogram Biosciences, South Francisco, California). Sequence analysis of baseline and pre-therapy (first three- or four-drug combination regimen) samples was performed on a subset of the patients who developed VF, using an FDA-approved kit (ViroSeq, Celetra Diagnostics, Alameda, California, USA).
The primary outcome measure was time to confirmed VF (two consecutive plasma HIV-1 RNA > 200 copies/ml). In May 2002, following the recommendation of an independent Safety Monitoring Committee who noted a lower annual VF rate than projected, the primary outcome was modified to include time to first VF or discontinuation of any component of randomized treatment due to study drug toxicity (toxicity-related discontinuation).
Secondary outcome measures included safety and tolerability of study regimens, time to VF, time to toxicity-related discontinuation, changes in CD4 cells and proportion with HIV-1 RNA < 50 copies/ml.
A Safety Monitoring Committee reviewed the study on two occasions following the Lan and DeMets approximation to the O'Brien and Fleming stopping boundaries for efficacy comparisons [14,15].
The primary outcome was analyzed on an intent-to-treat basis that included all available data through September 2004. Time to event distributions were estimated using the method of Kaplan and Meier and compared with the log-rank test, stratified by ACTG 388 treatment regimen and non-ACTG 388 participation. Statistical tests performed were two-sided, and P values < 0.05 were considered significant.
Toxicities were graded using the Division of AIDS Table for Grading Severity of Adult Adverse Experiences (August 1992). Adverse events analyses used all available data, censoring follow up data at time of study discontinuation or 56 days after permanent discontinuation of study treatment, and were restricted to patients who received study treatment. Toxicity endpoints included toxicity-related discontinuation of any component of the initial randomized study regimen or switch to an alternative antiretroviral medication.
Four patients never started study treatment and refused follow up. They were censored at day 0 for the primary outcome analysis and considered discontinued from study treatment at day 0.
Virologic and toxicity endpoints were verified in a blinded fashion by the study chair (MAF) or co-chair (ACC, JEF).
Analyses of treatment group differences in metabolic laboratory parameters used repeated measures analysis of variance. Lipid levels were categorized by the National Cholesterol Education Program (NCEP), and treatment group differences were evaluated by Kruskal–Wallis tests at each week measured [16,17]. Due to elevated triglycerides, non-HDL cholesterol levels were used. Lactic acidemia was defined as a lactate level above the site laboratory upper limit of normal.
HIV-1 RNA data were analyzed longitudinally according to proportion of patients with HIV-1 RNA < 50 copies/ml. Changes in CD4 cells from baseline to follow-up weeks were compared by the Wilcoxon test. As-treated analyses were also performed.
The study was designed with 87% power to detect a difference between 15 and 30% annual VF rates, using a log-rank test at a two-sided 0.05 level. The study was redesigned to have approximately 80% power to detect a difference between 15 and 25% annual combined endpoint (VF or toxicity discontinuation) rates, using a log-rank test at a two-sided 0.05 level over a median 3-year follow up. Statistical analyses were performed using SAS version 8.2 (SAS Institute Inc., Cary, North Carolina, USA).
Enrollment and patient characteristics
There were 236 patients randomized between 13 June 2001 and 31 January 2003; 118 were assigned to LPV/r + EFV and 118 to EFV + NRTI. The groups had similar baseline characteristics (Table 1). A total of 149 patients (63%) had participated in ACTG 388.
Of the patients in the EFV + NRTI group, 92 (78%) received zidovudine and lamivudine; 22 (19%) stavudine and lamivudine; and four (4%) other study-allowed nucleoside combinations.
Duration of follow up and treatment status
Median follow up was 110 weeks (2.1 years; range, 0–159 weeks). Four patients died, four never received study medication and refused follow up, and 30 prematurely discontinued from the study; 12 discontinued because of protocol-defined events, five were withdrawn because of non-compliance, five self-withdrew, five were lost to follow up, and three who met eligibility were withdrawn the first week due to site IRB eligibility requirement of minimum CD4 cells. The disposition of patients is noted in Fig. 1.
Of 232 patients who received study medication, 173 completed study treatment. There was a significant difference in rate of study medication discontinuation for LPV/r + EFV (n = 40) compared with EFV + NRTI (n=19; P < 0.001).
Total number of study endpoints included 21 VF endpoints (14, LPV/r + EFV; 7, EFV + NRTI) and 26 toxicity-related discontinuation endpoints (20, LPV/r + EFV; 6, EFV + NRTI).
There was a difference between treatment groups in the first of VF or toxicity-related discontinuation (P = 0.0015). Time to VF or toxicity-related discontinuation occurred significantly earlier after switching to LPV/r + EFV compared to EFV + two NRTI (Fig. 2).
In secondary analyses, the primary endpoint components were separately evaluated. There was a trend toward a difference between treatment in time to VF (Fig. 3a), with a suggestion of a lower VF rate for EFV + NRTI (P = 0.088). In an as-treated analysis (Fig. 3b), a similar trend toward a lower VF rate occurred with EFV + NRTI (P = 0.063). Evaluating time to treatment-related toxicity discontinuation (Fig. 4), there was a significantly greater rate of toxicities with LPV/r + EFV, mainly for increased triglycerides (P = 0.0021).
Overall, 165 patients (78, LPV/r + EFV; 87, EFV + NRTI) maintained virologic suppression (HIV-1 RNA < 50 copies/mL).
There was a slow increase in CD4 cells throughout study treatment. Mean ± standard deviation increases from baseline CD4 cells at weeks 48 and 96 were 40.4 ± 162.1 cells/μl and 67.8 ± 147.5 cells/μl, respectively, for LPV/r + EFV, and 17.4 ± 133.5 cells/μl and 43.6 ± 144.2 cells/μl, respectively, for EFV + NRTI. No significant differences in CD4 cells were noted between the groups at weeks 24, 48 or 96.
One patient had an AIDS-defining diagnosis (EFV + NRTI group), and four patients (two in each treatment group) died of sepsis, gastric adenocarcinoma, vehicle accident or drowning. None were judged related to study medication.
HIV drug resistance
At VF, genotypic resistance results were available for 21 patients (14, LPV/r + EFV; 7, EFV + NRTI). Pretreatment samples were available from 10 of the 14 patients receiving LPV/r + EFV and five of the seven patients receiving EFV + NRTI. At failure, M184V or I (5), K103N (5), V106M (1), M230L (1), P225H (1) in reverse transcriptase (RT) and L33V (1) in protease were present in the EFV + NRTI group, and M184V (1), K103N (5), V106 A or M (2), Y188H (1), G190A (2), V108I (1) in RT and L33V (2) and F53L (1) in protease in the LPV/r + EFV group.
One patient in each treatment group had two NNRTI resistance mutations in addition to K103N. One patient receiving EFV + NRTI who previously received zidovudine monotherapy failed with four thymidine analogue mutations in addition to K103N, M184V and L33V. No other primary protease resistance mutations were detected in the failure samples. Of the 15 patients with available pretreatment samples, none had major pre-existing mutations.
There was no difference in time to first grade 3 or greater signs or symptoms between the treatment groups (P = 0.47). Thirteen patients in the LPV/r + EFV group and 10 in the EFV + NRTI group developed one or more grade 3 or 4 signs or symptoms.
A trend toward a greater rate of first grade 3 or greater laboratory abnormalities was noted with LPV/r + EFV than with EFV + NRTI (P = 0.053). This difference was largely due to increased triglycerides (20, LPV/r + EFV; 5, EFV + NRTI). Forty-four patients in the LPV/r + EFV group and 37 in the EFV + NRTI group developed grade 3 or 4 laboratory toxicities.
Forty-five of 115 patients (39%) receiving EFV + NRTI developed asymptomatic elevated lactic acid levels compared with 42 of 110 (38%) receiving LPV/r + EFV (P = 0.89, Fisher's exact test). Lactic acid level increases were confirmed in 36 patients. Persistent lactic acidemia (≥ 3 consecutive elevated measurements) occurred in 22 patients (12, EFV + NRTI; 10, LPV/r + EFV group).
There was evidence of an interaction between treatment groups and time-related changes in metabolic parameters. Cholesterol increased with LPV/r + EFV compared to minimal changes with EFV + NRTI (P < 0.001). Non-HDL cholesterol increased with LPV/r + EFV and decreased with EFV + NRTI (P = 0.005). HDL cholesterol increased in both treatment groups; small but greater increases were noted with LPV/r + EFV (P = 0.010). There were greater increases in triglycerides with LPV/r + EFV (P = 0.018). Fasting insulin decreased with LPV/r + EFV compared with minimal increases with EFV + NRTI (P = 0.40).
Mean non-HDL cholesterol and triglyceride changes by week 24 were 9.1 ± 4.0 mg/dL and 257 ± 35 mg/dl, respectively, with LVP/r + EFV and −6.1 ± 3.6 mg/dl and 23 ± 41 mg/dl, respectively, with EFV + NRTI. Assessing NCEP categories, more patients receiving LPV/r + EFV reached a higher risk category for total cholesterol and triglycerides (P < 0.001). No differences were noted for non-HDL and HDL cholesterol.
Greater increases in fasting glucose levels were noted with EFV + NRTI (P = 0.053). Ordered American Diabetes Association categories  were not significantly different between treatment groups except for week 24 (P = 0.016) and week 48 (P = 0.011). Of 19 patients with baseline fasting glucose levels > 126 mg/ml, six had decreases (2, EFV + NRTI; 4, LPV/r + EFV). Of 214 patients with baseline normal fasting glucose levels, 13 developed levels > 126 mg/ml (10, EFV + NRTI; 3, LPV/r + EFV).
There was an interaction between time and treatment group with regard to changes from baseline in fasting insulin, with marginally higher levels in the EFV + NRTI group and decreases in the LPV/r + EFV group (P = 0.04). No difference between groups with respect to the homeostasis model assessment measurement of insulin resistance was found (P = 0.38).
Increasing use of potent combination antiretroviral therapies in the late 1990s, recognition of short- and long-term toxicities of antiretroviral therapies [4,19,20] and increasing complexity of initial combination antiretroviral regimens created a need to identify new potent and well-tolerated therapies that were more convenient. For patients who started with more complex antiretroviral regimens, it is important to determine new combination regimens that will continue to provide clinical benefits and minimize short- and long-term toxicities.
Toxicities associated with antiretroviral agents are often specific to the class of drug. Hyperlipidemia has been commonly associated with PI use, while mitochondrial toxicity (such as peripheral fat lipoatrophy) has been associated with nucleoside analog use [7,8,21–25]. Given the difficulties with adherence and adverse events with complex antiretroviral regimens, we hypothesized that simplified potent regimens which addressed class-related toxicities could provide long-term viral suppression and limit treatment-related toxicities. Based on available data with EFV and LPV/r, we compared a two-drug regimen of LPV/r + EFV with a three-drug regimen of EFV + two NRTI.
The study was initially designed to determine a difference in time to VF. It became apparent that this goal was not achievable based on high success rates in both treatment groups, with smaller than anticipated numbers of virologic failures observed in an interim Safety Monitoring Committee review. As a result, the study team elected to change the study endpoint from one focused on virologic outcome to a composite endpoint that took into account both regimen safety and virologic outcomes. As initial secondary study goals included assessing impact of adverse events, the team thought it reasonable to expand the primary outcome assessment to incorporate this important secondary measure.
We found that the three-drug regimen of EFV + NRTI provided greater long-term suppression and tolerability compared with the two-drug regimen of LPV/r + EFV. LPV/r + EFV was associated with a significantly greater rate of toxicity-related discontinuation and a trend toward a higher rate of VF, as seen in the intention-to-treat (P = 0.088) and the as-treated (P = 0.063) analyses. The higher rate of toxicity-related discontinuation was primarily related to elevations in triglycerides associated with LPV/r + EFV treatment. Increases in triglycerides have been previously reported with LPV/r [11–13]. Since elevations in triglycerides have been reported with EFV-based regimens [26,27], it is theoretically possible that there was an interaction between LPV/r and EFV that led to the higher rate of toxicity-related endpoints. Despite the open-label nature of the study, the majority of study endpoints were laboratory-based measures determined at protocol-specified frequencies, and less likely to be susceptible to subject and investigator biases.
Analyses of CD4 cells in the treatment groups showed a similar slow increase over time. Mean baseline CD4 cell count was 473 cells/μl, reflecting immunologic improvement that had occurred with previous treatment. Since patients enrolled in A5116 had to be virologically suppressed, only additional incremental increases in CD4 cell counts would be expected.
Analyses of HIV-1 RNA showed that the majority of patients maintained long-term viral suppression, reflecting the potency of the study regimens. In those patients who developed VF, most receiving EFV + NRTI failed with either K103N mutation alone or both M184 (V or I) and K103N mutation. In the LPV/r + EFV group, the major mutation noted at failure was the K103N mutation (5/14 patients) while other NNRTI resistance mutations were found in an additional four patients. Primary protease resistance mutations were uncommon in either treatment group; only one patient in the LPV/r + EFV treatment group developed the F53L mutation, which in combination with other protease mutations has been associated with lopinavir resistance . Fifteen of 21 patients with VF had pre-treatment samples available for testing; none had pre-existing mutations. These data would suggest that primary pre-existing resistance mutation were unlikely to have contributed to VF. To draw definitive conclusions, analysis of pretreatment samples among those who did not develop VF would be needed. We found no differences in frequencies of complex resistance patterns in the treatment groups, although the small number of failures limits our ability to assess factors that may have contributed to this.
The study also evaluated several metabolic parameters and included a metabolic substudy A5125s  to assess the metabolic impact of switching to a PI-sparing or NRTI-sparing regimen. Greater increases in triglycerides, total cholesterol, non-HDL cholesterol and HDL cholesterol were noted in the LPV/r + EFV group, with minimal changes or decreases in these values in the EFV + NRTI group. In spite of this increase in lipids, the A5125s substudy showed that LPV/r + EFV was associated with a significant increase in peripheral fat and improvement in fat wasting that has been observed with nucleoside-based regimens . Although greater increases in glucose levels were noted with EFV + NRTI, the increases seen were relatively small. Taken together, these findings are consistent with prior observations of lipid changes in some patients on combination antiretroviral therapy containing protease inhibitors, and that nucleoside analogs are related to the limb lipoatrophy that characterize the fat redistribution syndrome.
Results consistent with our findings were noted in the French Hippocampe study . This French study used a similar study strategy in an antiretroviral-naive population and found that NRTI-sparing regimens with LPV/r or indinavir with ritonavir were significantly less effective in attaining virologic suppression than nucleoside-containing regimens with EFV or nevirapine. In contrast, preliminary data from the ACTG A5142 study in previously untreated patients using regimens of EFV + LPV/r, LPV/r alone, or two NRTI with either EFV or LPV/r demonstrated no difference in time to viral suppression between the LPV/r + EFV or two NRTI + EFV groups . The treatment experience of the study populations, specific regimens, and duration of antiretroviral therapy differed between these two studies and our study, and may have contributed to the differing conclusions about the relative efficacy of NRTI-sparing and NRTI-containing regimens. Other studies have also demonstrated the durable effectiveness of a nucleoside-containing regimen with EFV [5,9,10,31], and underscore the importance of specific antiretroviral drugs in the overall long-term potency of combination regimens.
Our study demonstrates the complexities of assessing strategies to evaluate simplified class sparing regimens and demonstrated that a regimen of EFV + nucleoside analogues is better tolerated than a regimen of LPV/r + EFV. However, the metabolic substudy showed a benefit for peripheral lipoatrophy when switching to the nucleoside analog-sparing regimen.
A modification to the primary endpoint to a combined endpoint that included tolerability was made at the suggestion of a Safety Monitoring Committee. This combined endpoint more accurately reflects the trade-offs between efficacy and tolerability that occur in clinical practice and the strategy question that the study was designed to address. Since the design of this study, atazanavir, another protease inhibitor with a different metabolic profile than LPV/r has become available, and the use of combinations that include such new drugs might shift the balance of the evaluated strategy .
In summary, switching to EFV + NRTI led to lower rates of regimen failure than switching to LPV/r + EFV among patients who had achieved long-term suppression on previous more complex regimens. LPV/r + efavirenz treatment was associated with significant increases in lipids, especially triglycerides. Although the majority of patients maintained virologic suppression, there was a trend toward increased VF with LPV/r + EFV treatment in this study population.
These data were presented in part at the Twelfth Conference on Retroviruses and Opportunistic Infections. Boston, MA, February 2005 [abstract 162].
Other A5116 Protocol Team members and institutions
Anne Kmack, Marlene Cooper, Frontier Science and Technology Research Foundation, Amherst, NY; Ana Martinez, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; Nancy Tustin Children's Hospital Philadelphia, PA; Nicholas Hellmann ViroLogic, Inc, San Francisco, CA; and Jeffrey Schouten, University of Washington, Seattle WA.
The A5116 Trial Investigators: Participating ACTG investigators and institutions
Jose G. Castro, Hector H. Bolivar, University of Miami School of Medicine, Miami, FL; Jenifer Baer, Diane Daria, University of Cincinnati, Cincinnati, OH; Fred R. Sattler, Virgilio T. Clemente, University of Southern California, Los Angeles, CA; Debra Demarco, Mark Rodriguez, Washington University, St. Louis, MO; Christine Fietzer, Robyn Schacherer, University of Minnesota, Minneapolis, MN; Steven Johnson, Beverly Putnam, University of Colorado Health Sciences Center, Denver, CO; Barbara Gripshover, Barbara Philpotts, Case Western Reserve University, Cleveland, OH; Oluwatoyin Adeyemi, Baiba Berzins, Northwestern University, Chicago, IL; Melody Palmore, Bryan Thompson, Emory University, Atlanta, GA; Elizabeth Carver, Deitra Wade, Duke University Medical Center, Durham, NC; Jorge L. Santana, Olga I. Méndez, San Juan, PR; Michael F. Para, Kathy Watson, Ohio State University, Columbus, OH; Juan J. L. Lertora, Rebecca Clark, Tulane University, New Orleans, LA; Joseph J. Eron, Jr., Cheryl Marcus, Laurie Frarey, University of North Carolina, Chapel Hill, NC; Karen Cavanagh, Charles Gonzalez, New York University, New York, NY; Kenneth Fife, Jean Craft, Indiana University, Indianapolis, IN; Richard Reichman, Jane Reid, University of Rochester Medical Center, Rochester, NY; Erica B. Walsh, Joanne Frederick, University of Hawaii, Honolulu, HI; Harvey Friedman, Keith Mickelberg, University of Pennsylvania, Philadelphia, PA; Mallory Witt, Sadia Shaik, Harbor-University of California at Los Angeles, Los Angeles, CA; Ilene Wiggins, Dorcas Baker, Johns Hopkins University, Baltimore, MA; Sheila Dunaway, N. Jeanne Conley, University of Washington, Seattle, WA; Roy M. Gulick, Todd Stroberg, Cornell Chelsea Clinic, New York, NY.
Participating Italian investigators and institutions
Francesco Meneghetti, Anna Maria Cattelan, Azienda Ospedaliera di Padova, Padova; Giampiero Carosi, Francesco Castelli, University of Brescia, Brescia; GianMarco Vigevani, Amedeo Capetti, Ospedale Luigi Sacco, Milano; Vincenzo Vullo, Martina Carnevalini, University of Rome, Rome; Roberto Esposito, Giovanni Guaraldi, University of Modena, Modena; Francesco Mazzotta, Massimo Di Pietro, Ospedale S.M. Annunziata, Firenze; Giampietro Cadeo, Alberto Bergamasco, Spedali Civili, Brescia; Liliana Weimer, Elena A.P. Germinario, Maria F. Pirillo, Marina Giuliano, Istituto Superiore di Sanità, Rome.
Sponsorship: Supported by: the National Institute of Allergy and Infectious Disease grants AI27675, AI27664, AI25897, RR00044, AI27658, AI38858 (subcontract 200VC007), AI27673, RR00051, AI32770, AI25924, RR05096, AI38844, RR00046, AI25868, AI50410, RR00096, AI27665, AI34853, RR00052, AI27668, and RR00047, and by a grant from the Istituto Superiore di Sanità, National AIDS Clinical Research Program for years 2001–2003.
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