Robin Isaacs

Raltegravir with optimized background therapy for resistant HIV-1 infection.

BACKGROUND Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs. METHODS We conducted two identical trials in different geographic regions to evaluate the safety and efficacy of raltegravir, as compared with placebo, in combination with optimized background therapy, in patients infected with HIV-1 that has triple-class drug resistance in whom antiretroviral therapy had failed. Patients were randomly assigned to raltegravir or placebo in a 2:1 ratio. RESULTS In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups. CONCLUSIONS In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial

BACKGROUND Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in-vitro activity against HIV-1 strains including those resistant to currently available antiretroviral drugs. The aim of this study was to assess the safety and efficacy of raltegravir when added to optimised background regimens in HIV-infected patients. METHODS HIV-infected patients with HIV-1 RNA viral load over 5000 copies per mL, CD4 cell counts over 50 cells per muL, and documented genotypic and phenotypic resistance to at least one nucleoside reverse transcriptase inhibitor, one non-nucleoside reverse transcriptase inhibitor, and one protease inhibitor were randomly assigned to receive raltegravir (200 mg, 400 mg, or 600 mg) or placebo orally twice daily in this multicentre, triple-blind, dose-ranging, randomised study. The primary endpoints were change in viral load from baseline at week 24 and safety. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, with the number NCT00105157. FINDINGS 179 patients were eligible for randomisation. 44 patients were randomly assigned to receive 200 mg raltegravir, 45 to receive 400 mg raltegravir, and 45 to receive 600 mg raltegravir; 45 patients were randomly assigned to receive placebo. One patient in the 200 mg group did not receive treatment and was therefore excluded from the analyses. For all groups, the median duration of previous antiretroviral therapy was 9.9 years (range 0.4-17.3 years) and the mean baseline viral load was 4.7 (SD 0.5) log10 copies per mL. Four patients discontinued due to adverse experiences, three (2%) of the 133 patients across all raltegravir groups and one (2%) of the 45 patients on placebo. 41 patients discontinued due to lack of efficacy: 14 (11%) of the 133 patients across all raltegravir groups and 27 (60%) of the 45 patients on placebo. At week 24, mean change in viral load from baseline was -1.80 (95% CI -2.10 to -1.50) log10 copies per mL in the 200 mg group, -1.87 (-2.16 to -1.58) log10 copies per mL in the 400 mg group, -1.84 (-2.10 to -1.58) log10 copies per mL in the 600 mg group, and -0.35 (-0.61 to -0.09) log(10) copies per mL for the placebo group. Raltegravir at all doses showed a safety profile much the same as placebo; there were no dose-related toxicities. INTERPRETATION In patients with few remaining treatment options, raltegravir at all doses studied provided better viral suppression than placebo when added to an optimised background regimen. The safety profile of raltegravir is comparable with that of placebo at all doses studied.

Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection

BACKGROUND We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. METHODS We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure. RESULTS Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations. CONCLUSIONS When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study.

Background:Raltegravir is an HIV-1 integrase strand-transfer inhibitor with potent in vitro activity. This study explored the antiretroviral activity and safety of raltegravir in treatment-naive patients with plasma HIV-1 RNA levels ≥5000 copies/mL and CD4+ T-cell counts ≥100 cells/mm3. Methods:Multicenter, double-blind, randomized, controlled study of raltegravir at doses of 100, 200, 400, and 600 mg twice daily versus efavirenz at a dose of 600 mg/d, all in combination with tenofovir at a dose of 300 mg/d and lamivudine at a dose of 300 mg/d (clinicaltrials.gov identifier: NCT00100048). Results:In the 198 patients treated (160 on raltegravir and 38 on efavirenz), the mean HIV-1 RNA level ranged from 4.6 to 4.8 log10 copies/mL at baseline. At weeks 2, 4, and 8, the proportion of patients achieving an HIV-1 RNA level <50 copies/mL was greater in each of the raltegravir treatment groups than in the efavirenz group. By week 24, all treatment groups appeared similar, with plasma HIV-1 RNA levels <400 copies/mL in 85% to 98% of patients and <50 copies/mL in 85% to 95% of patients. These reductions were maintained through week 48 in 85% to 98% of patients and in 83% to 88% of patients, respectively. Five (3%) patients on raltegravir and 1 (3%) on efavirenz experienced virologic failure before week 48. Drug-related clinical adverse events were less common with raltegravir than with efavirenz. After 24 and 48 weeks of treatment, raltegravir did not result in increased serum levels of total cholesterol, low-density lipoprotein cholesterol, or triglycerides. Conclusions:Raltegravir at all doses studied was generally well tolerated in combination with tenofovir and lamivudine. Raltegravir exhibited potent and durable antiretroviral activity similar to that of efavirenz at 24 and 48 weeks but achieved HIV-1 RNA levels below detection at a more rapid rate.

Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals

Background:MK-0518 is a novel HIV-1 integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration [IC95] = 33 nM in 50% human serum) and good bioavailability in uninfected subjects. This study explored the antiretroviral activity and safety of MK-0518 versus placebo for 10 days as monotherapy in antiretroviral therapy-naive HIV-1-infected patients with plasma HIV-1 RNA levels of at least 5000 copies/mL and CD4+ T-cell counts of at least 100 cells/mm3. Methods:This was a multicenter, double-blind, randomized, placebo-controlled 2-part study, with the first part using MK-0518 in 1 of 4 doses (100, 200, 400, and 600 mg) versus placebo (randomized 1:1:1:1:1) given twice daily for 10 days of monotherapy. Patients were monitored for safety, pharmacokinetic parameters, and antiretroviral effect. Results:Thirty-five patients were enrolled (6-8 patients per treatment group) and completed 10 days of therapy; the mean baseline log10 HIV RNA level ranged from 4.5 to 5.0 copies/mL in each group. On day 10, the mean decrease from baseline in the log10 HIV RNA level was −0.2 copies/mL for the placebo group and −1.9, −2.0, −1.7 and −2.2 log10 copies/mL for the MK-0518 100-, 200-, 400-, and 600-mg treatment groups, respectively. All dose groups had superior antiretroviral activity compared with placebo (P < 0.001 for comparison of each dose with placebo). At least 50% of patients in each MK-0518 dose group achieved an HIV RNA level <400 copies/mL by day 10. Mean trough MK-0518 concentrations at each dose exceeded the IC95 of 33 nM. Study therapy was generally well tolerated. The most common adverse experiences were headache and dizziness; these were similar between active and control groups. There were no discontinuations because of adverse experiences and no serious adverse experiences. Conclusions:MK-0518 showed potent antiretroviral activity as short-term monotherapy and was generally well tolerated at all doses. Based on these results, part 2 of the study, a dose-ranging 48-week trial of MK-0518 versus efavirenz in a combination regimen, has been initiated.

3-Year suppression of HIV viremia with indinavir, zidovudine, and lamivudine

The use of antiretroviral therapy that includes an HIV protease inhibitor has markedly decreased morbidity and mortality in HIV-infected persons (1-3). In addition, antiretroviral combination therapy that includes a protease inhibitor can suppress viral load levels for up to 2 years (4-8). However, the long-term durability and toxicity of these regimens are unknown. We present results after 3 years of follow-up in patients who received three-drug therapy with indinavir, zidovudine, and lamivudine in a previously reported study (4, 5). Methods Study Design The study was originally designed as a randomized, double-blind comparison of three antiretroviral regimens: indinavir (Crixivan, Merck & Co., Inc., West Point, Pennsylvania), 800 mg every 8 hours; zidovudine (Retrovir, Glaxo Wellcome, Research Triangle Park, North Carolina), 200 mg every 8 hours, with lamivudine (Epivir, Glaxo Wellcome), 150 mg every 12 hours; and all three drugs together at the same specified doses (4, 5). Patients were encouraged to drink at least 1.5 L of fluid per day. We report on the patients who were originally assigned to receive three-drug therapy. Institutional review boards at each site approved the study and amendments, and all patients gave informed consent. Study Participants Eligible patients were HIV-infected adults who had received at least 6 months of zidovudine therapy but had never taken lamivudine or an HIV protease inhibitor. Patients had serum viral load levels of at least 20 000 copies/mL (Amplicor HIV Monitor Test, Roche Diagnostic Systems, Branchburg, New Jersey) and CD4 counts between 50 to 400 cells/mm3 at screening. Assessments Patients had study visits at least every 4 weeks through week 52 and every 8 weeks through week 156. At baseline and at each visit, a history was taken, a physical examination was performed, and standardized laboratory tests were conducted without regard to food intake. Serum was processed, stored at 70 C, and subsequently assayed for HIV RNA by using the Amplicor and ultradirect assays (4, 5). T-lymphocyte subgroups were quantified by using flow cytometry. Genotypic analysis of serum HIV RNA was performed as described elsewhere (5). Individual investigators graded adverse events according to standardized guidelines. A drug-related adverse event was one that the investigator assessed as possibly, probably, or definitely related to the study therapy. Nephrolithiasis was defined as the passing of macroscopic stones or gravel or flank pain with or without associated hematuria. During follow-up, investigators assessed lipodystrophy at one time point from October to December 1998 (after approximately 2.5 to 3.5 years of treatment). Patients were considered to have lipodystrophy if they had one or more of the following features without evidence of hypercortisolemia: truncal or central obesity with or without thinning of the extremities; accumulation of body fat in the abdomen, the neck (buffalo hump), the retroperitoneum, the face, or the breasts; and accumulation or redistribution of body fat in some areas that was out of proportion to other body areas. Statistical Analysis Antiretroviral activity was assessed by calculating 1) the proportions (with 95% CIs) of patients whose HIV RNA levels were less than 500 copies/mL (Amplicor assay) and those whose HIV RNA levels were less than 50 copies/mL [ultradirect assay] and 2) the median changes (plus interquartile ranges) from baseline in log10HIV RNA levels (Amplicor assay) and CD4 cell counts over time. Analyses were performed on an intention-to-treat basis. Patients who withdrew early from the study were considered to have had virologic failure at subsequent time points, except for two patients who withdrew for reasons that were not related to therapy and had HIV RNA levels less than 500 copies/mL at the time of withdrawal, as described elsewhere (5). Because the analyses included patients with observed values and those with imputed values, the term contributing patients is used. Among patients with at least two measurements, those who never achieved an HIV RNA level less than 500 copies/mL were considered to have experienced virologic failure. Those who achieved an HIV RNA level less than 500 copies/mL were considered to have experienced virologic failure if they had two consecutive measurements of HIV RNA levels that were at least 500 copies/mL but did not have subsequent re-suppression while receiving the same three-drug regimen. Role of the Study Sponsor Employees of the industry sponsor participated in the study as co-investigators. After designing the study with the input of the other study investigators, these employees implemented the protocol and coordinated data collection and statistical analyses. All investigators interpreted the data, determined the content of the paper, and decided whether to submit the paper for publication. Results Study Participants Originally, 33 patients were randomly assigned to receive three-drug therapy with zidovudine, lamivudine, and indinavir. Median age was 40 years (range, 30 to 62 years). Thirty-one patients (94%) were men, and 2 (6%) were women; 26 (79%) were white, 2 (6%) were African American, 3 (9%) were Latin American, and 2 (6%) were members of other racial or ethnic groups. At study entry, patients had taken zidovudine for a median of 28 months (range, 6 to 92 months) and had a median baseline serum HIV RNA level of 41 900 copies/mL (range, 7550 to 219 040 copies/mL) and a median baseline CD4 count of 133 cells/mm3 (range, 35 to 433 cells/mm3). Of the 33 patients, 12 (36%) discontinued therapy within 3 years: 7 because of increased viral load levels; 2 because of need for contraindicated medications (rifampin and cytotoxic chemotherapy); and 1 each because of nausea, patient request, and investigator recommendation after resolution of urinary tract obstruction. Nine patients experienced virologic failure (6 in the first year, 0 in the second year, and 3 in the third year). Antiretroviral Activity The percentages of contributing patients whose HIV RNA level decreased from baseline to less than 500 copies/mL and less than 50 copies/mL, respectively, were 78% (95% CI, 60% to 90%) and 75% (CI, 56% to 88%) at 1 year, 78% (CI, 60% to 90%) and 66% (CI, 47% to 81%) at 2 years, and 68% (CI, 49% to 83%) (21 of 31 patients) and 65% (CI, 45% to 80%) (20 of 31 patients) at 3 years (Figure 1). Patients experienced a median change in HIV RNA level from baseline of 2.07 log10 copies/mL (interquartile range, 2.39 to 1.61 log10 copies/mL) at 1 year, 2.07 log10 copies/mL (interquartile range, 2.40 to 1.61 log10 copies/mL) at 2 years, and 1.99 log10 copies/mL (interquartile range, 2.32 to 1.31 log10 copies/mL) at 3 years (Figure 2). The median increase in CD4 counts from baseline was 155 cells/mm3 (interquartile range, 95 to 230 cells/mm3) at 1 year, 209 cells/mm3 (interquartile range, 117 to 339 cells/mm3) at 2 years, and 230 cells/mm3 (interquartile range, 150 to 316 cells/mm3) at 3 years (Figure 2). Figure 1. Proportion of patients with serum HIV RNA levels less than 500 copies/mL and less than 50 copies/mL during 3 years of treatment with indinavir, zidovudine, and lamivudine. Figure 2. Median changes in serum HIV RNA level and CD4 cell count from baseline during 3 years of treatment with indinavir, zidovudine, and lamivudine. Genotypic Analysis of Viral Resistance For the nine patients who experienced virologic failure by year 3, results of genotypic analyses performed at baseline and at the time of virologic failure were similar to the results of the 2-year analysis (5). Briefly, six patients had preexisting zidovudine resistance, as evidenced by the presence of the reverse transcriptase T215Y substitution combined with M41L (four patients), K70R (one patient), or D67N/K70R/K219Q (one patient). One patient developed zidovudine resistance (M41L), and all nine developed lamivudine resistance (M184V). Five patients acquired protease substitutions that were previously associated with indinavir resistance (9): M46L/V82A (four patients) and L90M (one patient). In two additional patients, evidence of new protease substitutions (L10V or L63P/S/A) appeared during treatment; however, the significance of substitutions at these two naturally occurring polymorphic sites is unclear. Adverse Events Four patients experienced a serious drug-related adverse event related to nephrolithiasis. Two of these patients experienced urinary tract obstruction, and one withdrew from the study 2 months after the adverse event resolved. Two of these patients also had other serious drug-related adverse events (pain and abdominal pain). In total, 12 of 33 patients (36%) had at least one episode of clinical nephrolithiasis during 3 years of treatment and 7 of 33 patients (21%) had more than one episode. Initial episodes of nephrolithiasis occurred from 24 weeks to 3 years of treatment. A total of 64.6 person-years of follow-up occurred before the first episode of nephrolithiasis or before censoring at 3 years. Therefore, the incidence of nephrolithiasis was 1.86 per 10 person-years of follow-up. Of the 21 patients in active follow-up, 4 (19%) fulfilled the clinical definition of lipodystrophy. When random, nonfasting specimens obtained throughout the study were used, serum triglyceride levels greater than 8.47 mmol/L (750 mg/dL) were documented at least once in 8 of 33 patients (24%) and levels greater than 13.55 mmol/L (1200 mg/dL) were documented in 2 of 33 patients (6%). Serum glucose levels greater than 13.88 mmol/L (250 mg/dL) occurred at least once in 1 of 33 patients (3%). Total serum cholesterol level was measured retrospectively in frozen samples obtained after 0.5, 1, 2, and 3 years of follow-up. Seven of 30 patients (23%) had total serum cholesterol levels of at least 6.21 mmol/L (240 mg/dL), and 1 of 30 patients (3%) had a level of at least 7.76 mmol/L (300 mg/dL) at least once. Discussion Evidence shows that it will be difficult

Long-Term Efficacy and Safety of Raltegravir Combined with Optimized Background Therapy in Treatment-Experienced Patients with Drug-Resistant HIV Infection: Week 96 Results of the BENCHMRK 1 and 2 Phase III Trials

BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus infection. At week 96 (combined data), raltegravir (400 mg twice daily) plus optimized background therapy was generally well tolerated, with superior and durable antiretroviral and immunological efficacy, compared with optimized background therapy alone.

Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial

BACKGROUND Twice-daily raltegravir with once-daily tenofovir-emtricitabine is an effective initial antiretroviral regimen for patients with HIV-1. On the basis of pharmacokinetic data suggesting efficacy of once-daily raltegravir and because adherence is often improved with once-daily dosing, we aimed to compare these dosing schedules. METHODS In our international, double-blind, randomised, phase 3 non-inferiority study, we enrolled antiretroviral-naive patients with HIV RNA loads of more than 5000 copies per mL and no baseline resistance to tenofovir or emtricitabine at 83 centres worldwide. We randomly allocated patients (1:1) by use of a computer-generated sequence to receive raltegravir once daily (two 400 mg tablets taken together every 24 h), or twice daily (one 400 mg tablet every 12 h), both in combination with once-daily co-formulated tenofovir 300 mg plus emtricitabine 150 mg. The primary outcome was virological response at 48 weeks (viral RNA loads <50 copies per mL) in patients who received at least one dose of study drug, counting non-completers as failure. We assessed non-inferiority in terms of the proportion of patients in both treatment groups who achieved the primary outcome, with a non-inferiority margin of -10%. This study is registered with ClinicalTrials.gov, number NCT00745823. FINDINGS From Oct 15, 2008, to Nov 2, 2009, we randomly allocated 775 patients, of whom 382 (99%) of 386 patients in the once-daily group and 388 (99%) of 389 in the twice-daily group received at least one dose of study drug. At baseline, 304 (39%) of 770 treated patients had viral loads of more than 100,000 copies per mL and 188 (24%) had CD4 cell counts of fewer than 200 cells per μL. 318 (83%) of 382 patients in the once-daily group had virological response compared with 343 (89%) of 386 in the twice-daily group (difference -5·7%, 95% CI -10·7 to -0·83; p=0·044). Serious adverse events were reported in 26 (7%) of 382 once-daily recipients and 40 (10%) of 388 twice-daily recipients, and adverse events leading to discontinuation occurred in four (1%) patients in each group. INTERPRETATION Despite high response rates with both regimens, once-daily raltegravir cannot be recommended in place of twice-daily dosing. FUNDING Merck.

Residual human immunodeficiency virus (HIV) Type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years.

Residual viral replication persists in a significant proportion of human immunodeficiency virus (HIV)-infected patients receiving potent antiretroviral therapy. To determine the source of this virus, levels of HIV RNA and DNA from lymphoid tissues and levels of viral RNA in serum, cerebrospinal fluid (CSF), and genital secretions in 28 patients treated for < or =2.5 years with indinavir, zidovudine, and lamivudine were examined. Both HIV RNA and DNA remained detectable in all lymph nodes. In contrast, HIV RNA was not detected in 20 of 23 genital secretions or in any of 13 CSF samples after 2 years of treatment. HIV envelope sequence data from plasma and lymph nodes from 4 patients demonstrated sequence divergence, which suggests varying degrees of residual viral replication in 3 and absence in 1 patient. In patients receiving potent antiretroviral therapy, the greatest virus burden may continue to be in lymphoid tissues rather than in central nervous system or genitourinary compartments.

Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection.

Objectives:The purpose of this study was to evaluate the safety and efficacy of raltegravir vs efavirenz-based antiretroviral therapy after 96 weeks in treatment-naive patients with HIV-1 infection. Methods:Multicenter, double-blind, randomized study of raltegravir (100, 200, 400, or 600 mg twice a day) vs efavirenz (600 mg every day), both with tenofovir/lamivudine (TDF/3TC), for 48 weeks, after which raltegravir arms were combined and all dosed at 400 mg twice a day. Eligible patients had HIV-1 RNA ≥5000 copies per milliliter and CD4+ T cells ≥100 cells per microliter. Results:One hundred ninety-eight patients were randomized and treated; 160 received raltegravir and 38 received efavirenz. At week 96, 84% of patients in both groups achieved HIV-1 RNA <400 copies per milliliter; 83% in the raltegravir group and 84% in the efavirenz group achieved <50 copies per milliliter (noncompleter = failure). Both groups showed similar increases in CD4+ T cells (221 vs 232 cells/uL, respectively). An additional 2 patients (1 in each group) met the protocol definition of virologic failure between weeks 48 and 96; no known resistance mutations were observed in the raltegravir recipient; the efavirenz recipient had nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance mutations. Investigator reported drug-related clinical adverse events (AEs) were less frequent with raltegravir (51%) than efavirenz (74%). Drug-related AEs occurring in >10% of patients in either group were nausea in both groups and dizziness and headache in the efavirenz group. Laboratory AEs remained infrequent. Raltegravir had no adverse effect on total or low-density lipoprotein cholesterol or on triglycerides. Neuropsychiatric AEs remained less frequent with raltegravir (34%) than efavirenz (58%). There were no drug-related serious AEs in patients receiving raltegravir. Conclusions:In antiretroviral therapy-naive patients, raltegravir with TDF/3TC had potent antiretroviral activity, which was similar to efavirenz/TDF/3TC and was sustained to week 96. Raltegravir was generally well tolerated; drug-related AEs were less frequent in patients treated with raltegravir compared with efavirenz.