Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis.

BACKGROUND: As antiretroviral regimens for the treatment of HIV infection improve, trials providing data on long-term follow-up are increasingly important. METHODS: A regimen of tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) demonstrated superior virologic, immunologic and morphologic effects compared with a regimen of fixed-dose zidovudine/lamivudine (ZDV/3TC) and EFV through 96 weeks in a randomized open-label trial. After 96 weeks, patients on TDF + FTC transitioned to fixed-dose combination TDF/FTC. RESULTS: Through 144 weeks, significantly more patients in the TDF/FTC arm reached and maintained an HIV RNA level <400 copies/mL (71% receiving TDF/FTC and EFV vs. 58% receiving ZDV/3TC and EFV; P = 0.004), with a trend toward greater CD4 cell increase in the TDF/FTC arm (312 vs. 271 cells/mm; P = 0.09). Over 144 weeks of follow-up, more patients in the ZDV/3TC arm discontinued therapy because of adverse events (11% vs. 5%; P = 0.01) and no patients discontinued because of renal events. Patients in the ZDV/3TC arm had significantly less limb fat than patients in the TDF/FTC arm (5.4 vs. 7.9 kg; P < 0.001) at 144 weeks. CONCLUSIONS: Cumulative results from 3 years of follow-up suggest that a regimen of TDF/FTC and EFV demonstrates superior durability of viral load suppression and an improved safety and morphologic profile compared with ZDV/3TC and EFV.

Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes--a 96-week analysis.

BACKGROUND: In antiretroviral-naive patients, tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) demonstrated superior outcomes compared with fixed-dose zidovudine (ZDV)/lamivudine (3TC) and EFV through 48 weeks. Results through a 96-week extension phase are presented. METHODS: In this randomized, open-label, noninferiority trial, 517 antiretroviral-naive HIV-infected patients received TDF, FTC, and EFV (TDF + FTC + EFV) or ZDV/3TC and EFV (ZDV/3TC + EFV). The primary endpoint was the proportion of patients with an HIV RNA level <400 copies/mL in patients without baseline nonnucleoside resistance. RESULTS: Through week 96, significantly more patients receiving TDF + FTC + EFV achieved and maintained an HIV RNA level <400 copies/mL (75% receiving TDF + FTC + EFV vs. 62% receiving ZDV/3TC + EFV; P = 0.004). There was a trend toward greater virologic suppression to <50 copies/mL in the TDF + FTC + EFV group (67% vs. 61%; P = 0.16). The TDF + FTC + EFV group demonstrated a significantly greater increase in CD4 count (270 vs. 237 cells/mm; P = 0.036). No patient developed the K65R mutation. Limb fat at week 96 was significantly greater in the TDF + FTC + EFV group versus the ZDV/3TC + EFV group (7.7 vs. 5.5 kg; P < 0.001). CONCLUSION: Over 96 weeks, the combination of TDF, FTC, and EFV was superior to fixed-dose ZDV/3TC + EFV for achieving and maintaining an HIV RNA level <400 copies/mL and an increase in CD4 cells.

Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV.

BACKGROUND: Durable suppression of replication of the human immunodeficiency virus (HIV) depends on the use of potent, well-tolerated antiretroviral regimens to which patients can easily adhere. METHODS: We conducted an open-label, noninferiority study involving 517 patients with HIV infection who had not previously received antiretroviral therapy and who were randomly assigned to receive either a regimen of tenofovir disoproxil fumarate (DF), emtricitabine, and efavirenz once daily (tenofovir-emtricitabine group) or a regimen of fixed-dose zidovudine and lamivudine twice daily plus efavirenz once daily (zidovudine-lamivudine group). The primary end point was the proportion of patients without baseline resistance to efavirenz in whom the HIV RNA level was less than 400 copies per milliliter at week 48 of the study. RESULTS: Through week 48, significantly more patients in the tenofovir-emtricitabine group reached and maintained the primary end point of less than 400 copies of HIV RNA per milliliter than did those in the zidovudine-lamivudine group (84 percent vs. 73 percent, respectively; 95 percent confidence interval for the difference, 4 to 19 percent; P=0.002). This difference excludes the inferiority of the tenofovir DF, emtricitabine, and efavirenz regimen, indicating a significantly greater response with this regimen. Significant differences were also seen in the proportion of patients with HIV RNA levels of less than 50 copies per milliliter (80 percent in the tenofovir-emtricitabine group vs. 70 percent in the zidovudine-lamivudine group; 95 percent confidence interval for the difference, 2 to 17 percent; P=0.02) and in increases in CD4 cell counts (190 vs. 158 cells per cubic millimeter, respectively; 95 percent confidence interval for the difference, 9 to 55; P=0.002). More patients in the zidovudine-lamivudine group than in the tenofovir-emtricitabine group had adverse events resulting in discontinuation of the study drugs (9 percent vs. 4 percent, respectively; P=0.02). In none of the patients did the K65R mutation develop. CONCLUSIONS: Through week 48, the combination of tenofovir DF and emtricitabine plus efavirenz fulfilled the criteria for noninferiority to a fixed dose of zidovudine and lamivudine plus efavirenz and proved superior in terms of virologic suppression, CD4 response, and adverse events resulting in discontinuation of the study drugs. (ClinicalTrials.gov number, NCT00112047.)

Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial.

CONTEXT: Tenofovir disoproxil fumarate (DF) is a once-daily nucleotide analogue reverse transcriptase inhibitor. OBJECTIVE: To evaluate the efficacy and safety of tenofovir DF compared with stavudine in antiretroviral-naive patients. DESIGN, SETTING, AND PARTICIPANTS: A prospective, randomized, double-blind study conducted at 81 centers in the United States, South America, and Europe from June 9, 2000, to January 30, 2004. A total of 753 patients infected with HIV who were antiretroviral naive were screened and 602 patients entered the study. INTERVENTION: Patients were randomized to receive either tenofovir DF (n = 299) or stavudine (n = 303), with placebo, in combination with lamivudine and efavirenz. MAIN OUTCOME MEASURE: Proportion of patients with HIV RNA levels of less than 400 copies/mL at week 48. RESULTS: In the primary intent-to-treat analysis in which patients with missing data or who added or switched antiretroviral medications before week 48 were considered as failures, the proportion of patients with HIV RNA of less than 400 copies/mL at week 48 was 239 (80%) of 299 in patients receiving tenofovir DF and 253 (84%) of 301 in patients receiving stavudine (95% confidence interval, -10.4% to 1.5%), exceeding the predefined -10% limit for equivalence. However, equivalence was demonstrated in the secondary analyses (HIV RNA <50 copies/mL) at week 48 and through 144 weeks. Virologic failure was associated most frequently with efavirenz and lamivudine resistance. Through 144 weeks, the K65R mutation emerged in 8 and 2 patients in the tenofovir DF and stavudine groups, respectively (P =.06). A more favorable mean change from baseline in fasting lipid profile was noted in the tenofovir DF group at week 144: for triglyceride levels (+1 mg/dL for tenofovir DF [n = 170] vs +134 mg/dL for stavudine [n = 162], P<.001), total cholesterol (+30 mg/dL [n = 170] vs +58 mg/dL [n = 162], P<.001), direct low-density lipoprotein cholesterol (+14 mg/dL [n = 169] vs +26 mg/dL [n = 161], P<.001), and high-density lipoprotein cholesterol (+9 mg/dL [n = 168] vs +6 mg/dL [n = 154], P =.003). Investigator-reported lipodystrophy was less common in the tenofovir DF group compared with the stavudine group (9 [3%] of 299 vs 58 [19%] of 301, P<.001). The number of bone fractures and the renal safety profile were similar between the 2 groups. CONCLUSIONS: Through 144 weeks, the combination of tenofovir DF, lamivudine, and efavirenz was highly effective and comparable with stavudine, lamivudine, and efavirenz in antiretroviral-naive patients. However, tenofovir DF appeared to be associated with better lipid profiles and less lipodystrophy.

Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial.

BACKGROUND: Resistance to antiretroviral agents remains a leading cause of treatment failure for patients infected with HIV-1. OBJECTIVE: To describe the efficacy and safety of tenofovir disoproxil fumarate (tenofovir DF) compared with placebo in patients with detectable viral replication despite current antiretroviral therapy. DESIGN: Randomized, double-blind, placebo-controlled study through 24 weeks. After 24 weeks, all patients received open-label tenofovir DF for the remainder of the 48-week study. SETTING: 75 North American, European, and Australian HIV clinics. PATIENTS: 552 HIV-1-infected adults who were receiving antiretroviral therapy and had stable HIV-1 RNA levels ranging from 400 to 10,000 copies/mL. MEASUREMENTS: Change in HIV-1 RNA level (time-weighted average from baseline through week 24); proportion of patients with grade 3 or 4 laboratory abnormalities and adverse events; and genotypic HIV-1 resistance testing in a separate substudy at baseline, week 24, and week 48. RESULTS: A statistically significant decrease in HIV-1 RNA level through week 24 (the primary end point) was observed in the tenofovir DF group versus the placebo group (-0.61 log10 copies/mL vs. -0.03 log10 copies/mL, respectively [P < 0.001]; difference, -0.58 log10 copies/mL [95% CI, -0.68 to -0.49 log10 copies/mL]). In a virologic substudy, 94% of 253 patients had plasma isolates expressing reverse transcriptase mutations associated with nucleoside resistance mutations at baseline. Through week 24, the incidence of clinical adverse events was similar between patients receiving placebo and those receiving tenofovir DF (14% vs. 13%). No evidence of tenofovir DF-related toxicity was seen through week 48. CONCLUSION: In treatment-experienced patients with suboptimal viral suppression, tenofovir DF significantly reduced HIV-1 RNA level and had a safety profile similar to that of placebo.

Traumatic aortic transection: evidence for the osseous pinch mechanism.

Acute traumatic transection of the thoracic aorta is most commonly seen in vehicular trauma and is generally accepted to be due to differential deceleration. A second mechanism is proposed for this injury and that is the osseous pinch mechanism. We report a case where aortic transection occurred due to a crush injury and supports the latter mechanism.