JAIDS Journal of Acquired Immune Deficiency Syndromes:
Comparison of Once-Daily Atazanavir With Efavirenz, Each in Combination With Fixed-Dose Zidovudine and Lamivudine, As Initial Therapy for Patients Infected With HIV
Squires, Kathleen MD*; Lazzarin, Adriano MD†; Gatell, José M. MD, PhD‡; Powderly, William G. MD§; Pokrovskiy, Vadim MD, PhD||; Delfraissy, Jean-François MD¶; Jemsek, Joseph MD#; Rivero, Antonio MD**; Rozenbaum, Willy MD††; Schrader, Shannon MD‡‡; Sension, Michael MD§§; Vibhagool, Asda MD||||; Thiry, Alexandra PhD¶¶; Giordano, Michael MD¶¶
From the *Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA; †Vita Salute University San Raffaele, Milan, Italy; ‡Infectious Diseases and AIDS Units, Clinical Institute of Infectious Diseases and Immunology, Barcelona, Spain; §Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO; ||Federal AIDS Center, Moscow, Russia; ¶Service de Médecine Interne, Hôpital de Bicêtre, Paris, France; #Jemsek Clinic, Huntersville, NC; **Sección de Enfermedades Infecciosas, Hospital Universitario Reina Sofía, Córdoba, Spain; ††Service des Maladies Infectieuses et Tropicales, Hôpital Tenon, Paris, France; ‡‡Southampton Medical Group, Houston, TX; §§HIV Comprehensive Care Center, North Broward Hospital District, Ft. Lauderdale, FL; ||||Department of Medicine, Ramathibodi Hospital, Bangkok, Thailand; and ¶¶Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Wallingford, CT.
Received for publication August 4, 2003; accepted April 12, 2004.
Funded by Bristol-Myers Squibb.
Reprints: Michael Giordano, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492 (e-mail: Michael.Giordano@bms.com).
Background: Atazanavir, an azapeptide protease inhibitor (PI), has pharmacokinetics that allow once-daily dosing, and it is not associated with significant PI-associated dyslipidemia.
Methods: A randomized, double-blind, double-dummy, active-controlled, 2-arm study comparing the antiviral efficacy and safety of atazanavir 400 mg administered once daily with efavirenz 600 mg administered once daily in combination with open-label fixed-dose zidovudine plus lamivudine twice daily. The 810 treatment-naive patients were stratified by HIV RNA level. The primary efficacy end point was the proportion of treated patients with HIV RNA levels <400 copies/mL through week 48.
Results: At week 48, HIV RNA levels were <400 copies/mL in 70% of patients receiving atazanavir and 64% of patients receiving efavirenz (intent-to-treat, difference; 95% confidence interval: 5.2%; −1.2%, 11.7%). Median CD4+ cell counts increased at comparable magnitudes and rates in the 2 treatment arms (mean change at week 48: 176 cells/mm3 with atazanavir, 160 cells/mm3 with efavirenz). Atazanavir-treated patients relative to comparator-treated patients did not demonstrate significant increases in total cholesterol, fasting low-density lipoprotein cholesterol, or fasting triglycerides over 48 weeks of therapy. Atazanavir-linked bilirubin elevations infrequently resulted in treatment discontinuation (<1%). Atazanavir treatment did not increase fasting glucose or insulin levels.
Conclusions: For initial HIV treatment, a highly active antiretroviral therapy regimen of atazanavir/zidovudine/lamivudine is as efficacious and well tolerated as the combination of efavirenz/zidovudine/lamivudine.
Combination antiretroviral therapy has transformed the treatment of patients infected with HIV. Incorporation of protease inhibitors (PIs) into highly active antiretroviral therapy (HAART) has been specifically accompanied by a significant improvement in overall patient outcomes. 1 The combination of high pill burden, complex food and fluid requirements, poor drug tolerability, drug toxicities, and pharmacokinetic issues complicates treatment, however, and may lead to virologic treatment failure. 2,3 Adherence to therapy is also a critical issue because of its close association with virologic response. 2,4 In the case of PIs, decreased adherence has been related to high pill burden and significant side effects. 3,5,6 Consequently, the use of an antiretroviral regimen incorporating the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz has become a preferred initial therapy. 7 Efavirenz is an effective once-daily NNRTI with a low pill burden that may produce a less deleterious effect on lipid profiles than do current PIs. 8,9
Because of their effectiveness and demonstrated clinical benefit as components of HAART, PIs continue to be developed with an aim toward designing agents with a low pill burden, more convenient dosing, better tolerability, and less toxicity. Atazanavir is an azapeptide PI with a pharmacokinetic profile that supports once-daily dosing with 2 pills per day. 10 Phase 2 studies show that atazanavir produces rapid and durable suppression of HIV RNA and a durable increase in CD4+ cell count in treatment-naive and -experienced HIV-infected patients. 11–13 Treatment with atazanavir also results in significantly less hyperlipidemia and hypertriglyceridemia than with comparator PIs as seen in phase 2 studies. 11,13,14 Furthermore, in vitro studies suggest that atazanavir is not associated with insulin resistance, 15 another metabolic abnormality common to treatment with current PIs.
This report describes the results of a phase 3, randomized, double-blind, controlled trial comparing the antiviral efficacy and safety of atazanavir with efavirenz, each as part of a 3-drug antiretroviral regimen in combination with fixed-dose zidovudine plus lamivudine, in treatment-naive patients.
Patients were recruited from 91 centers in North America, South America, Europe, Asia, and South Africa. Patients were required to be ≥16 years old and to have plasma HIV RNA levels ≥2000 copies/mL and CD4+ cell counts ≥100 cells/mm3 (or ≥75 cells/mm3 if the patient had no prior history of any AIDS-defining illness). The presence of a suspected primary (acute) HIV infection, a newly diagnosed HIV-related opportunistic infection, or any medical condition requiring acute therapy at the time of enrollment disqualified patients from participation. No antiretroviral therapy was permitted during the 30 days before screening. Patients were excluded if they had been treated for >30 days with a nucleoside reverse transcriptase inhibitor (NRTI) and/or >7 days with an NNRTI or a PI. Patients who were pregnant or breast-feeding were also not eligible. Laboratory abnormalities leading to exclusion included alanine aminotransferase or aspartate amino-transferase levels ≥3 times the upper limit of normal or total serum bilirubin levels ≥1.5 times the upper limit of normal. All patients provided written informed consent.
Study Design and Outcomes
The trial was designed as a randomized, double-blind, double-dummy, active-controlled, 2-arm comparative study. The primary efficacy outcome was the proportion of treated patients with HIV RNA levels <400 copies/mL through 48 weeks of therapy (intent-to-treat analysis). Secondary comparative efficacy outcomes included the proportion of treated patients with HIV RNA levels <50 copies/mL through week 48, the proportion of patients completing 48 weeks of treatment with HIV RNA levels <400 copies/mL and <50 copies/mL at week 48 (astreated analysis), and changes in plasma log10 HIV RNA values and CD4+ cell counts from baseline through week 48. Treatment response was defined as 2 or more sequential HIV RNA measurements below the limit of quantification (LOQ), either <400 copies/mL or <50 copies/mL. Patients were considered to have had treatment failure if they had 2 sequential HIV RNA measurements above the specified LOQ. Patients were also considered to have treatment failure if they discontinued treatment for any reason, required any substitution or dose modification in nucleoside therapy, or had missing data. Treatment failure did not include patients with a newly diagnosed Centers for Disease Control and Prevention Class C AIDS event. Safety and tolerability assessments included the frequency and severity of adverse events, incidence of laboratory abnormalities, and changes from baseline at week 48 in metabolic parameters (glucose, insulin, and serum lipid concentrations).
Randomization of patients to the treatment regimens (1:1 ratio) was performed centrally and stratified by qualifying plasma HIV RNA level (<30,000 or ≥30,000 copies/mL) and investigative site using the method of Pocock and Simon. 16 Patients randomized to atazanavir received atazanavir, 400 mg, once daily as well as efavirenz placebo and fixed-dose zidovudine plus lamivudine (Combivir; GlaxoSmithKline, Research Triangle Park, NC); patients randomized to efavirenz received efavirenz (Sustiva; Bristol-Myers Squibb, New York, NY), 600 mg, once daily as well as atazanavir placebo and fixed-dose zidovudine plus lamivudine. Atazanavir and efavirenz treatments were blinded. Zidovudine plus lamivudine was administered open label as one 300- or 150-mg fixed-dose combination tablet twice daily.
Assessment and Monitoring
Patients enrolled in the study were evaluated at baseline; weeks 2, 4, 8, 12, and 16; and every 8 weeks thereafter through week 48. Interim history was obtained, targeted physical examinations were performed, and adverse events were recorded at all visits. Hematology and serum chemistry were assessed at all visits. Plasma HIV RNA levels, CD4+ cell counts, and fasting metabolic parameters were assessed at all scheduled visits except at week 2.
Samples for the HIV RNA measurements were collected using uniform techniques for all study sites. Whole blood was collected in PPT tubes (Vacutainer® Brand PPT Plasma Preparation Tube; Becton Dickinson, Franklin Lakes, NJ), frozen in situ at −70°C after centrifugation at 1100 g for 10 minutes, and sent to a central laboratory for further processing. HIV RNA levels were measured at screening and at baseline using the Roche AMPLICOR HIV-1 MONITOR™ (Roche Diagnostics, Basel, Switzerland) standard assay, version 1.0 or 1.5 (accuracy range: 400–750,000 copies/mL). HIV RNA levels were measured during the treatment phase using the Roche AMPLI-COR HIV-1 MONITOR ultrasensitive assay, version 1.0 or 1.5 (accuracy range: 50–75,000 copies/mL). Version 1.0 of the assays was used in North and South America, whereas version 1.5 was used in Europe, Asia, and Africa because of its enhanced ability to detect non-B HIV-1 clades more common to those regions.
Efficacy and safety analyses included all treated patients. A sample size of 750 patients was chosen to provide at least 90% power to demonstrate similar (noninferior) efficacy between the 2 regimens for the primary analysis comparing the proportion of treated subjects with HIV RNA levels <400 copies/mL through week 48. The sample size was based on an intent-to-treat analysis in which patients who dropped out or were lost to follow-up were counted as having failed treatment. Although all randomized patients did not remain on study at week 48, they were all included in the analysis so that the sample size was unaffected by patient dropout or loss to follow-up. Proportions were computed within the qualifying HIV RNA strata and were combined using a weighted average with weights proportional to the size of each stratum. The difference in proportions and 95% confidence interval were computed using a normal approximation. For the primary analysis, the treatment regimens were determined to be similar if the lower 95% confidence limit for the difference (atazanavir-efavirenz) in proportions exceeded −10%. The comparison of treatment regimens with respect to changes from baseline through week 48 in HIV RNA levels and CD4+ cell counts used time-averaged differences (TADs) and 95% confidence intervals for observed measurements. Week 48 mean percent changes from baseline and standard errors for lipid parameters (total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, and triglycerides) were computed on the log scale and then back-transformed.
Exploratory Analyses and Assessments
Additional analyses were performed to explore unexpected discrepancies when analyzing the <400 and <50 copies/mL viral load end points for the 2 treatment regimens. To further explore the sensitivity of the LOQ of 400 copies/mL, the proportion of patients with HIV RNA levels <200 copies/mL at week 48 was also computed for each treatment group. Additional analyses were performed to explore the distribution of HIV RNA levels between 50 and 400 copies/mL in patients achieving HIV RNA levels <400 copies/mL at week 48.
In addition, a laboratory assessment was conducted to examine the effects of plasma collection procedures on observed virologic response rates. Paired plasma specimens were collected in ethylenediaminetetraacetic acid (EDTA) and PPT tubes at week 52 and were quantitated for HIV RNA using the Roche AMPLICOR HIV-1 MONITOR ultrasensitive assay, version 1.0 or 1.5. Whole blood collected in EDTA-containing tubes (no heparin) was centrifuged in a swing-out bucket rotor at 800 g to 1600 g for 20 minutes within 6 hours of collection, and the plasma recovered was stored in secondary tubes. Whole blood was collected in PPT tubes that contained a gel barrier to assist in plasma separation and was centrifuged in a swing-out bucket rotor at 1100 g for 10 minutes within 2 hours of collection; the plasma recovered was stored in situ. Plasma-containing tubes were frozen on site and shipped on dry ice to the central laboratories. The samples remained at −70°C for 3 to 6 months before HIV RNA level assessments in April 2003. HIV RNA levels were assessed for all available samples for the week 52 visit. The proportions of samples with HIV RNA levels <400 and <50 copies/mL were evaluated (as-treated analysis).
Of the 1046 patients enrolled, 810 (77%) were randomized between February 15 and June 21, 2001. A total of 805 (99% of randomized patients) began therapy (atazanavir [N = 404], efavirenz [N = 401]). Of the patients included in the protocol, 144 (18%) discontinued treatment before the week 48 visit (Table 1). More patients on the efavirenz regimen than on the atazanavir regimen discontinued treatment during this time (20% vs. 16%), consistent with a slightly longer mean time on therapy in the atazanavir group compared with the efavirenz group (47 weeks vs. 44 weeks). The higher rates of discontinuation in the efavirenz arm were contributed to by slightly higher incidences of adverse events and patient withdrawal.
Baseline characteristics of the treated patients were evenly distributed across the treatment regimens (Table 2). Overall, 35% of the study population was female and 67% was nonwhite. Geographic representation included South America (34%), Europe (28%), Asia (16%), North America (14%), and Africa (9%). The median viral load was 4.88 log10 copies/mL, and the median CD4+ cell count was 282 cells/mm3.
In the primary analysis, 70% of the patients treated with atazanavir (281 of 404 patients) had HIV RNA levels <400 copies/mL at week 48 compared with 64% of patients treated with efavirenz (258 of 401 patients) (Fig. 1). The atazanavir-efavirenz difference estimate (95% confidence interval) was 5.2 (−1.2, 11.7), indicating similarity between the treatment regimens. The proportions of treated patients with HIV RNA levels <50 copies/mL through week 48 were 32% (131 of 404 patients) for the atazanavir group and 37% (150 of 401 patients) for the efavirenz group (see Fig. 1). Of patients completing 48 weeks of treatment (as-treated analysis), 81% and 84% of those receiving atazanavir and efavirenz, respectively, had HIV RNA levels <400 copies/mL at week 48; the proportions with HIV RNA <50 copies/mL were 44% and 51%, respectively. By week 12, atazanavir and efavirenz regimens had produced mean reductions in HIV RNA levels of 2.5 and 2.6 log10 copies/mL, respectively. The reductions reached 2.7 log10 copies/mL for both treatment regimens by week 24 and were maintained at that level through week 48.
Further evaluation of virologic response revealed that among patients with HIV RNA levels <400 copies/mL at week 48, most had HIV RNA levels <200 copies/mL. In the intent-to-treat analysis, week 48 response rates for the LOQ of 200 copies/mL were 62% (251 of 404 patients) in the atazanavir treatment group and 58% (234 of 401 patients) in the efavirenz treatment group. In the as-treated analysis, response rates were 70% in the atazanavir treatment group and 75% in the efavirenz treatment group. Evaluation of the number of patients whose HIV RNA level fell within specific viral load ranges <400 copies/mL showed that HIV RNA levels tended to concentrate near 50 copies/mL. Of the patients with HIV RNA between 50 and <400 copies/mL, 71% of patients in each treatment group had HIV RNA <200 copies/mL and 33% had HIV RNA <100 copies/mL (data not shown; as-treated analysis).
Analysis of paired specimens at week 52 confirmed the comparability in antiretroviral efficacy between atazanavir and efavirenz. Plasma collected in PPT tubes consistently yielded higher HIV RNA readings than plasma collected in EDTA tubes in both treatment groups, however. A total of 584 patients (300 administered atazanavir and 284 administered efavirenz) were evaluable in this analysis. HIV RNA levels (log10 copies/mL) at week 52 for this patient population are shown in Figure 2. PPT tubes consistently yielded higher HIV RNA levels than EDTA tubes between 50 and 400 copies/mL. In the overall assessment of HIV RNA by tube type, 95% of EDTA tube specimens compared with 84% of PPT tube specimens were below the LOQ of 400 copies/mL. Eighty-nine percent of EDTA tube specimens compared with 55% of PPT tube specimens were below the LOQ of 50 copies/mL. The degree of difference between tube types in the number of specimens calculated to contain HIV RNA levels less than a given LOQ was comparable for the atazanavir and efavirenz treatment arms (Table 3).
The regimens were comparable with respect to the magnitude and rate of CD4+ cell count increase (Fig. 3), which reached median levels of 455 and 446 cells/mm3 for the atazanavir and efavirenz treatment groups, respectively, at week 48. Although the TAD between the regimens in the change in CD4+ cell count was statistically significant (P < 0.001), favoring atazanavir, the magnitude of the difference (16 cells/mm3) did not reach the predefined criterion for similarity that would indicate clinical significance (50 cells/mm3).
The overall incidence of adverse events as well as the incidence of grade 3 to 4 adverse events was comparable between the treatment regimens. The incidence of grade 2 to 4 adverse events that were possibly, probably, likely, or certainly related to the study regimen was also comparable between the treatment arms (Table 4). The most common treatment-related grade 2 to 4 adverse event was nausea, which occurred with comparable frequency in both study arms. Rash and dizziness, characteristic of efavirenz therapy, were significantly more frequent in the efavirenz arm (P < 0.05), whereas jaundice and scleral icterus, mainly associated with atazanavir therapy, were significantly more common in the atazanavir arm (P < 0.05). One patient in the efavirenz/zidovudine/lamivudine arm experienced lactic acidosis syndrome. Serious adverse events were infrequent (10% for both regimens). Four patients (<1%) in each treatment group experienced a newly diagnosed Centers for Disease Control and Prevention Class C AIDS event during the study. Five deaths, all unrelated to study therapy, were reported during the trial; 3 of the deaths occurred after the discontinuation of study therapy. Two of the 5 deaths occurred in atazanavir-treated patients (tuberculous meningoencephalitis and central nervous system lymphoma), and 3 of the 5 deaths occurred in efavirenz-treated patients (tuberculosis, bronchial carcinoma/pneumonia, and gun shot wound).
Grade 3 to 4 laboratory abnormalities are also shown in Table 3. Grade 3 to 4 elevations in total bilirubin concentration, which were mainly indirect (unconjugated), occurred more frequently in the atazanavir treatment group than in the efavirenz treatment group (33% vs. <1%; P < 0.0001). The incidence of grade 3 to 4 total bilirubin elevations was comparable between hepatitis-negative and hepatitis-positive atazanavir-treated patients (as assessed by the absence or presence of hepatitis B virus [HBV] antigen or hepatitis C virus [HCV] antibody, data not shown). Grade 4 elevations in total bilirubin were reported in 25 of the 404 atazanavir-treated patients, of whom 20 underwent dose reduction. After dose reduction, 3 patients had a subsequent worst on-study bilirubin level of grade 1 to 2, 12 patients had a grade 3 elevation, and 5 had a recurrence of grade 4. Of the patients with recurrent grade 4 elevations, 2 (<1%) discontinued atazanavir therapy and 3 (<1%) continued atazanavir therapy at a lower dose. The atazanavir dose was also reduced in a single patient with jaundice but no grade 4 bilirubin elevation. Grade 3 to 4 elevations in aminotransferases were infrequent in both treatment groups, occurring in ≤4% of patients (see Table 4) and suggesting no direct correlation between elevated transaminases and total bilirubin in the atazanavir treatment group.
Lipid concentrations are presented at baseline and week 48 in Figure 4. Atazanavir treatment was associated with a more favorable lipid profile than was efavirenz treatment, as assessed by significant differences in the mean percent changes from baseline in total cholesterol, fasting LDL cholesterol, and fasting triglycerides at week 48 (P < 0.0001). Mean increases in these lipid parameters were 18% to 23% in the efavirenz arm, although no significant increases in total or fasting LDL cholesterol and a decrease of 9% in triglycerides were observed in the atazanavir arm. Mean HDL cholesterol levels were >40 mg/dL at week 48 on both regimens, but significantly greater mean percent increases in HDL cholesterol levels were observed in the efavirenz arm (P < 0.0001). At week 48, mean total cholesterol levels in both treatment arms remained within the desirable range (<200 mg/dL) and mean LDL cholesterol levels remained within the optimal or near-optimal range (<130 mg/dL) as defined by the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP III). 17
Glucose and insulin levels were measured at baseline and week 48. Mean fasting glucose levels at week 48 were comparable to those at baseline for both the atazanavir and efavirenz regimens. In the atazanavir treatment group, mean fasting glucose levels were 90 mg/dL at baseline and 93 mg/dL at week 48; in the efavirenz treatment group, they were 90 mg/dL at baseline and 94 mg/dL at week 48. Through week 48, mean fasting insulin levels increased (but not significantly) in patients in the atazanavir arm (11.3 μU/mL at baseline vs. 12.3 μU/mL at week 48). Among the efavirenz-treated patients, a significant (but not clinically relevant) mean increase of 1.4 μU/mL in fasting insulin was observed (9.9 μU/mL at baseline vs. 11.5 μU/mL at week 48; P = 0.04).
The development and incorporation of PIs into combination treatment regimens has been one of the most important advances in the management of HIV infection. Treatment with these drugs can significantly decrease HIV-related morbidity and mortality. 1,18,19 Although all approved PIs show substantial antiretroviral activity in vitro, rapid metabolism, predominantly by hepatic mechanisms, often necessitates frequent dosing to maintain plasma levels high enough to effectively suppress HIV viral replication. When exposure is inadequate, a second reduced-dose PI booster may be used to inhibit cytochrome P450-related metabolism. 20–22 Thus, although the incorporation of PIs into HAART regimens can substantially reduce plasma viral loads, increase CD4+ cell counts, slow HIV disease progression, and prolong life, in clinical practice, their success may be limited by pharmacokinetic issues as well as by those related to adherence and safety.
The pharmacokinetic profile of atazanavir, a potent azapeptide PI, allows for once-daily dosing without boosting as well as fewer pills, potentially leading to greater adherence. In the present study, atazanavir and efavirenz showed comparable efficacy when combined with fixed-dose zidovudine and lamivudine in treatment-naive patients over 48 weeks of therapy. Although the percentage of efavirenz-treated patients in this study achieving HIV RNA levels <400 copies/mL was consistent with that seen in another efavirenz study, the percentage of patients who reached levels <50 copies/mL in the present study was lower. 23 In the study reported here, 64% and 37% of the efavirenz-treated patients achieved these respective HIV RNA levels, whereas in the other study (a large randomized trial comprising 1266 patients), the respective response rates at 48 weeks among the 422 patients treated with the same doses of efavirenz, zidovudine, and lamivudine were 68% and 62%. Nevertheless, exploratory analyses revealed that at week 48, most patients who were classified as responders at the LOQ of 400 copies/mL but as failures at the LOQ of 50 copies/mL actually tended to have viral loads closer to 50 copies/mL than 400 copies/mL.
The apparent disparity between the efavirenz treatment regimen results at the LOQ of 50 copies/mL in this trial and other trials is of particular interest. Cross-trial comparisons of efficacy, in general, may not be valid for a number of reasons, including differences between patient baseline characteristics, trial procedures, and analysis techniques. 24 Importantly, PPT tubes were used throughout this randomized study to collect whole blood for the primary assessments of virologic efficacy using validated methodologies. A cross-sectional assessment at a single time point (week 52) conducted on all available samples identified large differences in HIV RNA levels measured in EDTA and PPT tubes influencing observed response rates, particularly at the LOQ of 50 copies/mL. The magnitude of these tube-dependent differences was comparable between treatment regimens. Higher HIV RNA values have been observed previously when using PPT tubes compared with EDTA tubes 25; however, the magnitude of the difference at 50 copies/mL has not been described in as large a sample as represented in this study. Potential explanations, such as whether virus associated with cell debris is more readily detectable in a PPT tube, require further exploration. The discrepancy in HIV RNA levels measured in EDTA and PPT tubes underscores the hazards of making cross-study comparisons but supports the integrity of the trial and the comparability in efficacy for atazanavir and efavirenz.
The overall safety profile of atazanavir was found to be comparable to that of efavirenz. The incidence of adverse events and the patterns of their occurrence were consistent with the known adverse effect profiles of atazanavir, efavirenz, and zidovudine plus lamivudine. Potentially serious adverse events were infrequent and were evenly distributed between patients in both treatment arms. Elevated total bilirubin levels were associated with atazanavir treatment; however, they were predominantly of the indirect (unconjugated) type and reversible, and they seemed to be clinically benign and unrelated to hepatic damage. Dose reductions, although not a recommended strategy for managing bilirubin levels, and bilirubin-related discontinuations were infrequent (5% and <1%, respectively). Grade 3 to 4 elevations in total bilirubin were not associated with grade 3 to 4 increases in hepatic transaminases.
Treatment with many PIs has been associated with increases in total cholesterol, LDL cholesterol, and triglycerides. These increases are sometimes large. Dyslipidemia of the magnitude observed with other PIs has the potential to worsen cardiovascular risk and frequently leads to a recommendation to use lipid-lowering therapy. Recent epidemiologic data suggest that HIV-infected patients may represent a rapidly emerging population at risk for cardiovascular disease. 26 In addition, treatment with PIs has been associated with lipodystrophy syndrome, which includes body shape changes, fat redistribution, and other metabolic abnormalities such as glucose intolerance. 27,28
In this study, confirming the observations made in previous studies, 11,13 treatment with atazanavir combined with fixed-dose zidovudine and lamivudine did not result in significant increases in total cholesterol, fasting LDL cholesterol, and fasting triglycerides through 48 weeks of therapy. The proportions of patients with fasting LDL cholesterol levels ≥160 mg/dL, which is the threshold level recommended by NCEP ATP III guidelines for lipid-lowering therapy and/or dietary intervention in the absence of underlying cardiovascular risk factors, 17 were 2% and 4% at baseline and 3% and 8% at week 48 for the atazanavir and efavirenz treatment groups, respectively. It is also noteworthy that the NCEP ATP III identifies HDL cholesterol levels <40 mg/dL as a strong independent predictor of coronary heart disease risk and that both atazanavir and efavirenz had beneficial effects on HDL cholesterol, increasing the levels to >40 mg/dL.
Treatment with atazanavir or efavirenz was also not associated with increases in plasma glucose or insulin levels, alterations that have been linked to lipodystrophy. 29 In vitro studies show that atazanavir does not inhibit glucose transport, suppress adipocyte differentiation, or interfere with lipid metabolism, as do other PIs. These in vitro studies provide a potential explanation for the drug’s favorable metabolic profile. 15
Atazanavir is comparable in efficacy and safety to efavirenz in the initial treatment of HIV infection. The 2 drugs are each administered once daily and have a low pill burden. Unlike other PIs, atazanavir does not produce clinically significant increases in total cholesterol, fasting LDL cholesterol, fasting triglycerides, insulin, or glucose, thus potentially reducing the use of lipid-lowering agents and the risk for future cardiovascular disease events that may be associated with treatment in HIV-infected patients. The results of this study demonstrate that atazanavir and efavirenz are agents that, in combination with nucleoside analogues, provide convenient and potent treatment regimens for initial HIV therapy.
1. Palella FJ, Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998;338:853–860.
2. Bartlett JA. Addressing the challenges of adherence. J Acquir Immune Defic Syndr. 2002;29(Suppl 1):S2–S10.
3. Bartlett J, DeMasi R, Quinn J, et al. Correlation between antiretroviral pill burden and durability of virologic response: a systematic overview [abstract ThPeB4998]. Presented at the XIII International AIDS Conference; Durban, South Africa; July 2000. In: Abstracts-On-Disk™ [CD-ROM]. Whitehouse, NJ: Merck Sharp & Dohme 2000.
4. Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133:21–30.
5. Bartlett JA, DeMasi R, Quinn J, et al. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults. AIDS. 2001;15:1369–1377.
6. Duran S, Savès M, Spire B, et al. Failure to maintain long-term adherence to highly active antiretroviral therapy: the role of lipodystrophy. AIDS. 2001;15:2441–2444.
7. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents [updated November 2003]. Available at: http://aidsinfo.nih.gov/guidelines/adult/AA111003.pdf
. Accessed November 14, 2003.
8. Hartmann M, Rump A, Brust J, et al. Evaluation of an efavirenz-containing regimen: an open-label, multicenter study. HIV Clin Trials. 2001;2:421–428.
9. 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. N Engl J Med. 1999;341:1865–1873.
10. O’Mara E, Mummaneni V, Randall D, et al. BMS-232632: a summary of multiple dose pharmacokinetic, food effect and drug interaction studies in healthy subjects [abstract 504]. Presented at the 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, January/February 2000. Available at: http://www.retroconference.org/2000/abstracts/504.htm
. Accessed July 28, 2003.
11. Sanne I, Piliero P, Squires K, et al. Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr. 2003;32:18–29.
12. Pantaleo G, Sanne I, Cahn P, et al. Atazanavir (BMS-232632): 48-week safety and efficacy vs nelfinavir, each in combination with stavudine and lamivudine, in treatment-naive, HIV-positive subjects (AI424-008) [abstract 011]. Presented at the 8th European Conference on Clinical Aspects and Treatment of HIV Infection; Athens, October 2001.
13. Haas DW, Zala C, Schrader S, et al. Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial. AIDS. 2003;17:1339–1349.
14. Cahn P, Pantaleo G, Gatell J, et al. Atazanavir: a once-daily protease inhibitor with a superior lipid profile [abstract]. Presented at the XIVth World Congress of Cardiology; Sydney, May 2002.
15. Parker RA, Wang S, Meyers D, et al. Differentiation of HIV protease inhibitors in models of lipid and glucose metabolism and gene expression in adipocytes and hepatocytes [abstract 100]. Antivir Ther. 2001;6(Suppl 4):67.
16. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975;31:103–115.
17. Expert Panel on Detection. Evaluation, and treatment of high blood cholesterol in adults. Executive summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486–2497.
18. Murphy EL, Collier AC, Kalish LA, et al. Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease. Ann Intern Med. 2001;135:17–26.
19. Gortmaker SL, Hughes M, Cervia J, et al. Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1. N Engl J Med. 2001;345:1522–1528.
20. Barry M, Gibbons S, Back D, et al. Protease inhibitors in patients with HIV disease. Clinically important pharmacokinetic considerations. Clin Pharmacokinet. 1997;32:194–209.
21. Moyle G. Use of HIV protease inhibitors as pharmacoenhancers. AIDS Reader. 2001;11:87–98.
22. Kempf DJ, Marsh KC, Kumar G, et al. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob Agents Chemother. 1997;41:654–660.
24. Phillips A. Trial and error: cross-trial comparisons of antiretroviral regimens. AIDS. 2003;17:619–623.
25. Mallen MM, Veselenak RL, Oates CW, et al. Comparison of VACUTAINE® brand PPT™ tubes with standard EDTA tubes using the Roche Amplicor HIV-1 monitor™ standard and ultrasensitive procedures [abstract]. Transfusion. 1999;39(Suppl 10):PS71.
26. Krishnaswamy G, Chi DS, Kelley JL, et al. The cardiovascular and metabolic complications of HIV infection. Cardiol Rev. 2000;8:260–268.
27. Henry K, Zackin R, Dube M, et al. ACTG 5056: metabolic status and cardiovascular disease risk for a cohort of HIV-1-infected persons durably suppressed on an indinavir-containing regimen (ATCG 372A) [abstract 656]. Presented at the 8th Conference on Retroviruses and Opportunistic Infections, Chicago, February 2001. Available at: http://retroconference.org/2001/abstracts/abstracts/abstracts/656.htm
. Accessed February 12, 2003.
28. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis. 2001;32:130–139.
29. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998;12(Suppl):F51–F58.
This article has been cited 140 time(s).
AIDS Research and Human RetrovirusesIncidence of Hyperbilirubinemia and Jaundice Due to Atazanavir in a Cohort of Hispanic PatientsAIDS Research and Human Retroviruses
AIDS Research and Human RetrovirusesShort Communication Fasting Increases Serum Concentrations of Bilirubin in Patients Receiving Atazanavir: Results from a Pilot StudyAIDS Research and Human Retroviruses
Scandinavian Journal of Infectious DiseasesLopinavir/ritonavir, atazanavir/ritonavir, and efavirenz in antiretroviral-naive HIV-1-infected individuals over 144 weeks: An open-label randomized controlled trialScandinavian Journal of Infectious Diseases
Bmc MedicineWhen to start antiretroviral therapy: as soon as possibleBmc Medicine
International HealthComparing the effectiveness of efavirenz and nevirapine for first-line antiretroviral therapy in a South African multicentre cohortInternational Health
Plos OneMonitoring HIV Viral Load in Resource Limited Settings: Still a Matter of Debate?Plos One
International Journal of Std & AIDSDifferences in implementation of HIV/AIDS clinical research in developed versus developing world: an evidence-based review on protease inhibitor use among women and minoritiesInternational Journal of Std & AIDS
Plos OneIs Ritonavir-Boosted Atazanavir a Risk for Cholelithiasis Compared to Other Protease Inhibitors?Plos One
Analysis of Neuropsychiatric Adverse Events During Clinical Trials of Efavirenz in Antiretroviral-Naive Patients: A Systematic Review
AIDS Reviews, 12(2):
Annals of PharmacotherapyAtazanavirAnnals of Pharmacotherapy
Antiretroviral (ARV) therapy. Advances and future possibilities
Medicina-Buenos Aires, 65(1):
Atazanavir - A review of its use in the management of HIV infection
Clinical Infectious DiseasesEfficacy and safety of atazanavir-based highly active antiretroviral therapy in patients with virologic suppression switched from a stable, boosted or unboosted protease inhibitor treatment regimen: The SWAN study (AI424-097) 48-week resultsClinical Infectious Diseases
Clinical Drug Investigation
Nucleoside and nucleotide reverse transcriptase inhibitors in children
Clinical Drug Investigation, 27(8):
Journal of Antimicrobial ChemotherapyLiver toxicity of antiretroviral combinations including atazanavir/ritonavir in patients co-infected with HIV and hepatitis viruses: impact of pre-existing liver fibrosisJournal of Antimicrobial Chemotherapy
Hiv Clinical TrialsShort-Term Effect of Ritonavir-Boosted Atazanavir in Hepatitis B and/or C Co-infected, Treatment-Experienced HIV PatientsHiv Clinical Trials
Expert Opinion on Drug Metabolism & ToxicologyEfavirenz in the therapy of HIV infectionExpert Opinion on Drug Metabolism & Toxicology
Infections in Medicine
Current issues in initiation of antiretroviral therapy
Infections in Medicine, 22():
Expert Opinion on PharmacotherapyEfavirenz/emtricitabine/tenofovir disoproxil fumarate fixed-dose combination: first-line therapy for all?Expert Opinion on Pharmacotherapy
Antimicrobial Agents and ChemotherapyPharmacokinetics of antiretroviral regimens containing tenofovir disoproxil fumarate and atazanavir-ritonavir in adolescents and young adults with human immunodeficiency virus infectionAntimicrobial Agents and Chemotherapy
Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial
Antiviral Therapy, 13(2):
Hiv Clinical TrialsUnboosted Atazanavir Plus Co-formulated Lamivudine/Abacavir as a Ritonavir-Sparing Simplification Strategy in Routine Clinical PracticeHiv Clinical Trials
Hiv Clinical TrialsBaseline Lipid Levels Rather Than the Presence of Reported Body Shape Changes Determine the Degree of Improvement in Lipid Levels After Switching to AtazanavirHiv Clinical Trials
Drug Metabolism and DispositionAtazanavir: Effects on P-glycoprotein transport and CYP3A metabolism in vitroDrug Metabolism and Disposition
Molecular PharmacologyEndoplasmic reticulum stress links dyslipidemia to inhibition of proteasome activity and glucose transport by HIV protease inhibitorsMolecular Pharmacology
Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides
Infectious Disease Clinics of North AmericaAntiretroviral management of treatment-naive patientsInfectious Disease Clinics of North America
Journal of Antimicrobial ChemotherapyEffectiveness and safety of didanosine, lamivudine and efavirenz versus zidovudine, lamivudine and efavirenz for the initial treatment of HIV-infected patients from the Spanish VACH cohortJournal of Antimicrobial Chemotherapy
InfectionHyperbilirubinemia during Atazanavir Treatment in 2,404 Patients in the Italian Atazanavir Expanded Access Program and MASTER CohortsInfection
AtherosclerosisNon-nucleoside reverse transcriptase inhibitor efavirenz increases monolayer permeability of human coronary artery endothelial cellsAtherosclerosis
Antimicrobial Agents and ChemotherapyEffect of concomitantly administered rifampin on the pharmacokinetics and safety of atazanavir administered twice dailyAntimicrobial Agents and Chemotherapy
Expert Review of Anti-Infective TherapyPediatric HIV infection: the state of antiretroviral therapyExpert Review of Anti-Infective Therapy
AIDS Research and Human RetrovirusesHepatitis C virus coinfection does not affect CD4 restoration in HIV-infected patients after initiation of antiretroviral therapyAIDS Research and Human Retroviruses
Journal of Antimicrobial ChemotherapyEfavirenz: a decade of clinical experience in the treatment of HIVJournal of Antimicrobial Chemotherapy
Journal of Clinical MicrobiologyOverestimation of Human Immunodeficiency Virus Type 1 Load Caused by the Presence of Cells in Plasma from Plasma Preparation TubesJournal of Clinical Microbiology
Current Hiv Research
Lipid Changes Associated with Antiretroviral Therapy: Results Differ by Reporting Approach
Current Hiv Research, 7(5):
Journal of Clinical MicrobiologyEvaluation of Effect of Specimen-Handling Parameters for Plasma Preparation Tubes on Viral Load Measurements Obtained by Using the Abbott RealTime HIV-1 Load AssayJournal of Clinical Microbiology
Initial regimens for the treatment-naive patient: Current understanding and practice
AIDS Reader, 18(6):
Journal of Clinical MicrobiologyCoamplification of HIV-1 Proviral DNA and Viral RNA in Assays Used for Quantification of HIV-1 RNAJournal of Clinical Microbiology
AIDS Research and Human Retroviruses
Immune reconstitution and predictors of virologic failure in adolescents infected through risk behaviors and initiating HAART: Week 60 results from the PACTG 381 cohort
AIDS Research and Human Retroviruses, 22(3):
Journal of Infectious Diseases
HIV-1 load quantitation: A 17-year perspective
Journal of Infectious Diseases, 194():
Hiv MedicineBritish HIV Association guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy 2008Hiv Medicine
Expert Review of Anti-Infective TherapyAtazanavir: its role in HIV treatmentExpert Review of Anti-Infective Therapy
Clinica Chimica ActaModification of tandem mass spectrometric method to permit simultaneous quantification of 17 anti-HIV drugs which include atazanavir and tipranavirClinica Chimica Acta
AIDS Patient Care and StdsImmunologic response to protease inhibitor-based highly active Antiretroviral therapy: A reviewAIDS Patient Care and Stds
Efficacy and safety of once-daily regimens in the treatment of HIV infection
Clinical Drug Investigation
Current and future antiretroviral treatment options in paediatric HIV infection
Clinical Drug Investigation, 28(6):
International Journal of Infectious DiseasesChronic viral hepatitis may diminish the gains of HIV antiretroviral therapy in sub-Saharan AfricaInternational Journal of Infectious Diseases
Expert Opinion on PharmacotherapyHIV protease inhibitors: recent clinical trials and recommendations on useExpert Opinion on Pharmacotherapy
Clinical Infectious DiseasesSafety, tolerability, and preliminary efficacy of 48 weeks of etravirine therapy in a phase IIb dose-ranging study involving treatment-experienced patients with HIV-1 infectionClinical Infectious Diseases
Hiv MedicineEfficacy and safety of boosted and unboosted atazanavir-containing antiretroviral regimens in real life: results from a multicentre cohort studyHiv Medicine
Hiv Clinical Trials
Atazanavir: The advent of a new generation of more convenient protease inhibitors
Hiv Clinical Trials, 6(1):
Journal of Infectious Diseases
Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia: Genetic screening is unnecessary
Journal of Infectious Diseases, 193():
Journal of Clinical VirologyThe effects of the Roche AMPLICOR HIV 1 MONITOR (R) UltraSensitive Test versions 1.0 and 1.5 viral load assays and plasma collection tube type on determination of response to antiretroviral therapy and the inappropriateness of cross-study comparisonsJournal of Clinical Virology
Journal of VirologyTMC125 displays a high genetic barrier to the development of resistance: Evidence from in vitro selection experimentsJournal of Virology
Initial highly-active antiretroviral therapy with a protease inhibitor versus a non-nucleoside reverse transcriptase inhibitor: discrepancies between direct and indirect meta-analyses
Enfermedades Infecciosas Y Microbiologia Clinica
Lipid alterations and cardiovascular risk associated with antiretroviral therapy
Enfermedades Infecciosas Y Microbiologia Clinica, 24():
AIDS Patient Care and StdsViro-immunologic response to ritonavir-boosted or unboosted atazanavir in a large cohort of multiply treated patients: The CARe studyAIDS Patient Care and Stds
Expert Opinion on Drug Metabolism & ToxicologyEfavirenz - Still first-line king?Expert Opinion on Drug Metabolism & Toxicology
Hiv Clinical TrialsEvaluation of efficacy, safety, pharmacokinetics, and adherence in HIV-1-infected, antiretroviral-naive patients treated with ritonavir-boosted atazanavir plus fixed-dose tenofovir DF/emtricitabine given once dailyHiv Clinical Trials
Janac-Journal of the Association of Nurses in AIDS CareLong-term suppression of HIV infection: Benefits and limitations of current treatment optionsJanac-Journal of the Association of Nurses in AIDS Care
Journal of Infectious DiseasesEffects of nevirapine, compared with lamivudine, on lipids and lipoproteins in HIV-1-uninfected newborns: The stopping infection from mother-to-child via breast-feeding in Africa lipid substudyJournal of Infectious Diseases
Antiviral activity and clinical efficacy of atazanavir in HIV-1-infected patients: a review
New Microbiologica, 30(2):
Drugs of TodayAtazanavir/ritonavir: A review of its use in HIV therapyDrugs of Today
Journal of Managed Care Pharmacy
Provider Prescribing of 4 Antiretroviral Agents After Implementation of Drug Use Guidelines in the Department of Veterans Affairs
Journal of Managed Care Pharmacy, 15(4):
Clinical Infectious Diseases
Antiretroviral therapy: The "when to start" debates
Clinical Infectious Diseases, 39():
Journal of Antimicrobial ChemotherapyFirst-line antiretroviral therapy with efavirenz or lopinavir/ritonavir plus two nucleoside analogues: the SUSKA study, a non-randomized comparison from the VACH cohortJournal of Antimicrobial Chemotherapy
Boosted Protease Inhibitor-Based or Nonnucleoside Reverse Transcriptase-Based HAART: Is There a Best Choice for Antiretroviral-Naive HIV-1 Infected Patients?
AIDS Reviews, 10(4):
AIDS Patient Care and StdsPrevalence and Impact of Body Physical Changes in HIV Patients Treated with Highly Active Antiretroviral Therapy: Results from a Study on Patient and Physician PerceptionsAIDS Patient Care and Stds
Considerations in selecting protease inhibitor therapy
AIDS Reviews, 6(4):
Expert Opinion on PharmacotherapyTreatment of dyslipidaemia in HIV-infected personsExpert Opinion on Pharmacotherapy
AIDS Patient Care and Stds
Appearance-related side effects of HIV-1 treatment
AIDS Patient Care and Stds, 20(1):
Clinical Infectious DiseasesInstantaneous Inhibitory Potential Is Similar to Inhibitory Quotient at Predicting HIV-1 Response to Antiretroviral TherapyClinical Infectious Diseases
Expert Opinion on PharmacotherapyReview of atazanavir: a novel HIV protease inhibitorExpert Opinion on Pharmacotherapy
Clinical Infectious Diseases
HIV-associated lipoatrophy: What are the kinder, gentler agents?
Clinical Infectious Diseases, 42(2):
Sequencing antiretroviral drugs for long-lasting suppression of HIV replication
New Microbiologica, 28(4):
Pathologie BiologieRecent and future therapeutic advances in the management of HIV infectionPathologie Biologie
Medical Journal of Australia
Ten years of highly active antiretroviral therapy for HIV infection
Medical Journal of Australia, 186(3):
Journal of Antimicrobial ChemotherapyLow incidence of severe liver toxicity in patients receiving antiretroviral combinations including atazanavirJournal of Antimicrobial Chemotherapy
Hiv Clinical Trials
Atazanavir plasma concentrations vary significantly between patients and correlate with increased serum bilirubin concentrations
Hiv Clinical Trials, 7(1):
Journal of Microbiological MethodsElevation of viral load by PCR and use of plasma preparation tubes for quantification of human immunodeficiency virus type 1Journal of Microbiological Methods
Hiv Clinical TrialsEfficacy and safety of 48 weeks of enfuvirtide 180 mg once-daily dosing versus 90 mg twice-daily dosing in HIV-infected patientsHiv Clinical Trials
Jaids-Journal of Acquired Immune Deficiency Syndromes
Insulin resistance and diabetes mellitus associated with antiretroviral use in HIV-infected patients: Pathogenesis, prevention, and treatment options
Jaids-Journal of Acquired Immune Deficiency Syndromes, 49():
Journal of Antimicrobial ChemotherapyAdverse cutaneous reactions associated with the newest antiretroviral drugs in patients with human immunodeficiency virus infectionJournal of Antimicrobial Chemotherapy
Journal of Antimicrobial ChemotherapyEfficacy and safety of replacing lopinavir with atazanavir in HIV-infected patients with undetectable plasma viraemia: final results of the SLOAT trialJournal of Antimicrobial Chemotherapy
Journal of Infectious DiseasesMaking sense of blipsJournal of Infectious Diseases
Clinical Infectious DiseasesCD4(+) T cell count recovery in HIV type 1-infected patients is independent of class of antiretroviral therapyClinical Infectious Diseases
Hiv Clinical TrialsEfficacy and Safety of Ritonavir-Boosted and Unboosted Atazanavir Among Antiretroviral-Naive PatientsHiv Clinical Trials
Hiv Clinical TrialsVirologic Response and Safety of the Abacavir/Lamivudine Fixed-Dose Formulation as Part of Highly Active Antiretroviral Therapy: Analyses of Six Clinical StudiesHiv Clinical Trials
AIDS Research and Human RetrovirusesEfficacy and Safety of Unboosted Atazanavir in Combination with Lamivudine and Didanosine in Naive HIV Type 1 Patients in SenegalAIDS Research and Human Retroviruses
Journal of Antimicrobial ChemotherapyLiver toxicity induced by non-nucleoside reverse transcriptase inhibitorsJournal of Antimicrobial Chemotherapy
Expert Opinion on PharmacotherapyAntiretroviral regimens for treatment-experienced patients with HIV-1 infectionExpert Opinion on Pharmacotherapy
Clinical Infectious DiseasesClass of Antiretroviral Therapy and CD4(+) T Cell Count Recovery: Independence QuestionedClinical Infectious Diseases
Atazanavir A Review of its Use in the Management of HIV-1 Infection
Journal of Antimicrobial ChemotherapyOnce-daily antiretroviral therapy: Spanish consensus statementJournal of Antimicrobial Chemotherapy
British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2006)
Hiv Medicine, 7(8):
Janac-Journal of the Association of Nurses in AIDS CareThe nurse practitioner's role in managing dyslipidemia and other cardiovascular risk factors in HIV-infected patients: Impact of antiretroviral therapyJanac-Journal of the Association of Nurses in AIDS Care
Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial)
Antiviral Therapy, 12(3):
New England Journal of Medicine
Initial treatment of HIV-1 infection
New England Journal of Medicine, 359(9):
International Journal of Std & AIDSThe impact of pharmacogenetics on HIV therapyInternational Journal of Std & AIDS
Expert Opinion on Drug Metabolism & ToxicologyClinical pharmacology, efficacy and safety of atazanavir: a reviewExpert Opinion on Drug Metabolism & Toxicology
Antiviral ResearchFifteen years of HIV Protease Inhibitors: raising the barrier to resistanceAntiviral Research
The 48-week efficacy of once-daily saquinavir/ritonavir in patients with undetectable viral load after 3 years of antiretroviral therapy
Hiv Medicine, 6(2):
Current Pharmaceutical Design
Current HIV treatment guidelines - An overview
Current Pharmaceutical Design, 12(9):
Annals of PharmacotherapyClinical outcomes associated with concomitant use of atazanavir and proton pump inhibitorsAnnals of Pharmacotherapy
Expert Opinion on PharmacotherapyEfavirenz: a reviewExpert Opinion on Pharmacotherapy
Use of metabolic drugs and fish oil in HIV-positive patients with metabolic complications and associations with dyslipidaemia and treatment targets
Hiv Medicine, 8(6):
Journal of Clinical VirologyIncreased levels of HIV RNA detected in samples with viral loads close to the detection limit collected in Plasma Preparation Tubes (TM) (PPT)Journal of Clinical Virology
Journal of Antimicrobial ChemotherapyReporting of adverse events in randomized controlled trials of highly active antiretroviral therapy: systematic reviewJournal of Antimicrobial Chemotherapy
Hiv MedicineTrends in uptake of recently approved antiretrovirals within a national healthcare systemHiv Medicine
British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2005)
Hiv Medicine, 6():
Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir
Clinical Pharmacokinetics, 44():
Lancet Infectious Diseases
Approach to salvage antiretroviral therapy in heavily anti retroviral-experienced HIV-positive adults
Lancet Infectious Diseases, 6(8):
Enfermedades Infecciosas Y Microbiologia Clinica
Spanish GESIDA/Nacional AIDS plan recommendations for antiretroviral therapy in HIV-infected adults (October 2004)
Enfermedades Infecciosas Y Microbiologia Clinica, 22():
International Journal of Std & AIDS
A review of the aetiology of dyslipidaemia and hyperlipidaemia in patients with HIV
International Journal of Std & AIDS, 16():
Clinical Infectious Diseases
Transient viremia in HIV-infected patients and use of plasma preparation tubes
Clinical Infectious Diseases, 41():
Archives of Pharmacal Research
Antiretroviral therapy 2006: Pharmacology, applications, and special situations
Archives of Pharmacal Research, 29(6):
Clinical Infectious DiseasesEfavirenz to nevirapine switch in HIV-1-infected patients with dyslipidemia: A randomized, controlled studyClinical Infectious Diseases
Antiretroviral therapy - Optimal Sequencing of therapy to avoid resistance
Digestive Diseases and SciencesA case study and review of pancreatitis in the AIDS populationDigestive Diseases and Sciences
AIDS Patient Care and Stds
Beyond efficacy: The impact of combination antiretroviral therapy on quality of life
AIDS Patient Care and Stds, 19(9):
Clinical Infectious Diseases
Body fat and other metabolic effects of atazanavir and efavirenz, each administered in combination with zidovudine plus lamivudine, in antiretroviral-naive HIV-infected patients
Clinical Infectious Diseases, 42(2):
Salvage therapy with atazanavir/ritonavir combined to tenofovir in HIV-infected patients with multiple treatment failures: randomized ANRS 107 trial
Antiviral Therapy, 11(2):
Jaids-Journal of Acquired Immune Deficiency Syndromes
Protease inhibitor-based regimens for HIV therapy - Safety and efficacy
Jaids-Journal of Acquired Immune Deficiency Syndromes, 45():
Journal of Antimicrobial ChemotherapyAtazanavir trough plasma concentration monitoring in a cohort of HIV-1-positive individuals receiving highly active antiretroviral therapyJournal of Antimicrobial Chemotherapy
Journal of Clinical MicrobiologyDiscordance between viral loads determined by Roche COBAS AMPLICOR human immunodeficiency virus type 1 Monitor (version 1.5) standard and ultrasensitive assays caused by freezing patient plasma in centrifuged Becton-Dickinson vacutainer brand plasma preparation tubesJournal of Clinical Microbiology
Journal of Antimicrobial ChemotherapyHigh levels of atazanavir and darunavir in urine and crystalluria in asymptomatic patientsJournal of Antimicrobial Chemotherapy
JAIDS Journal of Acquired Immune Deficiency SyndromesChanges in Lipids and Lipoprotein Particle Concentrations After Interruption of Antiretroviral TherapyJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesGemini: A Noninferiority Study of Saquinavir/Ritonavir Versus Lopinavir/Ritonavir as Initial HIV-1 Therapy in AdultsJAIDS Journal of Acquired Immune Deficiency Syndromes
atazanavir; efavirenz; protease inhibitors; highly active antiretroviral therapy; lipids; HIV
© 2004 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.