JAIDS Journal of Acquired Immune Deficiency Syndromes:
Less Lipoatrophy and Better Lipid Profile With Abacavir as Compared to Stavudine: 96-Week Results of a Randomized Study
Podzamczer, Daniel MD*; Ferrer, Elena MD*; Sanchez, Pochita RN*; Gatell, José M MD†; Crespo, Manel MD‡; Fisac, Cesar RD§; Lonca, Montse MD†; Sanz, Jose MD∥ ; Niubo, Jordi PharmD¶; Veloso, Sergio MD#; Llibre, Josep M MD**; Barrufet, Pilar MD††; Ribas, María A MD‡‡; Merino, Esperanza MD§§; Ribera, Esteban MD‡; Martínez-Lacasa, Javier MD‖‖; Alonso, Carlos MD¶¶; Aranda, Miquel MD##; Pulido, Federico MD***; Berenguer, Juan MD†††; Delegido, Antonio MD‡‡‡; Pedreira, Juan D MD§§§; Lérida, Ana MD‖‖‖; Rubio, Rafael MD***; Río, Luis del MD¶¶¶ ; for the ABCDE (Abacavir vs. d4T (stavudine) plus efavirenz) Study Team
From the *Infectious Disease Service, Hospital Universitari de Bellvitge, Barcelona, Spain; †Infectious Disease Service, Hospital Clinic, Barcelona, Spain; ‡Infectious Disease Service, Hospital Vall d'Hebron, Barcelona, Spain; §Clinical Nutrition Department, Hospital Universitari de Bellvitge, Barcelona, Spain; ‖Internal Medicine Service, Hospital Principe de Asturias, Alcalá de Henares, Spain; ¶Microbiology Service, Hospital Universitari de Bellvitge, Barcelona, Spain; #Internal Medicine Service, Hospital Joan XXIII, Tarragona, Spain; **Internal Medicine Service, Hospital de Calella, Calella, Spain; ††Internal Medicine Service, Hospital de Mataró, Mataró, Spain; ‡‡Internal Medicine Service, Hospital Son Dureta, Palma de Mallorca, Spain; §§Infectious Disease Service, Hospital General, Alicante, Spain; ‖‖Infectious Disease Service, Hospital Mutua de Terrassa, Terrassa, Spain; ¶¶Internal Medicine Service, Hospital Sant Joan, Reus, Spain; ##Internal Medicine Service, Hospital de Terrassa, Terrassa, Spain; ***Internal Medicine Service, Hospital 12 de Octubre, Madrid, Spain; †††Infectious Disease Service, Hospital Gregorio Marañon, Madrid, Spain; ‡‡‡Internal Medicine Service, Hospital Sant Pau i Santa Tecla, Tarragona, Spain; §§§Internal Medicine Service, Hospital Juan Canalejo, La Coruña, Spain; ‖‖‖Internal Medicine Service, Hospital Sant Llorenç, Viladecans, Spain; and ¶¶¶Centro Tecnico de Isotopos Radioactivos (CETIR) Medical Center, Barcelona, Spain.
Received for publication April 26, 2006; accepted October 16, 2006.
Presented in part at the 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, February 8-11, 2004 (abstract 716) and the 12th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 22-26, 2005 (abstract 587).
Trial registry information: Current Controlled Trials Ltd., Middlesex House, 34-42 Cleveland Street, London W1T 4LB, United Kingdom (available at: www.controlled-trials.com). Trial identification number: ISRCTN04750658.
Supported in part by Fundación para la Investigación y la Prevención del SIDA en España (Foundation for AIDS Research and Prevention, grant 36274/02) and Red de Investigación en SIDA (AIDS Research Network, Redg173).
D. Podzamczer, J. M. Gatell, E. Ribera, F. Pulido, J. Berenguer, and R. Rubio have received investigational grants and/or honoraria for lectures or advisory boards from GlaxoSmithKline and Bristol Myers Squibb, Spain.
Reprints: Daniel Podzamczer, MD, Infectious Disease Service, Hospital Universitari de Bellvitge, c/Feixa Llarga s/n. L'Hospitalet, 08907 Barcelona, Spain (e-mail: email@example.com).
Objective: To assess lipoatrophy, other toxicities, and efficacy associated with abacavir as compared with stavudine in HIV-infected antiretroviral-naive patients.
Methods: This was a prospective, randomized, open trial, stratified by viral load and CD4 cell count, conducted January 2001 to July 2004. Two hundred thirty-seven adult patients with HIV infection initiating antiretroviral therapy were assigned to receive abacavir (n = 115) or stavudine (n = 122), both combined with lamivudine and efavirenz. The primary endpoint was the proportion of patients with lipoatrophy as assessed by physician and patient observation at 96 weeks.
Results: A lower proportion of patients assigned to abacavir developed clinical signs of lipoatrophy (4.8% vs. 38.3%; P < 0.001). These observations were confirmed by anthropometric data. Dual energy x-ray absorptiometry (DEXA) scans performed in 57 patients showed significantly greater total limb fat loss in the stavudine arm (−1579 vs. 913 g; P < 0.001). The lipid profile in abacavir patients presented more favorable changes in the levels of triglycerides (P = 0.03), high-density lipoprotein cholesterol (HDLc; P < 0.001), and apolipoprotein A1 (P < 0.001) as well as in the ratio between total cholesterol and HDLc (P = 0.005). Throughout the study, a higher proportion of patients in the stavudine group received lipid-lowering agents as compared to the abacavir group (17% vs. 4%; P = 0.002). Similar virologic and immunologic responses were observed.
Conclusions: Assuming the limitations inherent to clinical assessment, this study shows a notably weaker association of abacavir with lipoatrophy than stavudine. DEXA scans and anthropometric measurements supported the clinical findings. In addition, the lipid changes that occurred were more favorable in patients receiving abacavir.
The use of highly active antiretroviral therapy (HAART) has contributed in great part to converting HIV into a chronic disease.1 Short-term toxicity and, particularly, long-term toxicity are important limitations of HAART, however.2-4 Morphologic and lipid abnormalities are observed in a considerable percentage of treated patients, generating concern about a possible increased risk of cardiovascular events in this population.5-8
The morphologic changes that can occur, also referred to as HIV-associated lipodystrophy, consist of a lipoatrophic process in peripheral areas, such as the arms, legs, buttocks, and face, and fat accumulation (lipoaccumulation) at the abdominal, breast, and dorsocervical regions. Despite the high prevalence of fat distribution change and its negative impact among the HIV-infected population receiving HAART, the pathogenesis of this condition is not completely understood. Although clinical signs of lipoatrophy and lipoaccumulation can be seen together in the same patient, there is growing evidence that these processes are distinct entities with different underlying pathophysiologic mechanisms.4,9 In fact, some authors have recently questioned the actual existence of a lipoaccumulation process in HIV-infected individuals and suggest that lipoatrophy is the distinguishing trait of HIV lipodystrophy.10
A number of factors, including certain antiretroviral families or specific drugs, virologic control, time from infection, duration of HAART, and demographics, have been associated with the development of HIV-associated lipodystrophy. Mitochondrial toxicity is thought to play a role in the lipoatrophy process.11 This may be the mechanism by which stavudine, and, to a lesser degree, other nucleoside analogues, such as zidovudine, are linked to lipoatrophy.12-15 The potential toxicity on mitochondrial DNA of other nucleosides, such as abacavir and lamivudine, and the nucleotide tenofovir seems to be lower. Hence, it is thought that there would be a smaller incidence of lipoatrophy with the use of these drugs. In a recent study, significantly less total limb fat was observed in the stavudine-containing arm as compared to the alternative tenofovir-containing option.16 Also, a more favorable change in the lipid profile from baseline was noted in the tenofovir group.
Abacavir is a potent well-tolerated nucleoside analogue that was licensed in the United States in 1999. A few randomized studies have recently proved its efficacy and tolerability in antiretroviral-naive patients.17,18 Few data on its potential contribution to morphologic and metabolic HAART-related abnormalities have been reported in this population, however.19
We present the results of the first randomized trial designed to compare the incidence of lipoatrophy between antiretroviral regimens as the primary endpoint. In this 2-year randomized multicenter trial initiated in 2001, the standard-of-care regimen of stavudine, lamivudine, and efavirenz was compared with a regimen substituting abacavir for stavudine. In addition, the virologic and immunologic efficacy, associated metabolic changes, and tolerability of the 2 regimens were compared.
Study Design and Patient Population
The Abacavir vs. d4T (stavudine) plus efavirenz (ABCDE) study was a randomized, open, multicenter trial conducted in 17 Spanish hospitals. The study was approved by the ethics committees of each hospital and by the Spanish Health Authorities (Agencia Española del Medicamento). Adult HIV-1-infected antiretroviral-naive patients with a viral load >500 copies/mL who gave written informed consent were recruited between January 2001 and June 2002 for participation.
Intervention and Follow-Up
Patients were centrally stratified according to HIV-1 RNA > or ≤30,000 copies/mL and CD4 counts > or ≤200 cells/μL and randomized to one of these arms: (1) 300 mg of abacavir twice daily, plus 150 mg of lamivudine twice daily, plus 600 mg of efavirenz once daily; or (2) 30 mg of stavudine twice daily (according to < or >60 kg of body weight) plus lamivudine and efavirenz at the same doses. The use of treatments other than the allocated ones, including lipid-lowering agents, was left to the researchers' discretion and was recorded for later analysis.
Clinical assessment and laboratory parameter controls were performed at baseline, at weeks 4 and 12, and every 12 weeks thereafter up to 96 weeks of follow-up.
Participants underwent an extensive physical examination to detect clinical signs of peripheral fat wasting (lipoatrophy) and central adiposity (lipoaccumulation) at weeks 48 and 96. Lipoatrophy features consisted of decreased subcutaneous fat tissue in the face, buttocks, and extremities, whereas lipoaccumulation features included increased abdominal girth, breast enlargement, and dorsal fat accumulation. The morphologic abnormality at the precise site was diagnosed when reported by the patient and confirmed by medical examination. For the purpose of the analysis, body fat abnormalities were categorized as lipoatrophy or lipoaccumulation. Therefore, patients with fat loss and fat accumulation were included in both categories.
Anthropometric measurements were done at baseline and at 48 and 96 weeks according to standard techniques described elsewhere20 and included height, weight, and circumferences at 4 body sites (waist, hip, midarm, and midthigh). An experienced nurse in the coordinating center trained participating physicians in the anthropometric procedures before the study began. The ratio between the waist and hip circumferences was also calculated. Additionally, a dual-energy x-ray absorptiometry (DEXA; Lunar DPX-L Equipment, Madison, WI) substudy was undertaken to determine the changes in total and regional body fat. Patients giving informed consent from 6 participating centers located near the DEXA center Centro Tecnico de Isotopos Radioactivos (CETIR) were enrolled for this purpose. Scans were performed at baseline and at the 48- and 96-week visits. Data from the DEXA scans were analyzed by an independent observer blinded to the patients' study arm.
At each visit, blood samples were drawn in the morning after an overnight fast. Blood cells; biochemical parameters, including alanine aminotransferase (ALT), alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), creatinine, and amylase; and CD4 cell counts (except for week 4) were measured according to routine methods at each center. A complete lipid profile, including total cholesterol (TC) and high-density lipoprotein cholesterol (HDLc), triglycerides, and apolipoproteins A1 and B, was determined at baseline and every 6 months from stored samples (−70°C). These measurements were centralized in the laboratory of the coordinating center (Hospital Universitari de Bellvitge) using standardized procedures. Low-density lipoprotein cholesterol (LDLc) was estimated with the Friedewald formula.
HIV-1 RNA was determined in each center using a polymerase chain reaction (PCR), branched DNA (bDNA), or nucleic acid sequence-based amplification (NASBA) method. When HIV-1 RNA was undetectable by any of these techniques in baseline and follow-up samples, results were confirmed by centralized determinations in the coordinating center with the 3.0 bDNA technique.
The 1993 Centers for Disease Control and Prevention (CDC) classification was used for AIDS-defining diseases. A diagnosis was considered definite when the disease was confirmed histologically and/or microbiologically and probable when only the clinical presentation plus the response to therapy were available. HIV-related symptoms, adverse effects, and other events were recorded, and a predefined short questionnaire was administered at every visit to assess adherence to antiretroviral therapy.21
The primary endpoint of the study was the presence of at least 1 clinical sign of lipoatrophy as defined previously, and the secondary endpoints were the presence of clinical lipoaccumulation signs; lipid changes; virologic, clinical, and immunologic efficacy; and tolerability.
All endpoints were analyzed using intent-to-treat (ITT) and on-treatment (OT) approaches. In the ITT analyses of toxicity, any adverse event occurring during follow-up was computed with the initially assigned regimen (missing values were not computed), and in the ITT analyses of virologic efficacy, switch equaled failure. Unless otherwise stated, the data presented are from the ITT analysis.
Estimation of sample size was based on the assumption that 20% of patients on stavudine and 5% on abacavir would present with lipoatrophy as assessed by clinical examination. To detect a difference of at least 15 percentage points, with 80% power and a significance level of 0.05, the sample size was determined to be 116 patients per arm, a figure that includes 20% of patients that might lost to follow-up.
Baseline characteristics were compared using the χ2 or Mann-Whitney U test, as appropriate. Proportions of patients with lipoatrophy or lipoaccumulation were compared using the Fisher exact test. The within- and between-group statistical comparisons of continuous data were performed using the Wilcoxon rank sum test and Mann-Whitney U test, respectively. Continuous data are reported as the mean (range). A 2-sided P value <0.05 was considered statistically significant. Statistical analyses were performed with the use of SPSS software, version 12.0 (SPSS, Chicago, IL).
A total of 257 patients were randomized, and among them, 237 (115 in the abacavir arm and 122 in the stavudine arm) were considered eligible for analysis (Fig. 1).
There were no statistically significant differences in baseline characteristics between arms, except for TC levels (Table 1). No differences were observed in any other hematologic or biochemical parameter (data not shown). More than 70% of the patients were men, approximately 90% were white, and approximately 40% had acquired HIV through heterosexual intercourse. In the abacavir and stavudine arms, respectively, 18% and 28% had prior AIDS, the median CD4 counts were 175 cells/μL and 201 cells/μL, and the median viral loads were 4.96 copies/mL and 4.92 copies/mL. Although the proportion of patients who acquired HIV through intravenous drug use was similar (30% in the abacavir arm and 28% in the stavudine arm), a trend to a higher proportion with hepatitis C virus (HCV) infection was observed in the abacavir arm (45% vs. 32%; P = 0.053).
At the study end, 56 patients had been lost to follow-up and morphologic data were not collected in 16 of the remaining patients. Hence, lipodystrophy was assessed in 165 (84 in the abacavir arm and 81 in the stavudine arm [70%]) of the 237 patients enrolled (Table 2). Among these 165 patients, 113 (68.5%) showed no clinical signs of lipodystrophy, 23 (13.9%) had lipoatrophy alone, 17 (10.3%) had lipoaccumulation alone, and 12 (7.3%) presented with the mixed form.
Four (4.8%) patients in the abacavir arm and 31 (38.3%) in the stavudine arm developed 1 or more clinical signs of lipoatrophy (difference of 33.5%, 95% confidence interval [CI]: 22% to 45%; P < 0.001). The OT analysis produced similar results (3 in the abacavir arm [4.3%] and 19 in the stavudine arm [32.2%], difference of 27.9%, 95% CI: 15.1% to 40.7%; P < 0.001). With regard to lipoaccumulation, fewer patients in the abacavir arm developed clinical signs of this alteration (9 in the abacavir arm [10.7%] vs. 20 in the stavudine arm 20 [24.7%], difference of 14%, 95% CI: 2.5% to 25.5%; P < 0.023; see Table 2).
Anthropometric Assessments and Dual-Energy X-Ray Absorptiometry Scans
During the first year of the study, both treatment groups presented with similar weight gains (3.13 kg in the abacavir group and 3.21 kg in the stavudine group). Between 48 and 96 weeks, however, weight continued to increase in the abacavir patients (1.57 kg, 4.70 from baseline), whereas a weight reduction occurred in the stavudine patients (−0.96 kg, 2.25 from baseline), which is a common finding in the course of peripheral fat loss.15
Regarding the measured body girths, both regimens exhibited significant increases at all sites, except at the hip in the stavudine group (Table 3). A significantly lower increase in the waist-to-hip ratio was observed in the abacavir group as compared to the group receiving stavudine (1.2% vs. 4.5%; P = 0.002). This difference was driven by a significant increase in waist girth in both arms accompanied by an increase in hip girth only in the abacavir arm.
At the end of study, patients with clinical signs of lipoatrophy presented with greater decreases in the hip (−1.1 vs. 2.1; P = 0.022), arm (0.0 vs. 1.7; P = 0.020), and leg (−0.8 vs. 2.3; P = 0.017) circumferences as compared to the remaining patients. Similarly, those with clinical signs of abdominal lipoaccumulation presented with greater increases in the waist perimeter (6.8 vs. 2.9; P = 0.005).
DEXA scans were performed in a subset of 57 patients (25 in the abacavir arm and 32 in the stavudine arm). Within this subgroup, both arms presented baseline characteristics similar to those of the total study population except for serum cholesterol concentration (data not shown). DEXA scans showed a net limb fat gain after 96 weeks in patients assigned to abacavir (913 g, range: 150-1677 g) as opposed to patients randomized to stavudine (−1578 g, range: −2294 to −862), with the difference being statistically significant (P < 0.001; Fig. 2). The scans also showed a marked difference in limb fat changes when comparing patients with or without clinical signs of lipoatrophy (−2103 vs. 45 g; P = 0.002). Regarding central fat, patients with abdominal lipoaccumulation presented with higher trunk fat increases than those without (3413 g, range: 656-7511 g vs. 817 g, range: −4076-7976 g; P = 0.014). The DEXA measurements (abacavir, 1225 g, range: −2840- 7976 g and stavudine, 996 g, range: −4076-7511 g; P = 0.58) did not confirm the difference between arms observed in the clinical examination (see Table 2).
Lipid Metabolism Changes
At 96 weeks, both treatments were associated with significant increases in the following parameters: TC (stavudine: 0.89 mmol/L [34 mg/dL]; P < 0.001 and abacavir: 1.09 mmol/L [42 mg/dL]; P < 0.001), LDLc (stavudine: 0.43 mmol/L [16.6 mg/dL]; P = 0.001 and abacavir: 0.56 mmol/L [21.6 mg/dL]; P < 0.001), HDLc (stavudine: 0.20 mmol/L [7.7 mg/dL]; P = 0.001 and abacavir: 0.47 mmol/L [18.2 mg/dL]; P < 0.001), triglycerides (stavudine: 0.85 mmol/L [75 mg/dL]; P < 0.001 and abacavir: 0.28 mmol/L [25 mg/dL]; P < 0.05), apolipoprotein A1 (stavudine: 0.17 g/L; P = 0.001 and abacavir: 0.31 g/L; P < 0.001), and apolipoprotein B (stavudine: 0.12 g/L; P = 0.001 and abacavir: 0.12 g/L; P < 0.001) (Fig. 3).
In the comparison between treatments, the abacavir patients presented with a lower increase in triglyceride levels (P = 0.03), a greater increase in HDLc and apolipoprotein A1 (P < 0.001), and a greater reduction in the TC/HDLc ratio (−1.51 vs. −0.06; P = 0.005). At the end of the study, a higher percentage of patients in the stavudine group had received lipid-lowering agents as compared to the abacavir group (17% vs. 4%; P = 0.002): statins (15% vs. 4%; P = 0.008) and fibrates (4% vs. 1%, P = 0.21).
Drug discontinuation (1 or more of the drugs received) attributable to adverse events was required in 20 (17.4%) abacavir patients (rash/hypersensitivity in 13, central nervous system symptoms in 5, peripheral neuropathy in 1, and opiate withdrawal in 1) and in 33 (27%) stavudine patients (mitochondrial toxicity in 23 [lipoatrophy in 14, peripheral neuropathy in 5, and symptomatic hyperlactatemia/metabolic acidosis in 4], central nervous system symptoms in 6, gastrointestinal disturbance in 1, dyslipidemia in 1, increased GGT level in 1, and opiate withdrawal in 1) (P = 0.075). Although “allergic symptoms” were observed in 13 patients receiving abacavir, a hypersensitivity reaction to abacavir19 was diagnosed in only 8 of them (7%).
Regarding grade 3 and 4 adverse events and laboratory abnormalities, there were significant differences between arms only in the frequency of increased GGT levels (23% vs. 12%; P = 0.022) and in the presence of rash/fever (5% vs. 0%; P = 0.011), which were higher in the abacavir arm. HCV-positive patients presented a higher rate of grade 3 or 4 GGT toxicity than HCV-negative patients (34% vs. 7%; P < 0.001).
Four patients (1.7%) died during the study period: 2 receiving stavudine (1 with cirrhosis and probable sepsis and 1 with lung adenocarcinoma) and 2 receiving abacavir (1 with acute myocardial infarction and 1 with sudden death).
After 96 weeks, a trend favoring abacavir in the proportion of patients with an HIV-1 RNA level <50 copies/mL was observed in the ITT analysis: 60.9% versus 47.5% (difference of 13.4%, 95% CI: 0.8 to 26.0; P = 0.05), whereas no differences were detected with the OT approach: 87.5% in the abacavir arm and 85.3% in the stavudine arm (difference of 2.2%, 95% CI: −8.9 to 13.3; P = 0.81). The differences in efficacy rates in the ITT analysis were not driven by differences in adherence (95% adherence [87% in both arms]) but, instead, by the proportion of patients who discontinued therapy (34.8% in the abacavir group vs. 48.3% in the stavudine group).
A significant increase in CD4 counts was observed in both arms: 263 cells/μL in the abacavir arm and 294 cells/μL in the stavudine arm (P = 0.34).
Twenty-four AIDS-defining diseases (17 confirmed and 7 probable) were diagnosed in 20 patients after a median period of 28 days (range: 1-515 days): 15 in the abacavir arm and 5 in the stavudine arm (P = 0.013). All but 1 were diagnosed in the first 6 months after initiation of therapy.
The results of the present study show a notably lower association between abacavir and the morphologic abnormalities associated with HAART and a more beneficial lipid profile when compared with stavudine. In addition, a trend to a better efficacy rate was observed in the ITT analysis in the abacavir arm, although no differences appeared in the OT analysis. Overall, both regimens were well tolerated.
Our clinical assessments showed a substantially lower incidence of clinical lipoatrophy signs in patients receiving abacavir (4.8%) as compared to patients receiving stavudine (38.3%). These results were confirmed by anthropometric assessment. Increases in all the variables studied were observed in both arms, except for hip girth in the case of stavudine. Also, a higher increase in the waist/hip ratio was found in this arm. Finally, DEXA scans performed in a subset of the overall population showed notable limb fat loss in stavudine patients, whereas a gain was observed in the abacavir group.
Two recent trials have also reported a milder impact on the body fat compartment in naive patients initiating antiretroviral therapy with nonthymidinic regimens. Shlay et al19 found fewer marked lipoatrophy-associated morphologic changes in patients receiving abacavir/lamivudine as compared with stavudine/didanosine. It is of note that the study by Shlay et al19 was a metabolic substudy within a randomized trial, involving a smaller number of patients, with various drugs as the third compound of the regimen and combining stavudine with didanosine.
In a 3-year randomized trial, investigator-reported lipodystrophy occurred less often in patients receiving tenofovir (3%) versus stavudine (19%), both combined with lamivudine and efavirenz.16 That study, unlike ours, was not designed to evaluate body fat changes, however, and DEXA scans were only available after 2 and 3 years of follow-up.
Although some authors have found differences in abdominal fat between nucleoside regimens,19,22 the role of antiretroviral drugs in lipoaccumulation remains controversial.10 In our study, the clinical examinations showed a higher frequency of lipoaccumulation in stavudine patients, but the more reliable objective data failed to confirm these findings. A possible explanation for this discrepancy is that the abdomen may acquire a more prominent appearance when there is gradual peripheral fat loss (pseudotruncal obesity).23 Overall, the impact of treatment on central fat accumulation was substantially lower than on peripheral fat loss. These results agree with recent findings suggesting a lack of association between the phenomena of lipoatrophy and lipoaccumulation.10,24
Regarding lipid metabolism, abacavir was associated with more favorable changes in terms of triglycerides, HDLc, apolipoprotein A1, and TC/HDLc, with this last parameter being proposed by many studies as a single powerful cardiovascular risk predictor.25 Conversely, a slightly higher, although nonsignificant, increase in LDLc was observed among abacavir patients. This result was probably influenced by the substantially higher proportion of patients treated with statins in the stavudine arm (15% vs. 4%), however.
Recent studies have linked stavudine-based antiretroviral therapy with higher elevations in triglycerides and LDLc levels and smaller increases in HDLc levels than those seen in regimens containing other nucleotide/nucleosides, such as tenofovir and, possibly, zidovudine.16,22,26 A better lipid profile as compared with stavudine was shown with tenofovir in a large randomized study conducted in antiretroviral-naive patients.16 Moreover, other data suggest that replacement of stavudine by tenofovir or abacavir may be associated with lipid profile improvements.27-30
Recent data from observational studies in the HIV population have shown an independent association between the incidence of cardiovascular disease and the classic risk factors, including lipid profile alterations.6,7 Thus, the more favorable lipid changes observed in our abacavir-containing regimen may have had a positive benefit in terms of cardiovascular risk.
This study was not powered for a comparison in terms of efficacy. Our data suggest similarly favorable virologic and immunologic results by OT analysis, however, and a trend favoring the abacavir arm by ITT analysis. This may be explained by the larger proportion of patients switching therapy or lost to follow-up in the stavudine arm.
Stavudine was associated with symptoms of mitochondrial toxicity and abacavir was associated with a hypersensitivity reaction in an expected proportion of patients.2,31
Our study has some limitations that should be discussed. First, in the absence of an objective case definition tool at the time the study was designed, HIV-associated lipodystrophy features were diagnosed subjectively. To date, the data regarding the accuracy of subjective assessments remain controversial.3,27,32,33 In addition, it is possible that there may have been some partiality in the examiners' judgments, because the morphologic assessments were performed in an open-label fashion at a time when there was emerging evidence pointing to stavudine as a contributor to lipoatrophy. Second, the proportion of patients lost to follow-up was high, although it did not differ from reported rates in similar studies. Unfortunately, the main objective of this study did not allow computation of these missing data as failures, as is done in efficacy trials. Despite these factors, our clinical diagnoses showed a high level of agreement with anthropometric changes and were confirmed by the outcome of DEXA scanning performed in a subset of patients. This fact, together with the magnitude of the difference in the effect size, makes us reasonably confident about our findings. Finally, caution should be used when interpreting the lipid findings in terms of cardiovascular risk, because a number of unmeasured risk factors might also have been affected.
In conclusion, this study shows that abacavir has a substantially less deleterious effect on body fat distribution (particularly peripheral fat) and lipid metabolism than stavudine. Our data offer strong support for the concept that thymidine analogue-sparing approaches are minimally associated with limb fat loss. Abacavir/lamivudine may be a good nucleoside backbone option for initiating antiretroviral therapy with a low risk for developing lipoatrophy, at least within the first 2 years. This is important, because there is no treatment for this worrisome complication of antiretroviral therapy in HIV-infected patients.
1. Mocroft A, Ledergerber B, Katlama C, et al. Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet. 2003;362:22-29.
2. Carr A. HIV lipodystrophy: risk factors, pathogenesis, diagnosis and management. AIDS. 2003;17(Suppl 1):S141-S148.
3. Tien PC, Grunfeld C. What is HIV-associated lipodystrophy? Defining fat distribution changes in HIV infection. Curr Opin Infect Dis. 2004;17:27-32.
4. Lichtenstein KA. Redefining lipodystrophy syndrome. Risk and impact on clinical decision making. J Acquir Immune Defic Syndr. 2005;39:395-400.
5. 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.
6. Friis-Moller N, Weber R, Reiss P, et al. Cardiovascular disease risk factors in HIV patients-association with antiretroviral therapy. Results from the DAD study. AIDS. 2003;17:1179-1193.
7. d'arminio A, Sabin CA, Phillips AN, et al. Cardio- and cerebrovascular events in the HIV-infected persons. AIDS. 2004;18:1811-1817.
8. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005;352:48-62.
9. Jacobson DL, Knox T, Spiegelman D, et al. Prevalence of, evolution of, and risk factors for fat atrophy and fat deposition in a cohort of HIV-infected men and women. Clin Infect Dis. 2005;40:1837-1845.
10. Bacchetti P, Gripshover B, Grunfeld C, et al. Fat distribution in men with HIV infection. J Acquir Immune Defic Syndr. 2005;40:121-131.
11. Brinkman K, Smeitink JA, Romijn JA, et al. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet. 1999;354:1112-1115.
12. Mallal SA, John M, Moore CB, et al. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS. 2000;14:1309-1316.
13. Saint-Marc T, Partisani M, Poizot-Martin I, et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS. 1999;13:1659-1667.
14. Nolan D, Hammond E, Martin A, et al. Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS. 2003;17:1329-1338.
15. Carr A, Miller J, Law M, et al. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS. 2000;14(Suppl):F25-F32.
16. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs. stavudine in combination therapy in antiretroviral-naive patients. A 3-year randomized trial. JAMA. 2004;292:191-201.
17. DeJesus E, Herrera G, Teofilo E, for the CNA30024 Study Team. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis. 2004;39:1038-1046.
18. Moyle GJ, DeJesus E, Cahn P, et al. Ziagen Once-Daily in Antiretroviral Combination Therapy (CNA30021) Study Team. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once-Daily in Antiretroviral Combination Study. J Acquir Immune Defic Syndr. 2005;38:417-425.
19. Shlay JC, Visnegarwala F, Bartsch G, et al. Body composition and metabolic changes in antiretroviral-naive patients randomized to didanosine and stavudine versus abacavir and lamivudine. J Acquir Immune Defic Syndr. 2005;38:147-155.
20. Lohman TG, Roche AF, Martorell R. Anthropometric Standardization Reference Manual. Champaign, IL: Human Kinetics Books; 1988.
21. Podzamczer D, Ferrer E, Consiglio E, et al. A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study). Antivir Ther. 2002;7:81-90.
22. Dubé MP, Parker RA, Tebas P, et al. Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides. AIDS. 2005;19:1807-1818.
23. Safrin S, Grunfeld C. Fat distribution and metabolic changes in patients with HIV infection. AIDS. 1999;13:2493-2505.
24. Gripshover B, Tien PC, Saag M, et al. Lipoatrophy is the dominant feature of the lipodystrophy syndrome in HIV-infected man [abstract 732]. In: Programs and Abstracts of the 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA, 2003. Alexandria, VA: Foundation for Retrovirology and Human Health; 2003:319.
25. Criqui MH, Golomb BA. Epidemiologic aspects of lipid abnormalities. Am J Med. 1998;105(Suppl):48S-57S.
26. Moyle GJ. Lipid abnormalities during ART: it's the drug, not the class. AIDS Read. 2004;14:15-22.
27. Martin A, Smith DE, Carr A, et al, for the Mitochondrial Toxicity (MITOX) Study Group. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS. 2004;18:1029-1036.
28. Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA. 2002;288:207-215.
29. Ribera E, Paradineiro J, Sauleda S, et al. Improvement of subcutaneous fat, lipid profile, and parameters of mitochondrial toxicity in patients with peripheral lipoatrophy when stavudine is switched to tenofovir: the LIPOTEST study [abstract 860]. Presented at: 12th Conference on Retroviruses and Opportunistic Infections; 2005; Boston.
30. Domingo P, Labarga P, Palacios R, et al, for the RECOVER Study Group. Improvement of dyslipidemia in patients switching from stavudine to tenofovir: preliminary results. AIDS. 2004;18:1475-1478.
31. Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002;359:727-732.
32. Schwenk A, Breuer P, Kremer G, et al. Clinical assessment of HIV-associated lipodystrophy syndrome: bioelectrical impedance analysis, anthropometry and clinical scores. Clin Nutr. 2001;20:243-249.
33. Gerrior J, Kantaros J, Coakley E, et al. The fat redistribution syndrome in patients infected with HIV: measurements of body shape abnormalities. J Am Diet Assoc. 2001;101:1175-1180.
Other members of the ABCDE Study Team include the following: J. Cosín, and M. Ramírez, Hospital Gregorio Marañón, Madrid; M. Javaloyas, Hospital Sant Llorenç, Viladecans; C. Cepeda, and M. Torralba, Hospital 12 de Octubre, Madrid; M. J. Barberá, M. Santín, I. Ruiz, C. Faz, A. Vila, D. Buisac, and F. Gudiol, Hospital Universitari de Bellvitge, Barcelona (Coordinating Center); J. Murillas, Hospital Clinic, Barcelona; I. Ocaña and V. Falco, Hospital Vall d'Hebron, Barcelona; E. Casas, A. Arranz, and J. de Miguel, Hospital Príncipe de Asturias, Alcalá de Henares; F. Vidal, Hospital Joan XXIII, Tarragona; S. Valero, Hospital de Calella, Calella; L. Force, Hospital de Mataró, Mataró; A. Salas, and C. Villalonga, Hospital Son Dureta, Palma de Mallorca; J. Portilla and V. Boix, Hospital Gral. de Alicante, Alicante; M. A. González and B. Coll, Hospital Sant Joan de Reus, Reus; and F. Del Molino and E. Anoro, Hospital de Terrassa, Terrassa.
This article has been cited 45 time(s).
Plos OneSystematic Review of Antiretroviral-Associated Lipodystrophy: Lipoatrophy, but Not Central Fat Gain, Is an Antiretroviral Adverse Drug ReactionPlos One
Hiv MedicineAbacavir and risk of myocardial infarction in HIV-infected patients on highly active antiretroviral therapy: a population-based nationwide cohort studyHiv Medicine
Expert Opinion on Drug SafetySafety of stavudine in the treatment of HIV infection with a special focus on resource-limited settingsExpert Opinion on Drug Safety
Jama-Journal of the American Medical Association
Antiretroviral treatment of adult HIV infection - 2008 recommendations of the International AIDS Society USA panel
Jama-Journal of the American Medical Association, 300(5):
Medicina ClinicaHIV infection. Irreversible mistakes not to be repeatedMedicina Clinica
A new era of antiretroviral drug toxicity
Antiviral Therapy, 14(2):
Disorders of Body Fat Distribution in HIV-1-Infected Patients
AIDS Reviews, 11(3):
A 6-month interruption improves adipose tissue of antiretroviral therapy function in HIV-infected patients: the ANRS EP29 Lipostop Study
Antiviral Therapy, 12(8):
Journal of Antimicrobial ChemotherapyThe role of efavirenz compared with protease inhibitors in the body fat changes associated with highly active antiretroviral therapyJournal of Antimicrobial Chemotherapy
AIDS Research and Human RetrovirusesZidovudine/lamivudine/abacavir plus tenofovir in HIV-Infected naive patients: A 96-week prospective one-arm pilot studyAIDS Research and Human Retroviruses
Journal of Antimicrobial ChemotherapyCurrent perspectives on the management and prevention of antiretroviral-associated lipoatrophyJournal of Antimicrobial Chemotherapy
Reviews in Endocrine & Metabolic DisordersPathophysiology of GHRH-growth hormone-IGF1 axis in HIV/AIDSReviews in Endocrine & Metabolic Disorders
Hiv MedicineImpact of switching from zidovudine/lamivudine to tenofovir/emtricitabine on lipoatrophy: the RECOMB studyHiv Medicine
European Journal of PediatricsLong-term body composition and metabolic changes in HIV-infected children switched from stavudine to tenofovir and from protease inhibitors to efavirenzEuropean Journal of Pediatrics
Virology JournalLiver steatosis in Chinese HIV-infected patients with hypertriglyceridemia: characteristics and independent risk factorsVirology Journal
Journal of Antimicrobial ChemotherapySwitching to lopinavir/ritonavir with or without abacavir/lamivudine in lipoatrophic patients treated with zidovudine/abacavir/lamivudineJournal of Antimicrobial Chemotherapy
European Journal of Clinical Microbiology & Infectious DiseasesNucleoside reverse transcriptase inhibitors in combination therapy for HIV patients: systematic review and meta-analysisEuropean Journal of Clinical Microbiology & Infectious Diseases
AIDS Research and Human RetrovirusesHow Much Fat Loss Is Needed for Lipoatrophy to Become Clinically Evident?AIDS Research and Human Retroviruses
Hiv Clinical TrialsA Meta-Analysis of Six Placebo-Controlled Trials of Thiazolidinedione Therapy for HIV LipoatrophyHiv Clinical Trials
Epidemiology, Assessment, and Management of Excess Abdominal Fat in Persons with HIV Infection
AIDS Reviews, 12(1):
AIDS Patient Care and StdsEfficacy and Safety of Atazanavir-Ritonavir Plus Abacavir-Lamivudine or Tenofovir-Emtricitabine in Patients with Hyperlipidaemia Switched from a Stable Protease Inhibitor-Based Regimen Including One Thymidine AnalogueAIDS Patient Care and Stds
Plos OneZidovudine/Lamivudine for HIV-1 Infection Contributes to Limb Fat LossPlos One
Journal of Clinical Endocrinology & MetabolismApproach to the human immunodeficiency virus-infected patient with lipodystrophyJournal of Clinical Endocrinology & Metabolism
Hiv Clinical TrialsOnce-daily abacavir/lamivudine and ritonavir-boosted atazanavir for the treatment of HIV-1 infection in antiretroviral-naive patients: a 48-week pilot studyHiv Clinical Trials
Current Hiv Research
The Changing Face of HIV/AIDS in Treated Patients
Current Hiv Research, 7(4):
Journal of Clinical EpidemiologyHierarchical modeling gave plausible estimates of associations between metabolic syndrome and components of antiretroviral therapyJournal of Clinical Epidemiology
International Journal of Clinical PracticeLong-term complications of antiretroviral therapy: lipoatrophyInternational Journal of Clinical Practice
Hiv MedicineObjective amount of limb fat in HIV-infected subjects with subjective diagnosis of lipoatrophyHiv Medicine
Jama-Journal of the American Medical Association
A 39-year-old man with HIV-associated lipodystrophy
Jama-Journal of the American Medical Association, 300(9):
Jaids-Journal of Acquired Immune Deficiency Syndromes
HIV and antiretroviral therapy: Lipid abnormalities and associated cardiovascular risk in HIV-infected patients
Jaids-Journal of Acquired Immune Deficiency Syndromes, 49():
Hiv Clinical TrialsEffectiveness and tolerability of oral administration of low-dose salmon oil to HIV patients with HAART-associated DyslipidemiaHiv Clinical Trials
Expert Opinion on Drug Metabolism & ToxicologyMetabolic complications of antiretroviral therapy in HIV-infected childrenExpert Opinion on Drug Metabolism & Toxicology
Scandinavian Journal of Infectious DiseasesAntiretroviral treatment of HIV infection: Swedish recommendations 2007Scandinavian Journal of Infectious Diseases
Hiv Clinical TrialsObjective Assessment of Facial Lipoatrophy Changes in a Cohort of HIV-Infected Patients Taking Combination Antiretroviral TherapyHiv Clinical Trials
Expert Opinion on Drug SafetyNephrotoxicity associated with antiretroviral therapy in HIV-infected patientsExpert Opinion on Drug Safety
American Journal of TherapeuticsAntiretroviral Therapy With HeartAmerican Journal of Therapeutics
Current Opinion in Infectious DiseasesShould HIV therapy be started at a CD4 cell count above 350 cells/μl in asymptomatic HIV-1-infected patients?Current Opinion in Infectious Diseases
JAIDS Journal of Acquired Immune Deficiency SyndromesThe Effect of Individual Antiretroviral Drugs on Body Composition in HIV-Infected Persons Initiating Highly Active Antiretroviral TherapyJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesGenotypic Resistance in HIV-Infected Naive Patients Receiving Abacavir Plus Lamivudine and EfavirenzJAIDS Journal of Acquired Immune Deficiency Syndromes
abacavir; cholesterol; HIV; lipids; lipoatrophy; lipodystrophy; stavudine
© 2007 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.