Skip Navigation


JAC Advance Access originally published online on May 14, 2008
Journal of Antimicrobial Chemotherapy 2008 62(2):234-245; doi:10.1093/jac/dkn191
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
62/2/234    most recent
dkn191v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Pérez-Molina, J. A.
Right arrow Articles by Moreno, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pérez-Molina, J. A.
Right arrow Articles by Moreno, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Reviews

The role of efavirenz compared with protease inhibitors in the body fat changes associated with highly active antiretroviral therapy

José A. Pérez-Molina1,*, Pere Domingo2, Esteban Martínez3 and Santiago Moreno4

1 Tropical Medicine and Clinical Parasitology Unit, Infectious Diseases Department, Hospital Universitario Ramón y Cajal, Madrid, Spain 2 Infectious Diseases Unit, Hospital de la Santa Creu i San Pau, Universitat Autònoma de Barcelona, Barcelona, Spain 3 Infectious Diseases Unit, Hospital Clínic, University of Barcelona-IDIBAPS, Barcelona, Spain 4 Infectious Diseases Department, Hospital Universitario Ramón y Cajal, Madrid, Spain

* Corresponding author. Tel: +34-913368108; Fax: +34 913368792; E-mail: japerezm.hrc{at}salud.madrid.org


   Abstract
Top
 Abstract
Introduction
 In vitro data
 Clinical data
 Non-comparative studies
 Comparative studies
 Data for lipid outcome
 Conclusions and clinical...
 Transparency declarations
 References
 
Highly active antiretroviral therapy plays a central role in the development of lipodystrophy syndrome, which may affect up to 50% of patients depending on the diagnostic criteria used. Most protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs) are involved in body fat changes and associated metabolic disturbances. In contrast, non-NRTIs have not been directly related to the onset of this syndrome. One of the most widely used methods to evaluate body fat changes is dual-energy X-ray absorptiometry (DEXA), which can detect differences in the distribution of body fat in patients with and without lipodystrophy. New information from a randomized open-label clinical trial suggests that efavirenz could have greater potential for causing lipoatrophy than lopinavir+ritonavir. This paper examines the impact of efavirenz on adipose tissue and body fat composition in order to evaluate whether this drug plays a role in the development of lipodystrophy. We have focused on the evidence obtained from comparative randomized clinical trials that use an objective measurement of fat distribution, such as DEXA. We analysed available in vitro data and evidence from non-comparative clinical trials.

Keywords: lipodystrophy , lopinavir , DEXA scan , antiretroviral drugs , HAART


   Introduction
Top
 Abstract
 Introduction
In vitro data
 Clinical data
 Non-comparative studies
 Comparative studies
 Data for lipid outcome
 Conclusions and clinical...
 Transparency declarations
 References
 
Lipodystrophy arising from the treatment of HIV-1 infection and its associated metabolic alterations (e.g. dyslipidaemia and insulin resistance) is a multifactorial syndrome. Although highly active antiretroviral therapy (HAART) plays a central role in the development of this syndrome, it is also known that adipose tissue disorders are already present in naive HIV-1-infected patients. The mechanisms underlying the onset of this syndrome may represent a response to independent or interdependent factors, such as long-lasting viral infection, host-related factors, specific drugs or a specific combination of drugs.1–9

The first drugs to be associated with lipodystrophy were the protease inhibitors (PIs),1,2,6,10 and this relationship was later confirmed by in vitro studies.11–17 The duration of the therapy with nucleoside reverse transcriptase inhibitors (NRTIs), especially thymidine nucleotides, was subsequently observed to be associated with the onset of lipoatrophy and lactic acidosis,3,7,18,19 mainly as a consequence of the inhibition of DNA polymerase {gamma} in the mitochondria.20,21 In contrast, non-NRTIs (NNRTIs) have not been directly related to the onset of lipodystrophy. In fact, these were first used in studies on switching therapy from PIs as a means of reversing or stabilizing PI-induced lipodystrophy.22–26 In those studies, the replacement of PIs by NNRTIs, generally after 1 year of follow-up, did not lead to any significant change in body fat (i.e. no improvement or worsening).

In clinical terms, lipodystrophy becomes evident by a loss of fat in the face and limbs that may be accompanied by an accumulation of fat on the trunk and the back of the neck. Incidence varies depending on the diagnostic criteria used, but up to 50% of the patients on HAART may experience this condition.2–4,6,7,27,28 Alterations in the distribution of body fat are a serious aesthetic problem that can stigmatize patients. Even if patients have controlled HIV infection, adhere to therapy and lead a normal life, lipodystrophy can make them look ill and potentially identify them as AIDS patients. It is no surprise, therefore, that in patients suffering from morphological changes, adherence to therapy may be compromised, thus leading to treatment failure.29 Furthermore, metabolic alterations such as dyslipidaemia and insulin resistance can increase the risk of cardiovascular diseases in the long term.30–34

Unfortunately, there are no objective criteria or case definitions for lipodystrophy. The evaluation of altered fat distribution by patients or physicians is easy; however, it does not allow for comparisons within the same patient or between different studies, because it is not objective. Yet, clinical research requires an evaluation that is as objective as possible in order to reliably determine the incidence of this condition, identify associated risk factors and evaluate the efficacy of preventive and therapeutic measures. In this sense, several different methods have been used to evaluate patients with lipodystrophy: anthropometric measurements, computed tomography, magnetic resonance imaging, sonography and dual-energy X-ray absorptiometry (DEXA).2–4,7,35–38 This technique analyses regional and whole-body composition and is the most widely used one. It has proved useful in the diagnosis and evaluation of lipodystrophy and can detect differences in the distribution of body fat in patients with and without lipodystrophy.38 Nevertheless, the results vary according to the manufacturer, site, operator and hardware and software versions used.39–43 Therefore, the results of DEXA, especially in multicentre studies involving several operators, must be interpreted with caution. The ideal solution would be a central analysis site with as few operators as possible so that variability in the measurements could be reduced.42

The recent results of a randomized open-label clinical trial suggest that efavirenz could have greater potential for causing lipoatrophy than lopinavir+ritonavir.44 This outcome is surprising, given that NNRTIs were not traditionally considered to be related to the development of lipodystrophy or at least were perceived as lower risk drugs than PIs. This paper aims to analyse the impact of efavirenz on adipose tissue and body fat composition and to evaluate whether this drug plays a role in the development of lipodystrophy. We searched MEDLINE and Embase for randomized clinical trials including efavirenz as part of the antiretroviral treatment schedule and using DEXA to measure fat distribution, as well as the most recent conference abstracts on HIV infection. We also searched for basic science studies on adipocytes in which efavirenz was used. Both clinical and adipocyte studies were included.


   In vitro data
Top
 Abstract
 Introduction
 In vitro data
Clinical data
 Non-comparative studies
 Comparative studies
 Data for lipid outcome
 Conclusions and clinical...
 Transparency declarations
 References
 
Adipocyte differentiation and metabolism seem to be very sensitive to HIV-1 infection, antiretroviral drugs or both. Historically, PIs were the first drugs associated with lipodystrophy and related metabolic disorders, whereas nucleoside analogues (mainly thymidine analogues) were later linked to the development of lipoatrophy. Several mechanisms have been postulated to explain the effects of PIs. Given that it is difficult to determine the adverse effects of a single drug on adipose tissue in patients taking combined antiretroviral treatment, in vitro models (mainly with mouse cells) have been used to examine the effects of these drugs on adipocyte metabolism and differentiation.

The potential mechanisms of the deleterious effects of PIs on fatty tissue include a negative effect on pre-adipocyte differentiation, impaired adipogenesis, promotion of adipocyte death, increased lipolysis and impairment of insulin signalling events and glucose transport. The inhibitory effects of PIs on adipogenesis have been related to the decreased expression of peroxisome proliferator-activated receptors or CCAAT enhancer-binding proteins (C/EBP{alpha}) or to altered expression or intranuclear localization of sterol regulatory element-binding protein (SREBP-1c).11–17,45–54 Nevertheless, the effects of PIs on the physiology of human adipocytes are not the same for all the drugs in this group. In this way, atazanavir does not seem to negatively affect adipocyte lipid synthesis or glucose transport, unlike ritonavir, lopinavir, saquinavir and nelfinavir.55

Information on the effect of nevirapine and efavirenz on adipocyte metabolism is very scarce. In a study evaluating the effects of nevirapine on brown adipocytes, this drug did not significantly impair cell biology and to some extent promoted adipocyte differentiation.56 In another study evaluating the effect of switching from indinavir to nevirapine on insulin metabolism and adipocyte apoptosis, only an improvement in the glucose/insulin ratio was demonstrated. Subcutaneous adipocyte apoptosis continued to occur in lipoatrophic areas, suggesting that this strategy cannot reverse lipoatrophy.57

To our knowledge, there is only one study on the role of efavirenz in this situation. El Hadri et al.58 attempted to analyse the effects of efavirenz on adipocyte differentiation and metabolism using an in vitro assay with murine (3T3-F442A) cells and human adipocytes exposed to efavirenz at different concentrations (0–50 µM). When incubated with pre-adipocytes during the differentiation process, efavirenz prevented these cells from accumulating lipids, and at high concentrations (40–50 µM), it also altered the magnitude of adipocyte differentiation. The latter effect was detectable even at low drug concentrations and did not seem to be related to activation of lipolysis, alteration in cell viability (this phenomenon was reversible upon drug withdrawal) or reduced baseline or insulin-stimulated glucose transport that would result in a decreased substrate availability for fatty acid biosynthesis. Nevertheless, the antilipogenic effect of efavirenz is the result of a dramatic down-regulation in the SREBP-1c expression through decreased mRNA levels and, consequently, the expression of the related mature 68 kDa protein. Because the mature form of SREBP-1c promotes the lipogenic gene expression, the significant decrease in the levels of the 68 kDa SREBP-1c protein probably contributes to impaired lipogenesis in efavirenz-treated cells. In this experiment, the inhibitory effect of efavirenz on cell triglyceride accumulation could be reversed by providing the cells with free fatty acids and by overexpression of a dominant positive form of SREBP-1c.

As the authors suggested, the effect of efavirenz on adipose tissue could be counteracted by de novo hepatic lipid synthesis. Moreover, although efavirenz can accumulate in the adipose tissue59 and intracellular concentrations seem to be higher than plasma concentrations,60 the concentrations used in this experiment were higher than those expected at the therapeutic levels. The average plasma Cmax in clinical studies ranges from 9.1 to 12.9 µM—levels over 12.7 µM are considered toxic and 3.1 µM is considered the minimum efficacious concentration.61–65 Further clinical investigation is warranted in this field to ascertain the medical relevance of these observations and whether efavirenz could also alter lipogenesis in hepatocytes.

Recently, Hammond et al.66 presented data regarding the effects of efavirenz and lopinavir on adipose tissue in HIV-infected patients initiating the first-line therapy. Biopsy samples were assessed for mitochondrial DNA and tissue histology, as well as for cytokine expression. There was no evidence that the use of efavirenz or lopinavir affected mitochondrial DNA depletion or cytokine expression in the adipose tissue, whereas thymidine analogues were strongly associated with mitochondrial DNA depletion and pathological changes characteristic of clinical lipoatrophy.

In summary, in vitro studies show that both PIs and NNRTIs may have an impact on adipocyte metabolism. Although the evidence is greater for PIs, information on the potential role of NNRTIs remains scarce and needs further evaluation.


   Clinical data
Top
 Abstract
 Introduction
 In vitro data
 Clinical data
Non-comparative studies
 Comparative studies
 Data for lipid outcome
 Conclusions and clinical...
 Transparency declarations
 References
 
Lipoatrophy has mainly been associated with NRTIs, especially thymidine analogues and, more specifically, stavudine.3,7,18,19,67,68 Therefore, several studies have explored the possibility of reversing lipoatrophy by switching from thymidine analogues to thymidine-sparing combinations. Nevertheless, once lipoatrophy is established, the results up to 1–2 years have not been promising and recovery of limb fat has been limited.69–76 On the contrary, the good tolerability and ease of use of NNRTIs meant that they were initially explored for reducing the toxicity and complexity of PI-based therapy.22,77–80 This, together with their antiviral efficacy, has made the combination of efavirenz+2 NRTIs one of the preferred combinations for naive patients.81,82 Unlike NRTIs or PIs, NNRTIs have not been directly related to lipodystrophy (specifically lipoatrophy) in cohort studies or clinical trials. To assess the potential role of efavirenz compared with PIs in the emergence of lipodystrophy, we reviewed comparative and non-comparative published clinical studies in which an objective measure of fat distribution, such as DEXA, was performed.


   Non-comparative studies
Top
 Abstract
 Introduction
 In vitro data
 Clinical data
 Non-comparative studies
Comparative studies
 Data for lipid outcome
 Conclusions and clinical...
 Transparency declarations
 References
 
Body fat has been measured by DEXA in five non-comparative trials in which efavirenz was the anchor drug: ABCDE83 (stavudine+lamivudine+efavirenz versus abacavir+lamuvudine+efavirenz), Gilead Study 93484 (tenofovir+emtricitabine+efavirenz versus zidovudine+lamivudine+efavirenz), ACTG 5125s85 (simplification to 2 NRTIs+efavirenz versus lopinavir+efavirenz), Gilead 90386 (tenofovir+lamivudine+efavirenz versus stavudine+lamivudine+efavirenz) and Sweet87 (switch from zidovudine/lamivudine+efavirenz to tenofovir/emtricitabine+efavirenz versus zidovudine/lamivudine+efavirenz) (Table 1). These studies show the expected impact of body fat on the population treated with efavirenz and NRTIs.83–86 Three involved naive patients and two involved a simplification strategy. In two of the studies (Gilead 903 and Gilead 934), DEXA was not used at the baseline visit, although body fat changes were measured on two occasions during therapy with an interval of 48 weeks between measurements. The follow-ups were long and, except for one case, there were evaluations at 96 weeks. In two of the studies, a clinical evaluation of lipoatrophy was also carried out.


View this table:
[in this window]
[in a new window]

  		Table 1. Study characteristics

 
In general, thymidine-analogue-sparing regimens showed a continuous weight gain up to week 144. In the ABCDE study, the weight gain was 913 g in the abacavir (ABC) arm compared with a loss of 1578 g in the stavudine arm. In ACTG 5125s, the gain was 782 g in the NRTI-sparing arm (a 10% increase on baseline) compared with a loss of 850 g (15%) in the arm including NRTIs with efavirenz. In ACTG 5142s, patients simplified therapy after at least 18 months on successful HAART (median time on antiretroviral therapy in the efavirenz+2 NRTIs arm was 127 weeks) and the NRTI pairs used in 25 of the 31 patients included thymidine analogues (stavudine 6; zidovudine 19). In Gilead 903 and 934, baseline DEXA was not performed because the design of the body composition substudy was established after the initiation of the main study. However, the results of these studies do not show whether body fat remained stable or not with prolonged antiretroviral therapy. Once again, the tenofovir-containing arms, unlike those containing stavudine or zidovudine, continued to show a significant gain in weight (tenofovir 300 g versus zidovudine 700 g in Gilead 934 and tenofovir 2900 g versus stavudine 600 g in Gilead 903). Furthermore, significant differences were also observed in total limb fat between the groups including stavudine or zidovudine compared with tenofovir at week 96: tenofovir 7.7 kg (n = 144) versus zidovudine 5.5 kg (n = 136) (P < 0.001). There were no significant differences in trunk fat between the groups. Diagnosis of lipodystrophy was based on the physician’s evaluation. In Gilead 903, clinical lipodystrophy was included among the adverse effects. In both studies, the incidence of lipodystrophy in the thymidine-analogue-sparing groups was very low: tenofovir 3% versus stavudine 19% at 144 weeks in Gilead 903 (P < 0.001) and abacavir 4.8% versus stavudine 38.3% at 96 weeks in the ABCDE study (P < 0.001).

Data from studies in which efavirenz is used as an anchor drug consistently show that when the backbone is composed of non-thymidine analogues, the long-term incidence of lipodystrophy is very low, with a significant gain in weight that continues at least until week 144. Even in those patients treated with zidovudine/lamivudine for a median of 2.9 years, the change to tenofovir/emtricitabine improves the limb fat by an average of 261 g. The development of clinical lipoatrophy in patients treated with efavirenz, after 2–3 years of therapy, has ranged from 15% to 38% when a thymidine analogue is used and from 3% to 4.8% when abacavir or tenofovir is used. Similarly, limb fat changes have ranged from a loss of 1578 g to a gain of 600 g in thymidine analogue-treated patients compared with a net gain of 300–2900 g in patients not treated with thymidine analogues.


   Comparative studies
Top
 Abstract
 Introduction
 In vitro data
 Clinical data
 Non-comparative studies
 Comparative studies
Data for lipid outcome
 Conclusions and clinical...
 Transparency declarations
 References
 
Four prospective randomized studies have compared alterations in body fat distribution using DEXA: ACTG 5005s88 (efavirenz versus nelfinavir versus efavirenz+nelfinavir), BMS-03489 (efavirenz versus non-boosted atazanavir), M03-61390 (simplification to lopinavir monotherapy after an induction period of 24–48 weeks of zidovudine/lamivudine+lopinavir versus zidovudine/lamivudine+efavirenz) and ACTG 514244 (efavirenz versus lopinavir versus efavirenz+lopinavir). In all four, the backbone included thymidine analogues, although in ACTG 5142, 34% of the patients received tenofovir instead of stavudine or zidovudine (in ACTG 5142, allocation of NRTIs was not randomized), and in M03-613, patients assigned to lopinavir monotherapy discontinued zidovudine+lamivudine. All patients underwent a DEXA scan at the baseline visit. This was compared with the follow-up scans at week 48, 96 or 144 (Table 1). The patients were mainly males aged 30–40. In ACTG 5142, the patients had a lower CD4 count, were older and the number of non-white patients was greater than in the other two studies (64% in ACTG 5142 versus 55% in BMS-034 and 49% in ACTG 5005s). Limb fat at baseline was slightly lower in the ACTG 5005s patients, whereas in the other three studies, it was almost normal.1,91

In ACTG 5005s, for the group as a whole, limb fat increased during the first 32 weeks and subsequently declined. Patients who received efavirenz did not show significant changes in limb fat at 144 weeks (an increase of 200 g, 2.4% from baseline; P = 0.90). However, in those patients who received nelfinavir-containing regimens, a weight loss of 1900 g corresponding to 23.8% from baseline (P = 0.05) was observed. After week 32, there was an additional decrease in limb fat of –8.7% per year in the combined nelfinavir and nelfinavir+efavirenz group when compared with efavirenz alone, after adjusting for the nucleoside backbone (P = 0.03). If those patients who received didanosine+stavudine are excluded and only those who were treated with zidovudine+lamivudine are considered, after week 32, limb fat changed by 2.7% per year with efavirenz and by –7.9% per year for the combined nelfinavir and nelfinavir+efavirenz group (P = 0.03). Trunk fat increased during the first 32 weeks and was maintained over time. The only group that presented a significant increase in body fat was the efavirenz group: 3500 g (32%) (P = 0.01) versus nelfinavir 300 g (2.7%) (P = 0.4) versus nelfinavir+efavirenz 600 g (6.9%) (P = 0.5). If we focus only on patients receiving zidovudine+lamivudine, after week 32, trunk fat changed by 18.9% per year with efavirenz and by –3.5% per year for the combined nelfinavir and nelfinavir+efavirenz arm (P < 0.0001).

In BMS-034, visceral, subcutaneous (appendicular) and total adipose tissue (VAT, SAT and TAT, respectively) did not change significantly within the efavirenz and atazanavir groups between the baseline and week 48 visit, and there were no differences between the efavirenz and atazanavir arms. As for the SAT to TAT ratio and the VAT to TAT ratio, no significant changes from baseline were observed in either treatment group. Although computed tomography results were comparable for the two treatment arms at baseline, there was a modest but statistically significant increase for the atazanavir group compared with the efavirenz group in VAT (33% versus 23%) and TAT (21% versus 10%). Nevertheless, in this study, the follow-up was only made up to 48 weeks, thus making it impossible to draw long-term conclusions.

In M03-613, a significant improvement in limb fat was observed at 96 weeks in the lopinavir monotherapy arm (18% versus –9%), whereas it was not observed for the trunk fat. Nevertheless, differences were more evident from 24 and 48 weeks onwards, maybe reflecting the effect of zidovudine discontinuation at that point.

ACTG 5142 compared three class-sparing regimens for naive subjects: lopinavir (soft-gel)+efavirenz, lopinavir+2 NRTIs and efavirenz+2 NRTIs. NRTIs were selected before randomization and the choice was zidovudine 42%, stavudine-XR 24% or tenofovir 34%. The study differs from previous trials in several ways, for example, the definition of lipoatrophy (not used previously in any clinical trial) or the non-randomized choice of NRTI. The median change from baseline through week 96 in limb fat was significantly different between the groups: lopinavir+efavirenz 18%, lopinavir 9.8% and efavirenz 1.4% (P ≤ 0.01 for all pairwise comparisons). However, the median change in the trunk fat did not disclose significant differences in any group: lopinavir 19%, lopinavir+efavirenz 17% and efavirenz 12%. The incidence of lipoatrophy (defined as >20% loss in limb fat) at week 96 was significantly different between the groups: efavirenz 32%, lopinavir 17% and lopinavir+efavirenz 9% (P values for pairwise comparisons: lopinavir+efavirenz versus lopinavir, P = 0.013; lopinavir+efavirenz versus efavirenz, P < 0.001; and lopinavir versus efavirenz, P = 0.007). If we look at the differences in the incidence of lipoatrophy at 96 weeks with regard to the NRTIs used, the highest percentage was observed with the thymidine analogues stavudine (42%) and zidovudine (27%), and the lowest percentage was observed with tenofovir (9%). All pairwise comparisons of NRTIs were significant: zidovudine versus tenofovir, P < 0.001; stavudine versus tenofovir, P < 0.001; and stavudine versus zidovudine, P = 0.038. Similarly, the incidence of lipoatrophy was greater in the efavirenz and lopinavir groups when these were associated with thymidine analogues (stavudine > zidovudine > tenofovir) (Table 2). A logistic regression model including a randomized arm and NRTIs was applied to the week 96 lipoatrophy data for the NRTI-containing regimens. For lipoatrophy, this analysis showed an odds ratio (OR) of 2.7 (95% CI: 1.5–4.6) for efavirenz versus lopinavir (P < 0.001), 1.9 (95% CI: 1.1–3.5) for stavudine versus zidovudine (P = 0.029) and 0.24 (95% CI: 0.12–0.5) for tenofovir versus zidovudine (P < 0.001). There were no interactions analyses to examine whether the effect of each NRTI was significantly different for efavirenz or lopinavir.


View this table:
[in this window]
[in a new window]

  		Table 2. Patients with >20% fat loss in efavirenz and lopinavir/ritonavir arms in ACTGs 5142

 
The most surprising aspect of these results is the analysis according to the number of subjects who presented a reduction of 20% or more in limb fat (taking this cut-off point as that which defines lipoatrophy). Although there is no objective definition of lipoatrophy, an incidence of 32% at 96 weeks seems to be well above that reported for patients treated with efavirenz, even more if we bear in mind that one-third of these patients received tenofovir. Furthermore, the number of patients with a limb fat loss ≥20% depended to a large extent on the NRTIs that formed the backbone: 51% with stavudine-XR, 49% with zidovudine and 12% with tenofovir. This behaviour was also observed with lopinavir, although less markedly: 33% for stavudine-XR, 16% for zidovudine and 6% for tenofovir. In this sense, the only regimen with no NRTI presented a significantly lower incidence (only 9%). In ACTG 5142, higher baseline CD4 cell count and lower gain in the body and trunk weight were associated with lipoatrophy and smaller gain in limb fat, independently of the antiretroviral regimen used. Analysing fat change as a continuous variable also found male sex, non-AIDS patient, lower baseline extremity fat and smaller increases in cholesterol and LDL cholesterol to be significantly associated with a smaller gain in limb fat. It seems that several factors other than antiretroviral therapy may be important in the pathogenesis of fat loss.92

How should these results be interpreted? First, we still need information on the baseline characteristics of the patients (body mass index, weight or dispersion of body mass values) to help us interpret correctly the variations observed. A gain in fat in patients who start with normal values may not be desirable or clinically irrelevant—in this sense, the patients in ACTG 5142 were within the normal range for limb fat values (7.1 kg).28,91,93, Furthermore, even if the definition of lipoatrophy is objective because it is based on DEXA, it is not validated as a measure of the presence of clinically significant lipoatrophy or even as a predictor of the development of lipoatrophy. In fact, patients with evident lipoatrophy have limb fat levels that are 40–50% lower than those in healthy patients;71,73,75,85,86 those with clinically apparent lipoatrophy have at least 30% limb fat loss regardless of baseline total fat or weight94 and anthropomorphic changes correlate modestly with DEXA measurements.89 Even in ACTG 5142, only 30% of the subjects with lipoatrophy as defined by DEXA reported fat loss.92 Therefore, a cut-off at 20% could be too sensitive in clinical terms.69 In addition, measurement by DEXA does not distinguish between subcutaneous and intra-abdominal fat.73,95

As far as thymidine analogues are concerned, it seems obvious that there is a clear relationship between the inclusion of these drugs in the antiretroviral regimen and a greater incidence of limb fat loss ≥20%. In fact, this was very low (9%) at 96 weeks in the NRTI-sparing group. Similarly, in ACTG 5125s, those patients whose regimens were simplified to lopinavir+efavirenz showed an average gain of 10% (782 g) in limb fat, despite the fact that they had been on thymidine-analogue-containing HAART for 18 months. What ACTG 5142 did reveal was a greater effect of thymidine analogues in the efavirenz group than in the lopinavir group. The OR of efavirenz versus lopinavir for developing lipoatrophy at 96 weeks was 2.7 (95% CI: 1.5–4.6). Nevertheless, no interaction test was carried out to determine whether the effect of the NRTIs (mainly thymidine analogues) was significantly greater in one group than in the other. What seems obvious is that if efavirenz alone had a potentially important role in the development of lipoatrophy, an impact on body fat would also have been observed in the lopinavir+efavirenz group. The behaviour of efavirenz may have been more neutral with respect to limb fat, in that lopinavir was more likely to be associated with fat gain and NRTIs with fat loss. This effect of greater fat gain in the limbs in the PI-containing regimens than in the PI-sparing regimens has also been observed in other studies.28

In summary, the results of comparative, randomized clinical trials seem to indicate that therapy with efavirenz leads to a gain in the limb fat in all cases. This gain, although modest (1.4%–9.3%), is higher than that produced by nelfinavir, similar to that of atazanavir and lower than that observed with lopinavir. Trunk fat also increases (3.2–32%), although with no significant differences with the PI comparator. Surprisingly, the incidence of lipodystrophy (defined as >20% loss in limb fat) in the ACTG 5142 trial was significantly higher than that of lopinavir (32% versus 17%) and was severely affected by the accompanying NRTI.


   Data for lipid outcome
Top
 Abstract
 Introduction
 In vitro data
 Clinical data
 Non-comparative studies
 Comparative studies
 Data for lipid outcome
Conclusions and clinical...
 Transparency declarations
 References
 
In general, it seems that the lipid profile worsens when the nucleoside backbone includes a thymidine analogue (more evident with stavudine than with zidovudine) than when it includes tenofovir or abacavir (Table 3). With tenofovir, in particular, plasma triglyceride levels remained unchanged or experienced minor increases. Cholesterol increased moderately with higher increases in HDL-C than in total cholesterol (TC), suggesting an improvement in the atherogenic profile. When efavirenz was combined with lopinavir or NRTI as the backbone in patients switching therapy, the lipid profile was significantly worse in the lopinavir group.85 The fact that all patients switched from PI-containing regimens probably contributes to this effect. Increases in triglycerides of over 400–500 mg/dL were more common with thymidine analogues (14–16% versus 3–4%) or lopinavir (8% versus 4%) than with the comparator, and the use of lipid-lowering agents was also more frequent with NRTIs (16–17% versus 4–11%).


View this table:
[in this window]
[in a new window]

  		Table 3. Lipid outcome in clinical studies

 
As for comparative trials between efavirenz and PIs, comparison with nelfinavir disclosed a slightly better lipid profile for efavirenz with a higher increase in HDL-C leading to a lower TC/HDL-C ratio. When compared with atazanavir (non-boosted), efavirenz showed a neutral lipid profile, with a slight increase in cholesterol levels and a stable atherogenic index (TC/HDL-C), whereas atazanavir improved its lipid figures in comparison with baseline. The figures for lipid outcome in ACTG 5142 were equivalent for efavirenz and lopinavir with regard to TC, HDL-C and non-HDL-C, whereas increases in triglycerides were significantly higher in the lopinavir arm. The worst performing arm was the NRTI-sparing regimen, which showed significant elevations in all the parameters tested.

Efavirenz generally behaves neutrally with respect to lipids (depending to a large extent on the accompanying NRTI), with increases in cholesterol that are usually accompanied by increases in HDL-C; therefore, the atherogenic index remains stable or even improves slightly. Therapy involving lopinavir usually leads to an increase in triglyceride values that is not always accompanied by an increase in cholesterol, whereas NRTI-sparing PI-containing regimens typically produce a much higher deterioration in lipids than that observed with lopinavir+2 NRTIs.44,83–86,89,96–100 In this sense, the progression of lipids in ACTG 5142 did in fact agree with the information from previous studies, and the greatest increases were detected with the NRTI-sparing regimens, whereas the lopinavir group had a significant increase in triglycerides in comparison with the efavirenz group. Nevertheless, we do not have the necessary number of patients with grades 3 and 4 cholesterol or increased triglyceride levels to enable us to provide a more accurate evaluation of these increases.

In summary, the efavirenz lipid profile seems to be neutral and is substantially affected by the NRTI backbone, the most favourable values being observed with tenofovir and abacavir. When compared with other PIs, efavirenz showed a profile that was very similar to that of nelfinavir (worse for cholesterol) or lopinavir (worse for triglycerides) and slightly worse than that of non-boosted atazanavir.


   Conclusions and clinical implications
Top
 Abstract
 Introduction
 In vitro data
 Clinical data
 Non-comparative studies
 Comparative studies
 Data for lipid outcome
 Conclusions and clinical...
Transparency declarations
 References
 
Lipodystrophy remains a major problem for HIV-infected patients. Aside from the metabolic complications that potentially contribute to increased cardiovascular risk, the change in the body appearance can be very stigmatizing. Therefore, any new data in this field are extremely relevant, as shown by the metabolic substudy of ACTG 5142.

ACTG 5142 compared the efficacy of two of the preferred regimens for naive patients, efavirenz+2 NRTIs and lopinavir+2 NRTIs, with the NRTI-sparing regimen efavirenz+lopinavir. This study showed the greater efficacy of efavirenz+2 NRTIs over lopinavir+2 NRTIs (proportion without virological failure at 96 weeks: 76% versus 67%) with no significant differences in the comparison with efavirenz+lopinavir (73%). CD4 lymphocyte recovery was significantly better with lopinavir than with efavirenz+2 NRTIs (285 versus 241 cells/mm3) and similar to that of lopinavir+efavirenz (268 cells/mm3). In the metabolic substudy, the incidence of lipoatrophy, defined as ≥20% loss of limb fat, was significantly higher in the efavirenz+2 NRTIs groups than in the lopinavir+2 NRTIs and efavirenz+lopinavir groups (32% versus 17% versus 9%).

To date, several studies that measure fat variation using DEXA have revealed that the potential role of efavirenz in the development of lipodystrophy is minimal or non-existent and that it depends on the NRTIs that form the backbone. The same cannot be said for lopinavir because before ACTG 5142 the effect of standard regimens containing NRTIs plus lopinavir on body fat was unknown. Direct comparisons of efavirenz with other third-arm drugs have been made in clinical trials with PIs. Patients treated with efavirenz in these studies gained weight and did not show significant losses of limb fat. The same occurred when the comparator was atazanavir, and only when patients received nelfinavir concomitantly was a significant reduction in limb fat observed. The results of ACTG 5142 are consistent with this: a 1.4% gain in limb fat was detected at week 96 for patients receiving efavirenz.

Even though the incidence of lipodystrophy has been significantly reduced by the avoidance of thymidine analogues and the availability of new antiretrovirals, it continues to be a serious problem for those who suffer from it. Therefore, it is essential to have long-term data on the potential for developing lipodystrophy of the most commonly used combinations and of those that include new drugs. To do this, we must have standardized criteria to objectively evaluate lipodystrophy. These criteria would enable us to compare the results of different studies using the same conditions for all, evaluate the long-term outcome of therapeutic and preventive measures, and even design studies to predict the appearance of morphological alterations associated with HAART.


   Transparency declarations
Top
 Abstract
 Introduction
 In vitro data
 Clinical data
 Non-comparative studies
 Comparative studies
 Data for lipid outcome
 Conclusions and clinical...
 Transparency declarations
References
 
J. A. P.-M. has received grant support and has served as a consultant for Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead and GSK. P. D. has received grant support and has served as a consultant/speaker for Bristol-Myers Squibb, Glaxo Smith Kline, Boehringer Ingelheim, Roche, Abbott, Janssen Cilag, Gilead Sciences, Pfizer and Merck Sharp and Dohme. E. M. has participated on advisory boards and received research grants, travel grants, or honoraria from Abbott, BMS, Boehringer- Ingelheim, Gilead, GSK and Janssen. S. M. has received grant support and has served as a consultant for Abbott Laboratories, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, GSK, MSD, Pfizer and Roche.


   References
Top
 Abstract
 Introduction
 In vitro data
 Clinical data
 Non-comparative studies
 Comparative studies
 Data for lipid outcome
 Conclusions and clinical...
 Transparency declarations
 References
 
1 Carr A, Samaras K, Chisholm DJ, et al. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet (1998) 351:1881–3.[CrossRef][Web of Science][Medline]

2 Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet (1999) 353:2093–9.[CrossRef][Web of Science][Medline]

3 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) 13:1659–67.[CrossRef][Web of Science][Medline]

4 Lichtenstein KA, Ward DJ, Moorman AC, et al. Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS (2001) 15:1389–98.[CrossRef][Web of Science][Medline]

5 Lichtenstein KA. Redefining lipodystrophy syndrome: risks and impact on clinical decision making. J Acquir Immune Defic Syndr (2005) 39:395–400.[CrossRef][Web of Science][Medline]

6 Martinez E, Mocroft A, Garcia-Viejo MA, et al. Risk of lipodystrophy in HIV-1-infected patients treated with protease inhibitors: a prospective cohort study. Lancet (2001) 357:592–8.[CrossRef][Web of Science][Medline]

7 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:F25–32.[CrossRef][Web of Science][Medline]

8 Munoz-Sanz A, Rodriguez-Vidigal FF, Domingo P. Pathogenesis of lipodystrophy and metabolic syndromes associated with HIV infection. Med Clin (Barc) (2006) 127:465–74.[CrossRef][Medline]

9 Giralt M, Domingo P, Guallar JP, et al. HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV-1/HAART-associated lipodystrophy. Antivir Ther (2006) 11:729–40.[Web of Science][Medline]

10 Miller KD, Jones E, Yanovski JA, et al. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet (1998) 351:871–5.[CrossRef][Web of Science][Medline]

11 Zhang B, MacNaul K, Szalkowski D, et al. Inhibition of adipocyte differentiation by HIV protease inhibitors. J Clin Endocrinol Metab (1999) 84:4274–7.[Abstract/Free Full Text]

12 Lenhard JM, Weiel JE, Paulik MA, et al. Stimulation of vitamin A(1) acid signaling by the HIV protease inhibitor indinavir. Biochem Pharmacol (2000) 59:1063–8.[CrossRef][Web of Science][Medline]

13 Caron M, Auclair M, Vigouroux C, et al. The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance. Diabetes (2001) 50:1378–88.[Abstract/Free Full Text]

14 Caron M, Auclair M, Sterlingot H, et al. Some HIV protease inhibitors alter lamin A/C maturation and stability, SREBP-1 nuclear localization and adipocyte differentiation. AIDS (2003) 17:2437–44.[CrossRef][Web of Science][Medline]

15 Domingo P, Matias-Guiu X, Pujol RM, et al. Subcutaneous adipocyte apoptosis in HIV-1 protease inhibitor-associated lipodystrophy. AIDS (1999) 13:2261–7.[CrossRef][Web of Science][Medline]

16 Vernochet C, Azoulay S, Duval D, et al. Differential effect of HIV protease inhibitors on adipogenesis: intracellular ritonavir is not sufficient to inhibit differentiation. AIDS (2003) 17:2177–80.[CrossRef][Web of Science][Medline]

17 Wentworth JM, Burris TP, Chatterjee VK. HIV protease inhibitors block human preadipocyte differentiation, but not via the PPAR{gamma}/RXR heterodimer. J Endocrinol (2000) 164:R7–10.[Abstract]

18 Smith DE, Carr A, Law M, et al. Thymidine analogue withdrawal for lipoatrophic patients on protease-sparing therapy improves lipoatrophy but compromises antiviral control: the PIILR extension study. AIDS (2002) 16:2489–91.[CrossRef][Web of Science][Medline]

19 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) 14:1309–16.[CrossRef][Web of Science][Medline]

20 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) 354:1112–5.[CrossRef][Web of Science][Medline]

21 Lee H, Hanes J, Johnson KA. Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase. Biochemistry (2003) 42:14711–9.[CrossRef][Web of Science][Medline]

22 Martinez E, Arnaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl J Med (2003) 349:1036–46.[Abstract/Free Full Text]

23 Ruiz L, Negredo E, Domingo P, et al. Antiretroviral treatment simplification with nevirapine in protease inhibitor-experienced patients with HIV-associated lipodystrophy: 1-year prospective follow-up of a multicenter, randomized, controlled study. J Acquir Immune Defic Syndr (2001) 27:229–36.[Web of Science][Medline]

24 Martinez E, Garcia-Viejo MA, Blanco JL, et al. Impact of switching from human immunodeficiency virus type 1 protease inhibitors to efavirenz in successfully treated adults with lipodystrophy. Clin Infect Dis (2000) 31:1266–73.[CrossRef][Web of Science][Medline]

25 Rey D, Schmitt MP, Partisani M, et al. Efavirenz as a substitute for protease inhibitors in HIV-1-infected patients with undetectable plasma viral load on HAART: a median follow-up of 64 weeks. J Acquir Immune Defic Syndr (2001) 27:459–62.[Web of Science][Medline]

26 Hirschel B, Flepp M, Bucher HC, et al. Switching from protease inhibitors to efavirenz: differences in efficacy and tolerance among risk groups: a case–control study from the Swiss HIV Cohort. AIDS (2002) 16:381–5.[CrossRef][Web of Science][Medline]

27 Bogner JR, Vielhauer V, Beckmann RA, et al. Stavudine versus zidovudine and the development of lipodystrophy. J Acquir Immune Defic Syndr (2001) 27:237–44.[Web of Science][Medline]

28 Mulligan K, Anastos K, Justman J, et al. Fat distribution in HIV-infected women in the United States: DEXA substudy in the Women’s Interagency HIV Study. J Acquir Immune Defic Syndr (2005) 38:18–22.[CrossRef][Web of Science][Medline]

29 Duran S, Saves M, Spire B, et al. Failure to maintain long-term adherence to highly active antiretroviral therapy: the role of lipodystrophy. AIDS (2001) 15:2441–4.[CrossRef][Web of Science][Medline]

30 Johnsen S, Dolan SE, Fitch KV, et al. Carotid intimal medial thickness in human immunodeficiency virus-infected women: effects of protease inhibitor use, cardiac risk factors, and the metabolic syndrome. J Clin Endocrinol Metab (2006) 91:4916–24.[Abstract/Free Full Text]

31 Jacobson DL, Tang AM, Spiegelman D, et al. Incidence of metabolic syndrome in a cohort of HIV-infected adults and prevalence relative to the US population (National Health and Nutrition Examination Survey). J Acquir Immune Defic Syndr (2006) 43:458–66.[CrossRef][Web of Science][Medline]

32 Bergersen BM. Cardiovascular risk in patients with HIV infection: impact of antiretroviral therapy. Drugs (2006) 66:1971–87.[CrossRef][Web of Science][Medline]

33 Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med (2007) 356:1723–35.[Abstract/Free Full Text]

34 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) 17:1179–93.[CrossRef][Web of Science][Medline]

35 Dinges WL, Chen D, Snell PG, et al. Regional body fat distribution in HIV-infected patients with lipodystrophy. J Investig Med (2005) 53:15–25.[CrossRef][Web of Science][Medline]

36 Schwenk A. Methods of assessing body shape and composition in HIV-associated lipodystrophy. Curr Opin Infect Dis (2002) 15:9–16.[Web of Science][Medline]

37 Martinez E, Bianchi L, Garcia-Viejo MA, et al. Sonographic assessment of regional fat in HIV-1-infected people. Lancet (2000) 356:1412–3.[CrossRef][Web of Science][Medline]

38 Carr A, Emery S, Law M, et al. An objective case definition of lipodystrophy in HIV-infected adults: a case–control study. Lancet (2003) 361:726–35.[CrossRef][Web of Science][Medline]

39 Kistorp CN, Svendsen OL. Body composition analysis by dual energy X-ray absorptiometry in female diabetics differ between manufacturers. Eur J Clin Nutr (1997) 51:449–54.[CrossRef][Web of Science][Medline]

40 Tothill P, Avenell A, Love J, et al. Comparisons between Hologic, Lunar and Norland dual-energy X-ray absorptiometers and other techniques used for whole-body soft tissue measurements. Eur J Clin Nutr (1994) 48:781–94.[Web of Science][Medline]

41 Pritchard JE, Nowson CA, Strauss BJ, et al. Evaluation of dual energy X-ray absorptiometry as a method of measurement of body fat. Eur J Clin Nutr (1993) 47:216–28.[Web of Science][Medline]

42 Smith DE, Hudson J, Martin A, et al. Centralized assessment of dual-energy X-ray absorptiometry (DEXA) in multicenter studies of HIV-associated lipodystrophy. HIV Clin Trials (2003) 4:45–9.[CrossRef][Web of Science][Medline]

43 Yang Y, Zhu WD, Paton NI. Comparison of dual-energy X-ray absorptiometry machines for measuring fat distribution changes of HIV-associated lipodystrophy. Antivir Ther (2004) 9:771–8.[Web of Science][Medline]

44 Haubrich R, Riddler S, DiRienzo D, et al. Metabolic outcomes of ACTG 5142: a prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection. 14th Conference on Retrovirus and Opportunistic Infections, Los Angeles, 25–28 February 2007.

45 Bastard JP, Caron M, Vidal H, et al. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet (2002) 359:1026–31.[CrossRef][Web of Science][Medline]

46 Dowell P, Flexner C, Kwiterovich PO, et al. Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors. J Biol Chem (2000) 275:41325–32.[Abstract/Free Full Text]

47 Kim RJ, Wilson CG, Wabitsch M, et al. HIV protease inhibitor-specific alterations in human adipocyte differentiation and metabolism. Obesity (Silver Spring) (2006) 14:994–1002.[Medline]

48 Lenhard JM, Croom DK, Weiel JE, et al. Dietary fat alters HIV protease inhibitor-induced metabolic changes in mice. J Nutr (2000) 130:2361–6.[Abstract/Free Full Text]

49 Lenhard JM, Furfine ES, Jain RG, et al. HIV protease inhibitors block adipogenesis and increase lipolysis in vitro. Antiviral Res (2000) 47:121–9.[CrossRef][Web of Science][Medline]

50 Miserez AR, Muller PY, Spaniol V. Indinavir inhibits sterol-regulatory element-binding protein-1c-dependent lipoprotein lipase and fatty acid synthase gene activations. AIDS (2002) 16:1587–94.[CrossRef][Web of Science][Medline]

51 Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem (2000) 275:20251–4.[Abstract/Free Full Text]

52 Nerurkar PV, Shikuma CM, Nerurkar VR. Sterol regulatory element-binding proteins and reactive oxygen species: potential role in highly-active antiretroviral therapy (HAART)-associated lipodystrophy. Clin Biochem (2001) 34:519–29.[CrossRef][Web of Science][Medline]

53 Riddle TM, Kuhel DG, Woollett LA, et al. HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus. J Biol Chem (2001) 276:37514–9.[Abstract/Free Full Text]

54 Rudich A, Vanounou S, Riesenberg K, et al. The HIV protease inhibitor nelfinavir induces insulin resistance and increases basal lipolysis in 3T3-L1 adipocytes. Diabetes (2001) 50:1425–31.[Abstract/Free Full Text]

55 Parker RA, Flint OP, Mulvey R, et al. Endoplasmic reticulum stress links dyslipidemia to inhibition of proteasome activity and glucose transport by HIV protease inhibitors. Mol Pharmacol (2005) 67:1909–19.[Abstract/Free Full Text]

56 Rodríguez de la Concepción M, Iglesias R, Yubero P, et al. Uncoupling protein and brown adipocyte mitochondrial as potential targets of reverse transcriptase inhibitor-induced lipodystrophy. Proceedings of the XIV International AIDS Conference, Barcelona, 7–12 July 2002.

57 Domingo P, Matias-Guiu X, Pujol RM, et al. Switching to nevirapine decreases insulin levels but does not improve subcutaneous adipocyte apoptosis in patients with highly active antiretroviral therapy-associated lipodystrophy. J Infect Dis (2001) 184:1197–201.[CrossRef][Web of Science][Medline]

58 El Hadri K, Glorian M, Monsempes C, et al. In vitro suppression of the lipogenic pathway by the nonnucleoside reverse transcriptase inhibitor efavirenz in 3T3 and human preadipocytes or adipocytes. J Biol Chem (2004) 279:15130–41.[Abstract/Free Full Text]

59 Dupin N, Buffet M, Marcelin AG, et al. HIV and antiretroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy. AIDS (2002) 16:2419–24.[CrossRef][Web of Science][Medline]

60 Almond LM, Hoggard PG, Edirisinghe D, et al. Intracellular and plasma pharmacokinetics of efavirenz in HIV-infected individuals. J Antimicrob Chemother (2005) 56:738–44.[Abstract/Free Full Text]

61 Tashima KT, Caliendo AM, Ahmad M, et al. Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug concentrations in HIV-1-infected patients receiving combination therapy. J Infect Dis (1999) 180:862–4.[CrossRef][Web of Science][Medline]

62 EMEA. Sustiva. Summary of Product Characteristics. http://www.emea.europa.eu/humandocs/Humans/EPAR/sustiva/sustiva.htm (26 February 2008, date last accessed).

63 Burger D, van der Heiden I, la Porte C, et al. Interpatient variability in the pharmacokinetics of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz: the effect of gender, race, and CYP2B6 polymorphism. Br J Clin Pharmacol (2006) 61:148–54.[CrossRef][Web of Science][Medline]

64 Smith PF, DiCenzo R, Morse GD. Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors. Clin Pharmacokinet (2001) 40:893–905.[CrossRef][Web of Science][Medline]

65 Donnerer J, Kronawetter M, Kapper A, et al. Therapeutic drug monitoring of the HIV/AIDS drugs abacavir, zidovudine, efavirenz, nevirapine, indinavir, lopinavir, and nelfinavir. Pharmacology (2003) 69:197–204.[CrossRef][Web of Science][Medline]

66 Hammond E, McKinnon B, Pace C, et al. Influence of NRT1 choice and efavirenz versus lopinavir options on lipoatrophy-associated adipose tissue toxicity: a longitudinal study. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 2008.

67 Shlay JC, Visnegarwala F, Bartsch G, et al. Body composition and metabolic changes in antiretroviral-naive patients randomized to didanosine and stavudine vs. abacavir and lamivudine. J Acquir Immune Defic Syndr (2005) 38:147–55.[CrossRef][Web of Science][Medline]

68 Yang Y, Wilder-Smith A, Panchalingam A, et al. Changes in body fat measured by DEXA in patients taking different formulations of stavudine. HIV Clin Trials (2005) 6:337–43.[CrossRef][Web of Science][Medline]

69 Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA (2002) 288:207–15.[Abstract/Free Full Text]

70 Carr A, Hudson J, Chuah J, et al. HIV protease inhibitor substitution in patients with lipodystrophy: a randomized, controlled, open-label, multicentre study. AIDS (2001) 15:1811–22.[CrossRef][Web of Science][Medline]

71 Moyle GJ, Sabin CA, Cartledge J, et al. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS (2006) 20:2043–50.[Web of Science][Medline]

72 Tavassoli N, Bagheri H, Sommet A, et al. Effects of discontinuing stavudine or protease inhibitor therapy on human immunodeficiency virus-related fat redistribution evaluated by dual-energy x-ray absorptiometry. Pharmacotherapy (2006) 26:154–61.[CrossRef][Web of Science][Medline]

73 Martin A, Smith DE, Carr A, et al. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS (2004) 18:1029–36.[CrossRef][Web of Science][Medline]

74 Moyle GJ, Baldwin C, Langroudi B, et al. A 48-week, randomized, open-label comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy. J Acquir Immune Defic Syndr (2003) 33:22–8.[Web of Science][Medline]

75 McComsey GA, Ward DJ, Hessenthaler SM, et al. Improvement in lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virus-infected patients switched from stavudine to abacavir or zidovudine: the results of the TARHEEL study. Clin Infect Dis (2004) 38:263–70.[CrossRef][Web of Science][Medline]

76 John M, McKinnon EJ, James IR, et al. Randomized, controlled, 48-week study of switching stavudine and/or protease inhibitors to combivir/abacavir to prevent or reverse lipoatrophy in HIV-infected patients. J Acquir Immune Defic Syndr (2003) 33:29–33.[Web of Science][Medline]

77 Negredo E, Cruz L, Paredes R, et al. Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with human immunodeficiency virus infection and long-lasting viral suppression. Clin Infect Dis (2002) 34:504–10.[CrossRef][Web of Science][Medline]

78 Martinez E, Conget I, Lozano L, et al. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS (1999) 13:805–10.[CrossRef][Web of Science][Medline]

79 Molina JM, Journot V, Morand-Joubert L, et al. Simplification therapy with once-daily emtricitabine, didanosine, and efavirenz in HIV-1-infected adults with viral suppression receiving a protease inhibitor-based regimen: a randomized trial. J Infect Dis (2005) 191:830–9.[CrossRef][Web of Science][Medline]

80 Maggiolo F, Ripamonti D, Ravasio L, et al. Outcome of 2 simplification strategies for the treatment of human immunodeficiency virus type 1 infection. Clin Infect Dis (2003) 37:41–9.[CrossRef][Web of Science][Medline]

81 Recommendations from the GESIDA/Spanish AIDS Plan regarding antiretroviral treatment in adults with human immunodeficiency virus infection (update January 2007). Enferm Infecc Microbiol Clin (2007) 25:32–53.[CrossRef][Web of Science][Medline]

82 Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents. Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents - A Working Group of the Office of AIDS Research Advisory Council, 1 December 2008.

83 Podzamczer D, Ferrer E, Sanchez P, et al. Less lipoatrophy and better lipid profile with abacavir as compared to stavudine: 96-week results of a randomized study. J Acquir Immune Defic Syndr (2007) 44:139–47.[CrossRef][Web of Science][Medline]

84 Pozniak AL, Gallant JE, DeJesus E, et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes—a 96-week analysis. J Acquir Immune Defic Syndr (2006) 43:535–40.[Medline]

85 Tebas P, Zhang J, Yarasheski K, et al. Switching to a protease inhibitor-containing, nucleoside-sparing regimen (lopinavir/ritonavir plus efavirenz) increases limb fat but raises serum lipid levels: results of a prospective randomized trial (AIDS Clinical Trial Group 5125s). J Acquir Immune Defic Syndr (2007) 45:193–200.[CrossRef][Web of Science][Medline]

86 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.[Abstract/Free Full Text]

87 Moyle GJ, Fisher RL. Switching from combivir [CBV] (AZT/3TC) to truvada [TVD] (TDF/FTC) preserves limb fat: results of a DEXA sub-study of a 48 week randomised study. In: Abstracts of the Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 2008. Alexandria, VA, USA: Foundation for Retrovirology and Human Health. Abstract 938.

88 Dube MP, Komarow L, Mulligan K, et al. Long-term body fat outcomes in antiretroviral-naive participants randomized to nelfinavir or efavirenz or both plus dual nucleosides: dual X-ray absorptiometry results from A5005s, a Substudy of Adult Clinical Trials Group 384. J Acquir Immune Defic Syndr (2007) 45:508–14.[CrossRef][Web of Science][Medline]

89 Jemsek JG, Arathoon E, Arlotti M, et al. Body fat and other metabolic effects of atazanavir and efavirenz, each administered in combination with zidovudine plus lamivudine, in antiretroviral-naive HIV-infected patients. Clin Infect Dis (2006) 42:273–80.[CrossRef][Web of Science][Medline]

90 Cameron D, da Silva B, Arribas JR, et al. Significant sparing of peripheral lipoatrophy by HIV treatment with LPV/r+ZDV/3TC induction followed by LPV/r monotherapy compared to EFV+ZDV/3TC. In: Abstracts of the Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 2008. Alexandria, VA, USA: Foundation for Retrovirology and Human Health. Abstract 44.

91 Engelson ES, Kotler DP, Tan Y, et al. Fat distribution in HIV-infected patients reporting truncal enlargement quantified by whole-body magnetic resonance imaging. Am J Clin Nutr (1999) 69:1162–9.[Abstract/Free Full Text]

92 Haubrich R, Riddler S, DiRienzo D, et al. Clinical associations of extremity fat loss from ACTG 5142: a prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for antiretroviral therapy (ART) of naive, HIV-1 infected subjects. In: Abstracts of the Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 2008. Alexandria, VA, USA: Foundation for Retrovirology and Human Health. Abstract 935.

93 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:F51–8.[CrossRef][Web of Science][Medline]

94 Podzamczer D, Ferrer E, Martinez E, et al. How much fat loss is needed for lipoatrophy to become clinically evident. In: Abstracts of the Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, MA, 2008. Alexandria, VA, USA: Foundation for Retrovirology and Human Health. Abstract 9412.

95 Mulligan K, Parker RA, Komarow L, et al. Mixed patterns of changes in central and peripheral fat following initiation of antiretroviral therapy in a randomized trial. J Acquir Immune Defic Syndr (2006) 41:590–7.[CrossRef][Web of Science][Medline]

96 Dube 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) 19:1807–18.[Web of Science][Medline]

97 Pulido F, Arribas JR, Moreno S, et al. Similar virologic and immunologic response to efavirenz or lopinavir/ritonavir-based HAART in a large cohort of antiretroviral-naive patients with advanced HIV infection. Eighth International Congress on Drug Therapy in HIV Infection, Glasgow, 12–16 November 2006.

98 Ward D, Bush L, Thiry A. Atazanavir/ritonavir and efavirenz NRTI-sparing regimens in treatment-naive adults: BMS-121 study. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 27–30 September 2006.

99 Allavena C, Ferre V, Brunet-Francois C, et al. Efficacy and tolerability of a nucleoside reverse transcriptase inhibitor-sparing combination of lopinavir/ritonavir and efavirenz in HIV-1-infected patients. J Acquir Immune Defic Syndr (2005) 39:300–6.[CrossRef][Web of Science][Medline]

100 da Silva B, Domingo P, Joly V, et al. Changes in lipid parameters during treatment with lopinavir/ritonavir (LPV/r) plus zidovudine/lamivudine (ZDV/3TC) induction followed by maintenance on LPV/r monotherapy compared to efavirenz (EFV)+ZDV/3TC through 96 weeks. Abstracts of the International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, Sydney, 2007. Abstract 54.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J Antimicrob ChemotherHome page
F. Maggiolo
Efavirenz: a decade of clinical experience in the treatment of HIV
J. Antimicrob. Chemother., November 1, 2009; 64(5): 910 - 928.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
62/2/234    most recent
dkn191v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Pérez-Molina, J. A.
Right arrow Articles by Moreno, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pérez-Molina, J. A.
Right arrow Articles by Moreno, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?