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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 11 5186-5192
Copyright © 2003 by The Endocrine Society

A Comparison of the Effects of Nevirapine and Nelfinavir on Metabolism and Body Habitus in Antiretroviral-Naive Human Immunodeficiency Virus-Infected Patients: A Randomized Controlled Study

Cesar Fisac, Nuria Virgili, Elena Ferrer, Maria J. Barbera, Emilio Fumero, Concepcio Vilarasau and Daniel Podzamczer

Endocrinology (C.F., N.V., C.V.) and Infectious Disease (E.F., M.J.B., E.F., D.P.) Services, Hospital Universitario de Bellvitge, 08907 L’Hospitalet de Llobregat, Barcelona, Spain

Address all correspondence and requests for reprints to: Cesar Fisac, R.D., Endocrinology and Nutrition Service, Hospital Universitario de Bellvitge, c/Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain. E-mail: cfisac{at}csub.scs.es.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
New HIV therapies have significantly increased survival, but are associated with multiple metabolic changes, most of them related to the protease inhibitors (PIs). The objective of this study was to elucidate and compare morphological and metabolic alterations in HIV-infected antiretroviral-naive patients receiving two nucleosides plus the PI nelfinavir (NFV) or the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP). Forty-three patients (NFV, n = 20; NVP, n = 23) receiving 6–12 months of treatment were analyzed. Morphological changes were evaluated by bioelectrical impedance analysis, standard anthropometrics, and clinical examination. Serum total cholesterol (TC), low-density and high- density (HDL-c) lipoprotein cholesterol, triglycerides, glucose, and insulin were determined, among other metabolic parameters. No baseline differences were observed between groups. TC increased in both arms (NVP, 11%; NFV, 17%). HDL-c also increased in both groups, although more markedly in those receiving NVP (44% vs. 20%); on-treatment levels were also elevated (1.57 vs. 1.28 mmol/liter). As a consequence of these changes, the TC/HDL-c ratio dropped by 22% in the NVP arm and remained stable in the NFV group. With the use of NFV, the TC/HDL-c ratio and attendant cardiovascular risk did not change. In contrast, NVP offered benefits regarding lipid status, as manifested by enhanced HDL-c concentrations and decreased TC/HDL-c ratios. Inclusion of NVP should be considered when deciding upon antiretroviral regimens for patients at high coronary risk.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
NEW COMBINED ANTIRETROVIRAL drug regimens have significantly contributed to decreased morbidity and mortality in HIV-infected patients (1). Nevertheless, these effective therapies are associated with multiple metabolic and body habitus changes, most of them related to the protease inhibitor (PI) class of drugs (2, 3, 4). Lipid profile alterations and insulin resistance are the most frequently reported metabolic derangements. The morphological changes occurring in this situation, also referred to as body fat redistribution syndrome, consist of central fat accumulation manifested by increasing abdominal girth and sc fat depletion in peripheral areas such as arms, legs, and face. These anthropometric and metabolic manifestations have been bunched together under the denomination of HIV- associated lipodystrophy syndrome, although it is still unclear whether they are interrelated components of a single phenomenon or have different etiologies. It is equally uncertain whether some or all of the changes are caused by the virus, the treatment, or both. Regarding treatment, the mitochondrial toxicity of the nucleoside analog reverse transcriptase inhibitors and the effects of PIs on the transcription factors responsible for regulating lipid metabolism pathways and adipocyte differentiation genes, either separately or synergistically, have been proposed as the two most feasible underlying mechanisms of the syndrome (4). The long-term clinical consequences of these metabolic abnormalities are not yet known. In the HIV-negative population, hyperlipidemia, insulin resistance, and visceral fat accumulation increase the risk for diabetes and cardiovascular disease (CVD). HIV-positive patients who develop manifestations of the syndrome might face similar health risks (5).

PIs are a major advance in the treatment of HIV infection, but, unfortunately, there is growing evidence that this drug class may play a significant role in the etiopathogenesis of the different components of the lipodystrophy syndrome (4, 6). The metabolic effects of these drugs seem to be compound-specific and differ for particular agents. For instance, some reports state that nelfinavir (NFV) induces a milder lipid profile and morphological alterations than other PIs, particularly ritonavir (7, 8). More favorable changes in lipid levels have been reported during therapy with nonnucleoside reverse transcriptase inhibitors. Recent data from the Atlantic Study have shown striking improvements in the antiatherogenic cholesterol fraction after 24 wk of nevirapine (NVP) treatment (9).

To date, metabolic and anthropometric data on this subject from randomized controlled studies are scarce. Hence, we prospectively collected glucose metabolism, lipid profile, and anthropometric parameters in a representative patient subset of the COMBINE Study, in which previously untreated HIV-positive patients were randomized to receive either the PI NFV or the nonnucleoside reverse transcriptase inhibitor NVP, both in combination with the nucleoside reverse transcriptase inhibitors zidovudine and lamivudine.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study design

The COMBINE Study was a randomized, open label, multicenter trial that compared the efficacy and safety of two highly active antiretroviral therapies. To be eligible, subjects had to be HIV-positive with HIV-1 RNA levels higher than 1500 copies/ml, treatment-naive, and free of AIDS-defining diseases. Participants (n = 142) were randomly assigned to either combivir (300 mg zidovudine and 150 mg lamivudine, twice daily) plus NFV (1250 mg, twice daily) or combivir plus NVP (200 mg twice daily). The protocol was approved by the hospital ethics committee, and participants gave their written informed consent for participation. The results of this study have been reported previously (10).

At the same time as the main study, anthropometric and biochemical determinations were performed in a subset of 54 patients at baseline and at 3-month intervals up to 12 months after the start of the study. Herein we present the baseline and last follow-up metabolic and anthropometric outcomes of those patients who continued the initially allocated treatment for at least 6 months and up to 12 months.

Morphological determinations

Development of morphological changes was evaluated prospectively by physician examination, patient self-perception, and anthropometric measurements. Participants underwent an extensive physical examination to determine the presence or absence of lipodystrophy. The following clinical signs were investigated: peripheral loss of sc fat tissue in the face, buttocks, arms, or legs; apparent gain of abdominal fat; development of dorsocervical fat pads; and breast enlargement in women. Patients were also asked whether they perceived changes in their body shape. Anthropometric determinations were carried out according to the standards of the World Health Organization (11) and included height, weight, triceps skinfold, and three circumferences (waist, hip, and mid-arm). Body mass index (BMI = weight in kilograms/height in square meters) and waist to hip ratio were also calculated. In addition, a single frequency bioelectrical impedance analysis (model 310e, Biodynamics Corp., Seattle, WA) was used to estimate total body water, fat-free mass, and fat mass. All measurements were performed by the same experienced examiner.

Laboratory methods

Venous blood was collected after an overnight fast. Serum was separated by centrifugation and was stored at 4 C until analysis. Concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), and triglycerides (TG) in serum were measured using enzymatic assays. HDL-c was determined after precipitation of apolipoprotein B (apo B)-containing lipoproteins with phosphotungstic MgCl2. Serum low-density lipoprotein cholesterol (LDL-c) levels were calculated from TC, HDL-c, and TG by the Friedewald equation (12). Apo A-I and B were measured by nephelometry. Serum glucose levels were measured by a glucose oxidase method using an autoanalyzer (Hitachi, Hialeah, FL). Serum insulin concentrations were determined by a specific immunoradiometric assay (Medgenix Diagnostics, Fleunes, Belgium) in which proinsulin did not cross-react. C Peptide was measured with a specific RIA. Finally, insulin sensitivity was estimated from fasting glucose and insulin values, according to homeostasis model assessment (13).

Data analysis

Two time points, baseline and follow-up, were used for the analysis. Follow-up data were defined as the last data collected from patients under the initially allocated treatment and without the start of metabolism-altering drugs (i.e. lipid-lowering agents).

To assess whether the subset of patients analyzed was representative of the whole, it was compared as a single group to the remaining COMBINE Study population. Differences in categorical and continuous data were examined by performing {chi}2 tests or independent-sample t tests, as appropriate. An identical statistical procedure was used to test baseline differences between the two study groups. Logarithmic transformation of TG values was necessary to attain a normal distribution. Treatment differences over time were analyzed by repeated measures ANOVA using general linear models. Within the same model, pairwise comparisons based on estimated marginal means were performed to test for within-treatment changes and between-treatment differences at each time point. All pairwise testing was adjusted for multiple comparisons using Bonferroni’s correction. Additionally, multivariate linear regression analyses were performed to examine the contributions of the different variables to the observed metabolic changes. Results are expressed as the mean ± SD unless otherwise noted. A two-tailed P value of 0.05 or less was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Patient selection and baseline characteristics

Eleven of the 54 patients participating in the study discontinued the allocated treatment before 6 months after initiation of therapy; thus, data from a total of 43 patients were included in the final analysis. Among these 43 patients, 5 initiated lipid-lowering therapy, and 3 discontinued the randomized treatment before month 12. Hence, follow-up data (as defined in the Data analysis section in Subjects and Methods) corresponded to 12-month data in 35 cases (19 on NVP), 9- month data in 5 cases (2 on NVP), and 6-month data in 3 cases (2 on NVP). Results did not change substantially after excluding the 8 patients with a shorter follow-up time from the analysis. The mean duration of antiretroviral treatment was comparable in the 2 options (NFV, 10.1 ± 3.4; NVP, 10.1 ± 3.5 months).

The study patients (NFV, n = 20; NVP, n = 23) displayed baseline characteristics similar to the remaining COMBINE Study population (n = 99) in terms of sex, age, weight, HIV risk practice, disease stage (14), viral load, and CD4 cell count (Table 1Go). Baseline characteristics of the study population did not differ between treatment arms. Both groups were similar in sex, age, anthropometric measurements, HIV risk practice, disease stage, CD4 cell count, and viral load (Tables 1Go and 2Go). None of the patients had a personal history of diabetes, CVD, hypothyroidism, obstructive liver disease, or chronic renal failure or reported the use of lipid- or insulin-altering agents 3 months before initiation of therapy. Two subjects in the NVP arm and one in the NFV arm had a family history of lipid disorders.


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  		TABLE 1. Baseline characteristics of selected patients and remaining COMBINE Study population

 

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  		TABLE 2. Anthropometric data

 
Morphological and glucose metabolism outcomes

Anthropometric data are presented in Table 2Go. As most subjects initiated the intervention with a current weight lower than their usual weight (data not recorded), an overall body weight gain was observed at the end of the study (2 ± 5 kg; P < 0.05), probably resulting from an improvement in their health status. As an immediate consequence of weight gain, overall statistically significant increases were observed in BMI (P < 0.05), waist girth (P < 0.01), mid-arm circumference (P < 0.01), and absolute and percentage term body fat (P < 0.01). The treatment groups did not differ with regard to absolute anthropometric changes or follow-up measurements.

None of the patients complained of abnormal changes in body shape at any time during the study. Clinical examinations agreed with the patient’s self-perception in all cases. To confirm our clinical assessment, we investigated whether any patient met anthropometric criteria of suspected lipodystrophy-like central adiposity as defined by a waist to hip ratio of 0.95 or more in men and 0.9 or more in women among subjects with BMI less than 28 kg/m2 (15) and/or suspected peripheral lipoatrophy, as defined by triceps skinfold less than 10% of the standard among persons with BMI of 20 kg/m2 or more (16). After an average of 10.1 ± 3.4 months of therapy, none of the patients met these criteria.

Glucose homeostasis parameters between the groups were comparable at baseline and follow-up (Table 3Go). Glucose levels remained stable and within the normal range. With respect to insulin and insulin resistance as assessed by the homeostasis model assessment score, NFV treatment (but not NVP treatment) resulted in a nonsignificant trend to increases. In the overall multivariate analysis, the absolute change in percentage of body fat proved to be the only variable independently associated with absolute changes in insulinemia (r2 = 0.28; P < 0.01) and insulin resistance (r2 = 0.24; P < 0.01).


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  		TABLE 3. Lipid and glucose metabolism data

 
Effects on lipid parameters

No significant differences in lipid parameters were found at baseline (Table 3Go). Treatment led to a comparable significant TC increase in both treatment arms [NVP, 11% (P < 0.05); NFV, 17% (P < 0.01)]; however, the mean follow-up concentration surpassed the recommended maximum level of 5.2 mmol/liter (17) only in the NFV option. Similarly, the mean HDL-c level increased significantly with both therapies (P < 0.001); nonetheless, this elevation was more enhanced in the NVP-containing group (44% vs. 20%; P < 0.05). Moreover, the on-treatment mean HDL-c level was also significantly higher in the NVP group (1.57 vs. 1.28 mmol/liter; P < 0.01). As a direct consequence of these changes, the mean TC/HDL-c ratio dropped by 22% in the NVP arm (P < 0.001), but did not vary in the NFV option. At follow-up, the mean TC/HDL-c ratio had significantly decreased in the NVP arm (from 4.5 to 3.5 mmol/liter; P < 0.001).

LDL-c concentrations could not be calculated in one patient under NVP at baseline and in four patients (two in each arm) at follow-up because of TG greater than 4.52 mmol/liter (400 mg/dl). While the mean LDL-c level did not vary in the NVP group, it increased by 16% in patients with the NFV option (from 3.1 to 3.6 mmol/liter; P < 0.05). Similar results were obtained when the serum non-HDL-c fraction (= TC - HDL-c) was analyzed. Regarding TG, fasting serum levels remained unchanged in the NVP arm, whereas a borderline significant increase occurred in the NFV option (from 1.5 to 2.2 mmol/liter; P = 0.06). At follow-up, TG levels did not differ between treatments. In both treatment groups, apo A-1 and apo B levels changed in parallel with HDL-c and LDL-c levels, respectively.

Figure 1Go shows the proportion of patients with high (or low, for HDL-c) lipid levels (17) and with TC/HDL-c ratios indicating coronary artery disease risk (>6.4 in men, >5.6 in women) (18). Although only 2 of 43 patients (1 in each arm) initiated treatment with TC more than 6.2 mmol/liter, 6 (31%) patients on NFV and 3 (13%) on NVP surpassed this level at follow-up. The proportion of NFV recipients with TG more than 2.3 mmol/liter and the proportion with LDL-c more than 4.1 mmol/liter both tripled, whereas no substantial variations occurred in those receiving NVP. At baseline, 11 subjects in each arm had HDL-c below 1.04 mmol/liter; however, at follow-up, only 2 on NVP and 4 on NFV maintained these suboptimal levels. Furthermore, the number of patients with a TC/HDL-c ratio greater than 6.4 (>5.6 in women) decreased from 5 to 2 in the NVP group and increased from 1 to 3 in the NFV option.



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  		FIG. 1. Proportion of patients with high serum TC, LDL-c, and TG levels; low serum HDL-c levels; and undesirable TC to HDL-c ratios (TC/HDL-c). *, P < 0.05.

 
Multivariate linear regression with absolute change in lipid parameters as the dependent variable was performed to investigate the contributions of other variables to the observed lipid changes. Sex, age, duration and type of therapy, baseline AIDS status, as well as pretreatment values and absolute changes in the anthropometric and biochemical parameters, as appropriate, were tested as explanatory factors. Using this model, the only factor associated with changes in HDL-c concentrations was the assigned treatment (r2 = 0.4; P < 0.05). Additionally, absolute changes in TC/HDL-c ratio were explained by both the assigned treatment and absolute changes in waist to hip ratio (r2 = 0.6; P < 0.05).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study both treatment options exerted specific effects on the measured lipid parameters, whereas no relevant morphological or glucose metabolism changes were detected during the period analyzed. Treatment-naive subjects receiving NVP in combination with the nucleoside analogs zidovudine/lamivudine presented significantly elevated serum TC and HDL-c levels and improved TC/HDL-c ratios. In contrast, patients who received NFV instead of NVP also showed elevated TC and HDL-c levels, but, concomitantly, had raised LDL-c concentrations. The mean TC/HDL-c ratio did not show significant variations in this treatment arm, as the HDL-c increase was offset by a similar TC elevation.

The inverse relation between the risk of developing CVD and HDL-c levels is well established. Prospective observational studies have shown that low HDL-c predicts increased CVD risk for any LDL-c level (19, 20, 21). Clinical trials also point to the benefit of increasing HDL-c levels with regard to CVD (22, 23, 24). In the present study the mean HDL-c level increased considerably in the NVP arm (44%) and, to a lesser extent, in the NFV arm (20%). Whereas this effect of NVP on HDL-c has been reported previously (9), controversy might arise with respect to NFV’s, because observational studies have recorded low or similar HDL-c levels in patients under PI-containing regimens compared with patients receiving PI-sparing treatments or healthy controls, or have found decreasing trends over time (2, 25). In a comparable study, van der Valk et al. (9) found similar increases in HDL-c levels (49%) in 34 treatment-naive patients receiving NVP in combination with 2 nucleoside reverse transcriptase inhibitors (stavudine/didanosine) for 24 wk. Regarding the PI drug class, varying repercussions on HDL-c levels have been reported. In van der Valk’s study (9) a significant 19% elevation was observed in the treatment arm containing the PI indinavir (same backbone treatment as with nevirapine). In the Swiss HIV Cohort longitudinal study comparing the effects of 3 different PIs (ritonavir, indinavir, and NFV) on the lipid profile, Périard et al. (7) reported a compound-specific effect. HDL-c levels remained unchanged in the ritonavir-containing group, increased slightly in the indinavir arm, and displayed a more pronounced, but still nonsignificant, elevation among NFV users (from 0.9 to 1.2 mmol/liter at follow-up). It is of note that in more than half of the patients NFV was administered in combination with saquinavir, which is known to exert a lesser effect on serum lipids.

Although guidelines to decrease CVD risk have traditionally focused on identifying subjects with increased levels of LDL-c and TC, several researchers have stated that the TC/HDL-c ratio is a superior measure of risk for coronary heart disease compared with either TC or LDL-c levels (18, 26, 27, 28, 29, 30). TC/HDL-c has also proven to be a better risk marker than the LDL-c/HDL-c ratio (18, 26, 31). On this basis, the TC and LDL-c increases observed in our NFV-containing treatment group may not imply increased risk of CVD, as the mean TC/HDL-c ratio remained unvaried (from 4.5 ± 1.0 to 4.5 ± 1.3). With respect to the NVP group, the 22% TC/HDL-c ratio decrease added to the relevant HDL-c improvement strengthens the idea that some cardiovascular benefit may be associated with its use.

A question remains as to whether the metabolic changes observed in our study population would have an effect on CVD risk; that is, whether conventional factors can change CVD risk in the HIV-positive population, as occurs in the general population. To date, data on the incidence and causes of CVD in the HIV-positive population are scarce and controversial (32, 33, 34). However, aside from the contribution to CVD risk of HIV infection itself or of the type and duration of therapy, numerous studies point to the participation of classical risk factors in the development of this disease (34, 35, 36, 37, 38). In the D:A:D study, an ongoing observational study involving more than 23,000 patients receiving combined therapy, the conventional risk factors, such us gender, age, cholesterol, and diabetes, predicted the risk of myocardial infarction, and this risk was found to rise with the number of years on antiretroviral therapy (34). In a recent study of 423 HIV-infected patients, Mercie et al. (35) concluded that only conventional risk factors (but not lipodystrophy, HIV status, or antiretroviral therapy) were independently associated with increased carotid artery intima-media thickness, a surrogate marker of atherosclerosis. Similarly, David et al. (36) observed that CVD appeared to be closely associated with traditional risk factors in a comparison of 16 HIV-infected patients with proven CVD and 32 HIV-infected matched controls. Therefore, although definitive data are still lacking, the evidence suggests that HIV-infected patients may benefit as much as HIV-negative subjects from improvements in the lipid profile. If this is so, and only taking into account the parameters measured, mean coronary heart disease risk would have decreased in our NVP group (by 50% if Framingham’s equation for the general population were applied), whereas no noticeable change in risk would have occurred in the NFV group. It should be noted that several unmeasured CVD-predisposing factors, such as C-reactive protein, cytokines, circulating homocysteine, and hemostatic parameters, may also have been affected by the tested treatments (39, 40). Hence, our results should be interpreted with caution in terms of CVD risk.

There were no onsets of lipodystrophy during the study period, as assessed by clinical examination, patient self- perception, and anthropometric measurements. This may be explained by the lower incidence of the syndrome observed among patients with NFV-containing regimens in comparison with other PIs (8) and the fact that stavudine (a nucleoside reverse transcriptase inhibitor) was not included in the backbone treatment; stavudine has been suggested as a probable contributor to the development of lipodystrophy syndrome (41, 42). There is evidence that early, sustained hypertriglyceridemia (>3 mmol/liter) is a predictor of the development and severity of lipodystrophy in HIV-treated patients (2); additionally, high TG levels are more frequently observed among those with the morphological syndrome (2, 43, 44). Insulinemia and insulin resistance are also frequently altered in the syndrome (2, 45, 46, 47). Consequently, the higher impact of the NFV-containing regimen on both TG levels and insulin resistance, although nonsignificant, creates a picture consistent with the concept that patients receiving NFV may be more likely to develop the syndrome.

The present study has some limitations. First, dietary information, such as alcohol consumption, was not recorded, so we cannot rule out that changes in diet habit may have accounted for some of the changes in plasma lipid levels. It is important to mention, however, that dietary changes do not seem to alter the TC/HDL-c ratio substantially (48). A potential source of bias may reside in the use of follow-up data previous to 1 yr of treatment in two dyslipidemic patients because of initiation of lipid-lowering therapy. Nevertheless, we believe that this element did not change the results, because previous works have observed that lipid parameters seem to reach steady levels at about 3 months of exposure to HIV therapy (49). Also, the trends for increases in both insulin and insulin resistance values observed in the NFV-containing group might have reached significance, in accordance with previous reports on PIs (45, 50), had the number of patients been larger, the studied period longer, or even the method for determining insulin resistance more accurate.

To summarize, one of the main concepts supported by our results is that inclusion of a PI in an antiretroviral regimen does not necessarily imply atherogenic lipid profile alterations. Patients under NFV had significantly elevated HDL-c levels, and their TC/HDL-c ratios remained stable, both strong markers of cardiovascular risk. This particular lipid profile effect, however, might be compound-specific and turn out to be different in the case of other PIs. In contrast, NVP use offered clear benefits in terms of lipid status, with a substantial capacity to elevate HDL-c levels and decrease TC/HDL-c ratios. Thus, inclusion of NVP should be considered when deciding upon antiretroviral regimens for subjects at high coronary risk, namely, patients with two or more risk factors, diabetes, or a previous cardiovascular event.

As the course of HIV infection has dramatically improved, physicians’ concerns can now focus on the adverse effects of HIV treatment regimens, such as metabolic disturbances and their potential clinical consequences. One practical way to gather data that may help in choosing optimum therapy is to include metabolic subtrials in studies of the viral and immunological efficacy of new regimens. Prospective epidemiological studies of cardiovascular incidence will confirm the long-term consequences of the metabolic findings.


   Footnotes
 
This work was supported in part by Glaxo, Roche, and Boehringer Ingelheim, Spain, by the Fundació August Pi i Sunyer, Spain, and by the Red Tematica Cooperativa de Investigacion en SIDA (Red de grupos 173) del FISss, Spain. It was presented in part at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 2000.

Abbreviations: apo, Apolipoprotein; BMI, body mass index; CVD, cardiovascular disease; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; NFV, nelfinavir; NVP, nevirapine; PI, protease inhibitor; TC, total cholesterol; TG, triglycerides.

Received November 20, 2002.

Accepted July 22, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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