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A randomized double-blind controlled study of 6 months of oral nutritional supplementation with arginine and Ω-3 fatty acids in HIV-infected patients

Pichard, Claude1,6; Sudre, Philippe2; Karsegard, Véronique1; Yerly, Sabine3; Slosman, Daniel Olivier4; Delley, Veronique2; Perrin, Luc3; Hirschel, Bernard2The Swiss HIV Cohort Study

ARTICLE

Objective: To evaluate the effects of an oral nutritional supplement enriched with two potentially immunostimulant compounds (arginine and Ω-3 fatty acids) on the changes in food intake, body composition, immune parameters and viraemia in HIV-infected outpatients.

Design: Six-month prospective randomized double-blind controlled study.

Setting: University hospital outpatient nutrition clinic.

Patients: Sixty-four HIV-infected outpatients with CD4 lymphocyte count ≥ 100 × 106/l.

Intervention: All patients received a daily oral nutritional supplement (606 kcal supplemented with vitamins, trace elements and minerals). In addition, half of the patients were randomized to receive 7.4 g arginine plus 1.7 g Ω-3 fatty acids.

Main outcome measures: Disease progression measured by AIDS-defining events, CD4 and CD8 lymphocyte counts, viraemia, tumour necrosis factor soluble receptors, nutritional status determined by anthropometric, bioelectrical impedance and dietetic assessment.

Results: Fifty-five patients completed the protocol. Compliance with and tolerance of oral nutritional supplement during the 6-month period was excellent. In both groups of patients the following were found: total energy intake was transiently increased and then returned to baseline level; nitrogen/energy intake ratio was increased throughout the study; gain of body weight and fat mass were approximately 2 and 1 kg, respectively, over 6 months, and were similar in both groups. In addition, CD4 and CD8 lymphocyte counts, viraemia, tumour necrosis factor soluble receptors remained statistically unchanged and were similar in both groups.

Conclusions: Enrichment of an oral nutritive supplement with arginine and Ω-3 fatty acids did not improve immunological parameters. However, body weight increased in both groups.

1Divisions of Nutrition, University Hospital, Geneva, Switzerland

2Infectious Diseases, University Hospital, Geneva, Switzerland

3Virology, University Hospital, Geneva, Switzerland

4Nuclear Medicine, University Hospital, Geneva, Switzerland.

5See Appendix for members.

6Requests for reprints to: Dr Claude Pichard, Clinical Nutrition and Diet Therapy, Geneva University Hospital, 1211 Geneva 14, Switzerland.

Sponsorship: Supported by Sandoz Nutrition, Bern, Switzerland.

Date of receipt: 4 April 1997; revised: 17 July 1997; accepted: 1 September 1997.

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Introduction

Nutritional status depends on an equilibrium between nutritional intake, intestinal absorption and metabolic needs. Reduced energy intake seems to be the prime determinant of HIV-associated weight loss [1]. The cause of the decrease in food intake remains incompletely understood, but may include the anorexic role of the mediators of infection [2,3] and psychological disturbances [4] related to a life-threatening illness. Adequate nutrient intake results in anabolism and body weight gain in spite of HIV infection [3,5,6], and decreases risk of progression to AIDS [7,8].

Subtle changes in the immune status are noted from the onset of HIV infection. They may be related to many factors, including nutritional deficiencies [7–11]. Immune function is modulated by several compounds such as vitamins (A, C, E), trace elements (iron, selenium, zinc, copper), amino acids (arginine, histidine) and lipids [8,9,11,12]. Because supplementation with arginine and extra long-chain fatty acids (frequently named fish-oil or Ω-3 fatty acids) correlates with improved immune function in various clinical conditions [13–19], we hypothesized that long-term (6 months) oral nutritional supplementation enriched with arginine and Ω-3 fatty acids may contribute to preserve the immune status of HIV-infected patients.

Despite the paucity of scientific data showing any benefits, the use of oral nutrient supplementation is widespread among HIV-positive patients. There are many reasons why prospective, double-blind, placebo-controlled trials of oral nutritional supplements have not been completed, and these include (i) the impossibility of producing a placebo that cannot be distinguished from the nutritional supplement, (ii) the necessity for long-term follow-up, ethical considerations and the difficulty for patients to accept long-term placebo oral nutritional supplements, and (iii) the presence of other variables that may influence disease progression and nutritional state, such as antiviral treatment and intercurrent infections.

Because of these constraints, only three prospective studies of prolonged (≥ 3 months) oral nutritional supplementation [20–22] have been published. One of these studies [22] was controlled and double-blinded, but was limited to 10 patients for a 4-month study period.

We present the results of a 6-month prospective double-blind, randomized, controlled study involving HIV-infected outpatients who were offered a complete oral nutritional supplement [606 kcal (2539 kJ) per day enriched with micronutrients such as vitamins, trace elements and minerals] either with 7.4 g arginine and 1.7 g Ω-3 fatty-acid enrichment or without these additional elements for 6 consecutive months. The aim of the study was to compare the progression of clinical, nutritional and immunological indicators during nutritional supplementation with or without arginine and Ω-3 fatty acids.

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Methods

Patients

Sixty-four adults patients with CD4 lymphocyte counts ≥ 100 × 106/l were enrolled into a prospective, double-blind, controlled study and randomly assigned to receive two daily oral nutritional supplements either with arginine and Ω-3 fatty-acid enrichment (Arg-Ω-3) or without enrichment (standard) for 6 consecutive months. Patients with changes in antiviral treatment during the preceding 8 weeks, those with symptomatic neuropathy or myopathy, neoplasia, endocrine disorders (pituitary dysfunction, diabetes mellitus, treated hyper-/hypothyroid activity), renal failure, liver cirrhosis, gastrointestinal resection, those treated for psychiatric disorders or active intravenous drug consumption were excluded. The study was approved by the Ethics Committee of the Department of Medicine (Geneva University Hospital) and all patients gave written informed consent. All subjects remained under routine treatment for HIV infection as provided in Swiss HIV Cohort Study (SHCS) in 1995–1996. In order to determine the overall impact of nutritional supplements, the patients included in the trial were also compared with patients who met the eligibility criteria for the trial and were followed during the study period in the SHCS [23]. Two hundred and thirty-six such patients were identified and compared with study patients in terms of change in weight, body mass index (BMI), CD4 and CD8 cell counts, and occurrence of opportunistic infections.

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Dietary intervention

General information on optimal food intake was provided at the beginning of the study to all patients by a dietician specialized in HIV and nutrition counselling. An oral nutritional supplement, enriched with vitamins, trace elements and minerals (Table 1), was prescribed and given as two daily servings (morning and evening) of 303 kcal to both groups of patients. The oral nutritional supplement was either enriched daily with 7.4 g arginine and 1.7 g Ω-3 fatty acids (Arg–Ω-3) or not enriched (standard). Overall food intake was monitored each month by a standard 3-day (non-consecutive) calorie count food intake questionnaire, which determined daily energy and protein intake. The nitrogen/energy intake ratio was then calculated as follows: [protein (g)/6.25]/energy (kcal).

Table 1

Table 1

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Measurements

Anthropometry and body composition

Body weight, with light clothes on and shoes off, was measured during monthly clinical examination and noted to the nearest 50 g and then reported as the percentage of ideal body weight and of ‘patient's usual healthy body weight’. Body height was measured to an accuracy of 0.5 cm and BMI computed as body weight/(height)2.

Tetrapolar body electrical bioimpedance was used to determine body composition as previously described [24] and used in HIV-infected patients [10,25,26]. An electrical current of 0.8 mA and 50 kHz was produced by a calibrated signal generator (BIOZ, New Cardicorp, Switzerland) and applied to the skin using adhesive electrodes (Unitrace, United Medical Supply, Englewood, Colorado, USA) placed on right-side limbs. Resistance and reactance were used to calculate total body water, fat and fat-free masses [24]. Dry fat-free mass was also calculated as fat-free mass minus total body water, as measured by bioimpedance analysis, in order to improve the determination of lean tissue and body protein masses, as previously reported [27–29].

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Tolerance

Appetite and gastrointestinal symptoms such as nausea, gastralgia, vomiting and diarrhoea were determined monthly by patients' responses to a standardized questionnaire.

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Immune status, viral load and clinical endpoints

Disease progression was assessed according to the occurrence of AIDS-defining events [30] and measurements of biological markers (see below). At time of inclusion, and after 3 and 6 months, venous samples were drawn for simultaneous determinations of total leukocytes, lymphocytes, CD4 and CD8 cell counts, p24 antigen and β2-microglobulin. Plasma samples were frozen at −70°C for later determination of viraemia [31] and levels of tumour necrosis factor soluble receptor 55 kDa α-subunit (sTNF-R55) and 75 kDa β-subunit (sTNF-R75) [32].

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Quality of life

Quality of life assessment was evaluated using a French language-validated self-applied questionnaire derived from the Medical Outcome Study 36-item short form health survey (SF-36) [33]. SF-36 is specifically designed to assess ambulatory patients who seek health care and integrates eight dimensions of health-related quality of life (physical functioning, physical role, emotional role, social functioning, pain, mental health, vitality, general health) to provide a numerical score interpreted from excellent to poor health status. The questionnaire was completed at time of inclusion, and thereafter at months 3 and 6.

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Statistical analysis

To minimize the potential for introducing bias, all randomized patients were included in the comparisons, irrespective of whether or not and for how long they complied with their allocated regimen (intention-to-treat analysis). Statistical methods for univariate group comparisons included χ2 tests for proportions and t tests for the continuous variables. Differences between trial participants and comparable patients simultaneously participating in the SHCS were assessed using odds ratios and 95% confidence intervals. A commercially available statistical package was used (SPSS for Windows; SPSS, Chicago, Illinois, USA). Results pertaining to the changes in continuous variables are expressed as means ± SEM. A post-hoc analysis was conducted to detect a potential difference with CD4 and CD8 cell counts below 400 and 800 × 106/l, respectively (at inclusion). The study protocol is available from the authors on request.

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Results

Baseline characteristics of patients

Patient characteristics regarding HIV mode of transmission, antiretroviral treatment and immune status at the time of study inclusion are shown in Table 2. None of the small differences between the groups were statistically significant. Patients' body weight (Table 2) and BMI were similar (BMI, 19–26 kg/m2). Patients' actual body weight was slightly lower than their ideal body weight. Body weight loss relative to usual weight during the 12 months prior to inclusion into the study was almost identical in both groups (Table 2) and did not exceed 7% of usual body weight. Initial fat-free mass and fat mass (Fig. 1) were not statistically different. Compared with healthy controls of similar sex and age, fat-free mass and fat mass of patients in both groups were at the lower limits of the normal range (data not shown) [28].

Table 2

Table 2

Fig. 1

Fig. 1

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Follow-up, food intake and tolerance

Of the 64 patients enrolled, 55 patients completed the entire protocol and were evaluated after 6 months of follow-up (i.e., 75.7% of patients in standard group versus 70.9% in the Arg–Ω-3 group).

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Non-supplement and supplement food intake

Fig. 2 shows overall food intake including oral nutritional supplement. Initial energy and protein intake was 2959 ± 155 and 2802 ± 180 kcal/kg daily, and protein intake 103.2 ± 6.7 and 97.0 ± 5.7 g daily, in standard (n = 31) and Arg-Ω-3 (n = 29) groups, respectively. Daily energy intake was 45.0 ± 2.5 and 41.5 ± 2.5 kcal/kg body weight per day and protein intake was 1.6 ± 0.1 and 1.4 ± 0.1 g protein/kg body weight per day, in standard and Arg-Ω-3 groups, respectively.

Fig. 2

Fig. 2

Protein intake increased by about 20% with oral supplementation and remained above baseline throughout the entire trial period. The mean number of servings of oral nutritional supplements ingested was similar in both groups, and remained stable with a reported monthly intake of 42–52 supplements (Fig. 2). An overall increase in energy intake of 9–17% was observed during the first 2 months of the study. Later, total energy intake decreased to levels similar to initial values because of a progressive and spontaneous reduction of non-supplement food intake (data not shown).

Anorexia and gastrointestinal tolerance clearly improved over time in contrast to diarrhoea. There was no significant difference between groups. Although tolerance to oral nutritional supplements was acceptable in both groups, it was the reason for discontinuation of supplements for nine patients (five in the Arg–Ω-3 group and four in the standard group). No toxic events were observed in either group.

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Anthropometrics and body composition change

Patients in both groups progressively gained weight, with a mean final gain of 1.9 ± 0.6 and 2.2 ± 0.6 kg in standard and Arg–Ω-3 groups, respectively (Fig. 1). Out of the 52 patients, six patients lost 0.3–5.0 kg, and four patients lost 0.5–4.4 kg in standard and Arg–Ω-3 groups, respectively, during the 6 months of supplementation. Body mass increased as a reflection of a combined gain of dry fat-free mass (from 14.1 to 14.7 kg and from 14.7 to 15.0 kg, in standard versus Arg–Ω-3 groups) and fat mass (Fig. 1). None of the differences were statistically significant.

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Immune status, viraemia and clinical endpoints

The variations of lymphocytes, CD4 and CD8 cell counts were similar in both groups and no statistically significant differences were detected in the changes between the two groups over the 6-month trial period (Table 3). There was no statistically significant change in viraemia and plasma sTNF-R55 and sTNF-R75 concentrations over time within or between the two groups.

Table 3

Table 3

The comparison of the changes in lymphocytes, CD4 and CD8 cell counts for patients whose initial CD4 counts were above or below 400 × 106 cells/l and for patients whose CD8 counts were above or below 800 × 106 cells/l did not indicate any clinically nor statistically significant difference between the two types of oral supplements.

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Influence of antiviral treatment

Antiviral treatment was similarly distributed in both groups at inclusion (Table 2). Zidovudine and didanosine treatments were initiated in three and two patients, respectively, in the standard group, and one patient each in the Arg–Ω-3 group during the study period.

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Quality of life

At inclusion, all eight dimensions of health-related quality of life were below the normal values but within 1 SD (standard versus Arg–Ω-3): physical functioning (92 ± 14 versus 91 ± 13), physical role (83 ± 31 versus 84 ± 29), emotional role (65 ± 40 versus 78 ± 35), social functioning (69 ± 28 versus 74 ± 23), pain (82 ± 23 versus 86 ± 18), mental health (60 ± 20 versus 66 ± 18), vitality (53 ± 17 versus 56 ± 19), general health (61 ± 18 versus 62 ± 20). No significant change was observed during the study period (data not shown).

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Comparison with non-supplemented patients of the SHCS

The SHCS group of 236 patients who met the study eligibility criteria were similar to the patients in this study with respect to weight, BMI, CD4 and CD8 lymphocyte counts. After 6 months of follow-up, however, only 23 of the SHCS non-supplemented patients (9.7%) had gained more that 5% of their initial body weight compared with 14 (26.4%) patients participating in the present trial. This difference was statistically significant, and supplemented patients were more than three times as likely to gain weight as non-supplemented SHCS participants (odds ratio, 3.32; 95% confidence interval, 1.4–7.46). The mean weight change between the two groups over the 6-month trial period was also statistically significant (P < 0.005). Trial participants gained almost 2 kg whereas non-supplemented patients lost an average of 0.5 kg (P ≤ 0.001). The changes in CD4 and CD8 lymphocyte counts was similar in both trial groups and the SHCS control group. Although seven (3%) opportunistic infections occurred in the non-supplemented group compared with none in the trial group, this difference was not statistically significant.

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Discussion

This study describes a group of 66 HIV-positive out-patients taking a balanced oral nutritional supplement (606 kcal per day, enriched with micronutrients) with or without arginine and Ω-3 fatty acids for 6 months. Comparison of before and after the trial suggests that both supplementation groups increased the nitrogen/energy intake ratio, body weight, dry fat-free mass and fat mass, and reduced the frequency of anorexia and gastrointestinal symptoms. Arginine and Ω-3 fatty-acid supplementation did not have an impact on the number of clinical endpoints and changes in CD4 and CD8 cell counts, viraemia and sTNF-R.

At inclusion, the comparison of actual body weight with ideal or usual body weight suggested that patients were slightly underweight but had exhibited no significant weight loss during the previous 12 months (Table 2). This suggests that they did not suffer from malnutrition, a fact further supported by body composition parameters (Fig. 1), which were not statistically different from those of healthy subjects with similar age and sex [28]. This study should therefore be regarded as an analysis of the impact of food supplementation with arginine and Ω-3 fatty acids on body composition and immune status, and not on refeeding.

Patients' compliance was remarkable with over 70% patients (n = 55) completing the 6-month trial. This might be explained by the selection of patients who were willing to undertake proactively a prolonged action that they believed potentially able to improve the course of their HIV infection but also by the low degree of anorexia and gastrointestinal symptoms at inclusion. This study confirms that prolonged oral nutritional supplementation is feasible in HIV-infected patients [20–22].

Symptomatic patients in both groups reported progressive improvement of anorexia and gastrointestinal symptoms. As previously reported [34–37], this may be related to nutritional counselling as well as to their decision to undertake a nutritional therapy that helped to improve their food intake, rather than to a direct effect of the nutritional supplement.

Fifty to 100% of the energy content of the oral nutritional supplementation (606 kcal daily) was added to the non-supplemental food intake during the first 2 months of the study, after which time the energy intake returned to baseline level. Because the number of ingested oral supplements remained stable, this suggests that a compensatory mechanism reduced spontaneous food intake (Fig. 2) when patients had an energy intake in excess of their metabolic needs, which has been reported to be about 2750 ± 670 kcal daily in similar patients [1]. This value is close to our patients' total food intake (Fig. 2). In addition, there was no difference between the two groups in the quality of the food intake or in the intake of vitamins, trace elements and other over-the-counter food supplements. On the other hand, the nitrogen/energy ratio was qualitatively improved by oral supplementation, as has previously been noted [22]. This effect was in addition to an ingested protein level of 120–130% of the recommended range at inclusion [38]. This suggests that nutritional supplements in clinically stable patients are selectively efficient to increase nitrogen intake and stimulate protein tissue deposition [3].

Body weight increases were associated with both fat-free mass and fat mass gains (Fig. 1), which demonstrated an expansion of body mass of mixed composition, but predominantly fat. Such an anabolism with fat deposition at different stages of the disease is associated with food intake in excess of metabolic needs in HIV-infected patients [3,39]. This observation is further supported by the comparison of our study patients with similar SHCS patients who received no oral nutritional supplementation and who did not gain body weight (P < 0.005).

The combined gain of about 0.5 kg of dry fat-free mass (non-fat tissue minus water) and 1 kg of fat mass in both groups of patients represented a theoretical metabolic excess of about 9 000–11 000 kcal. As protein and calorie intake during the 6 months of study were substantially above the recommended protein (1.2 g/kg body weight per day) and energy (35 kcal/kg body weight per day) requirements, it suggests that energy needs of HIV-infected patients were markedly higher than those of healthy subjects. This effect is thought to be related to malabsorption [40,41], reduced metabolic efficiency [3], and to some extent to modified energy expenditure due to HIV infection and possibly due to an increased diet-induced thermogenesis related to food intake in excess of metabolic needs [1,42]. It also suggests that protein intake in excess of basal needs with adequate energy intake can reduce lean tissue catabolism, which is all too frequently observed in infected patients, especially in those who are HIV-infected [43].

Early voluntary withdrawal of patients in this study due to intolerance of oral nutritional supplement was more frequent in the Arg–Ω-3-supplemented patients than in those on standard product (four versus one). This may be related to the lower palatability of synthetic Ω-3 fatty acids. Nevertheless, the difference in patients who did not complete the entire protocol probably did not influence our results because the number of patients who withdrew was small in both groups. Other trials with oral nutritional supplements without or with Ω-3 fatty-acid or arginine enrichment have reported similar good compliance [18,37,44,45].

Chlebowski et al. [44] and Süttmann et al. [22] demonstrated a 4 and 3 kg gain in body weight, respectively, in their HIV-infected patients on oral nutritional supplementation enriched with fish-oil and fish-oil-arginine for 6 and 4 months, respectively. Patients in the control groups on non-supplemented formula had no body weight gain in spite of the extra food intake, which suggests that either the excess nutrients were not metabolised or that the metabolic rate was higher in these patients. The authors explained this distinct increase in body weight as an effect of the so-called ‘immunostimulant compounds’, which may have downregulated the cytokine-related energy expenditure. However, our patients showed body weight gain in both groups. We have no rational explanation for this difference in findings compared with our study results.

Immune function is modulated by many compounds, including arginine and extra long-chain fatty acids (or Ω-3 fatty acids) [8,9,11–19]. Since we hypothesized that long-term oral nutritional supplementation enriched with arginine and Ω-3 fatty acids would contribute to preserve the immune status of HIV-infected patients, we measured the standard parameters used to follow HIV-infected patients' immune function such as CD4 lymphocyte count and sTNF-R as a reflection of cytokine activity [46,47]. sTNF-R55 and sTNF-R75 were elevated in HIV-infected patients and play the role of modulators of the antagonists or neutralizing agents of TNF secretion in response to HIV infection, and signalled an activation of the TNF-α system [47], although this finding is still debated [46]. In our study, patients showed no change of sTNF-R55 and sTNFR75 plasma levels, which suggests that the rate of HIV activity or other associated infections remained stable, a fact supported by the stability of viraemia in both patient groups during the study.

The trial results do not support our hypothesis that either long-term oral nutritional supplementation contributes to preserve the immune status of HIV-infected patients, or that enrichment with arginine and Ω-3 fatty acids stimulates immune cell activity. In contrast to previous studies [22,44], our study did not support the clinical use of an enriched diet to stimulate the immune system of HIV-infected patients for the duration and the quantity used in this study. However, the fat and lean body weight gain noted in our study patients compared with weight loss observed in the SHCS patients argues in favour of routine nutritional supplementation and counselling to prevent weight loss, which is a contributing factor in HIV disease progression from an epidemiological point of view [48].

The doses of arginine and Ω-3 fatty acids in our study were based on animal or preliminary human studies in HIV-infected patients [13–17,19,44,49–57]. More recently, Süttmann et al. [58] have shown improvement in the immune function of HIV-infected patients, using combined supplementation of arginine and Ω-3 fatty acids (7.5 and 1.8 g daily, respectively). Larger doses could have been tested but might have decreased patients' compliance (due to taste problems) or tolerance (due to aftertaste and gastric reflux).

At the time the study protocol was prepared, it had been reported that supplementation with arginine or Ω-3 fatty acids stimulated immune function and thus avoided the reduction of CD4 cell count in a crossover study involving six HIV-positive non-AIDS patients during a 6-month period (unpublished data), as well as in various other clinical conditions [13–17,19,44,58].

More recent reports have suggested a decrease in renal transplant rejection and inflammatory response in ulcerative colitis, suggesting a decrease in immune function secondary to Ω-3 fatty-acid administration. On the other hand, arginine has been repeatedly associated with immune function enhancement. In our study, the consequences of a combination of arginine and Ω-3 fatty acids may have been to cancel each other out. Therefore, future research should evaluate the effects of single compounds of immune-enhancing nutrients as well as other nutrients.

After 6 months of oral nutritional supplementation, all patients were given the option of continuing for an additional 6 months. Only six and nine patients in standard and Arg–Ω-3 groups, respectively, completed this period. A post-hoc analysis did not reveal conclusions that were different from those drawn after the 6-month study period.

The study design had the limitation of not including a prospective, randomized group without nutritional supplementation. There are many reasons why prospective, double-blind, placebo-controlled trials of oral nutritional supplements are difficult to complete, and amongst them is the production of a placebo that cannot be distinguished from the oral nutritional supplement, and the extreme difficulty in recruiting placebo patients at a time when various campaigns were taking place to promote oral nutritional supplementation in Geneva. To circumvent this methodological problem and to add strength to our results, we compared our study patients with those included in the SHCS who were not on nutritional supplementation. Standard immune competence markers and viraemia remained unchanged and similar in both groups during the study period. Influence of existing antiviral treatment at inclusion or antiviral drug treatment alterations during the study period was not likely because the modifications were rare and equally distributed in both groups (Table 2). Finally, the absence of a statistically significant difference should not be interpreted as the demonstration that the two treatments were equivalent. It is possible that a small (and therefore not clinically relevant) difference existed, but was not detected because of the relatively small sample size.

In conclusion, oral nutritional supplements balanced for protein and energy supplying 606 kcal daily for a 6-month period were well tolerated and resulted in body weight gain in HIV-infected patients. Supplement enriched with nutrients potentially active in stimulating immune function, such as arginine and Ω-3 fatty acids, produced statistically similar results. No improvement in immune status, as reflected by CD4 lymphocyte counts, sTNF-R and viraemia, was observed. Quantities of arginine and Ω-3 fatty acids other than those used in this study may be found to have beneficial effects on immune function. Oral nutritional supplementation and diet counselling are likely to continue to be indicated in HIV-infected patients as supportive measures to antiretroviral treatments.

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Acknowledgements

The authors are indebted to the physicians for their help in recruiting and following up patients; C. Willimann and M. Kruseman for their contribution to the data collection; H. Gallati for the measurements of TNF plasma; U. Kyle and H. Schneider for their helpful comments and editorial assistance; T. Perneger for his expertise in using and interpreting the SF-36 questionnaire.

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Appendix

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Members of the Swiss HIV Cohort Study

M. Battegay, Ph. Bürgisser, L. Jeannerod, M. Egger, P. Erb (President of the Laboratory Group), W. Fierz, M. Flepp (President of the Clinical Group), P. Francioli (President of the SHCS, University Hospital, Lausanne, Switzerland), P. Grob, U. Grüninger (Observers of the Federal Office of Public Health), B. Hirschel (President of the Scientific Board), B. Ledergerber, R. Lüthy, R. Malinverni, L. Matter, M. Opravil, F. Paccaud, L. Perrin, W. Pichler, M. Rickenbach (Manager of the Data Coordination Centre), O. Rutschmann, P. Vernazza, J. von Overbeck.

Keywords:

HIV; immunity; viraemia; nutritional status; tumour necrosis factor soluble receptors; body composition; electrical bioimpedance; food supplement; arginine; Ω-3 fatty acid

© Lippincott-Raven Publishers.