Evaluation of high-protein supplementation in weight-stable
HIV-positive subjects with a history of weight loss:
a randomized, double-blind, multicenter trial1–3
Fred R Sattler, Natasa Rajicic, Kathleen Mulligan, Kevin E Yarasheski, Susan L Koletar, Andrew Zolopa,
Beverly Alston Smith, Robert Zackin, and Bruce Bistrian for the ACTG 392 Study Team
ABSTRACT
Background: HIV patients with wasting are at increased risk of
opportunistic complications and fatality.
Objective: We hypothesized that augmenting dietary intake with
high-biologic-value protein would enhance weight and lean tissue in
weight-stable subjects with a prior unintentional weight loss of
쏜3%.
Design: Fifty-nine subjects with HIV RNA concentrations 쏝5000
copies/mL were randomly assigned to receive a 280-kcal supple-
ment containing 40 g whey protein or a matched isocaloric control
supplement without added protein twice daily for 12 wk.
Results: Before the study, intake of total energy and protein ex-
ceeded estimated requirements (44.3 앐 12.6 kcal 䡠 kgҀ1 䡠 dҀ1 and
1.69 앐 0.55 g 䡠 kgҀ1 䡠 dҀ1, respectively). Both supplements failed
to increase total energy intake because of decreases in self-selected
food intake. Changes in weight (0.8 앐 2.4 and 0.7 앐 2.4 kg) and lean
body mass (0.3 앐 1.4 and 0.3 앐 1.5 kg) did not differ significantly
between the whey protein and control groups, respectively. Waist-
to-hip ratio improved more with whey protein (Ҁ0.02 앐 0.05) than
with the control (0.01 앐 0.03; P ҃ 0.025) at week 6 but not at week
12. Fasting triacylglycerol increased by 39 앐 98 mg/dL with the
control supplement and decreased by 16 앐 62 mg/dL with whey
protein at week 12 (P ҃ 0.03). CD4 lymphocytes increased by 31 앐
84 cells/mm3 with whey protein and decreased by 5 앐 124 cells/mm3
with the control supplement at 12 wk (P ҃ 0.03). Gastrointestinal
symptoms occurred more often with whey protein.
Conclusions: A whey protein supplement did not increase weight
or lean body mass in HIV-positive subjects who were eating
adequately, but it did increase CD4 cell counts. The control
supplement with rapidly assimilable carbohydrate substituted for
protein increased cardiovascular disease risk factors. Careful di-
etary and weight history should be obtained before starting nu-
tritional supplements in subjects with stable weight loss and good
viral control. Am J Clin Nutr 2008;88:1313–21.
INTRODUCTION
In patients with HIV, weight loss 욷5% is associated with
increased risk of morbidity and mortality (1, 2). HIV wasting has
declined in the era of highly active antiretroviral therapy
(HAART) (3–5). However, data from the Nutrition for Healthy
Living (NFHL) cohort, which enrolled 713 participants between
1995 and 2003, showed that HIV wasting remains common dur-
ing HAART with nearly one-third of the cohort meeting the case
Am J Clin Nutr 2008;88:1313–21. Printed in USA. © 2008 American Society for Nutrition
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definitions of wasting (1). Recent data from the NFHL cohort
showed a 50% increase in the 6-mo risk of 욷5% unintentional
weight loss during HAART in 1998 –2003 compared with 1995–
1997 (6). Although reversal of wasting may occur with HAART
(7), lean tissue gain is often modest (8 –10). Finally, patients who
fail to respond to HAART are at risk of recurrent wasting, be-
cause HIV RNA concentrations have been shown to correlate
with the magnitude of weight loss (11, 12).
Efforts to replete body mass in HIV patients have included
strategies to enhance energy intake via parenteral and enteral
feeding (13–21). Few controlled studies have evaluated dietary
supplements (22, 23) and even fewer have focused on intake of
protein—a primary substrate for the synthesis of important func-
tional tissues. Some HIV patients with stable weight reported
consuming large amounts of energy but were unable to fully
restore lost weight (24, 25). Furthermore, protein intake but not
energy intake has been correlated with metabolically active body
cell mass (26). Thus, the failure to regain weight or lean tissue
may be partly due to inadequate or low-quality protein intake.
1
From the Keck School of Medicine, University of Southern California,
Los Angeles, CA (FRS); the Department of Biostatistics, Harvard School of
Public Health, Boston MA (NR); the University of California, San Francisco
and San Francisco General Hospital, San Francisco, CA (KM); the Depart-
ment of Internal Medicine, Washington University School of Medicine, St
Louis, MO (KEY); the Division of Infectious Diseases, Ohio State Univer-
sity, Columbus, OH (SLK); Stanford University, School of Medicine, Stan-
ford, CA (AZ); the Division of AIDS of the National Institute of Allergy and
Infectious Diseases, Bethesda, MD (BAS); the Department of Biostatistics,
Harvard School of Public Health, Boston, MA, and the Department of Med-
icine (RZ), Beth Israel Deaconess Medical Center, Harvard Medical School
(BB) Boston, MA.
2
Supported by the National Institute of Allergy and Infectious Diseases
through the Adult AIDS Clinical Trials Group U01 grants (AI20766, AI
69474, AI27663, AI25903, AI27673, AI46386, AI34853, AI27668,
AI27658, AI25897, AI34832, and AI32770) and the General Clinical Re-
search Programs, NCRR, M01 grants (RR00070, RR00034, RR00043,
RR00083, RR00052, RR00044, and RR00051). Biomune Systems, Inc, pro-
vided the whey protein and control supplements.
3
Reprints not available. Address correspondence to FR Sattler, Keck
School of Medicine, University of Southern California, LAC-USC Medical
Center, Room 6442, 1200 North State Street, Los Angeles, CA, 90033.
E-mail: fsattler@usc.edu.
Received July 30, 2006. Accepted for publication July 22, 2008.
doi: 10.3945/ajcn.2006.23583.
1313
1314 SATTLER ET AL
In other catabolic conditions, positive nitrogen balance is
achieved by increasing protein intake well in excess of the Rec-
ommended Dietary Allowance (RDA) (0.8 g 䡠 kgҀ1 䡠 dҀ1) while
maintaining energy intake in the physiologic range (27–29). Dur-
ing renal failure, negative nitrogen balance was improved by
increasing protein intake to 1.5–2.0 g 䡠 kgҀ1 䡠 dҀ1 but not by
increasing nonprotein intake to 40 kcal 䡠 kgҀ1 䡠 dҀ1 at a protein
intake of 0.8 –1.0 g 䡠 kgҀ1 䡠 dҀ1 (30). In patients with burns or
sepsis who achieve positive nitrogen balance, providing excess
nonprotein energy increased resting energy expenditure (31, 32)
and fat deposition (32) without further augmentation of LBM.
Similarly, hypercaloric feeding by total parenteral nutrition in
AIDS patients resulted in weight gain that was almost entirely
composed of fat (14).
In HIV, convenient and palatable dietary supplements can
increase total energy intake (33–37). Supplementing protein in-
take may improve nitrogen balance and protein synthesis (37–
39). Furthermore, providing amino acids such as glutamine may
increase body cell mass in AIDS wasting (19). We tested the
hypothesis that providing supplements containing substantial
high-biologic-value whey protein (undenatured milk protein,
containing all essential and nonessential amino acids and rich in
glutamine and cyst(e)ine) to increase protein intake to 1.5–2.0
g 䡠 kgҀ1 䡠 dҀ1 would enhance lean tissue accrual in HIV-
infected subjects.
SUBJECTS AND METHODS
Subjects
The study population consisted of subjects with confirmed
HIV-1 infection and stable weight loss, which was defined as
prior unintentional weight loss 쏜3% over the course of the
HIV-1 infection, but no change in weight 쏜3% during the 2 mo
before enrollment. Additional entry criteria included no evidence
of active opportunistic complications or evidence of malabsorp-
tion and HIV RNA concentrations 쏝5000 copies/mL, but
HAART was not required. The study was approved by the insti-
tutional review board at each participating site, and all subjects
provided written informed consent before enrollment. All as-
pects of the study were conducted in accordance with the Hel-
sinki Declaration of 1975 (revised in 1983).
Study regimen
After study entry, the subjects were randomly assigned to
receive 1 of 2 twice daily study regimens: a high-protein supple-
ment containing 40 g whey protein, 20.5 g carbohydrate, and
4.0 g fat per 280-kcal serving or an isocaloric control supplement
without the added protein, which contained 0.6 g casein (pro-
tein), 60.8 g carbohydrate (high-maltose rice syrup solids), and
4.0 g fat per 280-kcal serving (Biomune Systems Inc, Salt Lake
City, UT). The isocaloric control supplement was similar to the
whey protein supplement in color, texture, and taste (mango
flavored). Both supplements were to be taken twice daily be-
tween meals for 12 wk; thus, the supplements were intended to
increase total daily energy intake by 560 kcal. All subjects and
study personnel were blinded to treatment assignment.
Outcome assessments
In addition to the baseline visit, subjects were interviewed and
examined by a study physician, and outcome data were collected
at weeks 6 and 12. Body-composition measures were collected or
calculated and included standardized height and weight mea-
sured with a calibrated scale while subjects were wearing under-
wear and a gown, body mass index (BMI; weight in kilogram/
height squared in meters), absolute and percent LBM, and fat by
single-frequency bioelectrical impedance analysis (BIA; RJL
Quantum, Clinton Township, MI). For BIA, study coordinators
were certified in electrode placement and body positioning dur-
ing central training at AIDS Clinical Trials Group (ACTG) meet-
ings. Fat and LBM were calculated by using published equations
validated in HIV-infected and HIV-uninfected subjects (40). An-
thropometric measurements included waist, thigh, and hip cir-
cumferences according to standardized ACTG procedures. Self-
reported food intake was assessed by standardized ACTG data
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collection instruments. In brief, 3-d written food intake diaries
were administered and reviewed by certified dietitians for veri-
fication of entries and portion sizes before centralized calculation
of total energy and macronutrient intakes with Nutritionist V
software (First Databank Inc, San Bruno, CA).
Blood was collected after an overnight fast for lipids, glucose,
insulin, routine chemistries, complete blood counts, CD4 lym-
phocyte counts, HIV RNA concentrations, and total testosterone
concentrations in men at the local clinical laboratories before
study interventions. Insulin concentrations were determined in
specimens during batch testing at Quest Diagnostics Laboratory
(San Juan Capistrano, CA). Fasting glucose and insulin were
used to calculate static markers of insulin sensitivity, namely the
homeostasis model assessment of insulin resistance (HOMA-IR)
and the quantitative insulin sensitivity check index (QUICKI),
which are correlated with insulin sensitivity measured with the
hyperinsulinemic euglycemic clamp (41, 42).
Statistical considerations
The study plan was to accrue 56 subjects to provide an 80%
probability of detecting, at the 5% significance level, a clinically
relevant mean difference of 1.6 앐 2.0 kg in change in LBM from
baseline to study week 12 between the 2 dietary intervention
groups, assuming a 10% loss to follow-up. The primary endpoint
used the change in LBM from baseline to study week 12. Dif-
ferences between the 2 study arms were evaluated by using a
Wilcoxon’s rank-sum test for comparing medians from 2 con-
tinuous distributions. The same test was used to evaluate changes
in the remaining continuous measurements. Wilcoxon’s signed-
rank test was used for within-group comparisons. We also ana-
lyzed the primary endpoint using the repeated-measures analysis
(PROC MIXED procedure in SAS). In this analysis, we consid-
ered both the actual LBM values over time as well as the changes
in LBM. Either Fisher’s exact test or Pearson’s chi-square test
was used to evaluate the differences with respect to the discrete
variables, depending on a number of categories of a discrete
variable. Estimates of SD and interquartile range were given for
means and medians, respectively. Times to treatment discontin-
uation between the 2 study groups were compared by using the
log-rank test.
Evaluation of the primary endpoint was done by using an
intention-to-treat analysis. Results of the “as-treated” analysis
are reported as well. In cases of subjects missing the week 12
measurements needed for the primary endpoint evaluation, the
value was extrapolated by carrying forward the week 6 measure-
ments. Subjects missing both postbaseline values were deemed
ineligible for the analysis of the primary endpoint.
 WHEY PROTEIN SUPPLEMENTS FOR HIV-ASSOCIATED WASTING
Statistical analyses were performed by using the SAS statis-
tical package (software release 8.2; SAS Institute Inc, Cary, NC).
The figure was created by using R Computing Environment
(http://www.R-project.org).
RESULTS
Sixty subjects from 15 ACTG study sites were enrolled in this
multicenter trial from February to December 1999. Of the 59
subjects randomly assigned to this double-blind study (there was
one inadvertent enrollment of a subject who did not meet entry
1315
criteria), 29 subjects received the supplement containing whey
protein and 30 received the control supplement. The 2 study
groups were well balanced with respect to demographic charac-
teristics at baseline (Table 1). The median age for the 7 women
and 52 men was 41 y. Most of the subjects were white (66%), and
52 (88%) reported no prior use of intravenous drugs. The 2
groups were also balanced at baseline with respect to CD4 count,
Karnofsky performance status, and 3-mo prior antiretroviral
treatment, although one subject in the control group was not receiv-
ing antiretroviral therapy. The CD4 counts ranged from 33 to 1263
cells/mm3 (median ҃ 344 cells/mm3), and 85% of subjects had a

TABLE 1
Baseline characteristics of the study population1

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Whey protein Control
(n ҃ 29) (n ҃ 30) P value2
Male sex [n (%)] 26 (90) 26 (87) 0.99
Ethnicity/race [n (%)] 0.67
White, non-Hispanic 20 (69) 19 (63)
Hispanic 3 (10) 5 (17)
Black 3 (10) 5 (17)
Asian 2 (7) 1 (3)
Intravenous drug use, never [n (%)] 26 (90) 26 (87) 0.99
Antiretroviral history (n)
PI ѿ NRTI 16 17
PI ѿ NRTI ѿ NNRTI 8 7 0.52
NRTI ѿ NNRTI 4 3
Only NRTI 0 2
PI ѿ NNRTI 1 0
No antiretroviral therapy 0 1
Age (y)3 41 (31, 66) 41 (26, 58) 0.21
욷50 y of age [n (%)] 5 (17) 6 (20)
Karnofsky performance score3 90 (70, 100) 90 (80, 100) 0.74
CD4 lymphocytes [n (%)]4
쏝200 cells/mL 6 (21) 2 (6)
200-500 cells/mL 16 (56) 19 (63) 0.155
쏜500 cells/mL 7 (24) 8 (27)
HIV RNA (copies/mL)3 400 (쏝50, 1546) 200 (쏝50, 3196) 0.11
Body composition
Weight (kg) 63.7 앐 7.95 63.4 앐 10.7 0.79
BMI (kg/m2) 20.7 앐 2.3 21.1 앐 2.8 0.50
BMI 쏝 18.5 kg/m2 [n (%)] 6 (21) 6 (20) 0.95
Fat (%) 14.6 앐 6.5 14.0 앐 5.0 0.91
Selected blood tests
Hemoglobin (g/L) 14.3 앐 1.8 14.1 앐 1.5 0.49
Albumin (g/dL) 4.2 앐 0.8 4.3 앐 0.5 0.83
Glucose (mg/dL) 85 앐 11 90 앐 33 0.92
Insulin (␮IU/mL) 10.6 앐 6.4 10.6 앐 6.4 0.60
Testosterone (ng/dL) 441 앐 367 368 앐 353 0.51
Total cholesterol (mg/dL) 201 앐 54 211 앐 58 0.44
Fasting triacylglycerol (mg/dL) 199 앐 150 230 앐 158 0.44
HOMA-IR6,7 2.74 앐 2.2 2.12 앐 1.27 0.78
QUICKI6,8 0.26 앐 0.04 0.28 앐 0.07 0.79
1
NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; HOMA-IR, homeostasis model assessment of
insulin resistance; QUICKI, quantitative insulin sensitivity check index; PI, protease inhibitor.
2
P values for body composition, Karnofsky performance score, HIV RNA count, selected blood tests, HOMA-IR, and QUICKI are based on a Wilcoxon’s
rank-sum test on medians between the 2 study groups; P values for categorical variables are based on either the chi-square or Fisher’s exact test.
3
Values are medians; range in parentheses.
4
CD4 count unknown in one case (3%) in control group.
5
x៮ 앐 SD (all such values).
6
Calculations for the 39 subjects who had paired fasting insulin and glucose concentrations (baseline and week 12): 19 in the whey protein group and 20
in the control group.
7
Calculated as 关(If) ҂ (Gf)兴/22.5, where (If) is the fasting insulin concentration (␮IU/mL) and (Gf) is the fasting glucose concentration (mmol/L).
8
Calculated as 1/关log (If) ѿ log (Gf)兴, where (If) is the fasting insulin concentration (␮IU/mL) and (Gf) is the fasting glucose concentration (mg/dL).
1316 SATTLER ET AL

Karnofsky score of 90 or 100. Overall, the median HIV-1 RNA level
was 400 copies/mL (range: 쏝50 to 3196 copies/mL).
There were 35 subjects (15 treated with whey protein and 20
treated with the control supplement) who had extensively docu-
mented weight histories covering up to 50 wk before baseline. In
this group, there was no difference (P ҃ 0.67) in the median
change in weight during the pretreatment period from the respec-
tive whey protein group [0.2 kg; interquartile range (IQR): Ҁ0.6,
0.7) and control group (0.5 kg; IQR: Ҁ0.9, 1.0), providing evi-
dence of weight stability.
Of 59 eligible subjects, 41 subjects completed the study treat-
ment: 17 in the whey protein arm and 24 in the control group.
There was no evidence to suggest that the duration of treatment
differed between the 2 study arms (P ҃ 0.17). Five subjects in the
of subjects in the 2 treatment arms discontinued the treatment
because of nonprotocol-defined, low-grade toxicities or clinical
events. One subject in the whey protein group stopped the treat-
ment because of the use of a prohibited medication, and another
subject stopped treatment because they disliked the taste. Finally,
in the whey protein group, 15 subjects had at least grade II
gastrointestinal symptoms (eg, nausea, vomiting, bloating,
cramps, or diarrhea) compared with 7 subjects in the control
group (P ҃ 0.03).
Body-composition measures at baseline and study weeks 6
and 12 are shown in Table 2. For the primary outcome, there was
no difference in the change in LBM between the whey protein
(0.2 앐 1.4 kg) and control (0.3 앐 1.3 kg) groups after 6 wk (P ҃
0.76, Wilcoxon’s rank-sum test). After 12 wk of study therapy,
the respective changes were 0.3 앐 1.4 and 0.3 앐 1.5 kg (P ҃

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whey protein group discontinued the study treatment prema-
turely because of protocol-defined toxicities. An equal number 0.61) in the 2 groups. Furthermore, there was no change in LBM

TABLE 2
Outcome measures with study intervention

P value1
Whey protein group Control group Group effect Time effect

Weight (kg) — — 쏜0.05 0.01

Baseline
Week 6; ⌬ to week 6
Week 12; ⌬ to week 12
Total lean body mass (kg)
Baseline
Week 6; ⌬ to week 6
Week 12; ⌬ to week 12
Total fat mass (kg)
Baseline
Week 6; ⌬ to week 6
Week 12; ⌬ to week 12
Waist-to-hip ratio
Baseline
Week 6; ⌬ to week 6
Week 12; ⌬ to week 12
Waist-to-thigh ratio
Baseline
Week 6; ⌬ to week 6
Week 12; ⌬ to week 12
Thigh-to-waist-to-hip ratio
Baseline
Week 6; ⌬ to week 6
Week 12; ⌬ to week 12
Triglycerides (mg/dL)6
Baseline
Week 6; ⌬ to week 6
Week 12; ⌬ to week 12
CD4 lymphocytes (cells/mL)6
Baseline
Week 6; ⌬ to week 6
Week 12; ⌬ to week 12
63.4 앐 10.7 (29)2 63.7 앐 7.9 (30) — —
63.9 앐 10.9; 0.7 앐 1.8 (27) 64.9 앐 8.1; 0.7 앐 1.5 (27) — —
64.1 앐 10.5; 0.8 앐 2.4 (27) 64.3 앐 8.5; 0.7 앐 2.4 (25) — —
— — 쏜0.05 쏜0.05
54.2 앐 7.4 (29) 54.1 앐 5.7 (30) — —
54.3 앐 7.3; 0.2 앐 1.4 (27) 54.5 앐 6.1; 0.3 앐 1.3 (27) — —
54.4 앐 7.0; 0.3 앐 1.4 (27) 53.9 앐 6.1; 0.3 앐 1.5 (25) — —
— — 쏜0.05 0.04
9.2 앐 4.4 (29) 9.6 앐 4.8 (30) — —
9.7 앐 4.6; 0.4 앐 1.2 (27) 10.4 앐 4.9; 0.3 앐 0.8 (27) — —
9.7 앐 4.6; 0.5 앐 1.6 (27) 10.4 앐 6.1; 0.4 앐 1.7 (25) — —
— — 쏜0.05 쏜0.05
0.93 앐 0.06 (29) 0.92 앐 0.05 (30) — —
0.92 앐 0.06; Ҁ0.02 앐 0.05 (26)3 0.94 앐 0.05; 0.01 앐 0.03 (27) — —
0.93 앐 0.06; 0.00 앐 0.05 (26) 0.94 앐 0.06; 0.00 앐 0.04 (27) — —
— — 쏜0.05 0.03
1.89 앐 0.16 (29) 1.84 앐 0.17 (30) — —
1.81 앐 0.17; Ҁ0.10 앐 0.16 (26)4 1.84 앐 0.18; Ҁ0.01 앐 0.08 (27) — —
1.81 앐 0.24; Ҁ0.09 앐 0.22 (27) 1.85 앐 0.18; Ҁ0.01 앐 0.07 (27) — —
— — 쏜0.05 쏜0.05
47.26 앐 5.34 (29) 49.14 앐 5.89 (30) — —
49.40 앐 5.41; 2.61 앐 4.06 (26)5 49.22 앐 6.66; 0.22 앐 2.65 (27) — —
50.56 앐 10.23; 3.38 앐 9.55 (26) 49.01 앐 6.94; 0.41 앐 3.04 (27) — —
— — — —
230 앐 158 (29) 200 앐 15 (30) 0.037 —
NA8 NA — —
228 앐 155; Ҁ16 앐 62 (25) 200 앐 118; 39 앐 98 (22) — —
— — — —
365 앐 208 (28) 467 앐 285 (25) 0.037 —
NA NA — —
396 앐 226; 31 앐 84 (28) 462 앐 314; Ҁ5 앐 124 (25) — —

1
Repeated-measures analyses (PROC MIXED); time-by-group interactions were not significant for any of the variables.
2
x៮ 앐 SD; number of subjects for whom paired data are available in parentheses.
3
Significance of differences between groups in change from baseline at study week 6, P ҃ 0.025 (Wilcoxon’s rank-sum test).
4
P ҃ 0.014.
5
P ҃ 0.004.
6
Not tested at study week 6.
7
P value represents the difference between groups in the change from baseline to study week 12 (Wilcoxon’s rank-sum test).
8
Not applicable.
 WHEY PROTEIN SUPPLEMENTS FOR HIV-ASSOCIATED WASTING
across the time points by repeated-measures analyses. Similarly,
the respective changes in total weight of 0.7 앐 1.8 and 0.7 앐 1.5
kg for the 2 groups at study week 6 were not significantly dif-
ferent (P ҃ 0.96) nor were the changes of 0.8 앐 2.4 and 0.7 앐 2.4
kg at study week 12 (P ҃ 0.63). For fat, the respective changes
were 0.4 앐 1.2 and 0.3 앐 0.8 kg for the 2 groups at study week
6 (P ҃ 0.33) and 0.5 앐 1.6 and 0.4 앐 1.7 kg at study week 12,
respectively (P ҃ 0.40). Data for 54 subjects were available for
the evaluation of the primary endpoint in the intention-to-treat
analysis. For 2 of the 54 subjects who did not have LBM data
available from week 12, week 6 results were carried forward to
week 12. Similar results were obtained when week 6 data were
extrapolated by using a constant slope. The as-treated analysis of
the 41 subjects who completed the full 12 wk of study therapy
1317
whey protein arm and 24 in the control group who completed the
study. As designed, the change in dietary protein intake was
greater in the whey protein group than in the control group at
week 6 (68.7 앐 40.4 and Ҁ7.7 앐 35.6 g/d; P 쏝 0.001) and at
week 12 (64.4 앐 45.3 and Ҁ27.6 앐 38.5 g/d; P 쏝 0.01), which
resulted in a significantly greater total intake of protein per ki-
logram of body weight in the whey group at both time points.
Despite the significant differences in protein intake between the
groups, average total daily protein intake remained well above
the RDA (Table 3). Also, and as designed, the change in dietary
carbohydrate intake at week 6 was lower in the whey protein
group (Ҁ3.3 앐 109.6 and 85.8 앐 137.6 g/d; P 쏝 0.01), but at
week 12 the difference in change was not significant between the
groups (Ҁ34.4 앐 160.3 and 36.3 앐 108.9 g/d; P ҃ 0.19).

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showed no significant changes in LBM between the 2 groups (P
҃ 0.26). These outcomes were also analyzed after women were
excluded to determine whether there was a sex effect; all changes
remained nonsignificant (all P 쏜 0.10; data not shown) without
trends suggesting any benefit in terms of LBM, total weight, or
fat. Furthermore, baseline BMI was not related to changes in
weight in either group by Spearman correlation (whey protein:
Ҁ0.18, P ҃ 0.36; placebo: 0.32, P ҃ 0.12).
Changes in the variables listed in Table 2 over time were also
analyzed by using a repeated-measures analysis with treatment
group and time as model terms (PROC MIXED in SAS, with
each response variable analyzed separately; Table 2). To exam-
ine the presence of interaction, a time-by-treatment interaction
term was included in each of the models, but there was no sta-
tistically significant interaction in any of the models, possibly
because of insufficient statistical power based on the sample size
of the groups. Additional analyses showed that there was no
statistically significant effect of the treatment groups, but there
were significant effects of time for weight, total fat mass, and
waist-to-thigh ratio.
Intakes of total energy and macronutrients at baseline and at
study weeks 6 and 12 are shown in Table 3 for 17 subjects in the
Changes in dietary intake over time were also analyzed by
using a repeated-measures analysis, with treatment group and
time as model terms (PROC MIXED, with dietary measurements
as response variables analyzed separately). To examine the pres-
ence of an interaction, the time-by-treatment interaction term
was included in each of the 4 models, but there was no statisti-
cally significant interaction in any of the models. Again, this
result was possibly due to insufficient statistical power. Further-
more, for any of the 4 dietary measures, there was no statistically
significant effect of treatment group, but there was a significant
(P 쏝 0.01) related effect of time for each of the macronutrients.
The same results were reached in the analysis of ranks of the
continuous variable in place of the response variable in the
model.
As shown in Figure 1, there were no differences in the total
intake of energy per kilogram of body weight (includes both
self-selected food plus supplements) between the 2 study groups
at study week 6 or study week 12 (P 쏜 0.05 for each comparison).
Moreover, the change from baseline in total daily energy intake
at study week 12 did not differ significantly between the whey
protein (177 앐 991 kcal) and control (183 앐 831 kcal) groups (P
҃ 0.12; Figure 1). Although self-selected intake of total energy,

TABLE 3
Intake of total calories and macronutrients1

P value4
Baseline Week 6 Week 12 P value2 P value3 Group effect Time effect
Ҁ1 Ҁ1
Total energy (kcal 䡠 kg 䡠 d ) — — — 0.74 0.12 쏜0.05 쏝0.01
Whey protein group 42.6 앐 14.1 48.6 앐 13.8 (15) 47.4 앐 12.4 (15) — — — —
Control group 45.9 앐 10.9 50.6 앐 14.6 (20) 45.4 앐 14.5 (18) — — — —
Protein (g 䡠 kgҀ1 䡠 dҀ1) — — — 쏝0.0015 쏝0.015 쏜0.05 쏝0.01
Whey protein group 1.64 앐 0.53 2.62 앐 0.43 (15) 2.57 앐 0.51 (15) — — — —
Control group 1.74 앐 0.58 1.68 앐 0.60 (20) 1.40 앐 0.56 (18) — — — —
Carbohydrate (g 䡠 kgҀ1 䡠 dҀ1) — — — 쏝0.015 0.19 쏜0.05 쏝0.01
Whey protein group 5.15 앐 2.33 5.77 앐 2.71 (15) 5.29 앐 1.98 (15) — — — —
Control group 5.65 앐 1.18 6.97 앐 1.96 (20) 6.29 앐 1.75 (18) — — — —
Fat (g 䡠 kgҀ1 䡠 dҀ1) — — — 0.18 쏝0.01 쏜0.05 쏝0.01
Whey protein group 1.71 앐 0.63 1.67 앐 0.47 (15) 1.77 앐 0.58 (15) — — — —
Control group 1.87 앐 0.66 1.78 앐 0.70 (20) 1.62 앐 0.69 (18) — — — —
1
All values are x៮ 앐 SD; number of subjects for whom paired data were available at the time point and at baseline in parentheses.
2
Difference in change between groups from baseline to week 6 (Wilcoxon’s rank-sum test).
3
Difference in change between groups from baseline to week 12 (Wilcoxon’s rank-sum test).
4
Longitudinal analysis: repeated-measures analyses (PROC MIXED); time-by-group interactions were not significant for the macronutrients listed.
5
Significant changes were by study design to increase protein intake in the whey supplement group and to increase carbohydrate intake in the control
supplement group.
1318 SATTLER ET AL

kJ/kg/day

Kcal/kg/day
250
mean(SD) Fat Protein
Carbohydrate Study supplement

50.6(14.6)
48.6(13.8)
47.4(12.4)
45.9(10.9) 45.4(14.5) 200

45
42.6(14.1)

Downloaded from https://academic.oup.com/ajcn/article/88/5/1313/4648833 by guest on 13 October 2020

150

30

100

15

50

0 0
wk 0 wk 6 w k 12 wk 0 wk 6 wk 12
High Protein Control

FIGURE 1. Total caloric intake is shown at baseline (week 0) and after 6 and 12 wk of study therapy for the 17 subjects in the whey protein arm and the
24 subjects in the control group who completed the study. Each bar shows the amount of fat, carbohydrate, and protein in self-selected food and supplements.
The change from baseline in total daily energy intake at study week 12 did not differ significantly between the whey protein and control groups (P ҃ 0.12,
Wilcoxon’s rank-sum test). In the repeated-measures analysis, there was no significant interaction between treatment and time (total caloric intake: P ҃ 0.66;
difference from baseline: P ҃ 0.93). At study week 12, self-selected energy intake decreased less in the whey protein group (P ҃ 0.04, Wilcoxon’s rank-sum
test). The lack of a significant increase in total energy consumption was due to a decrease in self-selected energy intake at study weeks 6 and 12.

protein, carbohydrates, or fat (excludes energy provided by sup-
plements) did not change at study week 6 compared with base-
line, self-selected energy intake decreased less at study week 12
in the whey protein group (Ҁ325 앐 1032 kcal/d) than in the
control group (Ҁ777 앐 818 kcal/d) (P ҃ 0.04). The lack of a
significant increase in total energy consumption was due to a
decrease in the self-selected energy intake at study weeks 6 and
12 (Figure 1).
Several secondary outcomes were evaluated (Table 2). An
evaluation of the paired data at week 6 showed that the waist-to-
hip ratio decreased in the whey protein group but increased in the
control group (P ҃ 0.025). The waist-to-thigh ratio decreased to
a greater extent with whey protein (P ҃ 0.014 compared with
control), whereas the thigh-to-waist-to-hip ratio increased to a
greater extent in the whey protein group (P ҃ 0.004 compared
with control). At study week 12, there were no significant
changes in these variables (P 욷 0.09; Table 2). Fasting serum
triacylglycerol in subjects with paired data decreased at week 12
by 16 앐 62 mg/dL in the whey protein group and increased by 39
앐 98 mg/dL in the control group (P ҃ 0.035). There were no
significant changes in other lipids, fasting glucose, insulin,
HOMA-IR, or QUICKI (data not shown).
Another secondary outcome included assessment of the ef-
fects of whey protein on immune function. From baseline to week
12, in subjects in whom paired data were available, those treated
with whey protein had an average increase in CD4 lymphocytes
of 31 앐 84 cells/mL (P ҃ 0.04), whereas those who received the
control supplement had a slight decrease in CD4 lymphocytes of
 WHEY PROTEIN SUPPLEMENTS FOR HIV-ASSOCIATED WASTING
Ҁ5 앐 124 cells/mL (P ҃ 0.19). The difference in CD4 changes
from baseline to week 12 between the 2 study groups was sig-
nificant (P ҃ 0.03). The change from baseline to week 12 in CD4
counts was also analyzed with week 0 values as a covariate in a
nonparametric analysis of covariance model (PROC GLM in
SAS with response variable as ranks). In this analysis, the effect
of the treatment group was statistically significant (P ҃ 0.04).
DISCUSSION
In HIV-infected subjects with stable weight loss, 12 wk of
nutritional supplementation with high biologic quality (whey)
protein did not increase energy intake, weight, extremity circum-
ferences, or lean tissue more than did an isocaloric, high-
carbohydrate, low-protein control supplement. However, many
important lessons can be learned from this study. First, for sub-
jects who have reached new weight equilibrium by eating an
adequate diet and are not malnourished, dietary supplements
alone may not be sufficient to further restore weight or LBM.
Such individuals may have selected a level of total energy and
protein intake and/or a new activity level sufficient to maintain
their body weight in a stable range, albeit below their premorbid
weight and lean tissue status. Indeed, before the study interven-
tion began, the subjects’ energy intake (44.3 앐 12.6 kcal 䡠
kgҀ1 䡠 dҀ1) exceeded the estimated energy requirement, and
their protein intake (1.73 앐 0.63 g 䡠 kgҀ1 䡠 dҀ1) was 2-fold
greater than the RDA (0.8 g 䡠 kgҀ1 䡠 dҀ1) and within the range
that achieved positive nitrogen balance in other catabolic condi-
tions (30). It is, therefore, not surprising that the whey protein
supplement did not increase weight or lean tissue in these par-
ticipants, who were habitually consuming more than adequate
amounts of protein and energy.
Another important observation was that the increase in carbo-
hydrate intake with the control supplement worsened fasting
serum triacylglycerol. The small but significant changes in
waist-to-hip, waist-to-thigh, thigh to waist-to-hip ratios at study
week 6 also suggested that there was an unfavorable change in
body composition (increased central fat) with the high-
carbohydrate control supplement, which is predicted to increase
cardiovascular disease risk (43, 44). Similarly, in other con-
trolled studies of HIV-infected patients, oral liquid supplements
produced increases in fat without an apparent change in lean
tissue (33, 34). Thus, even with a relatively short course of
therapy, our results suggest that care should be taken when con-
sideration is given to prescribing supplements that increase the
intake of carbohydrate, particularly those that are rapidly assim-
ilable, in weight-stable patients who are below their premorbid
weights but who also have preexisting cardiovascular disease
risk factors such as dyslipidemia, hypertension, impaired glu-
cose intolerance, or insulin resistance (45). Worsening triacyl-
glycerol concentrations, which are highly sensitive to carbohy-
drate intake, and increasing abdominal girth would be expected
to accelerate atherosclerosis in a population already at increased
risk of cardiovascular disease morbidity (46).
Of some surprise was the observation that self-selected intakes
of energy decreased during treatment with the nutritional sup-
plements. This contrasts with results from other studies of HIV-
infected patients, in which nutritional supplementation has in-
creased total daily energy intake (33–37). Although we designed
the present study to provide supplements between meals, sub-
jects self-selected to consume lower quantities of their regular
1319
dietary foods. An important difference may be that most studies
of nutritional supplementation are performed in subjects with
inadequate nutritional intake, ongoing weight loss, and often
preexisting malnutrition in which the nutritional supplement
may reduce but does not totally compensate for the increased
intake and therefore leads to a net increase in energy intake. The
present study was conducted in weight-stable subjects with a
history of weight loss, a relatively normal BMI, and adequate
intakes of both protein and calories.
These observations emphasize the importance of obtaining a
careful weight and dietary history and quantification of total
energy and macronutrient intakes (by food diaries, food fre-
quency, or 24-h dietary recall questionnaires) before prescribing
nutritional supplements for patients with HIV. Supplements are
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expensive, and, if energy intake is shown to be sufficient and
protein intake is above the RDA, our results suggest that further
augmentation of energy or protein intakes is unlikely to improve
body composition or nutritional status in a population of weight-
stable subjects with relatively well-controlled HIV. Finally, the
whey protein supplement was not well tolerated, as evidenced by
the greater gastrointestinal symptoms and attrition in this group.
This was also reported in another study of relatively asymptom-
atic HIV patients ingesting 45 g whey protein/d (47). In a pop-
ulation that may already have an excessive medication burden,
such symptoms may either adversely affect medication adher-
ence or cause malabsorption of these therapies.
Of importance, subjects treated with whey protein had a sig-
nificant increase in CD4 lymphocytes compared with those re-
ceiving the control supplement. These findings are consistent
with other studies of whey protein supplements that produced
improvements in immune function, including in mononuclear
cell glutathione concentrations (33, 48 –50). It is possible that the
improvement in CD4 counts with the whey protein supplement
was related to a regression-to–the-mean because the baseline
counts were lower in the whey protein group, albeit not statisti-
cally significantly so. Regardless, the potential for benefits in
immune status provides additional impetus for testing whey pro-
tein in catabolic patients with active weight loss and severe CD4
lymphocyte or intracellular glutathione depletion.
This study had several limitations. In particular, these results
should not be extrapolated to other populations, such as those
with unstable or active weight loss or those with inadequate
intakes of energy and protein, for whom studies should be con-
ducted to establish the efficacy and utility of increasing energy
intake largely in the form of high-biologic-quality protein. In-
deed, whey protein improved weight by 3.6 앐 2.3 kg and lean
tissue by 1.5 앐 1.9 kg as measured by dual-energy X-ray ab-
sorptiometry in an open-label study of HIV-infected women with
malnutrition (51). Furthermore, we used a convenient, relatively
low-tech method, namely BIA, which has proven effective and
useful for the assessment of changes in lean tissue in persons with
AIDS wasting before the HAART era (52). However, the test has
not been validated in wasting populations at risk of or with
lipodystrophy (central fat accumulation or peripheral lipoatro-
phy) before this study. Other methods, such as dual-energy X-ray
absorptiometry, magnetic resonance imaging, or computed to-
mography, may have been more sensitive and accurate in detect-
ing small but significant changes in lean tissue. Similarly, an-
thropometric measures made by different examiners at the same
clinical research center and across multiple clinical sites has
1320 SATTLER ET AL
inherent limitations because of problems with interobserver vari-
ation. Finally, a more palatable formulation of whey protein
could have resulted in better adherence with less treatment-
limiting toxicities, which allowed more subjects to complete the
study. Also, lower doses given for a longer period of time might
have affected outcomes differently.
In summary, this randomized controlled study indicated that
consumption of a nutritional supplement with high-biologic-
quality protein was ineffective in augmenting weight or lean
tissue in a weight-stable, HIV-infected population with prior
weight loss but who were already ingesting protein at a range
shown to increase lean tissue under other catabolic conditions. In
addition, the whey protein supplement was associated with
greater treatment-limiting symptoms. However, CD4 lympho-
cyte counts increased significantly with whey protein consump-
tion. The increased intake of rapidly assimilable carbohydrate
with the control supplement resulted in short-term increases in
fasting triacylglycerol and waist-to-hip ratio—a surrogate for
central adiposity. Furthermore, both supplements were ineffec-
tive at increasing the intake of total energy because of self-
selected decreases in food intake. Thus, a careful weight history
and assessment of dietary intake of energy and macronutrients
should be undertaken before prescribing nutritional supplements
in HIV patients with a history of weight loss.
The authors gratefully acknowledge the study subjects, who committed
substantial time and effort to make this study successful. We also gratefully
acknowledge the late Robert Zackin, who provided immense support and
scientific input for the design and analysis of the study. We also appreciate
and recognize the contributions from the participating ACTG clinical re-
search sites: Jane Norris and Sandra Valle (Stanford University; A0501),
Robert J Fass and Laura Laughlin (Ohio State University, Columbus, OH;
A2301), Diane Havlir and Mark Jacobson (University of California at San
Francisco; A0801), Sherry Lassa-Claxton and Donna Marin (Washington
University, St Louis, MO; A2101), Luis Mendez and William Briggs (Uni-
versity of Southern California, Los Angeles, CA; A1201), Marshall Glesby
and Valery Hughes (Columbia-Cornell, New York, NY; A7803), N Jeanne
Conley and T Mac Hooton (University of Washington, Seattle, WA; A1401),
Cecilia Shikuma and Debbie Arakaki (University of Hawaii; Honolulu, HI;
A5201), Ilene Wiggins and Melody Higgins (Johns Hopkins University,
Baltimore, MD; A0201), Marla Werner and Carol Greisberger (University of
Rochester, Rochester, NY; A1101), Judith Feinberg and Diane Daria (Uni-
versity of Cincinnati, Cincinnati, OH; A2401), Jorge Santana and Santiago
Marrero (University of Puerto Rico; San Juan, Puerto Rico; A5401), and
Sarah Lammer (University of Colorado, Boulder, CO; A6101).
The authors’ responsibilities were as follows—FRS, KM, KEY, BAS, and
BB: responsible for designing the study, monitoring the conduct of the trial
for adherence to the protocol and safety, and interpreting the results; NR and
RZ: responsible for the analysis of the global data for the project and prep-
aration of data for the manuscript; and AZ and SLK: principal investigators
at the ACTG clinical research sites that contributed the most subjects to the
study. All authors contributed to the writing and editing of the manuscript.
None of the authors had any financial relations with Biomune Systems Inc or
any other conflicts of interest.
REFERENCES
1. Wanke CA, Silva M, Knox TA, Forrester J, Speigelman D, Gorbach SL.
Weight loss and wasting remain common complications in individuals
infected with human immunodeficiency virus in the era of highly active
antiretroviral therapy. Clin Infect Dis 2000;31:803–5.
2. Wheeler DA, Gibert CL, Launer CA, et al. Weight loss as a predictor of
survival and disease progression in HIV infection. Terry Beirn Commu-
nity Programs for Clinical Research on AIDS. J Acquir Immune Defic
Syndr Hum Retrovirol 1998;18:80 –5.
3. Dworkin MS, Williamson JM. AIDS wasting syndrome: trends, influ-
ence on opportunistic infections, and survival. J Acquir Immune Defic
Syndr 2003;33:267–73.
4. Smit E, Skolasky RL, Dobs AS, et al. Changes in the incidence and
predictors of wasting syndrome related to human immunodeficiency
virus infection, 1987-1999. Am J Epidemiol 2002;156:211– 8.
5. Jones J, Hanson D, Dworkin M, et al. Surveillance for AIDS-defining
opportunistic illnesses, 1992-1997. MMWR CDC Surveill Summ 1999;
48:1–22.
6. Tang AM, Jacobson DL, Spiegelman D, Knox TA, Wanke C. Increasing
risk of 5% or greater unintentional weight loss in a cohort of HIV-
infected patients, 1995 to 2003. J Acquir Immune Defic Syndr 2005;40:
70 – 6.
7. Carbonnel F, Maslo C, Beaugerie L, et al. Effect of indinavir on HIV-
related wasting. AIDS 1998;12:1777– 84.
8. Silva M, Skolnik PR, Gorbach SL, et al. The effect of protease inhibitors
on weight and body composition in HIV-infected patients. Aids 1998;
Downloaded from https://academic.oup.com/ajcn/article/88/5/1313/4648833 by guest on 13 October 2020
12:1645–51.
9. Shikuma CM, Zackin R, Sattler F, et al. Changes in weight and lean body
mass during highly active antiretroviral therapy. Clin Infect Dis 2004;
39:1223–30.
10. 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.
11. Rivera S, Briggs W, Qian D, Sattler FR. Levels of HIV RNA are quan-
titatively related to prior weight loss in HIV-associated wasting. J Acquir
Immune Defic Syndr Hum Retrovirol 1998;17:411– 8.
12. Zackin RA, Clark RA, Currier JS, Mildvan D. Predictive markers of
HIV-related weight loss and determination of differences between pop-
ulations with weight loss stratified by opportunistic processes. J Acquir
Immune Defic Syndr 1999;22:189 –93.
13. Grinspoon S, Mulligan K. Weight loss and wasting in patients infected
with human immunodeficiency virus. Clin Infect Dis 2003;36(suppl):
S69-78.
14. Kotler DP, Tierney AR, Culpepper-Morgan JA, Wang J, Pierson RN Jr.
Effect of home total parenteral nutrition on body composition in patients
with acquired immunodeficiency syndrome. JPEN J Parenter Enteral
Nutr 1990;14:454 – 8.
15. Kotler DP, Tierney AR, Ferraro R, et al. Enteral alimentation and reple-
tion of body cell mass in malnourished patients with acquired immuno-
deficiency syndrome. Am J Clin Nutr 1991;53:149 –54.
16. Singer P, Rubinstein A, Askanazi J, et al. Clinical and immunologic
effects of lipid-based parenteral nutrition in AIDS. JPEN J Parenter
Enteral Nutr 1992;16:165–7.
17. Cappell MS, Godil A. A multicenter case-controlled study of percuta-
neous endoscopic gastrostomy in HIV-seropositive patients. Am J Gas-
troenterol 1993;88:2059 – 66.
18. Melchior JC, Chastang C, Gelas P, et al. Efficacy of 2-month total
parenteral nutrition in AIDS patients: a controlled randomized prospec-
tive trial. The French Multicenter Total Parenteral Nutrition Cooperative
Group Study. AIDS 1996;10:379 – 84.
19. Shabert JK, Winslow C, Lacey JM, Wilmore DW. Glutamine-
antioxidant supplementation increases body cell mass in AIDS patients
with weight loss: a randomized, double-blind controlled trial. Nutrition
1999;15:860 – 4.
20. Miller TL, Awnetwant EL, Evans S, Morris VM, Vazquez IM, McIntosh
K. Gastrostomy tube supplementation for HIV-infected children. Pedi-
atrics 1995;96:696 –702.
21. Henderson RA, Saavedra JM, Perman JA, Hutton N, Livingston RA,
Yolken RH. Effect of enteral tube feeding on growth of children with
symptomatic human immunodeficiency virus infection. J Pediatr Gas-
troenterol Nutr 1994;18:429 –34.
22. Chlebowski RT, Beall G, Grosvenor M, et al. Long-term effects of early
nutritional support with new enterotropic peptide-based formula vs.
standard enteral formula in HIV-infected patients: randomized prospec-
tive trial. Nutrition 1993;9:507–12.
23. Chlebowski RT, Grosvenor M, Lillington L, Sayre J, Beall G. Dietary
intake and counseling, weight maintenance, and the course of HIV in-
fection. J Am Diet Assoc 1995;95:428-32; quiz 433-5.
24. Gibert CL, Wheeler DA, Collins G, et al. Randomized, controlled trial of
caloric supplements in HIV infection. Terry Beirn Community Programs
for Clinical Research on AIDS. J Acquir Immune Defic Syndr 1999;22:
253–9.
25. Lee PD, Pivarnik JM, Bukar JG, et al. A randomized, placebo-controlled
 WHEY PROTEIN SUPPLEMENTS FOR HIV-ASSOCIATED WASTING
trial of combined insulin-like growth factor I and low dose growth
hormone therapy for wasting associated with human immunodeficiency
virus infection. J Clin Endocrinol Metab 1996;81:2968 –75.
26. Williams SB, Bartsch G, Muurahainen N, Collins G, Raghavan SS,
Wheeler D. Protein intake is positively associated with body cell mass in
weight-stable HIV-infected men. J Nutr 2003;133:1143– 6.
27. Shaw SN, Elwyn DH, Askanazi J, Iles M, Schwarz Y, Kinney JM.
Effects of increasing nitrogen intake on nitrogen balance and energy
expenditure in nutritionally depleted adult patients receiving parenteral
nutrition. Am J Clin Nutr 1983;37:930 – 40.
28. Greig PD, Elwyn DH, Askanazi J, Kinney JM. Parenteral nutrition in
septic patients: effect of increasing nitrogen intake. Am J Clin Nutr
1987;46:1040 –7.
29. Geibig CB, Owens JP, Mirtallo JM, Bowers D, Nahikian-Nelms M,
Tutschka P. Parenteral nutrition for marrow transplant recipients: eval-
uation of an increased nitrogen dose. JPEN J Parenter Enteral Nutr
1991;15:184 – 8.
30. Macias WL, Alaka KJ, Murphy MH, Miller ME, Clark WR, Mueller BA.
Impact of the nutritional regimen on protein catabolism and nitrogen
balance in patients with acute renal failure. JPEN J Parenter Enteral Nutr
1996;20:56 – 62.
31. Elwyn DH, Gump FE, Munro HN, Iles M, Kinney JM. Changes in
nitrogen balance of depleted patients with increasing infusions of glu-
cose. Am J Clin Nutr 1979;32:1597– 611.
32. Burke JF, Wolfe RR, Mullany CJ, Mathews DE, Bier DM. Glucose
requirements following burn injury. Parameters of optimal glucose in-
fusion and possible hepatic and respiratory abnormalities following ex-
cessive glucose intake. Ann Surg 1979;190:274 – 85.
33. de Luis Roman DA, Bachiller P, Izaola O, et al. Nutritional treatment for
acquired immunodeficiency virus infection using an enterotropic
peptide-based formula enriched with n-3 fatty acids: a randomized pro-
spective trial. Eur J Clin Nutr 2001;55:1048 –52.
34. Pichard C, Sudre P, Karsegard V, et al. A randomized double-blind
controlled study of 6 months of oral nutritional supplementation with
arginine and omega-3 fatty acids in HIV-infected patients. Swiss HIV
Cohort Study. AIDS 1998;12:53– 63.
35. Rabeneck L, Palmer A, Knowles JB, et al. A randomized controlled trial
evaluating nutrition counseling with or without oral supplementation in
malnourished HIV-infected patients. J Am Diet Assoc 1998;98:434 – 8.
36. Stack JA, Bell SJ, Burke PA, Forse RA. High-energy, high-protein, oral,
liquid, nutrition supplementation in patients with HIV infection: effect
on weight status in relation to incidence of secondary infection. J Am
Diet Assoc 1996;96:337– 41.
37. Berneis K, Battegay M, Bassetti S, et al. Nutritional supplements com-
bined with dietary counselling diminish whole body protein catabolism
in HIV-infected patients. Eur J Clin Invest 2000;30:87–94.
38. Macallan DC, McNurlan MA, Milne E, Calder AG, Garlick PJ, Griffin
GE. Whole-body protein turnover from leucine kinetics and the response
1321
to nutrition in human immunodeficiency virus infection. Am J Clin Nutr
1995;61:818 –26.
39. Selberg O, Suttmann U, Melzer A, et al. Effect of increased protein
intake and nutritional status on whole-body protein metabolism of AIDS
patients with weight loss. Metabolism 1995;44:1159 – 65.
40. Kotler DP, Burastero S, Wang J, Pierson RN Jr. Prediction of body cell
mass, fat-free mass, and total body water with bioelectrical impedance
analysis: effects of race, sex, and disease. Am J Clin Nutr 1996;
64(suppl):489S–97S.
41. Lansang MC, Williams GH, Carroll JS. Correlation between the glucose
clamp technique and the homeostasis model assessment in hypertension.
Am J Hypertens 2001;14:51–3.
42. Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check
index: a simple, accurate method for assessing insulin sensitivity in
humans. J Clin Endocrinol Metab 2000;85:2402–10.
43. Cassidy AE, Bielak LF, Zhou Y, et al. Progression of subclinical coro-
nary atherosclerosis: does obesity make a difference? Circulation 2005;
Downloaded from https://academic.oup.com/ajcn/article/88/5/1313/4648833 by guest on 13 October 2020
111:1877– 82.
44. Ohira T, Shahar E, Chambless LE, Rosamond WD, Mosley TH Jr,
Folsom AR. Risk factors for ischemic stroke subtypes: the Atheroscle-
rosis Risk in Communities study. Stroke 2006;37:2493– 8.
45. Hadigan C, Meigs JB, Wilson PW, et al. Prediction of coronary heart
disease risk in HIV-infected patients with fat redistribution. Clin Infect
Dis 2003;36:909 –16.
46. 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.
47. Micke P, Beeh KM, Buhl R. Effects of long-term supplementation with
whey proteins on plasma glutathione levels of HIV-infected patients. Eur
J Nutr 2002;41:12– 8.
48. Moreno YF, Sgarbieri VC, da Silva MN, Toro AA, Vilela MM. Features
of whey protein concentrate supplementation in children with rapidly
progressive HIV infection. J Trop Pediatr 2006;52:34 – 8.
49. Bounous G, Baruchel S, Falutz J, Gold P. Whey proteins as a food
supplement in HIV-seropositive individuals. Clin Invest Med 1993;16:
204 –9.
50. Herzenberg LA, De Rosa SC, Dubs JG, et al. Glutathione deficiency is
associated with impaired survival in HIV disease. Proc Natl Acad Sci
U S A 1997;94:1967–72.
51. Agin D, Gallagher D, Wang J, Heymsfield SB, Pierson RN Jr, Kotler DP.
Effects of whey protein and resistance exercise on body cell mass,
muscle strength, and quality of life in women with HIV. AIDS 2001;15:
2431– 40.
52. Mulligan K, Zackin R, Clark RA, et al. Effect of nandrolone decanoate
therapy on weight and lean body mass in HIV-infected women with
weight loss: a randomized, double-blind, placebo-controlled, multi-
center trial. Arch Intern Med 2005;165:578 – 85.