Nutritional support in HIV infection and AIDS

Nutritional support in HIV infection and AIDS

Clinical Nutrition (1995) 14:197-212 © Pearson Professional Ltd 1995 REVIEW Nutritional support in HIV infection and AIDS C. J. GREEN Nutricia Resea...

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Clinical Nutrition (1995) 14:197-212 © Pearson Professional Ltd 1995

REVIEW

Nutritional support in HIV infection and AIDS C. J. GREEN Nutricia Research, PO Box 1, 2700 MA Zoetermeer, The Netherlands A B S T R A C T - - Weight loss and wasting are common features of HIV infection and AIDS.

Patterns of weight loss can be acute or chronic which appear to be related primarily to systemic infections and gastrointestinal pathology, respectively. However, weight loss is not inevitable, and periods of weight stability and weight gain have been documented. Reduced food intake appears to be a major cause of weight loss in HIV infection. Since time of death has been associated with degree of wasting, it seems reasonable to suggest that nutritional support may contribute to enhancing survival and quality of life. All patients should have early access to a qualified dietitian such that assessment of individual situations can be made and appropriate dietary advice given, within a multi-disciplinary approach. Choice of nutritional therapy should be made based on an assessment of the causes of weight loss and an assessment of gut function. Treating infections and alleviating symptoms is vital for ensuring effective nutritional support. Enhancing the energy and protein density of foods and use of oral supplements should be considered if a normal diet alone cannot meet nutritional requirements. Unnecessary dietary restrictions should be avoided. Enteral feeding is indicated for patients unable to meet their needs via the oral route, and in cases of inadequate gut function, parenteral nutrition may be necessary. There is currently insufficient clinical evidence to justify the need for special enteral formulae specifically for patients with HIV infection.

Introduction Acquired immunodeficiency syndrome (AIDS) is a pressing public health concern. As a result of impaired immune function caused by the human immunodeficiency virus (HIV), secondary opportunistic infections occur and there is an increased susceptibility to certain neoplasms. Weight loss is a common feature of HIV infection (1-4). A category of 'HIV wasting syndrome', defined as weight loss of greater than 10% of usual body weight associated with either chronic diarrhoea or chronic weakness and fever in the absence of other concurrent illnesses which would explain the condition, is included as an 'AIDS indicator disease' (1, 5). However, prospective analyses of weight change in HIV infected individuals have demonstrated that weight loss is not inevitable (6, 7). In addition, different patterns of weight loss have been documented (6). Acute severe weight loss was associated with systemic infections, and chronic progressive loss was associated in general with gastrointestinal disease (1). The clinical implications of weight loss and wast-

ing are manifold (l, 8-13) and both have been correlated with decreased survival time in patients with AIDS (1, 8-10). Changes in body composition are reported to occur in the early stages of HIV infection (14). HIV sero-positive homosexuals without enteric pathogens appear to be lighter and thinner than HIV sero-negative homosexuals (15-18), and progressive depletion of lean body mass (LBM) occurs as patients near death (8-10). In some patients, LBM is reduced out of proportion to weight loss, with body fat depleted to a lesser degree (16). It is not clear how different precipitators of weight loss (i.e. systemic or gastrointestinal infections) influence the composition of tissue lost (6). Furthermore, certain high risk groups may be at risk of depletion irrespective of HIV status (e.g. intravenous drug abusers) (19, 20). Decreased food intake is thought to be a major contributor to weight loss associated with HIV infection (1, 11, 35), and it is therefore reasonable to suggest that nutritional support may maximise ability to resist secondary infections and may prolong the quality and productivity of life (11-13, 21). This review will seek to address the proposed 197

198 NUTRITIONAL SUPPORT IN HIV INFECTION AND AIDS

mechanisms of weight loss, to review the literature in which nutritional support has been attempted in AIDS patients, to provide a rationale for nutritional support and to consider the most appropriate choice of enteral formulae for use in patients with HIV infection and AIDS. No consideration has been given to parenteral nutrition, although this is clearly an appropriate method of nutritional support in some patients. The needs of sub-groups of HIV infected individuals have not been specifically addressed, e.g. homosexuals, drug abusers and children, although it is likely that the principles discussed will be applicable to most patients.

Pathogenesis of wasting It has been assumed that weight loss is unexplained in a proportion of AIDS patients, perhaps as a direct result of HIV infection (22-24). However, this seems unlikely. In a recent retrospective review of the medical records of 420 outpatients with HIV infection (7), the majority who had lost weight had an obvious cause, namely opportunistic infections, psychosocial factors and drug-related problems. Most of the patients with seemingly unexplained weight loss had local oral lesions or symptoms suggestive of undiagnosed infection. The pathogenesis of wasting associated with HIV infection is thought to be multifactorial. The theoretical mechanisms involved, in addition to reduced food intake, are malabsorption, increased energy expenditure and altered metabolism (1, 25). These possibilities are discussed below.

Reduced energy and protein intake A large proportion of AIDS patients are reported to be at nutritional risk (3) and sub-optimal oral energy and protein intakes have been reported (2, 18). However, there is a relatively large body of data which suggests that intake in individuals with HIV infection and AIDS is comparable with control subjects (17, 26-29). Many factors are described in the literature which would serve to reduce food intake: lesions caused by fungi, viruses and Kaposi's sarcoma (present in the mucosa of mouth, pharynx and oesophagus), oral candidiasis, changes in taste perception, neurological problems (dysphagia, apathy, depression), extreme tiredness, toxoplasmosis (leading to confusion), dementia, oesophageal obstruction, abdominal pain, nausea, vomiting, diarrhoea and early satiety (11, 30, 31). Appetite may be decreased as a result of fever, infections, medication side effects (including radio-

therapy and chemotherapy) and emotional stress (3234). Social factors may also be a contributing cause, e.g. inability to obtain and prepare foods due to lack of equipment and money. Attempts to voluntarily lose weight may be an additional reason (11). In view of the extensive number of factors serving to reduce energy intake, it is surprising that there is such a dearth of evidence actually reporting reduced intake. This paradox may be explained by the fact that patients with secondary infections or weight losing patients have in general not been included in many studies. It has been shown that energy intake is decreased during secondary infection (23), and that acute weight loss episodes are likely to be related to systemic infections (6) and in turn with reduced energy intake (35). Periods of weight loss are thus probably associated with periods of decreased energy intake (11). Furthermore, patients with seemingly adequate energy intake may have gastrointestinal disease and malabsorption (see below).

Malabsorption and diarrhoea Weight loss that occurs in spite of apparently adequate energy intake may be attributed to gastrointestinal disease and malabsorption (32). Malabsorption of nutrients will lead to loss of energy in stools, as well as contribute to diarrhoea, e.g. matabsorption of fat results in steatorrhoea; lactose malabsorption causes fluid accumulation in the lumen, abdominal cramps and watery diarrhoea; impaired re-uptake of bile salts in the terminal ileum leads to increased bile salt concentration in the colon which may interfere with absorption and secretion of water and electrolytes thus increasing bowel motility (36, 37). Diarrhoea is clearly a widespread and distressing problem, occurring in 30 -60% patients (38). Kotler reported decreased total body potassium in patients with diarrhoea compared with those without, suggesting that diarrhoea may be associated with weight loss (16). Malabsorption may occur for a number of reasons, although the actual mechanisms in HIV infection are poorly understood (33). The gastrointestinal tract is vulnerable to opportunistic pathogens and secondary malignancies (21). Enteric pathogens that cause diarrhoea include bacteria (Mycobacterium aviumintracellulare, Clostridium difficiIe, Salmonellae, Shigellae), protozoa (Cryptosporidium, Microsporidium, Isospora), and viruses (Cytomegalovirus, Herpes simplex virus). Cryptosporidium is the most common infection, causing secretory diarrhoea which is refractory to treatment (21, 39). Enteric neoplasms include Kaposi's sarcoma and gastrointestinal lymphoma (21). Intestinal fistulae also lead to protein and elec-

CLINICAL NUTRITION 199

trolyte losses. In addition, drugs used for the treatment of HIV-related infections may cause diarrhoea (33, 40). Gastrointestinal symptoms observed in some patients appear to have no identifiable cause. This could be related, in part, to inadequate diagnostic techniques. However, lymphoid tissue along the gastrointestinal tract is a main target of HIV infection, leading to HIV enteropathy, i.e. villous atrophy, crypt hyperplasia and lymphatic infiltration in the jejunum (21, 41). Increased intestinal permeability has been demonstrated in advanced HIV infection in the presence or absence of enteric pathogens (42). It has also been suggested that ultrastructural changes in the duodenal mucosa could help to account for the gastrointestinal symptoms observed (43). Malabsorption of fat has been shown to be associated with duodenal villous abnormalities in male homosexual AIDS patients (44), and closely related to the degree of jejunal partial villous atrophy (45). However, malabsorption and enteric infections may be more influenced by sexual practices than HIV status (the 'gay bowel syndrome') (46). From an energy balance point of view, fat malabsorption is particularly significant due to its high energy density. Steatorrhoea has been described in HIV infection (15), and triolein and 14C glycerol palmitin malabsorption demonstrated, particularly in patients with chronic diarrhoea (15, 29, 44). However, in stable AIDS patients without intercurrent infections, only a minor degree of fat malabsorption was detected (28). In Macallan's prospective study of weight changes in HIV infection (6), a sub-group of patients showed chronic loss of weight which was associated with gastrointestinal symptoms or malabsorption in 68% of episodes. Of 21 subjects with this pattern of weight loss, however, only 5 had quantitatively significant malabsorption as assessed by the I4C triolein breath test. A trend towards decreased D-xylose absorption, an index of intestinal absorptive area, has been reported in clinically stable AIDS patients (29). D-xylose malabsorption has also been reported in patients with diarrhoea and abnormal jejunal and rectal biopsies (15), and in patients with diarrhoea but without identifiable pathogens (44). However, Sharkey failed to show any differences in xylose excretion in HIV positive or negative homosexual males who were free from enteric pathogens (17). Malabsorption of lactose is thought to be particularly common. Absolute lactase deficiency and decreased lactase activity have been demonstrated, even in the absence of an identifiable enteric infection (41, 47). There is little information in the literature regarding protein digestion and absorption in HIV in-

fection. Although hydrolysed protein or amino acidbased diets are frequently recommended for patients with HIV infection and AIDS (48, 49), this practice does not appear to be based on documentation of protein malabsorption or impaired exocrine pancreatic function. Bile salt malabsorption as a result of severe terminal ileal dysfunction in some patients is an additional problem which will contribute to diarrhoea (37), for which treatment with cholestyramine may be useful (42). Other factors which may contribute to diarrhoea include the secretory component of certain gastrointestinal infections, whereby even bowel rest does not completely stop diarrhoea (42). Decreased serum albumin levels have also been associated with diarrhoea in HIV infection (50), although whether this is a causative factor remains controversial (51). There is thus some evidence of impaired gut function in AIDS patients. Although it is not possible to determine the contribution of malabsorption and diarrhoea to weight loss, it has been suggested that these factors are likely to be significant causes of wasting (1), particularly in the setting of chronic weight loss (6). It seems difficult to generalise on the occurrence and extent of malabsorption associated with HIV infection, and it has been suggested by some that clinically significant malabsorption is not a major finding in AIDS patients (25). This uncertainty suggests that assessment of gut function should form an important part of individual assessment in these patients (52).

Increased energy expenditure Altered energy expenditure (EE) in HIV infection has been reported in several studies, most of which have reported mean increases in resting energy expenditure (REE) of approximately 10% in asymptomatic individuals with HIV infection compared with healthy controls, and of about 30% in patients with secondary infections (22-24, 53). Raised REE despite decreased LBM has been described (4), although others have shown a decrease in REE indicating an appropriate response to depletion (29). It has been suggested that increased REE may contribute to accelerated shortterm weight loss (23, 24), and that a high REE may be a predictor of secondary infection (24). However, there are inherent assumptions made in making short-term measurements of REE with extrapolation to 24 hours (54). Thus, these results should be interpreted with some caution. Moreover, evidence is emerging to show that 'compensation' for increases in REE occurs by a reduction in physical activity, such that although partitioning of EE is

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NUTRITIONAL SUPPORT IN HIV INFECTION AND AIDS

different, total EE (TEE) is unchanged or reduced (35, 55). In a study in which TEE was measured at different stages of HIV infection using the doubly-labelled water technique (35), weight loss episodes were associated with a decrease in TEE, mainly due to a decrease in activity-related EE. The decrease in energy intake observed in association with episodes of infection by far outweighed any increases in REE. Raised REE alone is thus unlikely to be a major factor in HIV-associated weight loss. Altered metabolism

HIV positive individuals and AIDS patients have been shown to be able to mount a normal anabolic response to an adequate nutritional stimulus (56, 57), although this contrasts with many clinical observations (25). A number of metabolic aberrations have been observed: relative loss of LBM compared with fat (16), abnormally elevated triglyceride levels (4), raised free fatty acid turnover (58), raised fat oxidation rates unrelated to counter-regulatory or thyroid hormone increases (53), elevated REE (4, 22-24, 53), endocrine abnormalities including changes in gonadal, adrenal and thyroid function (1) and poor results with repletion studies (59). An interesting feature of HIV infection is the documentation of an increase in insulin sensitivity, which is in contrast to that seen in other catabolic states (60, 61). Cytokines may well play a role in the wasting associated with HIV infection. Tumour necrosis factor (TNF) and interleukin- 1 (IL- 1) are released during infection and have been suggested to be responsible for the increased REE, fever, anorexia, and general body wasting associated with infection (1, 62). However, attempts to measure circulating levels of TNF in groups of HIV patients have not yielded consistent results (1, 23). The ability to detect circulating cytokines is largely a function of secondary infections rather than the HIV itself (62), and since cytokines have very short half-lives and most of their effects are autocrine and paracrine, they are often difficult to detect systemically. Although there is much evidence describing a number of metabolic abnormalities associated with HIV infection, links with wasting remain poorly defined (1). If indeed altered metabolism is a major factor in wasting associated with HIV infection, then it is likely that pharmacological means will be necessary to modify metabolism if nutritional support is to have the desired effect.

Nutritional strategies Wasting and weight loss have been associated or indi-

rectly linked with worsened clinical course, decreased survival, compromised immune function, increased risk of specific infections, organ dysfunction, reduced physical capacity, decreased quality of life and reduced drug efficacy (1, 8-13). The evidence reviewed suggests that inadequate nutrition as a result of reduced intake is a significant cause of weight loss. It has been suggested that individuals with HIV infection may enhance their survival time by aiming for a body mass index of 25-30 (11), although this remains to be investigated in prospective studies. Specific recommendations for energy and protein intake have not been established for persons with HIV infection (40), although there is little evidence to suggest that they will be different from other clinical circumstances where repletion or maintenance of nutritional status is required. Nutritional support is indicated for the same reasons as in other situations where oral intake alone cannot meet requirements, and it is reasonable to suggest that nutritional support may maximise the ability to resist secondary infections and may prolong the quality and productivity of life (12, 13, 21). Goals of nutritional therapy will depend on individual situations, and include preservation of LBM, provision of adequate levels of all nutrients, minimisation of symptoms of malabsorption, optimalisation of nutritional repletion following infection, improvement in tolerance to medications and treatments, enhancement of quality of life and palliation (63-67). A number of studies have described dietary counselling and the use of various nutritional supplements in HIV positive individuals and AIDS patients with weight loss. These are summarised in Table 1. In general, these studies suggest that supplementary feeding is beneficial, resulting in improvements in intake and various parameters of nutritional status. However, many of these studies were published in abstract form and little information can be derived from them. Even the most fundamental information is often lacking, such as the amount of supplement consumed. In general, small numbers of patients, often at different stages of disease, were studied over a short period of time. Statistical evaluations are frequently lacking and many of the reported observations are probably not statistically significant. There are relatively few studies that have specifically examined the effectiveness of enteral nutrition in depleted AIDS patients (summarised in Table 2), and of these most have not been peer reviewed (63, 75). In general, these studies indicate that enteral nutrition is feasible in many AIDS patients who are free of serious small intestinal disease, even in the event of systemic infection (66, 76). However, in general, the same criticisms apply to these studies as for the sup-

CLINICAL NUTRITION 201 Table 1

Studies examining effects of dietary advice and oral supplementation in patients with HIV infection and AIDS

Investigators

Subject

Study design

Feeding regimen

Result

DoMing et al (26)

17 asymptomatic (CDC 11) and 17 symptomatic (CDC IV) patients, 76% drug addicts

12 week evaluation of dietetic advice

Personalised advice, oral supplements and special food allowance payments as appropriate

Significant increase in intake of most nutrients, especially in CDC IV group compared with baseline No significant change in mean anthropometric values

Gaare et al (68)

10 AIDS patients with weight loss

3 month open trial to examine tolerance and body weight change with oral supplementation

Oral supplementation with 1000-1500 kcal/day of formula containing added arginine, fish oil and nucleotides

Diminished weight loss, increased T-cell subsets, decreased IgA (no statistical analyses)

Wandall et al (69)

14 AIDS and 5 HIV positive patients with weight loss > 5% in 3 months; no gastrointestinal pathology

8 week crossover study

4 week supplementation with MCT-containing enteral formula, followed by 4 weeks with no supplementation Amount of supplement not stated

Significant weight gain, increased midarm circumference and triceps skinfold during supplementation period

Chlebowski et al (70)

49 AIDS/HIV patients without intractable diarrhoea

Prospective study to assess adherence to supplements, mean use 68 days

Oral supplementation (480 ml/day) prescribed, either whole protein formula or high nitrogen peptide formula with fibre and omega-3 fatty acids

Well accepted, with intake of approx. 500 kcal/day from both supplements Subjective benefits: weight gain (58%), increased weU-being (63%), increased 'energy' (60%) in both groups

Btirger et al (71)

44 HIV patients with weight loss > 5% over preceding 3-6 months

Prospective evaluation of an intervention scheme, 3 months stage 1, > 4 wks (stage 2)

Nutritional counselling (stage 1), if no weight gain seen then oral supplement ( 1000-1500 kcal/day) prescribed (stage 2)

37 reached stage 2 Actual intake of supplement varied greatly 27 tolerated some supplement for > 4 weeks, 22 for > 8 weeks and 8 for > 12 weeks Weight gain occurred in 53%

Btirger et al (72)

54 malnourished homosexual HIV males, weight loss > 5% over preceding 3-6 months and/or BMI < 21.5 kg/m2

6 month prospective study

Dietary counselling, aiming for intake of 35 kcal/kg, plus additional 1000 kcal/day for patients with weight loss; use of supplements not mentioned

5/54 lost weight 31/54 maintained weight 18/54 increased weight

Chlebowski et al (49)

80 early stage largely asymptomatic HIV patients (56 evaluable)

6 month prospective randomised study

Oral supplementation with 400-600 ml/day standard whole protein formula or peptide-based supplement with fibre, fish oil, MCT and betacarotene

Schwenk et al (73)

75 patients, mostly with advanced disease

Evaluation of nutritional counselling as the first step of a nutritional intervention programme

Both supplements increased total energy intake by approx. 21% above baseline Marginally improved maintenance of weight (p = 0.04) and triceps sldnfold (p = 0.03), decreased blood urea nitrogen (p = 0.04) and hospitalisation rate (p = 0.02) with peptide-based formula No difference in gastrointestinal symptoms Dietary assessment and More than 50% of patients comprehensive advice for gained weight without improving intake other nutritional treatment; less effective in those with low spontaneous intake

202 NUTRITIONALSUPPORTIN HIV INFECTION AND AiDS Table 1 (contd.) Investigators

Subject

Study design

Feeding regimen

McKinley et al (13)

119 patients at various stages of disease

Retrospective review of patient charts comparing those who received nutrition intervention and those who did not

Dietary assessment, counselling, follow-up and use of supplements where necessary

Hellerstein et al (74)

39 HIV positive and AIDS outpatients

1.5 month prospective randomised double blind study

Table 2

Result

42/119 (35%) of subjects received nutritional intervention 26/42 (63%) of the intervention group gained or maintained weight compared with 42% of the non-intervention group Significantly increased % Oral supplementation with 400-600 ml/day lymphocyte count, decreased standard whole protein stool frequency and supplement or decreased number of peptide-based supplement hospitalisations in group with fibre, fish oil, MCT receiving peptide-based and and beta-carotene formula

Studies examining effects of enteral feeding in patients with HIV infection and AIDS

Investigators

Subject

Study design

Feeding regimen

Results

Kotler et al (76)

8 malnourished/ bedridden AIDS patients, severe systemic infections and weight loss

2 month prospective study

Supplemental enteral feeds via PEG with peptide-based formula; intake based on Harris Benedict + 20% + 500 kcal for 1st month, 150 kcal increase every other day as tolerated thereafter

Mean weight gain of 3 kg (not significant) Significant increase in total body potassium, body fat, serum albumin and total lymphocyte count

Brantsma et al (66)

14 AIDS patients (CDC IV) with opportunistic infections, cancers and/or neurological symptoms (terminally ill)

Retrospective review, feeding period of 8299 days

Various whole protein, peptide-based or elemental formulae given via percutaneous endoscopic gastrostomy (PEG)

Intake 1250-3650 kcal/day Weight increased in 6 patients, decreased in 6 patients Subjective improvement in quality of life

Singer et al (77)

AIDS patients, number not mentioned (approx. 28)

3 month randomised study

Oral use of 4-6 cans/day 'immuno-nutrition' or standard formula

Well tolerated with equivalent weight maintenance in both groups Significant improvement in IgA levels in 'immunonutrition' group

Siittmann et al (78)

13 advanced AIDS and 1 ARC patient with either severe weight loss or neurological deficits

Prospectively followed for a mean of 62 days

Home enteral nutrition via PEG using whole protein formula (mean intake 41.7 kcal/kg body weight)

Significant increases in body weight, body cell mass and total body fat, serum albumin and transferrin compared with initial measurements Well-tolerated with no significant PEG complications

Prospective evaluation for a median of 8.5 months (range 2-24)

Various whole protein or peptide-based formulae given via PEG or nasogastric tube; supplemented with oral nutrition in 11 subjects

Enteral nutrition resulted in significantly increased weight for age, weight for height and arm fat area, but did not result in significant changes in height for age or arm muscle area

Henderson et al (79) 18 children with symptomatic HIV infection and weight for height, weight for age or height for age below the fifth percentile, median age 6 months (range 3-159)

CLINICALNUTRITION 203 Table 2

(contd.)

Investigators

Subject

Study design

Feeding regimen

Result

Ockenga et al (80)

37 HIV infected patients with wasting, neurological deficits or dyspbagia, and 27 non-HIV infected patients receiving PEG feeding

Prospective evaluation for mean 194 days (range 6-781) in HIV group, mean 122 day (range 7-747) in controls

Type of formula/level of intake not described

No difference in mean survival time between groups PEG was well tolerated and suggested to be a safe route for long term feeding in advanced HIV infection

Chan et al (81)

24 AIDS outpatients with documented fat malabsorption

12 day double blind, randomised, controlled trial

Whole protein formula containing 35% energy from fat either as 85% MCT:15% LCT or 100% LCT, to provide 90% of requirements

Significant decreases in fecal weight and fecal fat compared with baseline, but no differences between the groups High MCT formula associated with less complaints of nausea and trends towards weight gain, decreased bowel frequency, stool weight and fecal fat

Craig et al (82)

24 AIDS patients with documented fat malabsorption

12 day double blind randomised trial

Total enteral nutrition with whole protein formula containing 35% energy from fat either as 85% MCT:15% LCT or 100% LCT, given orally 6 times/day

Average intake similar in both groups (2400 kcal/day) Trend towards decreased bowel frequency and abdominal symptoms in high MCT group, as well as significant decrease in stool nitrogen and stool fat, and significant increase in fat absorption

plemental studies, i.e poorly designed and reported. There is clearly a need for better designed clinical studies in well-defined subgroups of individuals with HIV infection. In view of the number of factors which contribute to weight loss in HIV infection, it seems logical that no single nutritional strategy is appropriate for all patients, and that nutritional support should not be viewed in isolation from other modes of therapy. Treating infection is vital for ensuring effective nutritional support (55), and weight gain has been noted after treatment of infection even without aggressive nutritional support (6, 83, 84). The risk of food and water-borne infection should be minimised and appropriate advice given for avoidance of food behaviour known to be associated with increased risk of infection with Salmonella and other enteric pathogens (31, 40, 85, 86). Consumption of tap and bottled waters are also associated with health risks in immuno-compromised persons (31, 87, 88), although recommendations to boil tap water remain controversial (31). W i t h respect to enteral feeding, it is recommended that a sterile technique is used during tube insertion and when

handling patients' enteral formulae and equipment (40, 63). Provision of adequate nutrition may also favour the response to medication by decreasing the incidence of adverse drug reactions (21). However, many commonly used drug therapies may have side effects which promote weight loss, described elsewhere (33, 34). This should be taken into consideration when assessing nutritional status and possible causes of weight loss. A scheme is proposed (Fig.) which helps to visualise the complicated scenario. This scheme highlights the importance of identifying the potential reasons for weight loss, the necessity for accurate diagnoses and treatment of infection and symptoms, and the need to give nutritional advice based on individual circumstances. It also highlights the potential central importance of impaired gut function in both systemic and chronic infection, and thus acute and chronic weight loss. This may be a focus for future therapeutic strategies. However, drawing general conclusions on the effect of HIV on nutritional status and vice versa is difficult due to insufficient well-designed studies (1, 75, 89) and further work is clearly needed to estab-

204

NUTRITIONAL SUPPORT 1N HIV INFECTION AND AIDS

anorexia decreased intake altered metabolism

side effects of drug therapy systemic infection

HIV

,~ compromised immune function

Ik

acute undernutrition

J

~

~

.~ ~.~

impaired gut ~, function

decreased helper/ inducer Tlymphoeytes

#

HIV

! !

HIV enteropathy increased gut permeability ultrastructural changes enteric neoplasms

J J chronic • undernutrition

neurologieM lesions oral lesions psychological/socialproblems decreased intake side effects of drug therapy

~1~

gastrointestinal infection

x

taalabsorption diarrhoea decreased intake side effects of drug therapy

ItIV

Fig. Proposedschematicillustrationof inter-relationshipsbetweenI-I/Vinfection,immunefunctionand undemutrition.

lish whether this hypothetical scheme is a reasonable model of the true situation. Early access to a dietitian is essential such that individual situations can be accurately assessed and nutritional therapy tailored accordingly (11, 63-65). Regular monitoring and adjustment of dietary advice should be performed as necessary (64, 65). Simple dietary advice and counselling has been proposed as the most appropriate initial intervention in HIV disease (30, 31, 65, 74, 85). If a patient does not succeed in preserving nutritional status and body weight in spite of the dietary advice given, or if it is clear that a patient will not be able to achieve adequate energy and protein from conventional foods alone, then commercially available diet preparations are indicated. Oral supplementation of the diet is often the simplest way to increase nutrient intake (90-92), efficacy of which has been examined in a wide variety of patient groups. In patients without HIV infection, this form of nutritional support has been shown to result in significant increases in nutritional intake (93-95), improved nutritional status (95-101), improved immune function and decreased infections (95, 102, 103), decreased length of hospital stay (102, 104) and decreased mortality (101). Enteral feeding should be considered if a patient cannot, will not, or should not eat but still has a func-

tional or partially functional gastrointestinal tract (63, 92). In HIV disease, enteral nutrition may be indicated for several reasons which lead to an inability to consume sufficient energy and protein via the oral route. Nasogastric or nasoduodenal enteral feeding is the method of choice for short-term use. A gastrostomy or jejunostomy should be considered if longer-term enteral nutritional support is anticipated (40). Nocturnal enteral feeding may be used to supplement oral intake. As in other clinical situations, intravenous nutrition should be employed if the gastrointestinal tract cannot be used (40, 59, 105). Anecdotally, the use of drugs to stimulate appetite is often reported to occur. The safety and efficacy of such treatment is, however, controversial. A recent review (106) suggested that megestrol acetate (a semisynthetic derivative of progesterone) has an important role to play in the treatment of anorexia in AIDS patients, although potential toxicities should be considered. Body weight gain was reported to be due to increased fat and lean tissue mass, although this remains to be confirmed in further studies (107). In addition, the negative side-effects may outweigh any benefits on body weight (108). Other possible pharmacological strategies in the treatment of weight loss in HIV infection which are also still in the experimental phase include new appe-

CLINICAL NUTRITION 205

tite stimulants (e.g. Dronabinol, the principal psychoactive substance present in cannabis), anabolic agents (growth hormone, insulin-like growth factor-l, anabolic steroids), anti-cytokine agents (pentoxifylline, thalidomide, n-3 polyunsaturated fatty acids) and anticatabolic agents/metabolic inhibitors (1,107-109). Exercise programmes may also be particularly important in combination with other strategies to enhance lean body mass deposition (110), although whether preservation of lean body mass can indeed improve survival in AIDS remains to be elucidated (11).

Composition of oral supplements and enteral formulae Recent guidelines for enteral and parenteral nuWition (63) addressed nutritional support in HIV infection, but failed to make any specific recommendations regarding composition of oral supplements or enteral formulae. In general, recommendations made in the literature are largely based on theoretical reasonings and personal opinion, which can be summarised as follows. Appropriate nutrient density should be ensured. If no diarrhoea or malabsorption is present, intact nutrients should be provided. A standard polymeric diet should thus be the first choice of formula for these patients. Hydrolysed or elemental formulae may be useful if the patient is intolerant to intact protein formula. In the case of fat malabsorption, low fat formulae and/or products containing MCT may be beneficial. Lactose-free formulae are indicated in patients with lactase deficiency. Increasing fibre intake may be beneficial in helping to form bulkier stools in some patients. Individual components of commercial formulae are considered below.

Protein It is often suggested that elemental or peptide-containing formulations should be used if polymeric diets are not tolerated (30, 40, 65). There are many anecdotal reports relating to successful enteral feeding with these types of formulations in HIV infected individuals. Unfortunately, few, if any, of these can be supported by published studies. Brinson reported 'immediate' resolution of diarrhoea with use of a partially hydrolysed protein source diet in AIDS patients without evidence of gastrointestinal pathology (50). It was suggested that the diarrhoea was related to low serum albumin and the resolution of it to an improvement in albumin levels, but this is unlikely to have been due to enteral feeding alone. Hickey and Weaver (48) recommended free amino

acid or peptide-containing formulations with a very low fat content (< 3%) even for patients with normal gut function, although studies have not demonstrated benefits of these diets compared with others. Kormas and Hynak-Hankinson (38) also stated that elemental formulae are 'more readily absorbed' in patients with malabsorption and therefore can be used for patients with gastrointestinal complications. However, their study to evaluate the acceptance of such formulae in patients with HIV infection revealed very low acceptability. Unfortunately no comparison was made with formulae containing other protein sources. Chlebowski (49) reported that a new peptide-based product developed specifically for AIDS patients provided superior nutritional management when used as a supplement over a 6 month period compared with a standard polymeric supplement, although difference in weight changes were small between the two groups (see Table 1). Comparable results were noted by others using similar products over a 1.5 month period (74). However, in both studies there were numerous differences between the two products, in terms of energy density, protein, fat and carbohydrate source and content, and fibre and beta-carotene content

(111). There is insufficient evidence at present to suggest that semi-elemental or elemental formulae will confer advantages over whole protein based diets in patients with HIV infection and AIDS, although in practice it is likely that they will continue to be utilised if tolerance to whole protein diets is a problem. In those with established exocrine pancreatic insufficiency, hydrolysates may be indicated, although use of pancreatic enzyme supplements in conjunction with whole protein feeds may be equally beneficial (112). Further research is necessary to attempt to establish whether the anecdotal reports of improved tolerance with hydrolysed formulae can be borne out in well defined sub-groups of patients.

Fat It is often said that patients with diarrhoea or malabsorption should restrict their intake of high-fat foods (65), and very low fat diets and medium chain triglyceride (MCT) containing diets are frequently recommended for HIV positive individuals (40, 48). Fat malabsorption has been reported (15, 44), but there has been little work which has specifically examined the benefits of low fat or MCT-containing diets in patients with established fat malabsorption. There certainly seems little justification in extremely low fat diets (< 3%) in patients with apparently normal gut function (48). It has been demonstrated that

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NUTRITIONAL SUPPORT IN HIV INFECTION AND AIDS

patients receiving a low fat diet during radiotherapy could not compensate for the reduced energy intake from fat by increasing their intake of carbohydrate and protein, which led to weight loss during treatment (36). Whether weight loss can be compensated for by decreased gastrointestinal symptoms and thus improved quality of life is not known. Medium chain triglycerides have several theoretical advantages relating to digestion and absorption (113, 114), although actual data documenting significant clinical benefits in malabsorption are limited. Two recent studies (81, 82) examined fat absorption in AIDS patients with documented fat malabsorption randomised to receive either a high MCT or high long chain triglyceride (LCT) formula as the sole source of nutrition for 12 days (see Table 2). In the latter study, fat absorption was significantly increased in the MCT group as' assessed by a decrease in stool fat content, although fat absorption was greater than 95% in both groups. Other differences between groups were not significant. Although one may argue that addition of MCT may be of benefit in spite of lack of documented evidence, MCT may reduce palatability and increase costs of formulations. In addition, it should!.,be noted that formulae with a high MCT content wili be at risk of failing to provide adequate essential "fatty acids (linoleic and alpha-linolenic) to meet current public health guidelines either in,terms o f absolute ambunt or ratio of omega 6:omega 3 fatty acids (115). Fat is a concentrated form of energy and should not be restricted unnecessarily. Indeed, even patients with confirmed fat malabsorption may benefit from raising the fat content of the diet (116). However, this will depend on individual tolerance. If possible, fat intake should be adjusted according to tolerance, and preferably some assessment of gut function should be made. Partial substitution of the fat source by MCT may be appropriate, although care should be taken to ensure that this does not compromise the provision of essential fatty acids. Awareness of the potential role of lipids in modulating inflammatory responses and influencing immune function is increasing (117), although much further work is necessary before appropriate recommendations can be made (see Novel Ingredients).

low lactose or lactose-free diet is appropriate (65). Lactose-free oral diets for AIDS patients who have normal gut function and can tolerate oral feeds have been recommended (118), although the logic behind such a recommendation is not apparent. In the absence of any cfinical evidence to suggest otherwise, a lowlactose oral diet should only be advised if absolutely necessary. However; in view of the reports of lactose intolerance in HIV infection (41, 47), and since avoidance of lactose per se will do no harm, it seems logical that enteral formulae for use in these patients should be clinically lactose free. Fibre There is little in the literature relating to fibre requirements or intake in HIV infected individuals. If possible, a fibre intake in line with current recommendations for healthy diets may be encouraged (119), but this will depend on individual tolerance and other factors affecting nutritional intake. A high fibre diet should not be recommended if this compromises energy intake. Reduction in fibre intake is often recommended in cases of gastrointestinal disease and diarrhoea (65). Little attention has been focused on tlae possibility of fibre as a method of alleviating diarrhoea through its fermentation to short chain fatty acids (SCFA) in the colon (120), although the potential benefit of this will be very much dependent on the cause of diarrhoea (e.g. fibre is unlikely to be of value in cases of steatorrhoea or bile salt malabsorption). Increasing fibre intake, and in particular the use of pectin, guar gum and soy polysaccharide in AIDS patients has been mentioned anecdotally (40). Others (48) have reported successful results with use of a 'BRAT' diet ibananas, rice, apples, tea and toast), but this diet is clearly unsuitable as a sole source of nutrition and no references are given to any clinical investigations. Soy polysaccharide, a fermentable fibre source, is commonly used in fibre-containing enteral formulae, but further research is required to establish whether this, or alternative sources of fibre, are beneficial in reducing (colonic-based) diarrhoea associated with HIV infection. Vitamins, minerals and trace elements

Carbohydrate Carbohydrate is a valuable energy source, particularly if fat restriction is genuinely necessary. In certain cases, such as bowel diseases resulting from gastrointestinal infections and non-specific enteropathies, a

Data detailing micronutrient intake and status in HIV sero-positive individuals are rather conflicting and confusing (17, 27, 121-123). Biochemical deficiencies of a number of micronutrients have been described at different stages of disease, in some cases in spite

CLINICAL NUTRITION 207

of seemingly adequate intakes (121, 122, 124-130). However, these results are by no means apparent in all patients; plasma levels of many micronutrients within the normal range or above normal have also been reported (121,124-126, 128, 131,132). Self-supplementation of vitamins, minerals and trace elements is thought to occur frequently (121, 133-135). Mean intakes of vitamins C, E zinc and iron in HIV positive individuals have often been reported to be at megadose levels, i.e. up to 10 times or more than recommended daily amounts (126, 135, 136). High plasma levels associated with self-supplementation have been observed, especially of folate and camitine (124). It is known that many micronutrients can influence immune function, and strong associations have been noted between certain vitamins and mood, neurological function and cognitive function (121, 137, 138). It has been suggested that deficits could exacerbate the progression and/or severity of disease (124), and that supplementation of certain micronutrients may be beneficial (107). Slower progression to AIDS associated with higher intakes of certain micronutrients has been described (135, 139). However, the possible clinical benefits of supplementation of vitamins and minerals in HIV infection are as yet unknown and it is clear that megadose intakes of some micronutrients may lead to deleterious effects (128, 136), and may even contribute to faster progression of disease (135). The difficulty in interpreting serum or plasma levels, and the fact that many patients already self-supplement with high doses of various vitamins, minerals and trace elements must also be recognised. Dietary assessment may be the most appropriate method of identifying risks of deficiencies and potential toxicity. Investigation of gut function will highlight potential losses, e.g. fat soluble vitamins due to fat malabsorption or vitamin B12 due to ileal disease. When oral intake is inadequate (e.g. in anorexia, or as a result of increased losses due to medications, vomiting or diarrhoea), it has been suggested that a daily multivitamin/mineral supplement, supplying 100% of recommended intakes for each nutrient is taken (65). A recent workshop of the HIV National Nutrition Team in the UK (140) concluded that while supplements may not be necessary or beneficial, in levels equal to dietary reference values (119) they are considered to be safe. There is at present insufficient evidence to suggest that oral supplements and enteral formulae should be enhanced with micronutrients at levels greatly in excess of dietary reference values. Much further study is required before appropriate recommendations can be made.

Novel ingredients There is much current interest in nutrients which are said to modulate immune function and improve outcome, e.g. arginine (141, 142), glutamine (143, 144), n-3 polyunsaturated fatty acids (109) and nucleotides (145). This interest has not surprisingly extended to AIDS. However, whether enhancement of the diet with any of these nutrients is applicable for AIDS patients remains speculative. Indeed, it is not yet clear whether stimulation or depression of immune function is desirable in HIV infection. Attempts to demonstrate the efficacy of these nutrients in improving outcome in situations such as burns (146), post-operative patients (147) and AIDS (49) have centred around producing 'cocktail' formulations with several novel nutrients and comparing these with a standard enteral feed. Although outcomes appear to be better in the novel formulae groups, fundamental differences between the products studied have not been accounted for, e.g. total energy and protein content, macronutrient ratios and sources of macronutrients. Mechanisms can never be deduced from these studies (148) and this approach has been criticised (149). Further studies are required to establish the role of novel nutrients and specialised formulations in HIV infection (89).

Conclusion

Weight loss is a well-documented phenomenon associated with HIV infection, and regression analyses indicate that degree of wasting can be related to time to death in patients with AIDS, which is not particularly surprising. It is well known that once metabolic and energy reserves are exhausted, death quickly ensues. Preservation of LBM is thus likely to be important for survival, and may improve quality of life and resistance to secondary infections. Although weight loss is common, periods of weight stability and weight gain have been observed in prospective studies. Weight loss periods are associated with decreased energy intake and different patterns of weight loss are seen depending on the presence of systemic or gastrointestinal infections. Improvements in nutritional status associated with nutritional support and appropriate treatment of infections have been described. Whether depletion is ultimately inevitable in HIV infection and whether early aggressive nutritional support can prevent the occurrence of weight loss requires further study. If wasting is indeed caused by factors in addition to reduced energy intake, then

208 NUTRITIONALSUPPORTIN HIV INFECTION AND AIDS

nutritional support alone is unlikely to completely counter this problem. Nutritional support is indicated as in other clinical circumstances where oral intake is insufficient to meet requirements. A number of studies have examined efficacy of nutritional support in individuals with HIV infection, although many of these have drawbacks in terms of study design. Thus in general, current nutritional guidelines are based on expert opinion, panel consensus, empirical data and even anecdotal experiences rather than on sound research. In general, fundamental dietetic principles should be applied within a multi-disciplinary approach. Identification of individual problems, correction of underlying infections and treatment of symptoms are likely to contribute to more effective dietary management. Adequate energy and protein intake should ideally be provided by a normal well-balanced diet. Addition of commercially available energy and protein supplements are useful to increase the energy and protein density of normal meals. Liquid oral supplements are often indicated either as supplements to a normal diet or as meal replacements. Taste preferences vary widely between individuals and a broad range of products with different tastes and textures is important. ff oral intake is severely impaired, enteral or parenteral nutrition may be indicated. Enteral feeding is always preferable if possible, and polymeric formulae should be the first choice when enteral feeding is instituted. If feeding is not well tolerated, steps should be taken to assess gut function and to tailor enteral feeding appropriately. There are anecdotal reports of improved tolerance with semi-elemental or elemental formulations, although this has not yet been investigated thoroughly and efficacy has not been documented. Fat malabsorption as well as lactase deficiency have been reported and in these cases benefit may be gained from lower fat and/or MCT-containing formulae and lactose-free formulations. However, dietary restrictions should not be imposed unnecessarily, and care should be taken to avoid inadequate provision of other nutrients (e.g. essential fatty acids) as a result of dietary modification. Dietary manipulations which could alleviate diarrhoea would be of great benefit. There is speculation that pharmacological levels of certain nutrients may have beneficial effects on immune function in HIV infection. However, greater understanding of the interaction between HIV infection and the immune system, and appropriately designed and controlled randomised studies to examine the effects of altering macronutrient ratios as well as inclusion of increased levels of micronutrients and novel ingredients on nutritional status, immunology and quality of life are necessary before compositional

modifications are adopted for routine use in HIV infection.

Acknowledgement The author thanks Ms Ingrid C.M. Slob for collection of the fiterature and Dr Carolyn Summerbell for helpful advice in the preparation of the manuscript.

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