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The Journal of Nutrition Vol. 129 No. 1 January 1999,
pp. 238S-242S
Department of Medicine and Cellular & Molecular Sciences, Division of Infectious Diseases, St. George's Hospital Medical School, London SW17 ORE, United Kingdom
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ABSTRACT |
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Abstract
Introduction
References
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AIDS wasting is not characterized by a single pathophysiological process but by a variety of processes that operate at different times. Acute wasting tends to be associated with secondary infections; chronic wasting is associated with gastrointestinal disease. Although resting energy expenditure is increased, total energy expenditure is reduced in individuals who are losing weight and it is usually reduced intake that commonly drives wasting. However, reduced intake is not an adequate explanation for the metabolic abnormalities that are seen in HIV infection. In particular, protein metabolism and lipid metabolism are abnormal, possibly representing inappropriate utilization of substrates. The response to nutrition may be impaired, particularly in terms of accrual of lean tissue but nutritional support may prolong survival. The impact of protease inhibitors on wasting in HIV infection is yet to be fully ascertained but despite antiviral therapy it seems that wasting is likely to remain a problem at least in some patients.
KEY WORDS: wasting · cachexia · HIV infection · AIDS
It is difficult to adequately define the pathophysiology of wasting in HIV infection and AIDS in a short article such as this. One of the reasons for this is that multiple pathologic processes operate concurrently in patients with AIDS. Although there is a single underlying deficit, i.e., the loss of CD4-positive T cells resulting in immunodeficiency, the clinical presentation is very diverse. This depends on the presence or absence of opportunistic infections and, if present, the nature of such infections. In addition, several malignancies occur which have their own independent metabolic effects. Furthermore local symptoms such as dysphagia due to esophageal candidiasis may directly influence food intake and precipitate wasting. Patients come from a very diverse background and HIV infection impacts upon their social and economic status in a variety of different ways. For example, the presence or absence of drug abuse may have a greater impact on nutritional status than the presence of HIV infection. On the basis of this, it is not surprising that there is no single defining pathophysiology to AIDS wasting. In this respect, it is important to make the distinction between the wasting that accompanies HIV infection and "AIDS Wasting Syndrome," which is more precisely defined. I will be dealing here more generally with the wasting accompanying HIV infection.
One of the features observed early on in studies of HIV-related wasting was that weight loss tends to be episodic. Acute episodes of weight loss tend to occur in association with acute opportunistic infections. Between such phases, weight recovery often occurs and we observed that many individuals remain weight-stable for prolonged periods. Although acute weight loss was significantly associated with opportunistic infections, particularly PCP pneumonia in the early studies, more chronic weight loss was found to be associated with gastrointestinal disease and malabsorption (Macallan et al. 1993 The premise that excessive weight loss is "bad for you" is self evident, but such a premise needs to be founded on good scientific evidence in the context of HIV infection. The impact of wasting on outcome has been elegantly demonstrated by the CPCRA studies recently published at ICAAC in 1995 and Vancouver in 1996 (Wheeler et al. 1995 The answer to this question can partly be found in the studies of Kotler et al. (1989) At a purely energetic level, wasting must be due to an imbalance between energy intake and energy expenditure such that any deficit must be fueled by consumption of body tissue, and any excess of intake results in accumulation of body tissue and weight gain. This model is useful, because it demonstrates the fundamental importance of energy balance in determining whether wasting occurs or not and enables us to assess the relative importance of intake and expenditure as contributors to energy deficit.
Several studies have shown increased resting energy expenditure or basal metabolic rate in HIV infection. Figure 1 shows one such study of men with HIV infection, AIDS, or AIDS with secondary infection (Grunfeld et al. 1992). It can be seen that there is a progressive increase in resting energy expenditure across the four groups. There are many other studies that have looked at resting energy expenditure, and found similar results, i.e., an increase in energy expenditure in HIV infection which is compounded by the presence of secondary infection. However, not all studies have found consistent results. This draws us to one of the important observations that must be made about the investigation of metabolism in HIV infection, and that is that considerable heterogeneity exists within measurements within any group of HIV-infected individuals. This is exemplified by data from Schwenck et al. (1996) reproduced in Fig. 2. Comparing the relationship between resting energy expenditure and body cell mass in a control group and in a group of HIV-infected patients, it can be seen that although the control values are very tightly clustered around their regression line, data from HIV-infected patients are very widely scattered; the group includes patients who are frankly hypermetabolic and those who are frankly hypometabolic. Such heterogeneity in metabolic parameters reflects the clinical heterogeneity of HIV-infected patients and, I believe, largely explains the apparently divergent results obtained in different studies.
There are two observations we need to make in answer to the question above. Firstly, we need to consider the relationship between resting energy expenditure and weight loss. Several studies have looked at this relationship. Data from our own measurements show that there does not appear to be a relationship between resting energy expenditure and weight change (Macallan et al. 1995
Although reduced intake commonly drives wasting, several metabolic features of AIDS are more consistent with a cachexic type response and may be counter-regulatory. For example, the adaptive reduction in resting energy expenditure seen in reduced intake is not observed in AIDS wasting. In addition, whole body protein turnover is markedly increased, a phenomenon observed in other inflammatory states, and this itself may be energy costly. Furthermore, lipid metabolism is altered such that de novo lipogenesis is markedly increased in AIDS patients. Such metabolic abnormalities affect the way in which wasting occurs and may well contribute to the preferential lean tissue depletion seen in patients with severe wasting. However, longitudinal studies of body composition suggest that the changes in lean and fat tissue are consistent with what would be expected from changes in dietary intake alone. Dr. Paton from our group at St. George's Hospital in London recently published an investigation of the relationship between loss of lean tissue and loss of weight in a large cohort of HIV-infected men measured longitudinally over a period of three months to one year (Paton et al. 1997
There is good evidence that during acute severe infections, such as sepsis, there is excessive loss of lean tissue relative to total weight loss. This was perhaps most clearly demonstrated by the study of Streat et al. (1987) Finally, I would like to allude to the impact of anti-retroviral treatment on protein and energy metabolism in HIV. Some people believe that the advent of effective anti-retroviral treatment will render nutrition support obsolete and wasting a thing of the past. Indeed, looking at individual cases, I am sure that many of you have seen cases such as that shown in Fig. 5a (data kindly provided by R. Ho, University of California, San Francisco). Following initiation of Indinavir therapy, the subject gained over 12 kg in weight and, indeed, this weight gain was associated with a gain in fat-free mass of a proportion not dissimilar to what would be expected. This man was clearly making a good response to anti-retroviral therapy in terms of treatment of his wasting. However, this is not always the case as shown in Fig. 5b where the case is seen of a man who made an excellent response to antiviral therapy in terms of his viral load which fell from more than 105 to undetectable. Despite this, his weight, which was 5 kg below his usual body weight, and his fat-free mass failed to increase with treatment. We clearly need more data on the effect of protease inhibitors and combination anti-retroviral regimes on weight but anecdotal reports suggest that wasting has not yet become a thing of the past. Early studies with Ritonavir did show that it prevented wasting which occurred in the placebo group, but such treatment did not result in gain of weight, although this may have been partly due to the formulation (unpublished data). At this stage there is a spectrum of opinions from the most pessimistic, that progressive wasting will still occur, to the most optimistic, that wasting will no longer occur.
In conclusion, I have demonstrated that reduced energy intake is commonly the primary driving force for HIV-related wasting and this, of course, is of vital importance, because energy intake is something that we can treat with nutrition support, albeit with varying degrees of success. However, protein metabolism is abnormal in HIV-infected individuals and there are situations such as severe rapid weight loss, failure to respond to nutrition support and inability to achieve adequate energy intake, in which adjunctive use of anabolic agents may be indicated.
INTRODUCTION
Abstract
Introduction
References
).
and 1996). These studies showed that even weight loss of 3% to 5% in the first four months of the study was associated with increased subsequent mortality and that the risk of opportunistic infections in those individuals with a 5% weight loss was significantly increased.
IS REPLETION OF WEIGHT ALL THAT WE NEED TO TARGET?
who demonstrated that it was loss of lean tissue, as reflected by total body potassium, that was associated with survival time. This has been more elegantly shown by Suttman et al. (1995) who found a clear relationship between body cell mass and survival in AIDS. It would, therefore, appear that we need to consider not just weight loss but loss of lean tissue and thus, in terms of therapy, not just repletion of weight, but repletion of lean tissue.
WHAT DRIVES HIV-RELATED WASTING?
IS ENERGY DEFICIT NORMALLY THE CONSEQUENCE OF REDUCED INTAKE OR INCREASED ENERGY EXPENDITURE?
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Fig 1.
Effect of HIV infection, AIDS and secondary infections on Resting Energy Expenditure. *p < 0.025, vs control group. **p < 0.0001 vs control group, p < 0.025 vs HIV+ group. ***p < 0.0001 vs control group, p < 0.01 vs HIV+ group. (From Grunfeld et al. 1992).
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Fig 2.
Resting Energy Expenditure relative to body cell mass in controls and HIV+ subjects. (From Schwenk et al. 1996 ).
recently demonstrated that there is a positive relationship between increasing plasma viral load and resting energy expenditure across a cohort of HIV-infected men.
DOES INCREASED ENERGY EXPENDITURE RESULT IN WASTING IN HIV INFECTION?
). Secondly, we need to recognize that resting energy expenditure is not the ultimate determinant of energy balance. The determinant of energy balance is total energy expenditure which also includes components for physical activity and diet-induced thermogenesis. We performed a study of total energy expenditure in 27 HIV-infected men, making 51 measurements over the course of their illness, and found that rather than being increased during weight loss, total energy expenditure was reduced during weight-losing episodes; there was a significant correlation between TEE and weight change (Fig. 3) (Macallan et al. 1995). Indeed, as disease progression occurs, although resting energy expenditure tends to increase a little, total energy expenditure tends to fall, such that those patients who are most ill have the lowest total energy expenditure, even when corrected for depletion of body mass (Macallan 1996). The reason for this is that, as patients become more and more unwell, their activity levels tend to reduce.
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Fig 3.
Relationship of Total Energy Expenditure (TEE) with rate of weight loss or gain in a cohort of HIV infected men. (From Macallan et al. 1995 ).
). Indeed, these data are entirely consistent with those of Grunfeld et al in patients with AIDS and secondary infection, which showed that the group with secondary infection were characterized by both progressive weight loss and a marked reduction in energy intake (Grunfeld et al. 1992). So we can conclude that although resting energy expenditure is increased (which may make extra demands upon intake and thus justify the recommendation that increased food provision be made available for HIV-infected individuals in hospitals and other institutions), studies of total energy expenditure demonstrate that it is not increased expenditure that drives wasting but a reduction in intake.
).
IS HIV-RELATED WASTING JUST DUE TO REDUCED INTAKE?
). Figure 4, which is based on data from DEXA scanning, shows that individuals are scattered around a regression line with a slope of about 0.6. In other words, for every 1 kg weight loss, there was approximately a 0.6 kg lean tissue loss. From previous published literature we can estimate that for weight loss due to reduced intake alone the predicted slope of such a regression line would be 0.61. That such a conclusion is not simply an artifact of the measurement modality is demonstrated by the reproducibility of the ratio of lean to total weight loss using a variety of different measurement techniques including bioelectrical impedance (BIA), total body water or skinfold measurement (Paton et al. 1997). Recent data from Schambelan and Mulligan's group in San Francisco resulted in a very similar conclusion: that the ratio of lean tissue to weight loss is less than 50% (Mulligan et al. 1997b). We can conclude, therefore, that the changes in body composition over long periods of time are consistent with energy deficit as being the primary cause of weight loss. We can also observe from these studies that the composition of weight recovered during spontaneous weight recovery is quite consistent with what would be expected from refeeding malnourished individuals.
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Fig 4.
Relationship between loss or gain of lean tissue (represented by fat-free mass, FFM) and loss or gain in weight in longitudinal follow up of men with HIV related weight loss. (From Paton et al. 1997 .
IS NUTRITION SUPPORT SUFFICIENT?
using in vivo neutron activation measurement of body composition. When such septic individuals were given aggressive nutrition support, it resulted in increased weight but not accumulation of lean tissue; all of the tissue gained was fat tissue. Is this the case for HIV infection? Referring to data from Kotler's group, when individuals with HIV infection were given parenteral nutrition for periods of between 4-42 weeks, an increase in weight was observed, but the increase in lean tissue, as reflected by total body potassium was very disappointing (Kotler et al. 1990). In other words, there was very little accrual of lean tissue. When he divided subjects up into those who had gastrointestinal disease and those with systemic infection, he found that patients with systemic infection failed to gain lean tissue despite aggressive nutrition support.
).
).
WASTING AND ANTI-RETROVIRAL THERAPY
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Fig 5.
Examples of weight graphs of HIV-infected men commencing potent anti-retroviral therapy. Fat-free mass (FFM) derived from DEXA measurement of body composition. (a) A 35 year old man with CD4 count of <10/mm3 whose usual body weight was 83 kg who experienced marked weight recovery on initiation of treatment. (b) A 56 year old man, CD4 count approximately 300/mm3, usual body weight (UBW) 75 kg who showed an excellent response in terms of viral load but no weight recovery. (Data kindly supplied by R. Ho, University of California, San Francisco.)
CONCLUSION
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FOOTNOTES |
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LITERATURE CITED |
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Abstract
Introduction
References
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