Nutritional management of HIV/AIDS in the era of highly active antiretroviral therapy: a review

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1 Nutritional management of HIV/AIDS in the era of highly active antiretroviral therapy: a review Marijka Batterham, Dannae Brown and Roger Garsia Abstract HIV/AIDS is a major global health problem and is currently the fourth leading cause of death in the world. Nutritional management of people with HIV/AIDS has become increasingly complex since the introduction of new antiretroviral agents taken in combinations referred to as highly active antiretroviral therapy (HAART). HAART has resulted in improved survival times. However, side effects and complications are common. Prior to the introduction of HAART, weight loss was the major nutritional issue in people with HIV/AIDS and was associated with an increase in morbidity and mortality. Although weight loss continues to occur in the post HAART era, HAART side effects and lipodystrophy syndrome have become the major focus of the literature. Lipodystrophy syndrome refers to subcutaneous peripheral fat loss and/or visceral adiposity often accompanied by metabolic abnormalities, particularly hyperlipidaemia and insulin resistance, in people with HIV/AIDS taking HAART. A formal definition for this syndrome has not yet been established which makes determination of the prevalence of the syndrome difficult. The cause of the syndrome remains elusive. However, it has been found to occur only in those people with HIV/AIDS taking antiretroviral therapy. It is likely that the syndrome is a direct consequence of the antiretroviral drugs interfering with normal metabolism or it may be a result of the immune reconstitution on successful therapy. The syndrome is of concern because of the potential increase in metabolic disorders related to hyperlipidaemia and insulin resistance. (Aust J Nutr Diet 2001;58: ) Key words: HIV, AIDS, nutrition, weight loss, fat redistribution syndrome, peripheral lipodystrophy syndrome, highly active antiretroviral therapy Introduction HIV/AIDS is a major global pandemic which continues to challenge medical and social science. This paper reviews nutritional issues prevalent throughout the disease history, both prior to and following the introduction of combination antiretroviral therapy referred to as highly active antiretroviral therapy (HAART). It provides a review of the scientific understanding of the causes of and potential therapies for nutritional problems encountered by dietitians practising in this area. Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) HIV infection had infected 36.1 million people worldwide at the end of 2000; approximately people worldwide are infected each day (1). More than 95% of new infections occur in the developing world where access to antiretroviral therapy is limited. At the end of 1999 there were people living with HIV/AIDS in Australia, including 900 women and 140 children (1). HIV is a bloodborne and sexually transmissable retrovirus. Untreated infection causes a progressive decline in immune function and consequential susceptibility to opportunistic infections and malignancy. Advanced infection almost always leads to the development of an AIDS defining illness (usually a secondary opportunistic infection or malignancy) at which time the sufferer is declared to have AIDS (2). In 1999 AIDS was the fourth leading cause of death in the world (3). HIV selectively depletes the helper or inducer subset of T lymphocytes expressing the CD4 + cell surface phenotype. CD4 is the major receptor recognised by the virus and cells not expressing this receptor cannot be infected by HIV (4). The CD + lymphocytes are, in part, responsible for the specific recognition of foreign antigens, and damage to these cells by HIV impairs the cellular immune system. In addition to the helper lymphocytes, monocytes (macrophages and related cells) and some B lymphocytes also carry the CD4 receptor at a low level and are therefore susceptible to HIV infection (4). Pharmacological management of HIV is currently based on two prognostic markers: the CD4 T cell count and the HIV RNA viral load. Even prior to recognition of HIV as the cause of AIDS, subnormal or failing CD4 T cell count was indicative of immune system decline and HIV disease progression (5). Viral load testing became readily available to the industrialised world in A high viral load is indicative of uncontrolled replication of the virus and is associated with poor prognosis and disease progression (6). Even without treatment some people with HIV/AIDS have a viral load less than the threshold of detection and are reported as HIV undetectable in the plasma. However, these people usually still manifest virus in the tissues. The Nutrition for Life program is funded by Merck, Sharpe and Dohme Australia Smart Foods Centre, University of Wollongong, New South Wales M. Batterham Msc (Nutr Diet), PhD, APD, HIV Nutrition Consultant Nutrition for Life progam (formerly HIV Dietitian, Department of Nutrition and Dietetics, Royal Prince Alfred Hospital and HIV Dietitian, Nutrition Unit, The Albion Street Centre, Sydney, NSW) HIV Medicine Unit, St Vincent s Hospital, Darlinghurst, New South Wales D. Brown MND, HIV Dietitian Department of Clinical Immunology, Royal Prince Alfred Hospital, Camperdown, New South Wales R. Garsia MBBS, PhD, FRACP, FRCPA, Senior Staff Specialist Immunologist Correspondence: M. Batterham, Smart Foods Centre, University of Wollongong, Northfield s Ave, Wollongong, NSW marijka@uow.edu.au Australian Journal of Nutrition and Dietetics (2001) 58:4 211

2 Antiretroviral therapy Since HIV was discovered as the cause of AIDS a concerted effort has been made to elucidate compounds that would inhibit HIV replication. The first of these agents, zidovudine, an azido-substituted nucleoside analogue was introduced over a decade ago. Nucleoside analogue reverse transcriptase inhibitors inhibit the reverse transcriptase enzyme, which is responsible for reverse transcription from RNA to DNA in the HIV replication process (see Figure 1). Reverse transcriptase inhibitors may also be non-nucleoside based, these are called nonnucleoside analogue reverse transcriptase inhibitors. Collectively these two forms are often referred to as reverse transcriptase inhibitors (7). Until the mid-1990s zidovudine and a number of other nucleoside analogues were the only available antiretroviral treatments. This class of drugs, the nucleoside analogue reverse transcriptase inhibitors, was initially trialled and used as monotherapy and later in dual combinations. Although the use of these agents resulted in rises in CD4 T cell counts, the high rates of drug toxicity at the doses first used and the emergence of viral resistance limited the duration of effectiveness of these agents (8). In the mid-1990s, the widespread availability of viral load testing and the introduction of a new class of antiretroviral medications, protease inhibitors, combined to change the approach to HIV therapy. HIV protease inhibitors inhibit the protease enzyme responsible for producing the mature virus (7) (see Figure 1). Viral load testing indicated that treatment with dual-nucleoside therapy was not resulting in a durable antiretroviral effect (9). Controlled trials of combinations containing a protease inhibitor as one of three initial agents led to the recommendation that the standard antiretroviral therapy regimen should contain three antiretroviral agents: two nucleosides plus a protease inhibitor, or two nucleosides plus a non-nucleoside reverse transcriptase inhibitor (10). To date this remains the generally recommended treatment regimen. The aim of antiretroviral treatment is to achieve and sustain a viral load which is undetectable in the plasma. Success of antiretroviral treatment is currently judged by virologic and immunologic measures. Those people with HIV/AIDS who achieve an undetectable plasma viral load appear to have an antiretroviral effect of a longer duration and a better rise in CD4 T cell counts than those whose viral load nadir was in a detectable range (9). Treatment with these triple combination regimens (referred to as highly active antiretroviral therapy) has resulted in both decreased AIDS-related morbidity and mortality (11) in Australia (12), the United States (13) and Europe (14). Despite its potency typically producing two to three log 10 reduction in viral load viral resistance develops quickly if strict adherence to the regimen is not maintained. For this reason, the decision to commence antiretroviral therapy must not be taken lightly (9) and detailed consideration is needed to choose regimens compatible with patient lifestyles, eating habits and work patterns. Furthermore, triple combination regimens can be associated with troublesome gastrointestinal side effects, only some of which are readily controlled with available agents. It is not clear how long the response to therapy can be sustained on these three drug regimens. Preliminary reports are now being presented in favour of four or five drug regimens for increased antiretroviral potency (9). However, each additional agent conveys an additional burden of pills and potential for drug interactions and side effects. Figure 1. Integration of HIV into the host cell and targets of antiretroviral action HIV Host CD4 T cell 3. Viral RNA is integrated into cellular DNA in the nucleus to create the Provirus which is then transcribed into RNA 5. A new mature virus is produced** 1. HIV binds to the cell and loses its outer envelope. 2. DNA copies of viral RNA are transcribed by reverse transcriptase * Provirus HIV RNA 4. RNA copies packaged into a new virus particle which bud from the cell * The reverse transcriptase enzyme is the target of two classes of antiretroviral agents: the nucleoside reverse transcriptase inhibitors and the nonnucleoside reverse transcriptase inhibitors. ** The HIV protease enzyme is responsible for the post-translational cleavage of two polyproteins necessary for the maturation and replication of invectious HIV virions. The protease inhibitors target this enzyme. 212 Australian Journal of Nutrition and Dietetics (2001) 58:4

3 Nutritional issues recognised prior to the availability of HAART It is important for practitioners working with people with HIV/AIDS to have an understanding of nutritional issues associated with HIV/AIDS prior to the availability of HAART. The development of viral resistance and the lifestyle changes necessary to maintain these drug regimens mean that HAART therapy is not always successful or may not produce a sustained response. Some people with HIV/AIDS choose not to take the therapy, and therefore the issues faced are similar to those seen before the introduction of HAART. In addition, ready access to HAART is not available in the parts of the world such as Africa and much of Asia where the pandemic is greatest. Therefore the nutritional management issues for those with active viral replication remain prominent throughout the world. Nutritional issues for children with HIV/AIDS are not discussed in this article, but there are some references (15,16) that address the nutritional issues for paediatric patients. Weight loss in people with HIV/AIDS Weight loss in people with HIV/AIDS has been documented since the early stages of the epidemic (17 19) and is recognised as a hallmark of the disease. Prognostic significance of weight loss The clinical significance of profound weight loss in HIV disease was first documented in 1989 by Chlebowski et al. (20) whose analysis demonstrated that those people with HIV/AIDS with a weight loss of greater than 20% of usual weight at diagnosis had a median survival of only 48 days compared with those with less than 10% weight loss whose median survival was 520 days (P < 0.01). Guenter et al. (21) in a study of 77 people with HIV/AIDS followed for a mean of 186 days, found a weight loss of more than 10% of usual body weight to be associated with a relative risk of death 8.3 times greater than those with less weight loss (P < 0.002). Palenicek et al. (22) analysed data from the multicentre AIDS cohort study which followed 962 men with HIV/AIDS who developed AIDS during the follow-up period between 1984 and They found that men who had unintentionally lost greater than or equal to 4.5 kg three to nine months prior to developing AIDS (relative hazard 1.43, P = 0.002) or who had lost greater than 10% of their baseline weight (relative hazard 1.45, P =0.08) had poorer survival, after their AIDS diagnosis, than those who had not. More recently, Wheeler et al. (23) demonstrated that even small weight losses are associated with an increased risk of morbidity and mortality. Proportional hazards models were analysed for the occurrence of opportunistic infection and death in 2382 people with HIV/AIDS in four different studies over the initial four-month period. A weight loss of up to 5% was associated with a relative risk of death of 1.26 (P < 0.01) and of opportunistic complications of 1.19 (P < 0.01) over the four-month period studied. A weight loss of 5% to 10% of usual weight was associated with a relative risk of death of 1.89 (P <0.001) and of opportunistic complications of 1.26 (P <0.01). Small weight losses (5% to 10%) are clinically significant and are associated with increased morbidity and mortality. HIV wasting syndrome HIV wasting syndrome refers to a specific set of criteria including weight loss that has been accepted as AIDSdefining illnesses in the USA since 1987 (24) and in Australia since 1988 (25). In this context, HIV wasting syndrome is defined as a weight loss of greater than 10% of usual body weight as well as either chronic diarrhoea (at least two stools per day for 30 days or more) or chronic weakness and fever (for 30 days or more) plus an HIVpositive diagnosis. Other causes of weight loss, for example, malignancy, tuberculosis, specific enteritis or any other secondary infection, must be excluded. HIV wasting syndrome constitutes a formal definition for diagnosis of AIDS and should be distinguished from weight loss associated with HIV. Body composition changes in weight loss associated with HIV The findings of Kotler et al. (19) that wasting was generally associated with intestinal abnormality microscopically, led to the expectation that the weight loss experienced in people with HIV/AIDS would be similar to that seen in simple starvation. In starvation, fat mass is lost in preference to muscle tissue and there is a compensatory fall in the resting metabolic rate to preserve energy stores. Using total body potassium to assess the body cell mass (i.e. metabolically active tissue), Kotler et al. (26) demonstrated at a mean weight of 82% of ideal, the mean total body potassium to height index (representing the body cell mass) was only 68% of ideal. This suggested that weight loss underrepresented the depletion in metabolically active tissue and people with HIV/AIDS were more severely malnourished than indicated by the weight loss alone. Body fat mass in the men studied was low compared to normal values. However, it was not significantly different in HIV-infected homosexual men to homosexual controls, reflecting a relative preservation of the fat compartments after HIV infection. The relative increase in total body water and extracellular water disguised the body cell mass depletion and minimised the weight loss. These results showing preferential loss of the fat free mass and preservation of the fat mass were more reminiscent of the wasting experience in trauma and sepsis rather than starvation. In a later study prior to antiretroviral treatment Kotler et al. (27) demonstrated the prognostic significance of the loss of body cell mass. At 100 days before death, weight still averaged 90% of usual whereas total body potassium had dropped to 71% of normal. By extrapolation, they determined that weight at death would be 66% of normal and body cell mass only 54% of normal. These findings were later supported by Ott et al. (28) who demonstrated decreases in body cell mass (using bioelectrical impedance analysis) before weight loss was detected. However, other researchers have found that fat loss predominates. Using anthropometry, Sharkey et al. (29) compared body composition in 35 HIV-positive men and homosexual controls and found that 70% of the decrease in weight in the HIV-positive group was fat Australian Journal of Nutrition and Dietetics (2001) 58:4 213

4 mass. Using bioelectrical impedance analysis, Schwenk et al. (30) compared body composition in 104 people with HIV/AIDS and comparable negative controls. Body cell mass as a percentage of weight was not significantly different between the two groups. However, body fat mass was lower in the HIV-positive group, even in the weight stable patients (P < 0.001). Body fat loss was more severe than loss of body cell mass even in the early stages of the disease. More recently Mulligan et al. (31) compared 32 HIVpositive men with weight loss of 10% or more of usual body weight and 46 men without weight loss and 32 healthy male controls. They found that while fat mass, fat free mass (measured by dual energy X-ray absorptiometry) and body cell mass (measured by bioelectrical impedance analysis) were all lower in HIV-positive males with weight loss than in the controls, two-thirds of the difference was fat mass. Longitudinal evaluation of the body composition changes revealed the loss in fat free mass was related to the baseline fat mass, with those having a fat percentage greater than 15% before weight loss losing only 16% of their body weight as fat free mass. Those with less than 15% of body weight as fat mass experienced a weight loss that was predominantly (70%) fat free mass. Confounding factors in studies of body composition in HIV It is likely these more recent studies may be influenced by the introduction of prophylaxis against opportunistic infections and more effective antiretroviral therapy. Early in the history of the epidemics in the Western world the body composition changes experienced may have differed to those detected in studies conducted since the introduction of antiretroviral therapies. Indeed Sharpstone et al. (32) demonstrated that both body composition and metabolic response differed depending on the opportunistic infection present. For example, protozoal diarrhoea resulted in decreased energy expenditure and decreased body fat, while those with mycobacterium avium-intracellulare had an elevated resting energy expenditure and a decreased muscle mass. These differences may have confounded early studies because opportunistic infections were common at the time. Additionally, the use of different body composition methodologies makes the comparison between studies difficult, a point highlighted by Paton et al. (33) who used a number of different body composition techniques to follow body composition changes in people with HIV/AIDS. As an example, in subjects gaining weight, usually in periods of clinical stability or recovery from opportunistic infection, the percentage of weight gained as fat free mass was 59% by anthropometry, 51% by dual energy X-ray absorptiometry, 3% by isotope dilution, and 20% by bioelectrical impedance analysis using the manufacturer s equation or 70% by bioelectrical impedance analysis using the Segal equation. Thus, studies demonstrate that abnormalities in body composition are common and heterogeneous. It is recommended that routine monitoring of body composition, using an appropriately-validated technique, be conducted throughout the disease progression to detect changes promptly. Prevalence of weight loss Wasting syndrome represented 5% of AIDS-defining illnesses reported in Australia in 1996 prior to the introduction of HAART (34). This figure underrepresents the prevalence of weight loss in HIV occurring as a result of secondary infection. Weight loss is likely to occur in most people with HIV/AIDS at some stage during the disease process (35). In some studies weight loss of more than 10% of their usual weight has been reported in more than 50% of people with HIV/AIDS (20,29,36 41). Two studies documented weight changes in HIVpositive populations longitudinally. Summerbell et al. (42) followed 420 people with HIV/AIDS attending an outpatient clinic over one year to determine the incidence of weight loss. One hundred and twenty-one of those studied had lost weight: opportunistic infections could account for the weight loss in 57 cases, psychosocial factors in 20 cases and drug-related problems in nine cases, leaving only 35 with unexplained weight loss. Macallan et al. (43) followed weight changes longitudinally in 30 people with HIV/AIDS for nine to 49 months (median 19 months). They documented two distinct patterns of weight loss; rapid severe weight loss and chronic relentless weight loss. Rapid weight loss was associated with an opportunistic infection in almost all cases. Chronic weight loss was often associated with gastrointestinal disease, particularly diarrhoeal disease. Episodes of weight gain were usually associated with recovery from infection. The observations of these authors suggest the metabolic disturbances in chronic and acute weight loss may be different. They suggest chronic weight loss resembles malnutrition with a reduced metabolic rate whereas acute weight loss resembles the catabolic state with an elevated metabolic rate and increased substrate cycling. Although the exact prevalence of weight loss is not known, it is ubiquitous in people with HIV/AIDS not receiving HAART. Weight loss is often associated with opportunistic infections, and weight gain with recovery. Weight should be monitored regularly throughout the disease progression. Current concepts of the causes of weight loss in patients with HIV/AIDS The cause of weight loss in people with HIV/AIDS is not always elucidated and it is usually of a multifactorial nature. Table 1 shows some of the factors implicated in weight loss associated with HIV. The heterogeneity of the clinical course of HIV disease has made accurate assessment of the prevalence and exact nature of weight loss associated with HIV difficult. It is clear, however, that weight loss is common and is associated with increased morbidity and mortality. The existing literature points to the primary causes of weight loss being the presence of a secondary infection and decreased energy intake (44,45). Malabsorption and metabolic abnormalities may also contribute to weight loss (45,51 58). Weight loss may be rapid or chronic and may alternate with periods of weight gain and weight stability (43). Weight loss may be from the fat free mass and/or the fat mass and the relative contribution from each component may be related to the cause of the weight loss (34,45,55). 214 Australian Journal of Nutrition and Dietetics (2001) 58:4

5 Nutritional issues since the introduction of HAART Weight loss and body composition Initial reports about the effect of the introduction of protease inhibitors on weight and body composition suggested that, although weight gain occurred for the majority of people with HIV/AIDS commencing HAART, the composition of the gain was primarily fat mass. Carbonnel et al. (67) described a sample of 186 people with HIV/AIDS receiving the protease inhibitor indinavir. One hundred and sixty of them were available for follow-up at a median time of 176 days. One hundred and nineteen (74.4%) of the 160 gained weight (mean 6.3 ± 3.8 kg), 13 (8.1%) remained weight stable, and 28 (17.5%) lost weight (mean 4.2 ± 3.0 kg). Although fat, fat free mass and the body cell mass all increased significantly, the increase was proportionally higher in the fat compartment. The increase in weight correlated significantly with the increase in CD4 cell count and the decrease in viral load. Silva et al. (68) compared weight and body composition prior to and after commencing a protease inhibitor regimen. Their results show a significant mean weight increase of 1.54 kg over a mean of 12.6 months of treatment. Although there was a small significant increase in fat free mass after commencing protease inhibitor therapy (0.56 kg), the relative amount of fat free mass to total body weight tended to decrease (by 0.78%, P = 0.08). The weight gain in this population was predominantly fat mass and was accompanied by a significant increase in energy intake, supporting the results of Carbonnel et al. (67) above. Weight and fat free mass gains were significantly greater in those who responded to their antiretroviral regimen with a decrease in viral load of at least 0.5 log after commencing treatment, further supporting a relationship between weight, fat free mass and viral load. Rivera et al. (69) also investigated the relationship between weight and prognostic HIV indicators early in the HAART era. They demonstrated a strong correlation (r = 0.70, P = ) between maximum prior weight loss and HIV RNA viral load in 33 people with HIV/AIDS referred for management of weight loss. In this same group, prior weight loss also correlated negatively with CD4 T cell count (r = 0.43, P = 0.01). In contrast Schwenk et al. (70) found that the introduction of an effective protease inhibitor regimen was unrelated to linear weight trend over a 28-week period in 63 undernourished people with HIV/AIDS. The prevalence of weight loss since the introduction of HAART is unclear although it has been shown to occur in at least a subset of those receiving therapy. Weight loss is particularly likely in those people with HIV/AIDS on suboptimal regimens or if therapy fails to decrease the viral load. Medication side effects Importantly, Schwenk et al. (70) comment that the high prevalence of side effects (particularly gastrointestinal in nature) on protease inhibitor therapy may have compromised the response to treatment. Gastrointestinal and systemic side effects resulting from HAART therapy were a leading cause of discontinuation of protease inhibitor treatment, with treatment failure second to these side effects as a reason for cessation of therapy (71). A comparison of side effect prevalence prior to and after the introduction of HAART is shown in Table 2. Side effects or symptoms of HIV and HAART, particularly diarrhoea and nausea are common. These symptoms are of nutritional concern as they may promote Table 1. Causes of HIV-associated weight loss Proposed cause and mechanisms of weight loss Comments Inadequate intake Decreased energy intake has been shown to be associated with weight loss in HIV (44,45). Appetite related Anorexia related to HIV, or a related or unrelated illness, or medication side effects (35) contributes to weight loss in HIV (30,45). Not appetite related Physical manifestations of HIV in the oral or digestive regions may result in decreased intake e.g. oral or oesophageal candidiasis, herpetic mucositis or oesophagitis, aphthous stomatitis, oesophageal cytomegalovirus infection, hairy leukoplakia, oral or pharyngeal Kaposi s Sarcoma or non-hodgkin s lymphoma, malignancy causing gastric infiltration or hepatomegaly (17). Isolation, poor cooking skills and poverty (46). Physical weakness or debilitation and inability to shop or prepare meals (46). Dementia (46). Malabsorption of nutrients Gut particularly susceptible to HIV infection (19). HIV may disrupt the gut mucosa increasing susceptibility to other infections such as cryptosporidia, microsporidia or mycobacterium avium intracellulare resulting in malabsorption and diarrhoea (47). HIV enteropathy (19), lactase deficiency (48), hypochlorhydria (49), and pancreatic disorders (50) may contribute to malabsorption. Metabolic abnormalities Hypermetabolism Cytokines Resting energy expenditure (REE) is increased in people with HIV/AIDS (both asymptomatic and symptomatic) when compared with healthy controls and/or accounting for the fat free mass (the metabolically active tissue) (45,51 58). Two studies have shown REE is not increased in HIV-positive subjects compared to healthy controls and accounting for the fat free mass (59,60). It may be that REE varies at different stages of disease progression (32) resulting in a net hypermetabolic state. Increases in cytokines (particularly Tumor Necrosis Factor alpha and interferon alpha) have been shown in some studies (58,61,62) in HIV-infected subjects. Other studies have shown no increase (53,63). Increased cytokine concentrations result in increased de novo lipogenesis resulting in futile cycling which results in net energy consumption and no energy production (64 66). Australian Journal of Nutrition and Dietetics (2001) 58:4 215

6 inadequate intake and weight loss. Indeed, Morgan- Jones (72) found that 55% of people with HIV/AIDS symptoms also reported weight loss. Together these studies suggest that weight loss continues to occur in many people with HIV/AIDS treated in the HAART era. It is unclear from current published studies how dependent is the relationship between HIV and weight on good virologic response and immune reconstitution. Even if good viral control does have a direct relationship with weight gain, the gain appears to be predominantly in fat mass and not fat free mass. In addition, not all people with HIV/AIDS have a good virological response to HAART. As many as 50% of those on HAART may not achieve an undetectable viral load (73,74), and in some of those who do, immune reconstitution is slow to occur. These groups may be exposed to an increased risk of long-term weight loss. In addition, the high prevalence of side effects on HAART may make it difficult to maintain a nutritionally adequate diet and weight. Lipodystrophy or fat redistribution syndrome Lipodystrophy represents a syndrome of altered body composition and metabolic abnormalities. The presentation may differ for each individual. However, it constitutes various combinations of peripheral subcutaneous fat wasting and/or visceral adiposity with or without hyperlipidaemia and/or insulin resistance. This syndrome only occurs in those receiving antiretroviral therapy. Since late 1997 much of the focus of concern regarding HAART-related side effects has been on a syndrome Table 2. A comparison of side effects prior to and after the introduction of highly active antiretroviral therapy (HAART) Pre-HAART Post-HAART Author Chlebowski et al. (1989) (20) Morgan-Jones (1998) (72) Country United States Australia Sample size 71 (no antiretroviral therapy) 150 (84 % taking HAART) Method Retrospective review of medical records Face-to-face survey Nutrition-related symptom Prevalence Diarrhoea 42% 66% Nausea 23% 48% Loss of appetite 18% 45% Stomach cramps or 8% 37% bloating Taste changes (a) 35% Vomiting (a) 25% (episodic) Pharyngitis (candida 54% (a) related) Dysphagia 21% 1% Cause (a) Not reported. Attributed to HIV per se, concurrent infections, HIV enteropathy Primarily attributed to initiation of HAART of body composition abnormalities usually accompanied by multiple metabolic abnormalities. To date this syndrome does not have a universally accepted title or case definition. The syndrome was initially called crix belly referring to its presence in patients taking Crixivan, a trade name for indinavir, the first licenced protease inhibitor in the USA. It was widely discussed on the Internet Crix list set up by those taking this drug to discuss issues related to its use. In the scientific literature the syndrome was first described as a syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in people receiving HIV protease inhibitors (75). The term lipodystrophy has been considered by many as a misnomer. Lipodystrophy refers to a rare condition of total or partial fat atrophy accompanied by hyperlipidaemia and insulin resistance, which may be inherited or acquired after some infectious illnesses such as measles (76). The abnormalities are sometimes referred to as fat redistribution syndrome (77) in the literature. However, in lieu of a formal name for the syndrome, lipodystrophy will be used throughout this text. Carr et al. (75) examined a population in Australia of 116 people with HIV/AIDS receiving protease inhibitors, 32 HIV patients who were protease inhibitor naïve, and 47 healthy men. They found that lipodystrophy occurred predominantly in those on protease inhibitor therapy, evidenced by 74 of 116 on protease inhibitor therapy reporting symptoms consistent with the syndrome versus only one protease inhibitor naïve patient. Lipodystrophy was associated with fat loss in all regions except the abdomen as shown on dual energy X-ray absorptiometry scans after a median of 10 months on the drug therapy. Those people with HIV/AIDS with lipodystrophy defined by self-reported central abdominal visceral adiposity and/or peripheral fat wasting experienced a relative weight loss of 0.5 kg per month and had significantly higher cholesterol, triglycerides, c-peptide, insulin and insulin resistance ratio than those taking protease inhibitors who did not develop lipodystrophy. Diabetes developed or worsened in three of those studied. Table 3 outlines the morphological abnormalities and biochemical abnormalities currently thought to be part of the syndrome. More recently the role of nucleoside analogue therapy in the aetiology of lipodystrophy has been examined. Gervasoni et al. (81) and Saint-Marc et al. (80) both found the morphological features of lipodystrophy to be related to two different nucleoside reverse transcriptase inhibitors. Both these studies differ from the initial study by Carr et al., not only by the attribution of the symptoms to a different class of antiretroviral therapy but also by the lack of association between the morphological changes and abnormalities of serum lipids and insulin resistance. The syndrome is complicated further by a distinct subset of people with HIV/AIDS who develop a syndrome of lipoatrophy and liver dysfunction associated with lactic acidaemia in people with HIV/AIDS using nucleoside reverse transcriptase inhibitors (90). This syndrome can be distinguished from lipodystrophy by the recent onset of symptoms and weight loss, with higher lactate and alanine transferase levels, lower albumin, cholesterol, triglycerides, glucose and insulin than those levels seen in the syndrome they associated with protease inhibitors. Currently proposed definitions of the syndrome are shown in Table Australian Journal of Nutrition and Dietetics (2001) 58:4

7 Epidemiology of lipodystrophy Body composition Without an accepted definition, estimating the prevalence of the syndrome is difficult. In their initial study, Carr et al. (75) reported 64% of their sample of people with HIV/AIDS taking protease inhibitors stated they experienced body composition changes (wasting of fat in the face, arms or legs with or without visceral adiposity), as opposed to only 3% of those who were protease inhibitor naïve (P = ). Gervasoni et al. (81) found only 10.5% (32 out of 306) of their female population using antiretroviral therapy developed body composition abnormalities (defined by increased breast size and abdominal girth associated with wasting of the lower limbs), almost half of the total sample (146/306) were taking protease inhibitors. The inclusion of increased abdominal girth in the Gervasoni criteria may explain the lower prevalence in this sample. However, the prevalence may differ between men and women. Using differing criteria, other researchers have found the prevalence of body composition abnormalities in their cohorts to be 47.3% (95), 65% (94), 50% (96) and 37.9% (97). Each of these cohorts was predominantly male with more than half the subjects using protease inhibitors. Our own data suggest a prevalence of 59% in those taking protease inhibitors (87). Emphasising the difficulties associated with varying definitions of the syndrome, Carter et al. (94) applied different definitions of lipodystrophy in their analysis of a single cohort (90% of whom were protease inhibitor experienced) and found the prevalence varied with the definition used. Using the Table 3. The morphological and biochemical abnormalities associated with lipodystrophy syndrome Parameter Changes reported Morphological Fat increase Increased waist girth resulting from increased visceral adipose tissue deposits (78) Fat decrease Wasting of peripheral subcutaneous fat deposits including the face, frequently resulting in the appearance of prominent veins in the arms and legs (79,80) Fat redistribution Increased breast size in women (81,82) Gynaecomastia in men (83) Buffalo humps (enlarged dorso-cervical fat pad) (82,84) Other isolated lipomas for example on the front of the neck, on the arms or shoulders (85) Weight Weight has been reported to increase (82,85), decrease (75), or remain stable (78,84,86) Biochemical Hyperlipidaemia Insulin resistance Increased serum total cholesterol (75,87) Increased low density lipoproteins (75) Decreased high density lipoproteins (75) Increased serum triglycerides (75,87) Normal or elevated serum fasting glucose (88) Increased serum fasting insulin (75,87) Increased serum C peptide (75) Decreased glucose tolerance (79,89) Other Increased serum lactate (90) Increased serum cortisol (86) Increased serum catecholamines (86) objective criteria established by the Australian National Centre for HIV Epidemiology and Clinical Research (see Table 4) the prevalence of lipodystrophy was 65% (94). When those studied were asked to self-report body composition changes consistent with the syndrome, the prevalence was 19% (94). The prevalence, and indeed the criteria, for excess lipomatosis are less clear. There have been several case reports (84,98 100) describing lipomas but discussion on the prevalence of this aspect of the syndrome is limited. Heath et al. (96) reported that 6% of 1035 people with Table 4. Proposed definitions for lipodystrophy syndrome Main criteria Definition Carr et al. (91) Morphological and metabolic abnormalities and must be taking a protease inhibitor Saint-Marc et al. (92) Morphological subdivided into 3 groups Fat wasting (face, arms, legs, buttocks) and/or visceral adiposity, buffalo hump plus one or more of the following: fasting serum total cholesterol 5.5 mmol/l or triglycerides 2.0 mmol/l; fasting C-peptide > 2.5mmol/L; impaired fasting glucose ( mmol/l) or diabetes mellitus ( 7.0 mmol/l) on fasting blood glucose; impaired glucose tolerance ( mmol/l) or diabetes mellitus ( 11.1 mmol/l) on two-hour blood glucose by oral glucose tolerance test. Lipoatrophic : subcutaneous fat loss (face, abdomen, thigh, buttocks, upper, lower limbs) and/or deep fat loss (facial cheeks, periauricular and orbital fat pads). Identified as a decrease in abdominal and thigh subcutaneous fat on computed tomography scans. Mixed condition : increased visceral adipose tissue, and a decreased subcutaneous to visceral adipose tissue ratio on computed tomography scans at the L4 level Obese : gain of subcutaneous adipose tissue related to excessive energy intake. SALSA (self-ascertained lipodystrophy assessment) (93) Morphological Fat depletion Fat gain Fat depletion and fat gain Carr et al. (91) Morphological Self rating of the severity (none = 0, mild=1, moderate=2, severe=3) of the lipodystrophy in each of six regions (face, arms, legs, buttocks, abdomen, neck) Mild arbitrarily defined as scores of 1 6 Moderate defined as scores of 7 12 Severe defined as scores Australian National Centre for HIV Epidemiology and Clinical Research (94) Morphological and metabolic Major criteria: < 20% body fat by dual energy X-ray absorptiometry, or waist circumference > 90 cm. Minor criteria: fasting serum total cholesterol > 5.5 mmol/l or fasting triglycerides > 2.0 mmol/l Australian Journal of Nutrition and Dietetics (2001) 58:4 217

8 HIV/AIDS in their treatment database had buffalo humps. However, the prevalence of other forms of lipomatosis is not discussed. The prevalence of lipodystrophy in protease inhibitor naïve populations requires further investigation. The initial study by Carr et al. (75) found only one such person (3%) developed the syndrome. Galli et al. (101) report a prevalence of 26% in women and 6.5% in men (n = 188 men and women) taking dual nucleoside-analogue reverse transcriptase inhibitor combinations. Gervasoni et al. (81) found 12 out of 306 (4%) women who were protease inhibitor naïve developed lipodystrophy compared with 20 out of 306 (7%) on protease inhibitors. Mallal et al. (102) reported 13% of people using nucleoside-analogue reverse transcriptase inhibitors developed peripheral subcutaneous fat wasting compared with 51% of those on protease inhibitors (total n = 227). Our own data showed that only three of 14 of those receiving antiretroviral therapy who were protease naïve (87) developed the syndrome. It is evident that lipodystrophy is not exclusive to those taking protease inhibitor therapy. However, current reports suggest the prevalence is lower on non-protease regimens and no case series of lipodystrophy have been reported in treatment-naïve patients to date. The self-ascertained lipodystrophy syndrome assessment group (total n = 227) suggest the pattern of body composition changes may be sex specific with a greater percentage of women reporting fat accumulation (97% of females compared with 81% of men) and less women reporting peripheral fat depletion than men (80% men, 73% women) (93). Serum abnormalities Few studies report on the prevalence of the serum metabolite abnormalities and usually only group means are compared. Carr et al. (75) found mean elevations of cholesterol, triglycerides, c-peptide insulin and a higher insulin resistance ratio in those people with HIV/AIDS on protease inhibitor therapy with lipodystrophy. Saint-Marc et al. (80) found no mean differences between those with peripheral fat wasting on long-term nucleoside-analogue reverse transcriptase inhibitors and untreated HIV-positive controls in fasting serum glucose, insulin, c-peptide, triglyceride, cholesterol, free fatty acids, testosterone, follicle stimulating hormone, luteinizing hormone, cortisol concentrations, CD4 T cell count and HIV viral load. Gervasoni et al. (81) also found no mean differences between the women with and without self-reported lipodystrophy in serum cholesterol, triglycerides, glucose, c- peptide, prolactin, growth hormone, testosterone, adrenocorticotrophic hormone, and urinary cortisol. Carr s data taken with Saint-Marc s suggest the serum metabolite abnormalities may be more likely to occur with protease inhibitor therapy. This relationship between protease inhibitor therapy and serum abnormalities is supported by Walli et al. (103) who compared serum lipid concentrations, insulin sensitivity (using intravenous insulin tolerance test) and oral glucose tolerance between people with HIV/AIDS treated with protease inhibitors and antiretroviral therapy naïve people, and HIV-negative controls. Those taking protease inhibitor therapy had significantly reduced insulin sensitivity, impaired glucose tolerance and increased cholesterol and triglycerides when compared with the other two groups. Gervasoni s data raise the possibility that the serum abnormalities may be sex specific, as mean differences in serum parameters were not found between those women with and without lipodystrophy despite a high usage of protease inhibitor therapy in their study population. A reduced prevalence of lipid abnormalities in women with lipodystrohpy versus men was also supported by the self-ascertained lipodystrophy syndrome assessment group (93) who reported a higher prevalence of elevated serum glucose, cholesterol and triglycerides in HIV-positive men than in women (most of whom were taking protease inhibitor therapy). Tsiodras et al. (104) have reported retrospectively on the five-year cumulative incidence (1993 to 1998) of newonset hyperglycaemia, hypercholesterolaemia, and hypertriglyceridaemia and report the percentages to be 5%, 24% and 13% respectively. The sample included 221 people with HIV/AIDS and most of the onsets occurred after the commencement of protease inhibitor therapy. Heath et al. (96) report a prevalence of hypertriglyceridaemia of 10% and hypercholesterolaemia of 12% in their sample of 1035 people with HIV/AIDS. Glucose abnormalities and insulin resistance Interest in insulin sensitivity began early in the study of HIV disease. Prior to the introduction of HAART, people with HIV/AIDS had been shown to have an increased insulin sensitivity (105). More recently reports of insulin resistance and of glucose abnormalities associated with protease inhibitor use (103,106) and lipodystrophy (107) have been published. Once again the prevalence of these abnormalities is not clear. Goebel and Walli described a prevalence of insulin resistance of 55% in patients taking protease inhibitors versus 27% in people with HIV/AIDS on nucleoside-analogue reverse transcriptase inhibitors alone (108). Elevated fasting serum insulin and a high insulin resistance ratio appear to be frequent while the development of frank diabetes is rare (75). As there is no accepted definition of the syndrome, the prevalence of lipodystrophy is difficult to determine. Studies in Australian cohorts suggest the prevalence of at least some aspects of the syndrome may be higher than 50%, especially in those people with HIV/AIDS who have received a protease inhibitor as antiretroviral therapy. Some of the elements appear to be gender specific, and the prevalence in women is particularly unclear. Proposed mechanisms underlying lipodystrophy Protease inhibitor interaction Carr et al. (109) proposed that protease inhibitors bind the cytoplasmic retinoic-acid binding protein-1, a molecule that binds most of the intracellular retinoic acid and may also inhibit the action of the lipoprotein receptor-related protein, a hepatic receptor important for chylomicron clearance, thus interfering with fatty acid metabolism. The theory is based on sequence homology between a sequence of 12 amino acids of the HIV protease and cytoplasmic retinoic-acid binding protein-1 and lipoprotein receptor-related protein. The protease inhibitors may not be virus specific but interfere with the homologous sequences in the adipocyte as well as HIV protease (109). 218 Australian Journal of Nutrition and Dietetics (2001) 58:4

9 Mitochondrial toxicity Brinkman et al. (110) propose that mitochondrial toxicity induced by nucleoside-analogue reverse transcriptase inhibitors may be an important factor in the development of the syndrome. They suggest that nucleoside-analogue reverse transcriptase inhibitors may inhibit the DNA polymerase γ, the sole enzyme responsible for mitochondrial DNA replication. By inhibiting this enzyme, mitochondrial toxicity is induced resulting in metabolic disturbances. Abnormality of the hypothalamic-pituitary-adrenal axis Renard et al. (86) propose that sympathetic stimulation may be sustained in chronic HIV infection and that there may be an increased catecholamine-mediated increase in lipolysis resulting in peripheral fat wasting. As visceral adipose tissue is usually more sensitive to catecholamines than peripheral subcutaneous fat (111) they propose the seemingly paradoxical increase in visceral adipose tissue may result from a yet unproven imbalance in catecholamine receptors in visceral adipose tissue. Previously increased peripheral lipolysis has been shown to occur in people with HIV/AIDS (62). Renard et al. (86) suggest this increased peripheral lipolysis may increase the visceral adipose tissue as the free fatty acids generated may be reesterified and shuttled as VLDL triglycerides and stored in visceral adipose tissue. The correlation between cortisol and visceral adipose tissue in their subjects with lipodystrophy suggests cortisol may also play a role in the visceral adipose tissue increase. Furthermore they suggest that, as HIV infection has been shown to induce cortisol resistance (112), good viral suppression on HAART may actually induce an increased sensitivity to cortisol, hence exacerbating the potential effect of cortisol on visceral adipose tissue (113). Previously, abnormalities in the steroidal axis, in particular an increase in the cortisol to dehydroepiandrosterone ratio, have been shown to correlate with malnutrition in men with HIV/AIDS (114). More recently a decrease in dehydroepiandrosterone concentrations has been associated with lipodystrophy (115). These relationships require further investigation. In summary, the causal mechanism or mechanisms of lipodystrophy syndrome remain elusive although it is likely that the antiretroviral medications may interfere with normal metabolic pathways. It is also possible that HIV infection itself and the body s response to the improvement in immune functioning on successful antiretroviral therapy may be involved. Impact of lipodystrophy Although formal studies have not yet been published, it has been discussed in the literature (116) and it is evident in clinical practice that the body composition changes associated with lipodystrophy have a devastating effect on the self-esteem and quality of life of patients developing this syndrome. Furthermore, there are concerns that lipodystrophy may have major morbidity in the long term. The visceral adiposity, insulin resistance and hyperlipidaemia experienced in lipodystrophy bear similarities to syndrome X (117) prevalent in Westernised countries. These abnormalities are epidemiologically associated with cardiovascular disease, type 2 diabetes and stroke (113,118,119). Already case reports of cardiovascular disease and diabetes in people with HIV/AIDS are appearing in the literature (89,103,120). Pancreatitis may also be a complication of the hypertriglyceridaemia (121). Thus, should lipodystrophy lead to premature vascular disease, it would be expected that people with HIV/AIDS would suffer serious adverse consequences in large numbers. Using calculations based on the Framingham data (122), Grunfeld (123) has estimated that the increases in LDL and VLDL cholesterol concentration which occur with protease inhibitor initiation would lead to only 1.41 new cases of coronary heart disease per 100 people with HIV/AIDS over ten years. The decreases in HDL concentrations would lead to 3.56 new cases of coronary heart disease per 100 people with HIV/AIDS over ten years. Therefore, he suggests that protease inhibitor treatment would increase the rate of atherosclerosis by only 0.14% per year. The death rate from AIDS at the San Francisco General Hospital was 14.78% in 1994 and 2.26% in Hence, the increase in cardiovascular risk is small compared to the decrease in morbidity resulting from the introduction of protease inhibitor therapy. Research from this same group (124) suggests that significant metabolic changes (increases in glucose, insulin, LDL and total cholesterol and triglycerides) begin early in the course of protease inhibitor treatment and are not accompanied by morphological changes, thus suggesting the metabolic abnormalities precede the morphological ones. Effect of HIV infection on lipids Early in the course of untreated HIV infection HDL concentrations decrease (66), and this is a risk factor for cardiovascular disease. As HIV infection progresses, LDL concentrations decrease. However, these LDL particles are the small and dense type and are associated with increased cardiovascular risk. When infection progresses to AIDS, triglyceride concentrations increase primarily due to an increase in VLDL (66). Free fatty acids also increase in AIDS (66). These changes in lipid metabolism may be cytokine mediated responses to chronic infection, as they have been reported in other infective states (125). While treatment of therapy-naïve HIV-positive patients with zidovudine results in decreased triglycerides (126) treatment with protease inhibitors increases triglyceride concentrations and low density lipoprotein levels increase to normal and HDL levels remain unchanged (123). Conclusions HIV infection is a complex disease process now further complicated by a unique set of side effects associated with HAART. Dietitians working in this area need to have a good understanding of the nutritional issues faced by people with HIV/AIDS both prior to and during the era of HAART. Weight loss is prominent in people with HIV/AIDS not taking HAART and continues to occur in people taking HAART. However, the prevalence is unclear. A new set of metabolic and morphological abnormalities referred to as lipodystrophy syndrome, has become the prominent nutritional issue in the HAART era. Medication side effects and disease complications such as diarrhoea, nausea and anorexia continue to affect people with HIV/AIDS. Australian Journal of Nutrition and Dietetics (2001) 58:4 219