Involuntary weight loss, or wasting, is one of the most common symptoms of HIV infection. It can occur at any stage of infection and usually suggests that the HIV disease is progressing. Weight loss may be quite substantial and get progressively greater. In addition, chronic unintended weight loss is associated with malnutrition, which may contribute to increased immune suppression.

The technical term 'wasting syndrome is usually used to describe a clinical syndrome in which an individual has lost more than 10% of his or her body weight in the absence of active infections or any other identifiable cause of weight loss.

Causes

Weight loss can result from malabsorption, diarrhoea, reduced food intake and altered metabolism. Wasting can occur in the absence of opportunistic infections or other identifiable causes of weight loss.

Malabsorption is impaired uptake of nutrients from the gut. Nutrients are normally absorbed from food in the intestines by cells that make up finger-like protrusions called villi that line the intestinal wall. Certain disease processes including HIV infection can cause the villi to wither and shorten, resulting in impaired absorption of nutrients. However, the association between HIV-associated wasting and malabsorption has been challenged by a study of over 100 people with wasting and diarrhoea which found that nutrient malabsorption was not associated with weight loss. Rather, reduced calorie intake and frequency of diarrhoea were associated with wasting (Beaugerie 1998).

Many people with HIV or AIDS experience diarrhoea at some point. It can occur in people who are very healthy or very ill, and be short-lived and occasional or continuous. In Africa, diarrhoea is a major cause of death in HIV-infected children, with one study finding that HIV-positive infants have an eleven-fold increased risk of dying from diarrhoea compared with uninfected infants.

Malabsorption and diarrhoea can be caused by a number of opportunistic infections, including:

• Parasitic infections such as Cryptosporidium, Isospora belli, Microsporidium, Entamoeba histolytica and Giardia lamblia

• Viral infections such as cytomegalovirus (CMV)

• Bacterial infections such as Mycobacterium avium intracellulare (MAI), Salmonella, Campylobacter and Shigella.

When people with HIV have diarrhoea, specific pathogens can often be identified in faecal samples. People with HIV may also experience diarrhoea for which no specific cause can be identified. This is often referred to as pathogen-negative diarrhoea.

A major cause of weight loss is reduced food intake. This may be a result of mouth ulcers and lesions due to candidiasis (thrush), herpes simplex, or other diseases may cause painful or difficult swallowing. Thrush, although not painful, may alter the sense of taste or cause nausea. Neuropsychological disorders associated with HIV infection can result in loss of appetite (anorexia). The depression and anxiety that may accompany a life-threatening illness often disrupt normal routines and also suppress the appetite. Psychosis and organic brain diseases such as HIV-associated dementia, toxoplasmosis, and cryptococcal meningitis can also inhibit a person's desire or ability to eat.

People with HIV may also experience changes in their metabolism which lead to weight loss. Depletion of lean body muscle mass has been observed in people at all stages of HIV infection. Kotler (1989a) reported that wasting syndrome is distinguished from starvation in that the former results in body-fat content preservation while body cell mass is depleted. This progressive wasting may result solely from the underlying HIV infection.

The catabolic or destructive effects of any debilitating illness or opportunistic infection may result in weight loss and generalised wasting without evidence of anorexia or malabsorption.

Wasting syndrome in the era of highly active antiretroviral therapy

Studies have found that starting highly active antiretroviral therapy (HAART) may improve weight loss and malnutrition (Raghavan 1998; Schwenk 1998; Yarasheski 2004). However, HAART may not prevent loss of body cell mass, a component of lean body mass or muscle, and weight gain after starting treatment may be in the form of fat.

Despite the impact of HAART on illness and death rates amongst HIV-infected people, wasting continues to be a problem for a significant minority of people. For example, United States researchers reported that around 20% of a group of 54 patients experienced reductions in body cell mass and body weight after commencing HAART (Berger 1997).

Another study, which looked at 552 patients between 1995 and 2000, found that weight loss continued to predict an increased risk of death in people taking HAART. Weight loss of just 3% or more from baseline was found to predict a poorer prognosis, and the study did not distinguish between loss of fat-free mass, body cell mass or fat cell mass when measuring weight loss (Tang 2002). However, longer-term follow-up of this cohort  found that  a history of ever using drugs, living in poverty, a CD4 cell count below 200 cells/mm³ , a viral load above 100,000 copies/ml, diarrhoea, nausea and thrush were all significantly associated with unintentional weight loss^[1].

In addition, the investigators found that the risk of 5% or greater weight loss increased by approximately 5% (p = 0.01) with each six month period of calendar observation between 1995 and 2004. This relationship remained significant after controlling for drug use, poverty, obesity, low CD4 cell count, high viral load, diarrhoea, nausea and thrush. This increase in risk did not appear to be associated with lipodystrophy.

Body fat and metabolic disorders associated with HAART differ from traditional HIV wasting. However, there is some overlap between traditonal HIV wasting and body fat redistribution which may make diagnosis and treatment difficult. Lipoatrophy (wasting of the face, arms and legs) is a key feature of body fat changes that have been linked to the nucleoside analogue reverse transcriptase inhibitors (NRTIs). Some experts originally contended that HAART-related wasting was largely due to the effects of HIV itself but, more recently, most experts have acknowledged that anti-HIV therapy plays an important part in the recent manifestation of wasting and body fat changes among people on HAART. For further discussion see Anti-HIV therapy: Body fat and metabolic changes whilst on treatment.

In resource-limited settings a number of studies have now shown that the presence of severe wasting at the time of treatment initiation is predictive of poorer survival after six months or one year on treatment. A Haitian study showed that one-third of those with wasting had died after 12 months, compared to less than one in ten of those without wasting^[2], while a study in Senegal found that a body mass index below 19 was a significant predictor of death on antiretroviral therapy^[3]. A study in Uganda found that a body mass index below 18 was a significant predictor of death during the first three months of antiretroviral therapy, but not thereafter^[4]. 

Other drugs that cause weight loss

Treatment-induced weight loss may occur as a side-effect of some drugs. High-dose sulphonamides, anti-mycobacterial agents and other medications have been associated with anorexia and subsequent weight loss. Fungal superinfections of any part of the gastro-intestinal tract can follow an extended course of antibiotics and may contribute to anorexia or diarrhoea.

Treatments for weight loss

In the United States, dronabinol is a licensed appetite stimulant for people with AIDS-related wasting. A similar drug, nabilone, is licensed in the Unted Kingdom for treating nausea, but not as an appetite stimulant. This approach to treating wasting may be used if a person has a poor appetite and weight loss is due to low food intake.

Megestrol acetate (Megace) has also been approved in the United States for reduced food intake and unexplained significant weight loss in people with AIDS. Although it has been shown to increase food intake, weight and quality of life, the weight gain it causes is primarily fat. Side-effects include diabetes, adrenal insufficiency, Cushing's syndrome, and reduced testosterone. See Megestrol acetate in Drugs used by people with HIV: Anti-wasting treatments for further information.

Drugs such as co-phenotrope (Lomotil) and tincture of opium as well as non-prescription anti-diarrhoea medicines such as loperamide (Imodium) are commonly used to relieve gastro-intestinal irritation and diarrhoea, and may reduce weight loss. Octreotide (Sandostatin) has been shown to be better than standard anti-diarrhoea treatments at reducing number of bowel movements and volume of diarrhoea in a controlled trial. It is thought to inhibit intestinal secretion and enhance water and electrolyte absorption.

High dose human growth hormone (HGH) can lead to significant increases in muscle in people with wasting syndrome. Traditionally, HGH is used in low doses to stimulate growth in people with hormone deficiency, or to treat catabolic states, where metabolism destroys body matter. As a treatment for wasting, it may be reserved for individuals with severe weight loss who have not responded to other treatments. Research suggests low doses are not effective in people with HIV-related wasting (Krentz 1993; Schambelan 1996; Lee 1996), although they have been shown to improve muscle function (Esposito 2004). HGH is an experimental treatment for HAART-related fat disorders, and its effectiveness remains unproven despite some promising observational data (Torres 1998). See Human growth hormone in Drugs used by people with HIV: Anti-wasting treatments for more information.

As high levels of the cytokine tumour necrosis factor may be a cause of wasting, studies are investigating TNF inhibitors as treatments. This approach to wasting remains experimental although thalidomide has shown some promise in early trials.

Liquid nutritional supplements may be helpful for people who eat but do not gain weight and for those who have difficulty eating solid food. There is no consensus about the time to begin such supplementation or the type of supplement that is most beneficial. Generally, however, a free amino acid elemental oral food supplement or an intact modular food supplement is used to augment a high calorie, high protein, low fat, lactose-free diet. Many formulations of these nutritional supplements are available. Use of these supplements may be individualised according to personal taste.

Total parenteral nutrition (TPN) is an intravenous method of nutritional supplementation reserved for people with severely compromised bowel function who are unable to meet their nutritional needs from food. The procedure involves infusing a liquid nutrient preparation directly into the bloodstream through a central venous line. TPN can improve lean body mass in people with HIV-related malabsorption and weight loss (Melchior 1996; Kotler 1990).

Treatment with testosterone

There has been much debate about the role of testosterone levels in AIDS wasting. Testosterone is the male hormone which promotes muscle growth. Following the observation of low levels of serum testosterone in many men with AIDS wasting, a condition known as hypogonadism, some treatment advocates and doctors have argued that correcting the testosterone deficiency may reverse wasting.

However, the relationship between HIV infection, testosterone production and AIDS wasting is still unclear. One recent study found no relationship between wasting and hypogonadism, but a review of patients in the Multicenter AIDS Cohort Study (MACS), a large United States cohort followed since 1985, found that testosterone levels fell before the onset of wasting (Dobs 1996). A study of testosterone levels in women with AIDS wasting found that more than half the women had low levels of testosterone (Grinspoon 1997).

Symptoms of testosterone deficiency include fatigue, reduced sex drive, impotence, depression and loss of appetite. These symptoms are common in advanced HIV disease, and may be associated with many other illnesses and malnutrition. Testosterone levels are reduced in chronic illnesses as an adaptive measure to conserve energy. Even when effective antiretroviral treatment reduces HIV levels and clears up opportunistic infections, some experts suggest that testosterone levels will not return to normal on their own.

Opportunistic infections can also lead to hypogonadism. Cytomegalovirus (CMV) disease can cause testicular atrophy, leading in turn to hypogonadism. Some drugs, such as ketoconazole (Nizoral), cimetidine (Tagamet), ganciclovir (Cymevene) and many chemotherapy drugs, also have a depressive effect on testosterone.

Testosterone injections or skin patches that deliver testosterone on a daily basis are being investigated as a way of maintaining testosterone levels, and some controlled studies have investigated the effectiveness of various testosterone preparations in encouraging the replacement of lean muscle tissue.

A randomised, controlled, double-blind trial of testosterone injections found that men who received testosterone gained muscle and weight, and reported feeling better in comparison to men who received placebo (Grinspoon 1998). However, benefits seem to be restricted to men with hypogonadism. Side effects include balding, possible masculisation of women, acne, testicular atrophy and breast development in men. The little available research into testosterone treatment in women with wasting suggests that women tend to gain fat rather than muscle (Miller 1998).

Trials of patches have indicated improved quality of life, increased body mass and few side-effects.

Synthetic testosterone and anabolic steroids such as stanozolol, oxandrolone (Oxandrin) and nandrolone decanoate(Deca-Dirabolin) are as effective as testosterone in treating AIDS-related wasting. However, some experts recommend testosterone in preference to the oral steroids due to liver side-effects.

Oxandrolone, administered at 20mg per day was shown in one study to produce significant weight gain, consisting of lean body tissue, fat and retained water during one year of follow-up (Poles 1997). A 12-week randomised study in 262 men found that oxandrolone at a 40mg daily dose significantly increased lean body mass; however liver enzyme and LDL cholesterol levels also increased significantly in those who received oxandrolone. Five per cent of oxandrolone-treated patients experienced moderate to severe increases in liver enzyme levels^[5].

Oxandrolone is already licensed in the United States for treating involuntary weight loss due to surgery, chronic infections, severe trauma or unknown problems. One study found that oxandrolone plus resistance exercise produced greater increases in lean body mass than resistance exercise alone^[6].

Nandrolone decanoate has been studied in men with low serum testosterone diagnosed with AIDS wasting syndrome. A 21 day study found that those who received nandrolone experienced significant increases in nitrogen retention that were correlated with gains in lean muscle mass of up to 0.9kg per week, without any programme of exercise.

Oxymetholone has been studied in a large placebo controlled study in Germany. It showed that after 16 weeks, individuals receiving 100mg twice daily had gained an average of 3.5kg, with the vast majority of weight gain occurring by week 4. Individuals who received a higher dose (150mg three times daily) gained slightly less weight (3kg). Around a quarter of patients who received the anabolic steroid at a dose of 100mg twice daily or 150mg three times daily developed liver enzyme elevations.

The researchers recommended an induction period of 8 to 10 weeks with 50mg twice daily and thereafter maintenance therapy with 50mg once daily or every other day. This regimen has shown sufficient weight and lean body mass gain while reducing hepatic side-effects (Hengge 2003).

Exercise to reverse wasting

Resistance training can increase lean body mass. For people with HIV-related wasting, resistance training is often recommended possibly in combination with steroid treatment. It is likely that exercise plus steroid will produces greater weight or muscle gain, although this is not always the case (Corcoran 2000; Bhasin 2000).

Side-effects of anabolic steroids

Steroids have a number of potentially serious side-effects, the most extreme of which is liver damage ande formation of tumours. The incidence of liver damage with steroid use is very low and linked to the dose and the length of time used.

Another potentially serious side-effect is the negative effect of testosterone and anabolic steroids on high density lipoprotein (HDL) cholesterol levels, increasing the risk of heart disease. Testosterone and anabolic steroids also increase the level of hematocrit, the proportion of the blood which is composed of red blood cells. This may become critical if elevated cholesterol levels are causing narrowing of the arteries, because red blood cells are more sticky than other components of the blood, and do not flow so easily through narrowed arteries. This may lead to blood clots and to less efficient transport of the oxygen-bearing red cells around the body, leading in turn to chest pain, heart attack or stroke.

Steroids also alter mood, energy and appetite levels, often in quite startling ways. Increased levels of male hormones will amplify aggressive tendencies. Some people become very aggressive and quick to get angry, a phenomenon called 'roid rage. Many steroid users are totally unaware that they can become obnoxious to people around them whilst on steroids. The steroid dosage should be decreased if signs of uncontrollable rage appear.

However, steroids can often improve mood and energy levels significantly, which may have other knock-on effects, such as enhanced energy for day-to-day activities such as preparing food. Steroid use needs to be accompanied by an increased food intake. Individuals who cannot afford the high protein, high carbohydrate diet which is the best diet for building muscle may not get the full benefit of the prescription. Steroids are often accompanied by a prescription for protein supplements and nutrient enriched sip drinks.

Anabolic steroids also affect hair growth. They can make the hairline recede faster and encourage hair loss on the head in men already 'programmed for significant hair loss. They can also encourage hair to grow on the back, shoulders and arms. In women growth of facial hair may occur as a result of steroid use.

Anabolic steroids also boost sex drive in men, and the sex drive will diminish quite dramatically once steroid use stops There may be some decrease in testicle size which is reversed on stopping the steroid. The return may take a few weeks depending on the dose and the length of the course.

In HIV-positive men with normal testosterone levels and good health, steroid use will have the effect of knocking out natural testosterone production, which takes several months to return once steroid use ceases.

There are anecdotal reports of dramatic increases in CD4 and CD8 cell counts whilst on anabolic steroid treatment. However, it is unclear whether these are newly produced cells or simply cells that have moved from another part of the body into the blood. It is also unclear how well these cells function. Other anecdotal reports from clinicians suggest that steroids may sometimes be associated with rapid worsening of Kaposis sarcoma.

For further information, see Anti-HIV therapy: Body fat and metabolic changes whilst on treatment and Anti-wasting treatments: Anabolic steroids in Drugs used by people with HIV.