Metabolism refers to a range of physical and chemical processes which maintain the human body, including the process of turning fat and sugar into energy.

A number of metabolic disorders have been reported among people taking anti-HIV therapy. These include:

• High triglycerides (a type of blood fat or lipid).

• High cholesterol.

• Insulin resistance.

• Diabetes.

• High blood sugar (glucose).

• High levels of lactate.

• Elevated ALT (a liver protein).

Defining the syndrome

There is some disagreement about the specificity of the metabolic changes which occur in people on HAART. A recent case control study designed to establish an objective case definition of lipodystrophy identified only two metabolic parameters - lowered HDL cholesterol and anion gap - which were specific to the HIV lipodystrophy syndrome. However, several cohort studies have suggested that large numbers of individuals receiving HAART suffer from the metabolic syndrome, regardless of clinically visible body fat changes. The WHO definition of the metabolic syndrome in HIV-negative people is fasting plasma glucose > 6.1mmol (110mg/dl) plus at least two of the following:

• Serum triglycerides above 1.69mM (150mg/dl) or serum HDL cholesterol below 0.9 mM (35mg/dl).

• Blood pressure above 140 / 90mmHg.

• Abdominal obesity defined as waist to hip ratio above 0.90, waist girth above 94cm or BMI above 30kg/m² in men.

This definition of the metabolic syndrome more consistently predicts cardiovascular disease than the NCEP definition (Lakka 2002).

Several metabolic parameters have also been shown to predict the development of body fat changes in people receiving HAART, including high triglyceride levels and high baseline cholesterol.

Causes of metabolic abnormalities

The causes of metabolic disorders and lipodystrophy are not well understood. A number of theories have been proposed, and ongoing research is trying to identify the causes and mechanisms of these fat and metabolic disorders. See Possible causes of body fat and metabolic changes for further discussion of this topic.

Changes in blood fats (lipids)

Changes in the levels of a variety of blood fats (known as lipids) often occur during treatment with protease inhibitors (PIs). People taking PIs commonly develop elevated levels of triglycerides and elevated levels of low density lipoprotein (LDL) or 'bad' cholesterol (Carr 1999; Mulligan 2000; Roth 1998; Tsiodras 2000). There is controversy over the extent to which modest lipid changes after starting treatment represent a normalisation brought about by suppression of HIV replication.

A key Australian study of lipodystrophy, hyperlipidaemia and diabetes in HIV-infected people found that those taking protease inhibitors were at greater risk of elevated triglycerides and cholesterol compared with people who had never taken PIs. High lipids, which are associated with an increased long-term risk of heart disease, occurred in 74% of the protease inhibitor recipients.

There was little difference between the protease inhibitors in the severity of lipodystrophy and metabolic disturbances, although the study did not investigate amprenavir (Carr 1999). Ritonavir has been associated with a greater risk of high triglycerides than the other protease inhibitors (Carr 1999; Periard) and even low dose ritonavir, used to boost concentrations of other PIs, has been associated with elevated triglycerides (McComsey 2002b). The experimental PI atazanavir may have little impact on lipids in treatment-naﶥ individuals, and tends to reduce elevated levels in people switching from nelfinavir. See Atazanavir - overview in Drugs used by people with HIV: Protease inhibitors for further details.

A study of 50 seroconverters in the MACS cohort has shown that lipid increases after commencing HAART represent a return to normal levels for the age group when subjects are matched with the NHANES III cohort of HIV-negative individuals. Cholesterol levels were depressed and triglyceride levels elevated after seroconversion (Riddler 2003).

Whilst low levels of high density lipoprotein (HDL) or 'good' cholesterol have also been linked to HAART, there is also evidence that low HDL is due to HIV infection, rather than antiretroviral therapy (Kingsley). However, the Atlantic study showed that whilst HDL cholesterol levels improved on nevirapine treatment, levels did not rise significantly above baseline in the indinavir-treated group, and the ratio of total cholesterol to HDL cholesterol rose among indinavir-treated patients. HDL levels have also been shown to rise on efavirenz treatment, suggesting that each class of drugs has specific effects on subsets of lipids (Van der Valk 2001a; Staszewski 1999; Van der Valk 2001c).

In the 2NN study improvements in HDL cholesterol levels in nevirapine-treated patients were similar to those seen in HIV-negative patients treated with statins, leading the investigators to suggest that nevirpaine may have a specific effect on HDL cholesterol (Van Leth 2004).

High triglycerides have long been recognised as a feature of advanced HIV infection and elevated lipids (both cholesterol and triglycerides) may occur among people on protease-sparing regimens. A study conducted at the Chelsea and Westminster Hospital in London, for example, found high triglycerides among 2-6% of people taking PI-sparing regimens and high cholesterol levels among 40% (Matthews 2000).

Elevated lipids among people taking PI-sparing regimens may also be due to the specific NRTIs. A study of 600 people who started treatment with efavirenz and 3TC plus either tenofovir or d4T found that d4T was associated with significantly greater rises in cholesterol and triglycerides despite equivalent antiviral activity after 48 weeks. Smaller increases in cholesterol were noted in the tenofovir arm, with an average increase of 0.64mmol/L against 1.37mmol/L. Further, no increases in levels of triglycerides were noted in the tenofovir arm of the trial although triglycerides increased by an average of 1.91mmol/L in those treated with d4T (Staszewski 2002). A significantly larger number of patients receiving d4T initiated lipid-lowering therapy during the study (10% vs 4%, p<0.001), with a rapid acceleration in the number of patients in the d4T group requiring lipid-lowering therapy between weeks 32 and 48 of the study (Staszewski 2003).

The effect of the non-nucleoside drugs (NNRTIs) on lipid levels appears to be mixed. Studies of people switching from a PI to an NNRTI suggest that lipid levels may fall slightly or remain static (Van der Valk 2001c; Martinez 2000). A French study reported that while nevirapine did not generally worsen metabolic abnormalities, it didnt improve pre-existing problems. When the group was broken down according to previous treatment, there were other significant differences in metabolic parameters. For example, an increase in triglycerides on nevirapine was associated with previous d4T therapy for greater than six months, while lipodystrophy was linked to previous PI therapy. Blood sugar abnormalities were linked to viral load below 1000 copies (Bentata-Pessayre 2000).

Comparison between the non-nucleosides suggests that the difference in effects on lipid levels is slight, although patients receiving nevirapine in the 2NN study (a randomised comparison of nevirapine or efavirenz) had significantly greater increases in HDL cholesterol, significantly larger decrease in the total cholesterol: HDL cholesterol ratio and significantly greater triglyceride reduction after commencing therapy (van Leth 2003).

High triglyceride levels and low HDL cholesterol levels have been associated with genetic variations. Specifically, polymorphisms in the Apo C-III gene, which governs the production of very low density lipoprotein (VLDL) cholesterol (the carriers of triglycerides) are associated with higher triglyceride and lower HDL levels in men receiving protease inhibitors (Fauvel). These polymorphisms are associated with higher average triglyceride and plasma lipoprotein levels in most studies in the general population, and commencing PI therapy results in a more pronounced increase in triglyceride levels in people with some of the polymorphisms. In HIV-positive men, elevated ApoC-III and triglyceride levels were associated with PI or NNRTI treatment by one group (Guest 2003), whilst another group found that women with lipid abnormalities had higher levels of ApoC-III production, which would interfere with normal hydrolysis of triglycerides. A third group has shown that PI or NNRTI treatment reduces APoB - VLDL cholesterol clearance, leading to increased triglyceride levels.

High levels of a metabolic amino acid called homocysteine are also a risk factor for cardiovascular disease. Several studies have reported high homocysteine levels among some people on HAART (Bernasconi; Meyers). Folate supplements readily reverse elevations in homocysteine.

See Measuring fats and sugar abnormalities in Anti-HIV therapy: Body fat and metabolic changes whilst on treatment for more information on these lipids and how they can be monitored.

Diabetes, hyperglycaemia and insulin resistance

Diabetes mellitus is a condition caused by the inability to use sugar in the blood properly. A high level of blood sugar, called hyperglycaemia, is a sign of diabetes. Diabetes is defined as a fasting glucose level over 7 millimols per litre.

Diabetes is treated with injections of insulin or oral hypoglycaemic drugs. Dietary change, such as reducing sugar intake, may be advised. People with diabetes are at increased risk of heart disease, kidney disease, blindness, and nerve damage.

Insulin is a hormone used to regulate sugar levels in the blood. Insulin resistance means the body is not able to use insulin properly to regulate sugar. Insulin resistance is one of the causes of diabetes, along with a lack of insulin.

High levels of insulin resistance have been noted in individuals with fat accumulation and with lipoatrophy (fat wasting), and these are closely correlated with high levels of soluble tumour necrosis factor receptors. Tumour necrosis factor is implicated in the development of diabetes, and high levels of TNF receptors are an indication that an inflammatory condition is present. However, the vast majority of people who develop lipoatrophy and insulin resistance have well controlled HIV levels, so HIV may not be driving this inflammatory reaction (Mynarcik). At present the cause is unknown.

Protease inhibitors and diabetes

Diabetes is considered a relatively rare side-effect of protease inhibitors. It was first associated with the use of protease inhibitors (PIs) in June 1997.

The proportion of people taking protease inhibitors who develop diabetes after a year of treatment seems to be under 4%. One study reported 1.4% developed high blood glucose at one year. Another study reported a 4% rate of diabetes and an 8% rate of glucose intolerance (Petit 2001). The French APROCO cohort found that 10% of patients developed diabetes over three years of PI therapy, with incidence steady over time (Saves 2002).

A review of the WIHS cohort in the US found that women receiving PI-containing HAART had an elevated risk of diabetes (2.8 cases per 100 patient years of treatment, compared to 1.4 per 100 patient years in the HIV-negative group, 1.2 per 100 patient years in the NRTI arm and 1.2 per 100 patient years in HIV-positive women who received no HIV therapy). The study reviewed 1785 women recruited between 1994 and 1998, who were asked to report if they had developed diabetes at each 6 monthly hospital visit (Justman 2003).

However, recent research points to other factors which may increase the risk of hyperglycaemia and diabetes in the context of HIV. In addition to PIs, factors such as combination antiretroviral therapy (HAART), co-infection with hepatitis C, baseline obesity or elevated blood sugar, and even HIV itself have all been identified as risk factors for the development of hyperglycaemia and diabetes.

Data from the Multicenter AIDS Cohort Study (MACS) shows that PIs, d4T and efavirenz are all associated with the development of diabetes and hyperglycaemia in HIV-infected people on treatment. Baseline measures showed that HIV-positive men who were not taking HAART were twice as likely to have diabetes as HIV-negative men, while the rate in the HIV-positive men on HAART was five times higher than the rate among HIV-negative men (Brown 2004; 2005).

When looking at new cases that developed between 1999 and 2003, nearly 20% of the HIV-positive men on HAART developed hyperglycaemia and 11% developed diabetes. The rate of new cases of diabetes in HIV-positive men not on HAART was 1.7 per 100 patient-years, just above the 1.4 per 100 patient-years seen in the HIV-negative group, and well below the 4.7 per 100 patient-years among the men on treatment. Interestingly the rate of new hyperglycaemia was higher in the HIV-negative group than in the HIV-positive group not on therapy (5.7 versus 3.8 per 100 patient-years) (Brown 2004; 2005).

This finding is at odds with an analysis of Medi-Cal insurance claims which found that individuals with HIV were significantly more likely to have diabetes than HIV-negative people, especially in the 18-24 age group (Currier 2002). However, a case control study in 49 cases and 98 controls suggests that traditional risk factors for diabetes account for much of the risk in HIV-positive patients (Yoon 2004). A study in women also found that body mass index (BMI), not HIV status or treatment history, was most likely to predict the presence of diabetes (Danoff 2005). On balance, current research suggests that the role of HIV as a risk factor for diabetes remains unproven.

Other studies also point to traditional diabetes risk factors producing hyperglycaemia and diabetes in HIV-infected people. For instance, a Spanish case control study has reported that obesity prior to starting HAART is an independent risk factor for the development of diabetes (Rosario 2003). A family history of diabetes and untreated high blood sugar levels prior to commencing therapy are also thought to increase the risk of diabetes.

Hepatitis C has also been identified as a risk factor for diabetes in several studies (Butt 2003; Petit 2001). An analysis of 1200 patients carried out by researchers at the Johns Hopkins University found that HCV-HIV coinfected patients had a five-fold higher risk of developing hyperglycaemia than HIV-monoinfected persons. The investigators noted that only one case of hyperglycaemia occurred in a patient who was neither hepatitis C-infected nor taking a protease inhibitor (Mehta 2003). Injecting drug use itself may also be a risk factor for diabetes, although the research to date is inconclusive.

Glucose and insulin levels should be measured prior to choosing a first treatment regimen to detect individuals at risk.

See Diabetes in the A to Z of illnesses for further details of this condition.

Impaired blood clotting in haemophiliacs

Since 1997 it has been noted that haemophiliacs receiving Factor VIII for clotting disorders have been experiencing unusual rates of bleeding whilst receiving protease inhibitor treatment. It has been suggested that protease inhibitors could interfere with blood clotting by inhibiting a human enzyme, the serine protease, necessary for proper blood clotting. However, a study has shown that PIs can only be associated with a slow down in clotting times at very high concentrations, far above those commonly seen in clinical studies (Ermolieff 1998).

Haemophiliacs may experience specific protease-related side-effects although it is not known if they are related to the metabolic changes discussed in this article. A study by Dr Stanworth and colleagues published in the journal Haemophilia earlier this year reported that 10 of 17 haemophiliacs on protease inhibitors experienced more bleeding and changes in bleeding patterns, in comparison to bleeding in the six months prior to protease therapy. Unusual bleeding sites were the knuckles, eyes and nose.

Interestingly, one recent study suggested that protease inhibitors may have the reverse effect on blood clotting, slowing the clearance of clots and increasing coagulability (Koppel 2002). Further research is needed to confirm these findings.

Sexual problems and other possible symptoms

Apart from body fat changes, there are few other physical signs or symptoms of high lipids and insulin resistance. NRTI-related wasting has been linked to fatigue and nausea. Possible signs of high blood sugar include increased thirst, blurred vision and frequent urination. There has been a case report of yellow-orange skin papules or spots called xanthomata (usually associated with high cholesterol) in a man who developed very high lipid levels after he began treatment with ritonavir/indinavir (Lister 1999).

There is a growing body of medical literature about a possible link between sexual dysfunction and HAART, particularly the PIs. A small number of people on HAART have experienced reduced sex drive and sexual dysfunction which may be linked to metabolic disorders (Martinez 1999b).

One study of nearly 200 HIV-infected men found that 24% of the men taking HAART reported sexual problems compared with only 4% of those who were not on HAART; the prevalence of sexual dysfunction was six times higher in the treated men, with PI therapy most associated with sexual problems. However, there was no difference in testosterone levels between treated and untreated men, and testosterone was seen to increase in men who started HAART (Collazos 2002).

Another study of approximately 900 HIV-infected men and women who were taking antiretroviral therapy has also linked PIs to sexual dysfunction (Schrooten 2001). In addition, this study found that symptomatic disease, use of tranquillisers, age, and contracting HIV through gay sex were also associated with reduced sexual potency and/or interest. A retrospective study of men who had been taking long-term antiretroviral therapy has also reported a link between PIs and sexual dysfunction. In particular, ritonavir was associated with the greatest risk of sexual dysfunction (Colson 2002). However, another study found no link between PIs and sexual dysfunction based on self-reports of over 150 HIV-infected men. Despite the fact that a majority of the men (65-74%) reported sexual dysfunction since starting HAART, there was no difference based on current or previous PI exposure (Lallemand 2002).

How anti-HIV drugs may cause or contribute to sexual dysfunction has not been established. Spanish researchers have suggested that an interaction between liver enzymes and protease inhibitors may cause an increase in oestrogen, and lead to sexual problems in some people on anti-HIV treatment (Patroni 2000). An English group have proposed that lipoatrophy may increase the activity of an enzyme called aromatase which breaks down male sex hormones into female ones (Goldmeier 2002).

See also Sexual problems in Symptoms and illnesses: A to Z of symptoms for details of management of these problems.

Other health implications

Acute necrotising pancreatitis is a life-threatening complication of extremely high triglyceride levels. This condition has a sudden onset, and causes severe abdominal pain, shock and collapse. It can be fatal even if treated early. Anecdotal reports from doctors suggest that cases of fatal protease-related pancreatitis have occurred in the United Kingdom.

One theory has linked fat and metabolic abnormalities to damage to the mitochondria caused by NRTIs (see Possible causes of body fat and metabolic changes in Anti-HIV therapy: Body fat and metabolic changes whilst on treatment for more details). Side-effects linked to mitochondrial damage include pancreatitis, nerve and muscle disorders, bone-marrow and liver toxicities and birth defects among infants exposed to NRTIs in the womb. Another rare but serious side-effect of NRTIs, linked to mitochondrial damage, is high lactic acid which may lead to a condition called lactic acidosis. This condition is associated with organ failure, liver damage and sepsis and often results in death. See Lactic acidosis / acidaemia in Symptoms and illnesses: A to Z of illnesses for more details.

Elevated lipid levels are also associated with increased risk of hardening and narrowing of the arteries and heart disease. See Heart disease and HAART in Anti-HIV therapy: Body fat and metabolic changes whilst on treatment for more details.

Bone disorders have been reported among people with HIV since the introduction of HAART. These disorders include weak or thinning bones (osteoporosis) , due to reduced bone density. Although the cause of these bone disorders is not yet known, people with HIV who have taken testosterone or other steroids, as well as lipid-lowering agents, may be at increased risk of bone pain (osteonecrosis). There is some evidence of an association between HAART and bone disorders but other research has found HIV, but not HAART, to be linked to bone disorders. See Osteoporosis in Symptoms and illnesses: A to Z of illnesses for further details.

Key research into lipid abnormalities

Van der Valk (2001c) studied lipid levels in 114 people taking nevirapine, or indinavir, or 3TC plus d4T/ddI. All were enrolled in the ATLANTIC study. Nevirapine produced a rise in HDL or 'good' cholesterol of 49% after 6 months of treatment, and a rise in several other lipid parametres, while HDL levels stabilised in people on 3TC or indinavir. LDL or 'bad' cholesterol rose significantly in the nevirapine and indinavir arms but this was offset by the increase in HDL cholesterol in the nevirapine arm.

Koppel (2002) reported decreased fibrinolysis and increased clotting among 266 people taking protease inhibitor therapy, correlating with triglyceride levels, insulin levels and body mass index.

Fauvel (2001) reported a significant association between apo C-III genotype and elevated triglycerides, low HDL cholesterol and protease inhibitor therapy in 60 consecutive male French patients. Plasma triglycerides increased with the number of variant alleles (-455 C/T, -482 C/T, and Sstl), and protease inhibitor treatment was found to have a synergistic effect when pre- and post-PI triglyceride levels were compared. This was most marked in individuals with the -455C polymorphism.

Bentata-Pessayre (2000) studied 128 individuals beginning nevirapine as first-line therapy, or those adding nevirapine to NRTIs, or those switching from a PI-containing regimen. 102 completed 6-12 months and 60 completed 18 months follow-up. Overall, there were no significant rises in fasting glucose or pp glucose, fasting C peptide or pp C peptide, or cholesterol. The rise in triglycerides was significant at 6-12 months but not at 0-18 months. Among the 50 pre-treated with NRTIs, cholesterol rose from 4.7 to 5.2 mmol/L and trigs rose from 1.3 to 1.8 (p=0.02 and p=0.03). Among those pre-treated with PIs, only triglycerides rose significantly from 2 to 2.3 mmol/L (p=0.03). Abnormal glucose was linked to viral load below 1000, fat abnormalities were linked to greater than 6 months PI therapy, triglyceride abnormalities were linked to greater than 6 months d4T therapy and cholesterol abnormalities were linked to alcohol consumption.

Roca (2002) reported mild increases in serum glucose, cholesterol and liver enzymes among people taking efavirenz-based HAART over 15 months but increases were not considered important.

Periard (1999) investigated lipid levels among 93 HIV-infected people taking PI-containing therapy and 28 non-PI-treated people from the Swiss HIV Cohort Study. Cholesterol rises from baseline were as follows: ritonavir (+2.0mmol/L, n=46), indinavir (+0.8 mmol/L, n=26) or nelfinavir (+1.2mmol/L, n=21). The increase was significant for ritonavir and nelfinavir. All 3 PIs were taken alone or with saquinavir, but the addition of saquinavir did not increase lipid levels. Only ritonavir was associated with significant increases in triglycerides.

Negredo (2002b) reported on a cross-sectional study of 454 people on HAART including a PI (108 women). Median CD4 count was 463 and 66% had viral loads below 200. 230 took indinavir, 109 ritonavir, 80 saquinavir, 31 nelfinavir, 4 ritonavir/saquinavir. Risk of high cholesterol at 12, 24 and 36 months was estimated to be 26%, 51% and 83% while the cumulative risk of high triglycerides was 31%, 60% and 78% respectively. Ritonavir was associated with faster onset of high triglycerides.

Matthews (2000) published a cross-sectional analysis of lipid elevations in 135 people taking efavirenz or nevirapine plus 2 NRTIs including d4T or AZT. Average duration of antiretroviral therapy was 132 days (range 67-275). Multivariate analysis showed that older age and triglyceride levels were independent predictors of raised cholesterol. Only elevated cholesterol was associated with elevated triglycerides. Specific drugs were not associated with high lipids.

Torti retrospectively studied lipid levels in 205 people who had been taking antiretroviral therapy for an average of 21.4 months. Median cholesterol had risen from 159mg/dL at baseline to 181.2mg/dL at follow-up. Median triglycerides had risen from 127mg/dL to 137mg/dL at follow-up. Multivariate analysis found viral load reduction and trig levels were associated with cholesterol increase. Infection with HCV was negatively associated with elevated cholesterol among people taking antiretrovirals. Elevated triglycerides were associated with male gender, age, protease inhibitor therapy and cholesterol increase by multivariate analysis. Age was not significantly associated with lipid elevations.

Moyle also reported (1999e) that saquinavir may produce a low rate of metabolic abnormalities compared with other PIs. 38 people (1 woman) were evaluated in this cross-sectional study. After 7 months treatment with saquinavir, mean triglycerides were elevated in 37% of patients but only 3 people (8%) had results deemed high (above 4.5 mmol/L).

Carr (1999c) updated data published in AIDS. Of the original 116 people, 14 had ceased protease therapy (two due to lipodystrophy), three were lost to follow-up and two had developed a new AIDS defining illness. The updated results looked at 31 people. After 18 months on the study, only 18% people reported no lipodystrophy. 63% lost more than 5% of their body mass, 66% had triglycerides over 2mm/dL, and 77% had cholesterol over 5mm/dL.

Carr (2000) reported that NRTI lipodystrophy was associated with abnormal liver function and high lactate levels. In comparison to PI lipodystrophy, it was associated with lower albumin, cholesterol, triglycerides, glucose and insulin.

Mulligan (2001) studied metabolic parametres in 20 HIV-infected people starting treatment with a protease inhibitor (PI)-based therapy, 9 commencing treatment with a 3TC-based regimen but no PI, and 12 on stable treatment with neither a PI nor 3TC. In the PI group, blood glucose levels, insulin, triglycerides, and total and LDL cholesterol all rose significantly. No significant changes occurred in the 3TC or stable therapy groups.

Pernerstorfer (2001) reported on differences in metabolic abnormalities in a prospective cohort of 27 HIV-infected men and 13 HIV-infected women with viral loads above 10,000 copies/ml on HAART. Pre-treatment fasting serum triglycerides, levels of insulin, leptin and low density lipoprotein (LDL) were similar in patients and controls at baseline. Serum high density lipoprotein (HDL) was lower in HIV-positive patients compare with matched controls and the LDL:HDL ratio was consequently higher. As expected, HDL was also lower and LDL:HDL ratio higher in men at baseline. Triglycerides, leptin LDL and HDL rose significantly in both sexes (p<0.05) but insulin and LDL:HDL ratio only increased significantly in women (p<0.02). In addition, triglycerides and leptin levels rose more steeply in women and baseline differences between men and women in terms of LDL levels and LDL:HDL ratio disappeared. While men and women gained fat mass, only women had a moderate correlation between the gain in serum leptin levels and in fat mass during HAART (p<0.03). This indicates that the preferential increase in leptin levels in women was not solely a function of increased fat mass. For both men and women, insulin increased during therapy but did not correlate fat mass increases. Serum cE-selectin is an endothelial activation marker which can indicate HIV-associated vascular inflammation and/or atherosclerosis and the development of cardiovascular disease. Baseline cE-selectin were significantly higher among HIV-infected individuals versus controls and HIV-infected men versus women. After six months of HAART, cE-selectin levels had fallen significantly among the men and there was no longer any significant difference between the sexes. The authors highlight that elevated insulin and triglycerides may increase the risk of heart disease, particularly in women, and leptin may promote atherogenesis.

Wit (1999) reported data from 190 people on ritonavir/saquinavir with or without d4T. There was no difference in lipid increases between the 2 groups. Average triglyceride increase in the dual PI group was 2.09 mmol/L and 2.28 mmol/L in the d4T group.

Saves (2002) reported on lipodystrophy and metabolic abnormalities among 614 people involved in the APROCO Study. At 12-20 months follow-up, 21% had some fat wasting in the limbs and/or face, 17% had isolated fat accumulation, 24% had mixed body fat syndrome, 23% had changes in glucose metabolism, 28% had triglycerides above 2.2 mM and 57% had cholesterol above 5.5mM. Age influence body fat and metabolic disorders. d4T was associated with fat wasting and ritonavir was associated with high triglycerides.

Lichtenstein (2001) reported a large review of metabolic and body fat abnormalities (HOPS). 548 people had no body fat changes, (group A); 325 people had 1-2 mild-moderate fat changes (B); 138 had 3-4 mild to moderate signs(C); and 6% had 5-6 signs including severe fat changes (D). Impaired glucose metabolism was seen in 5% group A, 6% group B, 9% group C and 17 group D. The study found that blood lipid levels increased relative to clinical symptoms.

Thiebaut (2000) analysed over 11,000 triglycerides measurements taken between 1996-1998 from 1825 individuals. 54% of observations were taken during PI treatment, 39% taken during non-PI treatment and 7% taken in the absence of treatment. Multivariate analysis revealed that older age, male gender, AIDS stage and PI usage were associated with increased triglycerides levels over time. This study found that nucleoside analogues were not associated with high triglycerides.

Roge (2001) randomised 114 PI naﶥ HIV infected individuals into a study of either indinavir or ritonavir or ritonavir/saquinavir plus 2 NRTIs. Non-fasting plasma triglyceride levels were followed over 96 weeks. Median triglycerides increased from 1.8 mmol/L in the ritonavir groups to 2.3 mmol/L at week 36. Triglycerides were not raised in the indinavir group. There was no baseline difference in triglycerides between the groups due to prior nucleoside use. CD4 above 200 at baseline was associated with lower triglycerides, although this difference disappeared following treatment.

Behrens (1999) conducted a prospective, cross-sectional study of 38 people treated with at least one protease inhibitor and 17 PI-naive people. A total of 27 (71%) people on PIs had evidence of hyperlipidaemia with 6 having elevated lipids (above 30mg/dL): 21 had high triglycerides; 10 had increased low-density and very low-density lipoproteins; and five had high cholesterol. PIs were significantly associated with higher fasting lipids. 18 of the PI group had impaired glucose tolerance and five had diabetes. Fasting concentrations of insulin, proinsulin and C-peptide were significantly increased in the PI group. Authors suggested beta-cell dysfunction in addition to peripheral insulin resistance.

Youle (1999) reported on 63 people treated with a salvage regimen which included ritonavir (100, 200 or 400mg twice daily) and indinavir (600 or 800mg twice daily). Baseline median cholesterol of 32 participants was 5.1 mmol/L (2 with significant elevations) and baseline triglycerides was 2.1 mmol/L with significantly high levels in 15 people. At 32 weeks follow-up, 30 exhibited a median 53% rise in cholesterol and a 88% rise in triglycerides. The rise in lipids was related to ritonavir dosing, but not to indinavir dosing. Higher doses of ritonavir were associated with higher lipid levels.

Lister (1999) reported a case of a man who developed dysbetalipoproteinaemia after starting treatment with ritonavir/indinavir. His symptoms included yellow-orange papules on the backs of his hands, diagnosed as eruptive xanthomata. His cholesterol had increased from 3.3 to 29.3 mmol/L and his triglycerides increased from 2.2 to 27.5 mmol/L. The skin condition resolved and his lipids normalised after stopping treatment with ritonavir.

Garcia (1999) analysed fat and metabolic measures in 221 people (CD4 counts over 500) treated with dual or triple combination for a year (Spanish EARTH studies). Mean fasting cholesterol, triglycerides and glucose levels did not increase among people on dual NRTI therapy or d4T/3TC/indinavir. Cholesterol and triglycerides did increase among people on d4T/3TC/ritonavir. High triglycerides among this group rose from 8 to 21 (of 33) after a year on therapy.

Nauss-Karol (1998) reported on lipid changes in people taking soft-gel saquinavir. Little or no elevation of triglyceride or cholesterol levels was seen in those receiving SGC saquinavir alone, whereas those receiving SGC SQV plus ritonavir experienced triglyceride elevations of 112-143% above normal.

Piliero (2002) reported lipid increases among 201 people enrolled in AI424-007 and 269 enrolled in AI424-008 who were randomised to atazanavir or nelfinavir. At week 48, the mean change in total cholesterol, fasting LDL cholesterol and fasting trigylcerides were between -7-+7% for atazanavir recipients and +23-+50 in the nelfinavir recipients. All differences were statistically significant.

Pedneault (2000) reviewed data from 348 adults and 268 children who were enrolled in 4 clinical trials of amprenavir. High triglycerides and high glucose were reported among 5% and 1% of participants on amprenavir, 4% and 3% indinavir (lower than reported in other studies), 1% and 1% placebo, and 29% and 8% dual PI. High cholesterol was 1% in all groups.

Dube (2002) studied metabolic parametres in 14 HIV-infected people commencing treatment with amprenavir-based triple therapy. A trend towards reduced insulin sensitivity occurred between weeks 24 and 48. Six people experienced worsening glucose tolerance by week 24. Fasting triglycerides, LDL cholesterol, HDL cholesterol and total cholesterol increased. Limb tissue, total body fat, trunk fat, limb fat and the ratio of trunk to limb fat increased over 48 weeks.

Lenhard (2000) reported in vitro and animal research findings that protease inhibitors affect distinct metabolic pathways. Amprenavir had little effect on fat cell production, but all the other PIs did. Indinavir only disrupted fat cell production in the presence of retinoic acid, but also seemed to alter retinoic acid signalling. Nelfinavir, saquinavir and ritonavir all inhibited fat cell production and fat cell breakdown (lipogenesis and lipolysis).

Para (1999) reported that delavirdine was not associated with lipid increases, hyperglycaemia nor lipodystrophy.

Jain (2002) reported a test-tube study which showed that lopinavir and nelfinavir decreased levels of gene expression and activity of a bone cell enzyme. Creation of fat was inhibited significantly by saquinavir and nelfinavir and moderately by lopinavir and ritonavir. Amprenavir and indinavir did not interfere with breakdown of blood fats or creation of fats.

Boubaker (2001) studied lactate levels among 880 people in the Swiss HIV Cohort Study. 8.3% had lactate above the upper limit of normal and 1% had moderate or severe elevations. High lactate was associated with fat wasting, high lipids and high blood glucose.

Gazzard (1999) conducted a retrospective analysis of 1878 patients who received delavirdine in five studies for a mean 32.6 to 44.7 weeks in combination with AZT, ddC, ddI or 3TC. Two studies were conducted in treatment-naive individuals. No significant elevations of triglycerides or glucose were seen in DLV recipients compared to those who received NRTIs alone. Elevated total cholesterol was reported with greater frequency in DLV recipients who participated in three studies of treatment-experienced patients compared to NRTI recipients, but this was not observed in treatment naive recipients. Body fat changes were not reported with greater frequency in DLV recipients in any study.

Henry (1998a) presented reviewed 135 people on PIs at his clinic and found 64 (48%) had high lipid levels (versus 7 of 120 people on non-PI regimens). Henry found many people met American criteria for intervention to reduce cholesterol levels: 35 of 53 (66%) ritonavir/saquinavir: 20 of 62 (32%) indinavir and 7 of 18 (39%) nelfinavir recipients.

Insulin resistance and diabetes

Brown (2004) reported that HIV-infected men using antiretroviral therapy have higher rates of hyperglycaemia (high blood glucose) and diabetes compared with HIV-negative men. The risk of existing and new-onset fasting hyperglycaemia was 23 times greater, and the risk of existing and new-onset diabetes was 45 times greater in HIV-positive men on HAART compared with HIV-negative men. The study looked at 1278 men (710 HIV-negative, 130 HIV-positive not taking HAART, and 438 HIV-positive on HAART) enrolled in the Multicenter AIDS Cohort Study (MACS) over the period of 1999-2003. Diabetes was defined as a fasting serum glucose >125 mg/dl and hyperglycaemia was >110 mg/dl. Among all 765 men with no sign of diabetes or high glucose at baseline, 104 new cases of hyperglycaemia occurred. The hyperglycaemia incidence rate (ie. new cases) among the HIV-negative men was 5.7 cases per 100 person-years (PY), 3.8/100 PY among the HIV-positive men not on HAART and 9.1/100 PY among HIV-positive men on HAART. After adjusting for age and BMI, the HIV-positive men on HAART were more than twice as likely to develop hyperglycaemia compared with HIV-negative men (rate ratio=2.16). Incidence of diabetes was four times higher among the HIV-positive/HAART group compared to the HIV-negative group (1.5/100 PY HIV-, 1.8/100 PY HIV+/HAART-, and 4.9/100 PY for HIV+/HAART+). Men using regimens containing any protease inhibitor, d4T, or efavirenz were all at increased risk for incident hyperglycaemia compared with the HIV-negative men (rate ratios=2.38, 2.77, and 3.16, respectively). But no specific drug was associated with a significantly increased risk compared with HAART in general. Risk of diabetes and hyperglycaemia was higher in men who had experienced lower CD4 counts.

Estrada (2002b) studied 34 HIV-infected men with lipodystrophy, as well as age-matched HIV-infected antiretroviral-naive controls and age-matched HIV-negative controls with normal body mass index. The 34 patients had received a protease inhibitor treatment for an average of 21.8 months and had taken AZT for an average of 28.5 months. Metabolic tests conducted on the men while fasting showed that those with lipodystrophy had higher insulin resistance, oral glucose tolerance, total cholesterol and LDL cholesterol and triglycerides levels than controls. Mean leptin levels were significantly lower in the men with lipodystrophy (2.85ng/dL vs 6.16 in the HIV-positive group and 4.57 in the HIV-negative group).

Noor (2002) reported that a single dose of indinavir in HIV-negative controls induced insulin resistance.

Tsiodras (2000) retrospectively analysed a cohort of 221 HIV-infected people observed between October 1993-October 1998. The cumulative incidence of new-onset hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and lipodystrophy was 5%, 24%, 19%, and 13%, respectively. All abnormalities were associated with protease inhibitor therapy, while anabolic steroids and psychotropic medications were associated with lipodystrophy only. The strongest association was between ritonavir and high triglycerides. The incidence of hyperglycemia, hypercholesterolemia, and lipodystrophy did not vary significantly across different PIs.

Petit (2000) tested 106 HIV-infected men before treatment and after 12 months on PI containing therapy using a range of weight and metabolic measures. Triglycerides and cholesterol rose significantly while fasting blood sugar insulinemia and insulin sensitivity were not significantly modified after PI therapy. 8.5% had glucose intolerance and 3.7% had diabetes after 12 months treatment. High lipids, weight gain and increased waist circumference were associated with suppression of HIV.

Duong (2001) studied insulin resistance among 29 HIV-HCV patients, 76 HIV patients, and 121 HCV controls. Lipoatrophy occurred more frequently in HIV-HCV patients in comparison with HIV patients (41% vs 14%, p =0.003). total cholesterol and triglyceride levels were significantly lower inco-infected people than in those with HIV alone. Insulin resistance was significantly associated with HCV coinfection.

Goebel (1999) reported that antiretroviral therapy is associated with insulin resistance among HIV-infected people. Rates of insulin resistance is 25% among people taking nucleosides; 50% among people on nucleosides plus a non-nucleoside (50%) and 55% among people taking nucleosides plus a protease inhibitor. The protease inhibitor most likely to cause insulin resistance is indinavir, followed by ritonavir, saquinavir, and nelfinavir.

Walli (1998) found evidence that HIV-positive people who receive protease inhibitors (PIs) are at significant risk of developing peripheral insulin resistance, and that this can lead to oral glucose intolerance or hyperlipidemia. 67 HIV-infected people were treated with PIs, 13 therapy-naive patients and 18 HIV-negative controls were tested for insulin sensitivity. Decreased insulin sensitivity occurred among those taking PIs compared with therapy-naive patients. Four people on PIs had impaired glucose tolerance and 9 were diabetic. 4/11 with normal glucose tolerance had peripheral insulin resistance; all therapy-naive patients had normal insulin sensitivity. All 67 people treated with protease inhibitors (either indinavir, saquinavir or nelfinavir) also experienced increases in total triglycerides and cholesterol.

Thiebaut (2000) compared insulin and lipids in 220 people with lipodystrophy and 361 people without lipodystrophy. In the lipodystrophy versus non-lipodystrophy groups, metabolic abnormalities occurred as follows: high insulin 17% versus 6%; high triglycerides 43% versus 13%; insulin resistance 34% versus 25%. There was no significant difference in cholesterol between the two groups. Prevalence of diabetes was 3% in both groups. Prevalence of insulin resistance or high lipids were higher in the group with fat accumulation compared with the group with fat wasting.

Dube (2001) conducted a prospective study of glucose tolerance in 10 people following the commencement of indinavir treatment. Mean fasting glucose increased from 85.3 mg/dl to 93.3 at week 8. Insulin sensitivity fell by 30% in 8 weeks.

Rodo reported that 15% of 298 people on PIs developed hyperglycaemia but only two people developed diabetes. Caldwell found 11.5% of 216 PI treated developed hyperglycaemia. A study of people on protease inhibitors for less than two months found no evidence of high sugar levels.

Munsiff reviewed medical records of 19 people who developed hyperglycaemia after commencing a PI-containing regimen. 9/19 had evidence of untreated hyperglycaemia before commencing HAART. The average time to onset was 4.7 months.

Justman reported on 1435 HIV-positive women and 350 HIV-negative women with similar HIV risk factors as controls participating in the Women's Interagency HIV Study. Diabetes incidence of diabetes was 1.5 cases per 100 patient years of follow-up. Women treated with protease inhibitors had a three-fold increased risk of developing diabetes, with 2.8 cases per 100 patient years, compared to 1.4 per 100 patient years in the HIV-negative group, 1.2 per 100 patient years in the NRTI arm and 1.2 per 100 patient years in HIV-positive women who received no HIV therapy. Obese and morbidly obese women were also found to have an increased risk of developing diabetes, but when these data were adjusted for anti-HIV drug use, women who used protease inhibitors were still found to be at increased risk compared to those treated with non-protease regimens. No single pI was found to be associated with the onset of diabetes, and there was no difference in the development of diabetes according to virologic suppression.

For references, see References - body fat and metabolic changes in Anti-HIV therapy: Body fat and metabolic changes whilst on treatment.

Research into sexual dysfunction and metabolic changes

Collazos (2002) prospectively studied 189 HIV-infected men for signs of sexual dysfunction. 351 evaluations were conducted from Sept. 1998 to Jan. 2001. 84% of evaluations were conducted while the subjects were on antiretroviral therapy. Only 4% of participants had low testosterone. Average testosterone and 17beta-estradiol levels were higher in men taking antiretroviral therapy. Despite this, prevalence of sexual dysfunction was 6 times higher among men on treatment. Compared with men not on treatment, those on PIs/NRTIs had an odds ratio (OR) of 9.5, while those on NNRTIs/NRTIs had an OR of 6.5, and those on all three drug classes had an OR of 8.9.

Schrooten (2002) reported the results of a survey of 904 HIV-infected individuals conducted in Europe 1998-1999. 40% of those taking PIs (308/766) reported reduced sexual interest, compared with 16% of the PI-naive patients (22/138). Sexual potency was also decreased in the PI recipients (34% versus 12%). Multivariate analysis found that a current PI-containing regimen, a history of PI treatment, symptomatic HIV infection, age, and HIV transmission via gay sex were associated with reduced sexual interest. Factors associated with decreased sexual potency were current use of a PI-containing regimen, symptomatic HIV disease, age and the use of tranquillisers.

References

See References - Body fat and metabolic changes.