Shortly after the introduction of HAART, reports of impaired fasting glucose, glucose intolerance, diabetes, and hyperlipidemia appeared in the HIV literature. Given the close temporal relationship to the introduction of PIs, studies focused on the association with PIs. However, other factors such as restoration of health, genetic predisposition, immune reconstitution, and body composition changes (including lipoatrophy and VAT hypertrophy) may also contribute to the disturbances in metabolism. To clarify these issues, several groups have given HIV antiretroviral drugs to healthy, HIV-seronegative volunteers in order to define direct drug effects. Another approach has been “switch studies,” where patients with suppressed viral load are randomized to change anti-retroviral drugs, eliminating the effects of suppression of HIV. In the sections below, the results in HIV-infected subjects will be compared to those in healthy volunteers to understand the effects of drug versus disease. These studies have led to the conclusion that metabolic effects are specific to certain drugs and not an effect of the PI class as a whole.
Insulin Resistance, Glucose Intolerance, and Diabetes
With the reports of rapid onset of diabetes after introduction of HAART with a PI, researchers looked for effects of PI on insulin resistance, hepatic glucose production, and insulin secretion.
Several factors contribute to the development of insulin resistance in the setting of HIV. Unlike other infectious states, in which insulin resistance is common, early in the epidemic, AIDS was found to be associated with an increase in insulin sensitivity (Table 25–4). Compared with healthy controls, insulin sensitivity was higher in stable patients with symptomatic HIV. However, with asymptomatic HIV infection, another early study found that there was no change in insulin sensitivity compared with healthy controls. Insulin resistance is common in healthy subjects. Thus, improvement of HIV infection alone may contribute to an observed decrease in insulin sensitivity. Subsequent studies found insulin resistance in ARV-naïve, HIV-infected subjects. Insulin resistance correlates with CD4 count.
TABLE 25–4Effect of HIV and AIDS status on glucose and lipid metabolism prior to the introduction of HAART. |Favorite Table|Download (.pdf) TABLE 25–4 Effect of HIV and AIDS status on glucose and lipid metabolism prior to the introduction of HAART.
| ||Insulin Resistance ||Total Cholesterol ||Triglyceride ||VLDL ||LDL ||HDL |
|HIV ||↔ ||↓ ||↑ (8%) ||↑ (7%) ||↓ (16%) ||↓↓↓ (36%) |
|AIDS ||↓ ||↓ ||↑↑↑↑ (99%) ||↑↑↑↑ (98%) ||↓↓↓ (31%) ||↓↓↓ (37%) |
Body composition influences insulin sensitivity. Patients studied early in the epidemic, were thin, if not cachectic. In recent studies body weight was higher, even in many ARV-naïve patients. Increased VAT has been linked to insulin resistance and worsened glucose tolerance in subjects with or without HIV disease. Upper trunk and neck SAT are also independently, strongly associated with insulin resistance. Likewise, severe lipoatrophy has been linked to insulin resistance and glucose intolerance regardless of HIV status. The lesser levels of lipoatrophy seen in most HIV-infected patients also contribute. Other traditional risk factors, such as physical inactivity, also play a role in HIV-infected subjects. It should be recognized that each of these factors may contribute in an additive way to insulin resistance.
Much attention has focused on the role of individual therapies in the induction of insulin resistance. Some PIs have been reported to decrease insulin-mediated glucose disposal (M/I during the hyperinsulinemic, euglycemic clamp, a technique during which insulin is infused at a steady rate and glucose infused to maintain euglycemia, which directly measures insulin action). In a double-blind, placebo-controlled study in healthy normal volunteers, a single dose of indinavir has been shown to decrease insulin-mediated glucose disposal by 34% (Table 25–5). Indinavir for 4 weeks has also been shown to cause a 17% decrease in insulin-mediated glucose disposal as well as deterioration in glucose tolerance. A single, full dose of ritonavir decreased insulin sensitivity by 15%. Lopinavir boosted by lower dose ritonavir likely has less of an effect on insulin sensitivity (see Table 25–5). In two studies, lopinavir/ritonavir given for 4 weeks caused no change in insulin sensitivity, whereas in shorter studies, lopinavir/ritonavir given for 1 to 5 days was associated with a 13% to 24% decrease in insulin sensitivity.
Of note, not all PIs decrease insulin-mediated glucose disposal. In double-blind, placebo-controlled studies, atazanavir and amprenavir had no effect on insulin sensitivity in healthy normal volunteers (see Table 25–5). NNRTIs have not been associated with insulin resistance. In studies where PIs are replaced with NNRTIs, insulin resistance improved.
TABLE 25–5Effect of protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and integrase inhibitors on glucose and lipid metabolism.1 |Favorite Table|Download (.pdf) TABLE 25–5 Effect of protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and integrase inhibitors on glucose and lipid metabolism.1
|Class/Drug ||Fasting Glucose ||Insulin2 Resistance || ||TG ||LDL ||HDL |
|Protease Inhibitors || || || || || || |
|Indinavir || |
| || |
|Ritonavir ||↔ || |
| || |
| || |
|↔ ||NA || || |
|NA ||NA |
| ||↑ ||↔↑ || |
|NA ||↔/↑ || ||↑ ||↔↑ ||NA |
|Amprenavir ||↔ || |
| ||↔↑ ||↑ (HIV-infected) || |
|Nelfinavir ||↔ ||↔ || ||↔↑ ||↑ || |
|Saquinavir ||NA ||NA || ||NA ||NA ||NA |
|Atazanavir ||↔ || |
(HIV-negative) || |
|NNRTI || || || || || || |
|Efavirenz ||↔/↑ ||NA ||NA ||↔/↑↑ ||↔/↑ || |
|Nevirapine ||↔ ||↔ || ||↔ ||↔/↑ ||↑↑↑ (49%) |
|Etravirine || || || ||↔ ||↔/↑ ||↑ |
|Rilpivarine || || || ||↔ ||↔/↑ ||↑ |
|NRTI || || || || || || |
|Stavudine ||NA ||NA || ||↔/↑ ||NA ||NA |
|Tenofovir ||↔ ||NA || ||↓ ||↓ ||↓ |
|Abacavir ||↔ ||↔ || ||↔/↑ ||↔/↑ || |
|Integrase Inhibitors || || || || || || |
|Raltegravir ||↔ ||↔ || ||↔ ||↔/↑ ||↔/↑ |
|Dolutegravir ||NA ||NA || ||↔/↑ ||↔/↑ ||↔/↑ |
|Elvitegravir ||NA ||NA || ||↔ ||NA ||NA |
The mechanism of insulin resistance with PIs includes the acute blockade of the peripheral insulin-regulated glucose transporter (GLUT)4. In vitro studies have shown that PIs (indinavir, ritonavir, and amprenavir) selectively inhibit 2-deoxyglucose transport into 3T3-L1 adipocytes without affecting early insulin signaling events or the translocation of intracellular GLUT4 to the surface. Indinavir has also been shown to block partially GLUT2, the glucose transporter postulated to be involved in glucose-sensing in the pancreas and regulation of insulin secretion. Recently, an analog of the peptidomimetic phenylalanine moiety found in all PIs has been shown to inhibit GLUT4-induced glucose transport in vitro. Because serum levels of PIs vary, some PIs, such as amprenavir, may block GLUT4 in vitro but have no effect in patients.
Increased insulin resistance has also been found in HIV-infected subjects on NRTI therapy. However, it is unclear if the effects of NRTIs are a direct effect of the drug, reactivation of the immune system, restoration of health, or changes in body composition. When stavudine was given to healthy volunteers, there was no decrease in M/I.
In addition to peripheral insulin resistance, impairment in insulin secretion was reported in HIV patients on PI therapy. In HIV-infected subjects treated with several PIs, beta cell function assessed by first-phase insulin secretion showed a 25% decrease. However, insulin secretion in the HIV-infected patients was higher than controls before PI therapy and was reduced only to that of controls after PI therapy. The HIV-infected patients had suppression of HIV RNA levels and increases in CD4 counts. More recently, healthy normal volunteers were given lopinavir/ritonavir for 4 weeks, and no effect was seen on first-phase insulin secretion. Thus, it is unlikely that currently used PIs alter insulin secretion.
Hepatic glucose production is also increased in some patients on PIs. Endogenous glucose production, comprised mostly of hepatic gluconeogenesis and glycogenolysis, is the largest determinant of fasting glucose. In studies of healthy normal volunteers, indinavir increased endogenous glucose production in the fasting state and blunted insulin suppression of endogenous glucose production during a hyperinsulinemic, euglycemic clamp. In humans, full dose ritonavir has a small detrimental effect on endogenous glucose production, while amprenavir had no effect.
Increased plasma levels of the NNRTI efavirenz, particularly in those with the slow metabolizing mutation in CYP2b6 are associated with higher glucose levels. In contrast, there was no relation between levels of lopinavir or stavudine and glucose parameters.
Adipocytokine levels in HIV infection may explain some of the results in glucose metabolism. Adiponectin, a hormone secreted by adipocytes, has been shown to increase peripheral and hepatic insulin sensitivity. Adiponectin levels inversely correlate with the amount of VAT in HIV-negative subjects. In patients with HIV-associated lipoatrophy, adiponectin levels are reduced; thus, low adiponectin levels have been proposed to mediate some of the insulin resistance in HIV. The mechanism which reduces adiponectin levels is unknown. Some have attributed the reduction to PI therapy. In vitro studies of cultured fat cells have suggested that PI treatment suppresses adiponectin mRNA and protein expression. However, two studies in healthy normal volunteers found that in fact adiponectin levels were increased during chronic treatment with the PIs indinavir or lopinavir/ritonavir; because adiponectin increases insulin sensitivity, the higher levels may explain why less insulin resistance is seen after 4 weeks of treatment compared to acute dosing. Levels of leptin, another hormone secreted by adipocytes, correlate with insulin resistance. However, some diseases with very low leptin levels also have insulin resistance. Leptin levels have been shown to be decreased in HIV patients with peripheral lipoatrophy.
HCV and possibly Hepatitis B (HBV) coinfection are also associated with increased fasting glucose levels and prevalence of diabetes. Treatment of HCV mono-infection with newer antiviral drugs reduces fasting glucose levels.
Epidemiological studies of diabetes in HIV infection have shown contradictory results for specific antiretroviral drugs, but similar results for other risk factors. Some studies have implicated the PIs indinavir, ritonavir or saquinavir, and the NRTIs stavudine or didanosine as associated with diabetes, but individual studies have found different drugs to be associated with diabetes and some found the very same drugs to be protective. Pre-therapy BMI, use of effective combination therapy, increase in or higher CD4 counts, weight gain with therapy, decreased physical activity, the presence of lipoatrophy, higher triglycerides and older age are associated with incident diabetes.
Current guidelines set forth by the Infectious Disease Society of America and similar European guidelines suggest measuring fasting glucose levels and/or hemoglobin A1c before and during anti-retroviral therapy. Given the controversies over which ARV induce diabetes, current guidelines refer to all patients with HIV. Hemoglobin A1c may not accurately reflect glucose levels in the presence of anemia of HIV.
Treatment of diabetes in HIV infection should follow the American Diabetes Association guidelines. There are studies of therapy of patients who have HIV-associated lipoatrophy and lipohypertrophy. Thiazolidinediones improve insulin resistance in patients with HIV-associated lipoatrophy and lipohypertrophy. Proliferation of lipomas has been reported in one patient with HIV-associated lipoatrophy. Given the recent findings that thiazolidinediones decrease BMD and may increase fracture risk, caution is warranted in HIV-infected patients as they may be at higher risk for bone loss and fracture. Metformin decreases hepatic glucose production and peripheral insulin resistance. Metformin should be used with caution in combination with NRTI therapy, because there is an increased rate of lactic acid production with NRTIs, especially stavudine and didanosine. Cases of severe acidosis have been reported when these drugs were used in combination with metformin. Dolutegravir, an HIV integrase inhibitor, slows metabolism of metformin by 50%; lower doses of metformin should be used in patients on dolutegravir. Leptin has been shown to improve glucose tolerance in lipoatrophic patients with or without HIV, but is not yet approved by the FDA.
Medications used to treat opportunistic infections are associated with hyperglycemia and hypoglycemia. Pentamidine, including that administered by aerosol delivery systems, causes pancreatic beta cell toxicity, acutely leading to hypoglycemia. Over the long term this medication causes diabetes mellitus. Hypoglycemia during pentamidine treatment is associated with increased length of treatment, higher cumulative doses, and renal insufficiency. Patients who develop hypoglycemia on pentamidine are at increased long-term risk of developing diabetes mellitus. These patients have low C peptide levels, suggesting beta cell destruction. Pentamidine, trimethoprim-sulfamethoxazole, and the nucleoside analogs didanosine and zalcitabine have been associated with acute pancreatitis. Megestrol acetate, which has intrinsic glucocorticoid activity, may be associated with diabetes mellitus in HIV-infected patients, perhaps through its glucocorticoid activity, although the rate of hyperglycemia in controlled clinical trials appears to be low. GH can also cause insulin resistance, leading to hyperglycemia and diabetes. Medications used in HIV-infected patients that can affect the endocrine system are listed in Table 25–2.
Alterations in lipid and lipoprotein profiles are common in patients infected with HIV. The observed changes can be due to HIV infection itself, antiviral medications, body composition changes, and immune reconstitution. A rational approach to disturbances in lipid metabolism is to assess each of the factors in a given patient. The following section reviews the lipid and lipoprotein profiles individually, with an emphasis on studies prospectively measuring fasting lipid levels.
HIV infection is associated with a mild increase in triglyceride and very low density (VLDL) cholesterol levels (see Table 25–4). Triglyceride and VLDL cholesterol levels rise in association with advancing HIV disease and correlate with HIV RNA levels. The host response to viral infections like HIV is induction of interferon alpha; in those with detectable viral loads, interferon alpha levels correlate with triglyceride levels. Decreased clearance of triglycerides and, to a lesser extent, increased VLDL production. Interferon alpha has been shown to induce these changes in animals.
Several antiviral medications can increase triglyceride levels. Full-dose ritonavir can cause a two- to threefold increase in triglyceride levels, probably by increased VLDL production (see Table 25–5). Because of its ability to inhibit the hepatic enzyme CYP3A4, ritonavir is used to increase the pharmacologic doses of other PIs metabolized through the same cytochrome system. Boosting doses of ritonavir (100 mg twice daily) have also been shown to increase triglycerides, albeit to a lesser extent. The combination lopinavir/ritonavir given to healthy normal volunteers increased triglycerides and VLDL cholesterol levels by 83% and 33%, respectively. Ritonavir-boosted tipranavir and fosamprenavir produce similar increases to those of lopinavir/ritonavir. Ritonavir-boosted atazanavir and darunavir appear to induce less increase in triglycerides. Not all unboosted PIs alter triglyceride levels; in healthy normal volunteers, administration of indinavir and atazanavir resulted in no change in triglyceride levels (see Table 25–5). The data are not clear for unboosted amprenavir and nelfinavir, but they are not commonly used as monotherapy.
The NNRTI efavirenz is associated with increased triglycerides. Again, this is not a class effect as other NNRTIs (eg, nevirapine, rilpivirine, and etravirine) have not been associated with alterations in triglyceride metabolism. The HIV integrase inhibitors (eg, raltegravir, dolutegravir, and elvitegravir) have no effect on triglycerides.
The effects of NRTIs on lipid metabolism have not been well studied. In some, but not all studies, stavudine use was associated with increased triglyceride levels. The most informative trial compared stavudine with tenofovir and found an increase in triglycerides in the stavudine arm, but not in the tenofovir arm. Given that all subjects got efavirenz, a likely interpretation is that there was a lipid-lowering effect of tenofovir. Other data support this interpretation, as switch studies or adding tenofovir to an effective ARV regimen lower lipids, but the effect on triglycerides in those studies is small.
The original clinical syndrome of HIV lipodystrophy was reported to be associated with increased triglyceride levels. One study found that 57% of patients with both peripheral lipoatrophy and central lipohypertrophy had triglyceride levels above 300 mg/dL. It has long been recognized that visceral obesity in the general population is associated with high triglycerides. However, recent data suggest that lower body fat is protective, as increased levels of lower body fat are associated with lower triglycerides in both HIV-infected patients and controls. Therefore, the loss of lower body fat in HIV-associated lipoatrophy is another reason why triglycerides are high in HIV infection. Hypertriglyceridemia is well known to be multifactorial; genes, diet, alcohol, and physical activity play a role. In HIV infection, one can add the synergistic effects of the host response to HIV itself, treatment with ritonavir and efavirenz, and HIV-lipoatrophy to the pathogenesis.
After the introduction of HAART, a reported increase in low density lipoprotein (LDL) cholesterol levels was largely attributed to PI therapy. It is now clear that factors other than PIs contribute to this rise in LDL cholesterol levels. In the early stages of HIV infection, LDL cholesterol levels fall (see Table 25–4). With effective therapy, LDL levels rise in response to suppression of HIV, independent of the type of therapy. Most, but not all PIs have been associated with increases in LDL levels, but average levels are not high. Studies in healthy normal volunteers have provided insight into the direct effects of PIs on cholesterol metabolism apart from those associated with HIV infection. Indinavir, ritonavir, lopinavir/ritonavir, and atazanavir all have no effects on LDL levels in healthy normal volunteers (see Table 25–5). In patients with HIV infection, treatment with the NNRTI nevirapine raises LDL levels. Studies that involve switching patients from PIs to the NNRTIs nevirapine or efavirenz found that LDL levels do not change. Hence, the increase in LDL seen in HIV infected patients is not solely an effect of PI therapy, but likely represents suppression of HIV and restoration to health. However, in switch studies, some drugs have been shown to have less of an effect on LDL (the PIs atazanavir, saquinavir, and darunavir; the NNRTIs rilpivirine and etravirine; and the integrase inhibitors). Tenofovir lowers LDL levels in both HIV-infected and non-infected subjects.
HIV infection and the NNRTIs have significant effects on HDL metabolism. Early in the course of HIV infection, prior to the appearance of clinically evident disease, HDL cholesterol levels decline to levels around 25 to 35 mg/dL (see Table 25–4). With advancing HIV disease, HDL levels continue to decline to less than 50% of baseline values. The pathogenesis of these changes is not well understood. Shortly after the introduction of PIs, one cross-sectional study reported decreased HDL levels in HIV-infected patients. However, subsequent studies have failed to show a decrease in HDL levels in either HIV-infected patients or healthy normal volunteers. Indeed, some studies have found modest increases (13%-21%) in HDL levels during treatment with indinavir, nelfinavir, amprenavir, and atazanavir therapy in prospective studies of HIV-infected patients.
More impressive is the nearly 50% increase in HDL cholesterol seen during treatment with the NNRTI nevirapine. Efavirenz has also been shown to increase HDL levels by 15% to 23%. When patients were switched from PIs to the NNRTIs efavirenz and nevirapine, somewhat smaller increases were seen again supporting the concept that HAART with PI induces small increases in HDL. The story is not as clear for the NNRTIs rilpivirine and etravirine, as HDL levels decrease when stable patients are switched from efavirenz to those drugs.
The integrase inhibitors raise HDL, but less than the NNRTI and possibly less than PI. Tenofovir is the NRTI with the least effect on HDL. Combination therapy with tenofovir as the backbone raises HDL less than other NRTI. Switching to tenofovir results in small decreases in HDL.
In some studies, HDL levels have been reported to be lower in patients with HIV-associated lipodystrophy, but the extent to which that decrease is due to HIV or the effects of ARV are not clear. Visceral obesity and upper trunk fat are associated with lower HDL levels.
Several changes in lipoprotein structure and function occur in HIV infection that might promote atherosclerosis. The hypertriglyceridemia of AIDS is accompanied by increases in the prevalence of small dense LDL or LDL-B, even in the absence of obesity. LDL-B is also more common with ARV regimens that increase triglycerides.
Levels of oxidized LDL, which promotes atherosclerosis more than native LDL, and a marker of LDL oxidation, IgG against oxidized LDL, are increased in HIV infection. Their levels are higher on PI regimens compared to NNRTI regimens. HDL from those with HIV infection has less paraoxonase-1 (PON1) activity, which protects LDL from oxidation. PON1 activity has been shown to be proportional to CD4 count and inversely proportional to HIV viral load. Treatment may not restore PON1 to normal, although the increase is highest with NNRTI. PON-3, which has less of a protective effect, is increased in HIV and restored toward normal by NNRTI. Myeloperoxidase levels are elevated; the extent to which they improve with ARV is not clear. Lipoprotein associated phospholipase A2 (Lp-PLA2 or platelet activating factor acetyl-hydrolase) activity is increased in HIV infection. When lipoproteins are oxidized, Lp-PLA2 produces lysophosphatidylcholine, which is pro-atherogenic. Lysophosphatidylcholine levels are elevated in HIV. PI- and NNRTI-based therapy does not restore Lp-PLA2 activity to normal, but integrase inhibitors have a greater effect.
Most studies find that HDL from untreated HIV-infected patients has decreased ability to mediate cholesterol efflux from macrophages, the first step in reverse cholesterol transport, which protects against atherosclerosis. All studies show that antiretroviral therapy improves the ability of HDL to mediate efflux. HIV infection of macrophages decreases their ability to provide cholesterol for HDL-mediated efflux.
Current guidelines recommend a fasting lipid panel be obtained before initiating or switching therapy, and repeated at least 1 month after starting or changing an ARV regimen. In those patients with uncontrollable hyperlipidemia, switching HIV therapy should be considered, if the regimen is one linked to the observed dyslipidemia and it is refractory to conventional treatment.
Hypolipidemic therapy should be tailored to the type of dyslipidemia. For patients with triglyceride levels greater than 500 mg/dL, fibrate therapy is recommended. Gemfibrozil and fenofibrate are effective in reducing triglyceride levels in patients infected with HIV, but those who start at high triglyceride levels do not reach normal levels. Fish oil lowers triglycerides, but raises LDL, leading to no net decrease in CVD risk. Niacin is effective and has the advantage of raising HDL levels as well as lowering triglycerides, but niacin-induced insulin resistance may be problematic in HIV-infected patients. HMG-CoA reductase inhibitors (drugs of the statin class) may be better second-line agents for lowering triglycerides. As with HIV-negative patients, combination pharmacologic therapy may be required to correct extremely elevated triglyceride levels.
HMG-CoA reductase inhibitors are effective, first-line agents for the treatment of hypercholesterolemia. However, there are multiple drug-drug interactions that are important in HIV-infected patients. Some statins are metabolized by CYP3A4 which is induced or inhibited by some ARV drugs. PIs, especially ritonavir, which is used to boost levels of many HIV ARV drugs to therapeutic levels, inhibit CYP3A4 which is the major metabolic pathway for simvastatin and lovastatin. Ritonavir-based regimens increase simvastatin levels by 5- to 32-fold, and multiple cases of rhabdomyolysis have been reported on such combinations. The combination of PI and simvastatin or lovastatin should not be used. Atorvastatin activity increases twofold, so 80 mg atorvastatin should be avoided.
Lopinavir/ritonavir increases rosuvastatin levels two- to fivefold, and tipranavir/ritonavir increases rosuvastatin levels twofold and atorvastatin levels eightfold by unknown mechanisms. If those PI combinations are used, only low doses of rosuvastatin and atorvastatin should be used. Thus, pitavastatin, pravastatin, and fluvastatin XL are recommended as first-line statins for patients on PI- or ritonavir-based HAART.
The effects of HIV protease inhibitors on glucose and lipid metabolism are shown in Table 25–5.
HIV, Antiretroviral Therapy, and Risk of Atherosclerosis
The changes in lipid and glucose metabolism seen in HIV raise the question about whether atherosclerosis increases due to HIV or its therapies. Multiple retrospective studies report an increased prevalence of CVD in HIV-infected patients. Some early studies also found an association with ARV therapy, particularly PI therapy, in addition to traditional risk factors such as age, gender, smoking, and LDL and HDL levels. A randomized trial of continuous versus intermittent therapy for HIV showed that continuous therapy has fewer cardiovascular complications. Smoking is more prevalent in those with HIV infection versus non-infected controls. Cross-sectional studies of the intima media thickness (IMT) of the carotid and femoral arteries by ultrasound have also shown that traditional CVD risk factors provide the dominant contribution to increased plaque. However, after adjusting for traditional CVD risk factors, HIV infection is an independent risk factor for increased IMT, similar in magnitude to male sex, diabetes, and smoking. As a consequence, a more aggressive to CVD prevention may be warranted.