The variable effects of PIs on mature adipocytes and on the adipocyte differentiation process are reflected in differences in lipid serum profiles of patients with HIV infections treated with various antiviral combinations. Early studies reported PI-induced dyslipidemia as a class effect.43,48–50,56–61 However, recent work demonstrates that the effect of PIs on serum lipids is variable.
Studies with earlier-generation PIs show that total cholesterol levels may increase by as much as 30% after 2–4 years of use and triglyceride levels by as much as 80%.18,72–76 In a recent study of 212 patients receiving PI-based ART, RTV- and LPV/RTV-containing regimens caused the highest incidence of hypercholesterolemia and hypertriglyceridemia after 12 months of therapy.72 These data were confirmed in a study of 353 previously treated patients who received LPV/RTV treatment. In this cohort, previous PI use was a predictor of worse hypertriglyceridemia and hypercholesterolemia, with as many as 25% of patients with triglycerides levels >400 mg/dL and 30% of patients with total cholesterol levels >240 mg/dL after 3 months of treatment.77 Similar effects, particularly with respect to high levels of RTV-induced lipid increases, have been observed in other studies in both adults78 and children.79
In a comparative study of 93 HIV-infected adults treated with PIs, RTV also produced higher levels of cholesterol, LDL cholesterol (LDL-C), and triglycerides than nelfinavir or indinavir (Table 3).73 Saquinavir has been shown to cause a slightly higher increase in lipids than indinavir or nelfinavir and, like nelfinavir, is more likely to cause severe hypertriglyceridemia.72
In a study of 187 HIV-positive patients, higher fasting serum cholesterol and lipid levels were associated with ART, particularly among patients treated with PI-containing regimens.80 Multivariate analysis revealed RTV, indinavir, saquinavir, and the NNRTI efavirenz to be associated with a significant increase in total cholesterol or LDL-C.
The 2 most recently developed PIs appear to have a more favorable lipid profile than previously developed agents. In an ongoing prospective phase II extension trial of atazanavir 400 mg with d4T and 3TC, median cholesterol, fasting LDL-C, and fasting triglycerides remained unchanged at 48 weeks (158 vs. 169 mg/dL, 101 vs. 101 mg/dL, and 115 vs. 126 mg/dL, respectively).18 In this trial, switching from nelfinavir to atazanavir resulted in a decrease in lipid levels by week 24.19 Similarly, in an open randomized study of fosamprenavir (GW433908) vs. nelfinavir administered with abacavir and 3TC, at 48 weeks, no significant change in mean triglyceride serum levels had occurred (151 mg/dL at baseline vs. 152 mg/dL at week 48), compared with a 30% increase in the nelfinavir group (from 154 mg/dL at baseline to 200 mg/dL at week 48). Mean total cholesterol (TC) and LDL-C values rose by approximately 25% in both groups: from 152 mg/dL to 197 mg/dL and from 86 mg/dL to 119 mg/dL, respectively, in the GW433908 group, and from 153 mg/dL to 202 mg/dL and from 89 mg/dL to 122 mg/dL, respectively, in the nelfinavir group. The incidence of grade 3-4 abnormalities in TC and triglycerides was <1%. High-density lipoprotein cholesterol (HDL-C) levels also increased in both arms, from 37 mg/dL in the fosamprenavir arm and 36 mg/dL in the nelfinavir arm to optimal values of 49 mg/dL and 44 mg/dL, respectively.76
Substitution of PI therapy with nevirapine, efavirenz, or abacavir has been studied as a strategy to improve both metabolic and morphologic abnormalities attributed to PIs. A relatively brief interruption in therapy (∼7 weeks) has resulted in a significant improvement in TC, LDL-C, and triglyceride levels,81 and most clinical studies have demonstrated improvements when substituting an NNRTI or an NRTI for a PI.44,82–85 In some studies, however, the changes were mixed or marginal, or lipid profiles did not improve.86–88 For instance, in one study, of 17 patients with lipodystrophy who switched from a PI to nevirapine, 7 of 17 (41%) had an objective improvement, as assessed by anthropomorphic measures, but none experienced a complete reversal in symptoms. In these patients, only triglyceride levels decreased.89 In another study, of 23 patients, most of whom (73%) were initially receiving indinavir, cholesterol decreased 22% and triglycerides 57% at 6 months following the switch to nevirapine.44 In 2 other such studies, however, improvements were marginal or did not occur.83,90
Recently, an open-label randomized study evaluated the effect of switching from a PI or an NNRTI to the NRTI abacavir in 20 patients who experienced therapy-induced lipodystrophy.91 After 48 weeks of treatment with abacavir, cholesterol levels decreased significantly but remained at or above 5.2 mM (200 mg/dL). A nonsignificant decrease in triglycerides was also observed.91 This trend was also observed in a recent randomized trial enrolling 460 patients treated with PIs and switching to nevirapine, efavirenz, or abacavir. The switch caused no significant changes in triglyceride levels with any of these agents, and decreases in TC in the abacavir group only after 12 months of treatment. In an intent-to-treat analysis at 12 months, 10, 6, and 13% of patients in the nevirapine, efavirenz, and abacavir groups, respectively, reached a protocol-defined endpoint—a nonsignificant difference. In an as-treated analysis, significantly more patients reached a virologic failure endpoint in the abacavir group (14%) than in the nevirapine (7%) or efavirenz (5%) groups (P = 0.03). However, significantly more patients discontinued treatment in the nevirapine and efavirenz groups (17% in both cases) than in the abacavir group (6%; P = 0.01) due to adverse events.92
These results suggest that PI-induced dyslipidemia is highly variable between individuals, depends on the PI used, whether it is boosted with RTV, and is more likely to occur with older agents. Substitution of the older PIs with nevirapine, efavirenz, or abacavir may lead to some improvement in lipids, although significant discrepancies exist between studies. Additionally, switching from a dual-NRTI plus PI combination to a triple-NRTI combination that would include abacavir is not recommended in those with documented or presumed NRTI resistance, due to the increased risk of virologic failure. With all of these PI substitution strategies, improvement in body habitus abnormalities has not been consistently demonstrated. It is hoped that with recently developed PIs such as fosamprenavir or atazanavir dyslipidemia will be reduced.
Insulin resistance, a key component of the lipodystrophy syndrome, is estimated to occur in 24% of adults over age 20 in the general population in the United States.93 Incidence and prevalence data for insulin resistance, disorders of glucose metabolism, and diabetes in HIV disease are derived from a limited number of studies, some with small data sets and some using nonuniform criteria for the determination of diabetes or insulin resistance. As observed in the general population, insulin resistance and impaired glucose tolerance are more common than diabetes mellitus and hyperglycemia in HIV-infected individuals treated with PI-containing regimens.94
Currently, the site(s) of insulin resistance is (are) not well documented. Recent studies show that insulin resistance is not confined to adipose tissue but also arises in skeletal muscle. Furthermore, pancreatic β-cells appear unable to release more insulin to compensate for the decrease in insulin sensitivity.101
Studies aiming to elucidate the mechanism of insulin resistance and glucose intolerance have used differentiated 3T3-L1 adipocytes in culture. However, as with lipid metabolism, different PIs appear to produce different mechanisms of resistance. Whereas a direct inhibition of the glucose transporter protein GLUT4 has been demonstrated with indinavir, RTV, amprenavir,102,103 and saquinavir,104 nelfinavir appears to inhibit glucose uptake by interfering with insulin-dependent GLUT4 translocation or activation at the level of protein kinase B within the signaling cascade that leads to GLUT4 activation.104,105 Concurrent increase in lipolysis even in the presence of insulin was also noted, suggesting a decrease in the antilipolytic activity of insulin.105 Furthermore, nelfinavir appears to increase the concentration of the GLUT1 glucose transporter and stimulate basal glucose transport independently of insulin action in 3T3-L1 preadipocytes and L6 myotube muscle cell precursors.104 Other studies demonstrate that insulin resistance is not confined solely to adipocyte-related mechanisms. Indinavir has been shown to reduce insulin-stimulated glycogen synthesis in HepG2 hepatoma cells. Since GLUT4 is not present in HepG2 cells, the inhibitory mechanism is not likely to include inhibition of this transporter.106
The prevalence of diabetes mellitus in the general adult population was estimated at 5.1% between 1988 and 1994.107 Among patients with HIV infection who developed the lipodystrophy syndrome often associated with PI treatment, 1–6% of patients will eventually develop new-onset diabetes (clinically similar to type II diabetes).94 Additionally, up to 60–85% of PI-treated patients will have evidence of some level of insulin resistance when intensively studied.33,50 The relationship between the introduction of PI therapy and the incidence of diabetes was demonstrated in an epidemiologic study carried out between 1994 and 2000 among HIV-positive members of the Northern California Kaiser Permanente Health Plan.108 The age-adjusted incidence of diabetes mellitus peaked in 1997 following the introduction of PIs in 1996 (from 97.1 cases per 10,000 in 1994 to 188.2, compared with 63.1 cases per 10,000 in 1994 to 82.3 in 1998 among HIV-seronegative individuals). Among members who were treated with early PIs, the incidence reached 319 cases per 10,000 in 1996 but decreased in 2000 to 100.8 cases per 10,000 (presumably due to the replacement of PIs with NNRTIs), compared with 83.4 and 88.4 cases per 10,000 in the seronegative and HIV population not treated with a PI, respectively. Multivariate Poisson regression modeling, adjusted for demographic factors, revealed a significant association between PI use and diabetes only when the models were stratified by year: the relative risk of diabetes for PI-treated members vs. no PI therapy was 2.49 (95% CI = 1.04–5.96).108 Although the time to development of diabetes or hyperglycemia is highly variable, studies have shown that alterations of glucose metabolism generally occur within 3 months after initiation of PI therapy,95,97 supporting the rapid rise in diabetes cases observed in the Northern California Kaiser Permanente Health Plan cohort.
Studies with PIs in healthy volunteers indicate that individuals who develop glucose intolerance or diabetes had first-degree relatives with diabetes or a family history of the disease,96 suggesting that the propensity of certain HIV-infected patients treated with PIs to develop diabetes may involve a genetic component. In a retrospective case-control study of 49 patients with HIV who developed diabetes, traditional risk factors such as high mean BMI, high prevalence of fat accumulation, as well as a family history were associated with the development of the disease. Furthermore, patients with HIV had higher levels of serum alanine aminotransferase (ALT) than matched controls (66.3 vs. 43.7 U/L, respectively; P = 0.013).109 These data suggest that in addition to traditional risk factors, ART-induced metabolic changes and liver injury evidenced by increased serum ALT may play a role in the pathogenesis of diabetes in HIV-infected individuals. Recently, a prospective multicenter cohort study identified 69 cases of diabetes in 1785 women, the incidence of diabetes among PI users was 2.8 cases per 100 patient-years (PY) compared with 1.2 cases per 100 PY among both reverse transcriptase inhibitor (RTI) users or ART-naive patients (P = 0.01), and 1.4 cases per 100 PY among HIV-negative individuals (P = 0.06). PI use, age, and BMI were identified by multivariate analysis as independent risk factors for the development of diabetes mellitus. However, because of the small number of cases that occurred compared with the benefit of PI therapy, monitoring for glucose intolerance among older, heavier patients should be considered rather than categorically avoiding PI treatment.110
Changes in bone mineral metabolism and bone histomorphometry were noted in HIV-infected individuals before the widespread use of potent ART.111–115 A recent prospective study has also reported asymptomatic osteonecrotic lesions of the hip using MRI in 15 of 339 HIV-infected patients (4.4%).116 This condition occurred predominantly in patients with hyperlipidemia, and in those using corticosteroids and alcohol, and appeared to be unrelated to combination ART.116 In another study evaluating 112 men including 60 patients treated with PIs, 35 on a non-PI regimen, and 17 untreated uninfected controls, 50% of those treated with PIs had osteopenia or osteoporosis according to the World Health Organization (WHO) classification, compared with 23% of those not treated with a PI and 29% of the control subjects (P = 0.02).117 However, when other risk factors such as low BMI, weight loss, steroid use, and smoking were taken into consideration, the association with PIs disappeared.118 A longitudinal study of 54 patients on a stable combination ART regimen for over a year suggests that loss in bone mineral density is related to initial BMI rather than to PI use; in fact, the data from this study suggest that indinavir, but not nelfinavir, is associated with increasing bone mineral density over time.119 The data suggest a shift in mesenchymal stem cell differentiation away from adipose to osteoblastic, an effect that may be related to tumor necrosis factor (TNF)-α activity.120,121
Equally unresolved is the putative association between adipose tissue redistribution and bone mineral density that would find its basis in differentiation reprogramming. Early findings suggested that osteopenia was independent from adipose tissue distribution.117 However, a multivariate regression analysis of fat distribution and bone density in a study enrolling 21 HIV-infected men with lipodystrophy, 20 HIV-infected men without lipodystrophy, and 18 age- and BMI-matched healthy controls showed an association between visceral fat accumulation and bone mineral density (P = 0.007).122 Further investigation suggested that indinavir and nelfinavir have opposite effects on intervertebral bone marrow fat and lumbar spine density (Fig. 3), supporting comparable differences inferred in other studies of PI-based mechanisms governing fat distribution and bone turnover.123
Non-PI antiretroviral agents in the treatment regimen may confound the effects of PIs on bone. For instance, NRTI-induced lactic acidemia has been associated with reduced spinal bone mineral density124; and, in a retrospective study of patients on dual NRTI-only therapy, whole-body dual-energy x-ray absorptiometry revealed a significant decrease, although within normal limits, in bone mineral density over a 2-year assessment period.125
In summary, the data linking PI-based therapy to osteopenia or osteoporosis are conflicting and methodologically problematic, particularly when other risk factors for bone disease are considered. Non-PI antiretroviral agents, HIV itself, and traditional conditions associated with diminished bone mineral density all may play a role in the relatively high rate of osteopenia seen in HIV-infected patients in several reports. Better-designed and well-controlled studies are needed to conclusively link or dissociate PI use and abnormalities bone metabolism.
Dyslipidemia is a major contributor to the development of coronary heart disease (CHD), and strict guidelines have been proposed to prevent the development of CHD in the general population.126 Hyperglycemia and diabetes cause physiological changes in the vascular system that increase the risk of atherosclerosis and may lead to coronary artery disease (CAD), myocardial infarction (MI), and stroke.127,128 Because PIs are associated to various extents with dyslipidemia, hyperglycemia, or both, there is concern regarding increased cardiovascular events in PI-treated HIV patients, with a number of anecdotal cases having been reported.129–133
Retrospective studies investigating the influence of ART on cardiovascular disease have yielded mixed results. In a study of 951 patients with HIV, 16 of whom had CHD (including 8 MIs), the incidence of CHD was associated with traditional risk factors, including cigarette smoking, hypertension, family history, and cholesterol levels, but not with PI use. In this study, however, longer exposure to NRTIs (3.7 vs. 2.5 years; P = 0.02) and low CD4+ cell counts also increased the risk of CHD.134 In a larger, short-term retrospective study using an anonymous database including 36,766 patients who had been treated at Veterans Administration hospitals, 41.6% of whom had been treated with PIs, there was no relationship between the incidence of cardiovascular or cerebrovascular events and combination ART over a median 17-month period of use.135 In an ongoing study including 4159 individuals with active HIV infections and 39,877 controls over the age of 35 enrolled in the Kaiser Permanente Medical Care Program (KPMCP) of Northern California, the prevalence of CHD events was analyzed over a 5.5-year period. During that time, 72 patients were hospitalized for CHD events, 47 of which were MIs. HIV-positive cases were at a significantly higher risk for CHD than HIV-negative cases (6.5/1000 PY vs. 3.8/1000 PY; P = 0.003).136 The rates of hospitalization for CHD were similar in PI-treated and non–PI-treated patients, however (6.7/1000 PY vs. 6.2/1000 PY; P = NS), suggesting no effect of PIs on CHD rate in this study as well. Additionally, because patients with no prior ART also had an increased risk of CHD (5.7/1000 PY), the data suggested that HIV or HIV comorbidities may contribute significantly to cardiovascular risk.
A number of studies, however, have shown a relationship between CHD and PI or ART use. A retrospective evaluation of 73,336 seropositive subjects treated with combination ART between 1996 and 1999 suggested that PI-containing regimens were associated with an increased incidence of MI with increasing length of exposure. The study analyzed an epidemiologic database including 68 French university hospitals belonging to 29 HIV treatment centers. Data collected included CD4 cell counts, HIV RNA levels, clinical events, treatment schedules, clinical trials (if applicable), mortality, and cause of death. Compared with the age-adjusted general population expectation of a rate of 10.8 MIs per 10,000 PY, patients who were exposed to PIs exhibited rates of 8.2, 15.9, and 33.8 MIs per 10,000 PY with PI exposures of <18 months, 18–29 months, and ≥30 months, respectively.137 Similarly, in a retrospective analysis of 5672 patients from the HIV Outpatient Study over 9 years, the rate of MIs was greater among patients treated with PIs (19 MIs in 3247 patients) than among those treated with non-PI regimens (2 MIs in 2425 patients).138 Additionally, in a cohort of 2671 patients with HIV treated with various regimens for 12 years, the incidence of CHD and cerebrovascular disease (ischemic stroke or transient ischemic attack) was evaluated at 5.9 events/1000 PY (43 cases) and 5.0 events/1000 PY (37 cases), respectively. This represents a 2- to 3-fold greater incidence than in the general population. Cases were more likely than controls to be associated with PI use (as a class, but not individually) and the NRTI d4T.139
However, in the absence of well-controlled studies, it is not possible to distinguish the relative contribution of PI-induced metabolic derangements, the degree of immunodeficiency, the state of chronic inflammation due to HIV infection, and traditional cardiac risk factors to the cardiac event rate. In an effort to address this important issue, the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study was designed to control for these variables. The study enrolled 23,468 patients from 11 previously established cohorts from 21 countries in Europe, the United States, and Australia between December 1999 and April 2001. One hundred new cases of MI were required to give the study sufficient power to detect a 2-fold difference in the incidence of MI between 2 comparable groups according to their exposure to combination ART. During the course of the study, patients were prospectively followed at each clinic visit. Standardized data collection forms were filled at enrollment and every 8 months thereafter. New cases of MI were reported to the study coordinator and coded according to the WHO Multinational Monitoring of Trends and Determinants in Cardiovascular Disease project.140 Twenty-four percent of patients were women, and the median age of the entire population was 39 years; 75% of patients had been previously exposed to combination ART, and 67.1% had been previously exposed to PIs. The incidence of MI increased with the duration of exposure to combination ART: from 0.24 relative rate for untreated patients to 1.34 for those exposed to combination ART for <1 year, 1.73 for those exposed for 2–3 years, 1.98 for those exposed for 3–4 years, and 2.55 for those exposed for >4 years of combination ART (P for trend <0.001). Older age (P < 0.001), smoking habit (P = 0.007), previous CVD (P < 0.001), and male gender (P = 0.04) were also associated with an increased incidence of MI, as were metabolic disorders such as higher cholesterol and triglyceride levels, hypertension, diabetes, and lipodystrophy.141 Although combination ART independently increased the relative rate of MI per year of exposure by 26%, it is important to emphasize that the overall risk of MI was still markedly lower than the risk of AIDS-defining illnesses seen before the advent of potent combination ART.
As in studies directly evaluating the effects of combination ART on CHD events, studies that have attempted to evaluate the effect of combination ART on surrogate markers for the risk of CHD have yielded mixed results. Because subclinical atherosclerosis is a surrogate marker of MI and stroke risk,142 studies have explored the potential of a relationship between carotid or femoral intima-media thickness (IMT) and PI use. In an early study of 102 patients, PI use was associated with an increased risk of atherosclerotic plaque; however, in this study, the comparative group comprised both patients treated with ART and therapy-naive individuals. Additionally, the baseline characteristics were not well balanced between groups; in particular, patients in the PI group had more advanced disease and lower CD4+ cell counts than controls.143 In another study evaluating HIV-infected patients treated with PIs, HIV-infected individuals who were treatment naive, and HIV-negative controls, carotid IMT was greater in the first 2 groups than in controls.144 Additionally, in a recent cross-sectional study in which baseline IMT values were established in 106 patients with HIV who had been treated with PIs for a median duration of 4 years, and progression was followed for an additional year, baseline IMT was greater in these patients than in matched, uninfected historical controls. Furthermore, the rate of progression of IMT at 1 year was greater in 21 of the patients than in historical HIV-negative individuals; progression was associated with age and duration of PI use.145
In a study of 168 HIV-infected patients that included 136 previously treated with PIs for a mean of 2 years and 68 HIV-negative individuals, however, the presence of plaque was exclusively associated with age, male gender, high HDL-C levels, smoking, and HIV infection, but not with PI use.146 Furthermore, a prospective, longitudinal, matched cohort study evaluating baseline characteristics of 134 individuals distributed evenly into 3 groups of uninfected subjects, HIV-positive PI-naive patients, and HIV-positive patients with a median PI use of at least 2 years, multivariate analysis identified increased age, higher BMI, TC, LDL-C, and triglycerides as risk factors for increased carotid IMTs. Carotid IMTs were similar for all 3 groups, suggesting that prior PI use did not increase the risk of atherosclerosis. Follow-up in this study will determine whether the rate of progression of carotid IMT is influenced by PI treatment.147
An increased incidence of CHD risks implies potential changes in cardiac function. However, a recent study found cardiac function (left ventricular systolic function and cardiac valve regurgitation) in patients treated with early PIs similar to that in patients treated with PI-free regimens. Interventricular septum thickness and left ventricle posterior wall thickness were somewhat greater in PI-treated patients, however, than in those treated with non–PI-containing regimens (P = 0.049 and 0.047, respectively).148
In summary, current data on cardiovascular risks associated with PIs in particular and combination ART in general are inconsistent. The preponderance of the data suggest that ART does increase the risk of CHD somewhat but that the absolute risk remains low compared with the risk of AIDS-related complications in the absence of treatment. As a result, this additional risk of cardiac disease attributed to ART should not be a deterrent to the use of ART if indicated. Additional follow-up of prospectively designed longitudinal studies (such as DAD) are needed to confirm these early findings, to place them into their appropriate clinical context, and to explore further treatment-specific effects.141
PI-based ART has dramatically improved the prognosis for HIV-infected patients. Problems with tolerability, however, have limited their use to some extent. Most of the older agents in this class are associated with significant GI symptoms. The newer PIs, fosamprenavir and atazanavir, however, exhibit a more favorable GI adverse event profile. Although atazanavir may cause significant hyperbilirubinemia in many patients, with jaundice in a proportion of them, this hyperbilirubinemia is infrequently a cause of treatment cessation. Rash may occur somewhat more commonly with fosampranavir than with other PIs, although again, this rarely requires stopping the drug. Educating patients and providing prophylactic management of short-term adverse effects as required are essential to prevent patients from skipping doses or discontinuing treatment. Most older PIs have demonstrated adverse effects on both lipid and glucose metabolism. Although most PIs significantly worsen lipid profiles, leading to both hypercholesterolemia and hypertriglyceridemia, atazanavir has a relatively neutral effect on plasma lipids and fosamprenavir appears to alter triglyceride levels to a minimal degree, if at all. These 2 recently approved PIs demonstrate improved subjective and metabolic tolerability profiles, which should lead to increased choice of PI-based therapy as a component of antiretroviral treatment.
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