JAIDS Journal of Acquired Immune Deficiency Syndromes:
Tolerability and Safety of HIV Protease Inhibitors in Adults
Sax, Paul E MD*; Kumar, Princy MD†
*Brigham and Women’s Hospital, Boston, MA, and †Georgetown University Hospital, Washington, DC.
Received January 29, 2004;
accepted for publication June 7, 2004.
Reprints: Paul Edward Sax, Brigham and Women’s Hospital, Division of Infectious Disease, 75 Francis Street, PBB-A-4, Boston, MA 02115 (e-mail: firstname.lastname@example.org).
Summary: Antiretroviral drugs are associated with both short-term and long-term adverse events. Like other HIV drugs, protease inhibitors (PIs) may affect metabolic processes influencing body shape and body tissue composition, appearance, bone integrity, and cardiovascular status. However, numerous confounding variables including age, cigarette smoking, body mass index (BMI), duration of HIV infection, degree of immunodeficiency, concomitant antiretroviral agents, extent of previous treatment, and duration of treatment all blur the relationship between PI use and adverse events. Recent data suggest that the early PIs appear to have greater effects on such surrogate markers of disease risk as insulin resistance and cholesterol and triglyceride levels than the recently developed PIs. These data also suggest that evaluation of PIs as a class should be reconsidered and that it is probably not appropriate to extrapolate safety data obtained from individuals treated with first-generation agents in the era of potent combination antiretroviral therapy to those treated with recently developed PIs. Because PIs remain a critical component of successful antiretroviral therapy, evaluation of potential long-term complications with prolonged PI use is essential, as is delineation of the significant differences in safety profiles among individual PIs.
Antiretroviral drug therapy is associated with both short- and long-term adverse effects. The magnitude of these events is often influenced by such variables as age, sex, body mass index (BMI), disease status, degree of immunodeficiency, and life style. From a clinical point of view, the acute adverse effects of rash, central nervous system (CNS) disturbance, nausea, vomiting, and diarrhea are true inconveniences to the patient at best and, at worst, mandate cessation of treatment. Such adverse effects may have a psychosocial, stigmatizing impact conducive to low self-esteem, anxiety, and depression if these events are perceived to be severe and frequent.1,2 Long-term therapy may cause potentially permanent and irreversible physiological damage leading to chronic or progressive pathologic conditions. Additionally, as a significant reduction in HIV-related mortality has occurred since the introduction of combination regimens in 1996, metabolic complications associated with combination antiretroviral therapy (ART) have emerged as a prominent cause of morbidity and poor quality of life among surviving patients.3 Antiretroviral treatment may also interfere with other medication(s), resulting in altered drug disposition and unwanted or even life-threatening events.4,5 Whether acute or chronic, severe adverse effects are the main reason for nonadherence to a given therapeutic regimen.6–11
SHORT-TERM ADVERSE EFFECTS ASSOCIATED WITH HIV PROTEASE INHIBITORS
Short-term adverse effects associated with therapy occur within hours or days of beginning treatment. When the clinical manifestations of these symptoms are mild, palliative therapy can often be provided on an as-needed basis, such as the use of loperamide to reduce diarrhea. Short-term adverse effects may resolve spontaneously or subside. In some cases, complete resolution only occurs if therapy is withdrawn. The severity of the short-term side effects associated with PI treatment varies with the agent used and some adverse effects occur with only a few agents in the class (Table 1).
Grade 3/4 recurrent or chronic diarrhea is the adverse effect most often associated with PIs,12 but it rarely occurs with such PIs as indinavir, atazanavir, or fosamprenavir (GW433908) (Table 1). In contrast, both nelfinavir and lopinavir/ritonavir (LPV/RTV) have been associated with grade 3/4 diarrhea in a significant number of patients.13–15 Caution must be exercised in comparing such adverse event data, however, because the clinical trials that produced the data may have involved different accompanying nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) drugs and patient populations. In one randomized, double-blind phase III study, 316 patients were randomly assigned to 1 of 2 nelfinavir doses (500 mg or 750 mg 3 times daily [tid]) or placebo; all received zidovudine/lamivudine (ZDV/3TC) as the NRTI backbone. Moderate or severe diarrhea occurred in 15 and 20% of the patients receiving nelfinavir 500 mg and 750 mg, respectively. Additionally, 2 (10%) of the 20 patients who experienced grade 3/4 diarrhea withdrew from the study.14 In a randomized, double-blind, multicenter, multinational study, 686 patients with >400 copies of HIV RNA per mL were randomly assigned to LPV/RTV (400 mg/100 mg bid) or nelfinavir 750 mg tid, both in combination with stavudine (d4T)/3TC. Moderate to severe diarrhea of possible, probable, or unknown relation to PIs was the most common adverse event in both treatment groups, occurring in 51/328 patients (15.6%) in the LPV/RTV arm and 56/327 patients (17.1%) in the nelfinavir arm.15 As shown in Table 1, diarrhea of this severity was rarely seen in treatment-naive patients treated with either fosamprenavir or atazanavir, occurring in 5 and 6% of patients, respectively.
Nephrolithiasis is a unique adverse effect of indinavir, occurring in as many as 12.4% of patients; the risk appears to increase over time, perhaps due to lower compliance with required fluid intake.16 In addition, indinavir can induce a retinoidlike effect characterized by dry skin, changes in hair, and fingernail and toe nail disorders.17 Both nephrolithiasis and retinoid toxicity appear to be increased with greater drug exposure, with a higher incidence of these complications when the agent is given boosted with RTV. Additionally, jaundice associated with indirect hyperbilirubinemia may occur with both indinavir and atazanavir (Table 2).18 In a dose-escalating phase II study of 420 antiretroviral-naive patients randomly allocated to atazanavir or nelfinavir, grade 3/4 elevations in total bilirubin (predominantly unconjugated) occurred asymptomatically in 20, 41, and 49% of subjects treated with atazanavir 200 mg, 400 mg, or 500 mg, respectively, compared with 1% in the nelfinavir group (P < 0.0001). Jaundice occurred only in atazanavir-treated subjects (6, 6, and 12% in the atazanavir 200 mg, 400 mg, and 500 mg groups, respectively).18 Bilirubin elevations were not associated with hepatotoxicity. In the extended phase of this study, when nelfinavir-treated patients were allowed to switch to the atazanavir arm, 76% of those who switched developed elevated bilirubin levels, including 13% with grade 3/4. Among those who continued on atazanavir 400 mg, 83% had elevated bilirubin levels; including 26% with grade 3/4. Jaundice appeared in 6% of patients who switched from nelfinavir to atazanavir.19 A number of laboratory abnormalities were also observed with PI treatment, most of which occurred in <10% of patients (Table 2).
Relationship of Tolerability to Adherence
Short-term adverse effects can be challenging, both for asymptomatic, previously untreated patients beginning their first regimen and for patients with more advanced HIV disease, in whom medication adverse effects may augment HIV-related symptoms. Frequently occurring or severe adverse effects (e.g., chronic diarrhea) can interfere with daily activities, including employment, and can be as stigmatizing as appearance-related adverse effects (e.g., jaundice or rash) or HIV disease itself. A variety of studies have reported a correlation between nonadherence to treatment and adverse effects. In the cross-sectional multicenter Adherence Italian Cohort Naive Anti-retrovirals (ICoNA) substudy enrolling 358 patients treated with combination ART, nonadherent participants had a higher mean overall symptom score (P < 0.001) and mean medication adverse effect score (P < 0.001) than compliant patients. In this study, nausea, anorexia, anxiety, confusion, insomnia, vision problems, taste perversion, and abnormal fat accumulation were significantly correlated with reduced adherence to treatment.20 In another multicenter study of 336 patients treated with 2 NRTIs and 1 PI, fatigue and diarrhea were the most often reported adverse effects of therapy (81.3 and 75%, respectively). Follow-up for 4 months demonstrated that patients with a high incidence of adverse effects at the onset of treatment were more likely to become nonadherent to treatment.2 Recently, in a retrospective study of 345 randomly selected antiretroviral-naive patients who initiated combination ART on 6 different regimens, the discontinuation rate was 61%, with 24% citing adverse events as the primary reason. Nausea (27%), diarrhea (18%), vomiting (16%), and gastrointestinal (GI) disturbances (12%) were the main reasons for discontinuation. CNS abnormalities (10%) were also cited as a reason for discontinuation.21 Demonstrating that appearance (as a marker of disease) can undermine the patient’s confidence and commitment to ART, the ICoNA study showed that adipose tissue alteration is also associated with nonadherence to treatment.22
Short-term adverse effects can be an impediment to continued therapy. They can include intolerable GI disturbances (most older PIs), renal toxicity (indinavir), jaundice (indinavir, atazanavir), and to a lesser extent CNS-associated events. These effects can often be managed with prophylactic or adjunctive therapy, and it is essential to educate patients on how to anticipate and manage potential short-term adverse effects to ensure the success of antiretroviral treatment. The management of short-term adverse effects has been addressed elsewhere.12,23,24
POTENTIAL LONG-TERM COMPLICATIONS OF HIV PROTEASE INHIBITOR–BASED THERAPY
HIV Infection vs. Protease Inhibitors: Relative Contribution to Adverse Events
The early stages of HIV infection induce metabolic and endocrine effects that are generally asymptomatic. As infection progresses and CD4+ cells are depleted, metabolic and endocrine adverse effects become evident. Endocrine alterations have been documented in the thyroid, adrenals, and gonads in some patients.25 In addition, HIV appears to affect pancreatic and liver function, impairing insulin clearance or glucose homeostasis or lipid metabolism.26–29 The introduction of PI-based combination therapy appears to have compounded this problem. In 1997 several reports described alterations in glucose metabolism in patients treated with the then recently approved PIs.30–32 Glucose intolerance was attributed to insulin resistance33–35 possibly associated with triglyceride storage defects,36 and lipodystrophy in PI-treated individuals was ascribed to lipid redistribution.37–43 Accumulating data on PIs suggested a possible causal relationship between PI use and abnormal lipid levels, hyperglycemia, insulin resistance, new-onset diabetes mellitus, and altered bone metabolism. The causal relationship between altered glucose metabolism and PI use was confirmed by the resolution of hyperglycemia or diabetes following PI discontinuation.31,33,34,44
The interrelatedness between insulin resistance, impaired glucose tolerance, dyslipidemia, and body habitus changes has been termed lipodystrophy syndrome and is currently the object of intense investigation.45 Lipodystrophy has been reported in the range of 5–75%46; the most likely explanations for this wide range are variations in case definition, different methods of assessment, and different length of follow-up among study subjects.47,48
The changes in body fat distribution observed in patients with the lipodystrophy syndrome during combination ART primarily involve subcutaneous lipoatrophy and central (visceral) adiposity. The former is most clinically evident in the extremities, face, and buttocks, whereas localized fat gain is most prominent in the midsection as well as the breast (gynecomastia in men) or supraclavicular or intrascapular (buffalo hump) areas. Because antiretroviral drugs are used in combination, identifying the specific treatment cause of lipodystrophy has been difficult. Early studies suggested that PIs were at the origin of the fat redistribution,43,49,50 but recent work suggests a significant role for NRTIs in the establishment of the syndrome,51 particularly lipoatrophy.52,53 Prospective data also demonstrate that the individual choice of the accompanying NRTI combination is important in determining the rate of peripheral fat loss.54 The adipose tissue loss associated with lipodystrophy is not to be mistaken for the increasing loss in lean body mass that occurs in many patients with progressing HIV disease. This condition, termed wasting syndrome when it exceeds a 10% decrease in body weight compared with baseline, appears unrelated to lipodystrophy and is strongly associated with viral load.55
In HIV-infected patients treated with PI-containing regimens, body habitus changes can be associated with hypercholesterolemia, hypertriglyceridemia, and insulin resistance.43,48–50,56–61 Recent reports also suggest that NRTIs alone or in combination with PIs are associated with lipodystrophy.62–65 Although such NRTIs as d4T and ZDV have been associated more specifically with lipoatrophy,53,66 it remains unclear whether the mechanism of NRTI-associated fat loss is related to that associated with the PI-induced fat accumulation; indeed, it has been suggested that NRTI-induced lipoatrophy may be related to mitochondrial toxicity.51
Because insulin plays a key role in the differentiation process of adipocytes (Fig. 1), insulin resistance may lead to alterations of lipid metabolism, as suggested by observed increases in triglyceride and cholesterol plasma concentrations. Additionally, fat redistribution associated with lipodystrophy may also interfere with insulin signaling,49,67 compounding the problem. Although the exact mechanism that leads to the lipodystrophy syndrome is unclear, various studies suggest that individual PIs target specific intracellular sites that may preferentially favor the development of either dyslipidemia or impaired glucose tolerance. Presumably, development of the lipodystrophy syndrome leads to an increased risk of both diabetes and cardiovascular disease. A recent study suggests that the paradoxical combination of fat loss and fat accumulation in different body compartments (visceral vs. subcutaneous, peripheral vs. truncal) is the result of a mobilization process,68 although other studies suggest otherwise.69 It has been proposed that the redistribution is related to the ubiquitous use of multidrug therapy containing at least an NRTI and a PI rather than to a PI alone.70 NRTIs have been shown to cause mitochondrial toxicity and lipoatrophy primarily via inhibition of mitochondrial DNA polymerase γ.71 Because white subcutaneous fat, located in the extremities and face, contains far fewer mitochondria than brown visceral fat, located predominantly in the abdomen and upper back, mitochondrial toxicity drives apoptosis disproportionately in white fat, resulting in white fat wasting, and brown fat remains the only available repository for lipids, resulting in redistribution of low-density lipoprotein (LDL) to brown fat (Fig. 2).70
Clinical Effects on Plasma Lipid Profile
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
PI Substitution and Dyslipidemia
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 and Glucose Homeostasis
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
Mechanism of Insulin Resistance
Dyslipidemia usually appears after 3–6 months of PI therapy,72,95 whereas studies in both HIV-seronegative volunteers96 and therapy-naive patients with HIV97 have shown that insulin resistance may develop within 4 weeks of starting indinavir. In the latter studies that evaluated lipids at 4 and 8 weeks, respectively, lipid levels remained unchanged at the time of evaluation. However, other studies suggest that indinavir, but not RTV or nelfinavir, causes insulin73 or steady-state plasma glucose levels to rise98 within 16–24 months of therapy. A study on healthy volunteers demonstrated that even a single dose of indinavir is capable of decreasing both total and nonoxidative insulin-stimulated glucose turnover.99 By contrast, in a study of 14 patients with stable HIV infection treated with amprenavir, increases in lipid levels and body fat occurred early, whereas insulin resistance and changes in fasting serum glucose had not happened by week 48.75 These studies suggest that although the development of insulin resistance may precede dyslipidemia with most PIs, exceptions, such as that seen with amprenavir, do exist. Similarly, a recent randomized study enrolled 30 healthy volunteers to evaluate the effects of 5 days of treatment with atazanavir, LPV/RTV, or placebo on glucose metabolism estimated with the hyperinsulinemic euglycemic clamp technique. Whereas LPV/RTV significantly decreased glucose disposal per unit of insulin and glucose storage rate compared with placebo (7.54 mg/kg• min/μU/mL vs. 9.87 mg/kg•min/μU/mL, P = 0.009; and 2.61 mg/kg•min vs. 4.01 mg/kg•min, P = 0.003, respectively), atazanavir had no effect on either of these parameters.100
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
Hyperglycemia and Diabetes Mellitus
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.
Risk Factors in the Development of Hyperglycemia and Diabetes
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.
ADVERSE OUTCOMES POTENTIALLY RELATED TO COMBINATION ART-INDUCED ADVERSE EVENTS
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.
Surrogate Markers for CHD Risk
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.
1. Duran S, Saves M, Spire B, et al. Failure to maintain long-term adherence to highly active antiretroviral therapy: the role of lipodystrophy. AIDS
2. Duran S, Spire B, Raffi F, et al. Self-reported symptoms after initiation of a protease inhibitor in HIV-infected patients and their impact on adherence to HAART. HIV Clin Trials
3. Powderly WG. Long-term exposure to lifelong therapies. J Acquir Immune Defic Syndr
. 2002;29(suppl 1):S28–S40.
4. Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet
5. O’Brien LW. Common HIV drug-drug interactions. AIDS Read
6. Dieleman JP, Jambroes M, Gyssens IC, et al. Determinants of recurrent toxicity-driven switches of highly active antiretroviral therapy. The ATHENA cohort. AIDS
7. Dorrucci M, Pezzotti P, Grisorio B, et al. Time to discontinuation of the first highly active antiretroviral therapy regimen: a comparison between protease inhibitor- and non-nucleoside reverse transcriptase inhibitor-containing regimens. AIDS
8. Mocroft A, Youle M, Moore A, et al. Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre. AIDS
9. d’Arminio Monforte A, Lepri AC, Rezza G, et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. I.CO.N.A. Study Group. Italian Cohort of Antiretroviral-Naive Patients. AIDS
10. van Roon EN, Verzijl JM, Juttmann JR, et al. Incidence of discontinuation of highly active antiretroviral combination therapy (HAART) and its determinants. J Acquir Immune Defic Syndr Hum Retrovirol
11. Bassetti S, Battegay M, Furrer H, et al. Why is highly active antiretroviral therapy (HAART) not prescribed or discontinued? Swiss HIV Cohort Study. J Acquir Immune Defic Syndr
12. Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet
13. Markowitz M, Conant M, Hurley A, et al. A preliminary evaluation of nelfinavir mesylate, an inhibitor of human immunodeficiency virus (HIV)-1 protease, to treat HIV infection. J Infect Dis
14. Saag MS, Tebas P, Sension M, et al. Randomized, double-blind comparison of two nelfinavir doses plus nucleosides in HIV-infected patients (Agouron study 511). AIDS
15. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med
16. Reiter WJ, Schon-Pernerstorfer H, Dorfinger K, et al. Frequency of urolithiasis in individuals seropositive for human immunodeficiency virus treated with indinavir is higher than previously assumed. J Urol
17. Garcia-Silva J, Almagro M, Pena-Penabad C, et al. Indinavir-induced retinoid-like effects: incidence, clinical features and management. Drug Saf
18. Sanne I, Piliero P, Squires K, et al. Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr
19. Murphy R, Pokrovskly V, Rozenbaum W, et al. Long-term efficacy and safety of atazanavir (ATV) with stavudine (d4T) and lamivudine (3TC) in patients previously treated with nelfinavir (NFV) or ATV: 108-week results of BMS Study 008/044. Paper presented at: 10th Conference on Retroviruses and Opportunistic Infections; February 10–14, 2003; Boston, MA.
20. Ammassari A, Murri R, Pezzotti P, et al. Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection. J Acquir Immune Defic Syndr
21. O’Brien ME, Clark RA, Besch CL, et al. Patterns and correlates of discontinuation of the initial HAART regimen in an urban outpatient cohort. J Acquir Immune Defic Syndr
22. Ammassari A, Antinori A, Cozzi-Lepri A, et al. Relationship between HAART adherence and adipose tissue alterations. J Acquir Immune Defic Syndr
. 2002;31(suppl 3):S140–S144.
23. Stenzel MS, Carpenter CC. The management of the clinical complications of antiretroviral therapy. Infect Dis Clin North Am
. 2000;14:851–878. vi.
24. Max B, Sherer R. Management of the adverse effects of antiretroviral therapy and medication adherence. Clin Infect Dis
. 2000;30(suppl 2):S96–116.
25. Sellmeyer DE, Grunfeld C. Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocr Rev
26. Hommes MJ, Romijn JA, Endert E, et al. Resting energy expenditure and substrate oxidation in human immunodeficiency virus (HIV)-infected asymptomatic men: HIV affects host metabolism in the early asymptomatic stage. Am J Clin Nutr
27. Hommes MJ, Romijn JA, Endert E, et al. Basal fuel homoeostasis in symptomatic human immunodeficiency virus infection. Clin Sci (Lond)
28. Hommes MJ, Romijn JA, Endert E, et al. Insulin sensitivity and insulin clearance in human immunodeficiency virus-infected men. Metabolism
29. Heyligenberg R, Romijn JA, Hommes MJ, et al. Non-insulin-mediated glucose uptake in human immunodeficiency virus-infected men. Clin Sci (Lond)
30. Visnegarwala F, Krause KL, Musher DM. Severe diabetes associated with protease inhibitor therapy. Ann Intern Med
31. Dube MP, Johnson DL, Currier JS, et al. Protease inhibitor-associated hyperglycaemia. Lancet
32. Eastone JA, Decker CF. New-onset diabetes mellitus associated with use of protease inhibitor. Ann Intern Med
33. Walli R, Herfort O, Michl GM, et al. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients. AIDS
34. Behrens G, Dejam A, Schmidt H, et al. Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS
35. Yarasheski KE, Tebas P, Sigmund C, et al. Insulin resistance in HIV protease inhibitor-associated diabetes. J Acquir Immune Defic Syndr
36. Kelley DE, Goodpaster BH. Skeletal muscle triglyceride: an aspect of regional adiposity and insulin resistance. Diabetes Care
37. Hengel RL, Watts NB, Lennox JL. Benign symmetric lipomatosis associated with protease inhibitors. Lancet
38. Herry I, Bernard L, de Truchis P, et al. Hypertrophy of the breasts in a patient treated with indinavir. Clin Infect Dis
39. Miller KD, Jones E, Yanovski JA, et al. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet
40. Lo JC, Mulligan K, Tai VW, et al. Buffalo hump” in men with HIV-1 infection. Lancet
41. Viraben R, Aquilina C. Indinavir-associated lipodystrophy. AIDS
42. Aboulafia DM, Bundow D. Images in clinical medicine” buffalo hump in a patient with the acquired immunodeficiency syndrome. N Engl J Med
43. Carr A, Samaras K, Chisholm DJ, et al. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet
44. Martinez E, Conget I, Lozano L, et al. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS
45. Carr A, Emery S, Law M, et al. An objective case definition of lipodystrophy in HIV-infected adults: a case-control study. Lancet
46. Bernasconi E. Metabolic effects of protease inhibitor therapy. AIDS Read
. 1999; 9:254–256,259–260,266–269.
47. Carter VM, Hoy JF, Bailey M, et al. The prevalence of lipodystrophy in an ambulant HIV-infected population: it all depends on the definition. HIV Med
48. Safrin S, Grunfeld C. Fat distribution and metabolic changes in patients with HIV infection. AIDS
49. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS
50. Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet
51. Brinkman K, Smeitink JA, Romijn JA, et al. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet
52. Chene G, Angelini E, Cotte L, et al. Role of long-term nucleoside-analogue therapy in lipodystrophy and metabolic disorders in human immunodeficiency virus-infected patients. Clin Infect Dis
53. Joly V, Flandre P, Meiffredy V, et al. Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: results of a substudy from a comparative trial. AIDS
54. Dube M, Zackin R, Tebas P, et al. Prospective study of regional body composition in antiretroviral-naive subjects randomized to receive zidovudine+lamivudine or didanosine+stavudine combined with nelfinavir, efavirenz, or both: A5005s, a substudy of ACTG 384. Antiviral Ther
55. Batterham MJ, Garsia R, Greenop P. Prevalence and predictors of HIV-associated weight loss in the era of highly active antiretroviral therapy. Int J STD AIDS
56. Tsiodras S, Mantzoros C, Hammer S, et al. Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study. Arch Intern Med
57. Purnell JQ, Zambon A, Knopp RH, et al. Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS
58. Heath KV, Hogg RS, Chan KJ, et al. Lipodystrophy-associated morphological, cholesterol and triglyceride abnormalities in a population-based HIV/AIDS treatment database. AIDS
59. Boufassa F, Dulioust A, Lascaux A, et al. Lipodystrophy in 685 HIV-1-treated patients: influence of antiretroviral treatment and immunovirological response. HIV Clin Trials
60. Segarra-Newnham M. Hyperlipidemia in HIV-positive patients receiving antiretrovirals. Ann Pharmacother
61. Lainka E, Oezbek S, Falck M, et al. Marked dyslipidemia in human immunodeficiency virus-infected children on protease inhibitor-containing antiretroviral therapy. Pediatrics
62. Madge S, Kinloch-de-Loes S, Mercey D, et al. Lipodystrophy in patients naive to HIV protease inhibitors. AIDS
63. Mallal SA, John M, Moore CB, et al. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS
64. Saint-Marc T, Partisani M, Poizot-Martin I, et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS
65. van der Valk M, Gisolf EH, Reiss P, et al. Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection. AIDS
66. Lichtenstein KA, Ward DJ, Moorman AC, et al. Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS
67. Schmitz-Peiffer C, Browne CL, Oakes ND, et al. Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat. Diabetes
68. Estrada V, Serrano-Rios M, Martinez Larrad MT, et al. Leptin and adipose tissue maldistribution in HIV-infected male patients with predominant fat loss treated with antiretroviral therapy. J Acquir Immune Defic Syndr
69. Hadigan C, Meigs JB, Wilson PW, et al. Prediction of coronary heart disease risk in HIV-infected patients with fat redistribution. Clin Infect Dis
70. Fessel W. Why some fat depots waste but others expand in patients using protease inhibitors: hypothesis and supporting data. Paper presented at: 7th Conference on Retroviruses and Opportunistic Infections; January 30–February 2, 2000; San Francisco, CA.
71. Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther
72. Calza L, Manfredi R, Farneti B, et al. Incidence of hyperlipidaemia in a cohort of 212 HIV-infected patients receiving a protease inhibitor-based antiretroviral therapy. Int J Antimicrob Agents
73. Periard D, Telenti A, Sudre P, et al. Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation
74. Katlama C, Pellegrin JL, Lacoste D, et al. MIKADO: a multicentre, open-label pilot study to evaluate the antiretroviral activity and safety of saquinavir with stavudine and zalcitabine. HIV Med
75. Dube MP, Qian D, Edmondson-Melancon H, et al. Prospective, intensive study of metabolic changes associated with 48 weeks of amprenavir-based antiretroviral therapy. Clin Infect Dis
76. Nadler J, Rodriguez-French A, Millard J, et al. The NEAT Study: GW433908 efficacy and safety in ART-naive subjects: final 48-week Analysis. Paper presented at: 10th Conference on Retroviruses and Opportunistic Infections; February 10–14, 2003; Boston, MA.
77. Martinez E, Domingo P, Galindo MJ, et al. Risk of metabolic abnormalities in patients infected with HIV receiving antiretroviral therapy that contains lopinavir-ritonavir. Clin Infect Dis
78. Manfredi R, Chiodo F. Disorders of lipid metabolism in patients with HIV disease treated with antiretroviral agents: frequency, relationship with administered drugs, and role of hypolipidaemic therapy with bezafibrate. J Infect
79. Cheseaux JJ, Jotterand V, Aebi C, et al. Hyperlipidemia in HIV-infected children treated with protease inhibitors: relevance for cardiovascular diseases. J Acquir Immune Defic Syndr
80. Mauss S, Stechel J, Willers R, et al. Differentiating hyperlipidaemia associated with antiretroviral therapy. AIDS
81. Hatano H, Miller KD, Yoder CP, et al. Metabolic and anthropometric consequences of interruption of highly active antiretroviral therapy. AIDS
82. Dieleman JP, Gyssens IC, Sturkenboom MJ, et al. Substituting nevirapine for protease inhibitors because of intolerance. AIDS
83. Barreiro P, Soriano V, Blanco F, et al. Risks and benefits of replacing protease inhibitors by nevirapine in HIV-infected subjects under long-term successful triple combination therapy. AIDS
84. Martinez E, Garcia-Viejo MA, Blanco JL, et al. Impact of switching from human immunodeficiency virus type 1 protease inhibitors to efavirenz in successfully treated adults with lipodystrophy. Clin Infect Dis
85. Hirschel B, Flepp M, Bucher HC, et al. Switching from protease inhibitors to efavirenz: differences in efficacy and tolerance among risk groups: a case-control study from the Swiss HIV Cohort. AIDS
86. Estrada V, De Villar NG, Larrad MT, et al. Long-term metabolic consequences of switching from protease inhibitors to efavirenz in therapy for human immunodeficiency virus-infected patients with lipoatrophy. Clin Infect Dis
87. Carr A, Hudson J, Chuah J, et al. HIV protease inhibitor substitution in patients with lipodystrophy: a randomized, controlled, open-label, multicentre study. AIDS
88. Drechsler H, Powderly WG. Switching effective antiretroviral therapy: a review. Clin Infect Dis
89. Raffi F, Bonnet B, Ferre V, et al. Substitution of a nonnucleoside reverse transcriptase inhibitor for a protease inhibitor in the treatment of patients with undetectable plasma human immunodeficiency virus type 1 RNA. Clin Infect Dis
90. De Luca A, Baldini F, Cingolani A, et al. Benefits and risks of switching from protease inhibitors to nevirapine with stable background therapy in patients with low or undetectable viral load: a multicentre study. AIDS
91. Moyle GJ, Baldwin C, Langroudi B, et al. A 48-week, randomized, open-label comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy. J Acquir Immune Defic Syndr
92. Martinez E, Arnaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl J Med
93. Meigs JB. Epidemiology of the insulin resistance syndrome. Curr Diab Rep
94. Dube MP. Disorders of glucose metabolism in patients infected with human immunodeficiency virus. Clin Infect Dis
95. Mulligan K, Grunfeld C, Tai VW, et al. Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acquir Immune Defic Syndr
96. Noor MA, Lo JC, Mulligan K, et al. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS
97. Dube MP, Edmondson-Melancon H, Qian D, et al. Prospective evaluation of the effect of initiating indinavir-based therapy on insulin sensitivity and B-cell function in HIV-infected patients. J Acquir Immune Defic Syndr
98. Beatty G, Khalili M, Abbasi F, et al. Quantification of insulin-mediated glucose disposal in HIV-infected individuals: comparison of patients treated and untreated with protease inhibitors. J Acquir Immune Defic Syndr
99. Noor MA, Seneviratne T, Aweeka FT, et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS
100. Noor M, Grasela D, Parker R, et al. The effect of atazanavir vs lopinavir/ritonavir on insulin-stimulated glucose disposal rate in healthy subjects. Paper presented at: 11th Conference on Retroviruses and Opportunistic Infections; February 8–11, 2004; San Francisco, CA.
101. Woerle HJ, Mariuz PR, Meyer C, et al. Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens. Diabetes
102. Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem
103. Murata H, Hruz PW, Mueckler M. Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS
104. Ben-Romano R, Rudich A, Torok D, et al. Agent and cell-type specificity in the induction of insulin resistance by HIV protease inhibitors. AIDS
105. Rudich A, Vanounou S, Riesenberg K, et al. The HIV protease inhibitor nelfinavir induces insulin resistance and increases basal lipolysis in 3T3-L1 adipocytes. Diabetes
106. Schutt M, Meier M, Jost MM, et al. The HIV protease inhibitor indinavir impairs glycogen synthesis in HepG2 hepatoma cells. Exp Clin Endocrinol Diabetes
107. Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988–1994. Diabetes Care
108. DeLorenze G, Horberg M, Karter A, et al. Incidence and prevalence of diabetes mellitus among HIV-infected patients in Northern California’s largest HMO. Paper presented at: 10th Conference on Retroviruses and Opportunistic Infections; February 10–14, 2003; Boston, MA.
109. Yoon C, Gulick R, Hoover D, et al. Case-control study of diabetes mellitus in HIV-infected patients. Paper presented at: 9th Conference on Retroviruses and Opportunistic Infections; February 24–28, 2002; Seattle, WA.
110. Justman JE, Benning L, Danoff A, et al. Protease inhibitor use and the incidence of diabetes mellitus in a large cohort of HIV-infected women. J Acquir Immune Defic Syndr
111. Goorney BP, Lacey H, Thurairajasingam S, et al. Avascular necrosis of the hip in a man with HIV infection. Genitourin Med
112. Gerster JC, Camus JP, Chave JP, et al. Multiple site avascular necrosis in HIV infected patients. J Rheumatol
113. Serrano S, Marinoso ML, Soriano JC, et al. Bone remodelling in human immunodeficiency virus-1-infected patients: a histomorphometric study. Bone
114. Paton NI, Macallan DC, Griffin GE, et al. Bone mineral density in patients with human immunodeficiency virus infection. Calcif Tissue Int
115. Hernandez Quero J, Ortego Centeno N, Munoz-Torres M, et al. Alterations in bone turnover in HIV-positive patients. Infection
116. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med
117. Tebas P, Powderly WG, Claxton S, et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS
118. Mondy K, Yarasheski K, Powderly WG, et al. Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virus-infected individuals. Clin Infect Dis
119. Nolan D, Upton R, McKinnon E, et al. Stable or increasing bone mineral density in HIV-infected patients treated with nelfinavir or indinavir. AIDS
120. Petruschke T, Hauner H. Tumor necrosis factor-alpha prevents the differentiation of human adipocyte precursor cells and causes delipidation of newly developed fat cells. J Clin Endocrinol Metab
121. Jain RG, Lenhard JM. Select HIV protease inhibitors alter bone and fat metabolism ex vivo. J Biol Chem
122. Huang JS, Rietschel P, Hadigan CM, et al. Increased abdominal visceral fat is associated with reduced bone density in HIV-infected men with lipodystrophy. AIDS
123. Huang JS, Mulkern RV, Grinspoon S. Reduced intravertebral bone marrow fat in HIV-infected men. AIDS
124. Carr A, Miller J, Eisman JA, et al. Osteopenia in HIV-infected men: association with asymptomatic lactic acidemia and lower weight pre-antiretroviral therapy. AIDS
125. Tsekes G, Chrysos G, Douskas G, et al. Body composition changes in protease inhibitor-naive HIV-infected patients treated with two nucleoside reverse transcriptase inhibitors. HIV Med
126. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA
127. Kaur J, Singh P, Sowers JR. Diabetes and cardiovascular diseases. Am J Ther
128. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA
129. Henry K, Melroe H, Huebsch J, et al. Severe premature coronary artery disease with protease inhibitors. Lancet
130. Behrens G, Schmidt H, Meyer D, et al. Vascular complications associated with use of HIV protease inhibitors. Lancet
131. Gallet B, Pulik M, Genet P, et al. Vascular complications associated with use of HIV protease inhibitors. Lancet
132. Vittecoq D, Escaut L, Monsuez JJ. Vascular complications associated with use of HIV protease inhibitors. Lancet
133. Flynn TE, Bricker LA. Myocardial infarction in HIV-infected men receiving protease inhibitors. Ann Intern Med
134. David MH, Hornung R, Fichtenbaum CJ. Ischemic cardiovascular disease in persons with human immunodeficiency virus infection. Clin Infect Dis
135. Bozzette SA, Ake CF, Tam HK, et al. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med
136. Klein D, Hurley LB, Quesenberry CP Jr, et al. Do protease inhibitors increase the risk for coronary heart disease in patients with HIV-1 infection? J Acquir Immune Defic Syndr
137. Mary-Krause M, Cotte L, Simon A, et al. Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS
138. Holmberg SD, Moorman AC, Williamson JM, et al. Protease inhibitors and cardiovascular outcomes in patients with HIV-1. Lancet
139. Moore R, Keruly J, Lucas G. Increasing incidence of cardiovascular disease in HIV-infected persons in care. Paper presented at: 10th Conference on Retroviruses and Opportunistic Infections; February 10–14, 2003; Boston, MA.
140. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, et al. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project: registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation
141. Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med
142. O’Leary DH, Polak JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med
143. Maggi P, Serio G, Epifani G, et al. Premature lesions of the carotid vessels in HIV-1-infected patients treated with protease inhibitors. AIDS
144. Seminari E, Pan A, Voltini G, et al. Assessment of atherosclerosis using carotid ultrasonography in a cohort of HIV-positive patients treated with protease inhibitors. Atherosclerosis
145. Hsue P, Lo JC, Franklin A, et al. Increased atherosclerotic progression in patients with HIV: the role of traditional and immunologic risk factors. Paper presented at: 10th Conference on Retroviruses and Opportunistic Infections; February 10–14, 2003; Boston, MA.
146. Depairon M, Chessex S, Sudre P, et al. Premature atherosclerosis in HIV-infected individuals: focus on protease inhibitor therapy. AIDS
147. Currier J, Kendall M, Henry K, et al. Carotid intima-media thickness in HIV-infected and uninfected adults: ACTG 5078. Paper presented at: 10th Conference on Retroviruses and Opportunistic Infections; February 10–14, 2003; Boston, MA.
148. Meng Q, Lima JA, Lai H, et al. Use of HIV protease inhibitors is associated with left ventricular morphologic changes and diastolic dysfunction. J Acquir Immune Defic Syndr
This article has been cited 20 time(s).
Journal of the International AIDS SocietyMetabolic complications and treatment of perinatally HIV-infected children and adolescentsJournal of the International AIDS Society
InfectionFirst italian consensus statement on diagnosis, prevention and treatment of cardiovascular complications in HIV-infected patients in the HAART era (2006)Infection
Expert Opinion on PharmacotherapyHIV protease inhibitors: recent clinical trials and recommendations on useExpert Opinion on Pharmacotherapy
Clinical Infectious Diseases
Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy
Clinical Infectious Diseases, 43(5):
Journal of Antimicrobial ChemotherapyMetabolic consequences and therapeutic options in highly active antiretroviral therapy in human immunodeficiency virus-1 infectionJournal of Antimicrobial Chemotherapy
Journal of Antimicrobial ChemotherapyUnmet therapeutic needs in the new era of combination antiretroviral therapy for HIV-1Journal of Antimicrobial Chemotherapy
Medecine Et Maladies Infectieuses"Adherence to antiretroviral therapy during HIV infection, a multidisciplinary approach of the literature"Medecine Et Maladies Infectieuses
Adverse side effects of antiretroviral therapy: relationship between patients perception and adherence
Medicina Clinica, 129(4):
New England Journal of Medicine
Class of antiretroviral drugs and the risk of myocardial infarction
New England Journal of Medicine, 356():
Journal of Infectious DiseasesRisk of Myocardial Infarction in Patients with HIV Infection Exposed to Specific Individual Antiretroviral Drugs from the 3 Major Drug Classes: The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) StudyJournal of Infectious Diseases
American Journal of Preventive MedicineSmoking cessation - A critical component of medical management in chronic disease popullationsAmerican Journal of Preventive Medicine
DermatitisAdverse cutaneous reactions to antimicrobials in patients with human immunodeficiency virus infectionDermatitis
AIDS Education and Prevention
Cigarette Smoking and HIV/AIDS: Health Implications, Smoker Characteristics and Cessation Strategies
AIDS Education and Prevention, 21(3):
Current HIV Research
In Patients with HIV-Infection, Chromium Supplementation Improves Insulin Resistance and Other Metabolic Abnormalities: A Randomized, Double-Blind, Placebo Controlled Trial
Current HIV Research, 8(2):
Nicotine & Tobacco ResearchImpact of a cell phone intervention on mediating mechanisms of smoking cessation in individuals living with HIV/AIDSNicotine & Tobacco Research
JAIDS Journal of Acquired Immune Deficiency SyndromesErratumJAIDS Journal of Acquired Immune Deficiency Syndromes
HIV; protease inhibitors; toxicity; side effects; metabolic complications; lipodystrophy; insulin resistance; hypercholesterolemia; hypertriglyceridemia
© 2004 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.