Tolerability and Safety of HIV Protease Inhibitors in Adults

Abstract

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.

In Vitro Characterization of GS-8374, a Novel Phosphonate-Containing Inhibitor of HIV-1 Protease with a Favorable Resistance Profile

“…As a class, PIs are associated with clinical off-target effects on lipid and glucose metabolism, manifested by elevated levels of cholesterol and triglycerides, type II diabetes, and a potentially increased risk for cardiovascular complications (30,38). In an independent study published in parallel with this report, Hruz et al (12) used both in vitro and in vivo models to assess the effects of GS-8374 on the glucose and lipid metabolism relative to those of selected clinically approved PIs.…”

“…In general, the long-term clinical benefit of PIs across all patient populations can be limited by various factors, including longterm safety and tolerability (3,27,38), resistance (36), and drug-drug interactions (18). Among these limitations, the development of viral resistance has been shown to be a major cause of therapy failure (1,43).…”

Metabolic abnormalities associated with HIV infection and antiretroviral therapy

“…Within the remaining classes, PIs and nucleoside/tide reverse transcriptase inhibitors (NRTIs) have the greatest effects on lipid metabolism. Most PIs, except for atazanavir, are associated with elevations in TC, triglycerides, and LDL-C [13]. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) can produce increases in TC, LDL-C, and triglycerides; however, substantial increases in HDL-C, especially with nevirapine, may be potentially benefi cial although further studies of the functional anti-infl ammatory properties of HDL-C are needed [14].…”

“…The abdominal fat accumulation in HIV-infected persons is associated with higher VAT. Factors associated with fat accumulation include use of certain PIs, increased age, greater body mass index, and more advanced HIV disease [12,13]. However, in recent years, one large case-cohort study suggested that increased VAT may not be associated with HIV or antiretroviral therapy [40].…”

Impact of metabolic complications on antiretroviral treatment adherence: Clinical and public health implications

“…Although other factors were once associated with lipoatrophy [19,20], exposure to specifi c nucleoside reverse transcriptase inhibitors (NRTIs; particularly stavudine) is now recognized as the major factor associated with lipoatrophy [21,22] mediated by NRTI-induced inhibition of mitochondrial DNA polymerase-gamma [23,24]. Risk factors for fat accumulation have been shown in longitudinal cohort studies to include increased age, higher baseline fat content, greater body mass index (BMI), white race, and low CD4 cell count at ART initiation [25].…”