A study of 363 HIV-positive patients in Sweden has revealed that patients receiving protease inhibitor treatment may be at increased long-term risk of thrombosis (fatal blood clots) when compared with untreated HIV-positive individuals due to the presence of higher levels of a protein which discourages the breakdown of blood clots.
The phenomenon was associated with the development of insulin resistance on PI therapy, and the risk was apparent regardless of whether patients had developed other metabolic abnormalities on PI therapy.
This study looked at metabolic and haemostatic markers in 363 HIV-positive individuals. 266 were receiving protease inhibitor-containing regimens and 97 were treatment-naïve. Patients on treatment had received a mean of 27 months of protease inhibitor treatment, and were more likely to have been diagnosed with AIDS and had been infected with HIV for longer (106 months vs 68 months), but at the time of this study, each group had similar CD4 cell counts – around 480 cells/mm3. Levels of hypertension, diabetes, smoking and family history of heart disease did not differ between the two groups. 16% of the PI group had metabolic disturbances, compared to 8% of the treatment-naïve group, a non-significant difference.
The study found significantly higher levels of plasminogen activator inhibitor type 1 (PAI-1) in the treated patients. The only factor significantly associated with elevated PAI-1 levels was protease inhibitor therapy, regardless of prior medical history, age, duration of therapy or AIDS diagnosis.
Plasminogen activator inhibitor type 1 (PAI-1) is a protein that inhibits the break down of fibrin in blood clots, and so high levels of PAI-1 will lead to increased clottjng of the blood. A reduced tendency to break down blood clots, called hypercoagulability, leads to a higher risk of thrombosis
PAI-1 production is stimulated by molecules that are present at high levels in people with insulin resistance, such as VLDL cholesterol and insulin, and elevated PAI-1 levels have been noted in cohorts of HIV-negative and HIV-positive people with insulin resistance. Elevated plasma levels of PAI-1 are associated with an increased risk of various cardiovascular problems, especially myocardial infarction.
Elevated levels of PAI-1 usually occur in the company of other cardiovascular risk factors, so these findings may have particular significance because of recent debate over the significance of cholesterol increases in people on Highly Active Antiretroviral Therapy (HAART). Dr Stefan Mauss, a German HIV clinician, has argued that because much of the cholesterol increase in patients on HAART comprises the less atherogenic VLDL cholesterol, cardiovascular risks may be lower in HIV patients than in HIV-negative people with similar cholesterol levels.
In this study, elevated PAI-1 levels were significantly associated with elevated triglyceride levels, elevated insulin levels and higher levels of visceral adipose tissue (visceral fat produces more PAI-1 than subcutaneous fat). However, the PAI-1 elevation was more severe in the PI-treated group; treatment-naïve patients with metabolic disturbances had PAI-1 levels similar to those of protease inhibitor recipients without metabolic disturbances. Metabolic `syndrome` was defined as the presence of two or more of: elevated blood pressure, elevated triglycerides >1.7mmol/L, HDL cholesterol 20ug/min, waist/hip ratio 30kg/m2.
No association could be found between particular protease inhibitors and elevated levels of PAI-1, but duration of exposure to ddI was correlated with elevated PAI-1 levels.
The lack of association between age or immune status and elevated PAI-1 levels led the authors to suggest that the increase was not mediated by the immune system or low-level inflammatory effects of chronic HIV infection.
When patients were re-evaluated after twelve months, two patients in the PI group had developed cardiovascular disease and one had developed high blood pressure, while one untreated patient also developed high blood pressure and another developed diabetes. Among patients in the PI group who switched or discontinued therapy, no significant change in PAI-1 levels was detected.
Koppel K et al. Hypofibrinolytic state in HIV-1 infected patients treated with protease inhibitor-containing highly active antiretroviral therapy. JAIDS 29: 441-449, 2002.