Protease inhibitors increase fibrinogen levels: increased risk for hardening of the arteries

Michael Carter
Published: 08 April 2008

Treatment with a protease inhibitor increases levels of a substance in the blood, fibrinogen, that is associated with hardening of the arteries, according to a US study published in the March 30th edition of AIDS. By contrast, patients treated with a non-nucleoside reverse transcriptase inhibitor (NNRTI) had lower fibrinogen levels than individuals who received a protease inhibitor, and also the HIV-negative control group.

HIV is associated with atherosclerosis, or hardening of the arteries, but the reasons for this are not fully understood. Earlier research suggests that treatment with a protease inhibitor increases the risk of atherosclerosis by 14% with each year of use.

Anti-HIV treatment can disturb the way the body metabolises lipids and glucose, leading to increased levels of cholesterol and blood sugars, and these are long-term risk factors for heart disease. But results from the D:A:D study have shown that protease inhibitor therapy increases the risk of atherosclerosis independent of such metabolic changes. Therefore the reason why protease inhibitors increase the risk of hardening of the arteries still needs to be explained.

Fibrinogen is an important substance involved in blood clotting and increased levels of fibrinogen are thought to contribute to hardening of the arteries. Inflammation, which can be caused by HIV, is thought to underlie the atherosclerosis that elevated fibrinogen levels can lead to. A meta-analysis of 31 prospective studies has shown that a 100mg/dl increase in fibrinogen levels increases the hazard ratio of illness or death due to vascular disease by 2.42 (95% CI, 2.24 – 2.60).

But studies investigating a connection between protease inhibitor therapy and fibrinogen levels have produced conflicting results. Increased adiposity (increased amounts of body fat) has been associated with elevations in fibrinogen levels. Anti-HIV therapy has been associated with the accumulation of fat around the trunk and between the shoulders.

The US FRAM Study (Fat Redistribution and Metabolic Changes in HIV Infection) employed MRI scans to monitor levels of adipose tissue in HIV-positive patients. Patients in the study also had regular blood tests. These meant that investigators were able to research the association between anti-HIV treatment, fat accumulation, inflammation, CD4 and viral load, and fibrinogen levels in a representative sample of HIV-positive patients.

A total of 1131 HIV-positive patients were included in the study, with recruitment taking place between 2000 – 2002. Some of the protease inhibitors now in routine use were not available at this time. The study design also included a control group that consisted of 281 HIV-negative 18- 30 year olds took part in a study into heart disease that took place in the mid 1980s.

Body fat and fibrinogen

Levels of subcutaneous fat were lower in HIV-positive men and women than the control group, and visceral fat was lower in HIV-positive men than the controls, but higher in HIV-positive women compared with controls (p = 0.009).

Median fibrinogen levels were 8% higher in HIV-positive men (345 mg/dl) compared with the men in the control group (320 mg/dl). Similarly, fibrinogen levels were 6% higher in HIV-positive women (373 mg/dl) than in the HIV-negative controls (352 mg/dl). After adjusting for lifestyle factors, demographics and levels of fat, fibrinogen levels were significantly higher (12%; p < 0.0001) in HIV-positive men than in HIV-negative men. However, there was no significant difference in fibrinogen levels between HIV-positive women and women in the control group.

Fibrinogen and antiretroviral therapy

Investigators then turned their attention to the effect of antiretroviral therapy on fibrinogen.

Patient treated with a protease inhibitor had median fibrinogen levels 11% higher than patients not taking this class of drugs (380 dg/ml vs. 341 dg/ml, p < 0.0001). Furthermore patients taking a ritonavir-boosted protease inhibitor (lopinavir/ritonavir included) had a 12% increase in their fibrinogen level compared to individuals not taking a protease inhibitor (p < 0.0001).

However, patients treated with an NNRTI had fibrinogen levels that were 9% lower than patients not taking this class of drug (median, 340 dg/ml vs. 372 dg/ml, p < 0.0001).

Levels of fibrinogen in patients taking both a protease inhibitor and an NNRTI were similar to those seen in control patients.

Multivariate analysis

Factors significantly associated with higher fibrinogen levels in patients with HIV included age, African-American race, visceral fat levels, total subcutaneous fat, smoking, and current HIV viral load. When the investigators controlled for these factors, they found that treatment with a protease inhibitor, particularly indinavir or ritonavir increased fibrinogen levels (p < 0.0001), whereas therapy with an NNRTI (nevirapine, p =0.001; efavirenz, p = 0.049) lowered fibrinogen levels.

C-reactive protein levels (CRP), a reliable marker of inflammation, were strongly associated with increased fibrinogen levels in both HIV-positive patients and controls. But when the investigators controlled for CRP, they found that treatment with a protease inhibitor was still associated with increased fibrinogen levels. Similarly, the association between NNRTI therapy and lower fibrinogen levels also remained.

“Use of protease inhibitors as a group was associated with elevated fibrinogen levels”, write the investigators, “elevation of fibrinogen levels…is seen with all protease inhibitors studied, suggesting a class effect.”

Although the study was not able to include analysis of recently approved protease inhibitors, the investigators emphasise that an association between increased fibrinogen levels was seen in patients treated with Kaletra (lopinavir/ritonavir) and an association between “ritonavir at boosting doses with higher fibrinogen levels. Most current protease inhibitor regimes utilize ritonavir boosting.”

The investigators suggest that protease inhibitors may have a direct effect on fibrinogen levels, a conclusion suggested by fibrinogen levels being independent of inflammation, as assessed by CRP levels.

NNRTI therapy’s association with lower fibrinogen levels could mean that therapy with this class of drug could help reduce a patient’s risk of heart disease. Treatment with NNRTIs is already thought to involve less of a risk of increased cholesterol and heart disease than many protease inhibitors.

Some limitations with the study are noted by the investigators, particularly its cross-sectional design. They call for further prospective studies to assess the relationship “between antiretroviral therapy and fibrinogen levels as well as cardiovascular disease.”

Reference

Madden E et al. Association of antiretroviral therapy with fibrinogen levels in HIV infection. AIDS 22: 707 – 715, 2008.